1H-indol-2-ylboronic acid

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

Procedure: A mixture of 3-(6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (80 mg, 0.27 mmol), 5-indoylboronic acid (66 mg, 0.41 mmol), and tetrakis(triphenylphosphine)palladium(0) (35 mg, 10 mol %) in toluene/ethanol (1:1, 3 mL) and 2 M aqueous sodium carbonate solution (1 mL) was heated in a Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was acidified with concentrated hydrochloric acid and then concentrated to dryness under reduced pressure. The crude residue was purified via reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column to provide 1-ethyl-6-(1H-indol-5-yl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine. MS (ES+): 375.2 (M+H)+ concentrated to dryness under reduced pressure The crude residue was purified via reverse-phase high performance liquid chromatography

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

Procedure: A mixture of 3-(6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (80 mg, 0.27 mmol), 5-indoylboronic acid (66 mg, 0.41 mmol), and tetrakis(triphenylphosphine)palladium(0) (35 mg, 10 mol %) in toluene/ethanol (1:1, 3 mL) and 2 M aqueous sodium carbonate solution (1 mL) was heated in a Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was acidified with concentrated hydrochloric acid and then concentrated to dryness under reduced pressure. The crude residue was purified via reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column to provide 1-ethyl-6-(1H-indol-5-yl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine. MS (ES+): 375.2 (M+H)+ concentrated to dryness under reduced pressure The crude residue was purified via reverse-phase high performance liquid chromatography

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the SEM-protected indole prepared in step 1 (0.99 g, 4.0 mmol) in THF (10 mL) at −40° C. was added n-BuLi (2.5 M in hexanes, 1.9 mL, 4.8 mmol). The mixture was stirred at −40° C. for 1 h and then triisopropyl borate (1.2 mL, 5.2 mmol) was added. The mixture was allowed to warm to room temperature while stirring for 18 h. To the reaction mixture was added 1N HCl (aq). The mixture was stirred at room temperature for 30 minutes. The mixture was then adjusted to pH˜5 using saturated NaHCO3 (aq) The mixture was extracted with ether. The combined ether extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% EtOAc/hex over 30 minutes) to provide the indole boronic acid (0.20 g, 17%). to warm to room temperature while stirring for 18 h The mixture was stirred at room temperature for 30 minutes was extracted with ether The combined ether extracts were washed with water and brine dried (Na2SO4) filtered concentrated in vacuo The residue was purified by silica gel chromatography (0-50% EtOAc/hex over 30 minutes)

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the SEM-protected indole prepared in step 1 (0.99 g, 4.0 mmol) in THF (10 mL) at −40° C. was added n-BuLi (2.5 M in hexanes, 1.9 mL, 4.8 mmol). The mixture was stirred at −40° C. for 1 h and then triisopropyl borate (1.2 mL, 5.2 mmol) was added. The mixture was allowed to warm to room temperature while stirring for 18 h. To the reaction mixture was added 1N HCl (aq). The mixture was stirred at room temperature for 30 minutes. The mixture was then adjusted to pH˜5 using saturated NaHCO3 (aq) The mixture was extracted with ether. The combined ether extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% EtOAc/hex over 30 minutes) to provide the indole boronic acid (0.20 g, 17%). to warm to room temperature while stirring for 18 h The mixture was stirred at room temperature for 30 minutes was extracted with ether The combined ether extracts were washed with water and brine dried (Na2SO4) filtered concentrated in vacuo The residue was purified by silica gel chromatography (0-50% EtOAc/hex over 30 minutes)

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the SEM-protected indole prepared in step 1 (0.99 g, 4.0 mmol) in THF (10 mL) at −40° C. was added n-BuLi (2.5 M in hexanes, 1.9 mL, 4.8 mmol). The mixture was stirred at −40° C. for 1 h and then triisopropyl borate (1.2 mL, 5.2 mmol) was added. The mixture was allowed to warm to room temperature while stirring for 18 h. To the reaction mixture was added 1N HCl (aq). The mixture was stirred at room temperature for 30 minutes. The mixture was then adjusted to pH˜5 using saturated NaHCO3 (aq) The mixture was extracted with ether. The combined ether extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% EtOAc/hex over 30 minutes) to provide the indole boronic acid (0.20 g, 17%). to warm to room temperature while stirring for 18 h The mixture was stirred at room temperature for 30 minutes was extracted with ether The combined ether extracts were washed with water and brine dried (Na2SO4) filtered concentrated in vacuo The residue was purified by silica gel chromatography (0-50% EtOAc/hex over 30 minutes)

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the SEM-protected indole prepared in step 1 (0.99 g, 4.0 mmol) in THF (10 mL) at −40° C. was added n-BuLi (2.5 M in hexanes, 1.9 mL, 4.8 mmol). The mixture was stirred at −40° C. for 1 h and then triisopropyl borate (1.2 mL, 5.2 mmol) was added. The mixture was allowed to warm to room temperature while stirring for 18 h. To the reaction mixture was added 1N HCl (aq). The mixture was stirred at room temperature for 30 minutes. The mixture was then adjusted to pH˜5 using saturated NaHCO3 (aq) The mixture was extracted with ether. The combined ether extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% EtOAc/hex over 30 minutes) to provide the indole boronic acid (0.20 g, 17%). to warm to room temperature while stirring for 18 h The mixture was stirred at room temperature for 30 minutes was extracted with ether The combined ether extracts were washed with water and brine dried (Na2SO4) filtered concentrated in vacuo The residue was purified by silica gel chromatography (0-50% EtOAc/hex over 30 minutes)

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

Procedure: Bis(benzonitrile)palladium(II)chloride (5.2 mg, 0.013 mmol) and 1,4-bis(diphenylphosphino)butane (6.7 mg, 0.015 mmol) in toleune (0.6 ml) are stirred for 20 minutes. (3-Amino-6-bromo-pyrazin-2-yl)-pyridin-3-yl-methanone (Intermediate AA) (0.075 g, 0.27 mmol), 5-indoylboronic acid (0.056 g, 0.35 mmol), ethanol (0.36 ml) and 1M Na2CO3 (0.65 ml) are added and the reaction is heated using microwave radiation at 140° C. for 20 minutes. The mixture is diluted with EtOAc and sat. aq. NaHCO3. The layers are separated and the aqueous layer is extracted with EtOAc. The combined organic extracts are dried (MgSO4), and purified by preperative HPLC (0-100% MeCN in water −0.1% TFA) to yield the title compound as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 11.27 (1H, s), 9.21 (1H, s), 9.09 (1H, s), 8.86 (1H, dd), 8.39-8.41 (1H, dt), 8.19 (1H, s), 7.99 (2H, s), 7.65-7.73 (2H, m), 7.5 (1H, d), 7.44 (1H, t), 6.53 (1H, s). MS m/z 316 [M+H]+ the reaction is heated at 140° C. for 20 minutes The layers are separated the aqueous layer is extracted with EtOAc The combined organic extracts are dried (MgSO4) purified by preperative HPLC (0-100% MeCN in water −0.1% TFA)

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

Procedure: N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-methyl-methanesulfonamide was reacted with indole boronic acid in general procedure A. Purification on silica yielded 194. NMR: (400 MHz, DMSO) 2.83 (s, 3H), 3.02 (s, 3H), 3.85 (t, J=4.7, 4H), 3.99 (t, J=4.7, 4H), 4.64 (s, 2H), 7.19 (t, J=7.7, 1H), 7.43 (m, 2H), 7.51 (m, 2H), 8.12 (d, J=7.3, 1H), 11.20 (s br, 1H) MS: (ESI+)[M+H]+ 458.01 Purification on silica

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

Procedure: N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-methyl-acetamide was reacted with indole boronic acid in general procedure A. Purification on silica yielded 193. NMR: 400 MHz; CDCl3 2.10, 2.18 (3H, s, 2 rotamers); 3.00 (3H, s); 3.84 (4H, m); 4.00 (4H, m); 4.73, 4.77 (2H, s, 2 rotamers); 7.26 (2H, m); 7.33 (1H, s); 7.42 (1H, m); 7.48 (1H, s); 8.13 (1H, m); 8.21 (1H, br s). MS: (ESI+): M+H (422) Purification on silica

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

Procedure: N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-methyl-methanesulfonamide was reacted with indole boronic acid in general procedure A. Purification on silica yielded 194. NMR: (400 MHz, DMSO) 2.83 (s, 3H), 3.02 (s, 3H), 3.85 (t, J=4.7, 4H), 3.99 (t, J=4.7, 4H), 4.64 (s, 2H), 7.19 (t, J=7.7, 1H), 7.43 (m, 2H), 7.51 (m, 2H), 8.12 (d, J=7.3, 1H), 11.20 (s br, 1H) MS: (ESI+)[M+H]+ 458.01 Purification on silica

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

Procedure: 3-Chloro-propane-1-sulfonic acid (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amide was reacted with indole boronic acid in general procedure A. Purification on silica yielded 3-chloro-propane-1-sulfonic acid [2-(1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-methyl-amide. Purification on silica

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

Procedure: 2-Methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxylic acid (2-methoxyethyl)-amide was reacted with indole boronic acid in general procedure A. Purification on silica yielded 189. NMR: 400 MHz; CDCl3 3.44 (3H, s); 3.60 (2H, m); 3.70 (2H, m); 3.92 (4H, t, J=4.8 Hz); 4.15 (4H, t, J=4.8 Hz); 6.74 (1H, br t); 7.30 (1H, d, J=7.8 Hz); 7.35 (1H, m); 7.52 (1H, d, J=8.0 Hz); 7.57 (1H, s); 7.82 (1H, s); 8.20 (1H, d, J=7.4 Hz); 8.30 (1H, br s). MS: (ESI+) M+H (438) Purification on silica