Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=5)[S:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=5)[S:24][CH:25]=4)=[CH:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccncc4)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4ccncc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-[2-(4-pyridyl)-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionate (864 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature overnight, and 1N hydrochloric acid (3 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-[2-(4-pyridyl)-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionic acid (771 mg, yield: 94%). This was recrystallized from ethanol. Melting point: 149–150° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:13]([N:17]1[C:25]2[N:24]=[C:23]([Cl:26])[NH:22][C:21]=2[C:20](=[O:27])[N:19]([CH2:28][CH2:29][CH2:30]/[C:31](=[N:34]/[H])/[NH:32]O)[C:18]1=[O:36])[CH2:14][CH2:15][CH3:16]>CN(C=O)C>[CH2:13]([N:17]1[C:25]2[N:24]=[C:23]([Cl:26])[NH:22][C:21]=2[C:20](=[O:27])[N:19]([CH2:28][CH2:29][CH2:30][C:31]2[N:32]=[C:10]([CH2:9][C:4]3[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=3)[O:12][N:34]=2)[C:18]1=[O:36])[CH2:14][CH2:15][CH3:16]
Reactant: [H]/N=C(/CCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCCc2noc(Cc3ccc(O)c(F)c3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C

Procedure:
A mixture of (3-fluoro-4-hydroxyphenyl)acetic acid (27 mg, 0.16 mmol) in DMF (1.5 ml) was treated with CDl (26 mg, 0.16 mmol) and left to react for 45 min. (1Z)-4-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxybutanimidamide (60 mg, 0.18 mmol) was added and the mixture heated in the microwave at 140° C. for 15 min. After cooling, the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated then concentrated and purified by MDAP. The title compound was obtained as a white solid (10 mg, 12%).
Reaction SMILES: [CH:1]12[C:7](=[O:8])[O:6][C:4](=O)[CH:2]1[CH2:3]2.[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([CH2:15][NH:16][NH2:17])=[CH:13][CH:12]=1>C(#N)C>[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([CH2:15][N:16]2[NH:17][C:4](=[O:6])[CH:2]3[CH:1]([CH2:3]3)[C:7]2=[O:8])=[CH:13][CH:12]=1
Reactant: O=C1OC(=O)C2CC12
Reactant: COc1ccc(CNN)cc1
Solvent: CC#N
Product: COc1ccc(CN2NC(=O)C3CC3C2=O)cc1
Temperature: 25 °C

Procedure:
1.0 g (8.92 mmol) 1,2-cyclopropanedicarboxylic acid anhydride is dissolved in 5 ml acetonitrile, 1.5 g (9.86 mmol) 4-methoxy-benzyl-hydrazine dissolved in 5 ml acetonitrile are added dropwise and the mixture is refluxed overnight. During cooling to RT a precipitate is formed, which is filtered off, washed with acetonitrile and dried in the vacuum dryer at 50° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]#[N:12])([O-])=O>[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]#[N:12]
Reactant: N#CCc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: N#CCc1ccccc1N
Reaction time: 2 h
Yield: 55.2 %

Procedure:
A suspension of (2-nitrophenyl)-acetonitrile (30 g, 185 mmol) and 10% palladium on carbon (2 g) in acetic acid (450 mL) was hydrogenated in a Parr apparatus under 30 psi pressure at ambient temperature for 2 hours. The mixture was filtered through a Celite® pad and the filtrate was concentrated in vacuo. The obtained residue was dissolved in ethyl acetate (250 mL). The resulting solution was washed with water (2×100 mL) and saturated sodium chloride (50 mL), and then dried over anhydrous sodium sulfate and concentrated in vacuo to yield product. The crude material was purified by column chromatography (100-200 mesh silica gel) using 8% ethyl acetate in petroleum ether as eluent to afford (2-aminophenyl)acetonitrile (13.5 g, 55%) as a solid. 1HNMR (CDCl3) δ ppm 7.3-7.1 (m, 2H), 6.9-6.7 (m, 2H), 3.7 (br, 2H), 3.5 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:28]([CH3:30])[CH3:29].CN(C=O)C>O>[CH:28]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)([CH3:30])[CH3:29]
Reactant: CC(C)Br
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2coc3cc(OC(C)C)ccc3c2=O)cc1
Reaction time: 3 h
Yield: 94.1 %

Procedure:
A mixture of Formononetin (1, 1.34 g, 5 mmol) (G. Y. Gao, et. al. Bioorg. Med. Chem. 2003, 11, 4069), K2CO3 (0.69 g, 5 mol), 2-bromopropane (1.23 g, 10 mmol) and DMF (10 mL) was refluxed with stirring for 3 hrs (TLC monitoring). The mixture was then cooled and evaporated in vacuo to give a residue which was treated with H2O (50 mL). The precipitate thus obtained was collected, purified by column chromatography (MeOH/CH2Cl2=1:100), and crystallization from EtOH to give 2 (1.46 g, 94% yield). M.p.: 245-246° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].FC1C(C)=C(C2C=CC(C(O)=O)=CC=2COC)C=CC=1.[Cl:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O.[F-].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1.O.CC(OC)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14]
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: OB(O)c1cccc(F)c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COCc1cc(C(=O)O)ccc1-c1cccc(F)c1C
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: COCc1cc(C(=O)OC)ccc1-c1cccc(F)c1Cl
Temperature: 90 °C

Procedure:
A mixture of methyl 4-bromo-3-(methoxymethyl)benzoate (Intermediate 1, Step 2, 3.00 g, 11.6 mmol), 2-chloro-3-fluorophenylboronic acid (2.42 g, 13.9 mmol), cesium fluoride (5.27 g, 34.7 mmol), palladium acetate (52 mg, 0.23 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (285 mg, 0.69 mmol) was prepared in dioxane (30 mL) and water (15 mL), and then heated at 90° C. for 1 hour. Additional amounts of 2-chloro-3-fluorophenylboronic acid (2.42 g, 13.9 mmol), palladium acetate (52 mg, 0.23 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (285 mg, 0.69 mmol) were added, and then the resulting mixture was maintained at 90° C. for 1 additional hour. The reaction mixture was diluted with MTBE (200 mL) and washed with water (2×100 mL) and brine (100 mL). The aqueous layers were extracted with MTBE (100 mL). The organic layers were combined, dried (MgSO4) and treated with activated charcoal. After filtration through a Celite pad, the solution was concentrated under vacuum. After purification by flash chromatography (silica, heptane/EtOAc), the title compound was obtained as a pale yellow oil. HPLC (Method A) Rt 4.9 min (Purity: 99.6%). LC/MS (Method B): 309.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:33][C:34](=[O:41])[C@@H:35](O)[CH2:36][CH:37]([CH3:39])[CH3:38]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([Br:27])[C:22]([O:26][C@H:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:34]([OH:41])=[O:33])=[C:23]([Br:25])[CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br
Reactant: COC(=O)[C@@H](O)CC(C)C
Product: CC(C)C[C@@H](Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br)C(=O)O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-3,5-dibromo-biphenyl-4-ol, and (S)-(−)-hydroxyisocaproic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 81-83° C.; MS m/e 645 (M−H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([C:12]1[CH:13]=[C:14]([OH:20])[C:15]([OH:19])=[CH:16][C:17]=1[CH3:18])(=[O:11])=[O:10].C([O:23][C:24](=[O:28])[CH:25](Cl)Cl)C.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]2[O:19][CH:25]([C:24]([OH:28])=[O:23])[O:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10]
Reactant: CCOC(=O)C(Cl)Cl
Reactant: Cc1cc(O)c(O)cc1S(=O)(=O)c1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1cc2c(cc1S(=O)(=O)c1cc(Cl)ccc1Cl)OC(C(=O)O)O2
Reaction time: 18 h

Procedure:
In a manner analogous to that described in Example 4, 21.3 g (64 mmol) of 4-(2,5-dichlorophenylsulphonyl)-5-methyl-1,2-benzenediol, 10.0 g (64 mmol) of dichloroacetic acid ethyl ester and 44.2 g (320 mmol) of potassium carbonate in 160 ml of 1,2-dimethoxyethane are boiled under reflux. After 18 hours, the reaction mixture is filtered and the solid filtration residue is washed twice with 1,2-dimethoxyethane. 44 g of fresh potassium carbonate and 10 g of dichloroacetic acid ethyl ester are added to the combined organic solutions and the whole is stirred for 5 minutes using a high-speed stirrer and boiled, while stirring normally, for a further 17 hours. Working up is carried out in a manner analogous to that described in Example 10. After drying carefully, 5-(2,5-dichlorophenylsulphonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is obtained in the form of white crystals having a melting point of 155°-157° (from diisopropyl ether).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1.[O:19]1[CH2:21][CH:20]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:21][CH:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[OH:19])[C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1
Reactant: c1cncc(C2CO2)c1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(n(CC(O)c3cccnc3)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.3 %

Procedure:
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (92 mg, 3.83 mmol) in 5 mL of DMF, 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.3 g, 1.27 mmol) was added and stirred at RT for 5 min. 3-(Oxiran-2-yl)pyridine (232 mg, 1.92 mmol) in DMF (5 mL) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture quenched with ice water, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by reverse phase chromatography to afford 250 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-3-yl)ethanol as the TFA salt.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([OH:27])[C:14]([C:24]([OH:26])=O)=[N:15][C:16]=2[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=[C:10]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH2:50]([O:52][C:53]([C:55]1([NH2:58])[CH2:57][CH2:56]1)=[O:54])[CH3:51].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.[Cl-].[Na+].O.Cl>[CH2:50]([O:52][C:53]([C:55]1([NH:58][C:24]([C:14]2[C:13]([OH:27])=[C:12]3[C:17](=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:15]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:34])[C:10]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:11]3)=[O:26])[CH2:57][CH2:56]1)=[O:54])[CH3:51]
Reactant: O=C(O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCOC(=O)C1(N)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOC(=O)C1(NC(=O)c2nc(-c3cccnc3)c3c(cc(-c4ccccc4)c(=O)n3Cc3ccccc3)c2O)CC1
Reaction time: 0.17 h
Yield: 36.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid (53 mg, 0.118 mmol) and HOBt (26 mg, 0.189 mmol) was dissolved in CH2Cl2 (3 mL). EDC (41 mg, 0.212 mmol) was added, and the resulting mixture was stirred for 10 min. 1-Amino-cyclopropanecarboxylic acid ethyl ester HCl salt (31 mg, 0.189 mmol) and Hunig's base (0.075 mL, 0.425 mmol) were added, and the mixture was stirred overnight. The mixture was diluted with EtOAc and brine, and 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-80% EtOAc/hexanes+1% AcOH) to give 24 mg of the title compound. MS: (+) m/z 561.40 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:20])[CH2:19][CH2:18][C:13]4([O:17]CCO4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[CH3:22]O>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([O:20][CH3:22])[CH2:11][CH2:12][C:13](=[O:17])[CH2:18][CH2:19]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CO
Reactant: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Agent: Cl
Product: COC1(c2ccc3c(c2)OCO3)CCC(=O)CC1
Yield: 70 %

Procedure:
A solution of 8-(1,3-Benzodioxol-5-yl)-1,4-dioxa-spiro[4.5]decan-8-ol (5.0 g, 1.8 mmole) in 100 mL methanol with 1 mL conc. hydrochloric acid was stirred for 22 hr and the solution concentrated in vacuo. The residue was purified by chromatography on silica eluting with ethyl acetate-hexane (1:19) to give the product (70%, mp: 84°-85° C.).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH2:17][OH:18].Cl[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH2:17][O:18][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1
Reactant: OCc1nc2c(N3CCOCC3)ccnn2c1Br
Reactant: Clc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1c(COc2ccc3ccccc3n2)nc2c(N3CCOCC3)ccnn12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of compound 83a (1 g, 3 mmol) and 2-chloroquinoline (780 mg, 4.76 mmol) in N,N-dimethylformamide (20 mL), 60% sodium hydride (200 mg, 5.00 mmol) was added in portions. The reaction mixture was stirred overnight at 80° C. and quenched by the addition of 20 mL of water. The solids were collected by filtration to afford compound 83b as a white solid. Mass Spectrum (LCMS, ESI pos.) Calcd. For C20H18BrN5O2: 440.1 (M+H). Found 440.2.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.Cl.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:30]3[CH2:31][CH2:32][N:27]([CH2:26][C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)[CH2:28][CH2:29]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: c1csc(CN2CCNCC2)c1
Agent: Cl
Product: O=C(N1CCN(Cc2cccs2)CC1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 18.5 %

Procedure:
The title compound of Example 2 (0.93 g, 3.20 mmol) was reacted with the product of Example 52 (0.57 g, 3.20 mmol) by the method of Example 4 with the modification described in Example 32. Following chromatographic separation, 0.26 g of the white solid title product was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[C:14](=[O:32])[CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:39]1[CH:43]=[CH:42][N:41]=[CH:40]1>CN(C=O)C>[N:39]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([S:9]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)[C:14](=[O:32])[CH2:13]3)(=[O:11])=[O:10])=[CH:5][CH:4]=2)[CH:43]=[CH:42][N:41]=[CH:40]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(CBr)cc3)CC2=O)CC1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(Cn4ccnc4)cc3)CC2=O)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A mixture of 4-[4-(bromomethyl)benzenesulfonyl]-1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (430 mg), potassium carbonate (112 mg) and imidazole (83 mg) in DMF (15 ml) was stirred at 70° C. for 1 hour. The reaction solution was concentrated, and to the residue was added water. The mixture was extracted with ethyl acetate, washed with water, sodium bicarbonate solution and brine, dried and concentrated, and the residue was recrystallized from ethyl acetate/hexane to give colorless crystals of 4-[4-(1H-imidazol-1-ylmethyl)benzenesulfonyl]-1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (421 mg).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[CH:25]1[C:34]2[C:29](=[C:30]([NH:35]N)[CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][N:26]=1>>[CH:25]1[C:34]2[C:29](=[C:30]([N:35]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)[CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][N:26]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Reactant: NNc1cccc2cnccc12
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4cnccc34)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-16) and isoquinolin-5-yl-hydrazine according to the method described for example 43. MS: M=444.5 (M+H)+
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:17]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=3)[CH2:12][CH2:11]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: c1ccc(C(CCN2CCCNCC2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1ccc(C(CCN2CCCN(Cc3ccc4ccccc4n3)CC2)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
The resulting 1-(3,3-diphenylpropyl)homopiperazine was dissolved in 3 mL of ethanol, mixed with 228 mg of 2-(chloromethyl)quinoline hydrochloride and 141 mg of potassium carbonate, and stirred at 70° C. for 14 hours. The mixture was cooled to room temperature and the ethanol was removed under reduced pressure, 20 mL of aqueous 2N sodium hydroxide was added and the mixture was extracted with 20 mL×2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate/methanol 95:5), to obtain 109 mg of the titled compound. This was treated with a hydrogen chloride solution in ether and the solvent was removed under reduced pressure and the residue was dried to give the hydrochloride salt of the titled compound.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][CH:12]2[O:16][CH2:15][CH2:14][O:13]2)[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:17][N:18]([CH3:22])[C:19]([N:7]1[C:8]([S:10][CH2:11][CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:20]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)c1n[nH]c(SCC2OCCO2)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)n1nc(C(C)(C)C)nc1SCC1OCCO1

Procedure:
3-t-Butyl-5-(1,3-dioxolan-2-yl-methylthio)-1H-1,2,4-triazole (7 g, 28.8 mmole), 2.8 ml (30.5 mmole) of dimethylcarbamoyl chloride, 8 ml (57 mmole) of triethylamine and 0.5 g (4.1 mmole) of 4-dimethylaminopyridine were dissolved in 50 ml of tetrahydrofuran (THF). The mixture was refluxed for four hours, concentrated in vacuo and partitioned between methylene chloride and dilute hydrochloric acid. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Chromatography on silica gel using ethyl ether/hexane gave 1-dimethylcarbamoyl-3-t-butyl-5-(1,3-dioxolan-2-yl-methylthio)-1H-1,2,4triazole, an oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH:27]=O>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:27][C:26]1[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: COc1cc(C=O)cc(OC)c1OC
Product: COc1cc(C=CC(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and 3,4,5-trimethoxybenzaldehyde (124 mg, 0.633 mmol) similar to Example 6 and isolated as a bright yellow solid (120 mg, 38%), 1H NMR (CDCl3): 7.65 (d, J=15.6 Hz, 1H), 7.42 (d, J=15.6 Hz, 1H), 7.34 (d, J=3.3 Hz, 1H), 7.12 (dd, J=3.3, 9.0 Hz, 1H), 6.93 (d, J=9.0 Hz, 1H), 6.85 (s, 2H), 4.48-4.34 (m, 4H), 3.90 (d, J=1.8 Hz, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14](=O)[CH3:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14](=[N:18][NH2:19])[CH3:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(=O)c1sc(-c2ccc(Cl)cc2)nc1C
Solvent: CCO
Solvent: O
Product: CC(=NN)c1sc(-c2ccc(Cl)cc2)nc1C
Yield: 90.6 %

Procedure:
In ethanol (10 ml), 1-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]-ethanone (205 mg) prepared in the Step 30-1-1 was dissolved, and hydrazine monohydrate (1.2 g) was added thereto. The mixture was heated under reflux for 21 hours. The mixture was concentrated under a reduced pressure, and then water was added thereto. The precipitated crystal was separated by filtration, washed with water, and dried to give the title compound (196 mg, 91%).