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

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

Procedure: A solution of 5-bromo-3-methyl-benzene-1,2-diamine (Maybridge, 3 g; 14.92 mmol) in formic acid (75 mL) was heated at reflux for 16 hours. Reaction mixture was concentrated under vacuum to give a brown oil. It was extracted by EtOAc from a saturated aqueous solution of NaHCO3, dried over MgSO4 and evaporated under vacuum to give the title compound as a pale yellow solid (3.07 g, 97%). 1H NMR (DMSO-d6) δ 12.92-12.34 (bs, 1H), 8.22 (s, 1H), 7.59 (br s, 1H), 7.17 (s, 1H), 3.33 (s, 3H). LC/MS (Method B): 211.0 (M+H)+. at reflux for 16 hours Reaction mixture was concentrated under vacuum to give a brown oil It was extracted by EtOAc from a saturated aqueous solution of NaHCO3 dried over MgSO4 evaporated under vacuum

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

Procedure: Isothiocyanatomethane (0.055 g, 0.746 mmol) in N,N-dimethylformamide (1.0 mL) was added dropwise slowly to a stirred solution of 5-bromo-3-methylbenzene-1,2-diamine (0.150 g, 0.746 mmol) in N,N-dimethylformamide (1.5 mL) at 0° C. The cold bath was removed, the reaction mixture was capped and stirred at room temperature for 48 h. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.157 g, 0.821 mmol) was added and the reaction mixture capped and heated at 40° C. overnight. The resulting mixture was diluted with methanol, filtered and purified using reverse-phase preparatory HPLC (10-50% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Fractions containing the desired product were combined and most of the solvent removed under reduced pressure. Acetonitrile was added and the resulting mixture loaded on a Strata ion exchange column. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol and was concentrated under reduced pressure and dried under high vacuum to give the desired product (0.128 g, 0.53 mmol, 72% yield) as a slightly yellow waxy solid. MS (ESI) m/z 240 [M]+, 242 [M+2]+. The cold bath was removed the reaction mixture was capped the reaction mixture capped heated at 40° C. overnight filtered purified reverse-phase preparatory HPLC (10-50% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) Fractions containing the desired product removed under reduced pressure Acetonitrile was added The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol The product eluted with the 5% ammonium hydroxide in methanol was concentrated under reduced pressure dried under high vacuum

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

Procedure: To a suspension of 4-bromo-2-methyl-6-nitro-phenylamine (20 g, 0.086 mol) in ethanol (200 mL) was added tin chloride dihydrate (49.2 g, 0.258 mol). The reaction mixture was heated to reflux for 14 h, cooled to room temperature, and concentrated in vacuo. The residue was diluted with ethyl acetate (150 mL) and treated with triethylamine (40 mL). The resulting slurry was filtered through a pad of celite, and the filtercake was rinsed with three portions ethyl acetate (50 mL). The filtrate was washed with saturated NaHCO3, water, and brine, then dried over Na2SO4 and filtered. After removal of the solvent, the residue was purified by flash chromatography on silica gel (30% EtOAc/hexane, then 5% MeOH/CH2Cl2) to yield the title compound (10.26 g, 59%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 6.77 (1H, d, J=2.0 Hz), 6.74 (1H, d, J=2.0 Hz), 2.16 (3H, s). LCMS (M+H)+ m/z 201. (t=0.83 min.). Procedure for the preparation of 1-[4-(3,4-diamino-5-methyl-phenyl)-piperazin-1-yl]-ethanone The reaction mixture was heated to reflux for 14 h concentrated in vacuo The residue was diluted with ethyl acetate (150 mL) treated with triethylamine (40 mL) The resulting slurry was filtered through a pad of celite the filtercake was rinsed with three portions ethyl acetate (50 mL) The filtrate was washed with saturated NaHCO3, water, and brine dried over Na2SO4 filtered After removal of the solvent the residue was purified by flash chromatography on silica gel (30% EtOAc/hexane

