Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[C:25]([CH2:29]Cl)=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[C-:31]#[N:32].[Na+].O>CN(C=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[C:25]([CH2:29][C:31]#[N:32])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(CCl)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc2cccc(CC#N)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-7-chloromethylbenzimidazole (0.83 g) and sodium cyanide (0.12 g) in DMF (10 ml) was stirred for 22 hours at room temperature. To the reaction mixture was added water and this mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off, and the residue was crystallized from ethyl acetate to givecolorless prisms (0.76 g, 94%), m.p. 180°-181° C.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1>>[CH3:6][O:5][C:3]([CH:2]1[CH2:7][CH2:8][N:10]1[CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)C(Br)CCBr
Reactant: CCOC(=O)N1CCC(N)CC1
Product: CCOC(=O)N1CCC(N2CCC2C(=O)OC)CC1
Yield: 50 %

Procedure:
The reaction of methyl 2,4-dibromobutanoate 17 with ethyl 4-aminopiperidine-1-carboxylate 18K yielded ethyl 4-(2-(methoxycarbonyl)azetidin-1-yl)piperidine-1-carboxylate as a yellow oil (50%). MS ISP (m/e): 271.3 (100) [(M+H)]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[SH:9].[CH:10](OCC)(OCC)OCC>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:10][S:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1S
Reactant: CCOC(OCC)OCC
Product: Brc1ccc2ncsc2c1

Procedure:
A 100 mL, one neck round bottom flask was charged with 2-amino-5-bromobenzenethiol (1.19 g, 5.83 mmol), triethyl orthoformate (9.70 ml, 58.3 mmol), 10 mL TFE, and a stirbar. A reflux condenser with a vacuum/nitrogen inlet was a fixed to the flask, and the system was degassed by evacuating to 5 mm Hg, and refilling with nitrogen. To the solution was added 200 mg dithiothreitol, and the reaction was heated using a 80° C. oil bath for 12 h. The reaction was cooled, and concentrated in vacuo. The crude was not characterized further.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3]([O:5][CH2:6][N:7]1[C:15]2[N:14]=[CH:13][N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:11]=2[C:10](=[O:23])[N:9]([CH3:24])[C:8]1=[O:25])=[O:4].[Cl:28]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]([CH3:27])([CH3:26])[C:3]([O:5][CH2:6][N:7]1[C:15]2[N:14]=[C:13]([Cl:28])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:11]=2[C:10](=[O:23])[N:9]([CH3:24])[C:8]1=[O:25])=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1c(=O)c2c(ncn2-c2ccccc2Cl)n(COC(=O)C(C)(C)C)c1=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(Cl)n2-c2ccccc2Cl)n(COC(=O)C(C)(C)C)c1=O
Reaction time: 8 h
Yield: 97 %

Procedure:
724 mg of [7-(2-chlorophenyl)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl 2,2-dimethylpropionate was suspended in 15 ml of N,N-dimethylformamide, and 760 mg of N-chlorosuccinimide was added thereto. The reaction solution was stirred overnight, and then diluted with ethyl acetate. The solution was washed with water and 1N hydrochloric acid, and dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated. Thus, 764 mg of [8-chloro-7-(2-chlorophenyl)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl 2,2-dimethylpropionate was obtained. This compound was mixed with 4 g of t-butyl piperazine-1-carboxylate. The mixture was heated at 150° C., and stirred for three hours. Ethyl acetate and water were added to the reaction mixture, and the mixture was separated. The organic layer was washed with 1N hydrochloric acid, and dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography. Thus, 724 mg of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3:2).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[CH:32]=[N:31][C:30](Br)=[CH:29][N:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:30]3[N:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: Nc1cnc(Br)cn1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Nc1cnc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and commercially available 2-amino-5-bromo-pyrazine (87 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (63 mg, 28%). MS (EI) 448.0 [(M)+]; mp 200° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[CH:26]1([NH2:29])[CH2:28][CH2:27]1.O>CCO>[CH:26]1([NH:29][C:3]([C:5]2[N:6]=[C:7]([C:24]#[N:25])[C:8]3[C:9](=[O:23])[N:10]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:11]=[CH:12][C:13]=3[C:14]=2[OH:15])=[O:4])[CH2:28][CH2:27]1
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NC1CC1
Solvent: O
Solvent: CCO
Product: N#Cc1nc(C(=O)NC2CC2)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 80 °C
Yield: 61.7 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (27 mg, 0.081 mmol) and cyclopropylamine (0.060 mL, 0.81 mmol) in 2 mL of EtOH was heated in a sealed tube at 80° C. for 4 h. After cooling to r.t., water (3 mL) were added. The mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (0-15% EtOAc/CH2Cl2) to give 18 mg of the title compound as a white solid. MS: (−) m/z 358.99 (M−1).
Reaction SMILES: C(OCC)(=O)C.[Cl:7][C:8]1[CH:9]=[C:10]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][C:17]2=[O:25])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:26][N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=O>CCOCC>[Cl:7][C:8]1[CH:9]=[C:10]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[C:28]3[CH2:29][CH2:30][CH2:31][N:27]3[CH3:26])[C:17]2=[O:25])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N2C(=O)Cc3ccccc32)cc1Cl
Reactant: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc(N2C(=O)C(=C3CCCN3C)c3ccccc32)cc1Cl

Procedure:
By the procedure of Example B1, except that ethyl acetate was used as eluant and ether to crystallize the product, 1-(3-chloro-4-methoxyphenyl)-2(1H,3H)-indolone (1.05 g, 3.84 mole) and N-methyl-2-pyrrolidone (0.62 ml, 6.42 mmoles) were converted to title product, 0.58 g, m.p. 126°-127.5°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([Cl:31])=[C:12]([CH:30]=2)[C:13]([NH:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH2:29])=[O:28])[CH:17]=2)=[O:14])[C:5]([F:32])=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].O.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[C:33]([NH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([Cl:31])=[C:12]([CH:30]=2)[C:13]([NH:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH2:29])=[O:28])[CH:17]=2)=[O:14])[C:5]([F:32])=[CH:4][CH:3]=1)(=[O:35])[CH3:34]
Reactant: NC(=O)c1cc(NC(=O)c2cc(-c3nc(N)ccc3F)ccc2Cl)n(-c2ccccc2)n1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(F)c(-c2ccc(Cl)c(C(=O)Nc3cc(C(N)=O)nn3-c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
To a solution of 5-(5-(6-amino-3-fluoropyridin-2-yl)-2-chlorobenzamido)-1-phenyl-1H-pyrazole-3-carboxamide (Preparation 1, 23 mg, 0.05 mmol) in acetic acid (2 mL) was added acetic anhydride (0.5 mL) and the reaction was stirred at room temperature for 18 hours. The reaction was poured into water (50 mL) and basified by the addition of solid potassium carbonate. The aqueous solution was extracted with ethyl acetate (50 mL) and the organic layer was washed with brine (50 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 40-60% EtOAc in heptanes followed by trituration in TBME to afford the title compound as a white solid (10 mg, 40%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([CH2:12][O:1][C:2]2[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: BrCC1CCCCC1
Reactant: CC(=O)c1cccc(O)c1
Product: CC(=O)c1cccc(OCC2CCCCC2)c1

Procedure:
Alkylation of 3′-hydroxy-acetophenone by bromomethylcyclohexane (2) was performed following the method given in Example 1. The product was purified by flash chromatography (5 to 30% EtOAc/hexane gradient) to give 1-(3-(cyclohexylmethoxy)phenyl)ethanone (103) as a colorless oil. Yield (3.17 g, 45%). 1H NMR (400 MHz, DMSO-d6) δ 7.50 (dt, J=1.4, 6.3 Hz, 1H), 7.36-7.42 (m, 2H), 7.16 (ddd, J=1.0, 2.7, 8.2 Hz, 1H), 3.80 (d, J=6.3 Hz, 2H), 2.54 (s, 3H), 1.60-1.80 (m, 6H), 1.10-1.30 (m, 3H), 0.90-1.10 (m, 2H).
Reaction SMILES: C(O)([C:3]([F:6])([F:5])[F:4])=O.Br[C:9]1[CH:26]=[C:25](/[CH:27]=[CH:28]/[CH:29]([C:34]2[CH:39]=[C:38]([Cl:40])[C:37]([Cl:41])=[C:36]([Cl:42])[CH:35]=2)[C:30]([F:33])([F:32])[F:31])[CH:24]=[CH:23][C:10]=1[C:11]([NH:13][CH:14]([CH3:22])[C:15]([O:17]C(C)(C)C)=[O:16])=[O:12]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[CH:29]([C:34]1[CH:39]=[C:38]([Cl:40])[C:37]([Cl:41])=[C:36]([Cl:42])[CH:35]=1)/[CH:28]=[CH:27]/[C:25]1[CH:24]=[CH:23][C:10]([C:11]([NH:13][C@H:14]([CH3:22])[C:15]([OH:17])=[O:16])=[O:12])=[C:9]([C:3]([F:6])([F:5])[F:4])[CH:26]=1
Reactant: CC(NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br)C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
TFA (1 mL) was added to a stirred solution of tert-butyl 2-(2-bromo-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)propanoate (1.0 g, 1.63 mmol) in CH2Cl2 (20 mL) at 0° C. and the reaction mixture was stirred at ambient temperature for 18 h. The volatiles were evaporated under vacuum and the residue was triturated with pentane to afford the title compound as brown solid (0.65 g, 67%): 1HNMR (400 MHz, DMSO-d6) δ 12.60 (bs, 1H), 8.82 (d, J=8.0 Hz, 1H), 7.99 (s, 1H), 7.92-7.89 (m, 3H), 7.51 (d, J=8.0 Hz, 1H), 7.08 (dd, J=15.6, 8.8 Hz, 1H), 6.88 (d, J=15.6 Hz, 1H), 4.88-4.83 (m, 1H), 4.41-4.34 (m, 1H), 1.34 (d, J=7.2 Hz, 3H); ESIMS: m/z 545.7 ([M−H]+); IR (KBr) 3410, 3281, 2928, 1728, 1172, 744 cm−1.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([C:23](O)=[O:24])[CH2:6]1)(=[O:3])[CH3:2].[CH2:26]([O:29][C:30]([C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([NH2:41])[CH:40]=1)[C:35]([NH2:37])=[O:36])=[O:31])[CH:27]=[CH2:28]>>[C:1]([S:4][CH:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[CH:7]([C:23](=[O:24])[NH:41][C:39]2[CH:38]=[C:34]([C:35](=[O:36])[NH2:37])[CH:33]=[C:32]([C:30]([O:29][CH2:26][CH:27]=[CH2:28])=[O:31])[CH:40]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)c1cc(N)cc(C(N)=O)c1
Reactant: CC(=O)S[C@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: C=CCOC(=O)c1cc(NC(=O)C2CC(SC(C)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc(C(N)=O)c1
Yield: 49.9 %

Procedure:
(2S,4S)-4-Acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-carboxypyrrolidine (0.75 g) was converted to the acid chloride and reacted with 3-allyloxycarbonyl-5-aminobenzamide (0.45 g) by a similar method to that described in example 12. The crude product was subjected to chromatography on silica gel, eluting with EtOAc and giving 4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonyl-5-carbamoylphenylcarbamoyl)pyrrolidine (0.58 g). Nmr (DMSO-d6): δ 1.92-2.06 (m, 1H); 2.3 (s, 3H); 2.79-2.83 (m, 1H); 3.38 (dd, 1H); 3.97-4.12 (m, 2H); 4.49 (dd, 1H); 4.83 (dt, 2H); 5.19 (dd, 2H); 5.25-5.43 (m, 2H); 5.97-6.11 (m, 1H); 7.31 (broad s, 2H); 7.54 (d, 2H); 8.04 (d, 2H); 8.12 (t, 1H); 8.26 (t, 1H); 8.31 (t, 1H); 10.0 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[CH2:11][CH3:12].C([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[CH2:11][CH3:12]
Reactant: CCc1cc2cc[nH]c2cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCc1cc2c(cc1Cl)NCC2
Yield: 77.2 %

