Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:35][C:32]2[CH:33]=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: COc1ccc(N)cn1
Product: COc1ccc(NC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)cn1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 6-methoxypyridin-3-amine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(6-methoxypyridin-3-yl)terephthalamide. MS (Q1) 493 (M)+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[S-2].[Na+].[Na+].[N+:9]([C:12]1[CH:13]=[C:14]([O:21][CH3:22])[CH:15]=[C:16]([N+:18]([O-])=O)[CH:17]=1)([O-:11])=[O:10]>O.CO>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([NH2:18])[CH:17]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=1
Reactant: COc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [S-2]
Solvent: CO
Solvent: O
Product: COc1cc(N)cc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 93.2 %

Procedure:
Sodium bicarbonate (5.62 g, 66.87 mmol) was added to a solution of sodium sulfide (5.5 g, 70.58 mmol) in deionized water (60 mL). When the sodium bicarbonate was completely dissolved, methanol (50 mL) was added, and the solution was cooled to 0° C. A precipitate formed, which was removed by filtration through a Celite pad. The filtered solution was added quickly to a solution of 3,5-dinitroanisole (7.36 g, 37.15 mmol) in methanol (50 mL). The resulting suspension was heated to reflux for 30 min and then the solution was concentrated in vacuo to remove methanol. The aqueous residue was poured into 200 mL of ice-water, and the resulting orange precipitate was collected by filtration. After air-drying, 3-methoxy-5-nitro-phenylamine (5.82 g, 93%) was obtained as light brown solid: ES(+)-HRMS m/e calculated for C7H8N2O3 (M+H)+ 169.0608, found 169.0608.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[CH:18]=[N:17][N:16]=4)=[N:8][C:7]=3[C:6]=2[CH:28]=1.CC1(C)C2[C:51](=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:50]C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(N(CC)CC)C.[C]=[O:79]>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:19]1[CH:18]=[N:17][N:16]=[C:15]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:5]3[CH:4]=[CH:3][C:2]([C:51]([OH:50])=[O:79])=[CH:28][C:6]=3[C:7]=2[N:8]=1
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: Fc1ccc(-n2cnnc2-c2nc3c(s2)CCOc2ccc(Br)cc2-3)c(F)c1
Reactant: [C]=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)c1ccc2c(c1)-c1nc(-c3nncn3-c3ccc(F)cc3F)sc1CCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 9-bromo-2-[4-(2,4-difluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (250 mg) in methanol (0.50 mL) was added palladium acetate (6 mg), XANTPHOS (31 mg) and triethylamine (2 mL) and the reaction heated at 70° C. under a balloon of carbon monoxide for 16 h. After cooling to room temperature, the mixture was filtered through Celite, washing with ethyl acetate. The filtrate was reduced in vacuo and redissolved in THF (8 mL) and ethanol (4 mL). Sodium hydroxide solution (43 mg in 4 mL of water) was added and the reaction stirred at room temperature for 16 h. The reaction was then acidified with 2 M hydrochloric acid and the resulting solid was filtered and air-dried to give 2-[4-(2,4-difluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-9-carboxylic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.[F-:23].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O>[F:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1
Reactant: BrCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CCOC(C)=O
Product: FCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-[4-(7-Bromoheptyloxy)phenyl]bromobenzene (0.25 g) in a solution of tetra n-butylammonium fluoride (tetrahydrofuran solution, 1M 2.9 ml) was heated to 50° C. for 2 hours. After cooling to ambient temperature, the solution was taken up into a mixture of ethyl acetate (20 ml) and water (20 ml). The separated organic layer was washed with water, brine, and dried over magnesium sulfate. Evaporation gave a residue which was chromatographed on silica gel (30 ml) eluting with a mixture of n-hexane and ethyl acetate (100:0-97:3, V/V). The fractions which contained the objective compound were collected and evaporated a residue which was triturated with n-hexane to give 4-[4-(7-Fluoroheptyloxy)phenyl]bromobenzene (104 mg).
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][OH:13])=[C:10](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1>C1COCC1>[CH3:34][O:33][C:31](=[O:32])[C:28]1[CH:27]=[CH:26][C:25]([O:13][CH2:12][C:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][O:9][C:10]=2/[CH:14]=[CH:15]/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:30][CH:29]=1
Reactant: OCc1c(-c2ccccc2)noc1/C=C/c1ccccc1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2/C=C/c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
A stirred solution of [3-phenyl-5-((E)-styryl)-isoxazol-4-yl]-methanol (1.50 g, 5.4 mmol) in THF (50 mL) was cooled in an ice bath. Sodium hydride (0.28 g of a 55% dispersion in mineral oil, 6.4 mmol) was added and the mixture was stirred for 30 min whilst allowing to warm to room temperature. To the resulting suspension was added methyl 6-chloropyridine-3-carboxylate (0.93 g, 5.4 mmol). After stirring for 2 h the reaction mixture was quenched with aqueous saturated sodium bicarbonate solution (20 mL). Evaporation of the organic solvent was followed by extraction with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, concentrated and purified by chromatography (silica, heptane:ethyl acetate=90:10 to 60:40) to afford the title compound as an off-white solid (0.78 g, 35%). MS: m/e=413.5 [M+H]+.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1([NH:10]C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3]>C(OCC)(=O)C>[Cl-:1].[CH2:2]([O:4][C:5]([C:7]1([NH3+:10])[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1(NC(=O)OC(C)(C)C)CC1
Reactant: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1([NH3+])CC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A saturated solution of HCl in ethyl acetate (20 mL) was added under nitrogen to a solution of 1-[[(1,1-dimethylethoxy)carbonyl]amino]cyclopropane carboxylic acid ethyl ester (10.07 g, 43.9 mmol), prepared in the previous step, in 20 mL of ethyl acetate at room temperature. After the addition, the reaction was stirred at room temperature for 1 h. The solid present was collected by filtration, rinsed with ethyl acetate and dried under reduced pressure to give 1-ethoxycarbonyl-cyclopropyl-ammonium chloride as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21][CH2:20][CH2:19]2)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[CH2:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:13](=[O:14])[CH2:12][N:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=3)=[O:34])=[CH:24][CH:23]=2)[CH2:19][CH2:20]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NCC(=O)N(CC(=O)Nc1ccc2c(c1)CCC2)c1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)Nc2ccc3c(c2)CCC3)c2ccccc2)c1
Yield: 19.4 %

Procedure:
The procedure is analogous to that described in Example 1, but 3.0 g of 2-(2-amino-N-phenylacetamido)-N-(5-indanyl)acetamide and 1.2 g of 3-methylphenyl isocyanate are used as the starting material. After recrystallization from acetonitrile, 0.8 g of N-(5-indanyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 210° C. is obtained.
Reaction SMILES: [P:1](Cl)(Cl)([S:3][CH2:4][CH2:5][CH3:6])=[O:2].C([N:11]([CH2:14][CH3:15])CC)C.[F:16][C:17]1([F:27])[C:21]([F:23])([F:22])[C:20]([F:25])([F:24])[CH2:19][CH:18]1[OH:26].C(N)C>CCCCCC.C(Cl)Cl>[CH2:14]([NH:11][P:1](=[O:2])([S:3][CH2:4][CH2:5][CH3:6])[O:26][CH:18]1[CH2:19][C:20]([F:24])([F:25])[C:21]([F:22])([F:23])[C:17]1([F:27])[F:16])[CH3:15]
Reactant: CCCSP(=O)(Cl)Cl
Reactant: CCN(CC)CC
Reactant: OC1CC(F)(F)C(F)(F)C1(F)F
Agent: CCN
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCSP(=O)(NCC)OC1CC(F)(F)C(F)(F)C1(F)F
Temperature: 20 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
10 g (0.05 mol) of S-propyl dichlorothiophosphate are dissolved in 500 ml of hexane and to the solution there are first added, between 0° and -5° C., 10 ml (0.07 mol) of triethylamine, and then 10 g (0.052 mol) of 2,2,3,3,4,4-hexafluorocyclopentan-1-ol, dissolved in 25 ml of methylene chloride. The mixture is stirred for 2 hours at 20° C. and 5 g (0.11 mol) of ethylamine are then added dropwise to the reaction mixture at 20° C. To complete the reaction, the mixture is stirred for 24 hours at 20° C., the solid is filtered off, and the solvent is distilled off under reduced pressure. The residue is then purified further by filtration through silica gel (cyclohexane:ethyl acetate=7:3 parts by volume). After the solvent has been distilled off, 8.5 g (47% of theory) of O-(2,2,3,3,4,4-hexafluorocyclopentyl) S-propyl N-ethylthiophosphoramidate of refractive index nD20 =1.4292 are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11])([O-:3])=[O:2].[CH3:12][C:13](=O)CC(=O)C>C(O)C.Cl>[CH3:12][C:13]1[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=2[N:11]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1cccc([N+](=O)[O-])c1N
Agent: Cl
Solvent: CCO
Product: Cc1nc2c([N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
3-Nitrobenzene-1,2-diamine (1.0 g) was dissolved in ethanol (90 mL) and 5N hydrochloric acid (24 mL), and to this solution was added 2,4-pentanedione (1.3 g). The mixture was heated for 3 hours under reflux, cooled down to room temperature and concentrated. To this concentrate was added ethyl acetate, and the mixture was washed successively with saturated aqueous sodium bicarbonate and water, and dried over sodium sulfate to give the title compound (1.1 g).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(Cl)Cl.[CH3:40][C:41]1[O:45][C:44](=[O:46])[O:43][C:42]=1[CH2:47][O:48][C:49](=[O:77])[C@@:50]([CH2:75]O)([CH3:74])[CH2:51][C@H:52]([NH:66][C:67]([C:69]1[NH:70][N:71]=[N:72][CH:73]=1)=[O:68])[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:56][CH:55]=1.CN1CCOCC1>>[CH3:40][C:41]1[O:45][C:44](=[O:46])[O:43][C:42]=1[CH2:47][O:48][C:49](=[O:77])[C@@:50]([CH2:75][O:15][C:13](=[O:14])[C@@H:9]([NH2:8])[CH:10]([CH3:11])[CH3:12])([CH3:74])[CH2:51][C@H:52]([NH:66][C:67]([C:69]1[NH:70][N:71]=[N:72][CH:73]=1)=[O:68])[CH2:53][C:54]1[CH:55]=[CH:56][C:57]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:58][CH:59]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1oc(=O)oc1COC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1oc(=O)oc1COC(=O)[C@](C)(COC(=O)[C@@H](N)C(C)C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
N-(t-Butoxycarbonyl)-L-valine (75 mg, 340 μmol), HOBt (47 mg, 0.34 mmol), EDCI (0.061 mL, 0.34 mmol), and DCM (1.8 mL, 29 mmol) were combined and stirred for 15 minutes. (2S,4R)-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester (150 mg, 290 μmol) and 4-methylmorpholine (38 μL, 340 μmol) were added, and the resulting mixture was stirred at room temperature for 3 hours, then evaporated. The crude material was purified by reverse phase column ((Interchim reverse phase chromatography column) to yield the title compound (60.8 mg; purity 98%) as a white solid. MS m/z [M+H]+ calc'd for C32H37N5O8, 620.26. found 620.3.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[C:10]1([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:23]=O>O1CCOCC1>[C:17]1([N:16]([CH2:23][CH2:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)=[O:3])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=O
Reactant: CC(=O)c1ccccn1
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C(CCN(c1ccccc1)c1ccccc1)c1ccccn1

Procedure:
2-acetylpyridine (121 mg), diphenyl amine (169 mg), and paraformaldehyde (40 mg) were reacted in dioxane (0.2 ml) at 130° C. for 2 hours.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][O:5]1.Cl.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C.C(O)CO>CO>[ClH:1].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][CH2:6][O:5]2)[CH2:25][CH2:24]1
Reactant: ClCCC1OCCc2ccccc21
Reactant: Clc1ccccc1N1CCNCC1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: OCCO
