2-Amino-3-methoxybenzonitrile

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-amino-3-methoxybenzonitrile (Example 127b) (0.98 g, 6.59 mmol) in CH2Cl2 (25.0 mL), a solution of BBr3 in CH2Cl2 (1.0M, 19.8 mL, 19.77 mmol) was added drop wise at −78° C. under a nitrogen atmosphere. The obtained mixture was stirred at −78° C. for 30 min, and then at room temperature overnight. The reaction was quenched with water, basified with saturated aqueous NaHCO3 (pH˜8) and extracted with CH2Cl2. The combined extract was dried with MgSO4, filtered and evaporated. The title compound was obtained in amount of 0.80 g (91%) as orange solid and was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (broad s, 1H), 6.82-6.87 (m, 2H), 6.46 (t, J=8.0 Hz, 1H), 5.34 (broad s, 2H). at room temperature overnight The reaction was quenched with water extracted with CH2Cl2 The combined extract was dried with MgSO4 filtered evaporated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-amino-3-methoxybenzonitrile (Example 127b) (0.98 g, 6.59 mmol) in CH2Cl2 (25.0 mL), a solution of BBr3 in CH2Cl2 (1.0M, 19.8 mL, 19.77 mmol) was added drop wise at −78° C. under a nitrogen atmosphere. The obtained mixture was stirred at −78° C. for 30 min, and then at room temperature overnight. The reaction was quenched with water, basified with saturated aqueous NaHCO3 (pH˜8) and extracted with CH2Cl2. The combined extract was dried with MgSO4, filtered and evaporated. The title compound was obtained in amount of 0.80 g (91%) as orange solid and was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (broad s, 1H), 6.82-6.87 (m, 2H), 6.46 (t, J=8.0 Hz, 1H), 5.34 (broad s, 2H). at room temperature overnight The reaction was quenched with water extracted with CH2Cl2 The combined extract was dried with MgSO4 filtered evaporated

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

Procedure: Prepared as in Example 53a from 2-amino-3-methoxybenzonitrile and benzoyl isocyanate as a light orange solid (280 mg, 95%). 1H NMR (400 MHz, DMSO-d6) δ 3.89 (s, 3H), 7.42 (t, J=3.2 Hz, 2H), 7.46 (d, J=3.6 Hz, 1H), 7.54 (t, J=8 Hz, 2H), 7.66 (t, J=7.6 Hz, 1H), 8.05 (d, J=8.6 Hz, 2H), 10.55 (s, 1H), 11.32 (s, 1H). MS 295 (MH+).

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Amino-3-methoxybenzonitrile (Step 2, 26.6 g, 179 mmol) was suspended in ethylenediamine (250 mL) and degassed thoroughly. To this was added sulfur powder (8 g, 251 mmol) slowly, then the reaction was heated to 60° C. and stirred 5 h. The reaction was then cooled, concentrated under reduced pressure, then treated with water (300 mL). The resulting suspension was collected by vacuum filtration and washed with water. The solid was purified via silica gel chromatography (50-100% EtOAc/hexanes). Fractions containing product were combined, the solvent removed under reduced pressure to give the title compound (17.3 g, 50%): HPLC MS RT=1.05 min, MH+=192.1; 1H NMR (DMSO-d6) δ: 3.81 (3H, s), 3.90 (4H, s), 6.65 (1H, t), 6.86 (1H, dd), 7.03 (1H, dd). degassed thoroughly The reaction was then cooled concentrated under reduced pressure treated with water (300 mL) The resulting suspension was collected by vacuum filtration washed with water The solid was purified via silica gel chromatography (50-100% EtOAc/hexanes) Fractions containing product the solvent removed under reduced pressure

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Amino-3-methoxybenzonitrile (Step 2, 26.6 g, 179 mmol) was suspended in ethylenediamine (250 mL) and degassed thoroughly. To this was added sulfur powder (8 g, 251 mmol) slowly, then the reaction was heated to 60° C. and stirred 5 h. The reaction was then cooled, concentrated under reduced pressure, then treated with water (300 mL). The resulting suspension was collected by vacuum filtration and washed with water. The solid was purified via silica gel chromatography (50-100% EtOAc/hexanes). Fractions containing product were combined, the solvent removed under reduced pressure to give the title compound (17.3 g, 50%): HPLC MS RT=1.05 min, MH+=192.1; 1H NMR (DMSO-d6) δ: 3.81 (3H, s), 3.90 (4H, s), 6.65 (1H, t), 6.86 (1H, dd), 7.03 (1H, dd). degassed thoroughly The reaction was then cooled concentrated under reduced pressure treated with water (300 mL) The resulting suspension was collected by vacuum filtration washed with water The solid was purified via silica gel chromatography (50-100% EtOAc/hexanes) Fractions containing product the solvent removed under reduced pressure

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

Procedure: 3-Methoxy-2-nitrobenzonitrile (Step 1, 43.3 g, 243 mmol) was suspended in AcOH (1000 mL) and degassed thoroughly. To this was added iron powder (40.7 g, 729 mmol) slowly. After 30 min an exotherm was observed and moderated by the use of an ice bath. After 2 h Celite was added and the entire mixture filtered through a pad of Celite. The Celite was washed well with AcOH, and the combined filtrates concentrated under reduced pressure to approximate volume of 100 mL AcOH. The residue was diluted with EtOAc (1000 mL), solid K2CO3 added and the mixture stirred overnight. The mixture was then filtered through Celite again and washed well with EtOAc. The solvent was removed under reduced pressure until a volume of approximately 500 mL EtOAc. This solution was washed with a saturated NaHCO3 solution (500 mL) and brine (300 mL) then the solvent removed under reduced pressure. The resulting solid was purified via silica gel chromatography (0-30% EtOAc/Hexanes). Fractions containing product were combined, the solvent removed under reduced pressure to give the title compound (26.6 g, 74%): HPLC MS RT=2.19 min, MH+=149.0; 1H NMR (DMSO-d6) δ: 3.77 (3H, s), 5.61 (2H, bs), 6.57 (1H, t), 6.96 (1H, dd), 7.00 (1H, dd). degassed thoroughly moderated by the use of an ice bath After 2 h Celite was added the entire mixture filtered through a pad of Celite The Celite was washed well with AcOH the combined filtrates concentrated under reduced pressure to approximate volume of 100 mL AcOH The residue was diluted with EtOAc (1000 mL), solid K2CO3 added The mixture was then filtered through Celite again washed well with EtOAc The solvent was removed under reduced pressure until a volume of approximately 500 mL EtOAc This solution was washed with a saturated NaHCO3 solution (500 mL) and brine (300 mL) the solvent removed under reduced pressure The resulting solid was purified via silica gel chromatography (0-30% EtOAc/Hexanes) Fractions containing product the solvent removed under reduced pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-amino-3-methoxybenzonitrile (Example 127b) (0.98 g, 6.59 mmol) in CH2Cl2 (25.0 mL), a solution of BBr3 in CH2Cl2 (1.0M, 19.8 mL, 19.77 mmol) was added drop wise at −78° C. under a nitrogen atmosphere. The obtained mixture was stirred at −78° C. for 30 min, and then at room temperature overnight. The reaction was quenched with water, basified with saturated aqueous NaHCO3 (pH˜8) and extracted with CH2Cl2. The combined extract was dried with MgSO4, filtered and evaporated. The title compound was obtained in amount of 0.80 g (91%) as orange solid and was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (broad s, 1H), 6.82-6.87 (m, 2H), 6.46 (t, J=8.0 Hz, 1H), 5.34 (broad s, 2H). at room temperature overnight The reaction was quenched with water extracted with CH2Cl2 The combined extract was dried with MgSO4 filtered evaporated

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

Procedure: Prepared as in Example 53a from 2-amino-3-methoxybenzonitrile and benzoyl isocyanate as a light orange solid (280 mg, 95%). 1H NMR (400 MHz, DMSO-d6) δ 3.89 (s, 3H), 7.42 (t, J=3.2 Hz, 2H), 7.46 (d, J=3.6 Hz, 1H), 7.54 (t, J=8 Hz, 2H), 7.66 (t, J=7.6 Hz, 1H), 8.05 (d, J=8.6 Hz, 2H), 10.55 (s, 1H), 11.32 (s, 1H). MS 295 (MH+).

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

Procedure: Prepared as in Example 53a from 2-amino-3-methoxybenzonitrile and benzoyl isocyanate as a light orange solid (280 mg, 95%). 1H NMR (400 MHz, DMSO-d6) δ3.89 (s, 3H), 7.42 (t, J=3.2 Hz, 2H), 7.46 (d, J=3.6 Hz, 1H), 7.54 (t, J=8 Hz, 2H), 7.66 (t, J=7.6 Hz, 1H), 8.05 (d, J=8.6 Hz, 2H), 10.55 (s, 1H), 11.32 (s, 1H). MS 295 (MH+).

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

Procedure: Prepared as in Example 53a from 2-amino-3-methoxybenzonitrile and benzoyl isocyanate as a light orange solid (280 mg, 95%). 1H NMR (400 MHz, DMSO-d6) δ3.89 (s, 3H), 7.42 (t, J=3.2 Hz, 2H), 7.46 (d, J=3.6 Hz, 1H), 7.54 (t, J=8 Hz, 2H), 7.66 (t, J=7.6 Hz, 1H), 8.05 (d, J=8.6 Hz, 2H), 10.55 (s, 1H), 11.32 (s, 1H). MS 295 (MH+).

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