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[ CAS No. 625471-18-3 ] {[proInfo.proName]}

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Cat. No.: {[proInfo.prAm]}

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3d Animation Molecule Structure of 625471-18-3

Chemical Structure| 625471-18-3

Chemical Structure| 625471-18-3

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Quality Control of [ 625471-18-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 625471-18-3 ]

Product Details of [ 625471-18-3 ]

CAS No. :	625471-18-3	MDL No. :	MFCD03094718
Formula :	C₁₀H₂₀N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AKQXKEBCONUWCL-QMMMGPOBSA-N
M.W :	200.28	Pubchem ID :	1501975
Synonyms :		Chemical Name :	(S)-tert-Butyl 3-aminopiperidine-1-carboxylate

Safety of [ 625471-18-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 625471-18-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 625471-18-3 ]
Downstream synthetic route of [ 625471-18-3 ]

[ 625471-18-3 ] Synthesis Path-Upstream 1~14

1
[ 1271240-70-0 ]
[ 625471-18-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	With 10% palladium on activated charcoal; hydrogen In ethanol	Azido derivative 42a (6.77 g, 29.9 mmol) and Pd/C catalyst (150 mg) were hydrogenated in ethanol (200 ml) at an atmospheric pressure overnight. The catalyst was filtered through Celite and the solvent was evaporated. Product 43a was obtained in a 90percent yield (5.39 g, 26.9 mmol) as a colorless liquid without further purification.¹H NMR, ¹³C NMR, and IR spectra were identical to those of 30. HRMS (ESI) C₁₀H₂₁O₂N₂ (M+H)⁺ calcd 201.1598, found 201.1597; [α]_D²⁰ +26.0 (c 0.308, EtOH).

Reference： [1] Tetrahedron, 2011, vol. 67, # 7, p. 1485 - 1500
[2] Patent: WO2005/305, 2005, A1, . Location in patent: Page 60
[3] Patent: WO2005/20976, 2005, A2, . Location in patent: Page/Page column 239
[4] Patent: WO2005/60949, 2005, A2, . Location in patent: Page/Page column 238

2
[ 1374353-02-2 ]
[ 625471-18-3 ]

Reference： [1] Patent: WO2005/20975, 2005, A2, . Location in patent: Page/Page column 236

3
[ 62414-68-0 ]
[ 625471-18-3 ]

Reference： [1] Tetrahedron, 2011, vol. 67, # 7, p. 1485 - 1500

4
[ 24424-99-5 ]
[ 625471-18-3 ]

Reference： [1] Tetrahedron, 2011, vol. 67, # 7, p. 1485 - 1500

5
[ 2577-48-2 ]
[ 625471-18-3 ]

Reference： [1] Tetrahedron, 2011, vol. 67, # 7, p. 1485 - 1500

6
[ 53912-80-4 ]
[ 625471-18-3 ]

Reference： [1] Tetrahedron, 2011, vol. 67, # 7, p. 1485 - 1500

7
[ 113304-84-0 ]
[ 625471-18-3 ]

Reference： [1] Tetrahedron, 2011, vol. 67, # 7, p. 1485 - 1500

8
[ 91599-79-0 ]
[ 625471-18-3 ]

Reference： [1] Tetrahedron, 2011, vol. 67, # 7, p. 1485 - 1500

9
[ 344-25-2 ]
[ 625471-18-3 ]

Reference： [1] Tetrahedron, 2011, vol. 67, # 7, p. 1485 - 1500

10
[ 143900-43-0 ]
[ 625471-18-3 ]

Reference： [1] Tetrahedron, 2011, vol. 67, # 7, p. 1485 - 1500

11
[ 98977-36-7 ]
[ 75-31-0 ]
[ 67-64-1 ]
[ 625471-18-3 ]

Reference： [1] Organic Process Research and Development, 2016, vol. 20, # 3, p. 602 - 608

12
[ 625471-18-3 ]
[ 902152-76-5 ]

Reference： [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 1061 - 1073
[2] Patent: WO2006/106326, 2006, A1, . Location in patent: Page/Page column 97

13
[ 50-00-0 ]
[ 625471-18-3 ]
[ 912368-73-1 ]

Yield	Reaction Conditions	Operation in experiment
3 g	Stage #1: at 20℃; for 24 h; Molecular sieve Stage #2: at 20℃; for 16 h;	To a stirred solution of aqueous formaldehyde (1.85 ml, 25 mmol, 37percent) and molecular sieves in methanol was added (S)-tert-butyl 3-aminopiperidine- 1 -carboxylate (5.0 g, 25 mmol) and reaction was stirred at room temperature for 24 h. Sodium borohydride (1.52 g,40 mmol) was added to the above mixture at room temperature and mixture was stirred for16 h. The reaction mixture was quenched with addition of ice water (30 mL) and thenextracted with EtOAc (3 x 100 mL). Combined organic extracts were dried over anhydrousNa2504 and concentrated to obtain 3.0 g of crude (S)-tert-butyl 3-(methylamino)piperidine-1 -carboxylate as pale yellow liquid. This material was used as such in the next step.‘H NMR (400 MHz, CDC13) ö ppm 1.38 (s, 9H), 1.5-1.7 (m, 4H), 1.71-1.90 (m, 2H), 2.18-2.27 (m, 3H), 2.75-2.90 (m, 1H), 3.50-3.92 (m, 2H).

Reference： [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 1061 - 1073
[2] Patent: WO2018/2437, 2018, A1, . Location in patent: Page/Page column 99

14
[ 625471-18-3 ]
[ 912368-73-1 ]

Reference： [1] Patent: WO2006/106326, 2006, A1,

[ 625471-18-3 ] Synthesis Path-Downstream 1~92

1
[ 2605-14-3 ]
[ 625471-18-3 ]
[ 953772-09-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 100℃; for 168h;	Step 1. Preparation of (S)-tert-butyl 3-(6-methoxybenzo[d]thiazol-2-ylamino)piperidine-1-carboxylateTo the solution of <strong>[2605-14-3]2-chloro-6-methoxybenzo[d]thiazole</strong> (2.6 g, 13 mmol) in 25 ml of NMP was added (S)-tert-butyl 3-(6-methoxybenzo[d]thiazol-2-ylamino)piperidine-1-carboxylate (5 g, 25 mmol) and DIPEA (2.6 ml, 15 mmol). The reaction solution was stirred at 100 C. for 7 days. The crude reaction solution was mixed with ethyl acetate (250 ml) and diluted aqueous sodium bicarbonate solution (80 ml) and the organic phase was separated. The separated organic layer was washed with water (2 60 ml) and brine (60 ml), then dried over sodium sulfate and evaporated in vacuo to give a brown oily product that was purified by flash chromatography over silica gel with ethyl acetate:hexane (35:65-50:50) to give (S)-tert-butyl 3-(6-methoxybenzo[d]thiazol-2-ylamino)piperidine-1-carboxylate (3.33 g, 9.16 mmol) as an ivory solid. ES/MS m/z 364.2 (MH+). Rt=2.2 min.

Reference： [1]Patent: US2008/45528,2008,A1 .Location in patent: Page/Page column 107-108

2
[ 447-61-0 ]
[ 625471-18-3 ]
1,1-dimethylethyl (3S)-3-([2-(trifluoromethyl)-phenyl]methyl}amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;5%-palladium/activated carbon; In ethanol; under 3102.97 Torr; for 2.5h;	1, 1-Dimethylethyl (3S)-3-aminopiperidine-1-carboxylate (L. OG, 5MMOL), 2- trifluoromethylbenzaldehyde (0.87g, 5MMOL), 5percent palladium on carbon (0.35g) and ethanol (40mL) were hydrogenated at 60psi for 2.5 h. using a Parr hydrogenator. The catalyst was filtered off and the filtrate evaporated in vacuo. The resultant oil was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (0: 100 to 75: 25), to give the title compound as an oil.
	With hydrogen;5%-palladium/activated carbon; In ethanol; under 3102.97 Torr; for 2.5h;	1, 1-Dimethylethyl (3S)-3-aminopiperidine-l-carboxylate (I. OG, 5MMOL), 2- trifluoromethylbenzaldehyde (0.87g, 5MMOL), 5percent palladium on carbon (0.35g) and ethanol (40mL) were hydrogenated at 60psi for 2.5 h. using a Parr hydrogenator. The catalyst was filtered off and the filtrate evaporated in vacuo. The resultant oil was purified by flash chromatography on silica, eluting with ethyl ACETATE/CYCLOHEXANE (0: 100 to 75: 25), to give the title compound as an oil.
	With hydrogen;5%-palladium/activated carbon; In ethanol; under 3102.97 Torr; for 2.5h;	1, 1-Dimethylethyl (3S)-3-AMINOPIPERIDINE-1-CARBOXYLATE (L. OG, SMMOL), 2- trifluoromethylbenzaldehyde (0.87g, 5MMOL), 5percent palladium on carbon (0.35g) and ethanol (40mL) were hydrogenated at 60psi for 2.5 H. using a Parr hydrogenator. The catalyst was filtered off and the filtrate evaporated in vacuo. The resultant oil was purified by flash chromatography on silica, eluting with ethyl ACETATE/CYCLOHEXANE (0: 100 to 75: 25), to give the title compound as an oil.

With hydrogen;palladium on activated carbon; In ethanol; under 3102.97 Torr; for 2.5h;

1, 1-Dimethylethyl (3S)-3-aminopiperidine-1-carboxylate (l. Og, 5mmol), 2- trifluoromethylbenzaldehyde (0.87g, 5mmol), 5percent palladium on carbon (0.35g) and ethanol (40mL) were hydrogenated at 60psi for 2.5 h. using a Parr hydrogenator. The catalyst was filtered off and the filtrate evaporated in vacuo. The resultant oil was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (0: 100 to 75: 25), to give the title compound as an oil.

Reference： [1]Patent: WO2005/305,2005,A1 .Location in patent: Page 61-62
[2]Patent: WO2005/20975,2005,A2 .Location in patent: Page/Page column 238
[3]Patent: WO2005/20976,2005,A2 .Location in patent: Page/Page column 241
[4]Patent: WO2005/60949,2005,A2 .Location in patent: Page/Page column 239-240

3
[ 120-92-3 ]
[ 625471-18-3 ]
1,1-dimethylethyl (3S)-3-(cyclopentylamino)-piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;palladium 10% on activated carbon; In methanol; under 3102.97 Torr;	1,1-Dimethylethyl (3S)-3-AMINOPIPERIDINE-L-CARBOXYLATE (2. 1G, 10. 5MMOL), cyclopentanone (4.65mL, 52. 5MMOL), and 10percent palladium on carbon (0.2g) in methanol (80ML) were hydrogenated at 60psi overnight in a Parr hydrogenator. The catalyst was filtered off and the filtrate evaporated in vacuo. The resultant oil was purified by flash chromatography on silica, eluting with ethyl ACETATE/CYCLOHEXANE (15: 85 to 30: 70), to give the title compound as an oil.
	With hydrogen;palladium 10% on activated carbon; In methanol; under 3102.97 Torr;	1, 1-Dimethylethyl (3S)-3-aminopiperidine-1-carboxylate (2. 1G, 10. 5MMOL), cyclopentanone (4.65mL, 52. 5MMOL), and 10percent palladium on carbon (0.2g) in methanol (80mL) were hydrogenated at 60psi overnight in a Parr hydrogenator. The catalyst was filtered off and the filtrate evaporated in vacuo. The resultant oil was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (15: 85 to 30: 70), to give the title compound as an oil
	With hydrogen;palladium on activated carbon; In methanol; under 3102.97 Torr;	1, 1-Dimethylethyl (3S)-3-AMINOPIPERIDINE-L-CARBOXYLATE (2. 1G, 10. 5MMOL), cyclopentanone (4. 65mL, 52. 5MMOL), and 10percent palladium on carbon (0.2g) in methanol (80mL) were hydrogenated at 60psi overnight in a Parr hydrogenator. The catalyst was filtered off and the filtrate evaporated in vacuo. The resultant oil was purified by flash chromatography on silica, eluting with ethyl ACETATE/CYCLOHEXANE (15: 85 to 30 : 70), to give the title compound as an oil.

With hydrogen;palladium on activated carbon; In methanol; under 3102.97 Torr;

1,1-Dimethylethyl (3S)-3-aminopiperidine-l-carboxylate (2. 1g, 10. 5mmol), cyclopentanone (4. 65mL, 52. 5mmol), and 10percent palladium on carbon (0.2g) in methanol (80mL) were hydrogenated at 60psi overnight in a Parr hydrogenator. The catalyst was filtered off and the filtrate evaporated in vacuo. The resultant oil was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (15: 85 to 30: 70), to give the title compound as an oil.

Reference： [1]Patent: WO2005/305,2005,A1 .Location in patent: Page 65
[2]Patent: WO2005/20975,2005,A2 .Location in patent: Page/Page column 242
[3]Patent: WO2005/20976,2005,A2 .Location in patent: Page/Page column 245
[4]Patent: WO2005/60949,2005,A2 .Location in patent: Page/Page column 243

4
[ 79710-86-4 ]
[ 625471-18-3 ]
1,1-dimethylethyl (3S)-3-[(tetrahydrofuran-3-ylmethyl)amino]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;5%-palladium/activated carbon; In ethanol; water; under 3102.97 Torr;	To 5percent palladium on carbon (0. 05G) under nitrogen was added a solution of 1,1- DIMETHYLETHYL- (3S)-3-AMINOPIPERIDINE-1-CARBOXYLATE (0. 50G, 2. 5MMOL) and tetrahydrofuran-3-carboxaldehyde (50percent W/W in water) (0. 50G, 2. 5MMOL) in ethanol (20mL). The reaction mixture was hydrogenated overnight at 60psi in a Parr hydrogenator. The catalyst was removed by filtration through Celite and the solvent removed in vacuo to give 1, 1-dimethylethyl (3S)-3-[(TETRAHYDROFURAN-3- ylmethyl) amino] PIPERIDINE-L-CARBOXYLATE as a colourless, slightly cloudy oil.
	With hydrogen;5%-palladium/activated carbon; In ethanol; water; under 3102.97 Torr;	To 5percent palladium on carbon (0. 05G) under nitrogen was added a solution of 1,1- dimethylethyl-(3S)-3-aminopiperidine-1-carboxylate (0.50g, 2. 5MMOL) and tetrahydrofuran-3-carboxaldehyde (50percent WLW in water) (0. 50G, 2. 5MMOL) in ethanol (20mL). The reaction mixture was hydrogenated overnight at 60psi in a Parr hydrogenator. The catalyst was removed by filtration through Celite and the solvent removed in vacuo to give 1, 1-dimethylethyl (3S)-3-[(tetrahydrofuran-3- ylmethyl) amino] PIPERIDINE-L-CARBOXYLATE as a colourless, slightly cloudy oil
	With hydrogen;5%-palladium/activated carbon; In ethanol; water; under 3102.97 Torr;	To 5percent palladium on carbon (0. 05G) under nitrogen was added a solution of 1,1- dimethylethyl-(3S)-3-aminopiperidine-1-carboxylate (0.50g, 2. 5MMOL) and tetrahydrofuran-3-carboxaldehyde (50percent W/W in water) (0. 50G, 2. 5MMOL) in ethanol (20mL). The reaction mixture was hydrogenated overnight at 60psi in a Parr hydrogenator. The catalyst was removed by filtration through Celite and the solvent removed in vacuo to give 1, 1-dimethylethyl (3S)-3-[(TETRAHYDROFURAN-3- ylmethyl) amino] piperidine-l-carboxylate as a colourless, slightly cloudy oil.

With hydrogen;palladium on activated carbon; In ethanol; water; under 3102.97 Torr;

To 5percent palladium on carbon (0.05g) under nitrogen was added a solution of 1,1- dimethylethyl- (3S)-3-aminopiperidine-l-carboxylate (0.50g, 2. 5mmol) and tetrahydrofuran-3-carboxaldehyde (50percent W/w in water) (0. 50g, 2. 5mmol) in ethanol (20mL). The reaction mixture was hydrogenated overnight at 60psi in a Parr hydrogenator. The catalyst was removed by filtration through Celite and the solvent removed in vacuo to give 1, l-dimethylethyl (35)-3-[(tetrahydrofuran-3-ylmethyl) amino] piperidine-1- carboxylate as a colourless, slightly cloudy oil.

Reference： [1]Patent: WO2005/305,2005,A1 .Location in patent: Page 67
[2]Patent: WO2005/20975,2005,A2 .Location in patent: Page/Page column 243
[3]Patent: WO2005/20976,2005,A2 .Location in patent: Page/Page column 246-247
[4]Patent: WO2005/60949,2005,A2 .Location in patent: Page/Page column 245

5
[ 29943-42-8 ]
[ 625471-18-3 ]
[ 1044670-84-9 ]

Yield	Reaction Conditions	Operation in experiment
		1, 1-Dimethylethyl- (3S)-3-aminopiperidine-l-carboxylate (2g, llmmol), 4H- tetrahydropyran-4-one (L. lg, llmmol) and dichloroethane (40mL) were stirred under nitrogen at room temperature for 15 min. Sodium triacetoxyborohydride (2.9g, 14MMOL) was added in 3 lots over 30 minutes and stirred overnight. The reaction was diluted with water (50ML) and made basic by addition of 2N NAOH solution. After stirring for lh, the mixture was extracted into dichloromethane, and the combined organic extracts washed with brine, dried (MGS04), filtered and evaporated in vacuo to give the title compound as an oil.
		1, 1-Dimethylethyl- (3S)-3-aminopiperidine-1-carboxylate (2g, llmmol), 4H- tetrahydropyran-4-one (1. 1 g, 1 lmmol) and dichloroethane (40mL) were stirred under nitrogen at room temperature for 15 min. Sodium triacetoxyborohydride (2.9g, 14MMOL) was added in 3 lots over 30 minutes and stirred overnight. The reaction was diluted with water (50mL) and made basic by addition OF 2N NAOH solution. After stirring for lh, the mixture was extracted into dichloromethane, and the combined organic extracts washed with brine, dried (MGS04), filtered and evaporated in vacuo to give the title compound as an oil.
		1, 1-Dimethylethyl-(3S)-3-aminopiperidine-1-carboxylate (2g, 11mmol), 4H- tetrahydropyran-4-one (L. LG, LLMMOL) and dichloroethane (40mL) were stirred under nitrogen at room temperature for 15 min. Sodium triacetoxyborohydride (2.9g, 14MMOL) was added in 3 lots over 30 minutes and stirred overnight. The reaction was diluted with water (50mL) and made basic by addition OF 2N NAOH solution. After stirring for LH, the mixture was extracted into dichloromethane, and the combined organic extracts washed with brine, dried (MGS04), filtered and evaporated in vacuo to give the title compound as an oil.

