[ CAS No. 108612-54-0 ] {[proInfo.proName]}

Name: 108612-54-0|tert-Butyl methyl(piperidin-4-yl)carbamate|97%
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SKU: A191686
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Quality Control of [ 108612-54-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 108612-54-0 ]

Product Details of [ 108612-54-0 ]

CAS No. :	108612-54-0	MDL No. :	MFCD02683051
Formula :	C₁₁H₂₂N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DJJOYDXRUBOZON-UHFFFAOYSA-N
M.W :	214.30	Pubchem ID :	2756806
Synonyms :

Calculated chemistry of [ 108612-54-0 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.91
Num. rotatable bonds :	4
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	64.2
TPSA :	41.57 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) :	2.77
Log Po/w (XLOGP3) :	1.24
Log Po/w (WLOGP) :	1.22
Log Po/w (MLOGP) :	1.15
Log Po/w (SILICOS-IT) :	0.76
Consensus Log Po/w :	1.43

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.69
Solubility :	4.42 mg/ml ; 0.0206 mol/l
Class :	Very soluble
Log S (Ali) :	-1.71
Solubility :	4.17 mg/ml ; 0.0195 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.72
Solubility :	4.08 mg/ml ; 0.0191 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.2

Safety of [ 108612-54-0 ]

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

Application In Synthesis of [ 108612-54-0 ]

* 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 [ 108612-54-0 ]
Downstream synthetic route of [ 108612-54-0 ]

[ 108612-54-0 ] Synthesis Path-Upstream 1~6

1
[ 139062-92-3 ]
[ 108612-54-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 72 h;	10 percent (m/m) moisture Pd/C (1.1 g) was added in a 250 mL flask. The flask was sealed and was evacuated and backfilled with nitrogen for three times. A methanol solution of 1-benzyl-4-(N-Boc-N-methyl)aminopiperidine (10.7 g, 35.2 mmol) was added to the flask. The flask was evacuated and backfilled with hydrogen for three times. The reaction mixture was stirred at room temperature for three days. The reaction progress was monitored by TLC. After finished, the reaction was evacuated and backfilled with nitrogen for three times again. The reaction resulting was filtered and concentrated in vacuo to afford 6.8 g desired product in white solid (90 percent).

Reference： [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 24, p. 4981 - 5001
[2] Tetrahedron Letters, 2017, vol. 58, # 20, p. 1976 - 1979
[3] Patent: US2012/71461, 2012, A1, . Location in patent: Page/Page column 144

2
[ 405057-76-3 ]
[ 108612-54-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	With hydrogen In methanol at 20℃; for 2 h;	To a solution of 1-(benzyloxycarbonyl)-4-(N-methyl-ferf- butyloxycarbonylamino)piperidine (0.35 g, 1 mmol) in anhydrous MeOH (20 ml_) was added Pd(OH)₂ (14.1 1 mg, 0.1 mmol), and the resulting mixture was stirred at room temperature for 2 h under H₂. After TLC showed the stating material was consumed, the solvent was filtered through silica gel, and the filtrate solvent was removed in vacuo to give crude 4-(N-methyl-ferf-butyloxycarbonylamino)piperidine (0.2 g, 60percent), which was used in the next step without further purification: ¹H NMR (400 MHz, CDCI₃) δ ppm 3.08 (d, J = 12.4 Hz, 2H), 2.67 (s, 3H), 2.65 (t, J = 14.2 Hz, 2H), 1.82 (s, 2H), 1.50-1.57 (m, 3H), 1.39 (s, 9H).

Reference： [1] Patent: WO2009/76387, 2009, A1, . Location in patent: Page/Page column 41
[2] Patent: WO2005/30209, 2005, A1, . Location in patent: Page/Page column 59

3
[ 7006-50-0 ]
[ 108612-54-0 ]

Reference： [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 24, p. 4981 - 5001
[2] Patent: US2012/71461, 2012, A1,
[3] Tetrahedron Letters, 2017, vol. 58, # 20, p. 1976 - 1979

4
[ 50541-93-0 ]
[ 108612-54-0 ]

Reference： [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 24, p. 4981 - 5001

5
[ 73889-19-7 ]
[ 108612-54-0 ]

Reference： [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 24, p. 4981 - 5001

6
[ 3612-20-2 ]
[ 108612-54-0 ]

Reference： [1] Patent: US2012/71461, 2012, A1,
[2] Tetrahedron Letters, 2017, vol. 58, # 20, p. 1976 - 1979

[ 108612-54-0 ] Synthesis Path-Downstream 1~86

1
[ 139062-92-3 ]
[ 108612-54-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 72h;	10 % (m/m) moisture Pd/C (1.1 g) was added in a 250 mL flask. The flask was sealed and was evacuated and backfilled with nitrogen for three times. A methanol solution of 1-benzyl-4-(N-Boc-N-methyl)aminopiperidine (10.7 g, 35.2 mmol) was added to the flask. The flask was evacuated and backfilled with hydrogen for three times. The reaction mixture was stirred at room temperature for three days. The reaction progress was monitored by TLC. After finished, the reaction was evacuated and backfilled with nitrogen for three times again. The reaction resulting was filtered and concentrated in vacuo to afford 6.8 g desired product in white solid (90 %).
	With hydrogen;palladium on activated charcoal; In methanol; for 4h;	Stage 3: tert-Butyl methyl(piperidin-4-yl)carbamate tert-Butyl 1-benzylpiperidin-4-yl(methyl)carbamate (1.0 g, 3.289 mmol, 1.0 eq.) was dissolved in MeOH (15 ml) and degassed with argon. Pd/C (300 mg) was then added and hydrogenation was carried out for 4 hours. After monitoring by TLC, the reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure. The crude product was used in the next stage without being purified further. Yield: 85% (600 mg, 2.803 mmol)

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4981 - 5001
[2]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979
[3]Patent: US2012/71461,2012,A1 .Location in patent: Page/Page column 144

2
[ 949557-71-5 ]
[ 108612-54-0 ]
[ 949559-34-6 ]

Yield	Reaction Conditions	Operation in experiment
87.8%	With potassium carbonate; L-proline;copper(l) iodide; In dimethyl sulfoxide; at 100℃;	Step A: Preparation of tert-butyl 1-(4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidin-4-yl(methyl)carbamate: A round-bottomed flask was charged with N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (100 mg, 0.142 mmol, prepared in Example 63, step A), <strong>[108612-54-0]tert-butyl methyl(piperidin-4-yl)carbamate</strong> (152 mg, 0.708 mmol), copper(I)iodide (5.39 mg, 0.0283 mmol), (S)-pyrrolidine-2-carboxylic acid (6.52 mg, 0.0566 mmol), K2CO3 (97.8 mg, 0.708 mmol) and DMSO (10 mL). The reaction mixture was stirred at 100 C. overnight. The reaction was cooled to ambient temperature and partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (98.5 mg, 87.8%). LRMS (APCI pos): m/e 693 (M-99).

Reference： [1]Patent: US2007/238726,2007,A1 .Location in patent: Page/Page column 119

3
[ 885698-98-6 ]
[ 108612-54-0 ]
[ 955979-04-1 ]

Yield	Reaction Conditions	Operation in experiment
62%	With caesium carbonate; In water; N,N-dimethyl-formamide; at 20℃; for 18h;	Reference Example 50; <n="90"/>[l-(2-ChIoro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yImethyl)-piperidin-4- yl]-methyl-carbamic acid tert-butyl ester; To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-tMeno[352- djpyrimidine (85 mg, 0.244 mmol) in DMF (2 mL) were added water (13 muL), methyl-piperidin-4-yl-carbamic acid tert-butyl ester (105 mg, 0.489 mmol) and cesium carbonate (159 mg, 0.489 mmol). The resulting mixture was stirred at RT for 18 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH. The resultant residue was purified by column chromatography to give the title compound as a pale brown solid (73 mg, 62 %).[M + H]+ 482.2

Reference： [1]Patent: WO2007/122410,2007,A1 .Location in patent: Page/Page column 88-89

4
2,6-dichloro-4-(difluoromethyl)pyridine-3-carbonitrile [ No CAS ]
[ 108612-54-0 ]
[ 960293-94-1 ]
C₁₈H₂₃ClF₂N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With triethylamine; In ethanol; at 20℃;Cooling with acetone-dry ice;	A solution of the above nicotinonitrile (2.4 g, 10.8 mmol) in ethanol (40 mL) was cooled in a dry ice/acetone bath. Triethylamine (1.5 mL, 11.0 mmol) and N-methyl, N-boc-4-aminopiperidine were added and the reaction mixture was allowed to warm gradually to room temperature overnight. The reaction was concentrated, taken up in ethyl acetate (200 mL) and washed with 1 N HCl (2*100 mL). The organic phase was dried (magnesium sulfate) and concentrated to provide a 4 to 1 mixture of addition products to the 6 and 2 position, respectively. These regioisomers were separated by silica gel chromatography using a gradient of ethyl acetate in hexanes as the mobile phase to provide 1.3 g (30%) of (6'-chloro-5'-cyano-4'-difluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-methyl-carbamic acid tert-butyl ester as a white solid.

Reference： [1]Patent: US2007/293533,2007,A1 .Location in patent: Page/Page column 13-14; 14

5
[ 108-23-6 ]
[ 108612-54-0 ]
[ 1001399-21-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine; In dichloromethane; toluene; at 20℃; for 17h;	Step 1 : 1 -Methylethyl 4-[[(1 ,1 -dimethylethyl)oxy]carbonyl}(methyl)amino]-1- piperidinecarboxylate (192)To a stirred solution of 1 ,1-dimethylethyl methyl(4-piperidinyl)carbamate (500 mg, 2.33 mmol) and Et3N (0.65 ml_, 4.66 mmol) in CH2CI2 (23 ml.) was added isopropylchloroformate (1.0 M in toluene, 2.6 ml_, 2.57 mmol) dropwise via an addition funnel at RT. The reaction mixture was stirred at RT for 17 hours, then washed with water (1 x 15 ml_), dried over MgSO4, filtered, and concentrated under reduced pressure to give 608 mg (87%) of the title product 192 as a colorless oil. 1H NMR (400 MHz, CDCI3): delta 4.88 (septuplet, J = 6.4 Hz, 1 H), 4.28 - 4.16 (m, 3 H), 2.77 - 2.71 (m, 2 H), 2.68 (s, 3 H), 1.62 - 1.57 (m, 2 H), 1.55 - 1.50 (m, 2 H), 1.44 (s, 9 H), 1.21 (d, J = 6.4 Hz, 6 H).

Reference： [1]Patent: WO2008/8895,2008,A1 .Location in patent: Page/Page column 162
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 10972 - 10994

6
[ 7006-50-0 ]
[ 108612-54-0 ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4981 - 5001
[2]Patent: US2012/71461,2012,A1
[3]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

7
[ 73889-19-7 ]
[ 108612-54-0 ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4981 - 5001

8
[ 841202-20-8 ]
[ 108612-54-0 ]
(1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl)-methyl-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%		EXAMPLE 255; N-1- [4- (BENZOTHIAZOL-2-YLOXY)-BENZYL]-PIPERIDIN-4-YL}-N-METHYL- methanesulfonamide; A. {1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-methyl-carbamic acid ter-butyl ester; A mixture of 4-(benzothiazol-2-yloxy)-benzaldehyde (4.4 g, 17.2 MMOL), METHYL-PIPERIDIN-4-YL-CARBAMIC acid tert-butyl ester (4.06 g, 18. 9 MMOL) in CICH2CH2CI (172 mL) was stirred at room temperature for 40 min. To the resulting reaction mixture was added NaBH (OAC) 3 portion wise over 1.5 h (4 x 1.82 g, 34.4 MMOL). The resulting mixture was stirred at room temperature for 24 h, filtered through diatomaceous earth and rinsed with CH2Cl2 (300 mL). The filtrate was washed with sat. aq. NAHCO3 (1 x 50 mL), dried (NA2SO4) and concentrated under reduced pressure to yield the crude product as a pale yellow oil. The crude product was purified on SI02 (330 g; 0-100% ethyl acetate/hexanes) to give a light yellow foam (3.75 g, 48% yield). MS (ESI) : mass calculated for C25H31N303S, 453.2 ; m/z found, 454.5 [M+H]+. 1H NMR (400 MHz, CDC13) : 7.73 (d, J = 8.1, 1 H), 7.66 (d, J = 8.1, 1 H), 7.41-7. 35 (m, 3H), 7.33-7. 23 (m, 3H), 4.13-3. 94 (m, 1H), 3.53 (s, 2H), 2.93 (d, J= 11.6, 2H), 2.74 (s, 3H), 2.08 (t, J = 11.6, 2H), 1.81-1. 69 (m, 2H), 1.65-1. 57 (m, 2H), 1.46 (s, 9H)

Reference： [1]Patent: WO2005/12296,2005,A1 .Location in patent: Page/Page column 170

9
[ 849226-51-3 ]
[ 108612-54-0 ]
[ 849226-54-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate;sodium iodide; In tetrahydrofuran; at 50℃; for 336h;	A suspension of METHYL-PIPERIDIN-4-YL-CARBAMIC acid tert-butyl ester (3.57 g, 16.7 MMOL), NAHCO3 (6.7 g, 79 MMOL), Nal (1.5 g, 10 MMOL) and 1- (2-chloro-ethyl)-3- (2, 6-DIMETHYL-PYRIDIN-4-YL)-UREA (Example D1, 2.14 g 9.4 MMOL) in THF (30 mL) is stirred at 50C for 14 days. The mixture is quenched with NA2CO3 (50 mL) and extracted with CH2CI2 (5 X 50 mL). The organic extracts are washed with sat. aq. NA2CO3 (30 mL), dried (NA2SO4), filtered and evaporated. The residue is purified by FC to provide the title compound.

Reference： [1]Patent: WO2005/30209,2005,A1 .Location in patent: Page/Page column 59

10
[ 405057-76-3 ]
[ 108612-54-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	With hydrogen;palladium hydroxide on carbon; In methanol; at 20℃; for 2h;	To a solution of 1-(benzyloxycarbonyl)-4-(N-methyl-ferf- butyloxycarbonylamino)piperidine (0.35 g, 1 mmol) in anhydrous MeOH (20 ml_) was added Pd(OH)2 (14.1 1 mg, 0.1 mmol), and the resulting mixture was stirred at room temperature for 2 h under H2. After TLC showed the stating material was consumed, the solvent was filtered through silica gel, and the filtrate solvent was removed in vacuo to give crude 4-(N-methyl-ferf-butyloxycarbonylamino)piperidine (0.2 g, 60%), which was used in the next step without further purification: 1H NMR (400 MHz, CDCI3) delta ppm 3.08 (d, J = 12.4 Hz, 2H), 2.67 (s, 3H), 2.65 (t, J = 14.2 Hz, 2H), 1.82 (s, 2H), 1.50-1.57 (m, 3H), 1.39 (s, 9H).
	With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; for 15h;	A mixture of 4- (TERT-BUTOXYCARBONYL-METHYL-AMINO)-PIPERIDINE-1-CARBOXYLIC acid benzyl ester (17.5 MMOL) and Pd-C (10%, 500 mg) in MeOH (150 mL) hydrogenated at atm. pressure and r. t. for 15 h. The mixture is filtered and evaporated. The residue is dissolved in CL 12CI2 (100 mL) and 1 M aq. NaOH (50 mL) is added. The mixture is stirred for 6 h at r. t. , then the phases are separated and the aq. phase is extracted with CH2CI2 (3 x 50 mL). The combined organic extracts are dried (NA2SO4), filtered and evaporated to provide the title compound.

Reference： [1]Patent: WO2009/76387,2009,A1 .Location in patent: Page/Page column 41
[2]Patent: WO2005/30209,2005,A1 .Location in patent: Page/Page column 59

11
3-[(benzyloxycarbonylcyclohexylmethyl)-(4-methoxybenzenesulfonyl)-amino]propionic acid [ No CAS ]
(benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluoroborate [ No CAS ]
[ 108612-54-0 ]
{(3-[4-(tert-butoxycarbonylmethylamino)piperidin-1-yl]-3-oxopropyl}-(4-methoxybenzenesulfonyl)-amino]cyclohexylacetic acid benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine; In hexane; dichloromethane;	(E) To a solution of 3-[(benzyloxycarbonylcyclohexylmethyl)(4-methoxybenzenesulfonyl)-amino]propionic acid (1.57 grams, 3.21 mmol) in methylene chloride (45 mL) were added sequentially triethylamine (1.12 mL, 8.04 mmol), methylpiperidin-4-ylcarbamic acid tert-butyl ester (0.89 grams, 4.15 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluoroborate (1.56 grams, 3.53 mmol). The result mixture was stirred for 16 hours at room temperature and then diluted with methylene chloride. The solution was washed successively with 0.5M hydrochloric acid solution, saturated sodium bicarbonate solution and brine. The solution was dried over magnesium sulfate and concentrated to yield an oil which was chromatographed on silica gel eluding with 50% ethyl acetate in hexane to afford [{(3-[4-(tert-butoxycarbonylmethylamino)piperidin-1-yl]-3-oxopropyl}-(4-methoxybenzenesulfonyl) amino]cyclohexylacetic acid benzyl ester as an oil (1.89 grams, 86%).

Reference： [1]Patent: US6153609,2000,A

12
[ 911693-45-3 ]
[ 108612-54-0 ]
[ 911693-60-2 ]

Yield	Reaction Conditions	Operation in experiment
25%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃;	Example 33; 3-{8-r2,6-difluorophenyl)-2-[4-(methylaminoVl-piperidmyl]-7-oxo-5,6,7.8- tetrahydropyrimido[4,5-(i]pyrimidin-4-yl)-7s/-f4-fluoropheriyl')-4-methylbenzamide; 33a) U-dimethylethyl {l-r8-(2,6-difluorophenylV4-r5-([r4- fluorophenypamino] carbon yl ) -2-methylphenyl )-7 -oxo-5 ,6 J , 8 - tetrahydrop yrimidof4, 5-c?pyrimidin-2- yll -4-piperidinyl I methyl carb amate; To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfmyl)-7-oxo-5,6,7,8- tetrahydropyrimido[4,5-<f]pyrimidin-4-yl]-iV-(4-fluorophenyl)-4-methylbenzamide (40 mg, 0.073 mmol) in THF (3 mL) and DMF (0.5 mL) were added 1,1- dimethylethyl methyl(4-piperidinyl)carbamate (49 mg, 0.229 mmol) and N,N- diisopropylethylamine (0.1 mL, 0.574 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. Flash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (12mg, 25 %). LC-MS m/z 702 (M + H)+.

Reference： [1]Patent: WO2006/104889,2006,A2 .Location in patent: Page/Page column 154

13
[ 911693-49-7 ]
[ 108612-54-0 ]
1,1-dimethylethyl {1-[8-(2,6-difluorophenyl)-4-(2-methyl-5-[(phenylmethyl)amino]carbonyl}phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]-4-piperidinyl}methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 20℃; for 264h;	Example 147; 1.1-dimethylethyl {l-\|"8-(2,6-difluorophenylV4-(2-methyl-5-[(phenylmethyl)amino]carbonyl}phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-; Compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8- tetrahydropyrimido[4,5-c(]pyrimidin-4-yl]-4-methyl-Lambda?-(phenylmethyl)benzamide (0.0811g, 0.144 mmol) was dissolved in CH2Cl2 (5 mL) and 1,1-dimethylethyl methyl(4-piperidinyl)carbarnate (0.0394 g, 0.18 mmol) and triethylamine (0.029 g, 0.288 mmol) were added. The reaction mixture was stirred for 4 days. Additional 1,1-dimethylethyl methyl(4-piperidinyl)carbamate (0.0788 g, 0.36 mmol) and triethylamine (0.058 g, 0.576 mmol) were added and the mixture was stirred under argon at room temperature for an additional 7 days. The solvents were pumped off in vacuo, and the residue taken up in EtOAc and washed with 1 N NaOH, brine, dried over anhydrous Na2SO4 filtered and evaporated. The residue was flash chromatographed on silica gel (20 g) eluted with 0-70% EtOAc / hexane. Some impurities remained, so the material was rechromatographed on silica gel (20 g) eluted with 0-50% EtOAc / hexane to give the title compound as a white amorphous solid, mp (dec) 146-15O0C. LC-MS m/z 698 (M+H)+, 2.66 min (ret time).
	With triethylamine; In dichloromethane; at 20℃; for 264h;	Compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6, 7,8- tetrahydropyrimido[4,5-(i]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide (0.0811 g, 0.144 mmol) was dissolved in CH2Cl2 (5 mL) and 1,1-dimethylethyl methyl(4- piperidinyl)carbamate (0.0394 g, 0.18 mmol) and triethylamine (0.029 g, 0.288 mmol) were added. The reaction mixture was stirred for 4 days. Additional 1,1-dimethylethyl methyl(4- piperidinyl)carbamate (0.0788 g, 0.36 mmol) and triethylamine (0.058 g, 0.576 mmol) were added and the mixture was stirred under argon at room temperature for an additional 7 days. The solvents were pumped off in vacuo, and the residue taken up in EtOAc and washed with 1 N NaOH, brine, dried over anhydrous Na2SO4 filtered and evaporated. The residue was flash chromatographed on silica gel (20 g) eluted with 0-70% EtOAc / hexane. Some impurities remained, so the material was rechromatographed on silica gel (20 g) eluted with 0-50% EtOAc / hexane to give the title compound as a white amorphous solid, mp (dec) 146- 15O0C. LC-MS m/z 698 (M+H)+, 2.66 min (ret time).

Reference： [1]Patent: WO2006/104889,2006,A2 .Location in patent: Page/Page column 226
[2]Patent: WO2007/147109,2007,A2 .Location in patent: Page/Page column 205

14
[ 916225-31-5 ]
[ 108612-54-0 ]
{1-[4-(2-acetylamino-4-methyl-thiazol-5-yl)-5-bromo-thiophene-2-sulfonyl]-piperidin-4-yl}-methyl-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In dichloromethane; at 20℃; for 0.5h;	4-[2-(acetylamino)-4-methyl-l ,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (300 mg; 0.72 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The reaction mixture is put under nitrogen. Triethylamine (0.5 ml; 3.61 mmol; 5 eq) and methyl-piperidine^-yl-carbamic acid tert-butyl ester (773.2 mg; 3.61 mmol; 5 eq) are added successively and the reaction mixture is stirred for 30 minutes at room temperature. It is then washed with water, NaHCO3 sat., brine and dried over MgSO4, affording the title compound (470 mg; quantitative).M (ESI): 593.5; M+(ESI): 595.3. HPLC (method A), Rt: 4.41 min (purity: 91%).

Reference： [1]Patent: WO2006/125803,2006,A1 .Location in patent: Page/Page column 59

15
[ 33301-41-6 ]
[ 108612-54-0 ]
[ 917610-02-7 ]

Yield	Reaction Conditions	Operation in experiment
63%	With triethylamine; In acetonitrile;Heating / reflux;	(a) tert-Butyl {l-[l-(diphenylmethyl)azetidin-3~yl]piperidin-4-yI}methylcarbamate A mixture of <strong>[108612-54-0]tert-butyl methyl(piperidin-4-yl)carbamate</strong> (0.71g, 3.3 mmol), 1- (diphenylmethyl)-azetidin-3-yl methanesulfonate (see J. Org. Chem.; 56; 1991; 6729; 0.92 EPO <DP n="40"/>g, 2.9 mmol), acetonitrile (40 mL) and triethylamine (0.36 g, 3.6 mmol) was heated to reflux overnight and then the solvent was removed by evaporation. The residue was dissolved in ethyl acetate and the solution was washed with aqueous NaHCO3. The organic solution was separated and the solvent removed by evaporation. The product was chromatographed on silica gel (ethyl acetate). There was obtained 0.79 g (63%) of tert- butyl {l-[l-(diphenylmethyl)azetidin-3-yl]piperidin-4-yl}methylcarbamate as an oil. 1H NMR (500 MHz, CDCl3): 1.4 (s, 9H), 1.5-1.9 (m, 7H), 2.7 (s, 3H), 2.8 (d, 2H), 2.9 (t, 2H), 3.0 (m, IH), 3.4 (t, 2H), 4.4 (s, IH), 7.2 (m, 2H), 7.3 (m, 4H), 7.4 (m, 4H); LCMS: m/z 436 (M+1)+.

