Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]1[O:21][C:20](=[O:22])[CH:19]([C:23](OCC)=O)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[O-].[Na+].BrC[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[CH:36][CH:35]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[O:22]=[C:20]1[O:21][C@@H:17]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:18][CH:19]1[CH2:23][C:34]1[CH:35]=[CH:36][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[CH:38][CH:39]=1
Reactant: CCOC(=O)C1C[C@H]([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Reactant: BrCc1ccc(-c2ccccn2)cc1
Agent: CC[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CC(Cc2ccc(-c3ccccn3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
A solution of the product from Example 107A (13.3 g, 35.27 mmol) in ethanol (140 mL) at 0° C. was treated with a solution of NaOEt (14.9 mL, 21% in ethanol) and solid 2-[4-(bromomethyl)phenyl]pyridine (12.05 g, 48.59 mmol), stirred at 25° C. for 16 hours, treated with a solution of LiOH monohydrate (8.9 g, 212.11 mmol) in water (35 mL), stirred at 25° C. for 5 hours, cooled to 0° C., adjusted to pH 5 by addition of 10% citric acid and then partitioned between dichloromethane and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. A solution of the concentrate in toluene (1 L) was heated at reflux for 16 hours, cooled and concentrated to give the title compound (10.55 g, 63% yield), which was used without further purification.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:11].O>C(Cl)Cl>[Cl:11]/[C:3](/[CH3:5])=[CH:2]/[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)CC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)/C=C(\C)Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 7.7 %

Procedure:
In a reaction vessel flushed with argon gas was placed 437.4 grams (3.36 moles) of ethyl acetoacetate in 500 ml of methylene chloride. The stirred solution was cooled to 0° C. and 700 grams (3.36 moles) of phosphorous pentachloride was added in portions at a rate such that the reaction mixture temperature did not exceed 5°. Upon completion of addition, the reaction mixture was stirred at 0°-5° for 16 hours. Five-hundred ml of water was added dropwise, and the layers in the resultant two-phase system were separated. The water layer was made alkaline with solid sodium bicarbonate and extracted with several 100-ml portions of methylene chloride. The organic layer from the reaction mixture was washed with water until all the solid material in it dissolved. The washed organic layer and the methylene chloride washings of the water layer were combined and dried with sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to a residual oil. The oil was first distilled under reduced pressure using a Vigreux column. Fractions boiling at 52°-65°/0.40-1.07×103Pa were combined and subjected to a second distillation under reduced pressure using a spinning band distilling system. Fractions boiling at 66°-70°/0.40-1.07×103Pa from the first distillation and fractions boiling at 66.5°-82°/1.20×103Pa from the second distillation were subjected to a third distillation under reduced pressure using a spinning band distilling system. The fraction, bp 46°/1.33×103Pa from the second distillation was combined with the fractions, bp 42°-45°/1.20×103Pa from the third distillation to give 38.4 grams of ethyl [E]-3-chloro-2-butenoate.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=1)=O.[NH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=[CH:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>C(OCC)(=O)C>[C:20]([C:10]1[CH:9]=[C:8]([NH:7][C:5]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([CH:37]=[CH:38][C:39]3[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=3)=[CH:29][CH:28]=2)=[O:4])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Nc1ccc(C=Cc2ccncc2)c2ccccc12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(C=Cc3ccncc3)c3ccccc23)cc1
Reaction time: 5 h

Procedure:
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (26 mmol), 1-amino4-(2-pyridin-4-yl-ethenyl)naphthalene (26 mmol), diisopropylethylamine (3.2 g, 25 mmol) and DMSO (75 mL) is heated to 55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4×50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 020 C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:14][O:15][C:16](=O)[O:17]C.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[CH3:14][O:15][C:16]([CH:10]1[CH2:9][CH:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[O:12][C:11]1=[O:13])=[O:17]
Reactant: CCCCCCCC1CCC(=O)O1
Reactant: COC(=O)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCC1CC(C(=O)OC)C(=O)O1
Temperature: 65 °C
Yield: 56.4 %

