5-formyl-2-hydroxybenzonitrile

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

Procedure: To a solution of 5-formyl-2-hydroxybenzonitrile (200 mg, 1.36 mmol) in acetic acid (4 mL) was added slowly concentrated nitric acid (0.8 mL) at 0° C. The resulting mixture was stirred for 5 hours. Then the mixture was poured into ice-water (40 mL) and ethyl acetate (100 mL). Organic was washed with brine (80 mL), dried over sodium sulfate and evaporated in vacuo, followed by column chromatography (petroleum ether/ethyl acetate=3:1) to give Intermediate 61 (250 mg, yield 96%). Organic was washed with brine (80 mL) dried over sodium sulfate evaporated in vacuo

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-bromo-4-hydroxybenzaldehyde (1.00 g, 4.97 mmol) in DMF (10 mL) was added cuprous cyanide (660 mg, 7.46 mmol). The mixture was heated at 180° C. for 8 hours. The solution was filtered off and purified by chromatography on silica gel (PE/EtOAc=8:1) (210 mg, 29%). The solution was filtered off purified by chromatography on silica gel (PE/EtOAc=8:1) (210 mg, 29%)

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

Procedure: To a solution of 2-hydroxybenzonitrile (4.70 g, 41.6 mmol) in acetic acid (40 mL) was added hexamethylenetetraamine (8.7 g, 62.4 mmol) and the mixture was heated to 120° C. for 2 h. The mixture was cooled to room temperature, followed by a standard aqueous/EtOAc workup and purified by silica gel column chromatography (PE:EA=1:1) to afford 5-formyl-2-hydroxybenzonitrile (Intermediate 47a) as a white powder (540 mg, 9%) and 3-formyl-2-hydroxybenzonitrile (Intermediate 47b) as a white powder (1.17 g, 19%). The mixture was cooled to room temperature purified by silica gel column chromatography (PE:EA=1:1)

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

Procedure: To a solution of 1,2-diphenylethanone (720 mg, 3.67 mmol), 5-formyl-2-hydroxybenzonitrile (Intermediate 47a) (450 mg, 3.06 mmol) and urea (551 mg, 9.18 mmol) in EtOH (23 mL) was added concentrated HCl (0.9 mL). The mixture was stirred at 90° C. for 40 h. Followed standard aqueous workup procedure and recrystallized from EA (6 mL), then further purified by prep-HPLC to afford Compound 96 as a white power (36 mg, 3%). 1H NMR (MeOH-d4 500 MHz): δ 7.50 (t, J=7.5 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.25 (s, 5H), 7.05 (t, J=2.5 Hz, 3H), 6.93 (d, J=8.5 Hz, 1H), 6.85 (t, J=4.0 Hz, 2H), 5.30 (s, 1H); MS (ESI): m/z 368.1 [M+1]+. recrystallized from EA (6 mL) further purified by prep-HPLC

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

Procedure: To a solution of 5-formyl-2-hydroxybenzonitrile (200 mg, 1.36 mmol) in acetic acid (4 mL) was added slowly concentrated nitric acid (0.8 mL) at 0° C. The resulting mixture was stirred for 5 hours. Then the mixture was poured into ice-water (40 mL) and ethyl acetate (100 mL). Organic was washed with brine (80 mL), dried over sodium sulfate and evaporated in vacuo, followed by column chromatography (petroleum ether/ethyl acetate=3:1) to give Intermediate 61 (250 mg, yield 96%). Organic was washed with brine (80 mL) dried over sodium sulfate evaporated in vacuo

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-bromo-4-hydroxybenzaldehyde (1.00 g, 4.97 mmol) in DMF (10 mL) was added cuprous cyanide (660 mg, 7.46 mmol). The mixture was heated at 180° C. for 8 hours. The solution was filtered off and purified by chromatography on silica gel (PE/EtOAc=8:1) (210 mg, 29%). The solution was filtered off purified by chromatography on silica gel (PE/EtOAc=8:1) (210 mg, 29%)

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

Procedure: To a solution of 2-hydroxybenzonitrile (4.70 g, 41.6 mmol) in acetic acid (40 mL) was added hexamethylenetetraamine (8.7 g, 62.4 mmol) and the mixture was heated to 120° C. for 2 h. The mixture was cooled to room temperature, followed by a standard aqueous/EtOAc workup and purified by silica gel column chromatography (PE:EA=1:1) to afford 5-formyl-2-hydroxybenzonitrile (Intermediate 47a) as a white powder (540 mg, 9%) and 3-formyl-2-hydroxybenzonitrile (Intermediate 47b) as a white powder (1.17 g, 19%). The mixture was cooled to room temperature purified by silica gel column chromatography (PE:EA=1:1)

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

Procedure: To a solution of 2-hydroxybenzonitrile (4.70 g, 41.6 mmol) in acetic acid (40 mL) was added hexamethylenetetraamine (8.7 g, 62.4 mmol) and the mixture was heated to 120° C. for 2 h. The mixture was cooled to room temperature, followed by a standard aqueous/EtOAc workup and purified by silica gel column chromatography (PE:EA=1:1) to afford 5-formyl-2-hydroxybenzonitrile (Intermediate 47a) as a white powder (540 mg, 9%) and 3-formyl-2-hydroxybenzonitrile (Intermediate 47b) as a white powder (1.17 g, 19%). The mixture was cooled to room temperature purified by silica gel column chromatography (PE:EA=1:1)

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

Procedure: To a solution of 1,2-diphenylethanone (720 mg, 3.67 mmol), 5-formyl-2-hydroxybenzonitrile (Intermediate 47a) (450 mg, 3.06 mmol) and urea (551 mg, 9.18 mmol) in EtOH (23 mL) was added concentrated HCl (0.9 mL). The mixture was stirred at 90° C. for 40 h. Followed standard aqueous workup procedure and recrystallized from EA (6 mL), then further purified by prep-HPLC to afford Compound 96 as a white power (36 mg, 3%). 1H NMR (MeOH-d4 500 MHz): δ 7.50 (t, J=7.5 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.25 (s, 5H), 7.05 (t, J=2.5 Hz, 3H), 6.93 (d, J=8.5 Hz, 1H), 6.85 (t, J=4.0 Hz, 2H), 5.30 (s, 1H); MS (ESI): m/z 368.1 [M+1]+. recrystallized from EA (6 mL) further purified by prep-HPLC

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

Procedure: To a solution of 5-formyl-2-hydroxybenzonitrile (200 mg, 1.36 mmol) in acetic acid (4 mL) was added slowly concentrated nitric acid (0.8 mL) at 0° C. The resulting mixture was stirred for 5 hours. Then the mixture was poured into ice-water (40 mL) and ethyl acetate (100 mL). Organic was washed with brine (80 mL), dried over sodium sulfate and evaporated in vacuo, followed by column chromatography (petroleum ether/ethyl acetate=3:1) to give Intermediate 61 (250 mg, yield 96%). Organic was washed with brine (80 mL) dried over sodium sulfate evaporated in vacuo

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-bromo-4-hydroxybenzaldehyde (1.00 g, 4.97 mmol) in DMF (10 mL) was added cuprous cyanide (660 mg, 7.46 mmol). The mixture was heated at 180° C. for 8 hours. The solution was filtered off and purified by chromatography on silica gel (PE/EtOAc=8:1) (210 mg, 29%). The solution was filtered off purified by chromatography on silica gel (PE/EtOAc=8:1) (210 mg, 29%)

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

Procedure: To a solution of 2-hydroxybenzonitrile (4.70 g, 41.6 mmol) in acetic acid (40 mL) was added hexamethylenetetraamine (8.7 g, 62.4 mmol) and the mixture was heated to 120° C. for 2 h. The mixture was cooled to room temperature, followed by a standard aqueous/EtOAc workup and purified by silica gel column chromatography (PE:EA=1:1) to afford 5-formyl-2-hydroxybenzonitrile (Intermediate 47a) as a white powder (540 mg, 9%) and 3-formyl-2-hydroxybenzonitrile (Intermediate 47b) as a white powder (1.17 g, 19%). The mixture was cooled to room temperature purified by silica gel column chromatography (PE:EA=1:1)