Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:31]=[CH:30][C:19]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:18]([F:32])[CH:17]=2)=[C:4]([O:33][CH3:34])[CH:3]=1.[CH3:35]B1OB(C)OB(C)O1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[F:32][C:18]1[CH:17]=[C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([CH3:35])=[CH:3][C:4]=2[O:33][CH3:34])[CH:31]=[CH:30][C:19]=1[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27]
Reactant: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(F)c1
Reactant: CB1OB(C)OB(C)O1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(F)c1
Yield: 58.4 %

Procedure:
Following General Procedure I, tert-butyl 4-(6-bromo-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)-2-fluorophenethylcarbamate (300 mg, 0.55 mmol) was reacted with trimethylboroxine (207 mg, 1.65 mmol) and Pd(pph3)4 (63 mg, 0.05 mmol) to afford the desired product (155 mg, 58%) as a brown solid. ESI MS m/z 483 [C26H27FN2O4S+H]+.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[S:24]1(=[O:33])(=[O:32])[CH2:30][CH2:29][NH:28][C:27](=[O:31])[CH2:26][NH:25]1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[Na][Na]>N1C=CC=CC=1.[Cu-]=O.C(Cl)(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([N:25]3[CH2:26][C:27](=[O:31])[NH:28][CH2:29][CH2:30][S:24]3(=[O:33])=[O:32])[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Reactant: O=C1CNS(=O)(=O)CCN1
Agent: O=[Cu-]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Na][Na]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1CN(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)S(=O)(=O)CCN1
Temperature: 115 °C

Procedure:
A mixture of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-7-carboxamide (0.99 g, 2.66 mmol), 1,2,5-thiadiazepan-4-one 1,1-dioxide from step 2 (0.41 g, 2.5 mmol) and copper (I) oxide (0.18 g, 1.25 mmol) in pyridine (13 mL) was heated in an oil bath at 115° C. overnight. The resultant mixture was treated with a mixture of chloroform (200 mL) and a saturated aqueous solution of ethylenediamine tetraacetic acid, disodium salt (200 mL) and stirred vigorously at room temp overnight in the presence of air. The slurry was filtered through a pad of Celite. The organic extract was separated, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was dissolved in DMSO and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1.C(=O)(O)[O-].[Na+].[CH:32]([S:35](Cl)(=[O:37])=[O:36])([CH3:34])[CH3:33].S(Cl)(Cl)(=O)=O>O.CC(C)=O>[CH:32]([S:35]([N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1)(=[O:37])=[O:36])([CH3:34])[CH3:33]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(=O)(Cl)Cl
Solvent: CC(C)=O
Solvent: O
Product: CC(C)S(=O)(=O)N1CC=C(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 45.6 %

Procedure:
(5R)-3-(4-(1,2,5,6-Tetrahydropyridin-4-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (380 mg, 1 mM) was dissolved in water (5 ml), which was then diluted with acetone (10 ml), and solid sodium bicarbonate (0.84 g, 10 mM) added. The mixture was stirred and cooled to 0° C., and isopropylsulfonyl chloride (285 mg, 2 mM) added dropwise. After stirring for 5 hours, an equal portion of sulfonyl chloride was added, and stirring continued for 18 hours. Most acetone was removed by evaporation, the residue diluted with water (50 ml), and extracted with ethyl acetate (3×20 ml). The extracts were washed with brine and dried (magnesium sulfate). The residual oil after evaporation was purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (205 mg).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[ClH:39].O>[Cl-].[NH+]1C=CC=CC=1>[ClH:39].[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[C@H:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 140 °C
Reaction time: 6 h

Procedure:
cis-7-Methoxy-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane (4 g) was dissolved in melted pyridinium chloride, prepared from a mixture of pyridine (20 ml) and conc. hydrochloric acid (21 ml) where the water was removed by distillation at 140° C. The mixture was heated at 140° C. for 3 hours and then at 150° C. for 6 hours. The mixture was cooled down to 100° C. Water was added (30 ml) and the mixture was cooled down to 30° C. Toluene (30 ml) and sodium hydroxide (32,5%) to pH 12 was added. The mixture emulsified and was again made pH 3 with conc. hydrochloric acid. The hydrochloride of cis-7-hydroxy-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane precipitated as a sticky product. It was dissolved in ethanol (200 ml) and water (10 ml), treated with active carbon, filtered and evaporated. Redissolved in ethanol (50 ml) and water until dissolved at 79° C. The product crystallised when the solution was cooled down to room temperature.
Reaction SMILES: [F:1]C(F)(F)C(F)CF.[F:9][C:10]([F:16])([F:15])[C:11]([F:14])=[CH:12][F:13].FC(F)(F)C(F)(Cl)C(F)(Cl)Cl>>[FH:1].[F:9][C:10]([F:16])([F:15])[CH:11]([F:14])[CH2:12][F:13]
Reactant: FC=C(F)C(F)(F)F
Agent: FC(F)(F)C(F)(Cl)C(F)(Cl)Cl
Agent: FCC(F)C(F)(F)F
Product: F

Procedure:
In one embodiment, 1,1,1,2,3-pentafluoropropane is prepared by hydrogenation of 1,1,1,2,3-pentafluoro-2-propene. In another embodiment, 1,1,1,2,3-pentafluoropropene is prepared by hydrogenation of 1,1,1,2,3-pentafluoro-2,3,3-trichloropropane (CFC-215bb). In some embodiments, hydrogen fluoride is produced as a by-product via the unintended dehydrofluorination of 1,1,1,2,3-pentafluoropropane over a hydrogenation catalyst, to produce 1,1,1,2-tetrafluoropropene and hydrogen fluoride. Under the hydrogenation conditions, 1,1,1,2-tetrafluoropropene is hydrogenated to 1,1,1,2-tetrafluoropropane. In some embodiments, hydrogen fluoride is produced as a by-product via the over hydrogenation of 1,1,1,2,3-pentafluoropropane which produces 1,1,1,2-tetrafluoropropane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:2]2[CH:3]=[C:4]3[CH2:10][CH2:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:12]=1
Reactant: OB(O)c1cccnc1
Reactant: Brc1cnc2c(c1)CCN2
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: c1cncc(-c2cnc3c(c2)CCN3)c1
Temperature: 100 °C
Yield: 60.8 %

Procedure:
5-Bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.5 mmol), 3-pyridinyl-boronic acid (370 mg, 3.0 mmol) and K2CO3 (694 mg, 5.0 mmol) are mixed in 6.5 mL of 1,4-dioxane and 0.65 mL of water. Argon gas is bubbled through the mixture for 10 min and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (178 mg, 0.25 mmol) is added. The mixture is heated at 100° C. for 16 hrs. Then the solvents are removed and EtOAc (50 mL) is added along with 30 mL of water. The mixture is filtered to remove any solid and the organic layer is separated. The aqueous layer is extracted with EtOAc (2×25 mL) and the organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 300 mg of 5-pyridin-3-yl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: N#N.[C:3]([O:9][C:10]1([C:13]2[N:14]=[C:15]([CH2:18][OH:19])[O:16][CH:17]=2)[CH2:12][CH2:11]1)(=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].CCN(CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:3]([O:9][C:10]1([C:13]2[N:14]=[C:15]([CH2:18][O:19][S:28]([CH3:27])(=[O:30])=[O:29])[O:16][CH:17]=2)[CH2:11][CH2:12]1)(=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)C(=O)OC1(c2coc(CO)n2)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OC1(c2coc(COS(C)(=O)=O)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(2-(hydroxymethyl)oxazol-4-yl)cyclopropyl pivalate (288 mg, 1.20 mmol) at 0° C. in CH2Cl2 (12.0 mL) was treated Et3N (0.22 mL, 1.57 mmol) followed by DMAP (15 mg, 0.12 mmol). Methanesulfonyl chloride (0.11 mL, 1.44 mmol) was then added dropwise and the reaction mixture was stirred for 1 h at rt. Water (5 mL) was added, the layers were separated, and the org. phase was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 06: tR=0.84 min, [M+H]+=318.19.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][S:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+].C(OCC)(=O)C>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][S:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc2oc(SCc3ccc(Cl)cc3)nc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Nc1ccc2oc(SCc3ccc(Cl)cc3)nc2c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
To a suspension of 2-(4-chlorobenzylthio)-5-nitrobenzo[d]oxazole (220 mg, 0.70 mmol) in ethanol/water (5 mL/5 mL) at 90° C. was added ammonium chloride (75 mg, 1.4 mmol), followed by iron powder (192 mg, 3.44 mmol). The resulting mixture was stirred for 4 h at 90° C. After cooling, ethyl acetate was added and the solution was passed through a pad of Celite®. The organic layer was then washed with brine, dried over anhydrous MgSO4 and evaporated to afford 190 mg (94%) of the title compound (LCMS RT=6.54 min, MH+ 290.9)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.O1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.Cl.N.[OH-].[Na+]>O>[CH3:15][CH:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]3)=[CH:3][CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=c1ccocc1
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
A stirred mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (1.0 g), 4H-pyran-4-one (0.52 g), water (20 ml), and concentrated hydrochloric acid (0.41 ml) was heated under reflux for 31/2 hours. The resultant solid was dissolved in the minimum of hot water and the solution was neutralised with aqueous ammonia to give the crude product, 1.16 g, m.p. 249°-256° C. The product was recyrstallised first from water to which a little 2N NaOH was added, and then from water alone to give the pure title compound, 0.82 g, m.p. 254°-256° C. (after melting and resolidifying at about 150° C.).
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[C:3]#[CH:4].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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.[Cu]I>[F:6][C:7]1[C:8]([C:4]#[C:3][C@@H:2]([OH:5])[CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: C#C[C@H](C)O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@H](C)O)c21

Procedure:
Using Method C above, (S)-but-3-yn-2-ol (36 mg, 0.53 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and CuI (2 mg) in a mixture of DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-butynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-70% EtOAc in hexanes gradient and trituration with petroleum ether. (Yield 32 mg, 75%).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][CH2:36][O:37]C=O)[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:40].O1CCCC1>CO>[ClH:40].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][CH2:36][OH:37])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCOC=O)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCO)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 7.6 h
Yield: 103.4 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.3 g.), conc. hydrochloric acid (1.6 g.), tetrahydrofuran (17.0 ml.) and methanol (17.0 ml.) was stirred at room temperature for 7.6 hours. After concentrating the resultant solution in vacuo, the residue was pulverized with a mixture of methanol and diisopropyl ether. The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-[2-(2-aminothiazol-4-yl)-2-(2-hydroxyethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 2.3 g.). Water (40 ml.) was added to the product and adjusted to pH 7.0 with sodium bicarbonate. After adjusting the solution to pH 4.0 with 1N hydrochloric acid, the solution was subjected to column chromatography on nonionic adsorption resin "Diaion HP-20" (Trademark, manufactured by Mitsubishi Chemical Industries Ltd.). The column was washed with water and eluted with 20% isopropyl alcohol. The eluate was concentrafted in vacuo and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-(2-hydroxyethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.50 g.).
Reaction SMILES: [C:1]1([S:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:29]=[CH:28][C:20]([CH:21]=[CH:22][C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=2)(=[O:13])=[O:12])[C:10]2[C:5](=CC=CC=2)[CH:4]=[CH:3][CH:2]=1.Cl.NCCC1C=CC(C=CC(OCC)=O)=CC=1.C1(OS([Cl:61])(=O)=O)C2C(=CC=CC=2)C=CC=1>>[Cl:61][C:4]1[CH:5]=[CH:10][C:1]([S:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:29]=[CH:28][C:20]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)(=[O:13])=[O:12])=[CH:2][CH:3]=1
Reactant: CCOC(=O)C=Cc1ccc(CCNS(=O)(=O)c2cccc3ccccc23)cc1
Reactant: O=S(=O)(Cl)Oc1cccc2ccccc12
Agent: CCOC(=O)C=Cc1ccc(CCN)cc1
Agent: Cl
Product: O=C(O)C=Cc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 88 %

Procedure:
ethyl 4-[2-(1-naphthylsulphonamido)-ethyl]-cinnamate from ethyl 4-(2-aminoethyl)-cinnamate hydrochloride and 1-napthylsulphochloride; m.p. 85°-86° C. (recrystallized from ethanol); yield 88% of theory, and therefrom by hydrolysis
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[OH-:9].[Ba+2].[OH-]>O>[CH3:1][NH:2][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:8])=[O:9]
Reactant: CN1CCCCC1=O
Reactant: [OH-]
Agent: [Ba+2]
Solvent: O
Product: CNCCCCC(=O)O
Temperature: 110 °C
Yield: 83.4 %

Procedure:
1-methyl-2-piperidone (5 ml, 44.1 mmol) was combined with barium hydroxide (3.8 g, 26.95 mmol) and water (55 ml). The suspension was warmed to 110° C. for 6 hours then cooled over an ice bath. Gaseous carbon dioxide was bubbled through the solution for 20 minutes. The suspension was filtered through a celite pad and the filtrate was concentrated to dryness. The residue was triturated with acetonitrile, collected, rinsed with ether and dried in vacuo to yield 5-(methylamino)pentanoic acid as a white solid (2.95 g). 5-(Methylamino)pentanoic acid (5 g, 38 mmol), and Sodium hydroxide (50% aqueous solution, 6.6 g, 82 mmol) were suspended in water (30 ml) and dioxane (20 ml). Di-tert-butyl dicarbonate (11 g, 50 mmol) was added, then the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water, acidified to approximately pH 5 with concentrated HCl and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give crude 5-[(tert-butoxycarbonyl)(methyl)amino]pentanoic acid as a thick clear oil (14 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.Cl.[NH2:13][CH2:14][C:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:13][CH2:14][C:15]2([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: NCC1(O)CCCCC1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(Br)ccc1NCC1(O)CCCCC1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 4-bromo-1-flouro-2-nitrobenzene (Wako Pure Chemical Industries, Ltd.), 1-(aminomethyl)cyclohexanol hydrochloride (J. Med. Chem. 1981, 24, 7-12.) and N,N-diisopropylethylamine.
Reaction SMILES: [I-].[CH3:2][C:3]1[N+:4]2[C:5](=[CH:33][N:34]([CH3:36])[CH:35]=2)[S:6][C:7]=1[C:8]1[C@H:9]([CH3:32])[C@@H:10]2[C@@H:27]([C@H:28]([OH:30])[CH3:29])[C:26](=[O:31])[N:11]2[C:12]=1[C:13]([O:15]CC1C=CC([N+]([O-])=O)=CC=1)=[O:14].P([O-])([O-])([O-])=O>C1COCC1.[Pd]>[CH3:2][C:3]1[N+:4]2[C:5](=[CH:33][N:34]([CH3:36])[CH:35]=2)[S:6][C:7]=1[C:8]1[C@H:9]([CH3:32])[C@@H:10]2[C@@H:27]([C@H:28]([OH:30])[CH3:29])[C:26](=[O:31])[N:11]2[C:12]=1[C:13]([O-:15])=[O:14]
Reactant: Cc1c(C2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)sc2cn(C)c[n+]12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Product: Cc1c(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)sc2cn(C)c[n+]12
Temperature: 25 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
To a solution of 89.1 mg of 4-nitrobenzyl (1S,5R,6S)-2-(3,6-dimethylimidazo[5,1-b]thiazolium-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate iodide in 2 ml of THF and 2 ml of {fraction (1/15)} M phosphate buffer (pH 6.8) was added 102.7 mg of 10% Pd-C. The reactor was purged with hydrogen, the reaction mixture was stirred at room temperature for 5 hours. The catalyst was collected by filtration, and washed with water. The filtrate was diluted with 20 ml of ethyl acetate 20 ml, separated, and the organic layer was further washed with water. The combined aqueous layer was concentrated under reduced pressure to a volume of about 30 ml. The concentrate was purified by column chromatography on DIAION HP-20 to give 17.0 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:9][NH:8][CH2:7][CH2:6]2.I[CH:17]([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][CH:17]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)[CH3:19]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CNCC2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(cc1[N+](=O)[O-])CN(C(C)C)CC2
Temperature: 65 °C
Yield: 89.6 %

Procedure:
6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (222 mg, 1.07 mmol) was taken in acetonitrile (5 mL), treated with 2-iodopropane (0.8 mL, 5.0 mmol) and potassium carbonate (600 mg, 4.35 mmol, Aldrich). The mixture was heated at 65° C. for 16 h, cooled, and partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, filtered, concentrated, and purified by chromatography on SiO2 (0 to 20% methanol/dichloromethane spiked with aqueous ammonia) to provide 2-(1-methylethyl)-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydro isoquinoline (0.24 g, 88%). 1H NMR (400 MHz, CDCl3) δ ppm 1.16 (d, J=6.4 Hz, 6 H), 2.76-2.84 (m, 2 H), 2.90-3.00 (m, 3 H), 3.70 (s, 2 H), 3.93 (s, 3 H), 6.80 (s, 1 H), 7.64 (s, 1 H); ESIMS (M+H)+=251.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.[CH3:25][O:26][C:27]([C:29]1[CH:30]=[N:31][C:32](Cl)=[N:33][CH:34]=1)=[O:28]>CN1CCCC1=O>[CH3:25][O:26][C:27]([C:29]1[CH:30]=[N:31][C:32]([N:22]2[CH2:23][CH2:24][CH:19]([N:5]([CH:2]3[CH2:4][CH2:3]3)[C:6](=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([C:13]4[O:17][CH:16]=[N:15][CH:14]=4)=[CH:11][CH:12]=3)[CH2:20][CH2:21]2)=[N:33][CH:34]=1)=[O:28]
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: Cl
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-chloro-pyrimidine-5-carboxylic acid methyl ester following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.48 min; Mass spectrum (ESI+): m/z=448 [M+H]+.