Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:13]1[CH2:18][C:17](=O)[CH2:16][CH2:15][C:14]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:21](#[N:25])[CH2:22][C:23]#[N:24].O>NCCC(O)=O.C(Cl)(Cl)Cl>[C:23]([C:22]([C:21]#[N:25])=[C:14]1[CH2:15][CH2:16][C:17](=[C:22]([C:21]#[N:25])[C:23]#[N:24])[CH2:18][CH:13]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])#[N:24]
Reactant: N#CCC#N
Reactant: CCCCCCCCCCCCC1CC(=O)CCC1=O
Agent: NCCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCC1CC(=C(C#N)C#N)CCC1=C(C#N)C#N
Reaction time: 8 h

Procedure:
A mixture of 2 g (0.0071M) of thus obtained 2-dodecyl-1,4-cyclohexane-dione and 1.4 g (0.0212M) of malononitrile was heated in a water bath to make a solution. β-alanine as a catalyst and 2 ml of water were added to the solution and stirred at a temperature between 40° C. and 50° C. for 8 hours to react the mixture. After cooling, the reacted mixture was dissolved in chloroform, and rinsed with water and dried. The dried material was concentrated under reduced pressure, and purified through silica gel column chromatography. As a result, 1.26 g of white crystal of 1,4-bis-(dicyanomethylene)-2-dodecyl cyclohexane was obtained. The obtained compound had a melting point of 97° C. and an infrared absorption band of 2250 cm-1 which corresponds to a cyano group.
Reaction SMILES: C([NH:13][C@H:14]([C:21]([NH:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1)(=O)CNC(C1C=CC=CC=1)=O.[Cl-].[Na+].C[C@H](NC([C@H]1N(C([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](N)CC(O)=O)=O)CCCNC(N)=N)=O)C(C)C)=O)CC2C=CC(O)=CC=2)=O)C(C)C)=O)CC2NC=NC=2)=O)CCC1)=O)C(O)=O>O>[NH2:13][C@H:14]([C:21]([NH:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][CH:26]([CH3:27])[CH3:28])=[O:22])[CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CNC(=O)c1ccccc1)C(=O)O
Agent: CC(C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CC(=O)O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)O)C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)C(=O)O
Reaction time: 0.33 h

Procedure:
50 μl of a solution containing 0.01 mole/liter of hippuryl-histidyl-leucine (substrate) and 0-100 μl of a test compound solution were added to 300 μl of a 0.2 M trishydrochloric acid buffer solution containing 0.2 mole/liter of sodium chloride. The total volume of said mixture was adjusted to 450 μl with water. Then, 50 μl of angiotensin-converting enzyme (ACE) isolated from pig's renal cortex were added to the mixture, and the mixture was allowed to stand at 37° C. for 20 minutes. The amount of histidyl-leucine produced from the substrate by the action of ACE was assayed microbiologically by the use of Leuconostoc mesenteroides P-60, and the ACE-inhibitory activity of the test compound was estimated therefrom.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C([O:38][C:39](=[O:49])[CH:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:41]Br)C1C=CC=CC=1.COC(C)(C)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.COC>[C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[O:7][CH2:41][CH:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:39]([OH:49])=[O:38])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC(O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(OCc1ccccc1)C(CBr)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COC
Agent: O=C([O-])[O-]
Solvent: COC(C)(C)C
Product: CC(=O)OC[C@H]1OC(OCC(C(=O)O)c2ccccc2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C

Procedure:
A mixture that consists of 34.83 g (100 mmol) of 2,3,4,6-tetra-O-acetyl-mannopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 35.8 g (110 mmol) of fine-powder cesium carbonate in 400 ml of dimethyl ether is cooled to 0° C. At 0° C., 47.88 g (150 mmol) of 2-phenyl-3-bromopropionic acid benzyl ester, dissolved in 30 ml of dimethyl ether, is added in drops over 10 minutes while being stirred vigorously. It is stirred for one hour at 0° C. 250 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of tetrahydrofuran. 5 g of palladium (10%) on activated carbon is added thereto and hydrogenated until hydrogen absorption is completed. Then, catalyst is filtered out, it is rewashed with a little tetrahydrofuran, the organic solutions are combined and evaporated to the dry state in a vacuum, dried, and the solvent is distilled off in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1.C(O)C>[OH-].[Na+].O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1

Procedure:
A solution of 0.01 mole of ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate in 12 ml. (0.012 mole) of IN sodium hydroxide solution and 5 ml. of 95% ethanol is refluxed for 30 minutes. The solution is diluted with water and the ethanol evaporated in vacuo. The remaining solution is filtered and the filtrate acidified with dilute HCl. The precipitated solid is collected by filtration and recrystallized from methanol-water to yield the product, 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:15][C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][C:21]=3[C:22]=2[N:23]=1.[Cl-].[NH4+:32]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:15][C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:27]=[CH:26][C:25]([C:28]([NH2:32])=[O:30])=[CH:24][C:21]=3[C:22]=2[N:23]=1
Reactant: [NH4+]
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3nncn3-c3ccc(F)cc3F)sc1CCO2
Agent: [Cl-]
Product: NC(=O)c1ccc2c(c1)-c1nc(-c3nncn3-c3ccc(F)cc3F)sc1CCO2

Procedure:
2-[4-(2,4-Difluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-9-carboxylic acid and ammonium chloride were reacted in the general amide coupling procedure to give 407. NMR: (CDCl3): 3.32-3.35 (2H, m), 4.32-4.30 (2H, m), 6.96-6.99 (1H, m, Ar), 7.09-7.14 (1H, m, Ar), 7.48-7.50 (1H, m, Ar), 7.54-7.58 (1H, m, Ar), 8.09-8.11 (1H, m, Ar) and 8.35 (1H, s, Ar). MS: (ESI+) MH+=425.95
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13]([N:15]2[CH2:19][C@@H:18]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@@:17]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[C@H:16]2[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=2[F:42])=[O:14])[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.O>[Cl:41][C:37]1[C:36]([F:42])=[C:35]([C@@H:16]2[C@:17]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[C@H:18]([CH2:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH2:19][N:15]2[C:13]([NH:12][CH2:11][CH:8]2[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)=[O:14])[CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)C1CCC(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@@H]1CN(C(=O)NCC2CCC(C(=O)O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
To a mixture of rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid methyl ester (65.0 mg, 0.105 mmol, example 21) in THF (4 mL) was added a solution of LiOH (Aldrich, 31.5 mg, 0.75 mmol) in water (2 mL) and the reaction mixture was stirred at rt for 6.5 hrs then more THF (2 mL) and water (1 mL) was added and stirred for 6 more hrs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 5-6), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]amino}-methyl)-cyclohexanecarboxylic acid (95.8 mg, 100%). HRMS (ES+) m/z Calcd for C31H35Cl2F2N3O3+H [(M+H)+]: 606.2097; Found: 606.2097.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][CH3:10])=[CH:4][CH:3]=1.[C:11]([CH:14]([C:20]([O:22]CC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=O)[CH3:12].C(O)(=O)C.CO>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:22])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([CH3:12])[N:9]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CNNc1ccc(F)cc1
Reactant: CCOC(=O)C(C(C)=O)C(=O)OCC
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)n(C)n(-c2ccc(F)cc2)c1=O
Temperature: 115 °C
Yield: 49.5 %

Procedure:
A mixture of 1-(4-fluorophenyl)-2-methylhydrazine (0.6 g, 4.28 mmol), diethyl 2-acetylmalonate (0.96 g, 4.75 mmol), and acetic acid (0.51 g, 8.49 mmol) in water (15 mL) is heated at 115° C. for 3 hours. The reaction is cooled and extracted with EtOAc twice. The organic phase is washed with saturated aqueous sodium chloride, dried over Na2SO4 and concentrated. The residue is purified by column chromatography on silica gel, eluting with DCM:MeOH (from 150:1 to 60:1) to afford the title compound (0.59 g, 49.5% yield). MS (m/z): 279 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2=[C:17]3[C:4]=1[CH2:5][CH:6](O)[N:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8]3=[N:9][CH:10]=[N:11]2.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2=[C:17]3[C:4]=1[CH:5]=[CH:6][N:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8]3=[N:9][CH:10]=[N:11]2
Reactant: COc1cc2ncnc3c2c(c1OC)CC(O)N3c1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc3c2c(c1OC)C=CN3c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7,8-dimethoxy-4-phenyl-5,6-dihydro-4H-1,3,4-triaza-phenalen-5-ol (91 mg, 0.28 mmol) (from Example 20, Step A, supra) and triethylamine (0.23 mL, 1.69 mmol) in dichloromethane (50 mL) at 0° C. was added methanesulfonyl chloride (0.087 mL, 1.12 mmol) (Aldrich). The reaction solution was the stirred at room temperature for 2 hours. The solution was then concentrated, the residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:4:0.05) as eluent to give the desired 7,8-dimethoxy-4-phenyl-4H-1,3,4-triaza-phenalene as a white solid. (Yield 47 mg, 55%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:28])=[CH:20][N:21]=[C:22](Cl)[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH3:35]>CN1CCN(C)C1=O.[Cl-].[Na+].O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:28])=[CH:20][N:21]=[C:22]([NH2:35])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: N
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3c(N)ncc(Cl)c23)C1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A suspension of Intermediate 26a (0.20 g), and potassium carbonate (0.31 g) in 1,3-dimethyl-2-imidazolidinone (3 ml, Tokyo Kasei Kogyo) was added with 25% aqueous ammonia (2 ml), and the mixture was stirred at 80° C. for 24 hours in a sealed tube. The reaction mixture was added with saturated brine (30 ml), and extracted 3 times with chloroform (30 ml for each time). The combined organic layer was washed twice with saturated brine (50 ml for each time), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=9:1) to obtain the title compound (64.4 mg).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:12]3[NH:13][CH:14]=[CH:15][N:16]=3)=[N:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][N:10]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: c1ccc(-c2nnc(-c3ncc[nH]3)s2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2-c2nnc(-c3ccccc3)s2)cc1
Temperature: 120 °C
Yield: 87 %

Procedure:
A mixture of 2-[2-(phenyl)-1,3,4-thiadiazol-5-yl]-1H-imidazole (0.285 g, 1.25 mmol), 1-fluoro-4-nitrobenzene (0.176 g, 1.25 mmol) and sodium carbonate (0.265 g, 2.50 mmol) in DMF (10 mL) was heated at 120° C. for 24 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and washed with water and brine. The combined organic fraction was dried (Na2SO4) and evaporated to dryness. The crude product was purified by chromatography on silica gel using hexane/ethyl acetate as an eluant to give the product (0.38 g, 87%) as a white solid; 1H NMR δ (DMSO-d6) 8.38 (2H, d, J=8.9 Hz), 7.98 (2H, dd, J=7.7, 1.6 Hz), 7.86 (2H, dd, J=8.8, 1.6 Hz), 7.81 (1H, s), 7.55 (3H, m), 7.43 (1H, dd, J=1.3 Hz); 13C NMR δ (DMSO-d6) 167.8, 159.1, 147.3, 142.6, 136.6, 131.6, 131.0, 129.5, 129.0, 128.1, 127.7, 126.2, 124.3; MS (m/z): 350.4 (M+, 100%).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][NH:16][C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[O:18])[N:14]=2)[CH2:7]1)(=O)=O.[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>CN(C)C=O>[C:24]([S:26][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][NH:16][C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[O:18])[N:14]=2)[CH2:9]1)(=[O:27])[CH3:25]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(CNC(=O)c3cccs3)cs2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(CNC(=O)c3cccs3)cs2)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-[4-(thiophene-2-carbonylamino)methyl-1,3-thiazol-2-yl]azetidine (623 mg, 1.67 mmol) (obtained as described in Reference Example 66(3)) in dimethylformamide (18 ml) was added potassium thioacetate (1.14 g, 10.0 mmol) at room temperature, and the mixture was stirred in an oil bath (90° C.) for 4 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) ethyl acetate as the eluant to afford 3-acetylthio-1-[4-(thiophene-2-carbonyl-amino)methyl-1,3-thiazol-2-yl]azetidine (490 mg, yield 91%) as a pale brown solid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH3:17])=[O:15])=[CH:9][C:8]=2[C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2C(OC(C)(C)C)=O)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[ClH:30].O1CCOCC1>CCOC(C)=O>[ClH:30].[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:15])[O:16][CH3:17])=[CH:9][C:8]=2[C@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: COC(=O)Nc1ccc(S(=O)(=O)C2CC2)c([C@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)Nc1ccc(S(=O)(=O)C2CC2)c([C@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To 85I (1.63 g, 3.84 mmol) in EtOAc (15.0 mL) at rt was added 4.0 N HCl in dioxane (30 mL, 120 mmol). The mixture was stirred at rt for 4.0 h. TLC and LC-MS indicated a clean formation of the product. After evaporation of solvent, 85J (1.31 g, 95% yield) was obtained as a white solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 0.98-1.10 (m, 3H) 1.21-1.33 (m, 1H) 2.10-2.20 (m, 1H) 2.24-2.34 (m, 2 H) 2.41-2.50 (m, 1H) 2.80-2.89 (m, 1H) 3.31-3.41 (m, 2H) 3.70 (s, 3H) 5.45 (t, J=7.69 Hz, 1H) 7.54 (dd, J=8.79, 2.20 Hz, 1H) 7.85 (d, J=8.79 Hz, 1H) 7.99 (d, J=2.20 Hz, 1H), LC-MS 325 (M+H).
Reaction SMILES: BrCC1C=CC(C(O)=O)=CC=1.Cl.CNOC.[CH:17]1([CH2:20][C:21]([OH:23])=O)[CH2:19][CH2:18]1.[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1>>[CH:17]1([CH2:20][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]2)=[O:23])[CH2:18][CH2:19]1
Reactant: OCC1CCNCC1
Reactant: O=C(O)CC1CC1
Agent: CNOC
Agent: Cl
Agent: O=C(O)c1ccc(CBr)cc1
Product: O=C(CC1CC1)N1CCC(CO)CC1
Yield: 73 %

