Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:21]3[S:20](=O)[CH2:19][C:18]=2[S:65][CH:66]([S:68][C:69]2[N:73]=[CH:72][NH:71][N:70]=2)[CH3:67])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:65][CH:66]([S:68][C:69]2[N:73]=[CH:72][NH:71][N:70]=2)[CH3:67])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(SC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2S(=O)C1)Sc1nc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: CC(SC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2SC1)Sc1nc[nH]n1
Reaction time: 0.33 h
Yield: 90.7 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol -4-yl)-2-trityloxyiminoacetylamino]-3-(1-methyl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (1.78 g : 1.69 mMol.) in dimethylformamide (15 ml) at -20° C. is added phosphorus trichloride (0.42 ml : 4.18 mMol.), and the mixture is stirred at the same temperature for 20 minutes. The reaction mixture is poured into two layers of cold aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer is taken, washed with water and brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene : ethyl acetate=2: 1) to give 7β-[(Z)-2- (2-t-butoxycarbonylaminothiazol-4-yl) -2-trityloxyiminoacetamido]-3-(1- methyl-1,2,4-triazol-3-ylthiomethylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester (1.59 g) as brown foam. Yield : 91%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([Li])CCC.IC.O>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[C:13]([CH3:20])=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC1C=C(Cl)C=CN1C(=O)OC(C)(C)C
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCCC1C=C(Cl)C=C(C)N1C(=O)OC(C)(C)C
Temperature: -42 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a stirred solution of 1-(tert-Butoxycarbonyl)-4-chloro-2-n-pentyl-1,2-dihydropyridine (4.67 g, 16.33 mmol) in 170 ml of THF at −42° C. was added n-butyllithium (7.84 mL, 19.61 mmol) dropwise via syringe. After the mixture had stirred at −42° C. for 1 h, iodomethane (3.1 mL, 48.99 mmol) was added and stirring was continued at −42° C. for 1 h and then at room temperature for 1 h. Water (50 mL) and ether (100 mL) were added, the layers were separated, the aqueous phase was extracted with ether (2×15 mL), and the combined organic extracts were washed with brine. The organic phase was dried over K2CO3 filtered through silica gel/Celite, and concentrated in vacuo to give the crude product. Purification by column chromatography with 5% EtOAc in hexanes afforded 3.6 g (74%) of the product. 1H NMR (250 MHz) d 5.62-5.59 (d, 1 H), 5.31 (br s, 1 H), 4.80-4.72 (q, 1 H), 2.13 (s, 1 H), 1.55-1.26 (m, 17 H), 0.89-0.84 (t, 3 H); 13C NMR (62.7 MHz) 153.0 (s), 136.9 (s), 126.5 (s), 119.3 (s), 112.2 (s), 81.4 (s), 54.1 (s), 31.6 (s), 31.5 (s), 28.1 (s), 24.2 (s), 22.4 (s), 21.9 (s), 13.9 (s), ppm. FT-IR (neat) 2927, 2855, 1706, 1634, 1391, 1128, 1087 cm−1.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=2)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([N:42]1[CH2:41][CH2:40][N:39]([C:45]2[CH:46]=[CH:47][C:48]([OH:51])=[CH:49][CH:50]=2)[CH2:44][CH2:43]1)=[O:16]
Reactant: Nc1onc(-c2cccc(F)c2)c1C(=O)O
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 68.5 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(3-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (483 mg, 1.26 mmol, 68%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:13]=O.C1(P(=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC#N>[C:11]([C:9]1[CH:10]=[C:2]([F:1])[CH:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[C:5]2/[CH:13]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])#[N:12]
Reactant: N#Cc1cc(F)cc2c(C=O)c[nH]c12
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)/C=C/c1c[nH]c2c(C#N)cc(F)cc12
Yield: 63.8 %

Procedure:
