2-bromo-1-cyclopropylpropan-1-one

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

Procedure: To a solution of N-(5-iodopyridin-2-yl)-4-methylbenzenesulfonamide (33.1 g) in DMF (400 mL) was added sodium hydride (60% oil dispersion, 3.89 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Then 2-bromo-1-cyclopropylpropan-1-one (23.5 g) was added to the obtained mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting solid was suspended in diisopropyl ether, the suspension was stirred for 1 hr, and the solid was collected by filtration. The obtained solid was dissolved in ethyl acetate (1100 mL) at 70° C., and hexane (400 mL) was dropwise added at 60° C. The mixture was allowed to cool to room temperature overnight. The resulting precipitate was collected by filtration, washed with hexane/ethyl acetate (1/1) 3 times, and dried to give the title compound (30.5 g) as a white solid. the mixture was stirred at room temperature overnight extracted with ethyl acetate The obtained organic layer was washed with brine dried over magnesium sulfate concentrated in vacuo the suspension was stirred for 1 hr the solid was collected by filtration The obtained solid was dissolved in ethyl acetate (1100 mL) at 70° C. hexane (400 mL) was dropwise added at 60° C to cool to room temperature overnight The resulting precipitate was collected by filtration washed with hexane/ethyl acetate (1/1) 3 times dried

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

Procedure: To a solution of N-(5-iodopyridin-2-yl)-4-methylbenzenesulfonamide (33.1 g) in DMF (400 mL) was added sodium hydride (60% oil dispersion, 3.89 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Then 2-bromo-1-cyclopropylpropan-1-one (23.5 g) was added to the obtained mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting solid was suspended in diisopropyl ether, the suspension was stirred for 1 hr, and the solid was collected by filtration. The obtained solid was dissolved in ethyl acetate (1100 mL) at 70° C., and hexane (400 mL) was dropwise added at 60° C. The mixture was allowed to cool to room temperature overnight. The resulting precipitate was collected by filtration, washed with hexane/ethyl acetate (1/1) 3 times, and dried to give the title compound (30.5 g) as a white solid. the mixture was stirred at room temperature overnight extracted with ethyl acetate The obtained organic layer was washed with brine dried over magnesium sulfate concentrated in vacuo the suspension was stirred for 1 hr the solid was collected by filtration The obtained solid was dissolved in ethyl acetate (1100 mL) at 70° C. hexane (400 mL) was dropwise added at 60° C to cool to room temperature overnight The resulting precipitate was collected by filtration washed with hexane/ethyl acetate (1/1) 3 times dried

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

Procedure: The solution of tert-butyl 2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (300.00 mg, 1.29 mmol), 2-bromo-1-cyclopropylpropan-1-one (342.98 mg, 1.94 mmol), Cs2CO3 (841.63 mg, 2.58 mmol), KI (42.88 mg, 0.26 mmol) in DMF (4 ml) were stirred at 25° C. for 18 h. After the reaction completed, the solution was partitioned between EtOAc and H2O. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column (Eluent: PE:EtOAc=10:1) to get tert-butyl 1-(1-cyclopropyl-1-oxopropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate as a white oil. (230 mg, yield 54%). the solution was partitioned between EtOAc and H2O The organic layer was separated dried over Na2SO4 evaporated under reduced pressure The residue was purified by flash column (Eluent: PE:EtOAc=10:1)

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

Procedure: The solution of tert-butyl 2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (300.00 mg, 1.29 mmol), 2-bromo-1-cyclopropylpropan-1-one (342.98 mg, 1.94 mmol), Cs2CO3 (841.63 mg, 2.58 mmol), KI (42.88 mg, 0.26 mmol) in DMF (4 ml) were stirred at 25° C. for 18 h. After the reaction completed, the solution was partitioned between EtOAc and H2O. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column (Eluent: PE:EtOAc=10:1) to get tert-butyl 1-(1-cyclopropyl-1-oxopropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate as a white oil. (230 mg, yield 54%). the solution was partitioned between EtOAc and H2O The organic layer was separated dried over Na2SO4 evaporated under reduced pressure The residue was purified by flash column (Eluent: PE:EtOAc=10:1)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-bromopyrimidin-2-amine (500 mg) in DMF (10 ml) was added 2-bromo-1-cyclopropylpropan-1-one (1.02 g) at room temperature, and the mixture was stirred at 100° C. for 24 h. The mixture was partitioned between EtOAc and 1 M NaOH, and the organic layer was washed with 1 M NaOH and brine successively, dried over MgSO4, concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (89 mg) as yellow crystals. The mixture was partitioned between EtOAc and 1 M NaOH the organic layer was washed with 1 M NaOH and brine successively dried over MgSO4 concentrated in vacuo purified by NH silica gel column chromatography (hexane/EtOAc)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-bromopyrimidin-2-amine (500 mg) in DMF (10 ml) was added 2-bromo-1-cyclopropylpropan-1-one (1.02 g) at room temperature, and the mixture was stirred at 100° C. for 24 h. The mixture was partitioned between EtOAc and 1 M NaOH, and the organic layer was washed with 1 M NaOH and brine successively, dried over MgSO4, concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (89 mg) as yellow crystals. The mixture was partitioned between EtOAc and 1 M NaOH the organic layer was washed with 1 M NaOH and brine successively dried over MgSO4 concentrated in vacuo purified by NH silica gel column chromatography (hexane/EtOAc)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-bromopyridazin-3-amine (1.0 g) in DMA (10 ml) were added 2-bromo-1-cyclopropylpropan-1-one (2.04 g) and NaHCO3 (0.966 g) at room temperature, and the mixture was stirred at 80° C. for 16 h. The mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.10 g) as yellow crystals. The mixture was partitioned between EtOAc and water the organic layer was washed with brine dried over MgSO4 concentrated in vacuo purified by silica gel column chromatography (hexane/EtOAc)

