Name: 5382-16-1|4-Piperidinol|98%
Brand: Ambeed
SKU: A100690
Price: 9.0 USD
Availability: InStock
Rating: 96 (40 reviews)

1
[ 5382-16-1 ]
[ 445-28-3 ]
[ 131269-81-3 ]

Reference： [1]Archiv der Pharmazie,1990,vol. 323,p. 889 - 893

2
[ 5382-16-1 ]
[ 68077-26-9 ]
[ 75001-74-0 ]

Reference： [1]Journal of Medicinal Chemistry,1980,vol. 23,p. 1358 - 1363

3
[ 5382-16-1 ]
[ 82419-35-0 ]
[ 82419-37-2 ]

Yield	Reaction Conditions	Operation in experiment
	In water; dimethyl sulfoxide;	EXAMPLE 4 140 mg of <strong>[82419-35-0]9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid</strong> and 404 mg of 4-hydroxypiperidine were added to 2 ml of dimethylsulfoxide. The mixture was stirred at a temperature of from about 100 to 110 C. (bath temperature) for 5.5 hours and the reaction mixture was concentrated to dryness in vacuo. Water was added to the residue and the mixture was neutralized with diluted hydrochloric acid to yield precipitate. The precipitate was collected by filtration, washed with water, and then recrystallized from ethanol to provide 66 mg of 9-fluoro-10-(4-hydroxy-1-piperidinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid with m.p. 220-240 C. (with decomposition). Analysis for C18 H19 FN2 O5; Calculated: C 59.66, H 5.29, N 7.73; Found: C 59.24, H 5.26, N 7.65.

Reference： [1]Chemical and Pharmaceutical Bulletin,1984,vol. 32,p. 4907 - 4913
[2]Patent: US4382892,1983,A

4
[ 5382-16-1 ]
[ 350-46-9 ]
[ 79421-45-7 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 1.0h;	Reference Example 5 Synthesis of Compound 12 [Show Image] Compound 11 (2.12 g, 15.0 mmol) and Compound 8 (1.82 g, 18.0 mmol) were dissolved in DMF (15 ml), potassium carbonate (2.52 g, 18.0 mmol) was added, and the mixture was stirred at 85C for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, followed by extraction with chloroform. After dried with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-acetonitrile) to obtain Compound 12 (3.10 g, yield 93%). mp 115.6-117C 1H-NMR (CDCl3 / TMS) deltappm: 1.62-1.74 (m, 2H), 1.99-2.02 (m, 2H), 2.87-2.95 (m, 2H), 3.47-3.54 (m, 2H), 3.82-3.88 (m, 1H), 6.85 (d, J = 8.7Hz, 2H), 7.19 (d, J = 8.7Hz, 2H).
92%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃;	Step: 3A-1Synthesis of l-(4-Nitro-phen -piperidin-4-ol.Procedure:K2C03 (2.44g, 0.0177mol) followed by l-Fluoro-4-nitro-benzene (lg, 0.00708mol) was added to a stirred solution of Piperidin-4-ol (0.86g, 0.00850mol) in DMF (5ml) and stirred at RT. The resulting reaction mixture was heated at 60C. The reaction was monitored by the TLC (50% EtOAc: hexane). The reaction mixture was cooled to RT, and ice was added into it to precipitate a solid which was collected to afford 1.45g (92% yield) of l-(4- Nitro-phenyl)-piperidin-4-ol.
86.14%	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 5.0h;	Weigh the compound 18 (10.00 g, 70.87 mmol) in a reaction flask,Piperidinol 26 (7.87 g, 77.96 mmol) was added sequentially,Potassium carbonate (11.74 g, 85.04 mmol),85 mL of DMF,70 heating and stirring,5h, stop reaction; filter,Filter insoluble solids,And rinsed with a small amount of DMF,The filtrate was poured into 650 mL of water,Static precipitation, solidification,The filter cake was dried at 60 C under vacuum for 14.56 gOrange solid 33, the yield was 86.14%.

