Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[Si:42]([O:49][CH2:50][CH2:51]O)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[O:30]1[C@H:31]2[O:32][CH2:33][CH2:34][C@H:35]2[C@@H:28]([O:27][C:26](=[O:36])[NH:25][C@@H:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:51][CH2:50][O:49][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])=[CH:20][CH:19]=2)[C@H:15]([OH:37])[CH2:14][N:13]([S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:29]1
Reactant: CC(C)(C)[Si](C)(C)OCCO
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCO[Si](C)(C)C(C)(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate was treated with 2-{[tert-butyl(dimethyl)silyl]oxy}-1-ethanol (J. Org. Chem. 1986, 51, 3388-3390)/triphenyl phosphine/diisopropyl azodicarboxylate as described above to provide the title compound as solid foam. 1H NMR (DMSO-d6): 0.0 (6H, s), 0.78 (3H, d), 0.82 (3H, d), 0.84 (9H, s), 1.2 (1H, dd), 1.37 (1H, quintuplet), 1.9-2.0 (1H, m), 2.37 (1H, dd), 2.6-2.8 (2H, m), 2.9 (1H, d), 2.98 (1H, dd), 3.2-3.3 (1H m), 3.4-3.5 (1H, m), 3.5-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 3.88 (2H, dd), 3.93 (2H, dd), 4.8 (1H, dt), 5.0 (1H, d), 5.45 (1H, d), 6.18 (2H, s), 6.78 (2H, d), 7.0-7.1 (3H, m), 7.18 (1H, d), 7.2 (1H, s), 7.28 (1H, d); MS: 751 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][O:6][C:5](=[O:8])[CH:4]=1.[CH2:9](O)[CH2:10]C>>[CH2:1]([O:2][C:3]1[CH2:7][O:6][C:5](=[O:8])[CH:4]=1)[CH2:9][CH3:10]
Reactant: CCCO
Reactant: COC1=CC(=O)OC1
Product: CCCOC1=CC(=O)OC1
Yield: 39 %

Procedure:
Preparation analogous to Example 91 from 4-methoxy-2(5H)-furanone and propanol; b.p.10 143°-145° C. Yield: 39%.
Reaction SMILES: O[CH:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].CC(O)=O.[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17]>CCO>[C:6]1([C:3]2[CH:2]=[N:17][N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:4]=2[NH2:5])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NNc1ccccn1
Reactant: N#CC(=CO)c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1c(-c2ccccc2)cnn1-c1ccccn1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 3-hydroxy-2-phenylacrylonitrile (3.4 mmol) in EtOH (6.8 mL) is added AcOH (0.66 mL) and 2-hydrazinopyridine (6.8 mmol) at room temperature. After stirred at 80° C. for 5 h, the reaction mixture is cooling and concentrated in vacuo. The residue is diluted with H2O and extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue is triturated with ether to give the title compound; 1H NMR (CDCl3) δ 6.27 (br, 2H), 7.11-7.14 (m, 1H), 7.21-7.25 (m, 1H), 7.40-7.48 (m, 4H), 7.65 (s, 1H), 7.79-7.84 (m, 1H), 8.02 (d, 1H), 8.35-8.37 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:12]=3[O:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CCN(CC)CC.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:32]([O:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:12]=3[O:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:34])[CH3:33]
Reactant: COc1ccc2c(-c3ccc(OC)c(O)c3)coc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(-c3ccc(OC)c(O[Si](C)(C)C(C)(C)C)c3)coc2c1
Reaction time: 12 h
Yield: 92.2 %

Procedure:
To a solution of 14 (3.51 g, 12.9 mmol) in CH2Cl2 (30 mL), under nitrogen, was added Et3N (1.98 mL, 14.2 mmol) followed by DMAP (0.162 g, 14.2 mmol) and TBSCl (2.4 g, 14.2 mmol) at 0° C. The reaction mixture was stirred for 12 h allowing too reach room temperature. The reaction was quenched with water, the phases separated, and the aqueous phase was extracted with CH2Cl2 (3×30 mL). The combined organic solutions were dried over MgSO4 and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, elution with hexanes) afforded 4.57 g (11.9 mmol, 92%) of the protected benzo[b]furan 15 as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[O:8][C:9]([CH2:15][C:16]([F:19])([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[O:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>O1CCCC1>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]2[O:8][C:9]([CH2:15][C:16]([F:19])([F:18])[F:17])([C:11]([F:12])([F:13])[F:14])[O:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Reactant: [H][H]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Yield: 71.2 %

Procedure:
57.4 g of the product from Example 15a were dissolved in 400 ml of tetrahydrofuran and hydrogenated in the presence of 4 g of catalyst (palladium on carbon, 10% by weight) for 5 hours at 30° C. at 50 bar with hydrogen. The mixture was then filtered, the solvent removed, and the remaining filtrate distilled under a high vacuum. 37 g of product (=63% of theory) were obtained with a boiling point of 83° C. at 0.07 mbar. 19F-NMR: -59.0 and -84.6 ppm; 1H-NMR: 2.98 ppm.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1.I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:14][CH:13]=1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(C(=O)OC)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)c1ccc(C(CC2CCCC2)C(=O)OC)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 67.2 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (2.3 mL of a 0.31M stock solution, 0.71 mmol) cooled to −78° C. was treated with a solution of 4-methoxycarbonylmethyl-benzoic acid methyl ester (66 mg, 0.31 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.85 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (86 mg, 0.40 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reaction mixture was then stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and stirred at 25° C. for 18 h. At this time, the reaction mixture was quenched by the slow addition of a saturated aqueous ammonium chloride solution (10 mL). The reaction mixture was then poured into water (50 mL). This solution was extracted into ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80/20 hexanes/ethyl acetate) afforded 4-(2-cyclopentyl-1-methoxycarbonyl-ethyl)-benzoic acid methyl ester (60.5 mg, 65.7%) as a clear oil: EI-HRMS m/e calcd for C17H22O4 (M+) 290.1518, found 290.1518.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH:10]([C:17]#[N:18])[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[SH2:26]>N1C=CC=CC=1>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH:10]([C:17](=[S:26])[NH2:18])[C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S
Reactant: N#CC1CCCc2ccc(-c3ccccc3)nc21
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)C1CCCc2ccc(-c3ccccc3)nc21
Reaction time: 12 h

Procedure:
2-Phenyl-8-cyano-5,6,7,8-tetrahydroquinoline (2 g.) was dissolved in pyridine (5 ml.) and triethylamine (1.3 ml.) and the solution treated with H2S gas for 6 hours and the reaction mixture allowed to stand at room temperature for 12 hours. The solvent was removed and the residual oil dissolved in dilute HCl, extracted with ether (2 × 50 ml.) and the extracts discarded. The aqueous solution was made basic and extracted into chloroform (3 × 50 ml.). The combined extracts were dried and evaporated in vacuo to give 2-phenyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide which was dissolved in ethanol (5 ml.), diluted with ether (25 ml.) and the solution saturated with HCl gas. The solvent was removed in vacuo and the residual solid recrystallised from methanol-ether giving hydrochloride of the title compound as colourless needles mpt. 211° C. Found: C, 63.41; H, 5.70; N, 8.94%. C16H16N2S. HCl requires: C, 63.04; H, 5.62; N, 9.19 %.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11]C)[CH:3]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Br.O>C(O)(=O)C>[CH3:1][C:2]1([CH3:19])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[OH:11])[CH:3]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cccc2c1CC(C)(C)C2N1CCCCC1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)Cc2c(O)cccc2C1N1CCCCC1

Procedure:
A mixture of the 4-methoxy compound from Step 3 above (5 g) and 48% aq. HBr (50 ml) in glacial acetic acid (50 ml) is refluxed for three hours. The mixture is poured into H2O, the pH added to 8-10 and extracted with methylene chloride. The organic extract is washed with sat'd NaCl, dried, filtered, evaporated and the residue chromatographed (silica gel, hexane/ether) affording the desired product as a green solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5](I)=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH3:21])=[CH:4][CH:3]=1
Reactant: O=S1(=O)NC(C2CCCCC2)=Nc2c(Cl)ccc(I)c21
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1-c1ccc(Cl)c2c1S(=O)(=O)NC(C1CCCCC1)=N2
Yield: 72.6 %

