3-bromo-5-fluorobenzene-1,2-diamine

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-bromo-5-fluorobenzene-1,2-diamine (10.1 g, 49 mmol) in formic acid (20 mL) was heated at 110° C. overnight. The reaction mixture was concentrated, and to the residue was added MeOH (5 mL) to form a precipitate. The precipitate was filtered and washed with MeOH (2 mL) to afford 4-bromo-6-fluoro-1H-benzo[d]imidazole as a yellow solid (10 g, yield, 73%). MS (ESI): m/z=215 [M+1]+. The reaction mixture was concentrated to the residue was added MeOH (5 mL) to form a precipitate The precipitate was filtered washed with MeOH (2 mL) to afford

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

Procedure: A suspension of 2-bromo-4-fluoro-6-nitroaniline (14 g, 59 mmol) and SnCl2 (66 g, 295 mmol) in EtOH (50 mL) was heated at reflux for 5 h. The reaction mixture was concentrated in vacuo. To the residue was added EtOAc (100 mL) and satd. aq. NaHCO3 (200 mL). The mixture was filtered over Celite® and washed with EtOAc (100 mL×3). The combined organic layers were washed with satd. aq. NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated in vacuo to afford 3-bromo-5-fluorobenzene-1,2-diamine as a gray solid (10.1 g, 100%). MS (ESI): m/z=205 [M+1]+. was heated at reflux for 5 h The reaction mixture was concentrated in vacuo To the residue was added EtOAc (100 mL) The mixture was filtered over Celite® washed with EtOAc (100 mL×3) The combined organic layers were washed with satd aq. NaHCO3, water, and brine, dried (MgSO4) filtered concentrated in vacuo

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

Procedure: A suspension of 2-bromo-4-fluoro-6-nitroaniline (14 g, 59 mmol) and SnCl2 (66 g, 295 mmol) in EtOH (50 mL) was heated at reflux for 5 h. The reaction mixture was concentrated in vacuo. To the residue was added EtOAc (100 mL) and satd. aq. NaHCO3 (200 mL). The mixture was filtered over Celite® and washed with EtOAc (100 mL×3). The combined organic layers were washed with satd. aq. NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated in vacuo to afford 3-bromo-5-fluorobenzene-1,2-diamine as a gray solid (10.1 g, 100%). MS (ESI): m/z=205 [M+1]+. was heated at reflux for 5 h The reaction mixture was concentrated in vacuo To the residue was added EtOAc (100 mL) The mixture was filtered over Celite® washed with EtOAc (100 mL×3) The combined organic layers were washed with satd aq. NaHCO3, water, and brine, dried (MgSO4) filtered concentrated in vacuo

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

Procedure: The title compound was prepared using an adaptation of the method of Cheeseman (Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (3.31 mL, 24.4 mmol) and 1,2-diamino-3-bromo-5-fluorobenzene (500 mg, 2.44 mmol) was heated to reflux under N2 for 5 h. The reaction mixture was dark brown. The reaction was allowed to cool to room temperature and the solid collected by vacuum filtration and rinsed with EtOH (30 mL). The brown solid was air dried for 1 hr to give 250 mg (39.6% crude yield). A portion of this solid was removed and dissolved in 1N NaOH (10 mL) and a few insoluble particles were removed by gravity filtration. The solution was treated with decolorizing carbon and the mixture was filtered through a pad of celite and the resulting solution acidified with 1N HCl. White crystals formed that were isolated by vacuum filtration and washed with water (20 mL). The crystals were dried in a drying pistol (0.05 torr, 78° C.) to yield 54.1 mg, mp 308°-310° C. (dec). 1H NMR (d6 -DMSO) δ6.2 (dd, 1H, JH6-8 =2.7, JH-F =9.3, ArH), 7.35 (dd, 1H, JH6-8 =2.4, JHF =8.4 Hz), 11.1 (br s, 1H, NH), 12.1 (brs, 1H, NH). EIHRMS calc. for C8H4BrFN2O2 : 257.9440, found 257.9455. was heated to reflux under N2 for 5 h the solid collected by vacuum filtration rinsed with EtOH (30 mL) dried for 1 hr to give 250 mg (39.6% crude yield) A portion of this solid was removed dissolved in 1N NaOH (10 mL) a few insoluble particles were removed by gravity filtration The solution was treated with decolorizing carbon the mixture was filtered through a pad of celite White crystals formed that were isolated by vacuum filtration washed with water (20 mL) The crystals were dried in a drying pistol (0.05 torr, 78° C.) to yield 54.1 mg, mp 308°-310° C. (dec)

