Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH2:17]>C(O)(=O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:16][CH2:17][C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1
Reactant: C=Cc1ccccn1
Reactant: C1=Cc2ccccc2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: C1=C(CCc2ccccn2)c2ccccc2C1

Procedure:
This compound is prepared as described by Dressler and Kurland J.O.C. 29, 175 (1964). Under nitrogen gas, 500 g. indene plus 5 g. potassium t-butoxide are stirred and heated to 130°. 2-Vinyl pyridine (220 g., 2.0 M) is added dropwise over a period of 1 hour keeping the temperature at 135°-145° C. during addition and for 2 hours after addition is completed. The reaction mixture is cooled and 25 ml. acetic acid is added, followed by filtration. A flash distillation yields 395 g. (84%) crude product boiling 160°-175°/0.3 mm. This is redistilled to give 353 g. (75%) of oil (3-[2[(pyridyl)ethyl]indene) boiling point 135°-140°/0.1 mm.
Reaction SMILES: C([S:5]([C:8]1[C:12]([CH:13]2[CH:18]3[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]3)[CH2:14]2)=[N:11][S:10][N:9]=1)(=O)=O)CCC.O.[SH-].[Na+]>CN(C=O)C>[SH:5][C:8]1[C:12]([C@H:13]2[CH:18]3[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]3)[CH2:14]2)=[N:11][S:10][N:9]=1
Reactant: CCCCS(=O)(=O)c1nsnc1C1CN2CCC1CC2
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CN(C)C=O
Product: Sc1nsnc1[C@@H]1CN2CCC1CC2
Temperature: 95 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of (3S) 3-(3-butylsulfonyl-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]octane (Chirality, 1997, in press.) (1.90 g, 6.0 mmol) in dry DMF (15 ml) was added sodium hydrosulfide monohydrate (1.67 g, 18.0 mmol) and the mixture was stirred at 95° C. for 3 h. The reaction mixture was concentrated in vacuo, added ice water and made less basic with 4 N hydrochloride acid. The precipitate was isolated by filtration to give 1.05 g (77%) of (3S)3-(3-mercapto-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]octane.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[CH2:18]([O:20][CH2:21][C:22](Cl)=[O:23])[CH3:19].O>C(Cl)Cl>[CH2:18]([O:20][CH2:21][C:22]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5])=[O:23])[CH3:19]
Reactant: CCOCC(=O)Cl
Reactant: CNc1cccc(N)c1C#N
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOCC(=O)Nc1cccc(NC)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(methylamino)benzonitrile (3.3 g) in methylene chloride (50 ml) is added pyridine (3.9 ml), and thereto is added dropwise ethoxyacetyl chloride (5 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure The resulting crude crystals are recrystallized from ethyl acetate-hexane to give the title compound (3.2 g) having the following physical properties.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=[O:26])[NH:11][C:12]1([C:15]2[N:16]=[N:17][C:18]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)[CH3:9])(C)(C)C.O1CCOCC1.[ClH:34]>C(Cl)Cl>[ClH:34].[ClH:34].[NH2:7][C@@H:8]([CH3:9])[C:10]([NH:11][C:12]1([C:15]2[N:16]=[N:17][C:18]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)=[O:26]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(c2ccc(-c3cn[nH]c3)nn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](N)C(=O)NC1(c2ccc(-c3cn[nH]c3)nn2)CC1
Reaction time: 1.5 h

Procedure:
((S)-1-{1-[6-(1H-pyrazol-4-yl)-pyridazin-3-yl]-cyclopropylcarbamoyl}-ethyl)-carbamic acid tert-butyl ester was dissolved in CH2Cl2 (1.0 mL) and 4M HCl dioxane (2 mL, 8 mmol) was added. After 1.5 h, the solvents were removed at 50° C. under a stream of N2. This material was dried under vacuum to yield 73 mg of the title compound, m/z 273.5 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:15])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8].[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](Cl)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C1C=CN=CC=1.CS(C)=O>[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([O:15][C:4]3[C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(O)c(-c2ccccn2)nc1C
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
5,6-Dimethyl-3-hydroxy-[2,2′]bipyridine (241 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (1.08 g), 4-dimethylaminopyridine (441 mg), and cesium carbonate (1.18 g) were suspended in dimethyl sulfoxide (6 ml), and the mixture was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (408 mg, yield 73%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.21) (0.150 g, 0.39 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.093 g, 0.42 mmol) according to the general procedure VI. Obtained as a white solid (0.10 g, 64%). MS (ISP) 407.3 [(M+H)+]; mp 215-217° C.
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[H-].[Na+].[Na].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1C(F)(F)F>CN(C)C=O>[CH:7]1[CH:8]=[CH:9][C:4]([NH:3][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[CH:5][CH:6]=1
Reactant: O=CNc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Temperature: 155 °C

