Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:19][CH2:20][CH2:21][N:22]1[C:27]2[CH:28]=[CH:29][C:30]([S:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][C:26]=2[O:25][CH2:24][C:23]1=[O:46])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]([CH2:19][CH2:20][CH2:21][N:22]1[C:27]2[CH:28]=[CH:29][C:30]([S:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][C:26]=2[O:25][CH2:24][C:23]1=[O:46])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(Sc1ccc2c(c1)OCC(=O)N2CCCN(C(=O)OCc1ccccc1)c1cccc[n+]1[O-])c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(Sc1ccc2c(c1)OCC(=O)N2CCCN(C(=O)OCc1ccccc1)c1ccccn1)c1ccccc1
Temperature: 40 °C

Procedure:
To a solution of titanium (IV) chloride in tetrahydrofuran under nitrogen atmosphere, is added and equimolar amount of stannous chloride dihydrate, and the mixture is stirred 1 hour at room temperature. Then, a solution of ethyl 3-[(4-{3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino]propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfanyl]-3-phenylpropanoate is added and the mixture heated 3 hours at 40° C. After evaporation of the solvent, ice and aqueous sodium bicarbonate are added, the mixture extracted with ethyl acetate, and the organic layers are combined and dried over sodium sulfate. The solvent is evaporated and ethyl 3-[(4-{3-[N-benzyloxycarbonyl-N-(2-pyridinyl)amino]-propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfanyl]-3-phenylpropanoate is isolated by column chromatography. A solution of ethyl 3-[(4-{3-[N-benzyloxycarbonyl-N-(2-pyridinyl)amino]-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfanyl]-3-phenylpropanoate in acetic acid is treated with a solution of 30% hydrobromic acid in acetic acid at room temperature overnight. The solvent is evaporated under reduced pressure, and the residue is treated with a saturated sodium bicarbonate solution. The aqueous mixture is extracted with dichloromethane. The organic extracts are dried over sodium sulfate, evaporated to small volume and the product is purified by flash chromatography
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1([C:11]([NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[C:18]([CH3:23])[CH:17]=[CH:16][N:15]=2)=O)[CH2:10][CH2:9]1.C(O)=O.C([N:29]([CH2:32][CH3:33])CC)C>>[CH:8]1([C:11]2[N:13]([CH2:7][C:1]3[CH:6]=[CH:5][C:4]([C:5]4[CH:6]=[CH:1][CH:2]=[CH:3][C:33]=4[C:32]#[N:29])=[CH:3][CH:2]=3)[C:14]3=[N:15][CH:16]=[CH:17][C:18]([CH3:23])=[C:19]3[N:20]=2)[CH2:10][CH2:9]1
Reactant: Cc1ccccc1
Reactant: Cc1ccnc(NC(=O)C2CC2)c1[N+](=O)[O-]
Reactant: CCN(CC)CC
Solvent: O=CO
Product: Cc1ccnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Yield: 83 %

Procedure:
Toluene (50 ml) was added to 4.0 g (9.7 mmol) of 2-[N-2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-4-methyl-3-nitropyridine, 4.5 g (97.8 mmol of formic acid 14.7 g (145.5 mmol) of triethylamine and 10% Pd--C (200 mg), followed by heating under reflux for 15 hours. After the reaction liquid was brought to room temperature and filtered to remove the catalyst, vacuum concentration was effected. Chloroform (100 ml) and water (100 ml) were added to the residue and the obtained mixture was caused liquid-liquid separation. The aqueous phase was further extracted with chloroform (50 ml) twice. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2.9 g of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine (yield 83%).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[F:11][C:12]([F:25])([F:24])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]([F:11])([F:24])[F:25])(=[O:22])=[O:21])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 2-trifluoromethoxybenzenesulfonyl chloride (2.35 g, 9.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a yellow oil (1.80 g, 57%). 1H-NMR (300 MHz, CDCl3) δ 7.96 (d, J=7.9 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 6.55 (s, 1H), 6.52 (s, 1H), 6.41 (s, 1H), 5.04 (s, 1H); 2.23 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])[CH:5]=1)([O-])=O.O.C1CCCCC=1.[ClH:27]>C(O)C.[Pd]>[ClH:27].[ClH:27].[ClH:27].[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])[CH:5]=1
Reactant: N[C@@H](CCCCNc1cc([N+](=O)[O-])ccn1)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: C1=CCCCC1
Solvent: O
Solvent: CCO
Product: Nc1ccnc(NCCCC[C@H](N)C(=O)O)c1
Yield: 66 %

