2-(4-methylphenyl)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:; See reaction.notes.procedure_details.

Procedure: The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (275 mg, 1.09 mmol) prepared in Example 1 (1a) and 2-(4-methylphenyl)ethanol (159 μL, 1.14 mmol) to give 306 mg of the title compound (colorless crystalline solid, yield: 90%).

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

Procedure: (17.9 g) as a colourless oil, from 4-methylbenzeneethanol (10.0 g) and 1,5-dibromopentane (50.7 g) with stirring at room temperature for 72 h. T.l.c. (ER-CX 1:19) Rf 0.29.

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

Procedure: 2-(4-Methylphenyl)ethyl alcohol (VIII) (2.72 g, 0.02 mole), 4-nitrochlorobenzene (IX: X=Cl) (3.15 g, 0.02 mole) and potassium hydroxide (1.4 g, 0.025 mole) were added to benzene (60 ml), and dicyclohexyl-18-crown-6 (0.2 g) was added thereto, followed by reaction at 60° C. for 10 hours. The reaction mixture was washed with water and concentrated, and the precipitated crystals were recrystallized from 95% ethanol to obtain 4.5 g of 4-[2-(4-methylphenyl)ethoxy]-nitrobenzene (VI) as white crystals (yield, 87.5%). was added followed by reaction at 60° C. for 10 hours The reaction mixture was washed with water concentrated the precipitated crystals were recrystallized from 95% ethanol to obtain

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 65% sodium hydride (1.1 g, 0.03 mole) in dimethylsulfoxide (30 ml) were added 2-(4-methylphenyl)ethyl alcohol (VIII) (2.72 g, 0.02 mole) and 4-nitrochlorobenzene (IX: X=Cl) (3.15 g, 0.02 mole). After heating to 30° C. for 5 hours with stirring, the reaction mixture was treated in the same manner as in Example 12 to obtain 4.6 g of 4-[2-(4-methylphenyl)ethoxy]nitrobenzene (VI) as white crystals (yield, 89.5%). the reaction mixture was treated in the same manner as in Example 12 to obtain

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 65% sodium hydride (1.1 g, 0.03 mole) in dimethylsulfoxide (30 ml) were added 2-(4-methylphenyl)ethyl alcohol (VIII) (2.72 g, 0.02 mole) and 4-nitrochlorobenzene (IX: X=Cl) (3.15 g, 0.02 mole). After heating to 30° C. for 5 hours with stirring, the reaction mixture was treated in the same manner as in Example 12 to obtain 4.6 g of 4-[2-(4-methylphenyl)ethoxy]nitrobenzene (VI) as white crystals (yield, 89.5%). the reaction mixture was treated in the same manner as in Example 12 to obtain

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

Procedure: A mixture of 2-(4-methylphenyl)ethyl alcohol (VIII) (13.6 g, 0.1 mole), 4-nitrochlorobenzene (IX: X=Cl) (15.8 g, 0.1 mole), toluene (92 g), tetra-n-butylammonium bromide (3.2 g, 0.01 mole) and a 50% aqueous sodium hydroxide solution (24 g) was stirred vigorously at 50° to 60° C. for 5 hours. The organic layer was separated, washed with water two times and then concentrated in vacuo. By recrystallizing the crude product from 95% ethanol, 20.6 g (yield, 80%) of 4-[2-(4-methylphenyl)ethoxy]nitrobenzene (VI) were obtained as white crystals. The organic layer was separated washed with water two times concentrated in vacuo By recrystallizing the crude product from 95% ethanol

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

Procedure: To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (20 mg, 0.043 mmol), 2-(p-tolyl)ethanol (29.1 mg, 0.213 mmol) and Ph3P-resin (55.8 mg, 0.213 mmol) in THF (2 mL) was added DEAD (0.014 mL, 0.085 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-(4-methylphenethoxy)phenyl)pyridin-3-yl)acetic acid (7.3 mg, 0.013 mmol, 30.6% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.17 (d, J=7.7 Hz, 3H), 7.09 (d, J=8.1 Hz, 2H), 7.02-6.93 (m, 3H), 5.80 (br. s., 1H), 4.25-4.13 (m, 2H), 2.96 (t, J=6.2 Hz, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.03 (s, 3H), 1.21 (br. s., 2H), 1.09 (s, 9H), 0.77 (s., 3H), 0.62 (s., 3H). 6H of piperidine were not resolved. LCMS (M+H)=559.15. mixture was filtered to remove polymer concentrated Mixture was then cooled purified by prep-HPLC