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

Procedure: The title compound was prepared using an adaptation of the method of Cheeseman (Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (3.31 mL, 24.4 mmol) and 1,2-diamino-3-bromo-5-fluorobenzene (500 mg, 2.44 mmol) was heated to reflux under N2 for 5 h. The reaction mixture was dark brown. The reaction was allowed to cool to room temperature and the solid collected by vacuum filtration and rinsed with EtOH (30 mL). The brown solid was air dried for 1 hr to give 250 mg (39.6% crude yield). A portion of this solid was removed and dissolved in 1N NaOH (10 mL) and a few insoluble particles were removed by gravity filtration. The solution was treated with decolorizing carbon and the mixture was filtered through a pad of celite and the resulting solution acidified with 1N HCl. White crystals formed that were isolated by vacuum filtration and washed with water (20 mL). The crystals were dried in a drying pistol (0.05 torr, 78° C.) to yield 54.1 mg, mp 308°-310° C. (dec). 1H NMR (d6 -DMSO) δ6.2 (dd, 1H, JH6-8 =2.7, JH-F =9.3, ArH), 7.35 (dd, 1H, JH6-8 =2.4, JHF =8.4 Hz), 11.1 (br s, 1H, NH), 12.1 (brs, 1H, NH). EIHRMS calc. for C8H4BrFN2O2 : 257.9440, found 257.9455. was heated to reflux under N2 for 5 h the solid collected by vacuum filtration rinsed with EtOH (30 mL) dried for 1 hr to give 250 mg (39.6% crude yield) A portion of this solid was removed dissolved in 1N NaOH (10 mL) a few insoluble particles were removed by gravity filtration The solution was treated with decolorizing carbon the mixture was filtered through a pad of celite White crystals formed that were isolated by vacuum filtration washed with water (20 mL) The crystals were dried in a drying pistol (0.05 torr, 78° C.) to yield 54.1 mg, mp 308°-310° C. (dec)

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

Procedure: 1,2-Diamino-3-bromo-5-fluorobenzene was prepared using an adaptation of the method of Bellamy et al., Tetrahedron Lett. 25:839 (1984). A mixture of 6-bromo-4-fluoro-2-nitroaniline (673 mg, 2.87 mmol) and SnCl2 2H2O (3.23 g, 14.3 mmol) dissolved in 6 mL ethyl acetate and 3 mL absolute ethanol was heated at 70° C. for 30 min. All the starting material had reacted as evidenced by TLC (silica gel, 2:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient solid NaHCO3 was added to bring the pH to 7.5. The reaction mixture was then extracted with 3×20 mL ethyl acetate and the combined organic phases washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a dark brown liquid 510 mg (86.7%). 1H NMR (CDCl3) δ3.64 (br s, 4H, 2(NH2)), 6.44 (dd, 1H, H5, J4-5 =2.7, JH-F =9.8), 6.72 (dd, 1H, H4, J4-5 =2.7, JHF =8.4). All the starting material had reacted poured into 20 mL crushed ice The reaction mixture was then extracted with 3×20 mL ethyl acetate the combined organic phases washed with sat'd NaCl solution The organic phase was dried (MgSO4), vacuum filtered the solvent rotary evaporated

