4-bromo-1H-indole-6-carbonitrile

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.104 mmol), 4-bromo-1H-indole-6-carbonitrile (252 mg, 0.114 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol) and sodium carbonate (44 mg, 0.415 mmol) were added to a 0.5-2 ml microwave vial and suspended in 1,4-dioxane (0.5 mL) and water (0.5 mL). The mixture was heated in the microwave at 140° C. for 20 min, then cooled and passed through a 1 g silica cartridge which was washed with methanol. The solvent was evaporated by blow down. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v) and purified by Mass Directed Auto Preparative HPLC (Method F). To the sample-containing fractions 2M HCl (aq) (ca. 1 ml) was added and the fractions were blown down. The residue was dissolved in DCM:methanol (ca. 50:50, v/v) and passed through a 1 g PS—NH2 cartridge, washing with DCM:methanol. Solvent was removed by blow down then the residue was suspended in 2 ml dioxane:water (1:1, v/v) and freeze dried to afford the title compound as a white solid (22 mg). cooled was washed with methanol The solvent was evaporated by blow down The residue was dissolved in 1.6 ml DMSO:methanol (1:1 v/v) and purified by Mass Directed Auto Preparative HPLC (Method F) To the sample-containing fractions 2M HCl (aq) (ca. 1 ml) was added The residue was dissolved in DCM washing with DCM Solvent was removed by blow down then the residue v/v) and freeze dried

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.104 mmol), 4-bromo-1H-indole-6-carbonitrile (252 mg, 0.114 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol) and sodium carbonate (44 mg, 0.415 mmol) were added to a 0.5-2 ml microwave vial and suspended in 1,4-dioxane (0.5 mL) and water (0.5 mL). The mixture was heated in the microwave at 140° C. for 20 min, then cooled and passed through a 1 g silica cartridge which was washed with methanol. The solvent was evaporated by blow down. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v) and purified by Mass Directed Auto Preparative HPLC (Method F). To the sample-containing fractions 2M HCl (aq) (ca. 1 ml) was added and the fractions were blown down. The residue was dissolved in DCM:methanol (ca. 50:50, v/v) and passed through a 1 g PS—NH2 cartridge, washing with DCM:methanol. Solvent was removed by blow down then the residue was suspended in 2 ml dioxane:water (1:1, v/v) and freeze dried to afford the title compound as a white solid (22 mg). cooled was washed with methanol The solvent was evaporated by blow down The residue was dissolved in 1.6 ml DMSO:methanol (1:1 v/v) and purified by Mass Directed Auto Preparative HPLC (Method F) To the sample-containing fractions 2M HCl (aq) (ca. 1 ml) was added The residue was dissolved in DCM washing with DCM Solvent was removed by blow down then the residue v/v) and freeze dried

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

Procedure: 1-(1-Methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (49 mg, 0.1 mmol) was dissolved in 1,4-Dioxane (0.4 mL) and added to 4-bromo-1H-indole-6-carbonitrile (22 mg, 0.1 mmol, available from Sinova) in a microwave vessel. 1,4-Dioxane (0.4 ml) was added followed by chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (1:1) (Solvias catalyst, 2 mg, 0.004 mmol, (heaped microspatula) available from ABCR) and a solution of potassium triphosphate (0.2 g, 0.1 mmol) in water (0.2 ml). The vessel was sealed and heated in CEM Discover using initial 150 W to 110° C. for 20 min. After cooling the solution was loaded onto a C18 SPE cartridge (pre-conditioned with MeCN/0.1% TFA) and flushed through with a further 3 ml MeCN/0.1% TFA. Solvent was removed by blowdown under a stream of nitrogen. The residue was dissolved in MeOH (0.5 ml) and loaded onto a SCX-2 SPE cartridge (1 g) pre-conditioned with MeOH. The material was left on the column for 1 hr then eluted with 2M ammonia/MeOH and evaporated to dryness. The sample was purified by Mass Directed AutoPrep (Method C) to afford the title compound (6.4 mg). The vessel was sealed heated in CEM Discover for 20 min After cooling the solution flushed through with a further 3 ml MeCN/0.1% TFA Solvent was removed by blowdown under a stream of nitrogen The residue was dissolved in MeOH (0.5 ml) then eluted with 2M ammonia/MeOH evaporated to dryness The sample was purified by Mass Directed AutoPrep (Method C)

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

Procedure: 1-(1-Methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (49 mg, 0.1 mmol) was dissolved in 1,4-Dioxane (0.4 mL) and added to 4-bromo-1H-indole-6-carbonitrile (22 mg, 0.1 mmol, available from Sinova) in a microwave vessel. 1,4-Dioxane (0.4 ml) was added followed by chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (1:1) (Solvias catalyst, 2 mg, 0.004 mmol, (heaped microspatula) available from ABCR) and a solution of potassium triphosphate (0.2 g, 0.1 mmol) in water (0.2 ml). The vessel was sealed and heated in CEM Discover using initial 150 W to 110° C. for 20 min. After cooling the solution was loaded onto a C18 SPE cartridge (pre-conditioned with MeCN/0.1% TFA) and flushed through with a further 3 ml MeCN/0.1% TFA. Solvent was removed by blowdown under a stream of nitrogen. The residue was dissolved in MeOH (0.5 ml) and loaded onto a SCX-2 SPE cartridge (1 g) pre-conditioned with MeOH. The material was left on the column for 1 hr then eluted with 2M ammonia/MeOH and evaporated to dryness. The sample was purified by Mass Directed AutoPrep (Method C) to afford the title compound (6.4 mg). The vessel was sealed heated in CEM Discover for 20 min After cooling the solution flushed through with a further 3 ml MeCN/0.1% TFA Solvent was removed by blowdown under a stream of nitrogen The residue was dissolved in MeOH (0.5 ml) then eluted with 2M ammonia/MeOH evaporated to dryness The sample was purified by Mass Directed AutoPrep (Method C)

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

Procedure: A solution of 4-bromo-1H-indole-6-carbonitrile (1 g, 4.50 mmol) in methanol (10 mL) was treated with 30% aqueous hydrogen peroxide (2.7 mL, 4.95 mmol) and a 1 M aqueous sodium hydroxide solution (5 mL) then heated at 40° C. for 1 h. The reaction mixture was cooled, treated with water and cooled in an ice-bath. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to obtain 4-bromo-1H-indole-6-carboxylic acid amide (1.05 g, 97%), which was transformed into the title boronic ester by the general method (Scheme 1) (0.80 g, 67%). The reaction mixture was cooled cooled in an ice-bath The resulting precipitate was collected by filtration washed with water dried in vacuo

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

Procedure: A solution of 4-bromo-1H-indole-6-carbonitrile (1 g, 4.50 mmol) in methanol (10 mL) was treated with 30% aqueous hydrogen peroxide (2.7 mL, 4.95 mmol) and a 1 M aqueous sodium hydroxide solution (5 mL) then heated at 40° C. for 1 h. The reaction mixture was cooled, treated with water and cooled in an ice-bath. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to obtain 4-bromo-1H-indole-6-carboxylic acid amide (1.05 g, 97%), which was transformed into the title boronic ester by the general method (Scheme 1) (0.80 g, 67%). The reaction mixture was cooled cooled in an ice-bath The resulting precipitate was collected by filtration washed with water dried in vacuo

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

Procedure: 4-Bromo-1H-indole-6-carbonitrile (207 mg), PS-BEMP (900 mg) and 4-nitrobenzenesulfonyl chloride (380 mg) were weighed to a round bottom flask, then N,N-Dimethylformamide (4 ml) was added and the reaction was stirred at RT. The reaction was filtered and washed with DMF. The DMF was evaporated and the residue was dissolved in DCM:methanol and passed through a 5 g SAX cartridge (preconditioned with methanol) washing with DCM:methanol. The residue was evaporated to afford the title compound, 360 mg as a pale orange solid. The reaction was filtered washed with DMF The DMF was evaporated the residue was dissolved in DCM washing with DCM The residue was evaporated

