N-methoxy-1-phenylmethanamine

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

Procedure: To a round bottom flask that has been fire dried, flushed with a continuous stream of argon, and equipped with a stir bean, DMF (4.8 ml) was added. To this stirring solution 5 (600 mg, 2.33 mmol), was combined with methoxybenzylamine (328 μL, 2.56 mmol), and PyBOP (1.33 g, 2.56 mmol). This solution was then cooled to a temperature of 0 degrees C. After 2 minutes diisopropylamine (1.7 ml, 9.67 mmol) was added and the entire solution was allowed to stir at room temperature overnight. The reaction was then diluted with roughly 60 ml of ethyl acetate and extracted 3× with saturated sodium bicarbonate, and 3× with 1M HCl in appropriate volumes to remove any unreacted starting materials. The ethyl acetate layer was isolated and dried over sodium sulfate. The ethyl acetate was removed using a rotary evaporator to yield a brownish film on the sides of the flask. Hexanes were added to the flask and refluxed. A solid then formed on the sides of the flask, and the hexanes were removed via rotary evaporator to give 709.0 mg of 6 (81% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.537 (bs, 1H), δ 9.092 (t, J=5.6 Hz, 1H), δ 7.49 (dd, J=9.4 Hz, J=2.4 Hz 1H), 8 (dd, J=8.8 Hz, J=2 Hz 1H), δ 7.268-7.228 (m, 2H), δ 6.91 (d, J=6.8 Hz, 2H), δ 6.82 (d, J=8.2 Hz, 1H), δ 4.48 (d, J=6 Hz, 2H), δ 3.729 (s, 3H). To a round bottom flask that has been fire dried flushed with a continuous stream of argon equipped with a stir bean, DMF (4.8 ml) was added extracted 3× with saturated sodium bicarbonate, and 3× with 1M HCl in appropriate volumes to remove The ethyl acetate layer was isolated dried over sodium sulfate The ethyl acetate was removed a rotary evaporator to yield a brownish film on the sides of the flask refluxed A solid then formed on the sides of the flask the hexanes were removed via rotary evaporator

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

Procedure: A solution of the pyrazinone 18-3 (5 g, 15.3 mmol) and 4 methoxybenzylamine (6.0 mL, 45.9 mmol) in EtOAc (60 mL) was heated at 80° C. for 2 h. The solution was cooled and filtered. The filtrate was concentrated in vacuo, the residue swished with MeOH and filtered to afford the title compound as a solid: The solution was cooled filtered The filtrate was concentrated in vacuo filtered

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The 2,6-dichloropurine (4.06 g, 21.5 mmol) was suspended in n-butanol (150 ml) and the 4 methoxybenzylamine was added (3.4 ml, 26 mmol). The solution turned clear and then cloudy a few minutes later. The solution was heated at 120° C. for 2 hr and then cooled. The n-butanol was evaporated followed by suspension of the residue in water and diethyl ether mixture. A solution of 2N NaOH (1.3 ml, 26 mmol) was added and the solution stirred for 10 min before filtration. The filtered precipitate was washed with water and a small portion of ether and then dried under vacuum. The residual liquor was left overnight and more crystals were collected the next day and washed with diethyl ether. cloudy a few minutes cooled The n-butanol was evaporated followed by suspension of the residue in water The filtered precipitate was washed with water a small portion of ether and then dried under vacuum The residual liquor was left overnight more crystals were collected the next day washed with diethyl ether

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The 2,6-dichloropurine (4.06 g, 21.5 mmol) was suspended in n-butanol (150 ml) and the 4 methoxybenzylamine was added (3.4 ml, 26 mmol). The solution turned clear and then cloudy a few minutes later. The solution was heated at 120° C. for 2 hr and then cooled. The n-butanol was evaporated followed by suspension of the residue in water and diethyl ether mixture. A solution of 2N NaOH (1.3 ml, 26 mmol) was added and the solution stirred for 10 min before filtration. The filtered precipitate was washed with water and a small portion of ether and then dried under vacuum. The residual liquor was left overnight and more crystals were collected the next day and washed with diethyl ether. cloudy a few minutes cooled The n-butanol was evaporated followed by suspension of the residue in water The filtered precipitate was washed with water a small portion of ether and then dried under vacuum The residual liquor was left overnight more crystals were collected the next day washed with diethyl ether

