Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:49](OC(C)(C)C)=[O:50])[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:25]([NH:27][C@@H:28]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:38])[NH:34][N+:35]([O-:37])=[O:36])=[O:26])[CH2:20][CH2:21][C:22](=[O:24])[NH2:23])=[O:17])=[O:13])[CH3:11])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[N:56]1([C:77]2[CH:88]=[CH:87][C:83]([N+:84]([O-:86])=[O:85])=[CH:82][C:78]=2[N+:79]([O-:81])=[O:80])[CH2:76][CH2:75][CH2:74][C@H:57]1C(N[C@H](C(NCC(O)=O)=O)CCC(=O)N)=O>>[N:56]1([C:77]2[CH:88]=[CH:87][C:83]([N+:84]([O-:86])=[O:85])=[CH:82][C:78]=2[N+:79]([O-:81])=[O:80])[CH2:76][CH2:75][CH2:74][C@H:57]1[C:16]([NH:18][C@H:19]([C:25]([NH:27][CH2:28][C:49]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:25]([NH:27][C@@H:28]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:38])[NH:34][N+:35]([O-:37])=[O:36])=[O:26])[CH2:20][CH2:21][C:22](=[O:24])[NH2:23])=[O:17])=[O:13])[CH3:11])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:50])=[O:26])[CH2:20][CH2:21][C:22](=[O:24])[NH2:23])=[O:17]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: NC(=O)CC[C@H](NC(=O)[C@@H]1CCCN1c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)NCC(=O)O
Product: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
Boc-Leu-Ala-Gly-Gln-D-Arg(NO2)-OBzl (350 mg, 0.45 m mol) was demasked with respect to the N-masking group and coupled with DNP-Pro-Gln-Gly-OH (210 mg, 0.45 m mol) in the manner similar to that of Example 1, paragraph 7).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[Br:10]Br>CC(O)=O>[Br:10][CH:5]1[C:6](=[O:8])[CH2:7][CH:2]([CH3:1])[CH2:3][C:4]1=[O:9]
Reactant: CC1CC(=O)CC(=O)C1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC1CC(=O)C(Br)C(=O)C1

Procedure:
To a stirred solution of 5-methylcyclohexane-1,3-dione (1.26 g, 10 mmol) in AcOH (20 mL) at r.t. was added bromine (1.6 g, 0.51 mL, 10 mmol) dropwise. The reaction was carried out according to Method A to give the title compound in quantitative yield as a light brown solid which was used without further purification. LCMS (ES+) 204.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7]CS([O-])(=O)=O)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].FC(F)(F)C1N=C(C(F)(F)F)NN=1.C(=O)([O-])[O-:30].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH3:1][C:2]1[S:6][C:5]([CH2:7][OH:30])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: Cc1sc(CCS(=O)(=O)[O-])cc1[N+](=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: FC(F)(F)c1n[nH]c(C(F)(F)F)n1
Agent: [K+]
Solvent: CC#N
Product: Cc1sc(CO)cc1[N+](=O)[O-]

Procedure:
1.0 g (3.98 mmol) (5-methyl-4-nitro-2-thienyl)methylmethane sulphonate, 0.82 g (3.98 mmol) 3,5-bis(trifluoromethyl)-1H-1,2,4-triazole, 0.93 g (5.97 mmol) potassium carbonate and 0.11 g (0.398 mmol) 18-crown-6 are heated under reflux in acetonitrile for 2 h. The cooled reaction mixture is evaporated, the residue taken up in 20 ml water and extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and the solvent is distilled off under vacuum. The product (1-[(5-methyl-4-nitro-2-thienyl)methyl]-3,5-bis(trifluoromethyl)-1H-1,2,4-triazole) is used in the next stage without purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:29])=[C:7]([C:21]([NH:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26])=[O:22])[C:8]([I:20])=[C:9]([C:18]=1[I:19])[C:10]([NH:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[O:11])(=[O:3])[CH3:2].[OH-].[Na+].[OH:32][CH:33]([CH2:36][O:37][CH3:38])[CH2:34]Cl>C(O)C(O)C.CO>[OH:26][CH2:25][CH:24]([NH:23][C:21](=[O:22])[C:7]1[C:6]([I:29])=[C:5]([N:4]([CH2:34][CH:33]([OH:32])[CH2:36][O:37][CH3:38])[C:1](=[O:3])[CH3:2])[C:18]([I:19])=[C:9]([C:10]([NH:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[O:11])[C:8]=1[I:20])[CH2:27][OH:28]
Reactant: COCC(O)CCl
Reactant: CC(=O)Nc1c(I)c(C(=O)NC(CO)CO)c(I)c(C(=O)NC(CO)CO)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(O)CO
Solvent: CO
Product: COCC(O)CN(C(C)=O)c1c(I)c(C(=O)NC(CO)CO)c(I)c(C(=O)NC(CO)CO)c1I
Reaction time: 44 h

Procedure:
5-Acetamido-N,N'-bis(1,3-dihydroxy-2-propyl)-2,4,6-triiodoisophthalamide (1036 g, 1.39 mol) was slurried in a mixture of propylene glycol (4170 ml) and methanol (4170 ml). After adding 18.25 M sodium hydroxide (114 ml, 2.08 mol), the mixture was heated at about 50°. When all or nearly all of the starting material was dissolved, the excess of methanol was evaporated in vacuo. Thereafter 2-hydroxy-3-methoxypropyl chloride (259 g, 2.08 mol) was added. The reaction mixture was heated at 50° for 44 hours and then stored at room temperature for 44 hours. Ater neutralization with concentrated hydrochloric acid, the reaction mixture was evaporated in vacuo. The residue was dissolved in methanol (3500 ml) and treated with a mixture of Dowex anion exchange resin 1×4 (2.87 kg) and Amberlite cation exchange resin (1.2 kg). The ion exchange resin was filtered off and washed with 80% aqueous methanol. The filtrate was evaporated in vacuo to dryness and the residue dissolved in isopropyl alcohol (5 1) at 80°. The product was precipitated by cooling to 13.5° and collected on a filter. Further purification was performed by recrystallization from isopropyl alcohol (4 1).
Reaction SMILES: [CH2:1]([O:8][C@:9]1([CH2:33]O)[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@H:10]1[OH:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.O.[H-].[Na+]>N1C=CC=CC=1.CN(C=O)C>[CH2:1]([O:8][C@@:9]12[CH2:33][O:32][C@@H:10]1[C@H:11]([N:23]1[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]1=[O:25])[O:12][C@@H:13]2[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn([C@@H]2O[C@H](COCc3ccccc3)[C@@](CO)(OCc3ccccc3)[C@@H]2O)c(=O)[nH]c1=O
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1cn([C@@H]2O[C@H](COCc3ccccc3)[C@]3(OCc4ccccc4)CO[C@H]23)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.9 %

Procedure:
A solution of compound 27 (2.26 g, 4.83 mmol) in anhydrous pyridine (20 cm3) was stirred at −40° C. and a solution of methanesulphonyl chloride (0.482 cm3, 4.83 mmol) in anhydrous pyridine (10 cm3) was added. The reaction mixture was stirred at room temperature for 17 h, water (5o cm3) was added, and the mixture was extracted with dichloromethane (2×100 cm3). The combined organic phase was washed with saturated aqueous sodium hydrogencarbonate (3×100 cm3), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1, v/v) as eluent to give an intermediate which after evaporation of the solvents was dissolved in anhydrous DMF (15 cm3). This solution was added dropwise to a suspension of 60% sodium hydride (461 mg, 11.5 mmol) in anhydrous DMF (15 cm3) at 0° C. The reaction was stirred at room temperature for 30 min, then quenched with water (60 cm3). After neutralisation using dilute aqueous hydrochloric acid, the mixture was dissolved in dichloromethane (150 cm3), washed with saturated aqueous sodium hydrogencarbonate (3×100 cm3) and dried (Na2SO4). The solvents were evaporated and the residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1, v/v) as eluent to give nucleoside 28 as a white foam (2.00 g, 93%). δH (CDCl3) 9.13 (1H, br s, NH), 7.55 (1H, d, J 1.4, 6-H), 7.40-7.26 (Bn), 5.99 (1H, d, J 2.5, 1′-H), 5.30 (1H, d, J 2.7, 2′-H), 4.88-4.57 (6H, m, 1″-Ha, 1″-Hb, Bn), 4.22-4.19 (1H, m, 4′-H), 3.92 (1H, dd, J 6.2, 10.8, 5′-Ha), 3.82 (1H, dd, J 3.7, 10.8, 5′-Hb), 1.91 (3H, d, J 1.3, CH3). δC (CDCl3) 163.8 (C-4), 150.3 (C-2), 137.6 (C-6), 137.5, 137.0 (Bn), 128.7, 128.6, 128.2, 128.0, 127.8, 127.3 (Bn), 109.8 (C-5), 85.7 (C-3′), 84.1 (C-1′), 83.5 (C-4′), 79.7 (C-1″), 73.9 (C-2′), 73.6 (C-5′), 68.6, 67.8 (Bn), 12.4 (CH3). FAB m/z 451 [M+H]+, 473 [M+Na]+. Found: C, 66.3; H, 5.9; N, 6.1; C25H26N2O6 requires C, 66.7; H, 5.8; N, 6.2%.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH:14]=[O:15].[Cl:16][C:17]1[CH:18]=[C:19]([SH:24])[CH:20]=[C:21]([Cl:23])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:16][C:17]1[CH:18]=[C:19]([S:24][C:2]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:5]=[C:4]([CH3:13])[C:3]=2[CH:14]=[O:15])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: Sc1cc(Cl)cc(Cl)c1
Reactant: Cc1nn(-c2ccccc2)c(Cl)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A solution containing 175 mg of 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde, 142 mg of 3,5-dichlorothiophenol and 132 mg of potassium carbonate in 5 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 60° C. for 2 h. The mixture was diluted with 10 ml of water and extracted three times with 8 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane for the elution to give 164 mg of 5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde as a yellow oil. Mass spectrum (EI) m/z 362 [M]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].O>CN1C(=O)CCC1>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:12]2[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: O=S1(=O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(N2CCS(=O)(=O)CC2)nc1
Yield: 41.1 %

Procedure:
A solution of methyl 6-chloronicotinate (3.43 g, 20 mmol), thiomorpholine 1,1-dioxide (2.70 g, 20 mmol) and sodium carbonate (2.54 g, 24 mmol) in NMP (40 mL) was heated to 90° C. for 3 days. The reaction mixture was poured into water and the white solid formed was filtered off to give 2.22 g 6-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-nicotinic acid methyl ester. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over Na2SO4, filtered and the solvents were evaporated. The residue was triturated with diethyl ether and the solid filtered off to yield another 1.18 g 6-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-nicotinic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27](O)=[O:28])[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.ON1C2C=CC=CC=2N=N1.O/[N:45]=[C:46](\[NH2:48])/[CH3:47]>CN(C=O)C>[C:21]([C:20]1[CH:19]=[N:18][N:17]2[CH:24]=[C:25]([C:27]3[O:28][N:48]=[C:46]([CH3:47])[N:45]=3)[CH:26]=[C:16]2[C:15]=1[NH:14][C@H:10]1[C@@H:11]([CH3:13])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]1)(=[O:23])[NH2:22]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(C(=O)O)cc12
Reactant: C/C(N)=N/O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1noc(-c2cc3c(N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@@H]4C)c(C(N)=O)cnn3c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
A mixture of 4-(((3S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-3-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid (120 mg, 0.297 mmol), EDC (68.4 mg, 0.357 mmol) and 1-hydroxybenzotriazole (54.7 mg, 0.357 mmol) in DMF (2 mL) was stirred at rt for 30 minutes. (Z)—N′-hydroxyacetimidamide (48.5 mg, 0.654 mmol) was added and the reaction mixture was stirred for 30 min at rt and 3 hr at 125° C. for 5 hr. After cooling to rt, The reaction mixture was partitioned between EtOAc (30 ml) and saturated NaHCO3 solution (30 ml). The organic layer was washed with saturated NaHCO3 solution (30 ml), 10% LiCl solution (2×30 ml) and brine (30 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to a yellow oil that was chromatographed on a 12 gm ISCO silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The pure fractions were concentrated to afford (3S,4S)-tert-butyl 3-((3-carbamoyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylpyrrolidine-1-carboxylate (50 mg, 0.110 mmol, 36.9% yield) as an off-white solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.27 (s, 2H), 7.48 (s, 1H), 3.88-3.50 (m, 4H), 3.21 (td, J=10.3, 4.4 Hz, 1H), 2.72 (d, J=6.4 Hz, 1H), 2.43 (s, 3H), 1.45 (d, J=13.6 Hz, 9H), 1.18 (d, J=6.8 Hz, 3H). MS (ES+) m/z: 442.2 (M+H); LC retention time: 2.991 min (analytical HPLC Method O).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[CH2:14]([NH:18][OH:19])[CH2:15][CH2:16][CH3:17]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:18]([CH2:14][CH2:15][CH2:16][CH3:17])[O-:19])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: CCCCNO
Reactant: CCOc1cc(C=O)ccc1OC
Product: CCCC[N+]([O-])=Cc1ccc(OC)c(OCC)c1

Procedure:
The title compound was prepared according to the procedures described in Examples 11 using 3-ethoxy-4-methoxybenzaldehyde and N-n-butylhydroxylamine. The title compound was isolated in 41.1% yield as a solid, m.p. 117.3° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13](O)=[O:14])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[BH4-].[Na+].O>S(Cl)(Cl)=O.O1CCOCC1>[OH:14][CH2:13][C:12]1[CH:11]=[C:10]([S:9][C:4]2[N:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1cccnc1Sc1cccc(C(=O)O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: N#Cc1cccnc1Sc1cccc(CO)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
Dissolve 3-(3-cyano-pyridin-2-ylsulfanyl)-benzoic acid (1.50 g, 5.85 mmol) in thionyl chloride (50 mL) and stir. Heat to reflux. After 2 hours, concentrate under reduced pressure to give a residue. Dissolve residue in dioxane (100 μL) and add sodium borohydride (2.21 g, 58.5 mmol). Heat to 50° C. After 2 hours, cool to ambient temperature and add water. Extract with ethyl acetate, combine organic layers, dry with sodium sulfate, filter and concentrate to give the title compound as a yellow oil (1.20 g, 85%): 1H NMR (DMSO-d6) δ 4.54 (d, 2H), 5.30 (t, 1H), 7.37 (dd, 1H), 7.43 (m, 3H), 7.50 (m, 1H), 8.29 (dd, 1H), 8.56 (dd, 1H).
Reaction SMILES: C1(CCC(O)CCC2C=CC=CC=2)C=CC=CC=1.[OH:19][CH:20]([CH2:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:37]([O:40][CH2:41]C)(=O)C>CCCCCC>[C:31]1([S:30][CH2:29][CH:20]([O:19][CH2:37][O:40][CH3:41])[CH2:21][S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(C)=O
Reactant: OC(CSc1ccccc1)CSc1ccccc1
Agent: OC(CCc1ccccc1)CCc1ccccc1
Solvent: CCCCCC
Product: COCOC(CSc1ccccc1)CSc1ccccc1

Procedure:
Using the procedure of Example 51 but 1,5-diphenyl-3-pentanol with the resultant compound of Example 15 gave, after silica gel chromatography using 15% ethyl acetate in hexane, 44 mg (31%) of the desired compound (Rf 0.27, 20% ethyl acetate in hexane). 1H NMR (CDCl3) δ 3.21 (dd, J=15, 6 Hz, 2H), 3.26 (dd, J=15, 6 Hz, 2H), 3.40 (s, 3H), 3.91 (pentet, J=6 Hz, 1H), 4.68 (s, 2H), 7.15-7.35 (m, 10H). Mass spectrum (M +NH4)+ =338.
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C-:9]#[N:10].C([Al+]CC)C.Cl>C1(C)C=CC=CC=1>[O:8]=[C:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([C:9]#[N:10])[CH2:2]1
Reactant: O=C1C=CCCCC1
Reactant: [C-]#N
Agent: CC[Al+]CC
Agent: Cl
Solvent: Cc1ccccc1
Product: N#CC1CCCCC(=O)C1

Procedure:
To 100 mL of toluene add 2-cyclohepten-1-one (11.0 g, 0.1 mol) and 200 mL (1M solution in toluene, 0.2 mol) of diethylaluminum cyanide. Monitor the reaction by thin-layer chromatography. Upon completion add 1M aqueous HCl until gas evolution ceases. Extract twice with 100 mL of ether. Dry the organic phase with Na2SO4. Filter off the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)=[CH:9][CH:8]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[NH3:14].[C:22]1([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:12]=[CH:11][C:10]([C:13]4[NH:17][C:16]5[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=5[N:14]=4)=[CH:9][CH:8]=3)[CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCCCCOc1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Product: N
Product: c1ccc(N2CCN(CCCCOc3ccc(-c4nc5ccccc5[nH]4)cc3)CC2)cc1
Yield: 84.6 %

Procedure:
A mixture of 2-[4-(4-chlorobutoxy) phenyl]-1H-benzimidazole (Example C) (0.25 g) and 1-phenylpiperazine (0.70 g) is stirred at 110° C. in dimethylformamide (20 mL) for 6 hours. The solvent is evaporated and the residue is purified by chromatography on silica gel eluting with 100:8:1 dichloromethane: ethanol: 0.880 aqueous ammonia to give 0.15 g of the title compound as a brown solid; mp 193°-196° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([F:21])=[C:7]([CH:16]=[C:17]([F:20])[C:18]=1[F:19])[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])(=[O:3])[CH3:2].[C:22](OC(=O)C)(=O)C.[CH3:29][CH:30]([NH2:33])[CH2:31][OH:32]>ClCCl>[CH2:14]([O:13][C:11](=[O:12])[C:10]([C:8](=[O:9])[C:7]1[CH:16]=[C:17]([F:20])[C:18]([F:19])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]=1[F:21])=[CH:22][NH:33][CH:30]([CH3:29])[CH2:31][OH:32])[CH3:15]
Reactant: CC(N)CO
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(OC(C)=O)c1F
Solvent: ClCCl
Product: CCOC(=O)C(=CNC(C)CO)C(=O)c1cc(F)c(F)c(OC(C)=O)c1F

Procedure:
To 7.64 g (0.025 mole) of the ethyl 3-acetoxy-2,4,5-trifluorobenzoylacetate (VIII) thus obtained were added 20 ml of acetic anhydride and 6 ml of ortho-ethyl formate and the mixture was refluxed for 2 hours and then condensed under reduced pressure. The residue was dissolved in 50 ml of dichloromethane, added 1.91 g (0.026 mole) of DL-2-aminopropanol and allowed to stand over night. Dichloromethane was distilled under reduced pressure and the residue was applied to silica gel column chromatography (solvent: mixture of toluene:ethyl acetate=1:1) to give 4.37 g of the ethyl-2-(3-acetoxy-2,4,5-trifluorobenzoyl)-3-(2-hydroxy-1-methylethyl)aminoacrylate (X) as pale yellow oily product. ##STR10##
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1COCC1.[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:20][C:14]1([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=C1C=CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(O)C=CCCC1
Yield: 95 %

Procedure:
Under nitrogen atmosphere, 20 mL of toluene was added to 3.05 g (5 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.48 g (5 mmol) of 2-cyclohexen-1-one in 5 mL of toluene was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 10 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL (×2) of an aqueous saturated sodium chloride solution, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 10 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 0.87 g of the desired product (yield 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.C(N(CC)CC)C>[C:12]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2c(c1)CCC2=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(c1)CCC2=O)c1ccccc1

Procedure:
5-Aminoindan-1-one (2.5 g) was reacted with benzoyl chloride (2.63 g) in dichloromethane and triethylamine to give 5-benzamidoindan-1-one which was reacted with benzaldehyde in a similar manner to Example 7a) to give N-(2-benzylidene-1-oxoindan-5-yl)benzamide which was reacted with hydrogen peroxide in a similar manner to Example 7b) to give an intermediate which was reacted with hydrazine hydrate in a similar manner to Example 7c) to give -(3N-phenyl-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)benzamide, m.p. 271° C., after chromatography of the reaction mixture.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[C:4]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[S:26][C:25]([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=4[F:34])=[N:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:12])[CH:3]=1.[CH:35]([OH:38])([CH3:37])[CH3:36]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:38][CH:35]([CH3:37])[CH3:36])[N:5]=[C:4]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[S:26][C:25]([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=4[F:34])=[N:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:12])[CH:3]=1
Reactant: N#Cc1c(N)cc(C(=O)NCC2CCN(Cc3cnc(-c4c(F)cccc4F)s3)CC2)nc1Cl
Reactant: CC(C)O
Product: CC(C)Oc1nc(C(=O)NCC2CCN(Cc3cnc(-c4c(F)cccc4F)s3)CC2)cc(N)c1C#N

Procedure:
According to the same procedure described in Example 204, using the compound prepared in Example 399 instead of the compound prepared in Example 215 and isopropanol instead of 1-cyclopropylethanol, the title compound having the following physical data was obtained.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[N:23]=2)[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=1[CH3:38])([CH3:8])[C:3]([O:5]CC)=[O:4].O.[OH-].[Na+].Cl>C1COCC1>[NH3:23].[CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=3)[N:23]=2)[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=1[CH3:38])([CH3:8])[C:3]([OH:5])=[O:4]
Reactant: CCCCC(Oc1ccc(OC(C)(C)C(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(OC(C)(C)C(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Product: N
Reaction time: 24 h
Yield: 89.7 %
Yield: 10 %

Procedure:
Ethyl 2-methyl-2-({2-methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)propanoate (9 mg, 0.02 mmol) was dissolved in THF (0.75 mL), water (0.25 mL) and aqueous NaOH (2M, 35 μl, 0.07 mmol) and the mixture heated at 80° C. for 16 hours. More aqueous NaOH (2M, 420 μl, 0.84 mmol) was then added and heating continued for an additional 24 hours. The mixture was then cooled, neutralised with aqueous HCl (2M), partitioned between EtOAc and water and the layers separated. The organic layer was then washed with brine, dried (Na2SO4) and reduced to give a pale yellow oil. Purification by SPE (aminopropyl, 1 g cartridge) loading in CHCl3 and eluting with dioxane and then 10% aqueous ammonia in dioxane afforded the title compound as a colourless gum (4.5 mg).