Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[S:11][CH2:10][CH2:9][CH2:8][S:7]1)=[O:5])[CH3:2].C([Li])CCC.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:17]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][CH2:8][CH2:9][CH2:10][S:11]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1SCCCS1
Reactant: ClCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)SCCCS1
Temperature: -25 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
A solution of 3.0 g (15.6 mmol) of 2-ethoxycarbonyl-1,3-dithiane in 40 ml of dry tetrahydrofuran was cooled under inert atmosphere to -78° C. and treated with 7.5 ml (15.6 mmol) of n-butyllithium. The resulting solution was warmed to -25° C., stirred for 20 min, recooled to -78° C., treated with 1.8 ml (15.6 mmol) of benzyl chloride, and stirred at ambient temperature for 16 h. After quenching with aqueous ammonium chloride, the mixture was extracted with ether, washed sequentially with water, aqueous sodium thiosulfate, and brine, dried over MgSO4, and concentrated in vacuo. Flash chromatography using 5% ethyl acetate in hexane gave 3.9 g (88%) of the desired compound. 1H NMR (CDCl3) δ 1.33 (t, J=7 Hz, 3H), 1.85 (qt, J=14, 3 Hz, 1H), 2.11 (dm, J=14 Hz, 1H), 2.69 (dt, J=14, 4 Hz, 2 H), 3.23 (ddd, J=14, 12, 3 Hz, 2H), 3.38 (s, 2H), 4.27 (q, J=7 Hz, 2H), 7.25-7.35 (m, 5H). Mass spectrum (M+NH4)+ =300.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:18])[CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)[C:5]([Cl:19])=[CH:4][N:3]=1.Cl.[CH3:21][N:22]1[CH:26]=[C:25]([NH2:27])[CH:24]=[N:23]1.C(N(C(C)C)C(C)C)C>CCCCO>[Cl:19][C:5]1[C:6]([N:8]([CH3:18])[CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)=[N:7][C:2]([NH:27][C:25]2[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: CN(c1nc(Cl)ncc1Cl)C1COC2C(O)COC21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1COC2C(O)COC21
Temperature: 150 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a suspension of 6-((2,5-dichloropyrimidin-4-yl)(methyl)amino)hexahydrofuro[3,2-b]furan-3-ol (342.2 mg, 1.12 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (185.0 mg, 1.38 mmol) in n-BuOH (5 mL) was added N-ethyldiisopropylamine (358.8 mg, 2.78 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/40) to give the title compound as a beige solid (156 mg, 38.0%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][CH2:11][CH2:12]2>C(Cl)(Cl)Cl>[Br:6][C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:15][CH:16]=1
Reactant: O=S(=O)(O)Cl
Reactant: Brc1cccc2c1CCCC2
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(Br)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.6 %

Procedure:
Chlorosulfonic acid (13.80 g, 7.93 ml, 118.00 mmol was added dropwise to a stirred solution of 5-bromo-1,2,3,4-tetrahydronaphthalene (prepared according to the procedure reported in the literature, WO2004/000792, 10.0 g, 47.4 mmol) in 50 ml chloroform at 0° C. The reaction mixture was then allowed to warm to about 25° C. and was stirred at the same temperature for 45 min. The progress of the reaction was monitored by TLC. The reaction mixture was then poured in ice-water (50 ml) and the mixture so obtained was extracted with chloroform (2×150 ml). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to obtain the title compound (12.0 g, 81.6%), which was taken ahead as such without further purification for the next step.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([N:19]2[CH2:24][CH2:23][N:22]([C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCN(C2CCCCC2)CC1

Procedure:
This example was prepared according to Example 1 by employing trans-2-phenyl-1-cyclopropanecarbonyl chloride and 1-cyclohexylpiperazine, which is commercially available from, for example, Sigma-Aldrich Corporation, to afford title compound as a white solid. m/z (ES+) M+1=313.2; HPLC tR=1.76 min. 1H NMR (500 MHz, CDCl3) δ 7.28-7.24 (m, 2H), 7.19-7.15 (m, 1H), 7.10 (d, J=7.9 Hz, 2H), 3.67-3.53 (m, 4H), 2.58-2.49 (m, 4H), 2.47 (dt, J=8.9, 1.3 Hz, 1H), 2.29-2.22 (m, 1H), 2.00-1.92 (m, 1H), 1.79 (dd, J=17.7, 3.4 Hz, 4H) 1.66-1.58 (m, 2H) 1.26-1.16 (m, 5H) 1.15-1.0 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:16][CH2:17][CH3:18])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[CH2:16][CH2:17][CH3:18])=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.9 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-2,4-octadienoic acid 2.47 g) and 4-nitrophenol (1.5 g) in 15 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide 1.86 g). The mixture was stirred at room temperature for 3 days. Crystallization of the crude product from 2-propanol furnished 2.5 g of (E,E)-5-(4-methoxyphenyl)-2,4-octadienoic acid 4-nitrophenyl ester, mp 90°-92° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH2:11])=[O:10])(=[O:4])[CH:2]=[CH2:3].[C:15](Cl)(=O)C=CC>>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH2:11])=[O:10])(=[O:4])[CH:2]=[CH:3][CH3:15]
Reactant: C=CC(=O)Nc1cccc(C(N)=O)c1
Reactant: CC=CC(=O)Cl
Product: CC=CC(=O)Nc1cccc(C(N)=O)c1

Procedure:
This was achieved by the same procedure as that used to make 3-propenoylaminobenzamide, namely the route of Example 4, except that 2.30 gm (20 mMole) of butenoyl chloride was used. The product obtained had a melting point of 211° C. to 212° C.
Reaction SMILES: [Na].[OH:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].Cl.Cl[CH2:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1>C(O)C>[NH:20]1[CH:21]=[C:17]([CH2:16][O:2][N:3]2[C:4](=[O:13])[C:5]3=[CH:12][CH:11]=[CH:10][CH:9]=[C:6]3[C:7]2=[O:8])[N:18]=[CH:19]1
Reactant: ClCc1c[nH]cn1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1OCc1c[nH]cn1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
A mixture of ethanol and 270 mg of sodium was cooled in an ice-bath and 1.91 g of N-hydroxyphthalimide was added to the mixture. 594 mg of 4-(chloromethyl)imidazole hydrochloride was added thereto under stirring at room temperature and the resulting mixture was stirred for 14 hours. The solvent was distilled off and SSB was added to the residue and the mixture was extracted with chloroform. The extract was washed with SSC and dried with sodium sulfate and then concentrated to dryness. The residue was recrystallized from a mixture of diisopropyl ether and ether to give 553 mg of N-((imidazol-4-yl)methoxy)phthalimide with mp 163°-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11](=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(Cl)cc1
Yield: 97.5 %

Procedure:
4-Chlorophenol (10 g), chloroacetone (10.8 g), anhydrous potassium carbonate (12.9 g) and potassium iodide (1.3 g) were added to acetone (100 ml) and heated under reflux for 6 hours. The reaction mixture was filtered and the filtrate was concentrated to obtain 4-chlorophenoxyacetone (14 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:15](O)([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:15][CH3:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
Prepare a solution of 4-bromo-phenol (17.30 g, 0.10 mol) and potassium carbonate (13.80 g, 0.1 mole) in isopropanol (175 mL). Heat the resulting mixture at reflux and stir overnight. Cool to ambient temperature, filter and condense the filtrate on a rotary evaporator. Dissolve the residual oil in ethyl acetate (250 mL) and extract twice with 5% sodium hydroxide (100 mL), separate and wash with brine. Kugelrohr distillation at 100°-120°, 0.05 mm, gives the title compound (12.86 g, 60%) as a clear liquid.
Reaction SMILES: [NH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11](=[O:14])[C:12](=[O:13])[N:4]([C:5]=23)[CH2:3][C:2]1=[O:15].C1COCC1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>C(OCC)C>[OH:14][C:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]2[C:5]3[N:4]([CH2:3][C:2](=[O:15])[NH:1][C:10]=3[CH:9]=[CH:8][CH:7]=2)[C:12]1=[O:13]
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CN2C(=O)C(=O)c3cccc(c32)N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CN2C(=O)C(O)(c3ccccc3)c3cccc(c32)N1
Reaction time: 8 h

Procedure:
A suspension was prepared from 4.3 g. of 1H-pyrrolo[1,2,3-de]quinoxalin-2,5,6(3H)-trione in 200 ml. of THF. 16 ml. of a 2.83 M phenylmagnesium bromide solution in diethyl ether (phenyl Grignard reagent) were added thereto while maintaining the temperature in the range 10°-15° C. The resulting reaction mixture was stirred overnight after which time, 200 ml. of a saturated aqueous amonium chloride solution were added. An additional 1500 ml. of diethylether were added and the ethereal layer decanted from the solids. The ethereal layer was dried and the ether removed therefrom in vacuo. The resulting residue, comprising 6-hydroxy-6-phenyl-1H-pyrrolo[1,2,3-de]quinoxalin-2,5(3H,6H)-dione melted at 259°-62° C. with decomposition after recrystallization from methanol; yielded = 2.4 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH:14]=2)=[CH:4][C:3]=1[C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=2[F:34])[N:25]=[N:24][N:23]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:28]1[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:27]=1[N:26]1[C:22]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]3=[CH:14][CH2:13][NH:12][CH2:11][CH2:10][CH2:9]3)[CH:4]=2)=[N:23][N:24]=[N:25]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc(N)c(-c3nnnn3-c3cccc(F)c3F)c2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(C2=CCNCCC2)cc1-c1nnnn1-c1cccc(F)c1F

Procedure:
(E)-tert-Butyl 5-(6-amino-5-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-3,4-dihydro-2H-azepine-1(7H)-carboxylate (14 mg, 29.9 μmol, 1 eq.) was diluted in 1:1 TFA:DCM (1.5 mL) and the mixture stirred at room temperature for 2 hours. The reaction was concentrated and purified by reversed-phase HPLC purification to give 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-((E)-2,5,6,7-tetrahydro-1H-azepin-4-yl)pyridin-2-amine in quantitative yield; 1H NMR (300 MHz, DMSO-d6): 9.0 (br s, 2H); 8.25 (m, 1H); 7.87-7.77 (m, 1H); 7.75-7.6 (m, 2H); 7.6-4.5 (m, 1H); 5.85 (m, 1H); 3.7 (m, 2H); 3.25 (m, 2H); 2.5 (m, 2H); 1.78 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOCC.[OH-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.9 %

Procedure:
1,1,1-Triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (750 mg, 1.77 mmol) was added to a solution of 1-(t-butoxycarbonyl)-4-(hydroxymethyl)piperidine (339 mg, 1.57 mmol, from Procedure 17, Step A) in methylene chloride (10 mL) and the mixture was stirred at rt. After 45 min., and additional portion of 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (150 mg, 0.35 mmol) was added. After an additional 30 min., ether (30 mL) and 1.3 N NaOH (10 mL) were added and stirring was continued for 20 min. The mixture was transferred to a separatory funnel with additional ether (30 mL) and 1.3 N NaOH (15 mL). The organic layer was separated, washed with water (20 mL), dried (sodium sulfate) decanted, and evaporated to give 291 mg of 1-(t-butoxycarbonyl)-4-piperidinecarboxaldehyde as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[Cl:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=2)=[O:33])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCN1CCOCC1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2cccc(Cl)c2)ccc1OCCN1CCOCC1
Reaction time: 8 h
Yield: 27.2 %

Procedure:
A solution of 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (0.040 g, 0.12 mmol) in CH2Cl2 (1 mL) was treated with 3-chlorophenyl isocyanate (0.015 mL, 0.125 mmol). The reaction was stirred overnight, and concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown solid (0.016 g, 27%). LCMS m/z (%)=490 (M+H35Cl35Cl, 100), 492 (M+H35Cl37Cl, 76), 494 (M+H37Cl37Cl, 15). 1H NMR (400 MHz, DMSO-d6) δ: 8.92 (s, 1H), 8.79 (s, 1H), 7.74 (t, J=2.0 Hz, 1H), 7.70-7.63 (m, 1H), 7.57 (dd, J=2.7, 6.3 Hz, 1H), 7.41 (d, J=2.7 Hz, 1H), 7.36-7.28 (m, 2H), 7.21 (d, J=9.0 Hz, 1H), 7.04 (dt, J=1.9, 7.4 Hz, 1H), 4.22-4.15 (m, 1H), 4.11-4.05 (m, 1H), 3.70 (s, 3H), 3.56-3.51 (m, 4H), 2.66-2.48 (m, 2H), 2.42-2.30 (m, 4H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([O:20][CH3:21])[CH:12]=2)=[CH:6][N:5]=1.[Cl-].[Ca+2].[Cl-].C(O)C>[Fe].O>[CH3:21][O:20][C:13]1[CH:12]=[C:11]([O:10][C:7]2[CH:6]=[N:5][C:4]([CH2:3][O:2][CH3:1])=[CH:9][CH:8]=2)[CH:16]=[CH:15][C:14]=1[NH2:17]
Reactant: COCc1ccc(Oc2ccc([N+](=O)[O-])c(OC)c2)cn1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: COCc1ccc(Oc2ccc(N)c(OC)c2)cn1
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of 2-(methoxymethyl)-5-(3-methoxy-4-nitrophenoxy)pyridine (27.0 g), iron (powder, 25.9 g), calcium chloride (1.03 g), ethanol (400 mL) and water (100 mL) was refluxed for 6 h. Then iron (powder, 12.9 g) and calcium chloride (1.03 g) were added to the mixture, and the whole was refluxed for further 2 h. The mixture was cooled to room temperature and filtered with celite. The filtrate was concentrated in vacuo to remove ethanol. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:3 to 3:1, volume ratio) to give the title compound (20.1 g, 83%) as a brown oil. MS 261 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:12])=[C:6]([N:27]2[CH:31]=[CH:30][CH:29]=[CH:28]2)[CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH3:12])=[C:6]([N:27]2[CH:31]=[CH:30][CH:29]=[CH:28]2)[CH:5]=1
Reactant: COc1ccc(CCN(C)CCOc2ccc([N+](=O)[O-])cc2-n2cccc2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(CCN(C)CCOc2ccc(N)cc2-n2cccc2)cc1OC
Yield: 99.1 %

Procedure:
A portion (0.53 g, 1.25 mmol) of the 1-[4-nitro-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane produced in (3) above was dissolved in 50 ml of a 1:1 solvent system of ethyl acetate and methanol and 10% Pd/C (0.15 g) was slowly added to the solution, which was thereafter stirred at ordinary temperatures for 10 min as hydrogen gas was injected. Thereafter, the reaction mixture was filtered through Celite and the filtrate was evaporated, with the residue being purified by being subjected to column chromatography on silica gel using, as an eluent, ethyl acetate containing methanol (10%). The fractions containing the end product were combined and the solvent was evaporated to yield the end compound 1-[4-amino-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (0.49 g) as a yellow oil.
Reaction SMILES: BrCC(CBr)=O.BrC[CH2:9][C:10]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])=O.[NH2:21][C:22]([NH2:24])=[S:23]>CO>[NH2:24][C:22]1[S:23][CH:9]=[C:10]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[N:21]=1
Reactant: NC(N)=S
Reactant: Cc1cc(C)c(C(=O)CCBr)c(C)c1
Agent: O=C(CBr)CBr
Solvent: CO
Product: Cc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 70 %