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

Procedure: The title compound was prepared using an adaptation of the method of Cheeseman (Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (3.31 mL, 24.4 mmol) and 1,2-diamino-3-bromo-5-fluorobenzene (500 mg, 2.44 mmol) was heated to reflux under N2 for 5 h. The reaction mixture was dark brown. The reaction was allowed to cool to room temperature and the solid collected by vacuum filtration and rinsed with EtOH (30 mL). The brown solid was air dried for 1 hr to give 250 mg (39.6% crude yield). A portion of this solid was removed and dissolved in 1N NaOH (10 mL) and a few insoluble particles were removed by gravity filtration. The solution was treated with decolorizing carbon and the mixture was filtered through a pad of celite and the resulting solution acidified with 1N HCl. White crystals formed that were isolated by vacuum filtration and washed with water (20 mL). The crystals were dried in a drying pistol (0.05 torr, 78° C.) to yield 54.1 mg, mp 308°-310° C. (dec). 1H NMR (d6 -DMSO) δ6.2 (dd, 1H, JH6-8 =2.7, JH-F =9.3, ArH), 7.35 (dd, 1H, JH6-8 =2.4, JHF =8.4 Hz), 11.1 (br s, 1H, NH), 12.1 (brs, 1H, NH). EIHRMS calc. for C8H4BrFN2O2 : 257.9440, found 257.9455. was heated to reflux under N2 for 5 h the solid collected by vacuum filtration rinsed with EtOH (30 mL) dried for 1 hr to give 250 mg (39.6% crude yield) A portion of this solid was removed dissolved in 1N NaOH (10 mL) a few insoluble particles were removed by gravity filtration The solution was treated with decolorizing carbon the mixture was filtered through a pad of celite White crystals formed that were isolated by vacuum filtration washed with water (20 mL) The crystals were dried in a drying pistol (0.05 torr, 78° C.) to yield 54.1 mg, mp 308°-310° C. (dec)

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

Procedure: 1,2-Diamino-3-bromo-5-fluorobenzene was prepared using an adaptation of the method of Bellamy et al., Tetrahedron Lett. 25:839 (1984). A mixture of 6-bromo-4-fluoro-2-nitroaniline (673 mg, 2.87 mmol) and SnCl2 2H2O (3.23 g, 14.3 mmol) dissolved in 6 mL ethyl acetate and 3 mL absolute ethanol was heated at 70° C. for 30 min. All the starting material had reacted as evidenced by TLC (silica gel, 2:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient solid NaHCO3 was added to bring the pH to 7.5. The reaction mixture was then extracted with 3×20 mL ethyl acetate and the combined organic phases washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a dark brown liquid 510 mg (86.7%). 1H NMR (CDCl3) δ3.64 (br s, 4H, 2(NH2)), 6.44 (dd, 1H, H5, J4-5 =2.7, JH-F =9.8), 6.72 (dd, 1H, H4, J4-5 =2.7, JH-F =8.4). All the starting material had reacted poured into 20 mL crushed ice The reaction mixture was then extracted with 3×20 mL ethyl acetate the combined organic phases washed with sat'd NaCl solution The organic phase was dried (MgSO4), vacuum filtered the solvent rotary evaporated

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

Procedure: The title compound was prepared using an adaptation of the method of Cheeseman (Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (3.31 mL, 24.4 mmol) and 1,2-diamino-3-bromo-5-fluorobenzene (500 mg, 2.44 mmol) was heated to reflux under N2 for 5 h. The reaction mixture was dark brown. The reaction was allowed to cool to room temperature and the solid collected by vacuum filtration and rinsed with EtOH (30 mL). The brown solid was air dried for 1 hr to give 250 mg (39.6% crude yield). A portion of this solid was removed and dissolved in 1N NaOH (10 mL) and a few insoluble particles were removed by gravity filtration. The solution was treated with decolorizing carbon and the mixture was filtered through a pad of celite and the resulting solution acidified with 1N HCl. White crystals formed that were isolated by vacuum filtration and washed with water (20 mL). The crystals were dried in a drying pistol (0.05 torr, 78° C.) to yield 54.1 mg, mp 308°-310° C. (dec). 1H NMR (d6 -DMSO) δ 6.2 (dd, 1H, JH6-8 =2.7, JH-F =9.3, ArH), 7.35 (dd, 1H, JH6-8 =2.4, JHF =8.4 Hz), 11.1 (br s, 1H, NH), 12.1 (brs, 1H, NH). EIHRMS calc. for C8H4BrFN2O2 : 257.9440, found 257.9455. was heated to reflux under N2 for 5 h the solid collected by vacuum filtration rinsed with EtOH (30 mL) dried for 1 hr to give 250 mg (39.6% crude yield) A portion of this solid was removed dissolved in 1N NaOH (10 mL) a few insoluble particles were removed by gravity filtration The solution was treated with decolorizing carbon the mixture was filtered through a pad of celite White crystals formed that were isolated by vacuum filtration washed with water (20 mL) The crystals were dried in a drying pistol (0.05 torr, 78° C.) to yield 54.1 mg, mp 308°-310° C. (dec)