84.74%	With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 1.0h;	To a stirred solution of 135 1-fluoro-4-nitrobenzene (3 g, 21.27 mmol, 1 eq) and 452 piperidin-4-ol (3.2 g, 31.91 mmol, 1.5 eq) in 47 DMF (20 mL) was added 64 K2CO3 (3.8 g, 27.65 mmol, 1.3 eq). Reaction mixture was stirred at 85 C. for 1 hr. Progress of reaction was monitored by LCMS. After consumption of starting material, reaction mixture was poured on ice cold water and precipitated 453 compound was filtered off and dried under vacuum. Solid was washed with diethyl ether and pentane to obtain 4 g (84.74%) of 1-(4-nitrophenyl)piperidin-4-ol. (0515) LCMS: 223 [M+1]+
78%	With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 1.0h;	To a solution of 14.1g (0.10mol) of 4-fluoronitrobenzene in 200mL of N, N-dimethylformamide were added 20.73 (0.15mol) of potassium carbonate and 10.1g (0.10mol) of 4-hydroxypiperidine and the mixture was stirred for 1 hour at 140C. The reaction mixture was cooled to room temperature and the mixture was treated with chloroform, then insoluble substances were removed off by filtration. The filtrate was condensed and the residue was recrystallized from ethanol to give 17. 27g (78%) of the title compound.
71%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 105℃; for 48.0h;	The 1-(4-Amino-phenyl)-piperidin-4-ol is prepared from p-fluoronitrobenzene by using the following multiple step procedure: Step 1: 1-(4-Nitro-phenyl)-piperidin-4-ol.; A 100 mL round bottom flask was dried in an oven overnight and cooled to room temperature under Ar(g). The flask was charged with fluoronitrobenzene (0.500 mL, 4.71 mmol), Piperidin-4-ol (0.619 g, 2.30 mmol) and dioxane (9.0 mL). To the resulting solution, diisopropyl ethyl amine (0.463 mL, 6.12 mmol) was added dropwise, and the reaction was allowed to stir at 105 C. for 48 h. The mixture was extracted with EtOAc (3×50 mL), and brine (2×50 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude mixture was then purified over silica (10% MeOH/90% CHCl3) affording a yellow solid (0.742 g, 3.34 mmol, 71% yield).
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	Example 7 1-(4-(4-(1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperidin-4-ol A mixture of 1-fluoro-4-nitrobenzene (0.588 mL, 5.55 mmol), 4-hydroxypiperidine (0.560 g, 5.54 mmol) and K2CO3 (1.50 g, 10.9 mmol) in dimethylformamide (DMF) (10 mL) was stirred at room temperature overnight. Water was then added to induce precipitation. The yellowish solid was collected by filtration (0.90 g).
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	A mixture of l-fluoro-4-nitrobenzene (0.588 mL, 5.55 mmol), 4-hydroxypiperidine (0.560 g, 5.54 mmol) and K2CO3 (1.50 g, 10.9 mmol) in DMF (10 mL) was stirred at room temperature overnight. Water was added to induce precipitation. The yellowish solid was collected by filtration (0.90 g).
	With potassium carbonate; In water; dimethyl sulfoxide; at 100℃; for 4.0h;	To a mixture of 1-fluoro-4-nitrobenzene (2.82 g, 20 mmol) and K2CO3 (6.92 g, 50 mmol) in dimethyl sulfoxide (20 mL) was added piperidin-4-ol (2.22 g, 22 mmol) and the reaction was heated to 100 C. for 4 hours. This solution was poured into 200 ml of water and extracted with ethyl acetate (30 mL*3). The organic phase was combined and washed with saturated brine and dried over anhydrous sodium sulfate.
1.025 g	With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 8.0h;Reflux;	A solution of 1-fluoro-4-nitrobenzene (0.658 g, 4.66 mmol), 4-hydroxypiperidine (0.590 g, 5.81 mmol) and DIEA (1.24 mL, 7.12 mmol) in anhyd CH3CN (7 mL) was refluxed for 8 hours. The volatiles were removed in vacuo and the residue was suspended in water (15 mL) to give a bright yellow suspension. The solid was collected by vacuum filtration, washed with water and dried in vacuo to give 1.025 g 1-(4-nitro-phenyl)-piperidin-4-ol. MS (MH+): 223
	With piperidine; potassium carbonate; In dimethyl sulfoxide; at 120℃; for 4.0h;	Piperidine in dimethyl sulfoxide (3 mL) -4-ol (1.4 mmol), 1- fluoro-4-nitrobenzene (1.6 mmol) and potassium carbonate (2.8 mmol) the mixture was heated for 4 hours at 120 . After cooling, then the mixture is poured in water, which is generatedThe solid was filtered and was washed with water and dried to produce a B1.
	With potassium carbonate; In N,N-dimethyl-formamide; at 40℃;	General procedure: Substituted amine (1.2 equiv) was added to a mixture of 4-fluoronitrobenzene (1 equiv) and K2CO3 (2.0 equiv) in DMF (7mL/g). The reaction mixture was stirred at 40C and followed by TLC. After completion of the reaction, the mixture was poured into stirring ice-water. The resulting precipitate was filtered and dried to obtain compounds 11 as a yellow solid.

Reference： [1]Patent: EP1988077,2008,A1 .Location in patent: Page/Page column 64
[2]Patent: WO2012/59932,2012,A1 .Location in patent: Page/Page column 112
[3]Patent: CN106905245,2017,A .Location in patent: Paragraph 0277; 0278; 0279; 0280
[4]Patent: US2019/106436,2019,A1 .Location in patent: Paragraph 0513-0515
[5]Synthesis,1981,p. 606 - 608
[6]Patent: EP1775298,2007,A1 .Location in patent: Page/Page column 38-39
[7]Patent: US2007/32478,2007,A1 .Location in patent: Page/Page column 147
[8]Journal of Physical Chemistry B,2000,vol. 104,p. 10191 - 10195
[9]Patent: US2009/54425,2009,A1 .Location in patent: Page/Page column 24
[10]Patent: WO2009/131687,2009,A2 .Location in patent: Page/Page column 133
[11]Patent: US2014/121200,2014,A1 .Location in patent: Paragraph 0356; 0357
[12]Patent: WO2014/183300,2014,A1 .Location in patent: Page/Page column 30
[13]Patent: KR2016/8881,2016,A .Location in patent: Paragraph 0120; 0121; 0122; 0123
[14]European Journal of Medicinal Chemistry,2019,vol. 163,p. 690 - 709

5
[ 5382-16-1 ]
[ 4701-17-1 ]
[ 207290-72-0 ]

Yield	Reaction Conditions	Operation in experiment
71%	In water;Reflux;	5-Bromothiophene-2-carboxaldehyde was placed in a reactor, and water was added thereto. 4-Hydroxypiperidine (3 eq) was added to the reactor, and the mixture was stirred for tens of minutes or overnight under reflux. Immediately after completion of reaction, the reaction mixture was filtered through filter paper, and the filtrate was cooled for tens of minutes with a flow of water and then for several hours with ice. The precipitated crystals were recovered through filtration under suction and washed with cold water. The crystals were dried and dissolved in chloroform. The chloroform solution was dried over sodium sulfate anhydrate, and the dried solution was filtered through a silica gel pad. The filtrate was washed with chloroform until the color thereof became faint. The filtrate was concentrated under reduced pressure until the start of crystallization. n-Hexane was added to the mixture, and stirring was performed overnight at room temperature. The formed crystals were recovered through filtration, washed with n-hexane, and dried under reduced pressure, to thereby yield 5-(4-hydroxypiperidin-1-yl)-thiophene-2-carboxaldehyde. By use of 5-bromothiophene-2-carboxaldehyde (42.30 g) and 4-hydroxypiperidine (67.30 g), amine incorporation was performed according to Production Step 1, to thereby yield 5-(4-hydroxy-piperidin-1-yl)-thiophene-2-carboxaldehyde (yield: 33.00 g, 71%). The thus-produced 5-(4-hydroxy-piperidin-1-yl)-thiophene-2-carboxaldehyde (10.56 g) and 3,4-dimethoxybenzyl cyanide (8.86 g) were subjected to condensation according to Production Step 2, to thereby yield (Z)-2-(3,4-dimethoxy-phenyl)-3-[5-(4-hydroxy-piperidin-1-yl)-thiophen-2-yl]-acrylonitrile (yield: 13.50 g, 73%). The thus-produced (Z)-2-(3,4-dimethoxy-phenyl)-3-[5-(4-hydroxy-piperidin-1-yl)-thiophen-2-yl]-acrylonitrile (20.00 g) was dissolved in chloroform (650 mL), and the solution was reacted with pyridine (6.41 g) and bromoacetyl bromide (14.13 g) according to Production Step 3 (Method A), to thereby yield bromo-acetic acid 1-[5-[(Z)-2-cyano-2-(3,4-dimethoxy-phenyl)-vinyl]-thiophen-2-yl]-piperidin-4-yl ester (yield: 23.00 g, 87%). The thus-produced bromo-acetic acid 1-[5-[(Z)-2-cyano-2-(3,4-dimethoxy-phenyl)-vinyl]-thiophen-2-yl]-piperidin-4-yl ester (2.30 g) was dissolved in chloroform (100 mL), and the solution was reacted with piperidine (533 mg) and triethylamine (658 mg) according to Production Step 4, to thereby yield the title compound (yield: 1.40 g, 60%).

