5-bromo-2-iodobenzonitrile

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

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a sealed tube were added 5-bromo-2-iodobenzonitrile 206-1 (500 mg, 1.6 mmol), 2-fluoropyridin-4-ylboronic acid 205-4 (229 mg, 1.6 mmol), Pd(PPh3)4 (94 mg, 0.08 mmol), Na2CO3 (516 mg, 4.9 mmol), toluene (2 mL), H2O (2 mL) and ethanol (0.5 mL). The reaction mixture was stirred at 120° C. overnight. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (5 ml) and extracted with ethyl acetate (8 mL×3). The combined organic phases were dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography and eluted with 15% ethyl acetate in hexane to give 5-bromo-2-(2-fluoropyridin-4-yl)benzonitrile 206-3. MS m/z 277.1 (M+1). After cooling to room temperature the solvents were evaporated the residue was redissolved in water (5 ml) extracted with ethyl acetate (8 mL×3) The combined organic phases were dried over Na2SO4 concentrated The residue was purified by silica gel flash chromatography eluted with 15% ethyl acetate in hexane

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

Procedure: To a solution of 5-bromo-2-iodobenzonitrile (5.00 g, 16.00 mmoles) in anhydrous tetrahydrofuran (80 ml) at −80° C. is added diisobutyl aluminium hydride (16.0 ml, 16.0 mmoles, 1M solution in toluene) dropwise over 10 minutes. The reaction mixture is stirred at −80° C. for a 1 hour, then allowed to warm to ambient temperature and stir overnight. Additional diisobutyl aluminium hydride (16.0 ml, 16.0 mmoles, 1M solution in toluene) is next added dropwise at room temperature, and the reaction mixture further stirred for 1 hour. After careful quenching with 2M hydrochloric acid (cooling in ice bath), the crude product is extracted with ethyl acetate (×2), then all organics are combined and dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure then purified by flash column chromatography (isohexane to 10% ethyl acetate in isohexane eluant) to afford 5-bromo-2-iodobenzaldehyde (0.85 g). to warm to ambient temperature stir overnight the reaction mixture further stirred for 1 hour After careful quenching with 2M hydrochloric acid (cooling in ice bath) the crude product is extracted with ethyl acetate (×2) dried over magnesium sulfate filtered The filtrate is evaporated under reduced pressure then purified by flash column chromatography (isohexane to 10% ethyl acetate in isohexane eluant)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a sealed tube were added 5-bromo-2-iodobenzonitrile 206-1 (500 mg, 1.6 mmol), 2-fluoropyridin-4-ylboronic acid 205-4 (229 mg, 1.6 mmol), Pd(PPh3)4 (94 mg, 0.08 mmol), Na2CO3 (516 mg, 4.9 mmol), toluene (2 mL), H2O (2 mL) and ethanol (0.5 mL). The reaction mixture was stirred at 120° C. overnight. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (5 ml) and extracted with ethyl acetate (8 mL×3). The combined organic phases were dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography and eluted with 15% ethyl acetate in hexane to give 5-bromo-2-(2-fluoropyridin-4-yl)benzonitrile 206-3. MS m/z 277.1 (M+1). After cooling to room temperature the solvents were evaporated the residue was redissolved in water (5 ml) extracted with ethyl acetate (8 mL×3) The combined organic phases were dried over Na2SO4 concentrated The residue was purified by silica gel flash chromatography eluted with 15% ethyl acetate in hexane

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

Procedure: To 5-bromo-2-iodobenzonitrile (7.4 g, 24.2 mmol) in THF (40 mL) at −78° C. was added diisobutylaluminium hydride (1 M in hexanes; 24.2 mL, 24.2 mmol) over 5 minutes, and the reaction was allowed to warm to room temperature and monitored by analytical tlc. After stirring overnight at room temperature, starting material was still present, so the mixture was cooled to 0° C. and additional diisobutylaluminium hydride (1 M in hexanes; 10.0 mL, 10.0 mmol) was added. After stirring for 2 hours at room temperature, no starting material was seen by analytical tlc, so the mixture was carefully quenched with freshly saturated aqueous Na2SO4 and diluted with EtOAc. The mixture was stirred vigorously for 1 hour and then filtered through Celite. The filtrate was concentrated, and the resulting oil solidified on standing. The solid was stirred vigorously in CH2Cl2 and 1N aqueous HCl, and the aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound. was cooled to 0° C. After stirring for 2 hours at room temperature was carefully quenched with freshly saturated aqueous Na2SO4 diluted with EtOAc The mixture was stirred vigorously for 1 hour filtered through Celite The filtrate was concentrated The solid was stirred vigorously in CH2Cl2 1N aqueous HCl, and the aqueous layer was separated extracted with CH2Cl2 The combined organic layers were dried over MgSO4 filtered concentrated

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

Procedure: 5-Bromo-2-iodobenzonitrile and 3-pyridylboric acid were dissolved in a mixture solution of aqueous 2 M sodium carbonate solution and toluene, then tetrakis(triphenylphosphine)palladium was added thereto, and the mixture was heated, stirred with heating in an argon atmosphere at 100° C. for 3 days to obtain 5-bromo-2-pyridin-3-ylbenzonitrile. EI: 258, 260. the mixture was heated

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

Procedure: 5-Bromo-2-iodobenzonitrile and 3-pyridylboric acid were dissolved in a mixture solution of aqueous 2 M sodium carbonate solution and toluene, then tetrakis(triphenylphosphine)palladium was added thereto, and the mixture was heated, stirred with heating in an argon atmosphere at 100° C. for 3 days to obtain 5-bromo-2-pyridin-3-ylbenzonitrile. EI: 258, 260. the mixture was heated

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A microwave vial was charged with N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate M, 0.320 g, 0.766 mmol), Xantphos (0.089 g, 0.153 mmol), 5-bromo-2-iodobenzonitrile (Combi-Blocks) (0.354 g, 1.150 mmol), Pd2(dba)3 (0.070 g, 0.077 mmol) and sodium tert-butoxide (0.147 g, 1.533 mmol). The mixture was diluted with toluene (7.66 ml), and purged with nitrogen, and stirred at 130° C. in the microwave for 30 minutes, until clean conversion to the desired product. The reaction was filtered over a plug of Celite, washing well with DCM. The filtrate was concentrated in vacuo and the crude material was directly adsorbed onto a 12-g RediSep Gold column and purified by silica gel chromatography, eluting with a gradient of 0% to 100% ethyl acetate in heptane, to provide 4-(4-bromo-2-cyanophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.248 g, 0.415 mmol, 54.2% yield) as yellow solid. purged with nitrogen The reaction was filtered over a plug of Celite washing well with DCM The filtrate was concentrated in vacuo purified by silica gel chromatography eluting with a gradient of 0% to 100% ethyl acetate in heptane

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

Procedure: To a solution of 5-bromo-2-iodobenzonitrile (9.21 g, 0.03 mol) in tetrahydrofuran (140 mL) at 0° C. was added BH3-THF (66 mL, 66 mmol, 1 M solution in tetrahydrofuran) dropwise over 1 hour. The reaction solution was stirred at room temperature for 10 minutes, and then heated to reflux for overnight. 10% aqueous HCl was added (to adjust to pH 2-3) and stirred for 20 minutes, then the mixture was basified with 10 M aqueous KOH up to pH>10. The mixture was extracted with ethyl acetate three times. Organics were combined, dried with sodium sulfate, filtered and concentrated in vacuo to yield 6.2 g of crude (5-bromo-2-iodophenyl)methanamine as a yellow oil. LCMS (ESI): M+H=311.7; 1H NMR (400 MHz, DMSO-d6): δ 7.71 (d, J=8.4 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.18 (dd, J=2.4, 8.4 Hz, 1H). heated to reflux for overnight stirred for 20 minutes The mixture was extracted with ethyl acetate three times dried with sodium sulfate filtered concentrated in vacuo

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

Procedure: To a solution of 5-bromo-2-iodobenzonitrile (9.21 g, 0.03 mol) in tetrahydrofuran (140 mL) at 0° C. was added BH3-THF (66 mL, 66 mmol, 1 M solution in tetrahydrofuran) dropwise over 1 hour. The reaction solution was stirred at room temperature for 10 minutes, and then heated to reflux for overnight. 10% aqueous HCl was added (to adjust to pH 2-3) and stirred for 20 minutes, then the mixture was basified with 10 M aqueous KOH up to pH>10. The mixture was extracted with ethyl acetate three times. Organics were combined, dried with sodium sulfate, filtered and concentrated in vacuo to yield 6.2 g of crude (5-bromo-2-iodophenyl)methanamine as a yellow oil. LCMS (ESI): M+H=311.7; 1H NMR (400 MHz, DMSO-d6): δ 7.71 (d, J=8.4 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.18 (dd, J=2.4, 8.4 Hz, 1H). heated to reflux for overnight stirred for 20 minutes The mixture was extracted with ethyl acetate three times dried with sodium sulfate filtered concentrated in vacuo

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

Procedure: 2-amino-5-bromobenzonitrile (100 g, 0.5 mol) was added during 1 hour to tert-butyl nitrite (117 mL, 0.75 mol) and iodine (250 g, 1.1 mol) in dry acetonitrile (600 mL) under nitrogen while maintaining the temperature between 30° C. and 35° C. Stirring was continued for 60 minutes at 23° C. Subsequent addition of saturated aqueous Na2SO3 (2 L) gave precipitate which was collected by filtration, and washed with hexanes to obtain 100 g (65%) of 5-bromo-2-iodobenzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J=2.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.64 (dd, J=2.4, 8.4 Hz, 1H). while maintaining the temperature between 30° C. and 35° C gave precipitate which was collected by filtration washed with hexanes

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