Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([NH2:26])=[CH:21][CH:20]=2.ClC(Cl)C>C(O)(C)(C)C>[CH3:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([NH:26][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[S:12][CH:13]=[CH:14][N:15]=4)[S:10][C:3]=13)=[CH:21][CH:20]=2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: Clc1ccnc2cc(-c3nccs3)sc12
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Product: Cc1cc2cc(Nc3ccnc4cc(-c5nccs5)sc34)ccc2[nH]1
Yield: 65.3 %

Procedure:
7-Chloro-2-thiazol-2-yl-thieno[3,2-b]pyridine (400 mg, 1.58 mmol) and 2-methyl-5-aminoindole (231 mg, 1.58 mmol) were dissolved in 6 mL of t-butyl alcohol and 6 mL of dichloroethane and the solution was heated to 85° C. After allowing the reaction to go dry overnight the reaction mixture was cooled and absorbed onto silica gel. Chromatography of the residue with 5% methanol:methylene chloride afforded 374 mg (68%) (2-methyl-1H-indol-5-yl)-(2-thiazol-2-yl-thieno[3,2-b]pyridin-7-yl)-amine. 1H NMR (400 MHz, DMSO) δ8.78 (s, 1H), 8.18 (d, 1H), 7.84 (m, 2H), 7.27 (m, 2H), 6.90 (d, 1H), 7.39 (d, 1H), 6.59 (d, 1H), 6.10 (s, 1H), 2.36 (s, 3H). LC-MS: 363 (MH+); HPLC RT: 5.01 min.
Reaction SMILES: C([O:8][C:9]1[C:14]([N:15]2[CH2:20][CH2:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17][CH2:16]2)=[CH:13][CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>[Pd].CO>[N:15]1([C:14]2[C:9](=[O:8])[NH:10][CH:11]=[CH:12][CH:13]=2)[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: O=C(OCc1ccccc1)N1CCN(c2cccnc2OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]cccc1N1CCNCC1
Reaction time: 3 h
Yield: 88 %

Procedure:
To a 10 mL round bottomed flask was added 10 mg (0.009 mmol) of 10% palladium on activated carbon which was then flushed with nitrogen. Next, a solution of 0.090 (0.22 mmol) of benzyl 4-[2-(benzyloxy)pyridin-3-yl]piperazine-1-carboxylate from Step A above in 4 mL of methanol was added and the resulting mixture was placed under an atmosphere of hydrogen gas at atmospheric pressure for 3 h. The reaction was then flushed with nitrogen and filtered through a pad of Celite®. The pad was washed with methanol and the combined organics were evaporated to dryness to afford the title compound as a clear gum (0.035 g, 88%). LC-MS: m/z (ES) 180.1 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][C:5]=2[C:6](=[O:10])[C:7]=1[CH:8]=[O:9].CN(C)C=O.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[C:23]#[CH:24]>C(N(CC)CC)C>[CH2:15]([C:12]1[CH:13]=[CH:14][C:4]2[O:3][C:2]([NH:1][CH:24]=[CH:23][C:22]([O:26][CH2:27][CH3:28])=[O:25])=[C:7]([CH:8]=[O:9])[C:6](=[O:10])[C:5]=2[CH:11]=1)[CH3:16]
Reactant: CCc1ccc2oc(N)c(C=O)c(=O)c2c1
Reactant: C#CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C=CNc1oc2ccc(CC)cc2c(=O)c1C=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A mixture consisting of 2.17 g of 2-amino-6-ethyl-4-oxo-4H-1-benzopyran-3-carboxaldehyde, 25 ml of dimethylformamide, 5 g of ethyl propiolate and 0.1 ml of triethylamine was stirred at 90° C. for one hour and then the mixture was allowed to stand at room temperature. The resulting crystals were collected by filtration and recrystallized from acetone to obtain 1.65 g of ethyl 3-(6-ethyl-3-formyl-4-oxo-4H-1-benzopyran-2-yl)aminoacrylate as colorless needles melting at 201°-203° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[C:8]([O:16]C)=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+]>Br>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:13])[F:14])[C:8]([OH:16])=[CH:7][C:5]=2[N:6]=1
Reactant: COc1cc2nc(N)sc2cc1OC(F)(F)F
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2cc(O)c(OC(F)(F)F)cc2s1
Temperature: 20 °C
Yield: 69.9 %

Procedure:
0.74 g of 2-amino-5-methoxy-6-(trifluoromethoxy)benzothiazole, in solution in 20 ml of 47% hydrobromic acid, are brought to reflux for 20 hours. After cooling to a temperature in the region of 20° C., the reaction mixture is poured in 20 ml of ice-cold water and the solution is basified using concentrated sodium hydroxide. The organic phase is then extracted with ethyl acetate, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (15 mm Hg, 2 kPa). The crude product thus obtained is purified by flash chromatography on a silica column, a dichloromethane/methanol (98/2 by volume) mixture being used as eluent. 0.49 g of 2-amino-5-hydroxy-6-(trifluoromethoxy)benzothiazole are thus isolated in the form of a white powder melting at 216° C. [(Analysis % calculated C: 38.40, H: 2.01, F: 22.78, N: 11.20, S: 12.82; % found C: 38.3, H: 1.9, F: 22.9, N: 11.2, S: 13.0); 1H N.M.R. spectrum (250 MHz, d6-(CD3)2SO, δ in ppm): 6.96 (broad s, 1H, aromatic H ortho to the OH), 7.54 (broad s, 2H, NH2), 7.61 (broad s, 1H, aromatic H meta to the OH), 9.95 (unresolved peak, 1H, OH)].
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(O[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])C.[NH2:20][C:21]([NH2:23])=[O:22]>C(#N)C>[CH2:18]([O:17][C:15]([C:14]1[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[NH:20][C:21](=[O:22])[NH:23][CH:13]=1)=[O:16])[CH3:19]
Reactant: O=Cc1ccc(F)cc1
Reactant: NC(N)=O
Reactant: CCOC=CC(=O)OCC
Solvent: CC#N
Product: CCOC(=O)C1=CNC(=O)NC1c1ccc(F)cc1
Temperature: 0 °C

Procedure:
4-(4-Fluoro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester was prepared using the Biginelli reaction following the procedure reported in WO 2007/101213). Briefly, to a solution of p-fluorobenzaldehyde (7.5 mL) in 200 mL acetonitrile was added ethyl 3-ethoxyacrylate (10.7 mL), urea (5.0 g) and freshly dried SiO2—NaHSO4 (3.7 g). The solution was heated at reflux for 18 hours, then cooled and poured into ice water. The precipitate was recovered by filtration and air-dried to yield 4-(4-fluoro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (18.8 g).
Reaction SMILES: O[C:2]1[C:11]2[CH2:10][CH:9]([CH2:12][CH3:13])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[C:11]2[CH2:10][CH:9]([CH2:12][CH3:13])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cnc2c(c1O)CC(CC)CC2
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(c1Cl)CC(CC)CC2

Procedure:
A solution of 3.5 g of ethyl 4-hydroxy-6-ethyl-5,6,7,8-tetrahydroquinoline-3-carboxylate in 35 ml phosphorus oxychloride is heated to reflux under nitrogen for five hours. The POCl3 is removed under vacuum, the residue is dissolved in CHCl3, and the solution is washed with cold 2N NaOH, saturated NaCl, then dried over anhydrous MgSO4, and evaporated to dryness. The crude product is purified through a short column of silica gel eluting with EtOAc. Removal of solvent under vacuum affords ethyl 4-chloro-6-ethyl-5,6,7,8-tetrahydroquinoline-3-carboxylate as an oil, which is used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:33](CC)CC)C.C([O-])(=O)C.[NH4+]>C(O)CCC.C(OCC)(=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:33]=[C:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[NH:15][CH:16]=2)=[CH:20][C:21]=1[C:26]([F:29])([F:28])[F:27]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccc(F)c(C(F)(F)F)c2)CC1
Reactant: CCN(CC)CC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.1 %

Procedure:
A mixture of 4-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (2900.00 mg; 6.71 mmol; 1.00 eq.), triethylamine (0.94 ml; 6.71 mmol; 1.00 eq.), and ammonium acetate (3618.76 mg; 46.95 mmol; 7.00 eq.) in 20 ml of n-butanol was placed in microwave (150° C.) for 20 min. after cooling to rt, the reaction mixture was diluted with 150 ml of ethyl acetate and washed with water, 5% NaHCO3aq, then brine and concentrated. The residue was treated with ether and collected whit solid as title compound (1500 mg, 54% yield).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[NH:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:31][C:32]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:33].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(#N)C.O>[CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]([CH2:31][C:32](=[O:33])[N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: CCOC(=O)c1ccc2c(C3CCCCC3)c3n(c2n1)CCNc1ccccc1-3
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc2c(C3CCCCC3)c3n(c2n1)CCN(CC(=O)N1CCOCC1)c1ccccc1-3
Temperature: 90 °C
Yield: 63.2 %

Procedure:
To a solution of ethyl 12-cyclohexyl-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-carboxylate (74 mg, 0.19 mmol) in N,N-dimethylformamide (2 ml) and acetonitrile (2 ml) were added 4-(2-chloroacetyl)morpholine (94 mg, 0.57 mmol), potassium iodide (64 mg, 0.38 mmol) and potassium carbonate (66 mg, 0.48 mmol), and the mixture was stirred with heating at 90° C. for 12 hr. The reaction mixture was allowed to cool to room temperature, and water was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography (ethyl acetate) to give ethyl 12-cyclohexyl-5-[2-oxo-2-(morpholin-4-yl)ethyl]-6,7-dihydro-5H-5,7a,8-triazadibenzo[a,e]azulene-9-carboxylate (62 mg, yield 63%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16][CH3:17])=[O:15])#[N:2].[OH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[C:23]([C:22]1[CH:26]=[CH:27][C:19]([O:18][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:8][O:9]3)=[CH:4][C:3]=2[C:1]#[N:2])=[CH:20][CH:21]=1)(=[O:24])[NH2:25]
Reactant: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(N)=O)cc3)c(C#N)cc21
Temperature: 110 °C
Yield: 22.2 %

Procedure:
Methyl 6-cyano-7-fluorochroman-4-carboxylate (300 mg, 1.28 mmol), 4-hydroxybenzamide (227 mg, 1.66 mmol) and potassium carbonate (423 mg, 3.06 mmol) were diluted with dry NMP (4 mL). The reaction was bubbled with argon for 10 minutes and then heated at 110° C. for 12 hours. The reaction was cooled and loaded directly onto a biotage 40M cartridge (silica gel), eluting with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield methyl 7-(4-carbamoylphenoxy)-6-cyanochroman-4-carboxylate (100 mg, 22.3% yield).
Reaction SMILES: CO[N:3]([CH2:12][OH:13])[C:4]1[N:9]=[C:8]([NH2:10])[N:7]=[C:6]([NH2:11])[N:5]=1.O>CC(O)C>[CH2:12]([NH:3][C:4]1[N:5]=[C:6]([NH2:11])[N:7]=[C:8]([NH2:10])[N:9]=1)[OH:13]
Reactant: CON(CO)c1nc(N)nc(N)n1
Solvent: O
Solvent: CC(C)O
Product: Nc1nc(N)nc(NCO)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
This example demonstrates the chemical solution 2 which was prepared as follows. In a 1-liter measuring flask were placed 100 g of methoxymethylolmelamine (“cymel 370” from Mitsui Cyanamide), 780 g of pure water, and 40 g of IPA. They were mixed with stirring at room temperature for 6 hours. Thus there was obtained around 10 wt % aqueous solution of methylolmelamine. This solution was incorporated with N-methylpyrrolidone as a swelling promoter.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[CH:7][C:6](O)=[C:5]([N+:10]([O-:12])=[O:11])[C:4]1=[O:13])[CH3:2].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:6]1[CH:7]=[CH:8][N:3]([CH2:1][CH3:2])[C:4](=[O:13])[C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1ccc(O)c([N+](=O)[O-])c1=O
Product: CCn1ccc(Cl)c([N+](=O)[O-])c1=O
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A suspension of 1-ethyl-4-hydroxy-3-nitro-1H-pyridine-2-one (1.0 g, 5.43 mmol) in POCl3 (8.33 g, 54.3 mmol) was heated at refluxed for 1 h. After cooling to room temperature, the solvent was evaporated under reduced pressure and water was carefully added to the chilled residue. The mixture was neutralized with 2 N NaOH, extracted with CHCl3, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The resulting solid was washed with Et2O to give 4-chloro-1-ethyl-3-nitro-1H-pyridin-2-one (0.58 g, 53% yield). 1H-NMR (CDCl3): δ, 7.48 (d, 1H, J=7.6 Hz), 6.37 (d, 1H, J=7.6 Hz), 4.07 (q, 2H, J=7.2 Hz), 1.40 (t, 3H, J=7.2 Hz). MS: calculated for C7H7ClN2O3+H 203.0; found: 203.1.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:27])[NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][C:16]=2[CH2:28][S:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:7]=1)C.[OH-].[Li+]>CO.O>[C:23]([NH:22][C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:34])=[O:3])[CH:11]=[CH:10][C:9]=2[O:12][CH3:13])=[C:16]([CH2:28][S:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:17]=1)=[O:27])([CH3:25])([CH3:26])[CH3:24]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(=O)NC(C)(C)C)cc2CSC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(C(=O)NC(C)(C)C)cc1CSC(C)(C)C

Procedure:
[3-(4-tert-Butylcarbamoyl-2-tert-butylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.46 mmol) was treated with lithium hydroxide in MeOH and H2O at 60° C. for 20 minutes to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:13](OCC)=[O:14])[CH:10]=2)[NH:5][C:4](=O)[CH2:3]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][OH:14])[CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: CCCCCC(C(=O)OCC)c1ccc2c(c1)C(C)(C)CC(=O)N2
Solvent: Cc1ccccc1
Product: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCN2
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
7 g of (RS)-ethyl 2-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-heptanoate were dissolved in 70 ml of toluene and treated, at 0° C., with 4.4 ml of a 10M solution of borane-dimethyl sulfide complex solution in toluene. The mixture was heated to 90° C. for 7 hours. After cooling to room temperature, the mixture was quenched by slow addition of 50 ml of 10% aqueous sodium carbonate solution. The mixture was stirred at room temperature for 30 min. and the phases were separated. The aqueous phase was extracted with two portion of 50 ml of ethyl acetate. The combined extracts were dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (SiO2, 25% ethyl acetate/hexanes). 1H NMR (CDCl3): 6.97 (d, J=2.0 Hz, 1H), 6.76 (dd, J=8.2, 2.0 Hz, 1H), 6.41 (d, J=8.2 Hz, 1H), 3.65 (dd, J=10.6, 5.9 Hz, 1H), 3.57 (dd, J=10.6, 7.9 Hz, 1H), 3.30-3.20 (m, 2H), 2.65-2.55 (m, 1H), 1.80-1.70 (m, 2H), 1.65-1.40 (m, 2H), 1.30-1.15 (m, 6H), 1.27 (s, 6H), 0.86 (t, J=6.6 Hz, 3H).
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]3[CH:40]=[N:41][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:43][CH:44]=3)[C:34]2=[O:49])[S:28][C:29]=1[C:30](O)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]3[CH:40]=[N:41][C:42]([C:45]([F:47])([F:48])[F:46])=[CH:43][CH:44]=3)[C:34]2=[O:49])[S:28][C:29]=1[C:30]([NH2:7])=[O:31]
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)nc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)nc3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 225-228° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.75 (br, 2H), 8.04 (d, J=8.1 Hz, 1H), 7.92-7.89 (m, 2H), 4.61 (s, 2H), 4.06-3.99 (m, 2H), 3.58-3.53 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 386.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[NH2-].[Na+].[CH3:12][CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1>O1CCCC1>[CH3:9][O:8][C:3]1[CH:4]=[C:5]([CH:15]2[CH2:14][CH:13]([CH3:12])[CH2:18][CH2:17][C:16]2=[O:19])[CH:6]=[CH:7][CH:2]=1
Reactant: COc1ccccc1Cl
Reactant: CC1CCC(=O)CC1
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(C2CC(C)CCC2=O)c1

Procedure:
Employing the general procedure of T. Kametani, et al., J. Chem. Soc. (C), 1971, 1047, 187 g o-chloroanisole was added to a mixture of 215 g of sodium amide, 3 liters of anhydrous tetrahydrofuran and 400 g of 4-methylcyclohexanone. The reaction was refluxed for 18 hours then quenched with saturated ammonium chloride. Concentration of the organic phase, dilution with water, extraction with ether and distillation of the residue from concentrating the ether extracts gave 90 g, b.p. 135° (0.07 mm), of product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:32])[NH:13][C:14](=[O:31])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27][S:28]([CH3:30])=[O:29])[CH:17]=2)=[CH:3]1.ClC1C=CC=C(C(OO)=[O:41])C=1>ClCCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:32])[NH:13][C:14](=[O:31])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27][S:28]([CH3:30])(=[O:41])=[O:29])[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cn(CCCS(C)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1cc(C2=C(c3cn(CCCS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 2 h
Yield: 26.8 %

Procedure:
90 mg of the product of Example 97 in 5 ml of dichloromethane were treated with 60 mg of 85% metachloroperbenzoic acid in 5 ml of dichloromethane. The solution was stirred for 2 hours and then washed with aqueous sodium bicarbonate. The solution was dried and concentrated. Chromatography of the residue on silica gel with dichloromethane/ethyl acetate (1:1) and recrystallization from ethyl acetate/hexane gave 25 mg of 3-(1-methyl-3-indolyl)-4-[1-(3-methylsulphonylpropyl)-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 225°-227° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[C:40]([F:42])[CH:41]=1>>[CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH:12]=[C:13]([C:38]2[CH:37]=[C:36]([F:35])[CH:41]=[C:40]([F:42])[CH:39]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2cc(F)cc(F)c2)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 40 %

Procedure:
The title compound was prepared in 40% yield from 2-(4′-chloro-5-trifluoromethanesulfonyloxy-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Intermediate C) and 3,5-difluorophenylboronic acid under the conditions described in Example 26, step (d). 1H-NMR (400 MHz, CDCl3): δ 7.90 (s, 1H), 7.72 (d, 1H), 7.60 (d, 1H), 7.58 (s, 1H), 7.52 (s, 2H), 7.15 (d, 2H), 6.83 (t, 1H), 3.80 (t, 1H), 3.70 (s, 3H), 2.04 (m, 1H), 1.73 (m, 1H), 0.95 (d, 6H.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[N:13][CH:14](Cl)[CH2:15][Cl:16])[C:11](=[O:18])[N:10]([CH3:19])[C:9]1=[O:20].[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(N(CC)CC)C.Cl>C(#N)C.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[N:13][CH:14]([NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[Cl:21])[CH2:15][Cl:16])[C:11](=[O:18])[N:10]([CH3:19])[C:9]1=[O:20]
Reactant: Nc1ccccc1Cl
Reactant: CN1C(=O)C(=NC(Cl)CCl)N(c2ccccc2F)C1=O
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN1C(=O)C(=NC(CCl)Nc2ccccc2Cl)N(c2ccccc2F)C1=O
Reaction time: 0.17 h

Procedure:
In this example 0.02 mol of 1-(2-fluorophenyl)-3-methyl-5-(1,2-dichloroethyl)imino-1,3-diazolidine-2,4-dione is dissolved in 20 ml of acetonitrile and then 0.02 of mol of 2-chloroaniline is added. After about 10 minutes, triethylamine is added to neutralize the byproduct HCl produced by the reaction. The mixture is stirred for five hours and 20 ml of ethyl ether is then added. The mixture is filtered and the filtrate evaporated under high vacuum affording 1-(2-fluorophenyl)-3-methyl-5-(1-2'chlorophenylamino-2-chloroethyl)imino-1,3-diazolidine-2,4-dione.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[F-:13].[K+].O>CC(N(C)C)=O>[F:13][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: [F-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=Cc1cc(F)ccc1[N+](=O)[O-]
Yield: 71 %

Procedure:
37 g (0.2 mol) of 5-chloro-2-nitrobenzaldehyde and 23.2 g (0.4 mol) of potassium fluoride in 300 ml of dimethylacetamide are stirred for 3 hours at 150° C. The solvent is then stripped off in vacuo and the residue is stirred with 200 ml of water. The aldehyde is extracted with methylene chloride, and the organic phase is separated off, dried and evaporated down. 24 g of 5-fluoro-2-nitrobenzaldehyde with a content of 86% are obtained.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[CH2:14])=[O:4].C[N+]1([O-])CC[O:21]CC1.C1COCC1.S([O-])([O-])(=O)=S.[Na+].[Na+].[OH2:37]>O=[Os](=O)(=O)=O>[OH:37][CH:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])[CH2:14][OH:21]
Reactant: O
Reactant: C=Cc1ccccc1CNC(=O)C(F)(F)F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1C(O)CO)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 1.7 g of 2,2,2-trifluoro-N-(2-vinylbenzyl)acetamide, 1.31 g of 4-methylmorpholine 4-oxide, 43 ml of THF, and 17 ml of water was added 1.85 ml of a 2.5% aqueous tetraoxoosmium solution, followed by stirring at room temperature for 16 hours. To the reaction mixture was added a 10% aqueous sodium thiosulfate solution, followed by stirring at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and washed with anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure to obtain 1.94 g of N-[2-(1,2-dihydroxyethyl)benzyl]-2,2,2-trifluoroacetamide.