Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH2:6][CH:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].S(=O)(=O)(O)O>C(#N)C>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: CCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Yield: 104.7 %

Procedure:
To a 500 mL flask, ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (20.00 g, 90%, 54.12 mmol), potassium persulfate (23.40 g, 86.60 mmol) and acetonitrile (180 mL) were added. The reaction mixture was stirred at room temperature. The sulfuric acid (10.82 g, 108.24 mmol) was added dropwise slowly. After added completely, the reaction mixture was heated to reflux for 2 hours. The reaction mixture was concentrated by rotary evaporator to remove most acetonitrile. Water (100 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate and concentrated by rotary evaporator to give the product (18.73 g) as a yellow solid in 89% yield. HPLC area normalization method content is 85%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=3[CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O1CCC[CH2:23]1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:18]([C:19]([O:21][CH3:23])=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=3[CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cccc2cc(-c3ccc([N+](=O)[O-])cc3)oc12
Reactant: C1CCOC1
Product: COC(=O)c1cccc2cc(-c3ccc([N+](=O)[O-])cc3)oc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A diazomethane-ether solution (prepared from 5.0 g of nitrosomethylurea) is added to a solution of 6.0 g of 2-(4-nitrophenyl)benzofuran-7-carboxylic acid in 60 ml of tetrahydrofuran and the mixture is stirred at room temperature for 1 hour. The reaction mixture is evaporated to remove solvent and the residue is dissolved in ethyl acetate. The solution is washed with water, dried and evaporated to remove solvent. The residue is washed with ethyl acetate and dried to give 3.82 g of methyl 2-(4-nitrophenyl)benzofuran-7-carboxylate as pale brown powder.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:15]=[C:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23]>C(#N)C>[C:9]1([NH:8][CH2:15][CH:16]2[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]2=[O:23])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C1CCC(=O)NC1=O
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(CNc2ccccc2)C(=O)N1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
30 ml absolute triethylamine and 2.75 ml freshly distilled aniline were added to a solution of 1.25 g 3-methylene piperidine-2,6-dione (M. J. Wanner and G. -J. Koomen, Tetrahedron Lett. 1992, 33, 1513-1516) in 100 ml acetonitrile and the mixture was stirred for 16 h at 80° C.
Reaction SMILES: ClCCCl.[Cl:5][C:6]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].[N+:15]([O-])([O-:17])=[O:16].[K+].S(=O)(=O)(O)O>C(Cl)Cl>[Cl:5][C:6]1[CH:13]=[C:12]([F:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=Cc1cc([N+](=O)[O-])c(F)cc1Cl
Reaction time: 1.33 h
Yield: 64.8 %

Procedure:
To 300 ml of 1,2-dichloroethane that had been cooled to 0° C. was added 31.3 g (0.197 mole) of 2-chloro-4-fluorobenzaldehyde, prepared by the method of Example 2, Steps A and B. Subsequently, 19.96 g (0.197 mole) of potassium nitrate was added to the reaction mixture, and dropwise addition of 300 ml of concentrated sulfuric acid followed while maintaining the temperature between 0° C. and 5° C. The reaction was complete after 80 minutes, and 750 ml of methylene chloride was added to the reaction mixture. The phases were separated, and the sulfuric acid phase was extracted three times with 150 ml of methylene chloride. The extracts were combined with the organic phase before being washed three times with 450 ml of water. The extracts were dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure, leaving an amber oil weighing 32.5 g as a residue. This oil was passed through a column of silica gel, eluting with ethyl acetate/heptane (1/4). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure, leaving 26.0 g of 2-chloro-4-fluoro-5-nitrobenzaldehyde as an amber oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[C:17]2[NH:18][CH2:19][CH2:20][O:21][C:16]=2[C:15]([F:22])=[CH:14][CH:13]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.FC1C=CC2=C3C=1OCCN3C(C(NC(=O)C)C)=N2>CC(O)=O>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([C:10]1[N:18]2[C:17]3[C:16]([O:21][CH2:20][CH2:19]2)=[C:15]([F:22])[CH:14]=[CH:13][C:12]=3[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)c2c1NCCO2
Agent: CC(=O)NC(C)c1nc2ccc(F)c3c2n1CCO3
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(NC(=O)OC(C)(C)C)c1nc2ccc(F)c3c2n1CCO3
Reaction time: 16 h

Procedure:
A solution of [(S)-1-(8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylcarbamoyl)ethyl]carbamic acid tert-butyl ester (440 mg, 1.297 mmol) in AcOH (15 mL) was stirred successively at 80° C. for 1 h, 100° C. for 5 h and then 85° C. for 16 h. Toluene was added and the reaction mixture concentrated in vacuo to give a mixture of the title compound and N-[1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)ethyl]acetamide. LCMS (Method B): RT 1.72 min [M+H]+ 264 & 2.51 min [M+H]+ 322
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[C-]#N.[Na+].[N:30]12CCN(CC1)C[CH2:31]2.O>CS(C)=O>[CH3:24][C:23]([CH3:26])([CH3:25])[CH2:22][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[CH:12][CH:11]=1)[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:31]#[N:30])[N:7]=1
Reactant: C1CN2CCN1CC2
Reactant: CC(C)(C)CN(Cc1ccc(Cn2cncn2)cc1)c1ccnc(Cl)n1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)CN(Cc1ccc(Cn2cncn2)cc1)c1ccnc(C#N)n1
Temperature: 70 °C
Reaction time: 5 h
Yield: 69167.1 %

Procedure:
(2-Chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-(4-[1,2,4]triazol-1-ylmethyl-benzyl)-amine (160 mg, 0.43 mmoles) and sodium cyanide (0.1 g, 2.2 mmoles) are dissolved in 5 ml of DMSO and 1,4-diaza bicyclo[2,2,2]octane (23 mg, 0.2 mmoles) is added at rt. The mixture is stirred at rt for 5 h at 70° C. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 50 g of desired 4-[(2,2-dimethyl-propyl)-(4-[1,2,4]triazol-1-ylmethyl-benzyl)-amino]-pyrimidine-2-carbonitrile in 32% yield.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:36]1(Br)[CH2:40][CH2:39][CH2:38][CH2:37]1.O>CN(C)C=O>[CH:36]1([N:15]2[C:16]([CH3:29])=[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:21][CH:20]=3)[C:13]([O:12][C@@H:1]3[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]3[OH:3])=[N:14]2)[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: BrC1CCCC1
Reactant: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OC(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.050 g) and cesium carbonate (0.20 g) in N,N-dimethylformamide (1 mL) was added cyclopentyl bromide (0.055 g) at 80° C., and the mixture was stirred for 30 minutes. After cooling to room temperature, water was added to the reaction mixture, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol), and successively by column chromatography on silica gel (eluent: dichloromethane/methanol=8/1) to give 1-cyclopentyl-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.034 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)CCC>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(cc(-c3ccccn3)n2Cc2ccccc2)n1
Temperature: 110 °C
Reaction time: 6 h
Yield: 40.3 %

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.10 g, 0.31 mmol, from Example 62, Step 2) and 2-(tributylstannyl)pyridine (0.11 g, 0.31 mmol, Aldrich) in toluene (6.0 mL) was degassed by a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol) was added and the mixture was stirred at 110° C. for 6 hours. Solvent was removed in vacuo and the residue was dissolved in MeCN, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes afforded desired product (40 mg, 40%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:38]=[CH:37][CH:36]=[CH:35][C:5]=1[C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=2)[CH2:13][CH2:12]1)=[O:7])[CH3:2].C(N(CC)CC)C.[C:46](Cl)(=[O:50])[O:47][CH2:48][CH3:49].[O:52]1CCC[CH2:53]1>>[CH2:1]([N:3]1[C:4]2[C:5](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:6](=[O:7])[N:8]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([N:17]([C:18]3[N:22]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[N:19]=3)[C:46](=[O:50])[O:47][CH2:48][CH3:49])[CH2:15][CH2:16]2)[C:53]1=[O:52])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: C1CCOC1
Reactant: CCNc1ccccc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCN(CCn2c(=O)c3ccccc3n(CC)c2=O)CC1
Reaction time: 1 h
Yield: 25 %

Procedure:
To a stirred mixture of 7.7 parts of 2-(ethylamino)-N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-ethyl]benzamide, 2 parts of N,N-diethylethanamine and 90 parts of tetrahydrofuran were added dropwise 1.6 parts of ethyl carbonochloridate. Upon completion, stirring was continued for 1 hour at room temperature. The reaction mixture was evaporated and 4-methyl-2-pentanone was added to the residue. The organic phase was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by HPLC using a mixture of methylbenzene and ethanol (90:10 by volume) as eluent. The pure fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 2.2 parts (25%) of ethyl [1-[2-[1-ethyl-1,4-dihydro-2,4-dioxo-3(2H)-quinazolinyl]ethyl]-4-piperidinyl]-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]carbamate; mp. 160.3° C. (compound 124).
Reaction SMILES: C(O)C.[OH-].[Na+].[N+](C1C=CC(C([O:15][CH2:16]/[CH:17]=[C:18](/[CH2:20][CH2:21]/[CH:22]=[C:23](\[CH3:35])/[CH2:24][CH2:25]/[CH:26]=[C:27](/[CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])\[CH3:28])\[CH3:19])=O)=CC=1)([O-])=O>O.C1(C)C=CC=CC=1>[CH2:25]([CH2:24][C:23](=[CH:22][CH2:21][CH2:20]/[C:18](=[CH:17]/[CH2:16][OH:15])/[CH3:19])[CH3:35])/[CH:26]=[C:27](/[CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])\[CH3:28]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)=CCC/C(C)=C/CCC(C)=CCC/C(C)=C/CO
Temperature: 50 °C
Reaction time: 2 h
Yield: 111 %

Procedure:
100 g of ethanol, 7.88 g of sodium hydroxide and 30 g of water were added to 75 g of geranylgeranyl p-nitrobenzoate (containing 0.98 g of geranylneryl p-nitrobenzoate and 67.35 g of geranylgeranyl p-nitrobenzoate) obtained as a cake in Example 7. The reaction mixture was stirred at 50°C. for 2 hours and cooled down to room temperature, to which 300 g of toluene and 200 g of water were added. The resulting organic phase was separated and washed twice with 200 g of water, and concentrated under reduced pressure to give 55 g of crude geranylgeraniol. This crude product was subjected to simple distillation (154°C., 0.5 mmHg) to give 42.1 g of a main fraction. The results of the analysis of the obtained fraction with gas chromatography under the same conditions as in Example 14 revealed that it contained geranylgeraniol with a purity of 97.8% and geranylnerol with a purity of 1.2%.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([NH:6][C@@H:7]2[CH2:11][C@H:10]([CH2:12][OH:13])[CH:9]=[CH:8]2)=[C:4]([N+:17]([O-])=O)[CH:3]=1.[CH2:20](O)CC>[Ni]>[Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[N:6]([C@@H:7]3[CH2:8][CH2:9][C@H:10]([CH2:12][OH:13])[CH2:11]3)[CH:20]=[N:17][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1N[C@H]1C=C[C@@H](CO)C1
Reactant: CCCO
Agent: [Ni]
Product: OC[C@H]1CC[C@@H](n2cnc3cc(Cl)c(Cl)cc32)C1
Reaction time: 2 h
Yield: 85 %

Procedure:
A mixture of (±)-cis-[4-(4,5-dichloro-2-nitroanilino)-2-cyclopenten-1-yl]methanol (5.00 g, 16.5 mmol) and Raney nickel (Aldrich, slurry in water, 500 mg wet) in n-propanol (250 mL) was shaken under hydrogen (50 psi) on a Parr shaker for 2 hours. The catalyst was filtered off, solvent evaporated in vacuo, and the residue dissolved in triethylorthoformate(300 mL)-methanesulfonic acid (200 mg). After 18 hours, the solution was concentrated to a syrup which was dissolved in 1N hydrochloric acid (40 mL) and stirred at ambient temperature overnight. The pH was adjusted to 7 with 1N sodium hydroxide and the solution extracted with chloroform (3×50 mL). The contents of the dried (sodium sulfate) chloroform solution was chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform as a colorless oil which solidified from ethyl acetate-hexanes to give white powder (3.98 g, 85%). m.p. 142°-145° C.; 1H-NMR(DMSO-d6) and mass spectrum(CI) consistent with structure.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:13][C:14]([N:16]2[CH:20]=[CH:19]N=C2)=[O:15])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.NCC[C:24]([N:26]([CH3:28])[CH3:27])=[O:25]>O1CCOCC1>[CH3:27][N:26]([CH3:28])[C:24](=[O:25])[CH2:19][CH2:20][NH:16][C:14]([NH:13][C:4]1[S:5][C:6]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)=[C:2]([CH3:1])[N:3]=1)=[O:15]
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccncc1
Reactant: CN(C)C(=O)CCN
Solvent: C1COCCO1
Product: Cc1nc(NC(=O)NCCC(=O)N(C)C)sc1-c1ccncc1
Temperature: 25 °C

Procedure:
To a stirred suspension of imidazole-1-carboxylic acid (4-methyl-5-pyridin-4-yl-thiazol-2-yl)-amide (example 18a) (0.15 g, 0.526 mmol) in dioxane (10 ml) is added 3-amino-N,N-dimethyl-propionamide (0.046 g, 0.526 mmol) in one portion. The reaction mixture is heated to reflux for 2 hours. The reaction mixture is allowed to cool to room temperature and the solvent is removed in vacuo. Trituration with ether/ethyl acetate yields the titled compound as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][N:15]3[CH3:18])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:21]1[CH2:31][CH2:30][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:22]1.C(OC(C1CCN(C2C=CC=CN=2)CC1)=O)C>CCOC(C)=O>[CH2:28]([O:27][C:25]([CH:24]1[CH2:30][CH2:31][N:21]([C:2]2[CH:20]=[CH:19][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:17]=[C:16]4[C:12]([CH:13]=[CH:14][N:15]4[CH3:18])=[CH:11][CH:10]=3)=[CH:4][N:3]=2)[CH2:22][CH2:23]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cn1ccc2ccc(NC(=O)c3ccc(Cl)nc3)cc21
Agent: CCOC(=O)C1CCN(c2ccccn2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc4ccn(C)c4c3)cn2)CC1

Procedure:
5′-(1-Methyl-1H-indol-6-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from 6-chloro-N-(1-methyl-1H-indol-6-yl)-nicotinamide and ethyl isonipecotate following a procedure similar to the one described in the synthesis of 5′43-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester above. The product was isolated by silica gel column purification with 20-40% EtOAc in hexanes gradient. HRMS m/z calcd for C23H26N4O3 [M+H]+: 407.2078. Found: 407.2076.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][CH2:11]I)=[CH:8][O:9][C:5]=2[CH:4]=1.[CH3:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:25]=1)[N:22]=[CH:21][CH:20]=[CH:19]2>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][CH2:11][N:29]3[CH2:30][CH2:31][N:26]([C:24]4[CH:25]=[C:16]([CH3:15])[CH:17]=[C:18]5[C:23]=4[N:22]=[CH:21][CH:20]=[CH:19]5)[CH2:27][CH2:28]3)=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(CCI)coc2c1
Reactant: Cc1cc(N2CCNCC2)c2ncccc2c1
Product: COc1ccc2c(CCN3CCN(c4cc(C)cc5cccnc45)CC3)coc2c1

Procedure:
8-{4-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methyl-quinoline was prepared by generally following the procedure outlined in example 9, step 6, starting from the step of 2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-methyl-8-piperazino quinoline (227 mg, 1 mmol). The product was purified by silica-gel column chromatography by initially eluting it with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown oil Yield: 210 mg (52%); (M+H): 402; 1HNMR (400 MHz, CDCl3):δ 8.81˜8.80 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.02˜7.99 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H) 7.46˜6.88 (m, 7H); 3.9 (s, 3H); 3.60˜2.82 (m, 12H); 2.5 (s, 3H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH2:25][CH2:26][CH2:27][C:28](O)=[O:29].[I-].ClC1C=CC=C[N+]=1C>>[CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:19]2[C:18]3[C:22](=[CH:23][CH:24]=[C:16]([O:15][CH3:14])[CH:17]=3)[NH:21][CH:20]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCCNC2)cc1
Reactant: COc1ccc2[nH]cc(CCCC(=O)O)c2c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: COc1ccc2[nH]cc(CCCC(=O)N3CCCC(Cc4ccccc4)C3)c2c1

Procedure:
Equimolar amounts of 3-benzylpiperidine and 4-(5-methoxyindol-3-yl)butanoic acid (preparation analogous to Example 1a) are reacted at room temperature with addition of 2-chloro-1-methyl-pyridinium iodide. After customary work-up, 3-benzyl-1-[4-(5-methoxyindol-3-yl)butanoyl]piperidine is obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]=[C:11]=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N-]=C=O.[NH2:16][C:17]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=2)[CH2:21][N:20]=[C:19]2[O:30][CH:31]=[CH:32][C:18]=12>>[NH2:16][C:17]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[CH2:1][CH2:2][CH2:3]4)=[O:12])[CH:24]=2)[CH2:21][N:20]=[C:19]2[O:30][CH:31]=[CH:32][C:18]=12
Reactant: NC1=c2ccoc2=NCN1c1cccc(N)c1
Reactant: O=C=Nc1ccc2c(c1)CCC2
Agent: [N-]=C=O
Product: NC1=c2ccoc2=NCN1c1cccc(NC(=O)Nc2ccc3c(c2)CCC3)c1

Procedure:
The compound was prepared following the procedure described in Example 232(b), using 5-indanyl isocyanate as the isocyanate of choice, and 4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine of choice. MS(ES) m/e 386 [M+H]+.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[F:17][C:18]([F:29])([F:28])[C:19]([O:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])=[O:20]>C(#N)C>[F:17][C:18]([F:29])([F:28])[C:19]([OH:21])=[O:20].[NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:22](=[O:27])[C:23]([F:24])([F:25])[F:26])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(-c2cccc(N)c2)cs1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: N=C(N)Nc1nc(-c2cccc(NC(=O)C(F)(F)F)c2)cs1
Product: O=C(O)C(F)(F)F

Procedure:
A mixture of 2-guanidino-4-(3-aminophenyl)-thiazole (1.2 g.) and trifluoroacetic anhydride (1.05 g.) was heated under reflux in acetonitrile for 3 hours. The mixture was cooled and the product (0.76 g.) filtered off to give 2-guanidino-4-(3-trifluoroacetylaminophenyl)thiazole trifluoroacetate, m.p. 152°-153° C.
Reaction SMILES: [Na].[C:2]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:3][C:4]([C:6](OCC)=[O:7])=O.Cl.[NH2:16][NH2:17]>C(O)C.O.Cl>[CH2:13]([O:12][C:2]([C:3]1[NH:16][N:17]=[C:6]([OH:7])[CH:4]=1)=[O:11])[CH3:14]
Reactant: NN
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(O)n[nH]1
Temperature: 80 °C

Procedure:
To a solution of 5 g Diethyl Oxalacetate sodium salt in 100 ml ethanol, 1.5 g hydrazine monohydrochloride were added and the reaction mixture was heated to 80° C. for 3 h. Then the solution was diluted with 100 ml of water containing 3 ml of halfconcentrated HCl and extracted with DCM (3×100 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was subjected to the next reaction step without further purification; Yield: 3.4 g
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:3]=1[CH:4]=O.C(O)C.[ClH:17].[C:18]([CH2:21][O:22][NH2:23])([OH:20])=[O:19].C(CON)(O)=O.C([O-])(=O)C.[Na+]>O>[Cl:17][CH:21]([O:22][N:23]=[CH:4][C:3]1[C:6]([Cl:13])=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[CH:2]=1)[C:18]([OH:20])=[O:19]
Reactant: Cl
Reactant: NOCC(=O)O
Reactant: O=Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)C(Cl)ON=Cc1cc([N+](=O)[O-])ccc1Cl

Procedure:
A warm solution of 2,6-dichloro-3-nitrobenzaldehyde, 1.8 gm. in 20 ml. of ethanol was stirred into a solution of 0.9 gm. (0.008 equivs.) of carboxymethoxylamine hemihydrochloride and 0.45 gm. of sodium acetate, anhyd., in 20 ml. of water at room temperature. The mixture was heated on the steam bath for one-half hour, and was then evaporated to dryness at room temperature. The residue was triturated with cold water, filtered, washed with cold water and dried in air to obtain 2.1 gm. (87.4%) of crude material melting at 76°-84° C. This was purified from aqueous-methanol to obtain 1.9 gm. of pale cream-colored product melting at 82°-85° C.