2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

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

Procedure: A 500 mL round-bottomed flask was charged with 2-bromo-N-tert-butyl-4-(2-cyanopropan-2-yl)-6-fluorobenzamide (34.5 g, 101 mmol, 1 equiv.) and potassium carbonate (27.9 g, 202 mmol, 2 equiv.) and the flask was subsequently purged with nitrogen (3 times). 1,4-dioxane (242 ml) and water (34.5 ml) were added. The E-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (28.0 g, 142 mmol, 1.4 equiv.) was then added by syringe. The reaction mixture was heated to 40° C. To the mixture was added bis(dibenzylideneacetone)palladium (2.33 g, 4.04 mmol, 0.04 equiv.) and tricyclohexylphosphine (2.27 g, 8.09 mmol, 0.08 equiv.) and the resulting mixture was heated with stirring at 90° C. (inner temperature)/100° C. (bath) for 2 h until reaction was complete. The reaction mixture was cooled to ambient temperature and quenched with 20% NaHSO3 solution (150 mL) followed by stirring for 2 hr. The mixture was extracted with EtOAc (2 times), dried over MgSO4, and concentrated under reduced pressure. The resultant product was dissolved with TFA (138 ml) in a 350 mL pressured bottle and heated to 100° C. (bath temp.) for 3 hr. The reaction mixture was transferred to a round-bottomed flask with toluene, and the TFA was removed under reduced pressure, then basified with 20% K2CO3 solution. The reaction mixture was extracted with EtOAc and then with DCM. Crystallization from methyl-tert-butylether afforded 2-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanenitrile (16.2 g, 69.6% yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.74 (s, 6 H) 6.60 (dd, J=6.99, 1.70 Hz, 1 H) 7.16-7.28 (m, 1 H) 7.36 (dd, J=13.03, 1.70 Hz, 1 H) 7.61 (d, J=1.89 Hz, 1 H) 11.31 (br. s., 1 H). the flask was subsequently purged with nitrogen (3 times) 1,4-dioxane (242 ml) and water (34.5 ml) were added the resulting mixture was heated until reaction The reaction mixture was cooled to ambient temperature quenched with 20% NaHSO3 solution (150 mL) by stirring for 2 hr The mixture was extracted with EtOAc (2 times) dried over MgSO4 concentrated under reduced pressure The resultant product was dissolved with TFA (138 ml) in a 350 mL heated to 100° C. (bath temp.) for 3 hr The reaction mixture was transferred to a round-bottomed flask with toluene the TFA was removed under reduced pressure The reaction mixture was extracted with EtOAc Crystallization from methyl-tert-butylether

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Di(cyclopenta-2,4-dien-1-yl)zirconium(IV) chloride (0.685 g, 2.344 mmol) was added to a solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.0 g, 39.1 mmol) in dichloromethane (15 mL) followed by ethoxyethyne (3.01 g, 43.0 mmol) at 0° C., and the mixture was stirred for 16 h at 25° C. Insoluble solids were filtered off, and filtrate was concentrated. Residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo to afford title compound (6.04 g, 78.13%) as oil. 1H NMR (400 MHz, CDCl3): δ 7.04 (d, J=14.0 Hz, 1H), 4.43 (d, J=14.8 Hz, 1H), 3.84 (q, J=7.2 Hz, 2H), 1.32-1.2 (m, 15H). Insoluble solids were filtered off filtrate was concentrated Residue was partitioned between ethyl acetate and water Organic layer was separated washed with brine dried over sodium sulphate filtered concentrated in vacuo

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

Procedure: (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (63 mg), palladium acetate (7.1 mg), tripotassium phosphate (67 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (26 mg), and water (0.35 ml) were added to an acetonitrile (4.0 ml) solution of the methyl 4-(5-bromo-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (50 mg) obtained in (Example 5.11) <Step 1>, and the obtained mixture was then stirred under heating in a nitrogen atmosphere for 2 hours at 90° C. Thereafter, ethyl acetate (50 ml) and a saturated sodium hydrogen carbonate aqueous solution (30 ml) were added to the reaction solution. After extraction of organic layers, water layers were extracted with ethyl acetate (50 ml). The organic layers were combined. The combined organic layer was washed with a saturated saline, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (silica gel: eluent; heptane:ethyl acetate=92:8-40:60), so as to obtain the title compound (31 mg) in the form of a yellow solid. obtained in (Example 5.11) <Step 1> After extraction of organic layers, water layers were extracted with ethyl acetate (50 ml) The combined organic layer was washed with a saturated saline was then dried over anhydrous sodium sulfate The solvent was distilled away under reduced pressure the obtained residue was then purified by silica gel column chromatography (silica gel: eluent; heptane:ethyl acetate=92:8-40:60)

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

Procedure: (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (63 mg), palladium acetate (7.1 mg), tripotassium phosphate (67 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (26 mg), and water (0.35 ml) were added to an acetonitrile (4.0 ml) solution of the methyl 4-(5-bromo-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (50 mg) obtained in (Example 5.11) <Step 1>, and the obtained mixture was then stirred under heating in a nitrogen atmosphere for 2 hours at 90° C. Thereafter, ethyl acetate (50 ml) and a saturated sodium hydrogen carbonate aqueous solution (30 ml) were added to the reaction solution. After extraction of organic layers, water layers were extracted with ethyl acetate (50 ml). The organic layers were combined. The combined organic layer was washed with a saturated saline, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (silica gel: eluent; heptane:ethyl acetate=92:8-40:60), so as to obtain the title compound (31 mg) in the form of a yellow solid. obtained in (Example 5.11) <Step 1> After extraction of organic layers, water layers were extracted with ethyl acetate (50 ml) The combined organic layer was washed with a saturated saline was then dried over anhydrous sodium sulfate The solvent was distilled away under reduced pressure the obtained residue was then purified by silica gel column chromatography (silica gel: eluent; heptane:ethyl acetate=92:8-40:60)

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

Procedure: (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (63 mg), palladium acetate (7.1 mg), tripotassium phosphate (67 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (26 mg), and water (0.35 ml) were added to an acetonitrile (4.0 ml) solution of the methyl 4-(5-bromo-4-methylthiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (50 mg) obtained in (Example 5.11) <Step 1>, and the obtained mixture was then stirred under heating in a nitrogen atmosphere for 2 hours at 90° C. Thereafter, ethyl acetate (50 ml) and a saturated sodium hydrogen carbonate aqueous solution (30 ml) were added to the reaction solution. After extraction of organic layers, water layers were extracted with ethyl acetate (50 ml). The organic layers were combined. The combined organic layer was washed with a saturated saline, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (silica gel:eluent; heptane:ethyl acetate=92:8-40:60), so as to obtain the title compound (31 mg) in the form of a yellow solid. obtained in (Example 5.11) <Step 1> After extraction of organic layers, water layers were extracted with ethyl acetate (50 ml) The combined organic layer was washed with a saturated saline was then dried over anhydrous sodium sulfate The solvent was distilled away under reduced pressure the obtained residue was then purified by silica gel column chromatography (silica gel:eluent; heptane:ethyl acetate=92:8-40:60)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-bromopyrazin-2-amine (200 mg, 1.149 mmol) in DME (2874 μL) was added (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (341 mg, 1.724 mmol), PdCl2(dppf)-CH2Cl2 adduct (94 mg, 0.115 mmol), and 2M Na2CO3 (958 μL). The reaction mixture was stirred at 130° C. in microwave reactor for 20 min. The reaction mixture was filtered through Celite and washed with EtOAc, the filtrate was partition between EtOAc and water. The aqueous was extracted by EtOAc three times, the combined organic was dried and concentrated. The crude material was purified by flash chromatography to give (E)-5-(2-ethoxyvinyl)pyrazin-2-amine. LCMS (m/z): 166.1 (MH+), 0.41 min. The reaction mixture was filtered through Celite washed with EtOAc the filtrate was partition between EtOAc and water The aqueous was extracted by EtOAc three times the combined organic was dried concentrated The crude material was purified by flash chromatography

