Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=O)[NH:24][C:23]=2[CH3:30])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:24][C:23]=2[CH3:30])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2cc(F)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCN1CCCC1

Procedure:
5-Fluoro-1,3-dihydro-indol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:12]1[C:18]#[N:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(N(CC)CC)C>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:12]1[C:18]([NH2:19])=[N:21][OH:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NO)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1

Procedure:
A solution of benzyl-(2S)-2-cyano-4,4-difluoropyrrolidine-1-carboxylate, hydroxylamine hydrochloride (1.4 eq.) and triethylamine (1.7 eq.) in ethanol was refluxed under nitrogen for 5 hours. Mixture was concentrated and residues taken up in ethyl acetate and washed with water and brine. Combined organics were dried over Na2SO4 and evaporated to give title compound as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH2:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCCl.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:12][C:13]2[CH:14]=[C:15]([N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])[CH:16]=[CH:17][CH:18]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: Nc1cccc(N2CCCC2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1CCCN1c1cccc(Nc2ncc(Br)cc2[N+](=O)[O-])c1
Yield: 65.4 %

Procedure:
A suspension of 5-bromo-2-chloro-3-nitropyridine (3.79 g, 16 mmol), 1-(3-aminophenyl)pyrrolidin-2-one (2.56 g, 15 mmol) and potassium carbonate (2.0 g, 15 mmol) in 1,2-dichloroethane (25 ml) was heated at reflux for 60 hours. The reaction was cooled, diluted with dichloromethane (200 ml) and extracted with water. The organic phase was then dried over anhydrous sodium sulphate, filtered and pre-adsorbed on to silica (25 g). Purification by column chromatography eluting with isohexane on a gradient of ethyl acetate (10%-40%) gave 1-[3-(5-bromo-3-nitropyridin-2-ylamino)phenyl]pyrrolidin-2-one as a red solid (3.7 g, 68%).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH:4]([C:7]1([CH3:27])[C:11](=[O:12])[NH:10][C:9]([C:13]2[C:21]3[N:20]=[C:19]([CH3:22])[N:18]([CH3:23])[C:17]=3[CH:16]=[CH:15][C:14]=2[C:24]([OH:26])=[O:25])=[N:8]1)([CH3:6])[CH3:5].C(O)(=O)C>CCOCC.CO>[CH:4]([C:7]1([CH3:27])[C:11](=[O:12])[NH:10][C:9]([C:13]2[C:21]3[N:20]=[C:19]([CH3:22])[N:18]([CH3:23])[C:17]=3[CH:16]=[CH:15][C:14]=2[C:24]([O:26][CH3:3])=[O:25])=[N:8]1)([CH3:6])[CH3:5]
Reactant: Cc1nc2c(C3=NC(C)(C(C)C)C(=O)N3)c(C(=O)O)ccc2n1C
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)c1ccc2c(nc(C)n2C)c1C1=NC(C)(C(C)C)C(=O)N1
Yield: 28.9 %

Procedure:
A solution of diazomethane in ether is added dropwise to a solution of the 4-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-1,2-dimethyl-5-benzimidazolecarboxylic acid (2.50 g, 7.6% mmol) in methanol until the yellow color persists. The reaction mixture is neutralized with acetic acid and concentrated in vacuo. Preparative HPLC (silica gel, ethyl acetate eluent) affords the title product as off-white crystals (0.750 g, 28.9%), mp 240°-242° C.
Reaction SMILES: Cl.[C:2]([O:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].CN1CCOCC1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[O:37]([C:44]1[CH:49]=[CH:48][C:47]([S:50][C:51]2([CH2:57][C:58](O)=[O:59])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl>C(Cl)Cl>[C:2]([O:6][NH:7][C:58](=[O:59])[CH2:57][C:51]1([S:50][C:47]2[CH:48]=[CH:49][C:44]([O:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:45][CH:46]=2)[CH2:52][CH2:53][O:54][CH2:55][CH2:56]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)ON
Reactant: O=C(O)CC1(Sc2ccc(Oc3ccccc3)cc2)CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)ONC(=O)CC1(Sc2ccc(Oc3ccccc3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
O-(tert-Butyl)hydroxylamine hydrochloride (9.57 g), 4-methylmorpholine (15.64 ml), hydroxybenzotriazole (6.87 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.5 g) was added to a solution of 2-[4-(4-phenoxyphenylthio)-tetrahydropyran-4-yl]acetic acid (17.5 g) in methylene chloride (200 ml). After stirring for 3 hours at room temperature, 0.5 M hydrochloric acid (200 ml) was added to the mixture, and the mixture extracted with methylene chloride. The solvent was removed from the combined extracts under reduced pressure. Silica gel chromatography of the residue and elution with 35%-80% ethyl acetate/hexane gave N-tert-butoxy-2-[4-(4-phenoxyphenylthio)-tetrahydropyran-4-yl]-acetamide (15.3 g) as an oil, which can be used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[N:13]=[C:12]([NH2:24])[N:11]=2)[C:7]([CH3:25])=[CH:6][C:5]=1[O:26][CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[C:40]([O:44][C:45](=[O:51])[NH:46][CH2:47][CH2:48][CH2:49]Br)([CH3:43])([CH3:42])[CH3:41]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:49][CH2:48][CH2:47][NH:46][C:45]([O:44][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:51])[CH:18]=3)[N:13]=[C:12]([NH2:24])[N:11]=2)[C:7]([CH3:25])=[CH:6][C:5]=1[O:26][CH3:27]
Reactant: COC(=O)c1cc(-c2cc(Sc3cccc(O)c3)nc(N)n2)c(C)cc1OC
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2cc(Sc3cccc(OCCCNC(=O)OC(C)(C)C)c3)nc(N)n2)c(C)cc1OC
Temperature: 25 °C
Reaction time: 37 h
Yield: 92.9 %

Procedure:
5-[2-Amino-6-(3-hydroxyphenylsulfanyl)pyrimidin-4-yl]-2-methoxy-4-methylbenzoic acid methyl ester (80 mg, 0.2 mmol) obtained in Step 1 above, cesium carbonate (124 mg, 0.38 mmol), and N,N-dimethylformamide (1.0 ml) were added to a reaction vessel. Then 3-bromopropylcarbamic acid tert-butyl ester (100 mg, 0.42 mmol) was added to the mixture. The mixture was stirred at room temperature for 37 hours. The reaction solution was diluted with ethyl acetate (100 ml), and sequentially washed twice with a saturated aqueous ammonium chloride solution (50 ml), twice with water (50 ml), and with a saturated aqueous sodium chloride solution (50 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate) to yield 5-{2-amino-6-[3-(3-tert-butoxycarbonylaminopropoxy)phenylsulfanyl]pyrimidin-4-yl}-2-methoxy-4-methylbenzoic acid methyl ester (103 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[S:5][CH:6]=1.Cl[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]2[CH2:24][CH3:25])=[CH:16][C:15]=1[F:30]>N1C=CC=CC=1>[CH2:24]([N:21]1[C:22]2[C:17](=[CH:16][C:15]([F:30])=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH:7]([C:4]4[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=4)[CH2:12]3)[CH:23]=2)[C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20]1)[CH3:25]
Reactant: Cc1csc(C2CNCCN2)c1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cc(C)cs4)C3)cc21
Yield: 24.1 %

Procedure:
A mixture of 10.92 g of 2-(4-methyl-2-thienyl)piperazine and 5.38 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 30 ml of pyridine was heated at reflux under argon for 18 hours, then allowed to cool and the solvent removed. The residue was triturated with methanol and ether, then filtered and dried, giving 2 g of the desired product, mp 230° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].[CH:29]([C:31]([CH3:33])=[O:32])=[CH2:30]>ClCCl.CCCCCCC.CC(C)([O-])C.[K+]>[CH2:1]([N:8]([CH2:30][CH2:29][C:31](=[O:32])[CH3:33])[S:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N+:16]([O-:18])=[O:17])(=[O:27])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: C=CC(C)=O
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of benzylamine (10.92 ml, 100 mmol) in dichloromethane (DCM) (150 ml) was added triethylamine (13.67 ml, 100 mmol) followed by a solution of 2-nitrobenzene-1-sulfonyl chloride (22.16 g, 100 mmol) in DCM (70 ml) at 5-10° C. with stirring. The mixture was stirred for 1 hour (complete by HPLC), stirring continued for 1 hour, washed with water, brine, most of DCM removed on a rotavap, Ethyl acetate (150 ml) was added, another 25-30 ml distilled off under reduced pressure. To the resulting solution potassium tert-butoxide (0.561 g, 5.00 mmol) was added followed by methyl vinyl ketone (9.07 ml, 110 mmol) with stirring in one portion at 20-25° C. The mixture was stirred for 1 hour at 20-25° C., diluted with heptane (70 ml), washed with brine+1N HCl (5 ml), organic phase was dried (MgSO4), evaporated to approx 100 ml, seeded with crystals of compound F (crystallisation started), cooled to 0-5° C., diluted slowly with heptane to approx 200 ml. The mixture was aged in ice for 1 hour, crystals collected, washed with heptane, dried on air to give N-benzyl-2-nitro-N-(3-oxobutyl)benzenesulfonamide (31.4 g, 87 mmol, 87% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.Cl[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][O:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: ClCc1ccccn1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(OCc2ccccn2)cc1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A mixture of 4-acetamidophenol (Sigma-Aldrich; 73.6 g), 2-chloromethylpyridine hydrochloride (80 g) and cesium carbonate (320 g) in DMF (1 L) was stirred at 70° C. for 2 days. The mixture was cooled, poured into water (2 L) and extracted with EtOAC (×6). The organic layers were washed with brine, dried (MgSO4) and filtered to give a tan solid (A-1, 114 g) which was used as such in the next step.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11].[C:12]([NH:15][CH:16]([C:18](O)=[O:19])[CH3:17])(=[O:14])[CH3:13].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C>[C:12]([NH:15][C@H:16]([C:18]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11])=[O:19])[CH3:17])(=[O:14])[CH3:13]
Reactant: CC(=O)NC(C)C(=O)O
Reactant: COc1ccc(N)c(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)[C@H](C)NC(C)=O)c(O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 9.8 %

Procedure:
To a solution of 2-amino-5-methoxyphenol hydrochloride (5.24 g, 29.8 mmol), N-acetyl-D,L-alanine (3.91 g, 29.8 mmol) and 1-hydroxybenzotriazole (4.03 g, 29.8 mmol) in DMF (5 mL) were added triethylamine (4.15 mL, 29.8 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.72 g, 29.8 mmol), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 1N hydrochloric acid, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (ethyl acetate to methanol:ethyl acetate=1:4), and triturated with ethyl acetate to give the title compound (740 mg, yield 9.8%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([OH:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(OCC)C>CO>[CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)([O-:31])(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C

Procedure:
Clopidogrel base was dissolved in methanol. p-Toluene sulphonic acid was added to the solution at 20° C. The reaction mixture was heated to reflux temperature for 2 hrs. The solution was cooled to room temperature and was added drop-wise to diethyl ether. The suspension was stirred at RT. The solid was filtered and dried at about 50° C. in a vacuum oven to give Clopidogrel tosylate similar to that obtained above.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH:3]([NH:8][C:9]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)=[O:24])=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6]C)=[O:5].O.[OH-].[Li+].Cl>C1COCC1>[CH3:1][CH:2]([CH3:36])[CH:3]([NH:8][C:9]([C:11]1[S:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=3)=[O:24])=[CH:20][CH:21]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)s1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)s1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3-methyl-2-(5-(4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl) thiazole-2-carboxamido)butanoate (Example 9, 100 mg) in THF (2 ml) was added 1 M aqueous solution of Lithium hydroxide monohydrate (0.38 ml) and the mixture was stirred at RT for 4 hours. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, concentrated under reduced pressure and then crystallized in EtOAc to give the title compound. Yield: 60 mg (62%); 1H NMR (DMSO-d6, 300 MHz): δ 12.97 (bs, 1H), 9.18 (s, 1H), 9.13 (s, 1H), 8.37 (d, 1H), 8.36 (s, 1H), 8.03 (d, 1H), 7.71 (d, 2H), 7.61 (d, 2H), 7.55 (dd, 1H), 7.5 (dd, 1H), 7.34 (d, 1H), 4.31, (m, 1H), 2.28 (m, 1H), 0.95 (d, 6H); MS (ES+): m/z 507 (M+1).
Reaction SMILES: Cl.[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:31]/[O:32][CH3:33])/[C:28](O)=[O:29])[N:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([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.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[NH2:48][C@@H:49]1[C:82](=[O:83])[N:51]2[C:52]([C:66]([O:68][CH:69]([C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=3)[C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)=[O:67])=[C:53]([CH2:56][S:57][C:58]3[CH:63]=[C:62]([CH3:64])[O:61][C:60](=[O:65])[CH:59]=3)[CH2:54][S:55][C@H:50]12>CN(C)C=O.N1C=CC=CC=1>[CH3:64][C:62]1[O:61][C:60](=[O:65])[CH:59]=[C:58]([S:57][CH2:56][C:53]2[CH2:54][S:55][C@@H:50]3[C@H:49]([NH:48][C:28](=[O:29])/[C:27](/[C:25]4[N:26]=[C:22]([NH:21][C:2]([C:3]5[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=5)([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)[S:23][CH:24]=4)=[N:31]\[O:32][CH3:33])[C:82](=[O:83])[N:51]3[C:52]=2[C:66]([O:68][CH:69]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[O:67])[CH:63]=1
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](N)[C@H]3SC2)cc(=O)o1
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3cc(C)oc(=O)c3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
A stirred solution of 2-(2-tritylaminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid hydrochloride (470 mg) and N,N-diisopropylethylamine (0.34 ml) in dimethylformamide (4 ml) was cooled to -55° to -60° C. and methanesulphonyl chloride (0.075 ml) was added. The mixture was stirred at the same temperature for 0.5 h and then a solution of diphenymethyl 7β-amino-3-(6-methyl-2-oxo-2H-pyran-4-ylthiomethyl)ceph-3-em-4-carboxylate (450 mg) in dimethylformamide (4 ml) was added, followed by pyridine (0.071 ml). The mixture was stirred at 0° C. for 1.5 h and then partitioned between ethyl acetate and citric acid solution. The organic phase was then washed successively with water, sodium bicarbonate solution, water and brine. The solution was dried over magnesium sulphate and evaporated. The product (576 mg) was isolated by column chromatography of the residue using gradient elution (Kieselgel 1:1 hexane:ethyl acetate going to neat ethyl acetate). υmax (CHCl3) 3400, 1780, 1710 and 1680(s). δ(CDCl3) 2.18 (3H, s), 3.46 (1H, d, J 18.3Hz), 3.61 (1H, d, J 18.4Hz), 3.85 (1H, d, J 12.3Hz), 3.96 (1H, d, J 12.3Hz), 4.08 (3H, s), 5.08 (1H, d, J 4.9Hz), 5.69 (1H, s), 5.78 (1H, s), 5.96 (1H, dd, J 4.9 and 8.9Hz), 6.74 (1H, s), 6.81 (1H, d, J 8.8Hz), 6.97 (1H, s), 7.02 (1H, s), 7.2-7.5 (25H, m). [Mass spectrum: +ve ion (3NOBA, Na+) MNa+ 1196].
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:2]#[CH:3].[CH2:12]([O:19][N:20]1[C:26](=[O:27])[N:25]2[CH2:28][C@H:21]1[CH2:22][CH2:23][C@H:24]2[C:29](Cl)=[N:30][OH:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.CCOC(C)=O>[C:7]([O:6][C:5](=[O:11])[NH:4][CH2:1][C:2]1[O:31][N:30]=[C:29]([C@@H:24]2[CH2:23][CH2:22][C@@H:21]3[CH2:28][N:25]2[C:26](=[O:27])[N:20]3[O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: O=C1N2C[C@@H](CC[C@H]2C(Cl)=NO)N1OCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
tert-Butyl prop-2-yn-1-ylcarbamate (0.37 g, 2.4 mmol) was added to the solution of (2S,5R)-6-(benzyloxy)-N-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbimidoyl chloride (˜2.0 mmol) in dry DCM (20 mL), followed by the addition of TEA (0.31 mL, 2.2 mmol) in dry DCM (2.0 mL) over a period of 30 minutes. The reaction mixture was stirred at rt overnight, then the mixture was diluted with EtOAc, washed with water and saturated sodium chloride. The organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (1:2 petroleum ether/EtOAc) to afford tert-butyl((3-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)isoxazol-5-yl)methyl)carbamate (180 mg, 21% for two steps) as a white solid. ESI-MS (EI+, m/z): 429.1 [M+H]+. 1H NMR (500 MHz, CDCl3): δ 7.45-7.35 (m, 5H), 6.24 (s, 1H), 5.09 (d, J=11.5 Hz, 1H), 4.93 (d, J=11.5 Hz, 1H), 4.58 (d, J=7.5 Hz, 1H), 4.43 (m, 2H), 3.32 (s, 1H), 2.86-2.84 (m, 1H), 2.68 (d, J=11.5 Hz, 1H), 2.34-2.30 (m, 1H), 2.23-2.18 (m, 1H), 2.10-2.04 (m, 1H), 1.82-1.78 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH:13]=[CH:12][C:11](OC)=[C:10]([C:16]#[N:17])[C:9]1=[O:18].O.[NH2:20][NH2:21].C(O)C>CN(C)C=O>[NH2:17][C:16]1[C:10]2[C:9](=[O:18])[N:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])[CH:13]=[CH:12][C:11]=2[NH:21][N:20]=1
Reactant: NN
Reactant: COc1ccn(-c2ccncc2Cl)c(=O)c1C#N
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: Nc1n[nH]c2ccn(-c3ccncc3Cl)c(=O)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
A mixture of 3′-chloro-4-methoxy-2-oxo-2H-[1,4′-bipyridine]-3-carbonitrile obtained in Step C (0.35 g), hydrazine monohydrate (0.17 g), ethanol (10 mL) and N,N-dimethylformamide (10 mL) was stirred at 60° C. for 2 hr. The solvent was evaporated under reduced pressure, to the residue was added isopropyl ether, and the mixture was stirred for 15 min. The precipitate was collected by filtration to give the title compound (0.30 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:11][CH3:12])[CH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4].[O:13]=[C:14](Cl)OC(Cl)(Cl)Cl>C(Cl)Cl>[CH2:11]([CH:2]1[CH:3]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)[O:4][C:14](=[O:13])[NH:1]1)[CH3:12]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCC(N)C(O)c1cccnc1
Solvent: ClCCl
Product: CCC1NC(=O)OC1c1cccnc1
Yield: 58 %

Procedure:
To a solution of 2-amino-1-pyridin-3-yl-butan-1-ol (150 mg, 0.90 mmol) in CH2Cl2 (5 mL) was added under argon NEt3 (314 μL, 5.63 mmol) at 0° C. Then, diphosgene was added over a period of 5 minutes and the temperature was allowed to warm from 0° C. to room temperature within 2 hours. The reaction mixture was quenched with ice cold water and a 2 M solution of Na2CO3, extracted with CH2Cl2, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using EtOAc in heptane from 0% to 100% in order to give the title compound (100 mg, 58%) as a mixture of diastereoisomers A and B. LC-MS: [M+H] 193.1; Rt 0.43 min; (LCMS method 1). A) 1H NMR (400 MHz, CHCl3-d): 8.70-8.62 (m, 1H), 8.60-8.56 (m, 1H), 7.76-7.71 (m, 1H), 7.42-7.35 (m, 1H), 5.78 (d, 1H), 4.08-3.98 (m, 1H), 1.21-1.05 (m, 2H), 0.84 (t, 3H). B) 1H NMR (400 MHz, CHCl3-d): 8.70-8.62 (m, 2H), 7.80-7.76 (m, 1H), 7.42-7.35 (m, 1H), 5.21 (d, 1H), 3.75-3.68 (m, 1H), 1.89-1.69 (m, 2H), 1.05 (t, 3H).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([CH3:13])[CH:8]([CH:9]=[C:10]([Cl:12])[Cl:11])[O:7][C:5](=[O:6])[CH2:4]1.[CH3:14]O>>[CH3:2][C:3]([CH3:13])([CH:8]([Cl:1])[CH:9]=[C:10]([Cl:12])[Cl:11])[CH2:4][C:5]([O:7][CH3:14])=[O:6]
Reactant: Cl
Reactant: CC1(C)CC(=O)OC1C=C(Cl)Cl
Reactant: CO
Product: COC(=O)CC(C)(C)C(Cl)C=C(Cl)Cl
Yield: 96 %

Procedure:
To 30 parts of methanol saturated with hydrogen chloride gas (concentration of hydrogen chloride: about 50%) was added 41.8 parts of 3,3-dimethyl-4-(2',2'-dichlorovinyl)-4-butanolide, followed by heating in a closed tubular reactor at 70°-80° C. for 3 hours. The reaction mixture was then treated in the same manner as Example 1. By the above procedure was obtained 49.8 parts of methyl 3,3-dimethyl-4,6,6-trichloro-5-hexenoate (yield 96%). This product was found to have properties identical with those of the product according to Example 1.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][O:3][CH2:2]1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:9]([O:16][C:5]([CH2:4][O:3][CH2:2][C:1]([OH:7])=[O:8])=[O:6])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: O=C1COCC(=O)O1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)COCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
Diglycolic anhydride (4.11 g, 31.9 mmol) was dissolved in methylene chloride and benzyl alcohol (3.3 g, 31.9 mmol) was added, followed by triethylamine (3.22 g, 31.9 mmol). The reaction mixture was stirred at room temperature for 4 hours. Toluene (20 mL) was added, volatiles were evaporated and the residue was dried on vacuum pump overnight to afford 7.17 g of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ4.17 (s, 2H), 4.26 (s, 2H), 5.18 (s, 2H), 7.21-7.42 (m, 5H).