Reference： [1]Synlett,1998,p. 383 - 384
[2]Synthetic Communications,2000,vol. 30,p. 1359 - 1364
[3]Patent: EP2218719,2010,A1 .Location in patent: Page/Page column 7-8

6
[ 5382-16-1 ]
[ 2785-89-9 ]
paraformaldehyde [ No CAS ]
[ 81490-74-6 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1981,vol. 20,p. 1010 - 1013

7
[ 5382-16-1 ]
[ 26032-72-4 ]
[ 881194-69-0 ]
[ 881194-89-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In butan-1-ol; at 120℃; for 12h;Product distribution / selectivity;	A mixture of compound, <strong>[26032-72-4]2,4-dichloro-6-phenyl-pyrimidine</strong> (13 g, 57.77 mmol), piperidin-4-ol (2.9 g, 28.88 mmol) and triethylamine (32.14 mL, 231.11 mmol) in butanol (110 mL) was stirred at 1200C for 12 hours under nitrogen atmosphere. The reaction mixture was then poured into water (250 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were collected, combined, washed with water (50 mL), dried over anhydrous sodium sulphate, and concentrated under vacuum. The residue thus obtained was purified by column chromatography using ethyl acetate-petroleum ether to give the two compounds, l-(4-chloro-6-phenyl- pyrimidin-2-yl)-piperidin-4-ol and 1 -(2-chloro-6-phenyl-pyrimidin-4-yl)-piperidin-4- ol in ratio 1:4 (overall yield: 51%). Spectral data for l-(4-chloro-6-phenyl-pyrimidin-2-yl)-piperidin-4-ol: M.P.: 105-1100C.1HNMR(400MHz,OmegaMUSDO-d6):delta8.03-8.0(m,2H),7.56-7.43 (m,3H),6.92(s, IH), 4.67(brs, IH),4.52-4.0(m,2H),4.02-3.98(m, IH),3.48-3.41 (m,2H),2.16-1.96(m, 2H), 1.59-1.50(m,2H). IR(KBr,cm"1):3327, 1564. MS:m/z(CI)290(M+, 100).Spectral data for l-(2~Chloro-6-phenyl-pyrimidin-4-yl)-piperidin-4-ol: M.P.: 120-1250C. EPO <DP n="222"/>1H NMR (400 MHz, DMSO-J6): delta 7.96-7.92 (m, 2H), 7.48-7.42 (m, 3H), 6.78 (s, IH), 4.21-4.10 (m, 2H), 4.08-4.0 (m, IH), 3.49-3.41 (m, 2H), 1.99-1.94 (m, 2H),1.66-1.57 (m, 2H). I IRR ((KKBBrr,, c cmm""11)):: 3333'77, 1591. MS: m/z (CI) 290 (M", 100).
	Product distribution / selectivity;	The following compounds presented in Examples 40-47 were prepared in accordance with Scheme 5, by a procedure analogous to that disclosed in Example 39, using starting materials with the appropriate substitution.

Reference： [1]Patent: WO2006/34473,2006,A2 .Location in patent: Page/Page column 220-221
[2]Patent: WO2006/34473,2006,A2 .Location in patent: Page/Page column 222

8
[ 5382-16-1 ]
[ 55676-22-7 ]
[ 265108-19-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 2071 - 2074

9
[ 5382-16-1 ]
[ 380844-49-5 ]
4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[3-(4-hydroxy-piperidin-1-yl)-propoxy]-6-methoxy-quinoline-3-carbonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 3965 - 3977

10
[ 5382-16-1 ]
[ 369-25-5 ]
[ 247035-19-4 ]

Yield	Reaction Conditions	Operation in experiment
	With dimethyl sulfoxide; In water; ethyl acetate;	Intermediate 34: Methyl 3-fluoro-4-(4-hydroxypiperidin-1-yl)benzoate Dimethyl sulfoxide (100 ml) was added to 24.5 g of 4-hydroxypiperidine to prepare a solution. <strong>[369-25-5]Methyl 3,4-difluorobenzoate</strong> (33.2 g) was added to the solution. The mixture was stirred at 120 C. for 8 hr. The reaction solution was then cooled to room temperature, and poured into 1,000 ml of water, followed by extraction twice with 750 ml of ethyl acetate. The combined organic layer was washed twice with 500 ml of saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under the reduced pressure to prepare 42.3 g of the title compound. Physicochemical Properties of Intermediate 34

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 2109 - 2130
[2]Patent: US6420558,2002,B1

