(2S)-3-bromo-2-methylpropan-1-ol

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

Procedure: The starting material, 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropyloxy)-(R)-2-methylpropane-1-methanesulfonate, was prepared as follows: (S)-2-methyl-3-bromopropanol was alkylated with benzyl bromide to produce (S)-2-methyl-3-bromo-1-benzyloxypropane, which was then combined with 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropanol, followed by hydrogenation with 10% Pd/C to remove the benzyl protecting group. The title compound was prepared by combining 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (0.7 g, 2.58 mmol) and 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropyloxy)-(R)-2-methylpropane-1-methanesulfonate (1.7 g, 2.58 mmol) essentially as described in Example 8 of International Patent Publication No. WO 96/33251. The resulting crude product was further purified by chromatography, eluting with 10:1 hexanes/ethyl acetate, and was recrystallized from heptane, followed by Kugelrohr distillation (b.p. 180-190° C. at 0.02 torr; yield 1.28 g).

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

Procedure: The starting material, 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropyloxy)-(R)-2-methylpropane-1-methanesulfonate, was prepared as follows: (S)-2-methyl-3-bromopropanol was alkylated with benzyl bromide to produce (S)-2-methyl-3-bromo-1-benzyloxypropane, which was then combined with 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropanol, followed by hydrogenation with 10% Pd/C to remove the benzyl protecting group. The title compound was prepared by combining 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (0.7 g, 2.58 mmol) and 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropyloxy)-(R)-2-methylpropane-1-methanesulfonate (1.7 g, 2.58 mmol) essentially as described in Example 8 of International Patent Publication No. WO 96/33251. The resulting crude product was further purified by chromatography eluting with 10:1 hexanes/ethyl acetate, and was recrystallized from heptane, followed by Kugelrohr distillation (b.p. 180-190° C. at 0.02 torr; yield 1.28 g).

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

Procedure: (S)-3-Bromo-2-methyl-1-propanol (150 mg), 4-bromo-3,5-dimethylphenol (98.5 mg) and potassium carbonate are stirred in 5 mL of acetonitrile at 80° C. for 4 h. The reaction mixture is cooled to room temperature, water is added and the reaction mixture is extracted with diethyl ether. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum to give a solid, used in the next step without further purification. Yield: 130 mg. the reaction mixture is extracted with diethyl ether The organic phase is separated dried over sodium sulfate concentrated under vacuum to give a solid used in the next step without further purification

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

Procedure: A 25 mL flask was charged with 4H-benzo[1,4]oxazin-3-one (0.100 g, 0.670 mmol), (S)-3-bromo-2-methylpropanol (0.103 g, 0.670 mmol) and cesium carbonate (0.208 g, 0.670 mmol) in MeCN (10 mL) and stirred at 40° C. for 2 days. The reaction mixture was quenched with water (5 mL), and the product extracted into EtOAc (2×10 mL). The combined organic layers were dried (Na2SO4) and evaporated to give the crude title compound (108LM40-37) (0.219 g). The reaction mixture was quenched with water (5 mL) the product extracted into EtOAc (2×10 mL) The combined organic layers were dried (Na2SO4) evaporated

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

Procedure: A 25 mL flask was charged with 4H-benzo[1,4]oxazin-3-one (0.100 g, 0.670 mmol), (S)-3-bromo-2-methylpropanol (0.103 g, 0.670 mmol) and cesium carbonate (0.208 g, 0.670 mmol) in MeCN (10 mL) and stirred at 40° C. for 2 days. The reaction mixture was quenched with water (5 mL), and the product extracted into EtOAc (2×10 mL). The combined organic layers were dried (Na2SO4) and evaporated to give the crude title compound (108LM40-37) (0.219 g). The reaction mixture was quenched with water (5 mL) the product extracted into EtOAc (2×10 mL) The combined organic layers were dried (Na2SO4) evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of (3-hydroxy-phenyl)-acetic acid methyl ester (0.75 g, 0.0045 mole) in anhydrous toluene (30 mL) was added (S)-(+)-3-bromo-2-methyl-1-propanol (0.90 g, 0.0059 mole). Polymer bound triphenylphosphine (2.4 g, 0.0072 mole, 3 mmol/g, Fluka Chemie) was then added, and the mixture was stirred for 15 minutes. The reaction mixture was then cooled to 0° C. and diisopropylazodicarboxylate (1.1 g, 0.00560 mole) was added In a dropwise fashion. After stirring at room temperature overnight, the crude reaction mixture was filtered, and the solid washed with toluene. After concentration of the filtrate in vacuo, the crude product was purified by column chromatography over silica gel (silica gel 60, EM Science) using 15% EtOAc:hexane as eluent to afford 0.86 g (63% yield) of the title compound as an oil: MS (ESI) 303.0 (M+2H+). was then added After stirring at room temperature overnight the crude reaction mixture was filtered the solid washed with toluene After concentration of the filtrate in vacuo, the crude product was purified by column chromatography over silica gel (silica gel 60, EM Science)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of (3-hydroxy-phenyl)-acetic acid methyl ester (0.75 g, 0.0045 mole) in anhydrous toluene (30 mL) was added (S)-(+)-3-bromo-2-methyl-1-propanol (0.90 g, 0.0059 mole). Polymer bound triphenylphosphine (2.4 g, 0.0072 mole, 3 mmol/g, Fluka Chemie) was then added, and the mixture was stirred for 15 minutes. The reaction mixture was then cooled to 0° C. and diisopropylazodicarboxylate (1.1 g, 0.00560 mole) was added In a dropwise fashion. After stirring at room temperature overnight, the crude reaction mixture was filtered, and the solid washed with toluene. After concentration of the filtrate in vacuo, the crude product was purified by column chromatography over silica gel (silica gel 60, EM Science) using 15% EtOAc:hexane as eluent to afford 0.86 g (63% yield) of the title compound as an oil: MS (ESI) 303.0 (M+2H+). was then added After stirring at room temperature overnight the crude reaction mixture was filtered the solid washed with toluene After concentration of the filtrate in vacuo, the crude product was purified by column chromatography over silica gel (silica gel 60, EM Science)

Conditions: temp:72.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-3-Bromo-2-methylpropan-1-ol (6.2 g, 40 mmol) was dissolved in dry CH3CN (100 mL) and dry, pulverized K2CO3 (10.4 g, 75 mmol) was introduced followed by 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (11.0 g, 50 mmol). The reaction mixture was heated at 72° C. for 20 h, cooled and filtered. The filtrate was evaporated to an oil, which was applied to a column of silica gel. Elution initially with hexanes, gradually increasing polarity to a mixture of hexanes/ethyl acetate (3:2) as eluent, provided the title compound (7.56 g, 64%) as an oil. dry was introduced cooled filtered The filtrate was evaporated to an oil, which Elution initially with hexanes gradually increasing polarity to a mixture of hexanes/ethyl acetate (3:2) as eluent

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

Procedure: A suspension of 2-[3-(3-chlorophenyl)-7-hydroxy-1-oxo-1H-isoquinolin-2-yl]-N-isopropylacetamide (INTERMEDIATE III.7) (347 mg, 0.936 mmol), K2CO3 (674 mg, 4.68 mmol) and (S)-(+)-3-bromo-2-methyl-1-propanol (0.48 mL, 4.7 mmol) in dry acetonitrile (5 mL) was stirred for 18 h at 80° C. The resultant mixture was poured into H2O (20 mL), cooled to 0° C. and filtered. The precipitate was washed with cold H2O and dried in vacuo to furnish 2-[3-(3-chlorophenyl)-7-((S)-3-hydroxy-2-methylpropoxy)-1-oxo-1H-isoquinolin-2-yl]-N-isopropylacetamide (382 mg, 0.862 mmol, 92%) as white solid. cooled to 0° C. filtered The precipitate was washed with cold H2O dried in vacuo

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

Procedure: 2-bromo-3-pyridinol (230 mg) and potassium carbonate (216 mg) was dissolved in methylethylketone (10 ml) and reacted for 30 minutes. Then, (S)-3-bromo-2-methyl-1-propanol (0.21 ml) was added to the solution and refluxed for 3 hours at 100° C. Potassium carbonate was filtered out and separated by flash chromatography under a silica gel phase (ethyl acetate:normal hexane=1:1). As a result, (S)-3-(2-bromopyridine-3-yloxy)-2-methyl-1-propanol (260 mg, yield: 80%) was obtained. reacted for 30 minutes Potassium carbonate was filtered out separated by flash chromatography under a silica gel phase (ethyl acetate:normal hexane=1:1)

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

Procedure: The starting material, 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropyloxy)-(R)-2-methylpropane-1-methanesulfonate, was prepared as follows: (S)-2-methyl-3-bromopropanol was alkylated with benzyl bromide to produce (S)-2-methyl-3-bromo-1-benzyloxypropane, which was then combined with 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropanol, followed by hydrogenation with 10% Pd/C to remove the benzyl protecting group. The title compound was prepared by combining 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (0.7 g, 2.58 mmol) and 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropyloxy)-(R)-2-methylpropane-1-methanesulfonate (1.7 g, 2.58 mmol) essentially as described in Example 8 of International Patent Publication No. WO 96/33251. The resulting crude product was further purified by chromatography, eluting with 10:1 hexanes/ethyl acetate, and was recrystallized from heptane, followed by Kugelrohr distillation (b.p. 180-190° C. at 0.02 torr; yield 1.28 g).

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

Procedure: The starting material, 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropyloxy)-(R)-2-methylpropane-1-methanesulfonate, was prepared as follows: (S)-2-methyl-3-bromopropanol was alkylated with benzyl bromide to produce (S)-2-methyl-3-bromo-1-benzyloxypropane, which was then combined with 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropanol, followed by hydrogenation with 10% Pd/C to remove the benzyl protecting group. The title compound was prepared by combining 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (0.7 g, 2.58 mmol) and 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy))-(R)-2-fluoropropyloxy)-(R)-2-methylpropane-1-methanesulfonate (1.7 g, 2.58 mmol) essentially as described in Example 8 of International Patent Publication No. WO 96/33251. The resulting crude product was further purified by chromatography eluting with 10:1 hexanes/ethyl acetate, and was recrystallized from heptane, followed by Kugelrohr distillation (b.p. 180-190° C. at 0.02 torr; yield 1.28 g).