[(E)-but-1-enyl]boronic acid

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

Procedure: To a sealed tube containing 1-(4-(5-bromo-1-ethylindolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Example 71, 16 mg, 0.019 mmol) in dioxane (1.0 mL) was added (E)-but-1-enylboronic acid (8 mg, 0.076 mmol), Pd2(dba)3 (9 mg, 10 μmol), 1,1′-bis(di-tert-butylphosphino)ferrocene (9 mg, 0.019 mmol) and potassium metaphosphate (5 mg, 0.038 mmol). The reaction mixture was purged with nitrogen for 1 min and then heated at 90° C. for 16 h. The reaction mixture was then diluted with EtOAc and 1N aq. HCl solution. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (11 mg, 64%) as a pale yellow solid after lyophilization. 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.06-8.05 (m, 1H), 7.94 (br s, 1H), 7.65-7.63 (m, 1H), 7.30-7.11 (m, 6.5H), 6.93 (d, J=7.0 Hz, 0.5H), 6.05-5.95 (m, 1H), 4.75-4.50 (m, 2H), 3.95-3.55 (m, 1H), 3.49-3.41 (m, 2H), 3.25 (t, J=6.8 Hz, 2H), 3.15-3.10 (m, 2H), 3.00-2.96 (m, 3H), 2.90-2.65 (m, 2H), 2.33 (s, 2H), 2.28 (s, 1H), 2.21-2.18 (m, 2H), 1.58-1.02 (m, 11 H), 1.03-0.95 (m, 5H), 0.93-0.87 (m, 3H), 0.77 (t, J=7.3 Hz, 2H), 0.69 (t, J=7.4 Hz, 1H); MS(ESI+) m/z 813.3 (M+H)+. The reaction mixture was purged with nitrogen for 1 min The reaction mixture was then diluted with EtOAc and 1N aq. HCl solution The organic layer was separated dried over MgSO4 concentrated in vacuo The residue was purified by preparative HPLC

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

Procedure: To a sealed tube containing 1-(4-(5-bromo-1-ethylindolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Example 71, 16 mg, 0.019 mmol) in dioxane (1.0 mL) was added (E)-but-1-enylboronic acid (8 mg, 0.076 mmol), Pd2(dba)3 (9 mg, 10 μmol), 1,1′-bis(di-tert-butylphosphino)ferrocene (9 mg, 0.019 mmol) and potassium metaphosphate (5 mg, 0.038 mmol). The reaction mixture was purged with nitrogen for 1 min and then heated at 90° C. for 16 h. The reaction mixture was then diluted with EtOAc and 1N aq. HCl solution. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (11 mg, 64%) as a pale yellow solid after lyophilization. 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.06-8.05 (m, 1H), 7.94 (br s, 1H), 7.65-7.63 (m, 1H), 7.30-7.11 (m, 6.5H), 6.93 (d, J=7.0 Hz, 0.5H), 6.05-5.95 (m, 1H), 4.75-4.50 (m, 2H), 3.95-3.55 (m, 1H), 3.49-3.41 (m, 2H), 3.25 (t, J=6.8 Hz, 2H), 3.15-3.10 (m, 2H), 3.00-2.96 (m, 3H), 2.90-2.65 (m, 2H), 2.33 (s, 2H), 2.28 (s, 1H), 2.21-2.18 (m, 2H), 1.58-1.02 (m, 11 H), 1.03-0.95 (m, 5H), 0.93-0.87 (m, 3H), 0.77 (t, J=7.3 Hz, 2H), 0.69 (t, J=7.4 Hz, 1H); MS(ESI+) m/z 813.3 (M+H)+. The reaction mixture was purged with nitrogen for 1 min The reaction mixture was then diluted with EtOAc and 1N aq. HCl solution The organic layer was separated dried over MgSO4 concentrated in vacuo The residue was purified by preparative HPLC

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

Procedure: To a sealed tube containing 1-(4-(5-bromo-1-ethylindolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Example 71, 16 mg, 0.019 mmol) in dioxane (1.0 mL) was added (E)-but-1-enylboronic acid (8 mg, 0.076 mmol), Pd2(dba)3 (9 mg, 10 μmol), 1,1′-bis(di-tert-butylphosphino)ferrocene (9 mg, 0.019 mmol) and potassium metaphosphate (5 mg, 0.038 mmol). The reaction mixture was purged with nitrogen for 1 min and then heated at 90° C. for 16 h. The reaction mixture was then diluted with EtOAc and 1N aq. HCl solution. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (11 mg, 64%) as a pale yellow solid after lyophilization. 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.06-8.05 (m, 1H), 7.94 (br s, 1H), 7.65-7.63 (m, 1H), 7.30-7.11 (m, 6.5H), 6.93 (d, J=7.0 Hz, 0.5H), 6.05-5.95 (m, 1H), 4.75-4.50 (m, 2H), 3.95-3.55 (m, 1H), 3.49-3.41 (m, 2H), 3.25 (t, J=6.8 Hz, 2H), 3.15-3.10 (m, 2H), 3.00-2.96 (m, 3H), 2.90-2.65 (m, 2H), 2.33 (s, 2H), 2.28 (s, 1H), 2.21-2.18 (m, 2H), 1.58-1.02 (m, 11 H), 1.03-0.95 (m, 5H), 0.93-0.87 (m, 3H), 0.77 (t, J=7.3 Hz, 2H), 0.69 (t, J=7.4 Hz, 1H); MS(ESI+) m/z 813.3 (M+H)+. The reaction mixture was purged with nitrogen for 1 min The reaction mixture was then diluted with EtOAc and 1N aq. HCl solution The organic layer was separated dried over MgSO4 concentrated in vacuo The residue was purified by preparative HPLC