(2S)-1-amino-3-phenoxypropan-2-ol

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

Procedure: To a solution of 1-(4-nitro-benzyl)-5-(2-oxo-propyl)-1H-indole-2-carboxylic acid benzyl ester (540 mg, 1.22 mmol) and 1-amino-3-phenoxypropan-2(S)-ol (245 mg, 1.46 mmol) in dichloroethane (20 ml) was added powdered sodium sulfate (1.73 g, 12.2 mmol), and the mixture was stirred for about one hour at room temperature under nitrogen. Acetic acid (87.9 mg, 0.084 ml, 1.46 mmol) and sodium triacetoxyborohydride (388 mg, 1.83 mmol) were added. After about 6 hours, additional sodium triacetoxyborohydride (194 mg, 0.915 mmol), acetic acid (0.2 ml, 3.5 mmol) and 1-amino-3-phenoxypropan-2(S)-ol (122 mg, 0.73 mmol) were added, and the mixture was stirred for about two days at room temperature under nitrogen. The reaction was then diluted with methylene chloride, washed with dilute sodium bicarbonate and brine, dried over sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was flash chromatographed on silica (55 g), eluting with 5% methanol/methylene chloride, to give the title compound (500 mg) as a mixture of diastereomers. After about 6 hours the mixture was stirred for about two days at room temperature under nitrogen washed with dilute sodium bicarbonate and brine dried over sodium sulfate filtered the solvent was removed in vacuo chromatographed on silica (55 g) eluting with 5% methanol/methylene chloride

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

Procedure: The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.65 (m, 2H), 1.95-2.10 (m, 2H), 2.06 (s, 3H), 2.50-3.20 (m, 5H), 3.55-3.75 (m, 2H), 3.96 (d, J=5.2 Hz, 2H), 4.15-4.25 (m, 1H), 5.70 (brs, 1H), 6.80 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.90-7.00 (m, 3H), 7.25-7.35 (m, 2H), 7.59 (d, J=9.0 Hz, 2H), 7.69 (d, J=9.0 Hz, 2H), 9.70 (s, 1H), 10.37 (s, 1H); MS (ES) m/z: 539.1 (MH+); HRMS Calcd. for C28H35N4O5S(MH+): 539.2328. Found: 539.2357.

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

Procedure: The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.65 (m, 2H), 1.95-2.10 (m, 2H), 2.06 (s, 3H), 2.50-3.20 (m, 5H), 3.55-3.75 (m, 2H), 3.96 (d, J=5.2 Hz, 2H), 4.15-4.25 (m, 1H), 5.70 (brs, 1H), 6.80 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.90-7.00 (m, 3H), 7.25-7.35 (m, 2H), 7.59 (d, J=9.0 Hz, 2H), 7.69 (d, J=9.0 Hz, 2H), 9.70 (s, 1H), 10.37 (s, 1H); MS (ES) m/z: 539.1 (MH+); HRMS Calcd. for C28H35N4O5S(MH+): 539.2328. Found: 539.2357.

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

Procedure: The title compound was prepared from 5-[4-(4-oxo-piperidine-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 36) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) according to the procedure of Example 73 as a pale yellowish solid; mp 208-210° C.; MS (ES) m/z: 454.0 (MH+); HRMS Calcd. for C24H27N3O4S (M+): 453.1723. Found: 453.1710.

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

Procedure: 5-[4-(4-Oxo-piperidine-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) (0.15 g, 0.5 mmol) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) (0.12 g, 0.75 mmol) were mixed in N,N-dimethylformamide (15 mL) and then treated with sodium triacetoxyborohydride (0.16 g, 0.75 mmol) and acetic acid (0.045 g, 0.75 mmol). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was quenched with 1N NaOH and then poured into a saturated aqueous NaHCO3. The aqueous solution was extracted with 1-butanol and the combined organic layers were concentrated. The residue was purified by preparative thin layer chromatography (10% MeOH/CH2CH2) to give the title compound as a pale yellowish solid; mp 218-220° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.30-1.60 (m, 2H), 1.80-2.00 (m, 2H), 2.50-3.00 (m, 5H), 3.00-3.50 (m, 3H), 3.50-3.70 (m, 2H), 3.85-4.00 (m, 3H), 4.48 (dd, J=9.8, 3.8 Hz, 1H), 6.85 (d, J=8.6 Hz, 2H), 6.90-6.97 (m, 3H), 7.04 (d, J=8.6 Hz, 2H), 7.25-7.38 (m, 3H); MS (ES) m/z: 456.0 (MH+); HRMS Calcd. for C24H29N3O4S(M+): 455.1878. Found: 455.1880. was quenched with 1N NaOH poured into a saturated aqueous NaHCO3 The aqueous solution was extracted with 1-butanol the combined organic layers were concentrated The residue was purified by preparative thin layer chromatography (10% MeOH/CH2CH2)

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

Procedure: 5-[4-(4-Oxo-piperidine-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) (0.15 g, 0.5 mmol) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) (0.12 g, 0.75 mmol) were mixed in N,N-dimethylformamide (15 mL) and then treated with sodium triacetoxyborohydride (0.16 g, 0.75 mmol) and acetic acid (0.045 g, 0.75 mmol). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was quenched with 1N NaOH and then poured into a saturated aqueous NaHCO3. The aqueous solution was extracted with 1-butanol and the combined organic layers were concentrated. The residue was purified by preparative thin layer chromatography (10% MeOH/CH2CH2) to give the title compound as a pale yellowish solid; mp 218-220° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.30-1.60 (m, 2H), 1.80-2.00 (m, 2H), 2.50-3.00 (m, 5H), 3.00-3.50 (m, 3H), 3.50-3.70 (m, 2H), 3.85-4.00 (m, 3H), 4.48 (dd, J=9.8, 3.8 Hz, 1H), 6.85 (d, J=8.6 Hz, 2H), 6.90-6.97 (m, 3H), 7.04 (d, J=8.6 Hz, 2H), 7.25-7.38 (m, 3H); MS (ES) m/z: 456.0 (MH+); HRMS Calcd. for C24H29N3O4S(M+): 455.1878. Found: 455.1880. was quenched with 1N NaOH poured into a saturated aqueous NaHCO3 The aqueous solution was extracted with 1-butanol the combined organic layers were concentrated The residue was purified by preparative thin layer chromatography (10% MeOH/CH2CH2)

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

Procedure: 1-[4-(4-Oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidine-4-one (which was obtained in Example 34) (0.16 g, 0.5 mmol) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) (0.12 g, 0.75 mmol) were mixed in 1,2-dichloroethane (10 mL) and then treated with sodium triacetoxyborohydride (0.16 g, 0.75 mmol) and acetic acid (0.045 g, 0.75 mmol). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was quenched with 1N sodium hydroxide (NaOH) and then poured into a saturated aqueous sodium bicarbonate (NaHCO3). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried and concentrated. The residue was purified by preparative thin layer chromatography (16% MeOH/CH2CH2) to give the title compound as a pale yellowish solid; mp >220° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.50-1.70 (m, 2H), 1.90-2.10 (m, 2H), 2.60-3.40 (m, 7H), 3.90-4.20 (m, 3H), 6.70-7.15 (m, 6H), 7.30 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H); MS (ES) m/z: 470.0 (MH+); HRMS Calcd. for C24H27N3O3S2 (M+): 469.1494. Found: 469.1488. was quenched with 1N sodium hydroxide (NaOH) poured into a saturated aqueous sodium bicarbonate (NaHCO3) The aqueous layer was extracted with dichloromethane the combined organic layers were dried concentrated The residue was purified by preparative thin layer chromatography (16% MeOH/CH2CH2)

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

Procedure: To a solution of 1-(4-nitro-benzyl)-5-(2-oxo-propyl)-1H-indole-2-carboxylic acid benzyl ester (540 mg, 1.22 mmol) and 1-amino-3-phenoxypropan-2(S)-ol (245 mg, 1.46 mmol) in dichloroethane (20 ml) was added powdered sodium sulfate (1.73 g, 12.2 mmol), and the mixture was stirred for about one hour at room temperature under nitrogen. Acetic acid (87.9 mg, 0.084 ml, 1.46 mmol) and sodium triacetoxyborohydride (388 mg, 1.83 mmol) were added. After about 6 hours, additional sodium triacetoxyborohydride (194 mg, 0.915 mmol), acetic acid (0.2 ml, 3.5 mmol) and 1-amino-3-phenoxypropan-2(S)-ol (122 mg, 0.73 mmol) were added, and the mixture was stirred for about two days at room temperature under nitrogen. The reaction was then diluted with methylene chloride, washed with dilute sodium bicarbonate and brine, dried over sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was flash chromatographed on silica (55 g), eluting with 5% methanol/methylene chloride, to give the title compound (500 mg) as a mixture of diastereomers. After about 6 hours the mixture was stirred for about two days at room temperature under nitrogen washed with dilute sodium bicarbonate and brine dried over sodium sulfate filtered the solvent was removed in vacuo chromatographed on silica (55 g) eluting with 5% methanol/methylene chloride

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

Procedure: To a solution of anhydrous DMSO (0.839 mmol, 2.5 eq.) in CH2Cl2 (4 mL) at −78° C. was added oxalyl chloride (2M in CH2Cl2, 0.536 mmol, 1.6 eq.) dropwise by syringe. The resulting mixture was stirred at −78° C. for 10 minutes before a solution of methyl 4-[(2R)-2-(hydroxymethyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example 62, 0.335 mmol, 1.0 eq.) in CH2Cl2 (4 mL) was added very slowly by syringe. The resulting reaction mixture was stirred at −78° C. for 2 hours, at which time triethylamine (2.01 mmol, 6.0 eq.) was added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature (about 10 minutes). To the resulting crude aldehyde was added (2S)-1-amino-3-phenoxy-2-propanol (0.67 mmol, 2.0 eq.) in a single portion followed by acetic acid (6.03 mmol, 18.0 eq.). The resulting mixture was stirred for 5 minutes before sodium triacetoxyborohydride (1.005 mmol, 3.0 eq.) was added in a single portion. The reaction mixture was stirred at room temperature for 3 hours. The triacetoxyborohydride was quenched by the addition of 1N NaOH until the pH reached 9-10. The resulting two-phase mixture was extracted with CH2Cl2. The organic extracts were dried over sodium sulfate, concentrated and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, CH2Cl2 to CH2Cl2:MeOH=100:3). The product was obtained as a pale yellow solid in 99% yield (two steps). MH+=448.3, retention time (LC-MS)=2.46 min. was added very slowly by syringe The resulting reaction mixture was added The cooling bath was removed was added in a single portion The triacetoxyborohydride was quenched by the addition of 1N NaOH until the pH The resulting two-phase mixture was extracted with CH2Cl2 The organic extracts were dried over sodium sulfate concentrated purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, CH2Cl2 to CH2Cl2:MeOH=100:3) The product was obtained as a pale yellow solid in 99% yield (two steps)

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

Procedure: A solution containing (2S)-1-amino-3-phenoxy-2-propanol (Example 53, 11.97 mmol, 1.0 eq.), (2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, 11.97 mmol, 1.0 eq.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23.98 mmol, 2.0 eq.), 1-hydroxybenzotriazole hydrate (23.94 mmol, 2.0 eq.), and triethylamine (23.94 mmol, 2.0 eq.) in CH2Cl2 (200 mL) was stirred at room temperature for 3 hours. To the resulting solution was added water and two-phase mixture was extracted with CH2Cl2. The organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=2:1). The product was obtained as a white solid in 77% yield. MH+=454.1, retention time (LC-MS)=3.03 min. was extracted with CH2Cl2 The organic extracts were washed with water and brine dried over anhydrous sodium sulfate concentrated purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=2:1) The product was obtained as a white solid in 77% yield

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

Procedure: 3.1 g of dimethyl 4-[2-[(E)-4-chloro-2-butenyloxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and 5.8 g (S)-2-hydroxy-3-phenoxypropylamine were dissolved in 35 ml of acetonitrile, and the resultant solution was refluxed under heating for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 30 ml of chloroform. After washing the solution with water three times, the organic layer was concentrated under reduced pressure. The residue obtained was subjected to column chromatography on silica gel. The product was eluted with chloroform-methanol (95:5 V/V), was converted to HCl salt, and then was treated with ether-ethyl acetate to give 1.8 g of dimethyl 4-[2-[(E)-4-[[(S)-2-hydroxy-3-phenoxypropyl]amino]-2-butenyloxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate HCl salt. under heating for 2 hours The reaction solution was concentrated under reduced pressure the residue was dissolved in 30 ml of chloroform After washing the solution with water three times the organic layer was concentrated under reduced pressure The residue obtained The product was eluted with chloroform-methanol (95:5 V/V) was treated with ether-ethyl acetate

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

Procedure: To a solution of anhydrous DMSO (0.839 mmol, 2.5 eq.) in CH2Cl2 (4 mL) at −78° C. was added oxalyl chloride (2M in CH2Cl2, 0.536 mmol, 1.6 eq.) dropwise by syringe. The resulting mixture was stirred at −78° C. for 10 minutes before a solution of methyl 4-[(2R)-2-(hydroxymethyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example 62, 0.335 mmol, 1.0 eq.) in CH2Cl2 (4 mL) was added very slowly by syringe. The resulting reaction mixture was stirred at −78° C. for 2 hours, at which time triethylamine (2.01 mmol, 6.0 eq.) was added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature (about 10 minutes). To the resulting crude aldehyde was added (2S)-1-amino-3-phenoxy-2-propanol (0.67 mmol, 2.0 eq.) in a single portion followed by acetic acid (6.03 mmol, 18.0 eq.). The resulting mixture was stirred for 5 minutes before sodium triacetoxyborohydride (1.005 mmol, 3.0 eq.) was added in a single portion. The reaction mixture was stirred at room temperature for 3 hours. The triacetoxyborohydride was quenched by the addition of 1N NaOH until the pH reached 9-10. The resulting two-phase mixture was extracted with CH2Cl2. The organic extracts were dried over sodium sulfate, concentrated and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, CH2Cl2 to CH2Cl2:MeOH=100:3). The product was obtained as a pale yellow solid in 99% yield (two steps). MH+=448.3, retention time (LC-MS)=2.46 min. was added very slowly by syringe The resulting reaction mixture was added The cooling bath was removed was added in a single portion The triacetoxyborohydride was quenched by the addition of 1N NaOH until the pH The resulting two-phase mixture was extracted with CH2Cl2 The organic extracts were dried over sodium sulfate concentrated purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, CH2Cl2 to CH2Cl2:MeOH=100:3) The product was obtained as a pale yellow solid in 99% yield (two steps)