Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[CH:7]=[C:6]([CH2:8][N:9]([CH:19]([CH3:21])[CH3:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[NH:5][CH:4]=1.[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>O1CCCC1>[CH:19]([N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:8][C:6]1[N:5]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])[CH:4]=[N:3][CH:7]=1)([CH3:21])[CH3:20]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)N(Cc1cnc[nH]1)c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N(Cc1cncn1COCC[Si](C)(C)C)c1cccc([N+](=O)[O-])c1
Reaction time: 0.75 h

Procedure:
To sodium hydride (149 mg, 55% in mineral oil, 3.42 mmol) in tetrahydrofuran (240 ml) was added a solution of (3H-imidazol-4-ylmethyl)-isopropyl-(3-nitro-phenyl)-amine (685 mg, 2.63 mmol) in tetahydrofuran (100 ml) and stirring was continued for 45 min at room temperature. The reaction mixture was cooled with an ice bath and 2-(trimethylsilyl)ethoxymethylchloride (439 mg, 2.63 mmol) was added. After stirring the suspension overnight the reaction was quenched with saturated sodium bicarbonate solution. Tetrahydrofuran was evaporated and the residue was extracted with ethyl acetate twice. The combined organic layers were washed with water, dried over magnesium sulphate and evaporated. The residue was purified using flash chromatography (SiO2; eluent: heptane/ethyl acetate=80:20) to yield a light yellow oil, (0.20 g, 20%); MS (ISP): 391.3 ((M+H)+.).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[CH3:15][C:16]1[CH:21]=[C:20]([C:22]([OH:24])=O)[CH:19]=[CH:18][N:17]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH3:1][C@H:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:22]([C:20]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:15])[CH:21]=1)=[O:24]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCNC[C@@H]2C)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.7 %

Procedure:
A mixture of 1,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (146 mg, 0.73 mmol), 2-methyl-4-pyridinecarboxylic acid (100 mg, 0.73 mmol), HBTU (277 mg, 0.73 mmol) HOBT (112 mg, 0.72 mmol) and DIPEA (0.38 mL, 2.19 mmol) in DMF (20 mL) was stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM and extracted with saturated sodium bicarbonate. The organic layer was collected and the solvent was evaporated off using the rotary evaporator. The solvent was difficult to remove so it was azeotroped twice with toluene. The residual solid was dissolved in DCM and purified using SP4. The fractions containing product were combined and evaporated to dryness on the rotary evaporator. The product was dissolved in 1,4-dioxane (7.5 mL) and 4M HCl in dioxane (2.5 mL) was added and the reaction stirred for 3 h. A few drops of water were then added and the mixture stirred for a further 45 min. The solvent was then evaporated off on the rotary evaporator. To remove the water, the residue was azeotroped twice with toluene. The residual solid was dissolved in methanol and transfered to an SCX column. Once loaded, the material was washed with 2 column volumes of methanol. The product was eluted from the column with 2M ammonia in methanol and the solvent removed under vacuum to give the title compound (70 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].C(=O)([O-])O.[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O>[C:13]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:7])[CH3:6])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)CCCN
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C)CCCNC(=O)c1ccccc1
Yield: 90.1 %

Procedure:
Into 300 ml of distilled water, were suspended 50 g of 3-aminopropyldimethylamine and 62 g of sodium hydrogencarbonate. To the suspension, while cooling in ice and stirring vigorously, was added dropwise 105 g (1.5 equivalents) of benzoyl chloride. After 6 hours of reaction at room temperature, the reaction mixture was acidified to pH 4 with concentrated hydrochloric acid and extracted with ethyl ether to remove the excess benzoyl chloride. The aqueous layer was adjusted to pH 12 with 5N aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extract was dried over sodium sulfate and stripped of the solvent by distillation under reduced pressure to give 91 g of 3-benzamidopropyldimethylamine. To this residue, was added a solution of 118 g (1 equivalent) of N-3-bromopropylphthalimide in 300 ml of tetrahydrofuran. After stirring at room temperature for 18 hours, the precipitated colorless crystals were collected by filtation, washed with tetrahydrofuran and dried to yield 188 g (90% yield) of colorless crystals of the quaternary ammonium salt. This salt was dissolved in 1,000 mg of 6N hydrochloric acid and heated at 110° C. for 8 hours to effect hydrolysis. After cooling, the precipitated phthalic and benzoic acids were removed by filtration and the filtrate was evaporated to dryness under reduced pressure to remove the excess hydrochloric acid. The residue was dissolved in distilled water and passed through a column of an ion exchange resin Dowex®-1 (Cl-type, 600 ml in volume). The effluent was evaporated to dryness under reduced pressure to yield 96 g (90% yield) of bis(3-aminopropyl)dimethylammonium trihydrochloride. This compound was too hygroscopic to determine its melting point. The PMR spectrum measured in heavy water showed the following δ values: 2.1-2.8 ppm, 4H (m), 2.4 ppm, 6H (s), 3.1-3.9 ppm, 8H (m) (wherein, the letters in parentheses indicate the signal types: m: multiplet; s: singlet). These values were in compliance with the assigned structure. The IR absorption maxima (in wave number, cm-1), as measured in KBr-tablet, were: 3425, 2975, 2625, 2000, 1600, 1480, 1470, 1350, 1320, 1300, 1230, 1200, 1160, 1140, 1060, 1040, 1000, 930, 840, and 760.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[C:4](=[O:32])[CH2:3]1.[Li+].[OH-]>O1CCCC1.CO>[CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[C:4](=[O:32])[CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)N(c2ccc(C)cc2)C(=O)CC3(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N2C(=O)CC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 50 °C

Procedure:
To a solution of 0.080 g (0.18 mmol) of ethyl 4-(2-(4,4-dimethyl-3,4-dihydro-N-(4-methylphenyl)-2(1H)-quinolinon-7-yl)ethynyl)benzoate (Compound 21) in 4.0 mL of tetrahydrofuran and 1.0 mL of methanol was added 1.0 mL (1.3 mmol) of 1.3M aqueous LiOH. The resulting solution was heated at 50° C. for 5 hours. The mixture was concentrated in vacuo, water was added, and the mixture was extracted with ether (2x). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting crude product was purified by recrystallization from acetonitrile to give the title compound as a yellow solid. PNMR (500 MHz, DMSO) d 1.31 (6 H, s), 2.35 (3 H, s), 2.59 (2 H, s), 6.32 (1 H, d, J=7.1 Hz), 7.10 (1 H, d, J=8.3 Hz), 7.23 (1 H, dd, J=8.1, 1.7 Hz), 7.32 (1 H, d, J=8.3 Hz), 7.42 (1 H, d, J=8.1 Hz), 7.51 (1 H, d, J=8.3 Hz), 7.84 (1 H, d, J=8.3 Hz).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([OH:22])[CH3:21])[CH:15]=2)[N:8]=1)=O.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31]N>>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([OH:22])[CH3:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CC(O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Reactant: NNc1ccccc1F
Product: CC(O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(1-hydroxy-ethyl)-phenyl]-1H-pyridazin-4-one (A-36) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=377.1 (M+H)+
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:32])[CH2:8][CH2:9][CH2:10][C:11]([CH3:31])(O)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH3:29])(O)[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:3]>[Pd].C(O)(=O)C>[CH3:26][CH:24]([CH2:23][CH2:22][CH2:21][CH:20]([CH2:19][CH2:18][CH2:17][CH:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][CH2:8][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:32])[CH3:31])[CH3:29])[CH3:27])[CH3:25]
Reactant: CC(C)CCCC(C)CCCC(C)(O)CCCCC(C)(O)CCCC(C)CCCC(C)C
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C

Procedure:
Then in 300 ml autoclave were placed 20 g of the distilled 2,6,10,15,19,23-hexamethyltetracosane-10,15-diol, 40 ml of glacial acetic acid and 1 g of 5 % palladium on active carbon and the mixture was hydrogenated at 200° C under a hydrogen pressure of 100 kg/cm2 for 10 hours. The catalyst was filtered off, the reaction mixture and the acetic acid was distilled off to afford squalane in 100 % conversion ratio, which was distilled through a packed column to give 14.2 g of the purified squalane.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C:12](O)=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.[NH:66]1[CH2:71][CH2:70][CH:69]([N:72]2[CH2:81][C:80]3[C:75](=[CH:76][CH:77]=[CH:78][CH:79]=3)[NH:74][C:73]2=[O:82])[CH2:68][CH2:67]1>O.C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[CH2:9][C:10]([CH2:11][C:12](=[O:13])[N:66]1[CH2:67][CH2:68][CH:69]([N:72]2[CH2:81][C:80]3[C:75](=[CH:76][CH:77]=[CH:78][CH:79]=3)[NH:74][C:73]2=[O:82])[CH2:70][CH2:71]1)([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(CC(=O)O)(Cc1ccc(C)c(C)c1)C(=O)OCC
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)(Cc1ccc(C)c(C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 10.0 g (29.7 mmol) 4-(3,4-dimethyl-phenyl)-3,3-bis-ethoxycarbonyl-butanoic acid, 10.5 g (32.7 mmol) TBTU, 4.2 g (30.5 mmol) HOBt, 5.8 mL (32.4 mmol) ethyldiisopropylamine, 270 mL THF and 30 mL water was stirred for 15 min at RT and then combined with 7.6 g (32.9 mmol) 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one. The reaction mixture was stirred for 5 h at RT and evaporated down under reduced pressure. The residue was stirred with 150 mL saturated NaHCO3 solution, suction filtered, washed with water and dried in the circulating air dryer.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([N:15]([CH3:17])[CH3:16])=[CH:10][C:9]=1[NH:18][C:19](=O)[CH2:20][C:21]([C:23]1C=C[CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1)=O)(C)(C)C.[C:33](O)([C:35](F)(F)F)=[O:34]>C(Cl)Cl>[CH3:17][N:15]([CH3:16])[C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[NH:7][C:33](=[O:34])[CH2:35][C:19]([C:20]3[CH:26]=[C:25]([CH:24]=[CH:23][CH:21]=3)[C:29]#[N:30])=[N:18][C:9]=2[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1N(C)C
Solvent: ClCCl
Product: Cc1cc2c(cc1N(C)C)N=C(c1cccc(C#N)c1)CC(=O)N2

Procedure:
The title compound was prepared from {2-[3-(3-Cyano-phenyl)-3-oxo-propionyl-amino]-4-dimethylamino-5-methyl-phenyl}-carbamic acid tert-butyl ester (Example M76) (0.24 g, 0.55 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pale yellow solid (114 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].O[CH2:11][CH2:12][C@H:13]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[O:9][CH2:11][CH2:12][C@H:13]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH3:14]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: C[C@H](CCO)N1C(=O)c2ccccc2C1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](CCOc1c(Cl)cccc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 301.7 %

Procedure:
To a solution of 2,6-dichlorophenol (14.9 mg, 0.0910 mmol) in THF (1.5 mL) was added (R)-2-(4-hydroxybutan-2-yl)isoindoline-1,3-dione (20 mg, 0.091 mmol) and triphenylphosphine (47.9 mg, 0.182 mmol) and the reaction mixture was cooled to 0° C. in an ice/water bath. DIAD (0.035 mL, 0.18 mmol) was added drop wise and the reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was allowed to warm to rt and stirred at rt for 16 h. The reaction mixture was concentrated under vacuum to yield a yellow oil that was purified by flash chromatography. Intermediate 8A (0.10 g, 96% yield) was isolated as a clear oil. LC-MS (ESI) 365 (M+H), RT=2.84 min (Method A).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][C:8]1[N:13]=[C:12]([C:14]2[N:15]=[C:16]([N:19]=[C:20]([NH2:22])[NH2:21])[S:17][CH:18]=2)[CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O.C(OCC)(=O)C.O1CCCC1>[NH2:21][C:20](=[N:19][C:16]1[S:17][CH:18]=[C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[N:13]=2)[N:15]=1)[NH2:22]
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)NCc1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
Methanesulfonyl chloride (0.58 ml) was added a mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (1.8 g) and pyridine (0.81 ml) in dichloromethane (40 ml) under ice-cooling and the mixture was stirred for 23 hours at ambient temperature. The reaction mixture was added a mixture of tetrahydrofuran, ethyl acetate and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was recrystallized-from an aqueous methanol to give 2-(diaminomethyleneamino)-4-(6-methanesulfonylaminomethylpyridin-2-yl)thiazole (0.4 g).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH2:10][Cl:11])[CH2:8][S:9][C@H:4]12.CN(C)C1C=CC=CC=1.Cl.[CH2:40]([O:42][N:43]=[C:44]([C:48]1[N:52]=[C:51]([NH2:53])[S:50][N:49]=1)[C:45](Cl)=[O:46])[CH3:41].Cl>C(Cl)Cl.O>[CH2:40]([O:42][N:43]=[C:44]([C:48]1[N:52]=[C:51]([NH2:53])[S:50][N:49]=1)[C:45]([NH:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:13])=[C:7]([CH2:10][Cl:11])[CH2:8][S:9][C@H:4]12)=[O:46])[CH3:41]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CCON=C(C(=O)Cl)c1nsc(N)n1
Agent: Cl
Solvent: O
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1nsc(N)n1
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 88.4 %

Procedure:
To a suspension of diphenylmethyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (27 g) in methylene chloride (300 ml) was added N,N-dimethylaniline (36.2 g) under cooling in an ice bath at 5° C. To the solution was added portionwise 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloride hydrochloride (syn isomer) (16.2 g) below 11° C. and the mixture was stirred for 45 minutes at 5° C. The reaction mixture was diluted with a mixed solvent of methylene chloride (100 ml) and water (200 ml) and adjusted to pH 2 with 1N hydrochloric acid. The organic layer was separated out, washed with water, dried over magnesium sulfate and evaporated to dryness. The residue was triturated in diethyl ether to give diphenylmethyl 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (32.4 g), mp 120° to 125° C. (dec.).
Reaction SMILES: C1([C@H](NCC2C=CC=C(C(C)(C)C)C=2O)[C@@H](NCC2C=CC=C(C(C)(C)C)C=2[OH:27])C2C=CC=CC=2)C=CC=CC=1.[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[CH:46]([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2.C(OO)(C)(C)C>C1(C)C=CC=CC=1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Zr+4]>[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[C:46]([OH:27])([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2
Reactant: CC(C)(C)c1cccc(CN[C@@H](c2ccccc2)[C@@H](NCc2cccc(C(C)(C)C)c2O)c2ccccc2)c1O
Reactant: COC(=O)C1Cc2cc(Cl)ccc2C1=O
Agent: [Zr+4]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)(C)OO
Solvent: Cc1ccccc1
Product: COC(=O)C1(O)Cc2cc(Cl)ccc2C1=O
Temperature: 65 °C
Reaction time: 3.5 h
Yield: 85 %

Procedure:
A chiral zirconium complex was prepared by rapidly stirring (forming a vortex) a mixture of zirconium(IV) acetylacetonate (43.5 mg, 0.089 mmol) and 2,2′-[[(1S,2S)-1,2-diphenyl-1,2-ethanediyl]bis(iminomethylene)]bis[6-(1,1-dimethylethyl)-phenol] (Formula IIIb wherein R6 is H, 0.096 g, 0.18 mmol) in toluene (1.00 mL) at 50° C. for one hour. The resulting solution was evaporated to dryness in vacuo, then a solution of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate (0.500 g, 2.23 mmol) (Formula IIa wherein R1 is OCH3 and R4 is Cl) in toluene (2.00 mL) was added. The reaction mixture was heated to 65° C., and then an aqueous solution of tert-butyl hydroperoxide (70%, 0.316 g, 0.340 mL, 2.46 mmol) was added. After 3.5 hours at 65° C., the reaction was quenched by adding an acetonitrile solution (7.00 mL) containing biphenyl (0.125 g) as an HPLC internal standard and cooling to ambient temperature. Analysis by quantitative and chiral HPLC showed 100% conversion of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate, forming methyl 5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate in 85% yield (85% chemoselectivity) and 94% enantiomeric excess of the S-enantiomer.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:22]=[C:21]([OH:23])[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=4)[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28]1(C)C=CC=CC=1.S(OC)(OC)(=O)=O>CCCCCC>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:22]=[C:21]([O:23][CH3:28])[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=4)[N:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccccc1
Reactant: CC(=O)Nc1ccc2nc(-c3ccc(C4CCCCC4)cc3)cc(O)c2c1
Solvent: CCCCCC
Solvent: COS(=O)(=O)OC
Product: COc1cc(-c2ccc(C3CCCCC3)cc2)nc2ccc(NC(C)=O)cc12
Temperature: 70 °C
Yield: 96 %

Procedure:
N-[2-(4-Cyclohexylphenyl)-4-hydroxy-quinolin-6-yl]-acetamide 35.7 g (0.099 moles) was placed in a 500 mL three neck round bottom flask equipped with a condenser, magnetic stirrer and nitrogen inlet with 250 mL of toluene. The material was suspended by stirring and 20.6 mL (0.21 moles) of dimethyl sulfate was added. The suspension was then heated with a silicone oil heating bath, to gentle reflux for 18 hr. After thwas time the reaction was allowed to cool and hexane was added. Solids were collected by vacuum filtration and washed with hexane. After drying, the solids were suspended in a 2 L Erlenmeyer flask with 1 L of 5% sodium hydroxide solution. The suspension was vigorously stirred and heated to 70° C. for 30 min. This converted the salt form of the material to the free base and removed some impurities. After cooling the solids were collected by vacuum filtration and washed with water. The product was dried in a vacuum oven to give 35.8 g (96%) of material, which contained about 30% of side products, with the N-methylated material constituting the major impurity. The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[CH:6]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:7](=[O:35])[N:8]([CH2:21][C:22]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]3)=[O:23])[CH2:9][CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=3[O:19][CH3:20])[C:4]=2[CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[CH:6]([CH2:36][CH:37]([CH3:38])[CH3:39])[C:7](=[O:35])[N:8]([CH2:21][C:22]([N:24]3[CH2:25][CH2:26][CH:27]([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]3)=[O:23])[CH2:9][CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=3[O:19][CH3:20])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)C1CCN(C(=O)CN2CC(c3cccc(OC)c3OC)c3cc(Cl)ccc3C(CC(C)C)C2=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(C2CN(CC(=O)N3CCC(C(=O)O)CC3)C(=O)C(CC(C)C)c3ccc(Cl)cc32)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64 mg of the compound from Example 20 (0.11 mol) are dissolved in 3.3 ml of dioxane/water (2:1), mixed with 165 μl of 1 N sodium hydroxide solution and stirred at room temperature overnight. The reaction solution is acidified (pH 2) with 1 N hydrochloric acid and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated in a rotary evaporator, and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 61 mg (100% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[NH:4][N:5]=[C:6]([Cl:9])[C:7]=1Cl.[CH3:11][O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][NH2:24])=[CH:15][CH:14]=1>C(O)C>[Cl:1][C:2]1[C:3](=[O:10])[NH:4][N:5]=[C:6]([Cl:9])[C:7]=1[NH:24][CH2:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([O:12][CH3:11])=[CH:14][CH:15]=1
Reactant: COc1ccc(CN)c2ccccc12
Reactant: O=c1[nH]nc(Cl)c(Cl)c1Cl
Solvent: CCO
Product: COc1ccc(CNc2c(Cl)n[nH]c(=O)c2Cl)c2ccccc12
Reaction time: 4 h

Procedure:
A mixture comprising 800 mg of 4,5,6-trichloro-3(2H)pyridazinone, 2.68 g of 4-methoxy-1-naphthylmethylamine and 10 ml of ethanol, was refluxed under stirring for 4 hours. After cooling, precipitated crystals were collected by filtration. Then, the product was dissolved in hot ethyl acetate and treated by silica gel. The filtrate was concentrated, and precipitated crystals were collected by filtration to obtain 330 mg of the above identified compound as colorless crystals having a melting point of from 228° to 231° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1.[CH2:10]([C:12]([CH2:14][CH3:15])=O)[CH3:11]>[Pt].C(O)(=O)C>[CH3:11][CH2:10][CH:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1)[CH2:14][CH3:15]
Reactant: Cc1ccc(N)cc1C
Reactant: CCC(=O)CC
Agent: [Pt]
Solvent: CC(=O)O
Product: CCC(CC)Nc1ccc(C)c(C)c1
Temperature: 60 °C
Reaction time: 0.9 h
Yield: 72.2 %

Procedure:
Amounts of 24.2 g (0.20 mole) of 3,4-xylidine 38.4 g (0.44 mole) of diethyl ketone, 1.2 g of 5% platinum on carbon, and 0.26 g (2 mole %) of glacial acetic acid were charged to an autoclave and the autoclave was sealed, evacuated, purged with hydrogen and then pressurized with hydrogen to 50 psi. The temperature of the autoclave was raised to 60° C. and held at 60°-68° C. for 0.9 hours (very little, if any, hydrogen was being absorbed at this point). The autoclave was vented and the product filtered to separate the catalyst. The lower, aqueous phase, of the filtrate was separated and the upper, organic phase, was evaporated to constant weight of 35.0 g. Analysis of the residue showed it to be 78.8% pure, corresponding to 28.7 g of N-3-pentyl-3,4-xylidine (72.2% yield).