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

Procedure: 4-Bromo-1H-indole-6-carbonitrile (207 mg), PS-BEMP (900 mg) and 4-nitrobenzenesulfonyl chloride (380 mg) were weighed to a round bottom flask, then N,N-Dimethylformamide (4 ml) was added and the reaction was stirred at RT. The reaction was filtered and washed with DMF. The DMF was evaporated and the residue was dissolved in DCM:methanol and passed through a 5 g SAX cartridge (preconditioned with methanol) washing with DCM:methanol. The residue was evaporated to afford the title compound, 360 mg as a pale orange solid. The reaction was filtered washed with DMF The DMF was evaporated the residue was dissolved in DCM washing with DCM The residue was evaporated

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.104 mmol), 4-bromo-1H-indole-6-carbonitrile (252 mg, 0.114 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol) and sodium carbonate (44 mg, 0.415 mmol) were added to a 0.5-2 ml microwave vial and suspended in 1,4-dioxane (0.5 mL) and water (0.5 mL). The mixture was heated in the microwave at 140° C. for 20 min, then cooled and passed through a 1 g silica cartridge which was washed with methanol. The solvent was evaporated by blow down. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v) and purified by Mass Directed Auto Preparative HPLC (Method F). To the sample-containing fractions 2M HCl (aq) (ca. 1 ml) was added and the fractions were blown down. The residue was dissolved in DCM:methanol (ca. 50:50, v/v) and passed through a 1 g PS—NH2 cartridge, washing with DCM:methanol. Solvent was removed by blow down then the residue was suspended in 2 ml dioxane:water (1:1, v/v) and freeze dried to afford the title compound as a white solid (22 mg). cooled was washed with methanol The solvent was evaporated by blow down The residue was dissolved in 1.6 ml DMSO:methanol (1:1 v/v) and purified by Mass Directed Auto Preparative HPLC (Method F) To the sample-containing fractions 2M HCl (aq) (ca. 1 ml) was added The residue was dissolved in DCM washing with DCM Solvent was removed by blow down then the residue v/v) and freeze dried

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

Procedure: 1-(1-Methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (49 mg, 0.1 mmol) was dissolved in 1,4-Dioxane (0.4 mL) and added to 4-bromo-1H-indole-6-carbonitrile (22 mg, 0.1 mmol, available from Sinova) in a microwave vessel. 1,4-Dioxane (0.4 ml) was added followed by chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (1:1) (Solvias catalyst, 2 mg, 0.004 mmol, (heaped microspatula) available from ABCR) and a solution of potassium triphosphate (0.2 g, 0.1 mmol) in water (0.2 ml). The vessel was sealed and heated in CEM Discover using initial 150 W to 110° C. for 20 min. After cooling the solution was loaded onto a C18 SPE cartridge (pre-conditioned with MeCN/0.1% TFA) and flushed through with a further 3 ml MeCN/0.1% TFA. Solvent was removed by blowdown under a stream of nitrogen. The residue was dissolved in MeOH (0.5 ml) and loaded onto a SCX-2 SPE cartridge (1 g) pre-conditioned with MeOH. The material was left on the column for 1 hr then eluted with 2M ammonia/MeOH and evaporated to dryness. The sample was purified by Mass Directed AutoPrep (Method C) to afford the title compound (6.4 mg). The vessel was sealed heated in CEM Discover for 20 min After cooling the solution flushed through with a further 3 ml MeCN/0.1% TFA Solvent was removed by blowdown under a stream of nitrogen The residue was dissolved in MeOH (0.5 ml) then eluted with 2M ammonia/MeOH evaporated to dryness The sample was purified by Mass Directed AutoPrep (Method C)

Conditions: temp:0.00; pressure:0.00; stir: