4-amino-2-methoxybenzonitrile

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

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methoxy-4-nitro-benzonitrile (500 mg, 2.81 mmol) was suspended into 4 mL AcOH/EtOAc (1:1) and the resulting mixture was heated to 75° C. to give a clear solution. Fe powder (313 mg, 5.61 mmol, 325 Mesh) was added and the mixture was stirred for 30 min, after which additional Fe powder (313 mg, 5.61 mmol, 325 Mesh) was introduced. The mixture was stirred at 75° C. for an additonal 30 min, and then cooled to rt and filtered, eluting with EtOAc. The filtrate was concentrated in vacuo, re-dissolved in EtOAc, filtered (eluting with EtOAc) and concentrated. Purification was achieved by silica gel flash chromatography with 0 to 10% MeOH in CH2Cl2 to give compound 848A as a tan solid. to give a clear solution The mixture was stirred at 75° C. for an additonal 30 min cooled to rt filtered eluting with EtOAc The filtrate was concentrated in vacuo re-dissolved in EtOAc filtered (eluting with EtOAc) concentrated Purification

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methoxy-4-nitro-benzonitrile (500 mg, 2.81 mmol) was suspended into 4 mL AcOH/EtOAc (1:1) and the resulting mixture was heated to 75° C. to give a clear solution. Fe powder (313 mg, 5.61 mmol, 325 Mesh) was added and the mixture was stirred for 30 min, after which additional Fe powder (313 mg, 5.61 mmol, 325 Mesh) was introduced. The mixture was stirred at 75° C. for an additonal 30 min, and then cooled to rt and filtered, eluting with EtOAc. The filtrate was concentrated in vacuo, re-dissolved in EtOAc, filtered (eluting with EtOAc) and concentrated. Purification was achieved by silica gel flash chromatography with 0 to 10% MeOH in CH2Cl2 to give compound 848A as a tan solid. to give a clear solution The mixture was stirred at 75° C. for an additonal 30 min cooled to rt filtered eluting with EtOAc The filtrate was concentrated in vacuo re-dissolved in EtOAc filtered (eluting with EtOAc) concentrated Purification

Conditions: temp:100.01; pressure:0.00; stir:

Procedure: 4-amino-2-methoxybenzonitrile (72.9 mg, 0.49 mmol), (R)-2-(8-chloro-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanol (150 mg, 0.49 mmol), Palladium acetate (11.05 mg, 0.05 mmol), 2-(Dicyclohexylphosphino)biphenyl (17.25 mg, 0.05 mmol)and Cesium carbonate (481 mg, 1.48 mmol) were added to a microwave vial. 1,2-dimethoxyethane (2 mL) and EtOH (0.500 mL) were added. The reaction mixture was flushed with argon and the mixture was run in a microwave for 60 minutes at 100°C. The solvent was decanted and the solids were washed with 5ml DCM. The solvent was evaporated and the crude product was purified on Si, 0-6% MeOH in DCM, yielding (R)-4-(4-(2-hydroxyethyl)-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-ylamino)-2-methoxybenzonitrile (27.0 mg, 13.17 %)

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

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methoxy-4-nitro-benzonitrile (500 mg, 2.81 mmol) was suspended into 4 mL AcOH/EtOAc (1:1) and the resulting mixture was heated to 75° C. to give a clear solution. Fe powder (313 mg, 5.61 mmol, 325 Mesh) was added and the mixture was stirred for 30 min, after which additional Fe powder (313 mg, 5.61 mmol, 325 Mesh) was introduced. The mixture was stirred at 75° C. for an additional 30 min, and then cooled to rt and filtered, eluting with EtOAc. The filtrate was concentrated in vacuo, re-dissolved in EtOAc, filtered (eluting with EtOAc) and concentrated. Purification was achieved by silica gel flash chromatography with 0 to 10% MeOH in CH2Cl2 to give compound 848A as a tan solid. to give a clear solution The mixture was stirred at 75° C. for an additional 30 min cooled to rt filtered eluting with EtOAc The filtrate was concentrated in vacuo re-dissolved in EtOAc filtered (eluting with EtOAc) concentrated Purification

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

Procedure: A solution of the compound obtained in Step 1 (670 mg, 4.52 mmol) and 3-methylglutaric anhydride (579 mg, 4.52 mmol) in THF (20 mL) was heated with reflux for 14 hr. The reaction solution was concentrated under reduced pressure to give 5-((4-cyano-3-methoxyphenyl)amino)-3-methyl-5-oxopentanoic acid (1.35 g, 4.89 mmol, quantitative) as a brownish-red oil. with reflux for 14 hr The reaction solution was concentrated under reduced pressure

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

Procedure: A solution of 2-methoxy-4-nitrobenzonitrile (750 mg, 4.21 mmol) and palladium on carbon (50 mg, 0.47 mmol) in methanol (15 mL) was stirred at room temperature for 48 hr under hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4-amino-2-methoxybenzonitrile (679 mg, 4.58 mmol, quantitative) as a brownish-red powder. The catalyst was removed by filtration the filtrate was concentrated under reduced pressure

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

Procedure: A solution of 2-methoxy-4-nitrobenzonitrile (750 mg, 4.21 mmol) and palladium on carbon (50 mg, 0.47 mmol) in methanol (15 mL) was stirred at room temperature for 48 hr under hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4-amino-2-methoxybenzonitrile (679 mg, 4.58 mmol, quantitative) as a brownish-red powder. The catalyst was removed by filtration the filtrate was concentrated under reduced pressure

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methoxy-4-nitro-benzonitrile (500 mg, 2.81 mmol) was suspended into 4 mL AcOH/EtOAc (1:1) and the resulting mixture was heated to 75° C. to give a clear solution. Fe powder (313 mg, 5.61 mmol, 325 Mesh) was added and the mixture was stirred for 30 min, after which additional Fe powder (313 mg, 5.61 mmol, 325 Mesh) was introduced. The mixture was stirred at 75° C. for an additional 30 min, and then cooled to rt and filtered, eluting with EtOAc. The filtrate was concentrated in vacuo, re-dissolved in EtOAc, filtered (eluting with EtOAc) and concentrated. Purification was achieved by silica gel flash chromatography with 0 to 10% MeOH in CH2Cl2 to give compound 848A as a tan solid. to give a clear solution The mixture was stirred at 75° C. for an additional 30 min cooled to rt filtered eluting with EtOAc The filtrate was concentrated in vacuo re-dissolved in EtOAc filtered (eluting with EtOAc) concentrated Purification

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

Procedure: 2-Methoxy-4-nitrobenzonitrile (5.0 g) and iron powder (7.84 g) were suspended in ethanol (150 mL), and concentrated hydrochloric acid (35 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hr, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the obtained solid was washed with hexane to give the title compound as a red-brown solid (yield: 3.05 g, 73%). extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography the obtained solid was washed with hexane

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methoxy-4-nitro-benzonitrile (500 mg, 2.81 mmol) was suspended into 4 mL AcOH/EtOAc (1:1) and the resulting mixture was heated to 75° C. to give a clear solution. Fe powder (313 mg, 5.61 mmol, 325 Mesh) was added and the mixture was stirred for 30 min, after which additional Fe powder (313 mg, 5.61 mmol, 325 Mesh) was introduced. The mixture was stirred at 75° C. for an additonal 30 min, and then cooled to rt and filtered, eluting with EtOAc. The filtrate was concentrated in vacuo, re-dissolved in EtOAc, filtered (eluting with EtOAc) and concentrated. Purification was achieved by silica gel flash chromatography with 0 to 10% MeOH in CH2Cl2 to give compound 848A as a tan solid. to give a clear solution The mixture was stirred at 75° C. for an additonal 30 min cooled to rt filtered eluting with EtOAc The filtrate was concentrated in vacuo re-dissolved in EtOAc filtered (eluting with EtOAc) concentrated Purification