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

Procedure: To a round bottom flask that has been fire dried, flushed with a continuous stream of argon, and equipped with a stir bean, DMF (4.8 ml) was added. To this stirring solution 5 (600 mg, 2.33 mmol), was combined with methoxybenzylamine (328 μL, 2.56 mmol), and PyBOP (1.33 g, 2.56 mmol). This solution was then cooled to a temperature of 0 degrees C. After 2 minutes diisopropylamine (1.7 ml, 9.67 mmol) was added and the entire solution was allowed to stir at room temperature overnight. The reaction was then diluted with roughly 60 ml of ethyl acetate and extracted 3× with saturated sodium bicarbonate, and 3× with 1M HCl in appropriate volumes to remove any unreacted starting materials. The ethyl acetate layer was isolated and dried over sodium sulfate. The ethyl acetate was removed using a rotary evaporator to yield a brownish film on the sides of the flask. Hexanes were added to the flask and refluxed. A solid then formed on the sides of the flask, and the hexanes were removed via rotary evaporator to give 709.0 mg of 6 (81% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.537 (bs, 1H), δ 9.092 (t, J=5.6 Hz, 1H), δ 7.49 (dd, J=9.4 Hz, J=2.4 Hz 1H), δ (dd, J=8.8 Hz, J=2 Hz 1H), δ 7.268-7.228 (m, 2H), δ 6.91 (d, J=6.8 Hz, 2H), δ 6.82 (d, J=8.2 Hz, 1H), δ 4.48 (d, J=6 Hz, 2H), δ 3.729 (s, 3H). 7-bromo-5-fluoro-1H-indole-2-carboxylic acid 3-hydroxy-benzylamide (7) To a round bottom flask that has been fire dried flushed with a continuous stream of argon equipped with a stir bean, DMF (4.8 ml) was added extracted 3× with saturated sodium bicarbonate, and 3× with 1M HCl in appropriate volumes to remove The ethyl acetate layer was isolated dried over sodium sulfate The ethyl acetate was removed a rotary evaporator to yield a brownish film on the sides of the flask refluxed A solid then formed on the sides of the flask the hexanes were removed via rotary evaporator

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

Procedure: To a round bottom flask that has been fire dried, flushed with a continuous stream of argon, and equipped with a stir bean, DMF (4.8 ml) was added. To this stirring solution 5 (600 mg, 2.33 mmol), was combined with methoxybenzylamine (328 μL, 2.56 mmol), and PyBOP (1.33 g, 2.56 mmol). This solution was then cooled to a temperature of 0 degrees C. After 2 minutes diisopropylamine (1.7 ml, 9.67 mmol) was added and the entire solution was allowed to stir at room temperature overnight. The reaction was then diluted with roughly 60 ml of ethyl acetate and extracted 3× with saturated sodium bicarbonate, and 3× with 1M HCl in appropriate volumes to remove any unreacted starting materials. The ethyl acetate layer was isolated and dried over sodium sulfate. The ethyl acetate was removed using a rotary evaporator to yield a brownish film on the sides of the flask. Hexanes were added to the flask and refluxed. A solid then formed on the sides of the flask, and the hexanes were removed via rotary evaporator to give 709.0 mg of 6 (81% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.537 (bs, 1H), δ 9.092 (t, J=5.6 Hz, 1H), δ 7.49 (dd, J=9.4 Hz, J=2.4 Hz 1H), δ (dd, J=8.8 Hz, J=2 Hz 1H), δ 7.268-7.228 (m, 2H), δ 6.91 (d, J=6.8 Hz, 2H), δ 6.82 (d, J=8.2 Hz, 1H), δ 4.48 (d, J=6 Hz, 2H), δ 3.729 (s, 3H). To a round bottom flask that has been fire dried flushed with a continuous stream of argon equipped with a stir bean, DMF (4.8 ml) was added extracted 3× with saturated sodium bicarbonate, and 3× with 1M HCl in appropriate volumes to remove The ethyl acetate layer was isolated dried over sodium sulfate The ethyl acetate was removed a rotary evaporator to yield a brownish film on the sides of the flask refluxed A solid then formed on the sides of the flask the hexanes were removed via rotary evaporator

