Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].[C:9](=N)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.O>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[N:6]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H](C)N
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](C)N=C(c1ccccc1)c1ccccc1
Reaction time: 15 h

Procedure:
To a solution of alanine methyl ester hydrochloride (10.0 g, 71.6 mmol) in 100 mL CH2Cl2 was added benzophenone imine (12.0 mL, 71.6 mmol). A white ppt gradually came out of solution as the reaction was allowed to proceed at rt for 15 h. The reaction was diluted with H2O and CH2Cl2, and the layers were separate, the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to afford methyl-N-(diphenylmethylene)alaninate as a viscous oil which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.62 (m, 2H), 7.47-7.29 (m, 6H), 7.19-7.16 (m, 2H), 4.16 (q, J =6.8 Hz, 1H), 3.7 (s, 3H, 1.40 (d, J=6.8 Hz, 3H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:24])[CH2:21][NH:22][CH3:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34]Br)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:24])[CH2:21][N:22]([CH2:34][CH2:33][NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH3:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CNCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCNC(=O)OC(C)(C)C)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.2 %

Procedure:
500 mg (1.42 mmol) of sarcosine benzyl ester p-toluenesulfonate, 478 mg (2.13 mmol) of 2-(tert-butoxycarbonylamino)-ethyl bromide, and 0.25 mL (2.13 mmol) of diisopropyl-ethylamine were dissolved in methylene chloride (10 mL), and then stirred at room temperature for approximately three days. After completion of the reaction, the reaction solution was concentrated and the residue obtained was purified by silica gel column chromatography (ethyl acetate) to yield 175 mg (38%) of {[2-(tert-butoxycarbonylamino)-ethyl]-methyl-amino}-acetic acid benzyl ester as a colorless viscous oil.
Reaction SMILES: [Br:1][CH:2]([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1>[Pd].C(OCC)(=O)C>[Br:1][CH:2]([F:16])[C:3]([F:14])([F:15])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)C(F)Br)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(OC(F)(F)C(F)Br)cc1
Yield: 101.4 %

Procedure:
700 ml of absolute ethyl acetate were added to 275 g of 4-(2-bromo-1,1,2-trifluoroethoxy)-nitrobenzene, and hydrogenation was carried out using 20 g of palladium on active carbon. The catalyst was filtered off and the solvent was removed. 251 g of the compound were obtained; this was pure according to NMR analysis.
Reaction SMILES: O1CCOCC1.[CH:7]1([C:13]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)(=[O:31])=[O:30])=[CH:25][C:24]=4[O:39][CH3:40])=[N:17][C:16]=3[N:15]([CH3:41])[N:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[ClH:42].O1CCOCC1>CCOCC>[Cl-:42].[CH:7]1([C:13]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)(=[O:30])=[O:31])=[CH:25][C:24]=4[O:39][CH3:40])=[N:17][C:16]=3[N:15]([CH3:41])[N:14]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Cl
Agent: COc1cc(S(=O)(=O)N2CCN(C)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Solvent: CCOCC
Solvent: C1COCCO1
Product: [Cl-]

Procedure:
To a 2 ml dioxane solution of 87 mg (0.17 mmol) of the compound obtained in Example 49, 0.1 ml (0.4 mmol) of a 4M dioxane hydrochloride solution was added. Ether was added to the resulting solution, and precipitated solids were collected by filtration. The solids were purified by recrystallization (ethanol) to obtain 52.1 mg (56%) of the captioned compound.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:12]1[CH2:17][CH2:16][CH:15](O)[CH2:14][CH2:13]1>>[O:12]1[CH2:17][CH2:16][CH:15]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14][CH2:13]1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Reactant: OC1CCOCC1
Product: CCOC(=O)/C(=N\OC1CCOCC1)C(C)=O
Yield: 37 %

Procedure:
Ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (3.0 g) was reacted with tetrahydro-4H-pyran-4-ol as described in Example 4a, Method 3, to give the title compound as a colourless liquid (1.69 g, 37%). νmax (film) 2950, 1740, 1695 cm-1. δH (CDCl3) 1.34 (3H, t), 1.82 (2H, m), 2.03 (2H, m), 2.40 (3H, s), 3.57 (2H, m), 3.91 (2H, m), 4.37 (2H, q), 4.54 (1H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[NH:13]1[CH2:14][CH2:15][CH:10]([O:9][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:11][CH2:12]1
Reactant: OC1CCNCC1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(OC2CCNCC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and 4-hydroxypiperidine by the method of Example 10 (b).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3ccccc3c2c1-c1ccc(C)cc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3ccccc3c2c1-c1ccc(C)cc1
Yield: 75.2 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-p-tolylbenzo[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.150 g; 0.415 mmol), LHMDS 1N in THF (0.462 mL; 0.462 mmol), 1-iodopropane (0.066 mL; 0.677 mmol) in DMF (6 mL) for 3 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-30%) in heptane furnished 0.126 g (75%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]([CH2:16][CH2:17][CH3:18])[C:12]([O:14][CH3:15])=[O:13])=[CH:3]1.[Br:19]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:19][C:3]1[N:2]([CH3:1])[C:10]2[C:5]([C:4]=1[CH:11]([CH2:16][CH2:17][CH3:18])[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: CCCC(C(=O)OC)c1cn(C)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC(C(=O)OC)c1c(Br)n(C)c2ccccc12

