[(2S)-吗啉-2-基]甲醇

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.95 g, 2 mmol) was reacted with (S)-morpholin-2-ylmethanol (0.34 g, 2.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.34 g, 33%). The compound was characterized by the following spectroscopic data:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.92 g, 2 mmol) was reacted with (S)-morpholin-2-ylmethanol (0.34 g, 2.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.30 g, 30%). The compound was characterized by the following spectroscopic data:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.92 g, 2 mmol) was reacted with (S)-morpholin-2-ylmethanol (0.34 g, 2.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.30 g, 30%). The compound was characterized by the following spectroscopic data:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(S)-(hydroxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (S)-Morpholin-2-yl-methanol following General Procedure C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(S)-(hydroxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (S)-Morpholin-2-yl-methanol following General Procedure C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Pyridine (0.207 ml, 2.56 mmol) and DMAP (0.021 g, 0.17 mmol) were added to a solution of (S)-morpholin-2-ylmethanol (A, Tyger Scientific Inc, 0.2 g, 1.71 mmol) in DCM (5.0 ml) followed by tert-butylchlorodiphenylsilane (0.526 ml, 2.05 mmol). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by column chromatography (ISCO, eluting with 10% MeOH/DCM) to provide (S)-2-((tert-butyldiphenylsilyloxy)methyl)morpholine B (INTERMEDIATE 48B, 0.26 g, yield: 43%). The reaction mixture was concentrated under reduced pressure the concentrate was purified by column chromatography (ISCO, eluting with 10% MeOH/DCM)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: RuPhospalladium(II)phenethylaminechloride (2.83 mg, 0.00388 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (1.81 mg, 0.00388 mmol), 4-(4-chlorophenyl)-2-iodo-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one (31.3 mg, 0.0776 mmol), (2S)-morpholin-2-ylmethanol (16.0 mg, 0.137 mmol), and tetrahydrofuran (0.63 mL) were combined in a rbf equipped with a stirbar. The flask was sealed with a septum then evacuated and refilled with argon three times. To this solution was added a solution of lithium bis(trimethylsilyl)amide) in tetrahydrofuran (1.0 M, 0.31 mL, 0.31 mmol). The sealed r×n was vigorously stirred @ 40° C. for 19 hr. The reaction was cooled to rt, quenched into saline, extracted into EA, washed with saline, dried over Na2SO4, filtered, and concentrated in vacuo. The crude oil was purified using column chromatography on silica gel (24 g ISCO column, gradient 100% DCM to 100% EA over 50 minutes; after unreacted starting material and dehalogenated starting material eluted, the eluant was switched to 5% MeOH in EA) to give the title compound (4.8 mg, 16%) as a mixture of diastereomers. LCMS: (FA) ES+ 393, 395. 1H NMR (400 MHz, DMSO) δ 7.78 (t, J=4.6 Hz, 1H), 7.38-7.35 (m, 2H), 7.15-7.11 (m, 2H), 5.59 (s, 1H), 4.80-4.75 (m, 1H), 4.34-4.31 (m, 1H), 3.91-3.79 (m, 1H), 3.61-3.35 (m, 6H), 3.24 (d, J=11.9 Hz, 1H), 3.11-3.07 (m, 2H), 2.81-2.69 (m, 1H), 2.22-2.14 (m, 1H), 2.02-1.88 (m, 1H). equipped with a stirbar The flask was sealed with a septum then evacuated refilled with argon three times quenched into saline extracted into EA washed with saline dried over Na2SO4 filtered concentrated in vacuo The crude oil was purified over 50 minutes eluted

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Benzyl chloroformate (0.598 mL, 0.956 mmol, 3.5 equiv) was added slowly to a solution of DIPEA (0.477 mL, 2.73 mmol, 10 equiv) and 2.20.1a (64 mg, 0.547 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 4 hours. EtOAc and saturated aqueous NaHCO3 solution were then added to the mixture. The phases were separated and the organic layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The remaining oil was purified by silica gel column chromatography (EtOAc/heptane, 40-100%) to give product 74 mg (54% yield). MS m/z (M+1) 252.2. The phases were separated the organic layer was extracted with EtOAc The combined organic layers were washed with brine dried over Na2SO4 concentrated The remaining oil was purified by silica gel column chromatography (EtOAc/heptane, 40-100%)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Pyridine (0.207 ml, 2.56 mmol) and DMAP (0.021 g, 0.17 mmol) were added to a solution of (S)-morpholin-2-ylmethanol (A, Tyger Scientific Inc, 0.2 g, 1.71 mmol) in DCM (5.0 ml) followed by tert-butylchlorodiphenylsilane (0.526 ml, 2.05 mmol). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by column chromatography (ISCO, eluting with 10% MeOH/DCM) to provide (S)-2-((tert-butyldiphenylsilyloxy)methyl)morpholine B (INTERMEDIATE 48B, 0.26 g, yield: 43%). The reaction mixture was concentrated under reduced pressure the concentrate was purified by column chromatography (ISCO, eluting with 10% MeOH/DCM)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.95 g, 2 mmol) was reacted with (S)-morpholin-2-ylmethanol (0.34 g, 2.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.34 g, 33%). The compound was characterized by the following spectroscopic data:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.92 g, 2 mmol) was reacted with (S)-morpholin-2-ylmethanol (0.34 g, 2.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.30 g, 30%). The compound was characterized by the following spectroscopic data: