1-(2-bromoethoxymethyl)-4-methoxybenzene

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

Procedure: To a tetrahydrofuran solution (2 ml) of tert-butyl 4-(7-chloro-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (Reference Example 9-3) (438 mg) was added dropwise at −20° C. a hexane solution (1.0 M, 1.32 ml) of lithium hexamethyldisilazide over 10 minutes. After the reaction solution was stirred for 30 minutes, was added dropwise a tetrahydrofuran solution of 1-(2-bromoethoxymethyl)-4-methoxybenzene (Journal of Medicinal Chemistry, 2007, 50(26), 6580-6595)(324 mg) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (315 mg). The reaction solution was brought to 0° C. over 30 minutes, and then stirred for 90 minutes. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-[7-chloro-3-{2-[(4-methoxybenzyl)oxy]ethyl}-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl]piperidine-1-carboxylate (189 mg). The reaction solution was brought to 0° C. over 30 minutes stirred for 90 minutes extracted with ethyl acetate The organic layer was washed with saturated sodium chloride solution dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography

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

Procedure: To a tetrahydrofuran solution (2 ml) of tert-butyl 4-(7-chloro-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (Reference Example 9-3) (438 mg) was added dropwise at −20° C. a hexane solution (1.0 M, 1.32 ml) of lithium hexamethyldisilazide over 10 minutes. After the reaction solution was stirred for 30 minutes, was added dropwise a tetrahydrofuran solution of 1-(2-bromoethoxymethyl)-4-methoxybenzene (Journal of Medicinal Chemistry, 2007, 50(26), 6580-6595)(324 mg) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (315 mg). The reaction solution was brought to 0° C. over 30 minutes, and then stirred for 90 minutes. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-[7-chloro-3-{2-[(4-methoxybenzyl)oxy]ethyl}-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl]piperidine-1-carboxylate (189 mg). The reaction solution was brought to 0° C. over 30 minutes stirred for 90 minutes extracted with ethyl acetate The organic layer was washed with saturated sodium chloride solution dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography

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

Procedure: A mixture of 1-(2-bromo-ethoxymethyl)-4-methoxy-benzene (42 mg) and 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (50 mg) in MeCN (1 mL) was stirred at room temperature for 16 h then heated to 80° C. under nitrogen overnight. A further 1.1 equivalents of 1-(2-bromo-ethoxymethyl)-4-methoxy -benzene were added and the mixture was heated at 80° C. for a further 48 h. The volatiles were evaporated and the crude product was purified by silica gel chromatography eluting with 0-10% of a 10% conc. NH3/MeOH solution in dichloromethane give 61 mg of an oil that was purified further by reverse phase HPLC (Gemini 5 μM C6 phenyl column) eluting with 5-95% MeOH/H2O containing 0.1% formic acid over 30 min with UV detection at 220 nm. The relevant fractions were combined and evaporated to afford the title compound (34 mg) as an oil. then heated to 80° C. under nitrogen overnight the mixture was heated at 80° C. for a further 48 h The volatiles were evaporated the crude product was purified by silica gel chromatography eluting with 0-10% of a 10% conc. NH3/MeOH solution in dichloromethane

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

Procedure: To a tetrahydrofuran solution (2 ml) of tert-butyl 4-(7-chloro-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (Reference Example 9-3) (438 mg) was added dropwise at −20° C. a hexane solution (1.0 M, 1.32 ml) of lithium hexamethyldisilazide over 10 minutes. After the reaction solution was stirred for 30 minutes, was added dropwise a tetrahydrofuran solution of 1-(2-bromoethoxymethyl)-4-methoxybenzene (Journal of Medicinal Chemistry, 2007, 50(26), 6580-6595)(324 mg) and 1,3-dimethyltetrahydropyrimidin-2(1H)-one (315 mg). The reaction solution was brought to 0° C. over 30 minutes, and then stirred for 90 minutes. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-[7-chloro-3-{2-[(4-methoxybenzyl)oxy]ethyl}-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl]piperidine-1-carboxylate (189 mg). The reaction solution was brought to 0° C. over 30 minutes stirred for 90 minutes extracted with ethyl acetate The organic layer was washed with saturated sodium chloride solution dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography