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[ CAS No. 181269-69-2 ] {[proInfo.proName]}

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

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3d Animation Molecule Structure of 181269-69-2

Chemical Structure| 181269-69-2

Chemical Structure| 181269-69-2

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Quality Control of [ 181269-69-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 181269-69-2 ]

SDS Specification

Alternatived Products of [ 181269-69-2 ]

Product Details of [ 181269-69-2 ]

CAS No. :	181269-69-2	MDL No. :	MFCD08460962
Formula :	C₁₁H₁₉NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VWSBNWIPICCWAM-UHFFFAOYSA-N
M.W :	213.27	Pubchem ID :	22644642
Synonyms :

Calculated chemistry of [ 181269-69-2 ]

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) :	-6.79 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.51
Log Po/w (XLOGP3) :	1.14
Log Po/w (WLOGP) :	1.45
Log Po/w (MLOGP) :	1.05
Log Po/w (SILICOS-IT) :	1.23
Consensus Log Po/w :	1.48

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.68
Solubility :	4.43 mg/ml ; 0.0208 mol/l
Class :	Very soluble
Log S (Ali) :	-1.71
Solubility :	4.13 mg/ml ; 0.0194 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 :	2.57

Safety of [ 181269-69-2 ]

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

Application In Synthesis of [ 181269-69-2 ]

* 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 [ 181269-69-2 ]
Downstream synthetic route of [ 181269-69-2 ]

[ 181269-69-2 ] Synthesis Path-Upstream 1~9

1
[ 181269-69-2 ]
[ 5773-58-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: With trifluoroacetic acid In dichloromethane at 20℃; for 1 h; Stage #2: With water In dichloromethane; water	To the solution of A0052-6 (300 mg, 1.41 mmol) in 3 ml dichloromethane was added 0.6 mL trifluoroacetic acid and the mixture was kept stirring for 1 hour at room temperature. Then the mixture was added 30 mL of NaOH (20percent, aq) and extracted with dichloromethane . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to obtain 122 mg of the crude product as yellow oil. The crude product was used for the next step without any further purification (yield: 75percent) . The structure was confirmed by ¹H NMR.

Reference： [1] Patent: WO2010/51374, 2010, A1, . Location in patent: Page/Page column 118; 119

2
[ 181269-69-2 ]
[ 4629-78-1 ]

Reference： [1] Patent: US2010/144745, 2010, A1, . Location in patent: Page/Page column 46

3
[ 181269-69-2 ]
[ 33557-57-2 ]

Reference： [1] Patent: WO2013/96744, 2013, A1,

4
[ 34737-89-8 ]
[ 24424-99-5 ]
[ 181269-69-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogen In ethyl acetate for 24 h;	Compound 28 (15.0 g, 0.0738 mol) and di-t-butyl dicarbonate (17.7 g, 0.0812 mol) were dissolved in EtOAc (400 ml). Palladium hydroxide catalyst (4 g) was added and the mixture was shaken on a Paar shaker under 40 psi of hydrogen pressure for 24 h. The resultant mixture was filtered through celite and the celite was washed with EtOAc. The filtrate was concentrated to give 15.73 g (0.0738 mol, 100percent) of the product 27B as a colorless oil. MS (ES for M-tBOC+1): m/e 114
97%	With hydrogen In ethanol at 20℃; for 4 h;	A mixture of l-benzyl-3-methylpiperidin-4-one (1 1.4 g, 56.1 mmol), Boc- anhydride (14.32 mL, 61.7 mmol), and 10percent palladium on carbon (0.597 g, 5.61 mmol) in ethanol (100 mL) was degassed under vacuum and nitrogen, then hydrogenated at 50 psi for 4 hours at room temperature. The catalyst was removed by filtration, rinsed with methanol, and the combined filtrate and rinses were concentrated in vacuo. The residue was purified over a 330 g silica gel column, eluting at 100 mL/min with an ethyl acetate/hexanes gradient to yield tert-butyl 3- methyl-4-oxopiperidine-l-carboxylate (11.66 g, 54.7 mmol, 97 percent yield) as an oil, which solidified upon standing. 3/4 NMR (CDC1₃, 400 MHz) δ 4.15 (m, 2H), 3.22 (] 1H), 2.79 (br m, 1H), 2.52-2.38 (m, 3H), 1.46 (s, 9H), 1.01 (d, J=6.8 Hz, 3H); m/z = 158.2 (M-tBu)⁺.
95%	With hydrogen In methanol at 20℃;	Synthesis of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate; In a high pressure vessel was added 1-benzyl-3-methyl-piperidin-4one (6.0 g, 29.52 mmol) which was dissolved in methanol (60 mL). Di-tertbutyl dicarbonate (8.37 g, 38.40 mmol) was added along with palladium hydroxide (829 mg, 5.90 mmol) and the reaction stirred at r.t. overnight under 55 psi hydrogen atmosphere. The reaction was vacuum filtered through celite and concentrated. The crude material was purified by flash chromatography (10percent ethyl acetate/heptanes) to give the title compound as a colorless oil (6.01 g, 28.21 mmol, 95percent).

95.33%	With palladium on activated charcoal; hydrogen In methanol at 20℃; for 16 h;	To a solution of 1- benzyl-3-methyl-piperidin-4-one (2.0 g, 9.84 mmol, 1.0 eq) and Boc2O (2.15 g, 9.84 mmol, 2.26 mL, 1.0 eq) in MeOH (50.0 mL) was added Pd/C (9.84 mmol, 1.0 eq) underN2. Thesuspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 20 °C for 16 hours. TLC (PE:EA = 5:1) showed the reaction was completed. The mixture was filtrated. The filtrate was concentrated in vacuum. The residue was purified by colunm chlomatography (PE:EA=Opercent15percent) to afford the title 0 (2.0 g, 9.38 mmol, 95.33percent yield) as colorless oil. ‘HNMR (400MHz, CHLOROFORM-d) = 4.16 -4.24 (m, 1 H), 3.22 - 3.33 (m, 1 H), 2.86 (brs, 1 H), 2.38 - 2.61 (m, 3 H), 1.51 (s, 9 H), 1.06 (d, J= 6.7 Hz, 3 H).
92%	With hydrogen In ethanol for 4 h; Inert atmosphere	A mixture of 1-benzyl-3-methylpiperidin-4-one (5.25 g, 25.8 mmol), BOC-anhydride (6.60 mL, 28.4 mmol), and 10percent palladium on carbon (0.275 g, 2.58 mmol) in ethanol (100 mL) was degassed under vacuum and nitrogen, then hydrogenated at 50 psi for 4 hours. The catalyst was removed by filtration, rinsed with methanol, and the combined filtrate and rinsings were concentrated in vacuo. The residue was purified over a 330 g silica gel column, eluting at 100 mL/min with a 10percent to 30percent ethyl acetate/hexanes gradient followed by 30percent ethyl acetate/hexanes to yield the title compound (5.07 g, 23.77 mmol, 92percent yield) as a colorless oil, which solidified upon standing. MS (ESI⁺)=158.1 (M-tert-Bu)⁺.
88%	With palladium on activated charcoal; hydrogen In methanol for 12 h;	Preparation of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate A solution of 1-benzyl-3-methylpiperidin-4-one (1.63 g, 8.018 mmol) and di-tert-butyl dicarbonate (1.925 g, 8.82 mmol) in 50 ml of Methanol was hydrogenated using H-Cube (Controlled H2 at 50 bar, flow rate 1.0 ml/min) with Pd-C cartridge. The reaction mixture was recirculated for 12 hours. After washing the H-Cube thoroughly with Methanol, the solvent was evaporated and the resulting oil was purified by silica gel chromatography to afford the title compound (1.5 g, 88percent).
81%	With hydrogen In methanol	1-BENZYL-3-METHYL-PIPERIDIN-4-ONE (6.5 g, 32.0 mmol) was dissolved in methanol (30 mL). Di-tert-butyl dicarbonate (10.46 g, 48.0 mmol) was added followed by palladium hydroxide (20percent, 100 mg) and the reaction shaken overnight at 55 psi under a hydrogen atmosphere. The reaction was filtered and concentrated in vacuo to give a clear oil. Flash column chromatography (75: 25 hexanes/ethyl acetate) afforded the title compound as a white solid. Wt.: 5. 5 G (81percent).APOS;H NMR (300 MHz, CDC13) 8 4.18 (M, 2H), 3.25 (M, 1H), 2.84 (M, 1H), 2.53 (M, 1H), 2.43 (M, 2H), 1.50 (s, 9H), 1.05 (d, 3H).
81%	With hydrogen In methanol	1-BENZYL-3-METHYL-PIPERIDIN-4-ONE (6.5 g, 32.0 mmol) was dissolved in methanol (30 mL). Di-tert-butyl dicarbonate (10.46 g, 48.0 mmol) was added followed by palladium hydroxide (20percent, 100 mg) and the reaction shaken overnight at 55 psi under a hydrogen atmosphere. The reaction was filtered and CONCENTRATED IN VACUO to give a clear oil. Flash column chromatography (75: 25 hexanes/ethyl acetate) afforded the title compound as a white solid. Wt.: 5.5 g (81percent).APOS;H NMR (300 MHz, CDC13) 8 4.18 (m, 2H), 3.25 (m, 1H), 2.84 (m, 1H), 2.53 (m, 1H), 2.43 (m, 2H), 1.50 (s, 9H), 1.05 (d, 3H).
78%	With hydrogen; palladium(II) hydroxide In ethanol at 20℃; for 6 h; Autoclave	Step 3: te/ -Butyl 3-methyl-4-oxopiperidine-1-carboxylate. To a solution of 1-benzyl-3- methylpiperidin-4-one (6 g, 29.5 mmol) in ethanol was added Boc-anhydride (8 g, 36.9 mmol), Pd(OH)₂ (2.4 g, 40percent wt of ketone) and the reaction mixture was stirred under hydrogen atmosphere (100 psi) in autoclave for 6 h at room temperature. After completion, the reaction mixture was concentrated in vacuo to obtain a crude residue which was purified by silica gel column chromatography (10-15percent EtOAc in hexane) to afford the title compound (8.8 g, 78percent). ¹ H NMR (400 MHz, CDCI₃): δ 4.20-4.16 (m, 2H), 3.29-3.22 (m, 1 H), 2.85 (br.s, 1 H), 2.57-2.38 (m, 3H), 1.49 (s, 9H), 1.04 (d, J = 6.4 Hz, 3H); LCMS: m/e 235 [M+Na]⁺
2.2 g	With hydrogen; palladium(II) hydroxide In ethyl acetate at 20℃;	A mixture of l-benzyl-3-methyl-4-piperidone (2.0 g, 9.84 mmol), di-tert-butyl dicarbonate (2.36 g, 10.8 mmol) and Example A.16 a) Preparation of intermediate (37)Pearlman's catalyst (palladium(II)hydroxide) (0.35 g, 2.46 mmol) in EtOAc (50 ml) was hydrogenated (3 bar, room temperature) overnight in a Parr shaker. The reaction mixture was filtered through a short pad of celite, the cake was washed with EtOAc, the filtrate was washed with water then brine, dried (MgS0₄) and evaporated till dryness, yielding 2.2 g of intermediate (37).
2.2 g	With 10 wt% Pd(OH)2 on carbon; hydrogen In ethyl acetate at 20℃;	a) Preparation of intermediate (A20)A mixture of l-benzyl-3-methyl-4-piperidone (2.0 g, 9.84 mmol), di-tert-butyl dicarbonate (2.36 g, 10.8 mmo 1) and Pearlman’ s catalyst (palladium(II)hydroxide) (0.35 g, 2.46 mmol) in EtOAc (50 ml) was hydrogenated (3 bar, room temperature) overnight in a Parr shaker. The reaction mixture was filtered through a short pad ofcelite, the cake was washed with EtOAc, the filtrate was washed with water then brine, dried (MgSO4) and evaporated till dryness, yielding 2.2 g of intermediate (A20).

Reference： [1] Patent: US2005/182095, 2005, A1, . Location in patent: Page/Page column 30
[2] Patent: WO2011/159852, 2011, A1, . Location in patent: Page/Page column 11-12
[3] Patent: US2010/113465, 2010, A1, . Location in patent: Page/Page column 34-35
[4] Patent: WO2018/5881, 2018, A1, . Location in patent: Page/Page column 126
[5] Patent: US2010/204274, 2010, A1, . Location in patent: Page/Page column 54-55
[6] Patent: US2013/324547, 2013, A1, . Location in patent: Paragraph 0495
[7] Patent: WO2004/58736, 2004, A1, . Location in patent: Page 26; 30
[8] Patent: WO2004/58709, 2004, A1, . Location in patent: Page 31; 35
[9] Patent: WO2016/120850, 2016, A1, . Location in patent: Page/Page column 42
[10] Patent: US2002/169155, 2002, A1,
[11] Patent: US2005/70549, 2005, A1,
[12] Patent: WO2013/21052, 2013, A1, . Location in patent: Page/Page column 30
[13] Patent: WO2014/23815, 2014, A1, . Location in patent: Page/Page column 43
[14] Patent: WO2016/120849, 2016, A1, . Location in patent: Page/Page column 70
[15] Patent: US2016/31908, 2016, A1, . Location in patent: Paragraph 1141; 1142; 1143
[16] Patent: WO2018/125880, 2018, A1, . Location in patent: Page/Page column 98-99

5
[ 79099-07-3 ]
[ 74-88-4 ]
[ 181269-69-2 ]

Yield	Reaction Conditions	Operation in experiment
45%	Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere Stage #2: at -78 - 20℃; for 3 h;	[0182] To a solution of tert-butyl 3-methyl-4-oxopiperidine-l-carboxylate (1.0 g, 5.00 mmol) in anhydrous THF (10 mL) was added LDA (3 mL, 6.0 mmol) dropwise at -78 °C under nitrogen atmosphere. After 30 minutes, Mel (852mg, 6.0 mmol) was added to the above solution at the same temperature, then the mixture was stirred at room temperature for another 3 hours. The mixture was quenched with saturated NH₄CI solution and was portioned between EtOAc (40 mL) and water (20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, and concentrated to give an orange oil. The residue was purified by silica gel column chromatography (petroleum ethenEtOAc = 20:1) to afford the compound as a colorless oil (500mg, 45percent). *H NMR (400 MHz, CDC1₃) δ 4.11 (m, 1H), 3.71 (m, 1H), 3.23 (m, 1H), 2.81 (br s, 1H), 2.47 (m, 3H), 1.47 (s, 9H), 1.03 (d, / = 6.8 Hz, 3H).
28%	Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere Stage #2: at 20℃; for 3 h;	To a solution of tert-butyl 4- oxopiperidine-l-carboxylate (1) (100 g, 0.5 mol) in anhydrous THF (1000, mL) was added LDA (300 mL) dropwise at -78^°C under nitrogen atmosphere. After 1 h, Mel (70.9g, 0.5 mol) was added to the same temperature and then the mixture was stirred at room temperature for another 3h. The mixture was quenched with saturated NH₄C1 solution and was portioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SC>4, and concentrated to give orange oil. The residue was purified by silica gel column chromatography (petroleum etherethyl acetate =20: 1) to afford the compound as light yellow oil (30.4 g, 28percent). MS m/z 214.23[M+H]⁺.
22.5%	Stage #1: With potassium hexamethylsilazane In tetrahydrofuran; toluene at 20℃; for 2 h; Stage #2: at 20℃;	Description 9; . tert-Butyl 3-methyl-4-oxo-1 -piperidinecarboxylate (D9); To a solution of tert-butyl 4-oxo-1 -piperidinecarboxylate (20 g, 0.1 mol) in anhydrous tetrahydrofuran (200 ml) was added a solution of potassium bis(trimethylsilyl)amide in toluene (260ml, 0.13mol) and stirred at room temperature. After 2h, iodomethane (8.04 ml, 0.13mol) was added and the mixture was stirred overnight at room temperature. The mixture was washed by water (100ml) and extracted with ethyl acetate (100ml). After separation, the organic layer was dried and purified by column chromatography on silica gel (30:1 petroleum ether/ethyl acetate) to give the title compound (racemic mixture) (4.8 g, 22.5 percent) as yellow liquid.¹H NMR (CDCI₃) δ: 1.05 (3H, d), 1.45 (9H, s), 2.35-2.55 (3H, m), 2.80 (1 H, m), 3.25 (1 H, m), 4.15 (2H, m).

16%	Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 20℃;	4m: (rac)-3-Methyl-4-oxo-piperidine-l-carboxylic acid tert-butyl ester NaH (60 wpercent in mineral oil) (75 mmol) was suspended in dry THF ( 200 mL), and a solution of Boc-piperidone in dry THF ( 150 mL) was added dropwise at room temperature. The reaction mixture was stirred for Ih at this temperature, then methyl iodide (75 mmol) was added. The reaction mixture was refluxed overnight, then diluted with water and extracted x3 with ethyl acetate. The combined organic extracts were washed with brine and dried on MgSO₄, filtered and evaporated. The crude product was purified twice on silica using 10percent ethyl acetate in heptane as eluent,as by-products were difficult to separate completely. Yield = 16percent <n="76"/>¹H NMR (CDCl₃): 1.03 (d, 3H); 1.48 (s, 9H); 2.34-2.58 (3H); 2.84 (br, IH); 3.25 (m, IH); 4.06-4.35 (2H).
10%	Stage #1: With sodium hydride In tetrahydrofuran at 20℃; for 0.5 h; Stage #2: at 20℃; for 18 h;	NaH (634 mg, 15.85 mmol) was added to a solution of tert-butyl 4-oxopiperidine-l-carboxylate (3 g, 15.1 mmol) in 40 mL of tetrahydrofuran at room temperature. The solution was stirred at room temperature for 30 minutes. 1.9 mL of iodomethane was added slowly. The mixture was stirred at room temperature overnight (about 18 hours) . Water was added and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried with anhydrous sodium sulfate, concentrated under vacuum to afford 3.5 g of crude product as yellow oil. The crude product was purified by chromatography eluted with petroleum ether: ethyl acetate=50:l to 10:1 to obtain 320 mg of the target product as colorless oil (yield: 10percent) . The structure was confirmed by ¹H NMR

Reference： [1] Patent: WO2014/113191, 2014, A1, . Location in patent: Paragraph 0181; 0182
[2] Patent: WO2018/71404, 2018, A1, . Location in patent: Paragraph 00128
[3] Patent: WO2008/119718, 2008, A1, . Location in patent: Page/Page column 47
[4] Patent: WO2009/106534, 2009, A1, . Location in patent: Page/Page column 74-75
[5] Patent: WO2010/51374, 2010, A1, . Location in patent: Page/Page column 118

6
[ 24424-99-5 ]
[ 181269-69-2 ]

Reference： [1] Patent: WO2004/112793, 2004, A1, . Location in patent: Page/Page column 140-141

7
[ 5773-58-0 ]
[ 24424-99-5 ]
[ 181269-69-2 ]

Reference： [1] Patent: WO2004/41777, 2004, A2, . Location in patent: Page 74
[2] Patent: US2007/191364, 2007, A1, . Location in patent: Page/Page column 25

8
[ 24424-99-5 ]
[ 1159982-52-1 ]
[ 181269-69-2 ]

Reference： [1] Patent: WO2013/96744, 2013, A1, . Location in patent: Page/Page column 198; 199

9
[ 181269-69-2 ]
[ 181269-70-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium tetrahydroborate In methanol at 0 - 20℃; for 3.5 h;	(i) tert-Butyl 4-hydroxy-3-methylpiperidine-1-carboxylate Sodium borohydride (0.265 g, 7.03 mmol) was added in several portions to a solution of (R,S)-tert-butyl-3-methyl-4-oxopiperidine-1-carboxylate (1.0 g, 4.68 mmol) in methanol (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for one hour, then warmed to room temperature and stirred for 2.5 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution and concentrated under reduced pressure in order to remove the methanol. This was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford the desired product as a colourless oil (quantitative yield). [0627] ¹H NMR (400 MHz, CDCl₃) δ ppm 0.87-0.94 (m, 3H), 1.33-1.88 (m, 3H), 1.38 (s, 9H), 2.23-4.08 (m, 5H). [0628] MS: ES+216
100%	at 0 - 25℃; for 3.5 h;	(i) tert-Butyl 4-hydroxy-3-methylpiperidine-l-carboxylate Sodium borohydride (0.265 g, 7.03 mmol) was added in several portions to a solution of (R,S)-ieri-butyl-3-methyl-4-oxopiperidine-l-carboxylate (1.0 g, 4.68 mmol) in methanol (10 mL) at 0°C. The reaction mixture was stirred at 0°C for one hour, then warmed to room temperature and stirred for 2.5 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution and concentrated under reduced pressure in order to remove the methanol. This was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford the desired product as a colourless oil (quantitative yield). H NMR (400 MHz, CDC1₃) δ ppm 0.87 - 0.94 (m, 3H), 1.33-1.88 (m, 3H), 1.38 (s, 9H), 2.23-4.08 (m, 5H). MS: ES+ 216
88%	With sodium tetrahydroborate In ethanol at 0℃; for 0.5 h;	NaBH₄(2.18 g, 57.7 mmol) was added to a solution of compound 27B (6.10 g, 28.8 mmol) in ethanol (200 ml) at 0° C. over a period of 20 min. After 30 min, the reaction mixture was concentrated. EtOAc (150 ml) was added, and the mixture was washed with brine, dried (Na₂SO₄), filtered, and concentrated to provide 5.45 g (25.5 mmol, 88percent) of compound 38 as a colorless oil. MS: m/e 160 (M-56).

Reference： [1] Patent: US2013/324576, 2013, A1, . Location in patent: Paragraph 0625; 0626; 0627; 0628
[2] Patent: WO2013/179024, 2013, A1, . Location in patent: Page/Page column 56-57
[3] Patent: US2005/182095, 2005, A1, . Location in patent: Page/Page column 38
[4] Patent: WO2004/41777, 2004, A2, . Location in patent: Page 74-75
[5] Patent: WO2013/96744, 2013, A1, . Location in patent: Page/Page column 199
[6] Patent: WO2018/26371, 2018, A1, . Location in patent: Paragraph 0170

[ 181269-69-2 ] Synthesis Path-Downstream 1~51

1
[ 5773-58-0 ]
[ 24424-99-5 ]
[ 181269-69-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N,N-dimethylethylenediamine; In dichloromethane; at 20.0℃; for 2.5h;	The crude product from Step A above (14 g, 0.124 mol) was dissolved in DCM (500 mL) and treated with di-tert-butyl dicarbonate (32 g, 0.15 mol). The reaction mixture was stirred at rt for 2 h then N, N-dimethylethylene diamine (2 ML) was added and the and the reaction mixture was stirred for another 30 min. The reaction mixture was washed with 5% citric acid, saturated NAHCO3 solution and brine, dried over MGS04, filtered, and concentrated to give 20.7 g of desired PRODUCT. 1H NMR (500 MHz, CDC13) : 8 4.18 (m, 2H), 3.22 (m, 1H), 2.80 (m, 1H), 2.55 (m, 1H), 2.42 (m, 2H), 1.47 (s, 9H), 1.02 (d, 3H).
	With dmap; triethylamine; In tetrahydrofuran; water; at 20.0℃; for 18.0h;	13.3: tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate; 6.8 g of <strong>[5773-58-0]3-methylpiperidin-4-one</strong>, 16.7 ml of triethylamine, 19.6 g of di-t-butyl dicarbonate and 0.7 g of dimethylaminopyridine are placed in a mixture of 300 ml of THF and 30 ml of water. Stirring is maintained at ambient temperature for 18 h. After evaporation of the THF, the reaction medium is treated with a saturated aqueous potassium hydrogen sulphate solution to a pH of 1, and then extraction is carried out with ethyl acetate until the aqueous phase is completely depleted. The organic phase is then washed with a saturated aqueous potassium hydrogen sulphate solution, and then with a saturated aqueous sodium hydrogen carbonate solution and, finally, with a saturated aqueous sodium chloride solution. After drying over MgSO4 and concentration to dryness, the crude obtained is chromatographed on silica gel, elution being carried out with a 98/2 dichloromethane/methanol mixture. 10.3 g of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate are obtained.

Reference： [1]Patent: WO2004/41777,2004,A2 .Location in patent: Page 74
[2]Patent: US2007/191364,2007,A1 .Location in patent: Page/Page column 25

2
[ 181269-69-2 ]
[ 181269-70-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 3.5h;	(i) tert-Butyl 4-hydroxy-3-methylpiperidine-1-carboxylate Sodium borohydride (0.265 g, 7.03 mmol) was added in several portions to a solution of (R,S)-tert-butyl-3-methyl-4-oxopiperidine-1-carboxylate (1.0 g, 4.68 mmol) in methanol (10 mL) at 0 C. The reaction mixture was stirred at 0 C. for one hour, then warmed to room temperature and stirred for 2.5 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution and concentrated under reduced pressure in order to remove the methanol. This was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford the desired product as a colourless oil (quantitative yield). [0627] 1H NMR (400 MHz, CDCl3) delta ppm 0.87-0.94 (m, 3H), 1.33-1.88 (m, 3H), 1.38 (s, 9H), 2.23-4.08 (m, 5H). [0628] MS: ES+216
100%	With methanol; sodium tetrahydroborate; at 0 - 25℃; for 3.5h;	(i) tert-Butyl 4-hydroxy-3-methylpiperidine-l-carboxylate Sodium borohydride (0.265 g, 7.03 mmol) was added in several portions to a solution of (R,S)-ieri-butyl-3-methyl-4-oxopiperidine-l-carboxylate (1.0 g, 4.68 mmol) in methanol (10 mL) at 0C. The reaction mixture was stirred at 0C for one hour, then warmed to room temperature and stirred for 2.5 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution and concentrated under reduced pressure in order to remove the methanol. This was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford the desired product as a colourless oil (quantitative yield). H NMR (400 MHz, CDC13) delta ppm 0.87 - 0.94 (m, 3H), 1.33-1.88 (m, 3H), 1.38 (s, 9H), 2.23-4.08 (m, 5H). MS: ES+ 216
88%	With sodium tetrahydroborate; In ethanol; at 0℃; for 0.5h;	NaBH4 (2.18 g, 57.7 mmol) was added to a solution of compound 27B (6.10 g, 28.8 mmol) in ethanol (200 ml) at 0 C. over a period of 20 min. After 30 min, the reaction mixture was concentrated. EtOAc (150 ml) was added, and the mixture was washed with brine, dried (Na2SO4), filtered, and concentrated to provide 5.45 g (25.5 mmol, 88%) of compound 38 as a colorless oil. MS: m/e 160 (M-56).

	With sodium tetrahydroborate; In ethanol; at 0 - 20℃; for 0.666667h;	To a solution of the piperidine prepared as described in Step B (20.7 g, 97 mmol) in ehtanol (200 mL) cooled in an ice bath was added portionwise sodium borohydride (4.41 g, 116 mmol). The reaction mixture was warmed to rt and stirred for 30 min. Water (50 ML) was added and after stirring for an additional 10 min, then reaction mixture was concentrated. The residue was partitioned between DCM and water, extracting 3 times with DCM. The combined organic layers were washed with water and brine, dried over anhydrous MGS04, filtered, and concentrated to give 21 g of alcohol product. The HNMR spectrum was complex due to rotameric isomers and the presence of stereoisomers.
	With potassium borohydride; In ethanol; at 0 - 20℃; for 2.5h;	To a solution of compound 3 (11.00 mmol) in ethanol (50 mL) was added KBH4 (0.712 g, 13.20mmol) slowly at 0 C . The reaction mixture was stirred at 0 Cfor 0.5 h and the stirred at RT for 2 h. The reaction mixture was pure into water (50 mL) and extracted with DCM (50 mL3). The organic layer was dried and concentrated to give the product

Reference： [1]Patent: US2013/324576,2013,A1 .Location in patent: Paragraph 0625; 0626; 0627; 0628
[2]Patent: WO2013/179024,2013,A1 .Location in patent: Page/Page column 56-57
[3]Patent: US2005/182095,2005,A1 .Location in patent: Page/Page column 38
[4]Patent: WO2004/41777,2004,A2 .Location in patent: Page 74-75
[5]Patent: WO2013/96744,2013,A1 .Location in patent: Page/Page column 199
[6]Patent: WO2018/26371,2018,A1 .Location in patent: Paragraph 0170

3
[ 867-13-0 ]
[ 181269-69-2 ]
[ 124-41-4 ]
[ 502609-65-6 ]

Yield	Reaction Conditions	Operation in experiment
82.5%	In tetrahydrofuran; methanol; at 20℃; for 4h;	1) To a cooled (0C) solution of diethylphosphonoacetic acid ethyl ester (0.46 ML, 2.31 mmol) in tetrahydrofuran (10 ML) under an atmosphere of nitrogen were added a solution of 28% sodium methoxide in methanol (0.43 ML, 2.31 mol), and then a solution of 0.45 g (2.1 mmol) of t-butyl ester of 3-methyl-4-oxopiperidine-1-carbxylic acid in tetrahydrofuran (5 ML) and stirred for 4 hours at room temperature.. After the reaction was completed, the solvent was evaporated under a reduced pressure, and water was added to the residue.. The mixture was extracted with ether, washed with water and saturated brine and dried over anhydrous sodium sulfate.. After drying, the ether extract was filtered and the filtrate was concentrated under a reduced pressure.. The residue was subjected to silica gel column chromatography (developing solvent, hexane:ethyl acetate=9:1) to obtain 0.47 g (yield 82.5 %) of 4-methoxycarbonylmethylene-3-methylpiperidine-1-carboxylic acid t-butyl ester.. Its physical property is shown below.1H-NMR(CDCl3) delta value: 1.15 and 1.19(3H, dx2, J=6.9), 1.47(9H, s), 1.66(1H, s), 2.05(1H, s), 2.40(1H, m), 2.69(1H, m), 2.91(1H, m), 3.31(1H, m), 3.69 and 3.70(3H, sx2), 5.63 and 5.69(1H, sx2).

Reference： [1]Patent: EP1431285,2004,A1 .Location in patent: Page 113

4
[ 181269-69-2 ]
[ 3886-69-9 ]
[ 723308-57-4 ]

Yield	Reaction Conditions	Operation in experiment
7%	With sodium triacetoxyborohydride; In dichloromethane; at 20℃;	()-3-METHYL-4-OXO-PIPERIDINE-L-CARBOXYLIC ACIDTERT-BUTYL ester (5.4 g, 25.3 mmol) was dissolved in dichloromethane (75 mL). R- (+)- 0-METHYLBENZYLAMINE (3.1 g, 3.2 mL, 25.3 mmol) was added followed by sodium triacetoxyborohydride (10.7 g, 50.6 MMOL). The reaction was stirred overnight at room temperature. LC/MS analysis revealed four components, with only one component clearly separated. The reaction was diluted with dichloromethane (150 mL) and extracted twice with water, once with brine and dried over MGS04. Filtration and concentration in vacuo afforded a white foam that was purified by flash column chromatography (84.5 : 15: 0.5 CH2CI2 : acetonitrile: NH40H) to afford a clear oil. The material was rechromatographed (89.5 : 10: 0.5 CH2CI2 : acetonitrile: NH40H) to afford the title compound as a clear oil. Wt.: 547 mg (7%). 1H NMR (300 MHz, CDCI3) B 7.31 (m, 3H), 7.22 (m, 2H), 3.85 (m, 3H), 2.68 (m, 1H), 2.46 (m. 1H), 2.17 (m, 1H), 1.67 (m, 1H), 1.40 (s, 9H), 1.30 (d, 3H), 1.08 (m, 2H), 0.97 (d, 3H) ; LC/MS M/Z 319 (M + H) +.
7%	With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃;	(+)-3-METHYL-4-OXO-PIPERIDINE-1-CARBOXYLIC ACID TERT-BUTYL ester (5.4 g, 25.3 mmol) was dissolved in dichloromethane (75 mL). R- (+)-A,-METHYLBENZYLAMINE (3.1 g, 3.2 mL, 25.3 mmol) was added followed by sodium triacetoxyborohydride (10.7 g, 50.6 mmol). The reaction was stirred overnight at room temperature. LC/MS analysis revealed four components, with only one component clearly separated. The reaction was diluted with dichloromethane (150 mL) and extracted twice with water, once with brine and dried over MgS04. Filtration and concentration in vacuo afforded a white foam that was purified by flash column chromatography (84.5 : 15: 0.5 CH2Cl2 : acetonitrile: NH40H) to afford a clear oil. The material was rechromatographed (89.5 : 10: 0.5 CH2CL2 : ACETONITRILE : NH40H) to afford the title compound as a clear oil. Wt.: 547 mg (7%).'H NMR (300 MHz, CDCl3) 8 7.31 (M, 3H), 7.22 (M, 2H), 3.85 (M, 3H), 2.68 (M, 1H), 2.46 (M. 1H), 2.17 (M, 1H), 1.67 (M, 1H), 1.40 (s, 9H), 1.30 (d, 3H), 1.08 (M, 2H), 0.97 (d, 3H); LC/MS m/z 319 (M + H) +.

Reference： [1]Patent: WO2004/58736,2004,A1 .Location in patent: Page 31
[2]Patent: WO2004/58709,2004,A1 .Location in patent: Page 36

5
[ 181269-69-2 ]
[ 2627-86-3 ]
[ 723308-56-3 ]

Yield	Reaction Conditions	Operation in experiment
10%	With sodium triacetoxyborohydride; In dichloromethane; at 20℃;	(+)-3-METHYL-4-OXO-PIPERIDINE-1-CARBOXYLIC acid TERT-BUTYL ester (5.4 g, 25.3 mmol) was dissolved in dichloromethane (75 mL). S- (-)--METHYLBENZYLAMINE (3.1 g, 3.2 mL, 25.3 mmol) was added followed by sodium triacetoxyborohydride (10.7 g, 50.6 mmol). The reaction was stirred at room temperature overnight. LC/MS analysis revealed four components, with only one component clearly separated. The reaction was diluted with dichloromethane (150 mL) and extracted water (2x), brine and dried over MGS04. The solution was filtered and concentrated in vacuo to afford a white foam that was purified by flash column chromatography (84.5 : 15: 0.5 dichloromethane: acetonitrile : NH40H) to afford a clear oil. This material was rechromatographed (89.5 : 10: 0.5 dichloromethane : acetonitrile: NH40H) to afford the title compound as a clear oil. Wt.: 820 mg (10%). 1H NMR (300 MHZ, CDC13) 8 7.31 (M, 3H), 7.22 (M, 2H), 3.85 (M, 3H), 2.68 (M, 1H), 2.46 (M. 1H), 2.17 (M, 1H), 1.67 (M, 1H), 1.40 (s, 9H), 1.30 (d, 3H), 1.08 (M, 2H), 0.97 (d, 3H); LC/MS M/Z 319 (M + H) +.
10%	With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃;	()-3-METHYL-4-OXO-PIPERIDINE-L-CARBOXYLIC acid ter-butyl ester (5.4 g, 25.3 mmol) was dissolved in dichloromethane (75 mL). S-(-)-a-Methylbenzylamine (3.1 g, 3.2 mL, 25.3 mmol) was added followed by sodium triacetoxyborohydride (10.7 g, 50.6 mmol). The reaction was stirred at room temperature overnight. LC/MS analysis revealed four components, with only one component clearly separated. The reaction was diluted with dichloromethane (150 mL) and extracted water (2x), brine and dried over MgS04. The solution was filtered and concentrated in vacuo to afford a white foam that was purified by flash column chromatography (84.5 : 15: 0.5 dichloromethane: ACETONITRILE : NH40H) to afford a clear oil. This material was rechromatographed (89.5 : 10: 0.5 dichloromethane: ACETONITRILE : NH40H) to afford the title compound as a clear oil. Wt.: 820 mg (10%). 1H NMR (300 MHz, CDC13) 8 7. 31 (m, 3H), 7.22 (m, 2H), 3.85 (m, 3H), 2.68 (m, 1H), 2.46 (m. 1H), 2.17 (m, 1H), 1.67 (m, 1H), 1.40 (s, 9H), 1.30 (d, 3H), 1.08 (m, 2H), 0.97 (d, 3H); LC/MS IIILZ 319 (M + H) +.

Reference： [1]Patent: WO2004/58736,2004,A1 .Location in patent: Page 26; 30-31
[2]Patent: WO2004/58709,2004,A1 .Location in patent: Page 31; 35-36

6
[ 34737-89-8 ]
[ 24424-99-5 ]
[ 181269-69-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogen;palladium dihydroxide; In ethyl acetate; under 2068.65 Torr; for 24h;	Compound 28 (15.0 g, 0.0738 mol) and di-t-butyl dicarbonate (17.7 g, 0.0812 mol) were dissolved in EtOAc (400 ml). Palladium hydroxide catalyst (4 g) was added and the mixture was shaken on a Paar shaker under 40 psi of hydrogen pressure for 24 h. The resultant mixture was filtered through celite and the celite was washed with EtOAc. The filtrate was concentrated to give 15.73 g (0.0738 mol, 100%) of the product 27B as a colorless oil. MS (ES for M-tBOC+1): m/e 114
97%	With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; under 2585.81 Torr; for 4h;	A mixture of l-benzyl-3-methylpiperidin-4-one (1 1.4 g, 56.1 mmol), Boc- anhydride (14.32 mL, 61.7 mmol), and 10% palladium on carbon (0.597 g, 5.61 mmol) in ethanol (100 mL) was degassed under vacuum and nitrogen, then hydrogenated at 50 psi for 4 hours at room temperature. The catalyst was removed by filtration, rinsed with methanol, and the combined filtrate and rinses were concentrated in vacuo. The residue was purified over a 330 g silica gel column, eluting at 100 mL/min with an ethyl acetate/hexanes gradient to yield tert-butyl 3- methyl-4-oxopiperidine-l-carboxylate (11.66 g, 54.7 mmol, 97 % yield) as an oil, which solidified upon standing. ¾ NMR (CDC13, 400 MHz) delta 4.15 (m, 2H), 3.22 (] 1H), 2.79 (br m, 1H), 2.52-2.38 (m, 3H), 1.46 (s, 9H), 1.01 (d, J=6.8 Hz, 3H); m/z = 158.2 (M-tBu)+.
95%	With hydrogen;palladium(II) hydroxide; In methanol; at 20℃; under 2844.39 Torr;	Synthesis of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate; In a high pressure vessel was added 1-benzyl-3-methyl-piperidin-4one (6.0 g, 29.52 mmol) which was dissolved in methanol (60 mL). Di-tertbutyl dicarbonate (8.37 g, 38.40 mmol) was added along with palladium hydroxide (829 mg, 5.90 mmol) and the reaction stirred at r.t. overnight under 55 psi hydrogen atmosphere. The reaction was vacuum filtered through celite and concentrated. The crude material was purified by flash chromatography (10% ethyl acetate/heptanes) to give the title compound as a colorless oil (6.01 g, 28.21 mmol, 95%).

95.33%	With palladium on activated charcoal; hydrogen; In methanol; at 20℃; under 2585.81 Torr; for 16h;	To a solution of 1- benzyl-3-methyl-piperidin-4-one (2.0 g, 9.84 mmol, 1.0 eq) and Boc2O (2.15 g, 9.84 mmol, 2.26 mL, 1.0 eq) in MeOH (50.0 mL) was added Pd/C (9.84 mmol, 1.0 eq) underN2. Thesuspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 20 C for 16 hours. TLC (PE:EA = 5:1) showed the reaction was completed. The mixture was filtrated. The filtrate was concentrated in vacuum. The residue was purified by colunm chlomatography (PE:EA=O%15%) to afford the title 0 (2.0 g, 9.38 mmol, 95.33% yield) as colorless oil. ?HNMR (400MHz, CHLOROFORM-d) = 4.16 -4.24 (m, 1 H), 3.22 - 3.33 (m, 1 H), 2.86 (brs, 1 H), 2.38 - 2.61 (m, 3 H), 1.51 (s, 9 H), 1.06 (d, J= 6.7 Hz, 3 H).
92%	With hydrogen;palladium 10% on activated carbon; In ethanol; under 2585.81 Torr; for 4h;Inert atmosphere;	A mixture of 1-benzyl-3-methylpiperidin-4-one (5.25 g, 25.8 mmol), BOC-anhydride (6.60 mL, 28.4 mmol), and 10% palladium on carbon (0.275 g, 2.58 mmol) in ethanol (100 mL) was degassed under vacuum and nitrogen, then hydrogenated at 50 psi for 4 hours. The catalyst was removed by filtration, rinsed with methanol, and the combined filtrate and rinsings were concentrated in vacuo. The residue was purified over a 330 g silica gel column, eluting at 100 mL/min with a 10% to 30% ethyl acetate/hexanes gradient followed by 30% ethyl acetate/hexanes to yield the title compound (5.07 g, 23.77 mmol, 92% yield) as a colorless oil, which solidified upon standing. MS (ESI+)=158.1 (M-tert-Bu)+.
88%	With palladium on activated charcoal; hydrogen; In methanol; under 37503.8 Torr; for 12h;	Preparation of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate A solution of 1-benzyl-3-methylpiperidin-4-one (1.63 g, 8.018 mmol) and di-tert-butyl dicarbonate (1.925 g, 8.82 mmol) in 50 ml of Methanol was hydrogenated using H-Cube (Controlled H2 at 50 bar, flow rate 1.0 ml/min) with Pd-C cartridge. The reaction mixture was recirculated for 12 hours. After washing the H-Cube thoroughly with Methanol, the solvent was evaporated and the resulting oil was purified by silica gel chromatography to afford the title compound (1.5 g, 88%).
81%	With hydrogen;palladium dihydroxide; In methanol; under 2844.39 Torr;	1-BENZYL-3-METHYL-PIPERIDIN-4-ONE (6.5 g, 32.0 mmol) was dissolved in methanol (30 mL). Di-tert-butyl dicarbonate (10.46 g, 48.0 mmol) was added followed by palladium hydroxide (20%, 100 mg) and the reaction shaken overnight at 55 psi under a hydrogen atmosphere. The reaction was filtered and concentrated in vacuo to give a clear oil. Flash column chromatography (75: 25 hexanes/ethyl acetate) afforded the title compound as a white solid. Wt.: 5. 5 G (81%).'H NMR (300 MHz, CDC13) 8 4.18 (M, 2H), 3.25 (M, 1H), 2.84 (M, 1H), 2.53 (M, 1H), 2.43 (M, 2H), 1.50 (s, 9H), 1.05 (d, 3H).
81%	With hydrogen;palladium hydroxide on carbon; In methanol; under 2844.39 Torr;	1-BENZYL-3-METHYL-PIPERIDIN-4-ONE (6.5 g, 32.0 mmol) was dissolved in methanol (30 mL). Di-tert-butyl dicarbonate (10.46 g, 48.0 mmol) was added followed by palladium hydroxide (20%, 100 mg) and the reaction shaken overnight at 55 psi under a hydrogen atmosphere. The reaction was filtered and CONCENTRATED IN VACUO to give a clear oil. Flash column chromatography (75: 25 hexanes/ethyl acetate) afforded the title compound as a white solid. Wt.: 5.5 g (81%).'H NMR (300 MHz, CDC13) 8 4.18 (m, 2H), 3.25 (m, 1H), 2.84 (m, 1H), 2.53 (m, 1H), 2.43 (m, 2H), 1.50 (s, 9H), 1.05 (d, 3H).
78%	With hydrogen; palladium(II) hydroxide; In ethanol; at 20℃; under 5171.62 Torr; for 6h;Autoclave;	Step 3: te/ -Butyl 3-methyl-4-oxopiperidine-1-carboxylate. To a solution of 1-benzyl-3- methylpiperidin-4-one (6 g, 29.5 mmol) in ethanol was added Boc-anhydride (8 g, 36.9 mmol), Pd(OH)2 (2.4 g, 40% wt of ketone) and the reaction mixture was stirred under hydrogen atmosphere (100 psi) in autoclave for 6 h at room temperature. After completion, the reaction mixture was concentrated in vacuo to obtain a crude residue which was purified by silica gel column chromatography (10-15% EtOAc in hexane) to afford the title compound (8.8 g, 78%). 1 H NMR (400 MHz, CDCI3): delta 4.20-4.16 (m, 2H), 3.29-3.22 (m, 1 H), 2.85 (br.s, 1 H), 2.57-2.38 (m, 3H), 1.49 (s, 9H), 1.04 (d, J = 6.4 Hz, 3H); LCMS: m/e 235 [M+Na]+
	With hydrogen;palladium dihydroxide; In methanol;	Step 1 3-Methyl-4-oxo-piperidine-1-carboxylic Acid Tert-Butyl Ester In a Parr shaker flask, 1-benzyl-3-methyl-4-piperidone (19 g, 93 mmol), di-tert-butyl dicarbonate (27 g, 121 mmol) and palladium hydroxide (2.6 g) were suspended in methanol (75 mL) and then purged with argon. The reaction mixture was then purged with hydrogen and placed on a Parr shaker apparatus for about 16 hours at about 44 psi of hydrogen. The catalyst was filtered over celite and washed with methanol. The crude product was chromatographed on silica gel, eluding with EtOAc/hexane (1:5) to give a white crystalline solid. 1H-NMR (CDCl3) delta: 0.97 (3H, d), 1.45 (9H, s), 2.37-2.53 (3H, m), 2.80 (1H, brs), 3.16-3.26 (1H, m), 4.11-4.18 (2H, m). ESI-MS m/z: 158 [M-CH=C(CH3)2+1].
	With hydrogen;palladium dihydroxide; In methanol;	Step 1: 3-Methyl-4-oxo-piperidine-1-carboxylic Acid Tert-Butyl Ester In a Parr shaker flask, 1-benzyl-3-methyl-4-piperidone (19 g, 93 mmol), di-tert-butyl dicarbonate (27 g, 121 mmol) and palladium hydroxide (2.6 g) were suspended in methanol (75 mL) and then purged with argon. The reaction mixture was then purged with hydrogen and placed on a Parr shaker apparatus for about 16 hours at about 44 psi of hydrogen. The catalyst was filtered over celite and washed with methanol. The crude product was chromatographed on silica gel, eluding with EtOAc/hexane (1:5) to give a white crystalline solid. 1H-NMR (CDCl3) delta: 0.97 (3H, d), 1.45 (9H, s), 2.37-2.53 (3H, m), 2.80 (1H, brs), 3.16-3.26 (1H, m), 4.11-4.18 (2H, m). ESI-MS m/z: 158 [M-CH=C(CH3)2+1].
2.2 g	With hydrogen; palladium(II) hydroxide; In ethyl acetate; at 20℃; under 2250.23 Torr;	A mixture of l-benzyl-3-methyl-4-piperidone (2.0 g, 9.84 mmol), di-tert-butyl dicarbonate (2.36 g, 10.8 mmol) and Example A.16 a) Preparation of intermediate (37)Pearlman's catalyst (palladium(II)hydroxide) (0.35 g, 2.46 mmol) in EtOAc (50 ml) was hydrogenated (3 bar, room temperature) overnight in a Parr shaker. The reaction mixture was filtered through a short pad of celite, the cake was washed with EtOAc, the filtrate was washed with water then brine, dried (MgS04) and evaporated till dryness, yielding 2.2 g of intermediate (37).
2.2 g	With 10 wt% Pd(OH)2 on carbon; hydrogen; In ethyl acetate; at 20℃; under 2250.23 Torr;	a) Preparation of intermediate (A20)A mixture of l-benzyl-3-methyl-4-piperidone (2.0 g, 9.84 mmol), di-tert-butyl dicarbonate (2.36 g, 10.8 mmo 1) and Pearlman? s catalyst (palladium(II)hydroxide) (0.35 g, 2.46 mmol) in EtOAc (50 ml) was hydrogenated (3 bar, room temperature) overnight in a Parr shaker. The reaction mixture was filtered through a short pad ofcelite, the cake was washed with EtOAc, the filtrate was washed with water then brine, dried (MgSO4) and evaporated till dryness, yielding 2.2 g of intermediate (A20).
	With 10 wt% Pd(OH)2 on carbon; hydrogen; In ethyl acetate; under 2585.81 Torr; for 12h;	A mixture of 1-benzyl-3- methylpiperidin-4-one (4.33 g, 21.3 mmol), Pd(OH)2/C (20% on active C, 1.0 g), and di-tert-butyl dicarbonate (5.1 1 g, 23.4 mmol) in EtOAc (30 mL) was stirred under 50 PSI of H2 over 12 h. Upon completion, the mixture was filtered through Celite, rinsing with EtOAc (10 mL), and the solvent was evaporated to give the crude product as a colorless oil. The crude was left on under high vac for 12 h to remove any trace di-tert-butyl dicarbonate, and the material was carried forward without any further purification or characterization.
	With 10 wt% Pd(OH)2 on carbon; In methanol;	Step 1 3-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester In a Parr shaker flask, 1-benzyl-3-methyl-4-piperidone (19 g, 93 mmol), di-tert-butyl dicarbonate (27 g, 121 mmol) and palladium hydroxide (2.6 g) were suspended in methanol (75 mL) and then purged with argon. The reaction mixture was then purged with hydrogen and placed on a Parr shaker apparatus for about 16 hours at about 44 psi of hydrogen. The catalyst was filtered over celite and washed with methanol. The crude product was chromatographed on silica gel, eluting with EtOAc/hexane (1:5) to give a white crystalline solid. 1H-NMR (CDCl3) delta: 0.97 (3H, d), 1.45 (9H, s), 2.37-2.53 (3H, m), 2.80 (1H, brs), 3.16-3.26 (1H, m), 4.11-4.18 (2H, m). ESI-MS m/z: 158 [M-CH=C(CH3)2+1].
	With 10 wt% Pd(OH)2 on carbon; hydrogen; at 40℃; under 2327.23 Torr; for 20h;	A mixture of compound 12-A (80 g, 0.39 mo 1,1 eq.) and Pd(OH)2/C (4 g) in ethanol (800 mL) was stirred under 45 psi of H2 at 40 C for 20 hours. TLC (PE/EtOAc = 5: 1) indicated completion. The suspension was filtered through a pad of celite and washed with EA (400 mL x 2), the filtrate was concentrated under reduced pressure to give a crude product of compound 32-A (80 g, crude) as colorless gum. (1041) 1H NMR: (400 MHz, CHLOROFORM-d) delta: 4.20 - 4.13 (m, 1H), 3.33 - 3.14 (m, 1H), 2.56 - 2.35 (m, 3H), 2.02 (s, 2H), 1.47 (s, 9H), 1.02 (d, J = 6.6 Hz, 3H).
	With palladium 10% on activated carbon; hydrogen; In ethanol; at 30℃; under 2585.81 Torr; for 5h;	1-Benzyl-3-methyl-piperidin-4-one (4.50 g, 22.14 mmol) and Boc2O (6.28 g, 28.78 mmol) were dissolved in ethanol (20.00 mL), and then added with Pd-C (10%, 1 g) in nitrogen atmosphere. The reaction system was vacuumed, displaced with nitrogen gas three times and with hydrogen gas three times, and the reaction solution was stirred under hydrogen atmosphere (50 psi) at 30 C for 5 hours. TLC showed that new products appeared and the raw materials were completely consumed. The reaction solution was filtered by DCM: MeOH = 10:1 (22 mL), concentrated, separated and purified by column chromatography (PE: EA = 3:1) to give compound 20A. 1H NMR (400MHz, deuterated chloroform) delta = 4.48 - 4.14 (m, 2H), 3.35 - 3.17 (m, 1H), 2.85 (br s, 1H), 2.59 - 2.35 (m, 3H), 1.51 - 1.47 (m, 9H), 1.05 (d, J=6.8 Hz, 3H).

Reference： [1]Patent: US2005/182095,2005,A1 .Location in patent: Page/Page column 30
[2]Patent: WO2011/159852,2011,A1 .Location in patent: Page/Page column 11-12
[3]Patent: US2010/113465,2010,A1 .Location in patent: Page/Page column 34-35
[4]Patent: WO2018/5881,2018,A1 .Location in patent: Page/Page column 126
[5]Patent: US2010/204274,2010,A1 .Location in patent: Page/Page column 54-55
[6]Patent: US2013/324547,2013,A1 .Location in patent: Paragraph 0495
[7]Patent: WO2004/58736,2004,A1 .Location in patent: Page 26; 30
[8]Patent: WO2004/58709,2004,A1 .Location in patent: Page 31; 35
[9]Patent: WO2016/120850,2016,A1 .Location in patent: Page/Page column 42
[10]Patent: US2002/169155,2002,A1
[11]Patent: US2005/70549,2005,A1
[12]Patent: WO2013/21052,2013,A1 .Location in patent: Page/Page column 30
[13]Patent: WO2014/23815,2014,A1 .Location in patent: Page/Page column 43
[14]Patent: WO2016/120849,2016,A1 .Location in patent: Page/Page column 70
[15]Patent: US2016/31908,2016,A1 .Location in patent: Paragraph 1141; 1142; 1143
[16]Patent: WO2018/125880,2018,A1 .Location in patent: Page/Page column 98-99
[17]Patent: EP3567030,2019,A1 .Location in patent: Paragraph 0249-0250

7
[ 24424-99-5 ]
[ 181269-69-2 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of 3-methyl-1-(phenylmethyl)-4-piperidinone (1.5 g, 7.4 mmol) in methanol (10 mL) was treated with 4.0 N HCI/dioxane (2.2 mL), followed by palladium hydroxide. The mixture was then reacted overnight with hydrogen gas at 50 psi. The reaction was then filtered through Celite, concentrated, and then taken up in THF (20 mL). The crude reaction mixture was then treated with triethylamine (2.3 mL), followed by di-tert-butyl dicarbonate (1.9 g, 8.9 mmol). The reaction was stirred for two hours, concentrated, taken up in dichloromethane and washed with saturated aqueous ammonium hydroxide, followed by brine. The organic layer was dried over magnesium sulfate and purified by column chromatography to provide 734 mg of 1,1-dimethylethyl 3-methyl-4-oxo-1-piperidinecarboxylate as a white solif. 1H NMR (400 MHz, CDCl3) delta ppm 1.0 (d, J=6.69, 3 H) 1.5 (s, 9 H) 2.4 (m, 2 H) 2.5 (m, 1 H) 2.8 (m, 1 H) 3.2 (m, 1 H) 4.2 (m, 2 H).

Reference： [1]Patent: WO2004/112793,2004,A1 .Location in patent: Page/Page column 140-141

8
[ 181269-69-2 ]
[ 593-56-6 ]
[ 817555-04-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran; water;	A solution of <strong>[181269-69-2]1,1-dimethylethyl 3-methyl-4-oxo-1-piperidinecarboxylate</strong> (367 mg, 1.72 mmpl) in THF (10 mL) was treated with methylhydroxylamine hydrochloride (503 mg, 6.02 mmol) followed by a solution of sodium hydrogencarbonate (506 mg, 6.02 mmol) in water (3 mL). The reaction was stirred vigorously overnight. The reaction was then filtered, diluted with water, and extracted with dichloromethane. The crude material was purified by column chromatography (0-10% ethyl acetate/hexanes) to provide 197 mg of the desired product as a white solid. 1H NMR (400 MHz, CDCl3) delta ppm 1.1 (d, J=6. 8 Hz, 3 H) 1.5 (s, 9 H) 2.5 (m, 1 H) 2.6 (m, 2 H) 3.5 (m, 4 H) 3.8 (s, 3 H).

Reference： [1]Patent: WO2004/112793,2004,A1 .Location in patent: Page/Page column 141

9
[ 181269-69-2 ]
[ 873-77-8 ]
4-(4-chloro-phenyl)-4-hydroxy-3-methyl-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; In tetrahydrofuran; diethyl ether;	Step 2 4-(4-Chloro-phenyl)-4-hydroxy-3-methyl-piperidine-1-carboxylic Acid Tert-Butyl Ester To 4-chlorophenyl magnesium bromide (49 mL, 49 mmol, IM in diethyl ether) at about 0 C. under argon, was added <strong>[181269-69-2]3-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester</strong> (7 g, 32.8 mmol) in THF (50 mL) over a period of about 1 hour. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water, then brine and dried over sodium sulfate. The solvent was evaporated and the crude residue was recrystallized in EtOAc to give a white solid. 1H-NMR (CDCl3) delta: 0.58 (3H, d), 1.45 (9H, s), 1.50-1.69 (2H, m), 1.76-2.13 (2H, m), 2.80 (1H, t), 3.10 (1H, t), 3.96 (2H, brs), 7.29 (4H, m). ESI-MS m/z: 252 [M-CH=C(CH3)2-H2O+1].
	With ammonium chloride; In tetrahydrofuran;	Step 2: 4-(4-Chloro-phenyl)-4-hydroxy-3-methyl-piperidine-1-carboxylic Acid Tert- Butyl Ester To 4-chlorophenyl magnesium bromide (49 mL, 49 mmol, 1M in diethyl 25 ether) at about 0 C. under argon, was added <strong>[181269-69-2]3-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester</strong> (7 g, 32.8 mmol) in THF (50 mL) over a period of about 1 hour. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water, then brine and dried over sodium sulfate. The solvent was evaporated and the crude residue was recrystallized in EtOAc to give a white solid. 1H-NMR (CDCl3) delta: 0.58 (3H, d), 1.45 (9H, s), 1.50-1.69 (2H, m), 1.76-2.13 (2H, m), 2.80 (1H, t), 3.10 (1H, t), 3.96 (2H, brs), 7.29 (4H, m). ESI-MS m/z: 252 [M-CH=C(CH3)2-H2O+1].
	With ammonium chloride; In tetrahydrofuran; diethyl ether; ethyl acetate;	Step 2 4-(4-Chloro-phenyl)-4-hydroxy-3-methyl-piperidine-1-carboxylic acid tert-butyl ester To 4-chlorophenyl magnesium bromide (49 mL, 49 mmol, 1M in diethyl ether) at about 0 C. under argon, was added <strong>[181269-69-2]3-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester</strong> (7 g, 32.8 mmol) in THF (50 mL) over a period of about 1 hour. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water, then brine and dried over sodium sulfate. The solvent was evaporated and the crude residue was recrystallized in EtOAc to give a white solid. 1H-NMR (CDCl3) delta: 0.58 (3H, d), 1.45 (9H, s), 1.50-1.69 (2H, m), 1.76-2.13 (2H, m), 2.80 (1H, t), 3.10 (1H, t), 3.96 (2H, brs), 7.29 (4H, m). ESI-MS m/z: 252 [M-CH=C(CH3)2-H2O+1].

Reference： [1]Patent: US2002/169155,2002,A1
[2]Patent: US2005/70549,2005,A1
[3]Patent: US2016/31908,2016,A1 .Location in patent: Paragraph 1144; 1145; 1146

10
[ 181269-69-2 ]
[ 512822-17-2 ]

Yield	Reaction Conditions	Operation in experiment
		18 ml of a sodium bis(trimethylsilyl)amide solution (2M) in THF are added to a suspension of 12.4 g of methoxymethyltriphenylphosphonium chloride in 25 ml of dry THF at 0. To the mixture obtained, 5.87 g of 3-methyl-4-oxo-piperidine-1-carboxylic acid tertbutyl ester in 25 ml of THF are slowly added, the mixture obtained is stirred at 0, diluted with EtAc and extracted with aqueous 1M HCI, saturated aqueous NaHCO3 solution and brine. The organic EPO <DP n="33"/>layer obtained is dried and solvent is evaporated. The evaporation residue obtained is subjected to filtration over silica gel and solvent of the filtrate obtained is evaporated. 3.6 g of the filtration residue obtained are dissolved in 150 ml of CH3CN, 1.68 g of cerium trichloride heptahydrate and 337 mg of NaI are added and the resulting mixture is stirred at 40 overnight. From the mixture obtained solvent is evaporated and the evaporation residue obtained is treated with EtAc. The mixture obtained is extracted with aqueous 1 M HCI, saturated aqueous NaHCO3 solution and brine. The organic layer obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to filtration over silica gel and solvent of the filtrate obtained is evaporated. 494 mg of the evaporation residue obtained and 1.18 g of magnesium monoperoxyphthalic acid hexahydrate in 36 ml ofEtOH/H2O (1 :1) are stirred at RT and diluted with EtAc. The mixture obtained is extracted with aqueous 1M HCI. The organic layer obtained is dried, solvent is evaporated and the evaporation residue is subjected to filtration and solvent of the filtrate obtained is evaporated. To a solution of 60 mg of the evaporation residue obtained, 71 mg of 3,5- bis(trifluoromethyl)phenylsulfonamide, 94 mg of EDC and 30 mg of DMAP in 2 ml of DMF and 84 mul of DIEA are added and the mixture obtained is snaked at RT. From the mixture obtained solvent is removed and the concentrated residue obtained is subjected to preparative HPLC on an RP-18 column (CH3CN/H2O (0.1% TFA). 4-(3,5- Bis-trifluoromethyl-benzenesulfonylaminocarbonyl)-cis -3-methyl-piperidine-i- carboxylic acid tert.-butyl ester and 4-(3,5- Bis-trifluoromethyl-benzenesulfonyl- aminocarbonyl)-trans-3-methyl-piperidine-1 -carboxylic acid tert.-butyl ester are obtained.

Reference： [1]Patent: WO2006/97292,2006,A1 .Location in patent: Page/Page column 31-32

11
[ 79099-07-3 ]
[ 74-88-4 ]
[ 181269-69-2 ]

Yield	Reaction Conditions	Operation in experiment
45%		[0182] To a solution of tert-butyl 3-methyl-4-oxopiperidine-l-carboxylate (1.0 g, 5.00 mmol) in anhydrous THF (10 mL) was added LDA (3 mL, 6.0 mmol) dropwise at -78 C under nitrogen atmosphere. After 30 minutes, Mel (852mg, 6.0 mmol) was added to the above solution at the same temperature, then the mixture was stirred at room temperature for another 3 hours. The mixture was quenched with saturated NH4CI solution and was portioned between EtOAc (40 mL) and water (20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, and concentrated to give an orange oil. The residue was purified by silica gel column chromatography (petroleum ethenEtOAc = 20:1) to afford the compound as a colorless oil (500mg, 45%). *H NMR (400 MHz, CDC13) delta 4.11 (m, 1H), 3.71 (m, 1H), 3.23 (m, 1H), 2.81 (br s, 1H), 2.47 (m, 3H), 1.47 (s, 9H), 1.03 (d, / = 6.8 Hz, 3H).
28%		To a solution of tert-butyl 4- oxopiperidine-l-carboxylate (1) (100 g, 0.5 mol) in anhydrous THF (1000, mL) was added LDA (300 mL) dropwise at -78C under nitrogen atmosphere. After 1 h, Mel (70.9g, 0.5 mol) was added to the same temperature and then the mixture was stirred at room temperature for another 3h. The mixture was quenched with saturated NH4C1 solution and was portioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SC>4, and concentrated to give orange oil. The residue was purified by silica gel column chromatography (petroleum etherethyl acetate =20: 1) to afford the compound as light yellow oil (30.4 g, 28%). MS m/z 214.23[M+H]+.
22.5%		Description 9; . tert-Butyl 3-methyl-4-oxo-1 -piperidinecarboxylate (D9); To a solution of tert-butyl 4-oxo-1 -piperidinecarboxylate (20 g, 0.1 mol) in anhydrous tetrahydrofuran (200 ml) was added a solution of potassium bis(trimethylsilyl)amide in toluene (260ml, 0.13mol) and stirred at room temperature. After 2h, iodomethane (8.04 ml, 0.13mol) was added and the mixture was stirred overnight at room temperature. The mixture was washed by water (100ml) and extracted with ethyl acetate (100ml). After separation, the organic layer was dried and purified by column chromatography on silica gel (30:1 petroleum ether/ethyl acetate) to give the title compound (racemic mixture) (4.8 g, 22.5 %) as yellow liquid.1H NMR (CDCI3) delta: 1.05 (3H, d), 1.45 (9H, s), 2.35-2.55 (3H, m), 2.80 (1 H, m), 3.25 (1 H, m), 4.15 (2H, m).

16%		4m: (rac)-3-Methyl-4-oxo-piperidine-l-carboxylic acid tert-butyl ester NaH (60 w% in mineral oil) (75 mmol) was suspended in dry THF ( 200 mL), and a solution of Boc-piperidone in dry THF ( 150 mL) was added dropwise at room temperature. The reaction mixture was stirred for Ih at this temperature, then methyl iodide (75 mmol) was added. The reaction mixture was refluxed overnight, then diluted with water and extracted x3 with ethyl acetate. The combined organic extracts were washed with brine and dried on MgSO4, filtered and evaporated. The crude product was purified twice on silica using 10% ethyl acetate in heptane as eluent,as by-products were difficult to separate completely. Yield = 16% <n="76"/>1H NMR (CDCl3): 1.03 (d, 3H); 1.48 (s, 9H); 2.34-2.58 (3H); 2.84 (br, IH); 3.25 (m, IH); 4.06-4.35 (2H).
10%		NaH (634 mg, 15.85 mmol) was added to a solution of tert-butyl 4-oxopiperidine-l-carboxylate (3 g, 15.1 mmol) in 40 mL of tetrahydrofuran at room temperature. The solution was stirred at room temperature for 30 minutes. 1.9 mL of iodomethane was added slowly. The mixture was stirred at room temperature overnight (about 18 hours) . Water was added and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried with anhydrous sodium sulfate, concentrated under vacuum to afford 3.5 g of crude product as yellow oil. The crude product was purified by chromatography eluted with petroleum ether: ethyl acetate=50:l to 10:1 to obtain 320 mg of the target product as colorless oil (yield: 10%) . The structure was confirmed by 1H NMR

Reference： [1]Patent: WO2014/113191,2014,A1 .Location in patent: Paragraph 0181; 0182
[2]Patent: WO2018/71404,2018,A1 .Location in patent: Paragraph 00128
[3]Patent: WO2008/119718,2008,A1 .Location in patent: Page/Page column 47
[4]Patent: WO2009/106534,2009,A1 .Location in patent: Page/Page column 74-75
[5]Patent: WO2010/51374,2010,A1 .Location in patent: Page/Page column 118

12
[ 181269-69-2 ]
tert-butyl cis-4-amino-3-methyl-1-piperidinecarboxylate [ No CAS ]
tert-butyl trans-4-amino-3-methyl-1-piperidinecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; under 2585.81 Torr;	Description 10; . tert-Butyl 4-amino-3-methyl-1 -piperidinecarboxylate (D10); <n="49"/>To a suspension of 10% Pd-C catalyst (120 mg) in ammonia-saturated methanol (50 ml) was added tert-butyl 3-methyl-4-oxo-1-piperidinecarboxylate (D9, 1.2 g, 5.6mmol) and the mixture was stirred overnight at room temperature under 50psi hydrogen atmosphere. The mixture was filtered, the solid washed by methanol (10ml) and the filtrate was concentrated to give the title compound (mixture of isomers) (1.2 g, 100 %). This was used without further purification.1H NMR (CDCI3) delta: 0.85 (3H, m), 1.38 (9H, m), 1.48-1.65 (3H, m), 1.74 (1 H, m), 2.28 (1 H, m), 2.60-4.1 1 (4H, m).

Reference： [1]Patent: WO2008/119718,2008,A1 .Location in patent: Page/Page column 47-48

13
[ 181269-69-2 ]
[ 1190843-66-3 ]
[ 1191250-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 2h;	3-(bromomethyl)phenyl pivalate (2.Og1 7.38 mmol) and triethyl phosphite (1.28 mL, 7.38 mmol) were heated at 150 0C for 4 hours. The solution was then cooled and the excess triethyl phosphite vacuumed off to give crude 3-[(diethoxyphosphoryl)methyl]phenyl pivalate. The crude product was dissolved in THF ( 21 mL) and <strong>[181269-69-2]tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate</strong> (1.57 g, 7.38 mmol; CASNo. 181269-69-2) followed by potassium f-butoxide ( 828 mg, 7.38 mmol) added. The reaction was stirred at r.t. for 2 hours and quenched with water. The aqeous phase was extracted with ethyl acetate(2x 25 mL) dried with magnesium sulfate and concentrated. The crude product was purified by flash chromatography (25% ethyl acetate/ heptane) to produce the title compound as an oil (980 mg, 2.62 mmol, 36%).
	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 2h;	3-(bromomethyl)phenyl pivalate (2.Og, 7.38 mmol) and triethyl phosphite (1.28 mL, 7.38 mmol) were heated at 150 0C for 4 hours. The solution was then cooled and the excess triethyl phosphite vacuumed off to give crude 3-[(diethoxyphosphoryl)methyl]phenyl pivalate. The crude product was dissolved in THF ( 21 mL) and tert-butyl S-methyM-oxopiperidine-i-carboxylate (1.57 g, 7.38 mmol; CASNo. 181269-69-2) followed by potassium /-butoxide ( 828 mg, 7.38 mmol) added. The reaction was stirred at r.t. for 2 hours and quenched with water. The aqeous phase was extracted with ethyl acetate(2x 25 mL) dried with magnesium sulfate and concentrated. The crude product was purified by flash chromatography (25% ethyl acetate/ heptane) to produce the title compound as an oil (980 mg, 2.62 mmol, 36%).
	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 2h;	3-(bromomethyl)phenyl pivalate (2.Og, 7.38 mmol) and triethyl phosphite (1.28 mL, 7.38 mmol) were heated at 150 0C for 4 hours. The solution was then cooled and the excess triethyl phosphite vacuumed off to give crude 3-[(diethoxyphosphoryl)methyl]phenyl pivalate. The crude product was dissolved in THF ( 21 mL) and tert-butyl S-methyW-oxopiperidine-i-carboxylate (1.57 g, 7.38 mmol; CASNo. 181269-69-2) followed by potassium f-butoxide ( 828 mg, 7.38 mmol) added. The reaction was stirred at r.t. for 2 hours and quenched with water. The aqeous phase was extracted with ethyl acetate(2x 25 mL) dried with magnesium sulfate and concentrated. The crude product was purified by flash chromatography (25% ethyl acetate/ heptane) to produce the title compound as an oil (980 mg, 2.62 mmol, 36%).

Reference： [1]Patent: WO2009/127943,2009,A1 .Location in patent: Page/Page column 28
[2]Patent: WO2009/127944,2009,A1 .Location in patent: Page/Page column 28
[3]Patent: WO2009/127948,2009,A1 .Location in patent: Page/Page column 26

14
[ 181269-69-2 ]
[ 1020325-38-5 ]
[ 1191288-06-8 ]

Yield	Reaction Conditions	Operation in experiment
79%		[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester (8.05 g, 20.7 mmol) and tert- butyl 3-methyl-4-oxopiperidine-1-carboxylate (4.20 g, 19.69 mmol; CASNo. 181269-69-2) were dissolved in THF (50 mL) and f-BuOK (3.31 g, 29.50 mmol) was added. The solution was stirred at r.t. for 1 hr. at which time it was quenched with water (10 mL) and extracted with ethyl acetate (3x 20 mL). The organics were dried with sodium sulfate and concentrated to give the olefin as a clear oil. The oil was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (5.0 mL) added at r.t. and the solution stirred for 1 hr. The reaction was then neutralized with sodium bicarbonate (20 mL) and extracted with dichloromethane (2x 50 mL). The organics were dried with sodium sulfate and concentrated. The crude product was purified by flash chromatography (35% ethyl acetate/ heptane) to produce the title compound as an oil (racemic mixture of E and Z isomers, 5.42 g, 15.57 mmol, 79%).
79%		[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester (8.05 g, 20.7 mmol) and tert- butyl 3-methyl-4-oxopiperidine-1-carboxylate (4.20 g, 19.69 mmol; CASNo. 181269-69-2) were dissolved in THF (50 mL) and f-BuOK (3.31 g, 29.50 mmol) was added. The solution was stirred at r.t. for 1 hr. at which time it was quenched with water (10 mL) and extracted with ethyl acetate (3x 20 mL). The organic? were dried with sodium sulfate and concentrated to give the olefin as a clear oil. The oil was dissolved in <n="27"/>dichloromethane (20 ml_) and trifluoroacetic acid (5.0 mL) added at r.t. and the solution stirred for 1 hr. The reaction was then neutralized with sodium bicarbonate (20 mL) and extracted with dichloromethane (2x 50 mL). The organics were dried with sodium sulfate and concentrated. The crude product was purified by flash chromatography (35% ethyl acetate/ heptane) to produce the title compound as an oil (racemic mixture of E and Z isomers, 5.42 g, 15.57 mmol, 79%).

Reference： [1]Patent: WO2009/127949,2009,A1 .Location in patent: Page/Page column 25
[2]Patent: WO2009/127948,2009,A1 .Location in patent: Page/Page column 25; 26

15
[ 181269-69-2 ]
[ 1020326-79-7 ]
[ 1191250-55-1 ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 2h;	Diethyl 3-(5-bromopyridin-2-yloxy)benzylphosphonate (7.50 g, 18.74 mmol) was dissolved in THF ( 50 ml.) and tert-butyl S-methyW-oxopiperidine-i-carboxylate (5.46 g, 25.6 mmol) followed by potassium t- butoxide ( 2.39 g, 21.30 mmol) added. The reaction was stirred at r.t. for 2 hours and quenched with water. The aqeous phase was extracted with ethyl acetate(2x 50 mL) dried with magnesium sulfate and concentrated give the olefin as a clear oil. The oil was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (5.0 mL) added at r.t. and the solution stirred for 1 hr. The reaction was then neutralized with sodium bicarbonate (20 mL) and extracted with dichloromethane (2x 50 mL). The organics were dried with sodium sulfate and concentrated. The crude product was purified by flash chromatography (60% ethyl acetate/ heptane) to produce the title compound as an oil (racemic mixture of E and Z isomers, 5.50 g, 15.34 mmol, 72%).
72%		Diethyl 3-(5-bromopyridin-2-yloxy)benzylphosphonate (7.50 g, 18.74 mmol) was dissolved in THF ( 50 mL) and tert-butyl S-methyM-oxopiperidine-i-carboxylate (5.46 g, 25.6 mmol) followed by potassium t- butoxide ( 2.39 g, 21.30 mmol) added. The reaction was stirred at r.t. for 2 hours and quenched with water. The aqeous phase was extracted with ethyl acetate(2x 50 mL) dried with magnesium sulfate and concentrated give the olefin as a clear oil. The oil was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (5.0 mL) added at r.t. and the solution stirred for 1 hr. The reaction was then neutralized with sodium bicarbonate (20 mL) and extracted with dichloromethane (2x 50 mL). The organics were dried with sodium sulfate and concentrated. The crude product was purified by flash chromatography (60% ethyl acetate/ heptane) to produce the title compound as an oil (racemic mixture of E and Z isomers, 5.50 g, 15.34 mmol, 72%).

Reference： [1]Patent: WO2009/127949,2009,A1 .Location in patent: Page/Page column 28
[2]Patent: WO2009/127948,2009,A1 .Location in patent: Page/Page column 28

16
[ 181269-69-2 ]
[ 1191250-62-0 ]
5-chloro-2-{3-[(3-methylpiperidin-4-ylidene)methyl]phenoxy}pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 2h;	2-[3-(bromomethyl)phenoxy]-5-chloropyridi?e (4.96g, 16.61 mmol) and triethyl phosphite (2.89 mL, 16.60 mmol) were heated at 150 0C for 4 hours. The solution was then cooled and the excess triethyl phosphite vacuumed off to give crude diethyl {3-[(5-chloropyridin-2-yl)oxy]benzyl}phosphonate. The crude product was dissolved in THF ( 21 mL) and tert-butyl S-methyW-oxopiperidine-i-carboxylate (4.25 g, 19.9 mmol; CASNo. 181269-69-2) followed by potassium f-butoxide ( 2.80 g, 24.9 mmol) added. The reaction was stirred at r.t. for 2 hours and quenched with water. The aqeous phase was extracted with ethyl acetate(2x 25 mL) dried with magnesium sulfate and concentrated give the olefin as a clear oil. The oil was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (5.0 mL) added at r.t. and the solution stirred for 1 hr. The reaction was then neutralized with sodium bicarbonate (20 mL) and extracted with dichloromethane (2x 50 mL). The organics were dried with sodium sulfate and concentrated. The crude product was purified by flash chromatography (60% ethyl acetate/ heptane) to produce the title compound as an oil (racemic mixture of E and Z isomers, 4.71 g, 14.94 mmol, 90%).
	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 2h;	2-[3-(bromomethyl)phenoxy]-5-chloropyridine (4.96g, 16.61 mmol) and triethyl phosphite (2.89 ml_, 16.60 mmol) were heated at 150 0C for 4 hours. The solution was then cooled and the excess triethyl phosphite vacuumed off to give crude diethyl {3-[(5-chloropyridin-2-yl)oxy]benzyl}phosphonate. The crude product was dissolved in THF ( 21 mL) and tert-butyl S-methyl^-oxopiperidine-i-carboxylate (4.25 g, 19.9 mmol; CASNo. 181269-69-2) followed by potassium f-butoxide ( 2.80 g, 24.9 mmol) added. The reaction was stirred at r.t. for 2 hours and quenched with water. The aqeous phase was extracted with ethyl acetate(2x 25 mL) dried with magnesium sulfate and concentrated give the olefin as a clear oil. The oil was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (5.0 mL) added at r.t. and the solution stirred for 1 hr. The reaction was then neutralized with sodium bicarbonate (20 mL) and extracted with dichloromethane (2x 50 mL). The organics were dried with sodium sulfate and concentrated. The crude product was purified by flash chromatography (60% ethyl acetate/ heptane) to produce the title compound as an oil (racemic mixture of E and Z isomers, 4.71 g, 14.94 mmol, 90%).

Reference： [1]Patent: WO2009/127949,2009,A1 .Location in patent: Page/Page column 28; 29
[2]Patent: WO2009/127948,2009,A1 .Location in patent: Page/Page column 29

17
[ 181269-69-2 ]
[ 900642-17-3 ]

Yield	Reaction Conditions	Operation in experiment
80%	With ammonium formate; sodium cyanoborohydride; In methanol; at 30℃; for 16h;Molecular sieve;	Step 1: tert-butyl 4-amino-3-methylpiperidine-1-carboxylate To a solution of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (10.00 g, 46.89 mmol) ammonium formate (17.74 g, 281.34 mmol) and molecular sieves (2.00 g) in MeOH (100.00 mL) was added NaCNBH3 (3.54 g, 56.27 mmol). The mixture was stirred at 30 C. for 16 hour. It was purified by SGC to afford tert-butyl 4-amino-3-methyl-piperidine-1-carboxylate (8.12 g, 37.89 mmol, 80%) as product. ESI-MS (EI+, m/z): 159.3 [M-56+H]+.
60%	With ammonium formate; sodium cyanoborohydride; In methanol; at 20℃; for 3h;Molecular sieve;	4n: (rac)-(cis/trans)-4-Amino-3-methyl-piperidine-l-carboxylic acid tert-butyl ester Compound 4m (13 mmol) was dissolved in MeOH (30 niL) and ammonium formate (75 mmol) and sodium cyanoborohydrate (14 mmol) was added followed by molecular sieves, (3A) (Ig). The reaction mixture was stirred for 3h at ambient temperature, then it was filtered and the solvent evaporated. The residue was purified on silica, using as eluent a gradient of ethyl acetate/ethanol/triethylamine (70:26:4) to ethyl acetate/ethanol /triethylamine (80:16:4) to yield the product as a mixture of stereoisomers as determined by NMR. Yield = 60%
	With formic acid; ammonium formate; sodium cyanoborohydride; In methanol; at 20℃; for 2h;	Into a 4-L round-bottom flask was placed methanol (3 L), formic acid (0.5 mL), HCOONH4 (84 g, 1.33 mol, 40.00 equiv) and tert-butyl 3-methyl-4-oxopiperidine-1- carboxylate (7 g, 32.82 mmol, 1.00 equiv).Then NaBH3CN (4.1 g, 2.00 equiv) was added into batchwise. The resulting solution was stirred for 2 hours at room temperature. The pH value of the solution was adjusted to 9 with sodium carbonate (5M in water). The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of H2O. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined. This resulted in 7.0 g (99% crude) of tert-butyl 4- amino-3-methylpiperidine-1-carboxylate as a white solid. 1H NMR (300 MHz, DMSO): 6.39(brs, 2H), 3.95-3.75(m, 1.5H), 3.70-3.60(m, 0.5H), 3.35-3.25(brs, 0.5H), 3.05- 2.95(m, 0.5H), 2.90-2.63(m, 1.5H), 2.45-2.25(brs, 0.5H), 2.10-2.00 (brs, 0.5H), 1.95- 1.85(m, 0.5H), 1.65-1.45(m, 1.5H), 1.35-1.25(m, 0.5H), 1.38(s, 9H), 1.20-1.10(m, 3H) ppm. LCMS (Method A, ESI): RT=1.02 min, m/z =215.0 [M+H]+.

Reference： [1]Patent: US2018/127370,2018,A1 .Location in patent: Paragraph 1339; 1338; 0899; 0897
[2]Patent: WO2009/106534,2009,A1 .Location in patent: Page/Page column 75
[3]Patent: WO2016/40515,2016,A1 .Location in patent: Paragraph 0309

18
[ 181269-69-2 ]
[ 1779-49-3 ]
[ 336182-47-9 ]

Yield	Reaction Conditions	Operation in experiment
83%		Synthesis of tert-butyl 3-methyl-4-methylenepiperidine-1-carboxylate; Methyltriphenylphosphonium bromide (13.70 g, 38.40 mmol) was dissolved in THF (100 mL) and cooled to 0 C. n-BuLi (17.7 mL, 44.3 mmol) was added dropwise and the solution stirred for 30 minutes. At this time <strong>[181269-69-2]tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate</strong> (6.29 g, 29.52 mmol) was added and the solution stirred at r.t. for 1 hour. The reaction was quenched with saturated ammonium chloride and the aqueous phase extracted with ethyl acetate (2×50 mL). The organics were dried with magnesium sulfate and dried. The crude material was purified by flash chromatography (10% ethyl acetate/heptanes) to give the title compound as a colorless oil (5.20 g, 24.64 mmol, 83%).
	With potassium tert-butylate; In dimethyl sulfoxide; at 20℃; for 16h;	To a solution of /er/-butyl 3-methyl-4-oxopiperidine-l-carboxylate (2.95 g, 13.9 mmol) in dimethylsulfoxide (45 mL) were added methyltriphenylphosphonium bromide (7.42 g, 20.8 mmol) and potassium /e/V-butoxide (2.33 g, 20.8 mmol) sequentially and the reaction mixture was allowed to stir for 16 h at ambient temperature. The reaction mixture was poured into water (200 mL) and the resulting mixture extracted with ethyl acetate (2 c 300 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (150 mL), dried (sodium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes: ethyl acetate - 100:0 to 70:30 to afford the title compound. MS: mz = 212.2 [M+H]

Reference： [1]Patent: US2010/113465,2010,A1 .Location in patent: Page/Page column 35
[2]Patent: WO2019/212927,2019,A1 .Location in patent: Page/Page column 64

19
[ 181269-69-2 ]
[ 4629-78-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In ethanol; dichloromethane; at 0 - 25℃;	Step 1: To a solution of racemic 3-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester in anhydrous DCM at 0 C., ethanolic-HCl was added slowly and the reaction mixture was allowed to stir at 25 C. for 3 h. TLC (hexanes/EtOAc 40% EtOAc) showed complete consumption of the starting material. The reaction mixture was evaporated to give racemic 3-methyl-piperidin-4-one hydrochloride which was used crude in the next reaction.

Reference： [1]Patent: US2010/144745,2010,A1 .Location in patent: Page/Page column 46

20
[ 181269-69-2 ]
[ 5773-58-0 ]

Yield	Reaction Conditions	Operation in experiment
75%		To the solution of A0052-6 (300 mg, 1.41 mmol) in 3 ml dichloromethane was added 0.6 mL trifluoroacetic acid and the mixture was kept stirring for 1 hour at room temperature. Then the mixture was added 30 mL of NaOH (20%, aq) and extracted with dichloromethane . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to obtain 122 mg of the crude product as yellow oil. The crude product was used for the next step without any further purification (yield: 75%) . The structure was confirmed by 1H NMR.

Reference： [1]Patent: WO2010/51374,2010,A1 .Location in patent: Page/Page column 118; 119

21
[ 106-39-8 ]
[ 181269-69-2 ]
4-(4-chloro-phenyl)-4-hydroxy-3-methyl-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%		A solution of 1-bromo-4-chlorobenzene (9.24 g, 48.2 mmol) in anhydrous THF (100 mL) was cooled to -78 C. and treated dropwise with 1.6 M n-butyllithium in hexanes (28.7 mL, 46.0 mmol). The mixture was stirred at -78 C. for 45 minutes, during which time a precipitate was observed, then the slurry was treated dropwise with a solution of <strong>[181269-69-2]tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate</strong> (4.9 g, 22.98 mmol) in anhydrous THF (50 mL). The reaction was stirred at -78 C. for 2 hours, then allowed to slowly warm to -20 C. and quenched with saturated ammonium chloride. The layers were separated, and the organic phase was concentrated in vacuo. The aqueous phase was extracted once with ethyl acetate (300 mL), and the organic phase was combined with the residue from the original organic phase. The mixture was washed 3× with water, and once with brine, then dried over sodium sulfate and concentrated in vacuo. The residue was digested in boiling hexanes (100 mL) for 1 hour, then the mixture was cooled to room temperature. The solids were collected by filtration, rinsed with a small amount of hot hexanes, and dried under vacuum to yield the title compound (6.25 g, 19.18 mmol, 83% yield) as a white powder. MS (ESI+)=252.2 (M-tert-BuO)+.
79%		A solution of l-bromo-4-chlorobenzene (21.87 g, 114 mmol) in anhydrous THF (250 mL) was cooled to -78 C and treated dropwise with n- butyllithium (43.5 mL, 109 mmol, 1.6 M in hexanes). The mixture was stirred at -78 C for 45 minutes, during which time a precipitate was observed, then the slurry was treated dropwise with a solution of tert-butyl 3-methyl-4-oxopiperidine-l-carboxylate (11.6 g, 54.4 mmol) in anhydrous THF (50 mL). The reaction was stirred at -78 C for 2 hours, then allowed to slowly warm to -20 C and quenched with saturated ammonium chloride. The layers were separated, and the organic phase was concentrated in vacuo. The aqueous phase was extracted once with ethyl acetate (300 mL), and the organic phase was combined with the residue from the original organic phase. The mixture was washed 3 times with water, and once with brine, then dried over sodium sulfate and concentrated in vacuo. The residue was digested in boiling hexanes (200 mL) for 1 hour, and then the mixture was cooled to room temperature. The solids were collected by filtration, rinsed with a small amount of hot hexanes, and dried under vacuum to yield tert-butyl 4-(4-chlorophenyl)-4-hydroxy-3- methylpiperidine-l-carboxylate (13.96 g, 42.8 mmol, 79 % yield) as a powder, m/z = 252.2 (M-tBuO)+.

Reference： [1]Patent: US2010/204274,2010,A1 .Location in patent: Page/Page column 55
[2]Patent: WO2011/159852,2011,A1 .Location in patent: Page/Page column 12

22
[ 181269-69-2 ]
[ 141-43-5 ]
[ 1237841-87-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 1093-(l-[3-chloro-6-(3-furanyl)-8-(trifluoromethyl)imidazo[l,2-a]pyridin-2-yl]carbonyl}-3- methyl-4-piperidinyl)-l,3-oxazolidin-2-one (Isomer 4) (Compound 210)Step A: (+/-)-l,l-dimethylethyl 4-[(2-hydroxyethyl)amino]-3-methyl-l-piperidinecarboxylate A solution of 1,1-dimethylethyl S-methyM-oxo-l-piperidinecarboxylate (1.85 g, 8.67 mmol, ARK PHARMA), ethanolamine (1.574 niL, 26.0 mmol), and AcOH (1.490 mL, 26.0 mmol) in methanol (40 mL) was stirred for 1 hour and then treated in one portion with sodium cyanoborohydride (1.635 g, 26.0 mmol). The mixture was stirred overnight and then poured into dichloromethane and washed with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and taken to a residue under reduced pressure to afford 1,1- dimethylethyl 4-[(2-hydroxyethyl)amino]-3-methyl-l-piperidinecarboxylate (2.15 g, 8.32 mmol, 96 % yield) as a yellow oil.

Reference： [1]Patent: WO2010/91411,2010,A1 .Location in patent: Page/Page column 199-200

23
[ 181269-69-2 ]
[ 4009-98-7 ]
[ 512822-17-2 ]

Yield	Reaction Conditions	Operation in experiment
		18 ml of a sodium bis(trimethylsilyl)amide solution (2M) in THF are added to a suspension of 12.4 g of methoxymethyltriphenylphosphonium chloride in 25 ml of dry THF at 0. To the mixture obtained, 5.87 g of 3-methyl-4-oxo-piperidine-1-carboxylic acid tertbutyl ester in 25 ml of THF are slowly added, the mixture obtained is stirred at 0, diluted with EtAc and extracted with aqueous 1M HCI, saturated aqueous NaHCO3 solution and brine. The organic EPO <DP n="33"/>layer obtained is dried and solvent is evaporated. The evaporation residue obtained is subjected to filtration over silica gel and solvent of the filtrate obtained is evaporated. 3.6 g of the filtration residue obtained are dissolved in 150 ml of CH3CN, 1.68 g of cerium trichloride heptahydrate and 337 mg of NaI are added and the resulting mixture is stirred at 40 overnight. From the mixture obtained solvent is evaporated and the evaporation residue obtained is treated with EtAc. The mixture obtained is extracted with aqueous 1 M HCI, saturated aqueous NaHCO3 solution and brine. The organic layer obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to filtration over silica gel and solvent of the filtrate obtained is evaporated. 494 mg of the evaporation residue obtained and 1.18 g of magnesium monoperoxyphthalic acid hexahydrate in 36 ml ofEtOH/H2O (1 :1) are stirred at RT and diluted with EtAc. The mixture obtained is extracted with aqueous 1M HCI. The organic layer obtained is dried, solvent is evaporated and the evaporation residue is subjected to filtration and solvent of the filtrate obtained is evaporated. To a solution of 60 mg of the evaporation residue obtained, 71 mg of 3,5- bis(trifluoromethyl)phenylsulfonamide, 94 mg of EDC and 30 mg of DMAP in 2 ml of DMF and 84 mul of DIEA are added and the mixture obtained is snaked at RT. From the mixture obtained solvent is removed and the concentrated residue obtained is subjected to preparative HPLC on an RP-18 column (CH3CN/H2O (0.1% TFA). 4-(3,5- Bis-trifluoromethyl-benzenesulfonylaminocarbonyl)-cis -3-methyl-piperidine-i- carboxylic acid tert.-butyl ester and 4-(3,5- Bis-trifluoromethyl-benzenesulfonyl- aminocarbonyl)-trans-3-methyl-piperidine-1 -carboxylic acid tert.-butyl ester are obtained.

Reference： [1]Patent: WO2006/97293,2006,A2 .Location in patent: Page/Page column 33-34

24
[ 181269-69-2 ]
[ 180149-25-1 ]
[ 1146733-30-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 3h;	Step 1: tert-butyl 4-[2-(5-methoxy-2-nitro-phenyl)-ethylamino]-3-methyl-piperidine-1-carboxylate 1.74 mL (29.0 mmol) acetic acid and 3.48 g (16.4 mmol) sodium triacetoxyborohydride were added at 0 C. to 2.50 g (12.7 mmol) 2-(5-methoxy-2-nitro-phenyl)-ethylamine and 2.93 g (13.7 mmol) tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (WO2004/41777) in 75 mL DCM and the mixture was stirred for 3 h at RT. The reaction mixture was combined at 0 C. with a saturated potassium carbonate solution and the aqueous phase was extracted several times with DCM. The combined organic phases were washed with water and saturated sodium chloride solution, dried on sodium sulphate, filtered and the filtrate was evaporated down. The residue was purified by flash chromatography. Yield: 4.50 g (90% of theoretical) ESI-MS: m/z=394 (M+H)+

Reference： [1]Patent: US2011/59954,2011,A1 .Location in patent: Page/Page column 81

25
[ 181269-69-2 ]
[ 420-04-2 ]
[ 1253415-55-2 ]

Yield	Reaction Conditions	Operation in experiment
31.3%	With pyridine; sulfur; at 100℃; for 3h;	Step 1; To a solution of tert-butyl-3-methyl-4-oxopiperidine-1-carboxylate (Compound 67: 200 mg, 0.938 mmol) in pyridine (1 mL), sulfur (60.1 mg, 1.876 mmol) and cyanamide (79 mg, 1.876 mmol) were added. The solution was then stirred at 100C for 3 hours. The reaction mixture was poured into iced water, and then extracted with ethyl acetate. The organic layer was washed with water, and then dried over anhydrous sodium sulfate. The solvent was concentrated in vacuo, and then purification by silica gel column chromatography (chloroform:methanol = 100:1 ? 100:2) yielded Compound 68 as a pale yellow foam (79 mg, 31.3%). LC/MS (Method C): 1.06 min, [M+H]+ = 267 1H-NMR (CDCl3) delta: 1.21 (3H, d, J = 6.9 Hz), 1.48 (9H, s), 2.83 (1H, m), 3.24-3.84 (2H, m), 4.28-4.60 (2H, m), 4.83 (2H, s).

Reference： [1]Patent: EP2426135,2012,A1 .Location in patent: Page/Page column 118

26
[ 37595-74-7 ]
[ 181269-69-2 ]
[ 1240971-20-3 ]

Yield	Reaction Conditions	Operation in experiment
97%		To a solution of <strong>[181269-69-2]tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate</strong> (3.2 g, 15 mmol) in tetrahydrofuran (60 mL) was added lithium bis(trimethylsilyl)amide solution in tetrahydrofuran(13.9 mL, 18 mmol, 1.3 M in THF) slowly at-78 C. The mixture was stirred at-78 C for 1.5 hours and then a solution of N-phenyl trifluoromethanesulfonimide (6.4 g, 18 mmcl) in tetrahydrofuran (30 mL) was added slowly. The reaction mixture was stirred at -78C for 0.5 hour, then slowly warm up to room temperature and stirred for 2 hours. The reaction mixture was diluted with H20 (50 mL), extracted with EtOAc (100 mL x 2), dried over Na2SO4,concentrated and the residue was purified by silica gel chromatography column (petroleum ether EtOAc = 50/1) to afford crude product (5.0 g, 97%) as yellow oil.1H NMR (400 MHz, CDCI3): 55.72 (s, IH), 4.18-3.91 (m, 2H), 3.68-3.57 (m, IH), 3.42-3.34 (m, 1H), 2.65-2.58(m, 1H), 1.47(s, 9H), 1.15(d, J 7.2 Hz, 3H).
78%		Step 4: tert-Butyl 3-methyl-4-(((trifluoromethyl) sulfonyl)oxy)-3,6-dihydropyridine-1 (2H)- carboxylate. To a solution of te/ -Butyl 3-methyl-4-oxopiperidine-1-carboxylate (7 g, 32.8mmol) in THF (70 mL) was added a solution of NaHMDS (66 mL, 65.7 mmol, 1 M in THF) dropwise at -78 C, stirred for 1.5 h at the same temperature, 1 ,1 ,1-trifluoro-/V-phenyl-/V- ((trifluoromethyl)sulfonyl)methanesulfonamide (23.4 g, 65.7 mmol) was added, the reaction mixture was warmed to room temperature and stirred for 16 h. After completion, the reaction mixture was quenched with addition of ice-cooled water and extracted using EtOAc. The combined organic layer was washed with 10% citric acid followed by 2N NaOH solution, dried over anhydrous Na2S04 filtered and concentrated to obtain a crude product which was purified by silica gel column chromatography (3-5% EtOAc in hexane) to afford the title compound (8.8 g, 78%). 1H NMR (400 MHz, CDCI3): delta 5.73-5.72 (m, 1 H), 4.12-3.96 (m, 2H), 3.61-3.40 (m, 2H), 2.62-2.61 (m, 1 H), 1.47 (s, 9H), 1.14 (d, J = 6.8 Hz, 3H).
61%		(2) tert-Butyl 3-methyl-4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylate Under N2 atmosphere, a solution of 1.0M lithium bis(trimethylsilyl)amide-tetrahydrofuran solution (2.7 mL, 2.73 mmol) was dissolved in dry tetrahydrofuran (8 mL). The mixture was cooled to -78C, was added dropwise a solution of <strong>[181269-69-2]tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate</strong> (530 mg, 2.49 mmol) in dry tetrahydrofuran (2 mL), stirred at the same temperature for an additional 30 minutes, and then was added dropwise a solution of N-phenylbis(trifluoromethyl)sulfonamide (888 mg, 2.49 mmol) in dry tetrahydrofuran (2 mL). The reaction mixture was warmed up to 0C, stirred for 1 hour, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/chloroform =8/1 ? 0/100), to give the title compound as a colorless oil (522 mg, yield 61%) . 1H NMR (CDCl3 400 MHz): 5= 1.16 (3H, d, J = 7 Hz), 1.48 (9H, s), 2.62 (1H, br s), 3.2-3.8 8 (2H, m), 3.9-4.3 (2H, m), 5.73 (1H, br s).

198 mg

A solution of diisopropylamine (0.182 mL, 1.3 mmol) in THF (4 mL) was cooled to - 78 C and nBuLi (2.5 M in hexanes, 0.52 mL, 1.3 mmol) was added dropwise. The mixture was stirred at -78 C for 30 min. Next, a solution of tert-butyl 3-methyl-4-oxopiperidine-1 -carboxylate (185 mg, 0.87 mmol) in THF (3 mL) was added slowly to the prepared solution of LDA at -78 C. After 40 min, a solution of N-phenyl bis(trifluoromethanesulfonimide) (PhNHTf) (402.9 mg, 1.13 mmol) in THF (3 mL) was slowly added. After 1.5 h, the cooling bath was removed and reaction mixture was allowed to warm to 25 C over the course of 1.5 h. Upon completion, the solution was quenched with sat. aq. NaHC03 (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed sequentially with 5% citric acid solution (5 mL), brine (5 mL), and then dried with sodium sulfate. Concentration of the organic layer resulted in a brown oily residue which was purified by flash column chromatography (heptane: EtOAc 1 :0 to 9: 1) to obtain the desired product (198 mg, 66%) as a colorless oil: 1H NMR (400 MHz, CDCI3) delta 5.75 (s, 1 H), 4.29-3.91 (m, 2H), 3.78-3.26 (m, 2H), 2.65 (s, 1 H), 1.49 (s, 9H), 1.21-1.15 (m, 3H).

Reference： [1]Patent: WO2018/137593,2018,A1 .Location in patent: Page/Page column 95; 96
[2]Patent: WO2016/120850,2016,A1 .Location in patent: Page/Page column 42
[3]Patent: EP2474540,2012,A1 .Location in patent: Page/Page column 42
[4]Patent: WO2016/120849,2016,A1 .Location in patent: Page/Page column 70

27
[ 181269-69-2 ]
[ 7341-96-0 ]
[ 1401034-50-1 ]

Yield	Reaction Conditions	Operation in experiment
55%		tert-Butyl 3-methyl-4-oxopiperidine-1-carboxylate (commercially available from Ryan Scientific, Mt. Pleasant, S.C.)(1.7 g, 7.97 mmol) and pyrrolidine (1.3 mL, 15.94 mmol) were dissolved in toluene (9 mL), and the solution was heated under reflux, with the removal of water under Dean-Stark conditions, for 5 hours. The solution was then cooled to room temperature and propiolamide (prepared as described in EP 1813606)(1.1 g, 15.94 mmol) was added. The reaction mixture thus obtained was heated overnight under reflux. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel eluting with 0% to 10% MeOH in DCM to give the title compound (2.1 g, 55% yield). 1H NMR (400 MHz, CDCl3) delta ppm 1.36 (3H, d, J=7.04 Hz), 1.52 (9H, s), 3.37-3.44 (1H, m), 3.77-3.84 (1H, m), 4.12-4.17 (1H, m), 6.48 (1H, d, J=9.39 Hz), 7.21 (1H, d, J=9.39 Hz) ppm; LC/MS m/z: 265 (M+1).

Reference： [1]Patent: US2012/244110,2012,A1 .Location in patent: Page/Page column 74-75

28
[ 181269-69-2 ]
[ 456-64-4 ]
[ 1240971-20-3 ]

Yield	Reaction Conditions	Operation in experiment
1.7 g		b) Preparation of intermediate (38)Reaction under N2. BuLi (1.6M in hexane) (3.52 ml, 5.63 mmol) was added dropwise at -20C to a solution of DIP A (0.791 ml, 5.63 mmol) in THF (8 ml) then the mixture was stirred at -20C for 20 minutes. A solution of intermediate (37) (1.0 g, 4.70 mmol) in THF (10 ml) was then added at -78C and the resulting mixture was stirred for 30 minutes at -78C. A solution of N-phenyltrifluoromethanesulfonimide (1.92 g, 5.16 mmol) in THF (6 ml) was added at -78C then the mixture was allowed to reach room temperature and was stirred overnight. The mixture was concentrated and purified by normal phase on (silicagel, 20-45muiotaeta, 450 g, mobile phase (80% heptane, 20% AcOEt)). The desired fractions were collected and the solvent was evaporated, yielding 1.7 g of intermediate
1.7 g		Reaction under N2. BuLi (1.6M in hexane) (3.52 ml, 5.63 mmol) was added dropwise at -20C to a solution of DIPA (0.79 1 ml, 5.63 mmol) in THF (8 ml) then the mixture was stirred at -20C for 20 minutes. A solution of intermediate (A20) (1.0 g,4.70 mmol) in THF (10 ml) was then added at -78C and the resulting mixture was stirred for 30 minutes at -78C. A solution of N-phenyltrifluoromethanesulfonimide (1.92 g, 5.16 mmol) in THF (6 ml) was added at -78C then the mixture was allowed to reach room temperature and was stirred overnight. The mixture was concentrated and purified by normal phase on (silicagel, 20-45jim, 450 g, mobile phase (80% heptane,20% AcOEt)). The desired fractions were collected and the solvent was evaporated, yielding 1.7 g of intermediate (A21).

Reference： [1]Patent: WO2013/21052,2013,A1 .Location in patent: Page/Page column 31
[2]Patent: WO2014/23815,2014,A1 .Location in patent: Page/Page column 44

29
[ 24424-99-5 ]
[ 1159982-52-1 ]
[ 181269-69-2 ]

Yield	Reaction Conditions	Operation in experiment
		Compound 2 (13.36 mmol) was dissolved in 20% HCI (50 mL). The reaction mixture was stirred under reflux for 2 days. The solvent was removed and the crude product was dissolved in THF (100 mL) and H20 (20 mL). Boc20 (5.83 g, 26.73 mmol ) and Na2CC>3 (4.25 g, 40.10 mmol) was added. The reaction mixture was stirred at RT overnight. The crude product was purified by column to give the product.

