(2S)-3-chloropropane-1,2-diol

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

Procedure: The title compound is prepared in analogy to Example 3 starting from 2-cyclohexyl-6-methoxy-isonicotinic acid, 3-chloro-4,N-dihydroxy-5-methyl-benzamidine and (S)-3-chloro-1,2-propanediol; LC-MS**: tR=1.01 min, [M+H]+=473.95; 1H NMR (CDCl3): δ: 8.08 (s, 1H), 7.94 (s, 1H), 7.48 (s, 1H), 7.30 (s, 1H), 4.18 (m, 1H), 4.10-4.14 (m, 2H), 4.03 (s, 3H), 3.84-3.95 (m, 2H), 2.84 (s br, 1H), 2.69-2.80 (m, 1H), 2.45 (s, 3H), 1.99-2.13 (m, 2H), 1.86-1.96 (m, 2H), 1.76-1.84 (m, 1H), 1.15-1.68 (m, 6H).

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

Procedure: The title compound is prepared in analogy to Example 3 starting from 2-cyclohexyl-6-methoxy-isonicotinic acid, 3-chloro-4,N-dihydroxy-5-methyl-benzamidine and (S)-3-chloro-1,2-propanediol; LC-MS**: tR=1.01 min, [M+H]+=473.95; 1H NMR (CDCl3): δ: 8.08 (s, 1H), 7.94 (s, 1H), 7.48 (s, 1H), 7.30 (s, 1H), 4.18 (m, 1H), 4.10-4.14 (m, 2H), 4.03 (s, 3H), 3.84-3.95 (m, 2H), 2.84 (s br, 1H), 2.69-2.80 (m, 1H), 2.45 (s, 3H), 1.99-2.13 (m, 2H), 1.86-1.96 (m, 2H), 1.76-1.84 (m, 1H), 1.15-1.68 (m, 6H).

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,3,4]oxadiazol-2-yl]-2-ethyl-6-methyl-phenol (100 mg, 264 μmol) and (S)-3-chloro-propane-1,2-diol (244 mg, 2.64 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1 mL) is stirred at 70° C. for 48 h. The mixture is diluted with EA (50 mL), washed with 1 M aq. NaOH solution (20 mL) followed by brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (86 mg) as a white solid; LC-MS**: tR=0.83 min, [M+H]+=454.12; 1H NMR (CDCl3): δ1.33 (t, J=7.5 Hz, 3H), 1.65-1.80 (m, 2H), 1.83-1.96 (m, 4H), 2.05-2.15 (m, 2H), 2.42 (s, 3H), 2.78 (q, J=7.3 Hz, 2H), 3.19-3.30 (m, 1H), 3.82-3.99 (m, 4H), 4.02 (s, 3H), 4.15-4.23 (m, 1H), 7.22 (s, 1H), 7.48 (s, 1H), 7.84 (s, 1H), 7.86 (s, 1H). washed with 1 M aq. NaOH solution (20 mL) dried over MgSO4 filtered concentrated The crude product is purified by prep

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,3,4]oxadiazol-2-yl]-2-ethyl-6-methyl-phenol (100 mg, 264 μmol) and (S)-3-chloro-propane-1,2-diol (244 mg, 2.64 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1 mL) is stirred at 70° C. for 48 h. The mixture is diluted with EA (50 mL), washed with 1 M aq. NaOH solution (20 mL) followed by brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (86 mg) as a white solid; LC-MS**: tR=0.83 min, [M+H]+=454.12; 1H NMR (CDCl3): δ1.33 (t, J=7.5 Hz, 3H), 1.65-1.80 (m, 2H), 1.83-1.96 (m, 4H), 2.05-2.15 (m, 2H), 2.42 (s, 3H), 2.78 (q, J=7.3 Hz, 2H), 3.19-3.30 (m, 1H), 3.82-3.99 (m, 4H), 4.02 (s, 3H), 4.15-4.23 (m, 1H), 7.22 (s, 1H), 7.48 (s, 1H), 7.84 (s, 1H), 7.86 (s, 1H). washed with 1 M aq. NaOH solution (20 mL) dried over MgSO4 filtered concentrated The crude product is purified by prep

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-[3-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-2-ethyl-6-methyl-phenol (150 mg, 395 μmol) and (S)-3-chloro-propane-1,2-diol (366 mg, 3.31 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1 mL) is stirred at 70° C. for 48 h. The mixture is diluted with EA (50 mL), washed with 1 M aq. NaOH solution (20 mL) followed by brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (95 mg) as a pale brown oil; LC-MS**: tR=0.88 min, [M+H]+=454.08; 1H NMR (CDCl3): δ1.34 (t, J=7.0 Hz, 3H), 1.67-1.79 (m, 2H), 1.82-1.96 (m, 4H), 2.04-2.15 (m, 2H), 2.43 (s, 3H), 2.79 (q, J=7.0 Hz, 2H), 3.18-3.29 (m, 1H), 3.81-3.99 (m, 4H), 4.01 (s, 3H), 4.15-4.22 (m, 1H), 7.30 (s, 1H), 7.49 (s, 1H), 7.93 (s, 1H), 7.94 (s, 1H). washed with 1 M aq. NaOH solution (20 mL) dried over MgSO4 filtered concentrated The crude product is purified by prep

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-[3-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-2-ethyl-6-methyl-phenol (150 mg, 395 μmol) and (S)-3-chloro-propane-1,2-diol (366 mg, 3.31 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1 mL) is stirred at 70° C. for 48 h. The mixture is diluted with EA (50 mL), washed with 1 M aq. NaOH solution (20 mL) followed by brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (95 mg) as a pale brown oil; LC-MS**: tR=0.88 min, [M+H]+=454.08; 1H NMR (CDCl3): δ1.34 (t, J=7.0 Hz, 3H), 1.67-1.79 (m, 2H), 1.82-1.96 (m, 4H), 2.04-2.15 (m, 2H), 2.43 (s, 3H), 2.79 (q, J=7.0 Hz, 2H), 3.18-3.29 (m, 1H), 3.81-3.99 (m, 4H), 4.01 (s, 3H), 4.15-4.22 (m, 1H), 7.30 (s, 1H), 7.49 (s, 1H), 7.93 (s, 1H), 7.94 (s, 1H). washed with 1 M aq. NaOH solution (20 mL) dried over MgSO4 filtered concentrated The crude product is purified by prep

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

Procedure: The title compound is prepared in analogy to Example 3 starting from 2-cyclohexyl-6-methoxy-isonicotinic acid, 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine and (S)-3-chloro-1,2-propanediol; LC-MS: tR=1.16 min, [M+H]+=468.08; 1H NMR (CDCl3): δ1.33 (t, J=7.5 Hz, 3H), 1.34-1.40 (m, 1H), 1.40-1.52 (m, 2H), 1.57-1.69 (m, 2H), 1.77-1.84 (m, 1H), 1.87-1.95 (m, 2H), 1.99-2.08 (m, 2H), 2.41 (s, 3H), 2.70-2.81 (m, 3H), 3.83-4.00 (m, 4H), 4.03 (s, 3H), 4.15-4.21 (m, 1H), 7.32 (s, 1H), 7.49 (s, 1H), 7.88 (s, 1H), 7.90 (s, 1H).

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

Procedure: The title compound is prepared in analogy to Example 3 starting from 2-cyclohexyl-6-methoxy-isonicotinic acid, 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine and (S)-3-chloro-1,2-propanediol; LC-MS: tR=1.16 min, [M+H]+=468.08; 1H NMR (CDCl3): δ1.33 (t, J=7.5 Hz, 3H), 1.34-1.40 (m, 1H), 1.40-1.52 (m, 2H), 1.57-1.69 (m, 2H), 1.77-1.84 (m, 1H), 1.87-1.95 (m, 2H), 1.99-2.08 (m, 2H), 2.41 (s, 3H), 2.70-2.81 (m, 3H), 3.83-4.00 (m, 4H), 4.03 (s, 3H), 4.15-4.21 (m, 1H), 7.32 (s, 1H), 7.49 (s, 1H), 7.88 (s, 1H), 7.90 (s, 1H).

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(4-phenyl-5-propyl-thiophen-2-yl)-propan-1-one (47 mg, 125 μmol) in isopropanol (2 mL) and 3 N aq. NaOH (0.5 mL) is treated with (S)-3-chloro-propane-1,2-diol (55 mg, 0.50 mmol) and the mixture is stirred at 70° C. for 14 h. Another portion of (S)-3-chloro-propane-1,2-diol (55 mg, 0.50 mmol) is added and stirring is continued at 70° C. for 24 h. The solvent is removed in vacuo and the residue is separated on prep. TLC plates with heptane:EA 2:1 to give 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(4-phenyl-5-propyl-thiophen-2-yl)-propan-1-one (15 mg) as a colourless resin; LC-MS: tR=1.05 min, [M+1]+=453.18. stirring is continued at 70° C. for 24 h The solvent is removed in vacuo the residue is separated on prep

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-(5-ethyl-4-p-tolyl-thiophen-2-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one (47 mg, 0.125 mmol) in ethanol (2 mL) and 3 N aq. NaOH (0.5 mL) is treated with (S)-3-chloro-propane-1,2-diol (90 μL) and the mixture is stirred at 60° C. for 20 h. Another portion of (S)-3-chloro-propane-1,2-diol (60 μL) is added and stirring is continued at 60° C. for 5 days. The reaction mixture is diluted with water and extracted with DCM. The solvent of the organic extract is evaporated and the crude product is purified on prep. TLC plates with heptane:EA 2:1 to give 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(5-ethyl-4-p-tolyl-thiophen-2-yl)-propan-1-one (6 mg) as a colourless resin; LC-MS: tR=1.05 min, [M+1]+=453.25; 1H NMR (CDCl3): δ 7.56 (s, 1H), 7.30-7.21 (m, 4H), 6.88 (s, 2H), 4.11-4.05 (m, 1H), 3.87-3.80 (m, 4H), 3.18-3.11 (m, 2H), 2.98-2.85 (m, 4H), 2.39 (s, 3H), 2.25 (s, 6H), 1.29 (t, J=7.6 Hz, 3H). stirring is continued at 60° C. for 5 days extracted with DCM The solvent of the organic extract is evaporated the crude product is purified on prep

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-(5-ethyl-4-p-tolyl-thiophen-2-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one (18 mg, 48 μmol) in ethanol (1.5 mL) and 3 N aq. NaOH (0.3 mL) is treated with (S)-3-chloro-propane-1,2-diol (30 μL) and the mixture is stirred at 60° C. for 14 h. The solvent is removed in vacuo and the residue is separated on prep. TLC plates with heptane:EA 2:1 to give 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(5-ethyl-4-o-tolyl-thiophen-2-yl)-propan-1-one (4 mg) as a colourless resin; LC-MS: tR=1.04 min, [M+1]+=453.28; 1H NMR (CDCl3): δ 7.45 (s, 1H), 7.92-7.08 (m, 4H), 6.87 (s, 2H), 4.11-4.04 (m, 1H), 3.87-3.80 (m, 4H), 3.16-3.10 (m, 2H), 2.97-2.90 (m, 2H), 2.64 (q, J=7.6 Hz, 2H), 2.24 (s, 3H), 2.17 (s, 6H), 1.20 (t, J=7.6 Hz, 3H). The solvent is removed in vacuo the residue is separated on prep

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (52 mg, 0.143 mmol) in 2-propanol (1 mL) and 3 N aq. NaOH (0.3 mL) is treated with (S)-3-chloro-propane-1,2-diol (79 mg, 0.71 mmol) and the mixture is stirred at 70° C. for 15 h. The reaction mixture is diluted with water and extracted with DCM. The solvent of the organic extract is evaporated and the crude product is purified on prep. TLC plates with heptane:EA 1:3 to give 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (14 mg) as a colourless resin; LC-MS: tR=1.03 min, [M+1]+=439.25; 1H NMR (CDCl3): δ 7.58 (s, 1H), 7.45-7.30 (m, 5H), 6.88 (s, 2H), 4.11-4.04 (m, 1H), 3.87-3.80 (m, 4H), 3.67-3.60 (m, 2H), 3.60-3.56 (m, 1H), 3.48-3.40 (m, 1H), 3.20-3.10 (m, 2H), 2.98-2.87 (m, 4H), 2.25 (s, 6H), 1.30 (t, J=7.6 Hz, 3H). extracted with DCM The solvent of the organic extract is evaporated the crude product is purified on prep