1-iodo-4-methoxybutane

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

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To N-isopropylcyclohexylamine (5.96 ml) in THF (30 ml) was added dropwise n-BuLi (1,6-M, 22.7 ml) at -78° C., and the mixture was stirred for 30 min, to which a THF (5 ml) solution of methyl isobutyrate (3.43 g) was added, and stirred at -78° C. for 45 min. Then, a HMPA (6.3 ml) solution of 1-iodo-4-methoxy-butane (9.05 g) was added to the mixture, and stirred at room temperature for 1 h to give methyl 2,2-dimethyl-6-methoxycaproate (4.81 g, 85%) after usual work-up. was added stirred at room temperature for 1 h

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

Procedure: To a solution of 3,4-dimethyl-4-(3-(1H-1,2,3-triazol-4-yl)phenyl)piperidine (Preparation 44, 50 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydrogencarbonate (25 mg, 0.29 mmol) and 1-iodo-4-methoxybutane (Preparation 15, 50 mg, 0.23 mmol). The resultant mixture was heated at 60° C. overnight and then cooled to room temperature. The residue given was partitioned between saturated aqueous sodium hydrogencarbonate solution (25 mL) and ether (15 mL). The phases were separated and the aqueous layer was further extracted with ether (2×15 mL). The combined extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography eluting with a gradient of CH2Cl2:MeOH:0.88 ammonia (100:8:1) to give the title compound as a colourless oil (15 mg, 22%). The residue given was partitioned between saturated aqueous sodium hydrogencarbonate solution (25 mL) and ether (15 mL) The phases were separated the aqueous layer was further extracted with ether (2×15 mL) The combined extracts were dried over MgSO4 filtered concentrated in vacuo The residue was purified by chromatography eluting with a gradient of CH2Cl2

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

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

Procedure: To a stirred solution of tert-butyl 3-(hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (205 mg, 0.74 mmol) and 4-methoxybutyl iodide (750 mg, 3.5 mmol) in dry THF (5 mL) under N2 was added 60& NaH in oil (0.14 g, 3.5 mmol). H2 evolution occurred. The mixture was heated at reflux for 8 h. The mixture was cooled, diluted with ether (90 mL), and washed with water (25 mL) and brine (25 mL), and dried over MgSO4. Removal of the solvent left an oil which was purified by flash chromatography on a 12-g silica cartridge eluted with a 0 to 100% EtOAc in hexanes gradient to afford tert-butyl 3-((4-methoxybutoxy)(phenyl)methyl)pyrrolidine-1-carboxylate (47 mg, 17%) as an oil. The mixture was heated at reflux for 8 h The mixture was cooled washed with water (25 mL) and brine (25 mL) dried over MgSO4 Removal of the solvent left an oil which was purified by flash chromatography on a 12-g silica cartridge eluted with a 0 to 100% EtOAc in hexanes gradient

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

Procedure: To a stirred solution of tert-butyl 3-(hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (205 mg, 0.74 mmol) and 4-methoxybutyl iodide (750 mg, 3.5 mmol) in dry THF (5 mL) under N2 was added 60& NaH in oil (0.14 g, 3.5 mmol). H2 evolution occurred. The mixture was heated at reflux for 8 h. The mixture was cooled, diluted with ether (90 mL), and washed with water (25 mL) and brine (25 mL), and dried over MgSO4. Removal of the solvent left an oil which was purified by flash chromatography on a 12-g silica cartridge eluted with a 0 to 100% EtOAc in hexanes gradient to afford tert-butyl 3-((4-methoxybutoxy)(phenyl)methyl)pyrrolidine-1-carboxylate (47 mg, 17%) as an oil. The mixture was heated at reflux for 8 h The mixture was cooled washed with water (25 mL) and brine (25 mL) dried over MgSO4 Removal of the solvent left an oil which was purified by flash chromatography on a 12-g silica cartridge eluted with a 0 to 100% EtOAc in hexanes gradient

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

Procedure: 10.70 g of 4-methoxybutyl iodide are taken up in 80 ml of acetonitrile. 14.43 g of triphenylphosphine are added and the reaction solution is heated to reflux for 16 hours. The reaction solution is concentrated by evaporation and the residue is admixed with diethyl ether. The suspension is stirred at room temperature for 30 minutes and the precipitated solid is filtered off and dried. The title compound is used for the next stage without further purification. the reaction solution is heated to reflux for 16 hours The reaction solution is concentrated by evaporation the precipitated solid is filtered off dried The title compound is used for the next stage without further purification

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

Procedure: 10.70 g of 4-methoxybutyl iodide are taken up in 80 ml of acetonitrile. 14.43 g of triphenylphosphine are added and the reaction solution is heated to reflux for 16 hours. The reaction solution is concentrated by evaporation and the residue is admixed with diethyl ether. The suspension is stirred at room temperature for 30 minutes and the precipitated solid is filtered off and dried. The title compound is used for the next stage without further purification. the reaction solution is heated to reflux for 16 hours The reaction solution is concentrated by evaporation the precipitated solid is filtered off dried The title compound is used for the next stage without further purification

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To N-isopropylcyclohexylamine (5.96 ml) in THF (30 ml) was added dropwise n-BuLi (1,6-M, 22.7 ml) at -78° C., and the mixture was stirred for 30 min, to which a THF (5 ml) solution of methyl isobutyrate (3.43 g) was added, and stirred at -78° C. for 45 min. Then, a HMPA (6.3 ml) solution of 1-iodo-4-methoxy-butane (9.05 g) was added to the mixture, and stirred at room temperature for 1 h to give methyl 2,2-dimethyl-6-methoxycaproate (4.81 g, 85%) after usual work-up. was added stirred at room temperature for 1 h

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To N-isopropylcyclohexylamine (5.96 ml) in THF (30 ml) was added dropwise n-BuLi (1,6-M, 22.7 ml) at -78° C., and the mixture was stirred for 30 min, to which a THF (5 ml) solution of methyl isobutyrate (3.43 g) was added, and stirred at -78° C. for 45 min. Then, a HMPA (6.3 ml) solution of 1-iodo-4-methoxy-butane (9.05 g) was added to the mixture, and stirred at room temperature for 1 h to give methyl 2,2-dimethyl-6-methoxycaproate (4.81 g, 85%) after usual work-up. was added stirred at room temperature for 1 h

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

Procedure: To a solution of 3,4-dimethyl-4-(3-(1H-1,2,3-triazol-4-yl)phenyl)piperidine (Preparation 44, 50 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydrogencarbonate (25 mg, 0.29 mmol) and 1-iodo-4-methoxybutane (Preparation 15, 50 mg, 0.23 mmol). The resultant mixture was heated at 60° C. overnight and then cooled to room temperature. The residue given was partitioned between saturated aqueous sodium hydrogencarbonate solution (25 mL) and ether (15 mL). The phases were separated and the aqueous layer was further extracted with ether (2×15 mL). The combined extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography eluting with a gradient of CH2Cl2:MeOH:0.88 ammonia (100:8:1) to give the title compound as a colourless oil (15 mg, 22%). The residue given was partitioned between saturated aqueous sodium hydrogencarbonate solution (25 mL) and ether (15 mL) The phases were separated the aqueous layer was further extracted with ether (2×15 mL) The combined extracts were dried over MgSO4 filtered concentrated in vacuo The residue was purified by chromatography eluting with a gradient of CH2Cl2