Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH3:24][CH:25]([OH:27])[CH3:26]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:27][CH:25]([CH3:26])[CH3:24])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: CC(C)O
Product: CCOC(=O)c1c(OC(C)C)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 11 step C from 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B) and propan-2-ol. Yellow solid (35 mg, 33%). LC-MS: 370 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:6]([C:7]23[CH2:13][N:10]4[CH2:11][CH:12]2[CH:8]3[CH2:9]4)=[N:5][S:4][N:3]=1.O.[SH2:15].[Na]>CN(C=O)C>[C:7]12([C:6]3[C:2]([SH:15])=[N:3][S:4][N:5]=3)[CH2:13][N:10]3[CH2:11][CH:12]1[CH:8]2[CH2:9]3
Reactant: S
Reactant: Clc1nsnc1C12CN3CC1C2C3
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Sc1nsnc1C12CN3CC1C2C3
Yield: 57.5 %

Procedure:
A solution of 1-(3-chloro-1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.02,6 ]heptane (3.0 g, 14 mmol) and sodium hydrogensulfide, monohydrate (3,14 g, 42 mmol) in dry DMF (80 ml) was stirred at room temperature under nitrogen for 1 h. The solvent was evaporated. Water was added and pH adjusted by addition of 4N HCl (pH 9). The mixture was cooled on ice and the product isolated by filtration to give 1,7 g (58%) of the title compound. M.p. 205-207° C. (Compound 26).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:4][CH:3]=1.O[C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1>ClCCl>[CH2:31]([O:30][C:28]([C:27]1[CH:33]=[CH:34][C:24]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:25][CH:26]=1)=[O:29])[CH3:32]
Reactant: OCCCCCCCCCCCCCOc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(O)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OCCCCCCCCCCCCCOc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
A mixture of 1-(4-chlorophenoxy)-13-tridecanol (3.27 g.; 0.01 M.), ethyl 4-hydroxybenzoate (2.49 g.; 0.015 M) and dicyclohexylcarbondiimide (3.09 g.; 0.015 M.) was heated at 100°-105° C. for 5 hours with stirring. The reaction mixture was cooled to room temperature, dichloromethane was added and the mixture was filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product (5.95 g.) was chromatographed on silica-gel (250 g.) in dichloromethane to give 1-(4-ethoxycarbonylphenoxy)-13-(4-chlorophenoxy)-tridecane (1.82 g.; 38%). M.P. 75°-7° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[S:21].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[C:25]2/[C:23](=[O:24])[NH:22][C:20](=[S:21])[S:19]/2)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=S)N1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(/C=C2\SC(=S)NC2=O)ccc1OCc1ccccc1

Procedure:
4-Benzyloxy-3-methoxy-benzaldehyde (29 g) was dissolved in acetic acid (16 g) and then rhodanine (16 g) and sodium acetate (36 g) added into. The solution was refluxed for one hour. The reaction solution was poured into water. The solid was filtered, washed with water and dried under vacuum.
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([NH:9][CH2:10][CH3:11])=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3].[CH2:15]1[O:17][CH2:16]1>C(O)C>[NH:1]([C:5]1[CH:13]=[CH:12][C:8]([N:9]([CH2:15][CH2:16][OH:17])[CH2:10][CH3:11])=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3]
Reactant: CCNc1ccc(NC(C)=O)c(C)c1
Reactant: C1CO1
Solvent: CCO
Product: CCN(CCO)c1ccc(NC(C)=O)c(C)c1

Procedure:
15.2g (0.08 mole) of 4-acetamino-3-methyl-N-ethylaniline obtained in Example 1, Part C, 4.2g (0.09 mole) of ethylene oxide and 50ml of ethanol were fed into an autoclave and reacted for 1 hour at 120° to 130° C in the closed autoclave. Thereafter, ethanol was distilled off to obtain crystals of 4-acetamino-3-methyl-N-(β-hydroxyethyl)-N-ethylaniline. The crystals were recrystallized from ethyl acetate to obtain 18.5g of white crystals.
Reaction SMILES: [CH:1]([CH:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[S:6][CH2:5][CH2:4]1)=O.[CH3:22][NH2:23]>C1C=CC=CC=1.CO>[CH3:22][N:23]=[CH:1][CH:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[S:6][CH2:5][CH2:4]1
Reactant: CN
Reactant: O=CC1CCSc2c1c1ccccc1n2-c1ccccc1
Solvent: c1ccccc1
Solvent: CO
Product: CN=CC1CCSc2c1c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-formyl-9-phenyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (1.4 g) in absolute benzene (20 ml) is added a 30% solution (1.5 ml) of methylamine in methanol. The mixture is stirred at room temperature for 3 hours and evaporated to give 4-methyliminomethyl-9-phenyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole as orange solid. The product is dissolved in a mixture of methanol (20 ml) and tetrahydrofuran (20 ml) and sodium borohydride (274 mg) is added thereto. The mixture is stirred at room temperature for 1 hour and evaporated.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.O>C1(C)C(CCO)=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Product: COC(=O)Cc1ccc(-c2ccc(OC)cc2)cc1
Yield: 96.3 %

Procedure:
After a 1M aqueous sodium carbonate solution (2.8 ml) and tetrakis(triphenylphosphine)palladium (0) (116 mg, 0.10 mmol) were added to a solution of methyl (4-bromophenyl)acetate (573 mg, 2.50 mmol) obtained in Example (3-1) and 4-methoxyphenylboronic acid (380 mg, 2.50 mmol) in a mixture of toluene-ethanol (6:1, 6 ml), the mixture was heated under reflux for 4 hours. After the temperature of the reaction mixture was returned to room temperature, the mixture was poured into water and extracted with ethyl acetate three times. The organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a yellow solid. It was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=95/5-80/20) to give methyl (4′-methoxy-1,1′-biphenyl-4-yl)acetate as a pale yellow powder (617 mg, yield: 96%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:35]=[CH:34][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[CH2:29]Cl)=[CH:23][C:22]=3[O:32][CH3:33])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].C1COCC1.[CH2:41]([NH:43][CH2:44][CH3:45])[CH3:42].[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]/[C:49]([OH:51])=[O:50]>CC(C)=O.C(OCC)C>[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]/[C:49]([OH:51])=[O:50].[CH2:1]([O:3][C:4]1[CH:35]=[CH:34][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[CH2:29][N:43]([CH2:44][CH3:45])[CH2:41][CH3:42])=[CH:23][C:22]=3[O:32][CH3:33])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)CCl)cc1OC
Reactant: CCNCC
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)CN(CC)CC)cc1OC
Reaction time: 15 h

Procedure:
0.55 g of the compound obtained in step A) above was mixed at 20° C. with 20 ml of THF and 10 ml of diethylamine. The reaction mixture was left to stand for 15 hours and then concentrated under vacuum. The residue was taken up with water, extracted with AcOEt and washed with 1N HCl and with water; it was dried over Na2SO4 and the solvent was evaporated off under vacuum. The residue is chromatographed on silica using DCM and then DCM/AcOEt (95/5; v/v) as the eluent to give 0.5 g of a wax, which was converted to a salt with 0.1 g of fumaric acid in 20 ml of acetone. The salt obtained is soluble in ethyl ether. m=0.2 g. M.p.=124° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]([C:14](OC)=[O:15])[CH2:4][O:3]1.[H-].C([Al+]CC(C)C)C(C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[CH:14]([CH:5]1[CH2:4][O:3][C:2]([CH3:18])([CH3:1])[N:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:15]
Reactant: COC(=O)C1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(C=O)COC1(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
The 3-tert-butyl 4-methyl 2,2-dimethyloxazolidine-3,4-dicarboxylate (6.42 g, 24.97 mmol) obtained in the above-described reaction was dissolved in toluene (50 ml) and cooled to −78° C.; subsequently, a toluene solution of diisobutylaluminum hydride (0.93 M) was slowly added dropwise. After 30 minutes, methanol was added to the mixture and the reaction was stopped; a 10% potassium sodium tartrate solution (150 ml) was further added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting concentrate was purified by silica gel column chromatography to produce tert-butyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate (4.22 g, 74% yield).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].Cl.[CH:20]1([NH:23][C:24]2[C:25]([NH2:31])=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O.C(O)(=O)C>[CH:20]1([N:23]2[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[N:31]=[C:15]2[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH2:22][CH2:21]1
Reactant: Nc1cc(F)ccc1NC1CC1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3cc(F)ccc3n2C2CC2)[nH]1
Yield: 3.5 %

Procedure:
The product is prepared according to the procedure described in Example 3, using 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 645 mg of N1-cyclopropyl-4-fluorobenzene-1,2-diamine hydrochloride and 330 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 3 ml of pyridine and 3 ml of dimethylformamide and then in 5 ml of acetic acid. After refluxing for two hours and purification by silica column chromatography, eluent: CH2Cl2/MeOH: 95/05, the residue obtained is purified by preparative HPLC/MS (method 1). After the acetonitrile has been evaporated off, the pH is brought to 8 using sodium bicarbonate (solid), then the aqueous phase is extracted with twice 25 ml of ethyl acetate, and the combined organic phases are dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 15 mg of 2-[(1-cyclopropyl-5-fluoro-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:27][C:28](O)=[O:29])=O)(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:43]1([S:49]([NH2:52])(=[O:51])=[O:50])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C1CCN2C(=NCCC2)CC1.[F:64][C:65]([F:70])([F:69])[C:66]([OH:68])=[O:67]>O1CCCC1.ClCCl>[F:64][C:65]([F:70])([F:69])[C:66]([OH:68])=[O:67].[Cl:26][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH:9]([CH2:27][C:28](=[O:29])[NH:52][S:49]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)(=[O:51])=[O:50])[CH2:10]1)(=[O:15])=[O:16])=[CH:25]2
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1CC(=O)O
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
In tetrahydrofuran (10 ml) was dissolved 1-tert-butoxycarbonyl-2-carboxymethyl-4-[(5-chloroindol-2-yl)sulfonyl]piperazine (1.00 g), followed by the addition of carbonyldiimidazole (1.06 g). The resulting mixture was heated overnight under reflux. After cooling to room temperature, the reaction mixture was added with benzenesulfonamide (685 mg), 1,8-diazabicyclo[5.4.0]-7-undecene (0.64 ml) and carbonyldiimidazole (353 mg). The resulting mixture was heated under reflux for 1 hour. The reaction mixture was then concentrated under reduced pressure. Dichloromethane was added to the residue and the solid thus precipitated was filtered off. The filtrate was washed successively with 1N hydrochloric acid and saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (Φ3.0×10.0 cm, dichloromethane:methanol=100:1), whereby pale brown foam was obtained. The resulting foam was dissolved in dichloromethane (10 ml), followed by the addition of trifluoroacetic acid (10 ml). After stirring at room temperature for 1 minute, the reaction mixture was concentrated under reduced pressure. Diethyl ether was added to the residue and the resulting precipitate was collected by filtration, whereby the title compound (496 mg, 31%) was obtained as colorless foam.
Reaction SMILES: C([N:8]1[CH2:11][CH:10]([O:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]3[N:19]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[N:20]=[CH:21][C:14]=23)[CH2:9]1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH:8]1[CH2:9][CH:10]([O:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]3[N:19]([C:22]4[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=4)[N:20]=[CH:21][C:14]=23)[CH2:11]1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CN(Cc5ccccc5)C4)ncnc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CNC4)ncnc32)cc1
Yield: 318.5 %

Procedure:
4-(1-Benzyl-azetidin-3-yloxy)-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (0.01 mmol, 46 mg) was dissolved in a mixture of ethyl acetate (5 mL) and methanol (5 mL). Palladium catalyst (30 mg, 65% by wt) was added to the reaction. The mixture was exposed to hydrogen gas for 60 minutes at room temperature and atmospheric pressure. The mixture was passed through celite to remove palladium catalyst. Removal of organic solvents in vacuo and purification by flash chromatography provided 4-(azetidin-3-yloxy)-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine as a white solid (11 mg, 5%). 1H NMR (400 MHz, MeOH-d4) δ (ppm): 8.45 (m, 2H); 8.37 (d, 2H); 8.05 (d, 2H); 4.54 (m, 1H); 4.35 (dd, 2H); 3.69 (m, 2H); 3.09 (s, 3H). LCMS (ESI), m/z 346.2 (M+H+, 100%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:65])[C:57]2[CH:62]=[C:61]([Cl:63])[CH:60]=[CH:59][C:58]=2[Cl:64])[CH2:52][CH2:51]1)=[O:49].Cl>CN(C=O)C.O>[Cl:64][C:58]1[CH:59]=[CH:60][C:61]([Cl:63])=[CH:62][C:57]=1[C:56]([N:53]1[CH2:52][CH2:51][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:22]([C:19]2[CH:18]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[OH:10])[NH:21][N:20]=2)=[O:24])[CH2:55][CH2:54]1)=[O:65]
Reactant: NCC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1
Reactant: O=C(O)c1cc(-c2ccccc2O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1)c1cc(-c2ccccc2O)[nH]n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 20 %

Procedure:
DIPEA (170.4 mg, 0.23 mL, 1.3 mmol) was added drop wise to 5-(2-Hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid (prepared by the method as described above) (60 mg, 0.29 mmol) in DMF (2 mL). EDCI (140.4 mg, 0.73 mmol) and HOBT (43.6 mg, 0.32 mmol) were then added. After 2 minutes, 2-Amino-1-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-ethanone in its HCl salt form (113.9 mg, 0.32 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue purified by column chromatography (using silica gel of 60-120 mesh and 10% MeOH in CHCl3 as eluent) to afford 28 mg (20% yield) of 5-(2-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 97.07%. 1H NMR (DMSO-d6): δ 13.3 (s, 1H), 10.3 (s, 1H), 8.0 (t, 1H), 7.8-7.4 (m, 4H), 7.28-7.1 (t, 1H), 7.1-7.05 (s, 1H), 7.02-6.8 (m, 2H), 4.3-4.1 (d, 2H), 3.8-3.6 (m, 4H), 3.55-3.42 (s, 2H), 3.3-3.1 (m, 3H).
Reaction SMILES: [C:1]1([CH:7]([O:11][C:12]2[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14](O)[C:13]=2[C:23](=O)[CH3:24])C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O-:29])(=[O:28])[CH3:27].[Na+].C(OC(=O)C)(=O)C>C(OCC)C>[C:26]([O:29][C:14]1[C:13]2[C:23]([CH3:24])=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][C:12]=2[C:17]([Cl:18])=[CH:16][C:15]=1[CH2:19][CH2:20][CH3:21])(=[O:28])[CH3:27]
Reactant: CCCc1cc(Cl)c(OC(C(=O)O)c2ccccc2)c(C(C)=O)c1O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CCCc1cc(Cl)c2oc(-c3ccccc3)c(C)c2c1OC(C)=O

Procedure:
A mixture of 2-phenyl-2-(2-acetyl-3-hydroxy-4-propyl-6-chlorophenoxy) acetic acid (Step b)(3.4 g, 9.3 mmol), anhydrous sodium acetate (6.8 g, 82 mmol) and acetic anhydride (50 mL) was refluxed for 1 hour. The mixture was cooled, diluted with diethyl ether and the salts filtered off. The filtrate was concentrated and the residue chromatographed on silica gel with 10% ethyl acetate in hexane to obtain the title compound, m.p. 86°-87° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].Cl>C1COCC1.CN(C1C=CN=CC=1)C.O.CCOC(C)=O>[C:1]([NH:8][C@H:9]([C:20]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=[O:22])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[O:15])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)C(F)(F)F)C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)C(F)(F)F)C(=O)C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.03 h
Yield: 98 %

Procedure:
A modification of a known procedure was followed (Kim et al., J. Org. Chem. 1985 50, 560–565). To a RT stirred solution of acid 6 (11.3 g, 34.6 mmol) in THF (100 mL) was added NMM (3.50 g, 34.6 mmol) and the reaction mixture was cooled to −15° C. (NaCl/ice/water bath). To the cooled reaction mixture was added a solution of benzyl chloroformate (6.17 g, 36.1 mmol) in THF (5 mL). After stirring at −15° C. for 2 min, the reaction mixture was warmed to 0° C. (ice/water bath) and stirred for 15 min. To the reaction mixture was added DMAP (1.05 g, 8.65 mmol) and reaction mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was then treated with EtOAc (100 mL), water (100 mL), and carefully acidified with an aqueous solution of HCl (1 M). The organic layer was separated and washed with an aqueous solution of HCl (0.1 M, 2×50 mL). The combined aqueous layers were then extracted with EtOAc (2×100 mL). The combined organic layers were washed with an aqueous solution of NaHCO3 (5% w/v, 4×50 mL), brine (100 mL), and dried over magnesium sulfate. Removal of the solvent in vacuo gave the desired product 8 as a white amorphous solid (14.2 g, 33.9 mmol, 98% yield): mp 72–73.5° C.; Rf=0.58 (3:7 EtOAc/hexane); 1H NMR (300 MHz, D6-DMSO) δ 9.39 (t, 1 H, J=5.1 Hz), 7.32–7.37 (m, 5 H), 5.04–5.16 (m, 2 H, rotamers), 3.94–4.06 (m, 1 H), 3.12–3.18 (m, 2 H), 1.45–1.70 (m, 4 H), 1.36 (s, 9 H) ppm; 13C NMR (75 MHz, D6-DMSO) δ 172.4, 156.2 (q, J=35 Hz), 155.6, 136.0, 128.4, 128.0, 127.7, 116.0 (q, J=286 Hz), 78.3, 65.8, 53.4, 28.2, 27.8, 25.0 ppm (CH2—NHCOCF3 peaks obscured by residual D6-DMSO); IR (thin film) 3333, 1709 cm−1; HRMS calculated (M+2H−Boc, C14H18F3N2O3) 319.1270. found 319.1215.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:28])[CH:12]([NH:13][C:14](=[O:27])[C:15](=[N:24][O:25][CH3:26])[C:16]3[N:17]=[C:18]([NH:21]C=O)[S:19][CH:20]=3)[C@H:4]2[S:3]1.[ClH:29].C(OCC)C>CO>[ClH:29].[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:28])[CH:12]([NH:13][C:14](=[O:27])[C:15](=[N:24][O:25][CH3:26])[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(NC=O)n1
Agent: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(=NC=O)[nH]1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-methyl-7-[2-methoxyimino-2-(2-formylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (9.0 g.) in methanol (90 ml.) was added concentrated hydrochloric acid (2.12 ml.) with stirring at room temperature, and the mixture was stirred for 7 hours at the same temperature. To the reaction mixture was gradually added diethyl ether till crystals started to precipitate. The mixture was allowed to stand for 30 minutes, and the precipitated crystals were collected by filtration, washed with diethyl ether and then dried to give white crystals of 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer), (7.9 g.) The remaining filtrate was concentrated till the total volume became half. To the concentrated filtrate was gradually added diethyl ether till crystals started to precipitate, and the mixture was allowed to stand for 1 hour. The precipitated crystals were collected by filtration, washed with diethyl ether and then dried to give further the same object compound (0.5 g.).