1, 1-Dimethylethyl-(3S)-3-aminopiperidine-1-carboxylate (2g, 11mmol), 4H- tetrahydropyran-4-one (1. lg, llmmol) and dichloroethane (40mL) were stirred under nitrogen at room temperature for 15 min. Sodium triacetoxyborohydride (2.9g, 14mmol) was added in 3 lots over 30 minutes and stirred overnight. The reaction was diluted with water (50mL) and made basic by addition of 2N NaOH solution. After stirring for lh, the mixture was extracted into dichloromethane, and the combined organic extracts washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the title compound as an oil

Reference： [1]Patent: WO2005/305,2005,A1 .Location in patent: Page 63-64
[2]Patent: WO2005/20975,2005,A2 .Location in patent: Page/Page column 240
[3]Patent: WO2005/20976,2005,A2 .Location in patent: Page/Page column 243
[4]Patent: WO2005/60949,2005,A2 .Location in patent: Page/Page column 241-242

6
[ 90176-80-0 ]
[ 625471-18-3 ]
[ 820985-25-9 ]

Yield	Reaction Conditions	Operation in experiment
		1,1-Dimethylethyl (3S)-3-AMINOPIPERIDINE-1-CARBOXYLATE (5G) and 4-fluoro-2- (trifluoromethyl) benzaldehyde (5. 15g, 26.8mmol) were allowed to stir in methanol for 16h at room temperature. Sodium borohydride (1.62g, 26. 8MMOL) was then added portionwise. The resulting solution was further stirred for 2h at room temperature. The solvent was evaporated IN VACUO, water was added, and the solution extracted with dichloromethane. The organic extracts were absorbed onto a methanol washed cationic ion exchange resin (Isolute SCX-2). The basic components were recovered from the column by elution with 7N ammonia in methanol. The resultant solution was concentrated in vacuo to yield the desired compound as an oil. This was further purified by column chromatography on silica gel, eluting with ethyl acetate/iso-hexane (0: 100 to 40: 60). The title compound was used in subsequent reactions without further purification. 'H NMR (300 MHz, CDCl3) ON : 7.37-7. 28 (m, 2H), 7.24-7. 20 (m, 1H), 3.80 (s, 2H), 3.52- 3.48 (m, 2H), 3. 32 (m, 3H), 3.12 (m, 1H), 2.08-2. 0 (m, 1H), 1.75 (m, 1H), 1.45 (s, 9H).

Reference： [1]Patent: WO2005/811,2005,A1 .Location in patent: Page/Page column 64

7
[ 1271240-70-0 ]
[ 625471-18-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	With 10% palladium on activated charcoal; hydrogen; In ethanol; under 760.051 Torr;	Azido derivative 42a (6.77 g, 29.9 mmol) and Pd/C catalyst (150 mg) were hydrogenated in ethanol (200 ml) at an atmospheric pressure overnight. The catalyst was filtered through Celite and the solvent was evaporated. Product 43a was obtained in a 90percent yield (5.39 g, 26.9 mmol) as a colorless liquid without further purification.1H NMR, 13C NMR, and IR spectra were identical to those of 30. HRMS (ESI) C10H21O2N2 (M+H)+ calcd 201.1598, found 201.1597; [alpha]D20 +26.0 (c 0.308, EtOH).
	With hydrogen;palladium 10% on activated carbon; In methanol; under 3620.13 Torr; for 16h;	A mixture of 1, 1-dimethylethyl (3S)-3-azidopiperidine-1-carboxylate (7. 5G) and 10percent palladium-on-carbon (0.75g) in methanol (LOOML) was hydrogenated in a Parr apparatus at 70 p. s. i. for 16 hours. The catalyst was removed by filtration through Celite and the solvent evaporated in vacuo to give an oil. The resultant title compound was used in subsequent reactions without further purification.
	With hydrogen;palladium on activated carbon; In methanol; under 3620.13 Torr; for 16h;	A mixture of 1, 1-dimethylethyl (3S)-3-azidopiperidine-1-carboxylate (7.5g) and 10percent palladium-on-carbon (0.75g) in methanol (LOOML) was hydrogenated in a Parr apparatus at 70 p. s. i. for 16 hours. The catalyst was removed by filtration through Celite and the solvent evaporated in vacuo to give an oil. The resultant title compound was used in subsequent reactions without further purification.

With hydrogen;palladium on activated carbon; In methanol; under 3620.13 Torr; for 16h;

A mixture of 1, 1-dimethylethyl (3S)-3-azidopiperidine-1-carboxylate (7.5g) and 10percent palladium-on-carbon (0.75g) in methanol (LOOML) was hydrogenated in a Parr apparatus at 70 p. s. i. for 16 hours. The catalyst was removed by filtration through Celite and the solvent evaporated in vacuo to give an oil. The resultant title compound was used in subsequent reactions without further purification.

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500
[2]Patent: WO2005/305,2005,A1 .Location in patent: Page 60
[3]Patent: WO2005/20976,2005,A2 .Location in patent: Page/Page column 239
[4]Patent: WO2005/60949,2005,A2 .Location in patent: Page/Page column 238

8
[ 1374353-02-2 ]
[ 625471-18-3 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;palladium 10% on activated carbon; In methanol; under 3620.13 Torr; for 16h;	A mixture of 1, 1-dimethylethyl (3S)-3-azidopiperidine-l-carboxylate (7. 5G) and 10percent palladium-on-carbon (0.75g) in methanol (LOOML) was hydrogenated in a Parr apparatus at 70 p. s. i. for 16 hours. The catalyst was removed by filtration through Celite and the solvent evaporated in vacuo to give an oil. The resultant title compound was used in subsequent reactions without further purification

Reference： [1]Patent: WO2005/20975,2005,A2 .Location in patent: Page/Page column 236

9
[ 22317-89-1 ]
[ 625471-18-3 ]
(3S)-3-(methylsulfonylmethanesulfonylamido)piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (methylsulphonyl)-methanesulphonyl chloride; tert-butyl (3S)-3-aminopiperidine-1-carboxylate With N-ethyl-N,N-diisopropylamine In dichloromethane Stage #2: With trifluoroacetic acid In dichloromethane	The N3-alkanesulfonyl derivatives of 3-aminopiperidine were synthesized by reacting the chiral or racemic forms of 3-amino-piperidine-1-carboxylxic acid tert-butyl ester with the respective alkanesulfonyl chloride (i-Pr2NEt, CH2C12) and deprotecting the N-Boc group (CF3CO2H, CH2Cl2). (3S)-3- (ethanesulfonylamido) piperidine : 1H-NMR (CD30D) : No. (ppm) 1.29 (t, 3H, J1 = 7.4 Hz), 1.50-1. 80 (m, 2H), 1.90-2. 10 (m, 2H), 2.89 (m, 2H), 3.05 (q, 2H, J1 = 7.4 Hz), 3.27 (m, 2H), 3.40 (d of d (br), 1H), 3.52 (m, 1H). 3S-Methylsulfonylmethanesulfonylamido-piperidine : 1H-NMR (CD30D) : 8 (ppm) 2.13- 2.30 (m, 2H), 2.40-2. 57 (m, 2H), 2.98 (m, 2H), 3.15 (s, 3H), 3.21 (m, 2H), 3.30 (br d, 1H), 3.74 (m, 1H).

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - WO2005/80389, 2005, A1 Location in patent: Page/Page column 36-37

10
[ 2766-74-7 ]
[ 625471-18-3 ]
[ 860354-77-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 1h;	Example 248; 5-Phenvl-3-ureido-thiophene-2-sulfonic acid (S)-piperidin-3-vlamide; tert-butyl (3S)-3-[(5-chloro-2-thienyl)sulfonyl]amino}piperidine-1-carboxylate. ; 5- Chlorothiophene-2-sulfonyl chloride (lg, 4. 6062mmol), tert-butyl (3S)-3-aminopiperidine-1- carboxylate (1.1070g, 5. 5274mmol), and 20mL dichloromethane were added to a 50mL round bottom flask. Diisopropylethylamine was then added with stirring. Let stir one hour. Wash reaction mixture with water, then dry over MgSO4. Filter, and concentrate filtrate to dryness; 1.75g, 99percent, 4. 60mmol.'H NMR (300 MHz, CDC13) 5 ppm 1.69 (m, 2 H), 1.80 (m, 2 H), 3.20 (m, 1 H), 3.31 (m, 1 H), 3.41 (m, 2 H), 3.56 (m, 1 H), 4.94 (d, 1 H), 6.94 (d, 1 H), 7.45 (d, 1 H).

Reference： [1]Patent: WO2005/66163,2005,A2 .Location in patent: Page/Page column 117

11
[ 860354-59-2 ]
[ 625471-18-3 ]
[ 1037743-62-6 ]

Yield	Reaction Conditions	Operation in experiment
40%	With trimethylaluminum; In tetrahydrofuran; at 18 - 25℃;	tert-butyl (3S'-3-f (f3-ffaminocarbonvl) aminol-5-bromo-2-thienvllcarbonvl)- aminolpiperidine-l-carboxvlate.; To a solution of methyl 3- [ (aminocarbonyl) amino] -5- bromothiophene-2-carboxylate (1.6 g, 5. 7 mmol) in dry THF (30 mL) was added a solution of [Me3Al/ <strong>[625471-18-3]tert-butyl (3S)-3-aminopiperidine-1-carboxylate</strong>] in THF (18 mL) (which was preformed by the addition of Me3Al (17.2 mL, 34.4 mmol) to a solution of tert-butyl (3S3-3- aminopiperidine-1-carboxylate (3.7 g, 17.2 mmol) in THF at-78°C and the resulting yellow solution was stirred at this temperature for IS mins) and the resulting deep yellow solution was warmed to rt and stirred overnight at this temperature. The reaction mixture was cooled with ice and saturated solution of Rochelle's salt was added to quench the reaction. The mixture was partitioned between EtOAc and H20, the aqueous layer was extracted with EtOAc (3x) and the combined organic extracts were washed with H20, brine and dried (MgS04). Evaporation gave a pale orange solid. Purification by Gilson (5percent H2O~95percent H20-MeCN) gave the desired product (1.0 g, 40percent) as off-white solid. IH NMR (300 MHz, DMSO-d6; 10.06 (s, 1H), 8. 02 (s, 1H), 7.89 (d, 1H), 6.71 (brs, 2H), 4.04 (m, 1H), 3.72 (m, 2H), 2.74 (m, 2H), 1.81 (m, 1H), 1. 68 (m, 1H), 1.52 (m, 1H), 1. 37 (s, 9H), 1.34 (m, 1H) ; LC/MS (ES, M+H=448).

Reference： [1]Patent: WO2005/66163,2005,A2 .Location in patent: Page/Page column 64
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 5130 - 5142

12
[ 103-63-9 ]
[ 625471-18-3 ]
[ 912368-77-5 ]

Yield	Reaction Conditions	Operation in experiment
52%	With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 1h;Microwave irradiation;	fe^-butvI (3S)-3-[(2-phenvIethyl)amino1piperidine-l-carboxyIate; tert-butyl (3S)-3- aminopiperidine-1-carboxylate (Ig, 5 mmol), (2-bromoethyl)benzene (925 mg, 0.69 ml, 5 mmol) and potassium carbonate (1.73g, 12.5 mmol) are added to a microwave tube and DMF (6 mL) is added. The mixture is heated at 9O0C for Ih. The phases are partitioned between EtOAc and water. The organic layer is washed with water and brine, dried and evaporated. The mixture is purified by MPLC (EtOAC/Hexane) to give794 mg (52 percent) of the title compound as a colorless oil LCMS (ES, M+H=305).

Reference： [1]Patent: WO2006/106326,2006,A1 .Location in patent: Page/Page column 72

13
[ 625471-18-3 ]
[ 5018-38-2 ]
[ 886584-07-2 ]

Yield	Reaction Conditions	Operation in experiment
74%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 80℃; for 15h;	3-(S)-(6-Chloro-5-methoxy-pyrimidin-4-ylamino)-piperidine-l-carboxylic acid tert-butyl ester. To a solution of (S)-3 -Amino- l-(tert-butyloxycarbonylpiperidine (2.30 g, 11.5 mmol) in isopropanol (30 mL), 4,6-dichloro-5-methoxypyrimidine (2.06 g, 1 1.5 mmol), described in the literature by Anderson et al., Org. Proc. Res. Dev. 1997, 1, 310, was added followed by DIPEA (4 mL, 23.0 mmol). The resulting solution was heated at 800C for 15 h. The reaction mixture was cooled down to room temperature and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum (20:80 to 100:0). The title compound was obtained as a colourless oil (2.91 g, 74percent). MS (ES+) m/e = 343, (ES-) m/e 341. 1H NMR (400 MHz, DMSO-d6) deltaH 1.45 (9H, s), 1.61 (IH, m), 1.70-1.79 (2H, m), 1.88-1.96 (IH, m), 3.33-3.39 (IH, m), 3.47-3.52 (2H, m), 3.61-3.66 (IH, m), 3.87 (3H, s), 4.12 (IH, br s), 5.49 (IH, br s), 8.16 (IH, s). [alpha]D23°C +20 (c = 0.1 in MeOH).

Reference： [1]Patent: WO2006/50249,2006,A1 .Location in patent: Page/Page column 45

14
[ 625471-18-3 ]
[ 902152-76-5 ]

Yield	Reaction Conditions	Operation in experiment
		Example 130; 4-{f(3S)-l-methylpiperidin-3-yllainino}-2-phenylthieno[3,2-elpyridine-7-carboxamide; (3S)- 1 -methylpiperidin-3-amine; To a solution of tert-butyl (35)-3-aminopiperidine-l- carboxylate (8.89 g, 44.4 mmol) in THF (176 mL) at 0 0C is added drop wise IM lithium aluminum hydride in THF (88.0 mL, 88.8 mmol). The resulting grey solution is warmed to rt and stirred under nitrogen overnight. A solution of 10% Rochelle's salt is added to the mixture at 0 0C until the bubbling ceased. The resulting mixture is extracted with copious amounts of EtOAc, followed by 1/1 MeOH/ CH2Cl2. The combined organic layers are dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound, which is used directly in the next reaction. GCMS (m/z 114).

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 1061 - 1073
[2]Patent: WO2006/106326,2006,A1 .Location in patent: Page/Page column 97

15
[ 690635-52-0 ]
[ 625471-18-3 ]
[ 912369-09-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 2h;	tert-butyl (3S)-3-[(7-cvano-2-iodothienof3,2-clpyridin-4-yl)aminolpiperidine-l- carboxylate; To a stirred solution of 4-chloro-2-iodothieno[3,2-c]pyridine-7-carbonitrile (2.5 g, 7.8 mmol) and tert-butyl (3iS)-3-aminopiperidine- 1-carboxylate (1.9g, 9.4 mmol) in NMP (14 mL) is added potassium carbonate (2.2 g, 15.6 mmol). The heterogeneous mixture is heated to 8O0C for 2h, cooled to rt, and then added to ~100- 150 mL of water. Filtration and drying yields the product as a dark brown solid (4.4 g, 100percent), which is used directly in the next step without purification. LCMS (ES, M+H=485; M-H, 483).

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 1061 - 1073
[2]Patent: WO2006/106326,2006,A1 .Location in patent: Page/Page column 103

16
[ 690635-65-5 ]
[ 625471-18-3 ]
[ 912369-14-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 100℃;	tert-butyl (3S)-34(7-cyano-2-phenyH131thiazolof4,5-clpyridm-4-yI)amino1piperidine-l- carboxylate; To a solution of 4-chloro-2-phenyl[l,3]thiazolo[4,5-c]pyridine-7-carbonitrile (189 mg, 0.690 mmol) in NMP (3.0 mL) is added potassium carbonate (229 mg, 1.66 mmol) and tert-butyl (35)-3-aminopiperidine-l-carboxylate (691 mg, 3.45 mmol). The reaction mixture is heated to 100 0C until LCMS indicated the completion of the reaction. The reaction mixture is then filtered, affording a viscous oil which is purified by silica gel column chromatography (100percent hexane to 100percent EtOAc) and concentrated to dryness to yield 255 mg of the title compound (85percent yield). 1H NMR delta 1.35 (s, 9H)5 1.96-1.69 (m, 4H), 2.90 (m, 2H), 4.07-3.66 (m, 2H), 4.16 (m, IH), 7.61 (m, 3H), 7.96 (br s, IH), 8.15 (m, 2H), 8.49 (s, IH). LCMS (ES, M+H=436).

