2-bromo-4-chloro-1-iodobenzene

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

Procedure: Under argon, 2.89 ml (20.7 mmol, 5.0 eq.) of triethylamine, 2.99 g (4.1 mmol) of 2-bromo-4-chloro-1-iodobenzene and 489 mg (4.97 mmol, 1.2 eq.) of ethynyl(trimethyl)silane were added successively to a solution of 73 mg (0.10 mmol, 0.025 eq.) of bis(triphenylphosphine)palladium(II) chloride and 20 mg (0.10 mmol, 0.025 eq.) copper(I) iodide in 27 ml of THF, and the mixture was stirred at RT overnight. The reaction mixture was then diluted with ethyl acetate and filtered through Celite, and the filtrate was concentrated under reduced pressure. After addition of ethyl acetate/water and phase separation, the organic phase was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures). Yield: 3.21 g (quant.) filtered through Celite the filtrate was concentrated under reduced pressure After addition of ethyl acetate/water and phase separation the organic phase was concentrated under reduced pressure The crude product was purified by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures)

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

Procedure: A microwave vial was charged with INTERMEDIATE M (0.500 g, 1.198 mmol), xantphos (0.139 g, 0.240 mmol), 2-bromo-4-chloro-1-iodobenzene (0.570 g, 1.796 mmol), Pd2(dba)3 (0.110 g, 0.120 mmol) and sodium tert-butoxide (0.230 g, 2.395 mmol). The mixture was diluted with toluene (11.98 mL), and purged with nitrogen, and stirred at 130° C. in the microwave for 15 minutes. After completion, the reaction was diluted with water, and washed with DCM. The organics were dried using a phase separator and concentrated under a vacuum. The material was then purified via silica gel MPLC, eluting with 0 to 50% ethyl acetate in heptanes to yield 4-(2-bromo-4-chlorophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.576 g, 0.949 mmol) as a light yellow solid. purged with nitrogen After completion, the reaction was diluted with water washed with DCM The organics were dried concentrated under a vacuum The material was then purified via silica gel MPLC eluting with 0 to 50% ethyl acetate in heptanes

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

Procedure: Under argon, 2.89 ml (20.7 mmol, 5.0 eq.) of triethylamine, 2.99 g (4.1 mmol) of 2-bromo-4-chloro-1-iodobenzene and 489 mg (4.97 mmol, 1.2 eq.) of ethynyl(trimethyl)silane were added successively to a solution of 73 mg (0.10 mmol, 0.025 eq.) of bis(triphenylphosphine)palladium(II) chloride and 20 mg (0.10 mmol, 0.025 eq.) copper(I) iodide in 27 ml of THF, and the mixture was stirred at RT overnight. The reaction mixture was then diluted with ethyl acetate and filtered through Celite, and the filtrate was concentrated under reduced pressure. After addition of ethyl acetate/water and phase separation, the organic phase was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures). Yield: 3.21 g (quant.) filtered through Celite the filtrate was concentrated under reduced pressure After addition of ethyl acetate/water and phase separation the organic phase was concentrated under reduced pressure The crude product was purified by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures)

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

Procedure: Under argon, 2.89 ml (20.7 mmol, 5.0 eq.) of triethylamine, 2.99 g (4.1 mmol) of 2-bromo-4-chloro-1-iodobenzene and 489 mg (4.97 mmol, 1.2 eq.) of ethynyl(trimethyl)silane were added successively to a solution of 73 mg (0.10 mmol, 0.025 eq.) of bis(triphenylphosphine)palladium(II) chloride and 20 mg (0.10 mmol, 0.025 eq.) copper(I) iodide in 27 ml of THF, and the mixture was stirred at RT overnight. The reaction mixture was then diluted with ethyl acetate and filtered through Celite, and the filtrate was concentrated under reduced pressure. After addition of ethyl acetate/water and phase separation, the organic phase was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures). Yield: 3.21 g (quant.) filtered through Celite the filtrate was concentrated under reduced pressure After addition of ethyl acetate/water and phase separation the organic phase was concentrated under reduced pressure The crude product was purified by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures)

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

Procedure: A RBF was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (8.25 g, 26.3 mmol, made via Method 42, Steps 1-2), 2-bromo-4-chloro-1-iodobenzene (10.02 g, 31.6 mmol), Xantphos (0.762 g, 1.316 mmol), Pd2(dba)3 (0.603 g, 0.658 mmol), and cesium carbonate (21.44 g, 65.8 mmol) were added. A reflux condenser was attached and the flask was lowered into a 110° C. heating bath for 1 h. The mixture was cooled to room temperature then filtered through celite with the aid of toluene. The filtrate was concentrated. The residue was taken up in 2-PrOH and concentrated to give a yellow solid with some tan chunks. The mixture was taken up in 2-PrOH and the resulting slurry was heated to boiling for 5 min to give a brown solution (after breaking up some solid with a spatula). The resulting solution was allowed to cool to RT while being stirred. The mixture became a thick slurry that was diluted with 2-PrOH and filtered. The collected solid was washed with 2-PrOH (3×), then dried under a stream of N2 (g) to give (E)-ethyl 3-(5-(benzylthio)-2-((2-bromo-4-chlorophenyl)amino)phenyl)acrylate (10.473 g, 20.83 mmol, 79% yield) as a bright-yellow solid. 1 H NMR (400 MHz, DMSO-d6)□=7.76-7.61 (m, 4 H), 7.38-7.27 (m, 5 H), 7.27-7.20 (m, 2 H), 6.88 (d, J=8.4 Hz, 1 H), 6.62-6.52 (m, 2 H), 4.27 (s, 2 H), 4.14 (q, J=7.1 Hz, 2 H), 1.22 (t, J=7.1 Hz, 3 H). m/z (ESI) 502.0 (M+H)+. were added A reflux condenser was attached was lowered into a 110° C. heating bath for 1 h then filtered through celite with the aid of toluene The filtrate was concentrated concentrated to give a yellow solid with some tan chunks the resulting slurry was heated to give a brown solution ( to cool to RT filtered The collected solid was washed with 2-PrOH (3×) dried under a stream of N2 (g)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A pressure vessel was charged with N-(2,4-dimethoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate E) (5.00 g, 8.81 mmol), 2-bromo-4-chloro-1-iodobenzene (5.59 g, 17.6 mmol) and Pd(dppf) Cl2 DCM (1.44 g, 1.76 mmol). Dioxane (44.1 mL) and t-butanol (44.1 mL) were added to the reaction vial followed by 1.9 M sodium carbonate in water (13.9 mL, 26.4 mmol). The reaction vial was then swept with nitrogen and sealed with a screw cap. The reaction mixture was stirred and sonicated for 5 min. The resulting light red mixture was then heated to 50° C. After 2 h, LC/MS indicated about 90% conversion of boronic ester to the desired product as [M+Na]+=652. The mixture was cooled to room temperature and filtered through a fritted funnel with EtOAc (150 mL). The filtrate was washed with brine. The organic layers were combined, dried with MgSO4, filtered and concentrated to afford a black oil. The mixture was purified by MPLC (300 g silica gel column eluting with 0 to 50% EtOAc:Heptane) to afford a white solid. MS (ESI): 651.8 [M+Na]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.64 (s, 3H), 3.66 (s, 3H), 5.18 (d, J=16 Hz, 1H), 5.24 (d, J=16 Hz, 1H), 6.31-6.41 (m, 2H), 6.95-7.04 (d, J=9 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.64 (d, J=6.1 Hz, 2H), 7.78-7.80 (m, 2H), 7.98 (d, J=2.25 Hz, 1H), 8.30 (d, J=9.4 Hz, 1H), 8.38 (s, 1H), 8.65 (m, 1H). sealed with a screw cap sonicated for 5 min

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

Procedure: A microwave vial was charged with INTERMEDIATE M (0.500 g, 1.198 mmol), xantphos (0.139 g, 0.240 mmol), 2-bromo-4-chloro-1-iodobenzene (0.570 g, 1.796 mmol), Pd2(dba)3 (0.110 g, 0.120 mmol) and sodium tert-butoxide (0.230 g, 2.395 mmol). The mixture was diluted with toluene (11.98 mL), and purged with nitrogen, and stirred at 130° C. in the microwave for 15 minutes. After completion, the reaction was diluted with water, and washed with DCM. The organics were dried using a phase separator and concentrated under a vacuum. The material was then purified via silica gel MPLC, eluting with 0 to 50% ethyl acetate in heptanes to yield 4-(2-bromo-4-chlorophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.576 g, 0.949 mmol) as a light yellow solid. purged with nitrogen After completion, the reaction was diluted with water washed with DCM The organics were dried concentrated under a vacuum The material was then purified via silica gel MPLC eluting with 0 to 50% ethyl acetate in heptanes