To a mixture of 5-fluoro-3-formyl-1H-indole-7-carbonitrile (D133) (8 g) in CH3CN (80 mL) was added ethyl (triphenylphosphoranylidene)acetate (30 g). The reaction was heated to reflux overnight. After the mixture was filtered, the filtrate was concentrated and purified by column chromatography to afford ethyl (2E)-3-(7-cyano-5-fluoro-1H-indol-3-yl)-2-propenoate (D134) (7 g) as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(COC2CCCCO2)cc1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
To a solution of 4-nitrobenzylalcohol (50 g, 0.326 mol) in ethyl acetate (EtOAc) (200 ml) were added 3,4-dihydropyran (35.7 ml, 0.392 mol) and CSA (camphor sulfonic acid) (379 mg, 1.63 mmol) under stirring at room temperature, and the mixture was stirred at room temperature for 1 hour. After the reaction completed, the reaction mixture was neutralized with saturated NaHCO3 solution and separated ethyl acetate layer was dried with MgSO4 and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 4-(2-tetrahydropyranyloxymethyl)nitrobenzene (74.5 g, 96%) as syrup.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH2:4]1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[C:41]([O:42][CH3:43])=[CH:40][C:29]2[CH2:30][C:31](=[O:39])[N:32]([CH2:35][CH2:36][CH2:37]Cl)[CH:33]=[CH:34][C:28]=2[CH:27]=1>[OH-].[Na+].C(OCC)(=O)C>[CH3:24][O:25][C:26]1[C:41]([O:42][CH3:43])=[CH:40][C:29]2[CH2:30][C:31](=[O:39])[N:32]([CH2:35][CH2:36][CH2:37][N:2]([CH3:1])[CH:3]3[CH2:12][CH2:11][C:10]4[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=4)[CH2:4]3)[CH:33]=[CH:34][C:28]=2[CH:27]=1
Reactant: CNC1CCc2cc(OC)c(OC)cc2C1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)C=C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3cc(OC)c(OC)cc3C1)C=C2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 2-methylamino-6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene (1.72 g, 0.0078 mol), triethylamine (1.09 ml, 0.0078 mol) and 1-(7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane (2.3 g, 0.0078 mol) is heated to a reaction temperature of 90° C. in steps within one hour and kept at this temperature for 2 hours. The initial suspension slowly changes into a clear solution and begins to precipitate in a jelly-like manner after about 30 minutes. The cooled reaction mixture is dissolved in 0.5M sodium hydroxide solution/ethyl acetate, the organic phase is washed with water, dried over magnesium sulphate, concentrated by evaporation in vacuo and purified over alumina (300 g), neutral, activity II, with methylene chloride and then with increasing quantities of ethanol (up to 20%). The hydrochloride is precipitated from a solution in acetone using ethereal hydrochloric acid. Yield: 1.39 g Mp: >125° C. (Decomp.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH2:9][CH2:10][CH2:11][CH:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH:13]=[CH2:14])=[C:4]([NH2:24])[N:3]=1.CN1CCOCC1.COC1N=C(OC)N=C(Cl)N=1.Cl.[CH3:44][O:45][C:46](=[O:55])[C@H:47]([CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[NH2:48]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH2:9][CH2:10][CH2:11][CH:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:48][C@H:47]([C:46]([O:45][CH3:44])=[O:55])[CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])=[O:20])=[CH:22][CH:23]=2)[CH:13]=[CH2:14])=[C:4]([NH2:24])[N:3]=1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Reactant: C=CC(CCCc1c(N)nc(N)nc1O)c1ccc(C(=O)O)cc1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C=CC(CCCc1c(N)nc(N)nc1O)c1ccc(C(=O)N[C@@H](CCC(=O)OC)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution containing 950 mg eq) of 4-[6-(2,6-diamino-4-hydroxypyrimidin-5-yl)hex-1-en-3-yl]benzoic acid as prepared in step F, 351 mg (1.2 eq) Of N-methylmorpholine, and 10.0 ml of anhydrous dimethylformamide, was vigorously stirred at ambient temperature for 5 minutes. To this solution was added 556 mg (1.1 eq) of 