Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[C:32]1[C:41]2[C:36](=[CH:37][C:38]([S:42](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:44])=[O:43])=[CH:39][CH:40]=2)[CH:35]=[CH:34][N:33]=1>>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:23]=1[C:32]1[C:41]2[C:36](=[CH:37][C:38]([S:42]([NH:9][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=3)(=[O:44])=[O:43])=[CH:39][CH:40]=2)[CH:35]=[CH:34][N:33]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: COc1cc(N)ncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1cc(NS(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)nccc3c2)ncn1
Reaction time: 1 h
Yield: 5.6 %

Procedure:
To a vial containing 6-methoxypyrimidin-4-amine (0.063, 0.503 mmol) in 2Me-THF (1 ml) was added lithium bis(trimethylsilyl)amide (237 μl, 0.237 mmol) at −78° C. and stirred for 1 h. To this was then added a solution of perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline-6-sulfonate (Intermediate LLL; 100 mg, 0.182 mmol) in 2Me-THF (1 ml) at −78° C. dropwise and stirred for 1 h. Reaction mixture was quenched with 3 drops of methanol and purified via reverse-phase chromatography with 0.1% NH4OH in ACN and water as mobile phase to obtain 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(6-methoxypyrimidin-4-yl)isoquinoline-6-sulfonamide (0.005 g, 6%) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.77 (d, J=5.77 Hz, 1H) 8.63 (s, 1H) 8.52-8.56 (m, 1H) 7.82-7.89 (m, 2H) 7.77 (d, J=8.80 Hz, 1H) 7.50 (d, J=7.83 Hz, 1H) 7.41 (d, J=8.12 Hz, 1H) 7.28 (br. s., 2H) 3.96 (s, 3H) 3.75 (s, 3H); m/z (ESI) 491.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:44])([F:43])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24]>>[F:19][C:20]([F:43])([F:44])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40][CH2:41][N:16]2[CH2:17][CH2:18][N:13]([C:9]3[CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14][CH2:15]2)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24]
Reactant: c1ccc(-c2ccnc(N3CCNCC3)c2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cc(-c4ccccc4)ccn3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(4-phenyl-pyridin-2-yl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[SH:30]>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:30][C:26]3[NH:25][CH:29]=[CH:28][N:27]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: Sc1ncc[nH]1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3ncc[nH]3)s2)c(C(=O)C2CCCC2)c1
Yield: 34.9 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(1H-imidazol-2-ylsulfanyl)-thiazol-2-yl]-urea (149 mg, 35%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 1H-imidazole-2-thiol (200 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]2[CH:15]=[CH:16][S:17][C:3]=12.Cl.[NH:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C([O-])(=O)C.[Na+]>C(O)CO.C(OC(=O)C)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[CH:15]=[CH:16][S:17][C:3]3=[C:2]([N:27]3[CH2:26][CH2:25][CH:24]([C:20]4[NH:21][CH:22]=[CH:23][N:19]=4)[CH2:29][CH2:28]3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: c1c[nH]c(C2CCNCC2)n1
Reactant: Fc1ccc(-c2cc(Cl)c3sccc3n2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: OCCO
Product: Fc1ccc(-c2cc(N3CCC(c4ncc[nH]4)CC3)c3sccc3n2)cc1
Temperature: 160 °C
Yield: 18 %

Procedure:
A mixture of 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (146 mg, 0.53 mmol), 4-(1H-imidazol-2-yl)piperidine. hydrochloride (U.S. Pat. No. 4,431,653) (100 mg, 0.53 mmole) and sodium acetate (50 mg) in ethylene glycol (10 mL) is stirred and heated at 160° C. for about 16 hours. It is then cooled, diluted with ethylacetate (15 mL), and washed with water (3×15 mL). The organic layer is dried over sodium sulfate, filtered, and concentrated. The residue is purified by preparative thin layer chromatography to give 5-(4-fluorophenyl)-7-(4-imidazol-2-ylpiperidyl)thiopheno[3,2-b]pyridine (36 mg, 18% yield) as a white solid, m.p. 95° C. (compound 1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:31]I.Cl>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:21]([CH3:31])[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nc4ccccc4[nH]3)c2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(-c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of 4-[3-(1H-benzoimidazol-2-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (0.83 g, 2.20 mmol) (obtained as described in method B) and NaH 60% oil (0.11 g, 4.39 mmol) in THF (10 mL) was stirred at room temperature for 1 h. Methyl iodide (0.27 mL, 4.39 mmol) was added and the resulting solution was stirred overnight. Water (15 mL) was added to the reaction solution, then the suspension was neutralized with 1N HCl and extracted with EtOAc (3×40 mL) The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was triturated with Et2O and the solid obtained filtered, to give 0.76 g (88%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:16]([C:17]([OH:19])=[O:18])=[C:5]2[N:6]=[C:7]([O:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH:8]=[CH:9][N:4]2[N:3]=1.CCN(CC)CC.CN(C(O[N:35]1[N:43]=[N:42][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN1C(=O)CCC1>[NH2:1][C:2]1[C:16]([C:17]([O:19][N:35]2[CH:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]3[N:42]=[N:43]2)=[O:18])=[C:5]2[N:6]=[C:7]([O:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CN(C)CCOc1ccn2nc(N)c(C(=O)O)c2n1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN(C)CCOc1ccn2nc(N)c(C(=O)ON3N=NC4C=CC=CC43)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.4 %

Procedure:
To a suspension of 2-amino-5-[2-(dimethylamino)ethoxy]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (80 mg, 0.3016 mmol) in NMP (1 mL) was added Et3N (37.24 mg, 51.29 μL, 0.3680 mmol). To the mixture was added TBTU (Boron Tetrafluoride Ion (1)) (109.0 mg, 0.3396 mmol) portionwise over a 5 minutes. The mixture was allowed to stir at room temperature for 20 minutes before being partitioned between ethylacetate and water. The aqueous layer was extracted twice with ethylacetate and the combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo to afford the product 3a,7a-dihydro-1H-benzo[d][1,2,3]triazol-1-yl 2-amino-5-(2-(dimethylamino)ethoxy)pyrazolo[1,5-a]pyrimidine-3-carboxylate as an oil (92 mg, 80% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=[C:6]([OH:8])[N:7]=1.[C:12]([O:15][C:16](=O)[CH3:17])(=O)[CH3:13]>CO.CN(C)C=O>[CH2:12]([O:15][CH2:16][C:17]1[NH:11][C:9](=[O:10])[C:3]2[C:2](=[N:7][C:6]([OH:8])=[CH:5][N:4]=2)[N:1]=1)[CH3:13]
Reactant: NC(=O)c1ncc(O)nc1N
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: CCOCc1nc2nc(O)cnc2c(=O)[nH]1

Procedure:
Obtained using the procedure described in Example 1, starting with 2.1 g (0.0136 mole) of 3-amino-5-hydroxy-2-pyrazinecarboxamide [prepared according to E. C. Taylor et al., J. Org. Chem. 1975, 40, 2341], 14.0 g (0.068 mole) of triethyl orthoethoxyacetate and 14.0 ml of acetic anhydride. Yld: 1.2 g (40%), m.p. 255°-256° C. (methanol/N,N-dimethylformamide).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].CC([O-])(C)C.[K+]>C1COCC1>[CH:1]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:13][CH2:14][CH2:15][CH2:16][C:17]3=[O:18])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1cccc2cnccc12
Reactant: O=C(Cl)CCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCCCN1c1cccc2cnccc12
Reaction time: 24 h
Yield: 106.2 %

Procedure:
To isoquinolin-5-amine (0.24 g, 1.665 mmol) in THF (5 mL) was added 5-bromopentanoyl chloride (0.223 mL, 1.665 mmol) followed by addition of THF (3 mL). The reaction was cooled with ice bath and to the above solution was added 1M KOtBu in THF (3.66 mL, 3.66 mmol). After 24 h, the reaction was quenched with H2O (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (10 mL) and dried (MgSO4) to afford 0.4 g of 33A as a dark solid. MS (ESI) m/z: 227 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].CCN(C(C)C)C(C)C>CS(C)=O>[CH2:23]([N:25]([CH2:26][CH3:27])[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)[CH3:24]
Reactant: CCNCC
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1nc2cc(C(=O)OC)ccc2nc1-c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.47 mmol) in DMSO (2 mL) was added diethylamine (173 mg, 2.37 mmol) and DIEA (170 mg, 1.32 mmol). The resulting solution was stirred overnight at 70° C. and then quenched by the addition of water/ice (40 mL), extracted with ethyl acetate (3×20 mL), the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. Purification via silica gel column chromatography (0.5%-4% ethyl acetate in petroleum ether) afforded methyl 3-(diethylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (100 mg, 60%).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]2[C:6](=[CH:7][C:8]([N+:20]([O-])=O)=[CH:9][CH:10]=2)[C:5]=1[OH:23])[CH:2]=[CH2:3].C(O)C.[H][H]>CC(C)=O.[Pd]>[CH2:1]([C:4]1[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][C:11]2[C:6](=[CH:7][C:8]([NH2:20])=[CH:9][CH:10]=2)[C:5]=1[OH:23])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCc1c(-c2ccccc2)cc2ccc([N+](=O)[O-])cc2c1O
Agent: [Pd]
Solvent: CCO
Solvent: CC(C)=O
Product: CCCc1c(-c2ccccc2)cc2ccc(N)cc2c1O

Procedure:
14 g of 2-Allyl-3-phenyl-7-nitro-1-naphthol prepared in step (4) were dissolved in 200 ml of acetone. 300 ml of ethanol and one pinchful of a 10% palladium on charcoal catalyst were added. The resulting mixture was hydrogenated at room pressure and temperature until the theoretical amount of hydrogen was absorbed. The catalyst was then removed by filtration and the residual solution was evaporated to dryness under reduced pressure. The resulting crystals were washed with petroleum ether, filtered off and dried under sulfuric vacuum.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[SH:15].Cl[C:17]1[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=1.[OH-].[K+]>CN(C)C=O.O>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[S:15][C:17]1[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=1
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: O=c1ccc(Cl)n[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc(Sc2ccc(Cl)cc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.2 %

Procedure:
Potassium t-butoxide (1.1 g) was added to a solution of 2,4-dichlorothiophenol (1.8 g) in N,N-dimethylformamide (DM F) (5 mL). The mixture was stirred at room temperature for 10 minutes and then 6-chloro 2H-pyridazin-3-one (1.31 g) was added. The reaction mixture was stirred at 100° C. for five hours. The mixture was then cooled to room temperature, poured into water (20 mL) and 20% potassium hydroxide (5 mL) was added. The resulting dark solution was extracted with ethyl acetate (2×10 mL). The aqueous layer was collected and the pH was adjusted to 3 with concentrated hydrochloric acid. The solution was then extracted with ethyl acetate (3×10 mL). The ethyl acetate layer was collected, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a crude product, which was purified by silica gel chromatography (1:1 ethyl acetate/hexane as eluent) to afford 6-(2,4-dichloro-phenylsulfanyl)-2H-pyridazin-3-one (418 mg, 15%); NMR 6.88 (d, 1H), 7.10 (d, 1H), 7.24 (dd, 1H), 7.48 (d, 11H), 7.52 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O-:24][C:25]#[N:26].[K+].O>C(O)(=O)C>[NH2:26][C:25]([N:6]([CH2:5][C:4]1[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=1[O:2][CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:24]
Reactant: COc1ccccc1CNc1ccccc1Oc1ccccc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1CN(C(N)=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.2 %

Procedure:
In 20 ml of acetic acid was dissolved 1.54 g of N-(2-methoxybenzyl)-2-phenoxyaniline synthesized in the same manner as in Example 1(1), and then an aqueous potassium cyanate solution (1.23 g of potassium cyanate and 10 ml of water) was added dropwise to the solution, followed by stirring at room temperature for 2.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:3) to give 1.69 g of N-aminocarbonyl-N-(2-methoxybenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[O:13][CH3:14].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:9][C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]1[CH:11]=[CH:12][C:2]([OH:1])=[C:3]([O:13][CH3:14])[CH:4]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)/C=C/c1ccc(O)c(OC)c1

Procedure:
25 g (0.13 mol) of (E)-4-hydroxy-3-methoxycinnamic acid were dissolved in 180 ml of methanol, and 5 ml of concentrated sulphuric acid were added. The solution was heated under reflux for 2 hours. The main amount of the methanol (about 150 ml) was then distilled off and the residue that remained was poured into 500 ml of ice-water. The precipitated ester was filtered off with suction, washed in succession with cold water, with a small amount of a cold saturated sodium bicarbonate solution and again with cold water and dried at 50° C. under a waterjet vacuum. Chromatography on 250 g of silica gel using dichloromethane/diethyl ether (19:1) yielded 21.78 g of (E)-4-hydroxy-3-methoxycinnamic acid methyl ester in the form of a light-yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[N:5][N:4]([CH2:9][CH2:10][CH2:11][CH2:12]Cl)[C:3]1=[O:14].[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(O)CCC>C(N(CC)CC)C>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[N:5][N:4]([CH2:9][CH2:10][CH2:11][CH2:12][N:25]2[CH2:24][CH2:23][N:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=3)[CH2:27][CH2:26]2)[C:3]1=[O:14]
Reactant: Cn1c(=O)cnn(CCCCCl)c1=O
Reactant: Clc1cccc(N2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Cn1c(=O)cnn(CCCCN2CCN(c3cccc(Cl)c3)CC2)c1=O
Yield: 44.9 %

Procedure:
The compound 4c (5.5 g; 0.025 mol) and 4-(3-chlorophenyl)piperazine (9.83 g; 0.05 mol) are heated for 3 hours in refluxing butanol (150 ml) in the presence of triethylamine (10 ml). The mixture is concentrated to dryness under vacuum, taken up in water and then extracted with ethyl ether (2×50 ml). The dried organic phases (Na2SO4) are concentrated to dryness under vacuum to give an oil which crystallizes from isopropyl ether (70 ml). After recrystallization from 2-propanol and drying under vacuum at 40° C., the compound 4 (4.24 g) is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[NH:10][C:9]1=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][O:20][CH3:21]>>[C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[N:10]([CH2:18][CH2:19][O:20][CH3:21])[C:9]1=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)NC2CCCC21
Reactant: COCCBr
Product: COCCN1C(=O)N(C(=O)OC(C)(C)C)C2CCCC21

Procedure:
The title compound was prepared in accordance with the general method of example 1, step 2 starting from (rac)-(3aSR,6aRS)-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acid tert-butyl ester (Example 1, step 1) and using 1-bromo-2-methoxyethane instead of iodoethane to yield the desired product as a light yellow oil which was directly used in the next step without further characterisation.
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(O[CH:16]1[CH2:20][CH2:19][CH:18](OCC)O1)C>O1CCOCC1>[C:3]1(=[O:12])[N:2]([N:1]2[CH:16]=[CH:20][CH:19]=[CH:18]2)[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]12
Reactant: CCOC1CCC(OCC)O1
Reactant: NN1C(=O)c2ccccc2C1=O
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1n1cccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To 10.0 g(61.7 mmol) of N-aminophthalimide was added a solution of 12 ml(72.4 mmol) of 2,5-diethoxytetrahydrofuran in 100 ml of dioxane and 10 ml of 5 N hydrohloric acid was added thereto. The reaction mixture was stirred for 1 hour and cooled to 5° C. The resulting precipitate was filtered, recrystallized from dioxane:water(1:3), washed with ethanol and dried to give 10.3 g of 1-phthalimidopyrrole. This product was dissolved in 60 ml of methanol and 3 ml of 82% hydrazine hydrate was slowly added thereto. After refluxing the reaction mixture for 30 min, cooled to 0°~5° C. and 1.5 ml of glacial acetic acid was added thereto. The resulting precipitate was filtered off and the filtrate was concentrated under the reduced pressure to remove methanol. The concentrate was washed with diethyl ether and vacuum-distilled to give 2.4 g of the desired compound(47.3%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[CH2:13][CH3:14])[CH2:9][CH:8]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:7]2)(=O)[CH3:2].[H][H]>>[CH2:13]([C:12]1[CH:11]=[C:10]2[C:6](=[CH:5][C:4]=1[CH2:1][CH3:2])[CH2:7][CH:8]([NH:15][C:16](=[O:21])[C:17]([F:19])([F:18])[F:20])[CH2:9]2)[CH3:14]
Reactant: [H][H]
Reactant: CCc1cc2c(cc1C(C)=O)CC(NC(=O)C(F)(F)F)C2
Product: CCc1cc2c(cc1CC)CC(NC(=O)C(F)(F)F)C2

Procedure:
Preferably in Step (v), N-(5-acetyl-6-ethyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide is treated with hydrogen gas to form N-(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide having Formula (XIII)
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Cl:9][C:10](Cl)=[CH:11][C:12]1([CH2:17][CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>CN1CCCC1=O.C(Cl)Cl>[Cl:9][CH:10]=[C:11]([C:12]1([CH2:17][CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13]1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC1(C=C(Cl)Cl)CCCC1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCC1(C(=CCl)Oc2ccccc2)CCCC1
Temperature: 210 °C
Yield: 87.7 %

Procedure:
140 g (4.2 mol) of sodium phenolate in 500 ml of N-methylpyrrolidone were heated to 200° C. 116 g (0.6 mol) of 1-(2,2-dichlorovinyl)-1-ethyl-cyclopentane were added dropwise so slowly that the reaction temperature did not fall below 195° C. The mixture was then stirred for a further hour at 210° C. After the mixture had cooled, it was diluted with methylene chloride and extracted several times by shaking with 2N sodium hydroxide solution. The organic phase, which had been dried over sodium sulphate, was concentrated in vacuo, and the residue was fractionated. 132 g (88% of theory) of 1-chloro-2-(1-ethylcyclopentyl)-2-phenoxy-ethylene of boiling point 115° to 125° C./0.1 mm Hg were obtained. ##STR17##
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[K+].Cl>O.C(O)C>[CH2:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCCBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
12.7 Grams (0.0917 mol) of p-hydroxybenzoic acid, 28.5 g of n-nonyl bromide and 10.2 g of potassium hydroxide were added to a mixture composed of 1,500 ml (milliliter) of ethanol and 200 ml of water, and the mixture was allowed to react under reflux for 10 hours. Further, 500 ml of water was added thereto, and the mixture was stirred for 3 hours. After the completion of the reaction, a concentrated hydrochloric acid was added to acidify the reaction mixture. Thereafter, the solvent was distilled off, and the remaining product was cooled to room temperature and then filtered to give a colorless solid. The solid was fully washed with water and re-crystallized from chloroform to give an intended product (yield 75%).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]([NH2:9])=[N:7][N:8]=2)[CH2:3][CH2:2]1.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:31](=O)[CH2:32][CH2:33][CH3:34])[C:26](OCC)=[O:27])=[CH:20][CH:19]=1)#[N:11]>ClC1C=CC(Cl)=CC=1Cl>[CH:1]1([C:4]2[N:5]=[C:6]3[NH:9][C:26](=[O:27])[C:25]([CH2:24][C:21]4[CH:22]=[CH:23][C:18]([C:13]5[C:12]([C:10]#[N:11])=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:19][CH:20]=4)=[C:31]([CH2:32][CH2:33][CH3:34])[N:7]3[N:8]=2)[CH2:3][CH2:2]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: Nc1nnc(C2CC2)[nH]1
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C3CC3)nn12
Yield: 21.3 %

Procedure:
A solution of 5-cyclopropyl-4H-1,2,4-triazol-3-amine (1 g) and ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (2.8 g) in 1,2,4-trichlorobenzene (20 mL) was stirred at 180° C. for 6 hr. After evaporation of the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.7 g, 21%).