Product: Clc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1

Procedure:
A mixture of 1-(2-chloroethyl)isochroman (LXIV, PREPARATION 2, 0.497 g, 2.53 mmol), 1-(2-chlorophenyl)piperazine dihydrochloride (XI, 0.952 g, 3.79 mmol), diisopropylethylamine (1.76 ml, 10.1 mmol) and ethylene glycol (5 ml) is heated at 100° for 16 hr. After cooling, the mixture is partitioned between ethyl acetate and saline. The organic phase is dried over magnesium sulfate, concentrated, and the residue chromatographed on silica gel eluting with methanol/dichloromethane (2/98) to give a material which is taken up in several mls of methanol. Methanol saturated with hydrochloric gas (6 ml) is added. After standing for several minutes, the mixture is concentrated under reduced pressure. Several mls of methanol are added back, followed by ether. The resulting solid is collected, washed with ether, and dried under vacuum to give the title compound; mp 197°-198°; MS ((m/z)) 356; IR (mineral oil) 1093, 1481, 743, 2436 and 2426 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[CH2:13]1CCN2C(=NCCC2)CC1.CI>CN(C=O)C.CCOCC>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]/[C:6]([O:8][CH3:13])=[O:7]
Reactant: Cc1ccccc1C=CC(=O)O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccccc1C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To 2-methylcinnamic acid (100 g; 617 mmol) in 1.2L of DMF was added DBU (112.6 g; 740 mmol) and 15 min later methyl iodide (131.3 g; 925 mmol) and left overnight. The solution was diluted in ether and washed with HCl (10%), H2O and brine. The solvent was removed to give 106.8 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[C:20]([NH:22][NH2:23])=[O:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:24].C([O:28][CH2:29][CH3:30])(=O)C>>[C:20]([C:16]1[CH:15]=[C:12]([CH:11]=[CH:30][C:29]=1[OH:28])[C:13]([NH:23][NH:22][C:20]([C:16]1[O:17][CH:18]=[CH:19][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)=[O:21])=[O:24])#[N:22]
Reactant: NNC(=O)c1occc1-c1ccc(OCc2ccccc2)cc1
Reactant: O
Reactant: CCOC(C)=O
Product: N#Cc1cc(C(=O)NNC(=O)c2occc2-c2ccc(OCc3ccccc3)cc2)ccc1O

Procedure:
A mixture of 3-(4-benzyloxyphenyl)-2-furancarboxylic acid hydrazide (compound of Reference Example 79, 0.44 g) and the compound of Reference Example 63 (0.50 g) in ethyl acetate (10 ml) was heated at reflux overnight while stirring. Water was added to the reaction solution, and the thus-precipitated crystals were collected by filtration and recrystallized from ethyl acetate, thereby giving 0.29 g of the desired compound. Melting point: 208-209° C.
Reaction SMILES: [C:1]1(C)[C:2]([S:7]([CH2:10][N+:11]#[C-:12])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[H-].[Na+].Br[C:17]([CH3:19])=[CH2:18].[CH3:20]S(C)=O>C(OCC)C>[N+:11]([CH:10]([S:7]([C:2]1[CH:1]=[CH:6][C:5]([CH3:20])=[CH:4][CH:3]=1)(=[O:8])=[O:9])[CH:17]([CH3:19])[CH3:18])#[C-:12]
Reactant: C=C(C)Br
Reactant: CS(C)=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: [C-]#[N+]C(C(C)C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution toluenesulfonylmethyl isocyanide (53 mg, 0.271 mmol) in DMSO (0.27 mL) and diethyl ether (0.27 mL) at room temperature was added NaH (60% suspension in oil, 21.71 mg, 0.543 mmol) in one portion as a solid. The resulting mixture was stirred for 20 min at room temperature after which time 2-bromopropene (0.038 mL, 0.407 mmol) was added and the reaction was stirred at for 1 h and then quenched by addition of water (8 mL) and extracted with EtOAc (8 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-30% EtOAc/Heptane) to afford 1-((l-isocyano-2-methylpropyl)sulfonyl)-4-methylbenzene (41 mg, 0.173 mmol, 64% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (d, J=7.1 Hz, 2H), 7.42 (d, J=7.1 Hz, 2H), 4.34 (s, 1H), 2.74 (s, 1H), 2.48 (s, 3H), 1.19 (dd, J=19.1, 6.6 Hz, 6H).
Reaction SMILES: [F:1][C:2]1([F:60])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39](N5CCOCC5)=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:48]([F:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[CH2:4][CH2:3]1.Cl.C(=O)([O-])[OH:63].[Na+].[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1([F:60])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([OH:63])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:48]([F:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[CH2:6][CH2:7]1
Reactant: O=C([O-])O
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(N6CCOCC6)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To 4.30 g (5.13 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-{1-[5-(morpholin-4-yl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 12, 14 ml of conc. hydrochloric acid, 36 ml of methanol and 40 ml of 1,4-dioxane were added, and the reaction solution was stirred at 70° C. for 1.5 hours. After completion of the reaction, the reaction solution was poured into 200 ml of saturated sodium hydrogencarbonate aqueous solution to which 14 ml of 6 N sodium hydroxide aqueous solution had been added and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=3/1-2/1 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. Toluene was added to the obtained residue and the precipitate was obtained by filtration to provide 2.60 g of the title compound as a white solid (yield: 78%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](CN)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:13]([O:19]C(=O)C(C)(C)C)(=O)[C:14]([CH3:17])([CH3:16])[CH3:15].[N:26]1C=CC=C[CH:27]=1>CN(C)C1C=CN=CC=1>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([N:26]([CH3:27])[C:13](=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: c1ccncc1
Reactant: NCC1CCC2(CC1)OCCO2
Reactant: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Agent: CN(C)c1ccncc1
Product: CN(C(=O)C(C)(C)C)C1CCC2(CC1)OCCO2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of (1,4-dioxaspiro[4,5]dec-8-yl)methylamine (11.0 g) in pyridine (64 ml) were added 4-dimethylaminopyridine (catalyst quantity) and pivalic acid anhydride (26.0 ml), and stirred at 90° C. for 2 hours. After completion of the reaction, the solvent was evaporated, ethyl acetate was added thereto, and sequentially washed with 1 N hydrochloric acid aqueous solution, 1 N aqueous solution of sodium hydroxide, and saturated brine. The organic layer was dried over sodium sulfate, then the solvent was evaporated, and the obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (12.9 g) as a pale brown oil. MS (ESI) m/z: 256 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([CH2:13][CH:14]=[CH2:15])[C:8](OCC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[C:1]1([CH:7]([CH2:13][CH:14]=[CH2:15])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCC(C(=O)OCC)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(CO)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.4 %

Procedure:
A solution of 6.0 g of ethyl 2-phenyl-4-pentenoate in 10 ml of tetrahydrofuran is added dropwise to a stirred suspension of 2.0 g of lithium aluminum hydride in 40 ml of tetrahydrofuran at room temperature. The resulting mixture is stirred at 40°-45° C. for 2 hours. Under ice-cooling, water (10 ml) is added dropwise to the reaction mixture in order to decompose the unreacted lithium aluminum hydride. The mixture is poured into 200 ml of ice-cold water and extracted with 200 ml of benzene. The extract is washed with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel with chloroform eluate to give 2.4 g of 2-phenyl-4-penten-1-ol as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH2:11])[C:8]=1[C:9]#[N:10].CCO[CH2:15][CH3:16]>[N+](C1C=CC=CC=1)([O-])=O.C1(=O)CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:8]=1[C:9]([NH2:10])=[C:15]1[C:16]([CH2:4][CH2:3][CH2:8][CH2:7]1)=[N:11]2
Reactant: COc1cccc(N)c1C#N
Reactant: CCOCC
Solvent: O=C1CCCCC1
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cccc2nc3c(c(N)c12)CCCC3
Temperature: 125 °C

Procedure:
6-Methoxyanthranilonitrile (14.0 g) was dissolved in nitrobenzene (150 ml) and cyclohexanone (18.45 g), and freshly fused zinc chloride (25.6 g) was added. The reaction mixture was warmed at 125° C. for 1.5 hr, cooled to room temperature, and poured into ether (1 l). The solid was collected, washed with ether, and distributed between 2-butanone and ammonium hydroxide. The organic phase was washed with brine, dried, filtered, and evaporated. The residue was recrystallized two times from ethyl acetate to give 13.7 g (63.8%), mp 187°-188° C.