Procedure:
To a mixture of 203 g 5-heptyl-dihydro-furan-2-one and 390 g dimethylcarbonate was slowly added 40 g of sodium hydride. The temperature increased to 65° C. After the temperature returned to room temperature, the reaction mixture was poured into saturated citric acid and extracted with hexane. The organic layer was dried and evaporated to dryness. The residue was distilled to yield 150.5 g of a colourless liquid.
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:45])[CH2:18][N:19]2[C:24](=[O:25])[CH:23]=[C:22]([CH2:26][CH2:27][CH3:28])[N:21]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:32][CH:31]=3)[C:20]2=[O:44])=[CH:13][CH:12]=1.[N:46]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:45])[CH2:18][N:19]2[C:24](=[O:25])[CH:23]=[C:22]([CH2:26][CH2:27][CH3:28])[N:21]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[NH:46][C:4](=[O:7])[O:5][N:43]=4)=[CH:34][CH:35]=3)[C:20]2=[O:44])=[CH:15][CH:16]=1
Reactant: CCCc1cc(=O)n(CC(=O)c2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: C1CCC2=NCCCN2CC1
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCc1cc(=O)n(CC(=O)c2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A mixture of hydroxylammonium chloride (0.89 g), sodium hydrogencarbonate (1.29 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-6-propyl-3,4-dihydropyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.63 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (30 mL), N,N′-carbonyldiimidazole (0.21 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.43 g, 60%).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:19]2[C:14](=[N:15][C:16]([CH3:22])=[CH:17][C:18]=2[CH:20]=[O:21])[S:13][C:12]=1[C:23]([NH2:25])=[O:24].[NH4+].[Cl-]>C1COCC1>[NH2:10][C:11]1[C:19]2[C:14](=[N:15][C:16]([CH3:22])=[CH:17][C:18]=2[CH:20]([OH:21])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:13][C:12]=1[C:23]([NH2:25])=[O:24]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Cc1cc(C=O)c2c(N)c(C(N)=O)sc2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(O)Cc2ccccc2)c2c(N)c(C(N)=O)sc2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 344 mg CeCl3 in 3 mL dry THF at −78° was added 0.70 mL 2 M benzylmagnesium chloride and the reaction was stirred 1.5 h under Ar. Then, 41 mg of 3-amino-4-formyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (see Example 16) was added and the reaction was stirred 3.5 h in the cold and then allowed to warm to room temperature over 0.5 h. Aqueous NH4Cl was added and the reaction was filtered through diatomaceous earth, washing with EtOAc, and the aqueous phase was separated and extracted 3 times more with EtOAc. The combined organics were dried, concentrated in vacuo, and re-dissolved in EtOAc with a trace MeOH and washed 3 times with aqueous NaHSO3. This was dried, concentrated in vacuo, and the product was purified on a prep plate developed with 5% MeOH—CH2Cl2. The product was re-dissolved in MeOH—CH2Cl2, filtered, concentrated and dried in vacuo at 60° C. providing 16.3 mg of the title compound as an orange solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12](=[O:13])[CH:11]=[N:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:8]=1)(=O)=O.[C:26]1([N:32]2[C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=[N:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:26]1([N:32]2[C:36]([C:7]3[C:12](=[O:13])[CH:11]=[N:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[CH:8]=3)=[CH:35][CH:34]=[N:33]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C
Reactant: O=c1cnn(-c2cccc(C(F)(F)F)c2)cc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=c1cnn(-c2cccc(C(F)(F)F)c2)cc1-c1ccnn1-c1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 8.8 %

Procedure:
5-oxo-2-[3-(trifluoromethyl)phenyl]-2,5-dihydropyridazin-4-yl trifluoromethanesulfonate (0.100 g), 1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.139 g), sodium carbonate (0.109 g) and tetrakis(triphenylphosphine)palladium(0) (0.0298 g) were suspended in a mixed solvent of toluene (2.06 mL), ethanol (0.52 mL) and water (0.52 mL), and the suspension was stirred at 100° C. for 6 hr under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, purified by NH silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane to give the title compound (0.0087 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][NH:7][NH2:8].[CH3:9][C:10]([CH3:17])([CH3:16])[C:11](=O)[CH2:12][C:13]#[N:14]>C(O)C>[C:10]([C:11]1[CH:12]=[C:13]([NH2:14])[N:7]([CH2:6][C@@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[N:8]=1)([CH3:17])([CH3:16])[CH3:9]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNC[C@@H]1CCCO1
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(C[C@@H]2CCCO2)n1

