Name: 59084-16-1|1-Acetylpiperidine-4-carbonyl chloride|98%
Brand: Ambeed
SKU: A193238
Rating: 96 (40 reviews)

1
[ 372-18-9 ]
[ 59084-16-1 ]
[ 84162-82-3 ]

Yield	Reaction Conditions	Operation in experiment
47%	With aluminum (III) chloride; at 20.0℃; for 1.5h;Reflux;	Intermediate 68: 1-[4-(2,4-Difluoro-benzoyl)-piperidin-1-yl]-ethanoneTo a rapidly stirred slurry of aluminum chloride (3.3 g, 24.7 mmol) and 1 ,3- difluorobenzene (10 mL) at ambient temperature was added 1-acetylpiperidine-4- carbonyl chloride (2.5 g, 13.2 mmol). The reaction mixture was heated at reflux (100C) for 1 .5 hours and then poured into 30 mL of ice water, the mixture was extracted with DCM (50 ml) and the organic layer was washed with water and dried over Na2S04. The solvent was removed in vacuo to give an oil. Trituration of the oil with pentane gave the title product (1 .75 g, 6.22 mmol, 47%) as a white solid. MS (ESI) m/z 268.3 (M + H+); HPLC (Novapak 150 X 3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1 % TFA, at 2 mL/min over 2 min.) M .04 min.
41%	With ammonium chloride; In dichloromethane; for 3.0h;Heating / reflux;	67g of 1,3-difluorobenzene and 133g of ammonium chloride were added to [150ML] of dichloromethane, and then the mixture was cooled to room temperature. 98g of [1-ACETYL-4-PIPERIDINECARBONYL] chloride in [50ML] of dichloromethane was added thereto dropwise, and then the mixture was stirred at an elevated temperature for 3 hours. The reaction mixture was poured to a mixture of ice and hydrochloric acid, and the resulting mixture was extracted with [200ML] of dichloromethane. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed from the filtrate to obtain 55.9g of the title compound (yield: [41%).]
36%	With ammonium chloride; In dichloromethane; at 20.0℃; for 3.0h;Reflux;	1) Preparation of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine 1,3-difluorobenzene(6.7g, 58.7 mmol) and ammonium chloride (13.3g, 250 mmol) are added to 15 ml of dichloromethane and cooled to room temperature; thereto is drop-added 50 ml of dichloromethane wherein 1-acetyl-4-piperidinyl carboxylic acid chloride (9.8g, 51.8 mmol) is dissolved. A reaction is carried out at reflux for 3 hours and the resulting mixture is poured into a mixture of ice and hydrochloric acid after completion of reaction. The mixture is extracted with dichloromethane (20ml*3). The organic phase is separated, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to obtain 5.01g of a product, with a yield of 36%.

36%	With ammonium chloride; In dichloromethane; at 20.0℃; for 3.0h;Reflux;	Add 1,3-difluorobenzene (6.7 g, 58.7 mmol) and ammonium chloride (13.3 g, 250 mmol) to 15 ml dichloromethane and cool to room temperature. 50 ml of dichloromethane in which 1-acetyl-4-piperidinylcarboxylic acid chloride (9.8 g, 51.8 mmol) was dissolved was added dropwise thereto, and the mixture was refluxed for 3 hours. After completion of the reaction, the mixture is poured into a mixture of ice and hydrochloric acid, extracted with 20 ml * 3 of dichloromethane, the organic phase is separated, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give 5.01 g of product. Yield is 36%.
48 g (36%)	aluminium chloride; In dichloromethane;	a) To a stirred of mixture of 56 ml of 1,3-difluorobenzene, 130 g of aluminium chloride and 147 ml of dichloromethane, a solution of 95 g of 1-acetyl-4-piperidinecarbonyl chloride in 50 ml of dichloromethane was added dropwise while cooling. Upon completion, stirring was continued for 3 hours at room temperature. The reaction mixture was poured out into a mixture of crushed ice and hydrochloric acid. The product was extracted with dichloromethane. The organic layer was dried, filtered and evaporated, yielding 48 g (36%) of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine as a residue (interm. 1).
48 parts (36%)	aluminium chloride; In dichloromethane;	EXAMPLE 1 To a stirred mixture of 65 parts of 1,3-difluorobenzene, 130 parts of aluminium chloride and 195 parts of dichloromethane was added dropwise a solution of 95 parts of 1-acetyl-4-piperidine-carbonyl chloride in 65 parts of dichloromethane while cooling. Upon completion, stirring was continued for 3 hours at room temperature. The reaction mixture was poured into a mixture of crushed ice and hydrochloric acid. The product was extracted with dichloromethane. The organic layer was dried, filtered and evaporated, yielding 48 parts (36%) of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine as a residue (intermediate 1).

Reference： [1]Patent: WO2013/12723,2013,A1 .Location in patent: Page/Page column 65
[2]Patent: WO2004/35573,2004,A1 .Location in patent: Page 7
[3]Patent: EP2322520,2011,A1 .Location in patent: Page/Page column 16
[4]Patent: JP5714152,2015,B2 .Location in patent: Page/Page column 21
[5]Journal of Heterocyclic Chemistry,1993,vol. 30,p. 445 - 451
[6]Patent: US6348457,2002,B1
[7]Patent: US4804663,1989,A

2
[ 1197-22-4 ]
[ 59084-16-1 ]
[ 113558-94-4 ]

Yield	Reaction Conditions	Operation in experiment
82%	With aluminium trichloride In dichloromethane

Reference： [1]Oinuma, Hitoshi; Miyake, Kazutoshi; Yamanaka, Motosuke; Nomoto, Ken-Ichi; Katoh, Hiroshi; et al. [Journal of Medicinal Chemistry, 1990, vol. 33, # 3, p. 903 - 905]

3
[ 59084-16-1 ]
[ 541-73-1 ]
[ 84162-85-6 ]

Yield	Reaction Conditions	Operation in experiment
50%	With aluminum (III) chloride at 20 - 90℃; for 4.16667h;	32.D 1-[4-(2,4-Dichloro-benzoyl)-piperidin-1-yl]-ethanone Aluminium chloride (11, 24 g, 84 mmol) is added portionwise to 23 mL of dichlorobenzene (200 mmol). To this suspension 8 g of 1-acetylisonipecotoyl chloride (42 mmol) was added also portionwise. The mixture was stirred 10 minutes at room temperature and then at 90° C. for 4 hours until TLC indicated completion of the reaction that changed from a yellow/orange solution changed into dark orange upon heating. Water was added and the solution was extracted three times with dichloromethane. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel with hexane: ethyl acetate (1:0 to 0:1) to give 6.3 g (50%) of the product as an orange oil. MS (m/e): 300.2 (M+).
50%	With aluminum (III) chloride at 90℃; for 4h;	73.1 Step 1 1-[4-(2,4-Dichloro-benzoyl)-piperidin-1-yl]-ethanone Acetylisonipecotoyl chloride (8 g, 42 mmol) was solved in dichlorobenzene and aluminium chloride (11.2 gr, 894 mmol) was added portionwise. The mixture was refluxed at 90° C. for 4 h after complexion of the reaction. Ice/water was added to the mixture that was extracted with dichloromethane. After chromatography from heptane to EtOAc the product was obtained as a yellow oil (6.3 g, 50%). MS (m/e): 300.2 (M+H+)
	With aluminium trichloride for 2h; Heating; Yield given;

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2009/29977, 2009, A1 Location in patent: Page/Page column 41
[2]Current Patent Assignee: ROCHE HOLDING AG - US2007/197531, 2007, A1 Location in patent: Page/Page column 53
[3]Strupczewski, Joseph T.; Allen, Richard C.; Gardner, Beth Ann; Schmid, Blaine L.; Stache, Ulrich; et al. [Journal of Medicinal Chemistry, 1985, vol. 28, # 6, p. 761 - 769]

4
[ 25503-90-6 ]
[ 59084-16-1 ]