11
[ 5382-16-1 ]
[ 334792-52-8 ]
[ 334792-54-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181

12
[ 5382-16-1 ]
[ 82702-31-6 ]
[ 334792-21-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181

13
[ 5382-16-1 ]
[ 1722-12-9 ]
[ 893755-98-1 ]

Yield	Reaction Conditions	Operation in experiment
81%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 18h;	Step 1 : 1-(2-Pyrimidinyl)-4-piperidinol (180) <n="157"/>4-Hydroxypiperidine (1.5 g, 14.7 mmol) was combined with 2-chloropyrimidine (1.5 g, 13.4 mmol) and diisopropylethylamine (6 ml_, 33.5 mmol) into 50 ml. acetonitrile. The mixture was heated at 80 0C for 18 hours. The reaction mixture was then concentrated to dryness and the crude residue was then purified on via flash column chromatography using a gradient of 0-60% ethylacetate/hexane to give 2.1 g (81%) of the desired compound 180 as a white solid. 1H NMR (400 MHz, CDCI3): delta 8.28 (d, J = 4.6 Hz 2 H), 6.49 (t, J = 4.8 Hz, 1 H), 4.49 - 4.33 (m, 2 H), 4.01 - 3.88 (m, 1 H), 3.37 - 3.21 (m, 2 H), 2.02 - 1.90 (m, 2 H), 1.60 - 1.45 (m, 2 H); LCMS (ESI): m/z 180 (M + H)+.

Reference： [1]Patent: WO2008/8895,2008,A1 .Location in patent: Page/Page column 155; 156
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 10972 - 10994

14
[ 5382-16-1 ]
XCH₂COOH [ No CAS ]
[ 3518-83-0 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2001,vol. 49,p. 988 - 998

15
[ 5382-16-1 ]
[ 23499-01-6 ]

Reference： [1]Synthesis,1981,p. 606 - 608
[2]Patent: CN106905245,2017,A

16
[ 5382-16-1 ]
[ 62965-10-0 ]
[ 325796-51-8 ]

Yield	Reaction Conditions	Operation in experiment
64%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 12h;	Step A [1S-(4-Hydroxy-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid benzyl ester To a cold solution (0 C.) of the Z-tert-leucine (3.48 g, 13.1 mmol) and 4-hydroxy piperidine (1.4 g, 13.7 mmol) in CH2Cl2 (40 ml) were added WSC (2.75 g, 14.4 g) followed by HOAt (18 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 12 hours and then washed with water and brine. The combined organic layer was dried over MgSO4 and the solvent removed under reduced pressure to furnish a yellow oil which was purified through flash chromatography. The desired compound was obtained in 64% yield. 1H NMR; delta (CDCl3), 7.34 (5H, s), 5.58 (1H, m), 5.08 (2H, m), 4.60 (1H, m), 3.91 (3H, m), 3.49-3.05 (2H, m), 1.91 (4H, m), 0.98 (9H, d, J=3.57); ESMS; +ve ion 371 [M+Na]; HPLC: RT=5.44 min.

Reference： [1]Patent: US6846825,2005,B1 .Location in patent: Page column 65-66

17
[ 5382-16-1 ]
[ 96606-37-0 ]
2,6-difluoro-4-(4-hydroxy-piperidin-1-yl)-benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With N-ethyl-N,N-diisopropylamine; In methanol; at 65℃; for 4h;	Example 7: Synthesis OF 3-AMINO-4-ETHOXY-6- (4-HYDROXY-PIPERIDIN-1-YL)- benzo [B] THIOPHENE-2-CARBOXYLIC acid amide To a solution of 1.0 g (6.4 mmol) of 2, 4,6-trifluorobenzonitrile in MEOH (35 mL) was added 0.65 g (6.4 mmol) of 4-hydroxypiperidine and 1.2 mL (6.7 mmol) OFF, N diiisopropylethylamine. The mixture was heated to 65 C FOR 4 h then cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 0.325 g (21 %) OF 2, 6-DIFLUORO-4- (4-HYDROXY- PIPERIDIN-L-YL)-BENZONITRILE as a white solid.