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

Procedure: To a suspension of 4-bromo-2-methyl-6-nitro-phenylamine (20 g, 0.086 mol) in ethanol (200 mL) was added tin chloride dihydrate (49.2 g, 0.258 mol). The reaction mixture was heated to reflux for 14 h, cooled to room temperature, and concentrated in vacuo. The residue was diluted with ethyl acetate (150 mL) and treated with triethylamine (40 mL). The resulting slurry was filtered through a pad of celite, and the filtercake was rinsed with three portions ethyl acetate (50 mL). The filtrate was washed with saturated NaHCO3, water, and brine, then dried over Na2SO4 and filtered. After removal of the solvent, the residue was purified by flash chromatography on silica gel (30% EtOAc/hexane, then 5% MeOH/CH2Cl2) to yield the title compound (10.26 g, 59%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 6.77 (1H, d, J=2.0 Hz), 6.74 (1H, d, J=2.0 Hz), 2.16 (3H, s). LCMS (M+H)+ m/z 201. (t=0.83 min.). Procedure for the preparation of 1-[4-(3,4-diamino-5-methyl-phenyl)-piperazin-1-yl]-ethanone The reaction mixture was heated to reflux for 14 h concentrated in vacuo The residue was diluted with ethyl acetate (150 mL) treated with triethylamine (40 mL) The resulting slurry was filtered through a pad of celite the filtercake was rinsed with three portions ethyl acetate (50 mL) The filtrate was washed with saturated NaHCO3, water, and brine dried over Na2SO4 filtered After removal of the solvent the residue was purified by flash chromatography on silica gel (30% EtOAc/hexane

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

Procedure: Isothiocyanatomethane (0.055 g, 0.746 mmol) in N,N-dimethylformamide (1.0 mL) was added dropwise slowly to a stirred solution of 5-bromo-3-methylbenzene-1,2-diamine (0.150 g, 0.746 mmol) in N,N-dimethylformamide (1.5 mL) at 0° C. The cold bath was removed, the reaction mixture was capped and stirred at room temperature for 48 h. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.157 g, 0.821 mmol) was added and the reaction mixture capped and heated at 40° C. overnight. The resulting mixture was diluted with methanol, filtered and purified using reverse-phase preparatory HPLC (10-50% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Fractions containing the desired product were combined and most of the solvent removed under reduced pressure. Acetonitrile was added and the resulting mixture loaded on a Strata ion exchange column. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol and was concentrated under reduced pressure and dried under high vacuum to give the desired product (0.128 g, 0.53 mmol, 72% yield) as a slightly yellow waxy solid. MS (ESI) m/z 240 [M]+, 242 [M+2]+. The cold bath was removed the reaction mixture was capped the reaction mixture capped heated at 40° C. overnight filtered purified reverse-phase preparatory HPLC (10-50% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) Fractions containing the desired product removed under reduced pressure Acetonitrile was added The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol The product eluted with the 5% ammonium hydroxide in methanol was concentrated under reduced pressure dried under high vacuum

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

Procedure: Isothiocyanatomethane (0.055 g, 0.746 mmol) in N,N-dimethylformamide (1.0 mL) was added dropwise slowly to a stirred solution of 5-bromo-3-methylbenzene-1,2-diamine (0.150 g, 0.746 mmol) in N,N-dimethylformamide (1.5 mL) at 0° C. The cold bath was removed, the reaction mixture was capped and stirred at room temperature for 48 h. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.157 g, 0.821 mmol) was added and the reaction mixture capped and heated at 40° C. overnight. The resulting mixture was diluted with methanol, filtered and purified using reverse-phase preparatory HPLC (10-50% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Fractions containing the desired product were combined and most of the solvent removed under reduced pressure. Acetonitrile was added and the resulting mixture loaded on a Strata ion exchange column. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol and was concentrated under reduced pressure and dried under high vacuum to give the desired product (0.128 g, 0.53 mmol, 72% yield) as a slightly yellow waxy solid. MS (ESI) m/z 240 [M]+, 242 [M+2]+. The cold bath was removed the reaction mixture was capped the reaction mixture capped heated at 40° C. overnight filtered purified reverse-phase preparatory HPLC (10-50% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) Fractions containing the desired product removed under reduced pressure Acetonitrile was added The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol The product eluted with the 5% ammonium hydroxide in methanol was concentrated under reduced pressure dried under high vacuum

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

Procedure: A mixture of 72 (1.27 g, 6.32 mmol) in formic acid (10 mL) was heated at reflux overnight. The reaction mixture was concentrated in vacuo to afford brown oil, which was treated with a satd. aq. NaHCO3. The aqueous solution was extracted with EtOAc (3×300 mL). The extracts were dried MgSO4), filtered and concentrated to afford 1.09 g (82%) of 5-bromo-7-methyl-1H-benzo[d]imidazole (74) as yellow solid; MS (ESI) m/z 211.1 [M+1]+. was heated at reflux overnight The reaction mixture was concentrated in vacuo to afford brown oil, which was treated with a satd The aqueous solution was extracted with EtOAc (3×300 mL) filtered concentrated

