Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][N:8]=[C:7]3[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:6]=23)[CH2:3][CH2:2]1.[OH-].[Na+].O>C(O)C>[CH:1]1([NH:4][C:5]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=[C:7]3[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:6]=23)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1ncc2c(NC3CC3)c(C(=O)O)cnc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of ethyl 4-cyclopropylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1 g, 0.0036 mole) in ethanol, sodium hydroxide solution (440 mg in 2 ml water) was added. The reaction mixture was stirred for about 14 hours at ambient temperature. Water was added and the reaction mixture was extracted with ethyl acetate. Aqueous layer was acidified by using hydrochloric acid (2N) to pH of about 4-5. White solid, which was obtained, was filtered and dried in vacuo.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[C:18](=[O:19])[CH:17]2[CH2:20][CH2:21][CH2:22][C:16]2=[N:15][C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]1=2>C(OCC)(=O)C.CCCCCC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[C:18](=[O:19])[C@H:17]2[CH2:20][CH2:21][CH2:22][C@H:16]2[NH:15][C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]1=2
Reactant: O=C1C2CCCC2=Nc2ccccc2N1Cc1ccc2ccccc2c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccc2ccccc2c1
Yield: 81 %

Procedure:
Using 9-(2-naphthylmethyl)-2,3,9,10a-tetrahydrobenzo[b]cyclopenta[1,4]diazepin-10(1H)-one, the titled compound was synthesized in substantially the same manner as in yield of 81%, m.p. 148.0°-148.5° C. (ethyl acetate-hexane).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3OS(C(F)(F)F)(=O)=O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:39][C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=1B(O)O.FC1C=C(F)C=CC=1C1C=CC2C(=CC=C(OC)C=2)C=1C(C1C=CC(OCCN2CCCCC2)=CC=1)=O>>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3[C:41]3[CH:42]=[CH:43][C:44]([F:46])=[CH:45][C:40]=3[F:39])=[O:16])=[CH:37][CH:38]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1ccc(F)cc1F
Agent: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)cc3F)ccc2c1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3ccc(F)cc3F)ccc2c1
Yield: 85.3 %

Procedure:
Couple trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-methoxynaphthalen-2-yl ester (1.4 g, 2.5 mmol) and 2,4-difluorophenyl boronic acid (1.2 g, 7.6 mmol) by the procedure used to prepare [2-(2,4-difluoro-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone to give yields 1.1 g (85%) of the title compound: mass spectrum (ion spray) m/z=516.3 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:41]1[N:42]=[C:43]([NH2:46])[S:44][CH:45]=1)[C:19]([NH:21][CH:22]1[C:39](=[O:40])[N:24]2[C:25]([C:36]([OH:38])=[O:37])=[C:26]([CH2:29][S:30][C:31]3[S:32][CH:33]=[N:34][N:35]=3)[CH2:27][S:28][C@H:23]12)=[O:20])=[O:14])(C)(C)C>C1(OC)C=CC=CC=1>[C:13]([CH2:15][O:16][N:17]=[C:18]([C:41]1[N:42]=[C:43]([NH2:46])[S:44][CH:45]=1)[C:19]([NH:21][CH:22]1[C:39](=[O:40])[N:24]2[C:25]([C:36]([OH:38])=[O:37])=[C:26]([CH2:29][S:30][C:31]3[S:32][CH:33]=[N:34][N:35]=3)[CH2:27][S:28][C@H:23]12)=[O:20])([OH:14])=[O:12]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Yield: 82.5 %

Procedure:
Trifluoroacetic acid (4 ml.) was added under ice-cooling to a stirred suspension of 7-[2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.0 g.) in anisole (1 ml.), and the resultant mixture was stirred for 70 minutes at ambient temperature. The reaction mixture was concentrated under reduced pressure and diethyl ether was added thereto. Precipitates were collected by filtration, washed with diethyl ether, dried, suspended in water (10 ml.) and then dissolved in a 10% aqueous solution of sodium hydroxide (pH 7-7.5). The solution was adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling and stirring and stirred for 30 minutes under ice-cooling. Precipitates were collected by filtration, washed with water and dried to give 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.75 g.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1cccc(OCCCCCBr)c1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(OCCCCCN2CCN(c3ccc(F)cc3)CC2)c1
Yield: 94.7 %

Procedure:
To a stirred solution of 1-(5-bromo-pentyloxy)-3-nitro-benzene (432 mg, 1.5 mmol) and 1-(4-fluoro-phenyl)-piperazine (297 mg, 1.65 mmol) in acetonitrile (5 mL) was added potassium carbonate (414 mg, 3.0 mmol). After refluxed for 6 hours, the reaction mixture was quenched with water (10 mL) followed by extraction with ethyl acetate (10 mL×3). The combined organic layers were washed with brine and then concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to give 1-(4-fluoro-phenyl)-4-[5-(3-nitro -phenoxy)-pentyl]-piperazine (549 mg, 1.42 mmol, 94%) as a yellow solid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:31]5[NH:35][C:34](=[O:36])[O:33][N:32]=5)=[CH:21][CH:20]=4)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]4[N:40]=[CH:41][N:42]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O1CCCC1>C(OCC)(=O)C>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:23][CH:24]=3)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]3[N:40]=[CH:41][N:42]=[C:12]23)[CH2:7][CH2:6]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
A mixture of 4-(1,4-dioxaspiro[4.5]dec-8-yl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.27 g), 6N hydrochloric acid (2 mL) and tetrahydrofuran (10 mL) was stirred at 40° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.2 g, 81%).
Reaction SMILES: [CH:1]([S:4][C:5]1[N:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].[CH2:13]([O:15][C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22](O)=[C:21]([F:27])[CH:20]=1)[CH3:14].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>C1COCC1>[CH2:13]([O:15][C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([O:12][CH2:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH:1]([CH3:3])[CH3:2])[N:10]=2)=[C:21]([F:27])[CH:20]=1)[CH3:14]
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CC(C)Sc1nccc(CO)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc(F)c(OCc2ccnc(SC(C)C)n2)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
(2-Isopropylsulfanyl-pyrimidin-4-yl)-methanol (0.08 g, 0.43 mmol) obtained in Step C of Preparation Example 24, 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.1 g, 0.43 mmol) obtained in Step D of Preparation Example 2 and triphenyl phosphine (0.114 g, 0.43 mmol) were dissolved in anhydrous THF (3 mL), and the mixture was stirred at room temperature for 10 minutes. Diisopropyl azodicarboxylate (0.085 mL, 0.43 mmol) was added slowly thereto. The mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure, and separated by column chromatography (eluent: 100% DCM) to obtain the title compound (0.14 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[C@@H:11]3[C@@H:6]([N:7]([C:15]([C:17]4[CH:25]=[CH:24][C:20]5[NH:21][CH:22]=[N:23][C:19]=5[CH:18]=4)=[O:16])[CH2:8][CH2:9][CH2:10]3)[CH2:5][C:4]=2[C:3]=1[OH:26].C(OCC)(OCC)O[CH2:29][CH3:30]>>[NH:21]1[C:20]2[CH:24]=[CH:25][C:17]([C:15]([N:7]3[C@H:6]4[C@H:11]([C:12]5[CH:4]=[C:3]6[O:26][C:29]([CH3:30])=[N:1][C:2]6=[CH:14][C:13]=5[CH2:5]4)[CH2:10][CH2:9][CH2:8]3)=[O:16])=[CH:18][C:19]=2[N:23]=[CH:22]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc2c(c1O)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Product: Cc1nc2cc3c(cc2o1)[C@@H]1CCCN(C(=O)c2ccc4[nH]cnc4c2)[C@@H]1C3
Temperature: 25 °C
Yield: 64 %

Procedure:
(cis-7-Amino-8-hydroxy-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-(1H-benzoimidazol-5-yl)-methanone (0.10 g) in triethyl orthoformate (0.5 mL) is stirred at 60° C. for 2 h. After cooling to room temperature, the mixture is concentrated and the residue is chromatographed on silica gel (dichloromethane/methanol 1:0→7:3) to afford the title compound. Yield: 64% of theory; LC (method 1): tR=2.28 min; Mass spectrum (ESI*): m/z=373 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]([C:15]23[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]4)[CH2:16]2)[CH2:22]3)[CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=[O:7])=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C:15]23[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]4)[CH2:16]2)[CH2:22]3)[CH2:9][CH2:10][CH2:11][C:12]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:13])=[O:7])=[CH:25][CH:26]=1
Reactant: O=C(O)CCCN(C(=O)c1ccc(Cl)cc1)C12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)CCN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCNC(=O)CCCN(C(=O)c1ccc(Cl)cc1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(1-adamantylamino)butyric acid and ethyl 3-aminopropionate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chlorobenzoyl)-4-(1-adamantylamino)butyryl]-3-aminopropionic acid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([I:30])=[C:25]([CH:29]=1)[C:26](O)=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([I:30])=[C:25]([CH:29]=1)[C:26]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])=[O:27]
Reactant: O=C(O)c1cc(Cl)ccc1I
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.70 g, 2.71 mmol), 5-chloro-2-iodobenzoic acid (0.66 g, 2.32 mmol), DIPEA (1.21 mL, 6.97 mmol) and HATU (1.06 g, 2.79 mmol) in DMF (5 ml) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHCO3 and brine successively. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hex) to afford the title compound. MS (ESI) 523 (M+H).
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:16][C@@H:15]2[C@@H:13]([CH2:14]2)[N:12]1[C:17](=[O:31])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28](=[O:30])[NH2:29])=[N:20]1)=[O:10])C1C=CC=CC=1>C1COCC1.CCOC(C)=O>[C:28]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([CH2:18][C:17]([N:12]2[C@H:11]([C:9]([OH:10])=[O:8])[CH2:16][C@@H:15]3[C@H:13]2[CH2:14]3)=[O:31])[N:20]=1)(=[O:30])[NH2:29]
Reactant: NC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)OCc2ccccc2)c2ccccc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(1R,3S,5R)-2-[2-(3-carbamoyl-indazol-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (3.9 g, 8.85 mmol) was dissolved in THF (120 mL) and EtOAc (120 mL). Air was removed from the flask and replaced with nitrogen three times. Pd/C 10% (390 mg) was added to the solution which was again degassed, placed under a hydrogen atmosphere, and stirred at RT for 4 h. The catalyst was removed through a pad of Celite and washed with EtOAc. Solvents were removed under reduced pressure and the foam thus obtained was used without further purification in the next step. MS (LCMS): 346.2 [M+NH4]+, 327.1 [M−H]−; tR (HPLC conditions f): 1.12 min.
Reaction SMILES: C1C=CC2[C:10]([C:18]3[CH:19]=[CH:20][C:21](O)=[CH:22][CH:23]=3)([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[O:9]C(=O)C=2C=1.Cl.NO.[OH-].[K+].OS(O)(=O)=O.CC[O:37][C:38](C)=[O:39]>CCCCCC.O>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[C:38]([OH:37])=[O:39])=[O:9])=[CH:12][C:13]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Reactant: CCOC(C)=O
Agent: Cl
Agent: NO
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: O
Product: O=C(O)c1ccccc1C(=O)c1ccc(O)c(-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
In a 100 mL r.b. flask equiped with a short column there was added the disubstituted derivative of phenolphthalein (2a) (2.0 g, 0.00425 mol), hydroxylamine hydrochloride (0.34 g, 0.0049 mol), potassium hydroxide (1.428 g 0.0255 mol) and 50 mL of H2O, and the mixture was stirred at 100° C. in an oil bath. The blue reaction mixture became homogeneous when it reached boiling. Within half an hour the colour had changed to brown. Following the reaction by thin layer chromatography (TLC) (20% EtOAc in hexane+3 drops AcOH), a new product was observed, but not all the starting material reacted. After 4 hr. no change had been observed and another portion of hydroxylamine hydrochloride (1.15 eq.) and potassium hydroxide (6.0 eq.) was added. An hour later, tlc indicated that no starting material remained. The reaction mixture was cooled to room temperature and it was acidified dropwise with concentrated H2SO4. A yellow precipitate was obtained. The reaction was stirred at 100° C. over night to complete the hydrolysis. The reaction mixture turned brown. It was filtered, washed 3× with hot diluted H2SO4 and then with H2O. It was recrystallized 2× (EtOAc/charcoal) to give 0.8 g, (58.4% yield) of a white product; 3a: mp 273° C.; 1H NMR (200 MHz, DMSO-d6) d 10.63 (s, 1H, COOH), 7.96 (d, j=8.0 Hz, 1H, CH-6), 7.74-7.34 (m, 10H, ArH), 7.02 (d, j=8.0 Hz, 1H, CH-5'). MS (EI) m/e 318 (M+); Anal. Calcd for C20H14O4: C, 75.47; H, 4.40; Found: C, 75.46; H, 4.62. ##STR21##
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[N:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Si]([C:22]#[N:23])(C)C>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[C:22]#[N:23])=[CH:4][CH:3]=1
Reactant: CSc1ccc(N=Cc2ccc(Cl)cc2)cc1
Reactant: C[Si](C)(C)C#N
Product: CSc1ccc(NC(C#N)c2ccc(Cl)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-chlorobenzylidene)-4-methylthioaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a pale yellow powder (yield 84%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:14]=[C:13](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:12]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]#[N:37])=[CH:31][CH:30]=2)=[C:11]([CH3:38])[N:10]=1.[CH2:39]([NH2:44])[CH2:40][CH2:41][CH2:42][CH3:43].[OH-].[Na+]>C(OCCCC)(=O)C.C(#N)C>[NH2:8][C:9]1[N:10]=[C:11]([CH3:38])[C:12]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([CH2:35][C:36]#[N:37])=[CH:33][CH:34]=2)=[C:13]([NH:44][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[N:14]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Oc2nc(N)nc(C)c2Cc2ccc(CC#N)cc2)c(C)c1
Reactant: CCCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCCCOC(C)=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (27.4 g) was slowly added to a suspension of the product from step (iii) (105.0 g) and n-pentylamine (62.9 g) in butyl acetate (877.8 g) and the mixture was heated at 120° C. for 2 hours. The mixture was cooled to 20° C. and 4% aq. NaOH (997.5 g) was added to the mixture. The organic layer was separated, washed with water (997.5 g) and 10% aq. NH4Cl (997.5 g) respectively and the solvent evaporated under reduced pressure to afford a solid. The solid was dissolved in acetonitrile (221.1 g) at 50° C. and the solution was cooled to 42° C., seeded and stirred at this temperature for 1 hour. After the mixture was cooled to 5° C. and stirred at 5° C. for 1 hour, the resulting precipitate was collected by filtration, washed with acetonitrile (2×31.5 g) and dried under reduced pressure to give the subtitle compound as a solid, 52.0 g; 1H NMR DMSO-d6: δ 7.23 (d, 2H), 7.11 (d, 2H), 6.17 (t, 1H), 5.68 (s, 2H), 3.96 (s, 2H), 3.73 (s, 2H), 3.27-3.22 (m, 2H), 2.00 (s, 3H), 1.47-1.40 (m, 2H), 1.28-1.19 (m, 2H), 1.17-1.09 (m, 2H), 0.82 (t, 3H).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH:25](=[C:5]1/[C:4](=[O:6])[NH:3][C:2](=[O:7])[S:1]/1)\[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CCCCCCCCCCCCCCCCCC=O
Reactant: O=C1CSC(=O)N1
Product: CCCCCCCCCCCCCCCCC/C=C1\SC(=O)NC1=O

Procedure:
TZD18 was prepared according to General Procedure A presented hereinabove using 2,4-thiazolidinedione and stearaldehyde as reactants.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH3:27][N:28]1[C:32]([NH2:33])=[CH:31][C:30]([CH3:34])=[N:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:33][C:32]2[N:28]([CH3:27])[N:29]=[C:30]([CH3:34])[CH:31]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: Cc1cc(N)n(C)n1
Product: Cc1cc(NC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)n(C)n1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 1,3-dimethyl-1H-pyrazol-5-amine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(1,3-dimethyl-1H-pyrazol-5-yl)terephthalamide. MS (Q1) 480 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[F:10])[C:5]#[N:6].[F:12]C1C([N+]([O-])=O)=CC(C#N)=CC=1[N+]([O-])=O.ClCl.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[F:10])[C:5]#[N:6].[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[F:10])[C:5]#[N:6]
Reactant: N#Cc1cc([N+](=O)[O-])c(F)c([N+](=O)[O-])c1
Agent: ClCl
Agent: N#Cc1cc(Cl)c(F)c(Cl)c1
Agent: O=S(=O)([O-])[O-]
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(F)c(F)c(Cl)c1
Temperature: 350 °C

Procedure:
Preparation of 3,5-dichloro-4-fluorobenzonitrile. During a 10-hour period a solution of 216 parts of 4-fluoro-3,5-dinitrobenzonitrile (prepared as in step (a), above) in 1500 parts of carbon tetrachloride, is vaporized by passing through a tubular nickel reactor maintained at about 350° C. and the vapors passed through a second nickel tubular reactor, maintained at about 350° C., and mixed therein with a stream of chlorine at a molar ratio of Cl2 :4-fluoro-3,5-dinitrobenzonitrile of about 6.0. The exiting vapors are collected, condensed and the condensate treated with MgSO4. The desired product, 3,5-dichloro-4-fluorobenzonitrile is isolated by vacuum distillation.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13]([OH:15])=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[NH2:21][C:22]1[C:23]([CH3:37])=[C:24]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:25]=[CH:26][CH:27]=1>CN(C=O)C.N1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13]([NH:21][C:22]2[C:23]([CH3:37])=[C:24]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH:25]=[CH:26][CH:27]=2)=[O:15])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc(C(C(=O)O)C2CCCC2)cc1
Reactant: Cc1c(N)cccc1CCC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(C(C(=O)Nc2cccc(CCC(=O)OC(C)(C)C)c2C)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.41 g (90% pure, 37.16 mmol) of (+/−)-{4-[(acetyloxy)methyl]phenyl}(cyclopentyl)acetic acid were dissolved in a mixture of 71.8 ml of DMF and 22.5 ml of pyridine, and 15.54 g (40.88 mmol) of 1-[bis(dimethylamino)methylene]-5-chloro-3-oxy-1H-benzotriazol-1-ium tetrafluoroborate and 8.75 g (37.16 mmol) of tert-butyl 3-(3-amino-2-methylphenyl)propanoate were added. The reaction mixture was stirred at RT overnight and then concentrated under high vacuum. The residue was taken up in 100 ml of ethyl acetate and washed successively with 10% strength aqueous citric acid, saturated sodium bisulfate solution and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→3:1). This gave 16.36 g (89.2% of theory) of the title compound.