4-bromo-1-iodo-2-(trifluoromethyl)benzene

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A vial containing 4-bromo-1-iodo-2-(trifluoromethyl)benzene was charged with potassium phosphate (0.130 g, 0.614 mmol), followed by a solution of N-(2,4-dimethoxybenzyl)-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (Intermediate H) (0.100 g, 0.175 mmol) and PdCl2(dppf)-CH2Cl2 (0.014 g, 0.018 mmol) in 1 mL of DMF. The vial was sealed and placed in a shaker block. The block was shaken for three hours at 85° C. The solution was filtered, washed with DMF and concentrated. The resulting solid was treated with a solution of TFA (0.270 mL, 3.51 mmol) in 1 mL of DCM. The vial was shaken at room temperature for two hours. The solution was concentrated and purified via reverse phase HPLC (8 min gradient elution 15 to 75% ACN/H2O, 0.1% TFA modifier) to afford 3-(4-bromo-2-(trifluoromethyl)phenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 3.95 (s, 3 H) 7.40-7.51 (m, 3 H) 7.69 (s, 1 H) 7.92-8.00 (m, 2 H) 8.03 (d, J=1.95 Hz, 1 H) 8.40 (s, 1 H). m/z (ESI) 515.9 (M+H)+. The vial was sealed The solution was filtered washed with DMF concentrated The vial was shaken at room temperature for two hours The solution was concentrated purified via reverse phase HPLC (8 min gradient elution 15 to 75% ACN/H2O, 0.1% TFA modifier)

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

Procedure: To a solution of 5-bromo-2-iodobenzotrifluoride (5.00 g) in dehydrated tetrahydrofuran (140 mL), n-butyl lithium (2.69 mol/L, solution in n-hexane, 5.30 mL) was added at −78° C. and the mixture was stirred at that temperature for 25 minutes. After adding a solution of cyclobutanone (999 mg) in tetrahydrofuran (5.00 mL), the mixture was brought to room temperature and stirred for 3 days. After adding a saturated aqueous solution of ammonium chloride under cooling with ice, two extractions were conducted with ethyl acetate. The combined organic layers were washed with water and thereafter dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-80:20) to give 1-[4-bromo-2-(trifluoromethyl)phenyl]cyclobutanol as a pale yellow oil (3.00 g). was brought to room temperature stirred for 3 days under cooling with ice, two extractions The combined organic layers were washed with water dried over anhydrous magnesium sulfate After removing the desiccant by filtration the filtrate was concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-80:20)