Procedure:
To a stirred solution of the product from Example 12B (232 mg, 2.0 mmol) in ethanol (4 mL) was added 4,4-dimethyl-3-oxopentanenitrile (250 mg, 2.0 mmol). The mixture was refluxed for 2 hours. The ethanol was removed by evaporation under reduced pressure and the crude product was dissolved in CH2Cl2 (10 mL), which was used directly for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH:9]([N:16](C2CCN(C)CC2)[CH3:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[CH2:25]1[CH2:29]O[CH2:27][CH2:26]1.[OH2:30]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][C:17](=[O:30])[N:16]([CH2:27][CH:26]1[CH2:4][CH2:9][N:16]([CH3:17])[CH2:29][CH2:25]1)[CH:9]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1CCC(N(C)C(c2ccccc2)c2cc(Br)ccc2N)CC1
Reactant: O
Reactant: C1CCOC1
Product: CN1CCC(CN2C(=O)Nc3ccc(Br)cc3C2c2ccccc2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-Bromo-2-[[(1-methyl-4-piperidyl)-methylamino]-phenyl-methyl]aniline (0.96 g, 2.5 mmol), N,N′-carbonyldiimidazole (0.4 g, 2.5 mmol) and THF (20 ml) is stirred overnight at 60° C. Water is added and the mixture is extracted with EtOAc. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]#[N:16])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]#[N:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC#N)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.5 %

Procedure:
A solution of trans (4-cyanomethyl-cyclohexyl)-carbamic acid tert-butyl ester (0.71 g, 3.00 mmol) in DCM (15 mL) was treated with trifluoroacetic acid (2 mL) and the mixture was stirred at ambient temperature for 2.5 hours, then concentrated under vacuum. The residue was purified by column chromatography using Isolute SCX-2 cartridge (eluting with MeOH then 2M NH3 in MeOH). The relevant fractions were combined and concentrated under vacuum to afford 0.40 g (97%) of trans (4-amino-cyclohexyl)-acetonitrile that was used without further purification. 1H NMR (400 MHz, CDCl3) δ: 3.52-3.42 (m, 2H), 2.69-2.60 (m, 1H), 2.26 (d, 2H), 1.94-1.83 (m, 4H), 1.70-1.57 (m, 1H), 1.24-1.06 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([C:26]3([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1.[OH-].[Na+]>C(Cl)Cl.CO>[C:1]1([C:7]2[N:11]3[N:12]=[C:13]([C:16]([F:19])([F:17])[F:18])[CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:20]2[CH:21]=[CH:22][C:23]([C:26]3([NH2:30])[CH2:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(C(F)(F)F)nn4c3-c3ccccc3)cc2)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3nc4ccc(C(F)(F)F)nn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a mixture of tert-butyl (1-{4-[3-phenyl-6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-3 (680 mg, 1.177 mmol, 1.0 eq) in DCM (7.6 mL) and methanol (4.8 mL) was added a solution of 4 M hydrogen chloride in dioxane (5.9 mL, 23.5 mmol, 20.0 eq) and the mixture was stirred for overnight at rt. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted with EtOAc (3×). The combined organic phases were washed with brine, dried and concentrated in vacuo. Purification was achieved by crystallization from diisopropyl ether. The resulting solid was filtered and dried under high vacuum overnight to give 440 mg (92% yield) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[ClH:9]>O>[CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Cl-:9].[NH2:6][C:7]([NH2:8])=[NH2+:2]
Reactant: Cl
Agent: CN1CC(=O)N=C1N
Solvent: O
Product: NC(N)=[NH2+]
Product: [Cl-]

