(5-Bromo-2-iodophenyl)methanamine

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

Procedure: To a stirred solution of (5-bromo-2-iodophenyl)methanamine (40 g, 0.129 mol) in N,N-dimethylformamide (500 mL) was sequentially added N,N-diisopropylethylamine (33.3 g, 0.257 mol), malononitrile (16.9 g, 0.257 mol) and CuBr (36.9 g, 0.257 mol). The mixture was stirred at room temperature overnight. After that, to the reaction mixture was added ether and 10% NH3 (1 L, 1:1) and stirred at room temperature overnight open to the air. The mixture was separated and the residue was extracted with ethyl acetate three times, and the combined organic extracts were washed with brine, filtered, and evaporated to yield 20 g (62%) of 3-amino-7-bromoisoquinoline-4-carbonitrile. LCMS (ESI): M+H=247.7; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.81 (dd, J=2.0, 9.2 Hz, 1H), 7.56 (d, J=9.2 Hz, 1H), 7.42 (s, 2H). stirred at room temperature overnight open to the air The mixture was separated the residue was extracted with ethyl acetate three times the combined organic extracts were washed with brine filtered evaporated

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

Procedure: To a solution of 5-bromo-2-iodobenzonitrile (9.21 g, 0.03 mol) in tetrahydrofuran (140 mL) at 0° C. was added BH3-THF (66 mL, 66 mmol, 1 M solution in tetrahydrofuran) dropwise over 1 hour. The reaction solution was stirred at room temperature for 10 minutes, and then heated to reflux for overnight. 10% aqueous HCl was added (to adjust to pH 2-3) and stirred for 20 minutes, then the mixture was basified with 10 M aqueous KOH up to pH>10. The mixture was extracted with ethyl acetate three times. Organics were combined, dried with sodium sulfate, filtered and concentrated in vacuo to yield 6.2 g of crude (5-bromo-2-iodophenyl)methanamine as a yellow oil. LCMS (ESI): M+H=311.7; 1H NMR (400 MHz, DMSO-d6): δ 7.71 (d, J=8.4 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.18 (dd, J=2.4, 8.4 Hz, 1H). heated to reflux for overnight stirred for 20 minutes The mixture was extracted with ethyl acetate three times dried with sodium sulfate filtered concentrated in vacuo

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

Procedure: To a solution of 5-bromo-2-iodobenzonitrile (9.21 g, 0.03 mol) in tetrahydrofuran (140 mL) at 0° C. was added BH3-THF (66 mL, 66 mmol, 1 M solution in tetrahydrofuran) dropwise over 1 hour. The reaction solution was stirred at room temperature for 10 minutes, and then heated to reflux for overnight. 10% aqueous HCl was added (to adjust to pH 2-3) and stirred for 20 minutes, then the mixture was basified with 10 M aqueous KOH up to pH>10. The mixture was extracted with ethyl acetate three times. Organics were combined, dried with sodium sulfate, filtered and concentrated in vacuo to yield 6.2 g of crude (5-bromo-2-iodophenyl)methanamine as a yellow oil. LCMS (ESI): M+H=311.7; 1H NMR (400 MHz, DMSO-d6): δ 7.71 (d, J=8.4 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.18 (dd, J=2.4, 8.4 Hz, 1H). heated to reflux for overnight stirred for 20 minutes The mixture was extracted with ethyl acetate three times dried with sodium sulfate filtered concentrated in vacuo

