164149-27-3

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

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

Procedure: A 2-butanone (7.6 mL) solution of 1.12 g of tert-butyl 4-(3-bromopropyl)-1-piperidinecarboxylate was added to a 2-butanone (7.0 mL) mixture of 0.50 g of 2-fluoro-4-hydroxybenzonitrile and 0.56 g of potassium carbonate, which was then heated to reflux for 6 hours and 30 minutes. After cooling down to room temperature, the reaction mixture was added to a mixture of ethyl acetate and water. The organic layer was separated, washed with water, and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to provide 0.72 g of tert-butyl 4-[3-(4-cyano-3-fluorophenoxy)propyl]-1-piperidinecarboxylate as colorless oily form. was then heated to reflux for 6 hours and 30 minutes The organic layer was separated washed with water dried with anhydrous magnesium sulfate by distilling off the solvent under reduced pressure The resultant residue was purified

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

Procedure: To a dimethylsulfoxide (130 mL) solution of 13.2 g of tert-butyl 4-(3-bromopropyl)-1-piperidinecarboxylate were added 5.13 g of 4-cyanophenol and 11.9 g of potassium carbonate at room temperature, which was then stirred at the same temperature for 26 hours. The reaction mixture was added to a mixture of toluene and water. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure to provide 14.5 g of tert-butyl 4-[3-(4-cyanophenoxy)propyl]-1-piperidinecarboxylate as white solid form. The organic layer was separated washed with a saturated sodium chloride aqueous solution dried with anhydrous magnesium sulfate by distilling off the solvent under reduced pressure

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

Procedure: To a dimethylsulfoxide (130 mL) solution of 13.2 g of tert-butyl 4-(3-bromopropyl)-1-piperidinecarboxylate were added 5.13 g of 4-cyanophenol and 11.9 g of potassium carbonate at room temperature, which was then stirred at the same temperature for 26 hours. The reaction mixture was added to a mixture of toluene and water. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure to provide 14.5 g of tert-butyl 4-[3-(4-cyanophenoxy)propyl]-1-piperidinecarboxylate as white solid form. The organic layer was separated washed with a saturated sodium chloride aqueous solution dried with anhydrous magnesium sulfate by distilling off the solvent under reduced pressure

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

Procedure: To a tetrahydrofuran (110 mL) solution of 10.7 g of tert-butyl 4-(3-hydroxypropyl)-1-piperidinecarboxylate was added 19.0 g of carbon tetrabromide under cooling with water, to which 15.0 g of triphenylphosphine was then added over a period of 13 minutes. This mixture was stirred at room temperature for 2 hours and 30 minutes and allowed to stand for 13 hours. To the reaction mixture were added water, ethyl acetate, and a saturated sodium chloride aqueous solution. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; hexane:ethyl acetate=3:1) to provide 13.2 g of tert-butyl 4-(3-bromopropyl)-1-piperidinecarboxylate as colorless oily form. was then added over a period of 13 minutes to stand for 13 hours The organic layer was separated washed with a saturated sodium chloride aqueous solution dried with anhydrous magnesium sulfate by distilling off the solvent under reduced pressure The resultant residue was purified

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

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

Procedure: Proceeding as described in Example 54, Step 3, 673 mg of 4-(3-bromo-propyl)-piperidine-1-carboxylic acid tert-butyl ester (2.2 mmol) was conyerted to approximately 180 mg 1-(3-Piperidin-4-yl-propyl)-1H-indole-2-carboxylic acid [2-(1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-amide, hydrochloride salt (MS: M+H=506; mp=146.4-146.9 C).

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

Procedure: The title compound is prepared as described in EXAMPLE 72, Part A, substituting 3-oxopiperazine-1-carboxylic acid benzyl ester for 3-oxopiperazine-1-carboxylic acid tert-butyl ester and 4-(3-bromopropyl)-piperidine-1-carboxylic acid tert-butyl ester for 7-bromomethyl-4-chloroquinazoline. The title compound is obtained as a white foam. 1H NMR (CDCl3, 300 MHz) δ7.38 (m, 5H), 5.12 (s, 2H), 4.18 (m, 4H), 3.73 (m, 2H), 3.33 (m, 4H), 2.66 (m, 2H), 1.58 (m, 6H), 1.42 (s, 9H), 1.38 (m, 3H). The title compound is prepared

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

Procedure: In a 100 ml round bottom flask, under a nitrogen atmosphere, were added 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]benzimidazole (550 mg, 1.84 mmol) and anhydrous N,N-dimethylformamide (59 ml). To this solution was added sodium hydride (60% in mineral oil, 81.04 mg, 2.03 mmol). The resulting mixture was stirred at room temperature for 60 minutes, and then 3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl bromide (620 mg, 2.03 mmol) was added. The resulting mixture was heated to 100° C. and stirred at this temperature for about three hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between ethyl acetate and brine. The aqueous fraction was extracted twice with brine. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography. The resulting mixture was heated to 100° C. stirred at this temperature for about three hours The reaction mixture was partitioned between ethyl acetate and brine The aqueous fraction was extracted twice with brine dried over sodium sulfate The solvents were removed in vacuo The desired title product was further purified by radial chromatography

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

Procedure: In a 100 ml round bottom flask, under a nitrogen atmosphere, were added 4-(ethenyl)-2-[(4-chlorophenoxy)methyl]benzimidazole (670 mg, 2.24 mmol) and anhydrous N,N-dimethylformamide (34 ml). To this solution was added sodium hydride (60% in mineral oil, 98.67 mg, 2.46 mmol). The resulting mixture was stirred at room temperature for 45 minutes, and then 3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl bromide (755 mg, 2.47 mmol) was added. The resulting mixture was heated to 100° C. and stirred at this temperature for about four hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between ethyl acetate and brine. The aqueous fraction was extracted twice with brine. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography. The resulting mixture was heated to 100° C. stirred at this temperature for about four hours The reaction mixture was partitioned between ethyl acetate and brine The aqueous fraction was extracted twice with brine dried over sodium sulfate The solvents were removed in vacuo The desired title product was further purified by radial chromatography

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

Procedure: A solution of 2-(4-chlorophenoxymethyl)-4-benzyloxy-benzimidazole (720 mg, 1.97 mmol, 1.0 eq) in dry N,N-dimethylformamide (8 ml, 0.25 M) was treated with sodium hydride (60% in mineral oil, 57 mg, 2.30 mmol, 1.2 eq). The resulting mixture was stirred at room temperature for thirty minutes and then 3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl bromide (7.24 mg, 2.36 mmol, 1.2 eq) was added to the reaction mixture. The resulting mixture was stirred at 70° C. for three hours. The reaction was quenched by the addition of water (1×30 ml). The aqueous fraction was extracted with diethyl ether (1×30 ml). The organic fractions were combined, washed with water (1×30 ml), then brine (1×30 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by flash chromatography to provide a white foam in 38% yield. The resulting mixture was stirred at 70° C. for three hours The reaction was quenched by the addition of water (1×30 ml) The aqueous fraction was extracted with diethyl ether (1×30 ml) washed with water (1×30 ml) brine (1×30 ml), and then dried over sodium sulfate The solvents were removed in vacuo The desired title product was further purified by flash chromatography to provide a white foam in 38% yield

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

Procedure: A solution of 4-hydroxy-2-(4-chlorophenoxymethyl)benzimidazole (500 mg, 1.82 mmol) in dry N,N-dimethylformamide (8 ml) was treated with sodium hydride (60% in mineral oil, 162 mg, 4.0 mmol, 2.2 eq). The resulting mixture was stirred at room temperature under a stream of nitrogen for about one hour. To this reaction mixture 3-[1-(t-butoxycarbonyl)piperidin-4-yl)propyl bromide (4.0 mmol, 2.2 eq) was added and the resulting mixture was stirred for three hours at 70° C. The reaction was quenched by the addition of 10 ml of water. The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined and washed with water (2×10 ml), and then brine (1×10 ml), and then dried over magnesium sulfate. The solvents were removed in vacuo to yield a light brownish crude material. The desired title product was further purified by flash chromatography. There is some substitution at the 7-position of the benzimidazole present, although the 4-substituted is the major isomer. the resulting mixture was stirred for three hours at 70° C The reaction was quenched by the addition of 10 ml of water The aqueous fraction was extracted with ethyl acetate (3×10 ml) washed with water (2×10 ml) brine (1×10 ml), and then dried over magnesium sulfate The solvents were removed in vacuo