Procedure:
A solution of 80 g of 2,4,6-trimethylphenyl bromoethyl ketone bromomethylketone and 35 g of thiourea in 250 ml of methanol is refluxed for 3 hours. After cooling the reaction mixture, the precipitate is filtered off and washed abundantly with diethyl ether. After concentration of the filtrate to a third of the initial volume, a second bath of crystals is recovered. Yield: 70%. m.p.=138 168° C. The hydrobromide prepared by the action of HBr in ethanol melts at 295° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[N:14][O:15][CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:17].O1CCOCC1>CO>[ClH:17].[CH3:16][O:15][N:14]=[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CON=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CON=C1CCNCC1
Temperature: 25 °C

Procedure:
4-Methoxyimino-piperidine-1-carboxylic acid tert-butyl ester in MeOH (10 mL) was treated with 4.0 M HCl/dioxane (1.0 mL) and stirred at room temperature over night. The solution was concentrated to yield 213 mg of the title compound without further purification. 1H NMR (DMSO, 300 MHz) δ ppm 2.47 (t, 2H, J=6.62 Hz), 2.68 (t, 2H, J=6.07 Hz), 3.17 (m, 4H), 3.77 (s, 3H), 9.08 (bs, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[N:7][C:2]([N:27]4[CH2:28][CH2:29][N:25]([CH3:24])[C:26]4=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)nn3)CC2)c(C)c1
Yield: 34.7 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 230 and 1-methylimidazolidin-2-one (68 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (62 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:13]([O:15][CH:16]2[CH2:20][CH2:19][CH:18]([C:21](O)=[O:22])[CH:17]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Cl)(=O)C([Cl:35])=O>ClCCl.CN(C=O)C>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:13]([O:15][CH:16]2[CH2:20][CH2:19][CH:18]([C:21]([Cl:35])=[O:22])[CH:17]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(OC1CCC(C(=O)O)C1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(OC1CCC(C(=O)Cl)C1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of 855 mg 3-(SR)-(1-(RS)-(3,5-bis(trifluoromethyl)phenyl)-ethoxy)-2-(RS)-phenylcyclopentane-1-(RS)-carboxylic acid in 20 mL of dry dichloromethane was treated with 2 drops of DMF followed by 0.36 mL of oxalyl chloride. After 1 hour the reaction was evaporated and the residual yellow oil was concentrated twice more from dichloromethane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([SH:11])[C:7]=1[C:8]([OH:10])=[O:9].[OH-].[K+].CS([C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=1)(=O)=O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([S:11][C:18]2[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=2)[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: O=C(O)c1c(S)cccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Sc2cccc(Br)c2C(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
7.0 g of 6-bromothiosalicylic acid was dissolved in 20 ml of an aqueous solution of 4.0 g of potassium hydroxide, and then, 6.9 g of 2-methylsulfonyl-4,6-dimethoxypyrimidine and 20 ml of dimethylformamide were added thereto. The mixture was stirred at room temperature for one hour and poured into a large amount of ice water. The aqueous solution was washed with chloroform and then, neutralized with hydrochloric acid. An oily substance thereby released was extracted with diethyl ether. The diethyl ether layer was dried and passed through a FURORIDIL short column. Diethyl ether was distilled off under reduced pressure to obtain 3.9 g of the desired compound as white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C([Sn](CCCC)(CCCC)[CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH:30]([C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)=[CH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: O=Cc1cc(Br)cs1
Reactant: CCCCCCCCCCC=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC=Cc1csc(C=O)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 4-bromo-2-thiophenecarboxaldehyde (35.0), tetrakis(triphenylphosphine)palladium(0) (4.23 g), 2,6-di-t-butyl-4-methylphenol (a few milligrams) and dry toluene (150 ml) was added tri-n-butyl-1-dodecenylstannane (92.0 g), dropwise at room temperature, under nitrogen. The solution was heated under reflux for four hrs, with stirring. After cooling to room temperature, the solution was filtered through a bed of celite, and the filter cake was washed with ether. The filtrate was evaporated and the residue purified by flash chromatography (silica; 5%, ethyl acetate-hexane). The appropriate fractions were collected and concentrated. The residue was distilled in a kugelrohr oven (170° C./0.3 mm mercury) to give 46.7 g (92%) of product, as an oil (ca. 4:1-trans:cis).