2-(4-chlorophenyl)ethanol

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:

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:

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

Procedure: (3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethyl-carbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (30 mg) was dissolved in DCM and 2(4-chloro-phenyl)-ethanol (5 equiv), triphenyl phosphine (5 eq.) and DIAD (4.5 eq.) added. The reaction mixture stirred at room temperature and was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH). The resulting compound was dissolved in 2 mL DCM and 1 mL 4N HCl (dioxane) was added. The mixture was stirred at room temperature for 1.5 hours and was concentrated. The residue was suspended in DCM, and TEA (3 eq.) was added to the mixture used in the following reaction sequence. ((R)-1-isocyanato-ethyl)-benzene (5 eq.) was added and reaction stirred at room temperature for 1 hour. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 866. was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH) The resulting compound was dissolved in 2 mL DCM 1 mL 4N HCl (dioxane) was added The mixture was stirred at room temperature for 1.5 hours was concentrated used in the following reaction sequence reaction stirred at room temperature for 1 hour The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH)

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

Procedure: (3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (30 mg) was dissolved in DCM and 2(4-chloro-phenyl)-ethanol (5 equiv), triphenyl phosphine (5 eq.) and DIAD (4.5 eq.) added. The reaction mixture stirred at room temperature and was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH). The resulting compound was dissolved in 2 mL DCM and 1 mL 4N HCl (dioxane) added. The mixture stirred at room temperature for 1.5 hours and was concentrated. The residue was suspended in DCM, TEA (3 eq.) added the mixture used in the following reaction sequence. In a separate vial EDC (3 eq.) and 2,5-dimethyl-oxazole-4-carboxylic acid (6 eq.) were dissolved in DCM and stirred 40 minutes. This solution was added to the above mixture stirred 12 hours. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 842. was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH) The resulting compound was dissolved in 2 mL DCM 1 mL 4N HCl (dioxane) added The mixture stirred at room temperature for 1.5 hours was concentrated used in the following reaction sequence stirred 40 minutes This solution was added to the above mixture stirred 12 hours The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH)

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

Procedure: 4-chlorophenethyl alcohol (0.11 g, 0.67 mmol) and triethylamine (0.37 mL, 2.68 mmol) were dissolved in CH2Cl2 (5 mL) at 0° C. Then it was treated with methanesulfonyl chloride (0.207 mL, 2.68 mmol), with stirring and warming to ambient temperature, until the indicated loss of starting material. The reaction mixture was concentrated in vacuo, then dissolved in DMF (1 mL) and added to a mixture of 2-hydroxy-4-imidazol-1-ylmethyl-benzonitrile (0.10 g, 0.50 mmol) and cesium carbonate (0.33 g, 1.0 mmol) in DMF (2 mL). The reaction mixture was heated at 30° C. for 18 h, then partitioned between EtOAc and H2O, the aqueous layer washed with EtOAc, the organic layers combined, washed with brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound after silica gel chromatography (0.1 to 0.2% CH3OH/NH4OH in CH2Cl2) and conversion to the hydrochloride salt. The reaction mixture was concentrated in vacuo dissolved in DMF (1 mL) The reaction mixture was heated at 30° C. for 18 h partitioned between EtOAc and H2O the aqueous layer washed with EtOAc washed with brine dried (Na2SO4) Filtration and concentration to dryness

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

Procedure: 2.40 g (15.2 mmol) of 2-(4-chlorophenyl)ethanol were added dropwise at 40° C. to a suspension of 680 mg (22.7 mmol) of sodium hydride (80% suspension in oil) in 40 ml of dry tetrahydrofuran, and the mixture was stirred until the evolution of hydrogen had ceased. The mixture was then allowed to cool to room temperature, whereupon 2.7 g (15.2 mmol) of 4,6-dichloro-5-methoxypyrimidine (Monatshefte Chem. 96, 1661 (1965) were added in portions. The mixture was stirred for 1 hour at room temperature and for 4 hours at 40° C. For work-up, the reaction mixture was poured into saturated ammonium chloride solution and extracted with diethyl ether. The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel using n-heptane/ethyl acetate (4:1). 4.0 g (88% of theory) of 4-[2-(4-chlorophenyl)ethoxy]-5-methoxy-6-chloropyrimidine was obtained in the form of a viscous oil which crystallized slowly upon drying (melting point 70°-71° C.). 96, 1661 (1965) were added in portions extracted with diethyl ether The combined organic phase was dried over magnesium sulfate concentrated in vacuo The residue was chromatographed on silica gel