Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])=[O:24].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:51][CH2:52][N:53]2[CH:57]=[CH:56][N:55]=[N:54]2)(=O)=O)=CC=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:51][CH2:52][N:53]4[CH:57]=[CH:56][N:55]=[N:54]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])=[O:24]
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OCCn2ccnn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCCn1ccnn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N′-(2,4-difluorophenyl)urea (55 mg), potassium carbonate (31 mg), and 2-(1H-1,2,3-triazol-1-yl)ethyl 4-methyl-1-benzenesulfonate (36 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C. for one hr. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 46 mg (yield 72%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([C:8]([OH:10])=O)[CH:4]=1)[CH3:2].C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:23][C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:25]=1[NH2:26]>CN(C=O)C>[CH3:23][C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:25]=1[NH:26][C:8]([C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[O:7][N:6]=1)=[O:10]
Reactant: CCc1cc(C(=O)O)no1
Reactant: Cc1cccc(C)c1N
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)Nc2c(C)cccc2C)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
5.1 g (0.04 mole) of 5-ethyl isoxazole 3-carboxylic acid are dissolved in 100 ml of DMF under nitrogen, 13 g (0.08 mole) of carbonyl diimidazole are added and the mixture is stirred for 2 h at room temperature. 9.7 g (0.08 mole) of 2,6-dimethyl aniline are added and the mixture is stirred again for 48 h. After removal of the precipitate formed by filtration and evaporation of the solvent, the residue is crystallized from petroleum ether. M.p.=82°. The yield is 73%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)=O.[CH:10]1[C:23]2[C:22]3([CH2:25][CH2:26][CH:27]=O)[CH2:24][CH:15]([C:16]4[C:21]3=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=2[CH:13]=[CH:12][CH:11]=1>O>[O:4]1[CH2:5][CH2:6][N:1]([CH2:27][CH2:26][CH2:25][C:22]23[CH2:24][CH:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=42)[C:14]2[C:23]3=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: O=CCCC12CC(c3ccccc31)c1ccccc12
Solvent: O=CO
Solvent: O
Product: c1ccc2c(c1)C1CC2(CCCN2CCOCC2)c2ccccc21
Temperature: 60 °C

Procedure:
To a mixture of morpholine (870 mg) and formic acid (460 mg) heated at 60° C. was added β-(9,10-dihydro-9,10-methano-9-anthryl)propionaldehyde (50 mg). The resultant mixture was stirred at 60° C. for 30 minutes and at 80° C. for 1.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-γ-morpholinopropyl-9,10-dihydro-9,10-methanoanthracene, which was converted into its hydrochloride. M.P. 173°-176.5° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8][CH2:7]1.Cl>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH2:7]1
Reactant: COCCOC1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: COCCOC1CCC(=O)CC1
Reaction time: 5 h

Procedure:
8-{[2-(Methyloxy)ethyl]oxy}-1,4-dioxaspiro[4.5]decane (D20) (1.6 g, 7 mmol), was dissolved in 20 mL of THF and HCl (25 eq., 5M, 35 mL) was added at Rt. The mixture was stirred at Rt for 5 hr. THF was then evaporated and the aqueous was extracted with dichloromethane (2×). Organics were washed once with water, dried over Na2SO4, filtered and the solvent was evaporated to afford the title compound, 1.3 g, complete conversion as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH2:15])=[N:11]1.C(N(CC)CC)C.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26](Cl)=[O:27]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:26](=[O:27])[C:25]2[C:24]([F:23])=[CH:32][CH:31]=[CH:30][C:29]=2[F:33])=[N:11]1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1ccn(Cc2ccc(Cl)cc2Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccn(Cc2ccc(Cl)cc2Cl)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
1-[(2,4-Dichlorophenyl)methyl]-1H-pyrazol-3-amine (40 μl, 0.23 mmol, Art-Chem GmbH) was dissolved in dichloromethane (2 ml). Triethylamine (64 μl, 0.46 mmol) and then 2,6-difluorobenzoyl chloride (49 mg, 0.28 mmol, Aldrich) were added and the reaction was stirred at room temperature for 2 h. The reaction was quenched by addition of water (5 ml). The organic phase was separated (by hydrophobic frit) and concentrated under a flow of nitrogen. The residue was purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid) (Method A). The appropriate fractions were concentrated in vacuo then under nitrogen flow. The sample was dissolved in methanol and applied to a 5 g aminopropyl ion exchange cartridge (prewashed with MeOH) and eluted with MeOH. The relevant fractions were combined and concentrated to give the title compound as a colourless solid (36 mg); LCMS: (System 1) MH+=382/384, tRET=3.47 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:14][NH2:15])[N:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:16]([O-])([O-])(OCC)[CH3:17]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:16]([CH3:17])=[N:15][N:14]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NNc1nncc(-c2ccc(F)cc2)n1
Reactant: CCOC(C)([O-])[O-]
Product: Cc1nnc2nc(-c3ccc(F)cc3)cnn12

Procedure:
A mixture of 0.57 g. of 5-(p-fluorophenyl)-3-hydrazino-1,2,4-triazine and 20 ml. of ethyl orthoacetate is refluxed for 4 hours, cooled and filtered. The desired product is recovered as a brown solid, m.p. 227.5°-231° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[NH2:22][C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1>>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([NH:22][C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:19]
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1ncccn1
Product: CN1C(C(=O)Nc2ncccn2)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 39 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-pyrimidine with a yield of 39% of theory.
Reaction SMILES: [OH2:1].[C:2](Cl)(=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:9][NH:10][C:11](=[O:28])[CH2:12][NH:13][CH2:14][C:15]1[C:20]([I:21])=[C:19]([NH2:22])[C:18]([I:23])=[C:17]([C:24]([OH:26])=[O:25])[C:16]=1[I:27]>CC(N(C)C)=O>[CH3:9][NH:10][C:11](=[O:28])[CH2:12][NH:13][C:14](=[O:1])[C:15]1[C:20]([I:21])=[C:19]([NH:22][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6])[C:18]([I:23])=[C:17]([C:24]([OH:26])=[O:25])[C:16]=1[I:27]
Reactant: CCCCC(=O)Cl
Reactant: O
Reactant: CNC(=O)CNCc1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Product: CCCCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCC(=O)NC)c1I
Reaction time: 8 h

Procedure:
Under agitation and water cooling, 31.5 ml. of valeroyl chloride is added dropwise to 45.8 g. (0.073 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzyl)-glycine methylamide (Iv a), m.p. 252°-253° C. (under decomposition), in 120 ml. of dimethylacetamide. After agitating the reaction mixture overnight at room temprature, the product is precipitated by adding water; then, the product is vacuum-filtered and purified by dissolving the corresponding sodium salt and separation of the free acid by the addition of a mineral acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](N)=[O:14])=[CH:11][CH:10]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.B#B.CCOCC.O>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][OH:14])=[CH:16][CH:17]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: Cc1ccc(Sc2ccc(C(N)=O)cc2)c([N+](=O)[O-])c1
Agent: B#B
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(Sc2ccc(CO)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
The product from Example 84b (0.5 g, 1.73 mmol) was dissolved in THF (15 mL) and cooled in an ice bath. To the cold solution under nitrogen was added diborane as a 1.0M solution in THF (3.6 mL, 3.6 mmol) and the resulting mixture allowed to warm to room temperature and stir overnight. The crude product was isolated by extractive workup (ether/water) and dried with MgSO4, filtered and concentrated under vacuum giving the crude title compound. Purification by flash chromatography on silica gel gave the alcohol as a bright yellow solid (0.392 g, 82%).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].Cl[C:6]([O:8][CH2:9][Cl:10])=[O:7].N1C=CC=CC=1>CCOCC>[CH:2]([O:4][C:6](=[O:7])[O:8][CH2:9][Cl:10])([CH3:3])[CH3:1]
Reactant: CC(C)O
Reactant: O=C(Cl)OCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)OC(=O)OCCl
Temperature: 0 °C
Yield: 91.9 %

Procedure:
2-Propanol (73.14 mmole, 5.6 mL) was added to a solution of chloromethyl chloroformate (73.85 mmole, 6.5 mL) in ether (100 mL). The reaction mixture was cooled to 0° C. and pyridine (74.18 mmole, 6 mL) was dropwise added with stirring. Thereafter, the reaction mixture was stirred at ambient temperature for 20 hours. The formed solids were filtered and the filtrate was washed with citric acid (1% aqueous), water, sodium bicarbonate solution (1%) and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to yield 10.26 g (92%) of a colorless oil. MS (ES+): m/e 152 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH2:13]([Mg]Cl)[CH:14]([CH3:16])[CH3:15]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=1
Reactant: CC(C)C[Mg]Cl
Reactant: COC(=O)c1ccc(C=O)cc1
Product: COC(=O)c1ccc(C(O)CC(C)C)cc1

Procedure:
This compound is made from 4-formyl-benzoic acid methyl ester and isobutylmagnesium chloride following the general method exemplified in Preparation 1.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.Br[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1>CN(C=O)C.O>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][CH2:12][CH2:11][N:7]1[CH:8]=[CH:9][C:4](=[O:3])[CH:5]=[CH:6]1
Reactant: Oc1ccncc1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccn(CCOC2CCCCO2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
Sodium hydride (1.27 g of a 50% suspension in mineral oil, 26.4 mmol) was added to a solution of 4-hydroxypyridine (2.5 g, 26 mmol) in DMF (50 ml) and the mixture stirred for 30 minutes. 2-(2-Bromoethoxy)tetrahydropyran (5.0 g, 23.9 mmol), (J. Am. Chem. Soc. 1948, 70, 4187), in DMF (5 ml) was added and the mixture heated at 80° C. for 3 hours. The reaction mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 97/3) to give 1-[2-(tetrahydropyran-2-yloxy)ethyl]-1,4-dihydro-4-pyridone (1.5 g, 28%). 1H NMR Spectrum: (DMSOd6) 1.39-1.68(m, 6H); 3.39-3.44(m, 1H); 3.64-3.78(m, 2H); 3.86-3.92(m, 1H); 4.20(t, 2H); 4.64(s, 1H); 6.95(d, 2H); 8.36(d, 2H) MS-ESI: 224 [MH]+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][O:9][C:10](=[O:27])[C@H:11]1[CH2:15][C@@H:14](O)[CH2:13][N:12]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].COC(=O)[C@H]1C[C@H](OC2C=CC3C(=CC=CC=3)C=2)CN1C(OCC1C=CC=CC=1)=O>>[CH3:8][O:9][C:10](=[O:27])[C@H:11]1[CH2:15][C@H:14]([O:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][N:12]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: Oc1cccnc1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: COC(=O)[C@H]1C[C@H](Oc2ccc3ccccc3c2)CN1C(=O)OCc1ccccc1
Product: COC(=O)[C@H]1C[C@H](Oc2cccnc2)CN1C(=O)OCc1ccccc1

Procedure:
The title compound was prepared from 3-hydroxy pyridine and N-Cbz-cis-4-hydroxy-D-proline methyl ester by substantially following the procedure used in the preparation of N-Cbz-trans-4-(2-naphthyloxy)-D-proline methyl ester, Example 6, Steps A and B.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:35])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[NH:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])=[CH:13][C:12]=1[CH3:34]>C1COCC1.O>[CH3:34][C:12]1[CH:13]=[C:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[NH:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])[CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:35])=[O:5]
Reactant: COC(=O)CCCCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
Lithium hydroxide monohydrate (120 mg, 2.86 mmol) was added to a solution of 5-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-pentanoic acid methyl ester from Example E83.1 (410 mg, 0.95 mmol) in THF (10 ml) and water (5 ml). The mixture was stirred for 24 h at room temperature and concentrated in vacuo. The residue was acidified with 1M HCl and extracted with chloroform. The organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 3% acetic acid:7% methanol:90% chloroform) to yield the title compound (105 mg, 26%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Cl:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCCCCCCCCOCc1ccccc1
Solvent: CN(C)C=O
Product: ClCCCCCCCCCCOCc1ccccc1

Procedure:
A mixture of 7 g of 10-benzyloxy-1-decanol, 8 ml of thionyl chloride, and 0.2 ml of dimethylformamide was heated to 50° to 60° C. for one hour. After the reaction was over, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in 50 ml of n-hexane, and after washing the solution with water, the solution was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off and the residue was applied to silica gel column chromatography and eluted with toluene to provide 6.7 g of oily 10-benzyloxy-1-chlorodecane. Boiling point 135°-140° C. (0.6-0.9 mm Hg).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].O=[C:8]1[C:14]2C=CC=[CH:18][C:13]=2[N:12]([C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:22][CH:21]=2)[CH2:11][CH2:10][CH2:9]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]=[C:2]1[C:5]2[CH:14]=[CH:8][CH:9]=[CH:10][C:11]=2[N:12]([C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:22][CH:21]=2)[CH2:13][CH2:18][CH2:3]1
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Temperature: -5 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
Methyltriphenylphosphonium bromide (4.30 g) is suspended in tetrahydrofuran (100 ml) and thereto is added potassium t-butoxide (1.58 g) under ice-cooling. The mixture is stirred at -5° C. for 1 hour and thereto is added 5-oxo-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.60 g) and the mixture is stirred at room temperature for 1 hour. The reaction solution is poured into ice-water (200 ml) and extracted with ethyl acetate. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:2), and recrystallized from ethyl acetate/n-hexane to give 5-methylidene-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.34 g) as white powder, m.p. 216°-217° C.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1/[C:12](=[N:16]/[OH:17])/[CH2:13][CH2:14][CH3:15].S(Cl)(Cl)=O.N1C=CC=CC=1.Cl>C(OCC)C>[CH2:13]([C:12]1[C:3]2[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=2[O:17][N:16]=1)[CH2:14][CH3:15]
Reactant: CCC/C(=N\O)c1cc(C(=O)OC)ccc1O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCc1noc2ccc(C(=O)OC)cc12
Temperature: 0 °C
Yield: 58.6 %

Procedure:
To an ice-cold stirred solution of methyl 4-hydroxy-3-[(1E)-N-hydroxybutanimidoyl]benzoate (170 mg, 0.7 mmol) in diethyl ether (5 mL) was added a mixture of thionyl chloride (60 μL, 0.8 mmol) and pyridine (580 μL, 7.2 mmol) in diethyl ether (5 mL). After 2.5 h the mixture was poured over ice-water and acidified to pH=1 with 1 N hydrochloric acid. The mixture was then partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, 10:1 hexanes/ethyl acetate) provided methyl 3-propyl-1,2-benzisoxazole-5-carboxylate (90 mg): 1H NMR (300 MHz, CDCl3): δ 8.36-8.35 (m, 1H), 8.07-8.04 (m, 1H), 7.52-7.49 (m, 1H), 3.95 (s, 3H), 2.96-2.91 (m, 2H), 2.00-1.87 (m, 2H), 1.09-1.04 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:15]([Cl:18])(Cl)=[O:16].O.C(OCC)(=[O:22])C>ClCCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([Cl:18])(=[O:16])=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2ccccc2)cc1
Reactant: CCOC(C)=O
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: O
Product: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a suspension of 22.4 g (146 mmol) of sulfur trioxide/DMF complex in 60 mL of anhydrous 1,2-dichloroethane at room temperature, was added a solution of 30 g (162 mmol) of benzylphenyl ether in 30 mL of anhydrous 1,2-dichloroethane. The resulting mixture was warmed to reflux and maintained there for 1 hour, cooled to room temperature and 10.8 mL (146 mmol) of thionyl chloride added. The reaction was then warmed to 75 C for 1 hour, cooled in an ice bath, 50 mL of water slowly added, then ethyl acetate. The layers were separated, washed with saturated sodium bicarbonate, brine, dried with magnesium sulfate, filtered and stripped. The resulting solids were triturated with hexane to afford 24.5 g of pure 4-(Benzyloxy)benzenesulfonyl chloride.
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.[CH3:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([CH:30]=O)[CH:20]=1>>[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][CH2:30][C:21]3[CH:20]=[C:19]([CH3:18])[N:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:22]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Reactant: Cc1cc(C=O)nn1-c1ccccc1
Product: COc1ccc(N2CCN(CCNCc3cc(C)n(-c4ccccc4)n3)CC2)cc1
Yield: 22.1 %

Procedure:
Compound 37 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 5-methyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([NH2:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([C:34](=O)[CH2:35][C:36](OCC)=[O:37])=[CH:33][C:28]=2[O:27][CH2:26]1>C1(OC2C=CC=CC=2)C=CC=CC=1>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([C:34]3[NH:13][C:11]4[N:10]([N:9]=[C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)[N:12]=4)[C:36](=[O:37])[CH:35]=3)=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: CCOC(=O)CC(=O)c1ccc2c(c1)OCO2
Reactant: Nc1nc(-c2ccc(Cl)cc2)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1cc(-c2ccc3c(c2)OCO3)[nH]c2nc(-c3ccc(Cl)cc3)nn12
Temperature: 170 °C
Reaction time: 2 h
Yield: 24.2 %

Procedure:
To a solution of 3-(4-chlorophenyl)-1H-1,2,4-triazol-5-amine (50 mg, 0.26 mmol) in diphenyether (2 ml) was added TsOH (2.2 mg, 0.01 mmol) and ethyl 3-(benzo[d][1,3]dioxol-5-yl)-3-oxopropanoate (81 mg, 0.34 mmol). After stirring 2 h at 170° C., the reaction was quenched by the addition of hexane (5 ml), the product was collected by filtration and washed with methanol (10 ml) and dried in an oven under reduced pressure to give 5-(benzo[d][1,3]dioxol-5-yl)-2-(4-chlorophenyl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a off-white solid (23.1 mg, 24%).
Reaction SMILES: [CH:1]([O-:3])=O.[NH4+].[C:5]1([CH2:11][N:12]2[C:16](=O)C(C(C)C)[N:14](C)[S:13]2(=[O:23])=[O:22])C=CC=[CH:7][CH:6]=1>CO.[Pd]>[CH2:5]([CH:11]1[N:12]([CH3:16])[S:13](=[O:23])(=[O:22])[NH:14][C:1]1=[O:3])[CH2:6][CH3:7]
Reactant: O=C[O-]
Reactant: CC(C)C1C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: CCCC1C(=O)NS(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a suspension of 3.5 g of 10% Pd/C in 150 ml of methanol containing ammonium formate (15 g) was added a solution of 2-phenylmethyl-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (7.1 g) in 50 ml of methanol under nitrogen. The mixture was stirred at room temperature for 7 hours, filtered through a pad of CELITE® and the residue was washed with methanol. The combined filtrate was concentrated in vacuo to afford 4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide 2-ammonium salt (Formula IV: R1 =H; R2 =isopropyl; R3 =methyl; as NH4+ salt).