(2-propan-2-ylphenyl)boronic acid

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A mixture of 3-acetyl-4-trifluoromethylsulfonyloxy-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 2 above (2.5 g, 7.2 mmol), 2-isopropylbenzeneboronic acid (1.8 g, 11 mmol), potassium carbonate (1.5 g, 11 mmol), and Pd(PPh3)4 (1.7 g, 1.4 mmol) was heated to reflux under inert atmosphere for 3 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography using a gradient elution of 25-75% EtOAc:hexanes to give the title compound (0.72 g; HPLC RT=21.79 min, method B). was heated to reflux under inert atmosphere for 3 h The solvent was removed under reduced pressure the residue was purified by flash column chromatography a gradient elution of 25-75% EtOAc

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (80 mg, 1 eq), 2-isopropylphenylboronic acid (65 mg, 1.75 eq), and tetrakis(triphenylphosphine)palladium (10 mg, 0.05 eq), in 1.0 M aqueous sodium carbonate (1.0 mL) and acetonitrile (1.0 mL) were heated to 140° C. for 10 min in a sealed microwave reactor. The crude reaction mixture was concentrated and purified using reverse phase HPLC to yield 298 (23 mg). ESI-MS: 363.1 (M)+. The crude reaction mixture was concentrated purified

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

Procedure: Methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (80 mg, 1 eq), 2-isopropylphenylboronic acid (65 mg, 1.75 eq), and tetrakis(triphenylphosphine)palladium (10 mg, 0.05 eq), in 1.0 M aqueous sodium carbonate (1.0 mL) and acetonitrile (1.0 mL) were heated to 140° C. for 10 min in a sealed microwave reactor. The crude reaction mixture was concentrated and purified using reverse phase HPLC to yield 298 (23 mg). ESI-MS: 363.1 (M)+. The crude reaction mixture was concentrated purified

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

Procedure: A mixed solution of 1 mL of water and 4 mL of dimethoxyethane was added into a flask into which 2-bromo-4-methylanisole (600 mg, 2.98 mmol), 2-isopropylphenylboronic acid (734 mg, 4.47 mmol), palladium acetate (16 mg, 0.074 mmol), triphenylphosphine (72 mg, 0.27 mmol), and potassium phosphate (1.12 g, 5.28 mmol) were already added, and then refluxed at normal temperature for 6 hours. After cooling to normal temperature, an ammonium chloride aqueous solution (5 mL) and 10 mL of diethylether were added thereto to separate an organic layer and extract residues with diethylether. The separated organic layer was dried with magnesium sulfate and volatile materials were removed to produce 850 mg of grey 4-methyl-2-(2′-isopropylphenyl)anisole solid. The anisole thus produced was dissolved in 5 mL of methylene chloride without separate purification, 3 mL of boron tribromide (1 M methylene chloride solution) was dropped thereonto at −78° C., and a reaction was carried out while the temperature slowly increased to normal temperature. After the reaction, a mixed solution of water (5 mL) and diethylether (10 mL) was added to separate an organic layer and extract an aqueous solution layer using diethylether (5 mL×3), and the separated organic layer was dried. Residues from which volatile components were removed at reduced pressure were purified using a silica gel chromatography tube in a mixed solvent of hexane and methylene chloride to produce 633 mg of white 4-methyl-2,6-(2′-isopropylphenyl)phenol solid. were already added refluxed at normal temperature for 6 hours After cooling to normal temperature to separate an organic layer extract residues with diethylether The separated organic layer was dried with magnesium sulfate and volatile materials were removed

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

Procedure: A mixture of 3-acetyl-4-trifluoromethylsulfonyloxy-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 2 above (2.5 g, 7.2 mmol), 2-isopropylbenzeneboronic acid (1.8 g, 11 mmol), potassium carbonate (1.5 g, 11 mmol), and Pd(PPh3)4 (1.7 g, 1.4 mmol) was heated to reflux under inert atmosphere for 3 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography using a gradient elution of 25-75% EtOAc:hexanes to give the title compound (0.72 g; HPLC RT=21.79 min, method B). was heated to reflux under inert atmosphere for 3 h The solvent was removed under reduced pressure the residue was purified by flash column chromatography a gradient elution of 25-75% EtOAc

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

Procedure: A mixture of 3-acetyl-4-trifluoromethylsulfonyloxy-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 2 above (2.5 g, 7.2 mmol), 2-isopropylbenzeneboronic acid (1.8 g, 11 mmol), potassium carbonate (1.5 g, 11 mmol), and Pd(PPh3)4 (1.7 g, 1.4 mmol) was heated to reflux under inert atmosphere for 3 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography using a gradient elution of 25-75% EtOAc:hexanes to give the title compound (0.72 g; HPLC RT=21.79 min, method B). was heated to reflux under inert atmosphere for 3 h The solvent was removed under reduced pressure the residue was purified by flash column chromatography a gradient elution of 25-75% EtOAc

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

Procedure: To a solution of 6-bromo-5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (65 mg, 0.134 mmol) in dioxane (1 mL) was added (2-isopropylphenyl)boronic acid (88 mg, 0.536 mmol), Pd(dppf)Cl2 (10 mg) and aq. 2N K3PO4 (0.2 mL). The mixture was heated at 100° C. for 5 h, cooled to RT and filtered. The filtrate was concentrated and dried to a residue which was purified by chromatography eluted with PE/EA (10:1 to 6:1) to give 5-(1-hydroxy-3-methylbutyl)-6-(2-isopropylphenyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 42.7% yield) as a solid. LCMS: [M+-THP-OH] 423 and TR=2.047 min. cooled to RT filtered The filtrate was concentrated dried to a residue which was purified by chromatography eluted with PE/EA (10:1 to 6:1)

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

Procedure: To a mixture of 6-bromo-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg, 0.093 mmol), Pd(dppf)Cl2 (7 mg, 0.01 mmol) and aq. 2N K3PO4 (0.4 mL) in dioxane (2 mL) was added 2-isopropylphenylboronic acid (30 mg, 0.183 mmol). The reaction was heated at 80° C. for 18 h, cooled to RT and filtered. The filtrate was extracted with EA (2×20 mL). The combined organic layers were washed with water (20 mL) and brine (15 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:1) to give 5-((4-chloro phenyl) (hydroxy)methyl)-6-(2-isopropylphenyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (50 mg, 93% yield) as a white solid. cooled to RT filtered The filtrate was extracted with EA (2×20 mL) The combined organic layers were washed with water (20 mL) and brine (15 mL) dried over Na2SO4 concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:1)