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

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

Procedure: Triethylamine (4.0 ml, 28.9 mmol) was added to a solution of (S)-3-amino-1,2-propanediol (2.2 g, 24.1 mmol) in a mixture of CH3CN/MeOH (80 mL/13 mL) at −10° C. under nitrogen. Chloroacetyl chloride (2.1 mL, 26.5 mmol) was then added dropwise at −10° C. over 30 min. The reaction mixture was allowed to reach room temperature and stirred for 16 h. The mixture was concentrated under vacuum and purified by flash column chromatography on silica gel, eluting with methanol/ethyl acetate (8/92), to give the title compound as a white solid (3.63 g, 90%). to reach room temperature The mixture was concentrated under vacuum purified by flash column chromatography on silica gel eluting with methanol/ethyl acetate (8/92)

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

Procedure: The title compound was prepared by a procedure similar to the one described for 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide using (S)-(−)-3-amino-1,2-propanediol (0.162 g 2.5 mmol) as the amine and without the addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (404.3 mg, 43%) as beige solid. 1H-NMR (CD3OD, 400 MHz) δ 8.31 (s, 1H), 7.92 (dd, 1H, J=2 Hz), 7.76 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.55 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.59 (q, 2H, J=12.4 Hz), 3.80 (m, 1H), 3.53 (m, 3H), 3.39 (m, 1H), 2.19 (s, 3H); ES-HRMS m/z 524.0630 (M+H C22H21BrF2N3O5 requires 524.0627). The title compound was prepared by a procedure similar to the one After reverse phase HPLC purification the organic extracts were concentrated under reduced pressure dried in vacuo

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

Procedure: 5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (9.32 g, 20.8 mmol) synthesized in Example (106c) was dissolved in methanol (200 mL), and (S)-(−)-3-amino-1,2-propanediol (5.01 g, 55.0 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (10.13 g, 32.3 mmol) were added, followed by stirring at room temperature overnight under nitrogen atmosphere. The solvent was distilled off under reduced pressure, water (300 mL) and ethyl acetate (200 mL) were added to the resulting residue, and the solution was separated. The organic layer was washed with saturated brine, subsequently dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%) to afford the desired product (9.32 g, yield 86%) as a colorless oil. The solvent was distilled off under reduced pressure, water (300 mL) and ethyl acetate (200 mL) were added to the resulting residue the solution was separated The organic layer was washed with saturated brine subsequently dried over anhydrous magnesium sulfate the solvent was distilled off under reduced pressure The resulting residue was purified silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%)

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

Procedure: 5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulfonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.07 g, 2.39 mmol) synthesized in Example (97e) was dissolved in methylene chloride (20 mL), and WSCI•HCl (732 mg, 3.82 mmol), (S)-(−)-3-amino-1,2-propanediol (500 mg, 5.49 mmol) and 4-dimethylaminopyridine (146 mg, 1.19 mmol) were added at room temperature, followed by stirring for 25 hours under nitrogen atmosphere. The reaction solution was diluted with ethyl acetate (50 mL), washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired product (666 mg, 54%) as a white solid. washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine subsequently dried over anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the resulting residue was purified silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%)

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

Procedure: 5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (338 mg, 0.759 mmol) synthesized in Example (18a) was dissolved in dichloromethane (10 mL), and (S)-(−)-3-amino-1,2-propanediol (105 mg, 1.15 mmol), WSCI•HCl (220 mg, 1.15 mmol) and 4-dimethylaminopyridine (185 mg, 1.51 mmol) were added, followed by stirring at room temperature for 3 days under nitrogen atmosphere. 1N hydrochloric acid (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%) to afford the desired product (265 mg, yield 68%) as a white solid. the solution was separated with dichloromethane (15 mL) The organic layer was washed with saturated brine subsequently dried over anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the resulting residue was purified silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%)

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

Procedure: 5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (338 mg, 0.759 mmol) synthesized in Example (18a) was dissolved in dichloromethane (10 mL), and (S)-(−)-3-amino-1,2-propanediol (105 mg, 1.15 mmol), WSCI•HCl (220 mg, 1.15 mmol) and 4-dimethylaminopyridine (185 mg, 1.51 mmol) were added, followed by stirring at room temperature for 3 days under nitrogen atmosphere. 1N hydrochloric acid (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%) to afford the desired product (265 mg, yield 68%) as a white solid. the solution was separated with dichloromethane (15 mL) The organic layer was washed with saturated brine subsequently dried over anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the resulting residue was purified silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%)

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

Procedure: A solution of 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 23) (70 mg, 0.174 mmol) in DMF (2 mL) was treated with EDC (40.1 mg, 0.209 mmol), HOBT (32.0 mg, 0.209 mmol) and N-ethylmorpholine (0.066 mL, 0.523 mmol) and after 3 min with (S)-3-aminopropane-1,2-diol (15.89 mg, 0.174 mmol). The resulting mixture was stirred at room temperature for 5 h then further EDC (40.1 mg, 0.209 mmol), N-ethylmorpholine (0.066 mL, 0.523 mmol), HOBT (32.0 mg, 0.209 mmol) and (S)-3-aminopropane-1,2-diol (15.89 mg, 0.174 mmol) were added and the mixture stirred for 16 h before concentrating in vacuo. The residue was partitioned between water and EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with saturated aqueous NaHCO3 (×3) then brine, dried over MgSO4 and concentrated in vacuo. Trituration of the residue with Et2O gave 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-N—((S)-2,3-dihydroxypropyl)benzamide (36 mg, 0.076 mmol, 43.5% yield) as a pale yellow solid. the mixture stirred for 16 h before concentrating in vacuo The residue was partitioned between water and EtOAc the layers were separated The aqueous phase was extracted with EtOAc the combined organic layers were washed with saturated aqueous NaHCO3 (×3) brine, dried over MgSO4 concentrated in vacuo

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

Procedure: A solution of 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 4) (90 mg, 0.211 mmol) in DMF (2 mL) was treated with EDC (48.5 mg, 0.253 mmol), HOBT hydrochloride (38.8 mg, 0.253 mmol) and N-ethylmorpholine (0.080 mL, 0.633 mmol) and after 3 min with (S)-3-aminopropane-1,2-diol (38.5 mg, 0.422 mmol). The resulting mixture was stirred at room temperature for 5 h then EDC (48.5 mg, 0.253 mmol), N-ethyl morpholine (0.080 mL, 0.633 mmol), HOBT (38.8 mg, 0.253 mmol) and further (S)-3-aminopropane-1,2-diol (38.5 mg, 0.422 mmol) were added and the corresponding mixture was stirred for 16 h then concentrated in vacuo. The residue was partitioned between water and EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed with saturated aqueous NaHCO3 (×3), then brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP to give 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N—((S)-2,3-dihydroxypropyl)benzamide (30 mg, 29%) as a white solid. LCMS (HpH, 2 min), Rt=0.75 min, MH+=500. the corresponding mixture was stirred for 16 h then concentrated in vacuo The residue was partitioned between water and EtOAc the layers were separated The aqueous phase was extracted with EtOAc (×2) the combined organic layers were washed with saturated aqueous NaHCO3 (×3) brine, dried over MgSO4 concentrated in vacuo The residue was purified by MDAP

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

Procedure: The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzoic acid obtained in step B of Example 2-2-1 and (S)-3-amino-1,2-propanediol (produced by Wako Pure Chemical Industries) in accordance with the same procedure as in the methods described in step C of Example 1-2-3.

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

Procedure: A solution of 2-chloro-4-(3-fluorophenyl)-6-methoxyquinoline-3-carbonitrile (65.0 mg, 0.208 mmol) and (S)-2,3-dihydroxypropylamine (114 mg, 1.25 mmol) in 10 mL of 2-propanol was heated in a sealed tube at 120° C. for 63 hours. Another portion of (S)-2,3-dihydroxypropylamine was added (50 mg), and the reaction was stirred for another 12 hours. The solution was concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC to provide the titled product (17 mg, 22%). Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C20H19FN3O3 (M+H+): 368.1405. Found 368.1398. The solution was concentrated in vacuo The crude residue was purified by preparative reversed phase HPLC

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

Procedure: A solution of 2-chloro-4-(3-fluorophenyl)-6-methoxyquinoline-3-carbonitrile (65.0 mg, 0.208 mmol) and (S)-2,3-dihydroxypropylamine (114 mg, 1.25 mmol) in 10 mL of 2-propanol was heated in a sealed tube at 120° C. for 63 hours. Another portion of (S)-2,3-dihydroxypropylamine was added (50 mg), and the reaction was stirred for another 12 hours. The solution was concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC to provide the titled product. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C20H19FN3O3 (M+H+): 368.1405. Found 368.1398. The solution was concentrated in vacuo The crude residue was purified by preparative reversed phase HPLC

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

Procedure: The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzoic acid obtained in step B of Example 2-2-1 and (S)-3-amino-1,2-propanediol (produced by Wako Pure Chemical Industries) in accordance with the same procedure as in the methods described in step C of Example 1-2-3.