Reference： [1]Patent: WO2006/106326,2006,A1 .Location in patent: Page/Page column 109

17
[ 690635-43-9 ]
[ 625471-18-3 ]
[ 912368-70-8 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 2h;	Step 7: tert-hutyl (SS^-S-frT-cyano^-bromothienofS^-cipyridin-^vDaminolpiperidine-l- carboxylate; To a stirred solution of 2-bromo-4-chlorothieno[3,2-c]pyridine-7-carbonitrile (0.48 g, 1.76 mmol) and tert-butyl (3iS)-3-aminopiperidine-l -carboxylate (0.40 g, 2.0 mmol) in NMP (5 mL) is added potassium carbonate (0.5 g, 3.52 mmol). The heterogeneous mixture is heated to 8O0C for 2h, cooled to rt, and then added to ~50 mL of water. The product (880 mg) is isolated by filtration and dried. The title compound is further purified using MPLC (SiO2; 30-50percent EtOAc/Hexanes gradient) to give 0.54 g, 70percent as a light yellow crystalline solid. 1H NMR delta 8.36 (s, IH), 8.08 (s, IH), 7.68 (m, IH), 4.02 (m, IH), 3.74 (m, IH), 3.50 (m, IH), 2.70-3.20 (m, 2H), 1.91 (m, IH), 1.74 (m, IH), 1.54 (m, IH), 1.30-1.45 (m, IH), 1.21 (s, 9H). LCMS (ES, M+H=437, 439; M-H, 435, 437).

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 1061 - 1073
[2]Patent: WO2006/106326,2006,A1 .Location in patent: Page/Page column 55
[3]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 7216 - 7221

18
[ 912369-29-0 ]
[ 625471-18-3 ]
[ 912369-30-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 130℃;	fe/f-butyl (3.->)-3-[(2-broino-4-cvanothieno[2,3-clpyridin-7-vpiaminolpiperidine-l- carboxylate; To a solution of 2-bromo-7-chlorothieno[2,3-c]pyridine-4-carbonitrile (2.80 g, 10.2 mmol) in NMP (10.0 mL) is added potassium carbonate (4.23 g, 30.6 mmol) and tert- butyl (3S)-3-aminopiperidine-l-carboxylate (4.92 g, 24.6 mmol). The reaction mixture is heated to 130 0C until LCMS indicates the reaction is complete. The reaction mixture is then cooled to rt and approximately 100 mL of water is added. The resulting solid is filtered and vacuum dried to afford the title compound. 1H NMR delta 8.47 (s, IH), 8.35 (s, IH), 7.90 (br s, IH), 4.14 (m, IH), 3.38 (m, IH), 3.24 (m, IH), 2.93 (m, 2H), 1.94-1.73 (m, 4H), 1.37 (s, 9H). LCMS (ES, M+H=338).

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 1061 - 1073
[2]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 7216 - 7221
[3]Patent: WO2006/106326,2006,A1 .Location in patent: Page/Page column 117

19
[ 1195-45-5 ]
[ 625471-18-3 ]
[ 915230-71-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	In dichloromethane; at 20℃; for 2h;	4-Fluorophenylisocyanate (137 mg, 1 rnrnol) was slowly dropped into a solution of (S)-3-amino-l-N-Boc-piperidine (200 mg, 1 mmol) in DCM (2 mL). The reaction mixture was stirred at ambient temperature for 2h and then the solvent was evaporated under reduced pressure to afford a residue oil (337 mg), which was used for the next step without further purification. Yield: 100percent; LCMS (RT): 7.9 min (Method B); MS (ES+) gave m/z: 338.1.

Reference： [1]Patent: WO2006/123244,2006,A2 .Location in patent: Page/Page column 24

20
[ 908111-35-3 ]
[ 625471-18-3 ]
[ 1073973-30-4 ]

Yield	Reaction Conditions	Operation in experiment
63%	With sodium t-butanolate;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; In toluene; at 120℃; for 0.25h;microwave irradiation;	2-Bromo-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (1.236 g), <strong>[625471-18-3](S)-3-amino-piperidine-1-carboxylic acid tert-butyl ester</strong> (0.6 g), Pd(OAc)2 (34.2 mg), DPPF (169.8 mg), and NaOtBu (588 mg) in toluene (8 mL) were mixed and microwaved at 120° C. for 15 min. Then the reaction mixture was concentrated and purified by Biotage column chromatography, eluted by 15percent EtOAc in hexane to give 3-[2-Cyano-5-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-phenylamino]-S-piperidine-1-carboxylic acid tert-butyl ester (1 g, 63percent). LCMS (M+H) m/z=532.

Reference： [1]Patent: US2008/269193,2008,A1 .Location in patent: Page/Page column 43

21
5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole [ No CAS ]
[ 625471-18-3 ]
[ 1035097-01-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In pyridine; at 55℃;	A 500 mL round bottom flask with a stirbar was charged with 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (28.0 g, 0.0996 mol, 1.00 eq), (S)-3-amino-Boc-piperidine (21.75 g, 0.109 mol, 1.09 eq), tris(dibenzylideneacetone)dipalladium (4.75 g, 5.18 mmol, 0.052 eq), racemic BINAP (7.44 g, 12.0 mmol, 0.12 eq), and sodium tert-butoxide (28.7 g, 0.299 mol, 3.00 eq). The flask containing the solids was then evacuated and back-filled with nitrogen three times to degas. Pyridine (200 mL) was then added, and the flask was again purged three times with vacuum and nitrogen. The dark greenish mixture was then stirred at 55° C. overnight under a nitrogen atmosphere. In the morning, the reaction was cooled to room temperature, diluted with 250 mL EtOAc, washed three times with 250 mL portions of 10percent NaHSO4, and the organic phase was evaporated. The residue was dissolved in toluene and loaded onto a silica column that had been packed with heptane. The column was washed with 5 column volumes of heptane, after which the desired product was eluted with EtOAc/heptane, to provide the title compound as a pale yellow foam (2.4 g, 81percent).1H NMR (CDCl3, 300 MHz): delta 7.86 (s, 1H), 7.54 (d, J=9.0 Hz, 1H), 6.72 (dd, J=2.1, 9.0 Hz, 1H), 6.31 (s, 1H), 5.59 (dd, J=3.0, 9.0 Hz, 1H), 4.10 (m, 2H), 3.75 (m, 2H), 3.52 (m, 1H), 3.38 (m, 1H), 3.07 (m, 1H), 2.88 (m, 1H), 2.20 (m, 2H), 2.05 (m, 2H), 1.75-1.65 (m, 8H), 1.46 (s, 9H).

Reference： [1]Patent: US2008/214614,2008,A1 .Location in patent: Page/Page column 60; 61

22
[ 1035096-83-3 ]
[ 625471-18-3 ]
[ 1035096-85-5 ]

Yield	Reaction Conditions	Operation in experiment
82%	With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; In toluene; at 80℃;	To a solution of 5-bromo-1-(4-methoxybenzyl)-1H-indazole (870 mg, 2.75 mmol) in toluene (10 mL) was added in succession (S)-tert-butyl 3-aminopiperidine-1-carboxylate (660 mg, 3.3 mmol), sodium tert-butoxide (475 mg, 5 mmol), and rac-(+/-)-BINAP (180 mg, 0.29 mmol). The flask was evacuated and refilled with nitrogen three times, after which Pd2 dba3 (83 mg, 1.5 mol percent) was added. The flask was again purged with nitrogen three times, and was then heated to 80° C. overnight. The solution was cooled to room temperature and then filtered through a pad of celite, washing with additional toluene. The toluene solution was then loaded directly onto a silica gel column that had been packed with heptane. The column was flushed with 2 column volumes of heptane, and then eluted with 40/60-EtOAc/heptane to afford the title compound (1.00 g 82percent).
	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 80℃;Inert atmosphere;	Example 8(S)-tert-Butyl 3-(l-(4-Methoxybenzyl)-lH-indazol-5-ylamino)piperidine-l-carboxylateTo a solution of 5-bromo-l-(4-methoxybenzyl)-lH-indazole (Example 7) in toluene was added, in succession, 1.2 equivalents of (S)-tert-butyl 3-aminopiperidine-l-carboxylate, sodium teri-butoxide (1.8 equivalents), and rac-(+/-)-BINAP (0.105 equivalents). The flask was evacuated and refilled with nitrogen three times, after which Pd2dba3 (1.5 mol percent) was added. The flask was again purged with nitrogen three times, and was then heated to 80 °C overnight. The solution was cooled to room temperature and then filtered through a pad of celite, washing with additional toluene. The toluene solution was then loaded directly onto a silica gel column that had been packed with heptane. The column was flushed with 2 column volumes of heptane, and then eluted with 40/60 - EtO Ac/heptane to afford the title compound

Reference： [1]Patent: US2008/214614,2008,A1 .Location in patent: Page/Page column 47
[2]Patent: WO2012/15760,2012,A1 .Location in patent: Page/Page column 22

23
[ 845889-21-6 ]
[ 625471-18-3 ]
[ 845889-22-7 ]

Yield	Reaction Conditions	Operation in experiment
70%		tert-butyl (3S)-3-f (f 2-f (aminocarbonyl) aminol-5-bromo-3-thienyllcarbonyl) aminol piperidine-1-carboxylate.; To a solution Boc-3- (S)-aminopiperidine (2 equiv) in tetrahydrofuran (10 vol. ) was added trimethyl aluminium (2. 0M in hexanes 2.2 equiv. ) drop wise at-40°C (keeping the temp <-5°C). The mixture was stirred for 15 minutes and slowly warmed to room temperature (~25°C). To this mixture was then added a suspension of methyl 2- [ (aminocarbonyl) amino] -5-bromothiophene-3-carboxylate (28.0 g, 1 equiv) in tetrahydrofuran (12 vol. ) at room temperature. The reaction mixture was stirred overnight (the suspension goes into a supernatant solution), cooled to-78°C and a solution of Rochelle's salt (10percent) in water (40 vol. ) added slowly. The mixture was allowed to warm and stirred for lhr at room temperature then extracted with ethyl acetate (20 vol. x 3). The combined organic extracts were washed with water (20 vol. x 1), brine (10 vol. x 2), dried (magnesium sulfate) and concentrated to afford a dark solid. Column chromatography (ethyl acetate/iso-hexanes, 50: 50) gave a pale brown solid (32.0 g, 70percent). 1H NMR (d6-DMSO, 8 10.9, s, 1H ; 8 9. 48, br s, 1H ; 8 9. 31, br s, 1H; 8 8.48, d, IH ; otilde; 8.10, s, 1H ; 8 7.57, d, 2H; 8 7.38, t, 2H; 8 7.23, t, 1H ; 8 7. 01, br s, 2H; 8 4.26, m, 1H; 8 3.29, m, 1H ; 8 3.11, m, 1H ; 8 2.94, m, 2H; 8 1.91, m, 2H; 8 1.69, m, 2H), LC/MS (APCI, ES, M+H=345)

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4242 - 4248
[2]Patent: WO2005/66163,2005,A2 .Location in patent: Page/Page column 70
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 5130 - 5142

24
[ 79-04-9 ]
[ 625471-18-3 ]
[ 1204608-06-9 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In 2-methyltetrahydrofuran; at 20 - 25℃;	l-Boc-3-(S)-aminopiperidine (120.0 g, 0.599 mol) was dissolved in 2- methyltetrahydrofuran (540 ml). Pyridine (58.14 ml, 0.719 mol) was added, followed by a line- wash of 2-methyltetrahydrofuran (60 ml). Chloroacetyl chloride (55.32 ml, 0.689 mol) was added dropwise, maintaining the temperature at about 21-25°C, followed by a line wash of 2- methyltetrahydrofuran (60 ml). After 2.5 h at ambient temperature, the reaction mixture was sampled for conversion to 6 by HPLC before the addition of a 16percent w/w aqueous solution of sodium chloride (360 ml). The mixture was stirred for 30 min before separating off the aqueous phase.
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 0.5h;	(all at 2.0 mL/min). Synthesis 1 (S)-4-amino-2-(phenylamino)-N-(piperidin-3-yl)thiazole-5-carboxamide (TCA-001); Chloroacetyl chloride (0.08 mL, 1 mmol) was added in one portion to (S)-3-amino-1-N- Boc-piperidine (200 mg, 1 mmol) and Hnig's base (0.261 mL, 1.5 mmol) in dichloromethane (5 mL). After stirring for 30 minutes, the reaction mixture was diluted with water and dichloromethane. The organic phase was separated, dried (Na2SO4), and concentrated in vacuo to give the crude chloroamide intermediate. In a separate vessel, potassium t-butoxide (112 mg, 1 mmol) was added portionwise to a stirred mixture of cyanamide (42 mg, 1 mmol) and phenylisothiocyanate (0.119 mL, 1mmol) in acetonitrile (0.5 mL). When the mixture had cooled to room temperature, a solution of the crude chloroamide in MeCN (1.5 mL) was added portionwise. The resulting mixture was heated at 50GC for 1 hour and then poured into water (50 mL) and diluted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated to a brown oil which solidified on standing. The solid was dissolved in a mixture of acetonitrile (5 mL) and triethylamine (0.2 mL) and irradiated in a microwave reactor at 140°C for 2 x 5 minutes. The mixture was diluted with methanol and the product was simultaneously isolated and deprotected by solid phase extraction on a 1g MP-TsOH cartridge, eluting with 2 M ammonia in methanol. The basic eluent was concentrated and the residue purified by preparative HPLC to give the title compound (21 mg, 0.066 mmol, 6.6percent). Rt = 2.17 min, 318 (M+H)+. 1H NMR: delta (ppm, d-6 DMSO, 400 MHz) 7.71 (s, 1 H), 6.75 (d, 2H, J = 7.8Hz), 6.51 (dd, 2H, J = 7.3, 8.6Hz)1 6.25 (t, 1 H, J = 7.4Hz), 3.26-3.57 (m, 1 H), 2.56-2.63 (m, 1 H), 2.45- 2.53 (m, 1 H, partially obscured by DMSO signal), 2.04-2.13 (m, 1 H), 1.96-2.04 (m, 1 H), 1.15-1.285 (m, 2H), 0.92-1.04 (m, 1H), 0.76-0.88 (m, 1 H).

Reference： [1]Patent: WO2009/133389,2009,A1 .Location in patent: Page/Page column 25-26
[2]Patent: WO2010/7389,2010,A1 .Location in patent: Page/Page column 52
[3]Organic Process Research and Development,2017,vol. 21,p. 310 - 316

25
[ 7087-68-5 ]
[ 625471-18-3 ]
[ 187949-86-6 ]
tert-butyl (3S)-3-([3-amino-5-(4-chlorophenyl)-2-thienyl]carbonyl}amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		tert-butyl (3S)-3-([3-amino-5-(4-chlorophenyl)-2-thienyl]carbonyl}amino)piperidine-1- carboxylate.; To a solution of 3-amino-5- (4-chlorophenyl) thiophene-2-carboxylic acid (5.0 g, 19.7 mmol) in dry DMF (40 mL) were added ter-butyl (3)-3-aminopiperidine-1-carboxylate (3.95g, 19.7 mmol) and HATU (15. Og, 39.4 mmol) at 0C. The resulting pale orange solution was stirred for 10 mins at this temperature whereupon N, N'-diisopropylethyl amine (7.8 mL, 43.3 mmol) was added drop-wise via a syringe. After the addition finished, the resulting orange solution was warmed to rt and stirred overnight. The mixture was partitioned between EtOAc and H2O and the organic layer was washed with brine, H20 and dried (MgS04). Evaporation gave a yellow oil. Purification by Biotage-Horizon system (30% EtOAcNo.45% EtOAc-hexanes) gave the desired product.'H NMR (300 MHz, DMSO-d6) 8 ppm 1.39 (s, 9 H) 1.40-1. 45 (m, 1 H) 1.46-1. 62 (m, 1 H) 1.63-1. 73 (m, 1 H) 1.76-1. 87 (m, 1 H) 2.65-2. 78 (m, 2 H) 3.68-3. 82 (m, 3 H) 6.53 (s, 2 H) 6.98 (s, 1 H) 7.31 (d, J=6. 97 Hz, 1 H) 7.49 (d, J=8. 00 Hz, 2 H) 7.61 (d, J=8. 00 Hz, 2 H); LC/MS (ES, M+H=436).

Reference： [1]Patent: WO2005/66163,2005,A2 .Location in patent: Page/Page column 109-110

26
ethyl 2-phenyl-5-([(trichloroacetyl)amino]carbonyl}amino)-1,3-oxazole-4-carboxylate [ No CAS ]
[ 625471-18-3 ]
tert-butyl (3S)-3-[({5-[(aminocarbonyl)amino]-2-phenyl-1,3-oxazol-4-yl}carbonyl)amino]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%		tert-butyl (3S)-3-[({5-[(aminocarbonyl)amino]-2-phenyl-1,3-oxazol-4- vllcarbonyl) aminolniperidine-l-carboxvlate.; To a solution of ethyl 2-phenyl-5- ( { [ (trichloroacetyl) amino] carbonyl} amino)-1, 3-oxazole-4-carboxylate (320 mg, 1.2 mmol) in anhydrous THF (10 mL) was added via cannula a solution of [Me3Al and tert-butyl (359-3- aminopiperidine-l-carboxylate] in THF (preformed by the careful addition of Me3Al (2. 0M in hexanes, 6.2 mL, 12.3 mmol) to a solution of <strong>[625471-18-3]tert-butyl (3S)-3-aminopiperidine-1-carboxylate</strong> (1.29 g, 6.45 mmol) in 20 mL of THF at 0°C and subsequently stirring at rt for 10 mins). The resulting yellow solution was stirred at rt for 10 h. The reaction mixture was cooled to 0°C and a 10percent aqueous solution of Rochelle's salt was added slowly to quench the reaction. The mixture was partitioned between EtOAc and H2O, the aqueous layer was extracted with EtOAc (3x) and the combined organic extracts were washed with H20, brine and dried (MgS04). Evaporation gave a pale yellow solid. Purification by Gilson (5percent-95percent H2O/MeCN) gave the title compound as yellow solid (50percent yield). LC/MS (ES, M+H=460).

Reference： [1]Patent: WO2005/66163,2005,A2 .Location in patent: Page/Page column 124-125

27
[ 1201495-95-5 ]
[ 625471-18-3 ]
[ 1201496-15-2 ]

Yield	Reaction Conditions	Operation in experiment
35%		To a solution of (S)-3-amino-l-Boc-piperidine (0.8-1.5 eq.) in THF, under nitrogen, was added 2N trimethylaluminium in hexanes (2.0-3.3 eq.), and the reaction mixture was allowed to stir at room temperature for 0.25-2 hours. After this time, a THF solution of 1- (aryl)-4-ureido-lH-pyrrole-3-carboxylic acid ethyl ester (0.59-3.26 mmol, 1.0 eq.), was added and the reaction mixture was heated at 65-70 0C for a period of 3.5-24 hours. After this time, the reaction mixture was allowed to cool and was then quenched by addition of a saturated solution of Rochelle's salt. After 0.25-0.5 hours, the mixture was extracted with EtOAc or DCM and the organic layer was washed with water, brine, dried and concentrated. The resultant residue was then purified by flash chromatography (silica, 12-12O g column, ISCO, 0-100percent EtOAc in DCM) to afford the title compound.[00186] (S)-3-[l-(3-FIuorophenyl)-4-ureido-lH-pyrroIe-3-carbonyl]-amino}- piperidine-1-carboxylic acid tert-buty\\ ester [00187] Following general method 5, employing l-(3-fluorophenyl)-4-ureido-lH-pyrrole-3-carboxylic acid ethyl ester, afforded the title compound as an orange solid (0.51 g, 35percent); LCMS (method B): Rtau = 3.38 min, M+H+ = 446; 1H NMR (CDCl3, 300 MHz): 9.15 (s, IH), 7.61 (d, J = 2.5 Hz, IH), 7.35 (dt, J = 8.2, 6.2 Hz, IH), 7.25 (br. s, IH), 7.15 (ddd, J = 8.2, 2.2, 0.9 Hz, IH), 7.07 (dt, J = 9.9, 2.2 Hz, IH), 6.95 (tdd, J = 8.2, 2.5, 0.9 Hz, IH), 6.36 (br. s, IH), 4.92 (s, 2H), 4.02 (m, IH), 3.62 (dd, J = 13.3, 3.5 Hz, IH), 3.49-3.33 (m, 3H), 1.93-1.52 (m, 4H), 1.46 (s, 9H).

Reference： [1]Patent: WO2009/151599,2009,A1 .Location in patent: Page/Page column 45

28
[ 56674-87-4 ]
[ 625471-18-3 ]
[ 876378-02-8 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1: tert-Butyl (3S)-3-[(4-oxo-1-adamantyl)carbonyl]amino}piperidine-1-carboxylate Oxalyl chloride (233 muL, 0.00275 mol) was added to <strong>[56674-87-4]4-oxoadamantane-1-carboxylic acid</strong> (97.08 mg, 0.0004998 mol) in methylene chloride (10 mL) at rt followed by 2 drops of DMF. After stirring the mixture at rt for 2 h, the volatiles were evaporated under reduced pressure. The residue was azeotropically evaporated twice with toluene and the resulting residue was dissolved in DCM (10 mL). To the solution was added tert-butyl (3S)-3-aminopiperidine-1-carboxylate (100.1 mg, 0.0004998 mol) and N,N-diisopropylethylamine (0.18 mL, 0.0010 mol). After stirring at rt for 1 h, the reaction mixture was diluted with DCM (100 mL) and washed with water, 1N HCl, and brine. The organic phase was dried over Na2SO4, filtered, and concentrated in-vacuo to provide the desired product. LCMS: (M -t-Bu+H)+=321.2.

Reference： [1]Patent: US2007/66584,2007,A1 .Location in patent: Page/Page column 25-26

29
[ 1256913-15-1 ]
[ 625471-18-3 ]
[ 1256913-37-7 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 2h;	(S)- ethyl 6-bromo- 1 -( 1 -(tert-butoxycarbonyl)piperidin-3 -vD-4-oxo- 1 ,4-dihydro- 1,8- naphthyridine-3 -carboxylateEthyl 2-(5-bromo-2-fluoronicotinoyl)-3-(dimethylamino)acrylate (Intermediate 3, 2.0 g, 5.79 mmol), (S)-tert-butyl 3 -aminopiperidine- 1 -carboxylate (1.160 g, 5.79 mmol), and potassium carbonate (2.042 g, 7.38 mmol) were combined in DMF (10.0 mL). The reaction mixture was heated at 90 0C for 2 h. The reaction mixture was cooled to 00C and IN HCl was slowly added until pH was 5. The resulting precipitate was collected by filtration, washed with water and dried overnight to yield a light yellow solid ( 2.1O g, 75percent). MS (ES) (M+H)+: 481 for C2IH26BrN3O5

Reference： [1]Patent: WO2010/136817,2010,A1 .Location in patent: Page/Page column 124

30
[ 1261302-02-6 ]
[ 625471-18-3 ]
[ 1261302-03-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In 1-methyl-pyrrolidin-2-one at 80℃; for 1.5h;

Reference： [1]Location in patent: scheme or table Zhao, Lianyun; Zhang, Yingxin; Dai, Chaoyang; Guzi, Timothy; Wiswell, Derek; Seghezzi, Wolfgang; Parry, David; Fischmann, Thierry; Siddiqui, M. Arshad [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7216 - 7221]

31
[ 5413-85-4 ]
[ 625471-18-3 ]
[ 1271240-99-3 ]

Yield	Reaction Conditions	Operation in experiment
72%	With triethylamine; In ethanol; at 110℃; for 48h;Autoclave;	Amino derivative 43a (200 mg, 1.0 mmol), 5-amino-4,6-dichloropyrimidine 16 (179 mg, 1.1 mmol), and triethylamine (0.59 ml, 4.3 mmol) were suspended in ethanol (40 ml) and heated to 110 °C in a pressure vessel over 48 h. After the reaction was completed (TLC controlled 50percent ethyl acetate/toluene), all the solvent was evaporated and the residue was chromatographed on a silica gel using a linear gradient of ethyl acetate in toluene. Product was obtained in 72percent yield (235 mg, 0.72 mmol) as a dark orange foam.1H NMR, 13C NMR, and IR spectra were identical to those of 33a. HRMS (ESI) C14H23O2N5Cl (M+H)+ calcd 328.1535, found 328.1536; [alpha]D20 +3.4 (c 0.355, EtOH).

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

32
[ 1193318-57-8 ]
[ 625471-18-3 ]
[ 1271240-81-3 ]

Yield	Reaction Conditions	Operation in experiment
80%	In 1,4-dioxane; at 20℃; for 0.5h;	Genaral procedure: Compounds 15a (1.1 mmol) or 15b (1.3 mmol) was added to the solution of amine (1 mmol) in dioxane (10 ml/mmol). The reaction mixture was stirred at rt for 30 min. The solvent was then evaporated and the product was purified on a silica gel.

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

33
[ 55583-59-0 ]
[ 625471-18-3 ]
[ 1271241-02-1 ]

Yield	Reaction Conditions	Operation in experiment
54%	With triethylamine; In butan-1-ol; at 140℃; for 48h;Autoclave;	Amino derivative 43a (1.05 g, 5.24 mmol), <strong>[55583-59-0]2,5-diamino-4,6-dichloropyrimidine</strong> 17 (1.03 g, 5.76 mmol), and triethylamine (3.1 ml, 22.53 mmol) were suspended in n-butanol (80 ml) and heated to 140 C in a pressure vessel over 48 h. After the reaction was completed, the solvent was evaporated and the residue chromatographed on a silica gel using a linear gradient of ethyl acetate in toluene. The product was obtained in a 54% yield (969 mg, 2.82 mmol) as a light orange foam.1H NMR, 13C NMR, and IR spectra were identical to those of 33b. HRMS (ESI) C14H24O2N6Cl (M+H)+ calcd 343.1644, found 343.1645; [alpha]D20 -31.1 (c 0.106, EtOH).

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

34
[ 143900-43-0 ]
[ 625471-18-3 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 1485 - 1500

35
[ 63810-78-6 ]
[ 625471-18-3 ]
[ 1270499-05-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1,1-dichloroethane; at 20 - 80℃; for 36h;	Example 76; ((S)-1-Methanesulfonyl-piperidin-3-yl)-[5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-amine; The General Procedure is According to that of the Above Scheme; Step 1; A solution of <strong>[63810-78-6]5-bromo-4-chloro-2-(methylthio)pyrimidine</strong> (4.8 g, 20 mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (4.8 g, 240 mmol) and diisopropylethylamine (6.2 g, 480 mmol) in dichloroethane (120 ml) was stirred at room temperature for 14 hours and then at 70 C. for 16 hours. Another equivalent of both (S)-tert-butyl 3-aminopiperidine-1-carboxylate and diisopropylethylamine were added and heating was continued at 80 C. for 6 hours. The reaction was cooled, washed with aqueous ammonium chloride, dried (MgSO4) and evaporated to give an oil that was purified by flash chromatography (0-50% ethyl acetate/dichloromethane) to give (S)-3-aminopiperidine-1-carboxylic acid tert-butyl ester as an oil. The oil was diluted with dichloromethane (100 ml) cooled to 5 C. and treated with trifluoroacetic acid (40 ml). After stirring at room temperature for 5 hours, all solvent was evaporated. The residue was dissolved in dichloromethane (150 ml) and washed with cold dilute aqueous sodium hydroxide. The organics were dried (MgSO4) and evaporated to give an oil that solidified on standing in ether/hexane to give (5-bromo-2-methylsulfanyl-pyrimidin-4-yl)-(S)-piperidin-3-yl-amine. MS (ES+): 304

Reference： [1]Patent: US2011/59118,2011,A1 .Location in patent: Page/Page column 97-98

36
[ 1345447-25-7 ]
[ 625471-18-3 ]
[ 1350733-40-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine; In dichloromethane; at 35℃; for 1h;	Method for svnthesising ferf-butyl (S)-3-(6-iodo-3-nitro-quinolin-4-ylamino)-piperidine- 1-carboxylate - E.24D.1 E.24Quinoline D.1 (1.5 g, 4.5 mmol) and fert-butyl (S)-3-amino-piperidine-1-carboxylate - ED.4 (988 mg, 4.9 mmol) are taken up in DCM (5 mL), combined with Et3N (620 mu, 4.5 mmol) and stirred for 1 h at 35°C. The solvent is removed, the residue is taken up in MeOH (10 mL), water (10 mL) and sat. K2C03 solution (2 mL), the precipitate is filtered off, washed with water (5 mL) and MeOH (5 mL), freeze-dried and product E.24 (2.1 g, 92 percent; HPLC-MS: MS(M+H)+ = 499; = 1 .212 min; method 1_FEC) is obtained.

Reference： [1]Patent: WO2011/144622,2011,A1 .Location in patent: Page/Page column 74

37
[ 1365838-89-6 ]
[ 814-68-6 ]
[ 625471-18-3 ]
[ 1365838-15-8 ]

Yield	Reaction Conditions	Operation in experiment
40%		Example 86:Lambda/-[(35)-1 -3thetaGammagammaIotaomicrongammaIota-3-rhorhobeta?etanuIota]-4-{ ^thetaGammarhoEtaomicronMuetanuGammathetaIotaEtagammaIota)-LambdaGamma-[1 ,3]Eta3Zetatheta[omicron[5,4- Jb]pyridin-2-yl-2,6-pyridinediamineA microwave vial was charged with A/-(6-chloro-4-(morpholinomethyl)pyridin-2- yl)thiazolo[5,4-jb]pyridin-2-amine (75 mg, 0.207 mmol), 1 , 1 -dimethylethyl (3S)-3-amino-1- piperidinecarboxylate (62.3 mg, 0.31 1 mmol), dicyclohexyl[2',4',6'-tris(1-methylethyl)-3,6- bis(methy.oxy)-2-biphenylyljphosphane (BrettPhos) (1 1.13 mg, 0.021 mmol), chloro[2- (dicyclohexylphosphinoJ-S.e-dimethoxy-Z-^-e'-tri-i-propyl-l , 1 '-biphenylj[2-(2- aminoethy.)phenyl]palladium(ll) (16.56 mg, 0.021 mmol) and tetrahydrofuran (1 mL). The system was sealed and placed under an atmosphere of nitrogen using a vacuum purge (3 times). Lithium bis(trimethylsilyl)amide, 1 M in tetrahydrofuran (0.622 mL, 0.622 mmol) was added and the vial was heated at 80 C in the preheated oil bath for 14 hours. The vial was cooled down to room temperature and the reaction mixture was partitioned between dichloromethane (10 mL) and saturated ammonium chloride (10 mL). After separation, the organic extract was dried using a hydrophobic frit and evaporated to dryness. The yellow residue was dissolved in dichloromethane (3 mL) and methanol (1 mL). The soiution was treated with 4M HCi in dioxane (0.5 mL, 2 mmol) and stirred at room temperature overnight. The solvent was evaporated to dryness. The yellow residue was dissolved in W-methyl-2-pyrrolidone (1 mL) and A/,A/-diisopropylethylamine (0.181 mL, 1.036 mmol). 2-Propenoyl ch.oride (0.034 mL, 0.415 mmol) was added and the reaction was stirred at room temperature for 1 hour. The mixture was subjected to purification by mass directed automated preparative HPLC (ammonium bicarbonate modifier) to afford the title compound (40 mg, 0.083 mmoi, 40 % yield) as a brown solid. LCMS (Method D): Rt 0.85 minutes; m/z 480 (MH+).

Reference： [1]Patent: WO2012/35055,2012,A1 .Location in patent: Page/Page column 208

38
[ 106-94-5 ]
[ 625471-18-3 ]
[ 1374242-24-6 ]

Yield	Reaction Conditions	Operation in experiment
57%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃;	Example 48[0304] Synthesis of (,S')-2-(3,5-dichlorophenylamino)-l-(3-(propyl(7H-pyrrolo[2,J]pyrimidin-4-yl)amino)piperidin- 1 -yl)ethanone:Reagents and conditions: a) DIEA, DMF, 1-bromopropane, 100 °C, overnight; b) 4-chloro-7- tosyl-7H-pyrrolo[2,3-d]pyrimidine, DIEA, DMF, 100 °C, 4 h; c) Dioxane.HCl, rt, 1 h; d) 2-(3,5- dichlorophenylamino)acetic acid, EDCI, HOBt, DIEA, DMF, rt, 15 h; e) K2C03, aq. MeOH, 60 °C, 1 h.[0305] Synthesis of (S)-tert-butyl 3-(propylamino)piperidine-l-carboxylate: A solution of(^-tert-butyl 3-aminopiperidine-l-carboxylate (500 mg, 2.49 mmol) and 1-bromopropane (335 mg, 2.74 mmol) and DIEA (0.11 mL, 6.24 mmol) in DMF (4 mL) was heated at 100 °C for overnight. After reaction was shown to be complete as indicated by TLC, the mixture was diluted with EtOAc (30 mL) and washed with water (2 x 15 mL). The organic layer was separated, dried over Na2S04, concentrated in vacuo to afford a residue which was purified by column chromatography (silica gel, gradient MeOH in CH2C12) to yield the titled intermediate (605 mg, 57percent). 1H NMR (400 MHz, DMSO-d6): delta 3.89-3.64 (m, 3H), 2.80-2.66 (m, 2H), 2.50- 2.35 (m, 3H), 1.89-1.83 (m, 2H), 1.61-1.58 (m, 2H), 1.38 (s, 9H), 1.35-1.29 9m, 2H), 0.82 (t, J = 7.2 Hz, 3H). ES-MS: m/z [M+l] = 243.

Reference： [1]Patent: WO2012/58645,2012,A1 .Location in patent: Page/Page column 107

39
[ 479633-63-1 ]
[ 625471-18-3 ]
[ 1374241-39-0 ]

Yield	Reaction Conditions	Operation in experiment
65%	With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 4h;	Example 1[0155] Synthesis of 2-(3-chloro-5-fluorophenylamino)-l-((lS')-3-(7H-pyrrolo[2,3-J]pyrimidin-4-ylamino)piperidin- 1 -yl)ethanone: Reagents and conditions: a) 4-Chloro-7-tosyl-7H-pyrrolo[2,3-J]pyrimidine, DIEA, DMF, 90 °C, 15 h; b) EtOH:HCl, rt, 30 min.; c) 2-(3-Chloro-5-fluorophenylamino)acetic acid, EDCI, HOBt, DIEA, DMF, rt, 5 h; e) K2C03, MeOH:H20, 50 °C, 2 h.[0156] Synthesis of (S)-ieri-butyl 3-(7-tosyl-7H-pyrrolo[2,3-J]pyrimidin-4- ylamino)piperidine-l-carboxylate: To a solution of (S)-l -benzyl -N-methylpiperidin-3-amine (2.2 g, 11.0 mmol) and 4-chloro-7-tosyl-7H-pyrrolo[2,3-J]pyrimidine (3.4 g, 11.0 mmol) in anhydrous DMF (30 mL), Et3N (3.8 mL, 27.6 mmol) was added and the reaction mixture was stirred at 90 °C for 4h. After completion of the reaction (TLC), the reaction mixture was diluted with EtOAc (100 mL) and was washed with water (3 X 40 mL). The EtOAc layer was then dried over Na2S04 and evaporated under vacuo to give a residue that was subjected to purification by column chromatography (silica gel, gradient EtOAc in hexanes) to afford the titled intermediate (3.4 g, 65percent). XH NMR (400 MHz, DMSO-d6): delta 8.22 (s, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 2.5 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 6.92 (s, 1H), 3.98-3.90 (m, 2H), 3.70-3.60 (m, 2H), 3.21- 2.90 (m, 1H), 2.17 (s, 3H), 1.97-1.78 (m, 2H), 1.71-1.60 (m, 2H), 1.12 (s, 9H). LC-MS: m/z [M+l] = 472.

Reference： [1]Patent: WO2012/58645,2012,A1 .Location in patent: Page/Page column 54-55

40
[ 1095822-25-5 ]
[ 625471-18-3 ]
[ 1374241-63-0 ]

Yield	Reaction Conditions	Operation in experiment
61%	With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 4h;	Example 21[0213] Synthesis of (lS')-l-(3-(lH-pyrazolo[3,4-J]pyrimidin-4-ylamino)piperidin-l-yl)-(3,5 -dichlorophenylamino)ethanone :Reagents and conditions: a) 4-Chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4- JJpyrimidine, DIEA, DMF, 90 °C, 15 h; b) (i) EtOH:HCl, rt, 30 min.; (ii) carbonate polymer supported resin, MeOH, rt, 1 h.; c) 2-(3,5-Dichlorophenylamino)acetic acid, EDCI, HOBt, DIEA, DMF, rt, 5 h.[0214] Synthesis of (S)-tert-butyl 3-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrazolo[3,4-J]pyrimidin-4-ylamino)piperidine-l-carboxylate: To a solution of (S)- 1 -benzyl -N- methylpiperidin-3-amine (4.3 g, 21.46 mmol) and 4-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-pyrazolo[3,4-J]pyrimidine (6.11 g, 21.5 mmol) in anhydrous DMF (40 mL), Et3N (4.4 mL, 32.2 mmol) was added and the reaction mixture was stirred at 90 °C for 4 h. After completion of the reaction as indicated by TLC, the reaction mixture was diluted with EtOAc (100 mL) and was washed with water (3 X 40 mL). The EtOAc layer was then dried over Na2S04 and evaporated in vacuo to give a residue that was subjected to purification by column chromatography (silica gel, gradient EtOAc in hexanes) to afford the titled intermediate (5.9 g, 61 percent). 1H NMR (400 MHz, DMSO-d6): delta 8.30 (s, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 5.59 (s, 2H), 4.09 (m, 2H), 3.72 (m, 1H), 3.53 (t, J = 8.0 Hz, 2H), 3.38 (m, 1H), 3.17 (m, 1H), 1.98 (m, 1H), 1.81 (m, 1H), 1.60 (m, 1H), 1.38 (m, 1H), 1.21 (s, 9H), 0.81 (t, J = 8.4 Hz, 2H), -0.09 (s, 9H). LC-MS: m/z [M+l] = 449.

Reference： [1]Patent: WO2012/58645,2012,A1 .Location in patent: Page/Page column 73

41
[ 1400580-11-1 ]
[ 625471-18-3 ]
[ 1400580-56-4 ]

Yield	Reaction Conditions	Operation in experiment
64%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 18h;	Step 1; (S)-tert-butyl 3 -(6-bromo-3 -carbamoylpyrrolo [ 1 ,2-b]pyridazin-4- ylamino)piperidine- 1 -carboxylate [00281] A solution of 6-bromo-4-chloropyrrolo[l,2-b]pyridazine-3-carboxamide (Intermediate 2, 171 mg, 0.62 mmol) and (S)-tert-butyl 3-aminopiperidine-l-carboxylate (125 mg, 0.62 mmol) in DMF (4 mL) was added DIPEA (0.326 mL, 1.87 mmol). The mixture was heated at 80 °C for 18 h then cooled to rt. Water (16 mL) was added and the resulting suspension was stirred for lh. The solids were filtered, rinsed with water (2x), and then dried to afford the crude product which was purified via silica gelchromatography (10percent to 50percent ethyl acetate in hexanes) to afford the title compound (175 mg, 64percent yield) as a pale yellow solid. XH NMR (DMSO-d6, 400 MHz) delta 10.89 (br s, 1H), 8.26 (s, 1H), 7.90 (d, J = 1.5 Hz, 1H), 7.00 (br m, 2H), 4.18 (s , 1H), 3.68 (m, 1H), 3.35 (m, 3H), 1.99 (m, 1H), 1.70 M, 1H), 1.57 (m, 1H), 1.23 br s, 9H).

Reference： [1]Patent: WO2012/125893,2012,A1 .Location in patent: Page/Page column 152-153

42
[ 13505-01-6 ]
[ 625471-18-3 ]
[ 1405128-56-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 100℃; for 16h;	3-Fluoro-4- nitropyridine (689 mg, 4.85 mmol, Chem Impex International, Wood Dale, IL) and (S)-3- (Boc-amino)piperidine (1.17 g, 5.82 mmol, Alfa Aesar, Ward Hill, MA,) were treated with dioxane (20 mL) and DIPEA (2.12 mL, 12.12 mmol) and heated in a flask with a reflux condenser to 100 C for 16 h. The reaction mixture was concentrated and the crude material was purified by silica gel chromatography (10-90% EtOAc in hexanes) to afford (S)-tert-buty (l-(4-nitropyridin-3-yl)piperidin-3-yl)carbamate (1.49 g, 4.62 mmol, 95 % yield) as a bright yellow crystalline solid. MS (ESI, pos. ion) m/z: 323.3 (M+l). .H NMR (400 MHz, CDCl3) delta ppm 8.11 - 8.17 (2 H, m), 7.27 (1 H, br. s.), 4.57 (1 H, br. s.), 3.86 (1 H, d, J=11.9 Hz), 3.73 (1 H, br. s.), 3.64 (1 H, d, J=l 1.9 Hz), 3.27 (1 H, br. s.), 3.07 - 3.20 (1 H, m), 1.97 - 2.06 (1 H, m), 1.81 - 1.91 (1 H, m), 1.73 (1 H, dtd, J=13.6, 9.1, 9.1, 4.3 Hz), 1.46 (9 H, s).

Reference： [1]Patent: WO2012/148775,2012,A1 .Location in patent: Page/Page column 109

43
[ 1493-27-2 ]
[ 625471-18-3 ]
[ 1023299-14-0 ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine; In ethanol; at 50℃; for 20h;	A mixture of 1- fluoro-2-nitrobenzene (0.19 mL, 1.77 mmol, Sigma-Aldrich), (s)-3-(boc-amino)piperidine (355 mg, 1.77 mmol, Sigma-Aldrich) and DIPEA (0.62 mL, 3.54 mmol) in EtOH (3,.5 mL) was heated at 50 °C and stirred for 20 h. After cooling to RT, the reaction mixture was concentrated. The residue was diluted with EtOAc and saturated NaHCC (aq.). The organic layer was washed with water, and brine and dried over Na2S04, filtered and concentrated to afford (S)-tert-buty\\ (l-(2-nitrophenyl)piperidin-3-yl)carbamate (536 mg, 1.67 mmol, 94 percent yield) as an orange oil. MS (ESI, pos. ion) m/z: 322.1 (M+l).

Reference： [1]Patent: WO2012/148775,2012,A1 .Location in patent: Page/Page column 106

44
[ 686344-50-3 ]
[ 625471-18-3 ]
[ 1408075-23-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; In ethanol; at 80℃; for 16h;	To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (100 mg, 0.267 mmol, leq.) in 3 mL of ethanol was added tert-butyl (3 S)-3-aminopiperidine-l -carboxylate (64 mg, 0.32 mmol, 1.2 eq.) and triethylamine (0.06 mL, 0.4 mmol, 1.5 eq.). The reaction was heated to 80° C for 16h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100percent ethyl acetate/hexanes to yield 137 mg (95percent) of tert-butyl (3S)-3- [8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-l - carboxylate. 1H NMR (300 MHz, CHLOROFORM- d) delta ppm 1.43 (br. s., 9 H) 1.60 - 1.76 (m, 2 H) 1.77 - 1.93 (m, 1 H) 2.08 - 2.22 (m, 1 H) 3.30 (br. s., 2 H) 3.60 (br. s., 1 H) 3.98 (br. s., 1 H) 4.42 (br. s., 1 H) 5.96 (d, J=7.54 Hz, 1 H) 7.14 - 7.68 (m, 8 H) 8.48 (s, 1 H), [M + H]+ 539.4.

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10022 - 10032
[2]Patent: WO2013/123335,2013,A1 .Location in patent: Page/Page column 50

45
[ 77542-18-8 ]
[ 625471-18-3 ]
[ 1441792-39-7 ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium carbonate; In ethanol; water; at 80℃; for 4h;	N-Ethyl-N-methyl-4-oxo-piperidinium iodide (8.0 g, 29.7 mmol) dissolved in deionized water (30 mL) was added to a refluxing solution of (5)-l-boc-3-aminopiperidine (5 g, 25 mmol) and potassium carbonate (K2C03) (3.5 g, 25 mmol) in ethanol (125 mL) at 80 °C. The heating was continued for 4 h and excess solvent was removed in vacuo. The aqueous layer was extracted with ethyl acetate (3 x 60 mL), and the combined organic layers were dried (Na2S04), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Si02, 1-5percent methanol in dichloromethane) to give the desired compound (5.8 g, 20.5 mmol, 82percent). MS: (ES) m/z calculated for C15H27N203 [M + H]+ 283.2, found 283.

Reference： [1]Patent: WO2013/82490,2013,A1 .Location in patent: Paragraph 0109

46
[ 446-11-7 ]
[ 625471-18-3 ]
(S)-tert-butyl 3-((4-methyl-2-nitrophenyl)amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 6h;Inert atmosphere;	Step A: A stirred solution of (5)-tert-butyl 3-aminopiperidine-1-carboxylate (0.500 g,2.49 mmol), 1-fluoro-4-methyl-2-nitrobenzene (0.387 g, 2.49 mmol) and N,Ndiisopropylethylamine (0.482 g, 3.74 mmol) in DMF under argon was heated to 110°C for 6 h (reaction completion monitored by TLC). The mixture was diluted with water and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2504 and concentrated under reduced pressure to afford (S)-tert-butyl 3-((4-methyl-2-nitrophenyl) amino) piperidine- 1 -carboxylate (I-15a). MS calculated for C17H24N304 (M-W) 334.18, found 334.0.
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 6h;Inert atmosphere;	Step A: A stirred solution of(S)-tert-butyl 3-aminopiperidine-1-carboxylate (0.500 g, 2.49 mmol), 1-fluoro-4-methyl-2-nitrobenzene (0.387 g, 2.49 mmol) and N,N-diisopropylethylamine (0.482 g, 3.74 mmol) in DMF under argon was heated to 110°C for 6 h (reaction completion monitored by TLC). The mixture was diluted with water andextracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrousNa2SO4 and concentrated under reduced pressure to afford (S)-tert-butyl3 -((4-methyl-2-nitrophenyl) amino) piperidine- 1 -carboxylate (I-15a). MS calculated forC17H24N304 (M-H) 334.18, found 334.0.
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 6h;Inert atmosphere;	Step A: A stirred solution of (S)-tert-butyl 3-aminopiperidine-1-carboxylate (0.500 g, 2.49 mmol), 1-fluoro-4-methyl-2-nitrobenzene (0.387 g, 2.49 mmol) and N,N-diisopropylethylamine (0.482 g, 3.74 mmol) in DIVIF under argon was heated to 110°C for 6 h (reaction completion monitored by TLC). The mixture was diluted with water andextracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrousNa2SO4 and concentrated under reduced pressure to afford (S)-tert-butyl3-((4-methyl-2-nitrophenyl) amino) piperidine-1-carboxylate (I-15a). MS calculated forC17H24N304 (M-H) 334.18, found 334.0.

	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 6h;Inert atmosphere;	Step A: A stirred solution of (S)-tert-butyl 3-aminopiperidine-i-carboxylate (0.500 g, 2.49 mmol), i-fluoro-4-methyl-2-nitrobenzene (0.387 g, 2.49 mmol) andN,N-diisopropylethylamine (0.482 g, 3.74 mmol) in DMF under argon was heated to 110°C for 6 h (reaction completion monitored by TLC). The mixture was diluted with water and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford (S)-tert-butyl 3-((4-methyl-2-nitrophenyl) amino) piperidine-i-carboxylate (I-15a). MS calculated forC17H24N304 (M-H) 334.18, found 334.0.
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 6h;Inert atmosphere;	Step A: A stirred solution of (S)-tert-butyl 3-aminopiperidine-1-carboxylate (0.500 g, 2.49 mmol), 1-fluoro-4-methyl-2-nitrobenzene (0.387 g, 2.49 mmol) and N,N25 diisopropylethylamine (0.482 g, 3.74 mmol) in DMF under argon was heated to 110°C for6h (reaction completion monitored by TLC). The mixture was diluted with water and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford (S)-tert-butyl 3-((4-methyl-2-nitrophenyl) amino) piperidine-1-carboxylate (I-15a). MS calculated for C17H24N304 (M-H) 334.18, found334.0.

Reference： [1]Patent: WO2013/184757,2013,A1 .Location in patent: Page/Page column 81
[2]Patent: WO2015/81463,2015,A1 .Location in patent: Page/Page column 27; 28
[3]Patent: WO2015/83059,2015,A1 .Location in patent: Page/Page column 32; 33
[4]Patent: WO2015/85482,2015,A1 .Location in patent: Page/Page column 31
[5]Patent: WO2016/189435,2016,A1 .Location in patent: Page/Page column 23; 24

47
[ 110651-92-8 ]
[ 625471-18-3 ]
[ 1607591-75-2 ]

Yield	Reaction Conditions	Operation in experiment
0.26 g	With triethylamine; In isopropyl alcohol; at 90℃; for 2.0h;	A mixture of <strong>[110651-92-8]7-chloro-6-nitrothieno[3,2-b]pyridine</strong> (166 mg, 0.774 mmol), tert-butyl (3S)-3-aminopiperidine-1-carboxylate (from Aldrich, 186 mg, 0.929 mmol) and triethylamine (0.32 mL, 2.3 mmol) in isopropyl alcohol (1.8 mL) was stirred at 90 C. for 2 h. After cooling to room temperature, solids were observed. Water was added which caused more solids to form. The yellow solids were filtered, washed with water, and dried to give 0.26 g of the desired product. LCMS calculated for C17H23N4O4S (M+H)+: m/z=379.1. Found: 379.0. 1H NMR (400 MHz, CDCl3) delta 9.40 (s, 1H), 9.29 (s, 1H), 7.84 (d, J=5.5 Hz, 1H), 7.49 (d, J=5.5 Hz, 1H), 4.42 (m, 1H), 3.83 (m, 1H), 3.46 (m, 3H), 2.12 (m, 1H), 1.83 (m, 3H), 1.41 (s, 9H) ppm

Reference： [1]Patent: US2014/121198,2014,A1 .Location in patent: Paragraph 0809; 0810

48
[ 108-86-1 ]
[ 625471-18-3 ]
[ 1589082-48-3 ]

Yield	Reaction Conditions	Operation in experiment
78%	With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; In toluene; at 100℃; for 24h;Inert atmosphere;	(S)-3-Phenylamino-piperidine-l-carboxylic acid tert-butyl ester [A058] A solution of (S)-3-Amino-piperidine-l-carboxylic acid tert-butyl ester (500 mg, 2.497 mmol), Pd2(dba)3 (95 mg, 0.104 mmol) and 2-Dicyclohexylphosphino-2'-(N,N- dimethylamino)biphenyl (61 mg, 0.156 mmol) in toluene (5 mL) was prepared under nitrogen. The solvent was degasses and sodium tert-butoxide (280 mg, 2.912 mmol) was added followed by bromobenzene (0.22 mL, 2.080 mmol). The reaction mixture was heated to 100 °C for 24 h. The reaction mixture was cooled to room temperature and concentrated by rotary evaporation. The residue was filtered through a plug of silica, eluting with ((. The eluent was concentrated by rotary evaporation. The crude residue was purified by chromatography on silica, eluting with cyclohexane containing 5 - 50percent EtOAc. The appropriate fractions were combined and concentrated to give the title compound [A058] (535 mg, 78percent) as a pale yellow oil that solidified on standing. LCMS method: 1, RT:5.51 min, MI 227 [M+H]; 'H NMR (lH, 500MHZ, CDC13) 7.20 - 7.17 (2H, m), 6.71 (1H, t), 6.64 (2H, d), 4.02 (1H, br s), 3.74 - 3.70 (1H, m), 3.63 (1H, br s), 3.39 (1H, br m), 3.09 (1H, br m), 2.89 (1H, br s), 2.02 - 1.99 (1H, m), 1.78 - 1.73 (1H, m), 1.59 - 1.51 (2H, m), 1.46 (9H, s).

