(3-bromo-2-methoxyphenyl)methanamine

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

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

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Hydrazine hydrate (7.8 g, 154 mmol) was added to a suspension of 2-{[3-bromo-2-(methyloxy)phenyl]methyl}-1H-isoindole-1,3(2H)-dione (26.7 g, 77.2 mmol) in EtOH (300 mL) and the reaction mixture was heated to 90° C. for 4 h. After cooling to room temperature, the mixture was filtered and the solid was washed with EtOAc (300 mL×2). The filtrate was evaporated to about 50 mL and filtered again. After removing the solvent, the residue was dissolved in 20 mL of MeOH, and then 1N HCl was added to obtain a white solid. Then the white solid was recrystallized from MeOH-Et2O to obtain 9.0 g of the product (yield: 46.3%). 1H NMR (400 MHz, D2O) δ 3.79 (s, 3H), 4.13 (s, 2H), 7.02 (t, J=7.6 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H); 13C NMR (100 MHz, D2O) δ 37.7, 60.2, 115.6, 125.3, 126.6, 128.8, 133.8, 153.7; MS: m/z 254.1 (M+); HPLC: retention time: 7.618 min; purity: 98.8%. After cooling to room temperature the mixture was filtered the solid was washed with EtOAc (300 mL×2) The filtrate was evaporated to about 50 mL filtered again After removing the solvent the residue was dissolved in 20 mL of MeOH 1N HCl was added to obtain a white solid Then the white solid was recrystallized from MeOH-Et2O

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Hydrazine hydrate (7.8 g, 154 mmol) was added to a suspension of 2-{[3-bromo-2-(methyloxy)phenyl]methyl}-1H-isoindole-1,3(2H)-dione (26.7 g, 77.2 mmol) in EtOH (300 mL) and the reaction mixture was heated to 90° C. for 4 h. After cooling to room temperature, the mixture was filtered and the solid was washed with EtOAc (300 mL×2). The filtrate was evaporated to about 50 mL and filtered again. After removing the solvent, the residue was dissolved in 20 mL of MeOH, and then 1N HCl was added to obtain a white solid. Then the white solid was recrystallized from MeOH-Et2O to obtain 9.0 g of the product (yield: 46.3%). 1H NMR (400 MHz, D2O) δ 3.79 (s, 3H), 4.13 (s, 2H), 7.02 (t, J=7.6 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H); 13C NMR (100 MHz, D2O) δ 37.7, 60.2, 115.6, 125.3, 126.6, 128.8, 133.8, 153.7; MS: m/z 254.1 (M+); HPLC: retention time: 7.618 min; purity: 98.8%. After cooling to room temperature the mixture was filtered the solid was washed with EtOAc (300 mL×2) The filtrate was evaporated to about 50 mL filtered again After removing the solvent the residue was dissolved in 20 mL of MeOH 1N HCl was added to obtain a white solid Then the white solid was recrystallized from MeOH-Et2O

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

Procedure: 1.1 g of potassium hydroxide (KOH) and 5.8 g of triphenyl phophine (Ph3P) were added to a solution of 1-azidomethyl-3-bromo-2-methoxy-benzene 7 in 100 mL of THF and 10 mL of water. The mixture was stirred overnight at room temperature. The mixture was quenched with aqueous concentrated hydrochloride. After standard acid/base aqueous work up, 3.9 g of crude 3-bromo-2-methoxy-benzylamine 8 was obtained (after two steps). The mixture was quenched with aqueous concentrated hydrochloride

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

Procedure: 1.1 g of potassium hydroxide (KOH) and 5.8 g of triphenyl phosphine (Ph3P) were added to a solution of 1-azidomethyl-3-bromo-2-methoxy-benzene 7 in 100 mL of THF and 10 mL of water. The mixture was stirred overnight at room temperature. The mixture was quenched with aqueous concentrated hydrochloride. After standard acid/base aqueous work up, 3.9 g of crude 3-bromo-2-methoxy-benzylamine 8 was obtained (after two steps). The mixture was quenched with aqueous concentrated hydrochloride

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

Procedure: 1.1 g of potassium hydroxide (KOH) and 5.8 g of triphenyl phosphine (Ph3P) were added to a solution of 1-azidomethyl-3-bromo-2-methoxy-benzene 7 in 100 mL of THF and 10 mL of water. The mixture was stirred overnight at room temperature. The mixture was quenched with aqueous concentrated hydrochloride. After standard acid/base aqueous work up, 3.9 g of crude 3-bromo-2-methoxy-benzylamine 8 was obtained (after two steps). The mixture was quenched with aqueous concentrated hydrochloride

