Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH:2]1[CH:3]=[CH2:4].[C:6]([O:9]C(=O)C)(=[O:8])[CH3:7].C(N(CCCC)CCCC)CCC.[C:26](O)(=[O:28])[CH3:27]>COCCOCCOC>[C:6]([O:9][CH:2]([CH2:5][O:1][C:26](=[O:28])[CH3:27])[CH:3]=[CH2:4])(=[O:8])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Reactant: C=CC1CO1
Solvent: CCCCN(CCCC)CCCC
Solvent: COCCOCCOC
Product: C=CC(COC(C)=O)OC(C)=O
Temperature: 125 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
A 300-mL autoclave was charged with 40 mL (0.50 mol) of 3,4-epoxy-1-butene, 60.0 g (0.59 mol) acetic anhydride, 3.7 g (0.02 mol) of tributylamine, 0.72 g (0.012 mol) acetic acid and 4.2 mL of diglyme. The autoclave was purged with nitrogen twice, then the vessel was pressurized to 8 bars (100 psig) with nitrogen. The agitator was started and an initial sample was taken. The mixture was heated to 125° C. During the course of 2 hrs, samples were taken every 15 min for analysis by GC. GC analysis of the crude mixture after 2 hrs revealed a 79% yield of 3,4-diacetoxy-1-butene with a 90% selectivity and 12% 3,4-epoxy-1-butene. The reaction was observed to be first order in 3,4-epoxy-1-butene with a first order rate constant of 0.017 min-1 (Table A). This example shows the catalytic effect of another tertiary amine with acetic acid as the co-catalyst.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([NH2:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.[CH:15]1([CH2:20][C:21](O)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:1][O:2][C:3](=[O:14])[CH:4]([NH:13][C:21](=[O:22])[CH2:20][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1
Reactant: COC(=O)C(N)Cc1cccc(O)c1
Reactant: O=C(O)CC1CCCC1
Product: COC(=O)C(Cc1cccc(O)c1)NC(=O)CC1CCCC1
Yield: 54.9 %

Procedure:
12.5 g (54.3 mmol) of 2-amino-3-(3-hydroxy-phenyl)-propionic acid methyl ester was reacted with cyclopentyl acetic acid (6.97 g, 54.3 mmol) as described in general procedure A. The compound was purified using gradient elution with ethyl acetate in hexanes to yield 9.1 g of 2-(2-cyclopentyl-acetylamino)-3-(3-hydroxy-phenyl)-propionic acid methyl ester.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.B(O)(O)[C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1>>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Product: Cc1ccc(-c2cc(-c3ccc(O)c(F)c3)nc3ccc(O)cc23)cc1
Yield: 85 %

Procedure:
This compound was prepared from 6b using p-tolylboronic acid according to method P. Orange powder; Yield: 85%; mp 184-188° C.; 1H-NMR (300 MHz, DMSO-d6) δ 2.44 (s, 3H), 7.07 (dd, J=8.8, 8.8 Hz, 1H), 7.12 (d, J=2.6 Hz, 1H), 7.31 (dd, J=9.1, 2.6 Hz, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.82 (s, 1H), 7.94 (dd, J=8.4, 2.1 Hz, 1H), 7.96 (d, J=9.0 Hz, 1H), 8.07 (dd, J=13.0, 2.0 Hz, 1H), 9.91 (s, 1H), 10.21 (s, 1H); MS (ESI) m/z 344 ([M−H]−), 346 ([M+H]+); Anal. Calcd for C22H16FNO2: C, 76.51; H, 4.67; N, 4.06. Found: C, 75.55; H, 4.50; N, 3.74.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].Cl.Cl.[Cl:8][C:9]1[C:10]([F:35])=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][C@H:29]4[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1.C(N(C(C)C)CC)(C)C.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:35])=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][C@H:29]4[CH2:34][CH2:33][CH2:32][N:31]([C:3](=[O:4])[CH2:2][N:49]5[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]5)[CH2:30]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)CCl
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O[C@H]1CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O[C@H]1CCCN(C(=O)CN2CCN(C)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chloroacetyl chloride (47 μl) was added to a solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)-piperidin-3-yloxy]quinazolin-4-amine dihydrochloride (250 mg) and diisopropylethylamine (373 μl) in methylene chloride (10 ml) and the mixture was stirred at ambient temperature for 1 hour. 1-Methylpiperazine (228 mg) was added, and the solution stirred for 1 hour before being washed with aqueous sodium hydroxide (2M, 10 ml) and water (10 ml). The organics were then purified by flash column chromatography eluting with methylene chloride/7N ammonia solution in methanol (97/3) to give a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give the title product as a white solid (0.135 g); 1H NMR Spectrum: (DMSO d6) 1.42-1.67 (m, 1H), 1.70-1.95 (m, 2H), 1.98-2.48 (m, 9H), 2.18 (s, 3H), 2.82-3.05 (m, 1H), 3.20-4.02 (m, 8H), 4.68 (m, 1H,), 7.30 (m, 1H), 7.34 (s, 1H), 7.44-7.60 (m, 2H), 7.82 (m, 1H), 8.38 (s, 1H), 9.64 (m, 1H); Mass Spectrum: (M+H)+ 543; melting point 120 to 121° C.
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][C:4]1[CH:5]=[C:6]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]=O)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)Cl>CC(O)C>[N:1](=[CH:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:17][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:4]([CH3:3])[CH:5]=1)[NH2:2]
Reactant: Cc1cc(Nc2ncnc3ccc(C=O)cc23)ccc1Oc1ccccc1
Reactant: NN
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1cc(Nc2ncnc3ccc(C=NN)cc23)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(6-Hydrazonomethylquinazolin-4-yl)-(3-methyl-4-phenoxyphenyl)amine is prepared by adding hydrazine (50 mg, 1.00 mmol) to a solution of 4-(3-methyl-4-phenoxyphenylamino)-quinazoline-6-carbaldehyde (250 mg, 0.70 mmol) in a 1:1 mixture of DCM:IPA (6 mL). After stirring at room temperature for 4 hours, excess hydrazine and solvent are removed under reduced pressure to give the desired hydrazone as a brown solid which is carried forward without purification.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH3:18][N:19]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]2)=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:18][N:19]1[C:27]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]2)=[N:20]1
Reactant: Cn1cc2ccccc2n1
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3c4ccccc4nn3C)c(C)nc12
Temperature: 100 °C
Yield: 28.1 %

Procedure:
8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (300 mg, 0.87 mmol), 2-methyl-2H-indazole (ref. J. Org. Chem. 2003, 68, 4093-4095, 230 mg, 1.76 mmol) and cesium carbonate (570 mg, 1.75 mmol) stirred in DMF (5 ml) and degassed by bubbling a stream of nitrogen through the mixture. PdCl2(PPh3)2 added and the mixture heated to 100° C. overnight. The mixture is added to water and extracted twice with ether. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography using a hexane-ethyl acetate gradient (100% hexane to 50% ethyl acetate in hexane) to give the title compound (85 mg, 28% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH3:26][N:27]([CH3:34])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH3:33].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:26][N:27]([CH3:34])[CH2:28][CH2:29][CH2:30][CH2:31][N:32]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH3:33]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: CNCCCCN(C)C
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CN(C)CCCCN(C)c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 150 °C
Yield: 23 %

Procedure:
A mixture of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.1 g), N-(4-dimethylaminobutyl)-N-methylamine (Intermediate 78, 1.07 g) and triethylamine (0.42 g) in NMP (6 mL) was stirred and heated in a sealed tube at 150° C. for 3 days. After cooling, the mixture was concentrated under vacuum and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM (10%) followed by repurification by HPLC (C18) to give (1aRS,7bSR)-5-{2-[N-(4-dimethylaminobutyl)-N-methylamino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.03 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:17]([I:20])[CH2:18][CH3:19]>CC(=O)C(C)(C)C>[I-:20].[CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[N+:13]([CH2:17][CH2:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(-c2cccnc2)ccc1[N+](=O)[O-]
Reactant: CCCI
Solvent: CC(=O)C(C)(C)C
Product: CCC[n+]1cccc(-c2ccc([N+](=O)[O-])c(C)c2)c1
Product: [I-]
Temperature: 102 °C
Reaction time: 12 h
Yield: 94.3 %

Procedure:
To pinacolone (200 mL, Aldrich) were added 3-(3-methyl-4-nitrophenyl)pyridine (5.3 g, 24.0 mmol) and propyliodide (17.0 g, 100.0 mmol, Fluka). The reaction was stirred at 102° C. for 12 h. Solids were collected and washed with MeOH (2×20 mL) to afford 3-(3-methyl-4-nitrophenyl)-1-propylpyridinium iodide (8.7 g, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.3 Hz, 3 H), 1.97-2.06 (m, 2 H), 2.62 (s, 3 H), 4.62 (t, J=7.3 Hz, 2 H), 7.98 (dd, J=8.5, 1.9 Hz, 1 H), 8.07 (d, J=1.1 Hz, 1H), 8.21 (d, J=8.6 Hz, 1 H), 8.29 (dd, J=8.1, 6.1 Hz, 1 H), 9.00 (d, J=8.4 Hz, 1 H), 9.12 (d, J=6.0 Hz, 1 H), 9.57 (s, 1 H); ESIMS (M+H)+=257.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([C@@H:13]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=[O:24])[CH2:14][N+:15]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.O1CCCC1.O>O1CCCC1>[NH2:15][CH2:14][C@H:13]([C@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[OH:24])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:26][CH:25]=1
Reactant: O=C1CCCCC1[C@@H](C[N+](=O)[O-])c1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: NC[C@@H](c1ccc(OCc2ccccc2)cc1)[C@H]1CCCC[C@H]1O
Reaction time: 8 h

Procedure:
A solution of 106.6 g (0.33 mol) of rac-(2S*)-2-[(R*)-4-(benzyloxy)-α-(nitromethyl)benzyl]cyclohexanone in 500 ml of dry tetrahydrofuran is added dropwise while stirring to a suspension of 28.6 g (0.75 mol) of lithium aluminium hydride in 500 ml of dry tetrahydrofuran under argon so that the temperature does not exceed 50°. The reaction mixture is stirred at 50° overnight and it is treated, after cooling to room temperature, with 300 ml of ethanol and subsequently with 100 ml of tetrahydrofuran/water (1:1). The separated precipitate is filtered off under suction while washing with methylene chloride and the filtrate is evaporated. The crystalline product obtained is recrystallized from methylene chloride/isopropyl ether. There is obtained rac-(1S*)-cis-2-[(R*)-α-(aminomethyl)-4-(benzyloxy)benzyl]cyclohexanol in the form of colourless crystals of m.p. 160°-161°.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13](NCCCN2CCSCC2)=[C:12]([N+:26]([O-])=O)[CH:11]=1)=[O:5]>C(Cl)Cl.CO>[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:29])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:26])[C:11]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5]
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1cccc(N)c1NCc1ccccc1

Procedure:
The same procedure is used as in (1). Rf value: 0.69 (silica gel; methylene chloride/methanol=9:1)
Reaction SMILES: Cl.[Br:2][C:3]1[C:20]([Br:21])=[CH:19][C:6]2[N:7](C(C)C)[C:8]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:9][C:5]=2[C:4]=1[N+:22]([O-:24])=[O:23].[C:25](N1CCNCC1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CCO>[Br:2][C:3]1[C:20]([Br:21])=[CH:19][C:6]2[NH:7][C:8]([N:10]3[CH2:11][CH2:12][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][CH2:15]3)=[N:9][C:5]=2[C:4]=1[N+:22]([O-:24])=[O:23]
Reactant: CC(C)n1c(N2CCNCC2)nc2c([N+](=O)[O-])c(Br)c(Br)cc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nc3c([N+](=O)[O-])c(Br)c(Br)cc3[nH]2)CC1
Temperature: 120 °C
Yield: 67.9 %

Procedure:
2,5,6-tribromo-4-nitro-1H-1,3-benzodiazole (Method 2A) (17.5 mmol, 7 g) was dissolved in EtOH (30 ml) with N-Boc-piperazine (52.5 mmol, 9.78 g). The resulting mixture was stirred at 120° C. until the reaction was complete (8 h) by LC/MS. The mixture was allowed to cool to RT and concentrated in-vacuo. The product was purified on silica gel using DCM/MeOH (99:1) to afford tert-butyl 4-(5,6-dibromo-4-nitro-1H-1,3-benzodiazol-2-yl)piperazine-1-carboxylate (6 g). m/z 405.8; rt 2.4 min.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[I:22]Cl.ClCCl.CCOC(C)=O>N1C=CC=CC=1>[I:22][C:21]1[C:15]2[C:16](=[N:17][CH:18]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:12][CH:11]=3)[N:14]=2)[NH:19][CH:20]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]ccc3n2)cc1
Reactant: ClI
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]cc(I)c3n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.79 %

Procedure:
To 2-(4-isopropylsulfonylphenyl)-5H-pyrrolo[2,3-b]pyrazine (9 g, 29.86 mmol) in pyridine (90.00 mL) at RT was added a 1M solution of iodine monochloride in dichloromethane (32.85 mL of 1 M, 32.85 mmol). The resulting dark brown solution was stirred at RT for 4 hours then taken into EtOAc and washed with aqueous sodium thiosulphate/NaHCO3×2 then with brine, then dried over MgSO4 and concentrated under reduced pressure. The solid residue was triturated with acetonitrile, filtered and washed with acetonitrile, dried in vacuo to give the subtitle compound (5.97 g, 13.97 mmol, 46.79%). 1H NMR (400.0 MHz, DMSO) δ 12.72 (s, 1H), 9.03 (s, 1H), 8.46 (d, J=8.5 Hz, 2H), 8.23 (s, 1H), 8.01 (d, J=8.5 Hz, 2H), 3.49 (t, J=6.8 Hz, 1H) and 1.20 (d, J=6.8 Hz, 6H) ppm; MS (ES+) 428.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][N:3]=1.[S:24]([NH2:34])(=[O:33])([C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)=[O:25].CO>C(O)CCC>[S:24]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:2]2[N:7]=[C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:9]3[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=3[F:16])[CH:5]=[CH:4][N:3]=2)=[CH:28][CH:27]=1)(=[O:25])(=[O:33])[NH2:34]
Reactant: Cc1ccc(F)c(N(CCCC(F)(F)F)c2ccnc(Cl)n2)c1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: CO
Solvent: CCCCO
Product: Cc1ccc(F)c(N(CCCC(F)(F)F)c2ccnc(Nc3ccc(S(N)(=O)=O)cc3)n2)c1
Temperature: 95 °C
Yield: 54.6 %

Procedure:
2-Chloro-4-(N-4,4,4,-trifluorobutyl-2-fluoro-5-methylanilino)pyrimidine (215 mg, 0.62 mmol) was dissolved in n-butanol (2 ml) and sulphanilamide (85 mg, 0.50 mmol) was added. The resulting suspension was treated with methanol until all the solid dissolved. The reaction mixture was heated at 95° C. for 12 hours and allowed to cool to ambient temperature. The solid that had precipitated was collected by filtration, washed with a small volume of methanol and dried in vacuo to yield a white solid (132 mg). NMR (400 MHz@373K): 1.85 (m, 2H), 2.31 (m, 2H), 2.35 (s, 3H), 3.97 (t, 2H), 6.04 (d, 1H), 7.29 (m, 3H) 8.02 (d, 1H), 10.00 (br s, 1H); MS (M+H)+: 484.4.
Reaction SMILES: Cl.NC1C=C(C(F)(F)F)C=CC=1S.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[CH:18][C:19]2[S:23][CH2:22][NH:21][C:20]=2[CH:24]=1.C=O.[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Cl:41])[C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34]>ClCCl.O.C(N(CC)CC)C>[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Cl:41])[C:38]=1[O:39][CH3:40])[C:33]([N:21]1[C:20]2[CH:24]=[C:16]([C:15]([F:14])([F:25])[F:26])[CH:17]=[CH:18][C:19]=2[S:23][CH2:22]1)=[O:34]
Reactant: FC(F)(F)c1ccc2c(c1)NCS2
Reactant: COc1c(Cl)cc(C(=O)Cl)cc1Cl
Agent: C=O
Agent: Cl
Agent: Nc1cc(C(F)(F)F)ccc1S
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(C(=O)N2CSc3ccc(C(F)(F)F)cc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-amino-4-trifluoromethylbenzenethiol hydrochloride (502 mg), and 5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole synthesized from 37% formalin (0.18 mL) and triethylamine (0.30 mL) in the same manner as in Example 38 were dissolved in dichloromethane (5 mL), and triethylamine (0.30 mL) and 3,5-dichloro-4-methoxybenzoyl chloride (354 mg) were added to the solution, and then the mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:1) to obtain the title compound (223 mg) as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16](F)[C:15]=2[C:22]#[N:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([NH:37][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:15]=2[C:22]#[N:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc(F)c2C#N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc(NCc3ccccc3)c2C#N)CC1
Temperature: 100 °C

Procedure:
To 655 mg (2.03 mmol) of 4-(2-cyano-3,6-difluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester dissolved in 10 mL DMF was added 560 mg (2 eq., 4.06 mmol) potassium carbonate and 243 μL (1.1 eq., 2.22 mmol) benzylamine. The mixture was heated to 100° C. for 5 days, cooled to room temperature and partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated. 4-(3-Benzylamino-2-cyano-6-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (288 mg) was precipitated from dichloromethane/hexanes.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[OH-].CC(O)C.[NH:23]1[CH:30]=[CH:29][C:27]([NH2:28])=[N:26][C:24]1=[O:25].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO.CN(C=O)C>[NH2:28][C:27]1[CH:29]=[CH:30][N:23]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24](=[O:25])[N:26]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: CO
Product: Nc1ccn(Cc2ccccc2)c(=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
A 0.1 M solution of tetra-N-butylammonium hydroxide in a mixture of MeOH and 2-propanol (90 mL, 9.0 mmol) was added dropwise to a stirred suspension of cytosine (1 g, 9.0 mmol) in DMF (70 mL). The solution became clear and benzyl bromide (2.14 mL, 18 mmol) was added dropwise. The reaction mixture was stirred at RT for 2 hours and then the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM with a gradient of 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield 4-amino-1-benzyl-1H-pyrimidin-2-one (1 g, 57% yield) as a white solid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:17][C:18]([CH3:21])(C)C)(=[O:16])[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].ClCC1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)CO1.CCCCCC>C(O)(C)(C)C.O1CCCC1>[C:12]([O:11][C:9]([C@:8]12[CH2:1][C@@:21]1([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:18][O:17][C:7]2=[O:16])=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: ClCC1(c2ccccc2)CO1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@]12C[C@@]1(c1ccccc1)COC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
Under nitrogen atmosphere, potassium t-butoxide (110 g, 0.78 mol) was added to a solution of di-t-butyl malonate (170 g, 0.78 mol) in t-butyl alcohol (1.5 L) in 3 portions at room temperature. After stirring at room temperature for 1 hour, the mixture was heated to 70° C. Then a solution of 2-chloromethyl-2-phenyloxirane (120 g) in tetrahydrofuran (500 mL) synthesized by the method described in J. Org. Chem. (1962, 27, 2241-2243) was added dropwise over 90 min. After stirring for 12 hours at 70° C., the mixture was cooled to room temperature and the solvent was evaporated. 10% Aqueous citric acid solution (500 mL) was added to the residue. The mixture was extracted with ethyl acetate (2.0 L), sequentially washed with water (500 mL) and saturated aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. After filtration and evaporation, the title compound (120 g, 3 step, yield 54%) was recrystallized from a mixed solution of hexane:diisopropyl ether=1:1 (600 mL) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[NH:9][C:8]2[C:3]1=[N:4][C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N:6][CH:7]=2.Cl[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(Cl)(Cl)Cl.O>[CH3:1][N:2]1[C:10](=[O:11])[N:9]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]2[C:3]1=[N:4][C:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[N:6][CH:7]=2
Reactant: Cn1c(=O)[nH]c2cnc(-c3ccccc3)nc21
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)ncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A mixture of 7,9-dihydro-9-methyl-2-phenyl-8H-purin-8-one (22.6 g), ethyl chloroacetate (13.5 g), potassium carbonate (15.2 g) and dimethylformamide (250 ml) is stirred at room temperature for one hour. To the reaction mixture are added water and chloroform, and the chloroform layer is separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude ethyl 8,9-dihydro-9-methyl-8-oxo-2-phenyl-7H-purin-7-acetate (26 g).