Procedure:
6-Chloro-5-ethylindole (D51) (0.62 g, 3.46 mmol) was treated with sodium cyanoborohydride as in the method of Description 10 to give the title compound (0.485 g, 77%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([OH:15])([CH3:14])[C:12]#[CH:13].O1CCCC1>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)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:13]#[C:12][C:11]([OH:15])([CH3:14])[CH3:10])=[CH:3][CH:4]=1)#[N:7]
Reactant: C#CC(C)(C)O
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc(C#N)cc1
Yield: 105.3 %

Procedure:
50 g (274.7 mmol) 4-bromobenzonitrile, 46.2 g (550 mmol) 3-methyl-1-butyne-3-ol, 0.97 g (1.38 mmol) bis(triphenylphosphine) dichloropalladium, 0.26 g (1.38 mmol) copper iodide and 2 g (7.6 mmol) triphenyl phosphine were added in a nitrogen stream, and 100 ml tetrahydrofuran (THF) and 20 ml triethylamine were added thereto, and the mixture was reacted at 80 ° C. for 15 hours. The reaction solution was concentrated and partitioned by adding 300 ml ethyl acetate and 300 ml water, and the organic layer was washed twice with 100 ml water and dried over magnesium sulfate anhydride. The solvent was distilled away, and about 250 ml heptane was added to the residual paste and stirred for a while, and the precipitated crystals were filtered to give 53.6 g crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:12]([O:14][C:15](=[O:23])[C:16](=[CH:19]OCC)[C:17]#[N:18])[CH3:13]>>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[NH:1][CH:19]=[C:16]([C:17]#[N:18])[C:15]([O:14][CH2:12][CH3:13])=[O:23]
Reactant: Nc1ccc2ccccc2n1
Reactant: CCOC=C(C#N)C(=O)OCC
Product: CCOC(=O)C(C#N)=CNc1ccc2ccccc2n1

Procedure:
Antaki, J. Am. Chem. Soc., 80, 3066-9 (1958) reports the condensation of 2-aminoquinoline and ethylethoxymethylenecyanoacetate to give ethyl 2-quinolylaminomethylenecyanoacetate which when distilled under reduced pressure afforded 1-oxo-1H-pyrimido[1,2-a]quinoline-2-carbonitrile. The compound demonstrated antischistosomal action.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[N:5]=[CH:6][CH:7]=[N:8]2.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>C(#N)C>[N:13]1([CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[N:5]=[CH:6][CH:7]=[N:8]3)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: BrCc1cccc2nccnc12
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: c1cc(Cn2ccnc2)c2nccnc2c1
Reaction time: 1.5 h
Yield: 20.5 %

Procedure:
A mixture of 15.5 parts of 5-(bromomethyl)quinoxaline, 23.5 parts of 1H-imidazole and 160 parts of acetonitrile was stirred for 1.5 hours at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted three times with 65 parts of dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane. The product was filtered off and dried, yielding 3 parts (20.5%) of 5-(1H-imidazol-1-yl-methyl)quinoxaline; mp. 121.2° C. (comp. 41).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C:3]=1N.Cl.[OH2:18]>>[Cl:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:2]([CH3:1])[C:3]=1[OH:18]
Reactant: Cc1cccc(Oc2cccc(Cl)c2)c1N
Reactant: O
Agent: Cl
Product: Cc1cccc(Oc2cccc(Cl)c2)c1O

Procedure:
A mixture of 2-methyl-6-(3-chlorophenoxy)aniline (40 g) and conc. hydrochloric acid (36 ml) in water (125 ml) was treated in a similar manner to that of Example 6-(1) to give oily 6-(3-chlorophenoxy)-o-cresol (13.9 g)
Reaction SMILES: N[C@@H]1CCN(C2C(Cl)=C(NC3N=[C:21]([NH:23][CH:24]4[CH2:26]C4)[C:20]4=[N:27][CH:28]=C(C#N)N4N=3)C=C(C#N)C=2)C[C@H]1O.[Cl:34][C:35]1[C:40]([NH:41][C:42]2[N:47]=[C:46]([NH:48][CH:49]3[CH2:51][CH2:50]3)[C:45]3=[N:52][CH:53]=[C:54]([C:55]#[N:56])[N:44]3[N:43]=2)=[CH:39][C:38]([C:57]#[N:58])=[CH:37][C:36]=1[N:59]1[CH2:64][CH2:63][C@@H:62]([NH:65][C:66](=O)[O:67]CCN(C)C)[C@H:61]([OH:74])[CH2:60]1>>[Cl:34][C:35]1[C:40]([NH:41][C:42]2[N:47]=[C:46]([NH:48][CH:49]3[CH2:51][CH2:50]3)[C:45]3=[N:52][CH:53]=[C:54]([C:55]#[N:56])[N:44]3[N:43]=2)=[CH:39][C:38]([C:57]#[N:58])=[CH:37][C:36]=1[N:59]1[CH2:64][CH2:63][C@@H:62]([NH:65][C:66]([N:23]2[CH2:21][CH2:20][N:27]([CH3:28])[CH2:26][CH2:24]2)=[O:67])[C@H:61]([OH:74])[CH2:60]1
Reactant: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CC[C@@H](N)[C@H](O)C2)c1
Reactant: CN(C)CCOC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1O
Product: CN1CCN(C(=O)N[C@@H]2CCN(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)C[C@H]2O)CC1

Procedure:
The title compound was prepared from (+/−)-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (byproduct from Example 177), using a method analogous to that used to prepare Example 181.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]([CH3:11])=O>>[CH:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:11])[CH3:8]
Reactant: CC(C)=O
Reactant: Nc1ccccc1
Product: CC(C)Nc1ccccc1

Procedure:
N-Isopropylaniline [NMR (200 MHz, DMSO-d6): δ1.13 (d, J=6.3 Hz, 6H); 3.58 (m, 1H); 5.30 (d, J=8.0 Hz, 1H); 6.49 (t, J=7.2 Hz, 1H); 6.55 (d, J=7.8 Hz, 2H); 7.06 (t, J=7,6 Hz, 2H)] was prepared from aniline and acetone via reductive amination using the general method described by Schellenberg (Schellenberg, K. A. J. Org. Chem. 1963, 28, 3259).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[C:26]=[O:27]>N1C=CC=CC=1.C(OCC)(=O)C>[F:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[NH:25][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:36])([F:38])[F:37])=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (200 mg, 0.58 mmol) was dissolved in pyridine (3.0 mL), 1-isocyanato-4-(trifluoromethoxy)benzene (132 μL, 0.88 mmol) was added, and the mixture was stirred at 70° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and washed successively with water (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=5/95→50/50), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (145 mg, 45%) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])[CH:4]=[CH:5][N:6]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].[OH-].[Na+]>O>[C:14]([NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[C:7]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[CH:8]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nccn1-c1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cccc(-n2ccnc2C)c1
Reaction time: 1 h
Yield: 97 %

Procedure:
3-(2-Methylimidazol-1-yl)aniline (11 g, 63.6 mmol) is added in portions to acetic anhydride (100 ml) at ambient temperature. After stirring for 1 hour the mixture is poured into water (300 ml). The resulting solution is cooled in an ice-bath and rendered alkaline with aqueous sodium hydroxide (12M). The product is filtered off, washed thoroughly with water and dried to yield 2j (12.3 g, 97%). Mp 238-240° C.
Reaction SMILES: Cl[CH2:2][CH:3]=O.[Cl:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]([NH2:15])=[S:14])[CH:9]=[CH:10][CH:11]=1>C(O)C>[Cl:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[S:14][CH:2]=[CH:3][N:15]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=CCCl
Reactant: NC(=S)Nc1cccc(Cl)c1
Solvent: CCO
Product: Clc1cccc(Nc2nccs2)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
Aqueous chloro acetaldehyde solution (15 mL) was added to a solution of 26A (15.5 g, 80 mmol) in ethanol (150 mL) and stirred at 60° C. for 16 h. The reaction mixture was concentrated in vacuo, and partitioned between ethyl acetate and water. The separated organic layer was washed with saturated NaCl, dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using 10% ethyl acetate in hexane to afford the title compound (15 g, 81%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H), 7.96 (t, J=2.1 Hz, 1H), 7.45-7.38 (dd, J1=2.0 Hz, J2=8.4 Hz, 1H), 7.37-7.26 (m, 2H), 7.02-6.95 (m, 2H). ESI-MS m/z: 211 (M+H)+.