Reference： [1]Patent: WO2005/12283,2005,A1 .Location in patent: Page/Page column 51

18
[ 5382-16-1 ]
[ 1435-49-0 ]
[ 245057-73-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 1.5h;Heating / reflux;	4-Hydroxypiperidine (50 g) was added portionwise to a stirred suspension ofpotassium fert-butoxide (1 10.9 g) in THF (900 mL) at room temperature and undernitrogen. The mixture was heated at reflux and l,2-dichloro-4-fluorobenzene (98 g) addeddropwise over 30 min. The mixture was stirred at reflux for another 1 h then cooled downs10 to room temperature, diluted with ethyl acetate (500 mL) and washed with water (500 mL).The organic phase was diluted further with ethyl acetate (500 mL) and extracted with 1Mhydrochloric acid (200 mL). The aqueous extract was adjusted to over pH 10 by additionof a solution of sodium hydroxide and extracted twice with tert-butylmethyl ether (750mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated1 5 under vacuum to yield the sub-title compound as a dark oil which was used as such in thenext step.MS (ESI+ve) 246/248 [M+H]+.H NMR 5 (CDC13) 1.60-1.70 (2H, m), 1.97-2.03 (2H, m), 2.75 (2H, td), 3.15 (2H,dt), 4.29-4.37 (1H, m), 6.78 (1H, dd), 7.00 (1H, d), 7.31 (1H, d).

Reference： [1]Patent: WO2005/73192,2005,A1 .Location in patent: Page/Page column 23
[2]Bioorganic and medicinal chemistry letters,2012,vol. 22,p. 6688 - 6693,6

19
[ 5382-16-1 ]
[ 84946-20-3 ]
1-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-hydroxypiperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In isoamylic alcohol; for 12h;Heating / reflux;	EXAMPLE 2 1-[1-(4-Fluorobenzyl)-1H-benzimidazol-2-yl]-4-hydroxypiperidine (3) A mixture of 3.9 g of 4-hydroxypiperidine, 5 g of 2-chloro-1-(4-fluorobenzyl)-benzimidazol in 30 mL of isoamylic alcohol is taken to reflux for 12 hours. Once the reaction has finished, the product is isolated by removal of the solvent under reduced pressure and redissolving the residue in 15 mL of ethyl acetate and 15 mL of water. The organic phase is decanted, and the aqueous phase is extracted again with 7 mL of ethyl acetate. The organic phases are brought together and the solvent is removed. The obtained residue is crystallized in toluene, obtaining 3.7 g of 1-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-hydroxypiperidine (3). 13C-NMR (CDCl3, delta in ppm): 34.17 (CH2), 47.05 (CH2), 48.64 (CH2), 67.04 (CH), 109.27 (CH), 143.40 (C), 163.37 (C).

Reference： [1]Patent: EP1564212,2005,A1 .Location in patent: Page 11
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4380 - 4384

20
[ 5382-16-1 ]
[ 67-64-1 ]
[ 5570-78-5 ]

Yield	Reaction Conditions	Operation in experiment
100%		A mixture of 4-hydroxypiperidine (10g, 0.10mol), acetone (21.8mL, 0.30mol), acetic acid (5.7mL, 0.10mol) and tetrahydrofuran (150mL) was stirred in an ice bath for 15 minutes. Sodium triacetoxyborohydride (31.3g, 0.15mol) was then added portionwise and the mixture was stirred for a further 10 minutes. The reaction mixture was then warmed and stirred at room temperature for 10 minutes and at 40C for 2.5 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in water (50mL). The aqueous solution was basified to pH9 with 0.88 ammonia and the solution was stirred for 30 minutes. The reaction mixture was then extracted with diethyl ether (2x200mL) and the combined extracts were dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography on silica gel, eluding with dichloromethane:methanol:0.88 ammonia, 96:4:1 to 90:10:1, to afford the title product as a yellow oil in quantitative yield, 14.6g. 1H-NMR(CDCl3, 400MHz) delta: 0.92-1.02(m, 6H), 1.41-1.57(m, 2H), 1.77-1.89(m, 2H), 2.07-2.23(m, 2H), 2.57-2.78(m, 3H), 3.43-3.85(brm, 2H) MS ES+ m/z 144 [MH]+
100%		Preparation 3 1 -lsopropyl-piperidin-4-olA mixture of 4-hydroxypiperidine (1Og, O.IOmol), acetone (21.8ml, 0.30mol), acetic acid (5.7ml, O.IOmol) and tetrahydrofuran (150ml) was stirred in an ice bath for 15 minutes. Sodium triacetoxyborohydride (31.3g, 0.15mol) was then added portion wise and the mixture was stirred for a further 10 minutes. The reaction mixture was then warmed and stirred at room temperature for 10 minutes and at 400C for 2.5 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in water (50ml). The aqueous solution was basified to pH9 with 0.88 ammonia and the solution was stirred for 30 minutes. The reaction mixture was then extracted with diethyl ether (2x200ml) and the combined extracts were dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 96:4:1 to 90:10:1 , to afford the title product as a yellow oil in quantitative yield, 14.6g.1HNMR(CDCI3, 400MHz) delta: 0.92-1.02(m, 6H), 1.41-1.57(m, 2H), 1.77-1.89(m, 2H), 2.07-2.23(m, 2H), 2.57-2.78(m, 3H), 3.43-3.85(brm, 2H) MS ES+ m/z 144 [MH]+
29%		To a stirred solution of piperidin-4-ol (1 g, 9.87 mmol) in DCE (100 ml) under an atmosphere of nitrogen was added acetic acid (1.78 g, 29.7 mmol) and acetone (5.72 g, 98.7 mmol). The reaction mixture was stirred for 12 h at RT before addition of STAB (6.29 g, 29.7 mmol).After stirring for 12 h at RT the reaction mixture was concentrated at reduced pressure to give a white solid. Purification by FCC [SiO2, eluting on a gradient from 98:2 EtOAc/MeOH to90:10:1 EtOAc/MeOH/NH3] to give the title compound (412 mg, 29 %) as a colourless oil.1H NMR (250 MHz, CHLOROFORM-J) delta ppm 4.97 (1 H, br. s.), 3.39 (1 H, m, J=8.6, 4.0Hz), 2.23 - 2.77 (3 H, m), 1.88 - 2.16 (2 H, m), 1.49 - 1.75 (2 H, m), 1.35 (2 H, m, J=12.6,9.3, 9.3, 3.6 Hz), 0.63 - 0.97 (6 H, m).

