Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20][O:21][CH:22]([O:39][CH3:40])[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33]OS(C)(=O)=O)=[CH:28][CH:27]=1.[I-].[Na+]>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[N:16]([CH2:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][CH:22]([O:39][CH3:40])[O:21][CH3:20])=[CH:31][CH:30]=1)[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CCOc1ccc(CCOS(C)(=O)=O)cc1)OC
Reactant: c1ccc(COc2cccc3cc[nH]c23)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCOc1ccc(CCn2ccc3cccc(OCc4ccccc4)c32)cc1)OC
Reaction time: 0.17 h

Procedure:
A mixture of 4-(2-hydroxyethyl)phenol (1 g), 3-bromopropionaldehyde dimethyl acetal (1.02 mL), cesium carbonate (2.83 g) and a catalytic amount of sodium iodide in acetone (15 mL) was stirred at room temperature overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on aminopropylated silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 3-[4-(2-hydroxy-ethyl)phenyloxy]propionaldehyde dimethyl acetal (1.22 g). This material was dissolved in methylene chloride (15 mL). To the solution were added triethylamine (0.85 mL) and methanesulfonyl chloride (0.43 mL) under ice-cooling, and the mixture was stirred for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with 0.5 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-[4-(2-methanesulfonyloxyethyl)-phenyloxy]propionaldehyde dimethyl acetal (1.49 g). To a solution of 7-benzyloxy-1H-indole (1.04 g) in N,N-dimethyl-formamide (10 mL) was added sodium hydride (55% 0.25 g) under ice-cooling, and the mixture was stirred for 10 minutes. To the reaction mixture were added the above 3-[4-(2-methane-sulfonyloxyethyl)phenyloxy]propionaldehyde dimethyl acetal (1.49 g) and a catalytic amount of sodium iodide, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1-5/1) to give 7-benzyloxy-1-{2-[4-(3,3-dimethoxypropoxy)phenyl]ethyl}-1H-indole. This material was dissolved in tetrahydrofuran (10 mL). To the solution was added 10% palladium-carbon powder (0.5 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (1.57 g).
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:35])[CH:12]([C:19]2[N:20]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[N:21]=[C:22]3[C:27]=2[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([C:36]([F:39])([F:38])[F:37])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([N:20]2[C:19]([CH:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:40])=[O:2])=[CH:5][C:6]=3[C:36]([F:38])([F:37])[F:39])=[O:35])=[C:27]3[C:22]([CH2:23][CH2:24][CH2:25][CH2:26]3)=[N:21]2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-acetylamino}-3-trifluoromethyl-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as brown solid. MS: m/e=558.2 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:6]=[C:5]([C:18]([OH:20])=O)[CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>>[NH:35]1[C:34]([NH:33][C:18]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=3)[N:6]=2)=[O:20])=[N:38][N:37]=[N:36]1
Reactant: COc1cc(C(=O)O)nc(-c2cccc([N+](=O)[O-])c2)c1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc(-c2cccc([N+](=O)[O-])c2)c1
Yield: 62.3 %

Procedure:
In the same manner as described in Example 1-(1), 4-methoxy-6-(3-nitrophenyl)-2-pyridinecarboxylic acid (0.4 g), carbonyldiimidazole (0.22 g) and 5-aminotetrazole (0.15 g) are reacted to give N-(5-tetrazolyl)-4-methoxy-6-(3-nitrophenyl)-2-pyridinecarboxamide (0.31 g). M.P. 269°-272.5° C. (decomp.) (wetted from about 250° C.) (recrystallized from dimethylformamide-ethyl acetate)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[CH:13][O:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C.Cl[Sn]Cl.[OH-].[Na+]>Cl>[O:12]1[CH:13]=[CH:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[N:11]1
Reactant: O=[N+]([O-])c1ccc(-c2ccon2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc(-c2ccon2)cc1
Reaction time: 4 h
Yield: 59.5 %

Procedure:
3-(4-Nitrophenyl)isoxazole (Intermediate 4, 8 g, 42 mmol) was added to acetic acid (126 ml) and then SnCl2 (39 g, 205 mmol) in HCl (42 ml) was added. The reaction was allowed to stir for 4 hours and then 1M NaOH was added to bring the solution to pH˜11. The water layer was extracted with EtOAc and then the organic layers were collected, dried over Na2SO4, and dried under vacuum to yield the product (4 g).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NCc2ccc(N(C)C)cc2)cc1
Yield: 29.1 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-dimethylaminobenzaldehyde (10.0 g) and 4-methoxyaniline (8.25 g) as starting materials, [(4-dimethylaminophenyl)methyl](4-methoxyphenyl)amine (5 g) was obtained. melting point: 92–94° C.
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:9][CH:10]=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Pd].C(O)(C)C>[C:3]1([CH2:9][CH2:10][OH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=CCc1ccccc1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: OCCc1ccccc1
Temperature: 85 °C
Yield: 97.8 %

Procedure:
Anhydrous isopropyl alcohol, 406 grams, aqueous potassium hydroxide, 60 grams of a 4 percent solution, and 1 gram of 3 percent palladium on carbon were charged to a 2-liter stainless steel autoclave. The autoclave was purged with hydrogen and heated to 85° C. The autoclave was pressurized to 1200 p.s.i.g. with hydrogen. Styrene oxide, 765 grams of 97 percent purity, was fed to the stirred autoclave over a 7-hour period at a uniform rate. Hydrogen pressure was maintained at 1100 to 1200 p.s.i.g. by alternately adding fresh hydrogen. Immediately after the adddition of styrene oxide, the reaction mixture was cooled to ambient temperature and analyzed by gas chromatography using an internal standard. The yield 2-phenylethanol was 92.2 percent based on a styrene oxide purity of 97.0 percent. The unrefined reaction mixture contained 1.12 l weight percent phenylacetaldehyde and 0.7 weight percent phenylpropanol-2. A portion of the reaction mixture, 1060 grams, was distilled to give 580 grams of 97.8 percent 2-phenylethanol. This is equivalent to 88.16 percent of the theoretical 2-phenylethanol and a recovery efficiency based on the gas chromatographic analysis of the unrefined product of 95.62 percent.
Reaction SMILES: C([O:3][C:4]([C@@:6]12[CH2:23][C@H:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15](C(OC(C)(C)C)=O)[C:14](=[O:31])[N:13]1[C@@:9](N)([CH2:10][C@@H:11]([O:32][C:33]3[C:42]4[C:37](=[CH:38][C:39]([O:43][CH3:44])=[CH:40][CH:41]=4)[N:36]=[C:35]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:34]=3)[CH2:12]1)[C:8](=[O:52])[NH:7]2)=[O:5])C.[Li+].[OH-:54]>C1COCC1.O.CO>[C:6]([O:54][C:14]([NH:13][C@@H:15]1[C:14](=[O:31])[N:13]2[C@@H:9]([CH2:10][C@@H:11]([O:32][C:33]3[C:42]4[C:37](=[CH:38][C:39]([O:43][CH3:44])=[CH:40][CH:41]=4)[N:36]=[C:35]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH:34]=3)[CH2:12]2)[C:8](=[O:52])[NH:7][C@@:6]2([C:4]([OH:3])=[O:5])[C@@H:22]([CH2:23]2)[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:31])([CH3:23])([CH3:22])[CH3:4]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCC[C@H](C(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@@]1(N)C(=O)N2
Reactant: [OH-]
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C/CCCC[C@H](C(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@@]1(N)C(=O)N2
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)O)C[C@H]5/C=C/CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)cc(-c3ccccc3)nc2c1
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)O)C[C@H]5C=CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)cc(-c3ccccc3)nc2c1

Procedure:
Following the experimental and purification procedure of Step 2i, (1S,4R,6S,13S,17R)-7-trans-13-tert-butoxycarbonyl-amino-17-(7-methoxy-2-phenylquin-olin-4-yloxy)-2,14-dioxo-3,15-diazatricyclo-[13.3.0.04,6]octadec-7-ene-4-carboxylic acid ethyl ester (185 mg, 0.265 mmol) was reacted with 64 mg (1.6 mmol) of LiOH in 15.5 mL of 9:5:1.5 of THF/H2O/MeOH to afford (1S,4R,6S,13S,17R)-7-trans-13-tert-butoxycar-bonylamino-17-(7-methoxy-2-phenylquinolin-4-yloxy)-2,14-dioxo-3,15-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (180 mg, 100%): 1H NMR (300 MHz, CD3OD) δ 1.14 (s, 9H), 1.20-1.51 (m, 5H), 1.53-1.58 (m, 1H), 1.70 (dd, J=9.9, 5.1 Hz, 1H), 1.86 (brs, 1H), 2.06 (brs, 1H), 2.28-2.59 (m, 3H), 2.65-2.73 (m, 1H), 3.94 (s, 3H), 4.07 (dd, J=11.3, 2.6 Hz, 1H), 4.23 (d, J=8.4 Hz, 1H), 4.64-4.70 (m, 2H), 5.54-5.68 (m, 3H), 7.10 (dd, J=9, 2 Hz, 1H), 7.26 (s, 1H), 7.39 (d, J=2.2 Hz, 1H), 8.02, 8.04 (2s, 2H), 8.12 (d, J=9.1 Hz, 1H). LC-MS (Method E-retention time: 1.57), MS m/z 685 (M++1). HRMS m/z (M+H)+ calcd for C38H45N4O8: 685.3238, found 685.3241. Step 5j: Preparation of Compound 5, Example 5 (1S,4R,6S,13S,17R)-7-trans-[4-Cyclopropanesul-fonylamino-carbonyl-17-(7-methoxy-2-phenylquinolin-4-yloxy)-2,14-dioxo-3,15-diazatricyclo[13.3.0.04,6]octa-dec-7-en-13-yl]carbamic acid tert-butyl ester
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:4].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1COCC1>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[S:7][C:8]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17]
Reactant: C1COCCN1
Reactant: O=C(CBr)Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Solvent: C1CCOC1
Product: O=C(CN1CCOCC1)Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
Compound 263 (196 mg, 0.49 mmol) was dissolved in THF (3.3 mL), morpholine (0.128 mL, 1.47 mmol) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was recrystallized from a mixed solvent (5:1) of hexane and acetone to afford the entitled Compound 264 (139 mg, 71%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)=O.S(O)(O)(=O)=O.[CH3:23][S:24][C:25](=[NH:27])[NH2:26].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:23][S:24][C:25]1[N:27]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[N:26]=1
Reactant: CSc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Reactant: CSC(=N)N
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CSc1ccc(-c2cc(C(F)(F)F)nc(SC)n2)cc1
Yield: 96.2 %

Procedure:
To a mixture of 4,4,4-trifluoro-1-[4-(methylthio)phenyl]butane-1,3-dione (5 g) and 2-methyl-2-thiopseudourea sulfate (5.1 g, 0.98 eq) in acetic acid (100 ml) was added sodium acetate (3 g, 2 eq) and heated under reflux for 8 h. The mixture was concentrated in vacuo and water (100 ml) added to give a solid, which was isolated by filtration to give the title compound as a yellow solid (5.8 g, quantitative).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[C:17]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=3[F:32])[CH:16]=2)[CH:11]=[CH:10][N:9]=1)(C)(C)C.Cl>O1CCOCC1>[Cl:31][C:29]1[CH:28]=[CH:27][C:26]([F:32])=[C:25]([C:17]2[CH:16]=[C:15]([NH:14][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH2:7])[N:13]=3)[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:30]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc(Nc2cc(-c3cc(Cl)ccc3F)nc3ncccc23)n1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nccc(Nc2cc(-c3cc(Cl)ccc3F)nc3ncccc23)n1
Yield: 82.5 %

Procedure:
88 mg of {4-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-ylamino]-pyrimidin-2-yl}-carbamic acid tert-butyl ester (cf. EXAMPLE 8a) were treated with 6 ml 4 m HCl in dioxane at ambient temperature for 4 hrs. After evaporation the product was digerated with ether and isolated by filtration to give 57 mg of N4-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyrimidine-2,4-diamine as hydrochloride salt with Rt˜1.36 min and correct mass found M+H˜367.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]2[SH:20])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.Br[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][CH2:37][N:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]1=[S:20])[CH3:43]
Reactant: Fc1ccc(-c2cnc(S)n2-c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1cc(-c2ccc(F)cc2)n(-c2ccc(Cl)cc2)c1=S
Temperature: 60 °C