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a degassed solution of 2,6-dichloro-3-iodopyridine (3.0 g, 11 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.2 g, 11 mmol) in 1,4-dioxane (20 mL) and water (1.0 mL) was added CS2CO3 (7.1 g, 22 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium chloride (357 mg, 0.54 mmol) under N2 protection. The resulting mixture was heated to 70° C. and stirred at this temperature overnight. The reaction was cooled, filtered through a pad of the celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. The resulting residue was purified using column chromatography (eluted with 0-20% EtOAc/DCM) to provide (E)-2,6-dichloro-3-(2-ethoxyvinyl)pyridine (1.96 mg, yield: 86%). MS (M+H)+: 218. The reaction was cooled filtered through a pad of the celite washed with ethyl acetate The combined filtrate was evaporated in vacuo The resulting residue was purified column chromatography (eluted with 0-20% EtOAc/DCM)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a degassed solution of 2,6-dichloro-3-iodopyridine (3.0 g, 11 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.2 g, 11 mmol) in 1,4-dioxane (20 mL) and water (1.0 mL) was added CS2CO3 (7.1 g, 22 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium chloride (357 mg, 0.54 mmol) under N2 protection. The resulting mixture was heated to 70° C. and stirred at this temperature overnight. The reaction was cooled, filtered through a pad of the celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. The resulting residue was purified using column chromatography (eluted with 0-20% EtOAc/DCM) to provide (E)-2,6-dichloro-3-(2-ethoxyvinyl)pyridine (1.96 mg, yield: 86%). MS (M+H)+: 218. The reaction was cooled filtered through a pad of the celite washed with ethyl acetate The combined filtrate was evaporated in vacuo The resulting residue was purified column chromatography (eluted with 0-20% EtOAc/DCM)

Conditions: temp:73.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 6-bromo-2-chloro-3-iodopyridine (8.0 g, 25.1 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.98 g, 25.1 mmol), cesium carbonate (16.38 g, 50.3 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.052, 2.51 mmol) was added 1,4-dioxane (100 mL) and H2O (10 mL). A steady stream of N2 was bubbled through the reaction mixture for 15 minutes then the mixture was heated to 73° C. for 20 h. The mixture was cooled to ambient temperature, diluted with EtOAc, and washed successively with H2O (2×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a step gradient of 0-10-60% EtOAc/Hexanes as eluent. MS (M+H): 261. A steady stream of N2 was bubbled through the reaction mixture for 15 minutes The mixture was cooled to ambient temperature diluted with EtOAc washed successively with H2O (2×) and brine (1×) The organic layer was dried over MgSO4 filtered concentrated in vacuo The residue was purified by silica gel column chromatography

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Di(cyclopenta-2,4-dien-1-yl)zirconium(IV) chloride (0.685 g, 2.344 mmol) was added to a solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.0 g, 39.1 mmol) in dichloromethane (15 mL) followed by ethoxyethyne (3.01 g, 43.0 mmol) at 0° C., and the mixture was stirred for 16 h at 25° C. Insoluble solids were filtered off, and filtrate was concentrated. Residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo to afford title compound (6.04 g, 78.13%) as oil. 1H NMR (400 MHz, CDCl3): δ 7.04 (d, J=14.0 Hz, 1H), 4.43 (d, J=14.8 Hz, 1H), 3.84 (q, J=7.2 Hz, 2H), 1.32-1.2 (m, 15H). Insoluble solids were filtered off filtrate was concentrated Residue was partitioned between ethyl acetate and water Organic layer was separated washed with brine dried over sodium sulphate filtered concentrated in vacuo

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

Procedure: A mixture of EXAMPLE 388A (0.65 g), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.735 g), palladium acetate (0.013 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.057 g), and potassium phosphate (0.788 g) in CH3CN (9 ml) and water (6 mL) was heated at reflux overnight. After it cooled to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica to give the title compound. at reflux overnight the reaction mixture was partitioned between water and ethyl acetate The aqueous layer was extracted with additional ethyl acetate three times The combined organic layers were washed with brine dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by flash column chromatography on silica

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

Procedure: A mixture of EXAMPLE 388A (0.65 g), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.735 g), palladium acetate (0.013 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.057 g), and potassium phosphate (0.788 g) in CH3CN (9 ml) and water (6 mL) was heated at reflux overnight. After it cooled to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica to give the title compound. at reflux overnight the reaction mixture was partitioned between water and ethyl acetate The aqueous layer was extracted with additional ethyl acetate three times The combined organic layers were washed with brine dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by flash column chromatography on silica