Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([N:11]([CH2:18][CH3:19])[CH2:12][C:13]#[C:14][C:15]([OH:17])=O)[CH3:10].CN1CCOCC1.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][C:32]([C:38]#[N:39])=[C:31]2[NH:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[C:43]([Cl:48])[CH:42]=1>O1CCCC1.N1C=CC=CC=1>[Cl:48][C:43]1[CH:42]=[C:41]([NH:40][C:31]2[C:30]3[C:35](=[CH:36][CH:37]=[C:28]([NH:27][C:15](=[O:17])[C:14]#[C:13][CH2:12][N:11]([CH2:9][CH3:10])[CH2:18][CH3:19])[CH:29]=3)[N:34]=[CH:33][C:32]=2[C:38]#[N:39])[CH:46]=[CH:45][C:44]=1[F:47]
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: CCN(CC)CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCN(CC)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Isobutyl chloroformate (0.061 g, 0.448 mmol) was dropwise added into an ice cold solution of 4-diethylamino-2-butynoic acid (0.104 g, 0.672 mmol) and N-methyl-morpholine (0.068 g, 0.672 mmol) in 10 mL of tetrahydrofuran under N2. After stirring for 30 min, a solution of 0.1 g (0.32 mmol) of 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-3-quinolinecarbonitrile in 1.5 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 1.5 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 15% methanol in ethyl acetate. The product was collected, and dried in vacuo to give 0.046 g (32%) of light brown solid; ESMS m/z 450.2, (M+H+); mp 117-120° C.
Reaction SMILES: CS[C:3](=[N:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C.[Hg](Cl)Cl>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:17]1[C:3]([N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[N:26][N:25]=[N:24]1
Reactant: CSC(=Nc1ccccn1)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Hg]Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nnnn2-c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 456 h
Yield: 84.7 %

Procedure:
Part C: To a solution of tert-butyl 4-(methylthio(pyridin-2-ylimino)methyl)piperazine-1-carboxylate (12.00 g, 36.0 mmol) in DMF (200 mL) at 25° C. was added sodium azide (11.60 g, 178 mmol), followed by mercury(II)chloride (10.90 g, 40.0 mmol), and the resulting mixture was stirred at 25° C. for 19 d. The mixture then was filtered, and the solids were washed with DMF. The combined filtrate was concentrated under vacuum, and the residue was diluted with ethyl acetate. The resulting mixture was filtered again. The filtrate was washed with water (×3) and brine, dried over anhyd. sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-20% diethyl ether/methylene chloride) to afford tert-butyl 4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate (10.10 g) as an off-white solid, following crystallization from a mixture of 1-chlorobutane/hexane; Mass Spec.: m/e: 332.11 (M+H)+ [calc'd: 332.17]; 1HNMR (300 MHz, CDCl3) δ 8.57 (m, 1H), 7.94 (m, 1H), 7.79 (d, 1H, J=8 Hz), 7.40 (m, 1H), 3.52 (m, 4H), 3.34 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[C:6]([CH:8]2[CH:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][CH2:10][N:9]2C(OC(C)(C)C)=O)[CH:7]=1.[ClH:30]>O1CCOCC1>[ClH:30].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[C:6]([CH:8]2[CH:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][CH2:10][NH:9]2)[CH:7]=1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)C1c1cc(N)ccc1S(=O)(=O)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C1CCNC1c1cc(N)ccc1S(=O)(=O)C(C)C

Procedure:
20F was treated with 4.0 N HCl in dioxane for 4.0 h. After removal of solvent, 20G was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.62 (d, J=8.00 Hz, 1H) 6.6-6.9 (m, 2H) 5.1 and 5.0 (d, 1H) 3.2-3.5 (m, 3H) 3.0 (m, 1H) 2.1-2.4 (m, 2H) 1.32 (d, J=7.6 Hz, 3H) 1.22 (d, J=7.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.[H-].[Na+].Br[CH2:16][CH:17]1[O:21][CH2:20][CH2:19][O:18]1.Cl>C(OCC)(=O)C.CN(C)C=O>[O:18]1[CH2:19][CH2:20][O:21][CH:17]1[CH2:16][N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[CH:7]=[CH:8][C:9]1=[O:12]
Reactant: BrCC1OCCO1
Reactant: Cc1cccc2ccc(=O)[nH]c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc2ccc(=O)n(CC3OCCO3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3 mL of an N,N-dimethylformamide solution containing 0.17 g of 8-methylquinolin-2(1H)-one, 0.13 g of 60% sodium hydride was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. Thereto was added 0.89 g of 2-bromomethyl-1,3-dioxolane, and the mixture was stirred at 90° C. for 48 hours. The reaction mixture was cooled to room temperature, then ethyl acetate and 1 mol/L hydrochloric acid were added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Chromatorex-NH, manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=8:1] to obtain 0.18 g of a pale yellow oily substance, 1-(1,3-dioxolan-2-ylmethyl)-8-methylquinolin-2(1H)-one.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].OS(O)(=O)=O.[I:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:31]#[N:32])[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>C1COCC1>[I:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([CH2:31][NH2:32])[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]([F:28])([F:29])[F:30])[CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: N#CC1(c2ccc(I)cc2)CCN(CCC(F)(F)F)CC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCC1(c2ccc(I)cc2)CCN(CCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
To a solution of LiAlH4 (1 M in THF, 6.5 mL, 6.5 mmol, 3.5 eq.) at 0° C. was added H2SO4 (0.31 mL, 5.58 mmol, 3 eq.) in a drop-wise fashion. The resulting white precipitate was stirred at 25° C. for 1 h. A solution of 4-(4-iodo-phenyl)-1-(3,3,3-trifluoro-propyl)-piperidine-4-carbonitrile (0.761 g, 1.86 mmol, 1 eq.) in THF (6 mL) was added and the mixture was heated at 40° C. for 3 h. The reaction was cooled to 0° C., quenched by addition of H2O (0.25 mL), 1 N NaOH (0.5 mL) and H2O (0.75 mL). The resulting slurry was filtered through a pad of celite, washed with EtOAc and then concentrated by rotary evaporation to give a yellow oil which was purified by flash column chromatography by eluting with 1.5% MeOH/1% Et3N/CH2Cl2 to give the title compound C-[4-(4-Iodo-phenyl)-1-(3,3,3-trifluoro-propyl)-piperidin-4-yl]-methylamine as a pale foam (0.139 g, 0.337 mmol, 18%). 1H NMR (300 MHz, CDCl3): δ 7.80 (d, 2H), 7.18 (d, 2H), 3.78 (t, 1H), 2.86 (s, 2H), 2.74 (m, 2H), 2.62 (m, 2H), 2.30 (m, 4H+NH2), 1.94 (ddd, 2H), 1.78 (m, 1H); MS(ESI): 413.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=[O:22])[CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>[Pt]=O.CO>[CH2:1]([O:3][C:4]([C:6]1([CH:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[C:11](=[O:22])[CH2:10]2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C2=CC(=O)N([C@@H](C)c3ccccc3)C2)CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: CCOC(=O)C1(C2CC(=O)N([C@@H](C)c3ccccc3)C2)CC1
Yield: 99 %

Procedure:
A 13.1 g (43.8 mmol) portion of 4-(1-ethoxycarbonylcyclopropyl)-1-[(S)-1-phenylethyl]-3-pyrrolin-2-one was dissolved 300 ml of methanol, mixed with 400 mg of platinum oxide and then stirred in an atmosphere of hydrogen for 18 hours. After completion of the reaction, the reaction solution was filtered and concentrated to yield 13.0 g (99 %) of the titled compound as an oily substance.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[C:15]([O:16][CH3:17])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[O:18][CH3:19])=[O:5].[C:20](OCC)(OCC)(OCC)[CH3:21]>>[CH3:20][C:21]1[O:5][C:4]([C:6]2[C:7]([O:18][CH3:19])=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][C:15]=2[O:16][CH3:17])=[CH:3][N:2]=1
Reactant: COC(=O)c1cc(OC)c(C(=O)CN)c(OC)c1
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Product: COC(=O)c1cc(OC)c(-c2cnc(C)o2)c(OC)c1
Temperature: 140 °C
Reaction time: 6 h

Procedure:
Methyl 4-(aminoacetyl)-3,5-dimethoxybenzoate hydrochloride was dissolved in triethyl orthoacetate, paratoluenesulfonic acid monohydrate (10 mg) was added to it, and stirred at 140° C. for 6 hours. The reaction liquid was cooled to room temperature, then triethyl orthoacetate was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=100/0 to 30/70) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=[N:17]N(C)C)[C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(O)C.C(OCC)(=O)C.BrC1C=C(C2N(C)[CH:42]=[N:41][C:40]=2C(F)(F)F)C=CC=1OC>C1(C)C=CC=CC=1.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[N:17]=[CH:40][N:41]([CH3:42])[C:11]=2[C:12]([F:13])([F:14])[F:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=NN(C)C)C(=O)C(F)(F)F)cc1Br
Reactant: COc1ccc(-c2c(C(F)(F)F)ncn2C)cc1Br
Solvent: CCO
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ncn(C)c2C(F)(F)F)cc1Br
Temperature: 25 °C

Procedure:
Using the general procedure of S. Ohara, K. Kawasaki, Y. Kawamura, and M. Tanaka (J. Heterocyclic Chem., 1990, 27, 487-495), silica gel (EM silica gel 60, 230-400 mesh) was dried under vacuum at 180° C. for 2 h. A suspension of 1.80 g of this activated silica gel was stirred in 9 mL of dry toluene and 3-(3-bromo-4-methoxyphenyl)-3-(dimethylhydrazono)-1,1,1-trifluoropropan-2-one (250 mg 0.71 mmol) was added as a solution in 5 mL of toluene. The resulting suspension was heated to reflux for 48 h, then allowed to cool to room temperature and stirred overnight. After the addition of 95% ethanol (20 mL) the mixture was stirred for 10 min and filtered. The silica gel was stirred with 20 mL of 95% ethanol and filtered, and the process was repeated again. Evaporation of the combined filtrates gave a pale amber oil. Flash column chromatography on 15 g of silica gel eluting with 10% ethyl acetate in hexane followed by 15% ethyl acetate in hexane gave 167 mg of 4-(3-bromo-4-methoxyphenyl)-5-trifluoromethyl-1-methylimidazole and 5-(3-bromo-4-methoxyphenyl)-4-trifluoromethyl-1-methylimidazole as a 6:1 mixture as determined by NMR. This material was recrystallized from a 65° C. solution in hexane (0.75 mL) and toluene (0.15 mL) cooled to -10° C. Recrystallization again from a 65° C. solution in hexane (0.75 mL) and toluene (0.15 mL) cooled to room temperature gave 112 mg of 4-(3-bromo-4-methoxyphenyl)-5-trifluoromethyl-1-methylimidazole as white crystals. Concentration of the mother liquors yielded 48 mg of 4-(3-bromo-4-methoxyphenyl)-5-trifluoromethyl-1-methylimidazole and 5-(3-bromo-4-methoxyphenyl)-4-trifluoromethyl-1-methylimidazole as a 1:1 mixture as determined by NMR. 4-(3-Bromo-4-methoxyphenyl)-5-trifluoromethyl-1-methylimidazole: 1H NMR (400 MHz, CDCl3): δ 7.78 (d, 1H, J=2 Hz), 7.75 (s, 1H), 7.47 (bd, 1H, J=8 Hz), 6.93 (d, 1H, J=8 Hz), 3.94 (s, 3H), 3.81 (s, 3H). Mass spectrum (ESI): m/e=335 (M+1).
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5](=[O:15])[C:6]1[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([OH:11])=O)[CH:7]=1)[CH3:3].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH2:2]([O:4][C:5]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[C:19]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:20]=1)=[O:11])=[O:15])[CH3:3]
Reactant: CCOC(=O)c1cccc(C(=O)O)c1
Reactant: CCOC(=O)CCc1ccccc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OC
Yield: 104.6 %

Procedure:
Following the procedure of Example 1, 30.6 g of isophthalic acid monoethyl ester monochloride and 30 g of ethyl 2-methoxybenzene propanoate were treated with 57 g of aluminum chloride in dichloromethane to provide 53.6 g of the desired title product, as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[C:5](=[O:32])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:19])=[CH:15][C:16]=2[Cl:18])[N:11](C(OC(C)(C)C)=O)[C:10]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[C:5](=[O:32])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:19])=[CH:15][C:16]=2[Cl:18])[NH:11][C:10]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)c1c(NCCC(=O)c2cccc(F)c2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1cccc(F)c1

Procedure:
Dissolve 3-[(m-fluorophenacyl)methylamino]-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride (5 mL). Add trifluoracetic acid (3 mL) and stir for 5 hours. Concentrate the reaction in vacuo, dilute with ethyl acetate (100 mL), wash with saturated sodium carbonate, dry over magnesium sulfate, filter and concentrate in vacuo. Recrystallize the residue from ethyl acetate/hexane to yield the title compound (760 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:22]2[CH:23]=[N:24][N:25](C(OC(C)(C)C)=O)[CH:26]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[C:22]1[CH:23]=[N:24][NH:25][CH:26]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)c(OC)c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cn[nH]c2)c(OC)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 4-bromo-3-methoxybenzoate (1.32 g, 5.39 mmol) in dioxane (30 mL) and water (5 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.901 g, 6.46 mmol), potassium phosphate (2.86 g, 13.47 mmol) and PdCl2(dppf) (0.197 g, 0.269 mmol) at RT. The reaction was stirred under argon at 100° C. for 3 hrs. The reaction mixture was diluted with EtOAc, washed with H2O. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in DCM (10 mL) and TFA (5 mL) was added. The reaction was stirred at RT for 1.5 hrs. Solvent was removed. The residue was taken into EtOAc, which was washed with NaHCO3 (3×) and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by normal phase chromatography. Desired product was isolated as white solid (0.86 g, 69% yield). LCMS (ESI) m/z: 233.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 2H), 7.73-7.66 (m, 1H), 7.66-7.56 (m, 2H), 3.98 (s, 3H), 3.94 (s, 3H).
Reaction SMILES: O.[CH2:2]([NH:9][C:10](=[O:19])[CH2:11][N:12]1[CH:15]([S:16][CH3:17])[CH2:14][C:13]1=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:24]O)(C)(C)C>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:2]([NH:9][C:10](=[O:19])[CH2:11][N:12]1[CH:15]([S:16]([CH3:17])=[O:24])[CH2:14][C:13]1=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CSC1CC(=O)N1CC(=O)NCc1ccccc1
Reactant: CC(C)(C)OO
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)C1CC(=O)N1CC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4RSR-(-)-N-Benzyl-(4-methylsulphinyl-2-oxoazetidin-1-yl )acetamide A solution of S(-)1,1'-bi-2-napthol (0.012 g, 4.2 μmol) in toluene (2 ml) was treated with titanium isopropoxide (0.012 g, 21 μmol) in water (6 mg, 0.033 mmol). The resulting mixture was stirred at room temperature for 1 h. A solution of (-)-N-Benzyl (4-methylthio-2-oxoazetidin-1-yl)acetamide (0.2 g, 0.76 mmol) in toluene was added. After 30 mins t-butylhydroperoxide (136 mg, 1.5 mmol) was added and the mixture stirred for 3h. After evaporation to dryness, the residue was purified by flash chromatography on silica (EtOAc/EtOH 6:1 to 3:1) to give (-)-N-benzyl-(4-methylsulphinyl-2-oxoazetidin-1-yl)acetamide as a solid, 70 mg, 33% m.p. 138-140° C, [α]D25 =-237° (c=1.35, EtOH).
Reaction SMILES: C[O-].[Na+].CO[C:6](=[O:10])[CH2:7][C:8]#[N:9].[CH3:11][CH:12]=[CH:13][C:14](=[O:17])[CH2:15][CH3:16]>CO>[CH3:16][CH:15]1[C:14](=[O:17])[CH2:13][CH:12]([CH3:11])[CH:7]([C:8]#[N:9])[C:6]1=[O:10]
Reactant: COC(=O)CC#N
Reactant: CC=CC(=O)CC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1C(=O)CC(C)C(C#N)C1=O
Temperature: 25 °C
Yield: 68.2 %

Procedure:
To a solution of sodium methoxide (162 grams, 3 moles) in 400 mls of anhydrous methanol is added, dropwise, 276 grams (3.2 moles) of methylcyanoacetate over a period of 1 hour at 60° C. with stirring. The resulting slurry is stirred at 60° C. for 10 minutes, whereupon 288 grams (3.0 moles) of 2-hexen-4-one is added over a 20 minute period. The resulting reaction mixture is stirred and heated at reflux for six hours, whereupon a distillation take-off condenser is affixed to the reaction flask and 240 mls of methanol are removed under reduced pressure (65 mm Hg). The reaction mixture is then cooled to room temperature and poured into 2 liters of water. Toluene (500 ml) is added and the mixture is transferred to a separatory funnel. The aqueous layer is removed and again extracted with toluene (500 mls). To the aqueous solution, 500 mls of 18% HCl are added with external cooling at 25° C., whereupon a solid material precipitates. The solid is filtered, dried and recrystallized from aqueous methanol to afford colorless needles of 3,6-dimethyl-2,4-dioxocyclohexanecarbonitrile (338 grams, 68.3% yield based on 2-hexen-4-one); m.p. 178°-179° C. The resulting product is represented by the following equilibrium mixture: ##STR21##
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH:5]=[N:4][CH:3]=1>[C].[Pd].C(O)C>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:6]2[C:2]([CH3:1])=[CH:3][N:4]=[CH:5]2)=[CH:9][CH:10]=1
Reactant: Cc1cncn1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1cncn1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
A mixture of 5-methyl-1-(4-nitrobenzyl)-1H-imidazole (1.4 g), 10% palladium carbon (200 mg) and ethanol (20 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hrs. Palladium carbon was removed from the reaction mixture by filtration, and the filtrate was concentrated. Recrystallization of the residue from ethyl acetate-hexane gave 1-(4-aminobenzyl)-5-methyl-1H-imidazole (1.17 g, 97%) as colorless prism crystals. melting point: 124-125° C.
Reaction SMILES: CC1(C)[O:9][CH:8]2[C@H:4]([C@@H:5]([CH2:19][I:20])[O:6][C@H:7]2[N:10]2[C:16](=[O:17])[NH:15][C:13](=[O:14])[C:12]([F:18])=[CH:11]2)[O:3]1>FC(F)(F)C(O)=O.O>[I:20][CH2:19][C@H:5]1[O:6][C@@H:7]([N:10]2[CH:11]=[C:12]([F:18])[C:13](=[O:14])[NH:15][C:16]2=[O:17])[C@H:8]([OH:9])[C@@H:4]1[OH:3]
Reactant: CC1(C)OC2[C@@H](O1)[C@@H](CI)O[C@H]2n1cc(F)c(=O)[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](CI)[C@@H](O)[C@H]2O)cc1F

Procedure:
5'-Deoxy-5'-iodo-2',3'-O-isopropylidene-5-fluorouridine (4 g) was treated with trifluoroacetic acid/water (9:1, 30 ml) for 15 minutes at room temperature. The solution was evaporated to dryness, co-evaporated with ethanol (2 × 100 ml) and the residue was recrystallized from ethyl acetate. Yield = 1.865 g (88%).
Reaction SMILES: [CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:23][NH:24][C:25]([NH2:27])=[O:26]>>[CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)/[C:10](=[N:23]\[NH:24][C:25]([NH2:27])=[O:26])/[C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: NNC(N)=O
Reactant: CC(C)N(CCN1C(=O)C(=O)c2cc(F)ccc21)C(C)C
Agent: Cl
Product: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2cc(F)ccc21)C(C)C
Yield: 86.5 %

Procedure:
By using 1-(2-diisopropylaminoethyl)-5-fluoroisatin and semicarbazide hydrochloride, a method analogous to that described in Example 6 was carried out to obtain (E)-1-(2-diisopropylaminoethyl)-5-fluoroisatin 3-semicarbazone having a melting point of 158°-160° C. (yield: 86.5%, recrystallizing solvent: chloroform-hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[CH2:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.C1(C(N)C2CCCCC2)CCCCC1.[H][H]>CO>[CH3:17][C@H:13]([C:14]([OH:16])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[CH:9]=1
Reactant: C=C(C(=O)O)c1ccc2cc(OC)ccc2c1
Reactant: [H][H]
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: CO
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Yield: 84.7 %

Procedure:
In a 100 ml autoclave, the inside atmosphere of which had previously been replaced with argon, were placed 0.45 g (2 mmoles) of 6-methoxy-α-methylene-2-naphthaleneacetic acid, 20 ml of methanol, and 0.39 g (2 mmoles) of dicyclohexylmethylamine. Then, 9.0 mg (0.010 mmole) of Ru((-)-T-BINAP)(O2CCH3)2 prepared according to the same manner as in Referential Example 3 except using (-)-T-BINAP in place of (-)-BINAP was added to the mixture to perform hydrogenation for 12 hours at a hydrogen pressure of 135 kg/cm2 and at a reaction temperature of 17° C. Thereafter, the solvent was distilled off to provide 0.39 g of naproxen. The yield was 84%.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:26])[CH:4]=[CH:5][C:6](=[O:25])[CH:7]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].Cl>N1C=CC=CC=1>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:19])[CH2:17][O:18][S:28]([CH3:27])(=[O:30])=[O:29])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:26])[CH:4]=[CH:5][C:6](=[O:25])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)COS(C)(=O)=O)[C@@]3(C)C[C@H](O)[C@@]12F

Procedure:
A solution of 16 grams of 9-fluoro-11β,21-dihydroxypregna-1,4,16-triene-3,20-dione in dry pyridine (200 ml) is reacted with methanesulfonyl chloride (5.0 ml) for 2 hours at 0° C. The mixture is poured into an excess of cold 2N-hydrochloric acid. The solid that separates from the resulting solution is isolated yielding 17.5g of the title compound, which is characterized by its nmr spectrum.