Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:15]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19](=[O:24])[C:16]=2[NH:17][N:18]=1)=[O:13])[CH3:2].[CH3:25]N(C=O)C.CI>CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:15]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19](=[O:24])[C:16]=2[N:17]([CH3:25])[N:18]=1)=[O:13])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCc1cccc(CC)c1NC(=O)c1n[nH]c2c1CCCCC2=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCCCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxamide (1.04 g, 3.211 mmol) in DMF (12 mL) Cs2CO3 (1.255 g, 3.85 mmol) and methyl iodide (0.22 mL, 3.532 mmol) were added. The reaction was stirred at room temperature for 1 h, then AcOEt (60 mL) was added and the organic phase washed with water (3×50 mL). The organic fraction was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (eluant: AcOEt/hexane 1/9) provided 0.99 g (91% yield) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18](Cl)=[O:19])[CH3:2].[Cl:21][C:22]1[C:23]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[C:37]2[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=2)=[CH:24][C:25]([F:29])=[C:26]([NH2:28])[CH:27]=1>C(Cl)Cl.N1C=CC=CC=1>[Cl:21][C:22]1[C:23]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[C:37]2[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=2)=[CH:24][C:25]([F:29])=[C:26]([NH:28][C:18]([C:5]2[C:6](=[O:17])[N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH:8]=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])=[O:19])[CH:27]=1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Cl
Reactant: Cn1cc(-c2cnccc2Oc2cc(F)c(N)cc2Cl)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(Cl)c(Oc2ccncc2-c2cnn(C)c2)cc1F
Yield: 37.7 %

Procedure:
To a solution of 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride (0.275 g, 0.929 mmol) in CH2Cl2 (2 mL) was added a suspension of 5-chloro-2-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine (0.148 g, 0.464 mmol) in pyridine (2.00 mL) at 0° C. The resultant mixture was stirred at ambient temp for 30 min. The solvent was completely evaporated and the residue was stirred in water. The precipitate was collected by filtration and was re-crystallized from acetonitrile to provide N-(5-chloro-2-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.101 g, 37.6% yield) as an off-white solid. The mesylate salt was prepared by treatment with one equivalent of methanesulfonic acid. 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 9.20 (s, 1H), 8.62 (d, J=5.5 Hz, 1H), 8.51 (m, 1H), 8.47 (s, 1H), 8.23 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.75 (d, J=11 Hz, 1H), 7.50 (m, 2H), 7.41 (m, 2H), 7.25 (d, J=2.5 Hz, 1H), 6.60 (d, J=5.5 Hz, 1H), 4.30 (q, J=6 Hz, 2H), 3.92 (s, 3H), 2.30 (s, 3H), 1.30 (t, J=6 Hz, 3H); MS (ESI) m/z: 578.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2.C([Li])CCC.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Cn1ncc2cc(Br)ccc21
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1ccc2c(cnn2C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-bromo-1-methyl-1H-indazole (Aldrich, 1.06 g, 5 mmol) in THF (22 mL) at −78° C. was added n-butyllithium (2.2 mL, 2.5 M, 5.5 mmol) slowly. The mixture was stirred for 20 minutes, and the solution of diethyl oxalate (0.68 mL, 5.0 mmol) in THF (5 mL) was added over one minute period. The reaction was kept at −78° C. for 40 minutes, and was quenched with saturated ammonium chloride solution and warmed to 25° C. The mixture was extracted with ethyl acetate, and the organic phase was washed with water, brine, and dried over sodium sulfate. Concentration and purification with flash column chromatography (hexanes/EtOAc) gave ethyl 2-(1-methyl-1H-indazol-5-yl)-2-oxoacetate. LCMS-ESI+: calc'd for C12H13N2O3: 233.2 (M+H+); Found: 233.0 (M+H+).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][N:17]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25].C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:31]([C:30]3[CH:29]=[CH:28][C:27]([N:17]([CH3:16])[C:18](=[O:26])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[CH:35][CH:34]=3)=[O:32])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Reactant: Cc1ccccc1C(=O)N(C)c1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)N(C)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A mixture of 0.291 g of 6,11-dihydro-5H-dibenz[b,e]azepine, 0.518 g of 4-[N-methyl-N-(2-methylbenzoyl)amino]benzoyl chloride and 0.182 g of triethylamine in 10 ml of tetrahydrofuran is stirred at room temperature for 2 hours. The solvent is removed, the residue diluted with water and extracted with dichloromethane. The extract is washed with 1N HCl water, 1M NaHCO3, brine and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and chilled to give 0.52 g of crystals, m.p. 160°-170° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([S:8]([C:11]1[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=1)(=[O:10])=[O:9])([CH3:7])[CH3:6])[CH3:2].CN1C=CN=C1S.ClC[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:7])([S:8]([C:11]1[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=1)(=[O:10])=[O:9])[CH2:6][C:36]1[CH:37]=[CH:38][C:33]([C:30]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)=[CH:34][CH:35]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)c1nccn1C
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: Cn1ccnc1S
Product: CCOC(=O)C(C)(Cc1ccc(-c2ccccc2)cc1)S(=O)(=O)c1nccn1C

Procedure:
3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-methyl-(1-methyl-1H-imidazolesulfonyl)-propionic acid ethyl ester Prepared from (1-Methyl-2-mercapto imidazole and 2-bromo ethyl propionate) (3.0 g, 12.2 mmol) and 4- chloromethylbiphenyl (2.97 g, 15 mmol). Yield 5.0 g (99%); low melting solid; MS 413 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[C:10](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C(O)c1ccsc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccsc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
2-bromo-3-thiophene carboxylic acid (1.0 eq, 12.56 g, 60.66 mmol) was suspended in CH2Cl2 (200 ml). Oxalyl chloride (1.1 eq, 5.9 ml, 67.16 mmol) and 5 drops of DMF were added, inducing formation of gas. The mixture was stirred overnight at room temperature and the volatiles were removed in vacuo. The resulting solid was suspended in dry methanol (150 ml) and the mixture heated to ebullition. Evaporation of the solvents afforded methyl 2-bromo-3-thiophene carboxylate (13.16 g, 98% yield) as a crude brown oil. LCMS (ES): 99% pure, m/z not detected; 1H NMR (CDCl3, 400 MHz) δ 3.88 (s, 3H), 7.23 (d, J=5.6, 1H), 7.56 (d, J=5.6, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:27][S:28]([C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>ClC1C=CC=CC=1Cl.Cl.COC(C)(C)C>[Cl:1][C:2]1[C:3]([NH:35][C:34]2[CH:33]=[CH:32][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:37][CH:36]=2)=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Agent: Cl
Solvent: COC(C)(C)C
Solvent: Clc1ccccc1Cl
Product: CS(=O)(=O)c1ccc(Nc2c(Cl)cnc3nc(-c4ccc(OCCN5CCOCC5)cc4)[nH]c23)cc1
Temperature: 180 °C
Yield: 26.5 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.02 g, 0.05 mmol) and 4-(methylsulfonyl)aniline (0.1 g) were dissolved in o-dichlorobenzene (0.7 ml) and 4 drops of concentrated HCl were added and the reaction mixture was heated in a microwave oven at 180° C. for 10 min. The reaction mixture was diluted with tert-butyl methyl ether (5 ml) and extracted with 2M HCl (10 ml). The aqueous phase was basified with 10M NaOH and extracted with EtOAc. The organic phase was evaporated in vacuo and the residue was dissolved in CH3CN (2 ml) and purified by HPLC-C is, giving the title product (7 mg, 26%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]=[C:28]=[S:29]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:19][C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[C:28]([NH:27][CH3:26])=[S:29])[CH2:14][CH2:13]1)[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CCNC(=O)OC(C)(C)C)N1CCC(NCc2ccsc2)CC1
Reactant: CN=C=S
Solvent: ClCCl
Product: CNC(=S)N(Cc1ccsc1)C1CCN([C@H](C)CCNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following general procedure H: to ((R)-3-{4-[(Thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (1.0 g, 2.72 mmol) in dry CH2Cl2 (20 ml) was added methylisothiocyanate (223 μl, 3.26 mmol). The reaction mixture was then allowed to stir at room temperature overnight under N2 pressure to yield {(R)-3-[4-(3-methyl-1-thiophen-3-ylmethyl-thioureido)-piperidin-1-yl]-butyl}-carbamic acid tert-butyl ester as yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Br:9])[N:3]=1.[F:10][C:11]([F:18])([F:17])[C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([N:14]2[CH:15]=[CH:16][C:12]([C:11]([F:18])([F:17])[F:10])=[N:13]2)[N:3]=1
Reactant: Cc1cc(Br)nc(Br)c1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)nc(-n2ccc(C(F)(F)F)n2)c1
Temperature: 90 °C

Procedure:
A mixture of 2,6-dibromo-4-methylpyridine (33 mmol, obtained according to the method disclosed by WO 94/22833), 3-trifluoromethyl-1H-pyrazole (21 mmol), potassium carbonate (45 mmol) and N,N-dimethylformamide ((50 mL) is heated at 90° C. for 4 hours. The reaction mixture is partitioned between ethyl acetate ands water. The separated organic phase is washed with brine, dried over sodium sulfate and evaporated in vacuo to provide an oily residue which is purified by flash chromatography. To yield 1.9 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][NH2:24])=[O:22])[C:9]=2[S:25][CH3:26])=[CH:4][CH:3]=1.[C:27](O)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][NH:24][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:22])[C:9]=2[S:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CSc1c(C(=O)NN)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CSc1c(C(=O)NNC(=O)C(C)(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.4 %

Procedure:
To a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(methylthio)-1H-pyrazole-3-carbohydrazide (7) (200 mg, 0.47 mmol), pivalic acid (8) (57 mg, 0.56 mmol) and EDCI (134 mg, 0.70 mmol) dissolved in CH2Cl2 (30 ml) was added DMAP (114 mg, 0.93 mmol) in one portion at room temperature. The reaction mixture was stirred at room temperature for 12 hrs, and then treated with 1N—HCl solution. The organic layer was collected, and evaporated under a vacuum. The crude mixture was further purified by preparative HPLC, to obtain 150 mg (63%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH-].[NH4+:18]>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reaction time: 1 h
Yield: 94 %

Procedure:
A mixture of 37.0 gm. (0.14 mole) of 2-chloro-3,5-dinitrobenzoyl chloride and 100 ml. of concentrated ammonium hydroxide is placed in a mortar, ground for ten minutes and allowed to stand for one hour. The yellow precipitate is removed by filtration and washed with water. There is obtained 32.3 gm (94%) of material melting at 181-3°.
Reaction SMILES: CN([CH:4]=[O:5])C.CS(C)=O.[C:10]1(C)[C:11](C)=[CH:12][CH:13]=[CH:14][CH:15]=1>>[C:15]1([O:5][C:4]2[CH:12]=[CH:11][CH:10]=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)C=O
Reactant: Cc1ccccc1C
Solvent: CS(C)=O
Product: c1ccc(Oc2ccccc2)cc1

Procedure:
Method G illustrates still another means for obtaining intermediate XIII. In this method, substituted propriolate ester XVI is reacted with amidoxime XVII in a suitable solvent (e.g., alcohol, acetonitrile, THF, dimethylsulfoxide (DMSO), acetone, DMF) at about 0° C. to the reflux temperature of the solvent for about 1-48 hours to obtain olefin XVIII wherein when R1 =H, a mixture of cis and trans isomers is obtained, and when R1 =alkyl or aryl, a mixture of E and Z isomers is obtained. Further treatment of olefin XVIII in solvents such as DMF, DMSO, diphenylether, xylene, and the like, at 0° C. to the reflux temperature of the solvent for about 1-48 hours affords intermediate XIII, preferably for 1 hour in diphenylether at 180°-200° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[CH2:23][OH:24])=[CH:17][CH:16]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:27][C@@H:28]([CH2:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:26]>>[C:11]([C:9]1[CH:8]=[C:7]([C:15]2[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[CH2:23][O:24][C:38]3[CH:37]=[CH:36][C:35]([CH2:34][C@H:28]([O:27][CH2:25][CH3:26])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:40][CH:39]=3)=[CH:19][CH:20]=2)[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: CC(C)(C)c1cc(-c2ccc(/C=C/CO)cc2)cc(C(C)(C)C)c1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2ccc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc2)cc1)OCC
Yield: 52 %

Procedure:
The title compound (110 mg, 51%) was prepared as a colourless gum from (E)-3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-prop-2-en-1-ol (127 mg, 0.39 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (99 mg, 0.41 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: FC1C=CC(C(Cl)=O)=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:39][CH:40]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:44]([NH:43][C:41](=[O:42])[C:38]2[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=2)=[S:45])=[C:28]([F:33])[CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1
Agent: O=C(N=C=S)c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (65 mg, yield 83%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([OH:18])=O)[CH2:14][S:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[C:35]([NH2:39])([CH3:38])([CH3:37])[CH3:36]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([NH:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:18])[CH2:14][S:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)N
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A solution of 2.67 g of N-benzyloxycarbonyl-4(R)-thiazolidinecarboxylic acid in 42 ml of dry tetrahydrofuran was stirred and cooled to -15° C. in an ice/salt bath while there were added 1.15 g of N-ethylmorpholine followed after 2 minutes by 1.87 g of isobutyl chloroformate. After a further 3 minutes 0.73 g of tert.butylamine was added dropwise and the mixture was then allowed to warm to room temperature and was stirred overnight. Tetrahydrofuran was removed by evaporation under reduced pressure and the residue was dissolved in dichloromethane. The solution was washed in sequence with water, 10% citric acid solution, water, saturated sodium bicarbonate solution and water, then dried over anhydrous sodium sulphate, filtered and evaporated to give 2.85 g of 3-(benzyloxycarbonyl)-N-tert.butyl-4(R)-thiazolidinecarboxamide as a solid which melted at 96°-98° C. after recrystallization from diethyl ether/n-hexane.
Reaction SMILES: [Li+].[OH-].Br[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]=[C:17]([O:27][C@H:28]4[C@H:32]5[O:33][CH2:34][C@@H:35]([OH:36])[C@H:31]5[O:30][CH2:29]4)[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]3=[CH:12][C:11]=2[Cl:37])=[CH:6][CH:5]=1.[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCOCC1.O>[Cl:37][C:11]1[CH:12]=[C:13]2[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([O:27][C@H:28]3[C@H:32]4[O:33][CH2:34][C@@H:35]([OH:36])[C@H:31]4[O:30][CH2:29]3)=[N:16][C:14]2=[N:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:5][CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(Br)cc3)c(Cl)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 80 °C

Procedure:
LiOH (1.3 ml, 3.90 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (107.7 mg, 0.132 mmol) were added to a stirred solution of (3R,3aR,6R,6aR)-6-[5-(4-bromophenyl)-6-chloro-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (776.2 mg, 1.332 mmol) and phenylboronic acid (201.9 mg, 1.656 mmol) in dioxane (10.5 ml) and water (1.3 ml). The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 80° C. for 20 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (100 ml) and water (100 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give an amber residue. This material was purified by flash chromatography, utilizing a 40 g silica RediSep Rf® column and employing a 0-70% EtOAc/hexane gradient followed by 70% EtOAc/hexane. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a yellow solid. LC-MS: calculated for C30H34ClN3O5Si 579.2 observed m/e: 580.24 (M+H)+ (Rt 1.36/2 min).
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:14]2[CH:15]=[C:16]([C:18]#[N:19])[O:17][C:13]=2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:20][OH:21]>>[Si:1]([O:8][CH:9]1[C:14]2[CH:15]=[C:16]([C:18](=[N:20][OH:21])[NH2:19])[O:17][C:13]=2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2oc(C#N)cc21
Product: CC(C)(C)[Si](C)(C)OC1CCCc2oc(C(N)=NO)cc21

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1d) using 4-{[t-butyl(dimethyl)silyl]oxy}-4,5,6,7-tetrahydro-1-benzofuran-2-carbonitrile (3.0 g, 11 mmol) that was obtained in Example 7 (7c) and a 40% aqueous solution of hydroxylamine (3.0 ml). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:7) as the eluent to afford the title compound (2.7 g) in a yield of 82% as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[NH:23][C:22]([CH:24]=O)=[C:21]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])[CH:20]=1>C(O)C.N1CCCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:24][C:22]2[NH:23][C:19]([CH3:18])=[CH:20][C:21]=2[C:26]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)=[O:27])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: Cc1cc(C(=O)N2CCN(C)CC2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CCN(C)CC2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.7 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-methyl-3-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-fluoro-phenyl)-3-[5-methyl-3-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (44.1 mg, 40%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[CH2:20]Br>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:20][C:19]2[CH:22]=[CH:23][C:24]([N+:25]([O-:27])=[O:26])=[C:17]([F:16])[CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1F
Product: N#Cc1ccc(N(Cc2ccc([N+](=O)[O-])c(F)c2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl) amino]pyrimidine and 3-fluoro-4-nitrobenzyl bromide