2-氰基-N-甲基乙酰胺

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

实验步骤: N-methyl cyanoacetamide (113 g., 1.15 mole), 2,4-pentanedione (115 g., 1.15 mole), piperidine (11.5 ml.) and anhydrous ethanol (250 ml.) are refluxed with stirring for 3 hours. The mixture is allowed to stand overnight at room temperature and the white crystalline precipitate is collected by filtration to give 1-methyl-3-cyano-4,6-dimethylpyrid-2-one, 144 g. (77.4% yield), mp. 202°-205° C. to stand overnight at room temperature the white crystalline precipitate is collected by filtration

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

实验步骤: N-methyl cyanoacetamide (113 g., 1.15 mole), 2,4-pentanedione (115 g., 1.15 mole), piperidine (11.5 ml.) and anhydrous ethanol (250 ml.) are refluxed with stirring for 3 hours. The mixture is allowed to stand overnight at room temperature and the white crystalline precipitate is collected by filtration to give 1-methyl-3-cyano-4,6-dimethylpyrid-2-one, 144 g. (77.4% yield), mp. 202°-205° C. to stand overnight at room temperature the white crystalline precipitate is collected by filtration

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 250 parts of water, 98 parts of N-methylcyanoacetamide and 169 parts of acetoacetic acid ethyl ester are initially placed in an autoclave, 40 parts of gaseous monomethylamine are injected, while stirring, and the reaction mixture is then heated at 90° C. for 3 hours, a pressure of 2.9 bars being generated. The batch is diluted with 400 parts of water, 80 parts of 61% strength sulphuric acid are added at 30°-35° C., the batch is cooled to 20° C. and the precipitate which has been formed is filtered off. 155.8 parts (95% of theory) of 1,4-dimethyl-3-cyano-6-hydroxypyrid-2-one with a melting point of 285° C. are obtained. are added at 30°-35° C. the batch is cooled to 20° C. the precipitate which has been formed is filtered off

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

实验步骤: To a 50 ml three necked round bottom flask, 4-(7-pivaloyl-5-((2-(trimethylsilyl)-ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzaldehyde (0.25 g, 0.0005 mole) and 2-cyano-N-methylacetamide (0.22 g, 0.0022 mole) was taken in ethanol (20 ml). To this reaction mixture, piperidine acetate (1.0 ml) was added dropwise at RT. After completion of the addition, reaction mixture was refluxed for 2 hr. After completion of the reaction, ethanol was distilled out under vacuum and water was added to the residue. The aq. layer was extracted with ethyl acetate. Combined organic layer was dried over Na2SO4, filtered and concentrated to afford crude product. The crude compound was purified by triturated with n-pentane, the pentane layer was decanted and solid was dried under vacuum to yield 0.255 g of 2-cyano-N-methyl-3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylamide which was converted to the title compound as described in Example 1, Step 2 above. After completion of the addition, reaction mixture was refluxed for 2 hr was distilled out under vacuum and water was added to the residue The aq. layer was extracted with ethyl acetate Combined organic layer was dried over Na2SO4 filtered concentrated to afford crude product The crude compound was purified by triturated with n-pentane the pentane layer was decanted solid was dried under vacuum

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

实验步骤: N-methyl cyanoacetamide (113 g., 1.15 mole), 2,4-pentanedione (115 g., 1.15 mole), piperidine (11.5 ml.) and anhydrous ethanol (250 ml.) are refluxed with stirring for 3 hours. The mixture is allowed to stand overnight at room temperature and the white crystalline precipitate is collected by filtration to give 1-methyl-3-cyano-4,6-dimethylpyrid-2-one, 144 g. (77.4% yield), mp. 202°-205° C. to stand overnight at room temperature the white crystalline precipitate is collected by filtration

实验步骤: 投料: 往100ml单口瓶中加入原料（2g，1.0eq），加入2-氰基-N-甲基乙酰胺（1.07g，1.0eq），加入44mlDMF溶解，滴加三乙胺（3.04ml，2.0eq），加完后升温至120°反应过夜\n监测: 第二天送HPLC，C4X-162914-2-1-3-S1,原料剩余44%，产物54%，停止反应\n后处理: 降温， 1、从反应液中取5ml反应液，加入12ml饱和亚硫酸氢钠溶液洗一遍，往反应液中加水，加EA萃取，收集有机相，旋干，得到黑色油状物，送HPLC，C4X-162914-2-1-3-P,图谱很杂，该后处理方法不可行 2、取5ml反应液，直接用油泵旋干反应液，加入DCM溶解，后加入1.2eq的戴斯马丁氧化剂和1.5eq的碳酸氢钠固体，搅拌1.5h，送LCMS，C4X-162914-YH，能看到目标产物的分子量，没有看到原料被氧化成羧酸的分子量，且还有其他杂峰，该后处理方法暂定

