反式-BETA-苯乙烯硼酸

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Methyl 5-amino-8-bromoisoquinoline-6-carboxylate was prepared by the procedure described for the synthesis of methyl 1-amino-4-bromo-2-naphthoate in Example 1, substituting 6-methyl-5-nitroisoquinoline for 2-methyl-1-nitronaphthalene and substituting [(E-2-phenylethenyl]boronic acid for potassium vinyltrifluoroborate.

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (see, e.g., Greig, I. R., et al., J Med Chem 2006, 49, 7487-92; Li, X., et al., J Med Chem 2003, 46, 5663-73). To a mixture of 50 (205 mg, 0.49 mmol), Pd(PPh3)4 (27 mg, 0.02 mmol) and (E)-2-phenylvinylboronic acid (112 mg, 0.74 mmol) in 1,4-dioxane: H2O (3 mL/2 mL) was added Na2CO3 (153 mg, 1.45 mmol), followed by stirring at 90° C. overnight. To the reaction mixture was added H2O (10 mL) and the aqueous layer was extracted with EtOAc (10 mL×2). The combined organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Crude was subjected to flash column chromatography on silica gel to provide the title compound (216 mg, 90%) as a light yellow oil which solidified upon standing. 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J=16.1 Hz, 1H), 7.74 (s, 1H), 7.63 (d, J=7.6 Hz, 2H), 7.41 (t, J=7.6 Hz, 2H), 7.39-7.33 (m, 3H), 7.30 (t, J=7.7 Hz, 3H), 7.07 (t, J=7.4 Hz, 1H), 6.98 (d, J=8.6 Hz, 2H), 6.95 (d, J=8.3 Hz, 2H), 5.69 (s, 2H), 4.51 (q, J=7.1 Hz, 2H), 2.71 (s, 3H), 1.49 (t, J=7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 165.76, 157.04, 156.79, 154.93, 152.39, 141.19, 136.28, 134.74, 133.60, 132.13, 129.69, 129.50, 128.81, 127.69, 127.33, 123.28, 118.94, 118.82, 116.48, 110.28, 61.93, 49.80, 16.30, 14.30. the aqueous layer was extracted with EtOAc (10 mL×2) The combined organic layer was washed with brine dried (Na2SO4) filtered concentrated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Methyl 2-bromo-4-fluorobenzoate (1.00 g), (E)-styrylboronic acid (0.89 g), tetrakis(triphenylphosphine)palladium(0) (0.50 g), and K3PO4 (2.28 g) were stirred in dioxane (17 mL) at 90° C. for 24 hours. The reaction mixture chromatographed on silica gel with 1-5% ethyl acetate/hexanes. The product in methanol (10 ml) was added to 20 wt % of fresh dry 5% Pd—C and stirred 4 days with H2 in a pressure bottle. The mixture was filtered through a nylon membrane and concentrated. The reaction mixture chromatographed on silica gel with 1-5% ethyl acetate/hexanes The product in methanol (10 ml) was added to 20 wt % of fresh dry 5% Pd—C The mixture was filtered through a nylon membrane concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Methyl 2-bromo-4-fluorobenzoate (1.00 g), (E)-styrylboronic acid (0.89 g), tetrakis(triphenylphosphine)palladium(0) (0.50 g), and K3PO4 (2.28 g) were stirred in dioxane (17 mL) at 90° C. for 24 hours. The reaction mixture chromatographed on silica gel with 1-5% ethyl acetate/hexanes. The product in methanol (10 ml) was added to 20 wt % of fresh dry 5% Pd—C and stirred 4 days with H2 in a pressure bottle. The mixture was filtered through a nylon membrane and concentrated. The reaction mixture chromatographed on silica gel with 1-5% ethyl acetate/hexanes The product in methanol (10 ml) was added to 20 wt % of fresh dry 5% Pd—C The mixture was filtered through a nylon membrane concentrated