To a suspension of 4-hydroxypiperidine (30 g) and Na2SO4 (20 g) in 600 ml of chloroform, is added 24 ml of acetone and stirred for 24 h at AT, then 120 g of sodium triacetoxyborohydride are gradually added, and stirred for a further 24 h at AT. 400 ml MeOH are added dropwise, stirring continued for 2 h at AT and the solvent evaporated in vacuo. The residue is redissolved in 40 ml water, basified, extracted with DCM and the organic layer is evaporated in vacuo. 24.1 g of the desired product are obtained.

Reference： [1]Patent: EP1595881,2005,A1 .Location in patent: Page/Page column 64
[2]Patent: WO2007/52124,2007,A1 .Location in patent: Page/Page column 17
[3]Patent: WO2009/121812,2009,A1 .Location in patent: Page/Page column 69
[4]Patent: US2009/233910,2009,A1 .Location in patent: Page/Page column 57
[5]Journal of Medicinal Chemistry,2019,vol. 62,p. 1203 - 1217

21
[ 5382-16-1 ]
[ 75-26-3 ]
[ 5570-78-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate; In methanol;Heating / reflux;	Intermediate 21: Methanesulfonic acid 1-isopropyl-piperidin-4-yl ester [] Step 1:; 4-Hydroxypiperidine (2.13g, 21.1mmol), K2CO3 (5.83g, 2eq.), 2-bromopropane (11.2g, 91 mmol, 4.3eq.) and MeOH (21.3ml) were refluxed together overnight. The reaction was allowed to cool to room temperature and quenched with 2M HCl solution (40ml) and extracted with TBME (40ml). The aqueous phase was basified to pH 14 with 2M NaOH solution and extracted with DCM (9 x 50ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated in vacuo to give 1-isopropyl-4-hydroxypiperidine (2.41g, 80%th) as a pale yellow oil.1H NMR (400MHz, CDCl3) delta3.67 (m, 1H), 2.85-2.66 (m, 3H), 2.33-2.20 (m, 2H), 1.99-1.38 (m, 5H), 1.04 (d, 6H).
35%	With potassium carbonate; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 12h;	In a similar fashion (Rl, GP A) 2-bromopropane (1.46 g, 11.86 mmol), gave the title compound (0.5 g, 35% yield) as oil after purification by FCC [SiO2, eluting with 85:15:2 DCM / MeOH / NH3].1H NMR (250 MHz, CHLOROFORM-J) delta ppm 4.97 (1 H, br. s.), 3.39 (1 H, m, J=8.6, 4.0 Hz), 2.23 - 2.77 (3 H, m), 1.88 - 2.16 (2 H, m), 1.49 - 1.75 (2 H, m), 1.35 (2 H, m, J=12.6, 9.3, 9.3, 3.6 Hz), 0.63 - 0.97 (6 H, m).
	With potassium carbonate; In methanol; for 12h;Reflux;	<Preparation of Intermediate 7> l-isopropyl-piperidin-4-oI 4-piperidinol (2.13 g, 21.1mmol) was added to methanol (21 mL), and potassium carbonate (5.83 g, 42.2 mmol) and 2-bromopropane (11.2 g, 90.7 mmol) were further added thereto, followed by refluxing for 12 hours while stirring. Then, the reaction mixture was mixed with 2M HCl (40 mL) and extracted three times with dichloromethane (50 mL). The organic layer thus obtained was dried over anhydrous magnesium sulfate, and filtered and distilled under reduced pressure to obtain the title compound (2.2g) as oil. 1H NMR (300 MHz, CDC13): delta 3.65(m, 1H), 2.76(m, 2H), 2.26(m, 3H), 1.92(m, 2H), 1.56(m, 2H), 1.02(d , 6H).

