[ CAS No. 135632-53-0 ] {[proInfo.proName]}

Name: 135632-53-0|tert-Butyl (piperidin-4-ylmethyl)carbamate|97%
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Quality Control of [ 135632-53-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 135632-53-0 ]

CAS No. :	135632-53-0	MDL No. :	MFCD01631214
Formula :	C₁₁H₂₂N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VHYXAWLOJGIJPC-UHFFFAOYSA-N
M.W :	214.30	Pubchem ID :	723429
Synonyms :

Calculated chemistry of [ 135632-53-0 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.91
Num. rotatable bonds :	5
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	64.11
TPSA :	50.36 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.73 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.71
Log Po/w (XLOGP3) :	1.24
Log Po/w (WLOGP) :	1.13
Log Po/w (MLOGP) :	1.15
Log Po/w (SILICOS-IT) :	1.2
Consensus Log Po/w :	1.49

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.62
Solubility :	5.14 mg/ml ; 0.024 mol/l
Class :	Very soluble
Log S (Ali) :	-1.9
Solubility :	2.73 mg/ml ; 0.0127 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.45
Solubility :	0.757 mg/ml ; 0.00353 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.17

Safety of [ 135632-53-0 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P305+P351+P338	UN#:
Hazard Statements:	H315-H319	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 135632-53-0 ]

* 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 [ 135632-53-0 ]
Downstream synthetic route of [ 135632-53-0 ]

[ 135632-53-0 ] Synthesis Path-Upstream 1~7

1
[ 7144-05-0 ]
[ 49761-82-2 ]
[ 135632-53-0 ]

Yield	Reaction Conditions	Operation in experiment
70%	at 25℃;	A solution of piperidinyl-4-methylamine (3.6 g) and N-tert-butoxycarbonylimidazole (5.3 g) in toluene (80 mL) was stirred at 25° C. overnight. The solution was then concentrated and the resultant residue was purified by column chromatography on silica gel (EtOAc/Hexane=1/2) to give Intermediate 227-I (4.7 g) in a 70percent yield. Intermediate 227-I (4.7 g) and Et₃N (2.7 mL) in 1-pentanol (20 mL) was reacted with 2,4-dichloro-6-aminopyrimidine (5.4 g) at 120° C. for 12 hours. After the solvent was removed, the residue was purified by column chromatography on silica gel (EtOAc/Hexane=1/9) to afford Intermediate 227-II (5.2 g) in a 70percent yield. A solution of Intermediate 227-II (1.0 g) treated with 1 M HCl (20 mL) in CH₂Cl₂(10 mL) was stirred at room temperature for 8 hours. After the solution was concentrated, the resultant residue was neutralization with NH₄OH, and extracted with CH₂Cl₂. The organic layer was separated and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using MeOH as an eluant) to afford Intermediate 227-III (636 mg) in a 90percent yield. Intermediate 222-III (790 mg) prepared from Example 222 was added to a solution of Intermediate 227-III (450 mg) in MeOH (20 mL). The mixture was stirred at 25° C. for 2 hours. NaBH(OAc)₃(2.0 g) was then added at 25° C. for 12 hours. After the solution was concentrated, a saturated aq. NaHCO₃solution was added to the resultant residue. The mixture was then extracted with CH₂Cl₂. The organic layer was separated and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using MeOH as an eluant) to afford Intermediate 227-IV (539 mg) in a 60percent yield. N¹-Morpholine-N¹-piperazine ethane (240 mg) was added to a solution of Intermediate 227-IV (160 mg) in 1-pentanol (1 mL). The mixture was stirred at 120° C. for 8 hours. The solution was concentrated and the residue was purified by column chromatography on silica gel (EtOAc/MeOH=5/1) to afford Intermediate 227-V (85 mg) in a 40percent yield. A solution of 20percent TFA/CH₂Cl₂(1 mL) was added to a solution of Intermediate 227-V (85 mg) in CH₂Cl₂(1 mL). The reaction mixture was stirred for 8 hours at room temperature and concentrated by removing the solvent. The resultant residue was purified by column chromatography on silica gel (21percent NH₃(aq)/MeOH=1/19) to afford Compound 227 (65 mg) in a 90percent yield. Compound 227 was then treated with 1 M HCl (1 mL) in CH₂Cl₂(1 mL) for 0.5 hour. After the solvents were removed, the residue was treated with ether and filtered to give hydrochloride salt of Compound 227. CI-MS (M⁺+1): 544.4.

Reference： [1] Patent: US2006/281712, 2006, A1, . Location in patent: Page/Page column 108-109

2
[ 173340-23-3 ]
[ 135632-53-0 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 2, p. 633 - 645
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 1, p. 119 - 139

3
[ 24424-99-5 ]
[ 7144-05-0 ]
[ 135632-53-0 ]

Reference： [1] Patent: US5374731, 1994, A,
[2] Patent: US4857301, 1989, A,
[3] Patent: WO2012/167423, 2012, A1, . Location in patent: Page/Page column 34-35
[4] Patent: US2014/121200, 2014, A1, . Location in patent: Paragraph 0158; 0159

4
[ 1175526-48-3 ]
[ 135632-53-0 ]

Reference： [1] Patent: US2014/171403, 2014, A1, . Location in patent: Page/Page column

5
[ 39546-32-2 ]
[ 135632-53-0 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 2, p. 633 - 645
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 1, p. 119 - 139

6
[ 375355-32-1 ]
[ 135632-53-0 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 2, p. 633 - 645
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 1, p. 119 - 139

7
[ 88915-26-8 ]
[ 135632-53-0 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 2, p. 633 - 645
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 1, p. 119 - 139

[ 135632-53-0 ] Synthesis Path-Downstream 1~38

1
[ 185-72-8 ]
[ 135632-53-0 ]
tert-butyl ({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl) carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	In methanol; at 20 - 60℃; for 4h;	tert-Butyl ({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl) carbamat e us a stirred solution ot tert-butyi (piperidin-4-ylmethyl)carbamate (22.3 g, lU4 mmoV in methanol (120 mL) was added 1, 6-dioxaspiro [2. 5] octane (14.2 g, 124 mmol, prepared according to Satyamurthy, Nagichettiar et al., Phosphorus SLzlfur, 1984, 19, 113) at room temperature. Then, the mixture was heated at 60 DEG C for 4 h. The volatile components were removed by evaporation and the resulting viscous oil was precipitated with a mixture of hexane and diethyl ether. The precipitate was collected by filtration and recrystallized from a mixture of n-hexane and 2-propanol to give the title compound 14.2 g (42%) as a colorless powder. MS (ESI) m/z: 329 (M+H) +. m. p.: 104 DEG C. lH-NMR (CDCl3, 300MHz) 8 ppm: 3.85-3. 70 (4 H, m), 3.00 (2 H, t, 6. 2 Hz), 2.88-2. 83 (2 H, m), 2.38-2. 27 (4 H, m), 1.69-1. 51 (8 H, m), 1.44 (9 H, s), 1.31-1. 23 (2 H, m). A signal due to OH was not observed. Anal. Calcd. for C17H32N204 : C, 62. 17 ; H, 9. 82 ; N, 8.53. Found: C, 62.07 ; H, 9. 92 ; N, 8. 58.
42%	In methanol; at 20 - 60℃; for 4h;	EXAMPLE 1; N-((1- [ (4-HYDROXYTETRAHYDRO-2H-PYRAN-4-YL) METHYL] piperidin-4-yl} methyl)-3- isopropyl-2-oxo-2, 3-DIHYDRO-LH-BENZIMIDAZOLE-L-CARBOXAMIDE HYDROCHLORIDE; Step 1. TERT-BUTYL ( {1- [ (4-H DY_ ROXVTETRAHVDRO-2H-PYRAN-4-VL) METHYLLPIPERIDIN-4- YL) carbamate; To a stirred solution of tert-butyl (piperidin-4-ylmethyl) carbamate (22.3 g, 104 mmol) in methanol was added 1, 6-dioxaspiro [2. 5] octane (14.2 g, 124 mmol, Satyamurthy, Nagichettiar et al., Phosphorus Sulfur, 1984, 19, 113) at ambient temperature. Then, the mixture was heated at 60C for 4h. The volatile components were removed by evaporation and the resulting viscous oil was precipitated with a mixture of hexane and diethylether. The precipitate was collected by filtration and recrystallized with a mixture of hexane and 2-propanol to give title compound 14.2 g (42%) as a colorless powder. MS (ESI) m/z: 329 (M+H. m. p.: 104C. 1H-NMR (CDC13) 8 : 1.23-1. 31 (2 H, m), 1.44 (9 H, s), 1.51-1. 69 (8 H, m), 2.27-2. 38 (4 H, m), 2.83-2. 88 (2 H, m), 3.00 (2 H, t, J=6.2 Hz), 3.70-3. 85 (4 H, m). Anal. Calcd. for CL7H32N204 : C, 62.17 ; H, 9.82 ; N, 8.53. Found: C, 62.07 ; H, 9.92 ; N, 8.58.
42%	In methanol; at 20 - 60℃; for 4h;	To a stirred solution oftert-butyl (piperidin-4-ylmethyl) carbamate (22.3 g, 104 mmol) in methanol was added1, 6-dioxaspiro [2.5] octane (14.2 g, 124 mmol, Satyamurthy, Nagichettiar et al., Phosphorus Sulfur, 1984,19, 113) at room temperature. Then, the mixture was heated at60 C for 4 h. The volatile components were removed by evaporation and the resulting viscous oil was precipitated with a mixture of hexane and diethylether. The precipitate was <Desc/Clms Page number 31>collected by filtration and recrystallized from a mixture of n-hexane and 2-propanol to give the title compound 14.2 g (42%) as a colorless powder. MS (ESI) m/z: 329 (M+H+). m. p.:104 C. H-NMR (CDC13) 5 : 1.23-1. 31 (2 H, m), 1.44 (9 H, s), 1.51-1. 69 (8 H, m), 2.27-2. 38 (4 H, m), 2.83-2. 88 (2 H, m), 3.00 (2 H, t, J=6. 2 Hz), 3.70-3. 85 (4 H, m). Anal. Calcd. forCl7H32N204 : C, 62.17 ; H, 9.82 ; N, 8.53. Found: C, 62.07 ; H, 9.92 ; N, 8.58.

42%

In methanol; at 18 - 60℃; for 4h;

1 (3 ! te7t-Butyl ( [ (4-hydroxytetrahvdro-2H-pyran-4-yl) methyl]piperidin-4-vl} methyl) carbamate; To a stirred solution of tert-butyl (piperidin-4-ylmethyl) carbamate (22.3 g, 104 mmol) in methanol (120 mL) was added 1, 6-dioxaspiro [2.5] octane (14.2 g, 124 mmol, prepared according to Satyamurthy, Nagichettiar et al., Phosphorus Sulfur, 1984, 19, 113) at room temperature. Then, the mixture was heated at 60C for 4 h. The volatile components were removed by evaporation and the resulting viscous oil was precipitated with a mixture of hexane and diethyl ether. The precipitate was collected by filtration and recrystallized from a mixture of n-hexane and 2-propanol to give the title compound 14.2 g (42%) as a colorless powder. MS (ESI) m/z : 329 (M+H) +. m. p.: 104C. H-NMR (CDC13) S ppm: 3.85-3. 70 (4 H, m), 3.00 (2 H, t, J=6. 2 Hz), 2. 88-2. 83 (2 H, m), 2.38-2. 27 (4 H, m), 1.69-1. 51 (8 H, m), 1.44 (9 H, s), 1.31-1. 23 (2 H, m). A signal due to OH was not observed. Anal. Calcd. for Cl7H32N204 : C, 62.17 ; H, 9.82 ; N, 8.53. Found: C, 62.07 ; H, 9.92 ; N, 8.58.

Reference： [1]Patent: WO2005/92882,2005,A1 .Location in patent: Page/Page column 39,40
[2]Patent: WO2005/21539,2005,A1 .Location in patent: Page/Page column 46-47
[3]Patent: WO2005/49608,2005,A1 .Location in patent: Page/Page column 30-31
[4]Patent: WO2005/73222,2005,A1 .Location in patent: Page/Page column 29-30

2
[ 24424-99-5 ]
[ 7144-05-0 ]
[ 135632-53-0 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; di-isopropyl ether	31.d d) d) 4-(tert.-Butyloxycarbonyl)aminomethyl-piperidine 10.8 g of 4-(aminomethyl)-piperidine are dissolved in 100 ml of CH2 Cl2, 25 g of di-tert.-butyl dicarbonate are added, and the resulting solution is stirred at room temperature for 3 hours. The residue after concentration is taken up in diisopropyl ether and extracted twice with 100 ml of 5% strength NaHSO4 solution each time, and the combined extracts are adjusted to pH 9 with Na2 CO3 and extracted three times with 250 ml of EA. Drying over Na2 SO4 and concentration in a rotary evaporator provides 6 g of the title compound as a colorless oil. Rf (SiO2, CH2 Cl2 /MeOH 9:1):0.12 MS (DCI):215 (M+H)
	In dichloromethane	V.A 5-(1-methyl-4-piperidinylmethylaminosulfonyl) isoquinoline STR23 A. Dissolve 1.14 g of 4-aminomethylpiperidine and 2.18 g of di-tert-butyl dicarbonate in 10 ml of dichloromethane. Stir 12 hours at room temperature. Dilute the mixture with 40 ml of dichloromethane and wash with saturated NaCl solution. Dry the organic layer with anhydrous magnesium sulfate and evaporate the solvent to obtain the product, 4-tert butyloxycarbonylaminomethyl piperidine.
	In dichloromethane at 20℃;	intermediate 7ferf-butyi piperidi n-4-y. methy.carbamate[090] A solution of 4-aminomethylpiperidine (242 mg, 2.12 mmol) and di-fe/t-butyS dicarbonate (B0C2O) (483 mg, 2.12 mmol) in CH2CI2 (5 mL) was stirred at room temperature overnight. The solution was then diluted with CH2CI2, washed with brine, dried over anhydrous a2S04, filtered, and concentrated under reduced pressure to give the title compound

In dichloromethane at 20℃;

7 tert-butyl piperidin-4-ylmethylcarbamate A solution of 4-aminomethylpiperidine (242 mg, 2.12 mmol) and di-tert-butyl dicarbonate (Boc2O) (463 mg, 2.12 mmol) in CH2Cl2 (5 mL) was stirred at room temperature overnight. The solution was then diluted with CH2Cl2, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound.

Reference： [1]Current Patent Assignee: SANOFI - US5374731, 1994, A
[2]Current Patent Assignee: MERCK & CO INC - US4857301, 1989, A
[3]Current Patent Assignee: HUTCHISON CHINA MEDITECH LTD. - WO2012/167423, 2012, A1 Location in patent: Page/Page column 34-35
[4]Current Patent Assignee: HUTCHISON CHINA MEDITECH LTD. - US2014/121200, 2014, A1 Location in patent: Paragraph 0158; 0159

3
[ 5399-92-8 ]
[ 135632-53-0 ]
[ 885594-79-6 ]

Yield	Reaction Conditions	Operation in experiment
30%	With triethylamine; In ethanol; at 80℃; for 3h;	To a solution of 4-chloro-lH-pyrazolo[3,4-^pyrimidine (J. Amer. Chem. SQC. 1957, 79, 6407-6413) (51 mg, 0.33 mmol) in ethanol (2 ml) was added triethylamine (100 mul, 0.72 mmol) and 4-(N-Boc-aminomethyl)piperidine (87 mg, 0.41 mmol). The solution was heated at 80 C for 3 hours, and then cooled to room temperature. The solution was evaporated to dryness and the residue purified by recrystallisation (isopropanol) to yield the intermediate NH-BOC protected product (33 mg, 30% yield).To the intermediate NH-BOC protected product (32 mg, 0.096 mmol) was added HCl (1 ml, 4M solution in dioxane, 4 mmol). The suspension was stirred at room temperature for 1 hour, and then diluted with diethyl ether (4 ml). The ethereal layer was discarded and the solid washed with a further portion of diethyl ether (2 ml). The ethereal layer was again discarded, and the resultant solid dried under high vacuum. The free base was liberated by dissolution of this material in methanol, loading onto an acidic resin SCX-2 cartridge, and elution from the cartridge with ammonia in methanol to give the title compound (21 mg, quantitative). LC/MS Rt 0.86 [M+H]+233
30%	With triethylamine; In ethanol; at 80℃; for 3h;	EXAMPLE 17; C-M-fiH-Pyrazolobeta^-c/ipyrimidin^-vO-piperidin^-v?-methvlamine <n="123"/>To a solution of 4-chloro-1/-/-pyrazolo[3,4-d]pyrimidine (J. Amer. Chem. Soc. 1957, 79, 6407-6413) (51 mg, 0.33 mmol) in ethano] (2 ml) was added triethylamine (100 mul, 0.72 mmol) and 4-(N-Boc-aminomethyl)piperidine (87 mg, 0.41 mmol). The solution was heated at 80 0C for 3 hours, and then cooled to room temperature. The solution was evaporated to dryness and the residue purified by recrystallisation (isopropanol) to yield the intermediate NH-BOC protected product (33 mg, 30% yield).