反应条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Tetrethylamine hydroxide (13.6 g, 18.4 mmol), tetrakis(triphenylphosphine)palladium(0) (142 mg) and trans-2-phenylvinylboronic acid (2.3 g, 15.3 mmol) are added to a solution of the product from example 1a) (2.00 g, 6.14 mmol) in N,N′-Dimethylacetamide (DMA) (30 ml). The mixture is then stirred at 110° C. for 24 hours. The reaction mixture is cooled to room temperature and poured into H2O. A gray crude product is obtained after filtration and washing with n-hexane. The crude product is purified by silicagel column chromatography with CH2Cl2, which result in a white solid (71% yield, mp.: 226° C.). The reaction mixture is cooled to room temperature A gray crude product is obtained after filtration washing with n-hexane The crude product is purified by silicagel column chromatography with CH2Cl2, which

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 2-chloro-9-methyl-7,9-dihydro-8H-purine-8-one <the compound of Reference Example 1> (200 mg), trans-2-phenylvinylboronic acid (192 mg), potassium carbonate (448 mg) and 1-methylpyrrolidin-2-one (3 ml) was added bis(tri-tert-butylphosphine)palladium (28 mg) under nitrogen atmosphere and the mixture was stirred at 150° C. under microwave irradiation for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid (50 ml) and the crude solids precipitated were collected by filtration. The obtained crude solids were purified by silica gel column chromatography (eluent: chloroform/methanol=100/0˜90/10) to give the title compound 179 mg. the crude solids precipitated were collected by filtration The obtained crude solids were purified by silica gel column chromatography (eluent: chloroform/methanol=100/0˜90/10)

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-Bromo-2-methoxypyridine (1.85 g, 9.84 mmol), (E)-phenylvinylboronic acid (4.3 g, 30 mmol), K2CO3 (4.0 g, 30 mmol) and PdCl2(dppf) (400 mg, 0.5 mmol) were stirred in DMSO (15 mL) under vacuum for 30 min. The flask was flushed with nitrogen and the mixture was heated to 90° C. for 30 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried, concentrated, and the residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25) to provide the title compound (1.93 g, 93%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=5.2 Hz, 1H), 7.51 (m, 2H), 7.40-7.22 (m, 4H), 7.02-6.94 (m, 2H), 6.78 (s, 1H), 3.95 (s, 3H). The flask was flushed with nitrogen Upon cooling the mixture was diluted with methylene chloride washed with 5% lithium chloride solution (5×) dried concentrated the residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25)