2,4-dimethoxy-6-chloro-1,3,5-triazine and this mixture was then stirred at room temperature for 40 minutes. Following additipn to the solution of 351 mg (1.3 eq) of N-methylmorpholine, and 795 mg (1.3 eq) of dry dimethyl-L-glutamate hydrochloride, the mixture was continuously stirred overnight at room temperature and the solvent then removed under reduced pressure. The product was dissolved in chloroform, and extracted with saturated aqueous sodium bicarbonate to remove unreacted acid, triazine and triazinone. The organic extract was dried over magnesium sulfate, filtered and evaporated to dryness to yield the product which was further purified by flash chromatography eluting with 1:10 methanol:chloroform. M.S. m/z=485.2269 (M+, calc. for C24H31N5O6 : 485.2274). 1H-N.M.R. (CDCl3, 300 MHz): 1.03-1.35 (m, 2H, CH2 --CH2CH2); 1.62 (m, 2H, CH2 --CH--CH=); 2.15 (t, 2H, CH2 -pyr, J=7.5 Hz); 2.0-2.5 (m, 4H, 2×CH2(glu) ; 3.18 (m, 1H, CH--C=); 3.56 (s, 3H, CH3O); 3.66 (s, 3H, CH3O); 4.70 (m, 1H, CHglu); 4.8-5.0 (m, 2Holef.,); 4.89 (s (broad), 2H, NH2); 5.6-5.9 (m, 3H, NH2 +CH=CH2); 7.08 (d, 2Harom., J=8 Hz); 7.50 (m, 1H, NHglu); 7.63 (d, 2Harom., J=8 Hz); 11.25 (s (broad), 1H, NHpyr).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:8][CH:7]=[C:6]([CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=1.C1OCCOCCOCCOCCOC1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:35]=1>O1CCCC1.O>[C:13]([O:12][C:11](=[O:17])[N:10]([CH2:9][C:6]1[CH:5]=[C:4]([Br:3])[N:8]([S:40]([C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)(=[O:42])=[O:41])[CH:7]=1)[CH3:18])([CH3:14])([CH3:15])[CH3:16]
Reactant: CN(Cc1c[nH]c(Br)c1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 7.4 g) in tetrahydrofuran (300 mL) was added a solution of tert-butyl [(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate (44.5 g) in tetrahydrofuran (60 mL) at 0° C., and 15-crown-5 (40.7 g) and pyridine-3-sulfonyl chloride (30.1 g) were added at the same temperature. The mixture was stirred at room temperature for 30 min, water was added and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with a mixed solvent of diisopropyl ether-hexane=1:1 to give the title compound as colorless crystals (yield 45.2 g, 68%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([CH3:11])[CH2:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9].CC(OC)(C)C.[OH-].[Na+].C(C(C)=O)C(C)C>P(=O)(O)(O)O>[CH3:1][O:2][C:3](=[O:12])[C@@H:4]([CH3:11])[CH2:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9]
Reactant: COC(=O)C(C)CCCC(C)=O
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: COC(C)(C)C
Product: COC(=O)[C@@H](C)CCCC(C)=O
Temperature: 10 °C
Reaction time: 51 h
Yield: 41.5 %

Procedure:
10.6 g (content 94.3%, 5.75 mmol) of a racemate of 2-methyl-6-oxoheptanoic acid methyl ester and 20.0 g of MTBE were suspended in 50.0 g of 0.1 M phosphoric acid buffered solution (pH 7.0). The suspension was cooled to 10° C., then, 2.0 g (moisture percentage 56%, enzymatic activity 4028 KU/Kg, reduced by dry product) of immobilized Aspergillus flavus ATCC11492 strain-derived esterase (prepared by a method described in JP-A No. 2003-70471) was added, and the mixture was stirred at 10° C. for 51 hours while maintaining pH at 7.0 to 7.5 by appropriately adding 4% NaOH aqueous solution. Thereafter, the reaction solution was filtrated using Radiolite (filtration aid, trade name: manufactured by Showa Chemical Industry Co., Ltd.), to remove the esterase. The resultant filtrate was extracted twice with 25 g and 12.5 g of methyl isobutyl ketone (MIBK), then, the resultant organic layers were combined and washed with 15% saline, to obtain a MIBK solution of optically active (S)-2-methyl-6-oxoheptanoic acid methyl ester (optical purity 98.9% ee, yield 41.5%). The optical purity was analyzed by HPLC [Chiralpak AS-H, 4.6 mm×25 cm (manufactured by Daicel Chemical Industries, Ltd.)] like in Example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)=[CH:13][CH:12]=3)[O:10][C:4]=2[CH:3]=1.[CH3:22][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]#[CH:25].C(N(CC)CC)C.O>CN(C=O)C.[Cu]I>[CH:19]1([CH2:18][O:17][C:14]2[CH:15]=[CH:16][C:11]([C:9]3[O:10][C:4]4[CH:3]=[C:2]([C:25]#[C:24][C@@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:22])[N:7]=[CH:6][C:5]=4[N:8]=3)=[CH:12][CH:13]=2)[CH2:21][CH2:20]1
Reactant: Clc1cc2oc(-c3ccc(OCC4CC4)cc3)nc2cn1
Reactant: C#C[C@H](C)NC(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](C#Cc1cc2oc(-c3ccc(OCC4CC4)cc3)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 13.1 %

Procedure:
To a solution of 6-chloro-2-(4-(cyclopropylmethoxy)phenyl) [1,3]oxazolo[4,5-c]pyridine (700 mg), tert-butyl (2S)-but-3-yn-2-ylcarbamate (1.13 g) and triethylamine (0.649 g) in DMF (10 mL) were added bistriphenylphosphinedichloropalladium(II) (163 mg) and copper(I) iodide (88.7 mg), and the mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction mixture was allowed to cool to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated under reduced pressure, and the obtained solid was washed with ethyl acetate to give the title compound (132 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([NH2:27])=[O:26].CO.C(Cl)Cl>CC1C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[C:5]([Cl:20])=[CH:4][N:3]=[C:2]([NH:21][C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:25]([NH2:27])=[O:26])[N:7]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)Nc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Cc1ccc(C(N)=O)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: C=CC(=O)Nc1ccccc1Nc1nc(Nc2cc(C(N)=O)ccc2C)ncc1Cl
Yield: 31.4 %

Procedure:
A solution of Intermediate 1 (1 g, 3.24 mmol) and 3-amino-4-methylbenzamide (584 mg, 3.89 mmol) in 0.08 M PTSA in 1,4-dioxane was heated to 90° C. for 48 h. TLC showed the completion of starting material (TLC system: 10% methanol/DCM, (Rf): 0.5). The reaction mixture was concentrated, quenched with water, and the precipitated solid was filtered and dried under vacuum. The crude solid was purified by silica gel column chromatography by using 3% methanol/DCM as eluents. The purified solid was further triturated with ether, filtered and dried under vacuum to get the title compound as an off-white solid (430 mg, 31%). 1HNMR (400 MHz, D6-DMSO) δ 2.17 (s, 3H), 5.78-5.81 (dd, 1H J=1.8, 10.1 Hz), 6.28-6.32 (dd, 1H J=1.8, 17 Hz), 6.43-6.50 (dd, 1H J=10.1, 17 Hz), 7.04-7.08 (m, 2H), 7.18-7.24 (m, 2H), 7.27 (br s, 1H), 7.52-7.54 (dd, 1H J=1.7, 7.9 Hz), 7.73-7.76 (m, 1H), 7.87 (br s, 1H), 7.92 (d, 1H), 8.03 (s, 1H), 8.39 (s, 1H), 8.62 (s, 1H), 10.19 (s, 1H). MS m/z: 423.5 (ES+, M+H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.C1(CC([NH:22][CH:23]2[C:45](=[O:46])[N:25]3[C:26]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=4)=[S:33])=[C:27]([CH:30]=[CH2:31])[CH2:28][S:29][C@H:24]23)=O)C=CC=CC=1.C(OC(C)C)(C)C>C(Cl)Cl.O.CO>[NH2:22][CH:23]1[C:45](=[O:46])[N:25]2[C:26]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[S:33])=[C:27]([CH:30]=[CH2:31])[CH2:28][S:29][C@H:24]12
Reactant: C=CC1=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC1=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of phosphorus pentachloride (366 mg) in methylene chloride (6ml) was added pyridine (0.142 ml) at -30° C. After the mixture was stirred for 30 minutes at the same temperature, p-nitrobenzyl 7-(2-phenylacetamido)-3-vinylthio-3-cephem-4-carboxylate (300 mg) was added thereto at -30° C. The mixture was stirred for 1 hour under the ice-cooling to the mixture was added methanol (0.38 ml) at -30° C., and the mixture was stirred for 2 hours at -15 ~-20° C. Water (0.4 ml) was added thereto under ice-cooling. Diisopropyl ether (5 ml) was added to the mixture to give a precipitate. The precipitate was collected, washed with water and diisopropyl ether successively and dried over phosphorus pentoxide to give p-nitrobenzyl 7-amino-3-vinylthio-3-cephem-4-carboxylate hdrochloride (181 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[C:16]([O:21][CH3:22])[N:15]=[C:14]([O:23][CH3:24])[N:13]=2)C#N)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].CN(C=[O:31])C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[C:16]([O:21][CH3:22])[N:15]=[C:14]([O:23][CH3:24])[N:13]=2)=[O:31])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN(C)C=O
Reactant: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(Cl)cc(Cl)c2)n1
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(Cl)cc(Cl)c2)n1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a stirred solution of (59) (9.6 g, 26 mmol) in anhydrous DMF (100 ml) under nitrogen atmosphere, was added 60% sodium hydride (1.05 g, 26 mmol). After 10 min., oxygen was bubbled into the reaction mixture for 4 hr. The mixture was partitioned between ether and aqueous saturated ammonium chloride solution. The organic layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was then purified by silica gel column chromatography (eluent, ether:hexanes (1:10)) to afford 7.36 g (80%) of the title compound as a white solid. m.p. 120-121° C.; 1H NMR (200 MHz, CDCl3) δ 1.22 (6H, d, J=7.0 Hz), 2.86 (1H, m), 3.96 (6H, s), 4.09 (3H, s), 7.60-7.74 (3H, m).
Reaction SMILES: P(Br)(Br)Br.[BrH:5].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([F:15])[CH:14]=1)[CH2:10]O>C(O)C>[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([F:15])[CH:14]=1)[CH2:10][Br:5]
Reactant: OCc1cc(F)cc(Br)c1
Reactant: Br
Agent: BrP(Br)Br
Solvent: CCO
Product: Fc1cc(Br)cc(CBr)c1
Temperature: 0 °C
Yield: 66 %

Procedure:
While phosphorus tribromide (3.65 g) was stirred, 47% aqueous hydrogen bromide solution (18.3 ml) was added in such a manner that the reaction temperature did not exceed 40° C. 3-Bromo-5-fluorobenzyl alcohol (7.70 g) in ethanol (6 ml) was added dropwise thereto, and the mixture was refluxed for 5 hours in an oil bath. The reaction mixture was cooled, and poured into ice/water, followed by extraction with n-hexane (150 ml). The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=30:1), to thereby yield 6.64 g of the target compound (yield: 66.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][OH:11])=[NH:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:30])([CH3:29])[CH2:20][CH:21]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:15]2=[CH:14][C:13]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.[CH:38](OCC)(OCC)OCC>B(F)(F)F.CCOCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[CH:38][O:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:29])([CH3:30])[CH2:20][CH:21]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:25])[CH3:26])[C:15]2=[CH:14][C:13]=1[C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1
Reactant: CCOC(OCC)OCC
Reactant: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(C(=N)NO)cc3Cl)nc2O1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(-c4ncon4)cc3Cl)nc2O1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a suspension of the product of Step A (61 mg, 0.11 mmol) in 5.0 mL of triethyl orthoformate was added one drop of BF3.Et2O. After stirring at 110° C. for 1 h, the reaction mixture was diluted with EtOAc (20 mL) and washed with saturated aq NaHCO3 (2×50 mL) and brine (50 mL). The organic layer was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+S cartridge using 7:13 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.27 (s, 9H), 1.48 (s, 3H), 1.56 (s, 3H), 1.84 (t, J=11.4, 1H), 2.27 (dd, J=6.2, 13.0, 1H), 5.50 (m, 1H), 5.84 (br. s, 1H), 7.01 (d, J=8.3, 2H), 7.16 (d, J=8.2, 2H), 7.45 (m, 1H), 7.58 (s, 1H), 7.96-8.04 (m, 2H), 8.77 (s, 1H).