5-Bromo-4-fluoro-2-iodotoluene

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

Procedure: 20 g (63.5 mmol) of 5-bromo-4-fluoro-2-iodotoluene, 10.5 g (73 mmol) of 4-n-propylphenylacetylene, 2.5 g (3.6 mmol) of bis(triphenylphosphine)palladium-(II) chloride and 300 mg (1.8 mmol) of copper(I) iodide are initially introduced in 250 ml of diisopropylamine, the mixture is heated under reflux for 3 h and cooled, and the precipitate formed is filtered off. The filtrate is evaporated in a rotary evaporator, and the residue obtained in this way is purified by column chromatography (SiO2, heptane). the mixture is heated under reflux for 3 h cooled the precipitate formed is filtered off The filtrate is evaporated in a rotary evaporator the residue obtained in this way is purified by column chromatography (SiO2, heptane)

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

Procedure: A mixture of N-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-isoquinolyl]cyclopropanecarboxamide (500 mg, 1.48 mmol), 1-bromo-2-fluoro-4-iodo-5-methyl-benzene (559 mg, 1.77 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (105 mg, 0.15 mmol) in ACN (6 mL) and saturated aqueous sodium carbonate (1 mL) was heated under microwave irradiation (Biotage) 120° C. for 20 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (12 g, Silica, 0-60% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid (385, 65%), which was used in the next step without further purification. washed with water (50 mL) The organic layer was separated dried over sodium sulfate filtered concentrated in vacuo to provide a residue that was purified by flash chromatography (12 g, Silica, 0-60% ethyl acetate in heptane) evaporated in vacuo

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A pressure tube was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (2.31 g, 7.37 mmol), 1-bromo-2-fluoro-4-iodo-5-methylbenzene (2.79 g, 8.84 mmol, Oakwood Chemicals), XantPhos (0.213 g, 0.369 mmol), Pd2(dba)3 (0.169 g, 0.184 mmol), and cesium carbonate (6.00 g, 18.43 mmol). The whole was purged with argon. Then toluene (14.74 ml) was added. The tube was sealed and heated in the heating block at 110° C. for 17 h. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through celite with an aid of EtOAc. The filtrate was concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (80 g), eluting with a gradient of 0% to 30% EtOAc in heptane, to provide (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methylphenyl)amino)phenyl)acrylate (3.19 g, 86% yield) as yellow solid. m/z (ESI) [M+H]+=500.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.09 Hz, 3 H) 2.04 (s, 3 H) 4.04 (q, J=7.11 Hz, 2 H) 4.16 (s, 2 H) 6.27 (d, J=11.05 Hz, 1 H) 6.47 (d, J=15.94 Hz, 1 H) 6.78 (d, J=8.41 Hz, 1 H) 7.09-7.26 (m, 6 H) 7.34 (dd, J=8.02, 0.68 Hz, 1 H) 7.53-7.66 (m, 3 H). The whole was purged with argon Then toluene (14.74 ml) was added The tube was sealed The mixture was cooled to room temperature diluted with EtOAc filtered through celite with an aid of EtOAc The filtrate was concentrated The crude material was absorbed onto a plug of silica gel purified by chromatography through a Redi-Sep pre-packed silica gel column (80 g) eluting with a gradient of 0% to 30% EtOAc in heptane

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

Procedure: A mixture of N-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-isoquinolyl]cyclopropanecarboxamide (500 mg, 1.48 mmol), 1-bromo-2-fluoro-4-iodo-5-methyl-benzene (559 mg, 1.77 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (105 mg, 0.15 mmol) in ACN (6 mL) and saturated aqueous sodium carbonate (1 mL) was heated under microwave irradiation (Biotage) 120° C. for 20 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (12 g, Silica, 0-60% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid (385, 65%), which was used in the next step without further purification. washed with water (50 mL) The organic layer was separated dried over sodium sulfate filtered concentrated in vacuo to provide a residue that was purified by flash chromatography (12 g, Silica, 0-60% ethyl acetate in heptane) evaporated in vacuo

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

Procedure: 20 g (63.5 mmol) of 5-bromo-4-fluoro-2-iodotoluene, 10.5 g (73 mmol) of 4-n-propylphenylacetylene, 2.5 g (3.6 mmol) of bis(triphenylphosphine)palladium-(II) chloride and 300 mg (1.8 mmol) of copper(I) iodide are initially introduced in 250 ml of diisopropylamine, the mixture is heated under reflux for 3 h and cooled, and the precipitate formed is filtered off. The filtrate is evaporated in a rotary evaporator, and the residue obtained in this way is purified by column chromatography (SiO2, heptane). the mixture is heated under reflux for 3 h cooled the precipitate formed is filtered off The filtrate is evaporated in a rotary evaporator the residue obtained in this way is purified by column chromatography (SiO2, heptane)

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

Procedure: A mixture of N-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-isoquinolyl]cyclopropanecarboxamide (500 mg, 1.48 mmol), 1-bromo-2-fluoro-4-iodo-5-methyl-benzene (559 mg, 1.77 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (105 mg, 0.15 mmol) in ACN (6 mL) and saturated aqueous sodium carbonate (1 mL) was heated under microwave irradiation (Biotage) 120° C. for 20 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (12 g, Silica, 0-60% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid (385, 65%), which was used in the next step without further purification. washed with water (50 mL) The organic layer was separated dried over sodium sulfate filtered concentrated in vacuo to provide a residue that was purified by flash chromatography (12 g, Silica, 0-60% ethyl acetate in heptane) evaporated in vacuo