Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)C.CN[C:10](=[S:13])[NH:11][NH2:12].[N:14]1C=CC=[CH:16][CH:15]=1>>[CH2:4]([O:3][CH2:1][N:14]1[CH:15]([CH3:16])[C:10](=[S:13])[N:11]=[N:12]1)[CH3:5]
Reactant: CNC(=S)NN
Reactant: CCOCC(=O)Cl
Reactant: c1ccncc1
Product: CCOCN1N=NC(=S)C1C
Reaction time: 18 h

Procedure:
Ethoxyacetyl chloride (57 g.) was added slowly to a stirred solution of 4-methylthiosemicarbazide (53.5 g.) in dry pyridine (500 ml.) at 0°-5°. The mixture was allowed to attain room temperature and stirring was continued for 18 hours. Following concentration under reduced pressure the residue was treated with a solution of sodium (21.4 g.) in ethanol (500 ml.) and the mixture was heated under reflux for 24 hours. Following concentration and acidification with hydrochloric acid a solid was obtained. After partial concentration the solid was collected and recrystallised from ethyl acetate to give 3-ethoxymethyl-4-methyl-1,2,3-triazoline-5-thione (53 g.), m.p. 137°-138°. The thione (44 g.) was desulphurised by slow addition to a solution prepared from nitric acid (75 ml.) water (150 ml.) and sodium nitrite (1.5 g.) at 15°-20°. Following subsequent basification with sodium carbonate and concentration the residue was extracted with ethanol-ether 1:1 and distilled to afford 3-ethoxymethyl-4-methyl-1,2,4-triazole (30 g.) b.p. 154°-156°/0.05 mm. The above compound (15 g.) dissolved in 48% aqueous hydrobromic acid (150 ml.) was heated under reflux for 24 hours and concentrated to dryness to give 3-hydroxymethyl-4-methyl-1,2,4-triazole.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:33]=[CH:32][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[O:21])=[C:18]([OH:31])[CH:17]=2)=[CH:7][CH:6]=1.[C:34](OC1C=CC=CC=1)(=[O:36])[CH3:35].C(N(CC)CC)C>C(Cl)Cl>[C:34]([N:2]=[N:3][CH2:4][C:5]1[CH:33]=[CH:32][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:30]=[CH:29][C:19]([C:20]([N:22]([CH:26]([CH3:27])[CH3:28])[CH:23]([CH3:25])[CH3:24])=[O:21])=[C:18]([OH:31])[CH:17]=2)=[CH:7][CH:6]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)Oc1ccccc1
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C=NN)cc2)cc1O)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N=NCc1ccc(OCCCCCOc2ccc(C(=O)N(C(C)C)C(C)C)c(O)c2)cc1
Reaction time: 8 h

Procedure:
A stirred solution of 4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide monohydrochloride (220 mg, 0.46 mmol) in 10 mL anhydrous methylene chloride is treated with phenyl acetate (73 uL, 0.51 mmol) and triethylamine (73 uL, 0.51 mmol). The solution is stirred overnight, concentrated in vacuo and the resulting liquid is purified by chromatography on silica gel (15 g) with 80°-100% ethyl acetate/hexane as the eluent to afford 4-[5-[4-(acetyliminoaminomethyl)phenoxy]pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide as a colorless foam:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25])[CH:17]=[N:18][C:19]=2[NH:20]CC=C)=[O:12])=[CH:6][CH:5]=1)[CH3:2].C(O)(=O)C.C1([SiH3])C=CC=CC=1>ClCCl.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>[NH2:20][C:19]1[N:18]=[CH:17][C:16]([C:24]([N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])=[O:25])=[CH:15][C:14]=1[NH:13][C:11](=[O:12])[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1
Reactant: C=CCNc1ncc(C(=O)N(CC)CC)cc1NC(=O)Cc1ccc(OCC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOc1ccc(CC(=O)Nc2cc(C(=O)N(CC)CC)cnc2N)cc1
Reaction time: 6 h
Yield: 75.2 %

Procedure:
To a degassed solution of 5-[[(4-ethoxyphenyl)acetyl]amino]-N,N-diethyl-6-(2-propenylamino)-3-pyridinecarboxamide (1.04 g, 2.53 mmol) in dichloromethane (20 mL) at room temperature was added palladium tetrakis (117 mg, 0.10 mmol), followed by acetic acid (580 μL, 10.14 mmol) and phenyl silane (625 μL, 5.07 mmol). The mixture was stirred for 6 hours. The reaction was then quenched with NaHCO3 saturated aqueous solution (50 mL) and extracted with EtOAc (20 mL). The aqueous phase was back-extracted with additional dichloromethane (2×20 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using silica gel flash chromatography ([3% MeOH+1% NH4OHaq] in CH2Cl2) to provide 705 mg of the title compound 6-amino-5-[[(4-ethoxyphenyl)acetyl]amino]-N,N-diethyl-3-pyridinecarboxamide (75.2% yield from 5-[[(4-ethoxyphenyl)acetyl]amino]-N,N-diethyl-6-(2-propenylamino)-3-pyridinecarboxamide). 1H-NMR (400 MHz, CDCl3): δ 1.18 (br s, 6H), 1.43 (t, J=7.0 Hz, 3H), 3.42 (br s, 4H), 3.69 (s, 2H), 4.04 (q, J=7.0 Hz, 2H), 4.73 (s, 2H), 6.91 (d, J=8.6 Hz, 2H), 7.26 (d, J=8.6 Hz, 2H), 7.38 (m, 1H), 7.78 (s, 1H), 7.95 (m, 1H). MS (ESI) (M+H)+: 372.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C:3](=[O:12])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1>C1COCC1>[CH3:1][CH:2]([CH3:13])[C:3](=[O:12])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1
Reactant: CC(C)C(=O)C=Cc1ccncc1
Solvent: C1CCOC1
Product: CC(C)C(=O)CCc1ccncc1

Procedure:
The title compound was prepared according to General Method 3 using 4-methyl-1-pyridin-4-yl-pent-1-en-3-one (Example B-16; 1.81 g), (Ph3P)3RhCl (0.5 g), and THF (100 mL) at 50 psi. The title compound was flash chromatographed using 98:2 CH2Cl2:MeOH as eluent. 1H NMR (CDCl3): δ1.15 (d, 6 H), 2.5-2.7 (m, 1 H), 2.7-2.8 (m, 2 H), 2.85-2.95 (m, 2 H), 7.1 (d, 2 H), 8.5 (d, 2 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:2]1.Br[CH2:25][CH2:26][CH2:27][S:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:22][C:17]([F:23])([C:8]1[N:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH2:25][CH2:26][CH2:27][S:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:2][CH2:3]2)[C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[N:9]=1)[C:18]([F:21])([F:20])[F:19]
Reactant: Fc1ccc2c(c1)nc(C(F)(F)C(F)(F)F)n2C1CCNCC1
Reactant: Fc1ccc(SCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(SCCCN2CCC(n3c(C(F)(F)C(F)(F)F)nc4cc(F)ccc43)CC2)cc1
Yield: 8.6 %

Procedure:
3.9 g 1-(Piperidin-4-yl)-5-fluoro-2-pentafluoroethyl-1H-benzoimidazole, 4.4 g 1-(3-bromo-propylsulfanyl)-4-fluoro-benzene and 2 g K2CO3 were stirred in 50 ml DMF at 100° C. for 2 h. After cooling the mixture was poured into water and was extracted 2× with ethyl acetate. The organic layer was tracted 3× with water, dried and evaporated. The resulting oil was purified by flash chromatography with dichloromethane, the purified fractions were dissolved in acetone after evaporation of the solvent, and the solution was acidified with etherical HCl. After evaporation of the solvent the resulting crystals were filtered with diisopropyl ether. The crystals were dissolved in acetone again and evaporated to a volume of 2 ml. The product crystallized as hydrochloride to give 0.5 g product (mp. 208–209° C.).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([O:17][C:18](=[O:34])[N:19]([CH2:23][C:24]1[CH:25]=[C:26]([F:33])[CH:27]=[C:28]2[C:32]=1[NH:31][CH:30]=[CH:29]2)[CH2:20][CH2:21][OH:22])([CH3:16])([CH3:15])[CH3:14]>ClCCl.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:19]([CH2:23][C:24]1[CH:25]=[C:26]([F:33])[CH:27]=[C:28]2[C:32]=1[NH:31][CH:30]=[CH:29]2)[CH2:20][CH2:21][O:22][S:9]([CH3:8])(=[O:11])=[O:10])=[O:34])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1cc(F)cc2cc[nH]c12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCOS(C)(=O)=O)Cc1cc(F)cc2cc[nH]c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
Add triethylamine (4.64 mL, 33.3 mmol) followed by methanesulfonyl chloride (1.29 mL, 16.65 mmol) to a solution of (5-fluoro-1H-indol-7-ylmethyl)-(2-hydroxyethyl)-carbamic acid tert-butyl ester (4.9 g, assume 15.14 mmol) in dichloromethane (70 mL) at 0° C. Stir the reaction mixture for 30 minutes at 0° C. Dilute with ethyl acetate (200 mL), wash with sequentially with saturated aqueous sodium bicarbonate (200 mL×3) and saturated aqueous sodium chloride (200 mL×2). Dry the organic phase over sodium sulfate and concentrate under reduced pressure to provide the desired compound as a yellow brown oil (5.9 g, >100%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(O[CH:13](OCC)[CH2:14][NH2:15])C>>[Cl:1][C:2]1[CH:9]=[C:8]2[C:5](=[CH:4][CH:3]=1)[CH:6]=[N:15][CH:14]=[CH:13]2
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(CN)OCC
Product: Clc1ccc2cnccc2c1

Procedure:
Commercially available 4-chlorobenzaldehyde (10 g) was cyclized with aminoacetaldehyde diethyl acetal according to the procedure of Hendrickson, et al., J. Org. Chem., 48, 3344 (1983), to give 6-chloroisoquinoline (600 mg). Nitration of the obtained product using the procedure of Campbell et al., J. Am. Chem. Soc., 68, 1559 (1946) gave 6-chloro-5-nitroisoquinoline (700 mg). Substitution of 6-chloro for thiomethoxide according to the procedure of Massie, Iowa State Coll. J. Sci., 21, 41 (1946) (Ca 41:3033 g) gave 6-methylthio-5-nitroisoquinoline (632 mg). This material (200 mg) was reduced using stannous chloride (2.0 g) and concentrated hydrochloric acid (30 ml) to give 5-amino-6-(methylthio) isoquinoline (143 mg). This material (140 mg) was coupled with 2-hexylthiodecanoic acid (prepared according to the procedures described in Examples 1 and 3) using the procedure described in Example 25 to give the title compound (80 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7]O)=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[CH:30]=[C:29]1[C:37]([O:39][CH2:40][CH3:41])=[O:38].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][N:28]2[C:32]3=[N:33][CH:34]=[CH:35][CH:36]=[C:31]3[CH:30]=[C:29]2[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc2cccnc2[nH]1
Reactant: OCc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cccnc2n1Cc1ccncc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.5 %

Procedure:
0.51 g (4.73 mmol) of 4-pyridylmethanol and then 1.24 g (4.73 mmol) of triphenyl-phosphine are successively added with stirring to a solution of 0.6 g (3.15 mmol) of ethyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate, obtained according to the protocol described in step 3.2, in 40 mL of dry tetrahydrofuran, maintained under an inert atmosphere. 0.82 g (4.73 mmol) of diethyl azodicarboxylate is then added dropwise at 0° C. The reaction mixture is stirred for 24 hours at room temperature and then concentrated under reduced pressure. A mixture of water and ethyl acetate (20 mL, v/v) is added and the pH of the reaction mixture is adjusted to 5-6 by adding acetic acid. The organic phase separated out is then washed twice with 10 mL of water and once with 10 mL of saturated sodium chloride solution and then dried over magnesium sulfate. After concentrating under reduced pressure, the resulting oil is purified by chromatography on a column of silica gel. 0.66 g of expected product is isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:15]([O-])([OH:17])=[O:16]>OS(O)(=O)=O>[CH3:12][C:11]1[C:10]([N+:15]([O-:17])=[O:16])=[C:9]2[C:4](=[CH:3][C:2]=1[CH3:1])[NH:5][C:6](=[O:14])[C:7](=[O:13])[NH:8]2
Reactant: Cc1cc2[nH]c(=O)c(=O)[nH]c2cc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc2[nH]c(=O)c(=O)[nH]c2c([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a solution of 1.90 g (10.0 mmol) of 6,7-dimethyl-1,4-dihydroquinoxaline-2,3-dione in 25 mL of H2SO4 (97%) kept in an ice bath was added dropwise 1.2 mL of HNO3 (69-70%) and the solution was stirred at room temperature for 48 h. It was poured into 300 mL of ice-water and stirred for 10 min. The mixture was filtered, washed with water, and dried to leave a yellow solid 1.40 g (60%). The solid was purified by DMSO/H2O precipitation followed by NaOH/HCl precipitation to leave 0.85 g of a yellow solid; mp>250° C.; 1H NMR (DMSO-d6), 2.079 (s,3), 2.246 (s,3), 7.048 (s,1), 11.770 (s,1), 12.030 (s,1). HRMS calcd. for C10H9N3O4 235.0588; found 235.0584.
Reaction SMILES: [N+](=[C:3]([C:8]([O:10][CH:11]([C:16]([Cl:19])([Cl:18])[Cl:17])[CH:12]=[C:13]([CH3:15])[CH3:14])=[O:9])[C:4]([O:6][CH3:7])=[O:5])=[N-]>CCCCCCCC.C(OCC)(=O)C.[Cu]>[Cl:17][C:16]([Cl:19])([Cl:18])[CH:11]1[CH:12]2[C:3]([C:4]([O:6][CH3:7])=[O:5])([C:13]2([CH3:15])[CH3:14])[C:8](=[O:9])[O:10]1
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC(C=C(C)C)C(Cl)(Cl)Cl
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: CCCCCCCC
Product: COC(=O)C12C(=O)OC(C(Cl)(Cl)Cl)C1C2(C)C
Yield: 96 %

Procedure:
To a refluxing suspension of copper powder (6.6 g, 0.104 mole) in 320 ml of n-octane was added dropwise in one hour a solution of methyl (±)-3-methyl-1-trichloromethyl-2-butenyl diazomalonate (6.6 g, 0.02 mole, prepared as described above for the ethyl ester) in 30 ml of n-octane. The reaction mixture was heated for 21/2 hours under reflux and then filtered while hot. The n-octane was evaporated from the filtate under vacuum to produce a residue which was dissolved in ethyl acetate. The solution was washed successively with aqueous 1 N hydrochloric acid, aqueous sodium bicarbonate, and aqueous sodium chloride. After drying the solution over magnesium sulfate, the ethyl acetate was removed by evaporation, yielding methyl (±)-4-trichloromethyl-6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate (5.77 g, 96% yield) as an oil. Trituration of the oil with ether afforded the crystalline lactone; mp, 118°-120°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=2)[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: N#CCCc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCc1cccc(Nc2nc(Cl)ncc2Cl)c1

Procedure:
3-(3-Amino-phenyl)-propionitrile (0.110 g, 0.000752 mol), 2,4,5-Trichloro-pyrimidine (0.152 g, 0.000828 mol), Potassium carbonate (0.125 g, 0.90 mmol), and DMF (1.0 mL, 0.014 mol) were heated at 85° C. for 90 min. The reaction mixture was diluted with H2O, extracted with CH2Cl2×3, dried over MgSO4, filtered, and concentrated under reduced pressure. Title compound isolated as a white solid. MP=111-112. HPLC purity: 95% LCMS: 295.10 (M+H) 1H-NMR (CDCl3, 400 MHz) δ 8.21 (d, J=0.8 Hz, 1H), 7.53-7.56 (m, 2H), 7.38 (dd, J=7.6 Hz, 7.8 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.6 Hz, 1H), 3.00 (dd, J=7.0 Hz, 7.3 Hz, 2H), 2.67 (dd, J=7.4 Hz, 7.2 Hz, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][C@@H:14]([CH3:16])[NH:13][CH2:12][C@@H:11]2[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[CH:23]=[CH:22][O:21][C:20]=1[C:24]([Cl:26])=[O:25]>C1C=CC=CC=1>[ClH:26].[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][C@@H:14]([CH3:16])[N:13]([C:24]([C:20]3[O:21][CH:22]=[CH:23][C:19]=3[CH3:18])=[O:25])[CH2:12][C@@H:11]2[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H]1CN(CCCc2ccccc2)[C@@H](C)CN1
Reactant: Cc1ccoc1C(=O)Cl
Solvent: c1ccccc1
Product: Cc1ccoc1C(=O)N1C[C@H](C)N(CCCc2ccccc2)C[C@H]1C
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 2 from a mixture of trans-1-(3-phenylpropyl)-2,5-dimethylpiperazine, 3-methyl-2-furoyl chloride and benzene.
Reaction SMILES: I[C:2]1[NH:6][C:5]([CH3:7])=[N:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[C:18]([C:22]#[CH:23])[CH:19]=[CH:20][CH:21]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:2]2[N:6]=[C:5]([CH3:7])[NH:4][CH:3]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ncc(I)[nH]1
