[ CAS No. 190906-92-4 ] {[proInfo.proName]}

Name: 190906-92-4|tert-Butyl 2-methyl-4-oxopiperidine-1-carboxylate|97%
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Quality Control of [ 190906-92-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 190906-92-4 ]

CAS No. :	190906-92-4	MDL No. :	MFCD04035608
Formula :	C₁₁H₁₉NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	213.27	Pubchem ID :	-
Synonyms :

Calculated chemistry of [ 190906-92-4 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.82
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	61.6
TPSA :	46.61 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) :	-6.89 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.58
Log Po/w (XLOGP3) :	1.0
Log Po/w (WLOGP) :	1.59
Log Po/w (MLOGP) :	1.05
Log Po/w (SILICOS-IT) :	1.23
Consensus Log Po/w :	1.49

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.59
Solubility :	5.43 mg/ml ; 0.0255 mol/l
Class :	Very soluble
Log S (Ali) :	-1.57
Solubility :	5.77 mg/ml ; 0.0271 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.56
Solubility :	5.91 mg/ml ; 0.0277 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.56

Safety of [ 190906-92-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 190906-92-4 ]

* 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 [ 190906-92-4 ]
Downstream synthetic route of [ 190906-92-4 ]

[ 190906-92-4 ] Synthesis Path-Upstream 1~11

1
[ 24424-99-5 ]
[ 190906-92-4 ]

Yield	Reaction Conditions	Operation in experiment
93%	With dmap In tetrahydrofuran at 0℃; for 2 h;	Step 1. tert-butyl 2-methyl-4-oxopiperidine-l-carboxylate [0757] Di-tert-butyl dicarbonate (1.09 g, 5.01 mmol) was added to a 0 °C solution of 2- methylpiperidin-4-one hydrochloride (1 : 1 mixture of isomers, 0.500 g, 3.34 mmol) and DMAP (0.817 g, 6.68 mmol) in dry THF (10 mL), and the resulting mixture was stirred at 0 °C for 2 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 mL) and ethyl acetate (70 mL) was added. The aqueous phase was separated and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 25-35percent ethyl acetate in hexanes) to afford tert-butyl 2-methyl-4-oxopiperidine- 1 -carboxylate (0.660 g, 93percent) as a white solid. 1H NMR (300 MHz, DMSO-i δ ppm 1.06 (d, J=6.74 Hz, 3 H), 1.40 (s, 9 H), 2.1 1 - 2.25 (m, 2 H), 2.36 - 2.45 (m, 1 H), 2.68 (dd, J=14.51, 6.6 Hz, 1 H), 3.25 - 3.36 (m, 1 H), 3.93 - 4.06 (m, 1 H), 4.42 - 4.48 (m, 1 H).

Reference： [1] Patent: WO2015/74064, 2015, A2, . Location in patent: Paragraph 0757
[2] Patent: US2003/232833, 2003, A1, . Location in patent: Page 15

2
[ 71322-99-1 ]
[ 24424-99-5 ]
[ 190906-92-4 ]

Reference： [1] Patent: US2004/186292, 2004, A1,
[2] Patent: US2004/6229, 2004, A1, . Location in patent: Page/Page column 16
[3] Patent: US2004/63744, 2004, A1, . Location in patent: Page/Page column 73
[4] Patent: EP1204659, 2003, B1, . Location in patent: Page/Page column 29-30
[5] Patent: EP1204660, 2004, B1, . Location in patent: Page 18

3
[ 126503-08-0 ]
[ 190906-92-4 ]

Yield	Reaction Conditions	Operation in experiment
48%	With toluene-4-sulfonic acid In acetone at 0 - 20℃;	To a solution of 1-t-butoxycarbonyl-2-methyl-4-piperidone ethylene ketal (6.00 g) obtained in reference example 82 in acetone (150 ml) was added p-toluenensulfonic acid monohydrate (4.40 g) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature overnight. After stirring, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed successively with a saturated sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to afford the title compound (2.40 g, yield: 48 percent) as a yellow oil. 1H NMR (500MHz, CDCl3) δ ppm : 1.18 (3H, d, J=7.0), 1.49 (9H, s), 2.20-2.30 (1H, m), 2.30-2.40 (1H, m), 2.45-2.55 (1H, m), 2.65-2.70 (1H, m), 3.25-3.35 (1H, m), 3.90-4.05 (1H, m), 4.20-4.30 (1H, m).

Reference： [1] Patent: EP1375482, 2004, A1, . Location in patent: Page 153

4
[ 849928-34-3 ]
[ 24424-99-5 ]
[ 190906-92-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With 5%-palladium/activated carbon; hydrogen In methanol for 8 h;	110 g (0.44 mol) of the compound prepared in the step (2) was dissolved in 800 ml of methanol, 186 g (0.66 mol) of di-tert-butyl dicarbonate was added, and 5percent by weight of palladium on carbon percent), Hydrogenation, the reaction for 8 hours, after the completion of the reaction filtration, palladium-carbon filter, with a small amount of methanol washing filter cake 2 times, the combined filtrate, vacuum distillation of methanol, 500 ml of ethyl acetate dissolved, L hydrochloric acid, potassium carbonate solution, saturated brine, dried over anhydrous sodium sulfate and evaporated to give 170 g of a pale yellow oil. Crystallization was carried out at about 0C using a 5: 1 mixture of petroleum ether and ethyl acetate , Filtered to obtain 85 grams of white solid, that is, broad-1-tert-butoxy-2-methyl-4-piperidine pay. Yield 95percent.

Reference： [1] Patent: CN103601669, 2016, B, . Location in patent: Paragraph 0046
[2] Patent: WO2008/45250, 2008, A1, . Location in patent: Page/Page column 29

5
[ 620-08-6 ]
[ 865-47-4 ]
[ 676-58-4 ]
[ 190906-92-4 ]

Yield	Reaction Conditions	Operation in experiment
47%	Stage #1: With phenyl chloroformate In tetrahydrofuran at -40℃; for 0.25 h; Stage #2: at -40 - 20℃; for 0.5 h;	A solution of 5 mL (49 mMol) 4-methoxypyridine in 200 mL tetrahydrofuran was cooled to -40°C, and then 6.9 mL (55 mMol) phenyl chloroformate were added dropwise. After stirring for 15 minutes, 20 mL (60 mMol) methyl magnesium chloride (3M in tetrahydrofuran) were added dropwise and the reaction mixture was allowed to warm to room temperature. After stirring for 30 minutes, the reaction mixture was cooled to -40°C and treated with 340 mMol potassium tert-butoxide. The reaction mixture was allowed to warm to room temperature. After stirring for 1 hour, the reaction mixture was cooled to -40°C and was treated with. 200 mL saturated aqueous oxalic acid. The reaction was warmed to 20°C and allowed to stir for 1 hour. The mixture was extracted 2 x 200 mL diethyl ether. The combined organic phases were washed sequentially with 4 x 100 mL 0.5 N sodium hydroxide, 2 x 100 mL saturated aqueous sodium bicarbonate, 3 x 100 mL deionized water, and 100 mL saturated aqueous sodium chloride. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexanes containing 40percent ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 4.9 gm (47percent) 1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine. EA: Calculated for: C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.78; H, 8.08; N, 6.76. A solution of 1.65 gm (7.81 mmol) 1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine in 20 mL tetrahydrofuran was cooled to -40°C and was then treated with 8.59 mL (8.59 mMol) lithium tri(sec-butyl)borohydride (1M in tetrahydrofuran). After stirring for 2 hours, the solution was treated with 3.37 gm (8.59 mMol) 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine and the solution was allowed to warm to room temperature. After stirring for 1 hour, the reaction was diluted with 250 ml diethyl ether and filtered through celite. The celite pad was rinsed with 250 mL diethyl ether and the combined filtrates concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexanes containing from 0-9percent ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 2.02 gm (75percent) of the title compound. ISMS: m/e = 346 (M+H)

Reference： [1] Patent: EP1204660, 2004, B1, . Location in patent: Page 17

6
[ 346424-89-3 ]
[ 190906-92-4 ]

Reference： [1] Patent: US2003/225281, 2003, A1, . Location in patent: Page 14-15

7
[ 1382774-58-4 ]
[ 24424-99-5 ]
[ 190906-92-4 ]

Yield	Reaction Conditions	Operation in experiment
40%	With sodium hydroxide In water at 20℃;	Description 156; 1.1-Dimethvlethvl 2-methvl-4-oxo-1-piperidinecarboxvlate (D156); To a solution of 2-methyl-4-piperidinone acetate (D154) (14g, 0.081 mol) in NaOH1M (30 ml) was added di-ferf butyl carbonate (18g, 0.081 mol) and the reactionmixture was stirred overnight at 20°C. The reaction mixture was diluted with ethylacetate (50ml) and extracted several time (50ml). The combined organic layers weredried (Na₂SO₄) and evaporated in vacua to give a crude oil that was purified on asilica pad by eluting with 11percent ethyl acetate in cyclohexane to afford the titlecompound (6.95g, 40percent) as a pale yellow oil;

Reference： [1] Patent: WO2006/24517, 2006, A1, . Location in patent: Page/Page column 104

8
[ 620-08-6 ]
[ 190906-92-4 ]

Reference： [1] Patent: CN103601669, 2016, B,

9
[ 190906-92-4 ]
[ 281652-10-6 ]

Yield	Reaction Conditions	Operation in experiment
0.53 g	With diethylamino-sulfur trifluoride In dichloromethane at 0 - 10℃;	A solution of 1-boc-2-methylpiperidin-4-one (0.55 g, 2.6 mmol, 1 eq) in dry DCM(7.5 mL) was cooled at 0°C and DAST (0.68 mL, 5.2 mmol, 2 eq) was added dropwise.The reaction was stirred overnight at 10°C, then diluted with DCM (10 mL), washed withNaHCO3 sat. solution (lOmL), 5percent citric acid solution in water (10 mL) and finally withbrine (10 mL). The organic layer was dried over anh. Na2504, filtered and evaporated.The residue was purified by flash chromatography on silica gel (eluent 10/90 EtOAc/petroleum ether) affording 0.53 g of pure 1-N-boc-4,4-difluoromethylpiperidine as white solid.

Reference： [1] Patent: WO2015/118019, 2015, A1, . Location in patent: Page/Page column 38

10
[ 190906-92-4 ]
[ 790667-43-5 ]
[ 790667-49-1 ]

Yield	Reaction Conditions	Operation in experiment
35%	Resolution of racemate	Resolve racemic 2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (15.0 g) using a CHIRALPAK ADTM (4.6 x 250nm) column, eluting with absolute ethanol at a flow rate of 1.0 ML/MINUTE (UV=220nm) to obtain isomer 1 (5.28 g, 35percent) and isomer 2 (5.01 g, 33percent). 1H NMR (CDCl3) : 4.7 (m, 1H), 4.2 (m, 1H), 3.3 (m, 1H), 2.7 (m, 1H), 2.5 (m, 1H), 2.3 (m, 1H), 2.2 (m, 1H), 1.5 (s, 9H), 1.2 (d, 3H); identical for both isomers.

Reference： [1] Patent: WO2004/94380, 2004, A1, . Location in patent: Page 26-27

11
[ 190906-92-4 ]
[ 790667-43-5 ]
[ 790667-49-1 ]

Yield	Reaction Conditions	Operation in experiment
35%	Resolution of racemate	Resolve racemic 2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (15.0 g) using a CHIRALPAK ADTM (4.6 x 250nm) column, eluting with absolute ethanol at a flow rate of 1.0 ML/MINUTE (UV=220nm) to obtain isomer 1 (5.28 g, 35percent) and isomer 2 (5.01 g, 33percent). 1H NMR (CDCl3) : 4.7 (m, 1H), 4.2 (m, 1H), 3.3 (m, 1H), 2.7 (m, 1H), 2.5 (m, 1H), 2.3 (m, 1H), 2.2 (m, 1H), 1.5 (s, 9H), 1.2 (d, 3H); identical for both isomers.

Reference： [1] Patent: WO2004/94380, 2004, A1, . Location in patent: Page 26-27

[ 190906-92-4 ] Synthesis Path-Downstream 1~78

1
[ 16587-47-6 ]
[ 190906-92-4 ]
[ 346591-72-8 ]

Yield	Reaction Conditions	Operation in experiment
45%		EXAMPLE 24 [0196] Preparation of (2S)-(-)-1-(1H-2-Methylindol-4-yl)oxy-3-[(2R,4R)-2-methyl-4-(6-methylbenzo[b]thiophen-2'-yl)piperidinyl]-2-propanol oxalate. [CHEMMOL-00060] [0197] Preparation of N-t-Butoxycarbonyl-4-hydroxy-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine. [CHEMMOL-00061] [0198] Scheme IA, Step A: To a solution of <strong>[16587-47-6]6-methylbenzo[b]thiophene</strong> (6.11 g, 41.21 mmol) in dry THF (90 mL) at -78 C. was added 1.6 M n-BuLi in hexanes (30.9 mL, 49.4 mmol). The solution was stirred at -78 C. for 40 min. The N-t-butoxycarbonyl-2-methyl-4-piperdone (5.27 g, 24.7 mmol) dissolved in THF (47 mL) was added via a cannula at -78 C. The reaction mixture as stirred at -78 C. for 3 h. The reaction was then quenched with 200 mL of water. The mixture was extracted (3×200 mL) with EtOAc. The combined organic layers were dried over MgSO4 and filtered. The filtrate was concentrated and run through a column of silica gel (17% EtOAc/hexanes) to give the intermediate title compound with some unreacted N-t-butoxycarbonyl-2-methyl-4-piperidone as an orange oil (6.75 9, 45%). IR (KBr) 1680, 1418, 1366, 1158 cm-1. Ion Spray MS 420 (M+CH3COO-)-.

Reference： [1]Patent: US2004/6229,2004,A1 .Location in patent: Page/Page column 28
[2]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2393 - 2397

2
[ 14315-11-8 ]
[ 190906-92-4 ]
4-hydroxy-2-methyl-4-(4-methyl-benzo[b]thiophen-2-yl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2393 - 2397

3
[ 66490-20-8 ]
[ 190906-92-4 ]
[ 346591-88-6 ]

Yield	Reaction Conditions	Operation in experiment
36%		EXAMPLE 43 [0279] Preparation of (2S)-(-)-3-[(2R,4R)-4-(6-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanol oxalate (A) and (2S)-(+)-3-[(2S,4S)-4-(6-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanol oxalate (B). [CHEMMOL-00089] [0280] Preparation of N-t-Butoxycarbonyl-4-(6-chlorobenzo[b]thiophen-2-yl)-4-piperidinol. [CHEMMOL-00090] [0281] Scheme IA, Step A: A solution of 6-chlorobenzo[b]thiophene (3.3424 g, 19.8 mmol, prepared in example 41) in dry THF (90 mL) at -78 C. was treated with 1.6 M n-BuLi in hexanes (12.5 mL, 20.0 mmol) for 1 h. To this was cannulated (N-t-butoxycarbonyl-2-methyl-4-piperidone (420152, 2.6672 g, 12.5 mmol) in THF (10 mL) and the reaction mixture was stirred at -78 C. for 3 h. The cold bath was removed and the reaction was quenched after 10 min with 100 mL of saturated aqueous NaHCO3 solution and the mixture was extracted with EtOAc (3×250 mL). The organic layers were washed with 100 mL of brine, combined, dried over MgSO4 and concentrated. Purification by PrepLC 500A (0-30% Et2O/hexanes) afforded unreacted 6-chlorobenzo[b]thiophene (2.0047 g, 60%) N-t-butoxycarbonyl-4-(4-chlorobenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol (0.2528 g, 3.3%, resulted from the 4-chloro contamination in the starting 6-chlorobenzo[b]thiophene), unreacted piperidone (0.4184 g, 16%) and the intermediate title piperidinol (2.7510 g, 36%). Ion Spray MS 382.0 (M+H)+.

Reference： [1]Patent: US2004/6229,2004,A1 .Location in patent: Page/Page column 39-40
[2]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2393 - 2397

4
[ 20532-33-6 ]
[ 190906-92-4 ]
N-t-butoxycarbonyl-4-(5-chlorobenzo[b]thiophen-2-yl)-4-(2-methyl)piperidinol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 33 [0221] Preparation of (2S)-3-[4-(5-Chlorobenzo[b]thiophen-2-yl)-2-methyl-1,2,3,6-tetrahydropyridyl]-1-(1H-indol-4-yl)oxy-2-propanols oxalate. [CHEMMOL-00072] [0222] Preparation of 4-(5-Chlorobenzo[b]thiophen-2-yl)-2-methyl-1,2,3,6-tetrahydropyridine and 4-(5-Chlorobenzo[b]thiophen-2-yl)-2-methyl-1,2,5,6-tetrahydropyridine. [CHEMMOL-00073] [0223] Scheme IA, Step A: A solution of <strong>[20532-33-6]5-chlorobenzo[b]thiophene</strong> (505.4 mg, 3.0 mmol) in dry THF (10 mL) at -78 C. is treated with 1.6 M n-BuLi in hexanes (2.2 mL, 3.3 mmol) for 1 h. To this is cannulated N-t-butoxycarbonyl-4-(2-methyl)piperidone (3.3 mmol) in THF (5 mL) and the reaction mixture is stirred at -78 C. for 2h, warmed to room temperature and stirred for an additional 1 h. The reaction is then quenched with 40 mL of saturated aqueous NaHCO3 solution. The mixture is then extracted with (3×50 mL) EtOAc. The organic layers are washed with 40 mL of brine, combined, dried over MgSO4 and concentrated. Purification with flash chromatography (25% EtOAc/hexanes) affords the intermediate title compound which is carried on to the next step.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2393 - 2397
[2]Patent: US2004/6229,2004,A1 .Location in patent: Page/Page column 32

5
[ 66490-33-3 ]
[ 190906-92-4 ]
[ 346591-85-3 ]

Yield	Reaction Conditions	Operation in experiment
15%		Preparation of (N-t-Butoxycarbonyl-4-(4-chlorobenzo[b]thiophen-2-yl-2-methyl-4-piperidinol. [CHEMMOL-00086] [0268] Scheme IA, Step A: A solution of 4-chlorobenzo[b]thiophene (1.6315 g, 9.67 mmol) in dry THF (20 mL) at -78 C. was treated with 1.6 M n-BuLi in hexanes (7.9 mL, 12.6 mmol) for 1 h. To this was cannulated (N-t-butoxycarbonyl-2-methyl-4-piperidone (420152, 3.2063 g, 15.0 mmol) in THF (15 mL) and the reaction mixture was stirred at -78 C. for 2h and then overnight while allowed to warm to -5 C. The reaction was quenched with 50 mL of saturated aqueous NaHCO3 solution and the mixture was extracted with EtOAc (3×100 mL). The organic layers were washed with 50 mL of brine, combined, dried over MgSO4 and concentrated. Purification by PrepLC 500A (0-15% EtOAc/hexanes) afforded unreacted 4-chlorobenzo[b]thiophene (1.2646 g, 78%), the intermediate title compound (566.9 mg, 15%), and unreacted piperidone (2.4304 g, 76%). Ion Spray MS 382 (M+H)+.

Reference： [1]Patent: US2004/6229,2004,A1 .Location in patent: Page/Page column 38
[2]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2393 - 2397

6
[ 90560-10-4 ]
[ 190906-92-4 ]
[ 346591-65-9 ]

Yield	Reaction Conditions	Operation in experiment
69%	With n-butyllithium; In tetrahydrofuran; hexane; at -78℃; for 3.75h;	To a solution of <strong>[90560-10-4]6-methoxybenzo[b]thiophene</strong> (1.93 g, 11.7 mmol) in dry THF (55 mL) at -78° C. was added 1.6 M n-BuLi in hexanes (8.06 mL, 12.9 mmol). The solution was stirred at -78° C. for 45 min. N-t-Butoxycarbonyl-2-methyl-4-piperidone (1.50 g, 7.03 mmol) dissolved in THF (40 mL) was added via a cannula at -78° C. The reaction mixture was stirred at -78° C. for 3 h. The reaction was then quenched with 55 mL of saturated aqueous NH4Cl solution. The mixture was extracted (1.x.400 mL) with EtOAc. The combined organic layers were then dried over MgSO4 and filtered. The filtrate was concentrated and purified by medium pressure chromatography (20percent EtOAc/hexanes) to give the intermediate title compound as a white foam (1.82 g, 69percent). IR (KBr) 3422 (br), 1690, 1666 cm1. FDMS m/e=378 (M+).
26 - 69%		Preparation of (+/-)N-t-Butoxycarbonyl-4-hydroxy-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine. [CHEMMOL-00033] [0138] Scheme IA, Step A: To a solution of <strong>[90560-10-4]6-methoxybenzo[b]thiophene</strong> (5.0 g, 30.4 mmol) in dry THF (60 mL) at -78° C. was added 1.6 M n-BuLi in hexanes (20.9 mL, 33.44 mmol). The solution was stirred at -78° C. for 90 min. The N-t-butoxycarbonyl-2-methyl-4-piperidone (3.89 g, 18.24 mmol) dissolved in THF (40 mL) was added via a cannula at -78° C. The reaction mixture was stirred at -78° C. for 3 h. The reaction was then quenched with 75 mL of saturated aqueous NaCl solution. The mixture was extracted with (1.x.75 mL, 2.x.125 mL) EtOAc. The combined organic layers were dried over CaCl2 and filtered. The filtrate was concentrated and purified by medium pressure chromatography (30percent Et2O/hexanes) to give the intermediate title compound as a yellow foam (1.798 g, 26percent). IR (KBr) 3009, 2978 cm-. Ion Spray MS 378 (M+H)+; 436 (M+CH3COO-)-.; EXAMPLE 45 [0292] Preparation of (2S)-(-)-1-(1H-Indol-4-yl)oxy-3-[(2R,4R)-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-2-propanol oxalate. [CHEMMOL-00093] [0293] Preparation of N-t-Butoxycarbonyl-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol. [CHEMMOL-00094] [0294] Scheme IA, Step A: To a solution of <strong>[90560-10-4]6-methoxybenzo[b]thiophene</strong> (1.93 g, 11.7 mmol) in dry THF (55 mL) at -78° C. was added 1.6 M n-BuLi in hexanes (8.06 mL, 12.9 mmol). The solution was stirred at -78° C. for 45 min. N-t-Butoxycarbonyl-2-methyl-4-piperidone (1.50 g, 7.03 mmol) dissolved in THF (40 mL) was added via a cannula at -78° C. The reaction mixture was stirred at -78° C. for 3 h. The reaction was then quenched with 55 mL of saturated aqueous NH4Cl solution. The mixture was extracted (1.x.400 mL) with EtOAc. The combined organic layers were then dried over MgSO4 and filtered. The filtrate was concentrated and purified by medium pressure chromatography (20percent EtOAc/hexanes) to give the intermediate title compound as a white foam (1.82 g, 69percent). IR (KBr) 3422 (br), 1690, 1666 cm-1 . FDMS m/e=378 (M+).

Reference： [1]Patent: US2003/232833,2003,A1 .Location in patent: Page 17
[2]Patent: US2004/6229,2004,A1 .Location in patent: Page/Page column 18; 41
[3]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2393 - 2397

7
[ 3781-90-6 ]
[ 190906-92-4 ]
[ 346592-55-0 ]

Yield	Reaction Conditions	Operation in experiment
48%		Scheme IA, Step A: To a solution of 4-methoxybenzo[b]thiophene (7.70 g, 46.9 mmol) in dry THF (230 mL) at -78 C. was added 1.6 M n-BuLi in hexanes (32.2 mL, 51.6 mmol). The solution was stirred at -78 C. for 45 min. N-t-Butoxycarbonyl-2-methyl-4-piperidone (6.00 g, 28.1 mmol) dissolved in THF (40 mL) was added via a cannula at -78 C. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. The reaction was then quenched with 600 mL of saturated aqueous NH4Cl solution. The mixture was extracted (1×1 L) with EtOAc. The combined organic layers were then dried over MgSO4 and filtered. The filtrate was concentrated and purified by medium pressure chromatography (silica gel, 25% Et2O/hexanes) to give the intermediate title compound as a white foam (5.06 g, 48%). mp 73-76 C. IR (CHCl3) 3474, 3350 (br) cm-1. IR (CHCl3) 3350 (br), 1680 cm-1. Ion Spray MS 378 (M+H)+; 260 (M-(Boc+H2O))+; 304 (M-74)+ (base peak); 436 (M+CH3COO-)-.

Reference： [1]Patent: US2003/232833,2003,A1 .Location in patent: Page 20
[2]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2393 - 2397

8
[ 120568-06-1 ]
[ 190906-92-4 ]
[ 346591-95-5 ]

Yield	Reaction Conditions	Operation in experiment
68%		Preparation of N-t-Butoxycarbonyl-2-methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)-4-piperidinol. [0317] Scheme IA, Step A: To a solution of 4-trifluoromethylbenzo[b]thiophene (0.440 g, 2.18 mmol) in dry THF (10 mL) at -78 C. was added 1.6 M n-BuLi in hexanes (1.50 mL, 2.39 mmol). The solution was stirred at -78 C. for 30 min. N-t-Butoxycarbonyl-2-methyl-4-piperidone (0.464 g, 2.18 mmol) dissolved in THF (5 mL) was added via a cannula at -78 C. The reaction mixture was warmed to room temperature over 18 h. The reaction was then quenched with 50 mL of saturated aqueous NH4Cl solution. The mixture was extracted (3×100 mL) with EtOAc. The combined organic layers were then dried over MgSO4, concentrated and purified by silica gel chromatography (10% EtOAc/hexanes) to give the intermediate title compound as a white foam (0.617 g, 68%). IR (KBr) 3416 (br), 1663 cm-1. Ion Spray MS 416 (M+H)+; 298 (M-(BOC+H2O))+; 342 (M-73)+ (base peak); 890 (2M+CH3COO).

Reference： [1]Patent: US2004/6229,2004,A1 .Location in patent: Page/Page column 44
[2]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2393 - 2397

9
[ 28560-16-9 ]
[ 190906-92-4 ]
[ 346592-19-6 ]

Yield	Reaction Conditions	Operation in experiment
37%		EXAMPLE 63 [0379] Preparation of (2S)-(-)-3-[(2R,4R)-4-(4,6-Dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol oxalate. [CHEMMOL-00116] [0380] Preparation of N-t-Butoxycarbonyl-4-(4,6-dimethylbenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol. [0381] Scheme IA, Step A: To a solution of 4,6-dimethylbenzo[b]thiophene (3.71 g, 22.9 mmol) in dry THF (115 mL) at -78 C. was added 1.6 M n-BuLi in hexanes (15.7 mL, 25.2 mmol). The solution was stirred at -78 C. for 1 h. N-t-butoxycarbonyl-2-methyl-4-piperidone (4.39 g, 20.6 mmol) dissolved in THF (10 mL) was added via a cannula at -78 C. The reaction mixture was allowed to warm to room temperature over 19 h. The reaction was then quenched with 240 mL of saturated aqueous NH4Cl solution. The mixture was extracted (3×500 mL) with EtOAc. The combined organic layers were dried over MgSO4 and filtered. The filtrate was concentrated and purified by medium pressure chromatography (silica gel, 10% EtOAc/hexanes) to give the intermediate title compound as a yellow foam (4.11 g, 37%). IR (CHCl3) 3550 (br), 1680 cm-1. Ion Spray MS 376 (M+H)+; 302 (M-74)+ (base peak); 434 (M+CH3COO-)-. 1HNMR (CDCl3) 7.42 (s, 1H), 7.14 (s, 1H), 6.94 (s, 1H), 4.45 (br m, 1H), 4.03-4.09 (br m, 1H), 3.35 (brt, 1H), 2.51 (s, 3H), 2.39 (s, 3H), 2.19 (dd, J=14.7, 6.8 Hz, 1H), 1.92-2.09 (m, 3H), 1.59 (s, 1H), 1.47 (s, 9H), 1.39 (d, J=7.3 Hz, 3H).

Reference： [1]Patent: US2004/6229,2004,A1 .Location in patent: Page/Page column 51
[2]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2393 - 2397

10
[ 205055-10-3 ]
[ 190906-92-4 ]
[ 346592-50-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2393 - 2397

11
[ 346592-74-3 ]
[ 190906-92-4 ]
[ 346592-75-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2393 - 2397

12
[ 310466-38-7 ]
[ 190906-92-4 ]
[ 346592-06-1 ]

Yield	Reaction Conditions	Operation in experiment
14%		EXAMPLE 56 [0349] Preparation of (2S)-3-[(2R,4R)-4-(4-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanol oxalate. [CHEMMOL-00107] [0350] Preparation of N-t-Butoxycarbonyl-4-(4-fluorobenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol. [0351] Scheme IA, Step A: To a solution of 4- and 6-fluorobenzo[b]thiophene (12.4 g, 81.7 mmol, prepared in example 55) in dry THF (415 mL) at -78 C. was added 1.6 M n-BuLi in hexanes (56.4 mL, 90.2 mmol). The solution was stirred at -78 C. for 1.5 h. N-t-butoxycarbonyl-2-methyl-4-piperidone (15.7 g, 73.5 mmol) dissolved in THF (40 mL) was added via a cannula at -78 C. The reaction mixture was stirred at -78 C. for 4 h. The reaction was then quenched with 300 mL of saturated aqueous NH4Cl solution. The mixture was extracted (2×500 mL) with EtOAc. The combined organic layers were then dried over MgSO4 and filtered. The filtrate was concentrated and purified by medium pressure chromatography (15% EtOAc/hexanes) to give the title compound as a white foam (3.66 g, 14%). 1HNMR (CDCl3) 7.54 (d, J=8.8 Hz, 1H), 7.25 (s, 1H), 7.22 (m, 1H), 6.96 (dd, J=9.0, 8.1, 1H), 4.31 (distt, 1H), 3.85 (m, 1H), 3.18 (dt, J=13.0, 2.9 Hz, 1H), 2.02-1.82 (m, 1H), 1.64 (dd, J=14.2, 6.8, 1H), 1.54-1.44 (m, 11H), 1.28 (d, J=6.8 Hz, 3H)

Reference： [1]Patent: US2004/6229,2004,A1 .Location in patent: Page/Page column 47-48
[2]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2393 - 2397

13
[ 1196-09-4 ]
[ 190906-92-4 ]
[ 346590-68-9 ]

Yield	Reaction Conditions	Operation in experiment
76%		EXAMPLE 116 [0623] Preparation of 1-(t-Butyloxycarbonyl)-2-methyl-4-(3-methylbenzo[b]thiophen-5-yl)-piperidin-4-ol. [CHEMMOL-00186] [0624] Scheme IA, step A: To a solution of 5-bromo-3-methylbenzo[b]thiophene (3.621 g, 15.9 mmol, from preparation 8) in diethyl ether (100 mL) was added magnesium (0.775 g, 31.9 mmol) and 1,2-dibromoethane (1.37 mL, 15.9 mmol). The mixture was heated at reflux for 4 hours then cooled to 20 C. for 18 hours. A solution of 1-(t-butyloxycarbonyl)-2-methyl-4-piperidone (3.74 g, 17.5 mmol) in tetrahydrofuran (15 mL) was added dropwise to the mixture. The mixture was stirred for 24 hours, then diluted with saturated ammonium chloride and extracted with ethyl acetate three times. The residue was purified by silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent) to give 4.36 g (76%) of the intermediate title compound as a yellow amorphous solid. FDMS m/e=362 (M++1).

Reference： [1]Patent: US2004/6229,2004,A1 .Location in patent: Page/Page column 80
[2]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2653 - 2656

14
[ 128851-73-0 ]
[ 190906-92-4 ]
4-benzofuran-6-yl-4-hydroxy-2-methyl-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2653 - 2656

15
[ 128868-60-0 ]
[ 190906-92-4 ]
4-benzofuran-4-yl-4-hydroxy-2-methyl-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-bromo-1-benzofuran With 1,1-Dibromoethane; magnesium In tetrahydrofuran; diethyl ether Stage #2: tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate In tetrahydrofuran; diethyl ether

Reference： [1]Rocco, Vincent P.; Spinazze, Patrick G.; Kohn, Todd J.; Honigschmidt, Nicholas A.; Nelson, David L.; Bradley Wainscott; Ahmad, Laura J.; Shaw, Janice; Threlkeld, Penny G.; Wong, David T.; Takeuchi, Kumiko [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 10, p. 2653 - 2656]

16
[ 38622-91-2 ]
[ 190906-92-4 ]
[ 866560-07-8 ]

Yield	Reaction Conditions	Operation in experiment
	With ethanol; potassium tert-butylate; In 1,2-dimethoxyethane; at 0 - 20℃; for 18h;Heating / reflux;	tert-Butyl 4-cyano-2-methylpiperidine-1-carboxylate; A solution of tert-butyl 2-methyl4-oxopiperidine-1-carboxylate (375 mg, 1.76 mmol) and p-toluenesulphonylmethyl isocyanide (790 mg, 4.05 mmol) was formed in 1,2-dimethoxyethane (10 mL) and cooled in an ice-bath. Ethanol (0.23 mL, 4.05 mmol) was added followed by the portionwise addition of potassium t-butoxide (691 mg, 6.16 mmol). The mixture was allowed to warm to room temperature then heated at reflux for 18 hours. The mixture was allowed to cool then poured into brine (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over magnesium sulphate (anhydrous), filtered and evaporated. The residue was purified by flash column chromatography on silica gel using a 20% ethyl acetate: 80% iso-hexane mixture as eluent to afford the crude product: tert-butyl 4-cyano-2-methylpiperidine-1-carboxylate: m/z (ES) 225 (M+H).

Reference： [1]Patent: US2007/254880,2007,A1 .Location in patent: Page/Page column 50

17
[ 346424-89-3 ]
[ 190906-92-4 ]

Yield	Reaction Conditions	Operation in experiment
		The solution of amine (145 g, 0.475 mol) in THF (200 mL) was added dropwise over one hour to a cooled solution of potassium t-butoxide (58.9 g) in THF (500 mL). The mixture was stirred at 0 C. for 2.5 hours and then warmed to room temperature over 1 hours with stirring. Another 50 mL of 1.0 M potassium t-butoxide in THF was added. After one hour, the solvent was removed under vacuum and the residue was dissolved in ethyl acetate (1 L). The organic solution was washed with saturated ammonium chloride (2?500 mL) which was back extracted with ethyl acetate (2?500 mL). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide 120. 6 g of crude material as an oil. This oil was then treated with 5 N HCl (700 mL) at reflux for about 14.5 hours. After cooling, the solution was rinsed with a mixture of ethyl acetate/diethyl ether (1:1, 2?300 mL). The aqueous layer was then concentrated to provide the piperidone salt. The above piperidone salt was then dissolved in water (200 mL) and THF (250 mL). The solution was then cooled to 0 C. and treated with 50% sodium hydroxide (35 mL) followed by dropwise addition of tert-butoxycarbonyl anhydride (106.7 g) in THF (100 mL) over one hour. The ice bath was then removed and the solution was stirred at room temperature for about 4 days. The pH was then adjusted to about 8 to 9. The THF was then removed under vacuum and the mixture is taken up in ethyl acetate (500 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2?500 mL). The organic extracts were combined, washed with brine (300 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to provide 36.81 g of title compound.

Reference： [1]Patent: US2003/225281,2003,A1 .Location in patent: Page 14-15

18
2-methyl-piperidin-4-one hydrochloride [ No CAS ]
[ 24424-99-5 ]
[ 190906-92-4 ]

Yield	Reaction Conditions	Operation in experiment
93%	With dmap; In tetrahydrofuran; at 0℃; for 2h;	Step 1. tert-butyl 2-methyl-4-oxopiperidine-l-carboxylate [0757] Di-tert-butyl dicarbonate (1.09 g, 5.01 mmol) was added to a 0 C solution of 2- methylpiperidin-4-one hydrochloride (1 : 1 mixture of isomers, 0.500 g, 3.34 mmol) and DMAP (0.817 g, 6.68 mmol) in dry THF (10 mL), and the resulting mixture was stirred at 0 C for 2 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 mL) and ethyl acetate (70 mL) was added. The aqueous phase was separated and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 25-35% ethyl acetate in hexanes) to afford tert-butyl 2-methyl-4-oxopiperidine- 1 -carboxylate (0.660 g, 93%) as a white solid. 1H NMR (300 MHz, DMSO-i delta ppm 1.06 (d, J=6.74 Hz, 3 H), 1.40 (s, 9 H), 2.1 1 - 2.25 (m, 2 H), 2.36 - 2.45 (m, 1 H), 2.68 (dd, J=14.51, 6.6 Hz, 1 H), 3.25 - 3.36 (m, 1 H), 3.93 - 4.06 (m, 1 H), 4.42 - 4.48 (m, 1 H).
	With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 96h;pH 8 - 9;	The piperidone salt was then dissolved in water (200 mL) and THF (250 mL). The solution was then cooled to 0 C. and treated with 50% sodium hydroxide (35 mL) followed by dropwise addition of tert-butoxycarbonyl anhydride (106.7 g) in THF (100 mL) over one hour. The ice bath was then removed and the solution was stirred at room temperature for about 4 days. The pH was then adjusted to about 8 to 9. The THF was then removed under vacuum and the mixture is taken up in ethyl acetate (500 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×500 mL). The organic extracts were combined, washed with brine (300 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to provide 36.81 g of title compound.

Reference： [1]Patent: WO2015/74064,2015,A2 .Location in patent: Paragraph 0757
[2]Patent: US2003/232833,2003,A1 .Location in patent: Page 15

19
[ 71322-99-1 ]
[ 24424-99-5 ]
[ 190906-92-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In chloroform; water;	A mixture of 2-methyl-4-piperidone (16.3 g), NaHCO3 (9.5 g) and di-tert-butyl dicarbonate (17.4 g) in water (50 ml) and CHCl3 (125 ml) was stirred at room temperature for six hours. 40 ml of water was then added and phases were separated. The aqueous layer was extracted with CHCl3 (4*30 ml) and the combined organic layer was dried over MgSO4 and concentrated to provided a residue which was purified by silica gel column chromatography to provide the N-Boc-2-methyl-4-piperidone (13.3 g).
	In tetrahydrofuran; water; at 0 - 20℃; for 96h;	The above piperidone salt was then dissolved in water (200 mL) and THF (250 mL). The solution was then cooled to 0 C. and treated with 50% sodium hydroxide (35 mL), followed by dropwise addition of tert-butoxycarbonyl anhydride (106.7 g) in THF (100 mL) over one hour period. The ice bath was then removed and the solution was stirred at room temperature for about 4 days. The pH was adjusted to about 8 to 9. The THF was then removed under vacuum and the mixture was taken up in ethyl acetate (500 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×500 mL). The organic extracts were combined, washed with brine (300 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to provide 36.81 g of the title compound
	With sodium carbonate; In chloroform; water; at 20℃; for 6h;	[0452] A mixture of 2-methyl-4-piperidone (16.3 g), NaHCO3 (9.5 g) and di-tert-butyl dicarbonate (17.4 g) in water (50 ml) and CHCl3 (125 ml) was stirred at room temperature for six hours. 40 ml of water was then added and phases were separated. The aqueous layer was extracted with CHCl3 (4×30 ml) and the combined organic layer was dried over MgSO4 and concentrated to provided a residue which was purified by silica gel column chromatography to provide the N-Boc-2-methyl-4-piperidone (13.3 g).

	With sodium hydrogencarbonate; In chloroform; water; at 20℃; for 16h;	A mixture of 12.4 gm (55 mMol) 2-methyl-4-oxopiperidine, 6.89 gm (82 mMol) sodium bicarbonate, and 13.1 gm (60 mMol) di(tert-butoxy) dicarbonate in 40 mL water and 100 mL chloroform was stirred at room temperature for 16 hours. The mixture was diluted with 25 mL deionized water and the phases were separated. The aqueous phase was extracted with 4 x 25 mL chloroform. The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 3:1 hexane:ethyl acetate containing 1% triethylamine. Fractions containing product were combined and concentrated under reduced pressure to provide 12.0 gm of the title compound as a slightly yellow oil.
		A solution of 160.0 gm (733 MMol) di(tert-butyl) dicarbonate in 300 ML tetrahydrofuran was added dropwise to a solution of 100.0 gm (698 MMol) 1,4-dioxa-8-azaspiro-[4,5]decane in 800 ML tetrahydrofuran over 1 hour.. The reaction mixture was stirred for 30 minutes after the addition was complete and was then concentrated under reduced pressure.. The residue was dissolved in 600 ML diethyl ether and was washed sequentially with 2 x 250 ML deionized water, 2 x 250 ML 5% aqueous sodium bicarbonate, and 250 ML saturated aqueous sodium chloride.. The organic phase was dried over potassium carbonate and concentrated under reduced pressure to provide 173.3 gm 8-(tert-butoxycarbonyl)-1,4-dioxa-8-azaspiro[4,5]decane. A solution of 76.0 gm (312 MMol) 8-(tert-butoxycarbonyl)-1,4-dioxa-8-azaspiro[4,5]decane in 760 ML diethyl ether was cooled to -78C and was treated with freshly distilled 49.5 ML (328 MMol) N,N,N',N'-tetramethylethylenediamine.. One equivalent of a sec-butyllithium solution was added dropwise over 1.5 hours, maintaining the temperature of the reaction mixture below -70C. After stirring for 4 hours at -78C, 38.9 ML (625 MMol) iodomethane were added over 10 minutes.. The reaction mixture was stirred for 10 minutes and was then allowed to warm gradually to room temperature.. The reaction mixture was treated with 300 ML deionized water and the phase were separated.. The aqueous phase was extracted with 300 ML diethyl ether.. The organic phases were combined, washed with 4 x 250 ML deionized water, dried over potassium carbonate and concentrated under reduced pressure.. The residue was subjected to silica gel chromatography, eluding with a gradient of hexanes containing from 7-20% ethyl acetate.. Fractions containing product were combined and concentrated under reduced pressure to provide 57.1 gm (71%) 7-methyl-8-(tert-butoxycarbonyl)-1,4-dioxo-8-azaspiro[4,5]decane as a clear oil.. This material was cooled to 0-5C and 279.2 ML trifluoroacetic acid were added.. After stirring for 10 minutes, 5.2 ML deionized water were added and the reaction mixture was heated at reflux for 2.5 hours.. The reaction mixture was cooled to room temperature and concentrated under reduced pressure.. The residue was dissolved in 60 ML ethyl acetate and 120 ML diethyl ether were added over 30 minutes with stirring.. The suspension was held in a freezer for 2 hours, filtered, and the solids washed with 30 ML cold diethyl ether to provide 23.5 gm (71.3%) 2-methyl-4-oxopiperidine as a white solid. A mixture of 12.4 gm (55 MMol) 2-methyl-4-oxopiperidine, 6.89 gm (82 MMol) sodium bicarbonate, and 13.1 gm (60 MMol) di(tert-butoxy) dicarbonate in 40 ML water and 100 ML chloroform was stirred at room temperature for 16 hours.. The mixture was diluted with 25 ML deionized water and the phases were separated.. The aqueous phase was extracted with 4 x 25 ML chloroform.. The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure.. The residue was subjected to silica gel chromatography, eluding with 3:1 hexane:ethyl acetate containing 1% triethylamine.. Fractions containing product were combined and concentrated under reduced pressure to provide 12.0 gm of the title compound as a slightly yellow oil.

Reference： [1]Patent: US2004/186292,2004,A1
[2]Patent: US2004/6229,2004,A1 .Location in patent: Page/Page column 16
[3]Patent: US2004/63744,2004,A1 .Location in patent: Page/Page column 73
[4]Patent: EP1204659,2003,B1 .Location in patent: Page/Page column 29-30
[5]Patent: EP1204660,2004,B1 .Location in patent: Page 18

20
[ 190906-92-4 ]
[ 208046-23-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 3.5h;Inert atmosphere;	(i) tert-Butyl 4-hydroxy-2-methylpiperidine-1-carboxylate To a solution of 1-Boc-2-methyl-4-piperidinone (1.0 g, 4.68 mmol) in methanol (10 mL) at 0 C. was added sodium borohydride (265 mg, 7.03 mmol) portionwise. The reaction was stirred under an atmosphere of nitrogen at 0 C. for 1 hour. It was then allowed to reach room temperature and stirred for a further 2.5 hours. The reaction was deemed complete by its LC-MS analysis and quenched using saturated ammonium chloride aqueous solution and the methanol removed under reduced pressure. The remaining aqueous layer was extracted using dichloromethane (25 ml×3), the combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the desired product, tert-butyl 4-hydroxy-2-methylpiperidine-1-carboxylate (1.0 g, 100%). [0615] MS ES+: 216.4
100%	With methanol; sodium tetrahydroborate; at 0 - 25℃; for 3.5h;Inert atmosphere;	(i) te -Butyl 4-hydroxy-2-methylpiperidine-l-carboxylate To a solution of l-Boc-2-methyl-4-piperidinone (l.Og, 4.68 mmol) in methanol (10 mL) at 0C was added sodium borohydride (265mg, 7.03 mmol) portionwise. The reaction was stirred under an atmosphere of nitrogen at 0C for 1 hour. It was then allowed to reach room temperature and stirred for a further 2.5 hours. The reaction was deemed complete by its LC-MS analysis and quenched using saturated ammonium chloride aqueous solution and the methanol removed under reduced pressure. The remaining aqueous layer was extracted using dichloromethane (25ml x 3), the combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the desired product, ieri-butyl 4-hydroxy-2-methylpiperidine-l-carboxylate (l.Og, 100%). MS ES+: 216.4
	With lithium aluminium tetrahydride; at 0 - 20℃; for 1h;	To a suspension of lithium aluminum hydride (1.30 g) in tetrahydrofuran (50 ml) was added dropwise 1-t-butoxycarbonyl-2-methyl-4-piperidone (2.40 g) obtained in reference example 83 with stirring under ice-cooling in a nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere.. After stirring, to the reaction mixture was added sodium sulfate decahydrate, and the resulting mixture was furthermore stirred at room temperature for 1 hour.. After removing insoluble materials by filtration, the filtrate was evaporated in vacuo.. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (1:1) as the eluent to afford a low polar compound (0.95 g, yield: 39 %) and a high polar compound (1.02 g, yield: 42 %) of the title compound, separately, as yellow oily products. High polar compound; 1H NMR (500MHz, CDCl3) delta ppm: 1.14 (3H, d, J=7.0), 1.30-1.40 (1H, m), 1.45-1.55 (1H, m), 1.46 (9H, s), 1.80-1.85 (1H, m), 1.90-1.95 (1H, m), 2.85-2.95 (1H, m), 3.90-4.00 (1H, m), 4.00-4.10 (1H, m), 4.45-4.55 (1H, m). Low polar compound; 1H NMR (500MHz, CDCl3) 6 ppm: 1.33 (3H, d, J=7.0), 1.46 (9H, s), 1.60-1.75 (3H, m), 1.80-1.90 (1H, m), 3.20-3.30 (1H, m), 3.80-3.8 5 (1H, m), 4.15-4.20 (1H, m), 4.25-4.35 (1H, m).

With methanol; sodium tetrahydroborate; at 0 - 20℃;

Step A. Preparation of tert-butyl 4-hydroxy-2-methylpiperidine-l -carboxylate[00121] To a solution of tert-butyl 2-methyl-4-oxopiperidine-l -carboxylate (727 mg, 3.41 mmol, Small Molecules Inc.) in MeOH (6.0 mL) at 0 0C was added sodium borohydride (193 mg, 5.11 mmol, Aldrich) in several portions. The reaction mixture was stirred at 0 0C for 1 hr and warmed up to room temperature and continuously stirred for another 2.5 hrs. The resulting mixture was then quenched with saturated NH4Cl aqueous solution and evaporated under reduced pressure to remove MeOH followed by extraction with CH2Cl2 (3X). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound (745 mg) as a colorless sticky oil which was used without further purification.

Reference： [1]Patent: US2013/324576,2013,A1 .Location in patent: Paragraph 0612; 0613; 0614; 0615
[2]Patent: WO2013/179024,2013,A1 .Location in patent: Page/Page column 55
[3]Patent: EP1375482,2004,A1 .Location in patent: Page 153-154
[4]Patent: WO2010/9183,2010,A1 .Location in patent: Page/Page column 56

21
[ 126503-08-0 ]
[ 190906-92-4 ]

Yield	Reaction Conditions	Operation in experiment
48%	With toluene-4-sulfonic acid; In acetone; at 0 - 20℃;	To a solution of 1-t-butoxycarbonyl-2-methyl-4-piperidone ethylene ketal (6.00 g) obtained in reference example 82 in acetone (150 ml) was added p-toluenensulfonic acid monohydrate (4.40 g) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature overnight. After stirring, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed successively with a saturated sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to afford the title compound (2.40 g, yield: 48 %) as a yellow oil. 1H NMR (500MHz, CDCl3) delta ppm : 1.18 (3H, d, J=7.0), 1.49 (9H, s), 2.20-2.30 (1H, m), 2.30-2.40 (1H, m), 2.45-2.55 (1H, m), 2.65-2.70 (1H, m), 3.25-3.35 (1H, m), 3.90-4.05 (1H, m), 4.20-4.30 (1H, m).

Reference： [1]Patent: EP1375482,2004,A1 .Location in patent: Page 153

22
[ 140-29-4 ]
[ 190906-92-4 ]
[ 676490-95-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In methanol; at 65℃; for 4.5h;	[0454] Benzyl cyanide (2.75 g) and N-Boc-2-methyl-4-piperidone (5 g) were added into a solution of KOH (3.52 g) in MeOH (23 ml) and the mixture was stirred at 65 C. for 4.5 hours. Then, solvents were removed under vaccum to provide a residue which was dissolved in EtOAc (200 ml). The organic solution was washed with water and concentrated to gave another residue which was purified by silica gel column chromatography to afforded desired products (5.5 g).

Reference： [1]Patent: US2004/63744,2004,A1 .Location in patent: Page/Page column 73

23
[ 190906-92-4 ]
[ 362704-45-8 ]

Yield	Reaction Conditions	Operation in experiment
41%		To a slurry of sodium hydride (250 mg, 6.25 mmol) in tetrahydrofuran (25 mL) was added tert-butyl P,P-dimethylphosphonoacetate (1.36 g, 6.05 mmol). After 15-20 min, a solution of the ketone (1.2 g, 5.68 mmol) from reaction (108b) in tetrahydrofuran (10 mL) was added to this homogeneous solution. The mixture was stirred for 3 h and was quenched with water (15 mL). The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried, and concentrated. The crude material was purified by silica gel chromatography (methylene chloride) to give the desired ester (732 mg, 41%). MS found: (M+H)+=312

Reference： [1]Patent: US2004/72802,2004,A1 .Location in patent: Page/Page column 61

24
C₁₁H₁₇NO₃ [ No CAS ]
[ 190906-92-4 ]

Yield	Reaction Conditions	Operation in experiment
100%		To a solution of the enone (1.2 g, 5.68 mmol) from reaction (108a) in tetrahydrofuran (10 mL) at -78 C. was added boron trifluoride dimethyl etherate (0.963 g, 6.8 mmol). After stirring for 30 min, lithium triethylborohydride (6.8 mL, 6.8 mmol, 1.0 M solution in tetrahydrofuran) was added. The mixture was stirred for 30 min at -78 C., then was warmed to -23 C. for 30 min. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (40 mL). The organic layer was washed with saturated ammonium chloride solution (10 mL), dried, and concentrated to give the desired ketone (crude weight 1.2 g, 100%). MS found: (M+H)+=214

Reference： [1]Patent: US2004/72802,2004,A1 .Location in patent: Page/Page column 61

25
C₁₁H₂₁NO₃ [ No CAS ]
[ 190906-92-4 ]

Yield	Reaction Conditions	Operation in experiment
65%	With oxalyl dichloride; dimethyl sulfoxide; triethylamine; In dichloromethane; at -78 - 20℃; for 0.5h;	To a solution of oxalyl chloride (18.0 mL, 18.0 mmol, 1.0 M solution in methylene chloride) in methylene chloride (50 mL) at -78 C. was added a solution of dimethylsulfoxide (2.81 g, 36 mmol) in methylene chloride (25 mL). After stirring for 10 min, a solution of the alcohol (3.6 g, 16.7 mmol) from reaction (114a) in methylene chloride (20 mL) was added dropwise. The mixture was stirred for 15 min. Triethylamine (8.42 g, 83.2 mmol) was added and the mixture was warmed to rt after 5 min. The mixture was diluted with ethyl acetate (300 mL) and saturated potassium dihydrogenphosphate solution (100 mL). The layers were separated and the organic layer washed with brine (100 mL), dried, and concentrated. Purification of the residue by silica gel chromatography gave the desired ketone (2.3 g, 65%). MS found: (M+H)+=214.

Reference： [1]Patent: US2004/72802,2004,A1 .Location in patent: Page/Page column 63

26
[ 2033-24-1 ]
[ 190906-92-4 ]
[ 796112-48-6 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium acetate; In methanol; at 20℃; for 36h;	To a solution of 2, 2-dimethyl-1, 3-dioxane-4,6-dione (MELDRUM S acid) (12.8 g) in MeOH (190 mL), ammonium acetate (1.4 g) and 1, 1-dimethylethyl 2-methyl-4-oxo-1- piperidinecarboxylate (19 g) were added. The solution was stirred at rt for 36 h, then MeOH was removed by evaporation under vacuum to afford the title compound (29.6 g) as a pale yellow solid. T. I. C. : CH: AcOEt=7: 3, Rf=0.22 (detection with ninhydrine). MS (ES/+): m/z=362 [M+Na] +. MS (ES/-): m/z=338 [M-H]-.

Reference： [1]Patent: WO2004/99143,2004,A1 .Location in patent: Page 48

27
[ 190906-92-4 ]
[ 790667-43-5 ]
[ 790667-49-1 ]

Yield	Reaction Conditions	Operation in experiment
33%; 35%	Resolution of racemate;	Resolve racemic 2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (15.0 g) using a CHIRALPAK ADTM (4.6 x 250nm) column, eluting with absolute ethanol at a flow rate of 1.0 ML/MINUTE (UV=220nm) to obtain isomer 1 (5.28 g, 35%) and isomer 2 (5.01 g, 33%). 1H NMR (CDCl3) : 4.7 (m, 1H), 4.2 (m, 1H), 3.3 (m, 1H), 2.7 (m, 1H), 2.5 (m, 1H), 2.3 (m, 1H), 2.2 (m, 1H), 1.5 (s, 9H), 1.2 (d, 3H); identical for both isomers.

