Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]1([S:9]([CH2:12][C:13]2[C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:17](OCC(=O)N)[C:16]([Br:31])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:32](OCC)(=[O:34])C.C(=O)([O-])O.[Na+].C[N:44]([CH:46]=[O:47])C>>[C:3]1([S:9]([CH2:12][C:13]2[C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:17]([NH:44][C:46](=[O:47])[CH2:32][OH:34])[C:16]([Br:31])=[CH:15][CH:14]=2)(=[O:10])=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(C)=O
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OCC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1NC(=O)CO
Reaction time: 7 h

Procedure:
Sodium hydroxide (0.14 g) was added to a solution of tert-butyl 6-(benzenesulfonylmethyl)-3-bromo-2-carbamoylmethoxybenzoate (Intermediate 37, 0.33 g) in DMF (5 mL) and the mixture was stirred for 7 hours. Ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were added to the mixture and the organic layer was separated, washed with water and brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 20-100%, to give tert-butyl 6-(benzenesulfonylmethyl)-3-bromo-2-(2-hydroxyacetylamino)-benzoate (0.17 g) as a yellow oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:23])[CH2:18][NH:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:25][C:26](Cl)=[O:27].[OH-].[K+]>O.ClCCl.C(O)(C)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:18][N:19]([CH2:20][CH2:21][CH3:22])[C:26](=[O:27])[CH2:25][O:23]2)=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCNCC(O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)CCl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: CCCN1CC(c2ccc(OCc3ccccc3)cc2)OCC1=O
Temperature: 25 °C
Yield: 66.7 %

Procedure:
Sodium hydroxide (22.5 g, 0.56 mol) in water (100 ml) was added to the amine from example 26 (26.0 g, 0.09 mol) in dichloromethane (400 ml) and the solution vigorously stirred at room temperature. Chloroacetylchloride (8.6 ml, 0.11 mol) was then added and the reaction mixture stirred for a further 60 minutes. The layers were separated and the aqueous layer re-extracted with dichloromethane (200 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give a colourless oil. Potassium hydroxide (15.0 g, 0.27 mol), isopropyl alcohol (400 ml) and the colourless oil residue were stirred together as an opaque solution with water (30 ml) for 2 hours. The reaction mixture was concentrated in vacuo and the yellow residue dissolved in ethyl acetate (200 ml). This was partitioned with water (200 ml) then brine (200 ml). The organic fraction was dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a white solid (19.9 g, 0.06 mol, 67%). 1H NMR (CDCl3, 400 MHz) δ: 0.95 (t 3H), 1.62 (m, 2H), 3.34 (m, 2H), 3.51 (m, 2H), 4.32 (d, 1H), 4.41 (d, 1H), 4.72 (dd, 1H), 5.04 (s, 2H), 6.98 (d, 2H), 7.31-7.43 (m, 7H). LRMS: m/z 326 (M-H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C(N(CC)CC)C.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>ClCCl>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CSc1nc(Cl)cc(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1nc(Cl)cc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Yield: 101.3 %

Procedure:
4,6-Dichloro-2-methylsulfanylpyrimidine (10 g) was dissolved in dichloromethane (200 ml) and triethylamine (20.6 g) was added. The mixture was stirred at room temperature and piperazine-1-carboxylic acid tert-butyl ester (9.54 g) was added in portions. The mixture was stirred at room temperature overnight. Mixture was washed with water (200 ml) then brine (100 ml). The organic layer was dried (MgSO4) then evaporated under reduced pressure to afford 4-(6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (17.9 g) as a white solid. 1H NMR (CDCl3): δ 6.11 (s, 1H), 3.58 (m, 4H), 3.44 (m, 4H), 2.42 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[S:7][C:8](S(CC)(=O)=O)=[N:9][N:10]=1)(=[O:5])=[O:4])[CH3:2].O.[NH2:17][NH2:18]>CO>[NH:17]([C:8]1[S:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:10][N:9]=1)[NH2:18]
Reactant: NN
Reactant: CCS(=O)(=O)c1nnc(S(=O)(=O)CC)s1
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)c1nnc(NN)s1
Reaction time: 0.33 h
Yield: 31.7 %

Procedure:
2,5-bis(ethanesulphonyl)-1,3,4-thiadiazole (67.5 g) was added portionwise to a stirred solution of hydrazine hydrate (25.8 g) in methanol (1000 ml) at room temperature. The mixture was then stirred for 20 minutes and filtered. The solid was crystallised from methanol to give 2-hydrazino-5-ethylsulphonyl-1,3,4-thiadiazole (16.5 g, mp 166°-167° C.). The corresponding semicarbazone was prepared from this compound by reaction with acetaldehyde, then with methylisocyanate by methods analogous to those of Example 1(c) and 1(d), and the title compound was generated by the method of Example 13, mp 151°-153° C.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]=O.CO.[C:24]([O-:27])([O-])=O.[K+].[K+]>O.CC(OC)(C)C>[CH3:20][O:27][CH2:24][N:8]([CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=O
Reactant: C[Si](C)(C)CNC(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: COC(C)(C)C
Product: COCN(C[Si](C)(C)C)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 100 %

Procedure:
Diphenyl-N-((trimethylsilyl)methyl)methanamine (5.5 g, 20.4 mmol) was added dropwise to mixture of 37% aqueous formaldehyde (2.9 g) and methanol (1.5 g) while stirring at 0° C. After the addition was complete the reaction mixture was stirred for 2 hours at 0° C. K2CO3 (3 g) was added and the solidified mixture was warmed to room temperature. Methanol (4 ml) was added. After one hour stirring at room temperature, tBME (50 ml) and water (5 ml) was added. The organic layer was separated and dried with Na2SO4. Evaporation under vacuum gave the crude product N-(methoxymethyl)diphenyl-N-((trimethylsilyl)methyl)methanamine (7.05 g, max. 20.4 mmol) as an oil, which solidified on standing overnight at room temperature. The product was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:41])[C@@H:13]([NH:23]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(S)CCCCCCC.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:41])[C@@H:13]([NH2:23])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: CCCCCCCCS
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CNC(=O)OC(C)(C)C)CC1

Procedure:
A solution of 1.71 g 4-[(S)-3-tert-butoxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionyl]-piperazine-1-carboxylic acid ethyl ester in 50 ml THF was stirred in the presence of 4 ml 1-octanethiol and 90 μl DBU. After 12 h the mixture was concentrated, the residue dissolved in dichloromethane and extracted with 0.1 M HCl. The aqueous phase was brought to pH9 by adding aqueous NaHCO3 before being extracted with dichloromethane. The product was obtained after evaporation of the solvent and was used in the subsequent reaction.
Reaction SMILES: [C:1]1(C)C=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.C1C=CC=CC=1.[OH:18][C@@H:19]1[C@:27]2([CH2:28][CH3:29])[C@H:22]([C@@H:23]3[CH2:37][CH2:36][C:35]4[C@H:30]([CH2:31][CH2:32][C:33](=[O:38])[CH:34]=4)[C@H:24]3[CH2:25][CH2:26]2)[CH2:21][CH2:20]1.[OH-:39].[Na+]>O1C=CCCC1.CO.O>[CH2:28]([C@:27]12[CH2:26][CH2:25][C@@H:24]3[C@@H:30]4[C:35]([CH2:36][CH2:37][C@H:23]3[C@@H:22]1[CH2:21][CH2:20][C@@H:19]2[O:18][CH:5]1[CH2:4][CH2:3][CH2:2][CH2:1][O:39]1)=[CH:34][C:33](=[O:38])[CH2:32][CH2:31]4)[CH3:29]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: [OH-]
Agent: C1=COCCC1
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: c1ccccc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC1CCCCO1
Reaction time: 2 h

Procedure:
Add with swirling a solution of p-toluenesulfonic acid (14 mg) in benzene (0.8 mole) to dl-17β-hydroxy-13-ethylgon-4-en-3-one (450 mg) in 2,3-dihydropyran (3 ml). After 2 hours, neutralize the reaction mixture with methanolic sodium hydroxide. Add water, together with some methanol, scratch the mixture and allow it to stand at 0° for about 70 hours. Filter to obtain the title compound (100 mg), m.p. 148°-152°; infrared absorption peaks at 6.0 μ, 6.2 μ, 9.02 μ, 9.42 μ, 9.68 μ, 9.85 μ, 10.25 μ (no hydroxyl band).
Reaction SMILES: S(=O)(O)[O-].[Na+].[CH:6](=O)[CH3:7].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C-:16]#[N:17].[Na+]>O>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][CH:6]([CH3:7])[C:16]#[N:17]
Reactant: [C-]#N
Reactant: CC=O
Reactant: Nc1ccccn1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C#N)Nc1ccccn1
Reaction time: 2 h
Yield: 67 %

Procedure:
To an aqueous solution of sodium bisulfite in an amount of 10.5 g/20 ml H2O, a 44% acetaldehyde solution in an amount of 10 g was added and refluxed with heating for 1 hour. Then, 9.4 g of 2-aminopyridine was added thereto and the reflux with heating was continued for additional 2 hours. Aqueous solution of sodium cyanide was added thereto in an amount of 7 g/10 ml H2O and reacted at 90° C. for 2 hours. The oil layer was separated and cooled to be crystallized (yield 11.6 g). The crystals were recrystallized from ethyl acetate to give α-(2-pyridylamino)propionitrile in an amount of 9 g (in 67% yield).
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:13][C:14]1[C:15]([C:24]([NH:26][NH2:27])=[O:25])=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2>>[C:1]1([CH:11]=[N:27][NH:26][C:24]([C:15]2[C:14]([OH:13])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[O:25])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=O)c1cc2ccccc2cc1O
Reactant: O=Cc1cccc2ccccc12
Product: O=C(NN=Cc1cccc2ccccc12)c1cc2ccccc2cc1O
Yield: 76 %

Procedure:
Following the general procedure of Example 1, condensation of 1naphthaldehyde and 3-hydroxy-2-naphthoic hydrazide gave a pale yellow solid (76%): mp 214° C.; 1H NMR d 11.73 (br s, 1 H), 11.05 (br s, 1 H), 8.72 (s, 1 H), 8.52 (d, 1 H, J=8.4 Hz), 8.13 (s, 1 H), 7.60-6.80 (m, 11 H); 13C NMR d 164.00, 154.31, 148.56, 135.99, 133.57, 130.80, 130.40. 130.30, 129.48, 128.81, 128.78, 128.29, 128.12, 127.37, 126.85, 126.31. 125.89, 125.54, 124.39, 123.84, 120.13, 110.75; HRMS Calcd for C22H16N2O2 :340.1212, found 340.1208; Anal. (C22H16N2O2) C, H, N.
Reaction SMILES: O1CCN([CH:7]=[C:8]([CH3:10])[CH3:9])CC1.[Cl:11][CH2:12][C:13](Cl)=[O:14].C(=O)(O)[O-:17].[Na+]>C(OCC)C>[Cl:11][CH2:12][C:13](=[O:14])[C:8]([CH3:9])([CH3:10])[CH:7]=[O:17]
Reactant: O=C([O-])O
Reactant: CC(C)=CN1CCOCC1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C=O)C(=O)CCl
Temperature: 0 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
210 g (1.5 mols) of 1-morpholino-2-methyl-prop-1-ene are added dropwise, in the course of one hour, to 169.0 g (1.5 mols) of chloroacetyl chloride, dissolved in 350 ml of diethyl ether, at 5° C. After the addition is complete, the mixture is stirred for a further 3 hours under reflux. The solution is poured onto 100 g of ice and brought to pH 5 with aqueous sodium bicarbonate solution, and the ether phase is separated off. The aqueous phase is extracted with 100 ml of diethyl ether, the organic phases are combined, and dried over sodium sulphate, the solvent is distilled off and the residue is distilled under the vacuum from a water jet. 136.4 g (61% of theory) of 4-chloro-3-keto-2,2-dimethylbutanal of boiling point 95°-98° C./14 mbar are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:21](#[N:25])[CH2:22][C:23]#[N:24].[O-2].[Al+3].[O-2].[O-2].[Al+3]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[C:22]([C:21]#[N:25])[C:23]#[N:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cccc(C(=O)c2cc(OC)cc(OC)c2)c1
Reactant: N#CCC#N
Agent: [Al+3]
Agent: [O-2]
Product: COc1cccc(C(=C(C#N)C#N)c2cc(OC)cc(OC)c2)c1
Temperature: 160 °C
Yield: 33.4 %

Procedure:
(3,5-dimethoxyphenyl)-(3-methoxyphenyl)methanone (0.31 g, 1.12 mmol), malononitrile (0.08 ml, 1.23 mmol), and aluminum oxide (0.57 g, 5.6 mmol) were mixed and heated in an oil bath at 160° C. overnight. After cooling down to r.t., the brown mixture was extracted with CH2Cl2 (50 ml), filtered through a Celite pad and concentrated to an oil, which was purified via flash column chromatography (5% EtOAc in hexane gradient to 20% EtOAc in hexane in about 40 min.) and lyophilized to give 2-[(3,5-dimethoxy-phenyl)-(3-methoxy-phenyl)-methylene]-malononitrile as a greenish solid (0.12 g, 34%): mp, 100-102° C.; 1HNMR (DMSO-d6) δ 7.47 (t, J=8 Hz, 1H, Ar), 7.22 (dd, J=2.36, 8 Hz, 1H, Ar), 7.16 (t, J=1 Hz, 1H, Ar), 6.96 (d, J=7 Hz, 1H, Ar), 6.78 (t, J=2 Hz, 1H, Ar), 6.62 (d, J=2 Hz, 2H, Ar), 3.79 (s, 3H, OCH3), 3.76 (s, 6H, 2OCH3); 13C NMR (DMSO-d6) δ 173.4, 160.3, 158.9, 137.5, 136.8, 130.1, 122.4, 118.0, 115.3, 114.1, 114.0, 108.1, 103.6, 82.9, 55.6, 55.5; Anal. Calcd. For C19H16N2O3: C, 71.24; H, 5.03; N, 8.74. Found: C, 71.10; H, 4.87; N, 8.59.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:35])[C@@H:12]([N:20]2[CH2:24][C:23]([O:25][C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])=[CH:22][C:21]2=[O:34])[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[OH-].[Li+]>O1CCCC1.C(OCC)(=O)C>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[O:25][C:23]1[CH2:24][N:20]([C@@H:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:36])=[O:2])=[CH:5][N:6]=2)=[O:35])[C:21](=[O:34])[CH:22]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3Cl)=CC2=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3Cl)=CC2=O)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.5 %

Procedure:
To a magnetically stirred mixture of 6-{(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}-nicotinic acid methyl ester (prepared as in Example 69, 80 mg, 0.16 mmol) in tetrahydrofuran (3.0 mL) was added 0.5N lithium hydroxide solution (1.0 mL, 0.5 mmol). After addition was complete the mixture was stirred at 25° C. for 4 h. The reaction mixture was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid, water, a saturated sodium chloride solution and dried over sodium sulfate. The crude product was recrystallized from ethyl acetate to afford 6-{(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}-nicotinic acid (10 mg, 13%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.73-1.42 (m, 6H) 1.41-1.90 (m, 7H) 4.28 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 4.99 (s, 1H) 5.01-5.10 (m, 1H) 7.31-7.57 (m, 3H) 8.14 (d, J=8.5 Hz, 1H) 8.25 (dd, J=8.5, 2.1 Hz, 1H) 8.84 (d, J=2.1 Hz, 1H) 11.26 (s, 1H) 13.18 (br. s., 1H). HR-ES-MS m/z calculated for C25H25ClFN3O5 [M+H]+ 502.1540, observed 502.1537.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[CH:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1>C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:13]2)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(C=CC(=O)O)c3cc(OC)ccc32)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(CCC(=O)O)c3cc(OC)ccc32)cc1
Reaction time: 8 h

Procedure:
To a solution of 3-[1-(4-Methoxy benzenesulfonyl)-5-methoxy-1H-indol-3-yl]-acrylic acid 118 (1.0 g, 2.6 mmol) dissolved in THF (14 mL), Pd/C (67 mg) was added in one portion. The solution was attached to the Parr hydrogenator. The reaction was allowed to proceed overnight at 20–22 psi. The solution was filtered over celite, and the palladium-celite pad was washed with ethyl acetate (40 mL), and methanol (20 mL). The combined washes/solution was evaporated under reduced pressure to afford straw colored oil that solidified after cooling under high vacuum. The crude was triturated with diethyl ether to leave behind off white solid as product 1. (0.620 g, 62%) 1H NMR(DMSO) δ 7.86 (d, J=9.2 Hz, 1H), 7.75 (d, J=8.4Hz, 1H), 6.92 (dd, J=2.4 Hz, 9.2 Hz, 1H), 6.88 (s, 1H), 6.83 (d, J=9.2 Hz, 2H), 3.76 (s, 3H), 2.96 (t, J=7.6 Hz, 14.8 Hz, 2H), 2.74 (t, J=7.6 Hz, 14.8 Hz, 2H) (M−1=388.6).
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[C:14]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[C:24]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:23][N:22]=3)[O:18][N:17]=2)[CH:13]=[C:12]([CH3:32])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:11])[CH2:8][NH:9][CH3:10])[CH3:2].Cl.[CH3:34][O:35][C:36](=[O:40])[CH2:37]CN.C(N(CC)CC)C>CO>[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:10][NH:9][CH2:8][C@H:7]([OH:11])[CH2:6][O:5][C:4]1[C:12]([CH3:32])=[CH:13][C:14]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[C:24]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:23][N:22]=3)[O:18][N:17]=2)=[CH:15][C:3]=1[CH2:1][CH3:2]
Reactant: COC(=O)CCN
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OC[C@@H](O)CNC
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OC[C@@H](O)CNCCC(=O)OC

Procedure:
A solution of the epoxide intermediate of Example 57 (step a, 150 mg, 368 μmol), β-alanine methyl ester hydrochloride (113 mg, 736 μmol) and triethylamine (93 mg, 920 μmol) in methanol (5 mL) is stirred at 60° C. for 20 h. The solvent is removed in vacuo and the crude product is purified on prep. TLC plates using DCM:methanol 10:1 to give the title compound (53 mg) as a colourless oil; LC-MS: tR=0.92 min, [M+H]+=511.18.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@H:5]([CH2:7][S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[NH2:6].[C:19]([S:22][CH2:23][CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](O)=[O:26])(=[O:21])[CH3:20]>CO>[CH3:2][O:3][C:4](=[O:18])[C@H:5]([CH2:7][S:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[NH:6][C:25](=[O:26])[CH:24]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:23][S:22][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CSCc1ccc(OC)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CSCc1ccc(OC)cc1)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
React S-(4-methoxybenzyl)-L-cysteine methyl ester hydrochloride (1.85 g) and 3-acetylthio-2-benzylpropionic acid (1.95 g) in the manner described in Example 1, Step 1 to give an amber oil. Chromatograph this oil on a column of silica gel (2L, 60-200 mesh) and elute with ethyl acetate:hexane 5:20 to give Isomer A, a clear oil (0.63 g), [α]D26 =-66.5° (MeOH), overlap Isomer A and Isomer B (0.28 g); and Isomer B, a clear oil (0.67 g), [α]D26 =+3.0° (MeOH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([C:22]#[N:23])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31].[C:33](OCC)(=O)[CH3:34]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([N:19]([CH2:30][CH3:31])[CH2:33][CH3:34])[CH:16]=[C:15]([C:22]#[N:23])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: N#Cc1cc(-c2nc(-c3ccc(F)cn3)no2)cc([N+](=O)[O-])c1
Reactant: CCI
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)c1cc(C#N)cc(-c2nc(-c3ccc(F)cn3)no2)c1
Temperature: 140 °C
Yield: 20 %

Procedure:
A mixture of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-nitrophenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (29 mg, 0.21 mmol) and ethyl iodide (98 μL, 1.2 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 140° C. for 2 hours. The reaction was cooled, diluted with ethyl acetate, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3:1:4 afforded 3 mg (20%) of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-diethylaminophenyl)-1,2,4-oxadiazole:
Reaction SMILES: CC1N(C)[N:6](C2C=CC=CC=2)[C:4](=[O:5])C=1N.C1C(=O)NC(=O)N(C2OC(COP(OC3C(O)C([N:41]4[C:47](=[O:48])[NH:46][C:44](=[O:45])[CH:43]=[CH:42]4)OC3CO)(O)=O)C(O)C2O)C=1.[NH3:53]>P([O-])([O-])([O-])=O>[NH:46]1[C:44](=[O:45])[C:43]2[NH:6][C:4](=[O:5])[NH:53][C:42]=2[NH:41][C:47]1=[O:48]
Reactant: O=c1ccn(C2OC(COP(=O)(O)OC3C(CO)OC(n4ccc(=O)[nH]c4=O)C3O)C(O)C2O)c(=O)[nH]1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Reactant: N
Agent: O=P([O-])([O-])[O-]
Product: O=c1[nH]c(=O)c2[nH]c(=O)[nH]c2[nH]1
Temperature: 37 °C

Procedure:
To each of the mixtures was added a reagent prepared by dissolving 1 μmol 4-aminoantipyrine and 2 units of uricase in 1.5 ml of 0.1M phosphate buffer (pH 6.5). After the resulting mixtures were maintained in a thermostat at 37° C. for about 5 minutes, the absorbance was measured at a wavelength of 555 nm with a spectrophotometer (Model 228, manufactured by Hitachi, Ltd.) using purified water as a control. The results obtained are shown in Table 3.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[C:8]1([C:14]2[CH:19]=CC(O)=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)(=O)C>[C:5]([O:4][C:1]1[CH:16]=[CH:15][C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:19][CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(-c2ccccc2)cc1
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(-c2ccccc2)cc1
Yield: 95.8 %

Procedure:
Into a 3-liter, 4-way flask equipped with a reflux cooling tube, 373.8 g of acetic anhydride and 248.0 g (1.46 mol) of 4-phenylphenol were introduced and the mixture was heated to cause reaction for 3 hours under agitation while keeping the temperature in the flask at 130° C. After the reaction, the reflux pipe was replaced with a distillation pipe and acetic anhydride and acetic acid were removed by distillation under decompression, after which n-heptane was added and the mixture was cooled. The precipitated crystal was filtered out and dried to obtain 296.8 g of 4-acetoxybiphenyl in a white crystal form. The yield relative to the material 4-phenylphenol was 96% (mol).