2-iodobenzonitrile

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

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

Procedure: A mixture of 6-bromo-2-naphthyl hydrosulfide (Step 2, 2.08 g, 8.7 mmol), 2-iodobenzonitrile (2 g, 8.56 mmol), copper(I) iodide (83 mg, 0.44 mmol) and potassium carbonate (2.4 g, 17.4 mmol) was degassed then isopropyl alcohol (10 mL) and ethylene glycol (0.97 mL, 17.4 mmol) added. The reaction was heated to 80° overnight. The cooled reaction mixture was poured into water and extracted with dichloromethane (x3). The combined organic layers were washed with ammonium chloride solution, water and brine, filtered, dried over MgSO4 and evaporated in vacuo to give 2-[(6-bromo-2-naphthyl)thio]benzonitrile (2.85 g, containing some 2,2′-dithiobis(6-bromonaphthalene)). 2.19 g of this was treated according to the method of Example 2 Step 4 to give 2-[(6-bromo-2-naphthyl)sulfonyl]benzonitrile (1.33 g, 56%). 1H NMR (500 MHz, CDCl3) δ 8.76 (1H, s), 8.41 (1H, d, J=8.0 Hz), 8.07 (1H, s), 7.94-7.79 (5H, m), 7.72-7.68 (2H, m); m/z (ES+) 372, 374 [MH+]. was degassed The reaction was heated to 80° overnight The cooled reaction mixture extracted with dichloromethane (x3) The combined organic layers were washed with ammonium chloride solution, water and brine filtered dried over MgSO4 evaporated in vacuo

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

Procedure: 6-(2,4-Difluorophenyl)-2-naphthyl hydrosulfide (Step 2, 0.78 g) was dissolved in isopropyl alcohol (15 mL). 2-Iodobenzonitrile (0.66 g, 2.88 mmol), copper(I) iodide (29 mg, 0.15 mmol), potassium carbonate (0.8 g, 5.79 mmol) and ethylene glycol (320 μL) were added and the reaction heated to 80° C. under nitrogen overnight. Ethyl acetate was added to the cooled reaction mixture and stirred for 15 minutes. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 10-20% ethyl acetate/isohexane, followed by recrystallisation from ethyl acetate/isohexane, to give 2-{[6-(2,4-difluorophenyl)-2-naphthyl]thio}benzonitrile (216 mg, 20%). 1H NMR (500 MHz, CDCl3) δ 8.04 (1H, s), 7.97 (1H, s), 7.88 (2H, t, J=7.8 Hz), 7.68 (2H, d, J=8.0 Hz), 7.54-7.48 (2H, m), 7.43-7.39 (1H, m), 7.28 (1H, t, J=7.6 Hz), 7.19 (1H, d, J=7.9 Hz), 7.03-6.95 (2H, m). The mixture was filtered the filtrate evaporated in vacuo The residue was purified by flash column chromatography on silica eluting with 10-20% ethyl acetate/isohexane followed by recrystallisation from ethyl acetate/isohexane

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

Procedure: 6-(2,4-Difluorophenyl)-2-naphthyl hydrosulfide (Step 2, 0.78 g) was dissolved in isopropyl alcohol (15 mL). 2-Iodobenzonitrile (0.66 g, 2.88 mmol), copper(I) iodide (29 mg, 0.15 mmol), potassium carbonate (0.8 g, 5.79 mmol) and ethylene glycol (320 μL) were added and the reaction heated to 80° C. under nitrogen overnight. Ethyl acetate was added to the cooled reaction mixture and stirred for 15 minutes. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 10-20% ethyl acetate/isohexane, followed by recrystallisation from ethyl acetate/isohexane, to give 2-{[6-(2,4-difluorophenyl)-2-naphthyl]thio}benzonitrile (216 mg, 20%). 1H NMR (500 MHz, CDCl3) δ 8.04 (1H, s), 7.97 (1H, s), 7.88 (2H, t, J=7.8 Hz), 7.68 (2H, d, J=8.0 Hz), 7.54-7.48 (2H, m), 7.43-7.39 (1H, m), 7.28 (1H, t, J=7.6 Hz), 7.19 (1H, d, J=7.9 Hz), 7.03-6.95 (2H, m). The mixture was filtered the filtrate evaporated in vacuo The residue was purified by flash column chromatography on silica eluting with 10-20% ethyl acetate/isohexane followed by recrystallisation from ethyl acetate/isohexane

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

Procedure: 3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (300 mg, 1.38 mmol) was dissolved in pyridine (10 ml), cooled in an ice bath and treated with sodium hydride (60% in mineral oil) (66 mg, 1.66 mmol) under argon. The resulting mixture was stirred for 5 minutes, treated with copper (I) bromide (277 mg, 1.93 mmol) and allowed to warm to room temperature over 30 minutes. A solution of 2-iodobenzonitrile (948 mg, 4.14 mmol) in pyridine (2 ml) was added and the mixture heated under reflux for 2.5 hours. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the title compound (180 mg); MS (ES+) m/e 319 [M+H]+. cooled in an ice bath the mixture heated under reflux for 2.5 hours to cool to room temperature the solvent removed in vacuo The resulting residue was purified by column chromatography eluting with a mixture of ammonia:methanol:dichloromethane (0.2:1.8:98)

