1-bromo-2,5-difluoro-4-phenylmethoxybenzene

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

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

Procedure: To 1-Benzyloxy-4-bromo-2,5-difluoro-benzene (47, 0.84 g, 2.80 mmol) in tetrahydrofuran (15.0 mL) and ether (15.0 mL), under an atmosphere of nitrogen at −78° C., n-butyllithium (1.20 mL, 2.50 M in hexane) was added slowly. After 20 minutes, 1-Triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (8, 0.82 g, 0.0027 mol, prepared as described in Example 5) was added to the reaction. After 20 minutes, the reaction was allowed to warm to room temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to a white solid (48, 10 g, 70.0%). After 20 minutes extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to a white solid (48, 10 g, 70.0%)

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

Procedure: To 1-Benzyloxy-4-bromo-2,5-difluoro-benzene (47, 0.84 g, 2.80 mmol) in tetrahydrofuran (15.0 mL) and ether (15.0 mL), under an atmosphere of nitrogen at −78° C., n-butyllithium (1.20 mL, 2.50 M in hexane) was added slowly. After 20 minutes, 1-Triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (8, 0.82 g, 0.0027 mol, prepared as described in Example 5) was added to the reaction. After 20 minutes, the reaction was allowed to warm to room temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to a white solid (48, 10 g, 70.0%). After 20 minutes extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to a white solid (48, 10 g, 70.0%)

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

Procedure: To 4-bromo-2,5-difluoro-phenol (41, 0.90 g, 0.0043 mol, prepared as described in Example 15, Scheme 3) in N,N-dimethylformamide (30.0 mL) were added sodium hydride (0.21 g, 60% in mineral oil, 0.0052 mol) and benzyl bromide (0.563 mL, 0.00474 mol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (47, 0.84 g, 65.0%). extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (47, 0.84 g, 65.0%)

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

Procedure: To 4-bromo-2,5-difluoro-phenol (595, 0.90 g, 0.0043 mol, prepared as described in Example 34, Scheme 61) in N,N-dimethylformamide (30.0 mL) were added sodium hydride (0.21 g, 60% in mineral oil, 0.0052 mol) and benzyl bromide (0.563 mL, 0.00474 mol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (600, 0.84 g, 65.0%). extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (600, 0.84 g, 65.0%)

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

Procedure: To 4-bromo-2,5-difluoro-phenol (595, 0.90 g, 0.0043 mol, prepared as described in Example 34, Scheme 61) in N,N-dimethylformamide (30.0 mL) were added sodium hydride (0.21 g, 60% in mineral oil, 0.0052 mol) and benzyl bromide (0.563 mL, 0.00474 mol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (600, 0.84 g, 65.0%). extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (600, 0.84 g, 65.0%)

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

Procedure: To 4-bromo-2,5-difluoro-phenol (595, 0.90 g, 0.0043 mol, prepared as described in Example 34, Scheme 61) in N,N-dimethylformamide (30.0 mL) were added sodium hydride (0.21 g, 60% in mineral oil, 0.0052 mol) and benzyl bromide (0.563 mL, 0.00474 mol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (600, 0.84 g, 65.0%). extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (600, 0.84 g, 65.0%)

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

Procedure: To 1-Benzyloxy-4-bromo-2,5-difluoro-benzene (47, 0.84 g, 2.80 mmol) in tetrahydrofuran (15.0 mL) and ether (15.0 mL), under an atmosphere of nitrogen at −78° C., n-butyllithium (1.20 mL, 2.50 M in hexane) was added slowly. After 20 minutes, 1-Triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (8, 0.82 g, 0.0027 mol, prepared as described in Example 5) was added to the reaction. After 20 minutes, the reaction was allowed to warm to room temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to a white solid (48, 10 g, 70.0%). After 20 minutes extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to a white solid (48, 10 g, 70.0%)

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

Procedure: To 4-bromo-2,5-difluoro-phenol (41, 0.90 g, 0.0043 mol, prepared as described in Example 15, Scheme 3) in N,N-dimethylformamide (30.0 mL) were added sodium hydride (0.21 g, 60% in mineral oil, 0.0052 mol) and benzyl bromide (0.563 mL, 0.00474 mol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (47, 0.84 g, 65.0%). extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (47, 0.84 g, 65.0%)

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

Procedure: To 4-bromo-2,5-difluoro-phenol (595, 0.90 g, 0.0043 mol, prepared as described in Example 34, Scheme 61) in N,N-dimethylformamide (30.0 mL) were added sodium hydride (0.21 g, 60% in mineral oil, 0.0052 mol) and benzyl bromide (0.563 mL, 0.00474 mol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (600, 0.84 g, 65.0%). extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered The filtrate was concentrated purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (600, 0.84 g, 65.0%)

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In two microwave vials were placed 4-[(phenylmethyl)oxy]-1H-indole (500 mg, 2.24 mmoL), 4-bromo-2,5-difluorophenyl phenylmethyl ether (prepared as described in part a), 559 mg, 1.87 mmoL), K3PO4 (990 mg, 4.67 mmoL), L-Proline (43 mg, 0.373 mmoL) and DMF (5 mL) and the mixture was degassed by sonication under a flow of argon. To each vial was added CuI (71 mg, 0.373 mmoL) and the solutions were heated to 140° C. in the microwave reactor. After 4 hours a second portion of L-Proline (43 mg, 0.373 mmoL) was added and heated for an additional hour. The two mixtures were partitioned between ethyl acetate (100 mL)/water (100 mL), the phases were separated and the aqueous phase re-extracted with ethyl acetate (100 mL). The combined organic phases were washed with sat. NH4Cl (2×100 mL), water (100 mL) and brine (2×100 mL) and finally dried over MgSO4. The combined crude materials were purified by flash chromatography (Biotage SP4, 40+M Cartridge) eluting with a gradient of 0 to 30% Et2O in hexane to give the title compound (D22), (258 mg). prepared the mixture was degassed by sonication under a flow of argon To each vial was added CuI (71 mg, 0.373 mmoL) After 4 hours a second portion of L-Proline (43 mg, 0.373 mmoL) was added heated for an additional hour The two mixtures were partitioned between ethyl acetate (100 mL)/water (100 mL) the phases were separated the aqueous phase re-extracted with ethyl acetate (100 mL) The combined organic phases were washed with sat. NH4Cl (2×100 mL), water (100 mL) and brine (2×100 mL) finally dried over MgSO4 were purified by flash chromatography (Biotage SP4, 40+M Cartridge) eluting with a gradient of 0 to 30% Et2O in hexane

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

Procedure: 4-bromo-2,5-difluorophenol (2 g, 9.57 mmol) was dissolved in DMF (19 mL) and to this was added Cs2CO3 (4.37 g, 13.34 mmol) and the solution was stirred for 15 minutes before benzyl bromide (1.64 g, 9.57 mmol) was added. After 1 hour at room temperature the mixture was partitioned between ethyl acetate (100 mL)/water (100 mL), the layers were separated and the aqueous extracted with ethyl acetate. The combined organics were washed with saturated NH4Cl (100 mL), water (100 mL) and brine (2×100 mL) and dried over MgSO4. The crude material (2.74 g) was filtered through a pad of silica and eluted with 20% Et2O in hexane to afford 4-bromo-2,5-difluorophenyl phenylmethyl ether after evaporation of the solvent (2.51 g, 88%). was added After 1 hour at room temperature the mixture was partitioned between ethyl acetate (100 mL)/water (100 mL) the layers were separated the aqueous extracted with ethyl acetate The combined organics were washed with saturated NH4Cl (100 mL), water (100 mL) and brine (2×100 mL) dried over MgSO4 The crude material (2.74 g) was filtered through a pad of silica eluted with 20% Et2O in hexane