Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][N+:4]([O-:6])=[O:5].CCN(CC)CC.[CH2:15]=[O:16].[CH3:17][OH:18]>>[CH:2]([C:3]([N+:4]([O-:6])=[O:5])([CH2:17][OH:18])[CH2:15][OH:16])([CH3:7])[CH3:1]
Reactant: CC(C)C[N+](=O)[O-]
Reactant: CO
Reactant: C=O
Solvent: CCN(CC)CC
Product: CC(C)C(CO)(CO)[N+](=O)[O-]
Reaction time: 72 h
Yield: 87 %

Procedure:
A solution of 2-methyl-1-nitropropane (38.7 g, 0.375 mol, prepared by the procedure of N. Kornblum, B. Tunbe, and H. Ungnade, J. Amer. Chem. Soc., 76, 3209 (1954) and NEt3 (Eastman, 3.79 g, 0.0375 mol) in CH3OH (50 mL) was added dropwise 37% aqueous formaldehyde solution (Mallinckrodt, 76.2 g, 0.938 mol) at a rate such that the reaction mixture temperature did not exceed 30°. After 72 h, the solution was concentrated under vacuum and the residue was dissolved in H2O (250mL). The solution was continuously extracted for 1 h with CH2Cl2 (1 L). The CH2Cl2 solution was dried (MgSO4), filtered, and concentrated to give 53.3 g (87%) of 2-isopropyl-2-nitro-1,3-propanediol, as a waxy, white solid mp 67°-72° (lit. mp 87°-88° B. M. Vanderbilt and H. B. Hass, Ind. Eng. Chem. 32, 34 (1940). In our hands this procedure failed to give the desired compound).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7]([O:16][CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:6]=1)=[O:4].[OH-].[Li+]>O1CCCC1.CO.O>[CH:18]1([CH2:17][O:16][C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[N:9][C:8]=2[N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1cnc(N2CCCC2)c(OCC2CCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(N2CCCC2)c(OCC2CCCC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 0.423 g (0.0014 mol) 6-cyclopentylmethoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid methyl ester in 5.5 mL tetrahydrofuran, 1.40 mL methanol and 1.4 mL water was added 2.8 mL of a 1M solution of lithium hydroxide in water and the mixture was stirred at room temperature for 4 h. The reaction mixture was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic phase was washed with water (2×) and brine, dried over sodium sulfate and evaporated to yield 0.396 g (0.0014 mol) of the title compound as white crystals melting at 204-206° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([CH2:26]O)[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].CS(Cl)(=O)=O.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>C(Cl)Cl.C(N(CC)CC)C.C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([Si:22]([CH3:23])([CH3:24])[CH3:25])[CH:19]=[C:18]([CH2:26][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CO)cc([Si](C)(C)C)c1
Reactant: C1CCNC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CN2CCCC2)cc([Si](C)(C)C)c1
Reaction time: 8 h

Procedure:
398 mg of the ethyl (RS)-(4-cyano-phenylamino)-(3-hydroxymethyl-5-trimethylsilanyl-phenyl)-acetate described in Example 156.3 were dissolved in 6 ml of CH2Cl2 g and 0.41 ml of triethylamine followed by 0.1 ml of methanesulphonyl chloride were added dropwise at 0° C. The mixture was stirred overnight and an intermediate was then isolated by extraction. This was taken up in 5 ml of THF and stirred together with 0.41 ml of triethylamine and 0.32 ml of pyrrolidine. By repeat extraction there was obtained a crude product, which was purified by column chromatography (cyclohexan/ethyl acetate). There were obtained 130 mg of ethyl (RS)-(4-cyano-phenylamino)-(3-pyrrolidin-1-ylmethyl-5-trimethylsilanyl-phenyl)-acetate as a light brown solid; MS: 460 ([M]+).
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.[CH2:16]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)[CH2:17][CH2:18][CH3:19]>C(Cl)Cl.O>[CH2:1]([NH:8][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCN
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCCCCNC(=O)c1ccc(CCCC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold solution of 16 g of n-heptylamine and 29.0 ml of triethylamine in 300 ml of methylene chloride was added dropwise a solution of 27.4 g of 4-butylbenzoylchloride in 100 ml of methylene chloride. The resulting mixture was stirred at room temperature for 41/2 hours and diluted with water. The organic layer was washed with 1N sodium hydroxide, brine, dried, and evaporated. The residual solid was recrystallized from hexane to yield N-heptyl-4-n-butylbenzamide, mp 37°-38° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:17]2[CH2:18][CH2:19][C@H:15]([F:14])[CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: F[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CC[C@H](F)C2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59.8 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.4 g, 2.34 mmol), (S)-3-fluoropyrrolidine hydrochloride (0.35 g, 2.8 mmol) and 4 Å molecular sieves (2.43 g) in DCE (10 mL). The reaction mixture was stirred for 2.5 h at room temperature. Sodium triacetoxyborohydride (0.99 g, 4.68 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane, gradient 30:70 to 100:0) to give 3-((S)-3-Fluoropyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil (0.342 g, 60%). 1H NMR (300 MHz, CDCl3): δ 5.34-5.10 (m,1H), 4.01-3.93 (m, 2H), 3.91-3.81 (m, 2H), 3.41-3.31 (m, 1H), 2.94-2.67 (m, 3H), 2.56-2.46 (m, 1H), 2.24-2.06 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20]>N1C=CC=CC=1>[C:18]([O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1)(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C1c2ccccc2C(=O)c2cc(O)ccc21
Solvent: c1ccncc1
Product: C=C(C)C(=O)Oc1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
0.2 mol of 2-hydroxyanthraquinone is dissolved in 600 ml of pyridine under an inert gas in a 1,000 ml brown glass flask with a dropping funnel and thermometer. 0.24 mol of methacryloyl chloride is then added dropwise in the course of 15 minutes, with ice-cooling. After the mixture has been stirred at room temperature for 20 hours, the pyridine is removed on a rotary evaporator. The crude crystalline product is suspended in 500 ml of 0.1N HCl, the suspension is filtered, the solid is taken up in water again and, after washing with sodium bicarbonate solution and water, the crude product is dried in vacuo. Yield of crude product: 90% of theory. Recrystallisation of the crude product from ethylene glycol monomethyl ether gives a 58% yield of 2-anthraquinonyl methacrylate as a yellow crystalline product; melting point: 184°-186° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)\[C:11]2[NH:15][C:14](=[O:16])[O:13][N:12]=2)[N:6]=1.[C:23](=O)([O-])[O-].[K+].[K+].IC>CC#N.CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)\[C:11]2[N:15]([CH3:23])[C:14](=[O:16])[O:13][N:12]=2)[N:6]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(CO/N=C(/c2ccccc2)c2noc(=O)[nH]2)cs1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CC#N
Product: Cn1c(/C(=N\OCc2csc(N)n2)c2ccccc2)noc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
To a solution of 3-[(Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-1,2,4-oxadiazol-5(4H)-one (2.89 g, 50% purity, 4.56 mmol, 1 eq.) in MeCN (50 ml) and DMF (10 ml) was added potassium carbonate (757 mg, 5.48 mmol, 1.2 eq.) followed by iodomethane (778 mg, 5.48 mmol, 1.2 eq.). The reaction was stirred at room temperature overnight. The reaction was quenched by addition of water and extracted with EtOAc (3×50 ml). The organics were combined, washed with aq. sat. NaCl, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give 3-[(Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-4-methyl-1,2,4-oxadiazol-5(4H)-one (930 mg, 61% yield) has a white solid.
Reaction SMILES: [CH2:1]1[O:7][P:5]([OH:8])(=[O:6])[CH2:4][O:3][C@H:2]1[CH2:9][N:10]1[C:15](=[O:16])[N:14]=[C:13]([NH2:17])[CH:12]=[CH:11]1.C1(NC(N2CCOCC2)=NC2CCCCC2)CCCCC1.Br[CH2:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]>>[CH3:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][CH2:40][O:6][P:5]1([O:7][CH2:1][C@H:2]([CH2:9][N:10]2[C:15](=[O:16])[N:14]=[C:13]([NH2:17])[CH:12]=[CH:11]2)[O:3][CH2:4]1)=[O:8]
Reactant: CCCCCCCCCCCCCCCCOCCCBr
Reactant: Nc1ccn(C[C@H]2COP(=O)(O)CO2)c(=O)n1
Agent: C1CCC(N=C(NC2CCCCC2)N2CCOCC2)CC1
Product: CCCCCCCCCCCCCCCCOCCCOP1(=O)CO[C@@H](Cn2ccc(N)nc2=O)CO1
Temperature: 80 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a heterogeneous solution of cyclic cidofovir (39 g, 0.131 mol., 1 equiv, purchased from Gilead Sciences) in N,N-DMF (2.0 L) under a nitrogen atmosphere was added N,N′-dicyclohexyl-4-morpholinecarboxamidine (DCMC) (0.131 mol, 38.51 g, 1 equiv.). This was stirred overnight. This dissolved most of the solid in the reaction mixture. To this solution was added 1-bromo-3-hexadecyloxypropane (238.45 g, 0.656 mol, 5 equiv.). The reaction mixture was heated to 80° C. and stirred for 6 hours. The crude reaction mixture was concentrated in vacuo at 80° C. The crude reaction mixture was absorbed on silica gel (300 g) and purified via column chromatography (800 g SiO2). The column was eluted with dichloromethane (6 L) to remove the excess 1-bromo-3-hexadecyloxypropane. The solvent phase was then switched to 9:1 CH2Cl2:EtOH(32 L). The product came off with this solvent system. Fractions 30-39 were combined to give hexadecyloxypropyl-cyclic cidofovir (17.8 g) in a 25% yield.
Reaction SMILES: Cl[C:2](=[N:11][N:12]=[C:13](Cl)[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])[C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[F:10].O.[NH2:24][NH2:25]>O1CCCC1>[F:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([F:9])[C:3]=1[C:2]1[N:24]=[N:25][C:13]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:12][N:11]=1
Reactant: NN
Reactant: Fc1cccc(F)c1C(Cl)=NN=C(Cl)c1c(F)cccc1F
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc(F)c1-c1nnc(-c2c(F)cccc2F)nn1

Procedure:
To a solution of 0.9 g of bis[chloro-(2,6-difluorobenzylidene)]hydrazine [prepared in the preceeding step b.)] in 18 ml of tetrahydrofuran of 40° C. temperature, 0.59 ml of hydrazine hydrate is dropped during 1 minute. After filtering, the precipitate is washed with water and dried to give 0.5 g of desired product as yellow crystals.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([C:26]#[N:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)C>[C:26]([C:13]([C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:27]
Reactant: [H][H]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Temperature: 25 °C

Procedure:
An autoclave was charged with 3.9 g of 79% pure (S)-1-benzyl-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine, 3 ml of ethanol and 156 mg of moist 5% palladium-carbon (water content 52% by weight), hydrogen was introduced thereinto and the autoclave was heated to raise the temperature to 60 and the pressure to 203 kPa, and the reaction was allowed to proceed. Five hours after the start of hydrogen introduction, no hydrogen absorption was observed any more, so that the reaction mixture was cooled to room temperature and depressurized. The reaction mixture was taken out, the catalyst was filtered off, and the filtrate obtained was analyzed by high performance liquid chromatography. (S)-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine was obtained in a yield of 36 mole percent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][C:8]2=[O:10]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: O
Solvent: CCO
Product: O=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Yield: 20.8 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (29 g, 0.135 mol), benzaldehyde (14.3 g, 0.135 mol) and borax (51.5 g, 0.135 mol) in ethanol (180 mL) and H2O (300 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-phenyl-chroman-4-one (8.5 g, 21%). 1H-NMR (CDCl3): 2.89 (dd, 1H), 3.06 (dd, 1H), 5.46 (dd, 1H), 6.95 (d, 1H), 7.37-7.46 (m, 5H), 7.58 (d, 1H), 8.02 (d, 1H).
Reaction SMILES: [NH2:1]CCNCCC[Si:8](OC)(OC)OC.[P:15]([OH:18])([OH:17])[OH:16].Cl.C=O>O>[PH:15](=[O:18])([O-:17])[O:16][NH2:1].[Si+4:8].[NH2:1][O:16][PH:15](=[O:18])[O-:17].[NH2:1][O:16][PH:15](=[O:18])[O-:17].[NH2:1][O:16][PH:15](=[O:18])[O-:17]
Reactant: CO[Si](CCCNCCN)(OC)OC
Reactant: OP(O)O
Agent: C=O
Agent: Cl
Solvent: O
Product: NO[PH](=O)[O-]
Product: [Si+4]

Procedure:
To a 500 ml three neck flask fitted with a reflux condenser and dropping funnel is added 55.6 g (0.25 mole)(of N-2-aminoethyl-3-aminopropyltrimethoxysilane. To this is added slowly a mixture of 70% phosphorous acid (0.5 mole), deionized water, and concentrated hydrochloric acid (60 grams). The mixture is heated to gentle reflux and 37% aqueous formaldehyde (0.50 mole) is added dropwise during one hour. The mixture is heated for an additional hour to complete the reaction.
Reaction SMILES: C(O)(=O)C.[Cl:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1.[CH2:18]1[C:23](=[O:24])[O:22][CH2:21][C:19]1=O.O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C:19]1[CH2:21][O:22][C:23](=[O:24])[CH:18]=1
Reactant: ClCCCNCc1ccc(Cl)nc1
Reactant: O=C1COC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: O=C1C=C(N(CCCCl)Cc2ccc(Cl)nc2)CO1
Yield: 40.8 %

Procedure:
4.26 ml (74.4 mmol) of acetic acid are added to 16.30 g (74.4 mmol) of 3-chloro-N-[(6-chloropyridin-3-yl)methyl]propan-1-amine (IVa-1 cf. also B. Latli et al. J. Med. Chem. 1999, 42, 2227-2234) in 300 ml of benzene, and the mixture is stirred at room temperature for 30 minutes. 9.68 g (96.7 mmol) of tetronic acid and 128 mg of 4-toluenesulphonic acid are then added, and the mixture is heated under reflux on a water separator for 2 hours. The reaction mixture is concentrated under reduced pressure, the residue is then taken up in the solvent mixture dichloromethane:methanol (95:5) and the mixture is washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate gives 9.15 g (33% of theory) of 4-[(3-chloropropyl)[(6-chloropyridin-3-yl)methyl]amino]furan-2(5H)-one.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:32])[C:22]([C:24]4[N:25]=[C:26]([NH:29]C=O)[S:27][CH:28]=4)=[O:23])[C:18](=[O:33])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1.P(Cl)(Cl)([Cl:36])=O>CO>[ClH:36].[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:32])[C:22]([C:24]4[N:25]=[C:26]([NH2:29])[S:27][CH:28]=4)=[O:23])[C:18](=[O:33])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(=NC=O)[nH]3)[C@H]2SC1
Solvent: CO
Product: Cl
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(N)n3)[C@H]2SC1

Procedure:
To a mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-formylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (24.8 g.) in methanol (500 ml.) was dropwise added phosphorus oxychloride (16.4 g.) over 15 minutes under cooling at 5° to 10° C. with stirring, and the mixture was stirred for 2.5 hours at the same temperature. The 3/4 amount of methanol was distilled off from the reaction mixture under reduced pressure, and the residue was pulverized in diethyl ether. The powder was collected by filtration and then dried to give 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid hydrochloride, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-imino- 2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: OCc1ccc2c(c1)COC2c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=Cc1ccc2c(c1)COC2c1ccc(F)cc1
Reaction time: 1 h
Yield: 88 %

Procedure:
1-(4′-Fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (66.0 g) was dispersed in toluene (660 ml) and manganese dioxide (594 g, type HMH, manufactured by Toso) was added over 1 hr at 15–30° C. The mixture was stirred at 20–30° C. for 1 hr. The reaction mixture was filtered and washed with toluene (330 ml). The solvent was evaporated under reduced pressure to give nearly pure 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde (57.6 g, 88%) as pale-yellow white crystals. Various spectrum data of the crystals were the same as those obtained in Example 18.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)=[CH:8][C:7]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)cc(COS(C)(=O)=O)c1=O
Reactant: CN1CCNCC1
Product: CC(C)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)cc(CN2CCN(C)CC2)c1=O
Yield: 88.5 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 88.5%).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[C:6]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=1.C(N(CC)CC)C.Cl[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].O>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:12][CH2:11]2)=[C:6]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=1
Reactant: CC(C)(C)c1cc(Br)ccc1N1CCNCC1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)N1CCN(c2ccc(Br)cc2C(C)(C)C)CC1
Temperature: 0 °C
Yield: 101.9 %

Procedure:
To a stirred suspension of 1-(4-bromo-2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 9, 0.300 g, 0.81 mmol) and triethylamine (564 μl, 4.05 mmol) in THF (10 mL) stirring at 0° C. was added ethyl chloro(oxo)acetate (0.144 mg, 1.05 mmol). The mixture was warmed to room temperature. After 16 h the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=80:20 to 50:50) to provide ethyl [4-(4-bromo-2-tert-butylphenyl)piperazin-1-yl](oxo)acetate (0.328 g, quant) as a white solid.
Reaction SMILES: [N:1]12[CH2:13][CH:5]([CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=31)[NH:4][CH2:3][CH2:2]2.[C:14]([O:17][C:18](=[O:20])[CH3:19])(=[O:16])[CH3:15]>C1C=CC=CC=1>[C:14]([O:17][CH:12]([CH3:11])[CH3:7])(=[O:16])[CH3:15].[C:18]([N:4]1[CH:5]2[CH2:13][N:1]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6]2)[CH2:2][CH2:3]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CC1CN2CCN1
Solvent: c1ccccc1
Product: CC(=O)N1CCN2CC1Cc1ccccc12
Product: CC(=O)OC(C)C

Procedure:
A mixture of 3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (10.5 g.) (the starting material of part A of Example 1), acetic anhydride (25 ml.) and benzene (50 ml.) was heated under reflux for four hours, then concentrated. Methanol was added to the residue, and the mixture was boiled and concentrated. Excess saturated potassium carbonate solution was added to an aqueous solution of the residue, and the mixture was extracted with chloroform. The chloroform extract was dried, filtered and concentrated. Recrystallization of the residue first from ether, then from ether-acetone, then from isopropyl acetate afforded 4-acetyl-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (2.25 g., m.r. 105°-106° C.), the compound of Formula VIII.