TRANS-2-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)STYRENE

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

Procedure: A solution of 3,5-dichloropicolinonitrile (1.0 eq.), (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stiffed at 100° C. for 2 hours, then 80° C. for 4 hours. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give a white solid. The two phases were separated the aqueous layer was extracted twice with ethyl acetate The combined organic layers were washed with brine dried over anhydrous MgSO4 concentrated en vacuo The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) to give a white solid

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

Procedure: A mixture of 5-bromo-2,3-dimethoxypyridine (0.50 g, 2.29 mmol), tripotassium phosphate (1.95 g, 9.17 mmol), tetrakistriphenylphosphine (0.27 g, 0.23 mmol) and (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (0.53 g, 2.29 mmol) was diluted with dioxane (6 ml) and water (1 ml) and heated in a microwave for 1 hour at 100° C. The reaction mixture was partitioned between ethyl acetate and water and the organics were dried (MgSO4), filtered and concentrated in vacuo to give yellow oil. The oil was purified by column chromatography (SiO2; 0-10% ethyl acetate in petrol) gave 2,3-dimethoxy-5-[(E)-2-phenylethenyl]pyridine as a colourless oil (116 mg, 21%). The reaction mixture was partitioned between ethyl acetate and water the organics were dried (MgSO4) filtered concentrated in vacuo to give yellow oil The oil was purified by column chromatography (SiO2; 0-10% ethyl acetate in petrol)

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

Procedure: A mixture of 5-bromo-2,3-dimethoxypyridine (0.50 g, 2.29 mmol), tripotassium phosphate (1.95 g, 9.17 mmol), tetrakistriphenylphosphine (0.27 g, 0.23 mmol) and (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (0.53 g, 2.29 mmol) was diluted with dioxane (6 ml) and water (1 ml) and heated in a microwave for 1 hour at 100° C. The reaction mixture was partitioned between ethyl acetate and water and the organics were dried (MgSO4), filtered and concentrated in vacuo to give yellow oil. The oil was purified by column chromatography (SiO2; 0-10% ethyl acetate in petrol) gave 2,3-dimethoxy-5-[(E)-2-phenylethenyl]pyridine as a colourless oil (116 mg, 21%). The reaction mixture was partitioned between ethyl acetate and water the organics were dried (MgSO4) filtered concentrated in vacuo to give yellow oil The oil was purified by column chromatography (SiO2; 0-10% ethyl acetate in petrol)

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

Procedure: To a flask containing 4-bromo-N-(4-methoxybenzyl)picolinamide (0.3 g) in 1,4-dioxane (1.1 mL) was added (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (0.22 g), Pd(dppf)—chloroform adduct (0.04 g) and 2M aqueous cesium carbonate (1.9 mL). The mixture was stirred at about 95° C. for about 12 h. The reaction was diluted with water and washed three times with CH2Cl2. The organic solution was filtered over Celite®, and concentrated under reduced pressure yielding (E)-N-(4-methoxybenzyl)-4-styrylpicolinamide as a deep yellow oil (0.25 g, 80%). LC/MS (Table-1, Method f) Rt=2.03 min; MS m/z 345 (M+H)+. This intermediate was then dissolved in 4.3 mL of 1,4-dioxane and treated with 0.87 mL of water and sodium periodate (0.75 g). After stirring for approximately 30 min at RT, osmium tetroxide (0.30 mL of a 0.1 M solution in t-butanol) was added to the reaction which was then stirred for about an additional 4 h at RT. The layers were separated and the organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The product was isolated by flash chromatography to give 4-formyl-N-(4-methoxybenzyl)picolinamide (0.25 g, 80%): LC/MS (Table 1, method-f) Rt=1.01 min; MS m/z 271 (M+H)+. washed three times with CH2Cl2 The organic solution was filtered over Celite® concentrated under reduced pressure

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

Procedure: To a flask containing 4-bromo-N-(4-methoxybenzyl)picolinamide (0.3 g) in 1,4-dioxane (1.1 mL) was added (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (0.22 g), Pd(dppf)—chloroform adduct (0.04 g) and 2M aqueous cesium carbonate (1.9 mL). The mixture was stirred at about 95° C. for about 12 h. The reaction was diluted with water and washed three times with CH2Cl2. The organic solution was filtered over Celite®, and concentrated under reduced pressure yielding (E)-N-(4-methoxybenzyl)-4-styrylpicolinamide as a deep yellow oil (0.25 g, 80%). LC/MS (Table-1, Method f) Rt=2.03 min; MS m/z 345 (M+H)+. This intermediate was then dissolved in 4.3 mL of 1,4-dioxane and treated with 0.87 mL of water and sodium periodate (0.75 g). After stirring for approximately 30 min at RT, osmium tetroxide (0.30 mL of a 0.1 M solution in t-butanol) was added to the reaction which was then stirred for about an additional 4 h at RT. The layers were separated and the organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The product was isolated by flash chromatography to give 4-formyl-N-(4-methoxybenzyl)picolinamide (0.25 g, 80%): LC/MS (Table 1, method-f) Rt=1.01 min; MS m/z 271 (M+H)+. washed three times with CH2Cl2 The organic solution was filtered over Celite® concentrated under reduced pressure

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

Procedure: A solution of 3,5-dichloropicolinonitrile (1.0 eq.), (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stiffed at 100° C. for 2 hours, then 80° C. for 4 hours. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give a white solid. The two phases were separated the aqueous layer was extracted twice with ethyl acetate The combined organic layers were washed with brine dried over anhydrous MgSO4 concentrated en vacuo The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) to give a white solid

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a vial containing 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-(4-bromophenyl)-1,2-pyrrolidinedicarboxylate (D78, 100 mg, 0.26 mmol), sodium carbonate (138 mg, 1.30 mmol), 4,4,5,5-tetramethyl-2-[(E)-2-phenylethenyl]-1,3,2-dioxaborolane (90 mg, 0.39 mmol) and Pd(PPh3)4 (30 mg, 0.026 mmol) were added dioxane (2 ml) and water (1 ml). The mixture was stirred for 2 h at 80° C. After cooling, the mixture was extracted with ethyl acetate. The organic layer was filtered by phase separator tube and evaporated. The residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (1:0 to 9:1) to afford the title compound as a light yellow solid (90 mg, 85%). Rt (HPLC): 7.02 min; MS: (ES/+) m/z: 308 (MH-Boc) C25H29NO4 requires 407. After cooling the mixture was extracted with ethyl acetate The organic layer was filtered by phase separator tube evaporated The residue was purified by chromatography on silica gel

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a vial containing 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-(4-bromophenyl)-1,2-pyrrolidinedicarboxylate (D78, 100 mg, 0.26 mmol), sodium carbonate (138 mg, 1.30 mmol), 4,4,5,5-tetramethyl-2-[(E)-2-phenylethenyl]-1,3,2-dioxaborolane (90 mg, 0.39 mmol) and Pd(PPh3)4 (30 mg, 0.026 mmol) were added dioxane (2 ml) and water (1 ml). The mixture was stirred for 2 h at 80° C. After cooling, the mixture was extracted with ethyl acetate. The organic layer was filtered by phase separator tube and evaporated. The residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (1:0 to 9:1) to afford the title compound as a light yellow solid (90 mg, 85%). Rt (HPLC): 7.02 min; MS: (ES/+) m/z: 308 (MH-Boc) C25H29NO4 requires 407. After cooling the mixture was extracted with ethyl acetate The organic layer was filtered by phase separator tube evaporated The residue was purified by chromatography on silica gel

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a vial containing 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-(4-bromophenyl)-1,2-pyrrolidinedicarboxylate (D78, 100 mg, 0.26 mmol), sodium carbonate (138 mg, 1.30 mmol), 4,4,5,5-tetramethyl-2-[(E)-2-phenylethenyl]-1,3,2-dioxaborolane (90 mg, 0.39 mmol) and Pd(PPh3)4 (30 mg, 0.026 mmol) were added dioxane (2 ml) and water (1 ml). The mixture was stirred for 2 h at 80° C. After cooling, the mixture was extracted with ethyl acetate. The organic layer was filtered by phase separator tube and evaporated. The residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (1:0 to 9:1) to afford the title compound as a light yellow solid (90 mg, 85%). Rt (HPLC): 7.02 min; MS: (ES/+) m/z: 308 (MH-Boc) C25H29NO4 requires 407. After cooling the mixture was extracted with ethyl acetate The organic layer was filtered by phase separator tube evaporated The residue was purified by chromatography on silica gel

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tert-butyl 2-(7-bromo-2-hydroxy-1,1-dimethyl-4-oxo-1,4-dihydronaphthalene-3-carboxamido)acetate (360 mg, 848 μmol, Example 53A-E) was dissolved in 1,4-dioxane (8485 μL) and then beta-styrylboronic acid pinacol ester (293 mg, 1273 mmol), potassium carbonate (2 M in water, 2121 μL, 4242 μmol) and tetrakis(triphenylphosphine)palladium (98.0 mg, 84.8 μmol) were added. The reaction was stirred at 80° C. for 4 hours. The reaction mixture was diluted with 100 mL of EtOAc, washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated to give crude product. The title compound was obtained by flash chromatography. washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous) separated dried over sodium sulfate concentrated to give crude product

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tert-butyl 2-(7-bromo-2-hydroxy-1,1-dimethyl-4-oxo-1,4-dihydronaphthalene-3-carboxamido)acetate (360 mg, 848 μmol, Example 53A-E) was dissolved in 1,4-dioxane (8485 μL) and then beta-styrylboronic acid pinacol ester (293 mg, 1273 mmol), potassium carbonate (2 M in water, 2121 μL, 4242 μmol) and tetrakis(triphenylphosphine)palladium (98.0 mg, 84.8 μmol) were added. The reaction was stirred at 80° C. for 4 hours. The reaction mixture was diluted with 100 mL of EtOAc, washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated to give crude product. The title compound was obtained by flash chromatography. washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous) separated dried over sodium sulfate concentrated to give crude product

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

Procedure: To a solution of tert-butyl 4-bromobenzoate (616 mg, 2.4 mmol) in 1,4-dioxane and water (4:1, 10 mL) were added (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (553 mg, 2.4 mmol), tetrakis(triphenylphosphine)palladium (58.9 mg, 0.05 mmol) and sodium carbonate (164 mg, 1.55 mmol). The mixture was stirred at 90° C. under nitrogen atmosphere for 18 hours. Once the start material was consumed, the resultant mixture was concentrated to give a residue and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=30:1) to give tert-butyl 4-(1-phenylvinyl)benzoate (0.59 g, 87.5%). 1H NMR (300 MHz, CDCl3): δ 7.96 (d, J=4.8 Hz, 2H), 7.41-7.26 (m, 7H), 5.55-5.53 (m, 2H), 1.61 (s, 9H). Once the start material was consumed the resultant mixture was concentrated to give a residue the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=30:1)