Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[CH:5]=[CH:6][C:7]=1I.[F:21][C:22]1[CH:27]=[CH:26][C:25](OB(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.O.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1
Reactant: Fc1cc(CCc2ccc3ccccc3c2)ccc1I
Reactant: OB(O)Oc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2ccc(CCc3ccc4ccccc4c3)cc2F)cc1
Reaction time: 4 h

Procedure:
A mixture of 7.00 g (=18.61 mmol) of the above 2-[2-(3-fluoro-4-iodophenyl)ethyl]naphthalene, 3.12 g (=22.30 mmol) of 4-fluorophenylboric acid, 3.86 g (=27.93 mmol) of K2CO3, 1.50 g (=4.65 mmol) of tetrabutylammonium bromide, 0.39 g (=0.56 mmol) of dichlorobis(triphenylphosphine)palladium(II), 0.30 g (1.12 mmol) of triphenylphosphine and 60 ml of a mixed solvent of toluene/water/ethanol in a ratio of 1:1:1 was stirred for 4 hours with reflux. The reaction mixture obtained was extracted thrice with toluene, and then the extract was washed thrice with water and dried with anhydrous MgSO4. After the solvent was evaporated under a reduced pressure, the obtained orange solid of 8.48 g was purified with silica gel chromatography using heptane/toluene in a ratio of 5:1 as the eluent to obtain a white solid of 7.37 g, which was further recrystallized using a mixed solvent of Solumix/heptane in a ratio of 1:1 to obtain the target compound in an amount of 5.02 g. The product was characterized as the target compound based on results of various instrumental analyses, and the phase transition of the product is notated as “C 108.1 I”.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of (5R)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1019, 25.2 g, 74.8 mmol) in methylene chloride (CH2Cl2, 150 mL) was treated with triethylamine (TEA, 15.15 g, 20.9 mL, 150 mmol, 2.0 equiv) at 25° C., and the resulting mixture was cooled down to 0-5° C. before methanesulfonyl chloride (MsCl, 10.28 g, 6.95 mL, 89.7 mmol, 1.2 equiv) was dropwise introduced into the reaction mixture at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 1 h under N2. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with H2O (100 mL) and CH2Cl2 (100 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (100 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the crude, (5R)-methanesulfonic acid 3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester (1020, 30.71 g, 31.04 g theoretical, 98.9%) as off-white powders, which was found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1020: C11H11FINO5S, LCMS (EI) m/e 416 (M++H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:19]([OH:20])[C:18]2[CH:22]=[CH:23][C:15]([Br:14])=[CH:16][CH:17]=2)[C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(=C(O)c2ccc(Br)cc2)c2ccccc21

Procedure:
Prepared analogously to Example 10(a) from 1-acetyl-2-indolinone and 4-bromo-benzoic acid in dry DMF in the presence of TBTU, HOBT and Hunig's base (20° C., overnight) and final purification by column chromatography on silica gel with CH2Cl2 /MeOH (20:1) as eluant.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)[N:18]=1.C(N(CC)CC)C>O1CCCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([C:17]3[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][N:26]=4)[N:18]=3)[CH2:11]2)=[CH:8][CH:9]=1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: COc1ccc([C@H]2CNCCO2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc([C@H]2CN(c3nc(-c4ccncn4)cc(=O)n3C)CCO2)cc1
Yield: 90.4 %

Procedure:
A solution of (S)-2-(4-methoxyphenyl)morpholine hydrochloride (0.30 g, 1.35 mmol), 2-chloro-3-methyl-6-(4-pyrimidyl)-pyrimidin-4-one (0.40 g, 1.75 mmol) and triethylamine (0.56 ml, 4.05 mmol) in tetrahydrofuran(6 ml) was refluxed for several hours. The reaction mixture was removed in vacuo. The residue was dissolved in 1N hydrochloric acid and extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel with ethyl acetate as the eluent to give the title compound (463 mg, 90%)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1>CCO.O=[Pt]=O>[CH2:1]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: O=C1CCCCN1c1cccc2cnccc12
Agent: O=[Pt]=O
Solvent: CCO
Product: O=C1CCCCN1c1cccc2c1CCNC2
Reaction time: 24 h

Procedure:
33A was hydrogenated at 55 psi in EtOH (20 mL) in the presence of PtO2 (30 mg). After 24 h, the reaction was filtered through Celite® and concentrated to afford 0.4 g of dark oil as desired product. MS (ESI) m/z: 231.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[NH:16][C:17]([C:21](O)=[O:22])=[C:18]([CH3:20])[N:19]=2)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[NH:16][C:17]([C:21]([NH:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:22])=[C:18]([CH3:20])[N:19]=2)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)[nH]c1C(=O)O
Reactant: NCc1cccnc1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)[nH]c1C(=O)NCc1cccnc1
Yield: 63 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methyl-1H-imidazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 63% yield: mp 203-204° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.70 (br s, 1H), 8.58-8.51 (m, 2H), 8.43 (d, J=3.9 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.50-7.29 (m, 6H), 6.23 (dd, J=7.8, 2.6 Hz, 1H), 6.07 (d, J=2.6 Hz, 1H), 5.16 (s, 2H), 4.40 (d, J=6.3 Hz, 2H), 2.47 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.2, 162.9, 162.0, 148.8, 147.8, 137.3, 135.9, 135.6, 135.4, 135.1, 130.8, 128.5, 128.2, 128.0, 127.4, 123.3, 101.6, 97.5, 70.0, 10.5; MS (ES+) m/z 416.3 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1.C(N(CC)CC)C.Cl.[CH2:18]([O:20][C:21]([NH:23][C:24]1([CH2:30][N:31]2[CH2:36][CH2:35][N:34]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH:46]=[CH2:47])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[CH2:33][C:32]2=[O:48])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:22])[CH3:19]>C(O)C>[CH2:18]([O:20][C:21]([NH:23][C:24]1([CH2:30][N:31]2[CH2:36][CH2:35][N:34]([S:37]([C:40]3[CH:41]=[CH:42][C:43]([CH:46]=[CH2:47])=[CH:44][CH:45]=3)(=[O:38])=[O:39])[CH2:33][C:32]2=[O:48])[CH2:25][CH2:26][N:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=2)[CH2:28][CH2:29]1)=[O:22])[CH3:19]
Reactant: OCc1cc(Cl)ccn1
Reactant: C=Cc1ccc(S(=O)(=O)N2CCN(CC3(NC(=O)OCC)CCNCC3)C(=O)C2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=Cc1ccc(S(=O)(=O)N2CCN(CC3(NC(=O)OCC)CCN(c4ccnc(CO)c4)CC3)C(=O)C2)cc1
Yield: 17.5 %

Procedure:
4-Chloro-2-(hydroxymethyl)pyridine (118 mg), triethylamine (500 mg) and ethanol (15 ml) were added to 1-{1-{[4-ethoxycarbonylamino-4-piperidinyl]methyl}-4-(4-vinylbenzenesulfonyl)-2-piperazinone hydrochloride (200 mg), to react at 150° C. for 15 hours in a sealed tube. The reaction solution was concentrated, a 10% aqueous sodium carbonate solution was added to the residue, the mixture was extracted with dichloromethane, dried, and concentrated. The resulting residue was dried, concentrated, purified by column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1), and crystallized from ether to obtain the title compound (40 mg) as pale yellow crystals.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[CH:23]([C:25]1[C:33]2[C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[O:30][C:29]=2[CH:28]=[C:27]([Sn:38]([CH3:41])([CH3:40])[CH3:39])[CH:26]=1)=[O:24].S([O-])([O-])(=O)=[O:43].[Na+].[Na+].CCOCC>N1C=CC=CC=1>[C:23]([C:25]1[C:33]2[C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[O:30][C:29]=2[CH:28]=[C:27]([Sn:38]([CH3:41])([CH3:40])[CH3:39])[CH:26]=1)([OH:43])=[O:24]
Reactant: C[Sn](C)(C)c1cc(C=O)c2c(c1)oc1ccccc12
Reactant: O=S(=O)([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: C[Sn](C)(C)c1cc(C(=O)O)c2c(c1)oc1ccccc12
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of tetra-n-butylammonium permanganate (5.1 g, 14.0 mmol) in anhydrous pyridine (35 mL) was transferred via cannula needle into a solution of the stannane 36 (5.0 g, 14.0 mmol) in anhydrous pyridine (35 mL) at 0° C. under a nitrogen atmosphere. The reaction was stirred for 30 min., then saturated aqueous sodium sulfate (50 mL) was added to quench the reaction. The mixture was then poured into ether and the layers separated. The organic layer was washed with 2N aqueous HCl (6 times with 100 mL), water (2 times) and then brine (2 times). The solution was dried with magnesium sulfate, then filtered and concentrated under vacuum to provide 4.8 g (92% yield) of the stannane 37 as a white solid.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=2[S:15][C:14]=1SC.[CH3:24][O:25][C:26](=[O:53])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:38](=[O:39])[CH2:37][S:36][C:35]2=[N:40][C:41]2[CH:46]=[C:45]([C:47](=[O:49])[CH3:48])[CH:44]=[CH:43][C:42]=2[NH:50][CH2:51][CH3:52])=[CH:29][CH:28]=1>>[C:47]([C:45]1[CH:44]=[CH:43][C:42]([NH:50][CH2:51][CH3:52])=[C:41]([N:40]=[C:35]2[N:34]([CH2:33][C:30]3[CH:31]=[CH:32][C:27]([C:26]([O:25][CH3:24])=[O:53])=[CH:28][CH:29]=3)[C:38](=[O:39])[C:37](=[C:14]3[N:13]([CH3:12])[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15]3)[S:36]2)[CH:46]=1)(=[O:49])[CH3:48]
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SCC(=O)N1Cc1ccc(C(=O)OC)cc1
Reactant: CSc1sc2c([n+]1C)CCCC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2SC3=C(CCCC3)N2C)C(=O)N1Cc1ccc(C(=O)OC)cc1

Procedure:
The title compound was prepared in a manner similar to Example 168 by condensing intermediate 3-methyl-2-methylthio-4,5,6,7-tetrahydro-benzothiazol-3-ium p-toluenesulfonate with 4-[2-(5-acetyl-2-ethylaminophenylimino)-4-oxothiazolidin-3-ylmethyl]benzoic acid methyl ester. MS(ESI): 577 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][NH2:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C1CCNCC1.[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])[CH3:28].N.S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][NH:17][S:36]([C:33]3[CH:34]=[CH:35][C:30]([CH:27]([CH3:29])[CH3:28])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: N
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: CC(C)c1ccc(S(=O)(=O)NCC(=O)NCC2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(4-chlorobenzyl)-4-((glycylamino)methyl}piperidine (14.8 mg, 0.05 mmol) in CHCl3 (2 mL) was treated with (piperidinomethyl)polystyrene resin (28 mg, 2.8 mmol/g), 4-isopropylbenzenesulfonyl chloride (1.5 equiv.) and stirred at 25° C. for 16 h. (Aminomethyl)polystyrene was added to scavenge the residual sulfonyl chloride and the reaction mixture was stirred at 25° C. for 16 h. Filtration and concentration afforded 1-(4-chlorobenzyl)-4-[{(4-isopropylphenylsulfonyl)glycyl}aminomethyl]piperidine (compound No. 869) (22.1 mg, 92%): The purity was determined by RPLC/MS (86%); ESI/MS m/e 478 (M++H, C24H32ClN3O3S).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1B(O)O>>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(Cl)cc4Cl)c3)cnc2c1F
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2,4-dichlorobenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(2′,4′-dichloro-2-fluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (4 mg, 3%): m/z (ES+) 434 [MH+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([OH:19])=O)=[CH:12][C:11]=3[CH:20]=2)[CH:2]=1.[CH3:21][N:22]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([NH:34][C:33]4[CH:35]=[CH:36][C:30]([CH2:29][N:22]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[CH3:21])=[CH:31][CH:32]=4)=[O:19])=[CH:12][C:11]=3[CH:20]=2)[CH:2]=1
Reactant: O=C(O)C1=Cc2cc(-c3cccnc3)ccc2OCC1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4cccnc4)ccc3OCC2)cc1)C1CCOCC1
Temperature: 25 °C
Yield: 23.5 %

Procedure:
To a solution of 7-(3-pyridyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15 g), 4-(N-methyl-N-(tetra-hydropyran-4-yl)aminomethyl)aniline (0.12 g) and triethylamine (0.16 ml) in dimethylformamide (50 ml) was added diethyl cyano-phosphate (0.1 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was purified with silica gel column (methanol/ethyl acetate/triethylamine) to give crude crystals, which were recrystallized from ethanol-hexane to give 7-(3-pyridyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)-methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 146) (0.06 g) as colorless crystals.
Reaction SMILES: C1(N([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)C2C=CC=CC=2)C=CC=CC=1>C(O)C>[C:18]1(=[O:19])[C:16]2[CH:15]=[C:14]3[CH:21]=[CH:14][CH:15]=[CH:16][C:21]3=[CH:20][C:17]=2[C:18](=[O:19])[CH2:17]1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: O=C1CC(=O)c2cc3ccccc3cc21
Temperature: 25 °C

Procedure:
Benz[f]indane-1,3-dione was synthesized according to J. Med. Chem., Vol. 16, paragraphs 1334 to 1339 (1973), and 2 g of this sample and 3.1 g of 4-(N,N-diphenylamino)benzaldehyde were heated with stirring in 20 ml of ethanol under reflux for 6 hours. After cooling to room temperature, the obtained crystal was separated by filtration, washed and recrystallized from chloroform-acetonitrile to obtain 4.3 g of Compound (1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11]C)[C@H:7]([CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:6][CH2:5]2.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C@H:7]([CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:6][CH2:5]2
Reactant: CCC(=O)NCC[C@@H]1CCc2cc(Br)c(OC)cc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC(=O)NCC[C@@H]1CCc2cc(Br)c(O)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
A solution of (S)-N-[2-(5-bromo-6-methoxyindan-1-yl)ethyl]propionamide (56.7 g, 174 mmol.) in dichloromethane (400 mL) was cooled to -30° C. To the solution was added dropwise slowly boron tribromide (95.8 g, 382 mmol.). The reaction mixture was stirred for 30 minutes while keeping at temperatures ranging from -20 to -15° C. The reaction mixture was poured into ice-water, which was stirred for further 10 minutes at room temperature. The organic matter was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel column chromatography (ethyl acetate) to afford the title compound (yield 51.12 g, 94%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[O-][Si]([O-])=O.[Mg+2].C1SC2C(NC(CC3SC=CC=3)=O)C(=O)N2C(C(O)=O)=C1C[N+]1C=CC=CC=1>ClCCl.C(OCC)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc([C@H]2CC[C@H](CO)CC2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(C[n+]3ccccc3)CSC12
Agent: O=[Si]([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Temperature: 25 °C

Procedure:
Trimethylsilyl chloride (305.6 g, 2.81 mol) was dropwise added to trans-4-methoxymethyl-1-(4-cyanophenyl)cyclohexane (322.5 g, 1.41 mol), sodium iodide (421.6 g, 2.81 mol) and acetonitrile (2.5 l), with stirring in nitrogen atmosphere at 35° C. over 30 minutes, followed by agitating the mixture for 20 minutes, cooling it down to 10° C., filtering the reaction mixture by suction, pouring the mother liquor in ice water (2 Kg), extracting with chloroform (1.5 l), twice washing the chloroform solution with a 10% by weight aqueous solution of sodium thiosulfate (0.5 l), further three times washing with water (1 l), distilling off chloroform, and three times recrystallizing the residue from toluene (300 ml) for purification to obtain trans-4-(4-cyanophenyl)cyclohexylcarbinol (182.5 g, 0.848 mol). M.P.: 108.5-110.8° C. A solution of this trans-4-(4-cyanophenyl)cyclohexylcarbinol (107.6 g, 0.500 mol) in dichloromethane (0.7 l) was instantaneously added to a solution of pyridinium chlorochromate (161.7 g, 0.750 mol) in dichloromethane (1 l), prepared in advance, with stirring, at room temperature, followed by agitating the mixture at room temperature for 1.5 hour, adding diethyl ether (1 l) to the resulting reaction solution, and subjecting the supernatant to column chromatography using Florisil® (made by Floridin Co., Ltd.) as a filler to obtain trans-4-(4-cyanophenyl)cyclohexylcarbaldehyde (101.2 g, 0.474 mol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26]([OH:28])=O)[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:29]1([NH:32][CH2:33][C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([O:42][CH3:43])[CH:35]=2)[CH2:31][CH2:30]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:25][C:26]([N:32]([CH:29]2[CH2:31][CH2:30]2)[CH2:33][C:34]2[CH:35]=[C:36]([O:42][CH3:43])[CH:37]=[C:38]([O:40][CH3:41])[CH:39]=2)=[O:28])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Reactant: COc1cc(CNC2CC2)cc(OC)c1
Product: COc1cc(CN(C(=O)CN(c2ccc3ncccc3c2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)cc(OC)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with cyclopropyl-(3,5-dimethoxy-benzyl)-amine
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36]CC)=[O:35])[CH:28]=[CH:27]4)=[CH:20][C:19]=2[CH3:39])=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1.Cl.O>O1CCCC1.CO>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([OH:36])=[O:35])[CH:28]=[CH:27]4)=[CH:20][C:19]=2[CH3:39])=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)c(C)c3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(-c2ccc3nc(C(=O)O)ccc3c2)ccc1OCc1c(-c2c(Cl)cccc2Cl)noc1C(C)C
Temperature: 90 °C
Yield: 99 %

Procedure:
A 1 N solution of sodium hydroxide (59.4 μL, 59.4 μmol) was added to ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-3-methylphenyl]-2-quinolinecarboxylate (17.1 mg, 29.7 μmol) in tetrahydrofuran and methanol (1:1, 594.3 μL) and the mixture was heated in the microwave at 90° C. for 10 minutes. After cooling, the mixture was neutralized with 1 N hydrochloric acid (59.4 μL), water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated to give 16.1 mg (99%) of 6-[4-({[3-(2,6-Dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-3-methylphenyl]-2-quinolinecarboxylic acid as a solid. 1H NMR (400 MHz, d6-DMSO): δ 13.37 (br s, 1H), 8.53 (d, J=8 Hz, 1H), 8.28 (s, 1H), 8.18-8.12 (m, 2H), 8.10 (d, J=8 Hz, 1H), 7.66-7.58 (m, 4H), 7.55 (dd, J=9, 7 Hz, 1H), 7.09 (d, J=9 Hz, 1H), 4.91 (s, 2H), 3.52 (septet, J=7 Hz, 1H), 1.98 (s, 3H), 1.36 (d, J=7 Hz, 6H). HRMS C30H24Cl2N2O4 m/z 547.1191 (M+H)+Cal; 547.1198 (M+H)+Obs.
Reaction SMILES: C(C1C(=O)NN=C(C2C=CC(F)=CC=2F)C=1)(O)=O.[CH2:19]([N:23]1[C:28](=[O:29])[C:27]([CH2:30][N:31]2C(=O)C3=CC=CC=C3C2=O)=[CH:26][C:25]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[F:49])=[N:24]1)[CH:20]([CH3:22])[CH3:21]>>[NH2:31][CH2:30][C:27]1[C:28](=[O:29])[N:23]([CH2:19][CH:20]([CH3:21])[CH3:22])[N:24]=[C:25]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[F:49])[CH:26]=1
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2C(=O)c3ccccc3C2=O)c1=O
Agent: O=C(O)c1cc(-c2ccc(F)cc2F)n[nH]c1=O
Product: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN)c1=O

Procedure:
Following the procedure of Example 24 (2), 2-isobutyl-6-(2,4-difluorophenyl)-4-phthalimidomethyl-2H-pyridazin-3-one was reacted to yield the title compound as a slightly yellow oil (yield: 98.4%).