Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[O:9]
Reactant: Nc1ccccn1
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccccn1)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 42 %

Procedure:
To a stirring solution of 5-chloro-2-nitrobenzoic acid (15 g, 74 mmol) in dichloromethane (300 mL) was added DMF (a few drops) followed by oxalyl chloride (11.3 g, 89 mmol). After stirring for 2 h, the solvent was removed in vacuo and the residue was redissolved in dichloromethane (300 mL). To this stirring solution was added pyridine (17.5 g, 222 mmol), followed by 2-aminopyridine (7 g, 74 mmol). After 24 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was separated and washed twice with 1 M citric acid, once with brine, twice with satd aq NaHCO3, and once with brine. The organic phase was then dried (MgSO4), filtered and concentrated in vacuo to a volume of about 25 mL, then diluted with diethyl ether, and sonicated. The resulting precipitate was filtered and dried in vacuo to give 8.63 g (42%) of an off-white solid.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH2:19]([N:22]1[C:26]([SH:27])=[N:25][N:24]=[N:23]1)[CH2:20][CH3:21]>P([O-])([O-])([O-])=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:27][C:26]3[N:22]([CH2:19][CH2:20][CH3:21])[N:23]=[N:24][N:25]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CCCn1nnnc1S
Agent: O=P([O-])([O-])[O-]
Product: CCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Yield: 33.7 %

Procedure:
7-Aminocephalosporanic acid (283.0 g.) and 1-propyl-1H-tetrazole-5-thiol (225.0 g.) were treated in 0.2M phosphate buffer solution (5.5 l.) in a similar manner to that of Preparation 28-(3) to give 7-amino-3-(1-propyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (125.0 g.).
Reaction SMILES: [C:1]([O:14][CH2:15][Cl:16])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[K+].[Br-]>CCOCC>[Cl-:16].[C:1]([O:14][CH2:15][N+:20]1[CH:21]=[CH:22][N:18]([CH3:17])[CH:19]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)OCCl
Reactant: Cn1ccnc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: CCCCCCCCCCCC(=O)OC[n+]1ccn(C)c1
Product: [Cl-]
Temperature: 25 °C

Procedure:
A mixture of 2.49 g (0.01 mol) chloromethyl n-dodecanoate and 0.82 g (0.01 mol) 1-methylimidazole were mixed and heated together at 90° for 3 hrs. On cooling to room temperature, anhydrous ether overnite. The solid was isolated by filtration under a nitrogen atmosphere and thoroughly washed with anhydrous ether. After drying in vacuo over calcium sulfate at room temperature, 2.4 g (0.007 mol), 70%, 10 was obtained as a white solid, mp 60°-63°; ir (KBr) 3400, 3110, 2960, 2920, 1750, 1470, 1140 and 770 cm-1 ; pmr (CDCl3) δ 10.8 (s, 1H), 8.0 (d, 2H), 6.4 (s, 2H), 4.2 (s, 3H), 2.4 (t, 2H), 1.4 (bs, 18H) and 0.9 (bt, 3H) ppm.
Reaction SMILES: C[O:2][C:3](=O)[C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:14][NH:15][NH2:16]>CO.O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]2[N:15]([CH3:14])[NH:16][C:3](=[O:2])[CH:4]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)C#Cc1ccc(F)cc1
Reactant: CNN
Solvent: CO
Solvent: O
Product: Cn1[nH]c(=O)cc1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
A suspension of (4-fluorophenyl)propynoic acid methyl ester (1.6 g, 9.0 mmol) in MeOH (10 mL) and H2O (10 mL) was heated at 60° C. and MeNHNH2 (0.5 mL, 9.4 mmol) was added. The reaction mixture was stirred at 60° C. for 20 min. then filtered. The residue was washed with H2O (10 mL) and MeOH (5 mL) and dried to give 5-(4-fluorophenyl)-1-methyl-1,2-dihydro-pyrazol-3-one (0.63 g, 36%). The filtrate was then concentrated under reduced pressure and the residue dissolved in EtOAc (20 ml) and washed with H2O (3×15 mL). The aqueous layer was acidified to pH 5.5 with 2 M citric acid solution (3×15 mL) and extracted with EtOAc (3×20 mL). The extracts were dried (MgSO4) and concentrated under reduced pressure to give 5-(4-fluoro-phenyl)-2-methyl-1,2-dihydro-pyrazol-3-one (0.2 g, 12%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:14]([N:21]1[CH2:32][CH2:31][C:24]2([O:28][C:27](=[O:29])[O:26][C:25]2=[CH2:30])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C(C)=CC=CC=1.CCCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[C:25]([OH:26])([CH3:30])[C:24]3([CH2:23][CH2:22][N:21]([CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:32][CH2:31]3)[O:28][C:27]2=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: C=C1OC(=O)OC12CCN(Cc1ccccc1)CC2
Solvent: CCCCCCC
Solvent: Cc1ccccc1C
Product: COc1ccc(CCN2C(=O)OC3(CCN(Cc4ccccc4)CC3)C2(C)O)cc1OC
Reaction time: 8 h
Yield: 94 %

Procedure:
19.9 g of 2-(3,4-dimethoxyphenyl)ethylamine are portionwise added to a solution of 25.9 g of 8-benzyl-4-methylene-2-oxo-1,3-dioxa-8-azaspiro[4,5]decane in 35 ml of anhydrous xylene under stirring. Meanwhile the temperature of the reaction mixture increases to 35° to 40° C. The reaction mixture is left to stand at room temperature overnight, then the crystalline reaction mixture is diluted with n-heptane and filtered. The solid precipitate obtained is recrystallized from ethanol to obtain the title compound in 94% yield, m.p.: 181°-183° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][NH2:18].[C:19]([CH2:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][C:25]=1[CH3:33])([OH:21])=[O:20].[CH2:34](N(CC)CC)[CH3:35].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:34]([O:21][C:19](=[O:20])[CH2:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](=[O:30])[NH:18][CH2:17][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:26][C:25]=1[CH3:33])[CH3:35]
Reactant: Cc1cc(C(=O)O)ccc1CCC(=O)O
Reactant: CCN(CC)CC
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(C(=O)NCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1C
Reaction time: 3 h

Procedure:
To a mixture of C-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-methylamine (0.2 g, 0.78 mmol) and 4-(2-carboxy-ethyl)-3-methyl-benzoic acid (0.173 g, 0.78 mmol) and DMAP (5 mg) in methylene chloride (5 mL) are added triethyl amin (0.12 mL, 0.86 mml) and EDCI (150 mg, 0.78 mmol) at room temperature. After stirred for 3 hrs, diluted with chloroform, washed with water, 1N HCl and 2 N NaOH aqueous. Concentration and column chromatography on silica gel gave the title compound (240 mg).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]2[CH:38]=[CH:37][C:20]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[C:25]([F:36])[CH:24]=3)=[CH:19][CH:18]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]([CH2:16][C:17]2[CH:38]=[CH:37][C:20]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[C:25]([F:36])[CH:24]=3)=[CH:19][CH:18]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(Cn3nc(C(C)(C)C)cc3-c3ccccc3)cc2)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1cc(-c2ccccc2)n(Cc2ccc(CNc3ccc(CCC(=O)O)c(F)c3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a solution of ethyl 3-[4-({4-[(3-tert-butyl-5-phenyl-1H-pyrazol-1-yl)methyl]benzyl}amino)-2-fluorophenyl]propanoate (150 mg, 0.29 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added 1 M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-80% ethyl acetate/hexane) to give the title compound (91 mg, yield 65%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.N#N.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>C1COCC1.CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccnc(Cl)n1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a mixture of Pd(PPh3)2Cl2 (0.9 g) and PPh3 (0.7 g) in THF (200 mL) and Et3N (300 mL) was added 2,4-dichloropyrimidine (40 g, 0.27 mol) under a stream of N2. After bubbling N2 into the solution for 15 min, Cul (0.5 g) was added, followed by (trimethylsilyl)acetylene (29 g, 0.29 mol). The mixture was heated at reflux for 4.5 h. The mixture was cooled to rt and filtered, washing with EtOAc. The filtrated was concentrated and the residue was diluted with hexanes (500 mL) and loaded directly onto a short pad of SiO2. The product was eluted with 10% EtOAc/hexanes to provide a light orange solid (49.3 g), which was used without further purification. TLC: Rf=0.42. mp 51-54° C. IR: 3125 (w), 2961 (w), 1557 (s), 1523 (s). 1H NMR: 8.58 (d, J=5.0 Hz, 1H), 7.30 (d, J=5.0 Hz, 1H), 0.28 (s, 9H). 13C NMR: 162.23, 160.16, 153.41, 122.52, 104.23, 100.75, 0.01. Anal. Calcd for C9H11ClN2Si: C, 51.29; H, 5.26; N, 13.29. Found: C, 51.45; H, 5.16; N, 13.33.
Reaction SMILES: Cl.Cl[C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[CH:5][C:4]=1[CH3:10].N1[CH2:19][CH2:18][CH:14]([C:15]([NH2:17])=[O:16])[CH2:13][CH2:12]1.[C:20](=O)([O-])O.[Na+]>O>[CH3:10][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH3:9])[C:3]=1[CH:20]1[CH2:19][CH2:18][CH:14]([C:15]([NH2:17])=[O:16])[CH2:13][CH2:12]1
Reactant: O=C([O-])O
Reactant: NC(=O)C1CCNCC1
Reactant: Cc1cncc(C)c1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cncc(C)c1C1CCC(C(N)=O)CC1
Yield: 4 %

Procedure:
A solution of 4-chloro-3,5-dimethylpyridine hydrochloride (0.10 g, 0.56 mmol) and isonipecotamide (0.22 mg, 1.7 mmol) in water (1.5 mL) was heated at 175° C. for 60 min, in a microwave reactor. The mixture was poured into a saturated solution of sodium hydrogen carbonate (20 mL), extracted with EtOAc (2×20 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 95:5) to furnish the title compound as a white solid (5 mg, 4%), m/z 234 (100%, [M+H]+); m/z (ESI) C13H20N3O requires 234.1601 found [M+H]+ 234.1600.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[OH:14][C:15]1([C:21]2[CH:22]=[C:23]([SH:26])[S:24][CH:25]=2)[CH2:19][CH2:18][O:17][CH:16]1[CH3:20]>>[OH:14][C:15]1([C:21]2[CH:22]=[C:23]([S:26][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]4)[S:24][CH:25]=2)[CH2:19][CH2:18][O:17][CH:16]1[CH3:20]
Reactant: CC1OCCC1(O)c1csc(S)c1
Reactant: CN1C(=O)CCc2cc(I)ccc21
Product: CC1OCCC1(O)c1csc(Sc2ccc3c(c2)CCC(=O)N3C)c1
Yield: 42 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-iodo-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with (2RS,3SR)-3-hydroxy-3-(2-mercaptothien-4-yl)-2-methyltetrahydrofuran to give (2RS,3SR)-3-hydroxy-2-methyl-3-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thien-4-yl]tetrahydrofuran in 42% yield as a foam;
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]([C:14]2[C:22]3[C:17](=[C:18]([O:23][CH3:24])[CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:15]=2)=[N:5][S:6][C:7]=1[CH2:8]OS(C)(=O)=O.[CH2:32]([NH2:34])[CH3:33].C(N(CC)CC)C>O1CCCC1.ClCCl>[ClH:1].[CH:26]1([CH2:25][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[C:14]([C:4]3[C:3]4[CH2:2][N:34]([CH2:32][CH3:33])[CH2:8][C:7]=4[S:6][N:5]=3)=[CH:15]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCN
Reactant: COc1cccc2c(-c3nsc(COS(C)(=O)=O)c3CCl)cn(CC3CCCCC3)c12
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1Cc2snc(-c3cn(CC4CCCCC4)c4c(OC)cccc34)c2C1
Product: Cl
Yield: 47.4 %

Procedure:
To a solution of methanesulfonic acid {4-chloromethyl-3-[1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-yl]-isothiazol-5-yl}methyl ester (90 mg, 0.19 mmol) in tetrahydrofuran (1 ml) was added ethylamine (0.186 ml, 0.37 mmol) and triethylamine (0.05 ml, 0.37 mmol) and the reaction mixture subjected to microwave irradiation at 150° C. for 15 minutes. The reaction mixture was poured into a separating funnel, diluted with dichloromethane (30 ml) and washed with 5% aqueous sodium carbonate solution (2×10 ml), brine (10 ml), dried over magnesium sulfate and the solvent removed in vacuo. The reaction was repeated on a 0.166 mmol scale to give the same intermediate. The crude products were combined and purified by flash column chromatography using ethyl acetate to give the title compound (36 mg, 0.09 mmol) as the free base. The free base was dissolved in dichloromethane and hydrogen chloride (2M solution in diethyl ether; 1 ml, 2 mmol) was added. The mixture was concentrated in vacuo to afford the title compound as a 1:1 hydrochloride salt. 1H NMR (400 MHz, CD3OD): 0.97-1.15 (2H, m), 1.15-1.27 (3H, m), 1.47 (3H, t, J 7), 1.52-1.61 (2H, m), 1.62-1.77 (3H, m), 1.81-1.95 (1H, m), 3.63 (2H, q, J 7), 3.95 (3H, s), 4.28 (2H, d, J 7), 4.62-4.75 (2H, m), 4.95-5.12 (2H, m), 6.77 (1H, d, J 8), 7.09 (1H, t, J 8), 7.43 (1H, s), 8.01 (1H, d, J 8); EsIMS: m/z 396.0 [M+H]+, 353.4, 351.3, 320.3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:27])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([OH:26])[CH:19]=2)[O:16][CH:17]=1)[CH3:2].Br[CH:29]([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:27])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:29]([CH3:31])[CH3:30])[CH:19]=2)[O:16][CH:17]=1)[CH3:2]
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(O)c2)n1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(OC(C)C)c2)n1
Reaction time: 8 h

Procedure:
A 5.0 g quantity of 1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one obtained in Example 101 was dissolved in 50 ml of dimethylformamide, 3.35 g of 2-bromopropane and 5.63 g of potassium carbonate were added thereto, and stirring was conducted overnight at room temperature. Water was added to the obtained mixture, ethyl acetate extraction was performed, followed by drying over anhydrous magnesium sulfate and distilling the solvent off. The residue was subjected to silica gel column purification (n-hexane:ethyl acetate=4:1), and the obtained crude crystals were recrystallized using ethanol, thereby yielding 2.99 g of white powdery 1-(2-ethoxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one.
Reaction SMILES: [C:1](=[O:13])([O:3][C:4]1([C:9](C)(C)C)[CH:6](CBr)[CH2:5]1)[NH2:2].Br[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18]O1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2([C:34]3=[CH:35][C:36]4[O:40][CH2:39][O:38][C:37]=4[CH:41]=[C:33]3[O:32][CH2:31]2)[C:23]1=[O:42].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[CH:20]1([CH:21]([NH:2][C:1](=[O:13])[O:3][C:4]([CH3:9])([CH3:6])[CH3:5])[CH2:16][CH2:15][N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]3([C:34]4=[CH:35][C:36]5[O:40][CH2:39][O:38][C:37]=5[CH:41]=[C:33]4[O:32][CH2:31]3)[C:23]2=[O:42])[CH2:19][CH2:18]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: BrCC1CCCCO1
Reactant: CC(C)(C)C1(OC(N)=O)CC1CBr
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: CC(C)(C)OC(=O)NC(CCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21)C1CC1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using tert-butyl-3-bromomethyl-1-cyclopropyl carbamate to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, tert-butyl [1-cyclopropyl-3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propyl]carbamate was obtained (91%) as a fluffy yellow solid: 1H NMR (300 MHz, CDCl3) δ7.28 (dd, J=7.7, 7.7 Hz, 1H), 7.13 (d, J=6.9 Hz, 1H), 7.02 (dd, J=7.2, 7.2 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.47 (s, 1H), 6.11 (d, J=4.9 Hz, 1H), 5.83 (d, J=5.5 Hz, 2H), 4.88 (dd, J=8.9, 7.0, Hz, 1H), 4.69 (br, 1H), 4.62 (dd, J=8.9, 1.7 Hz, 1H), 3.93-3.73 (m, 2H), 2.99 (br, 1H), 2.14-1.81 (m, 2H), 1.30 (s, 9H), 0.95-0.80 (m, 1H), 0.58-0.19 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.3, 177.3, 155.9, 155.7, 155.6, 148.8, 142.3, 142.2, 132.4, 129.0, 123.9, 123.3, 119.5, 119.4, 108.6, 103.1, 103.0, 101.5, 93.6, 80.4 (2C), 65.9, 58.2, 37.8, 37.5, 32.9, 32.7, 28.4, 16.1 (2C), 15.3, 3.9, 3.8, 3.0, 2.9; MS (ES+) m/z 501.3, (M+23), 479.28 (M+1), 423.2 (M−56), 379.3 (M−100).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH:4]=[C:5]1[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])[C:6]1=[O:19].[C:24](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.O>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH:4]=[C:5]1[N:9]([CH3:24])[C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])[C:6]1=[O:19]
Reactant: O=C([O-])[O-]
Reactant: O=C1NC(=Cc2ccccc2F)C(=O)N1c1cc(F)ccc1F
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN1C(=O)N(c2cc(F)ccc2F)C(=O)C1=Cc1ccccc1F
Yield: 189.9 %

Procedure:
The 5-(2-fluorobenzylidene)-3-(2,5-difluorophenyl)-imidazolidine-2,4-dione (1.25 g, 3.9 mmol), cesium carbonate (0.67 g, 2.06 mmol) and methyl iodide (0.84 g, 5.9 mmol) were allowed to stir overnight in DMF (15 mL), under a N2 atmosphere. The resulting solution was diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with brine (saturated), dried (over MgSO4), filtered and concentrated to give 1.3 grams of 5-(2-fluorobenzylidene)-3-(2,5-difluorophenyl)-1-methylimidazolidine-2,4-dione, m.p. 94°-97° C. (compound 106 under Table B).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[CH:20]=[C:19]([CH2:21][N:22]3[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]3)[CH:18]=[CH:17][N:16]=2)[CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1>>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:5]4[CH:6]=[C:7]([O:13][CH3:14])[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:20]=3)[CH2:23][CH2:24]2)=[CH:33][CH:32]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC(C)C
Product: COc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC(C)C)c(OC)c4)c3)CC2)cc1

Procedure:
1-[[2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (350 mg) and p-anisidine (123 mg) were condensed in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: [I-].[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:76]/[O:77][CH3:78])/[C:28]([NH:30][CH:31]2[C:74](=[O:75])[N:33]3[C:34]([C:58]([O:60][CH:61]([C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)[C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)=[O:59])=[C:35]([CH2:38][P+:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:36][S:37][C@H:32]23)=[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.[OH-].[Na+].C(Cl)(Cl)Cl.CO>ClCCl>[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:76]/[O:77][CH3:78])/[C:28]([NH:30][CH:31]2[C:74](=[O:75])[N:33]3[C:34]([C:58]([O:60][CH:61]([C:68]4[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=4)[C:62]4[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=4)=[O:59])=[C:35]([CH:38]=[P:39]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH2:36][S:37][C@H:32]23)=[O:29])[N:26]=1)([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=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
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 93 %

Procedure:
A solution of diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(triphenylphosphonio)methyl]-3-cephem-4-carboxylate iodide* (3.0 g, 2.5 m moles) in dichloromethane (40 ml) was shaken with 1N NaOH (10 ml) until the spot of the starting material disappeared on TLC (silica gel, CHCl3 --MeOH=10:1). Organic layer was separated and concentrated under reduced pressure. The residue was triturated with n-hexane and the product was collected by filtration to give 2.5 g (93%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=2)[NH2:25])[CH2:11][CH2:10]1.[C:28](Cl)(=[O:30])[CH3:29].CCN(CC)CC>C(Cl)Cl.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([NH:25][C:28](=[O:30])[CH3:29])[CH:26]=2)[CH2:13][CH2:14]1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(OCCCCN2CCN(c3cccc(Cl)c3Cl)CC2)cc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc(OCCCCN2CCN(c3cccc(Cl)c3Cl)CC2)ccc1C
Temperature: 25 °C
Yield: 34.5 %

Procedure:
A mixture of intermediate 63 (120 mg, 0.29 mmol), acetyl chloride (35 mg, 0.44 mmol) and Et3N (54 mg, 0.54 mmol) was dissolved in DCM and the solution was stirred at rt. The solution was diluted with water and extracted with DCM. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=100:1-30:1) to give N-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-methylphenyl)acetamide (compound 43) (45 mg, 35%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.56 (s, 1H), 7.18-7.13 (m, 2H), 7.07-6.88 (m, 3H), 6.62 (d, J=8.1 Hz, 1H), 3.99 (br, 2H), 3.26 (br, 4H), 2.92-2.75 (br, 6H), 2.21 (s, 3H), 2.19 (s, 3H), 1.86 (br, 6H). HPLC: 99%, RT 2.464 min. MS (ESI) m/z 449.8 [M+H]+.