Reference： [1]Patent: WO2004/94380,2004,A1 .Location in patent: Page 26-27

28
[ 190906-92-4 ]
(rac)-tert-butyl (cis)-4-hydroxy-2-methylpiperidine-1-carboxylate [ No CAS ]
(rac)-tert-butyl (trans)-4-hydroxy-2-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%; 20%	With sodium tetrahydroborate; at 20℃; for 2h;	Step 2. (r c)-tert-butyl (cis)-4-hydroxy-2-methylpiperidine-l-carboxylate and (r c)-tert-butyl (trans)-4-hydroxy-2-methylpiperidine-l-carboxylate [0758] Following the procedure found in Plettenburg, Oliver et. Al (PCT Int. AppL, 2007012421), sodium borohydride (213 mg, 5.6 mmol) was added portion-wise to a solution of tert-butyl 2- methyl-4-oxopiperidine- 1 -carboxylate (1.0 g, 4.7 mmol) in ethanol (10 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated in vacuo and then partitioned between water (40 mL) and ethyl acetate (40 mL). The aqueous layer was extracted twice with ethyl acetate (40 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 40-50% ethyl acetate in hexanes) to afford (rac)-tert-butyl (cis)-4-hy droxy-2-methylpiperi dine- 1 -carboxylate (367 mg, 36%) and (rac)-tert-butyl (trans)-4-hydroxy-2-methylpiperidine- 1 -carboxylate (205 mg, 20%) as white solids.
		Cis and trans N-Boc-2-methyl-piperidin-4-ol (25 and 26)213 mg (5.6 mmol) of NaBH4 were added portionwise at 00C to a solution of 1.0 g (4.7 mmol) 1-Boc-2-methyl-pipehdin-4-on in 10 ml_ EtOH. The mixture was stirred at room temperature for another 2 h. The solvent was removed by distillation and the remainder was dissolved in water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetated and the combined organic layers were dried over Na2SO4.After filtration the solvent was removed by distillation and the crude product was purified by column chromatography n-heptane/ethyl acetate (1/1) to yield 367 mg(36%) of the cis-isomer 25 and 205 mg (20%) of the trans-isomer 26 in addition to 97 mg (10%) mixture of both isomers.Cis-lsomer (25): EPO <DP n="46"/>1H-NMR (CDCI3): delta= 4.28 (1 H, m), 4.17 (1H, m), 3.82 (1 H, m), 3.26 (1H, m), 1.85 (1H, ddd, J= 14.7, 6.6, und 3.4 Hz), 1.77 (1 H, m), 1.66 (2H, m), 1.33 (3H1 d, J = 7.1 Hz).Trans-lsomer (26):1H-NMR (CDCI3): delta = 4.50 (1 H, m), 4.04 (1 H, m), 3.95 (1 H, m), 2.87 (1 H, dt, J = 2.9 und 13.6 Hz), 1.93 (1 H1 m), 1.83 (1H1 m), 1.53 (1H1 m), 1.32 (1H, m), 1.14 (3H1 d, J = 7.1 Hz).
	With sodium tetrahydroborate; In ethanol; at 0 - 20℃; for 2h;	213 mg (5.6 mmol) of NaBH4 were added portionwise at 00C to a solution of 1.0 g (4.7 mmol) 1-boc-2-methyl-pipehdin-4-on in 10 mL of ethanol. The mixture was stirred at room temperature for 2 h. The solvent was removed by distillation and the remainder was dissolved in water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried over Na2SO4. After filtration the solvent was removed by distillation and the crude product was purified by column chromatography (n-heptane/ethyl acetate 1/1) to yield 367 mg (36%) of the cis-isomer EPO <DP n="47"/>18 and 205 mg (20%) of the trans-isomer 19 in addition to 97 mg (10%) mixture of both isomers.Cis-lsomer (18): 1H-NMR (CDCI3): delta= 4.28 (1 H, m), 4.17 (1 H1 m), 3.82 (1 H, m), 3.26 (1 H, m), 1.85 (1 H, ddd, J= 14.7, 6.6, und 3.4 Hz), 1.77 (1 H, m), 1.66 (2H, m), 1.33 (3H, d, J = 7.1 Hz).Trans-lsomer (19):1H-NMR (CDCI3): delta = 4.50 (1 H, m), 4.04 (1 H, m), 3.95 (1 H1 m), 2.87 (1 H1 dt, J = 2.9 und 13.6 Hz)1 1.93 (1 H1 m), 1.83 (1 H, m), 1.53 (1 H1 m), 1.32 (1 H, m), 1.14 (3H, d, J = 7.1 Hz).

Reference： [1]Patent: WO2015/74064,2015,A2 .Location in patent: Paragraph 0758
[2]Patent: WO2007/240,2007,A1 .Location in patent: Page/Page column 44-45
[3]Patent: WO2007/12421,2007,A1 .Location in patent: Page/Page column 45

29
[ 190906-92-4 ]
tert-butyl cis-4-amino-2-methyl-1-piperidinecarboxylate [ No CAS ]
tert-butyl trans-4-amino-2-methyl-1-piperidinecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; hydrogen;palladium on activated charcoal; In methanol; at 20℃; under 2585.81 Torr; for 48h;	Description 15; . tert-Butyl 4-amino-2-methyl-1-piperidinecarboxylate (D15); To a suspension of Pd/C (cat.) in a solution of ammonia in MeOH (3N, 200 ml), tert-butyl2-methyl-4-oxo-1-piperidinecarboxylate (2g, 9.4mmol) was added at room temperature.Air in the vessel was displaced with nitrogen and subsequently with hydrogen. The contents of the vessel were stirred under hydrogen (50psi) at room temperature for two days, then filtered and the methanol was removed under vacuum to give the title compound (mixture of isomers) (800mg, 53%).1H NMR (CD3OD) delta:1.25 (3H, d), 1.45 (1 1 H, m), 1.95 (1 H, m), 2.05 (1 H, m), 3.12 (1 H, m),3.28 (1 H, m), 3.69 (1 H, m), 3.95 (1 H, m).

Reference： [1]Patent: WO2008/119718,2008,A1 .Location in patent: Page/Page column 50

30
[ 849928-34-3 ]
[ 24424-99-5 ]
[ 190906-92-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With 5%-palladium/activated carbon; hydrogen; In methanol; for 8h;	110 g (0.44 mol) of the compound prepared in the step (2) was dissolved in 800 ml of methanol, 186 g (0.66 mol) of di-tert-butyl dicarbonate was added, and 5% by weight of palladium on carbon %), Hydrogenation, the reaction for 8 hours, after the completion of the reaction filtration, palladium-carbon filter, with a small amount of methanol washing filter cake 2 times, the combined filtrate, vacuum distillation of methanol, 500 ml of ethyl acetate dissolved, L hydrochloric acid, potassium carbonate solution, saturated brine, dried over anhydrous sodium sulfate and evaporated to give 170 g of a pale yellow oil. Crystallization was carried out at about 0C using a 5: 1 mixture of petroleum ether and ethyl acetate , Filtered to obtain 85 grams of white solid, that is, broad-1-tert-butoxy-2-methyl-4-piperidine pay. Yield 95%.
	With hydrogen;palladium hydroxide on carbon; In ethyl acetate; at 20℃; for 2h;	Intermediate I.l.a.l (Scheme 1.1) Racemic tert-butyl 2-methyl-4-oxopiperidine-l-carboxylateStep 1 : To a degassed solution of racemic 2-methyl-Cbz-piperidinone (synthesis as described in International Applicaton No. PCT/US2006/27594, filed July 14, 2006, 50 g, 202 mmol) and Boc- anhydride (48.5 g, 222 mmol) in EtOAc (800ml) was added Pearlman's catalyst (11.36 g, 81 mmol). The reaction mixture was purged with hydrogen gas and stirred at rt for 2 h, filtered on a pad of celite washed with brine, dried over sodium sulfate, and concentrated in vacuo and stored without further purification to yield the desired product LRMS (M+l) = 214.

Reference： [1]Patent: CN103601669,2016,B .Location in patent: Paragraph 0046
[2]Patent: WO2008/45250,2008,A1 .Location in patent: Page/Page column 29

31
[ 253429-19-5 ]
[ 190906-92-4 ]
[ 325486-51-9 ]

Yield	Reaction Conditions	Operation in experiment
62%		A mixture of 0.55 gm (2.55 mMol) 5-fluoro-7-bromobenzofuran and 0.12 gm (5.14 mMol) magnesium in 5 mL diethyl ether was heated to 40C. To this mixture were added 0.23 mL (2.67 mMol) 1,2-dibromoethane dropwise and the mixture was stirred for 45 minutes. The mixture was cooled to room temperature and then a solution of 0.50 gm (2.35 mMol) 1-tert-butoxycarbonyl-2-methyl-4-oxopiperidine in 10 mL diethyl ether was added dropwise. The reaction mixture was stirred for 15 hours at room temperature and was then partitioned between 100 mL ethyl acetate and 20 mL 4.1N hydrochloric acid. The phases were separated and the organic phase was washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure to provide 0.68 gm of a residue. This residue was dissolved in 50 mL 1:1 dichloromethane:methanol and the resulting solution cooled to 0C. To this solution were added 0.68 gm sodium borohydride and the reaction mixture was allowed to warm gradually to room temperature. After 5 hours the reaction mixture was concentrated under reduced pressure. The residue was partitioned between water and dichloromethane. The phases were separated and the organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0-50% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.50 gm (62%) of the desired compound. MS: m/e = 350(M+1)

Reference： [1]Patent: EP1204659,2003,B1 .Location in patent: Page/Page column 31

32
[ 324748-95-0 ]
[ 190906-92-4 ]
1-(tert-butoxycarbonyl)-2-methyl-4-hydroxy-4-(5,6-difluorobenzofuran-7-yl)piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of 2.28 gm (9.8 mMol) 5,6-difluoro-7-bromobenzofuran in 30 mL tetrahydrofuran was cooled to -78C and then 9.8 mL (19.6 mMol) tert-butyllithium (1.7M in tetrahydrofuran) were added. After stirring for 30 minutes, a solution of 1.9 gm (8.9 mMol) 1-(tert-butoxycarbonyl)-2-methyl-4-oxo-piperidine in 20 mL tetrahydrofuran was added dropwise over 30 minutes. The reaction mixture was allowed to warm to room temperature over 16 hours and was then concentrated under reduced pressure. The residue was dissolved in 200 mL ethyl acetate and extracted sequentially with 50 mL 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The remaining organic phase was dried over magnesium sulfate and concentrated under reduced pressure to provide 1-(tert-butoxycarbonyl)-2-methyl-4-hydroxy-4-(5,6-difluorobenzofur-7-yl)piperidine.

Reference： [1]Patent: EP1204659,2003,B1 .Location in patent: Page/Page column 51

33
[ 346592-25-4 ]
[ 190906-92-4 ]
[ 346592-26-5 ]

Yield	Reaction Conditions	Operation in experiment
26%		Preparation of N-t-Butoxycarbonyl-4-(4,6-dimethoxybenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol. [0413] Scheme IA, Step A: To a solution of 4,6-dimethoxybenzo[b]thiophene (1.07 g, 5.52 mmol) in dry THF (30 mL) at -78 C. was added 1.6 M n-BuLi in hexanes (3.80 mL, 6.07 mmol). The solution was stirred at -78 C. for 45 min. N-t-butoxycarbonyl-2-methyl-4-piperidone (1.18 g, 5.52 mmol) dissolved in THF (7 mL) was added via a cannula at -78 C. The reaction mixture was allowed to warm to room temperature over 16 h. The reaction was then quenched with 65 mL of saturated aqueous NH4Cl solution. The mixture was extracted (2×100 mL) with EtOAc. The combined organic layers were then dried over MgSO4 and filtered. The filtrate was concentrated and purified by silica gel chromatography (20% EtOAc/hexanes) to give the intermediate title compound as a yellow foam (0.590 g, 26%). IR (CHCl3) 3474, 3350 (br) cm-1. IR (CHCl3) 3350 (br), 1680 cm-1. Ion Spray MS 408 (M+H)+; 390 (M-H20)+; 334 (M-74)+ (base peak); 466(M+CH3COO-)-. 1HNMR (CDCl3) 7.17 (s, 1H), 6.83 (d, J=2.0 Hz, 1H), 6.36 (d, J=2.0 Hz, 1H), 4.43 (br m, 1H), 3.97-4.00 (br m, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.33 (brt, 1H), 2.15 (dd, J=14.7, 6.8 Hz, 1H), 1.89-2.05 (m, 3H), 1.47 (s, 1H), 1.46 (s,9H), 1.37 (d, J=7.3 Hz, 3H).

Reference： [1]Patent: US2004/6229,2004,A1 .Location in patent: Page/Page column 55

34
[ 33295-53-3 ]
[ 190906-92-4 ]
[ 346592-42-5 ]

Yield	Reaction Conditions	Operation in experiment
60%		EXAMPLE 85 [0472] Preparation of (2S)-3-[(2R,4R)-4-(8-Methoxynaphth-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol oxalate. [CHEMMOL-00143] [0473] Preparation of N-t-Butoxycarbonyl-4-(8-methoxynaphth-2-yl)-2-methyl-4-piperidinol. [0474] Scheme I, Step A: To a solution of <strong>[33295-53-3]7-bromo-1-methoxynaphthalene</strong> (6.50 g, 27.4 mmol, prepared in example 84) in dry THF (140 mL) at -78 C. was added 1.6 M n-BuLi in hexanes (17.1 mL, 27.4 mmol). The solution was stirred at -78 C. for 45 min. N-t-Butoxycarbonyl-2-methyl-4-piperidone (5.85 g, 27.4 mmol) dissolved in THF (25 mL) was added via a cannula at -78 C. The reaction mixture was stirred at -78 C. for 5 h. The reaction was then quenched with 140 mL of saturated aqueous NH4Cl solution. The mixture was extracted (2×250 mL) with EtOAc. The combined organic layers were then dried over MgSO4 and filtered. The filtrate was concentrated and purified by medium pressure chromatography (silica gel, 25% EtOAc/hexanes) to give the intermediate title compound as a white foam (6.06 g, 60%). IR (CHCl3) 3350 (br), 1680 cm-1. Ion Spray MS 371 (M+H)+; 254 (M-117(-(Boc+H20)))+ (base peak); 430 (M+CH3COO-)-.

Reference： [1]Patent: US2004/6229,2004,A1 .Location in patent: Page/Page column 62-63

35
[ 190906-92-4 ]
[ 790667-44-6 ]
[ 790668-06-3 ]
[ 790667-91-3 ]
[ 790667-99-1 ]

Yield	Reaction Conditions	Operation in experiment
		Example 69 5-Chloro-2-(4-(4-((2-fluoro-4-(lH-tetrazol-l-yl)phenoxy)methyl)-2H-l,2,3-triazol-2-yl)-2-methylpiperidin-l-yl)pyrimidineStep 1: tert-EvXy 4-hydroxy-2-methylpiperidine-l-carboxylate; <n="123"/>To a solution of tert-butyi 2-methyl-4-oxopiperidine-l-carboxylate (0.94 g, 4.41 mmol) in methanol (5 niL) was added sodium borohydride (0.22 g, 5.73 mmol) and the reaction was stirred at room temperature for Ih. Water was added slowly, followed by ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford the desired product as a mixture of four stereoisomers, which was used in the next step without further purification.

Reference： [1]Patent: WO2009/14910,2009,A2 .Location in patent: Page/Page column 120-121

36
[ 620-08-6 ]
[ 865-47-4 ]
[ 676-58-4 ]
[ 190906-92-4 ]

Yield	Reaction Conditions	Operation in experiment
47%		A solution of 5 mL (49 mMol) 4-methoxypyridine in 200 mL tetrahydrofuran was cooled to -40C, and then 6.9 mL (55 mMol) phenyl chloroformate were added dropwise. After stirring for 15 minutes, 20 mL (60 mMol) methyl magnesium chloride (3M in tetrahydrofuran) were added dropwise and the reaction mixture was allowed to warm to room temperature. After stirring for 30 minutes, the reaction mixture was cooled to -40C and treated with 340 mMol potassium tert-butoxide. The reaction mixture was allowed to warm to room temperature. After stirring for 1 hour, the reaction mixture was cooled to -40C and was treated with. 200 mL saturated aqueous oxalic acid. The reaction was warmed to 20C and allowed to stir for 1 hour. The mixture was extracted 2 x 200 mL diethyl ether. The combined organic phases were washed sequentially with 4 x 100 mL 0.5 N sodium hydroxide, 2 x 100 mL saturated aqueous sodium bicarbonate, 3 x 100 mL deionized water, and 100 mL saturated aqueous sodium chloride. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexanes containing 40% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 4.9 gm (47%) 1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine. EA: Calculated for: C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.78; H, 8.08; N, 6.76. A solution of 1.65 gm (7.81 mmol) 1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine in 20 mL tetrahydrofuran was cooled to -40C and was then treated with 8.59 mL (8.59 mMol) lithium tri(sec-butyl)borohydride (1M in tetrahydrofuran). After stirring for 2 hours, the solution was treated with 3.37 gm (8.59 mMol) 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine and the solution was allowed to warm to room temperature. After stirring for 1 hour, the reaction was diluted with 250 ml diethyl ether and filtered through celite. The celite pad was rinsed with 250 mL diethyl ether and the combined filtrates concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexanes containing from 0-9% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 2.02 gm (75%) of the title compound. ISMS: m/e = 346 (M+H)

Reference： [1]Patent: EP1204660,2004,B1 .Location in patent: Page 17

37
[ 145100-51-2 ]
[ 190906-92-4 ]
[ 252563-92-1 ]

Yield	Reaction Conditions	Operation in experiment
75%		A solution of 5 mL (49 mMol) 4-methoxypyridine in 200 mL tetrahydrofuran was cooled to -40C, and then 6.9 mL (55 mMol) phenyl chloroformate were added dropwise. After stirring for 15 minutes, 20 mL (60 mMol) methyl magnesium chloride (3M in tetrahydrofuran) were added dropwise and the reaction mixture was allowed to warm to room temperature. After stirring for 30 minutes, the reaction mixture was cooled to -40C and treated with 340 mMol potassium tert-butoxide. The reaction mixture was allowed to warm to room temperature. After stirring for 1 hour, the reaction mixture was cooled to -40C and was treated with. 200 mL saturated aqueous oxalic acid. The reaction was warmed to 20C and allowed to stir for 1 hour. The mixture was extracted 2 x 200 mL diethyl ether. The combined organic phases were washed sequentially with 4 x 100 mL 0.5 N sodium hydroxide, 2 x 100 mL saturated aqueous sodium bicarbonate, 3 x 100 mL deionized water, and 100 mL saturated aqueous sodium chloride. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexanes containing 40% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 4.9 gm (47%) <strong>[190906-92-4]1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine</strong>. EA: Calculated for: C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.78; H, 8.08; N, 6.76. A solution of 1.65 gm (7.81 mmol) <strong>[190906-92-4]1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine</strong> in 20 mL tetrahydrofuran was cooled to -40C and was then treated with 8.59 mL (8.59 mMol) lithium tri(sec-butyl)borohydride (1M in tetrahydrofuran). After stirring for 2 hours, the solution was treated with 3.37 gm (8.59 mMol) 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine and the solution was allowed to warm to room temperature. After stirring for 1 hour, the reaction was diluted with 250 ml diethyl ether and filtered through celite. The celite pad was rinsed with 250 mL diethyl ether and the combined filtrates concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexanes containing from 0-9% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 2.02 gm (75%) of the title compound. ISMS: m/e = 346 (M+H)

Reference： [1]Patent: EP1204660,2004,B1 .Location in patent: Page 17

38
[ 141-43-5 ]
[ 190906-92-4 ]
[ 1237841-71-2 ]

Yield	Reaction Conditions	Operation in experiment
		Examples 104(+/-) cis-3-(l- { beta-chloro--^-furanylJ-S-^rifluoromethylJimidazo [ 1 ,2-a] pyridin-2- yl]carbonyl}-2-methyl-4-piperidinyl)-l,3-oxazolidin-2-one (Compound 205)Example 105(+/-) trans-3-(l-[3-chloro-6-(3-furanyl)-8-(trifluoromethyl)imidazo[l,2-a]pyridin-2- yl]carbonyl}-2-methyl-4-piperidinyl)-l,3-oxazolidin-2-one (Compound 206)Step A: 1,1-dimethylethyl 4-[(2-hydroxyethyl)amino]-2-methyl-l-piperidinecarboxylateTo a stirred solution of 1,1-dimethylethyl 2-methyl-4-oxo-l-piperidinecarboxylate (0.22g, 1.0 mmol) and ethanolamine (0.092g, 1.5 mmol) in methanol (20 mL) was added acetic acid (0.09g). The mixture was stirred for three hours at room temperature, and then sodium triacetoxyborohydride (0.32Og, 1.5 mmol) was added and the mixture was maintained at room temperature with stirring overnight. The mixture was diluted with water and extracted with ethyl acetate and the resulting organic phase was dried and concentrated under reduced pressure to afford 1,1-dimethylethyl 4-[(2-hydroxyethyl)amino]-2-methyl-l-piperidinecarboxylate (0.358 g, 1.4 mmol) suitable for direct use in the subsequent transformation.