Reference： [1]Patent: WO2006/46023,2006,A1 .Location in patent: Page/Page column 122
[2]Patent: WO2007/125315,2007,A2 .Location in patent: Page/Page column 120-121
[3]Journal of Medicinal Chemistry,2008,vol. 51,p. 2147 - 2157

4
[ 7144-05-0 ]
[ 49761-82-2 ]
[ 135632-53-0 ]

Yield	Reaction Conditions	Operation in experiment
70%	In toluene; at 25℃;	A solution of piperidinyl-4-methylamine (3.6 g) and N-tert-butoxycarbonylimidazole (5.3 g) in toluene (80 mL) was stirred at 25 C. overnight. The solution was then concentrated and the resultant residue was purified by column chromatography on silica gel (EtOAc/Hexane=1/2) to give Intermediate 227-I (4.7 g) in a 70% yield. Intermediate 227-I (4.7 g) and Et3N (2.7 mL) in 1-pentanol (20 mL) was reacted with 2,4-dichloro-6-aminopyrimidine (5.4 g) at 120 C. for 12 hours. After the solvent was removed, the residue was purified by column chromatography on silica gel (EtOAc/Hexane=1/9) to afford Intermediate 227-II (5.2 g) in a 70% yield. A solution of Intermediate 227-II (1.0 g) treated with 1 M HCl (20 mL) in CH2Cl2 (10 mL) was stirred at room temperature for 8 hours. After the solution was concentrated, the resultant residue was neutralization with NH4OH, and extracted with CH2Cl2. The organic layer was separated and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using MeOH as an eluant) to afford Intermediate 227-III (636 mg) in a 90% yield. Intermediate 222-III (790 mg) prepared from Example 222 was added to a solution of Intermediate 227-III (450 mg) in MeOH (20 mL). The mixture was stirred at 25 C. for 2 hours. NaBH(OAc)3 (2.0 g) was then added at 25 C. for 12 hours. After the solution was concentrated, a saturated aq. NaHCO3 solution was added to the resultant residue. The mixture was then extracted with CH2Cl2. The organic layer was separated and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using MeOH as an eluant) to afford Intermediate 227-IV (539 mg) in a 60% yield. N1-Morpholine-N1-piperazine ethane (240 mg) was added to a solution of Intermediate 227-IV (160 mg) in 1-pentanol (1 mL). The mixture was stirred at 120 C. for 8 hours. The solution was concentrated and the residue was purified by column chromatography on silica gel (EtOAc/MeOH=5/1) to afford Intermediate 227-V (85 mg) in a 40% yield. A solution of 20% TFA/CH2Cl2 (1 mL) was added to a solution of Intermediate 227-V (85 mg) in CH2Cl2 (1 mL). The reaction mixture was stirred for 8 hours at room temperature and concentrated by removing the solvent. The resultant residue was purified by column chromatography on silica gel (21% NH3 (aq)/MeOH=1/19) to afford Compound 227 (65 mg) in a 90% yield. Compound 227 was then treated with 1 M HCl (1 mL) in CH2Cl2 (1 mL) for 0.5 hour. After the solvents were removed, the residue was treated with ether and filtered to give hydrochloride salt of Compound 227. CI-MS (M++1): 544.4.

Reference： [1]Patent: US2006/281712,2006,A1 .Location in patent: Page/Page column 108-109

5
[ 10132-07-7 ]
[ 135632-53-0 ]
[ 917021-68-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	With triethylamine; In pentan-1-ol; at 120℃; for 12h;	A solution of piperidinyl-4-methylamine (3.6 g) and N-tert-butoxycarbonylimidazole (5.3 g) in toluene (80 mL) was stirred at 25 C. overnight. The solution was then concentrated and the resultant residue was purified by column chromatography on silica gel (EtOAc/Hexane=1/2) to give Intermediate 227-I (4.7 g) in a 70% yield. Intermediate 227-I (4.7 g) and Et3N (2.7 mL) in 1-pentanol (20 mL) was reacted with <strong>[10132-07-7]2,4-dichloro-6-aminopyrimidine</strong> (5.4 g) at 120 C. for 12 hours. After the solvent was removed, the residue was purified by column chromatography on silica gel (EtOAc/Hexane=1/9) to afford Intermediate 227-II (5.2 g) in a 70% yield. A solution of Intermediate 227-II (1.0 g) treated with 1 M HCl (20 mL) in CH2Cl2 (10 mL) was stirred at room temperature for 8 hours. After the solution was concentrated, the resultant residue was neutralization with NH4OH, and extracted with CH2Cl2. The organic layer was separated and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using MeOH as an eluant) to afford Intermediate 227-III (636 mg) in a 90% yield. Intermediate 222-III (790 mg) prepared from Example 222 was added to a solution of Intermediate 227-III (450 mg) in MeOH (20 mL). The mixture was stirred at 25 C. for 2 hours. NaBH(OAc)3 (2.0 g) was then added at 25 C. for 12 hours. After the solution was concentrated, a saturated aq. NaHCO3 solution was added to the resultant residue. The mixture was then extracted with CH2Cl2. The organic layer was separated and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using MeOH as an eluant) to afford Intermediate 227-IV (539 mg) in a 60% yield. N1-Morpholine-N1-piperazine ethane (240 mg) was added to a solution of Intermediate 227-IV (160 mg) in 1-pentanol (1 mL). The mixture was stirred at 120 C. for 8 hours. The solution was concentrated and the residue was purified by column chromatography on silica gel (EtOAc/MeOH=5/1) to afford Intermediate 227-V (85 mg) in a 40% yield. A solution of 20% TFA/CH2Cl2 (1 mL) was added to a solution of Intermediate 227-V (85 mg) in CH2Cl2 (1 mL). The reaction mixture was stirred for 8 hours at room temperature and concentrated by removing the solvent. The resultant residue was purified by column chromatography on silica gel (21% NH3 (aq)/MeOH=1/19) to afford Compound 227 (65 mg) in a 90% yield. Compound 227 was then treated with 1 M HCl (1 mL) in CH2Cl2 (1 mL) for 0.5 hour. After the solvents were removed, the residue was treated with ether and filtered to give hydrochloride salt of Compound 227. CI-MS (M++1): 544.4.

Reference： [1]Patent: US2006/281712,2006,A1 .Location in patent: Page/Page column 108-109

6
[ 6952-59-6 ]
[ 135632-53-0 ]
[ 943721-95-7 ]

Yield	Reaction Conditions	Operation in experiment
73%	With caesium carbonate In toluene at 90℃; for 24.1833h;	7 Example 7. Synthesis of {/m»5-4-[(2-{2-[3-(4-aminomethyl-piperidin-l-yl)-phenyl]- ethyI}-5-nitro-pyrimidin-4-yIamino)-methyl]-cyclohexyl}-methanol; Palladium (II) acetate (37 mg, 0.165 mmol) and 4, 5-bis(diphenylphosphino)-9,9- dimethylxanthene (143 mg, 0.247 mmol, Xantphos) were combined and the flask was evacuated and flushed three times with N2. Degassed PhCH3 (25 mL) was added and the solution was stirred for 5 min. 3-Bromobenzonitrile (1.0 g, 5.49 mmol) and Boc-4-(aminomethyl)-piperidine (1.4 g, 6.59 mmol) were added and the reaction was stirred for another 5 min. CS2CO3 (2.15 g, 6.59 mmol) was added and the flask was flushed with N2 for 1 min then heated to 90 0C for 24 h. The volatiles were removed and the crude residue was purified via flash chromatography (SiO2, 25-60% EA-Hexanes) to afford 1.27g (73%) of [l-(3-cyano-phenyl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester.[l-(3-Cyano-phenyl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester (1.27 g, 4.03 mmol) was dissolved in MeOH (300 mL). To this solution was added about 1.5 mL of Raney Nickel suspension in H2O. The flask was evacuated and backflushed with N2, evacuated, filled with H2, and maintained under balloon pressure. The reaction was stirred vigorously for 24 h then filtered through a 2 cm thick pad of Celite under a stream OfN2. The volatiles were removed and the crude residue was purified via flash chromatography (SiO2, 10-50% ((2:18:80-NH4OH:MeOH:CH2Cl2):CH2Cl2) to afford 455 mg (35%) of [1- (3-aminomethyl-phenyl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester. Trans- {4-[(2-chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl} -methanol (100 rag, 0.33 mmol) was dissolved in CH2Cl2 (10 mL) followed by Et3N (0.116 mL, 0.83 mmol). [l-(3-Ajtninomethyl-phenyl)-piperidin-4-ylmethyl]-caλamic acid tert-butyl ester (117 mg, 0.37 mmol) was dissolved in DMA:£tOH (2 mL, 1 : 1) and added to the reaction. The reaction was stirred at room temperature for 18 h, the volatiles removed and the crude purified via flash chromatography (SiO2, 5% MeOH-CH2Cl2) to afford {l-[3-(2-{4-[(trans- 4-hydroxyinethyl-cyclohexylinethyl)-arnino]-5-nitro-pyrimidin-2-ylj-ethyl)-phenyl]- piperidin-4-ylmethyl}-carbamic acid tert-bvyl ester which was redissolved in CH2Cl2 (10 mL). TFA (10 mL) was added and the reaction was stirred for 3 h. The crude was purified via flash chromatography (SiO2, 50-100% ((NH4OHrMeOHrCH2Cl2-^rISrSO)-CH2Cl2) to afford 136 mg of {trans-4-[(2-{2-[3-(4-aminomethyl-piperidin-l-yl)-phenyl]-ethyl}-5- nitro-pyrimidin-4-ylamino)-mcthyl]-cyclohcxyl} -methanol (85%), m/z 484.1 (M + H)+.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2007/76247, 2007, A1 Location in patent: Page/Page column 31-33

7
[ 51940-64-8 ]
[ 135632-53-0 ]
[ 1192711-51-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 20h;	To a solution of <strong>[51940-64-8]ethyl 2,4-dichloropyrimidine-5-carboxylate</strong> (221 mg, 1.00 mmol) and DIEA (0.347 mL, 2.00 mmol) in CH3CN (4 mL), a suspension of 4-N-Boc-aminomethyl piperidine (214 mg, 1.00 mmol) in CH3CN (4 mL) was added. The mixture was stirred at room temperature for 20 h. Water and EtOAc were added. The organic phase was separated, washed with IN HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give ethyl 4-(4-((tert-butoxycarbonyl)methyl)piperidin- 1 -yl)-2-chloropyrimidine-5- carboxylate (368 mg). MS 399.5 and 401.5 (M+H, Cl pattern).

Reference： [1]Patent: WO2009/131687,2009,A2 .Location in patent: Page/Page column 113

8
[ 934524-10-4 ]
[ 135632-53-0 ]
[ 1192711-41-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In 1,4-dioxane; at 70℃; for 20h;	A solution of <strong>[934524-10-4]2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (200 mg, 0.584 mmol), 4-N-Boc-aminomethylpiperidine (125 mg, 0.584 mmol) and triethylamine (0.160 mL, 1.15 mmol) in dioxane (5 mL) was stirred at 70 0C for 20 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo to give tert-butyl ( 1 -(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (303 mg).

Reference： [1]Patent: WO2009/131687,2009,A2 .Location in patent: Page/Page column 105

9
[ 151858-64-9 ]
[ 135632-53-0 ]
tert-butyl (1-(5-(pyridin-2-yl)thiophen-2-ylsulfonyl)piperidin-4-yl)methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃;	243 tert-Butyl piperidin-4-ylmethylcarbamate (0.100 g) in dichloromethane (2.3 mL) was treated with 5-(pyridin-2-yl)thiophene-2-sulfonyl chloride (0.133 g)5 followed by triethylamine (0.325 mL) at room temperature. After stirring the mixture at room temperature overnight, it was washed with IN hydrochloric acid, the organic layer was separated and filtered. Evaporation of the solvent and purification by column chromatography on silica gel (1-4% methanol in dichloromethane) provide the title compound (0.088 g) having the following physical data. 1H NMR (DMSO-d6): δ 8.58 (d, J = 5.0 Hz, IH), 8.08 (d, J = 8.0 Hz5 IH)5 7.95-7.90 (m, 2H), 7.63 (d, J = 4.0 Hz, IH), 7.40 (dd, J = 4.9, 7.5 Hz, IH), 6.88 (t, J = 5.8 Hz, IH), 3.63 (d, J = 11.5 Hz, 2H), 2.79 (t, J = 6.1 Hz, 2H), 2.36 (t, J = 10.5 Hz, 2H), 1.70 (d, J = 10.8 Hz, 2H), 1.33-1.30 (m, 10H), 1.2-1.13 (m, 2H); Mass data (APCI, Pos.): m/z 438 (M + H)+.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2010/80864, 2010, A1 Location in patent: Page/Page column 221-222

10
[ 72418-40-7 ]
[ 135632-53-0 ]
[ 1235473-72-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-phenylisoxazole-5-carbaldehyde; tert-butyl N-(4-piperidinylmethyl)carbamate With acetic acid In acetonitrile at 20℃; for 0.5h; Stage #2: With tetramethylammonium triacetoxyborohydride In acetonitrile Stage #3: With sodium hydrogencarbonate In water; acetonitrile	8 A solution of the compound prepared in Example 7 (2.00 g), tert-butyl piperidin-4- ylmethylcarbamate (2.72 g) and acetic acid (0.66 mL) in acetonitrile (60 mL) was stirred at room temperature for 30 minutes. Tetramethylammonium triacetoxyborohydride (9.12 g) was added and the reaction was stirred overnight. The reaction was then poured into a saturated aqueous sodium bicarbonate solution and the resulting mixture was extracted three times with ethyl acetate. The combined organics were dried with anhydrous magnesium sulfate and concentrated to a white solid. The solid was triturated with hexane to obtain the title compound (3.90 g) having the following physical data. 1H NMR (CDCl3): δ 7.83-7.79 (m, 2H), 7.48-7.43 (m, 3H)5 6.49 (s, IH), 4.66-4.57 (m, IH), 3.73 (s, 2H), 3.06-2.93 (m, 4H), 2.16-2.07 (m, 2H), 1.74-1.66 (m, 2H), 1.52-1.39 (m, 10H), 1 38-1.24 (m, 2H); Mass data (ESI, Pos.): m/z 372 (M + H)+.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2010/80864, 2010, A1 Location in patent: Page/Page column 108-109

11
[ 67443-38-3 ]
[ 135632-53-0 ]
[ 1289020-80-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere;	A suspension of 1.00 g (4.21 mmol) <strong>[67443-38-3]5-bromo-2-chloro-3-nitro-pyridine</strong>, 0.993 g (4.63 mmol) of piperidin-4-ylmethyl-carbamic acid ie/ -butyl ester, and 1.16 g (8.42 mmol) of potassium carbonate in N,N-dimethylformamide (10 mL) is stirred for 2 hours under argon. The mixture is diluted with water which causes a solid to precipitate from solution. The formed solid is collected by filtration, washed with water, and dried for 1 hour under vacuum at 50 C to give 1.57 g (90.0%) of (5'-bromo-3'-nitro-3,4,5,6- tetrahydro-2H-[l,2']bipyridinyl-4-ylmethyl)-carbamic acid ieri-butyl ester as a yellow solid.
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; for 4h;	General procedure: A mixture of 5-Bromo-2chloro-3-nitropyridine (2) (10mmol), organicamine compound (14mmol), and N,N-diisopropylethylamine (30mmol) in 1,4-dioxane (100mL) was stirred at room temperature for 4h. After the reaction was completed by TLC analysis, the volatiles were removed under reduced pressure. The mixture was extracted with CH2Cl2 (3×60mL) and washed with H2O (3×60mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo.The resulting residue was purified by column chromatography on silica gel (PE: EA=9:1) to obtain theintermediates 3a-j.