Procedure:
A solution of methyl 2-(1-methyl-1H-indol-3-yl)pentanoate (12b) (860 mg, 3.44 mmol) and N-bromosuccinimide (623 mg, 3.5 mmol) in tetrachloromethane (20 mL) was stirred at room temperature for 5 hours. The mixture was then filtered and the filtrate was washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the desired product (12c) as a brown oil without further purification (1.13 g, 3.44 mmol, 100%).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])=[O:11])=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][CH:9]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])=[O:11]
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirring solution of 2-t-butoxycarbonylamino-3-(1H-indol-3-yl)-N-(2-chlorobenzyl)propanamide (6.00 g, 14 mmol) in 30 ml of 70% aqueous trifluoroacetic acid (21 ml trifluoroacetic acid, 9 ml water) was allowed to stir overnight at room temperature. The progress of this deprotection reaction was monitored by thin layer chromatography.
Reaction SMILES: Cl.[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].O>N1C=CC=CC=1>[C:2]1([NH:8][NH:9][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:11]=2[F:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: NNc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(NNc1ccccc1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a stirred mixture, under nitrogen, of 72.3 g of phenylhydrazine hydrochloride in 600 ml of pyridine, cooled in an ice bath, was added, dropwise, 97.1 g of 2,4-difluorobenzoyl chloride, such that the reaction temperature did not exceed 15° C. The reaction mixture was stirred at ambient temperature for about 16 hours. Dilution of the mixture with water formed a precipitate which was collected, dried, and recrystallized from ethyl acetate to yield 98 g (79%) of 2,4-difluorobenzoic acid, 2-phenylhydrazide. Subsequent recrystallization from ethyl acetate afforded the analytical sample, m.p. 171°-173° C.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[S:15](=[O:17])(=[O:16])[N:14]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:13](=[O:24])[CH2:12]2)=[C:7]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=1.[C:37]1([CH2:43][S:44](Cl)(=[O:46])=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>N1C=CC=CC=1.CCOC(C)=O>[CH2:26]([O:25][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[N:11]1[CH2:12][C:13](=[O:24])[N:14]([CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[S:15]1(=[O:16])=[O:17])[CH2:4][C:3]1[CH:33]=[CH:34][CH:35]=[CH:36][C:2]=1[NH:1][S:44]([CH2:43][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:46])=[O:45])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(Cc3ccccc3N)cc2OCc2ccccc2)S1(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(Cc3ccccc3NS(=O)(=O)Cc3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-[4-(2-aminobenzyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (150 mg, 0.29 mmol) in pyridine (3 mL) is added α-tolylsulfonyl chloride (66 mg, 0.35 mmol) and the solution is stirred at ambient temperature for 1.5 h. The mixture is neutralized using 1N HCl solution, then diluted with EtOAc. The organic phase is washed with brine and water and is dried with MgSO4, and concentrated. The residue is purified by flash column chromatography to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12.C1OC1C.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:10][CH2:9][C:6]1[CH2:7][S:8][C@@H:3]2[C@H:2]([NH:1][C:26](=[O:27])[CH2:25][C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)[C:14](=[O:15])[N:4]2[C:5]=1[C:11]([OH:13])=[O:12]
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CCl)CS[C@H]12
Reactant: O=C(Cl)Cc1cccs1
Agent: CC1CO1
Solvent: ClCCl
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CCl)CS[C@H]12
Reaction time: 0.5 h

Procedure:
A suspension of the polymer ester of (6R, 7R)-7-amino-3-chloromethylceph-3-em-4-carboxylic acid. (5.00g, from example 31(a) was stirred in methylene chloride (100 ml) under nitrogen for 30 minutes at room temperature 18-21 degrees). The mixture was cooled to 0° and propylene oxide (1.74 g, 0.03 ml) was added, and stirring continued for 30 min. Thienylacetylchloride (3.0 ml. 3.89 g. 0.024 ml) was added dropwise over a period of 10 minutes maintaining the temperature 0°-5°. When the addition was completed, stirring was continued for 15 minutes at 0°-5° and then for a further 5 hours allowing the temperature to rise to room temperature. The reaction mixture was filtered and pulled as dry as possible. The product was washed in methylene chloride (3 × 40 ml), methanol (2 × 40 ml), water (4 × 40 ml) methanol (2 × 40 ml), and methylene chloride (3 × 40 ml) and dried to constant weight in vacuo at 30° to give the yellow-orange coloured polymer ester of (6R, 7R)-3-chloromethyl-7-(2-thienylacetamido) ceph-3-em-4-carboxylic acid (5.10 g). A sample of the product on suspending in methylene chloride, spraying with a 0.5% solution of ninhydrin in butan-1-ol, and warming gave an orange colouration indicating that the starting product had been consumed and the title product had been formed.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][C:33](B(O)O)=[C:34]([CH3:37])[CH:35]=2)[CH:30]=[N:29]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:33]5[CH:32]=[C:31]6[C:36](=[CH:35][C:34]=5[CH3:37])[N:28]([CH3:27])[N:29]=[CH:30]6)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Cc1cc2c(cnn2C)cc1B(O)O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cc6cnn(C)c6cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 1,6-dimethyl-indazole-5-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 10): tR=0.89 min; Mass spectrum (ESI+): m/z=503 [M+H]+.
Reaction SMILES: F[C:2]1[C:3]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>CC(N(C)C)=O.CCOC(C)=O>[OH:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][OH:25])[C:2]1[C:3]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)c(S(C)(=O)=O)cc1[N+](=O)[O-]
Reactant: OCCNCCO
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N(CCO)CCO)c(S(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 30 °C
Yield: 72.9 %

Procedure:
A mixture of 4 (1.48 g, 5.34 mmol) and diethanolamine (1.40 g, 13.3 mmol) in DMA (6 mL) was stirred at 30° C. for1 h, and then diluted with EtOAc (60 mL). The solution was washed with brine (2×) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with EtOAc/MeOH, followed by recrystallization from EtOAc/iPr2O, to give methyl 5-[bis(2-hydroxyethyl)amino]-4-(methylsulfonyl)-2-nitrobenzoate (5) (1.41 g, 73%): mp 99-100° C.; 1H NMR [(CD3)2SO] δ 8.56 (s, 1 H), 7.73 (s, 1 H), 4.62 (t, J=4.9 Hz, 2 H), 3.89 (s, 3 H), 3.59-3.49 (m, 8 H), 3.45 (s, 3 H). Anal. (C13H18N2O8S) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:27]([O:30][CH:31](Br)[CH3:32])(=[O:29])[CH3:28].[I-].[Na+]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH:31]([O:30][C:27](=[O:29])[CH3:28])[CH3:32])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OC(C)Br
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: [I-]
Agent: [Na+]
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(C)=O)=CCS[C@H]12)c1csc(N)n1

Procedure:
In the same manner as Example 1, sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) was reacted with 1-bromoethyl acetate in the presence of sodium iodide to give 1-acetoxyethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer), mp 100°-103° C. (decompn.).
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH2:34][C:35]([O:37]CC)=[O:36])[CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]4[C:30]5[C:25](=[N:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=5)[CH:24]=[CH:23][C:22]4=[O:33])[CH2:15][CH2:14]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O1CCCC1>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH2:34][C:35]([OH:37])=[O:36])[CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]4[C:30]5[C:25](=[N:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=5)[CH:24]=[CH:23][C:22]4=[O:33])[CH2:15][CH2:14]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CN(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(OC)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCC(N(CC(=O)O)Cc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
A solution of 90 mg of ethyl ((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)acetate in 0.2 mL of methanol and 1 mL of tetrahydrofuran, 0.2 mL of a 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with a 1 mol/L aqueous hydrochloric acid solution and neutralized, and the solvent was distilled off under reduced pressure. The resultant residue was purified by a resin; HP-20, made by Mitsubishi Chemical Corporation and an eluent of acetone to obtain 54 mg of ((2,3-dihydro(1,4)dioxino(2,3-c) pyridin-7-ylmethyl)(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)amino)acetic acid as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[O:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[O:28][CH2:27][CH2:26][N:25]([C:2]3[CH:3]=[C:4]([CH3:14])[C:5]4[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=4[C:12]=3[CH3:13])[CH2:24]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(C2CNCCO2)cc1
Reactant: Cc1cc(Br)c(C)c2c1OC(C)(C)C2
Product: COc1ccc(C2CN(c3cc(C)c4c(c3C)CC(C)(C)O4)CCO2)cc1
Yield: 56.1 %

Procedure:
By using 5-bromo-2,2,4,7-tetramethyl-2,3-dihydro-1-benzofuran (510 mg, 2.00 mmol) synthesized in Reference example 103 and 2-(4-methoxyphenyl)morpholine (773 mg, 4.00 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 412 mg (yield 56%).
Reaction SMILES: [Br:1][CH:2]([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].ClC(CC(O)=O)C(O)=O>>[CH2:6]([C:7]([OH:9])=[O:8])[C@H:2]([Br:1])[C:3]([OH:5])=[O:4]
Reactant: O=C(O)CC(Br)C(=O)O
Agent: O=C(O)CC(Cl)C(=O)O
Product: O=C(O)C[C@H](Br)C(=O)O
Yield: 88 %

Procedure:
In the reference cited above (J. A. Frick et al., 1992), the preparation of S-(−)-chlorosuccinic acid is simply described as: “S-aspartic acid was converted to S-chlorosuccinic acid by treatment with sodium nitrite in hydrochloric acid”. In the diagram on page 621 of the reference cited, the yield of the synthesis step from S-aspartic acid to S-chlorosuccinic acid is 70%. In the experimental part, the only example of preparation is provided for S-bromosuccinic acid, with a yield of 88%. The bromosuccinic acid preparation conditions are not the same as those described for chlorosuccinic acid, though they are taken as an example by analogy. From the industrial point of view, the synthesis of bromosuccinic acid described by Frick et al. is not very convenient in economic terms. In the first place, the dilutions of the reaction mixture are very high; by way of an example, S-(+)-aspartic acid is present to the extent of 5% w/v in the final reaction mixture. A distinct disadvantage arises in the case of isolation of the end product by extraction, which requires a substantial amount of ethyl acetate in order to obtain a 3% w/v solution of S-(−)-bromosuccinic acid. In addition, the end product, obtained with a stoichiometric yield of 88%, is not very pure, particularly as regards optical purity (e.e. =94%).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.[OH-].[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].[Al+3].C1C(O)=CC=C(S(O)(=O)=O)C=1>[CH2:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:9]1[O:11][CH2:10]1
Reactant: CCCCCO
Reactant: ClCC1CO1
Agent: CC(C)[O-]
Agent: O=S(=O)(O)c1ccc(O)cc1
Agent: [Al+3]
Product: CCCCCOCC1CO1
Temperature: 25 °C
Yield: 86 %

Procedure:
Amyl alcohol (132 g, 1.5 mole), 1.02 g (0.005 mole) of aluminum triisopropoxide and 2.64 g (0.015 mole) of p-phenolsulfonic acid were heated to 90° C. while stirring under a nitrogen gas atmosphere. To the reaction mixture, 92.5 g (1.0 mole) of epichlorohydrin was added dropwise over 1 hour, followed by stirring for 4 hours. It was found that the conversion ratio of the raw material epichlorohydrin was 100%, while the yield of the resulting halohydrin ether was 87%. To the reaction mixture, 300 mL of a 4N aqueous solution of sodium hydroxide was added and the resulting mixture was stirred at 60° C. for 6 hours. After cooling to room temperature, the water layer was removed and the residue was purified by distillation under reduced pressure, whereby 124 g of amyl glycidyl ether (1,2-epoxy-4-oxanonane) was obtained (total yield: 86%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O.C(N(CC)C(C)C)C>[O:1]([CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1)[Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1Nc2cc([N+](=O)[O-])ccc2OC1CCO
Agent: CCN(CC)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC1Oc2ccc([N+](=O)[O-])cc2NC1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
To solution of 4.8 g racemic-2-(2-hydroxyethyl)-6-nitro-3-oxo-4H-benz[1,4]oxazine in dimethylformamide (100 mL) and 3.4 mL diethylisopropylamine at 0° C. was added 4.7 g tert-butyldimethylsilylchloride. The reaction mixture was stirred at 0° C. for 20 minutes, at room temperature for 3 hour, concentrated and the resulting residue was partitioned between sodium bicarbonate solution and EtOAc. The aqueous phase was extracted with EtOAc and the combined organics washed with water, brine then dried over MgSO4. The solvent was removed by in vacuo and the crude material purified by column chromatography (hexanes/EtOAc) to yield 1 g of the desired product racemic-2-(2-t-butyldimethylsiloxyethyl)-6-nitro-3-oxo-4H-benz[1,4]oxazine MS (m/e): 353 (MH+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[CH2:19][C@H:20]3[C@@H:25]([C:26]=2[C:27]=1[CH3:28])[CH2:24][CH2:23][CH2:22][NH:21]3>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:21]3[CH2:22][CH2:23][CH2:24][C@@H:25]4[C:26]5[C:27]([CH3:28])=[C:15]([O:14][CH3:13])[CH:16]=[CH:17][C:18]=5[CH2:19][C@H:20]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1ccc2c(c1C)[C@H]1CCCN[C@H]1C2
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: COc1ccc2c(c1C)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-6-methoxy-5-methyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1.