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 2-{[3-bromo-2-(methyloxy)phenyl]methyl}-1H-isoindole-1,3(2H)-dione (26.7 g, 77.2 mmol) in EtOH (300 mL), hydrazine hydrate (7.8 g, 154 mmol) was added, and the reaction mixture was heated to 90° C. for 4 h. After cooled to room temperature, the mixture was filtered and the solid was washed with EtOAc (300 mL×2). The filtrate was concentrated to about 50 mL and filtered again. After removing the solvent, the residue was dissolved in 20 mL of MeOH, and then 1N HCl was added to obtain a white solid. Then the white solid was recrystallized with MeOH-Et2O to obtain 9.0 g of the product. Yield: 46.3%. 1H NMR (400 MHz, D2O) δ 3.79 (s, 3H), 4.13 (s, 2H), 7.02 (t, J=7.6 Hz, 1 H), 7.27 (d, J=8.0 Hz, 1 H), 7.57 (d, J=8.0 Hz, 1 H); 13C NMR (100 MHz, D2O) δ 37.7, 60.2, 115.6, 125.3, 126.6, 128.8, 133.8, 153.7; MS: m/z 254.1 (M+); HPLC: retention time: 7.618 min; purity: 98.8%. was added After cooled to room temperature the mixture was filtered the solid was washed with EtOAc (300 mL×2) The filtrate was concentrated to about 50 mL filtered again After removing the solvent the residue was dissolved in 20 mL of MeOH 1N HCl was added to obtain a white solid Then the white solid was recrystallized with MeOH-Et2O

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

Procedure: 10 mL of acetic acid (HOAc) was added to a solution of 3.9 g of 3-bromo-2-methoxy-benzylamine 8 and 3.1 g of methyl 2-(methylthio)-4,5-dihydro-1H-imidazole-1-carboxylate in 100 mL of methanol. The resulting solution was heated to a gentle reflux and refluxed overnight. The solution was cooled to room temperature, quenched with sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over magnesium sulfate. The mixture was then filtered. The solvents were removed under vacuum. The remaining residue was purified by chromatography on silica gel (10% saturated ammonia methanol in dichloromethane) to give (3-bromo-2-methoxy-benzyl-4,5-dihydro-1H-imidazol-2-yl)-amine 9. The resulting solution was heated to a gentle reflux refluxed overnight quenched with sodium hydroxide extracted with ethyl acetate The combined organic extracts were washed with brine dried over magnesium sulfate The mixture was then filtered The solvents were removed under vacuum The remaining residue was purified by chromatography on silica gel (10% saturated ammonia methanol in dichloromethane)

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

Procedure: 10 mL of acetic acid (HOAc) was added to a solution of 3.9 g of 3-bromo-2-methoxy-benzylamine 8 and 3.1 g of methyl 2-(methylthio)-4,5-dihydro-1H-imidazole-1-carboxylate in 100 mL of methanol. The resulting solution was heated to a gentle reflux and refluxed overnight. The solution was cooled to room temperature, quenched with sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over magnesium sulfate. The mixture was then filtered. The solvents were removed under vacuum. The remaining residue was purified by chromatography on silica gel (10% saturated ammonia methanol in dichloromethane) to give (3-bromo-2-methoxy-benzyl-4,5-dihydro-1H-imidazol-2-yl)-amine 9. The resulting solution was heated to a gentle reflux refluxed overnight quenched with sodium hydroxide extracted with ethyl acetate The combined organic extracts were washed with brine dried over magnesium sulfate The mixture was then filtered The solvents were removed under vacuum The remaining residue was purified by chromatography on silica gel (10% saturated ammonia methanol in dichloromethane)

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

Procedure: 1.1 g of potassium hydroxide (KOH) and 5.8 g of triphenyl phosphine (Ph3P) were added to a solution of 1-azidomethyl-3-bromo-2-methoxy-benzene 7 in 100 mL of THF and 10 mL of water. The mixture was stirred overnight at room temperature. The mixture was quenched with aqueous concentrated hydrochloride. After standard acid/base aqueous work up, 3.9 g of crude 3-bromo-2-methoxy-benzylamine 8 was obtained (after two steps). The mixture was quenched with aqueous concentrated hydrochloride

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