Reference： [1]Patent: WO2011/84985,2011,A1 .Location in patent: Page/Page column 95
[2]Bioorganic Chemistry,2020,vol. 100

12
[ 42098-25-9 ]
[ 135632-53-0 ]
[ 1338718-67-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With diisopropylethylamine; In ethanol; at 130℃; for 1h;Microwave irradiation;	Example 78Tert-Butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate A solution of <strong>[42098-25-9]5-chloro-1-methyl-4-nitro-1H-pyrazole</strong> (1.9 g, 11.77 mmol), 4-(boc-aminomethyl)piperidine (3.78 g, 17.66 mmol) and DIPEA (6.15 mL, 35.31 mmol) in EtOH (20 mL) was heated in a microwave at 130 C. for 1 hr. The solvent was removed under reduced pressure and the residue re-dissolved in DCM. The organic layer was washed with water, passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane) to yield tert-butyl (1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate as a yellow solid (3.95 g, 98%). To a solution of this solid (3.84 g, 11.30 mmol) in MeOH (125 mL) was added 10% Pd/C (0.42 g, 3.96 mmol) and ammonium formate (2.85 g, 45.2 mmol). The mixture was heated at 80 C. for 2.5 hr. The mixture was concentrated under reduced pressure and the residue was re-dissolved in EtOAc and washed with water. The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure to give tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate as a brown oil (3.49 g, 99%). 1H NMR (400 MHz, CDCl3) delta 7.04 (s, 1H), 4.63 (s, 1H), 3.64 (s, 3H), 3.11-3.07 (m, 6H), 2.67 (s, 2H), 1.77 (d, J=12.8 Hz, 2H), 1.45 (s, 9H), 1.39-1.26 (m, 2H). 1H hidden by water peak.
98%	With N-ethyl-N,N-diisopropylamine; In ethanol; dichloromethane; at 130℃; for 1h;Microwave irradiation;	Example 78 tert-Butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate A solution of <strong>[42098-25-9]5-chloro-1-methyl-4-nitro-1H-pyrazole</strong> from Example 1 (1.9 g, 11.77 mmol), 4-(boc-aminomethyl)piperidine (3.78 g, 17.66 mmol) and DIPEA (6.15 mL, 35.31 mmol) in EtOH (20 mL) was heated in a microwave at 130 C. for 1 hr. The solvent was removed under reduced pressure and the residue re-dissolved in DCM. The organic layer was washed with water, passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane) to yield tert-butyl (1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate as a yellow solid (3.95 g, 98%). To a solution of this solid (3.84 g, 11.30 mmol) in MeOH (125 mL) was added 10% Pd/C (0.42 g, 3.96 mmol) and ammonium formate (2.85 g, 45.2 mmol). The mixture was heated at 80 C. for 2.5 hr. The mixture was concentrated under reduced pressure and the residue was re-dissolved in EtOAc and washed with water. The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure to give tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate as a brown oil (3.49 g, 99%). 1H NMR (400 MHz, CDCl3) delta 7.04 (s, 1H), 4.63 (s, 1H), 3.64 (s, 3H), 3.11-3.07 (m, 6H), 2.67 (s, 2H), 1.77 (d, J=12.8 Hz, 2H), 1.45 (s, 9H), 1.39-1.26 (m, 2H). 1H hidden by water peak.

Reference： [1]Patent: US2011/251176,2011,A1 .Location in patent: Page/Page column 121-122
[2]Patent: US2013/79321,2013,A1 .Location in patent: Paragraph 0347; 0348

13
[ 6921-22-8 ]
[ 135632-53-0 ]
[ 1350917-86-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In ethanol; at 110℃; for 0.333333h;Microwave irradiation;	Step A - Synthesis of tert-butyl (1-(2-fluoro-6-nitrophenyl)piperidin-4~ yl)methylcarbamate (lnt-2a) To a solution of <strong>[6921-22-8]2,3-<strong>[6921-22-8]difluoronitrobenzene</strong></strong> (5.0 g, 31 mmol) in EtOH (25 mL) were added ieri-butyl piperidin-4-ylmethylcarbamate (8.1 g, 38 mmol), and A/,/V-diisopropyiethylamine (6.6 mL, 38 mmol). The reaction was irradiated to 110 C for 20 min by microwave. The crude reaction mixture was diluted with EtOAc, washed with 1 N HCI and brine, dried over MgS04 and concentrated to yield nitrobenzene lnt-2a ( 1.2 g, 99%) as yellow crystals. The crude product was used without further purification.

Reference： [1]Patent: WO2011/149874,2011,A2 .Location in patent: Page/Page column 58-59

14
[ 402-65-3 ]
[ 135632-53-0 ]
[ 1354356-04-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;	Example 32N-((l-(2-Fluoroisonicotinoyl)piperidin-4-yl)methyl)-6-(3-fluorophenyl)nicotinamide (93) [0235] Step 1 : To a mixture of tert-butyl piperidin-4-ylmethylcarbamate 93-1 (1.07 g, 5.0 mmol), <strong>[402-65-3]2-fluoroisonicotinic acid</strong> 93-2 (706 mg, 5.0 mmol) and HATU (1.90 g, 5.0 mmol) in DMF (20 mL) was added DIEA (2.5 mL, 15.0 mmol) at room temperature. The mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate (100 mL), washed with H20 and brine, dried over Na2S04, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, and eluted with 5% methanol indichloromethane to give tert-butyl (l-(2-fluoroisonicotinoyl)piperidin-4-yl)methylcarbamate 93-3 as a pale yellow solid. MS m/z 338.1 (M + 1)

Reference： [1]Patent: WO2012/3189,2012,A1 .Location in patent: Page/Page column 107-108

15
[ 6299-85-0 ]
[ 135632-53-0 ]
[ 1403933-24-3 ]

Yield	Reaction Conditions	Operation in experiment
69.4%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 3.33333h;	A 30 mL round-bottomed vial <strong>[6299-85-0]methyl 2,6-dichloropyrimidine-4-carboxylate</strong> (300 mg, 1 equiv.) was partially dissolved in anhydrous THF (5 mL). DIEA (278 muL, 1.1 equiv.) was added at once at 0 C. tert-Butyl(piperidin-4-ylmethyl)carbamate (311 mg, 1 equiv.) dissolved in THF (5 mL) was added at 0 C. in 5 min. The reaction mixture was warmed to RT in 3 h15. LC-MS showed mostly the desired product (2.77 min, M+1=385) and a small amount of the other regioisomer (3.28 min, M+1-isobutene=329). The solvent was evaporated and the residue was purified by biotage (SiO2, 10 g, Hex/EtOAc 9:1 to 1:1) to give the desired isomer (386.8 mg, 69.4%) as a white solid. LC-MS m/z 385 (M+1).

Reference： [1]Patent: US2012/270892,2012,A1 .Location in patent: Page/Page column 90

16
[ 50488-42-1 ]
[ 135632-53-0 ]
[ 1093395-71-1 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate; In methanol; at 120℃; for 0.5h;Microwave reactor;	In a 5-ml microwave vial equipped was placed potassium carbonate (1.38 g), tert-butyl(piperidin- 4-ylmethyl)carbamate (1.07 g), and <strong>[50488-42-1]2-bromo-5-trifluoromethylpyridine</strong> (1.13 g) in methanol. This was heated to 120C for 30 min in a microwave reactor. The mixture was cooled and concentrated in vacuo, and the residue was taken up in ethyl acetate. This was filtered through a plug of silica gel, and the eluent was concentrated in vacuo to provide /ert-butyl({l-[5- (trifluoromethyl)pyridin-2-yl]piperidin-4-yl}methyl)carbamate (1.45 g, 81%). This compound was taken up in 15 ml of dichloromethane and 15 ml of trifluoroacetic acid. The resultant mixture was stirred at room temperature for 2 h, and then concentrated and taken up in dichloromethane (20 ml) and saturated aqueous sodium bicarbonate. The mixture was extracted and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide 1.31 g (87%) of the title compound. Mass spectrum (ESI) 260.1 (M+l).

Reference： [1]Patent: WO2008/156715,2008,A1 .Location in patent: Page/Page column 25

17
[ 455-13-0 ]
[ 135632-53-0 ]
[ 1093395-69-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 90℃; for 15h;	A To a mixture of sodium tert-butoxide, l-iodo-4-(trifluoromethyl)benzene (686 μl) and tert-butyl (piperidin-4-ylmethyl)carbamate (1.00 g) in toluene (10 ml) was added l,l'-binaphthalene-2,2'- diylbis(diphenylphosphine) (286 mg) and tris-dibenzylideneacetone palladium(O) (211 mg). The mixture was heated to 9O0C for 15 h. The mixture was cooled to room temperature, concentrated in vacuo, and diluted with dichloromethane. This solution was filtered through a short plug of silica gel and concentrated. The residue was purified via flash chromatography on a Biotage Horizon, 4OM column, eluting with 10 column volumes of 33% ethyl acetate in hexanes to provide 1.36 g (81%) of the title compound. Mass spectrum (ESI) 303.0 (M+l).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/156715, 2008, A1 Location in patent: Page/Page column 24

