4-(bromomethyl)benzenesulfonamide

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

Procedure: The alkylation of 7-bromo-1-hydroxy-6-azaisoquinoline (1.00 g, 4.40 mmol) using 4-bromomethyl-benzene sulfonamide (1.67 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product. Step (2): 4-[1-oxo-7-(3-phenyl-prop-1-ynyl)-1H-6-azaisoquinolin-2-ylmethyl]benzenesulfonamide Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1

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

Procedure: The alkylation of 7-bromo-3-hydroxy-6-azaisoquinoline (1.00 g, 4.40 mmol) using 4-bromomethyl-benzene sulfonamide (1.67 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product. Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1

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

Procedure: To a solution of 7-methoxy-3-phenyl-1H-pyrazolo[3,4-c]pyridine (193 mg) obtained in Step C of Example 10 in THF (30 mL) was added sodium hydride (60% dispersion in mineral oil, 70 mg) at room temperature, and the mixture was stirred at room temperature for 10 min. 4-(Bromomethyl)benzenesulfonamide (220 mg) was added thereto at room temperature, and the mixture was stirred at room temperature for 3 days, and then overnight at 60° C. Sodium hydride (60% dispersion in mineral oil, 70 mg) and 4-(bromomethyl)benzenesulfonamide (220 mg) were added thereto, and the mixture was stirred at 60° C. for 10 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (173 mg). at room temperature, and the mixture was stirred at room temperature for 3 days overnight at 60° C the mixture was stirred at 60° C. for 10 hr the mixture was extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane)

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

Procedure: To a solution of 7-methoxy-3-phenyl-1H-pyrazolo[3,4-c]pyridine (193 mg) obtained in Step C of Example 10 in THF (30 mL) was added sodium hydride (60% dispersion in mineral oil, 70 mg) at room temperature, and the mixture was stirred at room temperature for 10 min. 4-(Bromomethyl)benzenesulfonamide (220 mg) was added thereto at room temperature, and the mixture was stirred at room temperature for 3 days, and then overnight at 60° C. Sodium hydride (60% dispersion in mineral oil, 70 mg) and 4-(bromomethyl)benzenesulfonamide (220 mg) were added thereto, and the mixture was stirred at 60° C. for 10 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (173 mg). at room temperature, and the mixture was stirred at room temperature for 3 days overnight at 60° C the mixture was stirred at 60° C. for 10 hr the mixture was extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and 4-(bromomethyl)benzenesulfonamide (124 mg, 0.496 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-70% ethyl acetate in pet ether) to afford the title compound as a solid (40 mg, 33%). the resultant reaction mixture The reaction mixture was cooled to RT filtered through celite the filtrate was concentrated under reduced pressure The obtained residue was purified by column chromatography (silica gel, 0-70% ethyl acetate in pet ether)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of 4-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.75 mmol) and 4-bromomethyl-benzenesulfonamide (94 mg, 0.375 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 16%). the resultant reaction mixture The reaction mixture was cooled to RT filtered through celite the filtrate was concentrated under reduced pressure The residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (154 mg, 1.118 mmol) and 4-bromomethyl-benzenesulfonamide (104 mg, 0.418 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-25% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 15.7%). the resultant reaction mixture The reaction mixture was filtered through celite the filtrate was concentrated under reduced pressure The obtained residue was purified by column chromatography (silica gel, 0-25% ethyl acetate in pet ether)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.281 mmol) in acetonitrile (5 mL) was added potassium carbonate (155 mg, 1.126 mmol) and 4-bromomethyl-benzenesulfonamide (84 mg, 0.337 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 15.7%). the resultant reaction mixture The reaction mixture was filtered through celite the filtrate was concentrated under reduced pressure The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (200 mg, 0.743 mmol) in acetonitrile (10 mL) was added potassium carbonate (307 mg, 2.228 mmol) and 4-(bromomethyl)benzenesulfonamide (370 mg, 1.48 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 300 mg of 4-((6-Bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)benzenesulfonamide crude product as a solid. the resultant reaction mixture The reaction mixture was cooled to RT filtered through celite the filtrate was concentrated under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of 5-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (100 mg, 0.310 mmol) in acetonitrile (20 mL), was added potassium carbonate (128.3 mg, 0.930 mmol) and 4-bromomethyl-benzenesulfonamide (155.2 mg, 0.620 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-70% ethyl acetate in pet ether) to afford title compound as a solid (70 mg, 46%). the resultant reaction mixture The reaction mixture was cooled to RT filtered through celite the filtrate was concentrated under reduced pressure The residue was purified by column chromatography (silica gel, 0-70% ethyl acetate in pet ether)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL), was added potassium carbonate (104 mg, 0.75 mmol) and 4-bromomethyl-benzenesulfonamide (125 mg, 0.5 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-70° A) ethyl acetate in pet ether) to afford title compound as a solid (40 mg, 33%). the resultant reaction mixture The reaction mixture was cooled to RT filtered through celite the filtrate was concentrated under reduced pressure The residue was purified by column chromatography (silica gel, 0-70° A) ethyl acetate in pet ether)

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

Procedure: 5-Chloro-N-[4-(methyloxy)-1H-indazol-3-yl]-N-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2-thiophenesulfonamide (for a preparation see Intermediate 8) (1.734 g, 3.66 mmol) was dissolved in DMF (2.4 mL) and an aliquot (0.1 mL, 0.15 mmol) added to 4-(bromomethyl)benzenesulfonamide (APAC Pharm) (0.15 mmol) and potassium carbonate (0.15 mmol) added last. The tubes were capped and shaken. Stood at room temperature for 18 h, more potassium carbonate (excess) added and reshaken the tubes. Filtered through alltech tube to remove inorganic solids, and washed tubes with MeOH (1 mL) and blown to dryness under a stream of nitrogen in a Radley's blow down unit. Redissolved in DCM (0.5 mL) and applied to a 10 g silica cartridge, and purified by chromatography on Flashmaster using a gradient of 0-100% DCM-(DCM with 20% EtOAc) over 20 min. The appropriate fractions were combined and evaporated in vacuo using the Genevac. The residue was dissolved in TBAF (1M, 0.5 mL) and heated in a microwave oven (50 Watts, 10 min, at approx 110° C. The sample was purified by MDAP on Atlantis column using Acetonitrile Water with a Formic acid modifier. The solvent was evaporated in vacuo using the Genevac to give the title compound (7.9 mg, 10%) LCMS (System A) RT=0.92 min, ES+ve m/z 513/515 (M+H)+ added last The tubes were capped Filtered through alltech tube to remove inorganic solids washed tubes with MeOH (1 mL) Redissolved in DCM (0.5 mL) purified by chromatography on Flashmaster over 20 min evaporated in vacuo The residue was dissolved in TBAF (1M, 0.5 mL) heated in a microwave oven (50 Watts, 10 min at approx 110° C The sample was purified by MDAP on Atlantis column The solvent was evaporated in vacuo