Procedure:
To a Schlenk reactor, 40 mL of deionized water was added, followed by 5 g (44.3 mmol) of creatinine. Under a high-purity argon atmosphere, the mixture was heated with stirring. After the temperature in reactor reached up to the predetermined temperature of 60° C., an aqueous solution of hydrochloric acid at a concentration of 18.5% was added via a constant pressure dropping funnel into the reactor. The molar ratio between creatinine and hydrochloride was set as 1:1.2. The reaction was kept with stirring for 0.5 h. By using a rotary evaporator, the moisture contained in the system was removed under reduced pressure. The solid product was transferred into a vacuum oven and dried at room temperature for 48 h, to give 6.58 g of creatinine-guanidinium chloride as a snow white solid product.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.O/[N:35]=[C:36](\[NH2:45])/[CH2:37][C:38](=[O:44])[N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[O:18][N:45]=[C:36]([CH2:37][C:38](=[O:44])[N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[N:35]=2)[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: N/C(CC(=O)N1CCCC1)=N\O
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](c2nc(CC(=O)N3CCCC3)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 59, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and (1Z)-N′-hydroxy-3-oxo-3-(1-pyrrolidinyl)propanimidamide, the title compound was obtained in 89% purity by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.I[CH2:15][CH2:16][C@H:17]1[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:22][C:19]1([CH3:23])[O:18][C@@H:17]([CH2:16][CH2:15][N:8]2[C:9](=[O:12])[CH:10]=[N:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:13][C:7]2=3)[CH2:21][O:20]1
Reactant: CC1(C)OC[C@H](CCI)O1
Reactant: COc1ccc2ncc(=O)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CC[C@H]3COC(C)(C)O3)c2n1
Temperature: 50 °C
Reaction time: 11 h
Yield: 90.2 %

Procedure:
In N,N-dimethylformamide (400 ml) were dissolved 6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (14.53 g, 82.00 mmol) and (4S)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (23.10 g, 90.20 mmol). Cesium carbonate (34.7 g, 1.06.6 mmol) was added to the solution and the mixture was stirred at 50° C. for 11 hours. After cooling in the air, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 22.58 g (90%) of the title compound in the form of a yellow orange oily product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1([NH2:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CS(C)=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Solvent: CS(C)=O
Product: Cc1ccc(Nc2ccccc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 95.8 %

Procedure:
A solution of 1-fluoro-4-methyl-2-nitrobenzene (1.0 g, 6.45 mmol) in DMSO (3 mL) was purged with a stream of nitrogen prior to addition of phenylamine (1.18 mL, 12.9 mmol) and then stirred in a sealed tube at 100° C. for 20 h. After cooling to RT, the reaction mixture was partitioned between EtOAc (200 mL) and water (150 mL). The organic layer was then washed with water (150 mL×3), followed by brine, then dried (Na2SO4) and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-40% DCM in cyclohexane) affording (4-Methyl-2-nitrophenyl)phenylamine as a red oil (1.41 g, 96%). 1H NMR (DMSO, 400 MHz): δ 9.21 (1H, s), 7.94-7.91 (1H, m), 7.43-7.26 (5H, m), 7.19-7.12 (2H, m), 2.27 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]([O:15]C)=[O:14])[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]([OH:15])=[O:14])[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C(=O)O)COC1(C)C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
Methyl 3-tert-butoxycarbonyl-2,2-dimethyloxazolidine-4-(R)-carboxylate (3.0 g) is dissolved in a mixture of tetrahydrofurane (THF)/H2O (3/1; 30 ml), and LiOH.H2O (684 mg) is added. After being subjected to agitation for 3 hours at room temperature, the reaction mixture is acidified with citric acid 1N (11 ml). THF is concentrated and the aqueous phase is extracted with ethyl acetate. The organic phase is dried on MgSO4, filtered and concentrated to obtain the expected product as a viscous orange oil (1.36 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][CH2:14][N:15]([CH2:28][CH2:29]Cl)[C:16]([N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1)=[O:17].O>O1CCCC1.C(OCC)(=O)C>[N:18]1([C:16]([N:15]2[CH2:28][CH2:29][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:8]#[N:9])[CH2:13][CH2:14]2)=[O:17])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: O=C(N(CCCl)CCCl)N1CCCc2ccccc21
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#CC1(c2ccccc2)CCN(C(=O)N2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.29 ml of phenylacetonitrile in 6 ml of tetrahydrofuran is introduced into a 25 ml three-necked flask. 0.38 g of sodium hydride is subsequently added at 0° C. The reaction medium is stirred at ambient temperature for 30 min and then, at 0° C., 0.5 g of N,N-bis(2-chloroethyl)-3,4-dihydroquinoline-1(2H)-carboxamide is added. The reaction mixture is brought to reflux for 3 h and then ice, water and ethyl acetate are added. The aqueous phase is extracted with ethyl acetate and then the organic phases are combined, washed with water and dried over sodium sulfate and then the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a heptane/methanol gradient from 1/0 to 95/5. 2.91 g of 1-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)-4-phenylpiperidine-4-carbonitrile are obtained.