Procedure:
Instead of 4-(bromomethyl)benzoic acid and N,O-dimethylhydroxylamine hydrochloride, cyclopropylacetic acid (869 mg) and 4-piperidinemethanol (1.00 g) were respectively used and treated by the same technique as in Reference Example 16-1(1) to give the titled compound as a colorless oil (1.25 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([F:1])[CH:3]=1)[CH3:18]
Reactant: CCO
Reactant: O=C(O)c1ccc(O)c(F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(O)c(F)c1
Temperature: 0 °C

Procedure:
A mixture of 3-fluoro-4-hydroxybenzoic acid (5.0 g), ethanol (100 ml) and concentrated sulfuric acid (1 ml) was refluxed for 1 day. The reaction mixture was poured into ice water, the crystal that was precipitated was filtered, then dried to provide the title compound (24.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9].I[CH3:13].[OH-].[K+]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([O:10][CH3:13])=[O:9]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: CI
Agent: [K+]
Agent: [OH-]
Product: COC(=O)c1c(N)cccc1Cl
Yield: 78.4 %

Procedure:
Using the procedure described above in Preparation 1, 5.0 g (0.029 mol) of 6-chloroanthranilic acid and 2.75 ml (0.044 mol) of iodomethane were reacted in the presence of 4.08 g (0.073 mol) of powdered potassium hydroxide to give 4.22 g (78%) of methyl 6-chloroanthranilate as an oil.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:34])[N:6]([CH3:33])[C:7]2[C:12]([C:13]=1[NH:14][C:15](=[O:17])[CH3:16])=[CH:11][C:10]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[C:9]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])[N:8]=2)(=[O:3])[CH3:2].C1COCC1.[BH4-].[Na+]>CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:10]2[CH:11]=[C:12]3[C:7](=[N:8][C:9]=2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]([CH3:33])[C:5](=[O:34])[C:4]([CH:1]([OH:3])[CH3:2])=[C:13]3[NH:14][C:15](=[O:17])[CH3:16])=[CH:19][CH:20]=1
Reactant: CC(=O)Nc1c(C(C)=O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1c(C(C)O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12

Procedure:
The product of Example 1 (65 mg), THF (3 mL), MeOH (0.33 mL) and NaBH4 (9.6 mg) were combined at room temperature. After 7 minutes the reaction was concentrated and then dissolved in EtOAc before washing with water and drying (Na2SO4). The concentrated residue was purified by preparative TLC (silica gel) eluted with EtOAc affording the title compound. HPLC/MS: 515.9 (M+1), 517.9 (M+3); Rt=3.68 min.
Reaction SMILES: Br[CH:2]1[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH:3]1Br.[I-].[Na+]>CC(C)=O>[O:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[O:7][CH:2]=[CH:3]1
Reactant: BrC1Oc2ccccc2OC1Br
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C1=COc2ccccc2O1
Reaction time: 2 h

Procedure:
73.45 mmol of the compound obtained in Step A above are dissolved in 125 ml of acetone; the solution is then stirred for 2 hours under reflux, in the presence of sodium iodide (359.9 mmol). After evaporating off the solvent, the residue is dissolved in a mixture of water/ethyl acetate (100 ml/200 ml). The organic phase is then washed with 20% aqueous sodium thiosulphate solution and then the aqueous phase is extracted twice with ethyl acetate. The organic phases are combined, dried over magnesium sulphate and then concentrated to dryness. Purification by chromatography over silica gel (petroleum ether/ethyl acetate: 95/5) allows the expected product to be obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:5]=2[O:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:5]=2[O:4][CH:3]=[C:2]1[CH3:1]
Reactant: BrCCCCBr
Reactant: CC1=COc2ccc(C)cc2C(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1=COc2ccc(C)cc2C(=O)N1CCCCBr

Procedure:
950 mg of 4,5-dihydro-3,7-dimethyl-1,4-benzoxazepin-5-one was dissolved in 30 ml of acetone, 4.3 g (4 equivalents) of 1,4-dibromobutane and 2.1 g (3 equivalents) of potassium carbonate were added, then the resultant mixture was heated and refluxed for 10 hours.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[O:3].[OH2:12]>>[NH:1]1[C:10](=[O:11])[C:9]2[NH:8][C:7](=[O:12])[NH:6][C:5]=2[NH:4][C:2]1=[O:3]
Reactant: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Reactant: O
Product: O=c1[nH]c(=O)c2[nH]c(=O)[nH]c2[nH]1
Temperature: 37 °C

Procedure:
50 mM tris-hydrochloric acid buffer (2.9 ml) and 0.1 ml of a 10 mM aqueous solution of xanthine are mixed, and this mixture is pre-heated at 37° C. After 0.01 ml of enzyme solution is added and gently mixed, the increase of absorbance at 293 nm per minute is determined using a spectrophotometer thermostated at 37° C. with distilled water as the control. The xanthine oxidase activity is expressed on the assumption that the amount of enzyme which produces 1 μmol of uric acid per minute under the conditions described above is taken as 1 unit (U).
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:26])[C@@H:18]([CH:19]=[C:20]([CH3:22])[CH3:21])[C@H:17]1[C:23](Cl)=[O:24].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[CH3:15][C:16]1([CH3:26])[C@@H:18]([CH:19]=[C:20]([CH3:21])[CH3:22])[C@H:17]1[C:23]([O:14][CH2:13][C:10]1[S:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:12][CH:11]=1)=[O:24]
Reactant: CC(C)=C[C@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: OCc1cnc(Oc2ccccc2)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)=C[C@H]1[C@@H](C(=O)OCc2cnc(Oc3ccccc3)s2)C1(C)C
Temperature: 20 °C
Reaction time: 17 h

Procedure:
2.07 g of (2-phenoxy-5-thiazolyl)-methanol were added to a solution of (1R,3S) 2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane-1-carboxylic acid chloride prepared from 1.68 g of the corresponding acid in 20 ml of benzene and 0.81 ml of pyridine were added dropwise thereto. The mixture was stirred at 20° C. for 17 hours and was poured into dilute aqueous hydrochloric acid. The decanted aqueous phase was extracted with ether and the combined organic phases were washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 1.6 g of (2-phenoxy-5-thiazolyl)-methyl (1R,3S) 2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane -1-carboxylate.