Procedure:
A mixture of 5-chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (290 mg, 0.68 mmol), 2-methoxyphenylboronic acid (122 mg, 0.80 mmol), Pd(PPh3)2Cl2 (10 mg, 2 mol %) in 1,2-dimethoxyethane (50 ml) and Na2CO3 (2M, 2 ml, 4 mmol) were refluxed under N2 for 2 h. The solvents were removed under reduced pressure and the residue was extracted with EtOAc (2×40 ml) and the organic layer was washed with saturated NaHCO3 (20 ml), dried (Na2SO4) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on SiO2 using EtOAc:n-hexane (1:2, v/v) as eluent, yielding 200 mg (73%) of 5-chloro-3-cyclohexyl-8-(2-methoxyphenyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless crystals.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[Cl:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1O>C(#N)C>[Cl:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[O:5][CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1
Reactant: Oc1ccc(F)cc1Cl
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c(Cl)c1

Procedure:
A mixture of 1-(diphenylmethyl)-3-azetidinyl methanesulfonate (363.8 g, 1.15 mol), potassium carbonate (330 g, 2.38 mol) and 2-chloro-4-fluorophenol (140 g, 0.96 mol) in acetonitrile (2.5 L) was heated under reflux for 4.5 hours. The cooled reaction mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate (1 L) and water (500 mL). The organic layer was separated, dried over sodium sulfate concentrated in vacuo and the residue was triturated with ethyl acetate/pentane/dichloromethane, 90:10:1, to afford the title compound as a white solid in quantitative yield, 350 g. 1H NMR (400 MHz, CDCl3) δ: 3.19 (m, 2H), 3.75 (m, 2H), 4.45 (m, 1H), 4.78 (m, 1H), 6.60 (m, 1H), 6.83 (m, 1H), 7.14 (m, 1H), 7.18-7.50 (m, 10H)
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:19]#[CH:20])[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[C:22]1[S:23][CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:26]=1>>[C:1]12([C:11]3[CH:12]=[C:13]([C:19]#[C:20][C:22]4[S:23][CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:26]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: C#Cc1ccc(OC)c(C23CC4CC(CC(C4)C2)C3)c1
Reactant: CCOC(=O)c1csc(Br)c1
Product: CCOC(=O)c1csc(C#Cc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)c1

Procedure:
In a manner analogous to Example 1(b) above, by reaction of 3.2 g (12 mmol) of 3-(1-adamantyl)-4-methoxyphenylacetylene with 2.8 g (12 mmol) of ethyl 2-bromo-4-thiophenecarboxylate, there were obtained, after chromatography on a silica column eluted with a mixture of hexane and ethyl acetate, 2.4 g (48%) of the expected ethyl ester with the melting point 88°-90° C.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=2)=[C:10]([CH3:26])[CH:9]=1)=[O:6].[OH-].[K+]>CO.O>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:11]2[C:10]([CH3:26])=[CH:9][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([OH:27])=[O:2])=[CH:13][C:12]=2[CH3:14])=[CH:17][C:18]=1[CH:23]([CH3:25])[CH3:24]
Reactant: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(C(C)C)c2)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(NC(=O)CC(=O)O)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-[4-(4-hydroxy-3-isopropyl-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid methyl ester (29 mg, 0.08 mmol) in a mixture of MeOH (1 mL) and H2O (1 mL) was added 3 N KOH (0.9 mmol, 0.3 mL). After stirring at RT for 4 h, H2O (10 mL) was added. The solution was washed with EtOAc (2×10 mL) and acidified with 1 N HCl. The aqueous solution was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine, dried and concentrated to give the title compound of Step E and Example 1 (20 mg) as a white solid. MS (APCI−) Calc.: 357.1, Found: 356.1 (M−1).
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:16])[CH2:5][CH:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].[C:17]12(CS(O)(=O)=O)C(C)(C)C(C[CH2:23]1)C[C:18]2=O>COC(OC)(C)C>[C:1]([CH2:3][C@H:4]1[O:16][C:17]([CH3:23])([CH3:18])[O:15][C@@H:6]([CH2:7][C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:5]1)#[N:2]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: CC(C)(C)OC(=O)CC(O)CC(O)CC#N
Solvent: COC(C)(C)OC
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Crude [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate, 15 g (61 mol), is dissolved in 150 mL of 2,2-dimethoxypropane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography after concentration in vacuo provides 11.8 g of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate as an off-white solid, mp 64.7°-68° C. with acceptable IR, NMR, C-NMR and analysis.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[SH:16][C:17]1[S:21][C:20]([S:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:19][N:18]=1>>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:16][C:17]2[S:21][C:20]([S:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:19][N:18]=2)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2]
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCCSc1nnc(S)s1
Product: CCCc1c(CSc2nnc(SCCCC(=O)OCC)s2)ccc(C(C)=O)c1O
Yield: 98.1 %

Procedure:
Using as starting materials 0.30 g of 4-acetyl-3-hydroxy-2-propylbenzyl chloride and 0.42 g of ethyl 4-[(5-mercapto-1,3,4-thiadiazol-2-yl]thio]butyrate, 0.59 g of oily ethyl 4-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]butyrate was obtained in a manner similar to Example 1.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[CH2:12][C:13](=O)[CH3:14].[NH2:16][CH2:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[OH:19]>>[OH:26][C:23]1[CH:22]=[CH:21][C:20]([CH:18]([OH:19])[CH2:17][NH:16][CH:13]([CH3:14])[CH2:12][CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][N:2]2[CH3:1])=[CH:25][CH:24]=1
Reactant: CC(=O)CC1c2ccccc2CCN1C
Reactant: NCC(O)c1ccc(O)cc1
Product: CC(CC1c2ccccc2CCN1C)NCC(O)c1ccc(O)cc1
Yield: 47 %

Procedure:
The same procedure as described in Example 1 was repeated, using (2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetone [Synthesis, 1001 (1988)]and 2-amino-1-(4-hydroxyphenyl)ethanol, to give crude crystals. The crude crystals were washed with ether to give crystals of Compound 31 in a yield of 47%.
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[CH3:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]=1[OH:33].N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:31]1\[CH:32]=[C:23]([CH3:22])[C:24](=[O:33])[C:25]2[C:30]\1=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: Cc1ccc2ccccc2c1O
Reactant: Nc1c(N)n2n(c1=O)CCC2
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: CCO
Solvent: O
Product: CC1=C/C(=N\c2c(N)n3n(c2=O)CCC3)c2ccccc2C1=O

Procedure:
0.58 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulphonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.58 mmol of 2-methyl-1-naphthol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:17]=[C:16]([NH2:18])[O:15][N:14]=1>N1C=CC=CC=1>[CH3:12][C:13]1[CH:17]=[C:16]([NH:18][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[O:15][N:14]=1
Reactant: Cc1cc(N)on1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
4-brombenzenesulfonyl chloride (solid) was added, in five portions, to a solution of 3-methyl-5-aminoisoxazole (3.82 g, 40 mmol) in dry pyridine (30 ml). This was stirred at room temperature for 3 h and the pyridine was removed under reduced pressure. The residue was dissolved in THF (300 ml) and a 5% NaOH solution (100 ml) was added. Stirring continued for 1 h at room temperature. The THF was removed under reduced pressure and the resultant residue was neutralized to pH 2 using concentrated hydrochloric acid. This was extracted with ethyl acetate (3×200 ml) and the combined organic layer was dried over MgSO4 and concentrated. The crude product was recrystallized using hexane/ethyl acetate giving N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide (9.2 g, 72% yield).
Reaction SMILES: C([S:4][C@@H:5]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:6]([NH:8][CH:9]1[CH:15]=[CH:14][C:13]2[CH:16]=[CH:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:19][C:12]=2[N:11]([CH2:26][C:27]([O:29]CC)=[O:28])[C:10]1=[O:32])=[O:7])(=O)C.C(O)C.[OH-].[Na+].Cl>O>[C:27]([CH2:26][N:11]1[C:12]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:13]=2[CH:14]=[CH:15][CH:9]([NH:8][C:6](=[O:7])[C@@H:5]([SH:4])[CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:10]1=[O:32])([OH:29])=[O:28]
Reactant: CCOC(=O)CN1C(=O)C(NC(=O)[C@H](Cc2ccccc2)SC(C)=O)C=Cc2ccc(-c3ccccc3)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CN1C(=O)C(NC(=O)[C@@H](S)Cc2ccccc2)C=Cc2ccc(-c3ccccc3)cc21
Yield: 86 %

Procedure:
To a mixture of 358 mg (0.657 mmol) of 3-[(S)-2-acetylthio-3-phenylpropionylamino]-1-ethoxycarbonylmethyl-8-phenyl-1H-[1]benzazepin-2-one obtained in the Example A-2 with 10 ml of degassed ethanol was added 3.3 ml of a degassed 1N aqueous solution of sodium hydroxide at 0° C. under a nitrogen atmosphere under stirring. The mixture thus obtained was stirred at room temperature for 2 hours and half. The reaction mixture was cooled and acidified with 1N hydrochloric acid and water was further added thereto. The white crystals thus precipitated were collected by filtration, washed with water and n-hexane and dried under reduced pressure. Thus, 267 mg of the title compound was obtained. Yield 86%.
Reaction SMILES: [IH:1].[NH2:2][NH:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[NH:5].[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:16]=1[CH:17]=O>C(O)(=O)C>[IH:1].[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:16]=1[CH:17]=[N:2][NH:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[NH:5]
Reactant: N=C(NN)NCc1ccccn1
Reactant: Cc1cccc(C)c1C=O
Agent: I
Solvent: CC(=O)O
Product: Cc1cccc(C)c1C=NNC(=N)NCc1ccccn1

Procedure:
A mixture of 2.93 g. of 1-amino-3-(2-pyridylmethyl)guanidine hydriodide and 1.34 g. of 2,6-dimethylbenzaldehyde [G. Lock and K. Schmidt, J. Prakt. Chem., 140, 229 (1934)] is dissolved in 5 ml. of glacial acetic acid at 100° C. After 2 hours the solidified reaction is triturated with water and filtered. Crystallization from absolute ethanol gives the desired product as colorless needles, m.p. 184°-186° C.
Reaction SMILES: [OH:1]O.[F:3][C:4]([F:37])([F:36])[C:5]1[CH:27]=[C:26]([S:28][C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:6]=1[NH:7][C:8](=[O:23])[C:9]1[C:10](=[C:12]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[C:14]([C:17]#[N:18])[C:15]=1[CH3:16])[OH:11].O>C(O)(=O)C>[F:37][C:4]([F:36])([F:3])[C:5]1[CH:27]=[C:26]([S:28]([C:29]2[CH:30]=[CH:31][C:32]([Br:35])=[CH:33][CH:34]=2)=[O:1])[CH:25]=[CH:24][C:6]=1[NH:7][C:8](=[O:23])[C:9]1[C:10](=[C:12]([C:19]([CH3:21])([CH3:22])[CH3:20])[CH:13]=[C:14]([C:17]#[N:18])[C:15]=1[CH3:16])[OH:11]
Reactant: OO
Reactant: Cc1c(C#N)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc(Sc2ccc(Br)cc2)cc1C(F)(F)F
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(C#N)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc(S(=O)c2ccc(Br)cc2)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
30% w/v Aqueous hydrogen peroxide solution (70 μl.) is added to a suspension of 2'-trifluoromethyl-4'-(4-bromophenylthio)-5-cyano-3-t-butyl-6-methylsalicylanilide (0.25 g.) in acetic acid (4 ml.), and the mixture heated at 70°-80° C. for 1 hour. Water (2 ml.) is then added and the solution is cooled slowly to room temperature. The crystalline solid which is thus obtained is separated by filtration and dried to give 2'-trifluoromethyl-4'-(4-bromophenylsulphinyl)-5-cyano-3-t-butyl-6-methylsalicylanilide, m.p. 178°-180° C.