Yield	Reaction Conditions	Operation in experiment
96.7%	With thionyl chloride; In toluene; at 40℃; for 6h;	To the nozzle with a drying tube with a condenser, a thermometer and a mechanical stirrer in a 100 mL four-necked flask, add step (1), The resulting <strong>[25503-90-6]N-acetyl-4-piperidinecarboxylic acid</strong> (17.2 g, 0.10 mol) and 50 mL of toluene were heated to a solid solution to give a homogeneous solution, 15 mL of the acid chlorination reagent, thionyl chloride was added, heated to 40 C and the temperature was maintained for 6 h and the reaction solution was distilled off under reduced pressure to dryness to obtain a residue which was washed with petroleum ether to give 18.3 g of a white or pale yellow solid in a yield of 96.7%. The reaction process used in the N-acetyl-piperidine-carboxylic acid chloride with thionyl chloride reagent amount, Calculated molar ratio, i.e., N-acetyl-piperidine-carboxylic acid: thionyl chloride chlorinating agent is 1: 2.
89.0%	With thionyl chloride; at 20℃; for 2h;	To thionyl chloride (685 mL) was added the compound (85.6 g, 0.50 mol) obtained in Reference Example 10, and the mixture was stirred at room temperature for 2 hrs. The precipitated crystals were collected by filtration, washed with diisopropyl ether (250 mL*2) and dried under reduced pressure at 30C for 8 hrs. to give the title compound (84.4 g, yield:89.0%). 1H-NMR (300 MHz, CDCl3)delta: 1.70-1.90 (2H, m), 2.05-2.26 (2H, m), 2.26 (3H, s), 2.90-3.25 (4H,m), 3.95-4.30 (2H, br), exchange proton in the range of about 3.5-4.5 ppm (2H, br)
		B) 40 g of the acid obtained above were heated under reflux in 200 ml of sulfonyl chloride. After 15 minutes, a brown coloration occurred, and the solution was cooled and allowed to react at room temperature for a further 2 hours. The sulfonyl chloride was then removed by evaporation, and the brownish-red solid which remained was washed first with toluene and then with petroleum ether and dried under reduced pressure. 49 g of crude 1-acetylpiperdine-4-carbonyl chloride were obtained.

	With thionyl chloride;	This compound is converted into its chloride by dissolving 1063 g N-acetyl isonipecotic acid into 6000 g thionyl chloride at room temperature and letting the mixture aside for 24 hours. The mixture is then diluted with n-hexane. The chloride precipitates and is recovered. 1300 g of the acid chloride is obtained. Its melting point is 120.
	With thionyl chloride; for 4h;	To a stirred solution of SOCI2 (30 ml) was added 1- acetylpiperidin-4-carboxylic acid (4.38 g, 25.6 mmol) portionwise and stirred at room temperature for 4 hrs . The acid chloride precipitated out of the solution and was filtered off. The solid was washed with Et2O and dried in vacuum. l-Acetylpiperidin-4-carboxyl chloride (4.74 g, 25.0 mmol) was slowly added to a solution of AlCl3 (6.67 g, 50.0 mol) in brombenzene (20 ml). The reaction mixture was heated under reflux for 2 hrs, cooled to room temperature, and poured into crushed ice. The aqueous mixture was extracted with CH2Cl2, the organic layer washed with brine and dried over Na2SO4, filtered and evaporated in vacuo to leave an oil . The oil was separated with flash chromatography (CH2Cl2/Me0H, 9 : 1) to leave the product as a white solid (4.77 g, 61.6 %) .1H-NMR (300 MHz, CDCl3) :delta 7.76-7.72 (m, 2 H), 7.58-7.54 (m, 2 H), 4.52-4.47 (m, 1 H), 3.86-3.82 (m, 1 H), 3.42- 3.35 (m, 1 H), 3.21-3.12 (m, 1 H)7 2.80-2.72 (m, 1 H), 2.04 (s, 3 H), 1.85-1.55 (m, 4 H)
	With thionyl chloride; In Petroleum ether; for 0.5h;	To 1-acetylisonipecotic acid (41.74 g, 243.8 mmol) was added thionyl chloride (200 mL), and the resulting mixture was stirred for 30 minutes. The mixture was diluted with petroleum ether. The precipitated solid was collected and washed with petroleum ether to afford 1-acetylisonipecotoyl chloride. This was added to a stirring mixture of cumene (120 mL) and aluminium chloride (69.6 g, 522 mmol) and the resulting mixture was stirred at 110 C. for 1 hour. The mixture was poured into ice, and extracted twice with ethyl acetate. The organic layers were combined, washed with brine, a dried over magnesium sulfate, filtered, and concentrated under reduced pressure. To the residue was added concentrated hydrochloric acid (100 mL), and the mixture was refluxed for 12 hours. The mixture was cooled to room temperature and was washed twice with diethyl ether. The aqueous solution was made basic with 8N sodium hydroxide solution and then extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the title compound (23.5 g, yield 41%).m.p.: 55-57 C.1H-NMR(CDCl3) delta: 1.27 (6H, d, J=6.8 Hz), 1.57-2.70 (5H, m), 2.70-2.83 (2H, m),2.97 (1H, septet, J=6.8 Hz), 3.16-3.22 (2H, m), 3.34-3.46 (1H, m), 7.30-7.34 (2H, m), 7.87-7.91 (2H, m).
	With thionyl chloride; at 20℃; for 6h;Inert atmosphere;	A mixture of <strong>[25503-90-6]1-acetyl-piperidine-4-carboxylic acid</strong> (10.00 g, 57.24 mmol) and thionyl chloride (20.85 g, 171.73 mmol) is stirred at room temperature for 6h under nitrogen atmosphere. Thionyl chloride is removed under reduced pressure and the residue is co-distilled with dichloromethane (2 x 200 mL). This acid chloride is then added dropwise to a suspension of bromobenzene (27.24 g, 171.73 mmol) and anhydrous aluminum chloride (9.25 g, 68.69 mmol) in 1 ,2-dichloroethane (200 mL) at 0 C under nitrogen atmosphere. The resulting mixture is stirred at room temperature for 16h, quenched to ice and extracted with dichioromethane (2 x 200 mL). The organic layer is washed with water (2 x 200 mL), brine (200 mL), dried over anhydrous Na2S04 and evaporated under vacuum. The resulting black residue is taken up in 6M aqueous HCI (200 mL), refluxed for 12h and concentrated to half of its original volume. The aqueous part is basified with 10% sodium bicarbonate and extracted with dichioromethane (2 x 200 mL), washed with water (2 x 200 mL), brine (200 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The crude material is purified by column chromatography using silica gel (60- 120) and dichloromethane/methanol as gradient elution to afford (4-bromo- phenyl)-piperidin-4-yl-methanone as yellow gum;
	With thionyl chloride; at 20℃; for 4h;	1-acetyl piperidine-4-carboxylic acid (3.0 g, 0.018 mol) was added to thionyl chloride (10 mL, 0.143 mol) in small portions and stirred for 4 h at room temperature. The reaction was concentrated under vacuum and co- evaporated with toluene (2 x 200 mL). The residue was dissolved (sparingly soluble) in 1 ,2-dichloroethane and added to the stirred suspension of anhydrous aluminum chloride in benzene (20 mL). The resulting mixture was refluxed for 2 h, poured into crushed ice and extracted with chloroform (2 x 200 mL). The combined organic layer was washed with brine, dried over anhydrous Na2S04 and evaporated to get the brown gum. The obtained gum was refluxed for 6 h with 6 N hydrochloric acid (60 mL). The reaction was cooled to room temperature and washed with diethyl ether (100 mL). The aqueous part was rendered basic with 10% sodium hydroxide and extracted with diethyl ether (2 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2S0 and evaporated to dryness. The residue was purified by column chromatography using silica gel (60-120) and petrol ether/ethyl acetate as gradient elution to afford the title compound; yield: 1.5 g (45%); LCMS (Method B): 190.3 (M+H), Rt: 2.01 min, purity: 85.3%; 1H N R (400 MHz, DMSO-d6): delta 7.45-7.34 (m, 5H), 3.13 (s, 1 H), 2.83 (s, 1 H), 2.50-2.48 (m, 2H), 1.80-1.70 (m, 1H), 1.30-1.25 (m, 3H), 1.14-1.19 (m, 1 H).
	With thionyl chloride; N,N-dimethyl-formamide; In 1,2-dichloro-ethane; at 0 - 60℃; for 4h;	To a suspension of <strong>[25503-90-6]1-acetylpiperidine-4-carboxylic acid</strong> 9 (5.0 g, 33 mmol) in 30 mL of 1,2-dichloroethane was slowly added SOCl2 (5 mL, 76 mmol) at 0 C, followed by catalytic amount of DMF. The mixture was stirred at 60 C for 4 h and then evaporated under vacuum. The residue acyl chloride was dissolved in 25 mL of 1,2-dichloroethane.To a solution of 2,3-dihydrobenzo[b][1,4]dioxine (4.49 g, 33 mmol) in 15 mL of 1,2-dichloroethane was slowly added Aluminum chloride (6.67 g, 50 mmol) at 0 C. Then a solution of acyl chloride in 25 mL of 1,2-dichloroethane was added dropwise. The mixture was stirred at 65 C for 16 h. The solution was then cooled to room temperature and followed by poured into 100 mL of ice cold water. The water layer was washed with DCM (25 mL × 3).The combined layer was dried over anhydrous sodium sulfate and then filtered to remove the precipitate and concentrated in vacuo. The residue was purified by silica gel chromatography using DCM/MeOH (97/3, V/V)as the eluent to afford 10a (3.89g, 41% yield) as a yellow oil. 1H NMR (400 MHz, CD3OD): delta 7.43 ( dd, J = 8.4, 2.0 Hz, 1H), 739 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.42 (d, J = 13.6 Hz, 1H), 4.18 (m, 4H), 3.87 (d, J = 13.6 Hz, 1H), 3.49 (m, 1H), 3.23 (m, 1H), 2.76 (m, 1H), 2.02 (s, 3H), 1.77 (t, 2H), 1.54 (m, 2H). MS (ESI) m/z: [M+H]+ 290.53, [M+Na]+ 312.56.
	With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 40℃; for 3h;	5 ml (0.076 mol) of thionyl chloride and 30 ml of dichloromethane were stirred in a 10 ml round bottom flask,Was added 5.0 g (0.033 mol) of synthetic <strong>[25503-90-6]N-acetylpiperidine-4-carboxylic acid</strong>,After the addition of 1 drop of DMF, 40 reaction 3 hours. The solvent was distilled off under reduced pressure,A brown solid was obtained which was fractionated in 25 ml of 1,2-dichloroethane and placed in a constant pressure dropping funnel for use.6.67 g (0.05 mol) of aluminum trichloride, 4.49 g (0.033 mol) of benzo-1,4-dioxane was added to 100 ml of threeThe product was added with 1,2-dichloroethane (12.5 ml), and the acid chloride solution was added dropwise at 0 C, and the reaction was heated at 65 C for 16 hours.Let cool, pour into 100ml ice water, separate the organic phase, the water phase were washed twice with 25ml dichloromethane, combined organic phase. noSodium sulfate was dried. Column separation, dichloromethane-ethyl acetate 97: 3 (v / v) to give 3.89 g of a yellow oil, yield40.7%:
	With thionyl chloride; In 1,2-dichloro-ethane; at 40 - 50℃; for 2h;	<strong>[25503-90-6]N-acetylpiperidine-4-carboxylic acid</strong> (1.3 g, 7.6 mmol) and 15 mL of 1,2-dichloroethane, Add to a 100mL three-necked flask and control the temperature at 40-50 C. Thionyl chloride (1 mL, 14 mmol) diluted with 3 mL of solvent was slowly added dropwise.After continuing to stir at this temperature for 2 hours,Add fluorobenzene (0.72mL, 7.6mmol) to the reaction systemAnd aluminum trichloride (2.0 g, 15 mmol), refluxed for 4 hours, cooled to room temperature, added ice water, stirred well, and allowed to stand for separation.The organic layer was washed with 20 mL × 2 of water, and concentrated under reduced pressure to obtain a brown oil (N-acetyl-4- (p-fluorobenzoyl) piperidine). N-acetyl-4- (p-fluorobenzoyl) piperidine,10 mL of water and 10 mL of concentrated hydrochloric acid were added to a 50 mL single-necked flask and refluxed for 10 hours.It was left to cool, washed with 20 mL of dichloromethane, washed with a 5% NaOH solution of the aqueous layer to adjust pH = 8-9, and extracted with 20 mL of dichloromethane, and the organic phases were combined and dried over anhydrous MgSO4. It was filtered and concentrated to give a white solid, which was directly used for the next reaction.
	With thionyl chloride; In cyclohexane; at 50℃; for 1h;	To a 500mL three-necked bottle, add 17.1g (0.1mol) <strong>[25503-90-6]1-acetylpiperidine-4-carboxylic acid</strong>, 200mL cyclohexane,Add 14.28g (0.12mol) sulfoxide chloride with stirring,Slowly warm up to 50 for 1 hour,The dry solvent cyclohexane and the remaining sulfoxide chloride were concentrated under reduced pressure to obtain a slightly yellow viscous substance intermediate A1-5,That is, 1-acetylpiperidine-4-formyl chloride (theoretical yield: 0.1mol), then add 200mL of dichloromethane to dissolve, to obtain intermediate A1-5 solution without further separation,This solution directly proceeds to the reaction of step (6).