Reference： [1]Patent: WO2014/52699,2014,A1 .Location in patent: Page/Page column 249-250

49
[ 3932-97-6 ]
[ 625471-18-3 ]
[ 1622003-20-6 ]

Yield	Reaction Conditions	Operation in experiment
57%	With triethylamine; zinc(II) chloride; In 1,2-dichloro-ethane; tert-butyl alcohol; at 20℃; for 1h;pH <= 7;	Step 1: (S)-tert-butyl 3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (Intermediate 1) To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (5 g, 23 mmol) in dichloroethane: t-butanol (50 ml, 1:1) was added dry zinc chloride (3.7 g, 27 mmol) and triethylamine (2.52 g, 25 mmol), and the mixture was stirred at rt for 1 h (pH should not be >7). To this mixture, (S)-tert-butyl 3-aminopiperidine-1-carboxylate (4.9 g, 25 mmol) was added and stirring continued at rt for 16 h. TLC showed formation of the major compound (0.2 Rf) and a minor other isomer (0.25 Rf) and ?10% starting material in 15% EtOAc: hexane solvent system. Solvents were evaporated, and crude was diluted with ice cold water (50 mL) and stirred for 5 min at rt to get a pale yellow gummy mass. The crude pale yellow gummy mass (6 g) was taken in 60 mL hexane and stirred for 10 min at rt to get a solid which was immediately filtered to get the pure desired compound (5 g, 57%). MS m/z: 381.1 (ES+, M+H).

Reference： [1]Patent: US2014/228322,2014,A1 .Location in patent: Paragraph 0380

50
(R)-3-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[4,5]thieno[3,2-e][1,4]diazepine-9-carboxylic acid [ No CAS ]
[ 625471-18-3 ]
C₂₃H₃₀N₄O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h;	Compound 1: To a solution of acid compound 7 (Ex 40; 200 mg, 0.7 mmol) in dimethylformamide (3.0 mL), l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium3-oxidehexafluorophosphate (HATU) (550 mg, 1.4 mmol) and diisopropylethylamine (280 mg, 2.1 mmol) were added at 0°C followed by the addition of (S)-l- Boc-3-aminopiperidine (173 mg, 0.8 mmol). The resulting mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was triturated with n-pentane to afford 1 (250 mg, 63percent) as a brown gummy solid. MS m/z (M+H): 459.4

Reference： [1]Patent: WO2014/149164,2014,A1 .Location in patent: Paragraph 00752

51
1'-oxo-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-pyrazino[1,2-a]indole]-7'-carboxylic acid [ No CAS ]
[ 625471-18-3 ]
(S)-tert-butyl 3-(1'-oxo-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-pyrazino[1,2-a]indol]-7'-ylcarboxamido)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 14h;Inert atmosphere;	(S)-tert-butyl 3-(l '-oxo-2 ' ,3 '-dihydro- 1 -spiro [cyclobutane- 1 ,4 '-pyrazino [1 ,2- a]indol]-7'-ylcarboxamido)piperidine-l-carboxylate (1): To a mixture of -oxo-2',3'-dihydro- H-spiro[cyclobutane-l,4'-pyrazino[l,2-a]indole]-7'-carboxylic acid (intermediate 7, Example 78; 150 mg, 0.55 mmol) and (S)-tert-butyl 3-aminopiperidine-l-carboxylate (111 mg, 0.55 mmol) in dry DMF (5.0 mL) were added DMAP (169 mg, 1.38 mmol) followed by EDCI.HC1 (213 mg, 1.11 mmol). The resultant reaction mixture was stirred at room temperature under nitrogen atmosphere for 14 h. The reaction mixture was diluted with ice water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were further washed with brine solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1 (190 mg, 76percent) as white solid. 1H NMR (500 MHz, DMSO-d6): delta 1.37 (s, 9H), 1.45 (m, 2H), 1.60 (m, 1H), 1.73 (m, 1H), 1.90 (m, 1H), 2.07 (m, 3H), 2.30 (m, 2H), 2.98 (m, 2H), 3.70 (m, 3H), 3.81 (m, 2H), 7.13 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 8.30 (m, 2H), 8.35 (s, 1H). MS m/z (M+H): 453.0

Reference： [1]Patent: WO2014/149164,2014,A1 .Location in patent: Paragraph 001147

52
[ 885500-55-0 ]
[ 625471-18-3 ]
ethyl 4-[(3S)-1-(tert-butoxycarbonyl)piperidin-3-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 150℃; for 1h;Microwave irradiation;	General procedure: 5.1.24 Ethyl 4-[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (7b) To a solution of 4 (400 mg, 1.78 mmol) in n-BuOH (2.0 mL) were added tert-butyl (3R)-3-aminopiperidine-1-carboxylate (712 mg, 3.56 mmol) and DIPEA (0.62 mL, 3.56 mmol). The mixture was heated in a microwave reactor at 150 C for 1 h. After cooling to room temperature, the reaction mixture was quenched with water, extracted with EtOAc, dried over MgSO4, and evaporated in vacuo. The crude mixture was purified by column chromatography on silica gel (hexane/AcOEt = 60:40 to 25:75) to give the product (525 mg, 76%) as a white powder. 5.1.25 Ethyl 4-[(3S)-1-(tert-butoxycarbonyl)piperidin-3-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (7c) Compound 7c was prepared from 4 in 32% yield as a white amorphous solid by a method similar to that described for 7b. 1H NMR (DMSO-d6) delta 1.03 (s, 9H), 1.15-1.99 (m, 8H), 1.30 (t, J = 7.2 Hz, 3H), 3.58-3.62 (m, 1H), 4.23-4.27 (m, 2H), 6.62 (m, 1H), 7.20-7.22 (m, 1H), 8.56 (s, 1H), 8.95-8.97 (m, 1H), 11.70 (br s, 1H); MS (ESI) m/z 389 [M+H]+.

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 4846 - 4859

53
[ 67-56-1 ]
[ 530-62-1 ]
[ 625471-18-3 ]
(S)-tert-butyl 3-((methoxycarbonyl)amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%		To a solution of 1, 1'-carbonyldiimidazole (2.5 g, 15.0 mmol) in anhydrous THF (5 mL) were added triethylamine (1.4 mL, 9.99 mmol) and methanol (0.61 mL, 15.0 mmol) dropwise at rt. The mixture was stirred at rt for 30 min, and a solution of (S) -tert-butyl -3-aminopiperidine-1-carboxylate (1.0 g, 4.99 mmol) in anhydrous THF (10 mL) was added. The resulting mixture was stirred at 75 for 5 h, and adjusted with dilute HCl (1 M) to pH 1. The resulting mixture was extracted with EtOAc (15 mL × 2) . The combined organic layers were washed with saturated aqueous sodium bicarbonate (10 mL × 2) , dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with Petroleum ether/EtOAc (v/v) 4/1 to give (S) -tert-butyl 3- ( (methoxycarbonyl) amino) piperidine-1-carboxylate as colorless liquid (1.07 g, 83) .1H NMR (400 MHz, CDCl3) : delta ppm 4.77 (br. s, 1H) , 3.66 (s, 3H) , 3.58-3.55 (m, 1H) , 3.36-3.32 (m, 1H) , 3.28-3.24 (m, 1H) , 1.84-1.81 (m, 1H) , 1.65-1.61 (m, 1H) , 1.56-1.48 (m, 2H) , 1.45 (s, 9H) and MS-ESI: m/z 159.2 [M-100+H] +.
83%		At room temperature, to N'N- carbonyl diimidazole (2.5g, 15.0mmol) in anhydrous THF (5mL) was addeddropwise a solution of triethylamine (1.4mL of, 9.99mmol), Stirred at room temperature, was slowly addeddropwise methanol (0.61mL, 15.0mmol), the reaction temperature 30min, was added dropwise (S) -1-Boc-3-amino (1M) pH of the solution of piperidine (1.0g, 4.99mmol) in anhydrous THF (10mL) solution, 75 ° C thereaction 5h, dilute hydrochloric acid solution was added Value is adjusted to about 1, ethyl acetate (15mL × 2).The organic phase was washed with saturated sodium bicarbonate solution (10mL × 2), dried combined organicAfter phase was dried over anhydrous Na 2 SO 4, the solvent was removed concentrate was subjected to columnchromatography (eluent: petroleum ether / ethyl acetate (v / v) = 4/1), To give 1.07g colorless oil: (S) -3 -((methoxycarbonyl) amino) piperidine-1-carboxylate, yield: 83percent.

Reference： [1]Patent: WO2016/34134,2016,A1 .Location in patent: Paragraph 00591
[2]Patent: CN105399698,2016,A .Location in patent: Paragraph 1844-1846

54
[ 2927-71-1 ]
[ 625471-18-3 ]
[ 1259009-67-0 ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 70℃; for 12h;	[A] (+ or-) - (S) -tert-Butyl 3 ( (2 chloro-5-fluoropyrimidin-4-yl)amino)piperidine-1-carboxylate[0537][0538]To a stirred a solution of 2 4-dichloro-5-fluoropyrimidine (1.8 g 10.8 mmol) in THF (30 mL) was added DIPEA (2.79 g 21.6 mmol) and (S) -tert-butyl 3-aminopiperidine -1-carboxylate (2.59 g 12.9 mmol) at room temperatue and the reaction mixture was stirred at 70 for 12 h. After TLC (petroleum etherEtOAc 31) showed the reaction was completed the reaction was quenched by the addition ot satd. aq. NH4Cl solution (50 mL) and extracted with EtOAc (3 x 50) . The combined organic extracts were dried over anhy. Na2SO4 filtered and concentrated in vacuo to give the title compound (3 g 84.0percent yield) as a yellow solid. MS 331.2 [M+H]+.
	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 80℃; for 17h;	Formation of tert-butyl (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]piperidine-1-carboxylate (5a) (1333) To a solution of <strong>[625471-18-3]tert-butyl (3S)-3-aminopiperidine-1-carboxylate</strong> (8.1 g, 40.4 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (6.6 g, 39.8 mmol) in isopropanol (80 mL) was added N,N-diisopropyl-N-ethylamine (9.0 mL, 51.7 mmol). The reaction mixture was warmed to 80° C. and stirred for 17 hours. All volatiles were removed at reduced pressure and the residue was dissolved in EtOAc. The organic layer was partitioned with water and the layers were separated. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 and purified by silica gel chromatography (0-50percent EtOAc/Hexanes) to afford the desired product, 5a. (1334) LCMS RT=3.3 (M+1) 331.1.
	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 80℃; for 17h;	To a solution of <strong>[625471-18-3]tert-butyl (3S)-3-aminopiperidine-1-carboxylate</strong> (8.1 g, 40.4 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (6.6 g, 39.8 mmol) in isopropanol (80 mL) was added N,N-diisopropyl-N-ethylamine (9.0 mL, 51.7 mmol). The reaction mixture was warmed to 80° C. and stirred for 17 hours. All volatiles were removed at reduced pressure and the residue was dissolved in EtOAc. The organic layer was partitioned with water and the layers were separated. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 and purified by silica gel chromatography (0-50percent EtOAc/Hexanes) to afford the desired product, 5a.

Reference： [1]Patent: WO2017/133657,2017,A1 .Location in patent: Page/Page column 125; 126
[2]Patent: WO2020/23813,2020,A1 .Location in patent: Paragraph 00361
[3]Patent: US9345708,2016,B2 .Location in patent: Page/Page column 166
[4]Patent: JP2015/38146,2015,A .Location in patent: Paragraph 0416

55
[ 50-00-0 ]
[ 625471-18-3 ]
[ 1061873-15-1 ]

Yield	Reaction Conditions	Operation in experiment
55%	With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; water; at 0 - 20℃; for 16h;	An aqueous solution of formalin (36-38 wt percent, 2.10 g, 25.2 mmol), sodium triacetoxyborohydride (2.13 g, 10.0 mmol), and acetic acid (0.0300 g, 0.500 mmol) were added to a solution of (S)-3-amino-1-tert-butoxycarbonylpiperidine (1.00 g, 4.99 mmol) in dichloromethane (10.0 mL) at 0° C., and the resulting mixture was stirred at room temperature for 16 hours. The reaction liquid was cooled to 0° C. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction liquid, and the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in hydrochloric acid (1.0 N), and the resulting mixture was extracted with ethyl acetate. A 48percent aqueous solution of sodium hydroxide was added to the aqueous layer for basification, and then the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (25.0 mL), and concentrated hydrochloric acid (5.0 mL) was added, and then the resulting mixture was stirred at 40° C. for 12 hours. The reaction liquid was concentrated and exsiccated, and then the residue was dissolved in distilled water. A 48percent aqueous solution of sodium hydroxide was added for basification, and then the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. (S)-3-Dimethylaminopiperidine (0.351 g, 2.74 mmol, 55percent) was obtained as a colorless oil.

Reference： [1]Patent: TW2016/2093,2016,A .Location in patent: Paragraph 0321

56
[ 313339-92-3 ]
[ 625471-18-3 ]
tert-butyl (3S)-3-[(6-chloro-5-cyanopyrazin-2-yl)amino]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;	To a solution of 3,5-dichloropyrazine-2-carbonitrile (1.00 g, 5.47 mmol) in DMF (10 mL) was added (S)-(+)-3-Amino-1-Boc-piperidine (1.38 g, 6.9 mmol) and DIPEA (2.0 mL, 10.94 mmol) in a dropwise manner. The mixture was stirred at room temperature for 60 min. The reaction mixture was evaporated under reduced pressure and the residue was purified by flash chromatography with 0 to 50percent ethyl acetate in cyclohexane to isolate tert-butyl (3S)-3-[(6- chloro-5-cyanopyrazin-2-yl)amino]piperidine-1-carboxylate (2.41 g, quantitative yield).

Reference： [1]Patent: WO2016/196776,2016,A2 .Location in patent: Paragraph 00817

57
[ 625471-18-3 ]
[ 860352-01-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: pyridine / 2-methyltetrahydrofuran / 2.5 h / 21 - 25 °C 2: 2-methyltetrahydrofuran; water / 19 - 26 °C 3: sodium methylate / methanol / 1.83 h / 21 - 24 °C 4: tetrahydrofuran / 2.5 h / 20 °C 5: triethylamine / methanol / 2.5 h / 20 °C 6: hydrogenchloride / water; methanol / 4 h / 20 - 50 °C

Reference： [1]Ball, Matthew; Jones, Martin F.; Kenley, Fiona; Pittam, J. David [Organic Process Research and Development, 2017, vol. 21, # 3, p. 310 - 316]

58
5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxylic acid [ No CAS ]
[ 625471-18-3 ]
tert-butyl (3S)-3-[[5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	O-(7-Azabenzotriazol-1-yl)-N, N, N?, N?-tetramethyluronium hexafluorophosphate (8.53 g, 22.4 mmol) was added to a solution of the acid of Preparation 14 (5.72 g, 15.0 mmol), tert-butyl (35)-3-aminopiperidine-1-carboxylate (4.49 g, 22.4 mmol) and triethylamine (6.06 g, 60 mmol) in N,N-dimethylformamide (150 mL). The reaction was stirred over night at room temperature. The mixture was evaporated under reducedpressure and resulting residue dissolved in diethyl ether (500 mL). This diethyl ether solution was washed with 10percent aqueous citric acid solution (3 x 50 mL) followed by 10percent aqueous ammonia, saturated brine solution and dried over magnesium sulphate, filtered and evaporated. The residue was purified by silica gel (100-200 mesh) column chromatography eluting with 50percent ethyl acetate in heptane to give the title compound asan amorphous solid (7.2g, 86percent).1H NMR (300 MHz, DMSO-d6) O = 9.47 (d, J=8.4, 1H), 8.27 (d, J=8.1, 1H), 8.21 (dd,J=2.9, 0.6, 1H), 7.89 (dd, J=8.7, 0.6, 1H), 7.39 (dd, J=8.8, 2.9, 1H), 7.25 (d, J=8.2,2H), 7.15 (d, J=7.8, 2H), 5.41 (d, J=6.1, 1H), 4.27 (h, J=6.8, 1H), 3.55 (s, 3H), 2.97 (s,2H), 2.26 (s, 3H), 1.77 (s, 1H), 1.62 (s, 2H), 1.50 ? 1.24 (m, 13H).UPLC-MS Method 2: Mass ion 564.26 (Mj, R = 2.63 mm.

Reference： [1]Patent: WO2017/46096,2017,A1 .Location in patent: Page/Page column 47; 48

59
5-[(1R,2S)-1-(4-bromophenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxylic acid [ No CAS ]
[ 625471-18-3 ]
tert-butyl (3S)-3-[[5-[(1R,2S)-1-(4-bromophenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃;	Using a procedure similar to that described for Preparation 14, but using the compound described in Preparation 23 and using 2M aqueous sodium hydroxide (2.5 equiv.) inN,N-dimethylformamide (10 mL/g) to obtain the intermediate acid, 5-[(1R,2S)-1-(4- bromophenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxylic acid, followed by a procedure similar to that described in Preparation 15 but using 0- (benzotriazol-1-yl)-N, N, N?, N?-tetramethyluronium hexafluorophosphate instead of 0- (7-Azabenzotriazol-1-yl)-N, N, N?, N?-tetramethyluronium hexafluorophosphate, the titlecompound was prepared as an off white amorphous solid (1.08 g, 54percent).1H NMR (300 MHz, DMSO-d6) O = 9.50 (d, J=8.4, 1H), 8.29 (d, J=8.1, 1H), 8.23 (d,J=2.8, 1H), 7.91 (d, J=8.7, 1H), 7.56 (d, 2H), 7.42 (dd, J=8.7, 2.9, 1H), 7.33 (d, 2H),5.45 (d, J=6.2, 1H), 4.30 (h, J=6.8, 1H), 3.91 ? 3.39 (m, 3H), 3.27 ? 2.71 (m, 2H), 1.78(s, 1H), 1.72 ? 1.56 (m, 2H), 1.51 ? 1.29 (m, 13H).