Procedure:
4 g (14.9 mmol) of Nε-(4-nitro-2-pyridyl)-L-lysine are suspended in 80 ml of ethanol and 8 ml of water in a 100 ml three-necked flask equipped with a thermometer and a reflux condenser. 6 g of palladium-on-charcoal (10% active and 50% moisture) are then introduced, followed by 40 ml of cyclohexene. The mixture is brought to reflux for 2 hours and is then cooled, before being filtered through celite. After having run 60 ml (4 eq) of 1N hydrochloric acid onto the filtrate, the latter is evaporated to dryness and the residue is taken up in ethanol and precipitated from acetone. After filtration, 3.4 g of product are obtained, i.e. a final yield of 66%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10](=O)[CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[N:9][CH:8]=2)[CH:7]=1
Reactant: O=C(CCC(F)(F)C(F)(F)F)NCc1ccc(Cl)cn1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)C(F)(F)CCc1ncc2ccc(Cl)cn12
Temperature: 25 °C

Procedure:
To a solution of the intermediate from Step F (7.1 g, 22.42 mmol) in 1,2-dichloroethane (30 mL) was added phosphorous oxychloride (10.45 mL, 112 mmol). The resulting mixture was refluxed for 18 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between water and ethyl acetate. The aqueous layer was neutralized with solid sodium bicarbonate and then extracted with ethyl acetate (3×). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give a light yellow solid. m/z=298.9 (M+H).
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[NH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>C(O)C>[O:19]=[C:20]1[N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:10][CH:27]=[C:21]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(NCc1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2)n(Cc2ccccc2)c1=O
Temperature: 25 °C

Procedure:
To a stirred solution of N-(phenylmethyl)-benzenecarboximidamide (i.e. the product from Step A) (2.54 g, 12.1 mmol) in ethanol (15 mL) was added diethyl ethoxymethylenemalonate (2.61 g, 12.1 mmol), and the reaction mixture was heated to reflux for 24 h. The reaction mixture was then allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 30% ethyl acetate in hexanes to afford the title product as a white solid (2.9 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>C(#N)C>[Br-:1].[CH3:22][C:19]1[CH:20]=[CH:21][N+:16]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:17][CH:18]=1
Reactant: BrCCCCCCCCc1ccccc1
Reactant: Cc1ccncc1
Solvent: CC#N
Product: Cc1cc[n+](CCCCCCCCc2ccccc2)cc1
Product: [Br-]
Yield: 78 %

Procedure:
(8-Bromo-octyl)-benzene (1 mmol) was added to a solution of 4-picoline (3 mmol) in acetonitrile, and the solution was refluxed for 24 hours. The acetonitrile was removed in vacuum and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no picoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (78%). 1HNMR (300 MHz, CDCl3, ppm) 9.26 (d, 2H), 7.84 (d, 2H), 7.14-7.28 (dd, 4H), 4.90 (t, 2H), 2.62 (s, 3H), 2.56 (t, 2H), 1.92-2.02 (m, 2H), 1.50-1.60 (m, 2H), 1.20-1.40 (br, 8H). 13CNMR, 158.92, 144.28, 142.86, 128.95, 128.56, 128.40, 125.76, 61.61, 36.19, 32.15, 31.71, 29.53, 29.42, 29.31, 26.37, 22.63.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[S:7][C:6]2=[N:8][CH:9]=[C:10]([CH:11]=[O:12])[N:5]2[N:4]=1.[CH3:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OO)(C)(C)C>C(#N)C.O>[CH2:16]([N:15]([CH3:14])[C:11]([C:10]1[N:5]2[C:6]([S:7][C:3]([N:2]([CH3:13])[CH3:1])=[N:4]2)=[N:8][CH:9]=1)=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)c1nn2c(C=O)cnc2s1
Reactant: CNCc1ccccc1
Agent: CC(C)(C)OO
Solvent: O
Solvent: CC#N
Product: CN(Cc1ccccc1)C(=O)c1cnc2sc(N(C)C)nn12
Temperature: 80 °C
Yield: 29 %

Procedure:
2-Dimethylamino-imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (116 mg, 0.591 mmol) was dissolved in dry acetonitrile (4 mL) and N-methylbenzylamine (0.768 mmol, 0.1 mL) and t-butylhydroperoxide (0.768 mmol, 5.5M, 0.14 mL) were added. The mixture was heated at 80° C. for 10 hours. The reaction mixture was diluted with water (4 mL) at room temperature and extracted with dichloromethane (3×8 mL). The combined organic layer was dried over sodium sulphate and concentrated in vacuo. The crude product was purified by flash chromatography (Isolute cartridge SiII, ethyl acetate:dichloromethane, 1:9 to 10:0) yielding 54 mg of 2-dimethylamino-imidazo[2,1-b][1,3,4]thiadiazole-5-carboxylic acid benzyl-methyl-amide as yellowish solid (29% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:6]#[N:7].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[N+:11]([C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH2:2][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:10]=1)[C:6]#[N:7])([O-:13])=[O:12]
Reactant: N#Cc1cc(CBr)cc([N+](=O)[O-])c1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(CN2CCCC2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a stirred solution of 3-(bromomethyl)-5-nitrobenzonitrile (1.50 g, 6.22 mmol) and pyrrolidine (0.53 g, 7.46 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.88 g, 18.68 mmol) dropwise at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was diluted with water (15 mL) and extracted with EtOAc (3×50 mL). The EtOAc solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 3-nitro-5-(pyrrolidin-1-ylmethyl)benzonitrile (1.30 g, 90%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.45 (br s, 1H), 8.39 (br t, 1H, J=1.6 Hz), 8.02 (br s, 1H), 3.78 (s, 2H), 2.56 (br s, 4H), 1.84 (br s, 4H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([NH:18][CH3:19])[N:12]=1.[OH-].[Na+]>>[Cl:10][C:11]1[N:12]=[C:13]([NH:18][CH3:19])[N:14]=[C:15]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]2)[N:16]=1
Reactant: CNc1nc(Cl)nc(Cl)n1
Reactant: O=C(O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CNc1nc(Cl)nc(N2CCC(C(=O)O)CC2)n1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
4-Piperidinecarboxylic acid (2.10 g, 16.3 mmol, 1.00 equiv) was added to the suspension prepared in step a. The resulting mixture was heated to 40° C. and treated with 1 N NaOH to maintain a pH of 9-10. The reaction mixture was stirred for 2 h at the same temperature and then used immediately in the next step without workup or purification. MS (ES+): m/e 428.9 [M+H]+.
Reaction SMILES: [N:1]1([C:8]2[N:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)C=[C:10]([N:17]3[CH2:20][CH:19](OS(C)(=O)=O)[CH2:18]3)[C:9]=2[CH3:26])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-]#[N:28].[Na+].C[N:31]([CH3:34])C=O>>[N:1]1([C:8]2[N:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:28]=[C:10]([N:17]3[CH2:20][CH:19]([C:34]#[N:31])[CH2:18]3)[C:9]=2[CH3:26])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(N2CC(OS(C)(=O)=O)C2)cc(C2CC2)nc1N1CCCCCC1
Reactant: CN(C)C=O
Reactant: [C-]#N
Agent: [Na+]
Product: Cc1c(N2CCCCCC2)nc(C2CC2)nc1N1CC(C#N)C1
Temperature: 120 °C
Yield: 60 %

Procedure:
A mixture of methanesulfonic acid 1-(6-azepan-1-yl-2-cyclopropyl-5-methyl-pyrimidin-4-yl)-azetidin-3-yl ester 190 (0.3 g, 0.8 mmol) and sodium cyanide (0.047 g, 1.0 mmol) in N,N-dimethylformamide (5 ml) is heated at 120° C. for 24 hours. The mixture is then cooled and concentrated in vacuo. The mixture is diluted with dichloromethane and washed two times with water. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo to afford 0.4 g of a crude mixture, which is purified by column chromatography (dichloromethane/ethanol 98/2). 0.10 g (60%) of 1-(6-azepan-1-yl-2-cyclopropyl-5-methyl-pyrimidin-4-yl]-azetidine-3-carbonitrile 183 is obtained.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[NH3:11]>>[C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].[NH4+:11]
Reactant: N
Reactant: O=C(O)CCCCC(=O)O
Product: O=C([O-])CCCCC(=O)O
Product: [NH4+]

Procedure:
Exceptions to this generalization are provided by the reactions of adipic acid with ammonia and with tert.butylamine. When adipic acid is reacted with two or more moles of ammonia, diammonium adipate is obtained in quantitative yield. However, if one reacts adipic acid with one mole of ammonia one can obtain ammonium hydrogen adipate as a pure crystalline salt. When adipic acid is reacted with two or more moles of tert.butylamine, bis-tert.butylammonium adipate is obtained in quantitative yield, but in this case it is not possible to obtain the mono-tert.butylammonium adipate as a pure crystalline compound. When one reacts 0.5 mole of adipic acid with 0.5 mole of tert.butylamine in methanol one obtains first 0.19 mole of the bis-salt, m.p. 185°-187° d. The second crop, 35.4 g, m.p. 91°-135°, might represent 0.17 mole of the crude mono-salt, but on recrystallization to effect purification the only pure compound isolated is the bis-salt. When one reacts 0.50 mole of adipic acid with 0.27 mole of tert.butylamine the product is 61.2 g of salt having m.p. 91°-101°, which cannot be pure mono-salt since this weight of product would represent a yield greater than 100%. Analysis for nitrogen gave 5.52% whereas the pure mono-salt would have 6.76% nitrogen. The product is, therefore, a mixture of mono-salt and adipic acid. Again all attempts to purify this product by crystallization gave only the bis-salt, and it is clear that in this case the bis-salt is so much less soluble than any other possible product that recrystallization always results in its precipitation except when a large excess of adipic acid is present. For a more detailed discussion of the amine salts of dibasic acids, both normal and anomalous, see J. E. Barry, M. Finkelstein and S. D. Ross, J. Org. Chem. 47, 64 (1982).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([NH:34][CH:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: CN1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC2CCN(C)CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 22.1 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using 1-methylpiperidin-4-amine (195 mg, 1.71 mmol) and N,N-diisopropylethylamine (147 mg, 1.14 mmol) instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol 40:40:20:0 to 0:75:20:5, 56 mg, 22%) which was obtained as an off-white solid. MS: m/e=446.2 [M+H]+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26].[CH3:33][N:34]([CH3:37])[CH:35]=[S:36]>CCCCCC.C1COCC1>[CH3:33][N:34]([CH3:37])[C:35](=[S:36])[CH:25]([C:24]1[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=1[O:22][CH3:21])[OH:26]
Reactant: CN(C)C=S
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(O)C(=S)N(C)C)c(OC)c1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 45.7 %

Procedure:
A 110 mL THF solution of lithium diisopropylamide (LDA) ( 80 mmol) was generated from a 1.6 M hexane solution of n-butyllithium (50 mL, 80 mmol) and diisopropylamine ( 11.2 mL, 80 mmol) at -10° C., then cooled to -78° C. A 50 mL solution of 2,4-dimethoxybenzaldehyde (12 g, 72 mmol) and N,N-dimethylthioformamide (6.8 mL, 80 mmol) was cooled to 0° C. and added to the -78° C. LDA solution at a rate keeping the temperature less than -70° C. The reaction mixture was stirred at -75° C. for 2.5 hours, allowed to warm to 0° C., quenched with saturated aqueous NH4Cl, and extracted with EtOAc three times. The EtOAc extracts were combined, washed with brine, dried (Na2SO4), concentrated, triturated with Et2O/ pet. ether, filtered, and dried in vacuo to give 8.4 g(46% yield) of product: mp 139-140° C.; 1H NMR (CDCl3) d 3.05 (s, 3H, NCH3), 3.50 (s, 3H, NCH3), 3.80 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 5.19-5.21 (d, 1H, J=7 Hz, OH), 5.72-5.74 (d, 1H, J=7 Hz, CH), 6.43-6.47 (m, 2H, ArH), 7.24(s, 1H, ArH); MS(FD) 255(M+). Anal. Calcd for C12H17NO3S: C, 56.45; H, 6.71; N, 5.49. Found: C, 56.64; H, 6.49; N, 5.59.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:15])[O:11][C:10]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](N)=[CH:21][CH:20]=1)([CH3:16])[CH2:9][C:8]2=[O:26])(=[O:3])[CH3:2].[ClH:27].N([O-])=O.[Na+].[C:32]([O:36][CH2:37][CH3:38])(=[O:35])[CH:33]=[CH2:34]>O.CC(C)=O>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:15])[O:11][C:10]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:34][CH:33]([Cl:27])[C:32]([O:36][CH2:37][CH3:38])=[O:35])=[CH:21][CH:20]=1)([CH3:16])[CH2:9][C:8]2=[O:26])(=[O:3])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CC(=O)Oc1cc2c(cc1Cl)OC(C)(COc1ccc(N)cc1)CC2=O
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CC(=O)c3cc(OC(C)=O)c(Cl)cc3O2)cc1

Procedure:
A procedure similar to that described in Preparation 5 was repeated, except that 1.44 g of 6-acetoxy-2-(4-aminophenoxymethyl)-7-chloro-2-methyl-4-oxochroman (prepared as described in Preparation 36), 1.8 ml of concentrated aqueous hydrochloric acid, 330 mg of sodium nitrite, 18 ml of acetone, 3.7 ml of ethyl acrylate, 330 mg of cuprous oxide and 3 ml of water were reacted, to afford 600 mg of the title compound as a pale yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([O:17][C:18](=[O:27])[CH2:19][N:20]1[C:24](=[O:25])[CH2:23][S:22][C:21]1=[S:26])[CH3:16].N1CCCCC1>ClCCl>[CH2:15]([O:17][C:18](=[O:27])[CH2:19][N:20]1[C:24](=[O:25])/[C:23](=[CH:13]/[C:11]2[O:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=3)=[CH:9][CH:10]=2)/[S:22][C:21]1=[S:26])[CH3:16]
Reactant: O=Cc1ccc(-c2cccc(I)c2)o1
Reactant: CCOC(=O)CN1C(=O)CSC1=S
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCOC(=O)CN1C(=O)/C(=C/c2ccc(-c3cccc(I)c3)o2)SC1=S
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
5-(3-Iodophenyl)furan-2-carbaldehyde (30 mg, 0.1 mmol) and ethyl-2-(4-oxo-2-thioxothiazolidin-3-yl)acetate (22 mg, 0.1 mmol) were dissolved in dichloromethane (7 mL), piperidine (20 μL) was added thereto, and the mixture was stirred at room temperature (25° C.) for 3 hours. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (3/7 (volume ratio)) as an eluent, to give the target compound 1 in a yield of 38 mg (yield 76.2%).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8])([OH:3])=[O:2].[N+](=[CH2:17])=[N-]>CCOCC>[CH3:17][O:2][C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8])=[O:3]
Reactant: O=C(O)c1cccc2c1C(=O)NC2=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1cccc2c1C(=O)NC2=O

Procedure:
To a suspension of 3-carboxyphthalimide (10 g) in ether (50 ml), a solution of diazomethane in ether was added slowly until a faint yellow colouration persisted. Excess of diazomethane was destroyed with acetic acid and the reaction mixture was evaporated to yield the desired compound.
Reaction SMILES: CS[C:3]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].O.[NH2:20][NH2:21]>CCO>[NH2:6][C:5]1[NH:21][N:20]=[C:3]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[C:4]=1[C:7]#[N:8]
Reactant: CSC(Nc1ccc([N+](=O)[O-])cc1)=C(C#N)C#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: N#Cc1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1N
Temperature: 0 °C

Procedure:
Dissolved 2-((methylthio)((4-nitrophenyl)amino)methylene)malononitrile in EtOH (100 mL) and added hydrazine hydrate (1 eq., 3.64 mL), then heated to reflux until complete by TLC (absence of starting material, 18 hrs). Poured into ice water and filtered to obtain 5-amino-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carbonitrile as a yellow powder.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C:9]1[N:10]=[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]2[C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)(C)(C)C.C(OCC)(=O)C>O1CCOCC1>[CH3:17][C:13]1[N:12]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=3)=[C:9]([NH2:8])[N:10]=[C:11]2[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc2nc(NC(=O)OC(C)(C)C)c(-c3cccc(C(F)(F)F)c3)n12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cccc2nc(N)c(-c3cccc(C(F)(F)F)c3)n12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4 M of Hydrogen chloride in 1,4-dioxane (0.8 mL) was added to [5-Methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-yl]-carbamic acid tert-butyl ester (compound r, 0.14 g, 0.00036 mol). The mixture was stirred at room temperature for 2 hours. Solvent evaporated to give 0.1 g as a yellow oil. Rf 0.42, 100% ethyl acetate; MS m/z 292 (M+H).