Reference： [1]Patent: WO2013/96744,2013,A1 .Location in patent: Page/Page column 198; 199

30
[ 181269-69-2 ]
[ 1774-47-6 ]
[ 862669-17-8 ]

Yield	Reaction Conditions	Operation in experiment
75%		In a round-bottom flask, trimethylsulfoxonium iodide (3.10 g, 14.07 mmol) was dissolved in dimethyl sulfoxide (20 mL) and cooled to 0 C. Sodium hydride (0.675 g, 16.88 mmol; 60% dispersion in mineral oil) was added to the frozen mixture and the mixture was allowed to warm to room temperature and stirred for 2 h. This mixture was then re-cooled to 0 C and 1,1 -dimethylethyl 3-methyl-4-oxo-l-piperidinecarboxylate (3.0 g, 14.07 mmol) in dimethyl sulfoxide (2 ml) was added to the frozen mixture and then allowed to warm to room temperature. The reaction mixture was stirred for 2 h. Water was slowly added to the reaction mixture, which was then transferred to a separatory funnel containing dichloromethane. The layers were separated. The aqueous phase was extracted with dichloromethane (3x), and the combined organics were washed with brine (2x), dried over Na2S04, filtered, and concentrated to a yellow oil. Purification by silica gel chromatography (10-80% ethyl acetate/hexanes) afforded the title compound (2.4 g, 75%>) as a yellow oil. MS(ES)+ m/e 228.1 [M+H]+.

Reference： [1]Patent: WO2014/8223,2014,A2 .Location in patent: Page/Page column 137

31
[ 181269-69-2 ]
[ 4637-24-5 ]
2-methyl-2-thiopseudouronium sulfate [ No CAS ]
[ 1567965-66-5 ]

Yield	Reaction Conditions	Operation in experiment
36%		[0183] Method K-Step b: Tert-butyl 8-methyl-2-(methylthio)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxylate [0184] A solution of tert-butyl 4-oxopiperidine-l-carboxylate (0.94 mmol) was added into 1 , 1 -dimethoxy-N,N-dimethylmethanamine (2 mL), the mixture was heated at 80 C for 12 hours. The solution was cooled down and concentrated under reduced pressure to an orange oil for next step. 2-methylthiouronium sulfate (88 mg, 0.47 mmol) in 4 mL of EtOH was treated with sodium ethoxide (64 mg, 0.47 mmol). After 30 min, a solution of the orange oil above in EtOH (1 mL) was added, and the mixture was stirred at 80 C for 12 hours. The reaction solution was cooled down to room temperature, concentrated under reduced pressure, and the residue was portioned between EtOAc(20 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, and concentrated to give an orange oil. The residue was purified by silica gel column chromatography (petroleum ether: EtO Ac = 5: 1) to afford the desired compound as an orange oil (100 mg, 36%). *H NMR (400MHz, CDC13) delta 8.25 (s, 1H), 3.75-3.70 (m, 3H), 3.49 (m, 1H), 2.94 (m, 1H), 2.56 (s, 3H), 1.41 (s, 9H), 1.26 (t, / = 7.2 Hz, 3H).

Reference： [1]Patent: WO2014/113191,2014,A1 .Location in patent: Paragraph 0183; 0184

32
[ 181269-69-2 ]
[ 1449-46-3 ]
tert-butyl 4-benzylidene-3-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%		To a stirred solution of benzyltriphenylphosphonium bromide in dry THF (20 mL), potassium tert-butoxide (2.0 g, 17.8 mmol) was added at rt and the resulting mixture was stirred for 1 h. Then tert-butyl 3-methyl-4-oxopiperidine-1 -carboxylate (2.0 g, 9.3 mmol) was added at rt and the reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated. To the resulting crude mixture, water (20 mL) was added and extracted with DCM (80 mL). The organic layer was dried over Na2S04 and concentrated. The resulting residue was purified by silicagel column chromatography to get tert-butyl 4-benzylidene-3- methylpiperidine-1 -carboxylate as a pale yellow liquid. Yield: 63% (1 .7 g). LCMS: (Method C) 232.0 (M-t-Bu+H), RT. 6.03 min, 95.27% (Max). H NMR (400 MHz, DMSO-d6): delta 7.34-7.29 (m, 2H), 7.21 -7.17 (m, 3H), 6.32 (s, 1 H), 3.37- 3.31 (m, 2H), 2.38-2.25 (m, 5H), 1 .45 (s, 9H), 1 .08 (d, J = 9.2 Hz, 3H).

Reference： [1]Patent: WO2014/159234,2014,A1 .Location in patent: Page/Page column 98

33
[ 181269-69-2 ]
[ 1613722-45-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium hexamethylsilazane / tetrahydrofuran / 3.5 h / -78 - 20 °C 1.2: -78 - 20 °C 2.1: potassium phosphate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / water; N,N-dimethyl-formamide / 80 °C 2.2: chiralpak AD

Reference： [1]George, Dawn M.; Breinlinger, Eric C.; Argiriadi, Maria A.; Zhang, Yang; Wang, Jianfei; Bansal-Pakala, Pratima; Duignan, David B.; Honore, Prisca; Lang, Qingyu; Mittelstadt, Scott; Rundell, Lian; Schwartz, Annette; Sun, Jiakang; Edmunds, Jeremy J. [Journal of Medicinal Chemistry, 2015, vol. 58, # 1, p. 333 - 346]

34
[ 867-13-0 ]
[ 181269-69-2 ]
4-ethoxycarbonylmethylene-3-methylpiperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.65 g		Sodium hydride (content 60%, 0.17 g) was cooled in an ice bath, of tetrahydrofuran (5 mL) was added triethyl phosphonoacetate (1.04 g) and stirred at room temperature for 1 hour. to the reaction mixture at room temperature was added <strong>[181269-69-2]3-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester</strong>(0.50 g) of tetrahydrofuran (5 mL)Solution, and stirred at 50 C for 2.5 hours. The reaction mixture was cooled to room temperature, and added water. The extract was extracted with ethyl acetate. The organic layer was washed with water, after washing with saturated saline, and then dried over anhydrous magnesium sulfate, and distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:N-hexane-ethyl acetate) to obtain the crude product, to give 4-ethoxycarbonylmethylene-3-methylpiperidine-1-carboxylic acid tert-butyl ester (0.65 g). The resulting compound (0.65 g) of ethanol(12 mL) was added 10% palladium on carbon (250 mg, wet) and stirred under a hydrogen atmosphere at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, and stirred at room temperature for 15 minutes. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, to give 4-ethoxycarbonylmethyl-3-methylpiperidine-1-carboxylic acid tert-butyl ester (0.64 g). To a solution of the obtained compound (0.64 g) in ethyl acetate (10 mL) at room temperature was added 4 mol / L hydrochloric acid (ethyl acetate solution, 10 mL) and stirred at room temperature for 39 hours. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate water was added to the residue, and extracted twice with dichloromethane-isopropanol (dichloromethane: isopropanol di-3: 1) mixed solvent. The organic layer was collected, the extract was dried with anhydrous sodium sulfate, and decompression, under, distillation, to give the title compound (0.39 g).
0.65 g		Reference Example 1 (0077) (3-Methylpiperidin-4-yl)acetic acid ethyl ester (0078) To a suspension of sodium hydride (60%, 0.17 g) in tetrahydrofuran (5 mL) was added triethyl phosphonoacetate (1.04 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a solution of <strong>[181269-69-2]3-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester</strong> (0.50 g) in tetrahydrofuran (5 mL) at room temperature, and the mixture was stirred at 50 C. for 2.5 hours. The reaction mixture was cooled to mom temperature and water was added. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give 4-ethoxycarbonylmethylene-3-methylpiperidine-1-carboxylic acid tert-butyl ester (0.65 g). To a solution of the obtained compound (0.65 g) in ethanol (12 mL) was added 10% palladium on carbon (250 mg, wet) at room temperature, and the mixture was stirred at room temperature under a hydrogen gas atmosphere for 18 hours. The reaction mixture was diluted with ethyl acetate and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give 4-ethoxycarbonylmethyl-3-methylpiperidine-1-carboxylic acid tert-butyl ester (0.64 g). To a solution of the obtained compound (0.64 g) in ethyl acetate (10 mL) was added 4 mol/L hydrochloric, acid (ethyl acetate solution, 10 mL) at room temperature, and the mixture was stirred at room temperature for 39 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added a saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with a mixed solvent of dichloromethane-isopropyl alcohol (dichloromethane/isopropyl alcohol=3/1) twice. The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the title compound (0.39 g).

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 3509 - 3519
[2]Patent: TW2016/5823,2016,A .Location in patent: Paragraph 0046
[3]Patent: US2016/289206,2016,A1 .Location in patent: Paragraph 0077; 0078

35
[ 181269-69-2 ]
[ 100-58-3 ]
tert-butyl 4-hydroxy-3-methyl-4-phenylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	In tetrahydrofuran; at 0 - 20℃; for 24h;	In a 100 mL round bottom flask terr-butyl 3-methyl-4-oxopiperidine-1-carboxylate (988 mg, 4.63 mmol) wasdissolved in tetrahydrofuran (20 mL) and cooled to 0 C. Phenylmagnesium bromide (7.72 mL,23.17 mmol) was added and the solution was warmed to ambient temperature and mixed for 24 h. The reaction was cooled to 0 C then 1 N hydrochloric acid was added (75 mL) and the aq. solution was extracted with ethyl acetate (3 X). The combined organic phase was dried over sodium sulfate, concentrated and purified by silica gel chromatography (eluting with hexane/ethyl acetate) to provide tert-butyl 4-hydroxy-3 -methyl-4-phenylpiperidine- 1 -carboxylate (1 .133 g, 84%) as a white solid. LCMS M/Z (M-OH,t-Bu) 218.

Reference： [1]Patent: WO2016/138114,2016,A1 .Location in patent: Page/Page column 92

36
[ 56278-50-3 ]
[ 181269-69-2 ]
tert-butyl 2-amino-3-(benzo[d]thiazol-2-yl)-4-methyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With morpholine; sulfur; at 85℃; for 12h;	To a solution of 2-(benzo[djthiazol-2-yl)acetonitrile (500 mg, 2.87 mmol) in ethanol (10 mL) was added <strong>[181269-69-2]tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate</strong> (324 mg, 2.87 mmol), elemental sulfur (90 mg, 2.87 mmol) and morpholine (243 mg, 2.87 mmol) at room temperature. After the addition, the resulting mixture was heated to reflux at 85 C for 12 h. Reaction progress was monitored by TLC. The reaction mixture was concentrated under vacuum pressure and the crude compound was purified by triturating with methanol to afford the title compound as yellow solid (450 mg, yield 39%). LCMS: [M+Hj = 401.90; R = 3.89 mm.

Reference： [1]Patent: WO2016/197078,2016,A1 .Location in patent: Paragraph 456; 457-458

37
[ 181269-69-2 ]
2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile [ No CAS ]
tert-butyl 2-amino-4-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 80℃; for 3h;	Step 1: tert-butyl 2-amino-4-methyl-3-(thiazolo[4,5-c]pyridin-2-yl)-4, 7- dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (0619) (0620) [277] To a stirred solution of 2-(thiazolo[4,5-c]pyridin-2-yl)acetonitrile (1 g, 5.70 mmol) in ethanol (10 mL) was added tert-butyl 3-methyl-4-oxopiperidine-l-carboxylate (1.2 g, 5.70 mmol), elemental sulphur (0.216 g, 5.70 mmol) and morpholine (0.495 g, 5.70 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 under vacuum pressure. After removal of solvent, the crude compound was purified by triturating with methanol to afford the title compound as a yellow solid (1 g, crude). This compound was used in the next step without further purification.

Reference： [1]Patent: WO2016/196910,2016,A1 .Location in patent: Paragraph 276; 277

38
[ 37595-74-7 ]
[ 181269-69-2 ]
[ 34846-90-7 ]
2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-amine [ No CAS ]
N-(isoxazol-3-yl)-2-oxooxazolidine-3-sulfonamide [ No CAS ]
(rac)-N-(isoxazol-3-yl)-7-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-sulfonamide [ No CAS ]
(rac)-N-(isoxazol-3-yl)-5-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A 250-mL round-bottom flask was charged with (Rac)-tert-butyl 3-methy 1-4-oxopiperidine-1-carboxylate (5.00 g, 23.4 mmol) and purged with nitrogen. THF (47.0 ml) was introduced and the reaction mixture was cooled to -78 °C in a dry ice-acetone bath. A solution of potassium /er/-butoxide (1.6 M in THF, 19.0 mL, 29.9 mmol) was added to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to 0 °C in an ice-water bath. After 30 min, the reaction mixture was cooled to -78 °C. Methyl 3 -methoxy aery late (5.29 ml, 49.2 mmol) was added dropwise to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to ambient temperature. After 2 h, the resultant red reaction mixture was cooled was cooled to -78 °C. N-phenyl bis-trifluoromethane sulfonamide (13.2 g, 37.0 mmol) was added to the vigorously stirred, cooled reaction mixture in one portion and the reaction mixture was subsequently allowed to warm to 0 °C in an ice-water bath. After 1 h, saturated aqueous sodium bicarbonate solution (100 mL) and EtOAc (100 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography in two portions (100-g silica gel Biotage column, eluent: gradient, 0 to 30percent EtOAc in heptane) to afford a mixture of (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-2-methy 1-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (11.75 g, 27.4 mmol, 117 percent yield) as a yellow solid.A 20-mL vial was charged with a mixture of (Rac)-(E)-tert-buty 1 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((lrifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-buty\ 3-(3-methoxy-3-oxoprop-1 -en-1 -yl)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (716 mg, 1.668 mmol), 2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny 1]-4-amine (Preparation 4h, 352 mg, 1.39 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (101 mg, 0.174 mmol), cesium carbonate (1.36 g, 4.17 mmol), tris(dibenzylideneacetone)dipalladium(0) (63.9 mg, 0.07 mmol), and 1,4-dioxane (6.95 mL) then sparged with nitrogen for 10 min. The needle was then removed and the reaction was heated to 100 °C. After 3 h, the reaction mixture was allowed to cool to ambient temperature and was diluted with EtOAc (15 mL) and filtered through a Celite® pad. The pad was rinsed with EtOAc (3 x 15 mL). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (50-g silica gel Biotage column, eluent: gradient, 0 to 35percent 3:1 EtOAc/EtOH in heptane with DCM as a 10percent additive) to afford a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-l-(2,3',5'-trifluoro-5-methoxy-[l,r-biphenyl]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-bu\y\ 5-methy 1-2-oxo-1-(2,3',5'-lrifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (587 mg, 1.17 mmol, 84.0percent) as a brown solid,A 20-mL vial was charged with a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxy late (587 mg, 1.173 mmol) and trifluoroacetic acid (5.86 mL) at ambient temperature. After 30 min, the reaction mixture was concentrated under reduced pressure, dissolved in DCM (15 mL) and carefully poured into saturated aqueous sodium bicarbonate solution (15 mL). The layers were separated and the aqueous layer extracted with additional DCM (3 x 15 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to afford a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-l-(2,3',5'-trifluoro-5-methoxy-[l,l'-biphenyl]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-lrifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (400 mg, 1.00 mmol, 85.0percent) as a tan amorphous solid, which was used without further purification.20-mL vial was charged with a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (400 mg, 1.00 mmol), N-(isoxazol-3-yl)-2-oxooxazol...