Procedure:
To a solution 1-(4-chloro-phenyl)-5-(4-fluoro-phenyl)-1H-imidazole-2-thiol (1 eq) in DMF is added a 1M solution of lithium bis(trimethylsilyl)amide in THF (1 eq) and ethyl 3-bromopropionate (1 eq) at room temperature. The mixture is heated at 60° C. for 2 hours and cooled to room temperature. The mixture is quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuum. The residue is purified by chromatography on silica to give 3-(1-(4-chlorophenyl)-5-(4-fluorophenyl)-1,2-dihydro-2-thioxoimidazol-3-yl)propionic acid ethyl ester.
Reaction SMILES: O1CCCC1.[F:6][C:7]([F:31])([F:30])[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[NH:18][C:19](=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[O:28])[CH:21]=1.[F:32][C:33]([F:40])([C:36]([F:39])([F:38])[F:37])[CH2:34][OH:35].C(N(CC)CC)C>C(OCC)(=O)C>[F:6][C:7]([F:30])([F:31])[C:8]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:10][C:9]=1[NH:18][C:19](=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([O:35][CH2:34][C:33]([F:40])([F:32])[C:36]([F:39])([F:38])[F:37])=[O:28])[CH:21]=1
Reactant: OCC(F)(F)C(F)(F)F
Reactant: O=C=Nc1cccc(C(=O)Nc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(=O)Nc2ccc(C(F)(F)F)cc2C(F)(F)F)c1)OCC(F)(F)C(F)(F)F
Yield: 70 %

Procedure:
First, to an anhydrous tetrahydrofuran solution (15 ml) of 0.5 g of N-(2,4-bistrifluoromethylphenyl)3-isocyanatobenzamide produced in Example 10-1 were added 0.40 g of 2,2,3,3,3-pentafluoro-n-propanol and 0.13 g of triethylamine, and the resultant mixture was stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate (20 ml), and an organic layer was washed with a 1N sodium hydroxide aqueous solution and 1N hydrochloric acid. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 0.49 g (yield 70%) of the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>[OH-].[K+].CCO>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: COc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C=C2CCc3cc(OCCn4ccnc4)ccc3C2=O)cc1
Yield: 84.9 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.200 g, 0.78 mmol) was reacted with p-anisaldehyde (0.117 g, 0.87 mmol) in 2 mL of 4% KOH in EtOH at room temperature overnight to afford 0.248 g (84%) of the title compound, mp 132-133° C.: APCI-MS m/e 375 (M+ +1).
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C([Li])CCC.[CH:18](OCC)=[O:19].C(O)(=O)C>O1CCCC1.CCCCCC>[CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[CH:18]=[O:19])[CH:2]=[CH2:3]
Reactant: CCOC=O
Reactant: C=CCn1cnc2ccccc21
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCn1c(C=O)nc2ccccc21
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of 10 g (0.053 mole) of 1-allylbenzimidazole in 75 ml of tetrahydrofuran cooled to -78° C. was added 20.68 ml (0.053 mole) of 2.6M n-butyllithium in hexane over a period of 15 minutes. After 30 minutes of stirring 4.28 ml (0.053 mole) of ethyl formate was added and the reaction allowed to stir for one hour. Acetic acid (3.03 ml, 0.053 mole) was added, the cooling bath removed and the mixture allowed to warm to -20° C. The mixture was poured into water and the product extracted (3×100 ml) with ethyl acetate. The extracts were combined, dried over magnesium sulfate and concentrated to a brown oil which was chromatographed on 350 g of silica gel using ethyl acetate-chloroform as the eluent, 2.3 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:19][S:20]SC>N1C=CC=CC=1>[CH3:19][S:20][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: O=Cc1cc(Br)c(O)c(OCc2ccccc2)c1
Reactant: CSSC
Solvent: c1ccncc1
Product: CSc1cc(C=O)cc(OCc2ccccc2)c1O
Temperature: 90 °C

Procedure:
A five liter flask equipped with a mechanical stirrer was charged with 100 g of 3-Bromo-4-hydroxy-5-benzyloxybenzaldehyde 80 g Cu powder, 80 mL methyldisulfide and 5 L pyridine, and the mixture was heated at 90° C. overnight with gentle stirring. The following day, the reaction mixture was filtered and most of the pyridine (1.3 L) was distilled off. The remaining solid residue was washed with about 2 L of methylene chloride and combined with the residue left after pyridine evaporation. The combined organic fraction was washed with 1.5N HCl until the dark methylene chloride layer turned light brown and the aqueous layer was clear. The resulting light brown methylene chloride layer was dried over MgSO4 and filtered through a bed of silica gel. Evaporation and crystallization from methylene chloride-hexane gave the title compound: NMR(200 MHz, CDCl3) δ 2.50 (t, SCH3), 5.20(s, OCH2Ar), 6.72(s, OH), 7.34-7.46(m, ArH), 9.78(s, ArCHO).
Reaction SMILES: [C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:19][C:18]3[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[S:15][CH2:14][CH2:13][C:12]=3[C:11]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:29][C:30]1[CH:45]=[CH:44][C:33]([O:34][CH2:35][CH2:36][NH:37][CH:38]2C[CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:32][CH:31]=1>>[C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:19]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:34][CH2:35][CH2:36][N:37]4[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]4)=[CH:44][CH:45]=3)[C:18]3[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[S:15][CH2:14][CH2:13][C:12]=3[C:11]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCc1ccc(OCCNC2CCCCC2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c3c(c2c1)CCSc1ccccc1-3
Agent: Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)c1c(n2Cc2ccc(OCCN3CCCCC3)cc2)-c2ccccc2SCC1

Procedure:
Following the same procedure in Example 102, using 9-(tert-Butyl-dimethyl-silanyloxy)-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulene (190 mg, 0.5 mmol) and [2-(4-chloromethyl-phenoxy)-ethyl]-cyclohexanyl-amine hydrochloride salt as the starting material, title compound was prepared as a brown solid. The compound was used in the next step without additional purification.
Reaction SMILES: [O:1]1[C@H:7]2[C@@H:2]1[C:3]([CH3:17])([CH3:16])[O:4][C:5]1[C:11]([CH3:12])=[C:10]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:8][C:6]=12.Cl([O-])(=O)(=O)=O.[Li+].[Cl-].[NH4+:25]>O1CCOCC1>[CH3:16][C:3]1([CH3:17])[C@H:2]([OH:1])[C@@H:7]([NH:25][CH2:2][CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:5]=2)[C:6]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: [NH4+]
Reactant: Cc1c([N+](=O)[O-])ccc2c1OC(C)(C)[C@@H]1O[C@H]21
Agent: [Cl-]
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1c([N+](=O)[O-])ccc2c1OC(C)(C)[C@H](O)[C@H]2NCCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of (3R*,4R*)-3,4-epoxy-2,2,8-trimethyl-7-nitro-3,4-dihydro-2H-1-benzopyran (600 mg, 2.55 mmol) in 1,4-dioxane (1.2 mL), lithium perchlorate (271 mg, 2.55 mmol) and 2-(phenylethyl)amine (0.384 mL, 3.06 mmol) were added at room temperature and the mixture was stirred at 80° C. for 1 hour. Upon the completion of the reaction, saturated ammonium chloride was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=4/1) and the aimed product was obtained as orange oily substance (yield: 99%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.[NH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].C1(C)C=CC=CC=1>C(O)(=O)C>[C:11]([CH2:10][CH2:9][N:8]1[C:1](=[O:7])[CH:2]=[CH:3][C:4]1=[O:6])([OH:13])=[O:12]
Reactant: O=C1C=CC(=O)O1
Reactant: NCCC(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(O)CCN1C(=O)C=CC1=O
Temperature: 140 °C
Yield: 54.9 %

Procedure:
To a solution of maleic anhydride (33.6 g, 377 mmol) and β-alanine (36.96 g, 377 mmol) in 400 mL of acetic acid was added 52 mL toluene, the mixture was an opaque suspension. Heating to 140° C. provided a clear solution, which was refluxed for 5 hours. To the solution was added 50 mL toluene and reflux was continued. In the next 4 hours 31 mL acetic acid/water mixture was separated by distillation using a Dean-Stark apparatus. The reaction mixture was cooled to 90° C. and solvent was removed via distillation with water aspiration. The residue viscous oil was taken up in 200 mL acetone and concentrated. The crude product was purified through a flash chromatography on silica gel with a gradient eluent of 5-12% methanol in dichloromethane to afford 35 g of 1 as white solid. 1H NMR (CDCl3) δ 6.70 (s, 2H), 3.81 (t, 7.2 Hz, 2H), 2.68 (t, 7.2 Hz, 2H), 2.14 (s, 1H).