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

Procedure: To a stirred solution of (5-bromo-2-iodophenyl)methanamine (40 g, 0.129 mol) in N,N-dimethylformamide (500 mL) was sequentially added N,N-diisopropylethylamine (33.3 g, 0.257 mol), malononitrile (16.9 g, 0.257 mol) and CuBr (36.9 g, 0.257 mol). The mixture was stirred at room temperature overnight. After that, to the reaction mixture was added ether and 10% NH3 (1 L, 1:1) and stirred at room temperature overnight open to the air. The mixture was separated and the residue was extracted with ethyl acetate three times, and the combined organic extracts were washed with brine, filtered, and evaporated to yield 20 g (62%) of 3-amino-7-bromoisoquinoline-4-carbonitrile. LCMS (ESI): M+H=247.7; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.81 (dd, J=2.0, 9.2 Hz, 1H), 7.56 (d, J=9.2 Hz, 1H), 7.42 (s, 2H). stirred at room temperature overnight open to the air The mixture was separated the residue was extracted with ethyl acetate three times the combined organic extracts were washed with brine filtered evaporated

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

Procedure: To a solution of 5-bromo-2-iodobenzonitrile (9.21 g, 0.03 mol) in tetrahydrofuran (140 mL) at 0° C. was added BH3-THF (66 mL, 66 mmol, 1 M solution in tetrahydrofuran) dropwise over 1 hour. The reaction solution was stirred at room temperature for 10 minutes, and then heated to reflux for overnight. 10% aqueous HCl was added (to adjust to pH 2-3) and stirred for 20 minutes, then the mixture was basified with 10 M aqueous KOH up to pH>10. The mixture was extracted with ethyl acetate three times. Organics were combined, dried with sodium sulfate, filtered and concentrated in vacuo to yield 6.2 g of crude (5-bromo-2-iodophenyl)methanamine as a yellow oil. LCMS (ESI): M+H=311.7; 1H NMR (400 MHz, DMSO-d6): δ 7.71 (d, J=8.4 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.18 (dd, J=2.4, 8.4 Hz, 1H). heated to reflux for overnight stirred for 20 minutes The mixture was extracted with ethyl acetate three times dried with sodium sulfate filtered concentrated in vacuo

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

Procedure: To a stirred solution of (5-bromo-2-iodophenyl)methanamine (40 g, 0.129 mol) in N,N-dimethylformamide (500 mL) was sequentially added N,N-diisopropylethylamine (33.3 g, 0.257 mol), malononitrile (16.9 g, 0.257 mol) and CuBr (36.9 g, 0.257 mol). The mixture was stirred at room temperature overnight. After that, to the reaction mixture was added ether and 10% NH3 (1 L, 1:1) and stirred at room temperature overnight open to the air. The mixture was separated and the residue was extracted with ethyl acetate three times, and the combined organic extracts were washed with brine, filtered, and evaporated to yield 20 g (62%) of 3-amino-7-bromoisoquinoline-4-carbonitrile. LCMS (ESI): M+H=247.7; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.81 (dd, J=2.0, 9.2 Hz, 1H), 7.56 (d, J=9.2 Hz, 1H), 7.42 (s, 2H). stirred at room temperature overnight open to the air The mixture was separated the residue was extracted with ethyl acetate three times the combined organic extracts were washed with brine filtered evaporated

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

Procedure: To a solution of 5-bromo-2-iodobenzonitrile (9.21 g, 0.03 mol) in tetrahydrofuran (140 mL) at 0° C. was added BH3-THF (66 mL, 66 mmol, 1 M solution in tetrahydrofuran) dropwise over 1 hour. The reaction solution was stirred at room temperature for 10 minutes, and then heated to reflux for overnight. 10% aqueous HCl was added (to adjust to pH 2-3) and stirred for 20 minutes, then the mixture was basified with 10 M aqueous KOH up to pH>10. The mixture was extracted with ethyl acetate three times. Organics were combined, dried with sodium sulfate, filtered and concentrated in vacuo to yield 6.2 g of crude (5-bromo-2-iodophenyl)methanamine as a yellow oil. LCMS (ESI): M+H=311.7; 1H NMR (400 MHz, DMSO-d6): δ 7.71 (d, J=8.4 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.18 (dd, J=2.4, 8.4 Hz, 1H). heated to reflux for overnight stirred for 20 minutes The mixture was extracted with ethyl acetate three times dried with sodium sulfate filtered concentrated in vacuo