Reference： [1]Patent: WO2006/137791,2006,A1 .Location in patent: Page/Page column 38-39

16
[ 724788-71-0 ]
[ 108612-54-0 ]
[ 924278-69-3 ]

Yield	Reaction Conditions	Operation in experiment
66%	In N,N-dimethyl-formamide; at 90℃; for 12h;	1 ,1-DimethylethyI methyl(4-piperidinyl)carbamate (419 mg, 1.96 mmol) and 8- ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine (400 mg, 1.96 mmol) were combined in DMF (0.2 ml_) and stirred at 9O0C over 12 hr. The solution was then concentrated and the residue purified via column chromatography (silica, 0-5% MeOH in DCM) yielding the title compound (540 mg, 66%) as an orange oil: LC/MS (ES) m/e 419 (M+H)+

Reference： [1]Patent: WO2007/16610,2007,A2 .Location in patent: Page/Page column 54

17
[ 394223-09-7 ]
[ 108612-54-0 ]
[ 924278-78-4 ]

Yield	Reaction Conditions	Operation in experiment
91%	In N,N-dimethyl-formamide; at 90℃; for 12h;	A solution of 2-(methyloxy)-8-(2-oxiranyl)-1 ,5-naphthyridine (712 mg, 3.51 mmol) and 1 ,1 -dimethylethyl methyl(4-piperidinyl)carbamate (751 mg, 3.51 mmol) in DMF (1 ml_) were heated to 900C. After 12h, the resulting solution was concentrated and purified via column chromatography (silica, 2% MeOH in DCM (1 % NH4OH) yielding the title compound as an orange oil (1.33 g, 91 %): LC/MS (ES) m/e 417 (M+H)+

Reference： [1]Patent: WO2007/16610,2007,A2 .Location in patent: Page/Page column 66

18
[ 760987-17-5 ]
[ 108612-54-0 ]
[ 930785-33-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	Example 38; Methyl (3-{2-[4-{4-[(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)methyl]benzyl}(methyl)amino piperidin-1-yl]ethoxy}phenyl)acetate; [Show Image] Step (i); Methyl [3-(2-{4-[(tert-butoxycarbonyl)(methyl)ainino]pipendin-1-yl}ethoxy)phenyl] acetate; [Show Image] tert-Butyl methyl(piperidin-4-yl)carbamate (331mg, 1.54mmol) and potassium carbonate (276mg, 2mmol) were suspended in dimethylformamide (6ml) and thereto was added portion wise at room temperature methyl [3-(2-bromoethoxy)phenyl]acetate (382mg, 1.4mmol), followed by stirring at room temperature overnight. After concentration, to the residue was added water-ethyl acetate and the mixture was separated by a separating funnel. The organic layer was washed with water and saturated brine and dried over sodium sulfate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to give the object compound 562mg as a colorless oil. Yield 89%. 1H NMR (CDCl3) delta7.22 (1H, t, J = 7.8 Hz), 6.89-6.75 (3H, m), 4.08 (2H, t, J = 5.8 Hz), 3.69 (3H, s), 3.59 (2H, s), 3.09-23.02 (2H, m), 2.79 (2H, t, J = 5.8 Hz), 2.73 (3H, s), 2.23-2.13 (2H, m), 1.79-1.59 (5H, m), 1.46 (9H, s).

Reference： [1]Patent: EP1939202,2008,A1 .Location in patent: Page/Page column 64

19
[ 455-19-6 ]
[ 108612-54-0 ]
C₁₉H₂₇F₃N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;thiophene; palladium 10% on activated carbon; In methanol; at 20℃;	Description 3; Methyl-[l-(3-trifluoromethyl-benzyl)-piperidin-4-yl]-amine (D3); A mixture of methyl-piperidin-4-yl-carbamic acid tert-butyl ester (26 g, 120 mmol) and 4-(trifluoromethyl)-benzaldehyde (22 g, 120 mmol) in methanol (250 ml) was hydrogenated at room temperature in the presence of palladium 10% on activated carbon (3 g) and a solution 0.005% of thiophene in methanol (3 ml). After uptake of hydrogen was finished, the reaction mixture was filtered off through a celite pad and the filtrate was evaporated in vacuo. The crude product was dissolved in a solution of 5N hydrochloric acid in isopropanol and the reaction mixture was refluxed for 30 minutes. After this period, the reaction mixture was diluted with further solution of 5N hydrochloric acid in isopropanol (50 ml) and refluxed for additional 30 min. The solvent was evaporated in vacuo and the crude product was precipitated from acetone.The solid formed was filtered off, suspended in dichloromethane and extracted with a saturated solution of ammonia. The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo to yield D3 (27.6 g, 85 %) as a solid. Ci4Hi9F3N2 requires 272; Found 273 (MH+).1H NMR (360 MHz, CHLOROFORM-^) delta ppm 1.31 - 1.45 (m, 3 H) 1.83 - 1.91 (m, 2 H) 2.05 (dt, J=I 1.53, 2.20 Hz, 2 H) 2.32 - 2.41 (m, 1 H) 2.43 (s, 3 H) 2.77 - 2.87 (m, 2 H) 3.54 (s, 2 H) 7.38 - 7.45 (m, 1 H) 7.48 - 7.54 (m, 2 H) 7.58 (s, 1 H).

Reference： [1]Patent: WO2008/128994,2008,A1 .Location in patent: Page/Page column 18

20
[ 4487-59-6 ]
[ 108612-54-0 ]
[ 1085841-40-2 ]

Yield	Reaction Conditions	Operation in experiment
85.5%	With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 14h;	A mixture of <strong>[4487-59-6]2-bromo-5-nitro-pyridine</strong> (4.74 g, 23.3 mmol), methyl-piperidin-4-yl- carbamic acid tert-butyl ester (5 g, 23.3 mmol), and triethylamine (5 mL) in N ,N- dimethylformamide (30 mL) was stirred at 90 0C for 14 h. Upon completion of the reaction, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was recrystallized from methanol and water to give methyl (5'-nitro-3,4,5,6-tetrahydro-2H- [l,2']bipyridinyl-4-yl)-carbamic acid tert-butyl ester (6.7 g, 85.5%) as brown crystals. LCMS calcd for C16H24N4O4 (m/e) 336, obsd 337 (M+H).

Reference： [1]Patent: WO2008/141976,2008,A1 .Location in patent: Page/Page column 50

21
[ 917835-63-3 ]
[ 108612-54-0 ]
[ 1095276-21-3 ]

Yield	Reaction Conditions	Operation in experiment
49%		A mixture of (7-Methoxy-2-oxoquinoxalin-l(2H)-yl)acetaldehyde (Intermediate 12, 0.36g, 1.96mmol) and methyl-piperidin-4-yl-carbamic acid tert-butyl ester (0.42g, 1.96mmol) was dissolved in tetrahydrofuran (10 mL). The solution was allowed to stir at room temperature for thirty minutes, after which time sodium triacetoxy borohydride (0.62g , 2.94 mmol) was added. The reaction mixture was stirred at room temperature for one hour, and then quenched with saturated sodium bicarbonate solution. The mixture was extracted with methylene chloride twice, and the combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude oil. Chromatography on silica gel eluting with 25% acetone in hexanes gave 400 mg (49%) of the title compound as a colorless oil. MS (ESP): 417 (MH+) for C22H32N4O41H NMR (CDCl.) delta ppm 1.44 (s. 9H); 1.58 - 1.73 (m, 4H); 2.12 - 2.26 (m, 2H); 2.61 - 2.75 (m, 5H); 3.07 (m, 2H); 3.90 (s, 3H); 4.25 - 4.37 (m, 2H); 6.81 (d, IH); 6.90 (dd, IH); 7.77 (d, IH); 8.10 (s, IH)

Reference： [1]Patent: WO2009/1126,2008,A1 .Location in patent: Page/Page column 92

22
[ 1003944-43-1 ]
[ 108612-54-0 ]
[ 1095276-18-8 ]

Yield	Reaction Conditions	Operation in experiment
57%		2-Oxo-l-(2-oxoethyl)-l,2-dihydroquinoline-7-carbonitrile (Intermediate 4, 4.95 g, 23.33 mmol) was refluxed in THF (50OmL) for 15 minutes, then cooled to room temperature, tert- Butyl rnethyl(piperidin-4-yl)carbamate (5 g, 23.33 mmol) was added and the reaction mixture was stirred for two hours. The reaction mixture was heated to 8O0C bath temperature for 30 minutes, then cooled to room temperature, and sodium triacetoxyborohydride (14.83 g, 69.99 mmol) was added in one portion. The reaction mixture was stirred under nitrogen over night. The solvent was removed under reduced pressure. The residue was taken up in dichloromethane (250 mL) and aqueous sodium hydrogen carbonate solution (saturated, 70 mL, pH adjusted to -10 with 15% NaOH). The aqueous phase was backextracted three times with dichloromethane (3x 100 mL) and the combined organic phases were dried over sodium sulfate. Chromatography was done on silica gel with hexanes/ acetone 2: 1, to give product as a colorless hard foam, 5.5 g (57%). MS (ESP): 411 (MH+) for C23H30N4O31H-NMR (DMSO-dfi) delta: 1.37 (s, 9H); 1.50 (m, 4H); 2.03 (m, 2H); 2.54 (m, 2H); 2.62 (s, 3H); 3.01 (m, 2H); 3.74 (m, IH); 4.35 (t, 2H); 6.78 (d, IH); 7.64 (dd, IH); 7.89 (d, IH); 8.00 (d, IH); 8.11 (brs, IH).

Reference： [1]Patent: WO2009/1126,2008,A1 .Location in patent: Page/Page column 91

23
[ 885618-31-5 ]
[ 108612-54-0 ]
[ 1147422-78-3 ]

Yield	Reaction Conditions	Operation in experiment
88%		To a stirred suspension of 2-chloro-4-mophiholin-4-yl-thieno[3,2-cf\|pyrimidine-6- carbaldehyde (1.0 g; 3.5 mmol), 4-N-Boc-4-iV-methylaminopiperidine (1.0 g; 4.7 mmol) and AcOH (0.2 mL) in 1,2-dichloroethane (25 mL) was added NaB(OAc)3H (1.0 g; 4.7 mmol). The reaction mixture was stirred at RT for 5 h upon which time it was quenched with saturated NaHCO3 solution (30 mL), diluted with H2O (50 mL) and extracted with EtOAc (200 mL). The organic layer was dried (Na2SO4) and concentrated to a yellow foam (1.84 g). This foam was dissolved in CH2Cl2 (20 mL) and treated with TFA (10 mL) at RT overnight (17 h). Volatiles were removed in vacuo, the residue was taken up in 2M HCl (30 mL) and washed with CH2Cl2 (40 mL). The aqueous layer was basified with saturated Na2CO3 solution, extracted into CH2Cl2, the organic layer separated (hydrophobic frit) and solvent evaporated to give the title compound as a pale yellow solid (1.18 g; 88 %). deltaH (400 MHz, CDCl3) 1.18-1.42 (m, 3H), 1.7-1.75 (m, 2H), 1.99-2.05 (m, 2H), 2.20-2.27 (m, <n="112"/>IH), 2.28 (s, 3H), 2.73-2.76 (m, 2H), 3.62 (s, 2H), 3.66-3.69 (m, 4H), 3.81-3.84 (m, 4H), 6.98 (s, IH).

Reference： [1]Patent: WO2009/53715,2009,A1 .Location in patent: Page/Page column 110-111

24
[ 1160938-26-0 ]
[ 108612-54-0 ]
[ 1160938-64-6 ]

Yield	Reaction Conditions	Operation in experiment
18%	With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 18h;	4-[(5-chloro-2-pyridinyl)methyl]oxy}-6'-(fluoro)-2/-/-1 ,3'-bipyridin-2-one (50 mg, 0.15 mmol), 4-(N-methyl-teff-butyloxycarbonylamino)piperidine (35.53 mg, 0.17 mmol) and K2CO3 (41.66 mg, 0.30 mmol) was dissolved in DMF (2 ml_) and the mixture was heated at 1 1 O0C for 18 h. After LCMS showed the stating material was consumed, the solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC to afford 4-[(5-chloro-2-pyridinyl)methyl]oxy}-6'-[4-(N-methyl-ferf- butyloxycarbonylamino)-1-piperidinyl]-2/-/-1 ,3'-bipyridin-2-one (10 mg, 18%): LCMS m/z 413 {M+H -100 [BOCJf .

Reference： [1]Patent: WO2009/76387,2009,A1 .Location in patent: Page/Page column 68

25
[ 1188914-99-9 ]
[ 108612-54-0 ]
[ 1188915-38-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h;	A mixture of 1.11 g (2.2 mmol) of 4-(terf-butyldimethylsilyloxy)-l-[4-chloro-6-(4-morpholinyl)-l ,3,5-triazin-2-yl]-2-(difluoromethyl)-lH-benzimidazole (Example 5), 0.48 g (2.3 mmol) of tert-butyl methyl(4-piperidinyl)carbamate, and 0.6 g DDPEA in 20 mL TetaF was stirred at room temperature for 1 hr. After dilution with water containing 1 mL acetic acid, the product was extracted in to EtOAc, washed successively with water and aq. NaHCO3, and dried. Chromatography on silica, eluting with CH2Cl2/hexane (19:1) gave 1.20 g (81% yield) of l-[4-[4-[ [terNbutyl(dimethyl)silyl]oxy}-2-(difluoromethyl)-lH- benzimidazol-l-yl]-6-(4-mophiholinyl)-l,3,5-triazin-2-yl]-4-piperidinyl(methyl)carbamate as an oil: 1H NMR (CDCl3) delta 7.90 (d, J = 8.0 Hz, IH), 7.47 (t, Jw = 53.6 Hz, IH), 7.26 (t, J = 8.1 Hz, IH), 6.83 (d, J = 7.5 Hz, IH), 4.89 (m, 2H), 4.27 (m, IH), 3.87 (m, 4H), 3.78 (m, 4H), 2.95 (m, 2H), 2.72 (s, 3H), 1.70-1.59 (m, 4H), 1.48 (s, 9H), 1.05 (s, 9H), 0.30 (s, 6H).

Reference： [1]Patent: WO2009/120094,2009,A2 .Location in patent: Page/Page column 114

26
[ 4752-10-7 ]
[ 108612-54-0 ]
[ 1192268-09-9 ]

Yield	Reaction Conditions	Operation in experiment
62%	In 1-methyl-pyrrolidin-2-one; at 80℃; for 72h;	Combine 1 ,4-dichlorophthalazine (5.00 g, 24.6 mmol), rer/-butyl methyl(piperidin-4-yl)carbamate (5.54 g, 25.8 mmol), and potassium carbonate (29.5 mmol; 4.08 g) in N-methylpyrrolidone (50.0 mL). Heat the reaction mixture at 80 C for 3 days and pour the reaction mixture into ice water. Filter via vacuum filtration to obtain a yellowish solid and dry at room temperature in a vacuum oven. Purify by silica gel chromatography (1 :1, hexaneiethyl acetate) to obtain the desired product (5.79 g, 62%). ES/MS m/z 377.2 (M+l).
37%	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃;	Preparation 1 tert-Butyl 1-(4-chlorophthalazin-1-yl)piperidin-4-yl(methyl)carbamateHeat a mixture of potassium carbonate (21.23 g, 153 6 mmol), 1,4-dichlorophthalazine (26 g, 128 mmol) and methyl-piperidin-4-yl carbamic acid tert-butyl ester (30.01 g, 134.4 mmol) in N-methylpyrrolidine (200 mL) at 80 C. overnight. Pour the reaction mixture into water, extract with dichloromethane, dry over Na2SO4, and concentrate under reduced pressure. Add diethylether and filter off the resulting solid (4-chlorophethalazin-1-ol from starting material impurity). Concentrate the filtrate. Purify the resulting residue by flash silica gel chromatography (hexane:ethyl acetate=2:1) to provide the title compound as a white solid (17.66 g, 37%). ES/MS m/z (37Cl) 377.0 (M+1).
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 6h;	To 5 mL of N-methylpyrrolidone (NMP) was added 0.21 g of 4- (N-Boc-methylamino) piperidine,0.2 g of 1,4-dichloropyrazine and0.28 g of potassium carbonate, heated to 80 C for 6 h.After completion of the reaction, 20 mL of saturated ammonium chloride solution was added and quenched,The organic phase was separated and the aqueous phase was extracted three times with dichloromethane and incorporated into an organic phase,Washed successively with saturated aqueous ammonium chloride solution and saturated brine,Then dried over anhydrous sodium sulfate, filtered to remove sodium sulfate and concentrated to give the crude product.The crude product was purified by column chromatography (200-300 mesh silica gel, eluent: n-hexane: ethyl acetate = 3: 1) to give the pure intermediateA.

Reference： [1]Patent: WO2009/134574,2009,A2 .Location in patent: Page/Page column 11-12
[2]Patent: US2010/324048,2010,A1 .Location in patent: Page/Page column 3
[3]MedChemComm,2017,vol. 8,p. 1332 - 1336
[4]Patent: CN106831718,2017,A .Location in patent: Paragraph 0029; 0032

27
[ 34584-69-5 ]
[ 108612-54-0 ]
[ 1227070-23-6 ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 48h;	Preparation 1 tert-Butyl l-(6-chloro-4,5-dimethylpyridazin-3-yl)piperidin-4-yl(methyl)carbamate; Heat a mixture of <strong>[34584-69-5]3,6-dichloro-4,5-dimethylpyridazine</strong> (11.0 g, 62.1 mmol), tert- butyl methyl(piperidin-4-yl)carbamate (23.3 g, 109 mmol), and powdered K2CO3 (17.2 g, 124 mmol) in DMSO (310 mL) at 120 0C for 2 d. Cool the reaction mixture, dilute with H2O, and filter off the solid. Rinse the solid with H2O, and dry under vacuum at 45 0C. Dissolve the solid in CH2CI2, and pass the solution through a pad of silica gel, eluting with CH2CI2. Concentrate the organic layer under reduced pressure to obtain the title compound as a yellow solid (14.3 g, 65%). ES/MS m/z (35Cl) 355.0 (M+l).
30%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 150℃; for 5h;	tert-Butyl piperidin-4-ylmethylcarbamate (3.8i g, i 7.8mmol), <strong>[34584-69-5]3,6-dichloro-4,5-dimethyl-pyridazine</strong> (3.Og, i7.Ommol), NMP (i4mL) and N,N-Diisopropylethylamine (4.43mL, 25.4mmol) were added to a round bottom flask and heated to iSO C for 5 h. The mixture was partitioned between EtOAc (i 00 mL) and i M Na2003 aq. (50 mL). The organic layer was washed with i M Na2003 aq. (5OmL),water (2 x 7OmL), brine (70 mL), before passage through a hydrophobic frit and concentrated in vacuo to give an orange/brown solid. The crude material was purified by silica flash chromatography using 0% EtOAc in heptane with tn ethylamine i% with a gradient increasing to 30% ethyl actetate. Fractions containing product were combined and concentrated in vacuo to afford tert-butyl N-[i -(6-chloro-4,5-dimethyl-pyridazin-3-yl)-4-piperidyl]-N-methyl-carbamate(i .8g,5.i mmol, 30% yield).1H NMR (400MHz, ODd3) s/ppm: 4.34-3.84 (m, 2H), 3.56-3.47 (m(br), 2H), 3.00 (t(br), Ji2.OHz,2H), 2.78 (s, 3H), 2.3i (s, 3H), 2.25 (s, 3H), i .93-i .80 (m, 2H), i .78-i .7i (m(br), 2H), i .47 (s, 9H).MS Method 2: RT: i .88 mi m/z 355.9 [M÷H]÷

Reference： [1]Patent: WO2010/56588,2010,A1 .Location in patent: Page/Page column 9
[2]Patent: WO2014/191737,2014,A1 .Location in patent: Paragraph 00235

28
[ 1188914-98-8 ]
[ 108612-54-0 ]
[ 1188915-36-7 ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 20h;	A mixture of 29 (873 mg, 2.2 mmol), tert-butyl methyl(4-piperidinyl)carbamate (566 mg, 2.64 mmol), and DIPEA (1.1 mL, 4.2 mmol)in THF (25 mL) was stirred at 20 C for 20 h. The solvent was removedunder vacuum and the residue was stirred in aq. HOAc, resulting in aprecipitate which was collected, washed with water, and dried.Recrystallization from CH2Cl2/MeOH gave tert-butyl 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl(methyl)carbamate (1.18 g, 93%): mp(CH2Cl2/MeOH) 182-184 C; 1H NMR (DMSO-d6) delta 7.89 (d, J=7.9 Hz,1H), 7.69 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.95 (d,J=7.8 Hz, 1H), 4.83-4.72 (m, 2H), 4.09 (br, 1H), 3,98 (s, 3H),3.81-3.79 (m, 4H), 3,70-3.69 (m, 4H), 3.07-2.93 (m, 2H), 2.66 (s, 3H),1.66 (m, 4H), 1.41 (s, 9H); Anal. Calcd. for C27H36F2N8O4: C, 56.4; H,6.3; N, 19.7; Found: C, 56.6; H, 6.3; N, 19.8%.

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1529 - 1545

29
[ 3660-90-0 ]
[ 108612-54-0 ]
[ 1258861-47-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃;	Preparation 5 tert-Butyl 1-(4-bromophthalazin-1-yl)piperidin-4-yl(methyl)carbamateCombine 1,4-dibromophthalazine (0.70 g, 2.38 mmol), N-methylpyrrolidone (7.0 mL), potassium carbonate (395 mg, 2.86 mmol), and methyl-piperidin-4-yl-carbamic acid tert-butyl ester (532 mg, 2.38 mmol). Heat at 80 C. overnight. Cool and pour into water. Collect the solid and dry in a vacuum oven at ambient temperature overnight to obtain the final product (0.96 g, 95%). ES/MS m/z (81Br) 421.0 (M+1).

Reference： [1]Patent: US2010/324048,2010,A1 .Location in patent: Page/Page column 4

30
[ 75-07-0 ]
[ 108612-54-0 ]
(1-ethylpiperidin-4-yl)-methylcarbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%		Step 1 : (l-Ethylpiperidin-4-yl)-meth lcarbamic acid tert-bv yl esterTo a solution of methylpiperidin-4-yl-carbamic acid tert-bv yl ester (2.0 g, 9.4 mmol) in dichloromethane (50 mL) was added acetaldehyde (1.65 mL, 27.9 mmol). The resultant dark red solution was stirred for 10 minutes, then sodium triacetoxyborohydride (2.97 g, 14.0 mmol) was added portionwise. After 20 hours at ambient temperature, the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution (100 mL) and dichloromethane (100 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (3 x 100 mL). The combined organic layer was (Na2S04), filtered and concentrated in-vacuo. The resultant residue was purified by flash chromatography (silica, 70 g column, Si-SPE, ethyl acetate followed by 10% methanol in dichloromethane) to afford the title compound as an orange oil (1.64 g, 72%). NMR (300 MHz, CDC13): 3.01 (d, J = 11.3 Hz, 2H), 2.74 (s, 3H), 2.41 (q, J = 7.2 Hz, 2H), 1.98 (t, J = 11.6 Hz, 2H), 1.76-1.72 (m, 5H), 1.46 (s, 9H), 1.08 (t, J = 7.2 Hz, 3H).

