Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[NH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])=[CH:6][CH:5]=1.C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[Br:1][C:14]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)=[C:11]([C:19]([F:22])([F:20])[F:21])[NH:12][C:13]=1[C:15]([F:16])([F:17])[F:18]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)c(C(F)(F)F)[nH]1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1[nH]c(C(F)(F)F)c(-c2ccc(Cl)cc2)c1Br
Yield: 34 %

Procedure:
Bromine (0.527 g, 0.17 mL, 0.0033 mol) is added to a solution of 3-(p-chlorophenyl)-2,5-bis(trifluoromethyl)pyrrole (0.94 g, 0.003 mol), acetic acid (6 mL) and sodium acetate (0.984 g, 0.012 mol). After 1 hour the reaction mixture is diluted with water and extracted with ether. The combined organic extracts are washed sequentially with water, sodium metabisulfite solution, water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a colorless oil. The oil is chromatographed using silica gel and eluted with methylene chloride to give the title compound as a colorless oil (0.4 g, 34%). Identified by IR and NMR spectral analyses.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.B(OC)(OC)[O:25]C.C(O)(=O)C.OO>C1COCC1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([OH:25])[CH:18]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: CC1(C)CCCC(C)(C)N1
Agent: OO
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Oc1cc(Br)ccc1F
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 85.3 %

Procedure:
To a solution of 2,2,6,6-tetramethyl piperidine (5.6 mL, 33.2 mmol) in THF at −20° C. was added n-BuLi (1.6 M in hexanes, 18.8 mL, 30 mmol). The mixture was stirred at −20° C. for 10 min before it was cooled to −78° C. 1-Bromo-4-fluorobenzene (2.95 mL, 27 mmol) was added over 10 min and the mixture was stirred at −78° C. for 2.0 h before trimethyl borate (6.0 mL, 54 mmol) was added. The mixture was stirred at −78° C. for 30 min and then at rt for 2.0 h. After it was cooled back to 0° C., glacial acetic acid (4.86 mL, 81 mmol) was added and stirred for 30 min, followed by addition of 30% H2O2 (4.86 mL, 81 mmol). The mixture was stirred at rt for 24 h, quenched by addition of MnO2 (40 mg). After stirring at rt for 30 min, the cloudy solution was filtered through a pad of wet Celite® and extracted with EtOAc. The EtOAc layer was washed with aqueous NaHSO3, brine and dried over Na2SO4. The crude residue was purified by flash column chromatography (EtOAc:hexanes=1:5) to give 4.4 g (85%) of 7A as a liquid. 1H NMR (400 MHz, CDCl3) δ ppm 5.39 (s, 1H) 6.90-6.98 (m, 2H) 7.14 (dd, J=8.13, 1.98 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O1CCCC1.[Cu]I>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:4][C:3]=1[CH3:10]
Reactant: c1nc[nH]n1
Reactant: Cc1cc(I)cc(C)c1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1cc(-n2cncn2)cc(C)c1Br
Temperature: 130 °C

Procedure:
A mixture of 2-bromo-5-iodo-1,3-dimethylbenzene (500 mg), 1,2,4-triazole (340 mg), potassium carbonate (770 mg), and copper(I) iodide (232 mg) in N-methyl-2-pyrrolidinone is stirred at 130° C. over night. More potassium carbonate (770 mg) and copper(I) iodide (232 mg) are added and the mixture is heated to 150° C. for 4 h. After cooling to room temperature the mixture is diluted with tetrahydrofuran and filtered. The filtrate is concentrated in vacuo and purified by HPLC on reversed phase to give the title compound. LC (method 7): tR=0.99 min; Mass spectrum (ESI+): m/z=252, 254 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:19]/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22])[C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])=[CH:5][CH:4]=1.[CH2:30]([N:37]=[C:38]=[O:39])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>ClCCl>[CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:19]/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22])[C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:38]([NH:37][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:39])=[CH:7][CH:8]=1
Reactant: CCCCCCCN=C=O
Reactant: CC(C)=CCC/C(C)=C/CN(C(=O)c1ccccc1N)c1ccc(N(C)C)cc1
Solvent: ClCCl
Product: CCCCCCCNC(=O)Nc1ccccc1C(=O)N(C/C=C(\C)CCC=C(C)C)c1ccc(N(C)C)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of N-(4-dimethylaminophenyl)-N-geranyl-2-aminobenzamide (0.8 g) in dichloromethane (10 ml) was added under ice-cooling heptyl isocyanate (0.56 g) and the mixture was stirred overnight while returning slowly to room temperature. After distilling off the solvent, the 10 residue was purified by a silica gel column chromatography (hexane:ethyl acetate=3:1) to give N-(4-dimethylaminophenyl)-N-geranyl-2-(3-heptylureido)benzamide (0.98 g, 89%) as an oily product.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12](OC)[CH2:13][Cl:14].S(=O)(=O)(O)O>O>[CH3:10][O:11][CH:12]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][Cl:14]
Reactant: NC(=O)c1ccccc1
Reactant: COC(CCl)OC
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(CCl)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
12.1 g of benzamide and 14.3 g of chloroacetaldehyde dimethyl acetal were agitated while being cooled in an ice bath, and into this, 7 ml of concentrated sulfuric acid was dripped over a period of 1 hour. After agitating this for 2 hours at room temperature, 200 ml of water was added to the reaction fluid, and this was extracted in 300 ml of chloroform. The extracted layer was washed twice with 100 ml of water, and the chloroform and excess chloroacetaldehyde dimethyl acetal were removed by distillation under reduced pressure, and 15.0 g of compound (1) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[N:6][C:7]=1F.[CH:22]([O:25][C:26]1[NH:30][N:29]=[C:28]([NH2:31])[CH:27]=1)([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]1[C:7]([NH:31][C:28]2[CH:27]=[C:26]([O:25][CH:22]([CH3:24])[CH3:23])[NH:30][N:29]=2)=[N:6][C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1
Reactant: C[C@H](Nc1nc(F)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c([N+](=O)[O-])cc2F)n[nH]1
Temperature: 55 °C
Yield: 40.6 %

Procedure:
To a solution of (S)-5,6-difluoro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine (Method 23; 0.60 g, 2.0 mmol) in THF (10 ml) at room temperature was added 5-isopropoxy-1H-pyrazol-3-amine (0.50 g, 3.0 mmol), and DIEA (0.29 g, 2.2 mmol). The reaction was then heated to 55° C. for 24 hours, cooled to room temperature, and quenched with water. The reaction was then extracted with DCM (2×75 ml), and the combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.34 g, 40%). 1H NMR (400 MHz, CD3OD) δ 8.00 (d, J=10.9 Hz, 1H), 7.45-7.35 (m, 2H), 7.07-7.03 (m, 2H), 5.88-5.71 (m, 1H), 5.48-5.30 (m, 1H), 4.58-4.29 (m, 1H), 1.68-1.56 (m, 3H), 1.34-1.28 (m, 6H). MS: Calcd.: 418. Found: [M+H]+ 419.
Reaction SMILES: C[Sn](C)(C)[C:3]1[S:7][C:6]([S:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:5][CH:4]=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1>CN1CCCC1=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:27][C:23]1[N:22]=[C:21]([C:3]2[S:7][C:6]([S:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:10])=[O:9])=[CH:5][CH:4]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: C[Sn](C)(C)c1ccc(S(=O)(=O)Oc2ccccc2)s1
Reactant: Cc1cccc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cccc(-c2ccc(S(=O)(=O)Oc3ccccc3)s2)n1
Temperature: 90 °C

Procedure:
A mixture of phenyl 5-(trimethylstannanyl)-2-thiophenesulfonate (1.3 g, 3.2 mmol) (WO 9827069), 2-bromo-6-methylpyridine (550 mg, 3.2 mmol) and dichlorobis(triphenylphosphine)palladium (II) (100 mg) in 1-methyl-2-pyrrolidinone (10 ml) was heated at 90° C. under argon for 4 hours. After cooling to room temperature the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography (1:10 ethyl acetate:pentane) to afford the title product (D11). MS (ES+) m/e 332 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[NH:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=1)[C:7]#N.O=[CH:24][C:25](=C)[CH3:26]>>[CH3:26][C:25]1[CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)[N:5]([C:4]2[CH:19]=[CH:20][C:21]([CH3:22])=[C:2]([CH3:1])[CH:3]=2)[CH:24]=1
Reactant: C=C(C)C=O
Reactant: Cc1ccc(NC(C#N)c2ccc(S(N)(=O)=O)cc2)cc1C
Product: Cc1cc(-c2ccc(S(N)(=O)=O)cc2)n(-c2ccc(C)c(C)c2)c1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(3,4-dimethylanilino)-α-(4-sulfamoylphenyl)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a slightly yellow powder (yield 43%), melting at 118-120° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13](=O)[CH:14]=[CH:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1.[C:27]([NH:30][NH2:31])([NH2:29])=[NH:28].[ClH:32]>Cl.C(O)C>[ClH:32].[C:27]([NH:30][N:31]=[C:13]([CH:14]=[CH:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH:12]=[CH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[NH:28])[NH2:29]
Reactant: O=C(C=Cc1ccc2ccccc2c1)C=Cc1ccc2ccccc2c1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: N=C(N)NN=C(C=Cc1ccc2ccccc2c1)C=Cc1ccc2ccccc2c1

Procedure:
Utilizing the general procedure of Example 1, 6.9 grams of 1,5-bis(2-naphthyl)-1,4-pentadien-3-one, 2.5 grams of aminoguanidine hydrochloride, 5 drops of concentrated hydrochloric acid, and 250 ml. of ethanol, and employing a 16 hour reflux period, 6.4 g. of the above compound is obtained, melting at 232°-234° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.N1C=CC=CC=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25]>ClCCl>[N+:10]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=[CH:8][C:6]=1[NH:7][C:24](=[O:25])[C:23]1[CH:22]=[C:21]([O:20][CH3:19])[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=1)([O-:12])=[O:11]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cc(OC)c(OC)c(OC)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 4-methoxy-2-nitroaniline (45 mmole, 6.8 g) in dichloromethane (120 ml) and pyridine (75 mmole, 6 ml) is added 3,4,5-trimethoxybenzoylchloride (50 mmole, 11.5 g) in dichloromethane (40 ml). The mixture is stirred at room temperature over night. The precipitate is filtered off and dried in vacuo to yield the title product as an orange solid (74%).
Reaction SMILES: [CH2:1]([Si]1(OC(C)C)N(C)[C@@H](C)[C@H](C2C=CC=CC=2)O1)[CH:2]=[CH2:3].[CH:21](=[O:30])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.CCOC(C)=O>C1(C)C=CC=CC=1>[C:24]1([CH2:23][CH2:22][C@@H:21]([OH:30])[CH2:3][CH:2]=[CH2:1])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=CC[Si]1(OC(C)C)O[C@@H](c2ccccc2)[C@H](C)N1C
Reactant: O=CCCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CC[C@H](O)CCc1ccccc1
Temperature: 21 °C
Reaction time: 18 h
Yield: 67.5 %

Procedure:
Enantioselective allylation of dihydrocinnamaldehyde to give (3R)-1-phenyl-hex-5-en-3-ol: To a solution of (4S,5S)-2-Allyl-2-isopropoxy-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (0.437 g, 1.5 mmol) in toluene (2.5 mL) was added dihydrocinnamaldehyde (0.132 mL, 1.0 mmol). The mixture was allowed to stir at ambient temperature (˜21° C.) for 18 hours. To this solution was added 1N HCl (4 mL) and EtOAc (4 mL) and the mixture was stirred for 10 min. The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organics were dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (5% EtOAc/hexanes) to afford 0.119 g (69%) of (3R)-1-phenyl-hex-5-en-3-ol in 94% enantiomeric excess (ee).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[NH2:13][OH:14]>C(O)C>[OH:14][NH:13][C:7](=[NH:8])[C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Reactant: NO
Solvent: CCO
Product: N=C(NO)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 105.6 %

Procedure:
To a solution of 4-(trifluoromethyl)benzonitrile (10 g) in ethanol (100 ml) was added 50% hydroxylamine aqueous solution (11.6 g), and stirred at 80° C. overnight. After completion of the reaction, the solvent was evaporated, and water was added thereto. The insoluble matter was collected by filtration, and then dried to give N-hydroxy-4-(trifluoromethyl)benzamidine (12.6 g).
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1>C(O)(=O)C.O=[Pt]=O>[CH:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: O=C(O)c1nccc2ccccc12
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C(O)C1NCCc2ccccc21
Yield: 45.4 %

Procedure:
A solution of 1-isoquinolinecarboxylic acid (1.67 g) in glacial acetic acid (25 mL) was hydrogenated at 60 p.s.i. over PtO2 (270 mg). When the reaction was complete, the mixture was filtered through diatomaceous earth (Celite), washing the solid pad with MeOH, and the filtrate was concentrated to dryness. The resultant white solid was triturated with cold water and filtered to provide the title compound (775 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:13]=[CH:12][C:6]([C:7](=[NH:11])OCC)=[CH:5][CH:4]=1.[CH2:14]([O:16][CH:17]([O:20][CH2:21][CH3:22])[CH2:18][NH2:19])[CH3:15]>C(O)C>[CH2:14]([O:16][CH:17]([O:20][CH2:21][CH3:22])[CH2:18][NH:19][C:7](=[NH:11])[C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:13][CH:12]=1)[CH3:15]
Reactant: CCOC(=N)c1ccc(F)cc1
Reactant: CCOC(CN)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(CNC(=N)c1ccc(F)cc1)OCC
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-fluorobenzimidate hydrochloride (18.5 g) in ethanol (90 mL) at 0° C. was added aminoacetaldehyde diethyl acetal (14.5 mL) and the resulting solution was kept at 5° C. overnight. The solvent was evaporated, the resulting oil was dissolved in 1N sodium hydroxide (200 mL), and the solution was extracted with dichloromethane. The organic extracts were dried and evaporated to yield N-(2,2-diethoxyethyl)-4-fluorobenzamidine as an oil (21 g); MS: m/z=255(M+1).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1.C1(C)C=CC=CC=1>CS(C)=O>[CH3:22][CH:23]1[NH:24][CH2:25][CH2:26][N:27]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[N:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[C:6]([C:19]([OH:21])=[O:20])[C:7](=[O:18])[C:8]3=[CH:9][C:10]=2[F:17])[CH2:28]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC1CNCCN1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 55 °C
Yield: 76 %

Procedure:
Forty grams of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid and 28.4 g (2.1 eq) of 2-methyl piperazine were put in suspension in DMSO (800 mL) under nitrogen blanket. The mixture was heated to 55° C. during 24 hours. Subsequently, toluene (200 mL) was added, the reaction mixture was cooled to 5° C., and held at this temperature overnight. The solution was filtered and dried under vacuum to obtain 43.5 g after assay (76% yield) of gatifloxacin.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:23])[C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[Br:32][CH:33]([CH2:37][CH2:38]Cl)[C:34](Br)=[O:35].[OH-].[Na+]>C(#N)C.O>[Br:32][CH:33]1[CH2:37][CH2:38][N:1]([C:2]2[CH:7]=[CH:6][C:5]([N:8]([CH3:23])[C:9](=[O:22])[C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)=[CH:12][CH:11]=3)=[CH:4][CH:3]=2)[C:34]1=[O:35]
Reactant: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N)cc1
Reactant: O=C(Br)C(Br)CCCl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(Br)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(4-Aminophenyl)-4-cyclohexyl-N-methylbenzamide (3.0 g) in acetonitrile (30 ml) was mixed with trisodium phosphate (0.95 g) and, at 0° C., 2-bromo-4-chlorobutyryl bromide (2.9 g) was added. After one hour, a solution of sodium hydroxide (0.85 g) in water (10 ml) was added and the mixture was stirred vigorously at room temperature for 6 hours. The same amount of sodium hydroxide solution was then added, and stirring was continued for 48 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase ethyl acetate/heptane 1:2). This resulted in the product with the molecular weight of 455.40 (C24H27BrN2O2); MS (ESI): 456 (M+H+).
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:3]1.CC(C)=[O:21].O>[B-](F)(F)(F)F.[Ag+].CO>[OH:21][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:3]1
Reactant: CC(C)=O
Reactant: O=C(O)CCCCCCCCC1=CC(Br)CC1=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCCCC1=CC(O)CC1=O
Reaction time: 2 h

Procedure:
To a stirred solution of 57.2 g. of crude 4-bromo-2-(8-carboxyoctyl)cyclopent-2-en-1-one (Example 100) in 500 ml. of acetone and 325 ml. of water at 3°C. is added 44.1 g. (0.226 moles) of silver fluoborate during a 15 minute period. The mixture is stirred at 0°-3°C. for 2 hours and filtered. The filtrate is diluted with water, saturated with solid sodium chloride, and extracted with ether. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Partition chromatography of the residue on Celite gives white crystals, m.p. 58°-66°C., λ max.MeOH = 223 mμ (7800); ν max (KBR) = 3340 (hydroxyl groups), 1705 (carbonyl groups), and 1625 cm-1 (olefin group).
Reaction SMILES: [CH:1](=[C:8]1[CH2:12][CH:11]([CH2:13][CH3:14])[O:10][C:9]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H][H]>[Pd].C(O)C>[CH2:1]([CH:8]1[CH2:12][CH:11]([CH2:13][CH3:14])[O:10][C:9]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC=C1CC(CC)OC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCC1CC(CC)OC1=O
Yield: 94.2 %

Procedure:
The product prepared above was hydrogenated following the general procedure described in Example I. For the reaction, 2.1 g 3-heptylidene-5-ethyldihydro-2(3H)-furanone (0.010 mole) was combined with 0.1 g 5% palladium on carbon and 5 ml ethanol and hydrogen gas slowly introduced for 1.5 hours. Upon removal of the catalyst and evaporation of the solvent, 2.0g (97% assay by GLC; 95% yield) 3-heptyl-5-ethyldihydro-2(3H)-furanone was recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[H-].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-n2ccnc2)cc1
Temperature: 130 °C

Procedure:
1-Chloro-4-fluorobenzene (16.3 g, 124 mmol) and imidazole (5.0 g, 73.4 mmol) are dissolved in N,N-dimethylformamide (30 ml) and admixed while stirring with sodium hydride (60% strength in mineral oil; 3.82 g, 95.4 mmol) and then heated at 130° C. for 5 hours. After cooling, the reaction mixture is slowly poured into water. The precipitate formed is subsequently filtered off, washed with petroleum ether and subsequently dried under reduced pressure. This gives 10.3 g of 1-(4-chlorophenyl)imidazole.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]([F:23])([F:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O>ClCCl>[Br:1][CH2:2][C:3]([N:19]1[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7]([F:22])([F:23])[F:6])[CH2:21][CH2:20]1)=[O:4]
Reactant: FC(F)(F)c1ccccc1CCN1CCNCC1
Reactant: O=C(Cl)CBr
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)N1CCN(CCc2ccccc2C(F)(F)F)CC1
Reaction time: 0.75 h

Procedure:
Bromoacetyl chloride (0.125 mL) was added slowly to a chilled (5 ° C.) solution of 1-[2-[2-(trifluoromethyl)phenyl]ethyl]piperazine (0.774 g) in dichloromethane (20 mL) and the mixture was stirred in an ice bath for 45 minutes, then at room temperature for 18 hours. After the addition of water (20 mL), the organic layer was separated and washed in turn with 0.5N hydrochloric acid and sodium bicarbonate solution. The dried (MgSO4) extract was evaporated to give 0.5 g of 1-(2-bromo-1-oxoethyl)-4-[2-[2-(trifluoromethyl)phenyl]ethyl]piperazine.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:19])[NH:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:7]([S:8]([N:13]1[CH:14]([C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:19])[CH2:15][CH2:16][CH2:17][NH:12]1)(=[O:10])=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: O=C(OCCCCc1ccccc1)C1CCCNN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCCCc1ccccc1)C1CCCNN1S(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
A solution of α-toluene sulfonyl chloride (1.12 g, 5.77 mmol) in CH2Cl2 was added to a CH2Cl2 solution containing 4-phenylbutyl perhydropyridazinecarboxylate (1.37 g, 5.2 mmol) and triethylamine (0.83 ml, 6 mmol). The reaction was stirred overnight at room temperature under nitrogen atmosphere, and then diluted to 50 ml CH2Cl2. The organic layer was washed with water, dried, and concentrated. The crude material was purified by silica gel column to yield 1.4 g (64%) final product as clear oil. Rf=0.60 (2:1 hexane:EtOAc). 1H NMR (CDCl3, 400 MHz): δ 1.68 (m, 8H); 2.67 (m, 2H); 2.90 (m, 1H); 3.38 (m, 2H); 4.22 (m, 5H); 7.32 (m, 10H). Anal. Calcd. for C22H28N2S1O4: C, 63.44; H, 6.78; N, 6.73, S, 7.70. Found: C, 63.86; H, 6.83; N, 6.41, S, 7.58.