4-Bromo-2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine

4-bromo-2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2, 3-e]pyridine 205 (8.1 g, 17.5 mmol, 1.0 eq.) was dissolved in 250 ml of dioxane and 2.6 g of tert sodium t-butoxide (26.3 mmol, 1.5 eq.) were added. After 16 h at 80 C., the reaction medium is cooled to temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in 100 ml of ethyl acetate and 100 ml of water are added. Then, the organic phase is extracted with ethyl acetate (3 times 20 ml). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The crude is triturated with dichloromethane and then vacuum filtration allows to produce compound 203 (58 g, 72%) as a yellowish solid. Rf=0.25 (ethyl acetate/petroleum ether=20/80). Mp>260 C. IR (v, cm-1, neat) 3898, 3851, 3819, 3800, 3749, 3742, 3731, 3687, 3674, 3668, 3646, 3627, 3565, 3099, 3019, 2930, 2844, 2798, 2588, 2216, 1912, 1595, 1567, 1473, 1406, 1382, 1330, 1282, 1263, 1206, 1120, 1098, 964, 953, 920, 813, 751, 670, 621, 603, 536, 524, 517, 506. 1H NMR (250 MHz, DMSO-d6, 20 C.) delta 12.60 (s, 1H), 7.97 (d, J=5.2 Hz, 1H), 7.26 (d, J=5.2 Hz, 1H), 6.62 (s, 1H). 13C NMR (63 MHz, DMSO-d6, 20 C.) delta 150.7 (Cq), 143.5 (CH), 123.2 (Cq), 121.9 (Cq), 119.3 (CH), 109.4 (CH), 83.2 (Cq). HRMS (+ESI) calculated for C7H4BrIN2 (M+H+): 322.8675, found: 322.8673Benzenesulfonyl chloride (4.8 g, 27mmol) was added dropwise into a solution of 4-bromo-2-iodo-1 H-pyrrolo[2, 3-b]pyridine (8.0 g, 24.7mmol), and 4- (Dimethylamino)pyridine (6.0 g, 50 mmol) in DCM (150 ml.) at room temperature. The mixture was stirred for 24 hrs. The organic layer was washed with 1 N HCI aqueous solution and then dried over magnesium sulfate and evaporated under reduced pressure. The solids formed were then suspended in suspended in acetonitrile, followed by filtration gave 4-bromo-2-iodo-1-(phenylsulfonyl)-1 H-pyrrolo[2, 3-b]pyridine. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H8BrlN2O2S: 464.1 ; found: 464.9.To an appropriate sized microwave vial, 4-bromo-2-iodo-1- (phenylsulfonyl)-1 H-pyrrolo[2, 3-b]pyridine (200 mg, 0.43 mmol), 6-(4, 4, 5, 5-tetramethyl- 1 , 3, 2-dioxaborolan-2-yl)isoindolin-1-one (123 mg, 0.47 mmol), sodium bicarbonate (127 mg, 1.23 mmol), 1 , 4-dioxane (3 ml.) and water (1.5 ml.) were added. The mixture was degassed with nitrogen for 10 minutes. Bis(triphenylphosphine)palladium(ll)dichloride (48mg, 0.043 mmol) was added and the solution heated at 105 C for 2h. After cooling to room temperature, the mixture was poured into water, and extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue 6-(4-bromo-1-(phenylsulfonyl)-1 H-pyrrolo[2, 3-b]pyridin-2- yl)isoindolin-1-one was used for next step. LCMS-ESI+ (m/z): [M+H]+ calcd for C2i H14BrN303S: 469.3; found: 469.9.A sealed tube containing a suspension of 5-(2~iodo-1-(phenylsulfonyl)- 1 H-pyrrolo[2, 3-b]pyridn-4-yl)-2-((tetrahydrQ-2H-pyran-4-yl)oxy)benzonitrile (100 mg, 0.171 mmol) and Pd(PPh?)4 (9 mg, 0.008 mmol) in a degassed mixture of dioxane/H20 (1.5mL, 4/1 ), was preheated at 85 C for 5 rnin. Next, K2C03 (59 mg, 0.43 mmol) and 2- (3, 6-dhydro-2H-pyran-4-yl)-4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolane (54 mg, 0.257 mmol), were added to the mixture and the reaction was additionally heated at 100 C in the sealed tube for 15 hrs. Afterwards, the crude material was allowed to reach room temperature. It was concentrated to dryness; the residue was triturated with EtOH and filtered through a short pad of Celite, washing the solids with CH2CI2. The filtrate was concentrated to dryness. The residue was purified by flash column chromatography on silica gel to afford 5-(2-(3, 6-dihydro-2H-pyran-4-yl)-1- (phenylsulfonyl)-l H-pyrroio [2, 3-b]pyridin-4-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H27N3O5S: 542.2; found: 542.24-bromo-2-iodo-1-(phenylsulfonyl)-1 H-pyrrolo[2, 3-b]pyridine (4.50 g, 9.72 mmol) and 4-(4-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)phenyl)morpholine (2.81g, 9.72 mmol) were taken up in 55 mL dioxane in a 250 mL rbf. The flask was evacuated and stirred vigorously under vacuum for 5 min. Bis(triphenylphosphine)palladium(ll) dichloride (479 mg, 0.68 mmol) and 1 N NaHC03 (19.4 mL, 19.4 mmol) and the reaction heated to 80 C for 6 hrs. The reaction was then cooled to rt and diluted with 100 mL EtOAc. After 5 min vigorous stirring the mixture was filtered thru Celite and extracted with EtOAc. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 4-(4-(4-bromo-1- (phenylsulfonyl)-l H-pyrrolo[2, 3-b]pyridin-2-yl)phenyl)morpholine. LCMS-ESI+ (m/z): [M+H]+ calcd for C23H2oBrN303S: 498.0, 500.0; found: 498.1 , 500.0.