Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:19]([C:17]1[CH:16]=[C:15]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)[CH:14]=[C:13]([NH:12][C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH:18]=1)([O-:21])=[O:20]
Reactant: Nc1cc(-c2cnc(C3(O)CCC3)s2)cc([N+](=O)[O-])c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Temperature: 100 °C
Yield: 60.1 %

Procedure:
A mixture of 2-chloro-4-(trifluoromethyl)pyrimidine (2.04 mL, 16.9 mmol), Intermediate 22 (4.69 g, 16.1 mmol), cesium carbonate (10.5 g, 32.2 mmol), XantPhos (1.40 g, 2.41 mmol) and Pd(OAc)2 (0.361 g, 1.61 mmol) in dioxane (100 mL) was heated to 100° C. overnight. Upon completion the reaction was cooled to room temperature and was diluted with ethyl acetate (100 mL) and filtered through Celite. After in vacuo concentration, purification by chromatography on silica gel (70:30 to 20:80 hexanes:ethyl acetate) provided 4.23 g (9.67 mmol, 60%) of 1-[5-(3-nitro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutanol as a bright yellow solid. MS APCI: [M+H]+ m/z 438.0. 1H NMR (400 MHz, Acetone): δ 9.74 (s, 1H); 8.96 (s, 1H); 8.85 (s, 1H); 8.60 (s, 1H); 8.24 (s, 1H); 8.15 (s, 1H); 7.40 (s, 1H); 5.64 (s, 1H); 2.86 (s, 2H); 2.72 (s, 2H); 2.47 (d, J=11.2 Hz, 2H). rhSYK=++.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[CH:22]([OH:37])[C:23]4[N:24]=[C:25]([NH:28]C(OC(CC)(C)C)=O)[S:26][CH:27]=4)[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1>C(O)=O>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[CH:22]([OH:37])[C:23]4[N:24]=[C:25]([NH2:28])[S:26][CH:27]=4)[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1
Reactant: CCC(C)(C)OC(=O)Nc1nc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Solvent: O=CO
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(O)c4csc(N)n4)[C@H]3SC2)s1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadizol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (2.30 g.) in 98% formic acid (25 ml.) was stirred for 2.5 hours at room temperature. After the reaction, formic acid was distilled off under reduced pressure. The residue was pulverized in acetonitrile (25 ml.), collected by filtration, washed with a small amount of acetonitrile and then dissolved in 5% sodium bicarbonate aqueous solution (14 ml.). The solution was adjusted to pH 6 with acetic acid and subjected to alumina column chromatography by using pH 5.0 acetate buffer as an eluent. The eluate containing the object compound (300 ml.) was adjusted to pH 3 with 10% hydrochloric acid and then washed twice with ethyl acetate (50 ml.). The aqueous layer was subjected to column chromatography (Amberlite XAD-4 prepared by Rohm & Haas Co.), and the column was washed with water and then eluted with 20% methanol aqueous solution (100 ml.), 50% methanol aqueous solution (100 ml.) and 70% methanol aqueous solution (400 ml.) in turn. The eluates containing the object compound (500 ml.) were collected and then methanol was distilled off at 30° to 35° C. under reduced pressure. The remaining aqueous solution was lyophilized to give pale yellow powder of 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (0.60 g.).
Reaction SMILES: Cl[P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O>O1CCCC1.[Zn]>[C:9]1([PH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
1.04 g (4.71 mmol) of chlorodiphenylphosphine was added dropwise under a nitrogen gas atmosphere to a suspension of 461 mg (7.05 mmol) of zinc (powder) in 10 cm3 of tetrahydrofuran and the mixture was stirred at 50° C. for one hour. To the reaction mixture was added dropwise 170 mg (9.43 mmol) of water. The mixture was stirred, and the organic layer was filtered. The filtrate was concentrated under reduced pressure to give 526 mg (2.82 mmol) of diphenylphosphine in 60% yield.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[CH:11]=1)[CH3:9])(C)(C)C.B(Br)(Br)Br>ClCCl>[NH2:7][C@H:8]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: COc1cccc([C@H](C)NC(=O)OC(C)(C)C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@H](N)c1cccc(O)c1
Temperature: 25 °C

Procedure:
To a solution of [(S)-1-(3-methoxyphenyl)ethyl]carbamic acid tert-butyl ester (3 g, 12 mmol) in dichloromethane (25 mL) at −78° C. was added BBr3 (1.0 M solution in dichloromethane) (26 mL, 26 mmol) dropwise. After the addition, the solution was warmed up to room temperature. The reaction mixture was quenched with methanol (100 mL) and concentrated under vacuum. This process was repeated until no white fumes were observed upon adding methanol. The title compound was obtained as pale yellow solid (2.6 g, quantitative yield). The crude product was used without any further purification
Reaction SMILES: [Na].[N+:2]([CH:5]([CH3:7])[CH3:6])([O-:4])=[O:3].[CH:8]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]2[O:16][CH2:17][O:18][C:10]=2[CH:9]=1.S(=O)(=O)(O)O.S(=O)(=O)(O)[O-].[Na+]>CO.O>[CH3:6][C:5]([N+:2]([O-:4])=[O:3])([CH3:7])[CH:14]([OH:15])[C:13]1[CH:8]=[CH:9][C:10]2[O:18][CH2:17][O:16][C:11]=2[CH:12]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(C)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C(O)c1ccc2c(c1)OCO2)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.9 %

Procedure:
A solution of 55.2 g (2.4 g atom) of sodium in 2.62 liters of methanol cooled to 25° C was added to 684 g (689.5 ml; 7.68 moles) of 2-nitropropane after which 360.4 g (2.4 moles) of piperonal were added. The solution was stirred at room temperature for 18 hours, cooled in an ice bath and acidified with 2.4 liters of 1N sulphuric acid. The resulting mixture was diluted with 5 liters of water, and an oil which precipitated was syphoned off and added to a rapidly stirred solution of 187.4 g (1.8 moles) of sodium bisulphate in 1.2 liters of water. The mixture was stirred for 15 minutes, after which the solid formed was separated and washed three times with ether. The organic layer was separated off, washed with brine, dried and concentrated to an oil which was crystallised from a mixture of 250 ml of toluene and 850 ml of hexane to give 1,1-dimethyl-2-hydroxy-2-(3,4-methylenedioxyphenyl)nitroethane m.p. 88°-91° (Yield 200.4 g). The mother liquor from the crystallisation was diluted with a further liter of hexane to give a further crop of the product, m.p. 88°-91° (49.9 g; total yield 250.3 g, 43.6%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:11][OH:12]>>[C:1]([N:4]1[CH2:9][CH2:8][C:7](=[N:11][OH:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: NO
Product: CC(=O)N1CCC(=NO)CC1

Procedure:
1-Acetyl-piperidin-4-one oxime was prepared from 1-acetyl-piperidin-4-one and hydroxylamine using conditions of General Method 1. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (1H, d, 3.2 Hz), 3.43-3.56 (4H, m), 2.48-2.56 (1H, m), 2.42 (1H, t, 6.2 Hz), 2.29-2.34 (1H, m), 2.17-2.26 (1H, m), 2.03 (3H, d, 4.2 Hz).
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=[O:5].Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl>[Cu](I)I.C1(C)C=CC=CC=1.O.CS(C)=O>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([NH:1][C@H:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=[O:5])=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC[C@@H](N)CC(=O)O
Agent: I[Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CC[C@H](CC(=O)O)Nc1ccc(C(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
(R)-3-Aminovaleric acid (12 kg), 1-bromo-4-trifluoromethylbenzene (34.6 kg), copper iodide (3.9 kg) and potassium carbonate (28.3 kg) were added to dimethylsulfoxide (120 liter), and the mixture was sealed under nitrogen atmosphere and stirred at 100-120° C. for 48 hours. After the reaction mixture was cooled, water (120 liter) and toluene (120 liter) were added, the value of the pH was adjusted to below 3 with addition of hydrochloric acid and the solution was separated. The aqueous layer was extracted with toluene (120 liter) and the combined organic layer was washed with water (120 liter). 25% ammonia water (60 liter) and water (60 liter) were added to the organic layer and extracted. The aqueous layer was adjusted to pH 3-4 with addition of hydrochloric acid and extracted with toluene (120 liter). The filtrate was concentrated in vacuo at 30-70° C. of the bath temperature, n-heptane (24 liter) was added to the residue and concentrated twice to give the titled compound as an oily residue. The product was used in the next step without further purification. MS (APCI) m/z: 262 [M+H]+.
Reaction SMILES: O=[C:2]([C:8]1[C:25]2[C:26]3[C:31]4[C:10](=[CH:11][CH:12]=[C:13]5[C:30]=4[C:29]4[C:16](=[CH:17][CH:18]=[C:19]6[C:28]=4[C:27]=3[C:22](=[CH:23][CH:24]=2)[CH:21]=[CH:20]6)[CH:15]=[CH:14]5)[CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].NN.[OH-].[Na+]>C(O)COCCO>[C:8]1([CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:25]2[C:26]3[C:31]4[C:10](=[CH:11][CH:12]=[C:13]5[C:30]=4[C:29]4[C:16](=[CH:17][CH:18]=[C:19]6[C:28]=4[C:27]=3[C:22](=[CH:23][CH:24]=2)[CH:21]=[CH:20]6)[CH:15]=[CH:14]5)[CH:9]=1
Reactant: O=C(O)CCC(=O)c1cc2ccc3ccc4ccc5ccc6ccc1c1c6c5c4c3c21
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Product: O=C(O)CCCc1cc2ccc3ccc4ccc5ccc6ccc1c1c6c5c4c3c21
Temperature: 25 °C
Yield: 88.5 %

Procedure:
The compound 82 (0.503 g, 1.26 mmol), 0.4 ml of 79% aqueous hydrazine, and 0.462 g (11.6 mmol) of sodium hydroxide were dissolved in 3.0 ml of diethylene glycol, followed by 90-minute refluxing in a 180-° C. oil bath. The excess hydrazine and water were distilled away, and the refluxing was continued for two more hours. After the reaction was completed, the solution was cooled back to room temperature, to precipitate a solid substance. The solid substance was collected by filtration, and was washed with ion-exchange water, followed by drying under reduced pressure. This solid substance was dispersed in 10 ml of xylene, and was heated to 140° C. In this manner, the solid substance was dissolved. After that, the substance was cooled slowly back to room temperature, to precipitate a solid substance. The solid substance generated here was collected by filtration, and was dried under reduced pressure, to obtain 0.431 g of the brownish-red solid substance 83. Here, 1HNMR was not measured, since its product was not soluble in any deuterated solvents.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: COC(=O)c1ccccc1N
Reactant: CS(=O)(=O)Cl
Product: COC(=O)c1ccccc1NS(C)(=O)=O

Procedure:
2-Methanesulfonylaminobenzoic acid methyl ester is prepared according to the general procedure outlined in Example 4, Step B, using 2-aminobenzoic acid methyl ester and methanesulfonyl chloride.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:14]1)=O.B.C1COCC1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@H](c2ccc(C(F)(F)F)cc2)C1
Agent: B
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)cc1
Yield: 43.8 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(4-trifluoromethylphenyl)piperidin-1-yl]methanone (18 mg, 0.046 mmol) was treated with BH3THF according to the above general procedure. Flash chromatography gave 7.6 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:13]Br.O>C(O)(=O)C>[Br:13][C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9](=[O:11])[CH3:10])=[C:3]([CH3:12])[C:2]=1[Cl:1]
Reactant: BrBr
Reactant: CC(=O)Nc1cccc(Cl)c1C
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(Br)c(Cl)c1C
Temperature: 10 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A suspension of N-(3-chloro-2-methylphenyl)acetamide (11.12 g, 60.63 mmol) in acetic acid (80 mL) was cooled to ca. 10° C. and then treated with bromine (9.28 mL, 181.11 mmol). The resulting mixture was stirred at rt for 2 h. The cooled solution was then poured into water (100 mL). The resulting solid was collected via filtration and rinsed with water. Thorough drying afforded 15.83 g of a pale yellow solid: MS (APCl) m/z 264 (M+2 isotope).
Reaction SMILES: F[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl-].[O:10]1[CH2:15][CH2:14][CH:13]([C@H:16]([NH3+:18])[CH3:17])[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[I:8][C:7]1[C:2]([NH:18][C@@H:16]([CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H]([NH3+])C1CCOCC1
Reactant: Fc1ncccc1I
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: C[C@@H](Nc1ncccc1I)C1CCOCC1
Temperature: 125 °C
Reaction time: 48 h
Yield: 34.4 %

Procedure:
To a re-sealable vial containing 2-fluoro-3-iodopyridine (2.14 g, 9.60 mmol), (S)- or (R)-1-(tetrahydro-2H-pyran-4-yl)ethanaminium chloride (1.2175 g, 7.35 mmol) and cesium carbonate (7.54 g, 23.14 mmol) was added DMAc (10 mL). The vial was subsequently sealed and placed in a 125° C. bath. After stirring at 125° C. for 48 h, the reaction mixture was cooled to room temperature and partitioned between EtOAc with water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with a minimal amount of water (2×), dried over Na2SO4, and concentrated to give a heterogeneous brown oil. The oil was diluted with EtOAc/Hexanes (1:3) and filtered. The solids were washed with EtOAc:Hexanes (1:3) and the filtrate was concentrated to give a brown oil. The resultant oil was purified on a Biotage system (40 g, gradient elution 2% EtOAc: 98% Hexanes to 10% EtOAc: 90% Hexanes, then isocratic 10% EtOAc: 90% Hexanes). The product (S)- or (R)-3-iodo-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)pyridin-2-amine (0.84 g, 2.53 mmol, 34.4% yield) was isolated as a clear colorless oil. LRMS (M+H+) m/z: calcd 333.0. found 333.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=[O:8].[Cl-].[Al+3].[Cl-].[Cl-].Cl.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:7]([C:3]2[C:2]([C:10]([OH:9])=[O:11])=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])=[CH:26][CH:25]=1
Reactant: Fc1ccccc1
Reactant: O=C1OC(=O)c2ncccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Al+3]
Product: O=C(c1ccc(F)cc1)c1cccnc1C(=O)O
Temperature: 25 °C

Procedure:
To a mixture of 2,3-pyridinedicarboxylic anhydride (16.5 g) and fluorobenzene (120 ml) was added, while stirring at room temperature, anhydrous aluminum chloride (23.1 g). The reaction mixture was stirred for 3 hours under reflux, which was cooled and poured into a mixture of hydrochloric acid and ice-water. This mixture was made to be pH 2-3 with an aqueous solution of potassium carbonate, which was subjected to extraction with ethyl acetate. The extract solution was washed with water and dried, then the solvent was distilled off to leave 3-(4-fluorobenzoyl)-2-pyridinecarboxylic acid as colorless crystals (11.0 g). m.p.152°-153° C. (recrystallized from methanol-ethyl acetate)
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:34]1([C:39]2[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>O.CCO.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:41]3[CH:42]=[CH:43][CH:44]=[C:39]([N:34]4[CH2:35][CH2:36][CH2:37][CH2:38]4)[CH:40]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Reactant: OB(O)c1cccc(N2CCCC2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cccc(N2CCCC2)c1

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)-benzyl]-4-methyl-1,3-oxazolidin-2-one (0.05 g, 0.084 mmol), 3-(pyrrolidino)phenyl boronic acid (0.032 g, 0.167 mmol), tetrakis(triphenylphosphine) palladium (5% mol) and sodium carbonate (0.019 g, 0.18 mmol) in 7 ml of water/EtOH/toluene (1:2:4) was heated to reflux for 4 h. TLC (EtOAc:hexane/1:1) showed that the reaction was over. The solvents were removed. Water (10 ml) was added. The organic was extracted with methylene chloride (3×10 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after flash column using EtOAc:hexane/6:4 as the eluant. LC-MS (M+1): 617.0.
Reaction SMILES: C([NH:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])C1C=CC=CC=1.[ClH:18]>C(O)C.[Pd]>[ClH:18].[NH2:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: CCOP(=O)(CNCc1ccccc1)OCC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOP(=O)(CN)OCC

Procedure:
A solution of diethyl N-benzylaminomethylphosphonate (30.1 g., 0.117 mole) in absolute ethanol (400 ml.) is treated with 0.9 N HCl in ethanol (130 ml.) and hydrogenated at 45 psi with 10% palladium on carbon (6.6 g.) for 19 hours. The resulting mixture is filtered through a packed pad of diatomaceous earth to remove the catalyst. Evaporation of the filtrate under reduced pressure gives a clear residue which is successively dissolved in ethanol and benzene and evaporated in vacuo to give diethyl aminomethylphosphonate hydrochloride (23.2 g.) as a white powder. nmr (DMSO-d6)τ 8.73 (t, 6, J=7Hz, CH2CH3), 6.76 (d, 2, J=13.5Hz, CH2), 5.87 (d of q, 4, J=7Hz and J=8Hz, CH2) and 1.42 (br s, 3, NH3).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1)[C:10]([OH:12])=O.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[NH2:31][CH:32]1[C:50](=[O:51])[N:34]2[C:35]([C:47]([OH:49])=[O:48])=[C:36]([CH2:39][S:40][C:41]3[N:45]([CH3:46])[N:44]=[N:43][N:42]=3)[CH2:37][S:38][C@H:33]12.C([O-])(=O)C>C(OCC)(=O)C.O.CN(C)C=O>[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1)[C:10]([NH:31][CH:32]1[C:50](=[O:51])[N:34]2[C:35]([C:47]([OH:49])=[O:48])=[C:36]([CH2:39][S:40][C:41]3[N:45]([CH3:46])[N:44]=[N:43][N:42]=3)[CH2:37][S:38][C@H:33]12)=[O:12]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1csc(C)n1
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(C)n1
Temperature: 40 °C
Yield: 36.6 %

Procedure:
Phosphorus oxychloride (0.26 g.) was added under ice-cooling to dimethylformamide (0.15 g.) and the mixture was warmed at 40° C. for 1 hour. Ethyl acetate (1.5 ml.) was added thereto and to the mixture was at a time added 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetic acid (syn isomer) (0.3 g.) with stirring and ice-cooling, after which the resulting mixture was stirred for 20 minutes at 0° to 5° C. On the other hand, bis(trimethylsilyl)acetamide (1.2 g.) was added to a suspension of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (0.53 g.) in ethyl acetate (7 ml.) and the mixture was stirred at ambient temperature. To this solution was dropwise added the above obtained ethyl acetate solution at -20° C. and the mixture was stirred for 2 hours at -10° to -20° C. Water (20 ml.) was added to the reaction mixture below -25° C. and eythyl acetate (20 ml.) was added thereto, after which the mixture was stirred. An insoluble material was filtered off and the ethyl acetate layer was separated. Water (15 ml.) was added to the ethyl acetate layer and the mixture was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated, washed with methylene chloride and methylene chloride in the aqueous layer was removed by bubbling of nitrogen gas. The aqueous solution was adjusted to pH 2.2 with 10% hydrochloric acid and precipitates were collected by filtration and dried to give 7-[2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.28 g.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=3)=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([S:30](C)(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:34]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=3)=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([NH2:34])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: Cc1cc(-c2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)ccc1F
Product: Cc1cc(-c2c(-c3ccc(S(N)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)ccc1F

Procedure:
The title compound was prepared according to the method of procedure Example 384, substituting 2-(3,4-difluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 105 mg, 27%). mp 243-245° C. 1H NMR (300 MHz, DMSO-d6) δ 2.2 (s, 3H), 7.01 (m, 2H), 7.25 (m, 1H), 7.45 (s, 1H), 7.47 (bs, 2H), 7.6 (m, 2H), 7.77 (d, J=9 Hz, 2H), 7.85 (m, 1H), 8.26 (s, 2H). MS (DCI/NH3) m/z 472 (M+H)+, 489 (M+NH4)+. Anal. calc. for C24H17F3N2O3S.0.5H2O: C, 58.59; H, 3.42; N, 8.91. Found: C, 57; H, 4.23; N, 8.89.