Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:15])=[CH:6][CH:5]=1)#[N:3].C(N(CC)CC)C.[Cl:25][CH2:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Cl:25][CH2:26][S:27]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:17][CH:16]=2)[C:10](=[O:15])[CH2:11]1)(=[O:29])=[O:28]
Reactant: N#Cc1ccc(CN2CCNCC2=O)cc1
Reactant: O=S(=O)(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2CCN(S(=O)(=O)CCl)CC2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of 1-(4-cyanobenzyl)-2-piperazinone hydrochloride (3.78 g) and triethylamine (6.27 ml) in dichloromethane (50 ml) was added a solution of chloromethanesulfonyl chloride (2.68 g) in dichloromethane (10 ml) at 0° C. and the mixture was stirred at 0° C. for 1 hour. The reaction solution was diluted with dichloromethane, washed with sodium bicarbonate solution and saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2) to give colorless crystals of 4-chloromethylsulfonyl-1-(4-cyanobenzyl)-2-piperazinone (4.01 g).
Reaction SMILES: C=C1OC(=O)C1.BrBr.[CH:9]([OH:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:23][CH2:24][C:25](=[O:30])[CH2:26][C:27](Br)=[O:28]>C(Cl)Cl.C(N(CC)CC)C>[Br:23][CH2:24][C:25](=[O:30])[CH2:26][C:27]([O:22][CH:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:28]
Reactant: O=C(Br)CC(=O)CBr
Reactant: OC(c1ccccc1)c1ccccc1
Agent: BrBr
Agent: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)CC(=O)OC(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
In 10.5 ml of methylene chloride there were dissolved 2.1 g of diketene, and at a temperature not exceeding -30° C., a solution of 4.0 g of bromine in 12.5 ml of methylene chloride was added dropwise to the solution with stirring. After the dropwise addition was completed, the mixture was maintained at 0° C. for 10 minutes. Separately, 3.68 g of benzhydrol were dissolved in 25 ml oof methylene chloride, followed by addition of 2.02 g of triethylamine. Under stirring at a temperature not exceeding -30° C., the solution of bromoacetoacetyl bromide prepared above was added dropwise. After the dropwise addition, the mixture was stirred at 0° C. for 40 minutes, at the end of which time it was washed with water. After drying over magnesium sulfate the solvent was distilled off under reduced pressure, whereupon 6.99 g of benzhydryl 4-bromo-3-oxobutyrate were obtained.
Reaction SMILES: O.NN.[C:4]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][O:29][N:30]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:23][CH2:22]1)(=[O:20])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(O)C>[NH2:30][O:29][CH2:28][CH2:27][CH:24]1[CH2:25][CH2:26][N:21]([C:4](=[O:20])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]1
Reactant: CCCCCCCCCCCCCCCC(=O)N1CCC(CCON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCC(=O)N1CCC(CCON)CC1
Temperature: 25 °C
Yield: 70.6 %

Procedure:
Hydrazine hydrate (0.14 ml, 2.96 mmol) was added to a solution of 2-[2-(1-(hexadecanoyl)piperidin-4-yl)ethoxy]isoindole-1,3-dione (1.52 g, 2.96 mmol) in ethanol (30 ml). The reaction mixture was heated to reflux for 75 min and cooled to room temperature. The formed precipitation was removed by filtration. The solvent of the filtrate was removed in vacuo. The crude product was purified by flash chromatography on silica (30 g), using a mixture of dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 800 mg of 1-[4-(2-(aminooxy)ethyl)piperidin-1-yl]hexadecan-1-one.
Reaction SMILES: [C:1]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[CH:29]([CH:31]=[CH2:32])=[O:30]>O1CCCC1>[OH:30][CH:29]1[NH:2][C:1](=[O:3])[C:4]2([C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:32][CH2:31]1
Reactant: C=CC=O
Reactant: NC(=O)C1c2ccccc2-c2ccccc21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1NC(O)CCC12c1ccccc1-c1ccccc12
Temperature: 50 °C
Yield: 112.7 %

Procedure:
Following the general procedure of Example 1, 20.9 g (0.1 mole) of 9-carbamoylfluorene were added to 300 ml of tetrahydrofuran. The solution was heated to 50° C. and stirred while 6 ml of benzyltrimethylammonium hydroxide were added in one portion. After stirring the reaction mixture at 50° C. for thirty minutes, 6.2 g (0.11 mole) of acrolein were added and the mixture was then heated at reflux for four hours. The reaction mixture was cooled to 25° C. and the solvent was removed by evaporation under reduced pressure to provide 29.9 g of 6'-hydroxyspiro(9H-fluorene-9,3'-piperidine)-2'-one and its tautomeric isomer 9-carbamoyl-9-(3-oxo-propyl)fluorene, m.p. 199°-201° C.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=O)C1C=CC=CC=1.O.[H][H]>C(O)C.[C].[Pd]>[CH3:20][N:19]([CH3:21])[C:17]([C@@H:12]1[CH2:13][C@@H:14]([OH:16])[CH2:15][NH:11]1)=[O:18]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-dimethylaminocarbonyl-4-hydroxypyrrolidine (5.97 g) in ethanol (60 ml), 10% palladium-carbon (containing water 50 (1.20 g) was added, and the mixture was hydrogenated at room temperature for 3 hours under an atmospheric pressure of hydrogen. After removal of the catalyst by filtration, the filtrate was evaporated to remove the solvent to give (2S,4R)-2-dimethylaminocarbonyl-4-hydroxypyrrolidine.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([C:15]([NH:17][NH2:18])=O)[O:12][N:11]=2)=[CH:6][CH:5]=1.Cl.[C:22](=N)([NH2:24])[CH3:23].[OH-].[Na+]>C1COCC1>[CH3:23][C:22]1[NH:18][N:17]=[C:15]([C:13]2[O:12][N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:20])([F:19])[F:1])=[CH:5][CH:6]=3)[CH:14]=2)[N:24]=1
Reactant: CC(=N)N
Reactant: NNC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a mixture of 3-(4-(trifluoromethoxy)phenyl)isoxazole-5-carbohydrazide (2.4 g, 8.5 mmol) and acetimidamide hydrochloride (1.2 g, 12.8 mmol) in dry THF (60 mL), was added NaOH (512 mg, 12.8 mmol). The mixture was then refluxed for 16 h, then cooled to RT and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford the title compound as a white solid (1.9 g, 71%). 1H NMR (500 MHz, DMSO-d6) δ 8.12 (d, J=7.2 Hz, 2H), 7.58 (s, 1H). 7.54 (d, J=6.4 Hz, 2H), 2.46 (s, 3H). MS (ES+) C13H9F3N4O2 requires: 310. found: 311 [M+H]+.
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[SH:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:9]2[C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:31]=[CH:32][C:8]=2[N:7]=1.[OH-].[Na+].Cl>C(O)C>[CH2:1]([S:5][C:6]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:9]2[C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:31]=[CH:32][C:8]=2[N:7]=1)[CH2:2][CH3:3]
Reactant: CCCI
Reactant: CCOC(=O)c1cccc2nc(S)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCSc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.2 %

Procedure:
Propyl iodide (0.37 g) was added to a solution of ethyl 2-mercapto-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylate (0.91 g) in ethanol (13 ml) containing 1N NaOH (4.0 ml) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was adjusted to about pH 4 with dilute hydrochloric acid to give crystals. The crystals were collected by filtration and purified by column chromatography on silica gel. Recrystallization from ethyl acetate-hexane gave colorless prisms (0.4 g, 40%), m.p. 177-178° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[N:23]1([NH2:31])[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:31][N:23]3[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]3)=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:6][CH:7]=1
Reactant: NN1CCS(=O)(=O)CC1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(NN1CCS(=O)(=O)CC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 4-thiomorpholinamine 1,1-dioxide (CAN 26494-76-8) as starting materials; MS (EI) 464.1 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([NH:14][NH2:15])([CH3:13])([CH3:12])[CH3:11].C(NNC(C)(C)C)(=O)C(C)(C)C>O>[C:1]([NH:15][NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)NN
Reactant: O=C(Cl)c1ccccc1
Agent: CC(C)(C)NNC(=O)C(C)(C)C
Solvent: O
Product: CC(C)(C)NNC(=O)c1ccccc1
Yield: 71 %

Procedure:
1-benzoyl-2-tert.-butylhydrazine was prepared in 71% yield by adding benzoyl chloride to a basic solution of t-butylhydrazine in water. The procedure was the same as that for preparing 1-pivaloyl-2-tert.-butylhydrazine in Example XIX A. The product has a melting range of 94°-95° C. and its infra-red spectrum was consistent with that of the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2.N1CCCCC1>C(O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C=C2C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
A stirred solution of 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (52 mg, 0.18 mmol), 5-fluoro-1,3-dihydro-indol-2-one (25 mg, 0.4 mmol) in 0.4 ml of ethanol was added dropwise with anhydrous piperidine (0.04 ml). The mixture was stirred at room temperature overnight. The precipitate was filtered under reduced pressure. The resulting solid was washed with anhydrous ethanol (0.2 ml×5), purified by silica gel column chromatography with dichloromethane:methanol (15:1) as eluents to give 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 38%) as a yellow solid
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][C:24]1([C:27]2[O:31][N:30]=[C:29]([NH:32][C:33](=O)[O:34]C3C=CC=CC=3)[CH:28]=2)[CH2:26][CH2:25]1.COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:33]([NH:32][C:29]2[CH:28]=[C:27]([C:24]3([CH3:23])[CH2:25][CH2:26]3)[O:31][N:30]=2)=[O:34])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC1(c2cc(NC(=O)Oc3ccccc3)no2)CC1
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5(C)CC5)on4)c3)c2cc1OC
Yield: 57.8 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) and phenyl 5-(1-methylcyclopropyl)isoxazol-3-ylcarbamate (93 mg, 0.36 mmol) were reacted according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-methylcyclopropyl)isoxazol-3-yl)urea as a colorless solid (80 mg, 58%). 1H NMR (300 MHz, DMSO-d6) δ 9.57 (brs, 1H), 9.01 (brs, 1H), 8.56 (s, 1H), 7.56-7.58 (m, 2H), 7.38-7.43 (m, 2H), 7.25 (m, 1H), 6.97 (m, 1H), 6.47 (s, 1H), 3.99-4.00 (2×s, 6H), 1.39 (s, 3H), 1.06-1.10 (m, 2H), 0.86-0.90 (m, 2H); LC-MS (ESI) m/z 462 (M+H)+.
Reaction SMILES: [NH2:1][NH2:2].C(O)(=O)C.[Cl:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH:15]([C:18](=O)[CH3:19])[C:16]#[N:17])=[C:10]([CH3:21])[CH:9]=1>C1(C)C=CC=CC=1>[NH2:17][C:16]1[NH:2][N:1]=[C:18]([CH3:19])[C:15]=1[C:11]1[C:12]([CH3:14])=[CH:13][C:8]([Cl:7])=[CH:9][C:10]=1[CH3:21]
Reactant: CC(=O)C(C#N)c1c(C)cc(Cl)cc1C
Reactant: NN
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(Cl)cc(C)c1-c1c(C)n[nH]c1N
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
Dissolve anhydrous hydrazine (0.91 g, 0.90 mL) in 20 mL toluene. Add glacial acetic acid (2.25 mL) and allow to stand at ambient temperature for 10 minutes until solution becomes cloudy white. Add a solution of 2-(4-chloro-2,6-dimethylphenyl)-3-oxobutanenitrile in 10 mL toluene, rinsing out the ketonitrile flask with an additional 5 mL toluene. Heat to reflux under N2 (130° C.) with Dean-Stark trap attached. Water will begin to accumulate after 10 minutes or so. After 2 hours, evaporate down and partition between 1.0 N NaOH (100 mL) and EtOAc (100 mL). Extract aqueous layer with EtOAc (2×100 mL), then pool the organic layers and dry over Na2SO4. Filter and evaporate to yellow oil (1.75 g). Use without further purification. LCMS=236.5 (M+); 234.5 (M−)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])=[N:6][CH:7]=1.[H-].[Na+].I[CH3:20]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([N:8]([CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH3:20])=[N:6][CH:7]=1
Reactant: COCCCNc1ncc(Br)cc1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCN(C)c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry round bottom flask containing 5-bromo-N-(3-methoxypropyl)-3-nitropyridin-2-amine (1.0 g, 3.45 mmol) in dry DMF (4.5 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (0.28 g, 7.02 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then iodomethane (0.66 mL, 10.6 mmol) was added dropwise. Upon complete addition, the mixture was allowed to warm to 23° C. After 19 h, the reaction was carefully diluted with water then extracted five times with EtOAc. The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-25% EtOAc in hexanes) to afford a light yellow oil as 5-bromo-N-(3-methoxy propyl)-N-methyl-3-nitropyridin-2-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (1H, d, J=2.3 Hz), 8.21 (1H, d, J=2.3 Hz), 3.79 (2H, m), 3.47 (2H, m), 3.33 (3H, s), 2.86 (3H, s), 2.01 (2H, m).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[S:11][C:10]([N:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[C:13]2=[O:28])=[N:9][C:8]=1[CH3:29])=O.O.[NH2:32]N>C(O)C>[CH3:29][C:8]1[N:9]=[C:10]([N:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=3)[C:13]2=[O:28])[S:11][C:7]=1[C:5]1[CH:4]=[CH:3][NH:2][N:32]=1
Reactant: NN
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)/C=C/N(C)C
Solvent: CCO
Solvent: O
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1-c1cc[nH]n1
Yield: 72 %

Procedure:
To a solution of (E)-1-(5-(3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)imidazolidin-2-one (0.44 g, 1.00 mmol) in ethanol (10 mL) was added hydrazine monohydrate (0.12 mL, 1.58 mmol). The reaction mixture was heated to reflux for 3 hours. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound as a colorless solid in 72% yield (0.30 g): mp 212-213° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3& CD3OD) δ 7.54-7.20 (m, 5H), 6.24 (s, 1H), 4.39 (s, 2H), 3.98-3.89 (m, 2H), 3.35-3.30 (m, 2H), 2.27 (s, 3H); 13C NMR (75 MHz, CDCl3 & CD3OD) δ 156.9, 155.8, 139.8, 130.2, 129.8, 129.3, 128.2, 125.6, 125.5, 122.0, 103.8, 47.2, 41.9, 41.8, 15.7; MS (ES+) m/z 408.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(F)(F)F)=[CH:4][CH:3]=1.[NH2:15][C:16]1[N:21]=[C:20]([NH2:22])[C:19]([CH2:23][C:24]2[CH:25]=[C:26]([O:39][CH2:40][CH3:41])[C:27](I)=[C:28]([O:30][S:31]([CH2:34][CH:35]([CH3:37])[CH3:36])(=[O:33])=[O:32])[CH:29]=2)=[CH:18][N:17]=1>>[NH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:27]2[C:26]([O:39][CH2:40][CH3:41])=[CH:25][C:24]([CH2:23][C:19]3[C:20]([NH2:22])=[N:21][C:16]([NH2:15])=[N:17][CH:18]=3)=[CH:29][C:28]=2[O:30][S:31]([CH2:34][CH:35]([CH3:36])[CH3:37])(=[O:32])=[O:33])=[CH:7][CH:6]=1
Reactant: O=C(Nc1ccc(Br)cc1)C(F)(F)F
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)C)c1I
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)C)c1-c1ccc(N)cc1

Procedure:
Starting from 225 mg (0.84 mmol) N-(4-bromo-phenyl)-2,2,2-trifluoro-acetamide and 214 mg (0.42 mmol) 2-methyl-propane-1-sulphonic acid 5-(2,4-diamino-pyrimidin-5-ylmethyl)-3-ethoxy-2-iodo-phenyl ester, 78 mg of the tide compound are obtained as a brown foam after two chromatography operations.
Reaction SMILES: [F:1][C:2]1[C:3]([N:18]2[C:22](=[O:23])[N:21]([CH:24]([F:26])[F:25])[C:20]([CH3:27])=[N:19]2)=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH2:8][CH:9]([Br:14])[C:10](OC)=[O:11])[CH:7]=1.O>C(O)(=O)C.[Fe]>[Br:14][CH:9]1[CH2:8][C:6]2[C:5](=[CH:4][C:3]([N:18]3[C:22](=[O:23])[N:21]([CH:24]([F:26])[F:25])[C:20]([CH3:27])=[N:19]3)=[C:2]([F:1])[CH:7]=2)[NH:15][C:10]1=[O:11]
Reactant: COC(=O)C(Br)Cc1cc(F)c(-n2nc(C)n(C(F)F)c2=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nn(-c2cc3c(cc2F)CC(Br)C(=O)N3)c(=O)n1C(F)F
Temperature: 40 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A solution of 9.0 g (0.020 mole) of methyl 3-[5- fluoro-4-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)-2-nitrophenyl]-2-bromopropionate in 100 mL of glacial acetic acid was stirred, and 9.0 mL of water was added. The reaction mixture was warmed to 40° C., and 9.0 g (0.16 mole) of iron powder was slowly added. Upon completion of addition the reaction mixture was allowed to cool to ambient temperature where it was stirred for 2 hours. The reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was diluted with water, and the mixture was extracted with 100 mL of ethyl acetate. The filtrate was concentrated under reduced pressure to yield 7.5 g of 1-(3-bromo-6-fluoro-3,4-dihydroquinolin-2(1H)-one-7-yl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([Mg]Br)[CH:12]([CH3:14])[CH3:13].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:10])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=CCc1cccc(F)c1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(O)Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
97 mg of 3-fluorobenzeneacetaldehyde and 0.386 mL of isobutyl magnesium bromide (2 M/diethyl ether solution) were dissolved in of 0.2 mL of THF, followed by stirring at room temperature for 1 hour. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform, and the organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using PLC (ethyl acetate:hexane=1:2) to obtain 102 mg (yield 74%) of a title compound as a pale yellow oily substance.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:6].S(Cl)([Cl:15])=O>N1C=CC=CC=1.ClC(Cl)Cl>[Cl:15][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:6]
Reactant: Cn1cccc1C(=O)NCCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cn1cccc1C(=O)NCCCl
Reaction time: 8 h

Procedure:
To a stirred solution of 40 parts of N-(2-hydroxyethyl)-1-methyl-1H-pyrrole-2-carboxamide in 450 parts of trichloromethane is added one drop of pyridine. Then there are added dropwise, during a 30 minutes-period, 28.3 parts of sulfinyl chloride (slightly exothermic reaction: temp. rises from 15° to 25° C). Upon completion, stirring is continued overnight at room temperature. The reaction mixture is evaporated and the residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is stirred in 2,2'-oxybispropane. The product is filtered off and dried, yielding 15 parts of N-(2-chloroethyl)-1-methyl-1H-pyrrole-2-carboxamide.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][N:28](C=O)[CH3:29].CNC>O.C1COCC1>[CH3:27][N:28]([CH3:29])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: CN(C)C=O
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 60 °C

Procedure:
To a mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.14 g of potassium carbonate and 3 ml of DMF, 3 ml of a THF solution of dimethylamine was added and stirred while heating at 60° C. for 3.3 hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the resultant crystals were washed with diethyl ether to give 0.27 g of dimethyl-{4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-yl}amine (hereinafter, referred to as “active compound 131”).