1-甲氧基-N-(三乙基氮胺基)sulfonylmethanimidate

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3-cyclohexyl-1,1,1-trifluoro-3-nitropropan-2-ol (2) (1.015 gm) and ([methoxycarbonylsulfamoyl]triethylammonium hydroxide, inner salt) (Burgess reagent) (2.2 gm) in benzene (10 mL) was heated to 70° C. for 1.5 hours. After cooling the reaction mixture to room temperature, the organic layer was decanted away from the solids and evaporated to dryness under reduced pressure. Purification of the crude product on silica gel chromatography (eluting with 2% ethyl acetate/hexane) gave (3,3,3-trifluoro-1-nitroprop-1-enyl)cyclohexane (0.62 gm, 66%). After cooling the reaction mixture to room temperature the organic layer was decanted away from the solids evaporated to dryness under reduced pressure Purification of the crude product on silica gel chromatography (eluting with 2% ethyl acetate/hexane)

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

实验步骤: N′-(Chloroacetyl)-3-(methyloxy)-4-nitrobenzohydrazide (1.00 g, 3.48 mmol) and Burgess' reagent (0.994 g, 4.17 mmol) in THF (15 mL) was heated to 120° C. for 20 minutes in the microwave. The reaction was complete by TLC. Purification by flash chromatography provided the title compound (0.802 g, 2.93 mmol, 85%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.04 (s, 3H), 5.16 (s, 2H), 7.72 (dd, J=8.4, 1.8 Hz, 1H), 7.84 (d, J=1.8 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H). Purification by flash chromatography

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The product from Step 1 (85 mg, 0.184 mmol) was taken up in THF (2 mL) in a microwave vial, and Burgess reagent (88 mg, 0.368 mmol) was added. The reaction was heated in the microwave at 100° C. for 30 min. The yellow reaction mixture was concentrated to dryness, and the resulting residue was purified by flash chromatography (25-100% ethyl acetate in hexanes) to afford N-(3-methyl-5-{2-[1-(1,3,4-oxadiazol-2-yl)cyclopropyl]-1,3-thiazol-5-yl}phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (18 mg, 22%) as a colorless solid. MS ESI: [M+H]+ m/z 445.0. 1H NMR (600 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.23 (s, 1H), 8.81 (d, J=4.9, 1H), 7.97 (s, 1H), 7.96 (s, 1H), 7.46 (s, 1H), 7.26 (d, J=4.9, 1H), 7.15 (s, 1H), 2.29 (s, 3H), 1.94-1.82 (m, 4H). rhSYK activity=+++ was added The yellow reaction mixture was concentrated to dryness the resulting residue was purified by flash chromatography (25-100% ethyl acetate in hexanes)

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

实验步骤: The product from Step 2 (80 mg, 0.172 mmol) was taken up in THF (2 mL) in a microwave vial, and Burgess reagent (82 mg, 0.344 mmol) was added. The reaction was irradiated in the microwave at 100° C. for 30 min. The yellow reaction mixture was concentrated to dryness, and the resulting residue was purified by column chromatography on silica (0-100% ethyl acetate in hexanes) to provide N-(3-methyl-5-{2-[2-(1,3,4-oxadiazol-2-yl)propan-2-yl]-1,3-thiazol-5-yl}phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (32 mg, 42%) as an off-white solid. MS ESI: [M+H]+ m/z 447.0. 1H NMR (600 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.20 (s; 1H), 8.81 (d, J=4.9, 1H), 7.97 (s, 2H), 7.44 (s, 1H), 7.26 (d, J=4.9, 1H), 7.14 (s, 1H), 2.29 (s, 3H), 1.87 (s, 6H). rhSYK activity=+++ was added The reaction was irradiated in the microwave at 100° C. for 30 min The yellow reaction mixture was concentrated to dryness the resulting residue was purified by column chromatography on silica (0-100% ethyl acetate in hexanes)

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The product from Step 1 (70 mg, 0.146 mmol) was taken up in THF (2.0 mL) in a microwave vial, and Burgess reagent (70 mg, 0.293 mmol) was added. The reaction was heated in the microwave at 100° C. for 30 min. The orange reaction mixture was concentrated to dryness, and the resulting residue was purified by flash chromatography (10-100% ethyl acetate in hexanes) to provide N-(3-methyl-5-{2-[2-methyl-2-(1,3,4-oxadiazol-2-yl)propyl]-1,3-thiazol-5-yl}phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (32 mg, 48%) as a colorless foam. MS ESI: [M+H]+ m/z 461.0. 1H NMR (600 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.16 (s, 1H), 8.80 (d, J=4.9, 1H), 7.94-7.83 (m, 2H), 7.42 (s, 1H), 7.25 (d, J=4.9, 1H), 7.08 (s, 1H), 3.39 (s, 2H), 2.27 (s, 3H), 1.43 (s, 6H). rhSYK activity=+++ was added The orange reaction mixture was concentrated to dryness the resulting residue was purified by flash chromatography (10-100% ethyl acetate in hexanes)

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

实验步骤: To a solution of N′-acetyl-3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanehydrazide (0.1 g, 0.21 mmol) in THF (2 mL) was added Burgess Reagent (75 mg, 0.315 mmol). The sealed vial was irradiated in the microwave at 100° C. for 15 min. The mixture was extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to afford (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one (58 mg, yield: 59%). 1H NMR (CDCl3): δ1.49-1.51 (m, 3H), 2.23-2.26 (m, 2H), 2.30-2.33 (m, 2H), 2.42 (s, 3H), 2.43-2.45 (m, 1H), 2.49-2.54 (m, 1H), 2.87-2.91 (m, 1H), 3.06-3.09 (m, 1H), 5.61-5.63 (m, 1H), 6.76-6.78 (d, 2H), 7.20-7.22 (m, 2H), 7.26-7.33 (m, 2H), 7.35-7.37 (m, 3H). The sealed vial was irradiated in the microwave at 100° C. for 15 min The mixture was extracted with EtOAc (3×30 mL) The combined organic layer was washed with brine (50 mL) dried over Na2SO4 filtered concentrated The residue was purified by preparative TLC

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N′-[2-(6-Bromopyridin-2-yl)acetyl]cyclopropanecarbohydrazide (200 mg, 0.67 mmol) and Burgess reagent (320 mg, 1.34 mmol) were combined in THF (4.0 mL) and heated at 100° C. for 25 min in a microwave. The reaction mixture was concentrated and directly purified by flash chromatography (10-100% EtOAc/hexanes) to afford the title compound as a colorless solid. The reaction mixture was concentrated directly purified by flash chromatography (10-100% EtOAc/hexanes)

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

实验步骤: A solution of 3-chloro-5-(trifluoromethyl)picolinaldehyde oxime (1.0 eq.) and Burgess reagent (1.5 eq.) in tetrahydrofuran (0.5 M) was heated to 65° C. and stirred for 1 hour. The reaction was cooled to room temperature and diluted with ethyl acetate and water. The organic layer was washed with water, brine, dried over anhydrous MgSO4, and concentrated en vacuo to give a solid that was carried onto the next step without further purification. The organic layer was washed with water, brine dried over anhydrous MgSO4 concentrated en vacuo to give a solid that was carried onto the next step without further purification

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

实验步骤: N-butanoyl-N′-[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl]-hydrazine (0.35 g, 0.75 mmol) obtained in Step 1 was added to a microwave reactor containing Burgess reagent (0.45 g, 1.88 mmol) in THF (2 mL). The capped reactor was placed in a microwave reactor and the mixture was irradiated at 140° C. for 15 min. The reaction product was purified by preparative HPLC to provide the title compound (0.21 g, 0.46 mmol, 61%) as yellow solid. The capped reactor was placed in a microwave reactor the mixture was irradiated at 140° C. for 15 min The reaction product was purified by preparative HPLC