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 6609 - 6628
[2]Patent: CN104003929,2016,B .Location in patent: Paragraph 0035; 0036
[3]Patent: EP1359145,2003,A1 .Location in patent: Page/Page column 34-35
[4]Heterocyclic Communications,2009,vol. 15,p. 401 - 405
[5]Journal of Medicinal Chemistry,1985,vol. 28,p. 761 - 769
[6]Journal of Heterocyclic Chemistry,1993,vol. 30,p. 445 - 451
[7]Journal of Medicinal Chemistry,2003,vol. 46,p. 5512 - 5532
[8]Patent: US5324725,1994,A
[9]Patent: US4432984,1984,A
[10]Patent: WO2007/7072,2007,A1 .Location in patent: Page/Page column 17-18
[11]Patent: US7008950,2006,B1 .Location in patent: Page/Page column 42-43
[12]European Journal of Medicinal Chemistry,2014,vol. 71,p. 259 - 266
[13]Patent: WO2015/14442,2015,A1 .Location in patent: Page/Page column 50
[14]Patent: WO2015/18475,2015,A1 .Location in patent: Page/Page column 42
[15]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 5178 - 5181
[16]Organic Letters,2016,vol. 18,p. 5364 - 5367
[17]Patent: CN103570705,2017,B .Location in patent: Paragraph 0081; 0082; 0083; 0084
[18]Journal of the American Chemical Society,2017,vol. 139,p. 8267 - 8276
[19]Journal of Medicinal Chemistry,2019,vol. 62,p. 1932 - 1958
[20]Patent: CN110437136,2019,A .Location in patent: Paragraph 0033; 0058-0076
[21]Patent: CN111004213,2020,A .Location in patent: Paragraph 0077; 0094-0095

5
[ 2973-50-4 ]
[ 59084-16-1 ]
2-(1-acetyl-piperidin-4-yl)-1<i>H</i>-indole-3-carbonitrile [ No CAS ]

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 5189 - 5191

6
[ 59084-16-1 ]
[ 927-80-0 ]
[ 455264-56-9 ]

Yield	Reaction Conditions	Operation in experiment
67%	With triethylamine In tetrahydrofuran at 20℃; for 120h;

Reference： [1]Brand, Stephen; De Candole, Benjamin C.; Brown, Julien A. [Organic Letters, 2003, vol. 5, # 13, p. 2343 - 2346]

7
[ 462-06-6 ]
[ 59084-16-1 ]
[ 25519-77-1 ]

Yield	Reaction Conditions	Operation in experiment
6.4 g	With aluminium trichloride In 1,2-dichloro-ethane for 2h; Heating;
	With aluminum (III) chloride In 1,2-dichloro-ethane for 4h; Reflux;	8 4-(p-fluorobenzoyl)piperidine N-acetylpiperidine-4-carboxylic acid (1.3 g, 7.6 mmol) and 15 mL of 1,2-dichloroethane, Add to a 100mL three-necked flask and control the temperature at 40-50 ° C. Thionyl chloride (1 mL, 14 mmol) diluted with 3 mL of solvent was slowly added dropwise.After continuing to stir at this temperature for 2 hours,Add fluorobenzene (0.72mL, 7.6mmol) to the reaction systemAnd aluminum trichloride (2.0 g, 15 mmol), refluxed for 4 hours, cooled to room temperature, added ice water, stirred well, and allowed to stand for separation.The organic layer was washed with 20 mL × 2 of water, and concentrated under reduced pressure to obtain a brown oil (N-acetyl-4- (p-fluorobenzoyl) piperidine). N-acetyl-4- (p-fluorobenzoyl) piperidine,10 mL of water and 10 mL of concentrated hydrochloric acid were added to a 50 mL single-necked flask and refluxed for 10 hours.It was left to cool, washed with 20 mL of dichloromethane, washed with a 5% NaOH solution of the aqueous layer to adjust pH = 8-9, and extracted with 20 mL of dichloromethane, and the organic phases were combined and dried over anhydrous MgSO4. It was filtered and concentrated to give a white solid, which was directly used for the next reaction.

Reference： [1]Orjales, Aurelio; Mosquera, Ramón; Toledo, Antonio; Pumar, M. Carmen; García, Neftalí; Cortizo, Lourdes; Labeaga, Luis; Innerárity, Ana [Journal of Medicinal Chemistry, 2003, vol. 46, # 25, p. 5512 - 5532]
[2]Current Patent Assignee: SOUTHEAST UNIVERSITY - CN110437136, 2019, A Location in patent: Paragraph 0058-0060

8
[ 59084-16-1 ]
[ 108-90-7 ]
[ 59084-15-0 ]

Yield	Reaction Conditions	Operation in experiment
	With aluminium trichloride In 1,2-dichloro-ethane Heating;
	With aluminum (III) chloride In 1,2-dichloro-ethane for 4h; Reflux;	12 4-(p-chlorobenzoyl)piperidine N-acetylpiperidine-4-carboxylic acid (1.3 g, 7.6 mmol) and 15 mL of 1,2-dichloroethane,Add to a 100 mL three-necked flask, control the temperature at 40-50 ° C, and slowly add sulfoxide (1 mL, 14 mmol) diluted with 3 mL of solvent. After continuing to react at this temperature for 2 hours,Add chlorobenzene to the reaction system(0.72 mL, 7.6 mmol) and aluminum trichloride (2.0 g, 15 mmol), refluxed for 4 hours, cooled to room temperature, added ice water, stirred well, and allowed to stand to separate.The organic layer was washed with 20 mL × 2 of water. The organic layer was concentrated to give a brown oil (N-acetyl-4- (p-chlorobenzoyl) piperidine). N-acetyl-4- (p-chlorobenzoyl) piperidine,10 mL of water and 10 mL of concentrated hydrochloric acid were added to a 50 mL single-necked flask and refluxed for 10 hours.Leave to cool, wash with 20 mL x 2 of dichloromethane,The aqueous layer was adjusted with 5% NaOH solution to pH = 8-9, and 20 mL of dichloromethane was extracted.The organic phases were combined and dried over anhydrous MgSO4. Filtered and concentrated to give a white solid,Proceed directly to the next reaction.

Reference： [1]Orjales, Aurelio; Mosquera, Ramón; Toledo, Antonio; Pumar, M. Carmen; García, Neftalí; Cortizo, Lourdes; Labeaga, Luis; Innerárity, Ana [Journal of Medicinal Chemistry, 2003, vol. 46, # 25, p. 5512 - 5532]
[2]Current Patent Assignee: SOUTHEAST UNIVERSITY - CN110437136, 2019, A Location in patent: Paragraph 0070-0072

9
[ 59084-16-1 ]
[ 71-43-2 ]
[ 25519-79-3 ]

Yield	Reaction Conditions	Operation in experiment
78.5%	Stage #1: 1-acetylpiperidine-4-carbonyl chloride; benzene With aluminum (III) chloride at 70℃; for 10h; Stage #2: With hydrogenchloride In water	1.2 N-acetyl-4-benzoylpiperidine To a 250 mL four-necked flask equipped with a drying tube with a drying tube and a thermometer, the resulting N-acetyl-4-piperidinecarboxylic acid chloride (18.3 g, 0.097 mol) and 50 mL of benzene, Heating and dissolving the reaction solution into a homogeneous phase, adding 35g anhydrous aluminum trichloride, heating to 70 °C, reflux reaction 10h. The resulting reaction solution was cooled to room temperature and then poured into ice water of 30 mL of ice and 50 mL of concentrated hydrochloric acid. After the hydrolysis was sufficiently hydrolyzed, the upper layer was separated by a separatory funnel. The aqueous layer was extracted three times with 50 mL of toluene and the layers were combined and washed three times with saturated sodium chloride water. The solution was evaporated to dryness and allowed to stand overnight to give 17.5 g of N-acetyl-4-benzoylpiperidine. The yield was 78.5%; The amount of N-acetylpiperidinyl chloride, aluminum trichloride, benzene used in the above reaction process, calculated as the molar ratio,That is, N-acetyl piperidine formyl chloride: aluminum trichloride: benzene is 1: 2.5: 5;
	With aluminium trichloride In 1,2-dichloro-ethane for 2h; Heating;
	With aluminum (III) chloride In 1,2-dichloro-ethane for 2h; Reflux;	1-acetyl piperidine-4-carboxylic acid (3.0 g, 0.018 mol) was added to thionyl chloride (10 mL, 0.143 mol) in small portions and stirred for 4 h at room temperature. The reaction was concentrated under vacuum and co- evaporated with toluene (2 x 200 mL). The residue was dissolved (sparingly soluble) in 1 ,2-dichloroethane and added to the stirred suspension of anhydrous aluminum chloride in benzene (20 mL). The resulting mixture was refluxed for 2 h, poured into crushed ice and extracted with chloroform (2 x 200 mL). The combined organic layer was washed with brine, dried over anhydrous Na2S04 and evaporated to get the brown gum. The obtained gum was refluxed for 6 h with 6 N hydrochloric acid (60 mL). The reaction was cooled to room temperature and washed with diethyl ether (100 mL). The aqueous part was rendered basic with 10% sodium hydroxide and extracted with diethyl ether (2 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2S0 and evaporated to dryness. The residue was purified by column chromatography using silica gel (60-120) and petrol ether/ethyl acetate as gradient elution to afford the title compound; yield: 1.5 g (45%); LCMS (Method B): 190.3 (M+H), Rt: 2.01 min, purity: 85.3%; 1H N R (400 MHz, DMSO-d6): δ 7.45-7.34 (m, 5H), 3.13 (s, 1 H), 2.83 (s, 1 H), 2.50-2.48 (m, 2H), 1.80-1.70 (m, 1H), 1.30-1.25 (m, 3H), 1.14-1.19 (m, 1 H).

	With aluminum (III) chloride In 1,2-dichloro-ethane at 0 - 65℃; for 16h;	Step 4. Synthesis of 1-(4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carbonyl)piperidin-1-yl)ethanone (10a) General procedure: To a suspension of 1-acetylpiperidine-4-carboxylic acid 9 (5.0 g, 33 mmol) in 30 mL of 1,2-dichloroethane was slowly added SOCl2 (5 mL, 76 mmol) at 0 °C, followed by catalytic amount of DMF. The mixture was stirred at 60 °C for 4 h and then evaporated under vacuum. The residue acyl chloride was dissolved in 25 mL of 1,2-dichloroethane.To a solution of 2,3-dihydrobenzo[b][1,4]dioxine (4.49 g, 33 mmol) in 15 mL of 1,2-dichloroethane was slowly added Aluminum chloride (6.67 g, 50 mmol) at 0 °C. Then a solution of acyl chloride in 25 mL of 1,2-dichloroethane was added dropwise. The mixture was stirred at 65 °C for 16 h. The solution was then cooled to room temperature and followed by poured into 100 mL of ice cold water. The water layer was washed with DCM (25 mL × 3).The combined layer was dried over anhydrous sodium sulfate and then filtered to remove the precipitate and concentrated in vacuo. The residue was purified by silica gel chromatography using DCM/MeOH (97/3, V/V)as the eluent to afford 10a (3.89g, 41% yield) as a yellow oil.
	With aluminum (III) chloride In 1,2-dichloro-ethane at 90℃; Inert atmosphere;

Reference： [1]Current Patent Assignee: SHANGHAI INSTITUE OF TECHNOLOGY - CN104003929, 2016, B Location in patent: Paragraph 0035; 0038; 0039
[2]Orjales, Aurelio; Mosquera, Ramón; Toledo, Antonio; Pumar, M. Carmen; García, Neftalí; Cortizo, Lourdes; Labeaga, Luis; Innerárity, Ana [Journal of Medicinal Chemistry, 2003, vol. 46, # 25, p. 5512 - 5532]
[3]Current Patent Assignee: MERCK KGAA - WO2015/18475, 2015, A1 Location in patent: Page/Page column 42
[4]Li, Dongsheng; Gao, Nana; Zhu, Ningyu; Lin, Yuan; Li, Yan; Chen, Minghua; You, Xuefu; Lu, Yu; Wan, Kanglin; Jiang, Jian-Dong; Jiang, Wei; Si, Shuyi [Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 22, p. 5178 - 5181]
[5]Granchi, Carlotta; Lapillo, Margherita; Glasmacher, Sandra; Bononi, Giulia; Licari, Cristina; Poli, Giulio; El Boustani, Maguie; Caligiuri, Isabella; Rizzolio, Flavio; Gertsch, Jürg; Macchia, Marco; Minutolo, Filippo; Tuccinardi, Tiziano; Chicca, Andrea [Journal of Medicinal Chemistry, 2019, vol. 62, # 4, p. 1932 - 1958]

10
[ 769911-41-3 ]
[ 59084-16-1 ]
1-acetyl-N-(3,4-dichlorophenyl)-N-{2-[4-(4-fluorobenzyl)piperidin-1-yl]ethyl}piperidine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine In dichloromethane at 0℃; for 1h;

Reference： [1]Imamura, Shinichi; Nishikawa, Youichi; Ichikawa, Takashi; Hattori, Taeko; Matsushita, Yoshihiro; Hashiguchi, Shohei; Kanzaki, Naoyuki; Iizawa, Yuji; Baba, Masanori; Sugihara, Yoshihiro [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 2, p. 397 - 416]

11
3,4-dichloro-N-(4-chlorobutyl)aniline hydrochloride [ No CAS ]
[ 59084-16-1 ]
[ 333986-49-5 ]

Yield	Reaction Conditions	Operation in experiment
79%	With triethylamine In dichloromethane at 20℃;

Reference： [1]Imamura, Shinichi; Nishikawa, Youichi; Ichikawa, Takashi; Hattori, Taeko; Matsushita, Yoshihiro; Hashiguchi, Shohei; Kanzaki, Naoyuki; Iizawa, Yuji; Baba, Masanori; Sugihara, Yoshihiro [Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 2, p. 397 - 416]

12
(3-chloro-propyl)-(3,4-dichloro-phenyl)-amine [ No CAS ]
[ 59084-16-1 ]
[ 333986-30-4 ]

Yield	Reaction Conditions	Operation in experiment
84%	With triethylamine In dichloromethane at 0℃; for 4h;

Reference： [1]Imamura, Shinichi; Ichikawa, Takashi; Nishikawa, Youichi; Kanzaki, Naoyuki; Takashima, Katsunori; Niwa, Shinichi; Iizawa, Yuji; Baba, Masanori; Sugihara, Yoshihiro [Journal of Medicinal Chemistry, 2006, vol. 49, # 9, p. 2784 - 2793]

13
3-chloro-N-(3-chloropropyl)-4-methylaniline hydrochloride [ No CAS ]
[ 59084-16-1 ]
[ 333985-70-9 ]

Yield	Reaction Conditions	Operation in experiment
87.1%	In 1-methyl-pyrrolidin-2-one at 20 - 26℃; for 2h;	13 The compound (3.06 g, 12.0 mmol) obtained in Reference Example 12 and N-methylpyrrolidone (15 mL) were charged and, after dissolution, the compound (1.14 g, 6.00 mmol) obtained in Reference Example 11 was added 3 times every 30 min. (total 1.5 equivalents) to give a yellow suspension. The suspension was stirred at 20-26°C for 1 hr., and water (45 mL) was added at 10-20°C to once give a yellow solution, followed by precipitation of a small amount of an oil. A seed crystal was added, and the crystals were gradually precipitated. After stirring at 20-26°C for 2 hrs., the crystals were collected by filtration, washed with water (6.0 mL) and dried to give the title compound (3.88 g, yield 87.1%) as white crystals. 1H-NMR (300MHz, CDCl3) δ: 1.61-1.77(4H,m), 1.96-2.05(5H,m), 2.33-2.44(5H,m), 2.84-2.90(1H,m), 3.51-3.56(2H,t), 3.74-3.80(3H,m), 4.49-4.54(1H,d), 6.96-7.33(3H,m).
85%	In 1-methyl-pyrrolidin-2-one at 20℃; for 18h;

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1359145, 2003, A1 Location in patent: Page/Page column 35 - 36
[2]Imamura, Shinichi; Ichikawa, Takashi; Nishikawa, Youichi; Kanzaki, Naoyuki; Takashima, Katsunori; Niwa, Shinichi; Iizawa, Yuji; Baba, Masanori; Sugihara, Yoshihiro [Journal of Medicinal Chemistry, 2006, vol. 49, # 9, p. 2784 - 2793]

14
3-(aminomethyl)pyrazolo[1,5-a]quinazolin-5-(4H)-one trifluoroacetate [ No CAS ]
[ 59084-16-1 ]
1-acetyl-N-((5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl)piperidine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine In N,N-dimethyl-formamide	96 A mixture of Example 92B (0.1 g, 0.47 mmol) and l-acetylpiperidine-4-carbonyl chloride (0.089 g, 0.47 mmol) in DMF (1 mL) and pyridine (1 mL) was stirred overnight. The precipitated solids were filtered and washed with H2O and Et2O then dried well. 1H NMR (500 MHz, DMSO- d6) δ ppm 1.32 - 1.41 (m, 1 H) 1.46 - 1.55 (m, 1 H) 1.69 (t, J=14.19 Hz, 2 H) 1.98 (s, 3 H) 2.35 - 2.41 (m, 1 H) 2.52 - 2.60 (m, 1 H) 3.00 (dd, J=12.21, 10.68 Hz, 1 H) 3.80 (d,J=13.73 Hz, 1 H) 4.20 (d, J=5.80 Hz, 2 H) 4.33 (d, J=13.43 Hz, 1 H) 7.47 - 7.52 (m, 1 H) 7.70 (s, 1 H) 7.86 - 7.92 (m, 1 H) 8.06 (d, J=8.24 Hz, 1 H) 8.15 (dd, J=7.93, 1.22 Hz, 1 H) 8.24 (t, 7=5.49 Hz, 1 H) 11.97 (s, 1 H).

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2007/149907, 2007, A2 Location in patent: Page/Page column 66

15
[ 59084-16-1 ]
[ 160296-40-2 ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 5512 - 5532

16
[ 59084-16-1 ]
[ 193217-39-9 ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 5512 - 5532

17
[ 493-09-4 ]
[ 59084-16-1 ]
1-(4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carbonyl)piperidin-1-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With aluminum (III) chloride; In 1,2-dichloro-ethane; at 65℃; for 15h;	Example A14; a) Preparation of intermedjate.3.5; 1-acetyl- 4-piperidinecarbonyl chloride (0.1227 mol) was added slowly at 5C to amixture of aluminum chloride (0.2699 mol) in 1,2-dichloro- ethane (25ml). Themixture was heated to 65C. 2,3-dihydro-l,4-benzodioxin (0.18405 mol) was added.25 The mixture was stirred at 65C for 15 hours, cooled to room temperature, poured outinto water and extracted with DCM. The organic layer was separated, dried (MgSC^),filtered and the solvent was evaporated till dryness. The residue (44.44g) was purified by column chromatography over silica gel (15-35 jtm) (eluent: DCM/MeOH 97.5/2.5).The pure fractions were collected and the solvent was evaporated. Part (0.2g) of theresidue (27g, 76%) was crystallized from MEK and DIPE. The precipitate was filteredoff and dried, yielding intermediate 35, melting point 102C.
3.89 g	With aluminum (III) chloride; In 1,2-dichloro-ethane; at 0 - 65℃; for 16h;	General procedure: To a suspension of 1-acetylpiperidine-4-carboxylic acid 9 (5.0 g, 33 mmol) in 30 mL of 1,2-dichloroethane was slowly added SOCl2 (5 mL, 76 mmol) at 0 C, followed by catalytic amount of DMF. The mixture was stirred at 60 C for 4 h and then evaporated under vacuum. The residue acyl chloride was dissolved in 25 mL of 1,2-dichloroethane.To a solution of 2,3-dihydrobenzo[b][1,4]dioxine (4.49 g, 33 mmol) in 15 mL of 1,2-dichloroethane was slowly added Aluminum chloride (6.67 g, 50 mmol) at 0 C. Then a solution of acyl chloride in 25 mL of 1,2-dichloroethane was added dropwise. The mixture was stirred at 65 C for 16 h. The solution was then cooled to room temperature and followed by poured into 100 mL of ice cold water. The water layer was washed with DCM (25 mL × 3).The combined layer was dried over anhydrous sodium sulfate and then filtered to remove the precipitate and concentrated in vacuo. The residue was purified by silica gel chromatography using DCM/MeOH (97/3, V/V)as the eluent to afford 10a (3.89g, 41% yield) as a yellow oil. 1H NMR (400 MHz, CD3OD): delta 7.43 ( dd, J = 8.4, 2.0 Hz, 1H), 739 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.42 (d, J = 13.6 Hz, 1H), 4.18 (m, 4H), 3.87 (d, J = 13.6 Hz, 1H), 3.49 (m, 1H), 3.23 (m, 1H), 2.76 (m, 1H), 2.02 (s, 3H), 1.77 (t, 2H), 1.54 (m, 2H). MS (ESI) m/z: [M+H]+ 290.53, [M+Na]+ 312.56.
3.89 g	With aluminum (III) chloride; In 1,2-dichloro-ethane; at 0 - 65℃; for 16h;	5 ml (0.076 mol) of thionyl chloride and 30 ml of dichloromethane were stirred in a 10 ml round bottom flask,Was added 5.0 g (0.033 mol) of synthetic N-acetylpiperidine-4-carboxylic acid,After the addition of 1 drop of DMF, 40 reaction 3 hours. The solvent was distilled off under reduced pressure,A brown solid was obtained which was fractionated in 25 ml of 1,2-dichloroethane and placed in a constant pressure dropping funnel for use.6.67 g (0.05 mol) of aluminum trichloride, 4.49 g (0.033 mol) of <strong>[493-09-4]benzo-1,4-dioxane</strong> was added to 100 ml of threeThe product was added with 1,2-dichloroethane (12.5 ml), and the acid chloride solution was added dropwise at 0 C, and the reaction was heated at 65 C for 16 hours.Let cool, pour into 100ml ice water, separate the organic phase, the water phase were washed twice with 25ml dichloromethane, combined organic phase. noSodium sulfate was dried. Column separation, dichloromethane-ethyl acetate 97: 3 (v / v) to give 3.89 g of a yellow oil, yield40.7%:

Reference： [1]Patent: WO2005/54201,2005,A1 .Location in patent: Page/Page column 42-43
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 1932 - 1958
[3]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 5178 - 5181
[4]Patent: CN103570705,2017,B .Location in patent: Paragraph 0081; 0082; 0083; 0084

18
[ 908094-01-9 ]
[ 59084-16-1 ]
C₉H₁₃N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In diethyl ether at 0 - 20℃;	36 Intermediate 37 was synthesized by Arndt-Eistert homologation of the acid chloride using the procedure described for 1-Chloro-3-(thiophen-2-yl)propan-2-one (intermediate 15). Reacting acid chloride (1.35 g, 7.1 mmol) with 40 ml of an ethereal diazomethane solution followed by passing HCl gas. The crude material was used as such in the next step. Synthesis of intermediate 38 was done using the procedure described above for the synthesis of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate was followed, reacting 1-chloro-3-(thiophen-2-yl)propan-2-one (1.16 g, 5.73 mmol) with acetic acid (0.66 mL, 0.69 g, 12 mmol) and triethylamine (1.60 mL, 1.16 g, 11.5 mmol). The crude intermediate 40 was used as such in the next step. Compounds 36 and 37 was synthesized using the procedure described above for the synthesis and purification of example 7, reacting 6,7,8,9-tetrahydrobenzo[g]indoline-2,3-dione (0.112 g, 0.557 mmol) with acetic acid 2-(1-acetyl-piperidin-4-yl)-2-oxo-ethyl ester (intermediate 40, 0.165 g, 0.724 mmol). Two products were isolated as white solids. Compound 36 (18.1 mg, 10% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 1.72-1.89 (m, 4H) 1.96-2.19 (m, 4H) 2.69-2.87 (m, 2H) 3.06-3.16 (m, 2H) 3.19 (t, J=5.81 Hz, 2H) 3.38-3.50 (m, 2H) 3.52-3.67 (m, 1H) 7.07 (d, J=8.84 Hz, 1H) 8.28 (br s, 1H) 8.54 (br s, 1H) 9.17 (d, J=8.59 Hz, 1H); Compound 37 (10 mg, 5% yield): 1H NMR (500 MHz, DMSO-D6) δ ppm 1.65-1.73 (m, 1H) 1.77-1.99 (m, 7H) 2.06 (s, 3H) 2.77 (t, J=11.44 Hz, 1H) 2.84 (t, J=6.10 Hz, 2H) 3.15-3.30 (m, 3H) 3.54 (t, J=11.14 Hz, 1H) 3.98 (d, J=13.73 Hz, 1H) 4.51 (d, J=13.73 Hz, 1H) 7.26 (d, J=8.85 Hz, 1H) 8.31 (d, J=8.85 Hz, 1H).

Reference： [1]Current Patent Assignee: PFIZER INC - US2005/101569, 2005, A1 Location in patent: Page/Page column 36-37

19
[ 98-82-8 ]
[ 59084-16-1 ]
[ 1267998-61-7 ]

Yield	Reaction Conditions	Operation in experiment
57%	With aluminum (III) chloride In 1,2-dichloro-ethane at 90℃; Inert atmosphere;
	at 110℃; for 1h;	20 To 1-acetylisonipecotic acid (41.74 g, 243.8 mmol) was added thionyl chloride (200 mL), and the resulting mixture was stirred for 30 minutes. The mixture was diluted with petroleum ether. The precipitated solid was collected and washed with petroleum ether to afford 1-acetylisonipecotoyl chloride. This was added to a stirring mixture of cumene (120 mL) and aluminium chloride (69.6 g, 522 mmol) and the resulting mixture was stirred at 110° C. for 1 hour. The mixture was poured into ice, and extracted twice with ethyl acetate. The organic layers were combined, washed with brine, a dried over magnesium sulfate, filtered, and concentrated under reduced pressure. To the residue was added concentrated hydrochloric acid (100 mL), and the mixture was refluxed for 12 hours. The mixture was cooled to room temperature and was washed twice with diethyl ether. The aqueous solution was made basic with 8N sodium hydroxide solution and then extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the title compound (23.5 g, yield 41%).m.p.: 55-57° C.1H-NMR(CDCl3) δ: 1.27 (6H, d, J=6.8 Hz), 1.57-2.70 (5H, m), 2.70-2.83 (2H, m),2.97 (1H, septet, J=6.8 Hz), 3.16-3.22 (2H, m), 3.34-3.46 (1H, m), 7.30-7.34 (2H, m), 7.87-7.91 (2H, m).

Reference： [1]Granchi, Carlotta; Lapillo, Margherita; Glasmacher, Sandra; Bononi, Giulia; Licari, Cristina; Poli, Giulio; El Boustani, Maguie; Caligiuri, Isabella; Rizzolio, Flavio; Gertsch, Jürg; Macchia, Marco; Minutolo, Filippo; Tuccinardi, Tiziano; Chicca, Andrea [Journal of Medicinal Chemistry, 2019, vol. 62, # 4, p. 1932 - 1958]
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US7008950, 2006, B1 Location in patent: Page/Page column 42-43

20
[ 333985-68-5 ]
[ 59084-16-1 ]
[ 333985-70-9 ]

Yield	Reaction Conditions	Operation in experiment
88%	In dichloromethane at 20℃; Cooling with ice;	4.1.10. 1-Acetyl- N-(3,4-disubstitutedphenyl)- N-(3-chloropropyl)-piperidine-4-carboxamide (12a-c): general grocedure General procedure: To an ice-cooled stirred suspension of anilines 11a-c(1.00 mmol) in DCM (3.00 mL) was added Et3N (0.40 mL,3.00 mmol) followed by 1-acetylpiperidine-4-carbonyl chloride(0.23 g, 1.20 mmol), and the mixture was stirred at room temperature for 5 h. Then it was poured to a saturated solution of sodiumbicarbonate (10.00 mL). The residue was extracted by EtOAc(20.00 mL 3), the organic layer was combined, then washed withwater (15.00 mL 3) and brine (10.00 mL), dried (MgSO4), filteredand concentrated in vacuo. The residue was purified by columnchromatography on silica gel to afford the title compound.4.1.10.1. 1-Acetyl- N-(3-chloro-4-methylphenyl)- N-(3-chloropropyl)piperidine-4-carboxamide (12a). White solid (88%), mp:112-114 C. 1H NMR (CDCl3, 500 MHz) d: 7.30 (d, J = 7.7 Hz, 1H),7.16 (d, J = 2.2 Hz, 1H), 6.98 (m, 1H), 4.53 (m, 1H), 3.77 (t,J = 7.1 Hz, 2H), 3.65-3.85 (m, 1H), 3.53 (t, J = 6.6 Hz, 2H), 2.76-2.97 (m, 1H), 2.43 (s, 3H), 2.26-2.49 (m, 2H), 2.03 (s, 3H), 1.52-2.12 (m, 6H). ESI-MS m/z: 372 [M+H]+.
70%	With triethylamine In dichloromethane for 1h; Cooling with ice;	1.2 Step 2: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-chloropropyl)-4-piperidinylcarboxamide The above prepared compound 1 (2.18 g, 10 mmol) was dissolved in dichloromethane (50 mL), and triethylamine (5.53 mL, 40 mmol) and 1-acetyl-4-piperidylformyl chloride (5.69 g, 30 mmol) were sequently added into the solution under ice cooling. The mixture was stirred for 1 hour under the same temperature, added with a saturated sodium bicarbonate solution (40 mL) under ice cooling, and diluted with dichloromethane (50 mL). The organic phase was separated, dried with sodium sulfate and concentrated. The concentrate was separated through column chromatography (dichloromethane/ethyl acetate=1/1, v/v) to obtain compound 2 as light brown oil (2.6 g, yield: 70%). 1HNMR (CDCl3, 300 MHz) δ: 7.33-7.30 (d, 1H, J=8.1 Hz), 7.18 (d, 1H, J=2.1 Hz), 6.99-6.96 (dd, 1H, J=1.8 Hz, 6.0 Hz), 4.53-4.50 (m, 1H), 3.79-3.74 (t, 2H, J=7.2 Hz), 3.55-3.51 (t, 2H, J=6.3 Hz), 2.85 (br-s, 1H), 2.43 (s, 3H), 2.41-2.34 (m, 2H), 2.05 (s, 3H), 2.00 (m, 3H), 1.84-1.54 (m, 4H).
70%	With triethylamine In dichloromethane at 20℃; for 1h; Cooling with ice;	1.2 Step 2:1 - acetyl - N - (3 - chloro -4 - methyl phenyl) - N - (3 - chloro-propyl) -4 - piperidine carboxamide The above preparation of compound 1 (2.18 g, 10 mmol) dissolved in dichloromethane (50 ml), and in a cold and it in turn is added to this solution triethylamine (5.53 ml, 40 mmol) and 1 - acetyl -4 - piperidine chloride (5.69 g, 30 mmol). At the same temperature under stirring the mixture to 1 hour. In a cold saturated aqueous solution of sodium bicarbonate was added under (40 ml), and dichloromethane is used for dilution (50 ml), the organic phase separated, dried sodium sulfate, concentrated. Concentrate the chromatographic separation by column chromatography (dichloromethane/ethyl acetate=1/1, v/v), to obtain the product 2 as a light brown oil (2.6 g, yield 70%).

With triethylamine In dichloromethane at 0℃; for 5h;

2.2; 5 A solution of (3-chloro-4-methyl-phenyl) -(3-chloro-propyl)-amine (20, 3.20 g, 14.70 mmol) in CH2Cl2 (100 mL) was cooled to 0° C. After the mixture was treated with triethylamine (4.9 mL, 35.28 mmol)and 1-acetyl-piperidine-4-carbonyl chloride (5.57 g, 29.40 mmol), it was allowed to stir for 5 h at 0 °C. Saturated NaHC03 was added to the mixure and the mixture was stirred for 20 min. The solvent was evaporated and the mixture was extracted with EtOAc. The organic layer was washed with 2N HCI and brine, dried (MgS04) and purified by flash column chromatography on silica gel (5% MeOH/EtOAc) to afford 18: ¹H NMR (CHC13) No. 1.55-1.8 (br, 4H), 2.0 (m, 3H), 2.05 (s, 3H), 2.3-2.4 (m, 2H), 2.45 (s, 3H), 3.52 (t, 2H), 3.3 (t, 2H), 6.97 (dd, 1H), 7.18 (t, 1H), 7.32 (d, 1H) ; ¹3C NMR (CHC13) 8 20.19,21.68, 28.94,31.17, 39.64, 42.64, 48.03, 126.63, 128.79, 132.47, 135.79, 137.12,141.27,169.27,174.58; ms (ES+) m/z 370 (M + H).

Reference： [1]Hu, Suwen; Wang, Zhilong; Hou, Tingjun; Ma, Xiaodong; Li, Jing; Liu, Tao; Xie, Xin; Hu, Yongzhou [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 5, p. 1157 - 1168]
[2]Current Patent Assignee: CHINESE ACADEMY OF SCIENCES; SHANGHAI TARGET DRUG; Shanghai Institute of Materia Medica (in: CAS) - US2011/251192, 2011, A1 Location in patent: Page/Page column 5
[3]Current Patent Assignee: Shanghai Institute of Materia Medica (in: CAS); CHINESE ACADEMY OF SCIENCES - CN106977511, 2017, A Location in patent: Paragraph 0077; 0080; 0081
[4]Current Patent Assignee: ROCHE HOLDING AG - WO2005/121145, 2005, A2 Location in patent: Page/Page column 88-89; 129

21
[ 59084-16-1 ]
2-amino-5-chloro-thiazole hydrochloride [ No CAS ]
[ 872002-06-7 ]

Yield	Reaction Conditions	Operation in experiment
26%	With triethylamine In dichloromethane at 20℃; for 12h;	38.1 To a solution of 5-chloro-thiazol-2-ylamine hydrochloride ( 115, 216 mg, 1.26 mmol) in DCM (3 mL) was added 1-acetyl-piperidine-4-carbonyl chloride (43, 282 mg, 1.49 mmol) and TEA (0.41 mL, 2.92 mmol ). The mixture was stirred for 12 h at RT. The reaction was quenched with water and the mixture was extracted with DCM. The organic layer was dried (Na2SO4), concentrated and purified by Si02 chromatography on (100% EtOAc) to afford 93 mg (26%) of 114: ¹H NMR (CDC13, 1 H not observed) 8 1.66- 2.04 (m, 4H), 2.12 (s, 3H), 2.54-2.71 (m, 1H), 2.72-2.84 (m, 1H), 3.10-3.25 (m, 1H), 3.85-3.99 (m, 1H), 4.54-4.65 (m, 1H), 7.23 (s, 1H).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2005/121145, 2005, A2 Location in patent: Page/Page column 167-168

22
C₂₅H₃₄ClN₅O [ No CAS ]
[ 59084-16-1 ]
1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3-[5-(4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2,2-dimethyl-propyl}-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	With triethylamine In dichloromethane	26.4 1-Acetyl-piperidine-4-carbonyl chloride (24 mg, 0.13 mmol) and TEA (0.02 mL, 0.14 mmol ) were added to a solution of 90 (25 mg, 0.054 mmol) in DCM (2 mL). The resulting solution was stirred overnight. The mixture was diluted with water and extracted with DCM. The combined DCM extracts were dried (Na2S04) and concentrated. The crude product was purified by Si02 column chromatography eluting with a CH2Cl2: MeOH: NH40H gradient (98: 1.4:0.14 to 93: 6:0.6 over 50 min. ) to afford 11-354 (9 mg, 27%) : (at)H NMR (DMSO-d6) No. 0.75 (s, 6H), 1.2-1.6 (m, 4H), 1.95 (s, 3H), 2.1 (s, 2H), 2.2-2.5 (m, 16H), 2.65-2.85 (m, 4H), 3.25-3.35 (m, 1H), 3.6-3.8 (m, 4H), 4.2- 4.3 (m, 1H), 7.25-7.5 (m, 3H), 8.95 (s, IH); ms (ES+) m/z 609 (M + H).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2005/121145, 2005, A2 Location in patent: Page/Page column 155-157

23
C₂₅H₃₂ClN₃O₂ [ No CAS ]
[ 59084-16-1 ]
1-acetyl-piperidine-4-carboxylic acid (3-chloro-4-methyl-phenyl)-{3-[5-(2,6-dimethyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-hydroxy-propyl}-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With pyridine In 1,2-dichloro-ethane at 50℃;	35.3 To a solution of 106 (0.13 g, 0.29 mmol) in DCE (5 mL) were added 1- acetyl-piperidine-4-carbonyl chloride (0.16 g, 0.82 mmol) and pyridine (0.94 mL, 1.17 mL). The solution was heated at 50 °C overnight. The mixture was cooled, diluted with DCM and washed with saturated NaHC03. The organic layer was dried (Na2SO4), filtered and evaporated. The crude product was purified by Si02 column chromatography eluting with CH2Cl2:MeOH:NH4OH (150:10:1) to afford 0.12 g (68 %) of 11-189: mp 107.9-109.8 °C; ms (ES+) m/z 595 (M + H).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2005/121145, 2005, A2 Location in patent: Page/Page column 164-165

24
[ 872002-00-1 ]
[ 59084-16-1 ]
[ 872002-01-2 ]

Yield	Reaction Conditions	Operation in experiment
57%	With triethylamine In dichloromethane at 0 - 40℃;	22.2 step 2-; To a solution of 100 (1.3 g, 6.14 mmol) in DCM (30 mL) were added 1-acetyl-piperidine-4-carbonyl chloride (3.49 g, 18.42 mmol) and TEA (3 mL, 22.09 mmol) at 0° C. After 20 min the solution was heated at 40° C. overnight. The mixture was diluted with DCM and washed sequentially with H2O, 2N HCl, saturated NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and evaporated. The crude product was purified by SiO2 column chromatography eluting with 5% MeOH/EtOAc to afford 1.28 g (57%) of 101: 1H NMR (CDCl3) δ 1.6-1.85 (m, 4H), 2.05 (s, 3H), 2.45 (s, 3H), 2.68 (t, 2H), 2.85 (t, 1H), 3.28 (d, 1H), 3.85-3.95 (m. 2H), 4.5 (d, 1H), 6.98 (dd, 1H), 7.2 (d, 1H), 7.33 (d, 1H).
	With triethylamine In dichloromethane at 0 - 40℃;	36.2 To a solution of 107 (1.3 g, 6.14 mmol) in DCM (30 mL) were added 1- acetyl-piperidine-4-carbonyl chloride (3.49 g, 18.42 mmol) and TEA (3 mL, 22.09 mmol) at 0° C. After 20 min the solution was heated at 40 °C overnight. The mixture was diluted with DCM and washed sequentially with HzO, 2N HCI, saturated NaHC03 and brine. The organic layer was dried (Na2S04), filtered and evaporated. The crude product was purified by Si02 column chromatography eluting with 5% MeOH/EtOAc to afford 1.28 g 957 %) of 108: ¹H NMR (CDC13) 8 1.6-1.85 (m, 4H), 2.05 (s, 3H), 2.45 (s, 3H), 2.68 (t, 2H), 2.85 (t, 1H), 3.28 (d, 1H), 3.85-3.95 (m. 2H), 4.5 (d, 1H), 6.98 (dd, 1H), 7.2 (d, 1H), 7.33 (d, 1H).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2007/191335, 2007, A1 Location in patent: Page/Page column 41
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2005/121145, 2005, A2 Location in patent: Page/Page column 165-166

25
[ 876319-03-8 ]
[ 59084-16-1 ]
1-acetyl-N-(3-(N-(4-(benzofuran-2-yl)thiazol-2-yl)thiophene-2-carboxamido)propyl)piperidine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In chloroform at 20℃;	20 A mixture of the amine prepared above (77 mg, 0.2 mmol) and N,N-diisopropylethylamine (139 μL, 0.8 mmol) was dissolved in chloroform (2 mL), and a portion of the solution (200 μL, 0.02 mmol) was added to a solution of 1-acetyl-isonipecotoyl chloride (7.6 mg, 0.04 mmol) in chloroform (200 μL). The reaction mixture was maintained at room temperature overnight.). The reaction mixture was maintained at room temperature overnight, then concentrated in vacuo. The resulting residue was dissolved in DMSO (200 μL) and subjected to HPLC purification (Method Z) to provide the title compound (4.5 mg) as a yellowish solid. LC/MS (ESI) m/z 537.1 [M+H]. HPLC retention time (Method C)=3.44 min.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2006/52416, 2006, A1 Location in patent: Page/Page column 27

26
[ 383865-57-4 ]
1-acetyl-piperidine-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide [ No CAS ]
[ 59084-16-1 ]

Yield	Reaction Conditions	Operation in experiment
22%		1-Acetyl-piperidine-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide Using <strong>[383865-57-4]2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol</strong> and 1 -acetyl-piperidine-4-carbonyl chloride the title compound was obtained as a white solid (22%), MS: m/e=41 9(M+H+).

Reference： [1]Patent: US2002/45615,2002,A1

27
[ 333795-08-7 ]
[ 59084-16-1 ]
[ 333995-93-0 ]

Yield	Reaction Conditions	Operation in experiment
39%	With hydrogenchloride; sodium hydrogencarbonate; triethylamine In ethyl acetate	1-Acetyl-N-[3-(4-benzyl-1-piperidinyl)propyl]-N-(3-pyridinyl)-4-piperidinecarboxamide Hydrochloride 1-Acetyl-N-[3-(4-benzyl-1-piperidinyl)propyl]-N-(3-pyridinyl)-4-piperidinecarboxamide Hydrochloride To a solution of N-[3-(4-Benzyl-1-piperidinyl)propyl]-3-pyridinamine (400 mg) in 6 ml of tetrahyfrofuran, triethylamine (0.719 ml) and 1-acetyl-4-piperidinecarbonyl chloride (180 mg) were added at 0° C., and the mixture was stirred for 2 h at 0° C. AcOEt (15 ml) and aq. NaHCO3 (15 ml) were added and the organic layer was separated. The aqueous layer was extracted with AcOEt (10 ml) twice. The combined AcOEt layer was washed with aq. NaHCO3 (10 ml) twice and brine (10 ml), dried over anhydrous MgSO4. After concentration, the residue was purified on Al2O3 column chromatography (hexane-AcOEt 1:1). After evaporation, to the residue 4N HCl in AcOEt (1.0 ml) was added and the resulting precipitate was collcted by filtration to give the title compound (251 mg, yield 39.0%). Free base: 1H NMR (CDCl3) δ 1.25 (2H, d, J=4.0 Hz, 11.6 Hz), 1.43-1.86 (11H, m), 2.04 (3H, s), 2.20-2.40 (4H, m), 2.50 (2H, d, J=6.6 Hz), 2.80 (3H, m), 3.66-3.79 (3H, m), 4.51 (1H, m), 7.10-7.57 (7H, m), 8.49 (1H, m), 8.65 (1H, m).