Reactant: C#Cc1cccc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a solution of 500 mg (2.40 mmol) of 5-iodo-2-methyl-1H-imidazole (CAS: [73746-45-9]) in 7 ml of DMF were added under an argon atmosphere 118 mg (0.17 mmol) of Bis(triphenylphosphine)palladium dichloride and 0.67 ml (4.81 mmol) of triethylamine. The mixture was stirred for 10 min at room temperature. Then 0.52 ml (575 mg, 4.09 mmol) of 3-chloro-1-ethynyl-benzene and 13.7 mg (0.072 mmol) of copper(I) iodide were added and the mixture was stirred for 1.5 h at 60° C. The mixture was concentrated in vaccuo, dissolved in a minimal volume of methylene chloride and purified by chromatography on 20 g of silicagel (gradient Heptane/EtOAc 85:15->EtOAc) to yield 430 mg (83%) of the title compound as an orange crystalline solid, MS: m/e=217.2, 219.2 (M+H+).
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)=[N+:14]=[N-:15]>>[ClH:1].[S:19]1[CH:20]=[CH:21][C:17]([CH2:16][N:13]2[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]3[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=3)[N:15]=[N:14]2)=[CH:18]1
Reactant: C#CCCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCc1ccsc1
Agent: Cl
Product: Nc1nc(CCCc2cn(Cc3ccsc3)nn2)c[nH]1
Yield: 46.1 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.090 g, 0.486 mmol) was reacted with 3-Azidomethyl-thiophene (0.081 g, 0.582 mmol) following the general procedure for click reactions outlined above to produce 4-[3-(1-Thiophen-3-ylmethyl-1H-[1,2,3]triazol-4-yl)-propyl]-1H-imidazol-2-ylamine hydrochloride (0.0727 g, 46%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.61 (s, 1H), δ 7.24 (s, 1H), δ 7.23 (d, 1H), δ 6.87 (d, δ 6.29 (s, 1H), δ 2.54 (t, 2H), 2.33 (t, 2H), δ 1.75 (m, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.6, 147.4, 147.3, 136.1, 127.9, 127.0, 126.9, 124.2, 122.2, 109.1, 53.1, 27.9, 24.3; HRMS (ESI) calcd for C13H16N6S (M+) 289.1229. found 289.1234.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:28])[CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]3C(OC(C)(C)C)=O)=[CH:9][CH:10]=2)[N:5]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:4]=1.[Cl:35]CCl>>[ClH:35].[CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:28])[CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]3)=[CH:9][CH:10]=2)[N:5]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:4]=1
Reactant: ClCCl
Reactant: CSc1nn(-c2ccccc2)c2cc(NC(=O)CC3CCCCN3C(=O)OC(C)(C)C)ccc12
Product: CSc1nn(-c2ccccc2)c2cc(NC(=O)CC3CCCCN3)ccc12
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed a solution of tert-butyl 2-(2-(3-(methylthio)-1-phenyl-1H-indazol-6-ylamino)-2-oxoethyl)piperidine-1-carboxylate (105 mg, 0.22 mmol, 1.00 equiv) in dichloromethane (5 mL). To the above mixture was introduce H2 (g). The resulting solution was stirred for 30 min at 0° C. The solids were collected by filtration to yield N-(3-(methylthio)-1-phenyl-1H-indazol-6-yl)-2-(piperidin-2-yl)acetamide hydrochloride as a gray solid.
Reaction SMILES: [N:1]1[CH2:2][O:3][CH:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[C-]#[N:12].[K+]>>[NH:12]=[C:2]1[C:4](=[O:3])[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:1]1
Reactant: C1=c2ccccc2=NCO1
Reactant: [C-]#N
Agent: [K+]
Product: N=C1Nc2ccccc2C1=O

Procedure:
The process according to claim 1 in which the 3,1-benzoxazine is reacted with potassium cyanide in an equimolar ratio or in the presence of a slight excess of potassium cyanide at a temperature of 100° C., to decarboxylate said 3,1-benzoxazine and obtain a 2-imino-3-indolinone.
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([N+:14]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:14][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[NH:9][C:8]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1[nH]c(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1[nH]c(C(C)(C)C)cc1N
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A mixture of methyl 5-tert-butyl-3-nitropyrrole-2-carboxylate (0.014 g, 0.062 mmol) and 10% Pd/C (3 mg) in dry MeOH (1 mL) was successively evacuated and purged with H2 three times, then shaken under an atmosphere of H2 (35 psi) for 1 h, diluted with CH2Cl2 and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give methyl 3-amino-5-tert-butylpyrrole-2-carboxylate as a bright yellow oil (0.012 g, 100%). 1H NMR (CDCl3) δ1.26 (s, 9H), 3.82 (s, 3H), 5.52 (d, J=2.8 Hz, 1H), 7.89 (br s, 2H). This material was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[C:15]4[C:22](=O)[CH2:21][CH2:20][CH2:19][N:16]43)=[CH:12][CH:11]=2)=[O:9])[CH:2]=1.Cl.[NH2:25][OH:26].N1C=CC=CC=1>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[C:15]4[C:22](=[N:25][OH:26])[CH2:21][CH2:20][CH2:19][N:16]43)=[CH:12][CH:11]=2)=[O:9])[CH:2]=1
Reactant: NO
Reactant: O=C(Nc1cccnc1)c1ccc2cc3n(c2c1)CCCC3=O
Agent: Cl
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1)c1ccc2cc3n(c2c1)CCCC3=NO
Yield: 77.6 %

Procedure:
9-Oxo-6,7,8,9-tetrahydro-pyrido[1,2-a]indole-3-carboxylic acid pyridin-3-ylamide (150 mg, 0.491 mmol), hydroxylamine hydrochloride (1.50 g, 21.6 mmol), and pyridine (3 mL) were combined in MeOH (40 mL) and heated to 60 □C for 20 h. The reaction was cooled and diluted with water (200 mL). The resulting precipitate was filtered, washed with water, then hexanes, and dried in a vacuum oven to give the title compound (122 mg, 78%) as an analytically pure mixture of oxime regioisomers (2:1).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:19][C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1COCC1.CN(C)C1C=CN=CC=1>[CH:1]1([N:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)[C:20]([Cl:19])=[O:22])[CH2:3][CH2:2]1
Reactant: C1CCC(CNC2CC2)OC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Cl)N(CC1CCCCO1)C1CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of cyclopropyl-(tetrahydro-pyran-2-ylmethyl)-amine (200 mg, 0.74 mmol) in THF (4 mL) is added triethylamine (144 μL, 1.036 mmol) and 4-dimethylaminopyridine (1.81 mg, 0.015 mmol). The mixture is cooled to 0° C., and triphosgene (88 mg, 0.296 mmol) is added in one portion. After stirring for 30 min at 0° C. and overnight at RT, water is cautiously added and the solution is extracted with AcOEt. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. TLC, Rf (CH2Cl2/MeOH 95:5)=0.9.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[I:9].[CH3:10][C:11]1[C:15]([C:16](O)=[O:17])=[C:14]([CH3:19])[O:13][N:12]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C>[CH3:10][C:11]1[C:15]([C:16]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([I:9])[CH:4]=2)=[O:17])=[C:14]([CH3:19])[O:13][N:12]=1
Reactant: Nc1ccc(Cl)c(I)c1
Reactant: Cc1noc(C)c1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: Cc1noc(C)c1C(=O)Nc1ccc(Cl)c(I)c1

Procedure:
4-Chloro-3-iodoaniline (1.01 g, 4 mmol) was used in procedure E with 3,5-dimethyl-4-isoxazolecarboxylic acid (0.565 g, 4 mmol), EDC (1.32 g, 6.8 mmol), TEA (0.5 mL), DMAP (50 mg, 0.4 mmol) at 23° C. for overnight. The crude reaction was purified by silica gel chromatography (0-15% ethyl acetate/CH2Cl2) to yield 3,5-dimethyl-N-(4-chloro-3-iodophenyl)isoxazole-4-carboxamide as a white solid.