2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (100 mg, 0.232 mmol) (Example 61) was dissolved in 1,4-dioxane (1.5 mL) and water (0.7 mL). 4,4,5,5-Tetramethyl-2-(phenylmethyl)-1,3,2-dioxaborolane (0.077 mL, 0.347 mmol), tetrakis(triphenylphosphine)palladium(0) (26.8 mg, 0.023 mmol) and potassium carbonate (96 mg, 0.695 mmol) were added and the mixture heated at 100° C. overnight. Ethyl acetate (10 mL) was added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. Purification by chromatography on silica gel, eluting with a gradient of 70% ethyl acetate in cyclohexane, afforded the title compound (33.3 mg). LCMS (A) m/z: 443 [M+1]+, Rt 1.28 min (acidic), Rt 0.97 min (basic). the mixture washed with water (2×5 mL) The organic layer was dried over MgSO4 filtered the solvent removed in vacuo Purification by chromatography on silica gel eluting with a gradient of 70% ethyl acetate in cyclohexane

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

Procedure: A 5 ml microwave vial was loaded with 5-bromo-2-(4-(morpholine-4-carbonyl)phenylamino)benzonitrile (125 mg, 0.259 mmol, Example 160A), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (79 mg, 0.362 mmol) and Pd(Ph3P)4 (15 mg, 0.013 mmol). Toluene (1 mL), MeOH (0.500 mL) and a 2 molar solution of Na2CO3 (0.324 mL, 0.647 mmol) were added, the flask flushed with nitrogen, sealed and heat to 110° C. for 4 hours. LCMS after 4 hours showed product and starting material (1:2.5 ratio) (product m/e−=396, consistent with [M−H]−). Additional 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (400 mg, 1.834 mmol) and Pd(Ph3P)4 (30 mg, 0.026 mmol), Toluene (1 mL), MeOH (0.500 mL) and a 2 molar solution of Na2CO3 (0.324 mL, 0.647 mmol) were added. The flask was flushed with nitrogen, sealed and heated to 110° C. for additional 8 hours. The reaction mixture was poured into a separating funnel loaded with water and dichloromethane. The layers were separated and the aqueous layer extracted one more time with dichloromethane. The combined organic layers were washed with brine and dried over MgSO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica, using a gradient from 100% CH2Cl2 to 50% CH2Cl2+50 EtOAc. Product containing fraction were combined and evaporated to dryness to give 42.3 mg 5-benzyl-2-(4-(morpholine-4-carbonyl)phenylamino)benzonitrile. (estimated purity 76%). The material was used without further purification. MS (ESI) m/e−=396, m/e+=398 consistent with [M−H]− and [M+H]+. the flask flushed with nitrogen sealed The flask was flushed with nitrogen sealed heated to 110° C. for additional 8 hours The reaction mixture was poured into a separating funnel The layers were separated the aqueous layer extracted one more time with dichloromethane The combined organic layers were washed with brine dried over MgSO4 filtered concentrated in vacuum The crude product was purified by column chromatography on silica Product containing fraction evaporated to dryness

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

Procedure: A 5 ml microwave vial was loaded with 5-bromo-2-(4-(morpholine-4-carbonyl)phenylamino)benzonitrile (125 mg, 0.259 mmol, Example 160A), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (79 mg, 0.362 mmol) and Pd(Ph3P)4 (15 mg, 0.013 mmol). Toluene (1 mL), MeOH (0.500 mL) and a 2 molar solution of Na2CO3 (0.324 mL, 0.647 mmol) were added, the flask flushed with nitrogen, sealed and heat to 110° C. for 4 hours. LCMS after 4 hours showed product and starting material (1:2.5 ratio) (product m/e−=396, consistent with [M−H]−). Additional 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (400 mg, 1.834 mmol) and Pd(Ph3P)4 (30 mg, 0.026 mmol), Toluene (1 mL), MeOH (0.500 mL) and a 2 molar solution of Na2CO3 (0.324 mL, 0.647 mmol) were added. The flask was flushed with nitrogen, sealed and heated to 110° C. for additional 8 hours. The reaction mixture was poured into a separating funnel loaded with water and dichloromethane. The layers were separated and the aqueous layer extracted one more time with dichloromethane. The combined organic layers were washed with brine and dried over MgSO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica, using a gradient from 100% CH2Cl2 to 50% CH2Cl2+50 EtOAc. Product containing fraction were combined and evaporated to dryness to give 42.3 mg 5-benzyl-2-(4-(morpholine-4-carbonyl)phenylamino)benzonitrile. (estimated purity 76%). The material was used without further purification. MS (ESI) m/e−=396, m/e+=398 consistent with [M−H]− and [M+H]+. the flask flushed with nitrogen sealed The flask was flushed with nitrogen sealed heated to 110° C. for additional 8 hours The reaction mixture was poured into a separating funnel The layers were separated the aqueous layer extracted one more time with dichloromethane The combined organic layers were washed with brine dried over MgSO4 filtered concentrated in vacuum The crude product was purified by column chromatography on silica Product containing fraction evaporated to dryness

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

Procedure: To a solution of 3-bromo-5-nitropyridine (LXXVII) (295 mg, 1.45 mmol) in dioxane (14 mL) was added 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (LXXVIII) (420 μL, 1.89 mmol), PdCl2(dppf)2, (120 mg, 0.15 mmol) and 2M aqueous K3PO4 (2.2 mL, 4.36 mmol). The reaction was microwaved at 90° C. for 2 h. The reaction was cooled and the organic phase was separated, dried over MgSO4 and evaporated under vacuum. The residue was purified by silica gel column chromatography (100% hexane 6:94 EtOAc:hexane) to give 3-benzyl-5-nitropyridine (LXXIX) as brown oil (117 mg, 0.54 mmol, 37% yield). 1H NMR (DMSO-d6) δ ppm 4.16 (s, 2H), 7.21-7.25 (m, 1H), 7.31-7.33 (m, 4H), 8.45-8.46 (m, 1H), 8.93 (d, J=2 Hz, 1H), 9.21 (d, J=3 Hz, 1H); ESIMS found for C12H10N2O2 m/z 215 (M+H). The reaction was microwaved at 90° C. for 2 h The reaction was cooled the organic phase was separated dried over MgSO4 evaporated under vacuum The residue was purified by silica gel column chromatography (100% hexane 6:94 EtOAc:hexane)

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

Procedure: Using ethyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (450 mg, 1.1 mmol) produced in Example 15(i), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 4.6 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (70 mg, 0.086 mmol), cesium carbonate (670 mg, 2.1 mmol), water (5 mL) and 1,2-dimethoxyethane (30 mL) as starting materials and in the same manner as in Example 13-B (iii), the title compound (174 mg, 43%) was obtained as a brown solid.

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

Procedure: Using ethyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (450 mg, 1.1 mmol) produced in Example 15(i), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 4.6 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (70 mg, 0.086 mmol), cesium carbonate (670 mg, 2.1 mmol), water (5 mL) and 1,2-dimethoxyethane (30 mL) as starting materials and in the same manner as in Example 13-B (iii), the title compound (174 mg, 43%) was obtained as a brown solid.

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

Procedure: Using ethyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (450 mg, 1.1 mmol) produced in Example 15(i), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 4.6 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (70 mg, 0.086 mmol), cesium carbonate (670 mg, 2.1 mmol), water (5 mL) and 1,2-dimethoxyethane (30 mL) as starting materials and in the same manner as in Example 13-B (iii), the title compound (174 mg, 43%) was obtained as a brown solid.

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

Procedure: Part C. To a solution of 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (70 mg, 0.16 mmol, 1.0 equiv) in dimethyl ether (1 mL) was added Na2CO3 (34 mg, 0.32 mmol, 2.0 equiv), benzyl boronic acid pinacol ester (87 μL, 0.40 mmol, 2.5 equiv), PdCl2(dppf) (11 mg, 0.02 mmol, 0.1 equiv) and water (0.1 mL) in a sealed tube. The reaction was immersed in an oil bath preheated to 100° C. After stirring for 4 hr, the reaction was cooled and the solvent was removed in vacuo. The crude product was purified by column chromatography [SiO2, methanol/dichloromethane, 0:100 to 10:90, v/v] and recrystallization (methanol/pentane) to give 2-(6-benzyl-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (41 mg, 65%). 1H NMR (400 MHz, CD2Cl2) δ 9.17 (s, 1H), 8.47 (s, 1H), 7.22-7.37 (m, 10H), 6.23 (bs, 1H), 4.59 (d, J=8.0 Hz, 2H), 4.19 (s, 2H), 2.72 (s, 3H); HRMS (M+H)+=401.14. The reaction was immersed in an oil bath preheated to 100° C the reaction was cooled the solvent was removed in vacuo The crude product was purified by column chromatography [SiO2, methanol/dichloromethane, 0:100 to 10:90 v/v] and recrystallization (methanol/pentane)

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

Procedure: A mixture of 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Frontier Scientific Inc., 90 mg, 0.411 mmol), 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (160 mg, 0.274 mmol), Pd2dba3 (12.54 mg, 0.014 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-i-propyl-1,1′-biphenyl (X-Phos, 13.06 mg, 0.027 mmol) (Strem Co.) was purged with argon and then treated with dioxane (2.50 mL), water (0.25 mL) and sodium carbonate (72.6 mg, 0.685 mmol) and heated under a microwave irradiation at 140° C. for 30 min. The mixture was filtered through a short plug of Celite® (diatomaceous earth), washed with EtOAc (×3), and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (pure hexanes to 30% EtOAc in hexanes) to give 4-(5-benzyl-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (110 mg, 62.8%) as a yellow syrup. m/z (ESI, +ve ion) 640.0 (M+H)+. was purged with argon The mixture was filtered through a short plug of Celite® (diatomaceous earth) washed with EtOAc (×3) concentrated chromatographed through a Redi-Sep pre-packed silica gel column (pure hexanes to 30% EtOAc in hexanes)

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 8-bromo-4-(1-methyl-piperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 231) (150 mg) in toluene/dioxane/water 10/1/1 (6 mL) in a screw-capped vial are added benzylboronic pinacol ester (151 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (50 mg) and potassium carbonate (137 mg). The vial is evacuated and filled with argon. The reaction mixture is stirred at 95° C. for 20 hours. Water is added to the reaction mixture, and the aqueous phase is extracted three times with dichloromethane. Pooled organic extracts are dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC-MS (Waters AutoPurification HPLC/MS System, Sunfire Prep C18 5 μm OBD 30×150 mm column, eluents: water/0.1% formic acid (A) and acetonitrile/0.1% formic acid (B), focus gradient from 23% (B) to 33% (B) in 10 minutes) to afford 8-benzyl-4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 66° C. The vial is evacuated filled with argon Water is added to the reaction mixture the aqueous phase is extracted three times with dichloromethane Pooled organic extracts are dried over magnesium sulphate filtered the solvent is removed under reduced pressure The residue is purified by preparative HPLC-MS (Waters AutoPurification HPLC/MS System, Sunfire Prep C18 5 μm OBD 30×150 mm column, eluents: water/0.1% formic acid (A) and acetonitrile/0.1% formic acid (B), focus gradient from 23% (B) to 33% (B) in 10 minutes)

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

Procedure: A mixture of 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Frontier Scientific Inc., 90 mg, 0.411 mmol), 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (160 mg, 0.274 mmol), Pd2dba3 (12.54 mg, 0.014 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (X-Phos, 13.06 mg, 0.027 mmol) (Strem Co.) was purged with argon and then treated with dioxane (2.50 mL), water (0.25 mL) and sodium carbonate (72.6 mg, 0.685 mmol) and heated under a microwave irradiation at 140° C. for 30 min. The mixture was filtered through a short plug of Celite® (diatomaceous earth), washed with EtOAc (×3), and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (pure hexanes to 30% EtOAc in hexanes) to give 4-(5-benzyl-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (110 mg, 62.8%) as a yellow syrup. m/z (ESI, +ve ion) 640.0 (M+H)+. was purged with argon The mixture was filtered through a short plug of Celite® (diatomaceous earth) washed with EtOAc (×3) concentrated chromatographed through a Redi-Sep pre-packed silica gel column (pure hexanes to 30% EtOAc in hexanes)

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

Procedure: Using ethyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (450 mg, 1.1 mmol) produced in Example 15(i), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 4.6 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (70 mg, 0.086 mmol), cesium carbonate (670 mg, 2.1 mmol), water (5 mL) and 1,2-dimethoxyethane (30 mL) as starting materials and in the same manner as in Example 13-B (iii), the title compound (174 mg, 43%) was obtained as a brown solid.