1-bromo-2-chloro-4-iodo-5-methoxybenzene

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (50.0 g, 160 mmol), 1-bromo-2-chloro-4-iodo-5-methoxybenzene (66.5 g, 191 mmol), xantphos (4.62 g, 7.98 mmol), Pd2(dba)3 (3.65 g, 3.99 mmol), and cesium carbonate (72.8 g, 223 mmol). A reflux condenser was attached and the reaction placed under nitrogen atmosphere. CPME (319 ml) was added and the reaction was heated at 90° C. for 36 h. The mixture was cooled to rt and partitioned between 1000 mL of EtOAc and 1000 mL of water. The layers were separated and the aqueous layer was extracted with 200 mL of EtOAc. The combined organic layers were poured through a silica plug to provide a brown solution. The solution was concentrated until about 100 mL of solvent was left, giving a heterogeneous brown sludge. Isopropanol (500 mL) was added to the solution and a yellow solid precipitated. The yellow solid was collected by vacuum filtration (rinsing with 200 mL isopropanol) to provide desired product (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylate (76.4 g, 143 mmol, 90% yield) as a yellow solid. m/z (ESI) 531.9 (M−H)−. A reflux condenser was attached The mixture was cooled to rt partitioned between 1000 mL of EtOAc and 1000 mL of water The layers were separated the aqueous layer was extracted with 200 mL of EtOAc The combined organic layers were poured through a silica plug to provide a brown solution The solution was concentrated until about 100 mL of solvent was left giving a heterogeneous brown sludge a yellow solid precipitated The yellow solid was collected by vacuum filtration (rinsing with 200 mL isopropanol)

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)-4-fluorophenyl)acrylate (1.60 g, 4.83 mmol), 1-bromo-2-chloro-4-iodo-5-methoxybenzene (2.013 g, 5.79 mmol), xantphos (0.140 g, 0.241 mmol), Pd2(dba)3 (0.111 g, 0.121 mmol), cesium carbonate (2.360 g, 7.24 mmol) and toluene (7.98 ml). The flask was kept under Argon, a reflux condenser was attached and the flask was lowered into a 110° C. heating bath and heated for 4 hours. The mixture was cooled to RT, diluted with EtOAc, and filtered through celite with the aid of EtOAc. The filtrate was concentrated. The oily residue was taken up in 2-PrOH (it remained an oil). The mixture was then concentrated to give a yellow solid with some oily solid present. The mixture was taken up in 2-PrOH to give a suspension, and the suspension was stirred overnight, which broke up the darker, oily solid. The mixture was filtered, and the filtered solid was washed with 2-PrOH (3×). The collected solid was dried on the filter under a flow of N2 (g) for 15 min to give ((E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)-4-fluorophenyl)acrylate (1.8 g, 3.27 mmol, 67.7% yield)as a bright-yellow solid. m/z (ESI) 548.1 a reflux condenser was attached was lowered into a 110° C. heating bath heated for 4 hours filtered through celite with the aid of EtOAc The filtrate was concentrated The mixture was then concentrated to give a yellow solid with some oily solid present to give a suspension The mixture was filtered the filtered solid was washed with 2-PrOH (3×) The collected solid was dried on the filter under a flow of N2 (g) for 15 min

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

Procedure: A solution of xantphos (0.265 g, 0.458 mmol), pd2(dba)3 (0.140 g, 0.153 mmol), 1-bromo-2-chloro-4-iodo-5-methoxybenzene (1.167 g, 3.36 mmol), (Z)-ethyl 3-(2-amino-5-(benzylthio)phenyl)but-2-enoate (1.000 g, 3.05 mmol), and potassium phosphate (1.945 g, 9.16 mmol) in 10 mL dioxane was heated to 100° C. for 2 hours. The reaction mixture was then poured into water and extracted with DCM. The organics were dried over MgSO4 and concentrated. The crude residue was used in the next step without purification. m/z (ESI) 546.0 (M+H)+. extracted with DCM The organics were dried over MgSO4 concentrated The crude residue was used in the next step without purification