Reference： [1]Patent: WO2011/73263,2011,A1 .Location in patent: Page/Page column 99

31
[ 3364-80-5 ]
[ 108612-54-0 ]
[ 1365627-67-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2052 - 2062

32
4-chloropyrimidine hydrochloride [ No CAS ]
[ 108612-54-0 ]
[ 1365155-72-1 ]

Yield	Reaction Conditions	Operation in experiment
78%		Stage (i): tert-Butyl methyl(1-(pyrimidin-4-yl)piperidin-4-yl)carbamatetert-Butyl methyl(piperidin-4-ylmethyl)carbamate (4.67 mmol, 1.0 eq) and 4-chloropyrimidine hydrochloride (14.0 mmol, 3.0 eq) were dissolved in 2-propanol (18 ml) and DIPEA (23.33 mmol. 5.0 eq) and refluxed for 16 hours. After monitoring by TLC, the reaction solution was diluted with ethyl acetate and sat. sodium hydrogen carbonate solution, and the phases were separated. The aqueous phase was washed with ethyl acetate. The combined organic phases were washed 1× with sat. NaCl solution, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate:ethanol 10:1+ammonia solution). Yield: 78%

Reference： [1]Patent: US2012/71461,2012,A1 .Location in patent: Page/Page column 134-135

33
[ 26371-07-3 ]
[ 108612-54-0 ]
[ 1365155-69-6 ]

Yield	Reaction Conditions	Operation in experiment
78%		Stage (i): tert-Butyl methyl(1-(3-(piperidin-1-yl)propanoyl)piperidin-4-yl)carbamate3-(Piperidin-1-yl)propanoic acid (3.183 mmol, 1.0 eq) was dissolved in dichloromethane (40 ml) and DIPEA (7.958 mmol, 2.5 eq) and cooled to 0 C.; EDCI (3.82 mmol, 1.2 eq) and HOBT (0.637 mmol, 0.2 eq) were added and stirring was carried out for 15 hours at RT. The mixture was then cooled to 0 C. again, tert-butyl methyl(piperidin-4-yl)carbamate (3.183 mmol, 1.0 eq) was added, and the reaction mixture was stirred for 16 hours at RT. Then the reaction mixture was diluted with ethyl acetate, washed with 10% ammonium chloride solution, sat. NaHCO3 solution and with sat. NaCl solution, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, ethyl acetate/ethanol). Yield: 78%

Reference： [1]Patent: US2012/71461,2012,A1 .Location in patent: Page/Page column 134

34
[ 898289-23-1 ]
[ 108612-54-0 ]
[ 1365155-24-3 ]

Yield	Reaction Conditions	Operation in experiment
64%		Stage (i): tert-Butyl methyl(1-((2-(pyrrolidin-1-yl)pyridin-4-yl)methyl)piperidin-4-yl)carbamatetert-Butyl methyl(piperidin-4-yl)carbamate (2.333 mmol, 1 eq) and 2-(pyrrolidin-1-yl)-isonicotinaldehyde (2.66 mmol, 1.14 eq) were dissolved in dichloromethane (15 ml), and acetic acid (5.459 mmol, 2.34 eq) and sodium triacetoxyborohydride (3.266 mmol, 1.4 eq) were added. The reaction mixture was stirred for 48 h at RT. When the reaction was complete (TLC monitoring), sat. sodium hydrogen carbonate solution was added to the reaction mixture and the phases were separated. The aqueous phase was extracted with dichloromethane (2×30 ml). The combined organic phases were washed with sat. NaCl solution, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, ethyl acetate:cyclohexane 2:1). Yield: 64%.

Reference： [1]Patent: US2012/71461,2012,A1 .Location in patent: Page/Page column 128

35
[ 38557-71-0 ]
[ 108612-54-0 ]
[ 1365156-90-6 ]

Yield	Reaction Conditions	Operation in experiment
47%	With potassium tert-butylate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 20℃; for 16h;Inert atmosphere; Reflux;	Stage 1: tert-Butyl methyl(1-(6-methylpyrazin-2-yl)piperidin-4-yl)carbamate KOBut (483 mg, 4.32 mmol, 2.5 eq) was added at room temperature to a solution of tert-butyl methyl(piperidin-4-yl)carbamate (stage 3 AMN-60) (370 mg, 1.72 mmol, 1 eq) and <strong>[38557-71-0]2-chloro-6-methylpyrazine</strong> (244 mg, 1.9 mmol, 1.1 eq) in toluene (50 ml) and the mixture was degassed for 30 min with argon. BINAP (64.5 mg, 0.103 mmol, 0.06 eq) and Pd2(dba)3 (31.6 mg, 0.034 mmol, 0.02 eq) were added and the reaction mixture was refluxed for 16 h. After cooling, concentration under reduced pressure was carried out. The residue was taken up in dichloromethane (50 ml) and washed with water (30 ml) and saturated sodium chloride solution (30 ml) and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure and the crude product so obtained was purified by column chromatography (Alox, 0.5% methanol/dichloromethane). The desired product was in the form of a brown solid. Yield: 47% (250 mg, 0.816 mmol)

Reference： [1]Patent: US2012/71461,2012,A1 .Location in patent: Page/Page column 146

36
[ 506-68-3 ]
[ 108612-54-0 ]
[ 1376609-38-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In dichloromethane; water; at 0 - 20℃; for 2.5h;	Preparation 21: (l-Cyano-piperidin-4- l)-methyl-carbamic acid tert-butyl esterTo a solution of methyl-pipcridin-4-yl-earbamic acid tert-butyl ester (2,G8g, 9,68mmol) in DCM (25mL) was added a slurry of NaHC03 (2.44g, 29.1mmol) in water (6mL). The resulting reaction mixture was cooled to 0 C and a solution of cyanogen bromide (1.23g, 1 1.6mmol) in DCM (3mL) was added dropwise over 1 min, before warming to r.t. and stirring for 2.5 h. The reaction mixture was diluted with water, the layers separated and the aqueous layer extracted with DCM. The combined organic extracts were washed with brine, dried (MgSC^), filtered and concentrated in vacuo to afford the title compound: RT = 3.12 min; m/z (ES+) = 240.17 [M + H]~.
	With sodium hydrogencarbonate; In dichloromethane; water; at 0 - 20℃;	Preparation 16: (l-Cyano-piperidin-4- l)-meth l-carbamic acid tert-butyl esterTo a solution of methyl-piperidin-4-yl-carbamic acid tert-butyl ester (2.08g, 9.68mmol) in DCM (25mL) was added a slurry of NaHC03 (2.44g, 29.1mmol) in water (6mL). The resulting reaction mixture was cooled to 0 C and a solution of cyanogen bromide (1.23g, 1 1.6mmol) in DCM (3mL) was added dropwise over 1 min, before warming to r.t. and stirring for 2.5 h. The reaction mixture was diluted with water, the layers separated and the aqueous layer extracted with DCM. The combined organic extracts were washed with brine, dried (MgS04), filtered and concentrated in vacuo to afford the title compound: RT = 3.12 min; mlz (ES+) = 240.17 [M + H]+.

Reference： [1]Patent: WO2012/66077,2012,A1 .Location in patent: Page/Page column 27
[2]Patent: WO2013/26587,2013,A1 .Location in patent: Page/Page column 28

37
[ 252723-17-4 ]
[ 108612-54-0 ]
[ 1383342-95-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; at 150℃; for 0.333333h;	A mixture of 5-bromo-4-cUoro-7-( henylsulfonyl)-7H^^ D5 (1.5 g),1,1-dimethylethyl methyl(4-piperidinyl)carbamate (1.294 g, 6.04 mmol, commercially available from e.g Fluorochem, Apollo, or Astatech) and N,N-diisopropylethylamine (1.758 mL, 10.06 mmol) was heated at 150C for 20 min. Crude product needs to be purified by silica chromatography eluting with 10-50% EtOAc in isohexane. The fractions have been collected and the solvent has been evaporated to give the product D24 in 0.763g. LC/MS [M+H]+ 549.71/ 551.79 (at) 1.50 min ( 2 min run)

Reference： [1]Patent: WO2012/80735,2012,A1 .Location in patent: Page/Page column 35; 36

38
[ 76561-16-5 ]
[ 108612-54-0 ]
[ 1464157-85-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With dmap; In N,N-dimethyl-formamide; at 20℃; for 16h;	Step 2: To a solution of 7-bromo-lH-benzo[d][l,3]oxazine-2,4-dione (400 mg, 1.65 mmol), tert-butyl methyl(piperidin-4-yl)carbamate (389 mg, 1.81 mmol) in DMF (5 mL) was added DMAP (20 mg, 0.16 mmol) at rt and stirred at same temperature for 16 h. The reaction mixture was added ice cooled water and extracted with EtOAc (3 *30 mL). The combined organic layer was washed with water, brine solution and dried over Na2S04 and was concentrated under reduced pressure to obtain the crude product. The crude product was washed with n-pentane to afford tert-butyl 1 -(2-amino-4-bromobenzoyl)piperidin-4- yl(methyl)carbamate (670 mg, 98%, LC-MS 94%). 1H NMR (400 MHz, CDC13) delta 6.93 (d, J = 8.4 Hz, 1H), 6.88 (s, 1H), 6.83 (d, J= 6.8 Hz, 1H), 4.42 (s, 3H), 4.21 (br s, 2H), 2.95 (s, 2H), 2.88 (s, 3H), 1.72-1.62 (m, 4H), 1.46 (s, 9H); MS (ESI) m/z 412/414 [Ci8H26BrN303 ]+.
	With dmap; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of <strong>[76561-16-5]7-bromo-1H-benzo[d][1,3]oxazine-2,4-dione</strong> (400 mg, 1.65 mmol), tert-butyl methyl(piperidin-4-yl)carbamate (389 mg, 1.81 mmol) in DMF (5 mL) was added DMAP (20 mg, 0.16 mmol) at rt and stirred at same temperature for 16 h. The reaction mixture was added ice cooled water and extracted with EtOAc (3*30 mL). The combined organic layer was washed with water, brine solution and dried over Na2SO4 and was concentrated under reduced pressure to obtain the crude product. The crude product was washed with n-pentane to afford tert-butyl 1-(2-amino-4-bromobenzoyl)piperidin-4-yl(methyl)carbamate (670 mg, 98%, LC-MS 94%). 1H NMR (400 MHz, CDCl3) delta 6.93 (d, J=8.4 Hz, 1H), 6.88 (s, 1H), 6.83 (d, J=6.8 Hz, 1H), 4.42 (s, 3H), 4.21 (br s, 2H), 2.95 (s, 2H), 2.88 (s, 3H), 1.72-1.62 (m, 4H), 1.46 (s, 9H); MS (ESI) m/z 412/414 [C18H26BrN3O3]+.

Reference： [1]Patent: WO2013/147711,2013,A1 .Location in patent: Page/Page column 241; 242
[2]Patent: US2014/371199,2014,A1 .Location in patent: Paragraph 0833

39
2-bromo-1-fluoro-4-methoxybenzene [ No CAS ]
[ 108612-54-0 ]
[ 1610033-28-7 ]

Yield	Reaction Conditions	Operation in experiment
26%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); lithium hexamethyldisilazane; In tetrahydrofuran; at 75℃; for 2h;Inert atmosphere;	[00207j 9A. tert-Butyl 1 -(2-fluoro-5 -methoxyphenyl)piperidin-4-yl(methyl)carbamate:To a solution of 2-bromo- 1 -fluoro-4-methoxybenzene (325 mg, 1.58 mmol) and tertbutyl methyl(piperidin-4-yl)carbamate (442 mg, 2.06 mmol) in THF (3 mL) purged with argon was added SPhos (52 mg, 0.13 mmol), Pd2(dba)3 (29 mg, 0.032 mmol), andLHMDS (1 M in THF) (3.2 mL, 3.2 mmol). After purging with argon for 2 mm, the reaction mixture was heated to 75 C for 2 h. The reaction was quenched with sat. aq. NaHCO3. The aqueous layer was extracted with EtOAc and the organic layer was washed with brine, dried, and concentrated. Purification via silica chromatography gave 9A (140 mg, 0.414 mmol, 26% yield). LC-MS Anal. Calc?d for C18H27FN203 338.20,found [M+H] 339.1. ?HNMR(400 MHz, CDC13) oe 6.92 (dd,J=12.1, 8.8 Hz, 1H), 6.54-6.29 (m, 2H), 4.38 - 3.98 (m, 1H), 3.76 (s, 3H), 3.60 - 3.35 (m, 2H), 2.89 - 2.55 (m, 5H),1.99- 1.81 (m, 2H), 1.78 - 1.59 (m, 2H), 1.48 (s, 9H).

Reference： [1]Patent: WO2014/78609,2014,A1 .Location in patent: Paragraph 00207

40
[ 14490-19-8 ]
[ 108612-54-0 ]
tert-butyl N-[1-(1-chloropyrido[3,4-d]pyridazin-4-yl)-4-piperidyl]-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.8%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 100.0℃; for 1.0h;	To a round bottomed flask were added tert-butyl piperidin-4-ylmethylcarbamate (0.29mL, 55mmol)1 ,4-dichloropyrido[3,4-d]pyridazine (1 3.48mL, 5Ommol) , N,N-diisopropylethylamine (26mL,1 5Ommol) , NMP (50mL) and heated to 100C for 1 hour. The reaction was diluted with EtOAc andwashed with water (5x1 OOmL). The organic layer was dried over sodium sulphate, filtered andconcentrated in vacuo. The resulting residue was purified by silica flash chromatography using 30%EtOAc in heptane using a slow isocratic elution and concentrated in vacuo to afford the majorregioisomer tert-butyl N-[1 -(1 -chloropyrido[3,4-d]pyridazin-4-yl)-4-piperidyl]-N-methyl-carbamate(1 .lg, 2.9mmol, 5.8%, 98% purity). Further mixed fractions of lower purity were also obtained.1H NMR (400MHz, ODd3) s/ppm: 9.46 (s, 1 H), 9.03 (d, J5.6Hz, 1 H), 7.94 (d, J5.6Hz, 1 H), 4.33(m(br), 1H), 4.22-4.12 (m(br), 2H), 3.29 (t, J12.5Hz, 2H), 2.83 (s, 3H), 2.11-1.97 (m, 2H), 1.90-1.81(m, 2H), 1.50 (s, 9H).MS Method 2: RT: 1 .73mm. m/z 378.9[M÷H]

Reference： [1]Patent: WO2014/191737,2014,A1 .Location in patent: Paragraph 00235

41
[ 105827-91-6 ]
[ 108612-54-0 ]
tert-butyl N-methyl-N-{1-[(2-chlorothiazol-5-yl)methyl]piperidin-4-yl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;	General procedure 1: 8.40 g (50 mmol) of 2-Chloro-5-(chloromethyl)thiazole, 10.70 g (50 mmol) of <strong>[108612-54-0]tert-butyl methyl(piperidin-4-yl)carbamate</strong>, and 6.90 g (50 mmol) of anhydrous K2CO3 were added to a 1000 ml three-necked flask containing 300 ml of dimethyl formamide (DMF). The mixture was stirred at room temperature for 6 h. A large amount of ice water was added to precipitate a solid. The solid was washed with large amounts of petroleum ether, filtered, and dried in a vacuum. A white powder consisting of N-methyl-N-{1-[(2-chloro-5-thiazolyl) methyl]-4-piperidinyl} carbamic acid tert-butyl ester (3a) (16.90 g) was obtained (yield 98%).
92.7 g	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;	[0095] 50 g of 2-chloro-5-chloromethylthiazole was added to a 1000 ml three-necked flask, and dissolved with 300 mlof DMF. Thereafter, 49.3 g of anhydrous K2CO3 was added, and 76.5 g of tert-butyl N-methyl-N-(piperidin-4-yl)carbamatewas added under stirring, followed by stirring at room temperature for 6h, till the reaction was complete as monitoredby TLC. Under stirring, a large amount of ice water was added to the reaction mixture. The solid was precipitated andfiltered, and the filter cake was washed with a large amount of petroleum ether, and then the filter cake was dried toobtain 92.7 g of a white powder tert-butyl N-methyl-N-{1-[(2-chlorothiazol-5-yl)methyl]piperidin-4-yl}carbamate (A).

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 97,p. 19 - 31
[2]Patent: EP3085701,2016,A1 .Location in patent: Paragraph 0095

42
[ 1193-21-1 ]
[ 108612-54-0 ]
tert-butyl (1-(6-chloropyrimidin-4-yl)piperidin-4-yl)(methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;	To a solution of 4,6-dichloropyrimidine (5.2 g, 35.0 mmol) in DMF (100 mL) were added tert- butyl methyl(piperidin-4-yl)carbamate (5.0 g, 23.3 mmol) and cesium carbonate (15.2 g, 46.7 mmol). After addition, the reaction mixture was heated at 80C for 16 h, at which time LCMS indicated the reaction had gone to completion. The solution was poured into ice water, and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel chromatography column (Hexanes/ethyl acetate = 5:1) to give the title compound (7.0 g, 92% yield) as a colorless oil.
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;	General procedure: 2,4-dichloropyrimidine (40 mmol), <strong>[108612-54-0]tert-butyl methyl(piperidin-4-yl)carbamate</strong> (41 mmol), and anhydrous K2CO3 (41 mmol) were added to a 1000 ml three-necked flaskcontaining 300 ml of DMF. The mixture was stirred at room temperaturefor 6 h. A large amount of ice water was added to precipitatea solid. The solid was washed with large amounts of petroleum ether, filtered, and dried in a vacuum. Flash chromatography (ethyl acetate-petroleum ether, 1:2) of the residue was performed to obtain white powder 3b (tert-butyl 1-(2-chloropyrimidin-4-yl) piperidin-4-yl (methyl)carbamate).

Reference： [1]Patent: WO2016/77375,2016,A1 .Location in patent: Page/Page column 176
[2]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 737 - 741
[3]European Journal of Medicinal Chemistry,2015,vol. 97,p. 19 - 31

43
[ 3934-20-1 ]
[ 108612-54-0 ]
t-butyl N-methyl-N-[1-(2-chloropyrimidin-4-yl)piperidin-4-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With triethylamine; In tetrahydrofuran; at 20℃; for 16h;	A solution of 2,4-dichloropyrimidine (2.0 g, 13.4 mmol) and ferf-butyl methyl(piperidin-4-yl)carbamate (2.7 g, 13.5 mmol) in THF (50 mL) was charged with tri ethyl amine (2.8 mL, 20.1 mmol) at 0 C. The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated and the residue was taken up in ethylacetate and the organic layer was washed with NH4CI solution followed by brine; dried over sodium sulphate, filtered and concentrated. The crude material obtained was purified by combi-flash companion (silica gel, CH3OH/CH2CI2) to provide ferf-butyl (l-(2- chloropyrimidin-4-yl)piperidin-4-yl)(methyl)carbamate 417m (2.4 g, 73%). Tl NMR (400 MHz, CDCI3): delta 7.93 (d, J = 5.6 Hz, 1H), 6,34 (d, J = 6.0 Hz, 1H), 4.41 (br s, 1H), 4.24 (br s, 1H), 2.87 U. ./ 1 1.2 Hz, 2H), 2.64 (s, 3H), 1.71 (br s, 2H), 1.58 (br s, 3H), 1.41 (s, 9H); ESI+APCI MS m/z 327 [M + H
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;	General procedure: 2,4-dichloropyrimidine (40 mmol), <strong>[108612-54-0]tert-butyl methyl(piperidin-4-yl)carbamate</strong> (41 mmol), and anhydrous K2CO3 (41 mmol) were added to a 1000 ml three-necked flaskcontaining 300 ml of DMF. The mixture was stirred at room temperaturefor 6 h. A large amount of ice water was added to precipitatea solid. The solid was washed with large amounts of petroleum ether, filtered, and dried in a vacuum. Flash chromatography (ethyl acetate-petroleum ether, 1:2) of the residue was performed to obtain white powder 3b (tert-butyl 1-(2-chloropyrimidin-4-yl) piperidin-4-yl (methyl)carbamate).

Reference： [1]Patent: WO2017/58503,2017,A1 .Location in patent: Page/Page column 419; 428-430
[2]European Journal of Medicinal Chemistry,2015,vol. 97,p. 19 - 31

44
[ 3245-44-1 ]
[ 108612-54-0 ]
t-butyl (1-[2-(propan-2-yl)phenoxy]ethyl}piperidin-4-yl)-N-methyl-carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate; potassium iodide; In acetone; for 48h;Reflux;	General procedure: Commercial 4-(N-methyl-Boc-amino)piperidine (0.015 mol) or 4-(Boc-N-amino)piperidine (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)ethyl bromide (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 as an eluting system.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 130 - 139

45
[ 1019374-12-9 ]
[ 108612-54-0 ]
t-butyl (1-[2-(t-butyl)phenoxy]ethyl}piperidin-4-yl)-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate; potassium iodide; In acetone; for 48h;Reflux;	General procedure: Commercial 4-(N-methyl-Boc-amino)piperidine (0.015 mol) or 4-(Boc-N-amino)piperidine (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)ethyl bromide (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 as an eluting system.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 130 - 139

46
[ 3245-43-0 ]
[ 108612-54-0 ]
t-butyl {1-[2-(biphenyl-2-yloxy)ethyl]piperidin-4-yl}-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate; potassium iodide; In acetone; for 48h;Reflux;	General procedure: Commercial 4-(N-methyl-Boc-amino)piperidine (0.015 mol) or 4-(Boc-N-amino)piperidine (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)ethyl bromide (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 as an eluting system.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 130 - 139

47
[ 4774-14-5 ]
[ 108612-54-0 ]
tert-butyl-N-[1-(6-chloropyrazin-2-yl)piperidin-4-yl]N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 2h;	Around-bottom flask charged with 2,6-dichloropyrazine (1.0 g, 6.7 mmol), 4- (N-Boc-methylamino)piperidine (1.43 g, 6.7), and DIEA (1.7g , 13 mmol) in DMF(20 mL) was kept at 100 C for 2h. The resulting mixture was poured into ice-water and extracted with ethyl acetate (3* 100 mL). The organic layers were successively washed with brine, dried with Na2S04, and concentrated in vacuo. The residue was triturated with PE to afford crude tert-butyl-N-[l-(6-chloropyrazin-2-yl)piperidin-4-yl]N- methylcarbamate (2.1 g, 96%) as a off-white solid. 1H NMR (300 MHz, CDC13): delta 1.48 (9H, s) 1.65-1.80 (4H, m), 2.72 (3H, s), 2.92-3.00 (2H, m), 4.12-4.37 (1H, m), 4.40-4.46 (2H, m), 7.78 (1H, s), 7.99 (1H, s). [M+H] Calc'd for Ci5H23ClN402, 327; Found, 327.

Reference： [1]Patent: WO2016/37005,2016,A1 .Location in patent: Paragraph 00385-00386

48
[ 35857-89-7 ]
[ 108612-54-0 ]
(1-(6-cyanopyridazine-3-yl)piperidin-4-yl)(methyl)carbamic acid tert-butylester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28.1%	With triethylamine; In ethanol; at 20℃;	Step 1) tert-butyl (1-(6-cyanopyridazin-3-yl)piperidin-4-yl)(methyl)carbamate To a solution of tert-butyl methyl(piperidin-4-yl)carbamate (605.8 mg, 2.83 mmol) and <strong>[35857-89-7]6-chloropyridazine-3-carbonitrile</strong> (796.5 mg, 5.71 mmol) in EtOH (15 mL) was added Et3N (1.14 g, 11.30 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/1) to give the title compound as a yellow solid (252.0 mg, yield 28.1%). LC-MS (ESI, pos. ion) m/z: 318.0 [M+H]+; 1H NMR (400 MHz, CDCl3) delta (ppm): 7.45 (d, J=9.6 Hz, 1H), 6.87 (d, J=9.6 Hz, 1H), 4.68 (d, J=13.0 Hz, 2H), 4.33 (t, J=6.7 Hz, 1H), 3.11 (t, J=12.2 Hz, 2H), 2.73 (s, 3H), 1.85 (d, J=11.8 Hz, 2H), 1.71 (m, 2H), 1.50 (s, 9H).
28.1%	With triethylamine; In ethanol; at 20℃;	Of methyl (piperidin-4-yl) -carbamic acid tert-butyl ester (605.8mg, 2.83mmol) and 6-chloro-pyridazin-3-carbonitrile (796.5mg, 5.71mmol)In ethanol (15mL) was added triethylamine (1.14g, 11.30mmol). The reaction was stirred overnight at room temperature, and then concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography (EtOAc / PE (v / v) = 1/1) to give the title compound as a yellow solid (252.0mg, yield28.1%).

Reference： [1]Patent: US2016/229837,2016,A1 .Location in patent: Paragraph 0559; 0560; 0561
[2]Patent: CN105461694,2016,A .Location in patent: Paragraph 0721; 0722; 0723; 0724

49
[ 33252-28-7 ]
[ 108612-54-0 ]
(1-(5-cyano-pyridin-2-yl)piperidin-4-yl)(methyl)carbamic acid tert-butylester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	Step 1) tert-butyl(1-(5-cyanopyridin-2-yl)piperidin-4-yl)(methyl)carbamate To a solution of 6-chloronicotinonitrile (200 mg, 1.44 mmol) and <strong>[108612-54-0]tert-butyl methyl(piperidin-4-yl)carbamate</strong> (620 mg, 2.88 mmol) in DMF (20 mL) was added K2CO3 (600 mg, 4.32 mmol). The reaction mixture was stirred at 120 C. for 2 hours, and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (40 mL) and the resulting mixture was washed with water (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (100% DCM) to give the title compound as a white solid (394 mg, yield 86%). LC-MS (ESI, pos. ion) m/z: 316.8 [M+H]+; 1H NMR (300 MHz, CDCl3) delta (ppm): 8.40 (d, J=2.4 Hz, 1H), 7.60 (dd, J=2.4 Hz, J=9 Hz, 1H), 6.61 (d, J=9 Hz, 1H), 4.51-4.56 (m, 3H), 2.91-3.01 (m, 1H), 2.70 (s, 4H), 1.80-1.74 (m, 2H), 1.55-1.69 (m, 2H), 1.45 (s, 9H).
86%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	To a solution of 6-chloronicotinonitrile (200 mg, 1.44 mmol) and fe/7-butyl methyl(piperidin-4-yl)carbamate (620 mg, 2.88 mmol) in DMF (20 mL) was added K2C03 (600 mg, 4.32 mmol). The reaction mixture was stirred at 120 C for 2 hours, and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (40 mL) and the resulting mixture was washed with water (20 mL), dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (100% DCM) to give the title compound as a white solid (394 mg, yield 86%).MS (ESI, pos. ion) m/z: 316.8 [M+H]+;1H NMR (300MHz, CDCl3) d (ppm): 1.45 (s, 9H), 1.55-1.69 (m, 2H), 1.80-1.74 (m, 2H), 2.70 (s, 4H), 2.91-3.01 (m, 1H), 4.51-4.56 (m, 3H), 6.61 (d, J= 9 Hz, 1H), 7.60 (dd, J= 2.4 Hz, J= 9 Hz, 1H), 8.40 (d, 7= 2.4 Hz, 1H).
86%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	To tert-butyl methyl (piperidin-4-yl)carbamate (620 mg, 2.88 mmol),6-Chloro-3-cyanopyridine (200 mg, 1.44 mmol) in DMF (20 mL)K2CO3 (600 mg, 4.32 mmol) was added.After the reaction system was stirred at 120 C for 2 hours,Cool to room temperature,It was concentrated under reduced pressure.To the residue was added DCM (40 mL).The resulting solution was washed with water (20 mL).Dry over anhydrous sodium sulfate,Filtered, and the filtrate was concentrated under reduced pressure.The residue obtained was purified by silica gel column chromatography (100%EtOAc)The title compound was obtained as a white solid (394mg, yield 86%).

Reference： [1]Patent: US2016/229837,2016,A1 .Location in patent: Paragraph 0407; 0408; 0409; 0410
[2]Patent: WO2019/99311,2019,A1 .Location in patent: Paragraph 000345
[3]Patent: CN109776522,2019,A .Location in patent: Paragraph 0512; 0522; 0523; 0524; 0525

50
[ 35857-89-7 ]
[ 108612-54-0 ]
(1-(5-cyano-pyridin-2-yl)piperidin-4-yl)(methyl)carbamic acid tert-butylester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;	Of methyl (piperidin-4-yl) - carbamic acid tert-butyl ester (620mg, 2.88mmol), 6- chloro-3-cyanopyridine (200mg, 1.44mmol) in DMF (20mL) was added K2CO3 ( 600mg, 4.32mmol). After the reaction was stirred at 120 2 hours, cooled toAt room temperature, and concentrated under reduced pressure. To the resulting residue was added DCM (40mL), and washed with water (20 mL), dried over anhydrous sodium sulfate, filteredAnd concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (100% DCM) to afford the title compound as a white solid (394mg, yield86%).

Reference： [1]Patent: CN105461694,2016,A .Location in patent: Paragraph 0512; 0513; 514; 0515

51
[ 131747-63-2 ]
[ 108612-54-0 ]
tert-butyl (1-((4-bromopyridin-2-yl)methyl)piperidin-4-yl)(methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With sodium cyanoborohydride; acetic acid; In methanol; at 20℃; for 16h;	4-Bromopicolinaldehyde (500 mg, 2.69 mmol) and ierf-butyl methyl(piperidin-4- yl)carbamate (634 mg, 2.96 mmol) were dissolved in 50 mL methanol. Sodium cyanoborohydride (254 mg, 4.04 mmol) and four drops of acetic acid were added and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and the crude was re-dissolved in dichloromethane, washed with sodium carbonate and sodium hydroxide. The organics were dried over sodium sulphate, filtered and concentrated under reduced pressure. The yellow oil obtained was purified by reverse phase using SP1® Purification System to give 573 mg (56percent yield) of the title compound. LRMS (m/z): 385 (M+1 )+.

Reference： [1]Patent: WO2016/202800,2016,A1 .Location in patent: Page/Page column 27

52
[ 1192721-95-1 ]
[ 108612-54-0 ]
42-O-[4-(tert-butoxycarbonyl(methyl)amino)piperidine-1-carbonyl]rapamycin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With pyridine; dmap; In dichloromethane; at 25℃; for 2h;	43-O- (4- nitrophenyl oxycarbonyl) - oxy rapamycin (0.3g, 0.28mmol) and 4- (N- t-butoxycarbonyl group -N- methylamino) piperidine (0.30g, after 1.4 mmol) was added to (10 mL) solution of methylene chloride, was added after the final dimethylaminopyridine (0.05 g of, catalytic amount) and pyridine (3mL), kept 25 addition was complete the reaction 2 hours, the reaction was complete, the reaction mixture poured into 100mL water and extracted twice with ethyl acetate, the combined extracts washed with water, dried over anhydrous sodium sulfate.Evaporated to dryness to give an oil which was purified by column chromatography to give a solid 121mg, yield: 50%.

Reference： [1]Patent: CN104530081,2016,B .Location in patent: Paragraph 0131; 0132

53
C₈H₈ClN [ No CAS ]
[ 108612-54-0 ]
1-[3'-(6''-cyclopropyl)pyridyl]-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

54
[ 13473-01-3 ]
[ 108612-54-0 ]
1-[3'-(6''-methoxyl)pyridyl]-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

55
[ 22109-30-4 ]
[ 108612-54-0 ]
1-[3'-(6''-ethoxyl)pyridyl]-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

56
[ 215437-47-1 ]
[ 108612-54-0 ]
1-[3'-(6''-benzyloxyl)pyridyl]-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

57
[ 26163-06-4 ]
[ 108612-54-0 ]
1-[3'-(6''-N,N-dimethyamino)pyridyl]-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

58
C₁₁H₉ClN₂ [ No CAS ]
[ 108612-54-0 ]
1-[3'-(5''-anilino)pyridyl]-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

59
[ 13472-84-9 ]
[ 108612-54-0 ]
1-[3'-(2''-methoxyl)pyridyl]-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

60
[ 177743-06-5 ]
[ 108612-54-0 ]
1-[3'-(2''-ethoxyl)pyridyl]-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

61
2-Benzyloxy-3-chloro-pyridine [ No CAS ]
[ 108612-54-0 ]
1-[3'-(2''-benzyloxyl)pyridyl]-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

62
[ 1355066-87-3 ]
[ 108612-54-0 ]
1-[3'-(2''-cyclopropyl)pyridyl]-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

63
C₈H₈ClN [ No CAS ]
[ 108612-54-0 ]
1-[3'-(5''-cyclopropyl)pyridyl]-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

64
[ 292068-12-3 ]
[ 108612-54-0 ]
1-[3'-(5''-phenyl)pyridyl]-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

65
[ 85148-26-1 ]
[ 108612-54-0 ]
1-[3'-(5''-trifluomethyl)pyridyl]-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

66
[ 69045-84-7 ]
[ 108612-54-0 ]
N-methyl tert-butyl [1-{3-chloro-5-(trifluoromethyl)pyridin-2-yl}piperidin-4-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 1643 - 1656
[2]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

67
[ 109-09-1 ]
[ 108612-54-0 ]
1-(2'-pyridyl)-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

68
[ 18368-63-3 ]
[ 108612-54-0 ]
1-[2'-(6''-methyl)pyridyl]-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

69
[ 39890-95-4 ]
[ 108612-54-0 ]
1-[2'-(6''-trifluoromethyl)pyridyl]-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

70
[ 52334-81-3 ]
[ 108612-54-0 ]
1-[2'-(5''-trifluoromethyl)pyridyl]-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

71
[ 22280-56-4 ]
[ 108612-54-0 ]
1-[2'-(3''-methyl-5''-nitro)pyridyl]-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

72
[ 7379-35-3 ]
[ 108612-54-0 ]
1-(4'-pyridyl)-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

73
[ 612-59-9 ]
[ 108612-54-0 ]
1-(3'-quinolyl)-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

74
[ 5332-24-1 ]
[ 108612-54-0 ]
1-(3'-quinolyl)-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

75
[ 611-35-8 ]
[ 108612-54-0 ]
1-(4'-quinolyl)-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

76
[ 14508-49-7 ]
[ 108612-54-0 ]
1-(2'-pyrazinyl)-4-(N-Boc-N-methyl)aminopiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;	General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1976 - 1979

77
C₁₁H₈BrN₃ [ No CAS ]
[ 108612-54-0 ]
C₁₇H₂₁N₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 200℃; for 3h;Microwave irradiation;	To a microwave tube were added the title compound from Preparative Example 2 (0.1 g, 0.19 mmol), <strong>[108612-54-0]tert-butyl methyl(piperidin-4-yl)carbamate</strong> (0.326 g, 0.76 mmol), n-butanol (4 mL), followed by N,N?-diisopropylethylamine (0.460mL, 1.33 mmol). The tube was sealed and heated at 200 C for 3 hours using a Biotage Initiator microwave. The solvents were removed under reduced pressure and NH4Cl saturated solution (25 ml) was added to the mixture followed by DCM(20 ml). The phases were separated and the aqueous layer was extracted with dichloromethane (2 x 20 ml). The organics were collected and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purifiedon HP-Sil SNAP cartridges using a Biotage Isolera One purification system employing a MeOH/DCM gradient (0/100 -> 10/90) to afford the title compound (0.055 g, 98 %). 1H-NMR (400 MHz, DMSO-d6) delta = 9.09 (d, 1 H), 8.37 (d, 1 H), 8.27 (d, 1 H), 7.50 (dd, 1H), 6.82 (d, 1H), 4.35(dt, 2H), 3.79 (s, 3H), 3.07 (m, 2H), 2.32 (s, 3H), 2.01-1.85 (m, 3H), 1.32-1.20 (m, 3H). MS (ESI); m/z = 296.48 [M+H]+

Reference： [1]Patent: EP3118202,2017,A1 .Location in patent: Paragraph 0130-0133

78
[ 391-77-5 ]
[ 108612-54-0 ]
tert-butyl (1-(6-fluoroquinolin-4-yl)piperidin-4-yl)(methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃; for 15h;Sealed tube;	To a homogeneous mixture of 4-chloro-6-fluoroquinoline (200.0 mg, 1.1 mmol) in anhydrous NMP (5 mL), in a sealable vial, was added 4-Boc-4-N-methyl- aminopiperidine (330.0 mg, 1.5 mmol) followed by DIPEA (0.8 mL, 4.6 mmol). The vial was sealed and the mixture was stirred at 120 C for 15 hours. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted twice more with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the crude product which was used without further purification, based on quantitative yield. MS(ES): m/z = 360 [M+H]+. tR = 0.75 min (Method A).

Reference： [1]Patent: WO2017/192811,2017,A1 .Location in patent: Paragraph 00164

79
2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione [ No CAS ]
[ 108612-54-0 ]
tert-butyl (1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)(methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 90℃; for 16h;Inert atmosphere;	tert-Butyl methyl(piperidin-4-yl)carbamate (21-1) (426 mg, 1.99 mmol) was dissolved in DMAC (3 mL) in a small vial under nitrogen.2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3- dione (1-3) (1.81 mmol) and Diisopropylethylamine (787 muL, 4.52 mmol) were addded by syringe and the reaction heated to 90 C for 16 hours. Shot reaction mixture directly on reversed phase isco 50g column 5-100% ACN/water w tfa and lyophilizaed fractions to give tert-butyl (1-(2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)(methyl)carbamate (0.80 g, 1.70 mmol, 94.0%) as a yellow solid. LC/MS (ES+): m/z 493 [M+Na]+

Reference： [1]Patent: WO2017/197056,2017,A1 .Location in patent: Page/Page column 369

80
(Z)-benzyl 2-(3-chloroquinoxalin-2(1H)-ylidene)-2-cyanoacetate [ No CAS ]
[ 108612-54-0 ]
(Z)-benzyl 2-(3-(4-((tert-butoxycarbonyl)(methyl)amino)piperidin-1-yl)quinoxalin-2(1H)-ylidene)-2-cyanoacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With triethylamine; In tetrahydrofuran; at 50℃;	To a mixture of (Z)-benzyl 2-(3-chloroquinoxalin-2(lH)-ylidene)-2-cyanoacetate (0.3 g, 888 umol), <strong>[108612-54-0]tert-butyl methyl(piperidin-4-yl)carbamate</strong> (0.28 g, 1.33 mmol) in THF (1.5 mL) was added Et3N (0.17 g, 1.77 mol). The reaction was stirred overnight at 50C, then diluted in water and extracted with AcOEt. The combined organic layers were dried over MgS04, filtered and concentrated. The residue was purified by column chromatography on silica gel (0 to 15% MeOH in DCM) to afford (Z)-benzyl 2-(3-(4-((tert-butoxycarbonyl)(methyl)amino)piperidin-l- yl)quinoxalin-2(lH)-ylidene)-2-cyanoacetate (333 mg, 72% yield)

Reference： [1]Patent: WO2018/183936,2018,A1 .Location in patent: Page/Page column 90; 95

81
[ 53844-02-3 ]
[ 108612-54-0 ]
tert-butyl (1-(2-(((benzyloxy)carbonyl)amino)ethyl)piperidin-4-yl)(methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N,N-dimethyl-formamide; at 50℃;	Example 56A tert-butyl (1-(2-(((benzyloxy)carbonyl)amino)ethyl)piperidin-4-yl)(methyl)carbamate To a mixture of benzyl (2-bromoethyl)carbamate (500 mg) in N,N-dimethylformamide (5 mL) was added triethylamine and tert-butyl methyl(piperidin-4-yl)carbamate (623 mg). The mixture was heated to 50 C. overnight. Thin layer chromatography showed the starting material was consumed. The reaction mixture was quenched with sodium bicarbonate mixture and was extracted with ethyl acetate (2*50 mL). The organic phase was concentrated and was purified by silica gel chromatography on a CombiFlash Teledyne Isco system eluting with 100% ethyl acetate to provide the title compound. LC/MS (ESI) m/z 392 (M+H)+.

Reference： [1]Patent: US2019/55264,2019,A1 .Location in patent: Paragraph 0732

82
[ 106-96-7 ]
[ 108612-54-0 ]
tert-butyl N-methyl-N-(1-prop-2-ynyl-4-piperidyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate; In tetrahydrofuran; at 25℃; for 16h;	To a solution of tert-butyl N-methyl-N-(4-piperidyl)carbamate (1.50 g, 7.00 mmol, CAS108612-54-0) and 3-bromoprop-1-yne (915 mg, 7.70 mmol, 663 uL, CAS106-96-70) in THF (30 mL) was added K2CO3 (2.90 g, 21.0 mmol). The reaction mixture was stirred at 25 C. for 16 hrs. On completion, the mixture was diluted with water (30 mL) and extracted with EA (3×80 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (1.50 mg, 85% yield) as yellow solid. 1H NMR (400 MHz, CDCl3) delta 4.16-3.61 (m, 1H), 3.29 (d, J=2.0 Hz, 2H), 3.01-2.90 (m, 2H), 2.73 (s, 3H), 2.35-2.21 (m, 3H), 1.81-1.72 (m, 2H), 1.69-1.63 (m, 2H), 1.46 (s, 9H).

Reference： [1]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 4177; 4178

83
1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxobenzimidazole-4-carbaldehyde [ No CAS ]
[ 108612-54-0 ]
tert-butyl N-[1-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxobenzimidazol-4-yl]methyl]-4-piperidyl]-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%		To a solution of 1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-4-carbaldehyde (160 mg, 556 umol, Intermediate WW) and tert-butyl N-methyl-N-(4-piperidyl)carbamate (119 mg, 556 umol) in a mixed solvents of THF (3 mL) and DMF (1.5 mL) was added AcOH until the pH=5-7. After the reaction mixture was stirred at 20 C. for 3 hours. NaBH(OAc)3 (177 mg, 835 umol) was added to the reaction mixture. The mixture was stirred at 20 C. for 12 hours. On completion, the reaction mixture was quenched by water (3 drops) and filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse phase (FA condition) to give the title compound (220 mg, 46% yield) as white solid. LC-MS (ESI+) m/z 486.2 (M+H)+.

Reference： [1]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 4138; 4139

84
1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxobenzimidazole-4-carbaldehyde [ No CAS ]
[ 108612-54-0 ]
tert-butyl N-[[1-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxobenzimidazol-4-yl]methyl]-4-piperidyl]methyl]-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%		To a solution of 1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-4-carbaldehyde (150 mg, 522 umol, Intermediate WW) and tert-butyl N-methyl-N-(4-piperidylmethyl)carbamate (119 mg, 522 umol, CAS138022-04-5) in THF (2 mL) and DMF (0.5 mL) was added HOAc (31.4 mg, 522 umol) at 25 C. The mixture was stirred for 0.5 hour, then NaBH(OAc)3 (221 mg, 1.04 mmol) was added. The mixture was stirred at 25 C. for 2 hours. On completion, the mixture was quenched by water (0.2 mL), and concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (180 mg, 69% yield) as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.48 (s, 1H), 8.24 (s, 1H), 7.08-6.97 (m, 2H), 6.85-6.72 (m, 1H), 5.28-5.22 (m, 1H), 3.78 (d, J=5.0 Hz, 5H), 3.68-3.51 (m, 2H), 3.10 (s, 2H), 3.04-2.94 (m, 2H), 2.94-2.90 (m, 1H), 2.86 (s, 4H), 2.81-2.72 (m, 1H), 2.27-2.20 (m, 1H), 1.71-1.62 (m, 2H), 1.46 (s, 9H), 1.39-1.21 (m, 2H); LC-MS (ESI+) m/z 500.4 (M+H)+.

Reference： [1]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 4271; 4272

85
[ 128277-26-9 ]
[ 108612-54-0 ]
tert-butyl methyl(1-(2-(pyridin-4-yl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)piperidin-4-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With triethylamine; In ethanol; for 20h;Reflux;	General procedure: 4-Chloropyrimidine 5a in absolute ethanol (0.05 mmol/mL) wascharged with 4-substituted- piperidine or piperazine (1.3-1.5 eq.) orpiperazine (10 eq.) and triethylamine or Hunig?s base (3 eq.), and themixture was stirred overnight at reflux while being monitored for disappearanceof 5a by TLC (1:1 ethyl acetate:hexanes). The mixture wasconcentrated, diluted with dichloromethane, and washed with 5% aq.NaHCO3. The aqueous layer was further extracted (2x) with dichloromethaneor ethyl acetate. The combined organic extracts werewashed with brine, dried, and concentrated to a residue that was trituratedeither in acetonitrile or diethyl ether. The solids were collectedand washed with an appropriate solvent, or further purified by flashsilica gel chromatography (ethyl acetate : hexanes) followed by crystallizationfrom ether/hexanes.

Reference： [1]Bioorganic and medicinal chemistry,2020

86
[ 1209458-80-9 ]
[ 108612-54-0 ]
[ 2641694-37-1 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate In 1-methyl-pyrrolidin-2-one at 80℃; for 2h;	A solution of tert-butyl methyl(piperidin-4-yl)carbamate (214 mg, 0.99 mmol, 1.0 equiv), 2-bromo-5-(trifluoromethyl)thiazole (232 mg, 0.99 mmol, 1.0 equiv) and K2CO3 (207 mg, 1.49 mmol, 1.5 equiv) in NMP (5 mL) was stirred for 2 hours at 80 C. Water (20 mL) was added and the resulting solution was extracted with 3 x 15 mL of ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. The crude product was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (2/3) to afford 343 mg (94% yield) of tert-butyl methyl(1-(5-(trifluoromethyl)thiazol-2- yl)piperidin-4-yl)carbamate as a white solid. LCMS (ESI, m/z): 366.1 [M+H]+.

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - WO2021/87025, 2021, A1 Location in patent: Page/Page column 48

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P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
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

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. 108612-54-0 ] {[proInfo.proName]}

Quality Control of [ 108612-54-0 ]

Related Doc. of [ 108612-54-0 ]

Product Details of [ 108612-54-0 ]

Calculated chemistry of [ 108612-54-0 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 108612-54-0 ]

Application In Synthesis of [ 108612-54-0 ]

[ 108612-54-0 ] Synthesis Path-Upstream 1~6

[ 108612-54-0 ] Synthesis Path-Downstream 1~86

Related Functional Groups of [ 108612-54-0 ]

Amides

Amines

Related Parent Nucleus of [ 108612-54-0 ]

Aliphatic Heterocycles

Piperidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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[ 108612-54-0 ]

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[ 108612-54-0 ]