2-(bromomethyl)-1-fluoro-3-methoxybenzene

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

Procedure: 2-(Bromomethyl)-1-fluoro-3-methoxybenzene (3.19 g, 14.57 mmol), (R)-3-(tert-butoxycarbonylamino)piperidine (3.0 g, 12.67 mmol), and K2CO3 (2.63 g, 19.01 mmol) were taken up in DMF (25 mL) in a 50 mL flask. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (100 mL), washed with water (50 mL, ×2), dried over MgSO4, filtered, and the solvent evaporated in vacuo. The residue was purified by flash chromatography (6-50% EtOAc/hexanes) to give (R)-tert-butyl 1-(2-fluoro-6-methoxybenzyl)piperidin-3-ylcarbamate. MS ESI calc'd. For C18H22FN2O3 [M+1]+ 339. found 339. washed with water (50 mL, ×2) dried over MgSO4 filtered the solvent evaporated in vacuo The residue was purified by flash chromatography (6-50% EtOAc/hexanes)

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

Procedure: The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-fluoro-6-methoxybenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.48-7.40 (m, 1 H), 7.32-7.28 (m, 1 H), 7.26-7.17 (m, 1 H), 7.04-6.99 (m, 1 H), 6.90 (dd, J=6.3, 8.3 Hz, 1 H), 6.78-6.69 (m, 2 H), 6.16-6.09 (m, 1 H), 5.62-5.55 (m, 2 H), 5.50-5.42 (m, 1 H), 4.30-4.24 (m, 2 H), 3.83 (d, J=1.8 Hz, 3 H), 2.94-2.78 (m, 2 H), 2.78-2.71 (m, 3 H), 2.07-2.03 (m, 2 H), 1.01-0.93 (s, 9 H); LC/MS (m/z) ES+=533.37 (M+1).

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

Procedure: To a solution of 4-chloro-2-methoxy-5-nitrophenol (0.67 g) and 2-fluoro-6-methoxy-benzyl bromide (0.66 g) in N,N-dimethylformamide (3 mL) was added potassium carbonate (0.54 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the resulting mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water and a mixed solvent (diethyl ether/n-hexane=1/3), and dried under reduced pressure to give 5-chloro-2-(2-fluoro-6-methoxybenzyloxy)-4-nitroanisole (0.97 g). This material was dissolved in tetrahydrofuran (15 mL). To the solution were added methanol (15 mL) and nickel(II) bromide (31 mg). To the mixture was added sodium borohydride (0.32 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−3/2) to give the title compound (0.79 g). the resulting mixture was stirred at room temperature for 30 minutes The precipitated crystals were collected by filtration The collected crystals were washed with water a mixed solvent (diethyl ether/n-hexane=1/3), and dried under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (82 mg, 2.054 mmol) was added to a solution of tert-butyl 2-oxopiperidin-3-ylcarbamate (200 mg, 0.933 mmol) in dimethylformamide (2 ml) at 23° C. and the resulting mixture was allowed to stir for 30 minutes. The mixture was then cooled to 0° C., and a solution of 2-(bromomethyl)-1-fluoro-3-methoxybenzene (214 mg, 0.977 mmol) in dimethylformamide (1.2 ml) added to the reaction mixture drop-wise. The resulting solution was allowed to stir for 90 minutes and was quenched with methanol. The mixture was then diluted with EtOAc, washed with water and brine, dried with magnesium sulfate, filtered and concentrated to afford tert-butyl 1-(2-fluoro-6-methoxybenzyl)-2-oxopiperidin-3-ylcarbamate. The crude product was progressed to the next step without purification. to stir for 90 minutes was quenched with methanol The mixture was then diluted with EtOAc washed with water and brine dried with magnesium sulfate filtered concentrated

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

Procedure: 2-(Bromomethyl)-1-fluoro-3-methoxybenzene (3.19 g, 14.57 mmol), (R)-3-(tert-butoxycarbonylamino)piperidine (3.0 g, 12.67 mmol), and K2CO3 (2.63 g, 19.01 mmol) were taken up in DMF (25 mL) in a 50 mL flask. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (100 mL), washed with water (50 mL, ×2), dried over MgSO4, filtered, and the solvent evaporated in vacuo. The residue was purified by flash chromatography (6-50% EtOAc/hexanes) to give (R)-tert-butyl 1-(2-fluoro-6-methoxybenzyl)piperidin-3-ylcarbamate. MS ESI calc'd. For C18H22FN2O3 [M+1]+ 339. found 339. washed with water (50 mL, ×2) dried over MgSO4 filtered the solvent evaporated in vacuo The residue was purified by flash chromatography (6-50% EtOAc/hexanes)