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

Procedure: 1,2-Diamino-3-bromo-5-fluorobenzene was prepared using an adaptation of the method of Bellamy et al., Tetrahedron Lett. 25: 839 (1984). A mixture of 6-bromo-4-fluoro-2-nitroaniline (673 mg, 2.87 mmol) and SnCl2 2H2O (3.23 g, 14.3 mmol) dissolved in 6 mL ethyl acetate and 3 mL absolute ethanol was heated at 70° C. for 30 min. All the starting material had reacted as evidenced by TLC (silica gel, 2:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient solid NaHCO3 was added to bring the pH to 7.5. The reaction mixture was then extracted with 3×20 mL ethyl acetate and the combined organic phases washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a dark brown liquid 510 mg (86.7%). 1H NMR (CDCl3) δ 3.64 (br s, 4H, 2(NH2)), 6.44 (dd, 1H, H5, J4-5 =2.7, JH-F =9.8), 6.72 (dd, 1H, H4, J4-5 =2.7, JHF =8.4). All the starting material had reacted poured into 20 mL crushed ice The reaction mixture was then extracted with 3×20 mL ethyl acetate the combined organic phases washed with sat'd NaCl solution The organic phase was dried (MgSO4), vacuum filtered the solvent rotary evaporated

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

Procedure: The title compound was prepared using an adaptation of the method of Cheeseman (Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (3.31 mL, 24.4 mmol) and 1,2-diamino-3-bromo-5-fluorobenzene (500 mg, 2.44 mmol) was heated to reflux under N2 for 5 h. The reaction mixture was dark brown. The reaction was allowed to cool to room temperature and the solid collected by vacuum filtration and rinsed with EtOH (30 mL). The brown solid was air dried for 1 hr to give 250 mg (39.6% crude yield). A portion of this solid was removed and dissolved in 1N NaOH (10 mL) and a few insoluble particles were removed by gravity filtration. The solution was treated with decolorizing carbon and the mixture was filtered through a pad of celite and the resulting solution acidified with 1N HCl. White crystals formed that were isolated by vacuum filtration and washed with water (20 mL). The crystals were dried in a drying pistol (0.05 torr, 78° C.) to yield 54.1 mg, mp 308°-310° C. (dec). 1H NMR (d6 -DMSO) δ6.2 (dd, 1H, JH6-8 =2.7, JH-F =9.3, ArH), 7.35 (dd, 1H, JH6-8 =2.4, JHF =8.4 Hz), 11.1 (br s, 1H, NH), 12.1 (brs, 1H, NH). EIHRMS calc. for C8H4BrFN2O2 : 257.9440, found 257.9455. was heated to reflux under N2 for 5 h the solid collected by vacuum filtration rinsed with EtOH (30 mL) dried for 1 hr to give 250 mg (39.6% crude yield) A portion of this solid was removed dissolved in 1N NaOH (10 mL) a few insoluble particles were removed by gravity filtration The solution was treated with decolorizing carbon the mixture was filtered through a pad of celite White crystals formed that were isolated by vacuum filtration washed with water (20 mL) The crystals were dried in a drying pistol (0.05 torr, 78° C.) to yield 54.1 mg, mp 308°-310° C. (dec)

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

Procedure: 1,2-Diamino-3-bromo-5-fluorobenzene was prepared using an adaptation of the method of Bellamy et al., Tetrahedron Lett. 25:839 (1984). A mixture of 6-bromo-4-fluoro-2-nitroaniline (673 mg, 2.87 mmol) and SnCl2 2H2O (3.23 g, 14.3 mmol) dissolved in 6 mL ethyl acetate and 3 mL absolute ethanol was heated at 70° C. for 30 min. All the starting material had reacted as evidenced by TLC (silica gel, 2:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient solid NaHCO3 was added to bring the pH to 7.5. The reaction mixture was then extracted with 3×20 mL ethyl acetate and the combined organic phases washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a dark brown liquid 510 mg (86.7%). 1H NMR (CDCl3) δ3.64 (br s, 4H, 2(NH2)), 6.44 (dd, 1H, H5, J4-5 =2.7, JH-F =9.8), 6.72 (dd, 1H, H4, J4-5 =2.7, JH-F =8.4). All the starting material had reacted poured into 20 mL crushed ice The reaction mixture was then extracted with 3×20 mL ethyl acetate the combined organic phases washed with sat'd NaCl solution The organic phase was dried (MgSO4), vacuum filtered the solvent rotary evaporated