Reference： [1]Patent: WO2010/91411,2010,A1 .Location in patent: Page/Page column 197

39
[ 1274804-81-7 ]
[ 190906-92-4 ]
[ 1274805-20-7 ]

Yield	Reaction Conditions	Operation in experiment
53%		STEP A: To a vial containing 4-((Lambda)-3-?iotaomicron 1iotaomicronEtaeta-4-gamma1-1 -rho1iotaepsiloneta 5upsilon1Gamma3eta -??1iota>- propylamino)-N-(5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazin-3-yl)-3- trifluoromethanesulfonyl-benzenesulfonamide (60 mg, 0.089 mmol) and 2-methyl-4-oxo- piperidine- l -carboxylic acid tert-butyl ester (47.3 mg, 0.222 mmol) was added methanol (3 mL) under nitrogen. The reaction mixture was stirred in an ice bath for 10 minutes and then acetic acid (6.10mu, 0.107 mmol) was added. After stirring in the ice bath for an additional 1 5 minutes, sodium cyanoborohydride (44.6 mg, 0.710 mmol) was then added, and the reaction was stirred at ambient temperature for 15 hours. The reaction mixture was concentrated, filtered, and purified via flash chromatography on silica gel(10-50% 7 NH3 in methanol in CH2C12) to afford 2-methyl-4-{3-[4-((J^)-3-mo holin-4- yl-l-phenylsulfanylmethyl-propylamino)-3-trifluoromethanesulfonyl- benzenesulfonylamino]-5,6-dihydro-8H-[ l ,2,4]triazolo[4,3-a]pyrazin-7-yl}-piperidine-l - carboxylic acid fer/-butyl ester (42 mg, 53 % yield). MS [m/z; (M+l )+]: 873.8

Reference： [1]Patent: WO2011/29842,2011,A1 .Location in patent: Page/Page column 126

40
[ 617-52-7 ]
[ 190906-92-4 ]
[ 1401995-15-0 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1: Preparation of 8-(tert-butoxycarbonyl)-3,7-dimethyl-2-oxo-1-oxa-8-azaspiro[4.5]dec-3-ene-4-carboxylic acid [Show Image] Dimethyl itaconate (1.11 g, 7.04 mmol) and 1-Boc-2-methyl-piperidin-4-one (1.5 g, 7.04 mmols) were added over 20 min to a solution of sodium methoxide (0.83 g, 15.49 mmol) in tetrahydrofuran (100 mL) maintained at 0C. The reaction mixture was stirred at 0C for 2 hours then 16 hours at RT under nitrogen. Wate was then added. The THF was removed under reduced pressure and the aqueous layer was acidified by addition of an aqueous solution of HCI (1.5 N). The aqueous layer was then extracted (EtOAc) and the combined organic layers were evaporated under reduced pressure. After purification by flash chromatography (silica), the title compound was obtained as an off white solid. 1H NMR (CDCl3, 400 MHz) delta 5.0 (s, 2H), 4.57-4.48 (m, 1 H), 4.15-4.02 (m, 1 H), 3.79-3.68 (m, 1 H), 3.31-2.78 (m, 1 H), 2.77-2.63 (m, 1 H), 2.68-2.56 (m, 1 H), 2.40-2.30 (m, 1 H), 2.23 (s, 1 H), 1.49 (s, 9H), 1.36-1.26 (m, 3H). LCMS (Method D) Mass found (M+ 226.2) Rt (min): 4.06; Area (%) 84.5 (Max. Chrom.).
		Step 1: Preparation of 8-(tert-butoxycarbonyl)-3,7-dimethyl-2-oxo-1-oxa-8-azaspiro[4.5Jdec- 3-ene-4-carboxylic acid Dimethyl itaconate (1.11 g, 7.04 mmol) and 1-Boc-2-methyl-piperidin-4-one (1.5 g, 7.04 mmols) were added over 20 min to a solution of sodium methoxide (0.83 g, 1 5.49 mmol) in tetrahydrofuran (100 mL) maintained at 0C. The reaction mixture was stirred at 0C for 2 hours then 16 hours at RT under nitrogen. Wate was then added. The THF was removed under reduced pressure and the aqueous layer was acidified by addition of an aqueous solution of HCI (1.5 N). The aqueous layer was then extracted (EtOAc) and the combined organic layers were evaporated under reduced pressure. After purification by flash chromatography (silica), the title compound was obtained as an off white solid. 1H NMR (CDCI3, 400 MHz) delta 5.0 (s, 2H), 4.57-4.48 (m, 1 H), 4.15-4.02 (m, 1 H), 3.79-3.68 (m, 1 H), 3.31-2.78 (m, 1 H), 2.77-2.63 (m, 1 H), 2.68-2.56 (m, 1 H), 2.40-2.30 (m, 1 H), 2.23 (s, 1 H), 1.49 (s, 9H), 1.36-1.26 (m, 3H). LCMS (Method D) Mass found (M+ 226.2) Rt (min): 4.06; Area (%) 84.5 (Max. Chrom.).

Reference： [1]Patent: EP2508526,2012,A1 .Location in patent: Page/Page column 100
[2]Patent: WO2012/130915,2012,A1 .Location in patent: Page/Page column 120-121

41
[ 22190-33-6 ]
[ 190906-92-4 ]
[ 1400288-96-1 ]

Yield	Reaction Conditions	Operation in experiment
54%	With sodium cyanoborohydride; acetic acid; In methanol; at 0 - 20℃;Inert atmosphere;	General procedure: A solution of indoline (20) (1.88 mL, 16.78 mmol), tert-butyl 3-oxopyrrolidine-1-carboxylate (22) (3.73 g, 20.13 mmol) in dry methanol (20 mL) was treated with AcOH (2.37 mL, 41.95 mmol) followed by NaCNBH3 (1.26 g, 20.13 mmol) at 0 C. ;The reaction was brought to room temperature and stirred for 3 h. ;The reaction was basified with 1 N NaOH solution and product was extracted into CH2Cl2. ;The combined CH2Cl2 layer was dried (Na2SO4) and solvent was evaporated to obtain crude product. ;The crude was purified by column chromatography (EtOAc:hexanes, 1:9) to obtain the title compound.

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 55,p. 94 - 107,14

42
[ 37595-74-7 ]
[ 190906-92-4 ]
[ 325488-26-4 ]
[ 252563-92-1 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃;Inert atmosphere;	In a 25 mL flask and under an atmosphere of nitrogen, to a solution of <strong>[190906-92-4]tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate</strong> (558 mg, 2.6 mmol) and 1,1,1-Trifluoro-N-phenyl-N-(trifluoromethyl)sulfonyl methanesulfonamide (1869 mg, 5.2 mmol) in anhydrous THF (5 mL) at -78 C. was added 1.0M LiHMDS in THF (5.23 mL, 5.2 mmol). The mixture was stirred overnight while slowly being allowed to warm at room temperature. The reaction was quenched with saturated NaHCO3. Then the mixture was extracted 3* with MTBE. The combined organic layers were dried with sodium sulfate, filtered and concentrated. A mixture of regioisomers (tert-butyl 6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1 (2H)-carboxylate and tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1 (2H)-carboxylate) was obtained as a pale yellow oil (397 mg, 44% yield).
		To a solution of <strong>[190906-92-4]tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate</strong> (12.5 g, 58.7 mmol) in THF (200 mL) at -70 was added LiHMDS (65 mL, 64.5 mmol, 1.0 mol/L in THF) . The mixture was stirred at -70 for 1 hour. Then N,N-Bis(trifluoromethylsulfonyl)aniline (23 g, 64.5 mmol) in THF (40 mL) was added to the reaction. The mixture was stirred at -70 to room temperature overnight. The reaction was quenched with 200 mL of sat. NH4Cl (200 mL) . The mixture was extracted with EtOAc (500 mL) . The organic layer was washed with H2O (200 mL) , brine (100 mL) and concentrated. The crude product was purified by chromatography using Petroleum ether/EtOAc = 1001 to 101 to give compound (20.3 g, 100%) as yellow oil. LCMS [column: C18; column size: 4.6 x 30 mm 5 mum; Dikwa Diamonsil plus; mobile phase: B (ACN) : A1 (0.02%NH4OAc + 5%ACN) ; gradient (B%) in 4 mins. 10-95-POS; flow rate: 1.5 ml/min] : Rt = 2.161 min; MS Calcd.: 345, MS Found: 290 [M -56 + H]+.

Reference： [1]Patent: US2013/324547,2013,A1 .Location in patent: Paragraph 0479; 0480
[2]Patent: WO2018/137619,2018,A1 .Location in patent: Page/Page column 67; 68

43
[ 37595-74-7 ]
5-(3,4-dimethoxyphenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine [ No CAS ]
[ 190906-92-4 ]
tert-butyl 4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)-2-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36 mg		Tert-butyl 4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl)-2-methyl-5,6-dihydropyridine-1(2H)-carboxylate (Mixture with regioisomer tert-butyl 4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl)-6-methyl-5,6-dihydropyridine-1(2H)-carboxylate, total is 60 mg, 0.116 mmol) was dissolved in Methanol (2.5 ml). The solution was treated with Hydrogen for 2.5 hrs at room temperature using H-Cube (Full H2, 1 mL/min, small size (30 mm) 10% Palladium on Carbon CatCart). 1 mL Toluene was added. Solvent was concentrated. The crude product was purified on silica-gel (Column Interchim 25 g, 30 muM) eluting with 12-100% EtOAc/Heptane to afford tert-butyl 4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)-2-methylpiperidine-1-carboxylate (36 mg, 0.069 mmol, 59% yield) as a white solid.

Reference： [1]Patent: US2013/324547,2013,A1 .Location in patent: Paragraph 0487; 0488

44
[ 190906-92-4 ]
2-methyl-piperidin-4-one hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; ethyl acetate; at 20℃;	Preparation 24: 2-Methyl-piperidin-4-one hydrochloride2-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1 g, 4.7 mmol) was dissolved inEtOAc (10 mL); to this was added 4 M HCI in 1,4-dioxane (10 mL). The sample was stirredat room temperature overnight and then evaporated to give the title compound. MS: [M+H] =114.
	With hydrogenchloride; In diethyl ether; at 0℃; for 2h;Inert atmosphere;	Step A: 2-Methylpiperidin-4-one hydrochloride [0225] To a round bottle flask containing tert-butyl-2-methyl-4-oxopiperidine-l - carboxylate (5 g, 23 mmol) under an atmosphere of nitrogen at 0 C was added hydrochloric acid in diethyl ether (24 ml, 47 mmol). The reaction mixture was stirred at 0 C for 2 hours, and then slowly stirred to room temperature overnight. The solvent was evaporated to afford a white solid as the titled product, that was further dried on high vacuum for 3 hours, before using in the next step.
	With hydrogenchloride; In diethyl ether; at 0℃; for 2h;Inert atmosphere;	To a round bottle flask containing tert-butyl-2-methyl-4-oxopiperidine- 1 -carboxylate (5 g, 23 mmol) under an atmosphere of nitrogen at 0C was added hydrochloric acid in diethyl ether (24 ml, 47 minol). The reaction mixture was stirred at 0C for 2 hours, and then slowly stirred to room temperature overnight. The solvent was evaporated to afford a white solid as the titled product, which was further dried on high vacuum for 3 hours, before using in the next step.

With hydrogenchloride; In diethyl ether; at 0 - 20℃;Inert atmosphere;

To a round bottle flask containing tert-butyl-2-methyl-4-oxopiperidine-l- carboxylate (5 g, 23 mmol) under an atmosphere of nitrogen at 0C was added hydrochloric acid in diethyl ether (24 ml, 47 mmol). The reaction mixture was stirred at 0C for 2 hours, and then slowly stirred to room temperature overnight. The solvent was evaporated to afford a white solid as the titled product, which was further dried on high vacuum for 3 hours, before using in the next step.

Reference： [1]Patent: WO2014/60770,2014,A1 .Location in patent: Page/Page column 142
[2]Patent: WO2014/101120,2014,A1 .Location in patent: Paragraph 0225
[3]Patent: WO2014/105666,2014,A1 .Location in patent: Paragraph 0230
[4]Patent: WO2014/101373,2014,A1 .Location in patent: Page/Page column 112

45
[ 5674-02-2 ]
[ 190906-92-4 ]
[ 1428901-18-1 ]

Yield	Reaction Conditions	Operation in experiment
450 mg		Under an argon atmosphere, in a 50-mL pear-shaped evaporating flask was weighed a solution of lanthanum chloride lithium chloride complex in THF (15.6 mL) and cooled to 0C. To the solution was added dropwise a solution of isobutylmagnesium chloride in THF (3.5 mL) and stirred at 0C for 3 hours. A solution of <strong>[190906-92-4]tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate</strong> (1 g) in THF (2.0 mL) was further added dropwise. The reaction solution was stirred at 0C for 1 hour, heated to 25C, poured to hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried over anhydrous magnesium sulphate. The filtrate was concentrated and the resulting residue was purified by silica gel chromatography (hexane:ethyl acetate = 9:1 ? 3:1) to give the titled compound (450 mg) having the following physical properties. TLC: Rf 0.51 (hexane:ethyl acetate = 3:1).

Reference： [1]Patent: EP2762466,2014,A1 .Location in patent: Paragraph 0274

46
2-azido-5-fluoropyrimidine [ No CAS ]
[ 190906-92-4 ]
(S)-tert-butyl 1-(5-fluoropyrimidin-2-yl)-6-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5(4H)-carboxylate [ No CAS ]
(S)-tert-butyl 1-(5-fluoropyrimidin-2-yl)-4-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5(4H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(S)-tert-butyl 1-(5-fluoropyrimidin-2-yl)-6-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5(4H)-carboxylate To a solution of (S)-<strong>[190906-92-4]tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate</strong> (2.76 g, 12.9 mmol) in toluene (100 mL) at 100 C. was added 2-azido-5-fluoropyrimidine (2.34 g, 16.8 mmol) as a solution in toluene (15 mL) followed by pyrrolidine (1.06 mL, 12.9 mmol). After stirring for 3 h at rt, the reaction was cooled to 0 C. and CH2Cl2 (100 mL) was added followed by NaHCO3 (2.17 g, 25.9 mmol) and mCPBA (4.47 g, 25.9 mmol). The reaction was allowed to warm to rt over 30 min followed by the addition of 1N NaOH (100 mL). The organic layer was separated and the water layer was extracted with CH2Cl2 two times. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. Chromatography on silica gel (0-100% ethyl acetatehexanes) provided the desired product as a 9:1 mixture of regioisomers (9:1=(S)-tert-butyl 1-(5-fluoropyrimidin-2-yl)-6-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5(4H)-carboxylate: (S)-tert-butyl 1-(5-fluoropyrimidin-2-yl)-4-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5(4H)-carboxylate (2.85 g, 66%). The minor regioisomer was separated by SFC (Chiralpak IC 5 mum 250*21 mm, mobile phase 70% CO2, 30% iPrOH) to provide the product as a white solid. MS (ESI) mass calcd. C15H19FN6O2, 334.16. m/z found, 335.2 [M+H]+. 1H NMR (500 MHz, CDCl3) delta 8.73 (s, 2H), 5.16 (d, J=16.1Hz, 1H), 4.96 (br s, 1H), 4.25 (d, J=16.4 Hz, 1H), 3.38-3.28 (m, 1H), 3.19-3.10 (m, 1H), 1.50 (s, 9H), 1.16 (d, J=7.0 Hz, 3H).

Reference： [1]Patent: US2014/275015,2014,A1 .Location in patent: Paragraph 0950; 0951; 0952

47
[ 1449-46-3 ]
[ 190906-92-4 ]
tert-butyl 4-benzylidene-2-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%		To a stirred solution of benzyltriphenylphosphonium bromide (8.1 g, 18.7 mmol) in dry THF (20 mL), was added potassium tert-butoxide (2.0 g, 17.8 mmol) at rt. The resulting mixture was stirred 1 h. Tert-butyl-2-methyl-4-oxopiperidine-1 -carboxylate (2.0 g, 9.3 mmol) was then added at the same temperature and the reaction mixture was stirred for 3 h. Solvents were evaporated. Water (20 mL) was added to the resulting crude product and was extracted with DCM (80 mL). The organic layer was dried over Na2S04 and concentrated. The crude product was purified by silica gel column chromatography (5% EtOAc in hexane) to get tert-butyl 4-benzylidene-2-methylpiperidine-1 -carboxylate as a colorless gummy liquid. Yield: 59% (1 .4 g). LCMS: (Method C) 232 (M-t-Bu+H), RT. 6.05 min, 95.8% (Max). H NMR (400 MHz, DMSO-d6): delta 7.36-7.31 (m, 2H), 7.31 -7.19 (m, 3H), 6.50-6.35 (m, 1 H), 4.36-4.32 (m, 1 H), 3.95-3.82 (m, 1 H), 2.93 (d, J = 1 1 .8 Hz, 1 H), 2.73-2.69 (m, 1 H), 2.50- 2.14 (m, 3H), 1 .35 (s, 9H),1 .01 (d, J = 8.0 Hz, 3H).

Reference： [1]Patent: WO2014/159234,2014,A1 .Location in patent: Page/Page column 95

48
[ 403-43-0 ]
[ 190906-92-4 ]
C₁₈H₂₂FNO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		According to Scheme 4: To a solution of 1 N lithium hexamethyldisilazide in dry tetrahydrofuran (4.69 ml, 4.69 mmol) at -78 C. was added a solution of N-tert-butoxycarbonyl-4-piperidone (1.0 g, 4.69 mmol) in dry diethyl ether (9 ml) dropwise and the mixture was stirred at -78 C. for 30 min. A solution of 4-fluorobenzoyl chloride (743 mg, 4.69 mmol) in dry diethyl ether was added. The mixture was allowed to warm to 25 C. overnight. Water was added, the solution was extracted 3 times with CH2Cl2, the combined organic layers were washed once with brine, dried over Na2SO4, filtrated and the solution was evaporated to dryness, redissolved in ethanol (25 ml) and tetrahydrofuran (11 ml), (2,4-Difluoro-benzyl)-hydrazine (731 mg, 4.62 mmol) was added and the mixture was stirred for 10 min at 25 C. The mixture was poured on 1N aqueous NaOH, extracted 3 times with ethyl acetate, the combined organic layers were washed with brine, dried over Na2SO4, filtrated and the solution was evaporated to dryness. The residue was dissolved in 4N HCl/dioxane (3 ml, 12 mmol) and stirred for 2 days. Solvents were evaporated and the crude product was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 257 mg of 1-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine, trifluoroacetate salt (7a). Rt=1.05 min (LC-method 4). Detected mass: 358.24 [M+H+]

Reference： [1]Patent: US2014/330009,2014,A1 .Location in patent: Paragraph 0437-0439

49
[ 623-51-8 ]
[ 190906-92-4 ]
C₁₆H₂₃NO₄S [ No CAS ]
5-tert-butyl 2-ethyl 4-methyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[01 74j Synthesis of 5 -tert-butyl 2-ethyl 4-methyl-6,7-dihydrothieno [3 ,2-c]pyridine- 2,5 (4H)-dicarboxylate was similar to that of ethyl 6,7-dihydro-4H-thieno [3 ,2-c]pyran-2- carboxylate in Example 3, except <strong>[190906-92-4]tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate</strong> was substituted for dihydro-2H-pyran-4(3H)-one. The mixture was purified by column chromatography (silica, petroleum ether/EtOAc = 8:1) to give product (336 mg, yield: 44%) as a white liquid. ESI-MS (M+H-56): 270.1.

Reference： [1]Patent: WO2015/89337,2015,A1 .Location in patent: Paragraph 0174

50
[ 623-51-8 ]
[ 190906-92-4 ]
C₁₄H₁₉NO₄S [ No CAS ]
5-(tert-butoxycarbonyl)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[01 74j Synthesis of 5 -tert-butyl 2-ethyl 4-methyl-6,7-dihydrothieno [3 ,2-c]pyridine- 2,5 (4H)-dicarboxylate was similar to that of ethyl 6,7-dihydro-4H-thieno [3 ,2-c]pyran-2- carboxylate in Example 3, except <strong>[190906-92-4]tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate</strong> was substituted for dihydro-2H-pyran-4(3H)-one. The mixture was purified by column chromatography (silica, petroleum ether/EtOAc = 8:1) to give product (336 mg, yield: 44%) as a white liquid. ESI-MS (M+H-56): 270.1.[01 75j Synthesis of 5 -(tert-butoxycarbonyl)-4-methyl-4,5 ,6,7-tetrahydrothieno [3,2- c]pyridine-2-carboxylic acid was similar to that of 6,7-dihydro-4H-thieno [3 ,2-c]pyran-2- carboxylic acid in Example 3. The crude product (240 mg, yield: 55%, white solid) was used in next step without further purification. ESI-MS (M+H-56): 242.0. ?H NMR (400 MHz, CDC13) (5:7.37 (s, 1H), 4.72-4.67 (m, 1H), 3.95-3.91 (m, 0.5H), 3.73-3.66 (m, 0.5H), 2.99-2.93 (m, 1H), 2.78-2.49 (m, 2H), 1.40-1.39 (m, 9H), 1.35 (d, J= 6.8 Hz, 1.5H), 1.26 (d, J= 6.8 Hz, 1.5H).

Reference： [1]Patent: WO2015/89337,2015,A1 .Location in patent: Paragraph 0174; 0175

51
[ 190906-92-4 ]
[ 952182-04-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With palladium 10% on activated carbon; ammonia; hydrogen; In methanol; under 2585.81 Torr; for 60h;	[0550] Preparation of tert-butyl 4-amino-2-methylpiperidine-l-carboxylate (26.37): To a solution of tert-butyl 2-methyl-4-oxopiperidine-l-carboxylate 26.36 (2.0 g, 9.38 mmol) in methanolic ammonia (~4N, 200 mL) was added Pd/C (10 mol%, 0.2 g). The resulting reaction mixture was stirred at 50 PSI for 60 h under hydrogen atmosphere. After completion of the reaction (TLC monitoring), the reaction mass was filtered through celite bed. The filtrate was dried under reduced pressure to get desired product 26.37 (2.0 g, quantitative yield) as semi solid. MS : 215.17 (M+H)+.

Reference： [1]Patent: WO2015/103060,2015,A1 .Location in patent: Paragraph 0550

52
[ 190906-92-4 ]
[ 281652-10-6 ]

Yield	Reaction Conditions	Operation in experiment
0.53 g	With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 10℃;	A solution of 1-boc-2-methylpiperidin-4-one (0.55 g, 2.6 mmol, 1 eq) in dry DCM(7.5 mL) was cooled at 0C and DAST (0.68 mL, 5.2 mmol, 2 eq) was added dropwise.The reaction was stirred overnight at 10C, then diluted with DCM (10 mL), washed withNaHCO3 sat. solution (lOmL), 5% citric acid solution in water (10 mL) and finally withbrine (10 mL). The organic layer was dried over anh. Na2504, filtered and evaporated.The residue was purified by flash chromatography on silica gel (eluent 10/90 EtOAc/petroleum ether) affording 0.53 g of pure 1-N-boc-4,4-difluoromethylpiperidine as white solid.

Reference： [1]Patent: WO2015/118019,2015,A1 .Location in patent: Page/Page column 38

53
[ 37595-74-7 ]
[ 190906-92-4 ]
[ 325488-26-4 ]

Yield	Reaction Conditions	Operation in experiment
100%		(0307) To a solution of 1-(tert-butoxycarbonyl)-2-methylpiperidin-4-one (1.00 g, 4.7 mmol) in tetrahydrofuran (10 mL) was added dropwise 1.5 mol/L solution of lithium diisopropylamide in tetrahydrofuran (3.7 mL, 5.6 mmol) at -78 C. The mixture was stirred for 10 minutes, then a solution of N-phenylbis(trifluoromethanesulfonimide) (1.9 g, 5.6 mmol) in tetrahydrofuran (5 mL) was added dropwise thereto, and the reaction mixture was gradually raised to room temperature. The mixture was stirred for 6 hours, then saturated aqueous ammonium chloride solution was added thereto, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrochloride solution, dried over anhydrous sodium sulfate, filtrated, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane:chloroform=5:1) to give the title compound (1.6 g, quantitative). (0308) 1H-NMR (400 MHz, CDCl3) delta: 1.18, 1.24 (d, J=6.8 Hz, 3H, diastereo ratio=3:2), 1.47 (s, 9H), 2.05-2.23 (m, 1H), 2.59-2.99 (m, 1H), 3.62-3.76 (m, 1H), 4.20-4.67 (m, 2H), 5.71, 5.75 (s, 1H, diastereo ratio=3:2). (0309) LC-MS: condition A R.T.=8.4 min ObsMS=368.0 [M+23]
100%		1- (tert- butoxycarbonyl) -2-methyl-4-one (1.00g, 4.7mmol) tetrahydrofuran solution (10mL) 1.5mol / L lithium diisopropylamide at -78C to tetrahydrofuran solution (3.7mL, 5.6mmol) it was dropped. After stirring for 10 minutes, N-phenyl-bis (trifluoromethanesulfonimide) (1.9g, 5.6mmol) It was added dropwise a tetrahydrofuran solution (5 mL), and was gradually warmed to room temperature. After stirring for 6 hours, saturated aqueous ammonium chloride was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: chloroform = 5: 1) to give the title compound (1.6 g, quantitative).
		In a three-necked bottle,Add Compound 108a2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester(2.13g, 10.0mmol),The system oil pump is pumped to replace argon three times.After injection of anhydrous tetrahydrofuran (40 mL), the system was cooled to -78 C.LiHMDS (12 mL, 1M) was slowly injected.Then stirred at this temperature for 30 min.Slow injectionCompound 108b was a solution of N-phenylbis (trifluoromethanesulfonyl) imine (4.28 g, 12.0 mmol) in tetrahydrofuran (30 mL).After feeding,The system was warmed to room temperature and stirred for 2.5 h.After the reaction is complete,Saturated NH4Cl (~ 30 mL) was quenched.Ethyl acetate extraction,Combined organic phases,After washing with saturated brine, it was dried and concentrated.Purified by column (ethyl acetate / petroleum ether = 0-10%;KMnO4 develops color) to obtain a colorless oily liquid compound 108c.2-methyl-4-((((trifluoromethyl) sulfonyl) oxy))-5,6-dihydropyridine(2H) -1 - carboxylate(3.3 g, yield> 100%).

Reference： [1]Patent: US2016/122319,2016,A1 .Location in patent: Paragraph 0306-0309
[2]Patent: JP2016/108326,2016,A .Location in patent: Paragraph 0232; 0233
[3]Patent: CN110862376,2020,A .Location in patent: Paragraph 0261; 0262; 0263; 0264

54
[ 460-00-4 ]
[ 190906-92-4 ]
tert-butyl 4-(4-fluorophenyl)-4-hydroxy-2-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Reference Synthesis Example 279 (1106) tert-Butyl 4-(4-fluorophenyl)-4-hydroxy-2-methylpiperidine-1-carboxylate (1107) To a tetrahydrofuran solution (10 mL) of 1-bromo-4-fluorobenzene (492 mg, 2.81 mmol), n-butyl lithium (1.62 M, hexane solution) (1.73 mL, 2.81 mmol) was added at -78 C. and the resultant mixture was stirred for 40 minutes. To the reaction solution, a tetrahydrofuran solution of <strong>[190906-92-4]tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate</strong> (500 mg, 2.34 mmol) was added and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, water was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product (729 mg) of the title compound.

Reference： [1]Patent: US9403798,2016,B2 .Location in patent: Page/Page column 133; 134

55
[ 183208-35-7 ]
[ 190906-92-4 ]
tert-butyl 4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyl-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
C₁₈H₂₂BrN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In methanol; at 120℃;Inert atmosphere;	Step 1: Preparation of tert-butyl 4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyl-5,6-dihydropyridine-1(2H)-carboxylate (26) (0550) A mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (2.2 g, 11.2 mmol) and <strong>[190906-92-4]tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate</strong> (2.0 g, 9.38 mmol) in MeOH (16 mL) was added with NaOMe (25 wt % in MeOH, 16 mL) at room temperature. The reaction mixture was stirred at 120 C. using a pressurized container. The solvent was removed from the resulting mixture, and the mixture was diluted with H2O and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica-gel column chromatography (Biotage flash purification system, EtOAc/Hex, KP-Sil) to give a mixture of 2-methyl and 6-methyl compounds (1.62 g, 37%) as a yellow solid with high viscosity.

Reference： [1]Patent: US2016/297815,2016,A1 .Location in patent: Paragraph 0549; 0550; 0551

56
[ 183208-35-7 ]
[ 190906-92-4 ]
5-bromo-3-(6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine [ No CAS ]
5-bromo-3-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%; 26%		Step 2: Preparation of 5-bromo-3-(6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (27) and 5-bromo-3-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (28) (0551) A mixture of the compound 26 (1.62 g, 4.13 mmol) and MeOH (9.9 mL) was added with HCl (1.25 M in MeOH, 9.9 mL) at room temperature, followed by stirring. The solvent was removed from the resulting mixture, and the mixture was subjected to alkalinization using 1N NaOH (aq.), followed by extraction with CH2Cl2. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica-gel column chromatography (Biotage flash purification system, CH2Cl2/MeOH, KP-Sil) to give the title compounds: 27 (470 mg, 39%) as a white solid and 28 (310 mg, 26%) as a pale yellow solid. (0552) 27: 1H NMR (400 MHz, DMSO-d6) delta 11.90 (br s, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.57 (s, 1H), 6.06 (br s, 1H), 3.50-3.48 (m, 1H), 3.09-3.04 (m, 1H), 2.83-2.76 (m, 1H), 2.42-2.32 (m, 1H), 2.28-2.23 (m, 1H), 1.15 (d, J=6.8 Hz, 3H); [M+H]+ 292 (0553) 28: 1H NMR (400 MHz, DMSO-d6) delta 11.88 (br s, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.56 (s, 1H), 6.18 (br s, 1H), 3.50-3.48 (m, 2H), 2.85-2.79 (m, 1H), 2.42-2.32 (m, 1H), 2.04-1.97 (m, 2H), 1.12 (d, J=6.4 Hz, 3H); [M+H]+ 292.

Reference： [1]Patent: US2016/297815,2016,A1 .Location in patent: Paragraph 0549; 0551; 0552; 0553

57
[ 56278-50-3 ]
[ 190906-92-4 ]
tert-butyl 2-amino-3-(benzo[d]thiazol-2-yl)-5-methyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate [ No CAS ]
tert-butyl 2-amino-3-(benzo[d]thiazol-2-yl)-7-methyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With morpholine; sulfur; In ethanol; at 85℃; for 12h;	To a solution of 2-(benzo[djthiazol-2-yl)acetonitrile (1 g, 5.74 mmol) in ethanol (10 mL) was added <strong>[190906-92-4]tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate</strong> (1.22 g, 5.74 mmol), elemental sulfur (183 mg, 5.74 mmol), and morpholine (496 mg, 5.74 mmol) at room temperature. After addition, the resulting mixture was heated to reflux at 85 C for 12 h and monitored by TLC. The reaction mixture was concentrated under vacuum pressure and the crude compound was purified by silica gel column chromatography eluting with 0-30% ethyl acetate in n-hexane to afford the mixture of title compounds as an off white solid (1.5 g, yield 65%). ?H NMR (DMSO-d6, 400MHz): 8.16 (d, J=7.86 Hz, 2H), 8.01 (d, J=7.86 Hz, 1H), 7.90 (d, J=7.86 Hz, 1H), 7.46 (t, J=7.63 Hz, 1H), 7.28-7.35 (m, 1H), 4.60-4.7 1 (m, 1H), 4.15-4.22 (m, 1H), 3.93-4.05 (m, 1H), 2.65-3.02 (m, 2H), 1.44 (s, 9H), 1.35 (d, J=6.47 Hz, 2H), 1.13 (d, J=6.94 Hz, 1H). LCMS: [M+Hj = 402.04; R = 3.74 mm.

Reference： [1]Patent: WO2016/197078,2016,A1 .Location in patent: Paragraph 472; 473-474

58
[ 157764-05-1 ]
[ 190906-92-4 ]
tert-butyl 2-amino-3-(5-fluorobenzo[d]thiazol-2-yl)-5-methyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate [ No CAS ]
tert-butyl 2-amino-3-(5-fluorobenzo[d]thiazol-2-yl)-7-methyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With morpholine; sulfur; In ethanol; at 80℃; for 3h;	To a solution of 2-(5-fluorobenzo[djthiazol-2-yl)acetonitrile 1(1.35 g, 7.032 mmol) in ethanol (15 mL) was added <strong>[190906-92-4]tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate</strong> 2 (1.50 g, 7.032 mmol), elemental sulphur (225 mg, 7.032 mmol) and morpholine (611 mg, 7.032 mmol) at room temperature. After the addition, the resulting mixture was heated to reflux at 80 C for 3 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was evaporated in vacuum up to dryness. The crude compound was purified by column chromatography eluting with 0-20% ethyl acetate in n-hexane to afford the title compound 3 and 4 as off white solid (2.8 g, yield 95%).

Reference： [1]Patent: WO2016/197078,2016,A1 .Location in patent: Paragraph 1116-1117

59
[ 36229-42-2 ]
[ 190906-92-4 ]
tert-butyl 4-(3-chlorophenyl)-4-hydroxy-2-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37.8%	In 2-methyltetrahydrofuran; at 0 - 20℃; for 16h;	A 1 M solution of (3-chlorophenyl)magnesium bromide (1.19 mL, 1.19 mmol) in MeTHF was added to a stirred solution of tert-butyl 2-methyl-4-oxopiperidine- 1- carboxylate (0.253 g, 1.19 mmol) in THF (5 mL) at 0C, and the mixture was stirred at rt for 16 h. The reaction mixture was quenched with saturated NH4C1 solution and extractedwith ethyl acetate. The combined organics were washed with brine, dried over Na2SO4, filtered, and evaporated. The crude compound was purified by silica gel chromatography to give 21 1A (146 mg, 37.8%) as a colorless oil. MS(ESI) m/z 326.0 (M+H).

Reference： [1]Patent: WO2017/40449,2017,A1 .Location in patent: Paragraph 00503

60
[ 591-51-5 ]
[ 190906-92-4 ]
tert-butyl 4-hydroxy-2-methyl-4-phenylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73.9%	In tetrahydrofuran; at -78 - 20℃; for 3h;	[00272] To a solution of phenyllithium (1.8M in Bu20, 7.16 ml, 12.89 mmol) in THF (15 mL) at -78oC was added dropwise l-boc-2-methyl-4-piperidinone (2.5 g, 11.72 mmol) in more THF (5 mL). The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction was quenched by pouring onto ice water. EtOAc (2x 25 mL) was added and the product extracted. The combined organics were dried (Na2S04), filtered and concentrated in vacuo. The crude residue was purified by chromatography on Si02 Eluting with 0-100% EtOAc in heptane to afford the title compound ( 2.97 g, 73.9%) as a yellow oil [00273] Method B: LC-MS: m/z = 192.0 (M-Boc)+, RT = 1.19 min.

Reference： [1]Patent: WO2017/59191,2017,A1 .Location in patent: Paragraph 00270-00273

61
2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile [ No CAS ]
[ 190906-92-4 ]
tert-butyl-2-amino-5-methyl-3-(thiazolo[4,5-c]pyridin-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate [ No CAS ]
tert-butyl 2-amino-7-methyl-3-(thiazolo[4,5-c]pyridin-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With morpholine; sulfur; In ethanol; at 85℃; for 3h;	[396] Step 1: tert-butyl-2-amino-5-methyl-3-(thiazolo[4,5-c]pyridin-2-yl) 4, 7- dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate and tert-butyl 2-amino-7-methyl-3- (thiazolo[4,5-c]pyridin-2-yl)-4, 7- dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (0843) (0844) To a solution of 2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile 1 (0.5 g, 2.85 mmol) in ethanol (10 mL) was added tert-butyl 2-methyl-4-oxopiperidine-l-carboxylate 2 (0.61 g, 2.85 mmol), elemental sulphur (91 mg, 2.85 mmol) and morpholine (0.24 mg, 2.85 mmol) at room (0845) temperature and the resulting reaction mixture was heated to reflux at 85 C for 3 h. Reaction was monitored by TLC. After the completion, reaction mixture was evaporated to dryness on rotavapour and the crude compound was triturated in methanol and dried to afford the mixture of title compounds as brown solid (1.3 g crude).

Reference： [1]Patent: WO2016/196910,2016,A1 .Location in patent: Paragraph 396

62
[ 190906-92-4 ]
tert-butyl cis-4-hydroxy-2-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With L-Selectride; In tetrahydrofuran; at -78℃; for 0.333333h;	EXAMPLE 72 Synthesis of 4-((c/'s-1-benzyl-2-methylpiperidin-4-yl)oxy)-3-chloro-//-(thiazol-2- yl)benzenesulfonamide Step 1. Preparation of te/f-butyl c/'s-4-hydroxy-2-methylpiperidine-1-carboxylate To a solution of terf-butyl 2-methyl-4-oxopiperidine-1-carboxylate (1.5 g, 7.03 mmol) in anhydrous tetrahydrofuran (1 10 mL) was added a 1.0 M solution of lithium tri- sec-butyl borohydride in tetrahydrofuran (8.10 mL, 8.1 mmol) at -78 C. The reaction mixture was stirred at -78 C for 20 minutes before it was quenched by addition of methanol (15 mL). The reaction mixture was diluted with water (300 mL) and dichloromethane (300 mL) and allowed to warm to ambient temperature. The aqueous layer was extracted with dichloromethane (2 chi 150 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 0 to 40% of ethyl acetate in hexanes to yield the title compound as a colorless solid (1.08 g, 71 % yield): H NMR (300 MHz, CDCI3) 4.32- 4.23 (m, 1 H), 4.20-4.13 (m, 1 H), 3.84-3.77 (m, 1 H), 3.24 (ddd, J = 13.6, 11.1 , 4.7 Hz, 1 H), 1.84 (ddd, J = 14.4, 6.6, 3.3 Hz, 1 H), 1.77-1.60 (m, 3H), 1.58-1.51 (m, 1 H), 1.44 (s, 9H), 1.31 (d, J = 7.1 Hz, 3H); MS (ES+) m/z 216.3.

Reference： [1]Patent: WO2017/201468,2017,A1 .Location in patent: Page/Page column 187

63
[ 190906-92-4 ]
tert-butyl trans-4-hydroxy-2-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With sodium tetrahydroborate; ethanol; at 20℃; for 2h;	EXAMPLE 73 Synthesis of 4-((frans-1-benzyl-2-methylpiperidin-4-yl)oxy)-3-chloro-//-(thiazol-2- yl)benzenesulfonamide Step 1. Preparation of te/f-butyl frans-4-hydroxy-2-methylpiperidine-1-carboxylate To a solution of terf-butyl 2-methyl-4-oxopiperidine-1-carboxylate (1.5 g, 7.03 mmol) in anhydrous ethanol (30 mL)) was added sodium borohydride (0.4 g, 10.55 mmol) and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue was diluted with water (15 mL) and a mixture of hexanes and ethyl acetate (1 : 1 , 30 mL). The aqueous layer was extracted with a mixture of hexanes and ethyl acetate (1 : 1 , 3 chi 50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography eluting with a gradient of 0 to 40% of ethyl acetate in hexanes afforded the title compound as a colorless solid (0.627 g, 41 % yield); H NMR (300 MHz, CDCIs) 4.51-4.42 (m, 1 H), 4.06-3.87 (m, 2H), 2.85 (dt, J = 13.5, 2.8 Hz, 1 H), 2.14-1.96 (m, 1 H), 1.94-1.77 (m, 2H), 1.56-1.45 (m, 1 H), 1.42 (s, 9H), 1.41-1.22 (m, 1 H), 1.12 (d, J = 7.1 Hz, 3H); MS (ES+) m/z 216.3 (M + 1).

Reference： [1]Patent: WO2017/201468,2017,A1 .Location in patent: Page/Page column 189-190

64
[ 271-63-6 ]
[ 190906-92-4 ]
tert-butyl 2-methyl-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylate [ No CAS ]
tert-butyl 6-methyl-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In methanol; at 20℃;Reflux;	To the solution of <strong>[190906-92-4]tert-butyl 2-methyl-4-oxo-piperidine-1-carboxylate</strong> (500 mg, 1 equiv.) in MeOH (5 mL), 1H-pyrrolo[2,3-b]pyridine (332 mg, 1.2 equiv.) and KOH (394 mg, 3equiv.) were added and the resulting mixture stirred at reflux temperature for 9 h and then overnight at room temperature. The reaction was quenched with saturated aq. ammonium chloride (25 mL) and extracted with ethyl acetate twice. The combined extracts were washed with brine, dried over Na2SO4 and solvent evaporated to afford the expected product as a mixture of two regioisomers (730 mg), which was used without furtherpurification in the next reaction step. LCMS: MW (calcd): 313.39; MS (ES, m/z): 314.3 [M+H].
	With potassium hydroxide; In methanol; at 20℃; for 27h;Reflux;	To a solution of tert-butyl 2-methyl-4-oxo-piperidine-l-carboxylate (500 mg, 1 equiv.) in MeOH (5.0 mL), lH-pyrrolo[2,3-6]pyridine (332 mg, 1.2 equiv.) and KOH (394 mg, 3 equiv.) were added, and the resulting mixture was stirred under reflux for 9 h and at RT for 18 h. The reaction was quenched by an addition of a saturated aq. solution of ammonium chloride (25 mL) and the mixture was extracted twice with ethyl acetate. Combined organic extracts were washed with brine, dried over Na2SC>4, filtered, and the solvent was removed in vacuo to afford the expected product as a mixture of two regioisomers (730 mg), which was used without further purification in the next reaction step. LCMS: MW (calc'd): 313.4; MS (ES+, m/z): 314.3 [M+H]+.

Reference： [1]Patent: WO2018/78360,2018,A1 .Location in patent: Page/Page column 137
[2]Patent: WO2019/43372,2019,A1 .Location in patent: Page/Page column 85

65
[ 4637-24-5 ]
pyrimidine-2-carboxamidine hydrochloride [ No CAS ]
[ 190906-92-4 ]
tert-butyl 5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.5 g		A mixture of <strong>[190906-92-4]tert-butyl 2-methyl-4-oxo-piperidine-1-carboxylate</strong> (2.3 g, 10.8 mmol) andDMFDMA(5 mL) was heated to 100 C for 2 hrs. The mixture was concentrated in vacuo. Theresidue was dissolved in in EtOH (50 mL) and pyrimidine-2-carboximidamide hydrochloride(3.55 g, 22.4 mmol) and K2C03 (3.86 g, 27.9 mmol) were added and the mixture was heated at90C overnight. After being cooled to rt, the resulting mixture was concentrated in vacuo and theresidue was purified by flash chromatography (eluting with DCM/MeOH=20: 1, v:v) to give tertbutyl 5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate (2.5 g) as yellow solid.

Reference： [1]Patent: WO2018/83106,2018,A1 .Location in patent: Page/Page column 49

66
[ 1000343-69-0 ]
[ 190906-92-4 ]
tert-butyl 2-methyl-4-(5-methyl-1H-indazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
tert-butyl 6-methyl-4-(5-methyl-1H-indazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (12.5 g, 58.7 mmol) in THF (200 mL) at -70 was added LiHMDS (65 mL, 64.5 mmol, 1.0 mol/L in THF) . The mixture was stirred at -70 for 1 hour. Then N,N-Bis(trifluoromethylsulfonyl)aniline (23 g, 64.5 mmol) in THF (40 mL) was added to the reaction. The mixture was stirred at -70 to room temperature overnight. The reaction was quenched with 200 mL of sat. NH4Cl (200 mL) . The mixture was extracted with EtOAc (500 mL) . The organic layer was washed with H2O (200 mL) , brine (100 mL) and concentrated. The crude product was purified by chromatography using Petroleum ether/EtOAc = 1001 to 101 to give compound (20.3 g, 100%) as yellow oil. LCMS [column: C18; column size: 4.6 x 30 mm 5 mum; Dikwa Diamonsil plus; mobile phase: B (ACN) : A1 (0.02%NH4OAc + 5%ACN) ; gradient (B%) in 4 mins. 10-95-POS; flow rate: 1.5 ml/min] : Rt = 2.161 min; MS Calcd.: 345, MS Found: 290 [M -56 + H]+. A mixture of mixture of tert-butyl 6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate and tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (20.3 g, 58.8 mmol) , 4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi(1,3,2-dioxaborolane) (14.4 g, 58.8 mmol) , Pd (dppf) Cl2 (4.8 g, 5.88 mol) and KOAc (11.5 g, 117.7 mmol) in 1,4-dioxane (300 mL) under N2 was stirred at 100 for 4 hours. The mixture was concentrated with silica gel and purified by chromatography using Petroleum ether/EtOAc = 201 to 101 to give the title compound (19 g, 100%) as yellow oil. LCMS [column: C18; column size: 4.6 x 30 mm 5 mum; Dikwa Diamonsil plus; mobile phase: B (ACN) : A1 (0.02%NH4OAc + 5%ACN) ; gradient (B%) in 4 mins. 40-95-POS; flow rate: 1.5 ml/min] : Rt = 2.279 min; MS Calcd.: 323, MS Found: 268 [M -56 + H]+. A mixture of mixture of tert-butyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate and tert-butyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (9.5 g, 29.2 mmol) , <strong>[1000343-69-0]6-bromo-5-methyl-1H-indazole</strong> (4.1 g, 19.5 mmol) , Pd(dppf)Cl2 (1.59 g, 1.95 mmol) and K2CO3 (8.07 g, 58.5 mmol) in 120 mL of 1,4-dioxane/water (v/v = 5/1) under N2 was stirred at 100 for 4 hours. The mixture was concentrated with silica gel and purified by chromatography using petroleum ether/EtOAc = 10/1 to 4/1 to give the title compound (5.0 g, 52%) as yellow oil. LCMS [column: C18; column size: 4.6 x 30 mm 5 mum; Dikwa Diamonsil plus; mobile phase: B (ACN) : A1 (0.02%NH 4OAc + 5%ACN) ; gradient (B%) in 4 mins. 10-95-POS; flow rate: 1.5 ml/min] : Rt = 2.311 min; MS Calcd.: 327, MS Found: 328 [M + H]+.

Reference： [1]Patent: WO2018/137619,2018,A1 .Location in patent: Page/Page column 67; 68; 69

67
[ 1000343-69-0 ]
[ 190906-92-4 ]
tert-butyl 2-methyl-4-(5-methyl-1H-indazol-6-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.65 g		To a solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (12.5 g, 58.7 mmol) in THF (200 mL) at -70 was added LiHMDS (65 mL, 64.5 mmol, 1.0 mol/L in THF) . The mixture was stirred at -70 for 1 hour. Then N,N-Bis(trifluoromethylsulfonyl)aniline (23 g, 64.5 mmol) in THF (40 mL) was added to the reaction. The mixture was stirred at -70 to room temperature overnight. The reaction was quenched with 200 mL of sat. NH4Cl (200 mL) . The mixture was extracted with EtOAc (500 mL) . The organic layer was washed with H2O (200 mL) , brine (100 mL) and concentrated. The crude product was purified by chromatography using Petroleum ether/EtOAc = 1001 to 101 to give compound (20.3 g, 100%) as yellow oil. LCMS [column: C18; column size: 4.6 x 30 mm 5 mum; Dikwa Diamonsil plus; mobile phase: B (ACN) : A1 (0.02%NH4OAc + 5%ACN) ; gradient (B%) in 4 mins. 10-95-POS; flow rate: 1.5 ml/min] : Rt = 2.161 min; MS Calcd.: 345, MS Found: 290 [M -56 + H]+. A mixture of mixture of tert-butyl 6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate and tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (20.3 g, 58.8 mmol) , 4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi(1,3,2-dioxaborolane) (14.4 g, 58.8 mmol) , Pd (dppf) Cl2 (4.8 g, 5.88 mol) and KOAc (11.5 g, 117.7 mmol) in 1,4-dioxane (300 mL) under N2 was stirred at 100 for 4 hours. The mixture was concentrated with silica gel and purified by chromatography using Petroleum ether/EtOAc = 201 to 101 to give the title compound (19 g, 100%) as yellow oil. LCMS [column: C18; column size: 4.6 x 30 mm 5 mum; Dikwa Diamonsil plus; mobile phase: B (ACN) : A1 (0.02%NH4OAc + 5%ACN) ; gradient (B%) in 4 mins. 40-95-POS; flow rate: 1.5 ml/min] : Rt = 2.279 min; MS Calcd.: 323, MS Found: 268 [M -56 + H]+. A mixture of mixture of tert-butyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate and tert-butyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (9.5 g, 29.2 mmol) , <strong>[1000343-69-0]6-bromo-5-methyl-1H-indazole</strong> (4.1 g, 19.5 mmol) , Pd(dppf)Cl2 (1.59 g, 1.95 mmol) and K2CO3 (8.07 g, 58.5 mmol) in 120 mL of 1,4-dioxane/water (v/v = 5/1) under N2 was stirred at 100 for 4 hours. The mixture was concentrated with silica gel and purified by chromatography using petroleum ether/EtOAc = 10/1 to 4/1 to give the title compound (5.0 g, 52%) as yellow oil. LCMS [column: C18; column size: 4.6 x 30 mm 5 mum; Dikwa Diamonsil plus; mobile phase: B (ACN) : A1 (0.02%NH 4OAc + 5%ACN) ; gradient (B%) in 4 mins. 10-95-POS; flow rate: 1.5 ml/min] : Rt = 2.311 min; MS Calcd.: 327, MS Found: 328 [M + H]+. A mixture of mixture of tert-butyl 2-methyl-4-(5-methyl-1H-indazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate and tert-butyl 6-methyl-4-(5-methyl-1H-indazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (5.0 g, 15.3 mmol) and Pd/C (1.0 g, 20%W) in MeOH (100 mL) under H2 (50 psi) was stirred at 50 for 7 days. The mixture was concentrated with silica gel and purified by chromatography using Petroleum ether/EtOAc = 21 to 11 to give the title compound (2.65 g, 53%) as yellow oil. 1HNMR (400 MHz, CDCl3) : delta 10.12 (br s, 1H) , 7.95 (s, 1H) , 7.52 (d, J= 8.0 Hz, 1H) , 7.30 (d, J = 6.8 Hz, 1H) , 4.67-4.20 (m, 1H) , 4.02-3.81 (m, 1H) , 3.32-3.01 (m, 2H) , 2.44 (d, J = 9.2 Hz, 3H) , 1.75-1.66 (m, 4H) , 1.51 (s, 9H) , 1.27-1.26 (m, 3H )

Reference： [1]Patent: WO2018/137619,2018,A1 .Location in patent: Page/Page column 67; 68; 69

68
[ 73183-34-3 ]
[ 190906-92-4 ]
tert-butyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
tert-butyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[190906-92-4]tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate</strong> (12.5 g, 58.7 mmol) in THF (200 mL) at -70 was added LiHMDS (65 mL, 64.5 mmol, 1.0 mol/L in THF) . The mixture was stirred at -70 for 1 hour. Then N,N-Bis(trifluoromethylsulfonyl)aniline (23 g, 64.5 mmol) in THF (40 mL) was added to the reaction. The mixture was stirred at -70 to room temperature overnight. The reaction was quenched with 200 mL of sat. NH4Cl (200 mL) . The mixture was extracted with EtOAc (500 mL) . The organic layer was washed with H2O (200 mL) , brine (100 mL) and concentrated. The crude product was purified by chromatography using Petroleum ether/EtOAc = 1001 to 101 to give compound (20.3 g, 100%) as yellow oil. LCMS [column: C18; column size: 4.6 x 30 mm 5 mum; Dikwa Diamonsil plus; mobile phase: B (ACN) : A1 (0.02%NH4OAc + 5%ACN) ; gradient (B%) in 4 mins. 10-95-POS; flow rate: 1.5 ml/min] : Rt = 2.161 min; MS Calcd.: 345, MS Found: 290 [M -56 + H]+. A mixture of mixture of tert-butyl 6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate and tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (20.3 g, 58.8 mmol) , 4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi(1,3,2-dioxaborolane) (14.4 g, 58.8 mmol) , Pd (dppf) Cl2 (4.8 g, 5.88 mol) and KOAc (11.5 g, 117.7 mmol) in 1,4-dioxane (300 mL) under N2 was stirred at 100 for 4 hours. The mixture was concentrated with silica gel and purified by chromatography using Petroleum ether/EtOAc = 201 to 101 to give the title compound (19 g, 100%) as yellow oil. LCMS [column: C18; column size: 4.6 x 30 mm 5 mum; Dikwa Diamonsil plus; mobile phase: B (ACN) : A1 (0.02%NH4OAc + 5%ACN) ; gradient (B%) in 4 mins. 40-95-POS; flow rate: 1.5 ml/min] : Rt = 2.279 min; MS Calcd.: 323, MS Found: 268 [M -56 + H]+.

Reference： [1]Patent: WO2018/137619,2018,A1 .Location in patent: Page/Page column 67; 68

69
[ 190906-92-4 ]
[ 1137949-58-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -78 °C 1.2: 0 - 20 °C 2.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate / 1,4-dioxane / 16 h / 110 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1.1: sodium hexamethyldisilazane / tetrahydrofuran / 1 h / -70 °C 1.2: -70 - 20 °C 2.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2019/62309, 2019, A1
[2]Current Patent Assignee: NANJING RUIJIE PHARMA TECH - WO2020/249064, 2020, A1

70
[ 271-63-6 ]
[ 190906-92-4 ]
tert-butyl 6-methyl-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of tert-butyl 2-methyl-4-oxo-piperidine-l-carboxylate (500 mg, 1 equiv.) in MeOH (5.0 mL), lH-pyrrolo[2,3-6]pyridine (332 mg, 1.2 equiv.) and KOH (394 mg, 3 equiv.) were added, and the resulting mixture was stirred under reflux for 9 h and at RT for 18 h. The reaction was quenched by an addition of a saturated aq. solution of ammonium chloride (25 mL) and the mixture was extracted twice with ethyl acetate. Combined organic extracts were washed with brine, dried over Na2SC>4, filtered, and the solvent was removed in vacuo to afford the expected product as a mixture of two regioisomers (730 mg), which was used without further purification in the next reaction step. LCMS: MW (calc'd): 313.4; MS (ES+, m/z): 314.3 [M+H]+; To a solution of two regioisomers, tert-butyl 2-methyl-4-(lH-pyrrolo[2,3-£]pyridin-3-yl)- 3,6-dihydro-2H-pyridine-l-carboxylate and tert-butyl 6-methyl-4-(lH-pyrrolo[2,3- £]pyridin-3-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (730 mg, 1 equiv.) in EtOH (15 mL), ammonium formate (734 mg, 5 equiv.) and 10 wt% Pd/C (195 mg) were added. The mixture was sealed in a reaction tube and stirred at 90 C for 90 min. The mixture was then filtered over a pad of Celite, the pad was washed thoroughly with MeOH, and the filtrate was evaporated to dryness to afford the expected product (780 mg), which was used in the next step without further purification. LCMS: MW (calc'd): 315.4; MS (ES+, m/z): 316.3 [M+H]+.

Reference： [1]Patent: WO2019/43372,2019,A1 .Location in patent: Page/Page column 85; 88

71
[ 72482-64-5 ]
[ 190906-92-4 ]
tert-butyl 5-(2,4-difluorobenzoyl)-2-methyl-4-oxopiperidine-1-carboxylate [ No CAS ]
tert-butyl 3-(2,4-difluorobenzoyl)-2-methyl-4-oxopiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[00221] To a solution of <strong>[190906-92-4]tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate</strong> (0.66 g, 3.09 mmcl) in toluene (7 mL) at 0 C (ice water bath) under nitrogen atmosphere was added LiHMDS (3.25 mL, 1 .0 M in THE, 3.25 mmol) and the resultant mixture was stirred at 0 CC for 7 mins. Then a solution of 2,4-difluorobenzoyl chloride (0.380 mL, 3.09 mmol) in toluene (1 .5 mL) was added and the resultant mixture was stirred at 0C for 15 mins. The reaction was then quenched by adding acetic acid (0.85 mL), Ethanol (1 .8 mL) and THE (3.5 mL). This crude mixture was used in the next cyclization steps directly.

Reference： [1]Patent: WO2019/97479,2019,A1 .Location in patent: Paragraph 00221

72
[ 72482-64-5 ]
[ 190906-92-4 ]
tert-butyl 3-(2,4-difluorophenyl)-6-methyl-6,7-dihydroisoxazolo[4,3-c]pyridine-5(4H)-carboxylate [ No CAS ]
tert-butyl 3-(2,4-difluorophenyl)-4-methyl-6,7-dihydroisoxazolo[4,3-c]pyridine-5(4H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%; 18%		[00221] To a solution of <strong>[190906-92-4]tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate</strong> (0.66 g, 3.09 mmcl) in toluene (7 mL) at 0 C (ice water bath) under nitrogen atmosphere was added LiHMDS (3.25 mL, 1 .0 M in THE, 3.25 mmol) and the resultant mixture was stirred at 0 CC for 7 mins. Then a solution of 2,4-difluorobenzoyl chloride (0.380 mL, 3.09 mmol) in toluene (1 .5 mL) was added and the resultant mixture was stirred at 0C for 15 mins. The reaction was then quenched by adding acetic acid (0.85 mL), Ethanol (1 .8 mL) and THE (3.5 mL). This crude mixture was used in the next cyclization steps directly.[00222] To the crude material from previous step (1 .092 g, 3.09 mmol in toluene, THE, EtOH, HOAc) was added DME (10 mL) was added hydroxylamine hydrochloride salt (2.559 g, 18.54 mmol) and DIPEA (6.48 mL, 37.1 mmol). After stirred at rtfor 16 hours, the mixture was diluted with EtOAc, washed with water and brine twice, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, (EtOAc/heptane, 20 to 50%) to give products as two isomers 3.lb-I and 3.lb-II.[00223] Less polar isomer 3.lb-I: (132 mg, 13% yield). LCMS (m/z): 351.5 [M+H].[00224] More polar isomer 3.lb-II: (194 mg, 18% yield). LCMS (m/z): 351.5 [M+H].

Reference： [1]Patent: WO2019/97479,2019,A1 .Location in patent: Paragraph 00221; 00222-00224

73
6-(2-methyl-2H-indazol-5-yl)benzo[d]thiazole [ No CAS ]
[ 190906-92-4 ]
tert-butyl 4-hydroxy-2-methyl-4-(6-(2-methyl-2H-indazol-5-yl)benzo[d]thiazol-2-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%		To a solution of 6-(2-methyl-2H-indazol-5-yl)benzo[d]thiazole (700 mg) in THF at -78C was added slowly a solution of n-BuLi (3.0 eq.) in hexanes. After 30 min, a solution of <strong>[190906-92-4]tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate</strong> (2.0 eq.) in THF was added and the temperature was allowed to rise slowly to room temperature over 16 h. The mixture was treated with saturated NH4Cl solution and extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate and evaporated. The residue was purified by silica gel flash column chromatography to afford tert-butyl 4-hydroxy-2-methyl-4-(6-(2-methyl-2H-indazol-5- yl)benzo[d]thiazol-2-yl)piperidine-1-carboxylate (0.56 g, 43%). MS m/z 479.2 [M+H]+.

Reference： [1]Patent: WO2020/5877,2020,A1 .Location in patent: Page/Page column 165-166

74
[ 388080-67-9 ]
[ 190906-92-4 ]
(R/S)-6-fluoro-3,9-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%		General procedure: A solution of [Int-1.2] (0.5 g, 2.83 mmol) and tert-butyl 4-oxopiperidine-l-carboxylate (0.564 g, 2.83 mmol) in EtOH (5 mL) was stirred at room temperature, until the formation of hydrazone intermediate. 2, 4, 6-Trichloro-1, 3, 5-triazine (0.208 g, 1.13 mmol) was added and reaction mixture was heated to 90 C for 8h. The reaction mixture was cooled to room temperature and the obtained precipitate was filtered and washed with cold EtOH. The crude product was obtained as a light orange solid (0.65 g, 95%) . UPLC-MS: tR = 1.31 min (method A);

Reference： [1]Patent: WO2020/12427,2020,A1 .Location in patent: Page/Page column 44; 45; 58; 59

75
[ 388080-67-9 ]
[ 190906-92-4 ]
(R/S)-6-fluoro-1,9-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6%		General procedure: A solution of [Int-1.2] (0.5 g, 2.83 mmol) and tert-butyl 4-oxopiperidine-l-carboxylate (0.564 g, 2.83 mmol) in EtOH (5 mL) was stirred at room temperature, until the formation of hydrazone intermediate. 2, 4, 6-Trichloro-1, 3, 5-triazine (0.208 g, 1.13 mmol) was added and reaction mixture was heated to 90 C for 8h. The reaction mixture was cooled to room temperature and the obtained precipitate was filtered and washed with cold EtOH. The crude product was obtained as a light orange solid (0.65 g, 95%) .

Reference： [1]Patent: WO2020/12427,2020,A1 .Location in patent: Page/Page column 44; 45; 59

76
[ 388080-67-9 ]
[ 190906-92-4 ]
(rac)-6-fluoro-3,9-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]-indole [ No CAS ]
(rac)-6-fluoro-1,9-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]-indole [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2020,vol. 63,p. 11169 - 11194

77
[ 375-72-4 ]
[ 73183-34-3 ]
[ 190906-92-4 ]
[ 1426231-87-9 ]
[ 1137949-58-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: Nonafluorobutanesulfonyl fluoride; tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Stage #2: bis(pinacol)diborane With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In 1,4-dioxane at 80℃; Overall yield = 83 percent; Overall yield = 3.77 g;	tert-Butyl 6-methyl-4-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylate (43a) and tert-Butyl 2-methyl-4-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyl oxy)-3,6-dihydro-2H-pyridine-1-carboxylate (43b) DBU (1.96 mL, 13.1 mmol, 1.4 equiv.) and perfluoro-1-butanesulfonyl fluoride (1.68 mL, 9.4 mmol) was added dropwise to a solution of N-Boc-2-methyl-piperidone (2.0 g, 9.4 mmol) in anhydrous THF (60 mL) at 0°C under argon atmosphere. The mixture was allowed to reach room temperature and stirred overnight. TLC monitoring the next day was performed to ensure complete conversion (if not complete DBU (0.25 equiv.) and perfluoro-1-butanesulfonyl fluoride (0.5 equiv.) can be added every 1.5 h). The reaction mixture was then treated with a saturated aqueous solution of NaHCO3 (50 mL) and extracted with Et2O (2 x 100 mL). The combined organic layers were dried over MgSO4,filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using a gradient solvent system of PE/EtOAc from 100/0 up to 95/5 to afford compounds 43a-43b (4.03 g, 87%) as a colorless oil containing a mixture of diastereoisomeres (7/3). Rf (PE/EtOAc 70/30) 0.37. Product 43a (main product) 1H NMR (250 MHz, CDCl3) δ 5.72 (m, 1H, CH), 4.78-4.57 (m, 1H, CH), 4.32-4.15 (m, 1H, CH), 3.08 - 2.89 (m, 1H, CH), 2.67 - 2.48 (m, 1H, CH), 2.26-2.13 (m, 1H, CH), 1.47 (s, 9H, 3 xC H3), 1.23 (d, J = 6.8 Hz, 3H, CH3). Product 43b 1H NMR (250 MHz, CDCl3) δ 5.76 (m, 1H, CH), 4.78 - 4.57 (m, 1H, CH), 4.51 - 4.34 (m, 1H, CH), 3.63 (ddt, J = 18.8 Hz, J = 4.7 Hz, J = 2.5 Hz, 1H, CH), 2.87 - 2.72 (m, 1H, CH), 2.11 - 2.00 (m, 1H, CH), 1.46 (s, 9H, 3 x CH3), 1.17 (d, J = 6.9 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd for C15H19F9NO5S [M+H]+: 496.0835, found: 496.0835.tert-Butyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (44a) and tert-Butyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (44b) (0152) To a solution of 43a-43b (5.0 g, 10.0 mmol) in 1,4-dioxane (50 mL) were added bis(pinacolato)diboron (2.9 g, 11.5 mmol, 1.15 equiv.), potassium acetate (3.5 g, 35.2 mmol, 3.5 equiv.) and dppf (170 mg, 0.3 mmol, 0.03 equiv.). The solution was degassed for 15 min and Pd(dppf)Cl2·DCM (245 mg, 0.3 mmol, 0.03 equiv.) was added. The mixture was then heated at 80°C overnight, cooled and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4,filtered and concentrated under vacuum. The crude residue was purified by silica gel column chromatography using a solvent system of PE/EtOAc 95/5 to afford compounds 44b-44b (3.77 g, 83 %) as a colorless oil containing a mixture of diastereoisomeres (7/3). Rf (PE/EtOAc 90/10) 0.19. Product 44a (main) 1H NMR (250 MHz, CDCl3) δ 6.41 - 6.33 (m, 1H, CH), 4.53 - 4.34 (m, 1H, CH), 4.12 - 3.94 (m, 1H, CH), 2.82 - 2.63 (m, 1H, CH), 2.26 - 2.09 (m, 2H, 2 x CH), 1.44 (s, 9H, 3 x CH3), 1.25 (s, 12H, 4 x CH3), 1.17 (d, J = 6.9 Hz, 3H, CH3). Product 44b 1H NMR (250 MHz, CDCl3) δ 6.48 - 6.42 (m, 1H, CH), 4.53 - 4.34 (m, 1H, CH), 4.20 (dt, J = 20.2 Hz, J = 3.8 Hz, 1H, CH), 3.66 - 3.51 (m, 1H, CH), 2.50 - 2.34 (m, 1H, CH), 2.09 - 1.98 (m, 1H, CH), 1.44 (s, 9H, 3 x CH3), 1.25 (s, 12H, 4 x CH3), 1.04 (d, J = 6.8 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd for C17H31BNO4 [M+H]+: 324.2341, found: 324.2342.

Reference： [1]Current Patent Assignee: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; UNIVERSITY OF ORLEANS - EP3915990, 2021, A1 Location in patent: Paragraph 0150-0152

78
[ 37595-74-7 ]
[ 73183-34-3 ]
[ 190906-92-4 ]
[ 1426231-87-9 ]
[ 1137949-58-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine With lithium dipropan-2-ylazanide In tetrahydrofuran at -78℃; for 0.5h; Stage #2: 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide In tetrahydrofuran at -78 - 20℃; for 11.5h; Stage #3: 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-4',4',5',5'-tetramethyl-1,3,2-dioxaborolane With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In 1,4-dioxane at 90℃; for 16h; Inert atmosphere;	40.1; 41.1; 40.2; 41.2 Step 1 Compound 40a (1 g, 4.69 mmol) was dissolved in THF (10 mL), LDA (2 M, 2.81 mL) was added dropwise at-78°C, stirring was conducted for 30 minutes. N-phenylbis(trifluoromethanesulfonyl) imine (2.01 g, 5.63 mmol) was thendissolved in 5 mL of THFand added dropwise to the above reaction solution at -78°C, after the dropwise addition, thetemperature of the reaction solution was slowly risen to 20°C (1.5h), and stirring was conducted overnight (10 h).Saturated ammonium chloride (20 mL) was added to the reaction solution, and then the reaction solution was extractedwith ethyl acetate (30 mL) twice. Organic phases were combined, dried with anhydrous sodium sulfate, and filtrated toobtain a filtrate. The filtrate was concentrated to obtain a crude product. The crude product was purified by a rapid columnpassing machine (PE:EA=5:1 to 1:1) to obtain a mixture of compounds 40b 1 and 40b2.Step 2 The mixture of 40b1 and 40b2 (1 g, 2.90 mmol) was dissolved in 1,4-dioxane (15 mL), bis(pinacolato)diboron(882.41 mg, 3.47 mmol), KOAc (568.39 mg, 5.79 mmol) and Pd(dppf)Cl2 (211.88 mg, 289.57 mmol) were added, andstirring was conducted at 90°C for 16 hours under nitrogen protection. The reactant was filtered and dried by a spinningmethod under reduced pressure to obtain a crude product. The crude product was purified by an automatic colum passing machine (PE:EA=5:1) to obtain a mixture of compounds 40c1 and 40c
	Stage #1: 1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine With lithium dipropan-2-ylazanide In tetrahydrofuran at -78℃; for 0.5h; Stage #2: 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide In tetrahydrofuran at -78 - 20℃; for 11.5h; Stage #3: 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-4',4',5',5'-tetramethyl-1,3,2-dioxaborolane With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In 1,4-dioxane at 90℃; for 16h; Inert atmosphere;	40.1; 41.1; 40.2; 41.2 Step 1 Compound 40a (1 g, 4.69 mmol) was dissolved in THF (10 mL), LDA (2 M, 2.81 mL) was added dropwise at-78°C, stirring was conducted for 30 minutes. N-phenylbis(trifluoromethanesulfonyl) imine (2.01 g, 5.63 mmol) was thendissolved in 5 mL of THFand added dropwise to the above reaction solution at -78°C, after the dropwise addition, thetemperature of the reaction solution was slowly risen to 20°C (1.5h), and stirring was conducted overnight (10 h).Saturated ammonium chloride (20 mL) was added to the reaction solution, and then the reaction solution was extractedwith ethyl acetate (30 mL) twice. Organic phases were combined, dried with anhydrous sodium sulfate, and filtrated toobtain a filtrate. The filtrate was concentrated to obtain a crude product. The crude product was purified by a rapid columnpassing machine (PE:EA=5:1 to 1:1) to obtain a mixture of compounds 40b 1 and 40b2.Step 2 The mixture of 40b1 and 40b2 (1 g, 2.90 mmol) was dissolved in 1,4-dioxane (15 mL), bis(pinacolato)diboron(882.41 mg, 3.47 mmol), KOAc (568.39 mg, 5.79 mmol) and Pd(dppf)Cl2 (211.88 mg, 289.57 mmol) were added, andstirring was conducted at 90°C for 16 hours under nitrogen protection. The reactant was filtered and dried by a spinningmethod under reduced pressure to obtain a crude product. The crude product was purified by an automatic colum passing machine (PE:EA=5:1) to obtain a mixture of compounds 40c1 and 40c
	Stage #1: 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide; 1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 0℃; Stage #2: 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-4',4',5',5'-tetramethyl-1,3,2-dioxaborolane With 1,1'-bis(diphenylphosphanyl)ferrocene; anhydrous potassium acetate In 1,4-dioxane at 80℃; for 14h;	A30 Preparation of intermediate 68: Bis(pinacolato)diboron (808.88 mg; 3.185 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (94.59 mg; 0.116 mmol), potassium acetate (852.65 mg; 8.687 mmol) and 1,1'- bis(diphenylphosphino)ferrocene (64.17 mg; 0.116 mmol) were added to a solution of intermediate 65 in 1,4-di oxane (37 mL) while N2 was bubbling. The reaction mixture was stirred at 80 °C for 14 hours. Then, the mixture was diluted with brine and extracted with EtOAc (3X). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 0-10 % EtOAc in Heptane). The desired fractions were combined and concentrated in vacuo to afford the product (700 mg; 37 %) as a white solid.

Stage #1: 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide; 1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 0℃; Stage #2: 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-4',4',5',5'-tetramethyl-1,3,2-dioxaborolane With 1,1'-bis(diphenylphosphanyl)ferrocene; anhydrous potassium acetate In 1,4-dioxane at 80℃; for 14h;

A30 Preparation of intermediate 68: Bis(pinacolato)diboron (808.88 mg; 3.185 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (94.59 mg; 0.116 mmol), potassium acetate (852.65 mg; 8.687 mmol) and 1,1'- bis(diphenylphosphino)ferrocene (64.17 mg; 0.116 mmol) were added to a solution of intermediate 65 in 1,4-di oxane (37 mL) while N2 was bubbling. The reaction mixture was stirred at 80 °C for 14 hours. Then, the mixture was diluted with brine and extracted with EtOAc (3X). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 0-10 % EtOAc in Heptane). The desired fractions were combined and concentrated in vacuo to afford the product (700 mg; 37 %) as a white solid.

Reference： [1]Current Patent Assignee: GUANGZHOU BAIYUNSHAN PHARMACEUTICAL HOLDINGS CO., LTD. - EP3950685, 2022, A1 Location in patent: Paragraph 0474-0476
[2]Current Patent Assignee: GUANGZHOU BAIYUNSHAN PHARMACEUTICAL HOLDINGS CO., LTD. - EP3950685, 2022, A1 Location in patent: Paragraph 0474-0476
[3]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2022/136174, 2022, A1 Location in patent: Page/Page column 109; 110
[4]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2022/136174, 2022, A1 Location in patent: Page/Page column 109; 110

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Precautionary Statements-General
Code	Phrase
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Prevention
Code	Phrase
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P321
P322
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Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
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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
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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
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Code	Phrase
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H302	Harmful if swallowed
H303	May be harmful if swallowed
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H311	Toxic in contact with skin
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H315	Causes skin irritation
H316	Causes mild skin irritation
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H319	Causes serious eye irritation
H320	Causes eye irritation
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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. 190906-92-4 ] {[proInfo.proName]}

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Calculated chemistry of [ 190906-92-4 ]

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Lipophilicity

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Water Solubility

Medicinal Chemistry

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Application In Synthesis of [ 190906-92-4 ]

[ 190906-92-4 ] Synthesis Path-Upstream 1~11

[ 190906-92-4 ] Synthesis Path-Downstream 1~78

Related Functional Groups of [ 190906-92-4 ]

Amides

Ketones

Related Parent Nucleus of [ 190906-92-4 ]

Aliphatic Heterocycles

Piperidines

Precautionary Statements-General

Prevention

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[ 190906-92-4 ]

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[ 190906-92-4 ]