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-Bromo-2-methoxypyridine (1.85 g, 9.84 mmol), (E)-phenylvinylboronic acid (4.3 g, 30 mmol), K2CO3 (4.0 g, 30 mmol) and PdCl2(dppf) (400 mg, 0.5 mmol) were stirred in DMSO (15 mL) under vacuum for 30 min. The flask was flushed with nitrogen and the mixture was heated to 90° C. for 30 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried, concentrated, and the residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25) to provide the title compound (1.93 g, 93%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=5.2 Hz, 1H), 7.51 (m, 2H), 7.40-7.22 (m, 4H), 7.02-6.94 (m, 2H), 6.78 (s, 1H), 3.95 (s, 3H). The flask was flushed with nitrogen Upon cooling the mixture was diluted with methylene chloride washed with 5% lithium chloride solution (5×) dried concentrated the residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of EXAMPLE 31C (100 mg), (E)-styrylboronic acid (39 mg), and bis(triphenylphosphine)palladium(II) dichloride (8 mg) in 7:3:3 dimethoxyethane:ethanol: 1N aqueous LiOH (2 mL) was heated under microwave conditions (CEM Discover) at 130° C. for 30 minutes The mixture was quenched with 1 NHCl and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated. The concentrate was purified by reverse phase HPLC (Zorbax SB-C18, 20-100% acetonitrile/water/0.1% trifluoroacetic acid) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 13.59 (br, 1H), 8.24 (m, 1H), 8.15 (d, 1H), 7.94 (m, 1H), 7.87 (m, 1H), 7.69 (d, 1H), 7.59 (m, 2H), 7.53 (m, 2H), 7.46 (m, 1H), 7.40 (m, 3H), 7.28 (m, 3H), 7.21 (m 1H), 6.87 (d, 1H), 4.87 (t, 2H), 4.17 (t, 2H), 2.34 (m, 2H). was quenched with 1 NHCl extracted with ethyl acetate The extract was dried (Na2SO4) filtered concentrated The concentrate was purified by reverse phase HPLC (Zorbax SB-C18, 20-100% acetonitrile/water/0.1% trifluoroacetic acid)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 6-Bromo-7-chloro-4H-pyrido[3,2-b][1,4]oxazin-3-one (15a) (22 g, 83.7 mmole) and trans-2-phenylvinylboronic acid (17.33 g, 117 mmole) were dissolved in 1,4-dioxane (300 mL) and the solution was degassed with argon. (Ph3P)4Pd (1.9 g, 2 mole %) was added, followed by a solution of potassium hydrogen carbonate (21 g, 210 mmole) in H2O (100 mL). The reaction was heated at reflux under argon overnight, then was cooled to room temperature and diluted with ethyl acetate (1 L). The solution was washed sequentially with H2O and brine, dried (Na2SO4), and concentrated in vacuo. The residue was slurried with chloroform (120 mL), then diluted with diethyl ether (100 mL). The precipitated product was collected by filtration and washed with ether to provide the product (16.4 g, 68%) as an off-white solid. the solution was degassed with argon (Ph3P)4Pd (1.9 g, 2 mole %) was added The reaction was heated at reflux under argon overnight The solution was washed sequentially with H2O and brine dried (Na2SO4) concentrated in vacuo diluted with diethyl ether (100 mL) The precipitated product was collected by filtration washed with ether

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-Bromo-2-methoxypyridine (1.85 g, 9.84 mmol), (E)-phenylvinylboronic acid (4.3 g, 30 mmol), K2CO3 (4.0 g, 30 mmol) and PdCl2(dppf) (400 mg, 0.5 mmol) were stirred in DMSO (15 mL) under vacuum for 30 min. The flask was flushed with nitrogen and the mixture was heated to 90° C. for 30 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried, concentrated, and the residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25) to provide the title compound (1.93 g, 93%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=5.2 Hz, 1H), 7.51 (m, 2H), 7.40-7.22 (m, 4H), 7.02-6.94 (m, 2H), 6.78 (s, 1H), 3.95 (s, 3H). The flask was flushed with nitrogen Upon cooling the mixture was diluted with methylene chloride washed with 5% lithium chloride solution (5×) dried concentrated the residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 6-Styryl-4H-pyrido[3,2-b][1,4]oxazin-3-one. To a solution of 6-bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (3.2 g, 14 mmol) in 1,4-dioxane (80 mL) was added trans-2-phenylvinylboronic acid (2.1 g, 14 mmol). After the reaction mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium(0) (0.129 g, 0.112 mmol) and a solution of K2CO3 (3.7 g, 27 mmol) in H2O (10.7 mL) were added. The reaction was heated at reflux for 17 h, then cooled to RT, and diluted with EtOAc (300 mL). The organic layer was separated, washed with H2O (300 mL), brine (300 mL), dried (Na2SO4), and concentrated. The solid residue was purified on SiO2 (5-10% EtOAc/CHCl3) to provide 1.5 g (43%) of the title compound as a solid. MS (ESI): exact mass calculated for C15H12N2O2, 252.09; m/z found, 253.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.53-7.00 (m, 9H), 4.66 (d, J=6.9, 2H). The reaction was heated at reflux for 17 h The organic layer was separated washed with H2O (300 mL), brine (300 mL) dried (Na2SO4) concentrated The solid residue was purified on SiO2 (5-10% EtOAc/CHCl3)