1-(2-chloroethoxy)-4-iodobenzene

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

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

Procedure: In a single neck, 100 mL round bottom flask was dissolved and stirred 1-(2-chloro-ethoxy)-4-iodo-benzene (530 mg, 1.88 mmol, 5.0 eq), in tetrahydrofuran (5 mL) under nitrogen, and the mixture cooled to −78° C. After 5 minutes of stirring, a hexane solution of n-BuLi (0.75 mL of 2.5 M, 1.88 mmol, 5.0 eq) was added via syringe. The reaction mixture was then stirred for 30 min at about −78° C. A tetrahydrofuran solution of 3-[6-(tert-butyl-dimethyl-silanyloxy)-pyridin-3-yl]-7-methoxy-4-methyl-2H-chromen-2-ol (150 mg, 0.376 mmol, 1 eq, in 2 mL), prepared as in Example 24, was then added, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature overnight. After about 18 hours, the reaction was worked-up with addition of saturated ammonium acetate solution and extraction with ethyl ether. The combined organic extracts were washed with brine and water, dried with anhydrous sodium sulphate, filtered and evaporated to yield a sticky semisolid residue. To this solid was added 0.2 mL HCl in 10 mL toluene at room temperature. The mixture was stirred for 2 hours at room temperature. The reaction was worked-up with sodium bicarbonate washing and extraction with ethyl acetate three times. The combined organic extracts were washed with brine and water, dried with anhydrous sodium sulphate, filtered and evaporated to yield a brown oil. The title product was isolated as a white semisolid foam via chromatography on silica gel eluted with 1:1 hexanes:ethyl acetate as eluent. In a single neck, 100 mL round bottom flask was dissolved The reaction mixture was then stirred for 30 min at about −78° C was then added the cooling bath was removed After about 18 hours the reaction was worked-up with addition of saturated ammonium acetate solution and extraction with ethyl ether The combined organic extracts were washed with brine and water dried with anhydrous sodium sulphate filtered evaporated to yield a sticky semisolid residue The mixture was stirred for 2 hours at room temperature The reaction was worked-up with sodium bicarbonate washing and extraction with ethyl acetate three times The combined organic extracts were washed with brine and water dried with anhydrous sodium sulphate filtered evaporated to yield a brown oil

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

Procedure: To a suspension of (2R)-2-methylpyrrolidine (0.60 g) and cesium carbonate (1.2 g) in acetonitrile (3 mL), 1-(2-chloroethoxy)-4-iodobenzene obtained in Example 60-(1) (0.87 g) was added and the mixture was heated to 100° C., at which it was stirred for 9 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 1:1) to give the titled compound (0.80 g, 78%) as a colorless oil. was added The reaction mixture was cooled to room temperature filtered to remove insoluble materials the filtrate was concentrated under reduced pressure The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 1:1)

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

Procedure: To a solution of 4-iodophenol (1.0 g) in acetonitrile (10 mL), cesium carbonate (3.0 g) and 1-bromo-2-chloroethane (0.8 g) were added and the mixture was heated to 100° C., at which it was stirred for 4 hours. Additional 1-bromo-2-chloroethane (1.0 g) was further added and stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=11:1) to give the titled compound (0.87 g, 68%) as a yellow oil. stirred at 100° C. for 4 hours The reaction mixture was cooled to room temperature filtered to remove insoluble materials the filtrate was concentrated under reduced pressure The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=11:1)

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

Procedure: To a suspension of (2R)-2-methylpyrrolidine (0.60 g) and cesium carbonate (1.2 g) in acetonitrile (3 mL), 1-(2-chloroethoxy)-4-iodobenzene obtained in Example 60-(1) (0.87 g) was added and the mixture was heated to 100° C., at which it was stirred for 9 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 1:1) to give the titled compound (0.80 g, 78%) as a colorless oil. was added The reaction mixture was cooled to room temperature filtered to remove insoluble materials the filtrate was concentrated under reduced pressure The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 1:1)

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

Procedure: To a solution of 4-iodophenol (1.0 g) in acetonitrile (10 mL), cesium carbonate (3.0 g) and 1-bromo-2-chloroethane (0.8 g) were added and the mixture was heated to 100° C., at which it was stirred for 4 hours. Additional 1-bromo-2-chloroethane (1.0 g) was further added and stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=11:1) to give the titled compound (0.87 g, 68%) as a yellow oil. stirred at 100° C. for 4 hours The reaction mixture was cooled to room temperature filtered to remove insoluble materials the filtrate was concentrated under reduced pressure The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=11:1)

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

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

Procedure: To a suspension of (2R)-2-methylpyrrolidine (0.60 g) and cesium carbonate (1.2 g) in acetonitrile (3 mL), 1-(2-chloroethoxy)-4-iodobenzene obtained in Example 60-(1) (0.87 g) was added and the mixture was heated to 100° C., at which it was stirred for 9 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 1:1) to give the titled compound (0.80 g, 78%) as a colorless oil. was added The reaction mixture was cooled to room temperature filtered to remove insoluble materials the filtrate was concentrated under reduced pressure The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 1:1)

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

Procedure: To a solution of 4-iodophenol (1.0 g) in acetonitrile (10 mL), cesium carbonate (3.0 g) and 1-bromo-2-chloroethane (0.8 g) were added and the mixture was heated to 100° C., at which it was stirred for 4 hours. Additional 1-bromo-2-chloroethane (1.0 g) was further added and stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=11:1) to give the titled compound (0.87 g, 68%) as a yellow oil. stirred at 100° C. for 4 hours The reaction mixture was cooled to room temperature filtered to remove insoluble materials the filtrate was concentrated under reduced pressure The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=11:1)

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

Procedure: To a suspension of (2R)-2-methylpyrrolidine (0.60 g) and cesium carbonate (1.2 g) in acetonitrile (3 mL), 1-(2-chloroethoxy)-4-iodobenzene obtained in Example 60-(1) (0.87 g) was added and the mixture was heated to 100° C., at which it was stirred for 9 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 1:1) to give the titled compound (0.80 g, 78%) as a colorless oil. was added The reaction mixture was cooled to room temperature filtered to remove insoluble materials the filtrate was concentrated under reduced pressure The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 1:1)

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

Procedure: To a solution of 4-iodophenol (1.0 g) in acetonitrile (10 mL), cesium carbonate (3.0 g) and 1-bromo-2-chloroethane (0.8 g) were added and the mixture was heated to 100° C., at which it was stirred for 4 hours. Additional 1-bromo-2-chloroethane (1.0 g) was further added and stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=11:1) to give the titled compound (0.87 g, 68%) as a yellow oil. stirred at 100° C. for 4 hours The reaction mixture was cooled to room temperature filtered to remove insoluble materials the filtrate was concentrated under reduced pressure The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=11:1)

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

Procedure: In a single neck, 100 mL round bottom flask was dissolved and stirred 1-(2-chloro-ethoxy)-4-iodo-benzene (530 mg, 1.88 mmol, 5.0 eq), in tetrahydrofuran (5 mL) under nitrogen, and the mixture cooled to −78° C. After 5 minutes of stirring, a hexane solution of n-BuLi (0.75 mL of 2.5 M, 1.88 mmol, 5.0 eq) was added via syringe. The reaction mixture was then stirred for 30 min at about −78° C. A tetrahydrofuran solution of 3-[6-(tert-butyl-dimethyl-silanyloxy)-pyridin-3-yl]-7-methoxy-4-methyl-2H-chromen-2-ol (150 mg, 0.376 mmol, 1 eq, in 2 mL), prepared as in Example 24, was then added, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature overnight. After about 18 hours, the reaction was worked-up with addition of saturated ammonium acetate solution and extraction with ethyl ether. The combined organic extracts were washed with brine and water, dried with anhydrous sodium sulphate, filtered and evaporated to yield a sticky semisolid residue. To this solid was added 0.2 mL HCl in 10 mL toluene at room temperature. The mixture was stirred for 2 hours at room temperature. The reaction was worked-up with sodium bicarbonate washing and extraction with ethyl acetate three times. The combined organic extracts were washed with brine and water, dried with anhydrous sodium sulphate, filtered and evaporated to yield a brown oil. The title product was isolated as a white semisolid foam via chromatography on silica gel eluted with 1:1 hexanes:ethyl acetate as eluent. In a single neck, 100 mL round bottom flask was dissolved The reaction mixture was then stirred for 30 min at about −78° C was then added the cooling bath was removed After about 18 hours the reaction was worked-up with addition of saturated ammonium acetate solution and extraction with ethyl ether The combined organic extracts were washed with brine and water dried with anhydrous sodium sulphate filtered evaporated to yield a sticky semisolid residue The mixture was stirred for 2 hours at room temperature The reaction was worked-up with sodium bicarbonate washing and extraction with ethyl acetate three times The combined organic extracts were washed with brine and water dried with anhydrous sodium sulphate filtered evaporated to yield a brown oil