Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[C:12]1([S:18]([C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C>CC(N(C)C)=O>[C:12]1([S:18]([C:21]2[CH:22]=[CH:23][C:24]([NH:25][C:5]([C:2]3([OH:1])[CH2:4][CH2:3]3)=[O:7])=[CH:26][CH:27]=2)(=[O:19])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C1(O)CC1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: C
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(S(=O)(=O)c2ccccc2)cc1)C1(O)CC1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
A solution of 1-hydroxycyclopropanecaboxylic acid (0.66 g, 6.44 mmol) in dry dimethylacetamide (10 ml) was stirred under a nitrogen atmosphere at -15° C. Thionyl chloride (0.77 g, 6.44 mmol) was added and the resulting mixture was allowed to stir at -15° C. for 1 hour. 4-Phenylsulfonylaniline (1.0 g, 4.29 mmol) was then added and the reaction mixture was stirred at -15° C. for a further 15 mins. The solution was then allowed to warm to room temperature where it was stirred overnight. The reaction mixture was poured onto ice, extracted with ethyl acetate, and the combined ethyl acetate portions were washed with 1M HCl. After drying (MgSO4) the ethyl acetate was removed by evaporation to give a buff-colored solid. Crystallization of this material from ethyl acetate/hexane yielded the title tertiary carbinol, (0.82 g, 60%) as a white solid; mp=214.5°-216° C. 1H-NMR (250 MHz, d6 -DMSO): 0.98 (m, 2H, 2 CH2), 1.15 (m, 2H, CH2), 6.63 (s, 1H, OH), 7.65 (m, 3H, ArH), 7.95 (m, 6H, ArH), 10.29 (s, 1H, NH). MS (CI, CH4): 318(M+1, 100).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH3:11])[C:5]=1[OH:12].[Cl:14]OC(C)(C)C.CCCCCC>C(OCC)(=O)C>[Cl:14][C:8]1[C:7]([OH:10])=[C:6]([CH3:11])[C:5]([OH:12])=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:13]
Reactant: COC(=O)c1ccc(O)c(C)c1O
Reactant: CC(C)(C)OCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(O)c(Cl)cc(C(=O)O)c1O
Reaction time: 2 h
Yield: 37 %

Procedure:
To a solution of 2,4-dihydroxy-3-methylbenzoic acid methyl ester (9.9 g) in ethyl acetate (100 ml) was added tert-butyl hypochlorite (12.3 ml) under ice-cooling. After stirring for 2 hours, hexane (200 ml) was added, and the mixture was cooled with ice to allow precipitation of crystals. The crystals were collected by filtration, and dissolved in a mixed solvent of methanol (20 ml) and tetrahydrofuran (THF, 20 ml). A 1 M lithium hydroxide solution (40 ml) was added to the solution, and the mixture was refluxed under heating for 18 hours. The reaction mixture was concentrated, and a 10% aqueous citric acid solution was added to the residue, which was followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (4.14 g, yield 37%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=1)O)C1C=CC=CC=1>[Pd].C(O)(=O)C.C(O)C>[CH2:30]([S:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:19][C:10]2[CH:11]=[C:12]([C:15]([F:17])([F:16])[F:18])[CH:13]=[CH:14][C:9]=2[OH:8])=[CH:26][CH:25]=1)(=[O:28])=[O:29])[CH3:31]
Reactant: CCS(=O)(=O)c1ccc(C(O)c2cc(C(F)(F)F)ccc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCS(=O)(=O)c1ccc(Cc2cc(C(F)(F)F)ccc2O)cc1
Reaction time: 2 h

Procedure:
A mixture of the product from example 3 step (iii) (0.225 g), 10% palladium on carbon (0.05 g) and acetic acid (2 drops) in ethanol (20 ml) was hydrogenated at 3 Bar for 2 h then SBar for 5 h. After filtration the solvent was evaporated under reduced pressure. Yield 0.16 g
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:24][CH3:25].N1C=CC=CC=1.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:3]([O:24][CH3:25])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80 mg, 0.236 mmol) was dissolved in dichloromethane (2.0 mL). Pyridine (2.0 mL) was added followed by benzoyl chloride (41 uL, 0.353 mmol). After stirring at room temperature for 2 hours, the solvent was removed and the residue was dissolved in 1 ml DMSO, methanol (1 mL) was added and precipitate was formed. The solid was collected by filtration to give N1-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]benzamide (64 mg, 0.144 mmol). 1H NMR (CDCl3-d) δ 2.12 (m, 4H), 3.67 (m, 2H), 3.99 (s, 3H), 4.17(m, 2H), 4.99 (m, 1H), 7.03(s, 1H), 7.04 (s, 1H), 7.14 (d, J=8.2 Hz, 1H), 7.53 (m, 3H), 7.94(d, J=7.8 Hz, 1H), 8.33 (s, 1H), 8.58 (s, 1H), 8.63 (d, J=8.2 Hz, 1H). LC/MS: MH+=444.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])[CH3:8].[C:24]([O:32][C@@H:33]1[CH2:41][C@@H:36]2[O:37][C:38](=[O:40])[CH2:39][C@@H:35]2[C@H:34]1/[CH:42]=[CH:43]/[C@H:44]([C:46]1[S:50][C:49]2[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=2[CH:47]=1)[OH:45])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.C(OCC)(=O)C>[C:24]([O:32][C@@H:33]1[CH2:41][C@@H:36]2[O:37][C:38](=[O:40])[CH2:39][C@@H:35]2[C@H:34]1/[CH:42]=[CH:43]/[C@H:44]([C:46]1[S:50][C:49]2[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=2[CH:47]=1)[O:45][Si:10]([C:7]([CH3:9])([CH3:8])[CH3:6])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)c3cc4ccccc4s3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)c1cc2ccccc2s1)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
A stirring mixture consisting of (3aR,4R,5R,6aS)-4-((R,E)-3-(benzo[b]thiophen-2-yl)-3-hydroxyprop-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (5a, limiting reagent) and imidazole (1.1 molar equivalents) in DMF (5 M in 5a) is cooled to 0° C. under a nitrogen atmosphere. A solution consisting of TBDPSCl (1.1 molar equivalents) in DMF is added slowly. Upon completion of the reaction, as judged by TLC, the reaction mixture is diluted with ethyl acetate and is washed with water and brine. The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product is purified by flash chromatography on regular silica gel eluted with hexanes-ethyl acetate to afford the title intermediate 6a.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([C:16](OC)=[O:17])=[CH:15][C:4]=2[N:3]=1.[BH4-].[Na+]>CCO>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc2c(c1)nc(N)c1ncccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc2cc(CO)ccc2c2cccnc12
Temperature: 80 °C

Procedure:
To a solution of methyl 5-aminobenzo[f][1,7]naphthyridine-8-carboxylate (from the previous step) (1.0 eq.) in EtOH (0.03M) was added NaBH4 (10 eq.) at 25° C. The solution was heated to 80° C. for 5 hours. After cooling to ambient temperature, the reaction mixture was concentrated en vaccuo. The residue was portionized between saturated NaHCO3 and EtOAc. The layers were separated and aqueous layer was extracted with EtOAc twice. The combined organic layer was washed with brine, dried over MgSO4 and concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM to give (5-aminobenzo[f][1,7]naphthyridin-8-yl)methanol as an off white solid: 1H NMR (methanol-d4): δ 8.82 (dd, 1H), 8.77 (dd, 1H), 7.26 (d, 1H), 7.70 (dd, 1H), 7.50 (d, 1H), 7.27 (dd, 1H), 4.66 (s, 2H). LRMS [M+H]=226.1.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH2:5][NH2:6])=[CH:14][CH:13]=1
Reactant: COc1ccc(S)cc1
Reactant: NCc1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COc1ccc(Sc2cccc(CN)c2)cc1
Yield: 88.9 %

Procedure:
The general procedure in example 39 was followed. 3-Iodobenzylamine (133 μL, 1.0 mmol), 4-methoxythiophenol (123 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 3-(4-methoxyphenyl)sulfanylbenzylamine (218 mg, 89% yield) as light yellow liquid. Column chromatographic solvent (CH2Cl2 (saturated with NH3)/MeOH=30/1). Rf=0.4 (CH2Cl2 (saturated with NH3)/MeOH=30/1), (Note: same Rf value as the starting material). 1H NMR (CDCl3, 300 MHz) δ 7.40 (dt, 2 H, J=1.8 Hz, 8.7 Hz), 7.19 (t, 1 H, J=7.8 Hz), 7.06-7.13 (m, 2 H), 7.01 (dt, 1 H, J=1.5 Hz, 7.5 Hz), 6.89 (dt, 2 H, J=2.1 Hz, 8.7 Hz), 3.82 (s, 3 H), 3.79 (s, 2 H), 1.40 (brs, 2 H). 13C NMR (CDCl3, 75 MHz) δ 159.9, 144.3, 139.0, 135.6, 129.3, 126.9, 126.7, 124.8, 124.3, 115.2, 55.7, 46.6. IR (neat, cm−1) 3373 (broad), 3072, 3060, 2939, 2836. MS (EI) m/z (relative intensity) 245 (100), 106 (60). HRMS (EI), Cald. for C14H15NOS 245.0869; Found 245.0862.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]3[C:14]4([CH2:15][CH2:16][C:5]=2[CH:4]=1)[CH:10]([CH2:11][NH:12][CH2:13]4)[CH2:9][CH2:8]3.[CH3:19]O.[OH-].[NH4+]>ClCCl>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]3[C:14]4([CH2:15][CH2:16][C:5]=2[CH:4]=1)[CH:10]([CH2:11][N:12]([CH3:19])[CH2:13]4)[CH2:9][CH2:8]3
Reactant: COc1ccc2c(c1)CCC13CNCC1CCC23
Reactant: CO
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC13CN(C)CC1CCC23
Yield: 88.5 %

Procedure:
Using the procedure of Example 1B but replacing the resultant compound of Example 1A (Compound 1A-a) with the resultant compound of Example 1A(Compound 1A-b), provided, after silica gel chromatography using 5% methanol and 0.5% ammonium hydroxide in dichloromethane, 102.0 mg (88.5%) of the title compound as a white solid.
Reaction SMILES: BrCCBr.[Mg].Br[C:7]1[CH:11]=[CH:10][S:9][CH:8]=1.[CH3:12][C@H:13]1[CH2:18][C:17](=[O:19])[CH2:16][CH2:15][O:14]1>C(OCC)C>[OH:19][C@:17]1([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[CH2:16][CH2:15][O:14][C@@H:13]([CH3:12])[CH2:18]1
Reactant: C[C@H]1CC(=O)CCO1
Reactant: Brc1ccsc1
Agent: [Mg]
Solvent: CCOCC
Solvent: BrCCBr
Product: C[C@H]1C[C@@](O)(c2ccsc2)CCO1
Yield: 19.7 %

Procedure:
A solution of 1,2-dibromoethane (5 g) in diethyl ether (10 ml) was added to a stirred suspension of magnesium (3 g) in diethyl ether (10 ml) to initiate the formation of a Grignard reagent. A mixture of 1,2-dibromoethane (16.7 g) and 3-bromothiophene (4 g) in diethyl ether (30 ml) was added dropwise. The mixture was stirred and heated to reflux for 2 hours. A solution of (2S)-2-methyltetrahydropyran-4-one (2 g) in diethyl ether (5 ml) was added and the mixture was heated to reflux for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 7:3 mixture of petroleum ether and ethyl acetate as eluent. There were thus obtained in turn (2S,4R)-4-hydroxy-2-methyl-4-(3-thienyl)tetrahydropyran (0.685 g, 18.5%) and the corresponding (2S,4S)-isomer (1 g, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:23]=[CH:22][C:15]([CH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[NH2:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:18][C@H:17]([C:19]([OH:21])=[O:20])[CH2:16][C:15]2[CH:14]=[CH:13][C:12]([F:11])=[CH:23][CH:22]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)O
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N[C@@H](Cc2ccc(F)cc2)C(=O)O)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (1.8 g) in dimethyl sulfoxide (30 mL) were added 4-fluorophenylalanine (2.54 g) and cesium carbonate (4.90 g), and the mixture was stirred at 90° C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 3.69 g, 100%).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][CH3:10])[O:4][C@H:3]1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([C:29]#[N:30])=[N:15][C:16]=2[NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N.[H][H]>C(O)C.[Pd]>[NH2:30][CH2:29][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[C@H:3]2[C@H:2]([OH:1])[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][CH3:10])[O:4]2)=[C:16]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:15]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(C#N)nc32)[C@H](O)[C@@H]1O
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CCO
Product: COC[C@H]1O[C@@H](n2cnc3c(NCCc4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
A solution of 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-(phenethylamino)-9H-purine-2-carbonitrile (2.9 g, 7.07 mmol) (preparation 47) in ethanol (300 ml), saturated with ammonia gas, was treated with 5% palladium on charcoal (1.0 g), pressurised to 1034 kPa (150 psi) with hydrogen gas in a sealed vessel and stirred at room temperature for 48 hr. The reaction mixture was filtered through Arbocel (trade mark) and the solvent removed under reduced pressure. The residue was dissolved in dichloromethane and the solvent removed under reduced pressure to give a product that was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (92:8:0.4) to give the title compound (1.7 g) as a foam. MS: 416 (MH+)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][C:12](=O)[C:13](F)(F)F)[CH:3]=1.Br.BrC[C:21]1[CH:26]=[CH:25][CH:24]=C[N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>O>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:24]=[CH:25][CH:26]=[CH:21][N:22]=2)[CH:3]=1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1sc(Br)cc1NCc1ccccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (500 mg, 1.51 mmol), 2-(bromomethyl)pyridine hydrobromide (457 mg, 1.81 mmol), cesium carbonate (1.72 g, 5.29 mmol) and DMA (15 mL) was stirred at 80° C. for 2 h. Then, water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was dissolved in MeOH (5 mL). To the solution were added potassium carbonate (500 mg) and water (2.5 mL). The mixture was stirred at room temperature for 1 h. After removal of the solvent at reduced pressure, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 70:30 hexane/EtOAc) to give the title compound (336 mg, 68%) as a yellow solid:
Reaction SMILES: O[N:2]=[C:3]([C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]2[NH:29][C:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)=[CH:30][CH:31]=1)([O-:23])=[O:22]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(C(F)(F)F)cc1
Yield: 30.7 %

Procedure:
Ethyl 2-hydroxyimino-3-oxo-3-(4-trifluoromethylphenyl)-propionate (24.6 g) and 4-nitrobenzylamine (14.0 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 2-(4-nitrophenyl)-5-(4-trifluoromethylphenyl)-imidazole-4-carboxylate (10.6 g). 9.0 g therefrom was dissolved in ethyl alcohol. 1 M Sodium hydroxide solution was added and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2-(4-nitrophenyl)-5-(4-trifluoromethylphenyl)imidazole-4-carboxylic acid (8.2 g), melting point 172-174° C. (decomposition).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][NH:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][NH:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: NCCNc1cccnc1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCCNc2cccnc2)cc1
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
4-geranyloxybenzoic acid(3.57 g) was dissolved in chloroform(60 ml) and triethylamine(3.60 ml), and then diphenylphosphinic chloride(2.48 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 3-(2-aminoethylamino)pyridine(2.24 g) added thereto, was stirred for 3 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 2.41 g of the aimed compound.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:15](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.O>[CH3:15][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A solution of 4-phenylpiperidine (1.0 g, 6.2 mmol) was dissolved in THF (20 mL) and treated with formaldehyde (2.6 mL of a 37% solution in water). To the stirred reaction mixture was added sodium triacetoxyborohydride (2.63 g, 12.4 mmol). The reaction mixture was maintained at room temperature for 1 h, and then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with 5% aqueous NaHCO3 and brine, then dried over MgSO4. Evaporation of the solvent yielded 1-methyl-4-phenylpiperidine 113 (1.06 g, 97%) as a colorless oil.
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[CH2:21]([O:23][C:24](=[O:30])[CH2:25][NH:26][CH:27]([CH3:29])[CH3:28])[CH3:22].CCN(C(C)C)C(C)C>ClCCl>[CH2:21]([O:23][C:24](=[O:30])[CH2:25][N:26]([C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12])[CH:27]([CH3:29])[CH3:28])[CH3:22]
Reactant: CCOC(=O)CNC(C)C
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CN(C(C)C)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reaction time: 3 h
Yield: 87.8 %

Procedure:
At room temperature, 3-Bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (4.57 g, 12.3 mmol) and Isopropylamino-acetic acid ethyl ester (2.15 g, 14.8 mmol), DIPEA (2.14 ml) were mixed in about 40 ml dichloromethane. After stirred for about 3 h, the solution was concentrated and the crude product was purified by chromatography to obtain 4.7 g solid rac-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-acetic acid ethyl ester. MS: 435 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:15]>CN(C=O)C>[F:28][C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:18][CH2:17][N:16]([C:14](=[O:15])[CH2:13][N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)[CH2:21][CH2:20]2)=[CH:27][CH:26]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1cccn1)N1CCN(c2ccc(F)cc2)CC1
Temperature: 80 °C

Procedure:
Pyrazole (112.33 mg, 1.65 mmol) was dissolved in DMF (10 mL). K2CO3 (228.05 mg, 1.65 mmol) and 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone (300 mg, 1.67 mmol) were added to it. The reaction was heated to 80° C. for 14 h. After completion, the reaction was cooled to room temperature, quenched with brine and then extracted with ethyl acetate. The organic layer was further washed with water (2×25 mL) and brine (2×25 mL) and dried over magnesium sulfate. The solvent was removed by rotary evaporation to give the crude product which was purified by column chromatography on silica gel using a solvent mixture (hexane/ethyl acetate=1/1) to afford the title compound as white solid. 1H NMR (400 MHz, CDCl3): 7.2-7.58 (d, 2H), 6.94-7.2 (t, 2H), 6.84-6.9 (dd, 2H), 6.32-6.36 (t, 1H), 5.6 (s, 2H), 3.76-3.82 (m, 2H), 3.68-3.74 (m, 2H), 3.04-3.1 (m, 2H), 3.0-3.04 (m, 2H). 13C NMR (400 MHz, CDCl3):165, 158, 146.5, 140, 130, 118.4, 118.2, 116, 115.8, 107, 54, 51, 50.8 45.8, 42.8.