Reference： [1]Patent: CN107531705,2018,A .Location in patent: Paragraph 0693-0694; 0695-702

39
[ 37595-74-7 ]
[ 181269-69-2 ]
[ 34846-90-7 ]
2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-amine [ No CAS ]
(rac)-tert-butyl 7-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-carboxylate [ No CAS ]
(rac)-tert-butyl 5-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A 250-mL round-bottom flask was charged with (Rac)-tert-butyl 3-methy 1-4-oxopiperidine-1-carboxylate (5.00 g, 23.4 mmol) and purged with nitrogen. THF (47.0 ml) was introduced and the reaction mixture was cooled to -78 °C in a dry ice-acetone bath. A solution of potassium /er/-butoxide (1.6 M in THF, 19.0 mL, 29.9 mmol) was added to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to 0 °C in an ice-water bath. After 30 min, the reaction mixture was cooled to -78 °C. Methyl 3 -methoxy aery late (5.29 ml, 49.2 mmol) was added dropwise to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to ambient temperature. After 2 h, the resultant red reaction mixture was cooled was cooled to -78 °C. N-phenyl bis-trifluoromethane sulfonamide (13.2 g, 37.0 mmol) was added to the vigorously stirred, cooled reaction mixture in one portion and the reaction mixture was subsequently allowed to warm to 0 °C in an ice-water bath. After 1 h, saturated aqueous sodium bicarbonate solution (100 mL) and EtOAc (100 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography in two portions (100-g silica gel Biotage column, eluent: gradient, 0 to 30percent EtOAc in heptane) to afford a mixture of (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-2-methy 1-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (11.75 g, 27.4 mmol, 117 percent yield) as a yellow solid.A 20-mL vial was charged with a mixture of (Rac)-(E)-tert-buty 1 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((lrifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-buty\ 3-(3-methoxy-3-oxoprop-1 -en-1 -yl)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (716 mg, 1.668 mmol), 2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny 1]-4-amine (Preparation 4h, 352 mg, 1.39 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (101 mg, 0.174 mmol), cesium carbonate (1.36 g, 4.17 mmol), tris(dibenzylideneacetone)dipalladium(0) (63.9 mg, 0.07 mmol), and 1,4-dioxane (6.95 mL) then sparged with nitrogen for 10 min. The needle was then removed and the reaction was heated to 100 °C. After 3 h, the reaction mixture was allowed to cool to ambient temperature and was diluted with EtOAc (15 mL) and filtered through a Celite® pad. The pad was rinsed with EtOAc (3 x 15 mL). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (50-g silica gel Biotage column, eluent: gradient, 0 to 35percent 3:1 EtOAc/EtOH in heptane with DCM as a 10percent additive) to afford a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-l-(2,3',5'-trifluoro-5-methoxy-[l,r-biphenyl]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-bu\y\ 5-methy 1-2-oxo-1-(2,3',5'-lrifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (587 mg, 1.17 mmol, 84.0percent) as a brown solid,

Reference： [1]Patent: CN107531705,2018,A .Location in patent: Paragraph 0693; 0695-0698

40
[ 37595-74-7 ]
[ 181269-69-2 ]
[ 34846-90-7 ]
2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-amine [ No CAS ]
C₂₂H₁₉F₃N₂O₂ [ No CAS ]
C₂₂H₁₉F₃N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A 250-mL round-bottom flask was charged with (Rac)-tert-butyl 3-methy 1-4-oxopiperidine-1-carboxylate (5.00 g, 23.4 mmol) and purged with nitrogen. THF (47.0 ml) was introduced and the reaction mixture was cooled to -78 °C in a dry ice-acetone bath. A solution of potassium /er/-butoxide (1.6 M in THF, 19.0 mL, 29.9 mmol) was added to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to 0 °C in an ice-water bath. After 30 min, the reaction mixture was cooled to -78 °C. Methyl 3 -methoxy aery late (5.29 ml, 49.2 mmol) was added dropwise to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to ambient temperature. After 2 h, the resultant red reaction mixture was cooled was cooled to -78 °C. N-phenyl bis-trifluoromethane sulfonamide (13.2 g, 37.0 mmol) was added to the vigorously stirred, cooled reaction mixture in one portion and the reaction mixture was subsequently allowed to warm to 0 °C in an ice-water bath. After 1 h, saturated aqueous sodium bicarbonate solution (100 mL) and EtOAc (100 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography in two portions (100-g silica gel Biotage column, eluent: gradient, 0 to 30percent EtOAc in heptane) to afford a mixture of (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-2-methy 1-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (11.75 g, 27.4 mmol, 117 percent yield) as a yellow solid.A 20-mL vial was charged with a mixture of (Rac)-(E)-tert-buty 1 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((lrifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-buty\ 3-(3-methoxy-3-oxoprop-1 -en-1 -yl)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (716 mg, 1.668 mmol), 2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny 1]-4-amine (Preparation 4h, 352 mg, 1.39 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (101 mg, 0.174 mmol), cesium carbonate (1.36 g, 4.17 mmol), tris(dibenzylideneacetone)dipalladium(0) (63.9 mg, 0.07 mmol), and 1,4-dioxane (6.95 mL) then sparged with nitrogen for 10 min. The needle was then removed and the reaction was heated to 100 °C. After 3 h, the reaction mixture was allowed to cool to ambient temperature and was diluted with EtOAc (15 mL) and filtered through a Celite® pad. The pad was rinsed with EtOAc (3 x 15 mL). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (50-g silica gel Biotage column, eluent: gradient, 0 to 35percent 3:1 EtOAc/EtOH in heptane with DCM as a 10percent additive) to afford a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-l-(2,3',5'-trifluoro-5-methoxy-[l,r-biphenyl]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-bu\y\ 5-methy 1-2-oxo-1-(2,3',5'-lrifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (587 mg, 1.17 mmol, 84.0percent) as a brown solid,A 20-mL vial was charged with a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxy late (587 mg, 1.173 mmol) and trifluoroacetic acid (5.86 mL) at ambient temperature. After 30 min, the reaction mixture was concentrated under reduced pressure, dissolved in DCM (15 mL) and carefully poured into saturated aqueous sodium bicarbonate solution (15 mL). The layers were separated and the aqueous layer extracted with additional DCM (3 x 15 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to afford a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-l-(2,3',5'-trifluoro-5-methoxy-[l,l'-biphenyl]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-lrifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (400 mg, 1.00 mmol, 85.0percent) as a tan amorphous solid, which was used without further purification.

Reference： [1]Patent: CN107531705,2018,A .Location in patent: Paragraph 0693; 0695-700

41
[ 37595-74-7 ]
[ 181269-69-2 ]
[ 34846-90-7 ]
(rac)-(E)-tert-butyl 3-(3-methoxy-3-oxoprop-1-en-1-yl)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
(rac)-(E)-tert-butyl 3-(3-methoxy-3-oxoprop-1-en-1-yl)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A 250-mL round-bottom flask was charged with (Rac)-tert-butyl 3-methy 1-4-oxopiperidine-1-carboxylate (5.00 g, 23.4 mmol) and purged with nitrogen. THF (47.0 ml) was introduced and the reaction mixture was cooled to -78 °C in a dry ice-acetone bath. A solution of potassium /er/-butoxide (1.6 M in THF, 19.0 mL, 29.9 mmol) was added to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to 0 °C in an ice-water bath. After 30 min, the reaction mixture was cooled to -78 °C. Methyl 3 -methoxy aery late (5.29 ml, 49.2 mmol) was added dropwise to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to ambient temperature. After 2 h, the resultant red reaction mixture was cooled was cooled to -78 °C. N-phenyl bis-trifluoromethane sulfonamide (13.2 g, 37.0 mmol) was added to the vigorously stirred, cooled reaction mixture in one portion and the reaction mixture was subsequently allowed to warm to 0 °C in an ice-water bath. After 1 h, saturated aqueous sodium bicarbonate solution (100 mL) and EtOAc (100 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography in two portions (100-g silica gel Biotage column, eluent: gradient, 0 to 30percent EtOAc in heptane) to afford a mixture of (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-2-methy 1-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (11.75 g, 27.4 mmol, 117 percent yield) as a yellow solid.

Reference： [1]Patent: CN107531705,2018,A .Location in patent: Paragraph 0693; 0695-0696

42
[ 181269-69-2 ]
[ 95-92-1 ]
tert-butyl 3-(2-ethoxy-2-oxoacetyl)-5-methyl-4-oxopiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45.6%		To a solution of tert-butyl 3-methyl-4-oxopiperidine-l-carboxylate (2) (30.4 g, 0.14 mol) in anhydrous THF (350 mL) was added LDA (2M, 84 mL) dropwise at -78 C under nitrogen atmosphere. The mixture was stirred at -78C for 1 h and diethyl oxalate (20.46 g, 0.14 mol) was added into the reaction solution. The resulting mixture was allowed to warm up to room temperature and stirred for 2h. The mixture was neutralized with 1 N HC1 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SC>4, concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum etherethyl acetate =10: 1) to afford the compound as a yellow oil (20 g, 45.6%). MS m/z 314.15[M+H]+.
		To a solution of tert-butyl 3 -methyl-4-oxo-piperidine- 1 -carboxylate (2.0 g, 9.38mmol, 1.0 eq) in THF (400.0 mL) was added LiHMDS (1 M, 11.26 mL, 1.20 eq) dropwise at -60 C. The mixture was stirred at -60 C for 30 mi Diethyl oxalate (1.51 g, 10.32 mmol, 1.41mL, 1.10 eq) was added dropwise at -60 C. Then the mixture was stirred at 20 C for 1 hr. TLC (PE:EA = 5:1) showed the reaction was completed. The reaction was quenched by saturated NH4C1 (20 mL) and extracted with EtOAc (60 mL*2). The combined organic layer was dried over Na2504, filtrated. The filtrate was concentrated in vacuum to afford the title0 (2.0 g, crude) as yellow oil.

Reference： [1]Patent: WO2018/71404,2018,A1 .Location in patent: Paragraph 00129
[2]Patent: WO2018/5881,2018,A1 .Location in patent: Page/Page column 126

43
[ 181269-69-2 ]
[ 40216-83-9 ]
tert-butyl 4-((2S,4R)-4-hydroxy-2-(methoxycarbonyl)pyrrolidin-1-yl)-3-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; acetic acid; N-ethyl-N,N-diisopropylamine; at 20℃; for 16h;	General procedure: To a solution of 1-t-Butoxycarbonyl-3-methyl-4-piperidone (2.83 g, 13.3 mmol) in dichloroethane (30 mL) at room temperature was added piperidine (1.58 mL, 16 mmol), AcOH (1.14 mL, 20 mmol), and sodium triacetoxyborohydride (4.24 g, 20 mmol). The mixture was stirred at room temperature for 16 h. The mixture was poured onto saturated sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 100% ethyl acetate in hexanes) to give the title compound as a mixture of diastereomers.

Reference： [1]Patent: US2018/72743,2018,A1 .Location in patent: Paragraph 1261-1262; 1422-1423

44
[ 91017-00-4 ]
[ 181269-69-2 ]
ethyl 3-(3'-methyl-[1,4'-bipiperidin]-3-yl)propanoate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 1-t-Butoxycarbonyl-3-methyl-4-piperidone (2.83 g, 13.3 mmol) in dichloroethane (30 mL) at room temperature was added piperidine (1.58 mL, 16 mmol), AcOH (1.14 mL, 20 mmol), and sodium triacetoxyborohydride (4.24 g, 20 mmol). The mixture was stirred at room temperature for 16 h. The mixture was poured onto saturated sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 100% ethyl acetate in hexanes) to give the title compound as a mixture of diastereomers.

Reference： [1]Patent: US2018/72743,2018,A1 .Location in patent: Paragraph 1261-1262; 1440-1441

45
[ 181269-69-2 ]
ethyl (S)-3-(pyrrolidin-2-yl)propanoate hydrochloride [ No CAS ]
tert-butyl 4-((S)-2-(3-ethoxy-3-oxopropyl)pyrrolidin-1-yl)-3-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 16h;	General procedure: To a solution of 1-tert-butoxycarbonyl-3-methyl-4-piperidone (213 mg, 1.0 mmol) in 1,2 dichloroethane (2.5 mL) was added pyrrolidine (0.123 mL, 1.5 mmol) and sodium triacetoxyborohydride (316 mg, 1.5 mmol). The mixture was stirred at room temperature for 16 h. Then 1 M sodium carbonate was added and the mixture was extracted with ethyl acetate (3*25 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound which was used without further purification.

Reference： [1]Patent: US2018/72743,2018,A1 .Location in patent: Paragraph 1338-1340; 1455-1456

46
[ 181269-69-2 ]
[ 689303-75-1 ]
tert-butyl 4-((S)-2-(3-methoxy-3-oxopropyl)pyrrolidin-1-yl)-3-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%		To a solution of the methyl (S)-3-(pyrrolidin-2-yl)propanoate (Example 46, Step 2, 3.7 g, 23.5 mmol) in 1,2-dichloroethane (60 mL) was added <strong>[181269-69-2]tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate</strong> (5.0 g, 23.5 mmol). The mixture was stirred at room temperature for 30 min. Na(OAc)3BH (15.0 g, 70.5 mmol, 3.0 equiv) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was then poured onto saturated sodium bicarbonate, extracted with dichloromethane (3*100 mL), dried over sodium sulfate, filtered, and concentrated to afford the crude product, which was purified by flash column chromatography twice to provide 3.1 g (37%) of the tert-butyl 4-((S)-2-(3-methoxy-3-oxopropyl)pyrrolidin-1-yl)-3-methylpiperidine-1-carboxylate as a colorless oil.

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 6190 - 6213
[2]Patent: US2018/72743,2018,A1 .Location in patent: Paragraph 1472-1473

47
[ 110-89-4 ]
[ 181269-69-2 ]
tert-butyl 3'-methyl-[1,4'-bipiperidine]-1'-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; acetic acid; at 20℃; for 16h;	To a solution of 1-t-Butoxycarbonyl-3-methyl-4-piperidone (2.83 g, 13.3 mmol) in dichloroethane (30 mL) at room temperature was added piperidine (1.58 mL, 16 mmol), AcOH (1.14 mL, 20 mmol), and sodium triacetoxyborohydride (4.24 g, 20 mmol). The mixture was stirred at room temperature for 16 h. The mixture was poured onto saturated sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 100% ethyl acetate in hexanes) to give the title compound as a mixture of diastereomers.

Reference： [1]Patent: US2018/72743,2018,A1 .Location in patent: Paragraph 1261-1262

48
[ 123-75-1 ]
[ 181269-69-2 ]
tert-butyl 3-methyl-4-(pyrrolidin-1-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 16h;	To a solution of 1-tert-butoxycarbonyl-3-methyl-4-piperidone (213 mg, 1.0 mmol) in 1,2 dichloroethane (2.5 mL) was added pyrrolidine (0.123 mL, 1.5 mmol) and sodium triacetoxyborohydride (316 mg, 1.5 mmol). The mixture was stirred at room temperature for 16 h. Then 1 M sodium carbonate was added and the mixture was extracted with ethyl acetate (3*25 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound which was used without further purification.

Reference： [1]Patent: US2018/72743,2018,A1 .Location in patent: Paragraph 1338-1340

49
[ 181269-69-2 ]
[ 193629-24-2 ]
tert-butyl (3S)-3-(2-ethoxy-2-oxoethyl)-3'-methyl-[1,4'-bipiperidine]-1'-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The product of Example 38, Step 1 (850 mg, 2.63 mmol) was dissolved in DMA (8.8 mL) before the addition of <strong>[181269-69-2]tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate</strong> (560 mg, 2.63 mmol). The reaction was then heated to 35 C. and stirred for 1 h. at this temperature. Then sodium triacetoxyborohydride (696 mg, 3.29 mmol) was added and the mixture was stirred for 24 h. at 35 C. The reaction was cooled to room temperature before being quenched with aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane (3), and then concentrated. The residue was taken up in ethyl acetate and washed with 1M HCl. The aqueous layer was then made basic (pH ?9) with 1M aqueous sodium hydroxide and extracted with dichloromethane (3), and the combine organics were dried over sodium sulfate and concentrated. The crude residue was purified by silica chromatography (40 to 60% ethyl acetate in hexanes) to yield the product as a mixture of diastereomers.

Reference： [1]Patent: US2018/72743,2018,A1 .Location in patent: Paragraph 1431-1432

50
[ 181269-69-2 ]
[ 1629-58-9 ]
C₁₆H₂₅NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30 g	With sodium methylate; In methanol; at 0 - 25℃; for 18h;Inert atmosphere;	Na (8.6 g, 0.375 mol, 1.0 eq) was added to MeOH (800 mL,) in many portions at 25 C and stirred until Na was disappeared and then was added compound 32-A (80 g, 37.5 mmol), EVK (31.55 g, 0.375 mol, 1.0 eq) was added to the above solution at 0 C dropwise over 5 mins under N2 atmosphere. The reaction mixture was stirred at 25 C for 18 hours. TLC (PE/EA = 5: 1) showed the starting materials were consumed completely. The mixture was quenched with saturated NH4CI (800 mL) and extracted with EA (800 mL x 2). The combined organic phase was dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give the residue, which was purified by prep-HPLC (base, (1044) (Phenomenex Gemini C18 25021.2mm5um, water (lOmM NH4HC03)-ACN as mobile phase, from 53-83%, Flow Rate (ml/min): 25) to give compound 32-B (30 g, yield; 42%) as a white solid. (1045) 1H NMR: (400 MHz, CHLOROFORM-d) delta: 4.03 - 3.73 (m, 1H), 3.01 - 2.59 (m, 3H), 2.55 - 2.36 (m, 3H), 1.75 (s, 3H), 1.48 (s, 9H), 1.22 (s, 3H).

Reference： [1]Patent: WO2018/125880,2018,A1 .Location in patent: Page/Page column 98; 99

51
[ 181269-69-2 ]
[ 1774-47-6 ]
tert-butyl 4-methyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium tert-butylate; In 1,2-dimethoxyethane; dimethyl sulfoxide; at 0 - 5℃; for 1h;	To a solution of potassium tert- butoxide (2 g, 18.3 mmol) in DMSO (16 ml_), trimethylsulfoxonium iodide (1467) (4 g, 18.3 mmol) was added in portions keeping the internal temperature between 20- 25 C and the mixture was then stirred at r.t. for 1.5 h. DME (4.5 ml.) was added and the solution was cooled to 0-5 C. Then, a solution of tert- butyl 3-methyl-4- oxopiperidine-1-carboxylate (3 g, 14 mmol) in a mixture of DME (4.5 ml.) and DMSO (1.5 ml.) was added dropwise keeping the internal temperature between 0-5 C and the reaction mixture was further stirred for 1 h. Water and EtOAc were added, the phases were separated and the aq. phase was extracted twice with EtOAc. The organic phases were combined, washed with water (x4), dried over MgS04 and concentrated under vacuum to give the title compounds as a racemic mixture (2.88 g, 90% yield).

Reference： [1]Patent: WO2019/180188,2019,A1 .Location in patent: Page/Page column 339

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

Ghs Hazard Statements

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