3,5-dibromo-4-methylaniline

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

Procedure: To a solution of 3,5-dibromo-4-methylaniline (4.17 g, 15.74 mmol) in CH2I2 (10 mL) was added tert-butylnitrite (3.0 mL, 23.61 mmol) slowly at 0° C. while stirring vigorously. The ice bath was removed and the reaction mixture was stirred at rt while the reaction was very exothermic, then placed it in a 80° C. oil bath and heated for 20 min. CH2I2 was distilled off under high vacuum, and the remaining residue was purified by flash chromatography eluting with 100% hexane to gave the title compound. The ice bath was removed the reaction mixture was stirred at rt while the reaction in a 80° C. heated for 20 min CH2I2 was distilled off under high vacuum the remaining residue was purified by flash chromatography eluting with 100% hexane

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

Procedure: To a solution of 3,5-dibromo-4-methylaniline (4.17 g, 15.74 mmol) in CH2I2 (10 mL) was added tert-butylnitrite (3.0 mL, 23.61 mmol) slowly at 0° C. while stirring vigorously. The ice bath was removed and the reaction mixture was stirred at rt while the reaction was very exothermic, then placed in 80° C. oil bath and heated for 20 min. CH2I2 was distilled off under high vacuum, and the remaining residue was purified by flash chromatography eluting with 100% hexane to give the title compound. The ice bath was removed the reaction mixture was stirred at rt while the reaction placed in 80° C. heated for 20 min CH2I2 was distilled off under high vacuum the remaining residue was purified by flash chromatography eluting with 100% hexane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (3,5-dibromo-4-methylphenyl)amine dissolved in water (80 mL) and concentrated HCl (7.5 mL) stirring for 20 min, then the mixture was cooled to 0˜5° C., and a solution of NaNO2 (3.4 g/40 mL H2O) was added. The reaction mixture was stirred for 2 h at 0˜5° C., then the suspension was added to a solution of hypophosphorous acid (50%, 27.9 g), and the mixture was cooled to 0° C. The mixture was stirred at room temperature overnight. Then it was extracted with CH2Cl2 (100 mL×2). The organic layer was washed with brine (30 mL) and dried over Na2SO4. After silica column chomatography, (eluted with petroleum ether), 3.57 g product was obtained, as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 2.57 (s, 3H), 6.89 (t, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H). the mixture was cooled to 0˜5° C. The mixture was stirred at room temperature overnight Then it was extracted with CH2Cl2 (100 mL×2) The organic layer was washed with brine (30 mL) dried over Na2SO4 After silica column chomatography, (eluted with petroleum ether), 3.57 g product was obtained, as a colorless liquid

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (3,5-dibromo-4-methylphenyl)amine dissolved in water (80 mL) and concentrated HCl (7.5 mL) stirring for 20 min, then the mixture was cooled to 0˜5° C., and a solution of NaNO2 (3.4 g/40 mL H2O) was added. The reaction mixture was stirred for 2 h at 0˜5° C., then the suspension was added to a solution of hypophosphorous acid (50%, 27.9 g), and the mixture was cooled to 0° C. The mixture was stirred at room temperature overnight. Then it was extracted with CH2Cl2 (100 mL×2). The organic layer was washed with brine (30 mL) and dried over Na2SO4. After silica column chomatography, (eluted with petroleum ether), 3.57 g product was obtained, as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 2.57 (s, 3H), 6.89 (t, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H). the mixture was cooled to 0˜5° C. The mixture was stirred at room temperature overnight Then it was extracted with CH2Cl2 (100 mL×2) The organic layer was washed with brine (30 mL) dried over Na2SO4 After silica column chomatography, (eluted with petroleum ether), 3.57 g product was obtained, as a colorless liquid

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (3,5-dibromo-4-methylphenyl)amine dissolved in water (80 mL) and concentrated HCl (7.5 mL) stirring for 20 min, then the mixture was cooled to 0˜5° C., and the solution of NaNO2 (3.4 g/30 mL H2O) was added. The reaction mixture was stirred for 2 h at 0˜5° C., then the suspension was added to hypophosphorous acid solution (50%, 27.9 g), which was cooled to 0° C. The mixture was stirred at room temperature overnight. Then it was extracted with CH2Cl2 (100 mL×2) and the combined organic layers were washed with brine (30 mL) and dried over Na2SO4. After silica column chromatography, (eluted with petroleum ether), 3.57 g product was obtained, as colorless liquid. 1H NMR (400 MHz, CDCl3): δ 2.57 (s, 3 H), 6.89 (t, J=8.0 Hz, 1 H), 7.50 (d, J=8.0 Hz, 2 H). the mixture was cooled to 0˜5° C. The mixture was stirred at room temperature overnight Then it was extracted with CH2Cl2 (100 mL×2) the combined organic layers were washed with brine (30 mL) dried over Na2SO4 After silica column chromatography, (eluted with petroleum ether), 3.57 g product was obtained, as colorless liquid

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

Procedure: To a solution of 3,5-dibromo-4-methylaniline (4.17 g, 15.74 mmol) in CH2I2 (10 mL) was added tert-butylnitrite (3.0 mL, 23.61 mmol) slowly at 0° C. while stirring vigorously. The ice bath was removed and the reaction mixture was stirred at rt while the reaction was very exothermic, then placed it in a 80° C. oil bath and heated for 20 min. CH2I2 was distilled off under high vacuum, and the remaining residue was purified by flash chromatography eluting with 100% hexane to gave the title compound. The ice bath was removed the reaction mixture was stirred at rt while the reaction in a 80° C. heated for 20 min CH2I2 was distilled off under high vacuum the remaining residue was purified by flash chromatography eluting with 100% hexane

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

Procedure: To a solution of 3,5-dibromo-4-methylaniline (4.17 g, 15.74 mmol) in CH2I2 (10 mL) was added tert-butylnitrite (3.0 mL, 23.61 mmol) slowly at 0° C. while stirring vigorously. The ice bath was removed and the reaction mixture was stirred at rt while the reaction was very exothermic, then placed in 80° C. oil bath and heated for 20 min. CH2I2 was distilled off under high vacuum, and the remaining residue was purified by flash chromatography eluting with 100% hexane to give the title compound. The ice bath was removed the reaction mixture was stirred at rt while the reaction placed in 80° C. heated for 20 min CH2I2 was distilled off under high vacuum the remaining residue was purified by flash chromatography eluting with 100% hexane

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

Procedure: The DNA ligase inhibitor L67 (10) was synthesized by incubation of ethyl chloroacetate with 3,5-dibromo-4-methylaniline in the presence of lithium carbonate in N-methyl-2-pyrrolidinone as the solvent at 100° C. for 16 hours to produce N-(3,5-dibromo-4-methylphenyl)glycine ethyl ester in 33% yield after recrystallization from ethanol.

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

Procedure: The DNA ligase inhibitor L67 (10) was synthesized by incubation of ethyl chloroacetate with 3,5-dibromo-4-methylaniline in the presence of lithium carbonate in N-methyl-2-pyrrolidinone as the solvent at 100° C. for 16 hours to produce N-(3,5-dibromo-4-methylphenyl)glycine ethyl ester in 33% yield after recrystallization from ethanol.

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

Procedure: The title compound was prepared by the method of Example 1, from 3,5-dibromo-4-methylaniline (2.64 g, 10 mmol), 1,1′-carbonyldiimidazole (1.64 g, 10 mmol) and 5-methoxy-6-trifluoromethylindoline (D11) (2.2 g, 10 mmol). Crude product was recrystallised from DMSO/water and washed with methanol and ether, to give the title compound (2.64 g, 52%), mp>250° C. Crude product was recrystallised from DMSO/water washed with methanol and ether

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

Procedure: The title compound was prepared by the method of Example 1, from 3,5-dibromo-4-methylaniline (2.64 g, 10 mmol), 1,1'-carbonyldiimidazole (1.64 g, 10 mmol) and 5-methoxy-6-trifluoromethylindoline (D11) (2.2 g, 10 mmol). Crude product was recrystallised from DMSO/water and washed with methanol and ether, to give the title compound (2.64 g, 52%), mp >250° C. Crude product was recrystallised from DMSO/water washed with methanol and ether

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (3,5-dibromo-4-methylphenyl)amine dissolved in water (80 mL) and concentrated HCl (7.5 mL) stirring for 20 min, then the mixture was cooled to 0˜5° C., and a solution of NaNO2 (3.4 g/40 mL H2O) was added. The reaction mixture was stirred for 2 h at 0˜5° C., then the suspension was added to a solution of hypophosphorous acid (50%, 27.9 g), and the mixture was cooled to 0° C. The mixture was stirred at room temperature overnight. Then it was extracted with CH2Cl2 (100 mL×2). The organic layer was washed with brine (30 mL) and dried over Na2SO4. After silica column chomatography, (eluted with petroleum ether), 3.57 g product was obtained, as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 2.57 (s, 3H), 6.89 (t, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H). the mixture was cooled to 0˜5° C. The mixture was stirred at room temperature overnight Then it was extracted with CH2Cl2 (100 mL×2) The organic layer was washed with brine (30 mL) dried over Na2SO4 After silica column chomatography, (eluted with petroleum ether), 3.57 g product was obtained, as a colorless liquid