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

Procedure: To a solution of N-(5-bromopyrazin-2-yl)-4-methylbenzenesulfonamide (1.73 g) in DMF (20 ml) was added NaH (60% in oil, 0.316 g) at 0° C., and the mixture was stirred at room temperature for 30 min. To the mixture was added 2-bromo-1-cyclopropylpropan-1-one (1.87 g) at room temperature, and the mixture was stirred overnight. The mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.02 g) as a solid. the mixture was stirred overnight The mixture was partitioned between EtOAc and water the organic layer was washed with brine dried over MgSO4 concentrated in vacuo purified by silica gel column chromatography (hexane/EtOAc)

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

Procedure: A mixture of 5-iodo-3-methylpyridin-2-amine (100 mg), 2-bromo-1-cyclopropylpropan-1-one (113 mg) and DMF (1 ml) was stirred at 80° C. under a dry atmosphere (CaCl2 tube) overnight. The mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (69.3 mg) as a pale yellow oil. The mixture was quenched with saturated NaHCO3 solution extracted with EtOAc The organic layer was separated washed with water and brine dried over MgSO4 concentrated in vacuo The residue was purified by NH silica gel column chromatography (hexane/EtOAc)

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

Procedure: To a solution of N-(5-iodopyridin-2-yl)-4-methylbenzenesulfonamide (33.1 g) in DMF (400 ml) was added NaH (40% oil dispersion, 3.89 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Then 2-bromo-1-cyclopropylpropan-1-one (23.5 g) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and concentrated. The resulting solid was suspended in IPE, stirred for 1 h, and collected by filtration. The crude product was dissolved in EtOAc (1100 ml) at 70° C., and hexane (400 ml) was added while the temperature was maintained at 60° C. Seed crystal was added, and the mixture was stirred at the same temperature for 1 h. Additional hexane (400 ml) was added at 60° C., and the mixture was allowed to cool to room temperature overnight. The precipitate was collected by filtration, washed with hexane/EtOAc (1/1) 3 times, and dried to give the title compound (30.5 g) as a white solid. the resulting mixture was stirred at room temperature overnight extracted with EtOAc The extract was washed with brine dried over MgSO4 concentrated stirred for 1 h collected by filtration The crude product was dissolved in EtOAc (1100 ml) at 70° C. hexane (400 ml) was added while the temperature was maintained at 60° C Seed crystal was added the mixture was stirred at the same temperature for 1 h Additional hexane (400 ml) was added at 60° C. to cool to room temperature overnight The precipitate was collected by filtration washed with hexane/EtOAc (1/1) 3 times dried

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

Procedure: To a solution of N-(5-iodopyridin-2-yl)-4-methylbenzenesulfonamide (33.1 g) in DMF (400 ml) was added NaH (40% oil dispersion, 3.89 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Then 2-bromo-1-cyclopropylpropan-1-one (23.5 g) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and concentrated. The resulting solid was suspended in IPE, stirred for 1 h, and collected by filtration. The crude product was dissolved in EtOAc (1100 ml) at 70° C., and hexane (400 ml) was added while the temperature was maintained at 60° C. Seed crystal was added, and the mixture was stirred at the same temperature for 1 h. Additional hexane (400 ml) was added at 60° C., and the mixture was allowed to cool to room temperature overnight. The precipitate was collected by filtration, washed with hexane/EtOAc (1/1) 3 times, and dried to give the title compound (30.5 g) as a white solid. the resulting mixture was stirred at room temperature overnight extracted with EtOAc The extract was washed with brine dried over MgSO4 concentrated stirred for 1 h collected by filtration The crude product was dissolved in EtOAc (1100 ml) at 70° C. hexane (400 ml) was added while the temperature was maintained at 60° C Seed crystal was added the mixture was stirred at the same temperature for 1 h Additional hexane (400 ml) was added at 60° C. to cool to room temperature overnight The precipitate was collected by filtration washed with hexane/EtOAc (1/1) 3 times dried

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Cyclopropyl-5-methyl-1H-imidazole was synthesized according to the following procedure: Under nitrogen with stirring formamidine acetate (15.62 g, 150 mmol) was suspended in 40 ml anhydrous ethanol. 2-bromo-1-cyclopropylpropan-1-one (2.64 g, 15 mmol) was added via syringe and the mixture was heated to 60° C. for 2 hours. Triethylamine (21 ml, 155 mmol) was then added and the reaction was heated for an additional 12 hours at 60° C. The solvent was removed under reduced pressure, and the residue was dissolved in 50 ml of water. An aqueous solution of saturated sodium bicarbonate (20 ml) was added, followed by sodium chloride until the solution became saturated. The mixture was placed in a separatory funnel and extracted with ethyl acetate (3×50 ml), the organic extracts combined, dried over magnesium sulfate, filtered and then the solvent removed under reduced pressure. The oily residue was washed with hexanes (2×100 ml) to remove any residual triethylamine, leaving an oily residue which was >90% pure by 1H-NMR, which was further purified by loading onto a silica gel column in ethyl acetate and eluting with 0 to 10% methanol in ethyl acetate. Yield 0.607 g, 33% the reaction was heated for an additional 12 hours at 60° C The solvent was removed under reduced pressure the residue was dissolved in 50 ml of water An aqueous solution of saturated sodium bicarbonate (20 ml) was added The mixture was placed in a separatory funnel extracted with ethyl acetate (3×50 ml) dried over magnesium sulfate filtered the solvent removed under reduced pressure The oily residue was washed with hexanes (2×100 ml) to remove any residual triethylamine leaving an oily residue which was further purified eluting with 0 to 10% methanol in ethyl acetate