methyl 2-(3-bromo-4-methoxyphenyl)acetate

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: Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (3-bromo-4-methoxy-phenyl)-acetic acid methyl ester and 2-formyl-5-methoxyphenylboronic acid. Prepared

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

Procedure: Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (3-bromo-4-methoxy-phenyl)-acetic acid methyl ester and 2-formyl-5-methoxyphenylboronic acid. Prepared

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

Procedure: To (3-bromo-4-methoxy-phenyl)-acetic acid (5.226 g, 21.32 mmol) in MeOH (52 mL) was added thionyl chloride (3.1 mL, 42.65 mmol), and the reaction was stirred at room temperature for 2 hours. Once no starting material was seen by analytical LCMS, the mixture was concentrated and then diluted with CH2Cl2 and aqueous 1N NaOH. The aqueous layer was separated and extracted with CH2Cl2, and the combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated to give the title compound. the mixture was concentrated diluted with CH2Cl2 and aqueous 1N NaOH The aqueous layer was separated extracted with CH2Cl2 the combined organic layers were washed with H2O dried over MgSO4 filtered concentrated

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

Procedure: To (3-bromo-4-methoxy-phenyl)-acetic acid (5.226 g, 21.32 mmol) in MeOH (52 mL) was added thionyl chloride (3.1 mL, 42.65 mmol), and the reaction was stirred at room temperature for 2 hours. Once no starting material was seen by analytical LCMS, the mixture was concentrated and then diluted with CH2Cl2 and aqueous 1N NaOH. The aqueous layer was separated and extracted with CH2Cl2, and the combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated to give the title compound. the mixture was concentrated diluted with CH2Cl2 and aqueous 1N NaOH The aqueous layer was separated extracted with CH2Cl2 the combined organic layers were washed with H2O dried over MgSO4 filtered concentrated

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

Procedure: (3-Bromo-4-methoxy-phenyl)-acetic acid methyl ester (Example 175-(1); 42 mg, 0.162 mmol), palladium acetate (2.5 mg, 0.011 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (9.0 mg, 0.022 mmol), potassium phosphate (69 mg, 0.324 mmol) and water (0.2 mL) were added to a solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 28; 53 mg, 0.108 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for two hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound as a colorless oil (35.0 mg, 60%). followed by extraction with dichloromethane The organic layer was dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1)

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

Procedure: (3-Bromo-4-methoxy-phenyl)-acetic acid methyl ester (Example 175-(1); 42 mg, 0.162 mmol), palladium acetate (2.5 mg, 0.011 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (9.0 mg, 0.022 mmol), potassium phosphate (69 mg, 0.324 mmol) and water (0.2 mL) were added to a solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 28; 53 mg, 0.108 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for two hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound as a colorless oil (35.0 mg, 60%). followed by extraction with dichloromethane The organic layer was dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1)

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

Procedure: (3-Bromo-4-methoxy-phenyl)-acetic acid methyl ester (Example 175-(1); 39 mg, 0.151 mmol), palladium acetate (2.2 mg, 0.010 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (8.2 mg, 0.020 mmol), potassium phosphate (64 mg, 0.303 mmol) and water (0.2 mL) were added to a solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 39-(5); 48 mg, 0.101 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for two hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound as a colorless oil (26.2 mg, 49%). followed by extraction with dichloromethane The organic layer was dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1)

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

Procedure: Trimethylsilyldiazomethane (2 M solution in diethyl ether, 0.306 mL, 0.612 mmol) was added to a solution of (3-bromo-4-methoxy-phenyl)-acetic acid (100 mg, 0.408 mmol) in methanol (1 mL) and toluene (4 mL), and the mixture was stirred at room temperature for 10 minutes. Acetic acid was added to the reaction mixture to terminate the reaction, and then the mixture was concentrated under reduced pressure to give the target compound as a colorless oil (100 mg, 95%). to terminate the reaction the mixture was concentrated under reduced pressure

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

Procedure: Following procedures analogous to those described in Example 1, 5-(3-bromo-4-methoxyphenyl)-4-chloronicotinonitrile was prepared from methyl(3-bromo-4-methoxyphenyl)acetate. Following procedures analogous to those described above for preparing compound 101 (Example 1), 5-(3-bromo-4-methoxyphenyl)-4-chloronicotinonitrile was treated with 5-aminoindole to produce 5-(3-bromo-4-methoxyphenyl)-4-(1H-indol-5-ylamino)nicotinonitrile 188. MS: 419.2 (M+H); melting range: 148-150° C.