18
[ 51-44-5 ]
[ 135632-53-0 ]
[ 1429345-57-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 14h;	Intermediate 11. tert-butyl (1 -(3 ,4-dichlorobenzoyl)piperidin-4-yl)methylcarbamate lorobenzoyl)piperidin-4-yl)methylcarbamate[00184] A mixture of tert-butyl piperidin-4-ylmethylcarbamate (lOOmg, 0.467 mmol), 3,4-dichlorobenzoic acid (98 mg, 0.51 mmol), HOBT (93 mg, 0.61 mmol) and EDC (1 16 mg, 0.607 mmol) in DMF (3 mL) was stirred for 5 min at rt and then N- methylmorpholine (0.205 mL, 1.87 mmol) was added. The reaction was stirred at rt for 14 h. The mixture was diluted with ethyl acetate (20 mL) and washed with 2x 40 mL of brine. The organic portion was dried over sodium sulfate, concentrated and purified by flash chromatography (12 g silica gel), eluting with 0-100% ethyl acetate/hexanes to give Intermediate 1 1 (163 mg, 90%) as a white solid. HPLC/MS (Method D) RT = 1.03 min, [M+l]+ 409. XH NMR (400 MHz, chloroform-D) δ ppm 1.03 - 1.30 (m, 2 H) 1.37 - 1.48 (m, 9 H) 1.63 - 1.88 (m, 3 H) 2.69 - 3.14 (m, 4 H) 3.57 - 3.83 (m, 1 H) 4.54 - 4.74 (m, 2 H) 7.21 (dd, J=8.21, 1.89 Hz, 1 H) 7.44 - 7.49 (m, 2 H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2013/48928, 2013, A1 Location in patent: Paragraph 00184

19
[ 1105193-32-5 ]
[ 135632-53-0 ]
[ 1433958-06-5 ]

Yield	Reaction Conditions	Operation in experiment
63%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;	1 ferf-Butyl ((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)carbamate: A mixture of ferf-butyl (piperidin-4-ylmethyl)carbamate (0.323 g, 1.505 mmol), 3-(6-chloropyridin-3-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole (0.1878 g, 0.752 mmol), and /'-Pr2NEt (0.329 ml_, 1.881 mmol) in DCM (10 ml.) was stirred at rt overnight. The DCM was removed under reduced pressure. 7 ml of anhydrous DMF was added. The mixture was heated at 70 °C for 4 h, cooled, and partitioned between 50% EtOAc in hexanes and water. The organic phase was separated, and the aqueous was further extracted with 50% EtOAc in hexanes twice. The combined organic phases were washed with water and brine, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0% - 40% EtOAc in hexanes) to afford the title compound as a white solid (0.21 g, 63%). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.88 (d, J = 1.96 Hz, 1 H), 8.04 - 8.12 (m, 1 H), 6.72 (d, J = 9.20 Hz, 1 H), 4.60 - 4.74 (br., 1 H), 4.51 (d, J = 13.31 Hz, 2H), 3.09 (t, J = 5.87 Hz, 2H), 2.96 (m, 2H), 1 .85 (d, J = 12.53 Hz, 3H), 1.48 (s, 9H), 1.29 (m, 2H). LCMS: fR = 1.03 min, 96%. MS (ESI): m/z 428 (M+H)+.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2013/66831, 2013, A1 Location in patent: Page/Page column 50

20
[ 1753-50-0 ]
[ 135632-53-0 ]
[ 1433958-07-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 70℃; for 5h;	The mixture of <strong>[1753-50-0]2-chloropyrimidine-5-carbonitrile</strong> (0.90 g, 5.74 mmol), ferf-butyl (piperidin-4- ylmethyl)carbamate (1.818 g, 8.48 mmol), and /'-Pr2NEt (2.506 mL, 14.35 mmol) in anhydrous NMP (10 mL) was heated at 70 C for 5 h, cooled to rt, and partitioned between 50% EtOAc/hexanes and water. The organic phase was separated, and the aqueous was further extracted with 50% EtOAc in hexanes twice. The combined organic phases were washed with water and brine, dried over MgS04, filtered, and concentrated under reduced pressure to afford the title compound as a brown solid (1.32 g, 71 %). 1H NMR (400 MHz, CHLOROFORM-d) delta 8.49 (s, 2H), 4.88 (d, J = 13.31 Hz, 2H), 4.54 - 4.75 (m, 1 H), 3.02 - 3.16 (m, 2H), 2.96 (m, 2H), 1.84 (br., 3H), 1.47 (s, 9H), 1.23 (m, 2H).

Reference： [1]Patent: WO2013/66831,2013,A1 .Location in patent: Page/Page column 55

21
[ 1431411-18-5 ]
[ 135632-53-0 ]
[ 1431411-96-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	In acetonitrile at 80℃; for 18h;
95%	In acetonitrile at 80℃; for 18h;	15 Example 15. Preparation of tert-butyl ((1-(6-carbamoylthieno [3,2-dj pyrimidin-4- yl)piperidin-4-yl)methyl)carbamate (Compound 57): A solution of 4-chlorothieno[3,2-d]pyrimidine-6-carboxamide (14; 0.128 g, 0.6 mmol) andtert-butyl (piperidin-4-ylmethyl)carbamate (0.193 g, 0.9 mmol) in CH3CN was heated at80 °C for 18 h. The reaction mixture was concentrated to dryness, suspended in EtOAc, washed with sat. NaHCO3, water, brine, dried (Na2SO4), and concentrated to dryness. The crude product was purified by flash chromatography (0 to 10% MeOH in CH2C12 gradient) to obtain tert-butyl ((1 -(6-carbamoylthieno [3 ,2-d]pyrimidin-4-yl)piperidin-4-yl)methyl)carbamate (Compound 57; 0.224 g, 95%). MS (ESI) calcd for C18H25N5035:391.17; found: 392 [M+H].

Reference： [1]Disch, Jeremy S.; Evindar, Ghotas; Chiu, Cynthia H.; Blum, Charles A.; Dai, Han; Jin, Lei; Schuman, Eli; Lind, Kenneth E.; Belyanskaya, Svetlana L.; Deng, Jianghe; Coppo, Frank; Aquilani, Leah; Graybill, Todd L.; Cuozzo, John W.; Lavu, Siva; Mao, Cheney; Vlasuk, George P.; Perni, Robert B. [Journal of Medicinal Chemistry, 2013, vol. 56, # 9, p. 3666 - 3679]
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2014/138562, 2014, A1 Location in patent: Page/Page column 70

22
[ 31872-63-6 ]
[ 135632-53-0 ]
tert-butyl N-[[1-(3-bromo-5-nitro-4-pyridyl)-4-piperidyl]methyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.80 g	With triethylamine; In tetrahydrofuran; at 70℃; for 5h;	Reference example 14: tert-butyl N-[[1-(3-bromo-5-nitro-4-pyridyl)-4-piperidyl]methyl]carbamate To a tetrahydrofuran (20 mL) solution of <strong>[31872-63-6]3-bromo-4-chloro-5-nitropyridine</strong> (CASNo.31872-63-6) (1.12 g) was added triethylamine (987 microL) and tert-butyl N-(4-piperidylmethyl)carbamate (CASNo.135632-53-0) (2.63 g), and stirred at 70 degrees C for 5 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, and sequentially washed with water and saturated brine. The organic layer was concentrated after drying. The obtained residue was purified by preparative medium pressure liquid chromatography (Yamazen Corp. YFLC-Wprep-2XY) (Hi-flash SI) (n-hexane : ethyl acetate = 1 : 1) to obtain the title compound (1.80 g) having the following physical property values. Description: pale yellow powder; TLC: Rf 0.50 (n-hexane : ethyl acetate = 1 : 1).

Reference： [1]Patent: EP2871179,2015,A1 .Location in patent: Paragraph 0334

23
[ 334792-52-8 ]
[ 135632-53-0 ]
3-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoic acid [ No CAS ]

Reference： [1]Patent: WO2015/104688,2015,A1

24
[ 334792-52-8 ]
[ 135632-53-0 ]
methyl 3-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.06%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene;	Step 1: Preparation of methyl 3-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-l-yl)-5- fluorobenzoate Using the same reaction conditions as described in step 4 of example 12, methyl 3- bromo-5-fluorobenzoate (lOOmg, 0.429 mmol) was coupled with tert-butyl (piperidin-4- ylmethyl)carbamate (HOmg, 0.515 mmol) using cesium carbonate (209mg, 0.643 mmol), xantphos (14mg, 0.025 mmol) and Pd2(dba)3 (8mg, 0.0085 mmol) in toluene (5mL) to get the crude product. The resultant crude was purified by 60-120 silica gel column chromatography using 2% methanol in DCM as eluent to obtain the title compound (HOmg, 70.06%). LCMS: 94.13%, m/z = 367.5 (M+l)+.

Reference： [1]Patent: WO2015/104688,2015,A1 .Location in patent: Page/Page column 25-26

25
[ 4463-59-6 ]
[ 135632-53-0 ]
C₂₀H₃₂N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; potassium iodide; In acetone; for 48h;Reflux;	General procedure: Commercial Boc-protected amines (0.015 mol) was dissolved in acetone (15 ml). Then K2CO3 (0.045 mol) and catalytic amount of KI were added followed by dropwise addition of (aryloxy)ethylbromide(0.018 mol). The reaction was refluxed for 48 h. Inorganic residues were filtered off and organic mixture was concentrated under reduced pressure. The obtained crude product was purified using silica gel with CH2Cl2/MeOH (9:0.7 v/v) as an eluting system.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5582 - 5591

26
[ 60211-57-6 ]
[ 530-62-1 ]
[ 135632-53-0 ]
3,5-dichlorobenzyl 4-(((tert-butoxycarbonyl)amino)methyl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 2006 - 2017

27
[ 611-35-8 ]
[ 135632-53-0 ]
tert-butyl (1-(quinolin-4-yl)piperidin-4-yl)methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine In ethanol at 100℃; for 16h; Sealed tube;	1 tert-Butyl (1-(quinolin-4-yl)piperidin-4-yl)methylcarbamate: General procedure: In a 25 mL reaction tube, ethyl piperidine-4-carboxylate (157 mg, 1.00 minol) and DIEA (153 mg, 1.18 minol) were added to a solution of 4-bromo-1,8-naphthyridine (190 mg, 0.91 minol) in ethanol (10 mL) at room temperature. The tube was sealed and the reactionminxture was heated to 100 °C and stirred for 16 h. After cooling to room temperature, the reactionminxture was diluted with water (20 mL) and the resultingminxture was extracted with DCM (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 1-(1,8-naphthyridin-4-yl)piperidine-4-carboxylate as yellow solid (211 mg, 8 1%). tert-butyl (1-(quinolin-4-yl)piperidin-4-yl)methylcarbamate was prepared from 4-chloroquinoline and tertbutyl piperidin-4-ylmethylcarbamate using Method H. The crude product was purified by flash chromatography eluting with MeOH in DCM (0% to 15% gradient) to yield tert-butyl N-[[1- (quinolin-4-yl)piperidin-4-yljmethyljcarbamate as light yellow solid (600 mg, 94%). MS: m/z = 342.1 [M+Hj.

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2017/106607, 2017, A1 Location in patent: Paragraph 00234; 00235; 00275

28
[ 10438-96-7 ]
[ 135632-53-0 ]
tert-butyl ((1-(N-methylsulfamoyl)piperidin-4-yl)methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With triethylamine In dichloromethane at 20℃; for 16h; Inert atmosphere;	20.1 Preparation 20 4-(aminomethyl)-N-methylpiperidine-1-sulfonamide (AM18) Step 1 [00252] Step 1 [00253] To a mixture of tert-butyl (piperidin-4-ylmethyl)carbamate (30 mg, 0.141 mmol) in CH2C12 (1 mL) was added methylsulfamoyl chloride (21 mg, 0.155 mmol) and Et3N (43 mg, 0.423 mmol). The mixture was stirred at rt for 16 h under N2. TLC (petroleum ether / EtOAc = 1/2) showed that a new major spot was observed. The mixture was diluted with CH2C12 (20 mL) and washed with brine (20 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC with petroleum ether/EtOAc = 1/2 to afford tert-butyl ((l-(N-methylsulfamoyl)piperidin-4- yl)methyl)carbamate (35 mg, 81%) as a yellow oil. 1H NMR (CDC13 400 MHz): δ 4.66-4.55 (m, 1H), 4.00-3.92 (m, 1H), 3.96 (d, J = 4.8 Hz, 2H), 3.03 (t, = 6.4 Hz, 2H), 2.80-2.69 (m, 5H), 1.76 (d, = 13.2 Hz, 2H), 1.62-1.55 (m, 1H), 1.43 (s, 9H), 1.33-1.20 (m, 2H).

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2017/132432, 2017, A1 Location in patent: Paragraph 00252-00253

29
[ 56146-83-9 ]
[ 135632-53-0 ]
methyl 2-((4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)sulfonyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With triethylamine; In dichloromethane; at 20℃; for 16h;	[00256] Step 1 [00257] To a mixture of tert-butyl (piperidin-4-ylmethyl)carbamate (100 mg, 0.469 mmol) in CH2C12 (2 mL) was added methyl 2- (chlorosulfonyl) acetate (89 mg, 0.516 mmol) and Et3N (95 mg, 0.938 mmol). The mixture was stirred at rt for 16 h. TLC (petroleum ether / EtOAc = 1/1) showed that the desired spot was observed and TLC (CH2Cl2/MeOH = 10/1) showed that the starting material was consumed completely. The mixture was quenched with H20 (20 mL) and extracted with CH2C12 (3 X 20 mL). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC with petroleum ether / EtOAc = 1/1 to afford methyl 2-((4-(((tert- butoxycarbonyl)amino)methyl)piperidin-l-yl)sulfonyl)acetate (100 mg, 61%) as a white solid. 1H NMR (CDC13 400 MHz): delta 4.70-4.59 (m, 1H), 3.93 (s, 2H), 3.85 (d, J = 12.4 Hz, 2H), 3.80 (s, 3H), 3.04 (t, 7 = 6.0 Hz, 2H), 2.86 (dt, J = 2.0, 12.0 Hz, 2H), 1.78 (d, / = 10.4 Hz, 2H), 1.70- 1.53 (m, 1H), 1.44 (s, 9H), 1.38-1.24 (m, 2H).

Reference： [1]Patent: WO2017/132432,2017,A1 .Location in patent: Paragraph 00256-00257

30
[ 42288-26-6 ]
[ 135632-53-0 ]
tert-butyl N-[[1-[2-(4-cyanoanilino)acetyl]-4-piperidyl]methyl]carbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 7984 - 7999

31
[ 52140-59-7 ]
[ 135632-53-0 ]
tert-butyl (1-(2’-oxospiro[cyclohexane-1,3'’-indoline]-4-yl)piperidin-4-yl)methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 4H-spiro[cyclohexane-1,3'-indole]-2’,4(1‘H)-dione; tert-butyl N-(4-piperidinylmethyl)carbamate With triethylamine; zinc(II) chloride In methanol at 50℃; for 1h; Stage #2: With sodium cyanoborohydride In methanol at 0 - 50℃; for 7h;	14 Typical Procedure for the Preparation of Piperidines, Exemplified by the Preparation of intermediate 103, 4-[4-(aminomethyl)piperidin- 1 -yl] spiro[cyclohexane- 1 ,3’-indol] -2(1 ‘H)-onedi-trifluoroacetic acid salt, Mixture of Two Isomers A solution of spiro[cyclohexane-1,3'’-indoline]-2’, 4-dione (200 mg, 0.9 mmol), tert-butyl piperidin-4-ylmeth- ylcarbamate (218 mg, 1.0 mmol), ZnC12 (37 mg, 0.3 mmol) and Et3N (470 mg, 4.6 mmol) in MeOR (10 mE) was stirred at 50° C. for 1 h. The mixture was cooled to 0° C. before portionwise addition of NaI3H3CN (243 mg, 3.9 mmol) and thrther stirring at 50° C. for 7 h. The reaction mixture was concentrated in vacuo, the residue partitioned between H20 (80 mE) and EtOAc (50 mE), the aqueous layer extracted with EtOAc (2x50 mE), combined organics dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal silica, mesh size:60-120, 0% to 2% MeOR in DCM) to give tert-butyl (1 -(2’-oxospiro[cyclohexane- 1 ,3’-indoline] -4-yl)piperidin- 4-yl)methylcarbamate (300 mg, 78%) as a yellow gum as a mixture of isomers.

Reference： [1]Current Patent Assignee: SOSEI GROUP CORPORATION - US2018/105491, 2018, A1 Location in patent: Paragraph 0722; 0723; 0724; 0725

32
[ 52147-97-4 ]
[ 135632-53-0 ]
tert-butyl N-({1-[(E)-2-phenylethenesulfonyl]piperidin-4-yl}methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2.5h;	To a solution of (E)-2-phenylethene-1-sulfonyl chloride (104 mg, 0.51 minol) in DCM (5 ml) was added N,N-diisopropylethylamine (0.39 ml, 2.33 minol) followed by tert5 butyl N-(piperidin-4-ylmethyl)carbamate (100 mg, 0.47 minol). The reaction was stirred at r.t.for 2.5 h. The reaction mixture was washed with saturated sodium bicarbonate (2 mL). The organic layer was dried over anhydrous Mg504, filtered and solvent removed in-vacuo. The crude product was purified by silica flash column chromatography (0-50% EtOAc : heptane) to give the title compound as white solid. yleld: 175 mg (99%)LC/MS tR 1.38 min; MS (ESj m/z 403 [M+H] (D)

Reference： [1]Patent: WO2018/172251,2018,A1 .Location in patent: Paragraph 00113; 00114; 00115

33
[ 6304-16-1 ]
[ 7677-24-9 ]
[ 135632-53-0 ]
C₂₀H₃₀N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of compound 24 in 10 mL of DCM was added compound 1A (400 mg, 1.9 mmol, 1.0 eq) followed by Ti(Oi-Pr)4 (532 mg, 1.9 mmol, 1.0 eq) at 15C and the reaction was stirred for 16 hours at 15C. After stirring, TMSCN (278 mg, 2.8 mmol, 1.5 eq) was added dropwise at 15C and the reaction was stirred for 1 hour at thistemperature. The reaction was warmed to 40C and stirred continuously for another 16 hours at40C. The reaction was monitored by TLC and allowed to run until complete. The reaction was concentrated under vacuum, then d 20 mL of ethyl acetate and 0.53 mL of brine were added, and the mixture filtered. The filtrate was washed twice with 30 mL of saturated aqueous Na2CO3, dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give 600 mg of crudecompound 25 as a yellow oil.

Reference： [1]Patent: WO2018/195075,2018,A1 .Location in patent: Page/Page column 55; 71

34
[ 1675-46-3 ]
[ 135632-53-0 ]
tert-butyl ((1-(3-(2-(trifluoromethyl)-10H-phenothiazin-10-yl)propyl)piperidin-4-yl)methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95.9%	With potassium carbonate; sodium iodide In butanone at 80℃; for 48h;	35.1 Step 1 Nal (225 mg, 1.5 mmol) and K2C03 (414 mg, 3 mmol) were added to 1-1 [l0-(3- chloropropyl)-2-(trifluoromcthyl)- 10//-phcnothiazinc \| (515 mg, 1.5 mmol) and tert-butyl piperidin-4-ylmethylcarbamate (479 mg, 2.25 mmol) in 2-butanone (8 mL). The mixture was heated to 80 °C for 48 h. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc = 50%-l00%) to get a yellow solid (750 mg, 95.9%). LC-MS: R, = 1.88 min; ESI m/z 522 [M+l]+.

Reference： [1]Current Patent Assignee: CAMP4 THERAPEUTICS CORPORATION INC - WO2019/195789, 2019, A1 Location in patent: Paragraph 00463-00464

35
[ 287714-35-6 ]
[ 135632-53-0 ]
2-[4-(tert-butoxycarbonylaminomethyl)piperidin-1-yl]pyrimidine-5-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1650 mg	With Pd2C17H14O6C3H6O; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 70℃; for 0.5h;Inert atmosphere;	Tert-butyl (piperidin-4-ylmethyl)carbamate (1400 mg, 6.5 mmol, 1.0 equiv) and <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (1180 mg. 6.8 mmol, 1.05 equiv) in dioxane (28.0 mL, 0.23 M) were treated with cesium carbonate (5.27 g, 16.2 mmol, 2.5 equiv) and Pd(dba)2acetone (440 mg, 0.48 mmol, 0.075 equiv) was added. The solution was purged with nitrogen (3x). Xantphos (558 mg, 0.96 mmol, 0.15 equiv) was then added in one portion.The suspension turned from dark red to yellow green within a few minutes. It was then heated at 70 C for 30 min, at which time LC/MS analysis showed the presence of the desired product. The mixture was cooled to room temperature and filtered through a pad of Celite, washing with dichlorom ethane (20 mL, 3x). The solvent was concentrated to dryness and the residue subjected to normal phase purification eluting with hexane : ethyl acetate (40 - 100%). The product fractions were collected, combined, and concentrated to give 2-[4-(tert- butoxycarbonylamino-methyl)-piperidin-l-yl]-pyrimidine-carboxylic acid methyl ester as an off-white solid. (1650 mg). LC/MS: RT = 3.23 min; m/z = 351.6 [M+H]+.

Reference： [1]Patent: WO2020/14409,2020,A1 .Location in patent: Paragraph 0287; 0288

36
[ 33216-52-3 ]
[ 135632-53-0 ]
[ 1221567-88-9 ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 1717 - 1735

37
[ 444287-84-7 ]
[ 135632-53-0 ]
tert‐butyl ((1‐(2‐((2‐(2,6‐dioxopiperidin‐3‐yl)‐1,3‐dioxoisoindolin‐4‐yl)amino)‐2‐oxoethyl) piperidin‐4‐yl)methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate; sodium iodide In tetrahydrofuran at 20℃;

Reference： [1]Konstantinidou, Markella; Oun, Asmaa; Pathak, Pragya; Zhang, Bidong; Wang, Zefeng; ter Brake, Frans; Dolga, Amalia M.; Kortholt, Arjan; Dömling, Alexander [ChemMedChem, 2021, vol. 16, # 6, p. 959 - 965]

38
[ 41270-66-0 ]
[ 135632-53-0 ]
[ 2760612-78-8 ]

Yield	Reaction Conditions	Operation in experiment
74 %	With potassium carbonate In acetonitrile at 80℃;	24.1 (1) Weigh 10g of compound c prepared in Example 1, 9.66g of 4-Boc-aminomethylpiperidine, and 7.78g of K2CO3 in a 250mL eggplant-shaped bottle, add 100mL of acetonitrile to dissolve, heat at reflux at 80°C for 12 hours, TLC Detect the reaction process; after the reaction is completed, use column chromatography purification method (cyclohexane/ethyl acetate 3/1) to purify compound k-3 (((1-(5,6-diphenylpyrazine-2 -yl)piperidin-4-yl)methyl)tert-butyl carbamate, Tert-butyl ((1-(5,6-diphenylpyrazin-2-yl)piperidin-4-yl)methyl)carbamate). Yield 74%, white solid.
74 %	With potassium carbonate In acetonitrile at 80℃;	24.1 (1) Weigh 10g of compound c prepared in Example 1, 9.66g of 4-Boc-aminomethylpiperidine, and 7.78g of K2CO3 in a 250mL eggplant-shaped bottle, add 100mL of acetonitrile to dissolve, heat at reflux at 80°C for 12 hours, TLC Detect the reaction process; after the reaction is completed, use column chromatography purification method (cyclohexane/ethyl acetate 3/1) to purify compound k-3 (((1-(5,6-diphenylpyrazine-2 -yl)piperidin-4-yl)methyl)tert-butyl carbamate, Tert-butyl ((1-(5,6-diphenylpyrazin-2-yl)piperidin-4-yl)methyl)carbamate). Yield 74%, white solid.
74 %	With potassium carbonate In acetonitrile Heating;

Reference： [1]Current Patent Assignee: ZHENGZHOU UNIVERSITY - CN113968824, 2022, A Location in patent: Paragraph 0242-0247
[2]Current Patent Assignee: ZHENGZHOU UNIVERSITY - CN113968824, 2022, A Location in patent: Paragraph 0242-0247
[3]Zhang, Kun; Hu, Kaizhao; Li, Qian; Li, Min; Gao, Ke; Yang, Kecheng; Zhao, Bing; Shi, Xiao-Jing; Zhang, Lirong; Liu, Hong-Min [Journal of Medicinal Chemistry, 2023, vol. 66, # 11, p. 7221 - 7242]

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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

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

[ CAS No. 135632-53-0 ] {[proInfo.proName]}

Quality Control of [ 135632-53-0 ]

Related Doc. of [ 135632-53-0 ]

Product Details of [ 135632-53-0 ]

Calculated chemistry of [ 135632-53-0 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 135632-53-0 ]

Application In Synthesis of [ 135632-53-0 ]

[ 135632-53-0 ] Synthesis Path-Upstream 1~7

[ 135632-53-0 ] Synthesis Path-Downstream 1~38

Related Functional Groups of [ 135632-53-0 ]

Amides

Amines

Related Parent Nucleus of [ 135632-53-0 ]

Aliphatic Heterocycles

Piperidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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[ 135632-53-0 ]

Related Parent Nucleus of
[ 135632-53-0 ]