1-piperidin-4-ylethanol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (±)-1-(4-Piperidinyl)ethanol (see reference: WO 9725992A, 12.44 g, 65.7 mmol) in 1,2-dichloroethane (500 mL) was stirred at room temperature and BOC2O (14.36 g, 65.8 mmol) was added followed by Et3N (19 mL, 136 mmol). The stirred mixture was heated at gentle reflux for 15 min and then allowed to cool to room temperature and stirred overnight. The solution was washed twice with 10% citric acid, once with 10% Na2CO3, dried over MgSO4, filtered and concentrated to afford (±)-1,1-dimethylethyl 4-(1-hydroxyethyl)-1-piperidinecarboxylate (14 g, 93% yield) as a light amber oil. 1H NMR (400 MHz, DMSO-d6): δ 4.35 (d, 1H, J=4.8 Hz), 3.92 (m, 2H), 3.32 (m, 1H), 2.59 (m, 2H), 1.68 (m, 1H), 1.47 (m, 1H), 1.34 (s, 9H), 1.25 (m, 1H), 1.08-0.88 (m, 2H), 0.97 (d, 3H, J=6.4 Hz). The stirred mixture was heated at gentle reflux for 15 min The solution was washed twice with 10% citric acid, once with 10% Na2CO3 dried over MgSO4 filtered concentrated

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 11.00 g (46.43 mmol) of 2,5-dibromopyridine, 6.00 g (46.43 mmol) of piperidin-4-ylethanol and 6.74 g (48.76 mmol) of potassium carbonate in 8 mL of DMSO are placed in an autoclave. The mixture is then heated at 160° C. for 20 hours. The reaction mixture is allowed to cool to room temperature and then taken up in ethyl acetate and water. The aqueous phase is separated out and extracted twice with ethyl acetate, and the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. to cool to room temperature The aqueous phase is separated out extracted twice with ethyl acetate the combined organic phases are washed with saturated aqueous sodium chloride solution dried over sodium sulfate the filtrate is concentrated under reduced pressure

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 11.00 g (46.43 mmol) of 2,5-dibromopyridine, 6.00 g (46.43 mmol) of piperidin-4-ylethanol and 6.74 g (48.76 mmol) of potassium carbonate in 8 mL of DMSO are placed in an autoclave. The mixture is then heated at 160° C. for 20 hours. The reaction mixture is allowed to cool to room temperature and then taken up in ethyl acetate and water. The aqueous phase is separated out and extracted twice with ethyl acetate, and the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. to cool to room temperature The aqueous phase is separated out extracted twice with ethyl acetate the combined organic phases are washed with saturated aqueous sodium chloride solution dried over sodium sulfate the filtrate is concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared as in Example 1 starting from 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid and 1-(piperidin-4-yl)ethanol. The crude product was purified by flash chromatography using CH2Cl2-MeOH as a gradient eluent (100:0-90:10). 1H NMR (400 MHz, CDCl3): 1.22 (3H, d), 1.30-1.41 (3H, m), 1.62 (1H, m), 1.77 (1H, m), 2.00 (1H, m), about 2.78 (1H, m), 3.01 (2H, t), about 3.18 (1H, m), about 3.64 (1H, m), 3.77 (2H, q), about 4.48 (1H, m), about 4.75 (1H, m), 6.20 (1H, d), 6.58 (1H, d), 7.02 (1H, s), about 7.28 (1H, broad s), 7.40 (1H, distorted d), 7.43 (1H, distorted dd), 7.75 (1H, d), 11.44 (1H, broad s). The crude product was purified by flash chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (±)-1-(4-Piperidinyl)ethanol (see reference: WO 9725992A, 12.44 g, 65.7 mmol) in 1,2-dichloroethane (500 mL) was stirred at room temperature and BOC2O (14.36 g, 65.8 mmol) was added followed by Et3N (19 mL, 136 mmol). The stirred mixture was heated at gentle reflux for 15 min and then allowed to cool to room temperature and stirred overnight. The solution was washed twice with 10% citric acid, once with 10% Na2CO3, dried over MgSO4, filtered and concentrated to afford (±)-1,1-dimethylethyl 4-(1-hydroxyethyl)-1-piperidinecarboxylate (14 g, 93% yield) as a light amber oil. 1H NMR (400 MHz, DMSO-d6): δ 4.35 (d, 1H, J=4.8 Hz), 3.92 (m, 2H), 3.32 (m, 1H), 2.59 (m, 2H), 1.68 (m, 1H), 1.47 (m, 1H), 1.34 (s, 9H), 1.25 (m, 1H), 1.08-0.88 (m, 2H), 0.97 (d, 3H, J=6.4 Hz). The stirred mixture was heated at gentle reflux for 15 min The solution was washed twice with 10% citric acid, once with 10% Na2CO3 dried over MgSO4 filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 0.200 g (1.55 mmol) of 1-piperidin-4-yl-ethanol and 0.200 g (0.663 mmol) of 3-chloro-N-(2,5-dichloro-pyridin-3-yl)-benzamide in acetonitrile (10 mL) is heated at 175 C in a microwave reactor for 14 hours. The mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to give 0.170 g (65.0%) of 3-chloro-N-[5′-chloro-4-(1-hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-benzamide as a yellow oil. is heated at 175 C in a microwave reactor for 14 hours concentrated under reduced pressure The residue is purified by flash silica gel chromatography

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An autoclave is charged with 11 g (46.43 mmol) of 2,5-dibromopyridine, 6 g (46.43 mmol) of piperidin-4-ylethanol and 6.74 g (48.76 mmol) of potassium carbonate in 8 ml of DMSO. This charge is subsequently heated at 160° C. for 20 hours.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-(1'-hydroxyethyl)-piperidine (13 g, m.p. 65°-68° C.) in ethanol (25 ml) was neutralized with 5 N hydrogen bromide in ethanol. After removal of the solvent in vacuo, the residue was distilled twice with chloroform and finally dried at 0.05 mm Hg. The oily residue was mixed with phosphorous tribromide (25 ml) and heated on the steam bath for 2 hours. After cooling, the mixture was treated with ether (250 ml) to give a crystalline precipitate which was filtered off and washed with ether to give (A) as hygroscopic crystals. Recrystallization from acetonitrile gave material with m.p. 146°-48° C. After removal of the solvent in vacuo the residue was distilled twice with chloroform finally dried at 0.05 mm Hg The oily residue was mixed with phosphorous tribromide (25 ml) heated on the steam bath for 2 hours After cooling the mixture was treated with ether (250 ml) to give a crystalline precipitate which was filtered off washed with ether

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 11.00 g (46.43 mmol) of 2,5-dibromopyridine, 6.00 g (46.43 mmol) of piperidin-4-ylethanol and 6.74 g (48.76 mmol) of potassium carbonate in 8 mL of DMSO are placed in an autoclave. The mixture is then heated at 160° C. for 20 hours. The reaction mixture is allowed to cool to room temperature and then taken up in ethyl acetate and water. The aqueous phase is separated out and extracted twice with ethyl acetate, and the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. to cool to room temperature The aqueous phase is separated out extracted twice with ethyl acetate the combined organic phases are washed with saturated aqueous sodium chloride solution dried over sodium sulfate the filtrate is concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared as in Example 1 starting from 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid and 1-(piperidin-4-yl)ethanol. The crude product was purified by flash chromatography using CH2Cl2-MeOH as a gradient eluent (100:0-90:10). 1H NMR (400 MHz, CDCl3): 1.22 (3H, d), 1.30-1.41 (3H, m), 1.62 (1H, m), 1.77 (1H, m), 2.00 (1H, m), about 2.78 (1H, m), 3.01 (2H, t), about 3.18 (1H, m), about 3.64 (1H, m), 3.77 (2H, q), about 4.48 (1H, m), about 4.75 (1H, m), 6.20 (1H, d), 6.58 (1H, d), 7.02 (1H, s), about 7.28 (1H, broad s), 7.40 (1H, distorted d), 7.43 (1H, distorted dd), 7.75 (1H, d), 11.44 (1H, broad s). The crude product was purified by flash chromatography