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

Procedure: A mixture of 72 (1.27 g, 6.32 mmol) in formic acid (10 mL) was heated at reflux overnight. The reaction mixture was concentrated in vacuo to afford brown oil, which was treated with a satd. aq. NaHCO3. The aqueous solution was extracted with EtOAc (3×300 mL). The extracts were dried MgSO4), filtered and concentrated to afford 1.09 g (82%) of 5-bromo-7-methyl-1H-benzo[d]imidazole (74) as yellow solid; MS (ESI) m/z 211.1 [M+1]+. was heated at reflux overnight The reaction mixture was concentrated in vacuo to afford brown oil, which was treated with a satd The aqueous solution was extracted with EtOAc (3×300 mL) filtered concentrated

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

Procedure: To a suspension of 4-bromo-2-methyl-6-nitroaniline (2.0 g, 8.7 mmol) in EtOH (20 mL) was added SnCl2 (5.0 g, 26.1 mmol). The reaction mixture was heated at reflux for 14 h, cooled to RT and concentrated in vacuo. The residue was diluted with EtOAc (100 mL) and partitioned between satd. aq. NaHCO3 solution (200 mL). The resulting slurry was filtered through a pad of Celite® and the wet cake was washed with EtOAc (3×50 mL). The filtrate was washed sequentially with satd. aq. NaHCO3, water, and brine, dried (MgSO4), filtered and concentrated in vacuo to afford 1.27 g (72%) of 5-bromo-3-methylbenzene-1,2-diamine (72) as yellow oil: MS (ESI) m/z=201.1 [M+1]+. The reaction mixture was heated at reflux for 14 h concentrated in vacuo The residue was diluted with EtOAc (100 mL) partitioned between satd The resulting slurry was filtered through a pad of Celite® the wet cake was washed with EtOAc (3×50 mL) The filtrate was washed sequentially 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 solution of 5-bromo-3-methyl-benzene-1,2-diamine (Maybridge, 3 g; 14.92 mmol) in formic acid (75 mL) was heated at reflux for 16 hours. Reaction mixture was concentrated under vacuum to give a brown oil. It was extracted by EtOAc from a saturated aqueous solution of NaHCO3, dried over MgSO4 and evaporated under vacuum to give the title compound as a pale yellow solid (3.07 g, 97%). 1H NMR (DMSO-d6) δ 12.92-12.34 (bs, 1H), 8.22 (s, 1H), 7.59 (br s, 1H), 7.17 (s, 1H), 3.33 (s, 3H). LC/MS (Method B): 211.0 (M+H)+. at reflux for 16 hours Reaction mixture was concentrated under vacuum to give a brown oil It was extracted by EtOAc from a saturated aqueous solution of NaHCO3 dried over MgSO4 evaporated under vacuum

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

Procedure: To a stirred solution of compound 4-bromo-2-methyl-6-nitroaniline (5.0 g) in EtOH (85 ml) and water (43 ml) were added iron powder (6.0 g) and CaCl2 (4.8 g) at room temperature and the resulting reaction mixture was then heated at reflux for 4 h. The mixture was then cooled to room temperature, filtered through Celite, and washed with EtOH. The filtrate was concentrated and the resulting residue was diluted with DCM. The DCM layer was successively washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (4.0 g) as a dark brown solid. the resulting reaction mixture was then heated at reflux for 4 h filtered through Celite washed with EtOH The filtrate was concentrated the resulting residue was diluted with DCM The DCM layer was successively washed with water and brine dried over Na2SO4 concentrated in vacuo

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

Procedure: To a stirred solution of 5-bromo-3-methylbenzene-1,2-diamine (4 g) in DMF (80 ml) was added NaH (40% oil dispersion, 800 mg) at 0° C., and the reaction mixture was stirred for another 30 min at the same temperature. A solution of ethyl chloroformate (1.9 g) in DMF (10 ml) was added dropwise thereto at 0° C. and then the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into saturated NH4Cl solution, and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (2.5 g) as a yellow solid. at 0° C. and then the resulting reaction mixture was stirred at room temperature for 1 h extracted with EtOAc The extract was washed with brine dried over Na2SO4 concentrated in vacuo The residue was purified by silica gel column chromatography (hexane/EtOAc)