3-bromobenzamide

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: To a solution of m-bromobenzonitrile (2 g, 10 mol) in DMSO (6 mL) was added 30% H2O2 (5 g, 13 mmol) and K2CO3 at 0° C., and stirred at room temperature for 30 min. The mixture was poured into water and filtered, the solid was washed with water, dried to got the compound 0601-142 (1.8 g, 82%) as a white solid. LCMS: 200 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 7.41 (t, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.70 (dd, J1,2=8.0, 0.8 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 8.03 (t, J=1.6 Hz, 1H), 8.06 (s, 1H). filtered the solid was washed with water dried

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

Procedure: To a stirred mixture 3-bromobenzoic acid amide (0.76 g; 3.8 mmol) and toluene (25 mL), Pd(PPh3)4 (0.180 g; 0.16 mmol), a solution of Na2CO3 (2.543 g; 24 mmol) in H2O (10 mL), and one of 3-methoxyphenylboronic acid (1.132 g; 7.45 mmol) in EtOH (10 mL) were added. The mixture was refluxed for 1 h under vigorous stirring, cooled, and the acqueous phase extracted with AcOEt. The combined organic layers were dried over Na2SO4 and concentrated. Purification of the residue by column chromatography (cyclohexane/EtOAc 1:1 then 4:6) and recrystallization gave the desired product (0.64 g) as white solid. Yield 74%. Mp: 138–40° C. (EtOH). MS (EI): m/z 227 (M+, 100%). 1H NMR (CDCl3): δ 3.88 (s, 3H); 5.71 (br s, 1H); 6.11 (br s, 1H); 6.94 (m, 1H); 7.18 (m, 2H); 7.39 (t, 1H); 7.53 (t, 1H); 7.77 (m, 2H); 8.05 (t, 1H) ppm. IR (Nujol): 3327, 3148, 1676, 1640, 1613, 1584 cm−1. The mixture was refluxed for 1 h under vigorous stirring cooled the acqueous phase extracted with AcOEt The combined organic layers were dried over Na2SO4 concentrated Purification of the residue by column chromatography (cyclohexane/EtOAc 1:1 4:6) and recrystallization

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

Procedure: To a solution of 3-bromobenzonitrile (0.91 g, 5 mmol) in dioxane (19 mL), NaBO3.4H2O (2.12 g, 13.78 mmol) and H2O (19 mL) were added. The mixture was stirred at 80° C. 16 hours (h), cooled, added of H2O and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and evaporated. Purification of the residue by column chromatography (hexane/EtOAc 2:8) and recrystallization gave the desired product as colorless tablets. Yield 80% (EtOH). Mp: 156–7° C. (lit. 156° C.) (Pearson, D. E. et al., J. Org. Chem., 28: 3147–3149, (1963)). MS (EI): m/z 199 (M+); 183 (100%). 16 hours (h), cooled extracted with CH2Cl2 The combined organic layers were dried over Na2SO4 evaporated Purification of the residue by column chromatography (hexane/EtOAc 2:8) and recrystallization

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-bromobenzoyl chloride (21.75 g) in THF (20 ml) was added a 40% solution (50 ml) of methylamine in methanol at 0° C. and the mixture was stirred at 0° C. for 1 h. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, the mixture was washed with water and brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (18.6 g) as colorless powder crystals. The solvent was evaporated under reduced pressure the residue was dissolved in ethyl acetate the mixture was washed with water and brine dried (magnesium sulfate) concentrated under reduced pressure The residue was recrystallized from ethyl acetate-hexane

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

Procedure: Triethylamine (151.3 mg, 208.4 μL, 1.495 mmol) was added to a stirred solution of tert-butyl N-[5-(4-(isopropylsulfonyl)phenyl)-3-ethynylpyrazin-2-yl]-N-tertbutoxycarbonyl-carbamate (75 mg, 0.1495 mmol), 3-bromobenzamide (44.85 mg, 0.2242 mmol), copper (I) iodide (3.417 mg, 0.01794 mmol) and PdCl2(PPh3)2 (5.247 mg, 0.007475 mmol) in DMF (1.5 mL) and the reaction was stirred at 120° C. for 5 minutes under fixed power (300 W) microwave conditions. The reaction mixture was cooled to ambient temperature and diluted with EtOAc and 1MHCl/brine (1:1). The layers were separated and the aqueous layer was extracted with ethyl acetate (×2). The combined organics extracts washed with brine (×2), dried over (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (5 mL) and TFA (1 mL, 12.98 mmol) was added. The reaction was stirred at ambient temperature for 40 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a beige solid (11 mg, 17% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.18 (d, 6H), 3.45 (sept, 1H), 7.22 (br s, 2H), 7.53 (br s, 1H), 7.57 (t, 1H), 7.91 (d, 2H), 7.94 (d, 2H), 8.10 (s, 1H), 8.24 (d, 2H), 8.29 (d, 1H) and 8.78 (s, 1H) ppm; MS (ES+) 421.1. The reaction mixture was cooled to ambient temperature The layers were separated the aqueous layer was extracted with ethyl acetate (×2) The combined organics extracts washed with brine (×2) dried over (MgSO4) concentrated in vacuo The residue was dissolved in DCM (5 mL) The reaction was stirred at ambient temperature for 40 hours The solvent was removed in vacuo the residue azeotroped with DCM (×2) and ether (×2) The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] The fractions were collected freeze-dried

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

Procedure: 3-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)benzamide. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (72 mg, 0.109 mmol) and 3-bromobenzamide following General Procedure A. Flash chromatography (10-40% EtOAc/hexanes) yielded the title compound as a white solid (52 mg, 96%): 1H NMR (CD3OD, 600 MHz) δ 8.23 (s, 1H), 8.03 (s, 1H), 7.83 (m, 1H), 7.53 (m, 1H), 7.35 (m, 1H), 7.18-7.09 (m, 5H), 3.30 (t, 1H, J=6.0 Hz), 2.53 (t, 2H, J=7.5 Hz), 1.92-1.86 (m, 2H), 1.65-1.55 (m, 2H), 1.34-1.29 (m, 6H), 0.87 (s, 9H), 0.09 (s; 3H), −0.03 (s, 3H); 13C NMR (CD3OD, 150 MHz) δ 166.2, 151.6, 143.3, 136.6, 135.4, 131.3, 130.8, 128.8, 128.7, 126.9, 126.1, 124.0, 122.9, 122.6, 69.2, 36.8, 36.3, 32.0, 29.6, 29.5, 25.7, 25.6, 18.5, −5.3, −5.4.

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

Procedure: 3-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)benzamide. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (72 mg, 0.109 mmol) and 3-bromobenzamide following General Procedure A. Flash chromatography (10-40% EtOAc/hexanes) yielded the title compound as a white solid (52 mg, 96%): 1H NMR (CD3OD, 600 MHz) δ 8.23 (s, 1H), 8.03 (s, 1H), 7.83 (m, 1H), 7.53 (m, 1H), 7.35 (m, 1H), 7.18-7.09 (m, 5H), 3.30 (t, 1H, J=6.0 Hz), 2.53 (t, 2H, J=7.5 Hz), 1.92-1.86 (m, 2H), 1.65-1.55 (m, 2H), 1.34-1.29 (m, 6H), 0.87 (s, 9H), 0.09 (s; 3H), −0.03 (s, 3H); 13C NMR (CD3OD, 150 MHz) δ 166.2, 151.6, 143.3, 136.6, 135.4, 131.3, 130.8, 128.8, 128.7, 126.9, 126.1, 124.0, 122.9, 122.6, 69.2, 36.8, 36.3, 32.0, 29.6, 29.5, 25.7, 25.6, 18.5, −5.3, −5.4.

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

Procedure: A 10 mL conical vial equipped with magnetic spin vane was charged with 3-bromobenzamide (0.200 g; 1.00 mmol; Ex IV-6), 3-fluoro-4-formyl-phenyl boronic acid (0.185 g; 1.1 mmol), tetra-n-butyl ammonium bromide (0.323 g; 1.0 mmol), Pd(OAc)2 (0.0011 g; 0.005 mmol), K2CO3 (0.345 g; 2.5 mmol) and sealed with a septum. The vial was evacuated/backfilled with nitrogen (×3), water was added via syringe and the mixture was stirred at 80° C. for 2.5 h. Upon cooling, the mixture was poured into water, layered with Et2O and sonicated ca. 2 min. Solid was collected by filtration and washed with Et2O, affording the title compound as a cream-colored solid (used without further purification). LC/MS (method A) 2.02 min; m/z 244 (M+H). A 10 mL conical vial equipped with magnetic spin vane sealed with a septum was added via syringe Upon cooling sonicated ca. 2 min Solid was collected by filtration washed with Et2O

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

Procedure: To a solution of m-bromobenzonitrile (2 g, 10 mol) in DMSO (6 mL) was added 30% H2O2 (5 g, 13 mmol) and K2CO3 at 0° C., and stirred at room temperature for 30 min. The mixture was poured into water and filtered, the solid was washed with water, dried to got the compound 0601-142 (1.8 g, 82%) as a white solid. LCMS: 200 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 7.41 (t, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.70 (dd, J1,2=8.0, 0.8 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 8.03 (t, J=1.6 Hz, 1H), 8.06 (s, 1H). filtered the solid was washed with water dried

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

Procedure: To a stirred mixture 3-bromobenzoic acid amide (0.76 g; 3.8 mmol) and toluene (25 mL), Pd(PPh3)4 (0.180 g; 0.16 mmol), a solution of Na2CO3 (2.543 g; 24 mmol) in H2O (10 mL), and one of 3-methoxyphenylboronic acid (1.132 g; 7.45 mmol) in EtOH (10 mL) were added. The mixture was refluxed for 1 h under vigorous stirring, cooled, and the acqueous phase extracted with AcOEt. The combined organic layers were dried over Na2SO4 and concentrated. Purification of the residue by column chromatography (cyclohexane/EtOAc 1:1 then 4:6) and recrystallization gave the desired product (0.64 g) as white solid. Yield 74%. Mp: 138–40° C. (EtOH). MS (EI): m/z 227 (M+, 100%). 1H NMR (CDCl3): δ 3.88 (s, 3H); 5.71 (br s, 1H); 6.11 (br s, 1H); 6.94 (m, 1H); 7.18 (m, 2H); 7.39 (t, 1H); 7.53 (t, 1H); 7.77 (m, 2H); 8.05 (t, 1H) ppm. IR (Nujol): 3327, 3148, 1676, 1640, 1613, 1584 cm−1. The mixture was refluxed for 1 h under vigorous stirring cooled the acqueous phase extracted with AcOEt The combined organic layers were dried over Na2SO4 concentrated Purification of the residue by column chromatography (cyclohexane/EtOAc 1:1 4:6) and recrystallization