2.2 g

With potassium carbonate; In methanol; for 12h;Reflux;

4-piperidinol (2.13 g, 21.1 mmol) was added to methanol (21 mL), and potassium carbonate (5.83 g, 42.2 mmol) and 2-bromopropane (11.2 g, 90.7 mmol) were further added thereto, followed by refluxing for 12 hours while stirring. Then, the reaction mixture was mixed with 2M HCl (40 mL) and extracted three times with dichloromethane (50 mL). The organic layer thus obtained was dried over anhydrous magnesium sulfate, and filtered and distilled under reduced pressure to obtain the title compound (2.2 g) as oil. [0331] 1H NMR (300 MHz, CDCl3): delta 3.65 (m, 1H), 2.76 (m, 2H), 2.26 (m, 3H), 1.92 (m, 2H), 1.56 (m, 2H), 1.02 (d, 6H).

Reference： [1]Patent: EP1593679,2005,A1 .Location in patent: Page/Page column 39
[2]Patent: WO2009/121812,2009,A1 .Location in patent: Page/Page column 66
[3]Patent: WO2012/93809,2012,A2 .Location in patent: Page/Page column 48-49
[4]Patent: US2013/274268,2013,A1 .Location in patent: Paragraph 0329-0331

Yield	Reaction Conditions	Operation in experiment
		Example 103 By an analogous procedure to that described in example 101 starting with 2,6-dichloro-9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)purine and 4-hydroxypiperidine was prepared 2-chloro-6-(4-hydroxy-1-piperidinyl) -9-(beta-D-ribofuranosyl)purine (W. Kampe et al, Patent No. DE 2157036); mass spectrum (ESI) m/z 386 [M+H]+.

23
[ 5382-16-1 ]
[ 23806-24-8 ]
1-[3-(dmethylamino)propyl]-3-ethylcarbodiimide hydrochloride [ No CAS ]
(4-Hydroxy-1-piperidinyl)(3-methyl-thien-2-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-ol; In N,N-dimethyl-formamide;	Step A. (4-Hydroxy-1-piperidinyl)(3-methyl-2-thienyl)methanone To a solution of <strong>[23806-24-8]3-methyl-2-thiophenecarboxylic acid</strong> (1.76 g, 12.39 mmol), 1-[3-(dmethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.85 g, 14.87 mmol), 1-hydroxybenzotriazole (2.18 g, 16.10 mmol), N-methylmorpholine (1.88 g, 18.58 mmol) and 4-hydroxypiperidine (1.25 g, 12.39 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 72 hours. The reaction mixture was poured into water (100 mL) and extracted with chloroform. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel Merck-60 (eluant: ethyl acetate) to afford the title compound (1.78 g, 7.9 mmol). MS ((+)ESI, m/z): 226 [M+H]+ 1H NMR (DMSO-d6, 300 MHz) d 7.35 (d, J=5.0 Hz, 2H), 6.90 (d, J=5.0 Hz, 2H), 4.74 (d, J=4.4 Hz, 1H), 3.82 (m, 2H), 3.65 (m, 1H), 3.01 (m, 2H), 2.22 (s, 3H), 1.77 (m, 2H) and 1.34 (m, 2H).

Reference： [1]Patent: US2002/28832,2002,A1

24
[ 383865-57-4 ]
[ 5382-16-1 ]
4-Hydroxy-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%		4-Hydroxy-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide Using <strong>[383865-57-4]4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine</strong> and piperidin-4-ol the title compound was obtained as yellow solid (50%). MS: m/e=393 (M+H+).

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

25
[ 5382-16-1 ]
[ 6940-78-9 ]
[ 6665-86-7 ]
[ 140439-26-5 ]