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

Procedure: 3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (300 mg, 1.38 mmol) was dissolved in pyridine (10 ml), cooled in an ice bath and treated with sodium hydride (60% in mineral oil) (66 mg, 1.66 mmol) under argon. The resulting mixture was stirred for 5 minutes, treated with copper (I) bromide (277 mg, 1.93 mmol) and allowed to warm to room temperature over 30 minutes. A solution of 2-iodobenzonitrile (948 mg, 4.14 mmol) in pyridine (2 ml) was added and the mixture heated under reflux for 2.5 hours. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the title compound (180 mg); MS (ES+) m/e 319 [M+H]+. cooled in an ice bath the mixture heated under reflux for 2.5 hours to cool to room temperature the solvent removed in vacuo The resulting residue was purified by column chromatography eluting with a mixture of ammonia:methanol:dichloromethane (0.2:1.8:98)

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

Procedure: 3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (300 mg, 1.38 mmol) was dissolved in pyridine (10 ml), cooled in an ice bath and treated with sodium hydride (60% in mineral oil) (66 mg, 1.66 mmol) under argon. The resulting mixture was stirred for 5 minutes, treated with copper (I) bromide (277 mg, 1.93 mmol) and allowed to warm to room temperature over 30 minutes. A solution of 2-iodobenzonitrile (948 mg, 4.14 mmol) in pyridine (2 ml) was added and the mixture heated under reflux for 2.5 hours. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the title compound (180 mg); MS (ES+) m/e 319 [M+H]+. cooled in an ice bath the mixture heated under reflux for 2.5 hours to cool to room temperature the solvent removed in vacuo The resulting residue was purified by column chromatography eluting with a mixture of ammonia:methanol:dichloromethane (0.2:1.8:98)

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

Procedure: 3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (300 mg, 1.38 mmol) was dissolved in pyridine (10 ml), cooled in an ice bath and treated with sodium hydride (60% in mineral oil) (66 mg, 1.66 mmol) under argon. The resulting mixture was stirred for 5 minutes, treated with copper (I) bromide (277 mg, 1.93 mmol) and allowed to warm to room temperature over 30 minutes. A solution of 2-iodobenzonitrile (948 mg, 4.14 mmol) in pyridine (2 ml) was added and the mixture heated under reflux for 2.5 hours. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the title compound (180 mg); MS (ES+) m/e 319 [M+H]+. cooled in an ice bath the mixture heated under reflux for 2.5 hours to cool to room temperature the solvent removed in vacuo The resulting residue was purified by column chromatography eluting with a mixture of ammonia:methanol:dichloromethane (0.2:1.8:98)

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

Procedure: 3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (300 mg, 1.38 mmol) was dissolved in pyridine (10 ml), cooled in an ice bath and treated with sodium hydride (60% in mineral oil) (66 mg, 1.66 mmol) under argon. The resulting mixture was stirred for 5 minutes, treated with copper (I) bromide (277 mg, 1.93 mmol) and allowed to warm to room temperature over 30 minutes. A solution of 2-iodobenzonitrile (948 mg, 4.14 mmol) in pyridine (2 ml) was added and the mixture heated under reflux for 2.5 hours. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the title compound (180 mg); MS (ES+) m/e 319 [M+H]+. cooled in an ice bath the mixture heated under reflux for 2.5 hours to cool to room temperature the solvent removed in vacuo The resulting residue was purified by column chromatography eluting with a mixture of ammonia:methanol:dichloromethane (0.2:1.8:98)

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

Procedure: 3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (300 mg, 1.38 mmol) was dissolved in pyridine (10 ml), cooled in an ice bath and treated with sodium hydride (60% in mineral oil) (66 mg, 1.66 mmol) under argon. The resulting mixture was stirred for 5 minutes, treated with copper (I) bromide (277 mg, 1.93 mmol) and allowed to warm to room temperature over 30 minutes. A solution of 2-iodobenzonitrile (948 mg, 4.14 mmol) in pyridine (2 ml) was added and the mixture heated under reflux for 2.5 hours. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the title compound (180 mg); MS (ES+) m/e 319 [M+H]+. cooled in an ice bath the mixture heated under reflux for 2.5 hours to cool to room temperature the solvent removed in vacuo The resulting residue was purified by column chromatography eluting with a mixture of ammonia:methanol:dichloromethane (0.2:1.8:98)

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

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

Procedure: Prepare a solution of 4-cyano-5-ethyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-thiophene-2-carboxylic acid ethyl ester (0.26 mmol), 2-iodobenzonitrile (41 mg, 0.18 mmol), 2M aqueous Na2CO3 (0.6 mL, 1.2 mmol) and tetrakis(triphenylphosphine)-palladium(0) (20 mg, 0.02 mmol) in 3 mL of dioxane and heat to 80° C. under nitrogen. After 3 hours cool to room temperature, dilute with 50 mL of EtOAc and wash with water (2×10 mL) and brine (1×10 mL). Dry the organics over Na2SO4, filter and evaporate. Chromatograph on silica gel (100/0 to 3/1 toluene/EtOAc) to give the title compound as a yellow foam. Yield=61 mg (91%). HPLC=80%. After 3 hours cool to room temperature wash with water (2×10 mL) and brine (1×10 mL) Dry the organics over Na2SO4 filter evaporate