Reference： [1]Patent: WO2017/46096,2017,A1 .Location in patent: Page/Page column 47; 48; 52

60
[ 625471-18-3 ]
[ 350511-08-9 ]
(S)-tert-butyl 3-(5-((5-tert-butyloxazol-2-yl)methylthio)thiazol-2-ylamino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃;	j00333] The mixture of MFW2434 (150 mg, 0.45 mrnoi), (S)-tert-butyi 3-aminopiperidine- 1.-carboxylate (160 mg, 0.81 mrnol) and DIEA (150 mg, 1.13 mrnol) in NMP (1 mU) was stirred at 140 Oc; for overnight. The residue was extracted with chloroform and iso-propanol (4:1). The organic phase was washed with brine (20 mL) and dried over Na2SO4. After removal of the solvent, the residue was purified by silica gel (MeOH/DCM = 0-20percent) to obtain MFW2-824 (136 mg, yield 67percent). LCMS (miz): 453 [M + Hr.

Reference： [1]Patent: WO2017/44858,2017,A2 .Location in patent: Paragraph 00333

61
[ 1188914-98-8 ]
[ 625471-18-3 ]
[ 1188915-67-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;	Reaction of 8 with <strong>[625471-18-3]tert-butyl (3S)-3-amino-1-piperidinecarboxylate</strong>, as for the synthesis of 62a, gave tert-butyl (S)-3-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylate (77a) in 90percent yield: 1H NMR (DMSO-d6) (rotamers) d 8.12-7.58 (m, 3H), 7.38 and 7.38 (2t, J = 8.2 Hz, 1H), 6.95 and 6.94 (2d, J = 7.8 Hz, 1H), 3.97 (s, 3H), 3.78-3.69 (m, 10H), 2.99-2.94 and 2.85-2.83 (2m, 2H), 1.97-1.93 and 1.78-1.76 (2m, 2H), 1.58-1.19 (m, 11H).

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 5859 - 5874

62
[ 3639-21-2 ]
[ 625471-18-3 ]
(S)-tert-butyl 3-(2-ethyl-2-hydroxybutanamido)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.4 g	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h;	5.1 Step 1: (S)-tert-Butyl 3-(2-ethyl-2-hydroxybutanamido)piperidine- 1-carboxylate To a stirred solution of(S)-tert-butyl 3-aminopiperidine-i-carboxylate (2.0 g, 10 mmol) inDCM (100 ml) was added 2-ethyl-2-hydroxybutanoic acid (1.45 g, ii mmol) followed byEDC, HOBt and DMAP at 0°C, then the reaction mixture was stirred at rt for 16 h. Thereaction mixture was diluted with DCM and washed with water. The organic layer was dried evaborated. The crude compound was purified by flash chromatography to obtain 1.4 g of the product.‘H NMR (400 MHz, CDC13) ö ppm 0.75 (t, 6H), 1.36 - 1.62 (m, 12H), 1.61 - 1.77 (m, 5H),2.85 - 3.10 (m, 2H), 3.45 - 3.70 (m, 3H), 4.88 (m, 1H), 7.38 (m, 1H).

Reference： [1]Current Patent Assignee: ORION S R L - WO2018/2437, 2018, A1 Location in patent: Page/Page column 30

63
[ 1415638-13-9 ]
[ 124-63-0 ]
[ 625471-18-3 ]
(S)-tert-butyl 3-(((5-bromo-1-methyl-1H-pyrazol-4-yl)methyl)amino)-piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.7 g	Stage #1: (5-bromo-1-methyl-1H-pyrazol-4-yl)methanol; methanesulfonyl chloride With triethylamine In dichloromethane at 20℃; for 2h; Cooling with ice; Stage #2: tert-butyl (3S)-3-aminopiperidine-1-carboxylate With potassium carbonate In acetonitrile at 80℃; for 16h;	24.1 Step 1: (S)-tert-Butyl 3-(((5-bromo- 1-methyl-1H-pyrazol-4-yl)methyl)amino)- piperidine- 1-carboxylate To an ice-cold stirred solution of(5-bromo-1-methyl-1H-pyrazol-4-yl)methanol (5.10 g,26.7 mmol) in CH2C12 (50 nil) were added TEA (11.23 nil, 8.15 g, 80.6 mmol) andmethanesulfonyl chloride (2.50 ml, 3.70 g, 32.3 mmol). The resulting solution was stirred for2h at RT. The reaction mixture was diluted with DCM, washed with water and brine, driedand evaporated. The residue (3.10 g, 11.52 mmol) and (S)-tert-butyl 3-aminopiperidine- 1-carboxylate (2.30 g, 11.52 mmol) were dissolved in ACN (35 ml) and K2C03 (4.77 g, 34.57mmol) was added. The resulting mixture was heated to 80 °C for 16 h. The solvent was evaporated off and the residue was dissolved in mixture of EtOAc, washed with water, dried and evaporated. The residue was purified by flash chromatography yielding 1.70 g (S)-tertbutyl 3 -(((5 -bromo- 1-methyl- 1H-pyrazol-4-yl)methyl)amino)-piperidine- 1 -carboxylate.LC-MS,m/z 373.1 (M+1).

Reference： [1]Current Patent Assignee: ORION S R L - WO2018/2437, 2018, A1 Location in patent: Page/Page column 48; 49

64
[ 120237-76-5 ]
[ 625471-18-3 ]
(S)-tert-butyl 3-(5-methylthiazole-4-carboxamido)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6 g	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0℃; for 16h;	To a stirred solution of <strong>[120237-76-5]5-methylthiazole-4-carboxylic acid</strong> (4.0 g, 27.97 mmol, W02008/016192) and (S)-tert-butyl 3-aminopiperidine-1-carboxylate (6.15 g, 30.76 mmol) in DCM were added EDC.HC1 (6.51 g, 41.95 mmol), HOBt (6.42 g, 41.95 mmol) andDMAP (8.53 g, 69.93 mmol) at 0C. The reaction mixture was stirred for 16 h. The reaction mixture was diluted with DCM, washed with water, brine, dried and evaborated. The crude product was purified by flash column to obtain 6.0 g of the product.LC-MS (ES+) [M+1]:326.2.

Reference： [1]Patent: WO2018/2437,2018,A1 .Location in patent: Page/Page column 39

65
[ 50-00-0 ]
[ 625471-18-3 ]
[ 912368-73-1 ]

Yield	Reaction Conditions	Operation in experiment
3 g		To a stirred solution of aqueous formaldehyde (1.85 ml, 25 mmol, 37%) and molecular sieves in methanol was added (S)-tert-butyl 3-aminopiperidine- 1 -carboxylate (5.0 g, 25 mmol) and reaction was stirred at room temperature for 24 h. Sodium borohydride (1.52 g,40 mmol) was added to the above mixture at room temperature and mixture was stirred for16 h. The reaction mixture was quenched with addition of ice water (30 mL) and thenextracted with EtOAc (3 x 100 mL). Combined organic extracts were dried over anhydrousNa2504 and concentrated to obtain 3.0 g of crude (S)-tert-butyl 3-(methylamino)piperidine-1 -carboxylate as pale yellow liquid. This material was used as such in the next step.?H NMR (400 MHz, CDC13) oe ppm 1.38 (s, 9H), 1.5-1.7 (m, 4H), 1.71-1.90 (m, 2H), 2.18-2.27 (m, 3H), 2.75-2.90 (m, 1H), 3.50-3.92 (m, 2H).

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 1061 - 1073
[2]Patent: WO2018/2437,2018,A1 .Location in patent: Page/Page column 99

66
tert-butyl 5,6-difluoro-3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-1-carboxylate [ No CAS ]
[ 625471-18-3 ]
(S)-tert-butyl 3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-5,6-difluoro-1H-indole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h;	(S)-tert-butyl 3-aminopiperidine-1-carboxylate (14 mg, 0.069 mmol), and diisopropylethylamine (12 muL, 0.069 mmol) were added to a stirring solution of tert-butyl 5,6-difluoro-3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-1-carboxylate (30 mg, 0.063 mmol) in THF (1 mL). The reaction mixture was stirred for 1h at room temperature. The mixture was diluted with EtOAc (50 mL), washed with a saturated solution of NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to a afford the title compound (38 mg, 0.063 mmol, 100percent yield) as a yellow solid.

Reference： [1]Patent: WO2018/13867,2018,A1 .Location in patent: Paragraph 202

67
7-bromo-3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-1-(2-trimethylsilylethoxymethyl)indole-6-carbonitrile [ No CAS ]
[ 625471-18-3 ]
tert-butyl (3S)-3-[[4-[7-bromo-6-cyano-1-(2-trimethylsilylethoxymethyl)indol-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.45%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 2h;	A mixture of 7-bromo-3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-1-(2-trimethylsilylethoxymethyl)indole-6-carbonitrile (100.00 mg, 188.03 umol, 1.00 ^^), <strong>[625471-18-3]tert-butyl (3S)-3-aminopiperidine-1-carboxylate</strong> (48.96 mg, 244.44 umol, 1.30 eq), DIEA (121.50 mg, 940.15 umol, 164.20 uL, 5.00 eq) in NMP (2.00 mL) was stirred at 140 C for 2 h. The reaction mixture was poured into water 50 mL, and extracted with EtOAc (20 mL*3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EtOAc=10:1 to 1:1) to afford the title compound (100.00 mg, 143.75 umol, 76.45percent yield) as a yellow solid.

Reference： [1]Patent: WO2018/13867,2018,A1 .Location in patent: Paragraph 498

68
3-(2-chloro-5-ethylpyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile [ No CAS ]
[ 625471-18-3 ]
(S)-3-(5-ethyl-2-(piperidin-3-ylamino)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%		To a mixture of tert-butyl (S)-3-((4-(6-cyano-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-ethylpyrimidin-2-yl)amino)piperidine-1-carboxylate and tert-butyl (S)-3-((4-(6-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-ethylpyrimidin-2-yl)amino)piperidine-1-carboxylate (0.7 g, 1.56 mmol, 1.0 eq, crude) in EtOAc (5 mL) was added HCl/ EtOAc (4 M, 7.82 mL, 20 eq). The mixture was stirred at 25C for 3 hrs. It was concentrated in reduced pressure at 45C and purified by prep-HPLC: (column: Phenomenex luna (2) C182505010u; mobile phase: [water (0.225percentFA)-ACN]; Bpercent: 0percent-30percent, 20min) and prep-HPLC: (column: Waters Xbridge Prep OBD C18150305u; mobile phase: [water (0.225percentFA)-ACN]; Bpercent:5percent-25percent, 12min) to afford (S)-3-(5-ethyl-2-(piperidin-3-ylamino)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (48 mg, 132.64umol, 8.48percent yield, 96percent purity) as a yellow solid.

Reference： [1]Patent: WO2018/13867,2018,A1 .Location in patent: Paragraph 546

69
3-(2-chloro-5-ethylpyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbonitrile [ No CAS ]
[ 625471-18-3 ]
tert-butyl (3S)-3-((4-(6-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-ethylpyrimidin-2-yl)amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 120℃; for 5h;Inert atmosphere;	A mixture of 3-(2-chloro-5-ethylpyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbonitrile (0.26 g, 707 umol, 1.00 eq), tert-butyl (S)-3-aminopiperidine-1-carboxylate (170 mg, 848 umol, 1.20 eq), Pd2(dba)3 (64.7 mg, 70.7 umol, 0.10 eq), BINAP (44.0 mg, 70.7 umol, 0.10 eq) and Cs2CO3 (461 mg, 1.41 mmol, 2.00 eq) in dioxane (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120C for 5 hrs under N2 atmosphere. TLC (Petroleum ether: EtOAc = 1: 1, Rf = 0.24) and HPLC indicated one major new spot with larger polarity was detected. The reaction mixture was added silicone to remove Pd2(dba)3 (64.7 mg, 70.7 umol, 0.10 eq), the mixture was stirred 30 mins then was filtered and the solvent was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether: EOAc = 1: 1). tert-butyl (3S)-3-((4-(6-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-ethylpyrimidin-2-yl)amino)piperidine-1-carboxylate (0.15 g, 282 umol, 40percent yield) was obtained as red oil.

Reference： [1]Patent: WO2018/13867,2018,A1 .Location in patent: Paragraph 561

70
[ 625471-18-3 ]
[ 478646-33-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 1 h / 0 - 20 °C 2: hydrogenchloride / ethyl acetate / 1 h / 20 °C

Reference： [1]Current Patent Assignee: SYROS PHARMACEUTICALS INC - WO2018/13867, 2018, A1

71
[ 882562-40-5 ]
[ 625471-18-3 ]
(S)-tert-butyl 3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 135℃; for 0.75h;Microwave irradiation;	A solution of 3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (700 mg, 1.73 mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (382 mg, 1.91 mmol), and diisopropylethylamine (0.60 mL, 3.46 mmol) in NMP (9.0 mL) was heated for 45 min at 135 C in a microwave (MW) reactor. The mixture was diluted with EtOAc (200 mL), washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to a yellow oil. The residue was purified by SiO2 chromatography (EtOAc in DCM, 0 to 100percent gradient) to afford the title compound (694 mg, 1.22 mmol, 64percent yield) as a light pink solid.

Reference： [1]Patent: WO2018/13867,2018,A1 .Location in patent: Paragraph 172

72
6-bromo-3-(2-chloro-5-ethylpyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole [ No CAS ]
[ 625471-18-3 ]
(S)-tert-butyl 3-((4-(6-bromo-1H-indol-3-yl)-5-ethylpyrimidin-2-yl)amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 16h;Sealed tube;	[583] In a sealed vial, a solution of 6-bromo-3-(2-chloro-5-ethylpyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (370 mg, 0.776 mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (223 mg, 1.164 mmol), and DIPEA (0.54 mL, 3.10 mmol) in NMP (0.8 mL, 1 M) was heated for 16 h at 130 C in an oil bath. The mixture was then diluted with MeTHF (20 mL), washed with water (2x20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (2 mL), and 5 M NaOH (3 mL) was added. The reaction mixture was then stirred at 50 C for 3 h until full conversion. The reaction mixture was cooled down to RT, and crude product was then extracted with MeTHF (3x15 mL). Combined organic extract was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography (EtOAc in a (1:1) mixture of DCM and Hexanes, 0 to 30percent gradient). The title compound (250 mg, 0.50 mmol, 64percent yield) was obtained as a pale brown solid.

Reference： [1]Patent: WO2018/13867,2018,A1 .Location in patent: Paragraph 582

73
[ 3639-21-2 ]
[ 625471-18-3 ]
(S)-tert-butyl 3-(5,5-diethyl-2,4-dioxooxazolidin-3-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: benzotriazol-1-ol; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 16 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16 h

Reference： [1]Current Patent Assignee: ORION S R L - WO2018/2437, 2018, A1

74
[ 38267-96-8 ]
[ 625471-18-3 ]
(S)-tert-butyl 3-((6-bromoquinazolin-4-yl)amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 85℃; for 2.5h;	To a solution of (S)-1-Boc-3-aminopiperidine (6.20g, 30.99mmol) in isopropanol (20mL), was slowly added 6-bromo-4-chloroquinazoline (5.00g, 20.66mmol) and DIPEA (5.33g, 41.32mmol). The mixture was stirred at 85C for 2.5h, and cooled to room temperature. After the saturated NaCl solution was added, the reaction mixture was extracted by EtOAc. Dried over anhydrous Na2SO4, the liquid was concentrated and purified by silica gel chromatography (CH2Cl2/CH3OH, 100:1) to produce compound 11 (7.15g, 85%) as a yellow solid. 1H NMR (400MHz, CDCl3) delta 8.66 (s, 1H, ArH), 7.98 (s, 1H, ArH), 7.89-7.79 (m, 2H, ArH), 6.98 (s, 1H, NH), 4.41-4.39 (m, 1H, CH), 3.82-3.32 (m, 4H, 2×CH2), 2.45-2.28 (m, 2H, CH2), 1.98-1.75 (m, 2H, CH2), 1.48 (s, 9H, 3×CH3) ppm. MS (ESI) m/z: [M+H]+=406.9, 408.9.

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2018,vol. 33,p. 651 - 656
[2]Bioorganic and Medicinal Chemistry,2019,vol. 27

75
2,4,6-trichloropyrido[3,4-d]pyrimidine [ No CAS ]
[ 625471-18-3 ]
C₁₇H₂₁Cl₂N₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;	General procedure: To a mixture of intermediate 21 (1 mmol) and DIPEA (1.5 mmol) in THF, amine (1.1 mmol) was added under stirring. The mixture was stirred for about 0.5 h?2 h at room temperature. The solvent was removed under reduced pressure and the residue was suspended in water. The solid was collected by filtration, washed with water and dried to obtain intermediates 22a?h.

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3619 - 3633

76
[ 3512-75-2 ]
[ 625471-18-3 ]
C₁₇H₂₇N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; at 100℃; for 16h;Inert atmosphere; Sealed tube;	To a mixture of tris(dibenzylideneacetone)dipalladium(O) (CAS: 51364-51-3; 57 mg,0.062 mmo 1), 2-dicyclohexylphosphino-2 ?-(N,N-dimethylamino)biphenyl (CAS:213697-53-1; 33 mg, 0.084 mmol) and sodium tert-butoxide (135 mg, 1.40 mmol) in1 ,4-dioxane (5 mL) at rt and under N2 atmosphere, (S)-(-)-3-amino- 1 -Boc-piperidine(CAS: 216854-23-8; 0.23 mL, 1.2 mmol) and <strong>[3512-75-2]4-chloro-2,6-dimethylpyridine</strong> (0.127 mL, 1 mmol) were added. The mixture was heated at 100 °C for 16 h in a sealed tube. Brine and DCM were added and the organic layer was separated, dried over MgSO4, filtered and evaporated under vacuum. The residue thus obtained was purified by flash column chromatography (Si02 amino functionalized; EtOAc in heptane, 0/100 to100/0) and the desired fractions were concentrated in vacuo affording intermediate 18 as a yellow oil (203 mg, 67percent yield).

Reference： [1]Patent: WO2018/109202,2018,A1 .Location in patent: Page/Page column 47

77
[ 625471-18-3 ]
[ 912368-73-1 ]

Reference： [1]Patent: WO2006/106326,2006,A1
[2]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29

78
6-methyl-5-((3-(2-(methylsulfinyl)pyrimidin-4-yl)pyridin-2-yl)oxy)naphthalen-1-amine [ No CAS ]
[ 625471-18-3 ]
(S)-tert-butyl 3-((4-(2-((5-amino-2-methylnaphthalen-1-yl)oxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 110℃;Inert atmosphere;	To a 2 L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 5- [[3-(2-methanesulfinylpyrimidin-4-yl)pyridin-2-yl]oxy]- 6-methylnaphthalen-1-amine (75 g, 192 mmol), tert-butyl (3S)-3-aminopiperidine-1- carboxylate (152 g, 768 mmol), 1,4-dioxane (1 L) and DIPEA (98 g, 768 mmol). The resulting solution was stirred at 110 °C in an oil bath overnight, cooled to rt and concentrated in vacuo. The residue was purified via flash silica chromatography (solvent gradient: 20percent ethyl acetate in petroleum ether and then 2percent methanol in DCM) to yield 50.5 g (5 0percent) of the title compound as a yellow solid. LCMS: (ES, mlz): [M+H] = 527.

Reference： [1]Patent: WO2018/166528,2018,A1 .Location in patent: Paragraph 0215; 0216

79
3,3-difluoro-N-(6-methyl-5-((3-(2-(methylsulfinyl)pyrimidin-4-yl)pyridin-2-yl)oxy)naphthalen-1-yl)cyclopentanecarboxamide [ No CAS ]
[ 625471-18-3 ]
(3S)-tert-butyl 3-((4-(2-((5-(3,3-difluorocyclopentanecarboxamido)-2-methylnaphthalen-1-yl)oxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With triethylamine; In 1,4-dioxane; at 120℃; for 20h;Sealed tube;	3,3 -Difluoro-N-(6-methyl-5 -((3 -(2-(methylthio)pyrimidin-4-yl)pyridin-2- yl)oxy)naphthalen-1-yl)cyclopentanecarboxamide (245 mg, 0.469 mmol) and (S)-tert-butyl 3- aminopiperidine-1-carboxylate (141 mg, 0.703 mmol) were combined in 1,4-dioxane (3 mL). Triethylamine (142 mg, 0.196 mL, 1.41 mmol) was then added and the flask was sealed and placed in a 120 °C oil bath. After 20 h, the mixture was diluted with EtOAc (75 mL), and washed with saturated NaHCO3(aq) (25 mL), H20 (10 mL), and then saturated NaC1(aq) (10 mL). The solution was dried (Mg504), filtered and concentrated in vacuo. The crude was purified by flash chromatography through silica gel (0 ? 100percent EtOAc/hexanes) to provide 130 mg (42percent yield) of the title compound as an orange wax. LCMS (ESI) [M+H] = 659.2, rt = 1.92 mm.

Reference： [1]Patent: WO2018/166528,2018,A1 .Location in patent: Paragraph 0954; 0955

80
3-methyl-N-(6-methyl-5-((3-(2-(methylsulfinyl)pyrimidin-4-yl)pyridin-2-yl)oxy)naphthalen-1-yl)cyclopentanecarboxamide [ No CAS ]
[ 625471-18-3 ]
(3S)-tert-butyl 3-((4-(2-((2-methyl-5-(3-methylcyclopentanecarboxamido)naphthalen-1-yl)oxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With triethylamine; In 1,4-dioxane; at 120℃; for 20h;Sealed tube;	3 -Methyl-N-(6-methyl-5-((3 -(2-(methylsulfinyl)pyrimidin-4-yl)pyridin-2- yl)oxy)naphthalen-1-yl)cyclopentanecarboxamide (276 mg, 0.55 1 mmol) and (S-tert-butylaminopiperidine-1-carboxylate (166 mg, 0.827 mmol) were combined in 1,4-dioxane (3 mL). Triethylamine (167 mg, 0.230 mL, 1.65 mmol) was then added and the flask was sealed and placed in a 120 °C oil bath. After 20 h, the mixture was diluted with EtOAc, and washed with saturated NaHCO3(aq), then saturated NaC1(aq), dried (Mg504), filtered and concentratedvacuo. The crude was purified by flash chromatography through silica gel (0 ? 60percent EtOAc/DCM) to provide 254 mg (72percent yield) of the title compound as an off-white foam. LCMS (ESI) [M+H] = 637.4, rt = 2.04 mm.

Reference： [1]Patent: WO2018/166528,2018,A1 .Location in patent: Paragraph 0987; 0988

81
[ 101079-64-5 ]
[ 625471-18-3 ]
tert-butyl (S)-3-(5-bromo-3-nitrothiophene-2-carboxamido)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 40℃; for 15h;	(S)-1-Boc-3-aminopiperidine (3.57 g, 17.85 mmol) was added dropwise to a solution in which 37 5-bromo-3-nitrothiophene-2-carboxylic acid (4.5 g, 17.85 mmol), 42 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinum 3-oxide hexafluorophosphate (HATU; 20.37 g, 53.6 mmol), 43 diisopropylethylamine (DIPEA; 11.54 g, 89 mmol), and 44 dimethylformamide (50 mL) were mixed, and the resulting mixture was stirred at 40°C for 15 hours. An organic layer was collected by extracting the reaction mixture with ethyl acetate and a saturated aqueous sodium bicarbonate solution. The collected organic layer was washed with brine solution, dried over sodium sulfate, concentrated under reduced pressure, and purified with MPLC to obtain a yellow 45 solid target compound (6.2 g, 80percent). 1H NMR (400 MHz, DMSO-d6) delta 8.86 (d, 1H), 7.88 (s, 1H), 3.82 (m, 1H), 2.94 (m, 2H), 1.85 (m, 1H), 1.67 (m, 1H), 1.40 (s, 9H), 1.39 (m, 4H).

Reference： [1]Patent: EP3418275,2018,A1 .Location in patent: Paragraph 0096

82
6-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-5-fluoro-1H-indole [ No CAS ]
[ 625471-18-3 ]
(S)-tert-butyl 3-((4-(6-bromo-5-fluoro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 70℃; for 16h;	To a solution of 6-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-5-fluoro-lH-indole (410 mg, 1.04 mmol) and (.V)-/<?/7-butyl 3 -aminopiperidine-l -carboxylate (234 mg, 1.14 mmol) in anh. NMP (2.1 mL), was added DIPEA (0.55 mL, 3.12 mmol). The reaction mixture was stirred at 70 C for 16 h. The mixture was then diluted with EtOAc, washed with brine (2x20 mL), dried over anh. Na SCU, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc in hexanes, 0 to 100% gradient) to afford the title compound (355 mg, 0.635 mmol, 61% yield) as a pale yellow oil that crystallized overtime.

Reference： [1]Patent: WO2019/143719,2019,A1 .Location in patent: Paragraph 352; 353

83
6-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole [ No CAS ]
[ 625471-18-3 ]
(S)-tert-butyl 3-((4-(6-bromo-1-(phenylsulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 1h;	A mixture of l-(benzenesulfonyl)-6-bromo-3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]indole (Example 1, step 2; 1.00 g, 1.94 mmol, 1.00 eq ), (.V)-/<?/ -buLyl (3S)-3-aminopiperidine-l- carboxylate (388.54 mg, 1.94 mmol, 1.00 eq) and DIEA (N,N-diisopropylethylamine; 752.18 mg, 5.82 mmol, 1.02 mL, 3.00 eq) in NMP (N-methyl-2-pyrrolidone; 10.00 mL) was stirred at l40C for lhr . The mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 2). Combined organic layers were washed with brine (100 mL x 2), dried over Na2S04, filtered, and concentrated under reduced pressure to a yellow oil. The residue was purified by SiCT chromatography (PE/EtOAc, 10:1 to 5:1) to afford the title compound (1.13 g, 86%) as a yellow solid.

Reference： [1]Patent: WO2019/143719,2019,A1 .Location in patent: Paragraph 101

84
[ 625471-18-3 ]
[ 1630086-20-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: TEA / dimethyl sulfoxide / 18 h / 80 °C 2: potassium carbonate / N,N-dimethyl-formamide / 2 h / 155 °C 3: pyridine / dichloromethane / 18 h / 20 °C 4: trifluoroacetic acid / dichloromethane / 2 h / 20 °C

Reference： [1]Feldman, Hannah C.; Vidadala, Venkata Narayana; Potter, Zachary E.; Papa, Feroz R.; Backes, Bradley J.; Maly, Dustin J. [ACS Chemical Biology, 2019, vol. 14, # 12, p. 2595 - 2605]

85
[ 1083169-00-9 ]
[ 625471-18-3 ]
C₁₇H₂₇N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; tert-butyl XPhos; In 1,4-dioxane; at 95 - 100℃; for 0.5h;Inert atmosphere; Sealed tube;	NaO/-Bu (119 mg, 1.24 mmol) was added to a stirred suspension of Pd2dba3 (22.7 mg, 24.7 nmol) and /BuXPhos (31.5 mg, 74.2 pmol) in l,4-dioxane (15 mL) in a sealed tube and under N2 atmosphere at room temperature. The reaction mixture was stirred at 95 C for 5 min, then a mixture of (S)-(+)-3-amino- 1 -boc-pipcrdinc [625471-18-3] (129 mg, 0.64 mmol) and <strong>[1083169-00-9]4-bromo-2-methoxy-6-methylpyridine</strong> [1083169-00-9] (100 mg, 0.49 mmol) in l,4-dioxane (5 mL) was added under N2 atmosphere at 95 C. The reaction mixture was stirred at 100 C for 30 min. The mixture was diluted with NaHCCh (sat., aq.) and extracted with EtOAc. The organic layer was dried (MgS04), filtered and the solvents were evaporated in vacuo. The crude mixture was purified by flash column chromatography (Si02, EtOAc in heptane, gradient from 5/95 to 100/0) to afford intermediate 55 (130 mg, 82%).

Reference： [1]Patent: WO2019/243528,2019,A1 .Location in patent: Page/Page column 65-66

86
[ 1083169-00-9 ]
[ 625471-18-3 ]
C₁₂H₁₉N₃O [ No CAS ]

Reference： [1]Patent: WO2019/243528,2019,A1

87
[ 5198-88-9 ]
[ 625471-18-3 ]
tert-butyl (3S)-3-[(2-bromothiazol-4-yl)carbamoylamino]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		A mixture of <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong> (4.0 g, 19.2 mmol), DPPA (6.2 ml_, 29 mmol) and TEA (4.0 ml_, 29 mmol) in toluene (80 ml_) was heated at reflux for 45 min. The colourless mixture turned brown with strong evolution of gas which ceased after a few minutes to give a refluxing black solution. The mixture was cooled and treated with (S)-tert- butyl 3-aminopiperidine-carboxylate (CAS 625471-18-3; 3.85 g, 19.2 mmol) and the mixture heated at reflux. The solvent was removed by evaporation and the resultant gum was purified by flash chromatography using cyclohexane/EtOAc as eluent to provide tert-butyl (3S)-3-[(2-bromothiazol-4-yl)carbamoylamino]piperidine-1-carboxylate, (4.72 g, 60%). m/z ES+ [M+H]+ 406

Reference： [1]Patent: WO2020/30924,2020,A1 .Location in patent: Page/Page column 59

88
[ 1159819-32-5 ]
[ 625471-18-3 ]
[ 2410944-52-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide / 1 h / 20 °C 1.2: 60 h / 70 °C 2.1: acetyl chloride / methanol / 3 h / 20 °C

Reference： [1]Current Patent Assignee: ARTIOS PHARMA - WO2020/30925, 2020, A1

89
[ 1159819-32-5 ]
[ CAS Unavailable ]
[ 625471-18-3 ]
[ 2410945-16-1 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: 1,1'-carbonyldiimidazole; tert-butyl (3S)-3-aminopiperidine-1-carboxylate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 4-[4-(trifluoromethyl)phenyl]pyrazin-2-amine In N,N-dimethyl-formamide at 70℃; for 60h;	215.a A solution of (S)-(+)-3-amino-1-Boc-piperidine (84 mg, 0.418 mmol) and 1,1'- carbonyl-diimidazole (71 mg, 0.439 mmol) in DMF (4 mL) was stirred at rt for 1 h. After this time the solvent was removed in vacuo, the residue dissolved in DMF (1 mL) and added to a stirred suspension of 4-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (50 mg, 0.209 mmol) and sodium hydride in DMF (3.5 mL). The resulting mixture was warmed to 70 °C for 60 h. The reaction media was diluted with EtOAc, washed with saturated NaHCO3 and brine (x3), dried and evaporated. The residual material was purified by column chromatography, eluting with 0- 20% MeOH/DCM + 0.1% TEA to afford tert-butyl (3S)-3-[[6-[4-(trifluoromethyl)-phenyl]- pyrazin-2-yl]carbamoylamino]piperidine-1-carboxylate (92 mg, 94%). m/z ES+ [M+H]+ 466.

Reference： [1]Current Patent Assignee: ARTIOS PHARMA - WO2020/30925, 2020, A1 Location in patent: Page/Page column 182

90
[ 54932-72-8 ]
[ 625471-18-3 ]
C₁₇H₂₅ClN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; for 14h;Inert atmosphere; Reflux;	General procedure: Nitrogen was purged through a stirred solution of <strong>[54932-72-8]4-bromo-1-chloro-2-methylbenzene</strong> (258muL, 1.95mmol) in 1,4-dioxane (5mL) for 30min rac-BINAP (363mg, 1.95mmol), caesium carbonate (1.27g, 3.89mmol), 1-Boc-piperazine (363mg, 1.95mmol) and Pd(OAc)2 (87mg, 0.039mumol) and stirred at reflux for 14h under N2. The reaction was filtered through celite and concentrated in vacuo. The residue was dissolved in EtOAc (20mL), filtered through celite and washed with additional EtOAc (50mL). The organic layer was washed with water (2×20mL) and brine (2×20mL), dried with Na2SO4 and concentrated in vacuo. The crude residue was purified by column chromatography (100% CyHex to 10% EtOAc/CyHex) to obtain the protected intermediate as a solid (413mg, 68%). MS, m/z=255 (100) [M-tBu]. The intermediate was dissolved in a 1:3 mixture of TFA/DCM (4mL) and stirred at 20C for 1h. The solvent was evaporated in vacuo and the crude residue dissolved in EtOAc (10mL) which was successively washed with a 10% solution of NaHCO3 (10mL), water (10mL) and brine (10mL). The organic layer dried with Na2SO4 and concentrated in vacuo to obtain 92 as a solid (211mg, 76%).

Reference： [1]European Journal of Medicinal Chemistry,2020,vol. 195

91
[ 280582-23-2 ]
[ 625471-18-3 ]
(S)-tert-butyl 3-(2-chloro-5-morpholinopyrimidin-4-ylamino)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With triethylamine In ethanol at 80℃;	3.3-1 Step 3-1: Preparation of (S)-tert-butyl 3-(2-chloro-5-morpholinopyrimidine-4-ylamino)piperidine-1-carboxylate 4-(2,4-dichloropyrimidin-5-yl)morpholine (5.0 g, 21.26 mmol) obtained in step 1-2 of Example 1,After tert-butyl (S)-3-aminopiperidine-1-carboxylate (4.7 g, 23.50 mmol) and triethylamine (4.5 mL, 32.0 mmol) were dissolved in ethanol (107 mL),The reaction mixture was stirred at 80° C. overnight.After removing the solvent of the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was recovered.The obtained organic layer was washed with brine and dried over sodium sulfate. After the filtrate was concentrated under reduced pressure, medium pressure liquid chromatography (silica gel, hexane:ethyl acetate = 20:1) was used to obtain the target compound (6.0 g, 71%)

Reference： [1]Current Patent Assignee: VORONOI INC - KR2020/137087, 2020, A Location in patent: Paragraph 0195-0201

92
[ 625471-18-3 ]
[ 436799-33-6 ]
tert-butyl N-[(3S)-1-[5-(trifluoromethyl)pyridin-3-yl]piperidin-3-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%		A suspension of 3-Bromo-5-(trifluoromethyl)pyridine (1.5 g, 1.0 eq.), (S)-3-Boc-aminopiperidine (1.7 g, 1.3 eq.) and Cs2CO3 (2.9 g, 1.4 eq.) in anh.1,4-dioxane (20.0 mL) was sparged with ar- gon over 20 min and after this Pd2(dba)3 (0.30 g, 0.05 eq.) and Xantphos (0.38 g, 0.1 eq.) were added. The reaction tube was closed and reaction was stirred at 140 C for 2 days. The mixture was filtered through celite pad and concentrated in vacuo. Product was purified on FCC (SiHP; Hex:EtOAc), dissolved in EtOAc and scavenger QuadraSil MP (2.7 g) was added. The mixture was stirred overnight at RT. Scavenger was filtered off and washed with EtOAc. The solvent was concentrated to give the product (1.9 g, 82% yield) as a yellow solid. ESI-MS: 346.1 [M+H]+.

Reference： [1]Patent: WO2021/116446,2021,A1 .Location in patent: Page/Page column 233

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P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere