Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:15]([CH3:17])=O)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][O:20][NH2:21]>CO>[CH2:1]([O:8][N:9]=[C:10]([C:15](=[N:21][O:20][CH3:19])[CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(=NOCc1ccccc1)C(C)=O
Reactant: CON
Agent: Cl
Solvent: CO
Product: CON=C(C)C(=NOCc1ccccc1)C(=O)OC
Yield: 91 %

Procedure:
To a solution of 4.0 g (17 mol) of methyl 2-benzyloxyiminoacetoacetate in 50 ml of methanol, 1.56 g (18.7 mmol) of methoxyamine hydrochloride was added and the mixture was heated under reflux for 3 hours. After distilling the solvent off under reduced pressure, 50 ml of water was added and the mixture was extracted twice with 50 ml of diethylether and then washed with water and a saturated aqueous sodium chloride. The organic layer was dried over with anhydrous magnesium sufate and the solvent was distilled off to obtain a residue, which was then purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 4.11 g yield:91%) of methyl 2-benzyloxyimino-3-methoxyiminobutyrate as a colorless oil.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12>[Pd].C(O)(=O)C>[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][NH:6][C:5]=12
Reactant: c1cnc2nccn2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: c1cn2c(n1)NCCC2

Procedure:
4.2 g imidazo[1,2-a]pyrimidine hydroperchlorate were heated for 8 h in an acetic acid solution with palladium on activated charcoal, with H2 fed in. Subsequent filtration, removal of the solvent and addition of diethyl ether yielded the 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine hydroacetate in the form of colorless crystals, which were recrystallized from ethanol.
Reaction SMILES: [C:1]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[S:3])[NH2:2].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=O.Br.C([O-])([O-])=O.[K+].[K+]>CCO>[N:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:2]=[C:1]([C@H:4]3[CH2:8][CH2:7][CH2:6][N:5]3[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[S:3][CH:17]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(N)=S
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nc(-c2ccncc2)cs1
Yield: 37 %

Procedure:
A stirred mixture of (R)-tert-butyl 2-carbamothioylpyrrolidine-1-carboxylate (373 mg, 1.6 mmol), 4-(bromoacetyl)pyridine.HBr (455 mg, 1.6 mmol), K2CO3 (224 mg, 1.6 mmol) and EtOH (20 mL) was heated at reflux for 4 h. The mixture was cooled and concentrated. The residues was taken up in EtOAc (90 mL), washed with 0.5 M aq NaoH (20 mL) and brine (20 mL), and dried over Na2SO4. Removal of the solvent left an amber oil (410 mg). A 379-mg portion of the crude product was purified by chromatography on a 12-g silica gel cartridge, eluted with a 0-100% EtOAc in hexanes gradient to afford (R)-tert-butyl 2-(4-(pyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxylate (200 mg, 37%) as a tan solid. LC-MS Method 1 tR=1.20 min, m/z=332.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][C@H:48]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:49]1[CH:50]=[C:51]([P:55]([CH3:60])(=[O:59])[O:56][CH2:57][CH3:58])[CH:52]=[CH:53][CH:54]=1>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:47][C@H:48]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:49]2[CH:50]=[C:51]([P:55]([CH3:60])(=[O:59])[O:56][CH2:57][CH3:58])[CH:52]=[CH:53][CH:54]=2)=[O:10])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1
Reactant: CCOP(C)(=O)c1cccc([C@H](N)c2ccccc2)c1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(C)(=O)c1cccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (7.9 g, 25.7 mmol) and Et3N (7.09 g, 70.2 mmol) in MeCN (50 ml) was added HATU (10.7 g, 28.2 mmol). The mixture was stirred for 10 min at room temperature and then ethyl 3-((R)-amino(phenyl)methyl)phenyl(methyl)phosphinate, 24-e, (6.79 g, 23.4 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with saturated NH4Cl. The organic layer was dried over sodium sulfate and concentrated under vacuum to provide the crude product, 24-f, (18.8 g) as red oil. The crude product was used for the next step directly.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1.[ClH:17]>C(O)C.[Pd]>[ClH:17].[ClH:17].[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NC1=NCCC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cc(N)ccc1NC1=NCCC1

Procedure:
The product compound of Example 8 was dissolved in 1.2 liter of ethanol containing 53.4 ml of concentrated hydrochloric acid and hydrogenated at 2 psi over 5% palladium on carbon. After removal of catalyst by filtration, the filtrate was concentrated in vacuo to give 85 g of the title compound. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl.C[N:15]1C=CC=C1.C(C(OCC)=O)#N.C(=O)(O)[O-].[Na+]>C(O)C>[NH:15]=[C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1cccn1C
Reactant: Cn1cccc1
Agent: CCOC(=O)C#N
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: CCOC(=O)C(=N)c1cccn1C

Procedure:
Ethyl 1-methylpyrrole-2-acetate: A stream of dry hydrogen chloride is passed at a moderate rate through a solution of 12.5 g of N-methylpyrrole and 16.8 g of ethyl cyanoformate in 125 mls of ethanol-free chloroform at 22° C. for 31/2 hours. The reaction mixture is added dropwise with stirring to a 1.5 liter solution of 5% sodium bicarbonate. The chloroform layer is separated, dried over Na2SO4 and evaporated in vacuo at room temperature to give a brown oil (ethyl α-imino-1-methylpyrrole-2-acetate). The oil is dissolved in 125 ml of ethanol. Hydrogen sulfide is passed through the solution vigorously for 45 mins at 22° C. The mixture is allowed to stand for 16 hrs. The solvent is evaporated in vacuo. The residue is taken up in chloroform. Sulfur is removed by filtration. The chloroform is evaporated in vacuo. The residue is distilled in vacuo to give 15.5 g (60% yield) of oily ethyl 1-methylpyrrole-2-acetate, b.p. 64°-66° C. at 0.06 Torr.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N:12]1([CH2:17][CH2:18][CH2:19][CH2:20]N)[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][CH2:18][CH2:19][CH2:20][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: NCCCCn1ccnc1
Product: O=C1c2ccccc2C(=O)N1CCCCn1ccnc1

Procedure:
A mixture of 0.01 mole of phthalimide and 0.01 mole of 1H-imidazol-1-butanamine was heated in an oil bath at 140° for 1 hour. The reaction mixture was cooled to obtain the desired product.
Reaction SMILES: [C:1]([CH2:5][CH:6]([CH3:10])[C:7](Cl)=[O:8])([O:3]C)=[O:2].[C:11]([CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16]1)([O:13]C)=[O:12]>>[C:1]([CH2:5][CH:6]([CH3:10])[C:7]([N:16]1[C@H:15]([C:11]([OH:13])=[O:12])[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)=[O:8])([OH:3])=[O:2]
Reactant: COC(=O)CC(C)C(=O)Cl
Reactant: COC(=O)C1Cc2ccccc2CN1
Product: CC(CC(=O)O)C(=O)N1Cc2ccccc2C[C@H]1C(=O)O

Procedure:
Using the method described in example 8, beginning from 3-carbomethoxy 2-(RS) methylpropionic chloride and 3-(RS) carbomethoxy 1,2,3,4-tetrahydro isoquinoline, the following are obtained successively:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=O)=[C:5]2[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].COC1C=CC(P2SP(C3C=CC(OC)=CC=3)[S:32]2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[S:32])[NH2:13])=[C:5]2[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: NC(=O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Reactant: COc1ccc(P2SP(c3ccc(OC)cc3)S2)cc1
Product: NC(=S)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1

Procedure:
Reaction of 5-chloro-3-phenylsulfonylindole-2-carboxamide with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane (Lawesson's reagent) according to the procedure of Example 18 gave the title compound. Chromatographic purification on silica gel was carried out using 30% ethyl acetate-methylene chloride, followed by 50% ethyl acetate-methylene chloride. The pure product had mp 207°-210° C. Anal. calcd for C15H11ClN2O2S2 : C, 51.35; H, 3.16; N, 7.98. Found: C, 50.84; H, 3.08; N, 8.04. NMR (DMSO-d6) δ12.90 (1H, s), 10.71 (1H, s), 10.70 (1H, s), 8.0-8.6 (2H, m), 7.84 (1H, d, J=2 Hz), 7.54-7.66 (3H, m), 7.46 (1H, d, J=8.5 Hz), 7.30 (1H, dd, J=8.5, 2 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][CH2:14][CH:15]([N:18]=[C:19]=S)[CH2:16][CH3:17]>C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[S:9](=[O:11])(=[O:10])[N:12]=[C:19]([NH:18][CH:15]([CH2:16][CH3:17])[CH2:14][CH3:13])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Reactant: CCC(CC)N=C=S
Solvent: CCOC(C)=O
Product: CCC(CC)NC1=NS(=O)(=O)c2ccc(Cl)cc2N1

Procedure:
The title compound was prepared from 2-amino-4-chlorobenzenesulfonamide and 3-pentyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 224-226° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 0.88 (t, 6H, 2×CH3), 1.33-1.66 (m, 4H, 2×CH2), 3.65 (m, 1H, CH), 7.1 (br.s, 1H, NH), 7.21-7.32 (m, 2H, ArH), 7.68 (d, 1H, ArH), 10.30 (br.s, 1H, NH); MS: m/e 301-303 (M+); (C12H16N3Cl1O2S1) calc. C, 47.76; H, 5.34; N, 13.92; found C, 47.74; H, 5.49; N, 13.93.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:45])[C@@H:24]([NH:25][C:26](=[O:44])/[C:27](/[C:31]4[N:32]=[C:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[S:34][CH:35]=4)=[CH:28]\[CH2:29][CH3:30])[C@H:21]3[S:20](=[O:46])[CH2:19][CH:18]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1.ClCCl>[C:40]([O:39][C:37]([NH:36][C:33]1[S:34][CH:35]=[C:31](/[C:27](=[CH:28]/[CH2:29][CH3:30])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:45])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[CH:18][CH2:19][S:20](=[O:46])[C@H:21]23)=[O:44])[N:32]=1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS(=O)[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=CCS(=O)[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Yield: 90.7 %

Procedure:
To a solution of 7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-cephem-4-carboxylic acid 1-oxide diphenylmethyl ester (265 mg) in a mixture of anisole (0.8 ml) and dichloromethane (1.5 ml) is added trifluoroacetic acid (1 ml) at 0° C. with stirring. After 45 minutes' stirring, the mixture is concentrated in vacuum. The residue is washed with petroleum ether and ether to give 7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-cephem-4-carboxylic acid 1-oxide (180 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)(O)[C:11]1[CH:10]=[C:9]([F:24])[CH:8]=[CH:7][C:6]=1[S:5]2.S(C1C=CC=CC=1C(OC(=O)C1C=CC=CC=1S(O)(=O)=O)=O)(O)(=O)=O.C(O)(=O)CC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[C:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)[C:11]1[CH:10]=[C:9]([F:24])[CH:8]=[CH:7][C:6]=1[S:5]2
Reactant: CN1CCC(C2(O)c3ccc(Cl)cc3Sc3ccc(F)cc32)CC1
Agent: O=C(OC(=O)c1ccccc1S(=O)(=O)O)c1ccccc1S(=O)(=O)O
Solvent: CCC(=O)O
Product: CN1CCC(=C2c3ccc(Cl)cc3Sc3ccc(F)cc32)CC1

Procedure:
Dehydration is accomplished by heating 6.4 g. (0.018 mol) of the above thioxanthene-9-ol for one hour with 6.5 g. (0.035 mol) of o-sulfobenzoic anhydride in 100 ml. of propionic acid. Workup the reaction mixture affords 4-(6-chloro-2-fluoro-9-thioxanthenylidene) 1-methylpiperidine, isolated as the hydrochloride salt, m.p. 264°-265° C.
Reaction SMILES: [OH:1][C:2]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][CH3:13])[CH2:8][CH2:7]1)=[O:4].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br.C(N(CC)CC)C>>[OH:1][C:2]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:3]([O:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([N:12]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])[CH3:13])[CH2:10][CH2:11]1)=[O:4]
Reactant: CN[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Reactant: BrCCCCCCCCCBr
Solvent: CCN(CC)CC
Product: CN(CCCCCCCCCBr)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Temperature: 70 °C
Reaction time: 94 h

Procedure:
Trans-4-(methylamino)cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 5, 0.5 g, 0.001 mol), 1,9-dibromononane (2.9 mL, 0.01 mol) and triethylamine (0.44 mL, 0.003 mol) were mixed together under nitrogen atmosphere and stirred at 70° C. for 94 hours. The reaction mixture was evaporated and purified by column chromatography with silica gel, eluting with chloroform/methanol (from 100 to 4:1) to give the title compound as a brown oil (55%).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]2[C:16]3[CH:15]=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][C:11]=3[NH:10][C:9](=[O:20])[C:8]=2[N:21]=1)(=O)C.Cl>O>[NH2:4][C:5]1[S:6][C:7]2[C:16]3[CH:15]=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][C:11]=3[NH:10][C:9](=[O:20])[C:8]=2[N:21]=1
Reactant: CC(=O)Nc1nc2c(=O)[nH]c3cc(C(=O)O)ccc3c2s1
Agent: Cl
Solvent: O
Product: Nc1nc2c(=O)[nH]c3cc(C(=O)O)ccc3c2s1
Yield: 85.6 %

Procedure:
2-acetamido-4-oxo-4,5-dihydrothiazolo[4,5-c]quinoline-7-carboxylic acid (102 mg, 0.34 mmol) was stirred at 120° C. in aqueous 6N HCl overnight. Water was added and the compound was filtered and dried to provide 2-amino-4-oxo-4,5-dihydrothiazolo[4,5-c]quinoline-7-carboxylic acid as a black solid (76 mg, 86% yield). LCMS (ES): 95% pure, m/z 262 [M+1]+, 1H NMR (DMSO-d6, 400 MHz) δ 7.60 (d, J=8.4, 1H), 7.70 (dd, J=1.2, J=8.0, 1H), 7.99 (d, J=1.2, 1H), 11.94 (s, 1H) ppm.
Reaction SMILES: [CH:1]([N:3]([CH2:5][C:6](O)=O)C)=O.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[C:10]#[CH:11].C(OC(=O)C)(=O)C>>[CH3:1][N:3]1[CH:5]=[CH:6][C:10]([C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:11]1
Reactant: C#CC(=O)OCC
Reactant: CN(C=O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccn(C)c1
Yield: 71.3 %

Procedure:
Using 117.1 g (1 mol) of N-formylsarcosine, 98.1 g (1 mol) of ethyl propiolate and 638 ml of acetic anhydride, a reaction and post treatment were conducted in a similar manner as in Referential Example 1. The resulting brown oil was distilled under reduced pressure and a 103°-104° C. fraction was collected under 4 mmHg, whereby 109.19 g of the title compound were obtained (yield: 71.3%).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH3:47])=[C:10]([CH:46]=2)[C@@H:11]([C:34]2[C:43]([CH3:44])=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][C:35]=2[CH3:45])[O:12]C(=O)[C@@H](NS(C2C=CC(C)=CC=2)(=O)=O)CC2C=CC=CC=2)[CH:5]=[CH:4][N:3]=[CH:2]1>CN(C)C=O>[OH:12][C@H:11]([C:34]1[C:35]([CH3:45])=[CH:36][C:37]([C:38]([OH:40])=[O:39])=[CH:42][C:43]=1[CH3:44])[C:10]1[CH:46]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:7]=[CH:8][C:9]=1[CH3:47]
Reactant: COC(=O)c1cc(C)c([C@@H](OC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2ccc(C)cc2)c2cc(-n3ccnc3)ccc2C)c(C)c1
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ccnc2)cc1[C@H](O)c1c(C)cc(C(=O)O)cc1C

Procedure:
The compound obtained in Example 5 was treated in the same manner as in Example 2 to give 13.8 g of (S)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid, melting point 286-288° C. (decomposition), optical rotation [α]D21 -261.5° (c=1.0, dimethylformamide).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]2[N:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=[C:3]12.S(=O)(=O)(O)O.[CH3:19][CH2:20]O>>[CH2:19]([O:12][C:11]([C:9]1[CH:10]=[C:3]2[C:2](=[O:1])[CH2:7][CH2:6][CH2:5][N:4]2[N:8]=1)=[O:13])[CH3:20]
Reactant: O=C(O)c1cc2n(n1)CCCC2=O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2n(n1)CCCC2=O
Temperature: 100 °C

Procedure:
To a mixture of 4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine-2-carboxylic acid (16 g, 89 mmol) in 170 mL EtOH is added slowly 12 mL concentrated sulphuric acid and the reaction mixture is heated to 100° C. for 2 h. The reaction mixture is cooled to RT and concentrated under reduced pressure. The residue is poured on ice, neutralized by the addition of an aqueous saturated solution of NaHCO3 and extracted with DCM. The combined organic phases are washed with water and brine, dried on MgSO4 and the solvent are removed under reduced pressure. Yield: 17 g. HPLC-MS: Rt=1.79 min, (M+H)+=209.
Reaction SMILES: Cl.[Cl:2]C1C=C(CCC[NH2:13])C=CC=1Cl.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[CH2:22][CH2:23][C:24](O)=O>>[ClH:2].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[CH2:22][CH2:23][CH2:24][NH2:13]
Reactant: O=C(O)CCc1c(Cl)cccc1Cl
Reactant: NCCCc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: NCCCc1c(Cl)cccc1Cl

Procedure:
Intermediate 3 was prepared according to the procedures described in Intermediate 1 using 3-(2,6-dichlorophenyl)propanoic acid as the starting material. LC-MS (ESI) m/z 204.0 (M+H)+, RT=1.46 min (Method B).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][CH:9]([F:61])[O:10][N:11]=[C:12]([C:36]1[N:37]=[C:38]([NH:41]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:39][CH:40]=1)[C:13]([NH:15][C@@H:16]1[C:34](=[O:35])[N:18]2[C:19]([C:31]([O-:33])=[O:32])=[C:20]([CH2:23][N+:24]3[N:25]([CH3:30])[CH:26]=[CH:27][C:28]=3[CH3:29])[CH2:21][S:22][C@H:17]12)=[O:14]>>[NH2:41][C:38]1[S:39][CH:40]=[C:36]([C:12](=[N:11][O:10][CH:9]([F:8])[F:61])[C:13]([NH:15][C@@H:16]2[C:34](=[O:35])[N:18]3[C:19]([C:31]([O-:33])=[O:32])=[C:20]([CH2:23][N+:24]4[N:25]([CH3:30])[CH:26]=[CH:27][C:28]=4[CH3:29])[CH2:21][S:22][C@H:17]23)=[O:14])[N:37]=1
Reactant: Cc1ccn(C)[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOC(F)F)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn(C)[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOC(F)F)c3csc(N)n3)[C@H]2SC1

Procedure:
7β-[2-(2-Aminothiazol-4-yl)-2-(difluoromethoxyimino)acetamido]-3-(2,5-dimethyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer) was prepared from trifluoroacetic acid salt of 7β-[2-difluoromethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(2,5- dimethyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer) according to a similar manner to that of Example 29.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][OH:30].[BH4-].[Na+].[ClH:33]>C(O)C.CO.O1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[ClH:1].[ClH:33].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][OH:30])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: NCCNCCO
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [BH4-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CNCCNCCO)ccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-chloro-5-formyl-N-(tricyclo [3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.244 g, Example 1b), 2-(2-aminoethylamino)-ethanol (0.154 g), p-toluenesulfonic acid (0.005 g) and toluene (30 ml) were refluxed together under Dean-Stark conditions for 3 hs, cooled and concentrated under reduced pressure to give an oil. This was dissolved in ethanol (30 ml) and cooled to 0° C. under a nitrogen atmosphere. Solid sodium borohydride (0.030 g) was added portionwise to this and the mixture stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure and the residue purified by column chromatography over silica gel (eluting with 7:3:0.3 dichloromethane/methanol/35% aqueous ammonia) to give the free base. This was dissolved in methanol (10 ml) and treated with 4M hydrochloric acid in dioxane (4 ml) to give a solid precipitate. This was filtered off and washed with diethyl ether to afford the title compound as a solid (0.165 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C@:8]2([CH3:30])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:29])[C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[N:9]2)[C:5]([F:31])=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([NH2:41])=[O:40])=[N:37][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([NH:41][C:2]2[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C@:8]3([CH3:30])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:29])[C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=4)=[N:9]3)[N:7]=2)=[O:40])=[N:37][CH:38]=1
Reactant: NC(=O)c1ccc(Cl)cn1
Reactant: C[C@@]1(c2nc(Br)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccc([N+](=O)[O-])cc2)=N1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@]1(c2nc(NC(=O)c3ccc(Cl)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccc([N+](=O)[O-])cc2)=N1
Temperature: 110 °C

Procedure:
A mixture of A sealable vial was charged with N-((4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)-4-nitrobenzamide (8a, 0.297 g, 0.588 mmol), 5-chloropicolinamide (intermediate 18, 0.101 g, 0.647 mmol), cesium carbonate (0.479 g, 1.470 mmol, Aldrich), Pd2(dba)3 (0.040 g, 0.044 mmol, Strem), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.102 g, 0.176 mmol, Aldrich), and 1,4-dioxane (4 mL). The reaction was purged with Argon and heated to 110° C. overnight. The reaction mixture was filtered through celite and the filter cake was washed with EtOAc. The filtrate was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via silica gel flash chromatography (gradient 0-35% EtOAc in hexanes) to afford the title compound as a light yellow solid. MS m/z=581 [M+H]+. Calculated for C24H17ClF4N6O5: 580.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])=[CH:10][CH:9]=1.CC(C)=O.O>O1CCCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:12][CH:13]=1
Reactant: O=C(O)CCCc1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OCCCCc1ccc(Br)cc1
Yield: 77.9 %

Procedure:
Lithium aluminum hydride (759 mg) was added to a solution of 4-(4-bromophenyl)butyric acid (3.12 g) in tetrahydrofuran (90 mL) under ice-cooling, and the mixture was stirred under ice-cooling for one hour. Acetone and water were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1→10:1→7:1 5:1) to give 4-(4-bromophenyl)butan-1-ol (2.29 g, quant.).