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

Procedure: To a round bottom flask that has been fire dried, flushed with a continuous stream of argon, and equipped with a stir bean, DMF (4.8 ml) was added. To this stirring solution 5 (600 mg, 2.33 mmol), was combined with methoxybenzylamine (328 μL, 2.56 mmol), and PyBOP (1.33 g, 2.56 mmol). This solution was then cooled to a temperature of 0 degrees C. After 2 minutes diisopropylamine (1.7 ml, 9.67 mmol) was added and the entire solution was allowed to stir at room temperature overnight. The reaction was then diluted with roughly 60 ml of ethyl acetate and extracted 3× with saturated sodium bicarbonate, and 3× with 1M HCl in appropriate volumes to remove any unreacted starting materials. The ethyl acetate layer was isolated and dried over sodium sulfate. The ethyl acetate was removed using a rotary evaporator to yield a brownish film on the sides of the flask. Hexanes were added to the flask and refluxed. A solid then formed on the sides of the flask, and the hexanes were removed via rotary evaporator to give 709.0 mg of 6 (81% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.537 (bs, 1H), δ 9.092 (t, J=5.6 Hz, 1H), δ 7.49 (dd, J=9.4 Hz, J=2.4 Hz 1H), 8 (dd, J=8.8 Hz, J=2 Hz 1H), δ 7.268-7.228 (m, 2H), δ 6.91 (d, J=6.8 Hz, 2H), δ 6.82 (d, J=8.2 Hz, 1H), δ 4.48 (d, J=6 Hz, 2H), δ 3.729 (s, 3H). To a round bottom flask that has been fire dried flushed with a continuous stream of argon equipped with a stir bean, DMF (4.8 ml) was added extracted 3× with saturated sodium bicarbonate, and 3× with 1M HCl in appropriate volumes to remove The ethyl acetate layer was isolated dried over sodium sulfate The ethyl acetate was removed a rotary evaporator to yield a brownish film on the sides of the flask refluxed A solid then formed on the sides of the flask the hexanes were removed via rotary evaporator

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

Procedure: A solution of the pyrazinone 18-3 (5 g, 15.3 mmol) and 4 methoxybenzylamine (6.0 mL, 45.9 mmol) in EtOAc (60 mL) was heated at 80° C. for 2 h. The solution was cooled and filtered. The filtrate was concentrated in vacuo, the residue swished with MeOH and filtered to afford the title compound as a solid: The solution was cooled filtered The filtrate was concentrated in vacuo filtered

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

Procedure: A solution of the pyrazinone 18-3 (5 g, 15.3 mmol) and 4 methoxybenzylamine (6.0 mL, 45.9 mmol) in EtOAc (60 mL) was heated at 80° C. for 2 h. The solution was cooled and filtered. The filtrate was concentrated in vacuo, the residue swished with MeOH and filtered to afford the title compound as a solid: The solution was cooled filtered The filtrate was concentrated in vacuo filtered

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

Procedure: To a round bottom flask that has been fire dried, flushed with a continuous stream of argon, and equipped with a stir bean, DMF (4.8 ml) was added. To this stirring solution 5 (600 mg, 2.33 mmol), was combined with methoxybenzylamine (328□L, 2.56 mmol), and PyBOP (1.33 g, 2.56 mmol). This solution was then cooled to a temperature of 0 degrees C. After 2 minutes diisopropylamine (1.7 ml, 9.67 mmol) was added and the entire solution was allowed to stir at room temperature overnight. The reaction was then diluted with roughly 60 ml of ethyl acetate and extracted 3× with saturated sodium bicarbonate, and 3× with 1M HCl in appropriate volumes to remove any unreacted starting materials. The ethyl acetate layer was isolated and dried over sodium sulfate. The ethyl acetate was removed using a rotary evaporator to yield a brownish film on the sides of the flask. Hexanes were added to the flask and refluxed. A solid then formed on the sides of the flask, and the hexanes were removed via rotary evaporator to give 709.0 mg of 6 (81% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.537 (bs, 1H), δ 9.092 (t, J=5.6 Hz, 1H), δ 7.49 (dd, J=9.4 Hz, J=2.4 Hz 1H), δ (dd, J=8.8 Hz, J=2 Hz 1H), δ 7.268-7.228 (m, 2H), δ 6.91 (d, J=6.8 Hz, 2H), δ 6.82 (d, J=8.2 Hz, 1H), δ 4.48 (d, J=6 Hz, 2H), δ 3.729 (s, 3H). To a round bottom flask that has been fire dried flushed with a continuous stream of argon equipped with a stir bean, DMF (4.8 ml) was added extracted 3× with saturated sodium bicarbonate, and 3× with 1M HCl in appropriate volumes to remove The ethyl acetate layer was isolated dried over sodium sulfate The ethyl acetate was removed a rotary evaporator to yield a brownish film on the sides of the flask refluxed A solid then formed on the sides of the flask the hexanes were removed via rotary evaporator

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

Procedure: To a round bottom flask that has been fire dried, flushed with a continuous stream of argon, and equipped with a stir bean, DMF (4.8 ml) was added. To this stirring solution 5 (600 mg, 2.33 mmol), was combined with methoxybenzylamine (328□L, 2.56 mmol), and PyBOP (1.33 g, 2.56 mmol). This solution was then cooled to a temperature of 0 degrees C. After 2 minutes diisopropylamine (1.7 ml, 9.67 mmol) was added and the entire solution was allowed to stir at room temperature overnight. The reaction was then diluted with roughly 60 ml of ethyl acetate and extracted 3× with saturated sodium bicarbonate, and 3× with 1M HCl in appropriate volumes to remove any unreacted starting materials. The ethyl acetate layer was isolated and dried over sodium sulfate. The ethyl acetate was removed using a rotary evaporator to yield a brownish film on the sides of the flask. Hexanes were added to the flask and refluxed. A solid then formed on the sides of the flask, and the hexanes were removed via rotary evaporator to give 709.0 mg of 6 (81% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.537 (bs, 1H), δ 9.092 (t, J=5.6 Hz, 1H), δ 7.49 (dd, J=9.4 Hz, J=2.4 Hz 1H), δ (dd, J=8.8 Hz, J=2 Hz 1H), δ 7.268-7.228 (m, 2H), δ 6.91 (d, J=6.8 Hz, 2H), δ 6.82 (d, J=8.2 Hz, 1H), δ 4.48 (d, J=6 Hz, 2H), δ 3.729 (s, 3H). To a round bottom flask that has been fire dried flushed with a continuous stream of argon equipped with a stir bean, DMF (4.8 ml) was added extracted 3× with saturated sodium bicarbonate, and 3× with 1M HCl in appropriate volumes to remove The ethyl acetate layer was isolated dried over sodium sulfate The ethyl acetate was removed a rotary evaporator to yield a brownish film on the sides of the flask refluxed A solid then formed on the sides of the flask the hexanes were removed via rotary evaporator

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

Procedure: The procedure of Example VI is repeated using 15.0 g of O-methylbenzaldoxime, and 20.0 g of sodium cyanoborohydride in 100 ml of methanol. Bulb to bulb distillation of the crude product affords the title compound as a colorless liquid. Bulb to bulb distillation of the crude product