2-bromo-5-chlorobenzaldehyde

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

Procedure: 2-Bromo-5-chlorobenzaldehyde (20.5 g) from Example 72 was dissolved with dry methanol (200 ml), followed by sodium borohydride (1.06 g) at 0° C., and the mixture was stirred for 30 minutes. After addition of acetone, the solvent was removed under reduced pressure, water was added the obtained residue, and then extracted with ether. The organic layer was washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, to give the title compound (19.5 g; 94%) the solvent was removed under reduced pressure, water was added the obtained residue extracted with ether The organic layer was washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution dried over anhydrous sodium sulfate The solvent was removed under reduced pressure

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the solution of 2-bromo-5-chlorotoluene (25 g) in acetic anhydride (100 ml) and sulfuric acid (20 ml) was added dropwise chromium(VI) oxide (36.5 g) in acetic anhydride (200 ml) for 3 hours at -15° C. The mixture was stirred for 1 hour at -5° C. and then poured into ice-cooled water, and extracted with ether. The organic layer was washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was suspended in ethanol (100 ml) and 3N-HCl (200 ml) and refluxed for 1 hour. After removal of the solvent, water was added to the residue, and extracted with ether. poured into ice- extracted with ether The organic layer was washed with water and saturated sodium chloride solution dried over anhydrous sodium sulfate After removal of the solvent under reduced pressure 3N-HCl (200 ml) and refluxed for 1 hour After removal of the solvent, water was added to the residue extracted with ether

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

Procedure: Benzo[b]thiophene (1.12 g) was dissolved in tetrahydrofuran (50 ml). This solution was cooled to −78° C., and a solution of 1.58 M hexane (10.5 ml) of n-butyllithium was added dropwise to the solution, and the mixture was stirred for 15 minutes at −78° C. Then, 5-chloro-2-bromobenzaldehyde (3.15 g) dissolved in tetrahydrofuran (50 ml) was added dropwise to the reaction mixture, and the mixture was stirred for two hours at room temperature. Aqueous solution of saturated ammonium chloride was added to the reaction mixture, and then the solvent was evaporated from the filtrate under reduced pressure to give the residue. Ethyl acetate and water were added to the residue obtained, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 1-benzothien-2-yl(5-bromo-2-chlorophenyl) methanol (4.75 g). Imidazole (1.08 g) and tert-butyl dimethylchlorosilane (2.99 g) were added to a solution of 1-benzothien-2-yl(5-bromo-2-chlorophenyl)methanol in dimethylformamide (100 ml), and the mixture was stirred for three hours at 70° C. Water was added to the reaction mixture, and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, the solvent was evaporated therefrom under reduced pressure to give the residue, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain [1-benzothien-2-yl(5-bromo-2-chloro phenyl)methoxy](tert-butyl) dimethylsilane (3.34 g). was added dropwise to the reaction mixture the mixture was stirred for two hours at room temperature the solvent was evaporated from the filtrate under reduced pressure to give the residue obtained extracted with ethyl acetate The organic layer was dried over magnesium sulfate the solvent was evaporated from the filtrate under reduced pressure to give the residue the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate)

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

Procedure: Benzo[b]thiophene (1.12 g) was dissolved in tetrahydrofuran (50 ml). This solution was cooled to −78° C., and a solution of 1.58 M hexane (10.5 ml) of n-butyllithium was added dropwise to the solution, and the mixture was stirred for 15 minutes at −78° C. Then, 5-chloro-2-bromobenzaldehyde (3.15 g) dissolved in tetrahydrofuran (50 ml) was added dropwise to the reaction mixture, and the mixture was stirred for two hours at room temperature. Aqueous solution of saturated ammonium chloride was added to the reaction mixture, and then the solvent was evaporated from the filtrate under reduced pressure to give the residue. Ethyl acetate and water were added to the residue obtained, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 1-benzothien-2-yl(5-bromo-2-chlorophenyl) methanol (4.75 g). Imidazole (1.08 g) and tert-butyl dimethylchlorosilane (2.99 g) were added to a solution of 1-benzothien-2-yl(5-bromo-2-chlorophenyl)methanol in dimethylformamide (100 ml), and the mixture was stirred for three hours at 70° C. Water was added to the reaction mixture, and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, the solvent was evaporated therefrom under reduced pressure to give the residue, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain [1-benzothien-2-yl(5-bromo-2-chloro phenyl)methoxy](tert-butyl) dimethylsilane (3.34 g). was added dropwise to the reaction mixture the mixture was stirred for two hours at room temperature the solvent was evaporated from the filtrate under reduced pressure to give the residue obtained extracted with ethyl acetate The organic layer was dried over magnesium sulfate the solvent was evaporated from the filtrate under reduced pressure to give the residue the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate)

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

Procedure: Benzo[b]thiophene (1.12 g) was dissolved in tetrahydrofuran (50 ml). This solution was cooled to −78° C., and a solution of 1.58 M hexane (10.5 ml) of n-butyllithium was added dropwise to the solution, and the mixture was stirred for 15 minutes at −78° C. Then, 5-chloro-2-bromobenzaldehyde (3.15 g) dissolved in tetrahydrofuran (50 ml) was added dropwise to the reaction mixture, and the mixture was stirred for two hours at room temperature. Aqueous solution of saturated ammonium chloride was added to the reaction mixture, and then the solvent was evaporated from the filtrate under reduced pressure to give the residue. Ethyl acetate and water were added to the residue obtained, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 1-benzothien-2-yl(5-bromo-2-chlorophenyl)methanol (4.75 g). Imidazole (1.08 g) and tert-butyl dimethylchlorosilane (2.99 g) were added to a solution of 1-benzothien-2-yl(5-bromo-2-chlorophenyl)methanol in dimethylformamide (100 ml), and the mixture was stirred for three hours at 70° C. Water was added to the reaction mixture, and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, the solvent was evaporated therefrom under reduced pressure to give the residue, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain [1-benzothien-2-yl(5-bromo-2-chloro phenyl)methoxy](tert-butyl) dimethylsilane (3.34 g). was added dropwise to the reaction mixture the mixture was stirred for two hours at room temperature the solvent was evaporated from the filtrate under reduced pressure to give the residue obtained extracted with ethyl acetate The organic layer was dried over magnesium sulfate the solvent was evaporated from the filtrate under reduced pressure to give the residue the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate)

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

Procedure: methyl 7-chloro-isoquinoline-3-carboxylate was prepared using the procedure described in example 12A: 2-bromo-5-chlorobenzaldehyde was reacted with methyl 2-acetamidoacrylate at 110° C. for 24 hours to yield methyl 7-chloro-isoquinoline-3-carboxylate (25%) as brown solid. methyl 7-chloro-isoquinoline-3-carboxylate was prepared

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

Procedure: Benzo[b]thiophene (1.12 g) was dissolved in tetrahydrofuran (50 ml). This solution was cooled to −78° C., and a solution of 1.58 M hexane (10.5 ml) of n-butyllithium was added dropwise to the solution, and the mixture was stirred for 15 minutes at −78° C. Then, 5-chloro-2-bromobenzaldehyde (3.15 g) dissolved in tetrahydrofuran (50 ml) was added dropwise to the reaction mixture, and the mixture was stirred for two hours at room temperature. Aqueous solution of saturated ammonium chloride was added to the reaction mixture, and then the solvent was evaporated from the filtrate under reduced pressure to give the residue. Ethyl acetate and water were added to the residue obtained, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 1-benzothiene-2-yl(5-bromo-2-chlorophenyl) methanol (4.75 g). Imidazole (1.08 g) and tert-butyl dimethylchlorosilane (2.99 g) were added to a solution of 1-benzothiene-2-yl(5-bromo-2-chlorophenyl) methanol in dimethylformamide (100 ml), and the mixture was stirred for three hours at 70° C. Water was added to the reaction mixture, and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, the solvent was evaporated therefrom under reduced pressure to give the residue, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain [1-benzothiene-2-yl(5-bromo-2-chloro phenyl)methoxy](tert-butyl) dimethylsilane (3.34 g). was added dropwise to the reaction mixture the mixture was stirred for two hours at room temperature the solvent was evaporated from the filtrate under reduced pressure to give the residue obtained extracted with ethyl acetate The organic layer was dried over magnesium sulfate the solvent was evaporated from the filtrate under reduced pressure to give the residue the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate)

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

Procedure: 2-Bromo-5-chlorobenzaldehyde (20.5 g) from Example 72 was dissolved with dry methanol (200 ml), followed by sodium borohydride (1.06 g) at 0° C., and the mixture was stirred for 30 minutes. After addition of acetone, the solvent was removed under reduced pressure, water was added the obtained residue, and then extracted with ether. The organic layer was washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, to give the title compound (19.5 g; 94%) the solvent was removed under reduced pressure, water was added the obtained residue extracted with ether The organic layer was washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution dried over anhydrous sodium sulfate The solvent was removed under reduced pressure

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the solution of 2-bromo-5-chlorotoluene (25 g) in acetic anhydride (100 ml) and sulfuric acid (20 ml) was added dropwise chromium(VI) oxide (36.5 g) in acetic anhydride (200 ml) for 3 hours at -15° C. The mixture was stirred for 1 hour at -5° C. and then poured into ice-cooled water, and extracted with ether. The organic layer was washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was suspended in ethanol (100 ml) and 3N-HCl (200 ml) and refluxed for 1 hour. After removal of the solvent, water was added to the residue, and extracted with ether. poured into ice- extracted with ether The organic layer was washed with water and saturated sodium chloride solution dried over anhydrous sodium sulfate After removal of the solvent under reduced pressure 3N-HCl (200 ml) and refluxed for 1 hour After removal of the solvent, water was added to the residue extracted with ether

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

Procedure: Benzo[b]thiophene (1.12 g) was dissolved in tetrahydrofuran (50 ml). This solution was cooled to −78° C., and a solution of 1.58 M hexane (10.5 ml) of n-butyllithium was added dropwise to the solution, and the mixture was stirred for 15 minutes at −78° C. Then, 5-chloro-2-bromobenzaldehyde (3.15 g) dissolved in tetrahydrofuran (50 ml) was added dropwise to the reaction mixture, and the mixture was stirred for two hours at room temperature. Aqueous solution of saturated ammonium chloride was added to the reaction mixture, and then the solvent was evaporated from the filtrate under reduced pressure to give the residue. Ethyl acetate and water were added to the residue obtained, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 1-benzothien-2-yl(5-bromo-2-chlorophenyl) methanol (4.75 g). Imidazole (1.08 g) and tert-butyl dimethylchlorosilane (2.99 g) were added to a solution of 1-benzothien-2-yl(5-bromo-2-chlorophenyl)methanol in dimethylformamide (100 ml), and the mixture was stirred for three hours at 70° C. Water was added to the reaction mixture, and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, the solvent was evaporated therefrom under reduced pressure to give the residue, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain [1-benzothien-2-yl(5-bromo-2-chloro phenyl)methoxy](tert-butyl) dimethylsilane (3.34 g). was added dropwise to the reaction mixture the mixture was stirred for two hours at room temperature the solvent was evaporated from the filtrate under reduced pressure to give the residue obtained extracted with ethyl acetate The organic layer was dried over magnesium sulfate the solvent was evaporated from the filtrate under reduced pressure to give the residue the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate)

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

Procedure: Benzo[b]thiophene (1.12 g) was dissolved in tetrahydrofuran (50 ml). This solution was cooled to −78° C., and a solution of 1.58 M hexane (10.5 ml) of n-butyllithium was added dropwise to the solution, and the mixture was stirred for 15 minutes at −78° C. Then, 5-chloro-2-bromobenzaldehyde (3.15 g) dissolved in tetrahydrofuran (50 ml) was added dropwise to the reaction mixture, and the mixture was stirred for two hours at room temperature. Aqueous solution of saturated ammonium chloride was added to the reaction mixture, and then the solvent was evaporated from the filtrate under reduced pressure to give the residue. Ethyl acetate and water were added to the residue obtained, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 1-benzothien-2-yl(5-bromo-2-chlorophenyl)methanol (4.75 g). Imidazole (1.08 g) and tert-butyl dimethylchlorosilane (2.99 g) were added to a solution of 1-benzothien-2-yl(5-bromo-2-chlorophenyl)methanol in dimethylformamide (100 ml), and the mixture was stirred for three hours at 70° C. Water was added to the reaction mixture, and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, the solvent was evaporated therefrom under reduced pressure to give the residue, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain [1-benzothien-2-yl(5-bromo-2-chloro phenyl)methoxy](tert-butyl) dimethylsilane (3.34 g). was added dropwise to the reaction mixture the mixture was stirred for two hours at room temperature the solvent was evaporated from the filtrate under reduced pressure to give the residue obtained extracted with ethyl acetate The organic layer was dried over magnesium sulfate the solvent was evaporated from the filtrate under reduced pressure to give the residue the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate)