5-bromo-2-chlorobenzoyl chloride

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

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

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

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

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

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

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

Procedure: To a solution of 5-bromo-2-chlorobenzoyl chloride 21d (3.41 g, 13.4 mmol) and 1-ethoxy-2,3-difluoro-benzene 23b (2.42 g, 15.2 mmol) in dichloromethane (50 mL) was added anhydrous aluminium chloride (1.82 g, 13.7 mmol) in portions over 1 hours at 0° C. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with hydrochloric acid (10 mL, 2 M) and extracted with dichloromethane (40 mL×4). The combined layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 23d as yellow oil (5.03 g, 100%). This material was not further purified. The reaction mixture was quenched with hydrochloric acid (10 mL, 2 M) extracted with dichloromethane (40 mL×4) The combined layers were dried over anhydrous sodium sulfate filtered The filtrate was concentrated in vacuo

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

Procedure: To a solution of 5-bromo-2-chlorobenzoyl chloride 21d (3.4 g, 13.4 mmol) and 1,2-difluoro-3-methoxybenzene 21b (2.4 g, 16.7 mmol) in dichloromethane (40 mL) was added anhydrous aluminium chloride (1.82 g, 13 mmol) at 0° C. The mixture was stirred at 0° C. for 16 hours. Then the reaction mixture was quenched with hydrochloric acid (4 mL, 2 M) and warmed up to room temperature. The mixture was extracted with dichloromethane (40 mL×4). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 21e as yellow liquid (5.4 g, 96.4%). This material was not further purified. Then the reaction mixture was quenched with hydrochloric acid (4 mL, 2 M) warmed up to room temperature The mixture was extracted with dichloromethane (40 mL×4) The combined organic layers were dried over anhydrous sodium sulfate filtered The filtrate was concentrated in vacuo

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-bromo-2-chloro-benzoic acid 15a (7.24 g, 30.8 mmol) in toluene (100 mL) were added thionyl chloride (3.6 mL, 49.2 mmol) and N,N-dimethylformamide (0.2 mL, 2.6 mmol) in turn at 0° C. The mixture was warmed up to 100° C. and stirred for 4 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give the title compound 21d as yellow oil (7.82 g, 100%). This material was not further purified. The reaction mixture was cooled to room temperature concentrated in vacuo

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

Procedure: By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (20 mg, 0.063 mmol) obtained in Example 1, (3), and 5-bromo-2-chlorobenzoyl chloride (0.0945 mmol), the title compound (8 mg, yield 24%) was obtained as pale yellow crystals in the same manner as that of Example 1, (4).

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.05 g, 0.154 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 5-bromo-2-chlorobenzoyl chloride (0.134 g, 0.529 mmol) and triethylamine (1.0 mL, 13.6 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.021 g (26% yield) of pure product: MS (ES) m/z 523 (M+1). Upon cooling the mixture was poured onto a biotage prepak column the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient)

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

Procedure: Anhydrous aluminum trichloride (155 g, 1.16 mol) was suspended in methylene chloride (2050 mL) under a nitrogen protection. To the resulting mixture was added anisole (125 mL, 1.15 mol) in one batch at −5° C. After stirring for 20 mins, to the mixture was added dropwise a solution of 5-bromo-2-chlorobenzoyl chloride in methylene chloride (300 mL). The resulting mixture was reacted at −5° C. for 3 h. TLC indicated the completion of reaction. To the reaction mixture was poured 2N hydrochloric acid. The resulting mixture was separated into an organic phase and an aqueous phase. The organic phase was washed with a saturated sodium bicarbonate solution for two times and with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and evaporated by rotation to produce a solid. To the solid was added ethanol (150 mL), and the resulting mixture was washed and starched for 30 mins and filtered. The filter cake was oven dried to produce 265 g of a product in a yield of 71%. The resulting mixture was reacted at −5° C. for 3 h the completion of reaction The resulting mixture was separated into an organic phase The organic phase was washed with a saturated sodium bicarbonate solution for two times and with a saturated sodium chloride solution dried over anhydrous sodium sulphate evaporated by rotation to produce a solid the resulting mixture was washed starched for 30 mins filtered dried