Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:6]([CH2:12]Cl)=[N:7]2.O.[N:23]1[C:31](=[S:32])[C:30]2[NH:29][CH:28]=[N:27][C:26]=2[NH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:6]([CH2:12][S:32][C:31]1[N:23]=[CH:24][N:25]=[C:26]3[C:30]=1[N:29]=[CH:28][NH:27]3)=[N:7]2
Reactant: Cc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Reactant: S=c1nc[nH]c2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1-n1c(CSc2ncnc3[nH]cnc23)nc2cccc(Cl)c2c1=O
Yield: 52.6 %

Procedure:
Prepared according to Procedure C using Intermediate 2j (200 mg, 0.626 mmol), 6-kinases -mercaptopurine monohydrate (93 mg, 0.546 mmol), K2CO3 (95 mg, 0.689 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 125 mg of an off-white solid (46%), mp 213.9° C. 1H NMR (DMSO-d6) δ: 13.53 (br s, 1H); 8.49 (s, 1H); 8.44 (s, 1H); 7.78 (t, J=7.9 Hz, 1H); 7.63 (d, J=8.2 Hz, 1H); 7.59 (d, J=7.7 Hz, 1H); 7.49 (d, J=6.9 Hz, 1H); 7.24-7.41 (m, 3H); 4.32-4.45 (m, 2H); 2.14 (s, 3H). 13C NMR (DMSO-d6) ppm: 158.9, 157.2, 154.2, 151.5, 149.7, 149.6, 143.5, 136.1, 135.9, 135.1, 133.2, 131.3, 130.3, 130.0, 129.9, 129.1, 127.6, 127.1, 117.8, 32.4, 17.5. MS (ES): m/z 438.0 (M+). Anal. calcd. for C21H15ClN6OS: C, 58.00; H, 3.48; Cl, 8.15; N, 19.32; S, 7.37. Found: C, 58.05; H, 3.38; Cl, 8.89; N, 18.38; S, 7.00.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH:10]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:9]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: NCCc1ccc(C(CCCC(=O)O)c2cccnc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=C(O)CCCC(c1ccc(CCNS(=O)(=O)c2ccc(F)cc2)cc1)c1cccnc1

Procedure:
Prepared analogously to Example 10e from 5-(4-(2-aminoethyl)phenyl)-5-(3-pyridyl)pentanoic acid and 4-fluorobenzenesulphonic acid chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O.C(=O)([O-])O.[Na+].[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21]>O1CCCC1>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([C:16]([F:15])([F:26])[F:27])[CH:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cccc(O)c1)c1cccc(C(F)(F)F)c1
Yield: 108.4 %

Procedure:
To a solution of 3-aminophenol (11.3 g, 104 mmol) in tetrahydrofuran (250 mL) were added water (250 mL) in which sodium hydrogen carbonate (10.6 g, 126.4 mmol) has been dissolved and 3-(trifluoromethyl)benzoyl chloride (22.4 g, 107 mmol), and the mixture was vigorously stirred at room temperature for 2 hr. The aqueous layer was separated, and the organic layer was diluted with ethyl acetate (150 mL) and washed with saturated brine (150 mL). The combined aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate and hexane to give title compound (31.7 g) as pale-brown crystals.
Reaction SMILES: [K].[CH3:2][S:3][C:4]1[C:9]([F:10])=[CH:8][NH:7][C:6](=[O:11])[N:5]=1.[CH2:12](Br)[C:13]#[CH:14]>CN(C)C=O>[CH2:14]([N:7]1[CH:8]=[C:9]([F:10])[C:4]([S:3][CH3:2])=[N:5][C:6]1=[O:11])[C:13]#[CH:12]
Reactant: CSc1nc(=O)[nH]cc1F
Reactant: C#CCBr
Agent: [K]
Solvent: CN(C)C=O
Product: C#CCn1cc(F)c(SC)nc1=O
Yield: 71 %

Procedure:
The potassium salt of 4-methylthio-5-fluoropyrimid-2-one (0.005 mol) and propargyl bromide (0.06 mol) were stirred together in dimethylformamide (20 ml) for 40 hrs at room temperature. The mixture was then filtered; the filtrate evaporated at reduced pressure (1 mm Hg) and the residue extracted with chloroform (60 ml). The chloroform solution was washed with 1 N NaOH, with water, and dried (MgSO4) before evaporation; yield 71%, m.p. 101°-102° C. (ethyl acetate). (Found: C, 48.50; H, 3.62. Calc. for C8H7SN2O: C, 48.48; H, 3.56).
Reaction SMILES: N#N.Cl[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([CH2:16][C:17]2[C:22]([Cl:23])=[CH:21][N:20]=[CH:19][C:18]=2[Cl:24])=[N:6][N:5]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C=O)C>[Cl:24][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:23])[C:17]=1[CH2:16][C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:5][N:6]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: C1COCCN1
Agent: N#N
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(N3CCOCC3)c2c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 78.7 %

Procedure:
A solution under stirring and dry N2 of 4-chloro-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (1 g, 2.82 mmoles), prepared as described in example 45, in DMF (25 ml), at room temperature, was added with morpholine (0.73 g, 8.46 mmoles) and the temperature was raised to 100° C. After 14 hours the whole was brought to dryness and the solid partitioned between water and CH2Cl2. The organic phase was washed with water, anhydrified and brought to dryness to give a solid which was flash chromatographed (eluent hexane/ethyl acetate 6:4, then in gradient up to 3:7) to give 0.9 g of the title compound (yield: 79%). m.p.: 179-180° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.Cl[C:20]1[C:25]([CH:26]=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C(=O)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([O:18][C:20]4[C:25]([CH:26]=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:13]([C:14]([F:16])([F:17])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: O=Cc1cccnc1Cl
Reactant: Oc1ccc2c(nnn2CC2CC2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=Cc1cccnc1Oc1ccc2c(nnn2CC2CC2)c1C(F)(F)F
Temperature: 25 °C

Procedure:
1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-ol (9-5, 35 mg, 0.14 mmol, 1 equiv.) and 2-chloropyridine-3-carbaldehyde (29 mg, 0.20 mmol, 1.5 equiv.) were dissolved in N,N-dimethylacetamide (1.5 mL) and treated with cesium carbonate (89 mg, 0.27 mmol, 2 equiv.). The mixture was irradiated at 100° C. in a microwave reactor for 30 minutes, cooled to ambient temperature and poured into water (30 mL). The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo to afford the titled compound 417.
Reaction SMILES: BrC1C=CC(O[C:7]2[C:20]3[C:19](=[O:21])[C:18]4[C:13](=[C:14](OC5C=CC(Br)=CC=5)[CH:15]=[CH:16][CH:17]=4)[C:12](=[O:30])[C:11]=3[CH:10]=[CH:9][CH:8]=2)=CC=1.[OH-].[K+].[C:35]1([CH3:42])[CH:40]=[CH:39][C:38]([SH:41])=[CH:37][CH:36]=1>CN(C=O)C>[CH3:42][C:35]1[CH:40]=[CH:39][C:38]([S:41][C:7]2[C:20]3[C:19](=[O:21])[C:18]4[C:13](=[C:14]([S:41][C:38]5[CH:39]=[CH:40][C:35]([CH3:42])=[CH:36][CH:37]=5)[CH:15]=[CH:16][CH:17]=4)[C:12](=[O:30])[C:11]=3[CH:10]=[CH:9][CH:8]=2)=[CH:37][CH:36]=1
Reactant: Cc1ccc(S)cc1
Reactant: O=C1c2cccc(Oc3ccc(Br)cc3)c2C(=O)c2cccc(Oc3ccc(Br)cc3)c21
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2cccc3c2C(=O)c2cccc(Sc4ccc(C)cc4)c2C3=O)cc1
Temperature: 110 °C

Procedure:
10 parts of 1,5-bis(4-bromophenoxy)anthraquinone, 8 parts of potassium hydroxide, and 9 parts of 4-toluenethiol were added to 100 parts of DMF, and the mixture was stirred under heat at 110° C. for 3 hours. The precipitated solid after cooling was filtered, washed, and dried, to give 6.5 parts of an intermediate (1,5-bis(4-methylphenylthio)anthraquinone).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 54.7 %