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

实验步骤: N-butanoyl-N′-[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl]-hydrazine (0.35 g, 0.75 mmol) obtained in Step 1 was added to a microwave reactor containing Burgess reagent (0.45 g, 1.88 mmol) in THF (2 mL). The capped reactor was placed in a microwave reactor and the mixture was irradiated at 140° C. for 15 min. The reaction product was purified by preparative HPLC to provide the title compound (0.21 g, 0.46 mmol, 61%) as yellow solid. The capped reactor was placed in a microwave reactor the mixture was irradiated at 140° C. for 15 min The reaction product was purified by preparative HPLC

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

实验步骤: A solution of 2-cyclopentyl-6-methoxy-isonicotinic acid hydrazide (870 mg, 3.70 mmol), 4-benzyloxy-3-ethyl-5-methyl-benzoic acid (1.00 g, 3.70 mmol) and DIPEA (1.44 g, 11.1 mmol) in DCM (30 mL), TBTU (1.43 g, 4.44 mmol) is added. The mixture is stirred at rt for 1 h before diluted with EA (150 mL) and water (50 mL). The org. phase is separated, washed with sat. aq. NaHCO3 solution (50 mL) followed by brine (50 mL), dried over MgSO4, filtered and concentrated. The remaining pale yellow oil is dissolved in THF (50 mL) and Burgess reagent (1.23 g, 5.18 mmol) is added. The mixture is stirred at 110° C. for 15 min under microwave irradiation before it is diluted with EA (200 mL) and washed twice with water (50 mL). The org. extract is dried over MgSO4, filtered and concentrated and the crude product is purified by CC on silica gel eluting with heptane:EA 1:9 to give 4-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-2-cyclopentyl-6-methoxy-pyridine (750 mg) as a pale yellow oil; LC-MS**: tR=1.06 min, [M+H]+=470.21. phase is separated washed with sat. aq. NaHCO3 solution (50 mL) dried over MgSO4 filtered concentrated The remaining pale yellow oil is dissolved in THF (50 mL) The mixture is stirred at 110° C. for 15 min under microwave irradiation before it washed twice with water (50 mL) extract is dried over MgSO4 filtered concentrated the crude product is purified by CC on silica gel eluting with heptane:EA 1:9

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

实验步骤: A solution of 2-cyclopentyl-6-methoxy-isonicotinic acid hydrazide (870 mg, 3.70 mmol), 4-benzyloxy-3-ethyl-5-methyl-benzoic acid (1.00 g, 3.70 mmol) and DIPEA (1.44 g, 11.1 mmol) in DCM (30 mL), TBTU (1.43 g, 4.44 mmol) is added. The mixture is stirred at rt for 1 h before diluted with EA (150 mL) and water (50 mL). The org. phase is separated, washed with sat. aq. NaHCO3 solution (50 mL) followed by brine (50 mL), dried over MgSO4, filtered and concentrated. The remaining pale yellow oil is dissolved in THF (50 mL) and Burgess reagent (1.23 g, 5.18 mmol) is added. The mixture is stirred at 110° C. for 15 min under microwave irradiation before it is diluted with EA (200 mL) and washed twice with water (50 mL). The org. extract is dried over MgSO4, filtered and concentrated and the crude product is purified by CC on silica gel eluting with heptane:EA 1:9 to give 4-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-2-cyclopentyl-6-methoxy-pyridine (750 mg) as a pale yellow oil; LC-MS**: tR=1.06 min, [M+H]+=470.21. phase is separated washed with sat. aq. NaHCO3 solution (50 mL) dried over MgSO4 filtered concentrated The remaining pale yellow oil is dissolved in THF (50 mL) The mixture is stirred at 110° C. for 15 min under microwave irradiation before it washed twice with water (50 mL) extract is dried over MgSO4 filtered concentrated the crude product is purified by CC on silica gel eluting with heptane:EA 1:9