实验步骤: 投料: 往20ml平行反应瓶中加入原料3,4-二羟基-5-硝基苯甲醛（200mg，1.0eq），加入2-氰基-N-甲基乙酰胺（107mg，1.0eq），加入4.5mlDMF溶解，加完后升温至120°反应。\n监测: 反应2h，取样送LCMS，C4X-162914-2-1-2-S1，从PDA看基本上是原料，从离子流看有目标产物分子量，也有原料分子量，原料和目标产物在LCMS里没分开，跑HPLC，看到有两个峰，14.118min是原料，14.517min是产物。原料反应了5%左右，继续搅拌过夜。 第二天取样送HPLC，C4X-162914-2-1-2-S2，产物有60%，原料40%，继续反应过夜 第三天，取样送HPLC，C4X-162914-2-1-2-S3，反应变杂，产物出峰附近很多杂峰。停止反应。

实验步骤: 投料: 往20ml平行反应瓶中加入3,4-二羟基-5-硝基苯甲醛（200mg，1.0eq），加入2-氰基-N-甲基乙酰胺（214mg，2.eq），加入6ml异丙醇溶解，搅拌30min，后加入哌啶盐酸盐（60mg，0.45eq），加完后搅拌30min，升温至80°回流反应。\n监测: 搅拌2h，TLC监测，DCM：MEOH10:1,没有新点生成，继续反应 再搅拌2h后，TLC监测，仍没有新点生成， 反应过夜后，TLC监测，还没有新点生成， 送LCMS，全是原料。 停止反应

实验步骤: 投料: 往100ml单口瓶中加入原料3,4-二羟基-5-硝基苯甲醛（1个，1.0eq）， 加入2-氰基-N-甲基乙酰胺（1.07g，2.0eq），加入22mlDMF溶解，后滴加三乙胺（1.52ml，2.0eq），加完后升温至120°回流过夜。\n监测: 反应过夜后，送HPLC和LCMS，C4X-162914-2-1-4-S1,原料基本反应完全，停止反应。\n后处理: 反应降温，旋干溶剂。得到黑色油状物。\n纯化: 冰浴下往黑色油状物中加入12ml（醋酸：浓盐酸=10:3）的混合溶液，后室温搅拌打浆2h，后过滤，并用冰水冲洗滤饼，收集滤饼干燥，得到墨绿色固体，送HNMR和LCMS，确认结构正确，C4X-162914-2-1-4-P1，包含一点醋酸溶残。

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

实验步骤: N-methyl cyanoacetamide (113 g., 1.15 mole), 2,4-pentanedione (115 g., 1.15 mole), piperidine (11.5 ml.) and anhydrous ethanol 250 ml. are refluxed with stirring for 3 hours. The mixture is allowed to stand overnight at room temperature and the white crystalline precipitate is collected by filtration to give 1-methyl-3-cyano-4,6-dimethylpyrid-2-one, 144 g. (77.4% yield), mp. 202°-205° C. are refluxed to stand overnight at room temperature the white crystalline precipitate is collected by filtration

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

实验步骤: N-methyl cyanoacetamide (113 g., 1.15 mole), 2,4-pentanedione (115 g., 1.15 mole), piperidine (11.5 ml.) and anhydrous ethanol 250 ml. are refluxed with stirring for 3 hours. The mixture is allowed to stand overnight at room temperature and the white crystalline precipitate is collected by filtration to give 1-methyl-3-cyano-4,6-dimethylpyrid-2-one, 144 g. (77.4% yield), mp. 202°-205° C. are refluxed to stand overnight at room temperature the white crystalline precipitate is collected by filtration

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

实验步骤: 0.394 g (9.95 mmol) of 60% sodium hydride in mineral oil is added in small amounts to a solution, cooled to 0-5° C., of 0.483 g (4.93 mmol) of N-methylcyanoacetamide in 7 ml of anhydrous dimethylformamide. Stirring is continued at this temperature for 10 minutes and then a solution of 1.0 g (4.93 mmol) of 2-(aminoethyl)-6-chloronicotinic acid fluoride in 5 ml of dimethylformamide is added. The medium is stirred overnight at ambient temperature and then a further 0.197 g (4.93 mmol) of 60% sodium hydride is added in small amounts. Stirring is continued at this temperature for 10 minutes and then 0.56 ml (9.78 mmol) of acetic acid is added. 60 ml of water are subsequently added and the solid is filtered off, rinsed with water and then dried in an oven. 1.30 g of the expected product are obtained. Melting point: 283-284° C. MH+=281. Yield=94%. The medium is stirred overnight at ambient temperature Stirring is continued at this temperature for 10 minutes the solid is filtered off rinsed with water dried in an oven