Procedure:
A mixture of methyl thiosalicylate (0.85 g, 5.1 mmol), 2-cyano-6-methylpyridine (0.60 g, 5.1 mmol), triethylamine (1.10 ml, 7.9 mmol) and toluene (1.1 ml) was refluxed for 9 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (0.71 g, 55%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>CCO.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:15]=2)[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1Cc2cc(Br)ccc2N(Cc2ccccc2)C1
Reactant: OB(O)c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1Cc2cc(-c3ccccc3)ccc2N(Cc2ccccc2)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
Compound 89A (150 mg, 0.36 mmol), phenylboronic acid (57 mg, 0.47 mmol) and 2N aqueous Na2CO3 (1.25 mL, 2.5 mmol) in a mixed solvent of toluene (1.5 mL) and EtOH((0.5 mL) were stirred at RT for 30 min while N2 was allowed to bubble through the mixture, and then tetrakis(triphenylphosphine)-palladium (0) (30 mg) was added. The mixture was stirred at 90° C. under N2 for 1 h. After cooling to RT, the mixture was extracted with EtOAc (15 mL×3), and organic extracts were washed with brine, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (10-50%) in hexane to give the title compound (80 mg, 67%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[NH:8][CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]1[C:37]2[C:32](=[N:33][CH:34]=[CH:35][CH:36]=2)[N:31]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:30]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[N:8]([CH2:28][C:29]2[C:37]3[C:32](=[N:33][CH:34]=[CH:35][CH:36]=3)[N:31]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:30]=2)[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14]
Reactant: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nc(Cn2ccc(C(F)(F)F)c(Oc3cc(Cl)cc(Cl)c3)c2=O)c2cccnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask charged with 3-(3,5-dichlorophenoxy)-4-(trifluoromethyl)pyridin-2(1H)-one (0.500 g, 1.54 mmol) and potassium carbonate (0.213 g, 1.54 mmol) was added dimethylformamide (5 mL). To this under N2 was added tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.482 g, 1.54 mmol) as a solution in dimethylformamide (2 mL). This was allowed to stir at room temperature. After 16 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (3×50 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on a pre-packed silica gel Redi Sep 40 gram column, eluting with 0-50% ethyl acetate in hexanes to afford the title compound. 1H NMR (DMSO-d6) δ 8.72 (d, J=4.5 Hz, 1H), 8.26-8.22 (m, 1H), 8.11 (d, J=7.2 Hz, 1H), 7.43 (dd, J=8.0 Hz, J=4.6 Hz, 1H), 7.30-7.28 (m, 1H), 7.05-7.02 (m, 2H), 6.70 (d, J=7.2 Hz, 1H), 5.60 (s, 2H), 1.62 (s, 9H). HRMS (M+1)=555.0826.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(Cl)Cl.Cl.[NH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C([O-])(O)=O.[Na+]>O>[CH2:33]([O:32][C:30]([CH2:29][CH2:28][NH:27][CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:31])[CH3:34]
Reactant: CCOC(=O)CCN
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCNC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reaction time: 3 h

Procedure:
6.4 g of ethyl 3-ethoxy-2-(2,3,4,5-tetrafluoro-benzoyl)-acrylate are initially introduced into 30 ml of methylene chloride. A solution of 3.1 g of ethyl 3-amino-propionate hydrochloride in 12 ml of water is added to this. A solution of 1.7 g of NaHCO3 in 20 ml of water is added dropwise to the two-phase mixture with vigorous stirring. After the dropwise addition is complete, the mixture is stirred for a further 3 hours. The phases are then separated, and the organic phase is washed with water and dried over Na2SO4. After concentration, 7.8 g of the title compound remain.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:13][OH:14]>>[OH:14][N:13]=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: NO
Reactant: O=C(O)C(=O)c1cccc(O)c1
Product: O=C(O)C(=NO)c1cccc(O)c1
Reaction time: 0.42 h

Procedure:
2-(3-Hydroxyphenyl)glyoxylic acid (3.32 g.) and 1 N-methanol solution of hydroxylamine (45 ml.) were refluxed with stirring for 25 minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 1 N-aqueous solution of sodium hydroxide (70 ml.). An aqueous solution was washed with ether, acidified with dil. hydrochloric acid and then extracted with ethyl acetate. The extract was washed, dried and treated with an activated charcoal. The solvent was distilled off to give 2-hydroxyimino-2-(3-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (2.9 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10]Cl)=[O:8])=[CH:5][C:4]=1[CH3:14].[C:15]([NH:18][C:19]1[C:20]([I:35])=[C:21]([N:30]([C:32](=[O:34])[CH3:33])[CH3:31])[C:22]([I:29])=[C:23]([C:26]([O-:28])=[O:27])[C:24]=1[I:25])(=[O:17])[CH3:16].[K+].[I-].[Na+]>CN(C=O)C>[C:15]([NH:18][C:19]1[C:20]([I:35])=[C:21]([N:30]([C:32](=[O:34])[CH3:33])[CH3:31])[C:22]([I:29])=[C:23]([C:26]([O:28][CH2:10][O:9][C:7](=[O:8])[C:6]2[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[C:4]([CH3:14])[CH:5]=2)=[O:27])[C:24]=1[I:25])(=[O:17])[CH3:16]
Reactant: COc1ccc(C(=O)OCCl)cc1C
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)OCOC(=O)c2c(I)c(NC(C)=O)c(I)c(N(C)C(C)=O)c2I)cc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Chloromethyl 4-methoxy-3-methylbenzoate (Intermediate 8) (2.38 g, 11.0 mmol) in dry DMF (100 ml) is added dropwise at 50° C. to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (6.7 0 g, 10.0 mmol) and sodium iodide (75 mg, 0.50 mmol) in dry DMF (140 ml). The precipitate is removed by filtration after stirring for 4.5 hours and 16 hours at room temperature, and the solvent is removed at reduced pressure. The residue is dissolved in chloroform (100 ml) and washed four times with a saturated sodium hydrogen carbonate solution. After drying with magnesium sulfate the solvent is removed at reduced pressure to give the title compound:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3](=[O:11])[C:2]1=[O:12].FC(F)(F)S([O-])(=O)=O.[F:21][C:22]([I+]C1C=CC=CC=1)([F:27])[C:23]([F:26])([F:25])[F:24].CN(C)C=O>C(OCC)(=O)C>[F:21][C:22]([F:27])([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:11])[C:2](=[O:12])[NH:1]2)[C:23]([F:26])([F:25])[F:24]
Reactant: FC(F)(F)C(F)(F)[I+]c1ccccc1
Reactant: O=c1[nH]c2ccccc2[nH]c1=O
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]c2ccc(C(F)(F)C(F)(F)F)cc2[nH]c1=O
Temperature: 45 °C
Reaction time: 8 h
Yield: 5.8 %

Procedure:
A mixture of 0.5 g of 2(1H), 3(4H)-quinoxalinedione, 1.60 g of pentafluoroethylphenyliodonium trifluoromethanesulfonate and 10 ml of dimethylformamide was stirred overnight on an oil bath at 45° C. Ethyl acetate was then added to the reaction mixture and the unreacted 2(1H), 3(4H)-quinoxalinedione was removed by filtration (recovery of the starting material: 0.13 g). Water was added to the filtrate and, after rendering the mixture neutral, the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off. A small amount of methylene chloride was added to the residue and the precipitated crystals were collected by filtration to obtain 0.05 g of 6-pentafluoroethyl-2(1H), 3(4H)-quinoxalinedione as colorless crystals. Yield 6% (conversion yield, 8%). Melting Point (after recrystallized from acetonitrile): 317°-320° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-:15].[Na+]>O.OO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:13]([NH2:14])=[O:15])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: [OH-]
Agent: [Pd]
Agent: OO
Agent: [Na+]
Solvent: O
Product: NC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 50 °C

Procedure:
A solution of 1-(3,4-dichlorophenyl)-1-cyclobutane carbonitrile (70 g) prepared in a similar manner to that described in Example 1 in industrial methylated spirit (200 ml) was mixed with a solution of sodium hydroxide (3.7 g) in water (5 ml) and 30% hydrogen peroxide solution added dropwise. The mixture was heated at 50° C. for one hour and then stirred with 10% palladium on charcoal (0.5 g) for one hour. The mixture was filtered and evaporated to dryness to give 1-(3,4-dichlorophenyl)-1-cyclobutane-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:18]([C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([CH:32]=O)[CH:22]=1)[CH2:19][CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][CH2:32][C:23]3[CH:22]=[C:21]([CH2:18][CH2:19][CH3:20])[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:24]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Reactant: CCCc1cc(C=O)nn1-c1ccccc1
Product: CCCc1cc(CNCCN2CCN(c3ccc(OC)cc3)CC2)nn1-c1ccccc1
Yield: 41.3 %

Procedure:
Compound 39 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 5-propyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=O)[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=3)[CH2:14][CH2:13]2)=[C:5]([N+:31]([O-])=O)[CH:4]=1.B.O1CCCC1>O1CCCC1>[NH2:31][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([C:26]([F:28])([F:27])[F:29])[CH:19]=2)[CH2:14][CH2:13]1
Reactant: COc1ccc(NC(=O)CN2CCN(c3ccc(OC)c(C(F)(F)F)c3)CC2)c([N+](=O)[O-])c1
Agent: B
Solvent: C1CCOC1
Product: COc1ccc(NCCN2CCN(c3ccc(OC)c(C(F)(F)F)c3)CC2)c(N)c1
Temperature: 55 °C

Procedure:
N-(4-Methoxy-2-nitro-phenyl)-2-[4-(4-methoxy-3-trifluoromethyl-phenyl)-piperazin-1-yl]acetamide (6.1 g; 11 mmol) iss dissolved in 70 ml tetrahydrofurane. Borane-tetrahydrofurane complex (90 ml of 1M THF solution) is added at 10° C. and the mixture is warmed to 55° C. for 4 hours. After cooling to room temperature, the solvent is evaporated under vacuum and the residue is taken with ethanol and acidified with hydrochloric acid. Heating to 50° C. takes place for 60 min. Upon overnight cooling, the unreacted compound is separated by filtration. The liquid phase is dried under vacuum, taken up with water and, after removal of the undissolved solid, saturated sodium hydrogencarbonate solution is added. The aqueous phase is extracted with ethylacetate and the organic layer is dessicated prior to evaporation. The residue is purified by silicagel chromatography (methylene chloride/methanol/32% aqueous ammonia 95:5:0.5). The title compound can be directly used for the following step.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]([C:19]([O:21][CH3:22])=[O:20])=[C:11]([CH3:23])[N:10]=1)C1C=CC=CC=1.C1COCC1.[H][H]>[C].[Pd].C(O)C>[OH:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]([C:19]([O:21][CH3:22])=[O:20])=[C:11]([CH3:23])[N:10]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc(C(=O)OC)c(OCc2ccccc2)nc1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1cc(C(=O)OC)c(O)nc1C
Yield: 48.2 %

Procedure:
A mixture of dimethyl 2-(benzyloxy)-6-methylpyridine-3,5-dicarboxylate (14.4 g), 10% palladium carbon (containing 55% water, 9.00 g), THF (20 mL), and ethanol (20 mL) was stirred at room temperature for 1 hour in a hydrogen atmosphere. The catalyst was filtered off, and then, the obtained filtrate was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to obtain the title compound (4.96 g).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.[CH2:22]([CH2:29][C:30](=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:14]([O:13][C:11]([CH2:10][N:7]1[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3][CH:2]([NH:1][CH:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:29][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:8]1=[O:9])=[O:12])([CH3:16])([CH3:17])[CH3:15]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CSc2ccccc21
Product: CCOC(=O)C(CCc1ccccc1)NC1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O

Procedure:
The compound obtained in Example 7 was reacted with ethyl benzylpyruvate in the same manner as described in Example 9. Thus, there was obtained 5-t-butoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in the form of an oily material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH2:9])=[CH:4][C:3]=1[Cl:20].C(=O)([O-])[OH:22].[Na+]>C1(C)C=CC=CC=1>[Cl:20][C:3]1[CH:4]=[C:5]([C:8]2([CH2:10][O:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[CH2:9][O:22]2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: C=C(COc1ccc(OC)cc1)c1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(OCC2(c3ccc(Cl)c(Cl)c3)CO2)cc1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To a solution of 1,2-dichloro-4-{1-[(4-methoxyphenoxy)methyl]ethenyl}benzene (15.1 g) in toluene (161 ml) was added methachloroperbenzoic acid (21.6 g), and the mixture was stirred at 60° C. for 14 hr. The reaction mixture was cooled to 0° C., and diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.08 g).