Procedure:
the formanilide is treated with a one-molar equivalent of sodium hydride in dimethylformamide and the resulting solution of the sodium salt is treated with 2-chloro-5-nitrobenzotrifluoride (U.S. Pat. No. 3,657,350) at an elevated temperature (e.g., 155° C., reflux), to give the 4-nitrodiphenylamine (J. Organic Chemistry, 42, 1786 (1977) and references therein).
Reaction SMILES: NC1S[C:4]([N+:7]([O-])=O)=[CH:5]N=1.C(O)(=[O:13])CC.N(OS(=O)(=O)O)=O.S(=O)(=O)(O)N.[N+:27]([C:30]1[S:34][C:33]([N:35]=[N:36][C:37]2[CH:55]=[CH:54][C:40]([N:41]([CH2:50][CH2:51][CH2:52][CH3:53])[CH2:42][CH2:43][C:44](OCC#N)=[O:45])=[CH:39][CH:38]=2)=[N:32][CH:31]=1)([O-:29])=[O:28]>CC(C)=O.O.C(O)(=O)C>[N+:27]([C:30]1[S:34][C:33]([N:35]=[N:36][C:37]2[CH:38]=[CH:39][C:40]([N:41]([CH2:50][CH2:51][CH2:52][CH3:53])[CH2:42][C:43](=[C:44]=[O:45])[O:13][CH2:5][C:4]#[N:7])=[CH:54][CH:55]=2)=[N:32][CH:31]=1)([O-:29])=[O:28]
Reactant: Nc1ncc([N+](=O)[O-])s1
Reactant: CCCCN(CCC(=O)OCC#N)c1ccc(N=Nc2ncc([N+](=O)[O-])s2)cc1
Reactant: CCC(=O)O
Agent: NS(=O)(=O)O
Agent: O=NOS(=O)(=O)O
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CCCCN(CC(=C=O)OCC#N)c1ccc(N=Nc2ncc([N+](=O)[O-])s2)cc1
Reaction time: 0.5 h

Procedure:
2-amino-5-nitrothiazole (2.9 parts) was set stirring at 5° C. with a mixture of acetic acid and propionic acid, 86:14 (50 parts). Nitrosyl sulphuric acid 40% (7.0 parts) was added below 5° C. and the mixture was stirred for 30 mins. The diazo solution was added gradually to a stirred coupling mixture of N-butyl, N-2(cyanomethoxycarbonylethyl)-aniline (5.2 parts), acetone (50 parts), water (200 parts) and sulphamic acid (0.5 parts). After one hour the product was isolated by filtration, washed with cold water and dried to yield, 4-(5-nitrothiazol-yl-azo)-N-butyl-N-(2-cyanomethoxycarbonylethyl)aniline (2.9 parts) λmax=571 nm (acetone).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:6]=[N:5][CH:4]=1.S(Cl)([Cl:14])=O>>[ClH:14].[Cl:14][CH2:2][C:3]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:6]=[N:5][CH:4]=1
Reactant: CC(C)Cn1cncc1CO
Reactant: O=S(Cl)Cl
Product: CC(C)Cn1cncc1CCl
Product: Cl
Temperature: 90 °C

Procedure:
To 5-hydroxymethyl-1-isobutylimidazole (2.5 g), thionyl chloride (20 ml) was added by portions at 0° C., and the mixture was heated for 30 minutes under nitrogen atmosphere at 90° C. The mixture was allowed to be at room temperature. The solvent was distilled off under reduced pressure and the obtained residue was dissolved in methanol and the solvent was distilled off again under reduced pressure. The obtained solid was recrystallized from ethyl acetate, to give 5-chloromethyl-1-isobutylimidazole hydrochloride (3.0 g) as colorless crystals.
Reaction SMILES: [CH2:1]([N:4]([CH2:7][CH3:8])[CH2:5][CH3:6])[CH:2]=[CH2:3].[C:9]1([PH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)C(C)CP(C1C=CC=CC=1)C1C=CC=CC=1)C>>[CH2:5]([N:4]([CH2:1][CH2:2][CH2:3][P:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][CH3:8])[CH3:6]
Reactant: C=CCN(CC)CC
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: CCN(CC)C(C)CP(c1ccccc1)c1ccccc1
Product: CCN(CC)CCCP(c1ccccc1)c1ccccc1

Procedure:
A mixture of 17 g (0.15 mole) allyl diethyl amine and 30.70 g (0.165 mole, 10% excess) of diphenyl phosphine is reacted in the usual manner with u.v. irradiation for 17 hours. A subsequent analysis of the reaction mixture indicated that about one third of the reactants was converted. The only product formed was the desired adduct, 2-diethylaminopropyl diphenylphosphine. It was isolated as a clear colorless liquid (Table 3).
Reaction SMILES: [OH2:1].[OH-:2].[Li+].[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16]C)=[O:15])=[C:8]2[S:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=1.Cl>O1CCCC1.O>[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([OH:16])=[O:15])=[C:8]2[S:18]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=1)(=[O:2])=[O:1]
Reactant: [OH-]
Reactant: COC(=O)c1[nH]c2ccc(Cl)cc2c1Sc1cc(C)cc(C)c1
Reactant: O
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(S(=O)(=O)c2c(C(=O)O)[nH]c3ccc(Cl)cc23)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Lithium hydroxide monohydrate (0.33 g, 0.0079 mol) was added to a solution of methyl 5-chloro-3-(3,5-dimethylphenylthio)indole-2-carboxylate (1.0 g, 0.0026 mol) in tetrahydrofuran (30 mL) and water (30 mL), then reaction was stirred at room temperature for 4 days. After dilution with water the mixture was acidified with 1N HCl and extracted with ethyl acetate. Organic reaction was washed with brine and dried. Evaporation of the solvent furnished 0.94 (100%) of title compound, mp 277-278° C. (from ethanol).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:9]#[CH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+]>O>[NH3:4].[O:6]1[CH2:2][CH2:3][N:4]=[C:5]1[NH:7][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:9]#[CH:10]
Reactant: C#CC(NC(=O)NCCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C#CC(NC1=NCCO1)c1ccccc1
Product: N
Temperature: 25 °C
Yield: 146 %
Yield: 3 %

Procedure:
A solution of 136 mg of 1-(2-chloro-ethyl)-3-(1-phenyl-prop-2-ynyl)-urea (Formula 29) in 5 mL of water was heated at 100° C. for 2.5 hours. The reaction mixture was cooled to room temperature. Then, sodium carbonate (saturated solution) was added to the mixture until the pH was greater than 8. The mixture was extracted with ethyl acetate. Combined ethyl acetate was washed with brine, dried over sodium sulfate and concentrated. Column chromatography (3-5% 7N NH3 in MeOH/CH2Cl2) gave 84 mg of (4,5-Dihydro-oxazol-2-yl)-(1-phenyl-prop-2-ynyl)-amine (Formula 30) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.49 (d, J=2.0 Hz, 1H), 3.66-3.75 (m, 2H), 4.22-4.28 (m, 2H), 5.58 (d, J=2.0 Hz, 1H), 7.26-7.31 (m, 1H), 7.33-7.36 (m, 2H), 7.52-7.54 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[F:14][C:15]([F:36])([F:35])[O:16][C:17]1[CH:34]=[CH:33][C:20]2[NH:21][C:22]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([O-])=[O:29])=[CH:26][CH:25]=3)=[N:23][C:19]=2[CH:18]=1>>[F:36][C:15]([F:14])([F:35])[O:16][C:17]1[CH:34]=[CH:33][C:20]2[NH:21][C:22]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[O:29])=[CH:26][CH:25]=3)=[N:23][C:19]=2[CH:18]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C([O-])c1ccc(-c2nc3cc(OC(F)(F)F)ccc3[nH]2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3cc(OC(F)(F)F)ccc3[nH]2)cc1

Procedure:
Compound 481 was prepared from 4-morpholinoaniline and 4-(5-trifluoromethoxy-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C25H21F3N4O3: 483.17; found: 482.93.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.C(NC(C)C)(C)C.[Li].C(NC(C)C)(C)C.[Li]CCCC.[Br:29][C:30]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34]([CH2:40][C:41]#[N:42])=[CH:35]2.CI>C1COCC1>[Br:29][C:30]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34]([CH:40]([CH3:2])[C:41]#[N:42])=[CH:35]2
Reactant: CC(C)[N-]C(C)C
Reactant: N#CCc1ccc2c(Br)cccc2c1
Agent: [Li+]
Agent: [Li]
Agent: [Li]CCCC
Solvent: CI
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C#N)c1ccc2c(Br)cccc2c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of LDA [lithium diisopropylamine prepared from diisopropylamine (1.49 g, 14.8 mmol) and n-BuLi (9.25 mL, 14.8 mmol, 1.6M solution in hexanes)]in THF (80 mL) at -78° C. was added (5-bromo-2-naphthalenyl) acetonitrile (3.80 g, 13.4 mmol) in THF (70 mL) dropwise over 45 minutes. The resulting orange solution was stirred at -78° C. for 10 minutes and MeI (1.90 g, 13.4 mmol) was added in one portion. The reaction mixture was stirred at -78° C. for 1 hour and quenched with saturated NH4Cl (20 mL). The solution was warmed to room temperature and the volatiles removed in vacuo. The residue was diluted with H2O (100 mL) and extracted with Et2O (3×150 mL). The combined organic layers were dried (MgSO)4) and concentrated in vacuo to give the crude product as a yellow oil. This residue was purified by flash chromatography (SiO2) with elution by hexane/CH2Cl2 (2:1), followed by hexane/CH2Cl2 (3:2) to give the title compound as a colorless oil (2.74 g, 79%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[CH:6]=1.CCN(CC)CC.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[Br:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][O:13][C:7]1[CH:6]=[C:5]([CH:12]=[CH:11][C:8]=1[CH:9]=[O:10])[O:4][CH2:3][CH2:2][NH:1][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCCOc1ccc(C=O)c(OCc2ccccc2Br)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1ccc(OCCNC(=O)c2ccccc2)cc1OCc1ccccc1Br

Procedure:
4-(2-Aminoethoxy)-2-(2-bromobenzyloxy)benzaldehyde (200 mg, 0.43 mmol) was dissolved in CH2Cl2 (20 ml) and Et3N (87.02 mg, 0.12 ml, 0.86 mmol) was added to the solution, followed by stirring for 2˜3 min. Benzoyl chloride (60.45 mg, 50 μl, 0.43 mmol) was also added before additionally stirring at room temperature for 2 hours. After completion of the reaction, the reaction solution was extracted with brine and CH2Cl2 (×3). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in a vacuum. The residue was purified using column chromatography (ethyl acetate/n-hexane=1/5→1/3) to afford the object compound (white solid, 78 mg, 40%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:13])[CH3:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH2:14]>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[O:14]=[C:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:13])[CH3:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O
Reactant: CC(=O)Nc1ccc2c(c1)CCC2
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(c1)CCC2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of N-(2,3-dihydro-1H-inden-5-yl)acetamide (50 g, 0.29 mol) in 150 mL of acetic acid and 40 mL of actic anhydride was added a solution of chromium trioxide in a mixed solution (30 mL of water and 140 mL of acetic acid) dropwise at 10° C. by external cooling. After stirring overnight, the solution was poured into 2 L of ice water under vigorously stirring. The resulting solid was filtered, washed with cooled EtOH to give N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acetamide. 1H-NMR (300 MHz, CDCl3) δ ppm 7.90 (s, 1H), 7.66˜7.70 (m, 2H), 7.22˜7.25 (m, 1H), 3.09˜3.13 (m, 2H), 2.66˜2.70 (m, 2H), 2.22 (s, 3H);
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][CH2:12]Cl.[OH:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19]>ClCCl>[CH3:10][O:11][CH2:12][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1cccc(O)c1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cccc(C(=O)OC)c1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
At about 0° C., diisopropylethylamine (1.7 g, 13.1 mmol) and methoxymethyl chloride (635 mg, 7.9 mmol) were sequentially added to a solution of methyl 3-hydroxybenzoate (1 g, 6.6 mmol) in dry dichloromethane (10 mL). The resulting mixture was maintained at ambient temperature for about 3 hours. Following standard extractive workup, the crude product was purified by flash column chromatography on silica gel (2×16 cm, petroleum ether/ethyl acetate=10/1 elution) to give the title product (1.03 g, 80%). 1H NMR (300 MHz, CDCl3) δ 7.71-7.69 (m, 2H), 7.36 (dd, 1H, J=7.8, 1.8 Hz), 7.25 (dd, 1H, J=7.8, 1.8 Hz), 5.22 (s, 2H), 3.92 (s, 3H), 3.50 (s, 3H); LC-MS: m/z=197 (MH)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14](Br)=[CH:13][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]1[CH:21]=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[H][H]>[Pd].C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]1[CH:21]=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(Br)n(COCc2ccccc2)c1C=O
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccn(COCc2ccccc2)c1C=O
Yield: 103 %

Procedure:
To 43 ml of toluene solution containing 3.66 g (10.0 mmol) of ethyl 1-benzyloxymethyl-5-bromo-2-formyl-1H-pyrrol-3-carboxylate obtained in Reference example 17-(c) were added 2.1 ml of N,N-diisopropylethylamine and 0.4 g of 5% palladium-active carbon, and the mixture was stirred under 1 atm hydrogen atmosphere at room temperature for 6 hours. After completion of the reaction, insoluble material was removed by filtration from the reaction mixture, ethyl acetate was added to the filtrate, and the filtrate was washed successively with water and a saturated aqueous solution of sodium chloride. The organic layer after separation was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.96 g the title compound as a pale yellowish solid substantially quantitatively.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:8][C:7]=1[CH3:37].[OH-].[Na+].Cl>O1CCCC1.C(OCC)C>[CH3:37][C:7]1[CH:8]=[C:9]([S:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=3)=[N:16][C:15]=2[CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:38])=[O:2]
Reactant: COC(=O)CCc1ccc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COc2ccccc2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COc2ccccc2)ccc1CCC(=O)O
Temperature: 25 °C

Procedure:
3-{2-Methyl-4-[4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionic acid methyl ester (100 mg, 0.1796 mmol) is dissolved in tetrahydrofuran (1 mL) and 5N NaOH (1 mL) is added. The mixture is heated to reflux until the conversion is complete. Upon complete conversion, the reaction is cooled to room temperature and 5N HCl (1 mL) is added. The mixture is diluted with diethyl ether and extracted with 1N HCl. The organic layer is washed with water and brine, then dried over anhydrous sodium sulfate. Concentration of the solvent reveals the pure 3-{2-Methyl-4-[4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionic acid in near quantitative yield (93 mg, 0.170 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:23]O>>[CH3:23][O:15][C:14](=[O:16])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=2)=[CH:8][CH:9]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: -10 °C

Procedure:
5.1 g of the product from step C were dissolved in methanol (50 ml). The solution was cooled to −10° C. and treated with thionyl chloride (3 ml) and subsequently heated under reflux for 1 hour. The reaction mixture was evaporated and the residue dissolved in ether. The ether phase was washed with water, dried and evaporated to yield 5.1 g of a reddish brown oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC([CH:18]=[O:19])=CC=1)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:43])=[C:34]([N:37]4[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38]4)[CH:35]=3)[C:30](=[O:44])[C:29]([C:45]([OH:47])=[O:46])=[CH:28]2)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:43])=[C:34]([N:37]4[CH2:41][CH2:40][CH:39]([N:42]=[CH:1][C:2]5[CH:7]=[CH:6][C:5]([O:19][CH3:18])=[CH:4][CH:3]=5)[CH2:38]4)[CH:35]=3)[C:30](=[O:44])[C:29]([C:45]([OH:47])=[O:46])=[CH:28]2)=[CH:23][CH:22]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: O=Cc1ccccc1
Reactant: NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)C1
Product: COc1ccc(C=NC2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3)C2)cc1

Procedure:
In the described fashion of Example 1 replacing benzaldehyde with 4-N,N-dimethylaminobenzaldehyde and using the acid (1) (R=cyclopropyl) described in Example 19 one obtains 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-(4-N,N-dimethylaminobenzylidene)amino-1-pyrrolidinyl)-quinoline-3-carboxylic acid (3) (R=cyclopropyl, Z=4-N,N-dimethylaminophenyl).