Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C>[Si:17]([O:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1

Procedure:
A solution of ethyl 4-hydroxycyclohexanecarboxylate (5 g), tert-butyl(chloro)diphenylsilane (8.30 mL) and imidazole (2.17 g) in DMF (50 mL) was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (12.2 g).
Reaction SMILES: C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[OH:25][C@@H:26]([C@H:28]1[C:49](=[O:50])[N:30]2[CH:31]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])[C:32](=O)[C@H:33]([CH3:34])[C@H:29]12)[CH3:27].FC(F)(F)S(O)(=O)=O.[SH:59][C@@H:60]1[CH2:64][N:63]([C:65]([O:67][CH2:68][C:69]2[CH:74]=[CH:73][C:72]([N+:75]([O-:77])=[O:76])=[CH:71][CH:70]=2)=[O:66])[C@H:62]([C:78]([N:80]2[CH2:85][CH2:84][N:83]([CH2:86][CH2:87][O:88][C:89](=[O:91])[NH2:90])[CH2:82][CH2:81]2)=[O:79])[CH2:61]1>C(#N)C>[C:89]([O:88][CH2:87][CH2:86][N:83]1[CH2:82][CH2:81][N:80]([C:78]([C@@H:62]2[CH2:61][C@H:60]([S:59][C:32]3[C@H:33]([CH3:34])[C@@H:29]4[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:49](=[O:50])[N:30]4[C:31]=3[C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])[CH2:64][N:63]2[C:65]([O:67][CH2:68][C:69]2[CH:70]=[CH:71][C:72]([N+:75]([O-:77])=[O:76])=[CH:73][CH:74]=2)=[O:66])=[O:79])[CH2:85][CH2:84]1)(=[O:91])[NH2:90]
Reactant: NC(=O)OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(CCOC(N)=O)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 28.6 %

Procedure:
91 μl of diphenylphosphoryl chloride and 77 μl of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 152 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 2.0 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. 176 μl of diisopropylethyl-amine and a solution of 318 mg of (2S,4S)-4-mercapto-2-[4-(2-carbamoyloxyethyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine trifluoromethane-sulfonate (prepared as described in Preparation 53) in 2.0 ml of dry acetonitrile were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 2 hours, after which it was allowed to stand overnight in a refrigerator. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with an aqueous solution of sodium hydrogencarbonate. The mixture was then extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was then removed from the extract by distillation under reduced pressure, and the resulting residue was purified by chromatography through a Lobar column (Merck, LiChroprep Si60, size B), using a 5:1 by volume mixture of ethyl acetate and methanol as the eluent to give 99 mg of the title compound, as a powder.
Reaction SMILES: [OH-].[Na+].O.[C:4]1([CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)[OH:5].[Cl:12][C:13]1[CH:14]=[C:15]([F:20])[C:16](F)=[N:17][CH:18]=1>CS(C)=O>[Cl:12][C:13]1[CH:14]=[C:15]([F:20])[C:16]([O:5][C:4]2[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=2)=[N:17][CH:18]=1
Reactant: Oc1ccc(O)cc1
Reactant: Fc1cc(Cl)cnc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Reaction time: 0.33 h
Yield: 26.1 %

Procedure:
A solution of NaOH (1.76 g, 0.044 mol) in a few ml of water was added to hydroquinone (4.86 g, 0.040 mol) in 250 ml DMSO. The mixture was stirred under nitrogen for 20 minutes. 5-Chloro-2,3-difluoropyridine (6.0 g, 0.040 mol) was added. The reaction mixture was heated at 60°-70° C. for 3 hours, then poured over ice. Aqueous NaOH was added to pH 12 and the solid diether side-product was filtered off. The filtrate was acidified, extracted with ether, treated with Norite adsorbent, and the solvent was removed by rotary evaporation to give a yellow oil which solidified on standing and was purified by high pressure liquid chromatography (HPLC) (80% hexane/20% ethyl acetate) to give a white solid (2.5 g, 26% yield, m.p. 90°-92° C.).
Reaction SMILES: N[C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:14])([F:13])[CH2:11][OH:12].FC(F)(F)C(O)=O.N(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+]>>[Cl:8][C:3]1[C:2]([O:12][CH2:11][C:10]([F:14])([F:13])[F:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: OCC(F)(F)F
Reactant: Nc1cccnc1Cl
Agent: CC(C)(C)ON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)COc1cccnc1Cl
Temperature: 55 °C
Yield: 62.6 %

Procedure:
A reactor vessel is charged with 3-amino-2-chloropyridine (2.7 g, 21 mmol), 2,2,2-trifluoroethanol (15 g, 150 mmol), and trifluoroacetic acid (3.63 g, 31.8 mmol). The solution is cooled to the range 0° C. to 5° C. and then the reagent t-butyl nitrite (2.51 g of a 96% solution, 23.4 mmol) is added drop-wise to the vessel maintaining the temperature in the range 0° C. to 5° C. After stirring a few minutes the solution is transferred drop-wise to a reactor vessel containing 2,2,2-trifluoroethanol (20 g, 200 mmol) maintained at 55° C. The temperature rose to 70° C. during the drop-wise addition of the diazonium salt reaction mass. After cooling the solution, it neutralized with aqueous saturated sodium bicarbonate solution and then extracted with MTBE. The solvent is removed by evaporation to obtain 2-chloro-3-(2,2,2-trifluoroethoxy)pyridine as a crude oil (3.36 g) with an actual yield of 62.6%.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:30][C@@H:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:32][OH:33])=[N:4][C:5]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([F:19])[CH:17]=3)[N:12]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:11]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[CH3:45][S:46]([O:33][CH2:32][C@@H:31]([NH:30][C:3]1[C:2]([F:1])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([F:19])[CH:17]=3)[N:12]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[CH:11]=2)[N:4]=1)[C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:48])=[O:47]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](CO)C(C)(C)C)c(F)cc3C#N)c3cc(F)cnc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](COS(C)(=O)=O)C(C)(C)C)c(F)cc3C#N)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of (S)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-((1-hydroxy-3,3-dimethylbutan-2-yl)amino)nicotinonitrile, 98a, (3.77 g, 7.17 mmol) and triethylamine (1.25 mL, 8.96 mmol) in dichloromethane (75 mL) was added methanesulfonyl chloride (0.69 mL, 8.96 mmol). The solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and water (100 mL) and EtOAc (200 mL) were added. The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure to afford 4.22 g of the desired product as a yellow foamy solid that was used without further purification: LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 604.45 (M+H) retention time=2.03 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+].OB(O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1>C1(C)C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:21]([C:17]1[CH:16]=[C:15]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:19][CH:18]=1)([O-:23])=[O:22]
Reactant: Brc1cccnc1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=[N+]([O-])c1cccc(-c2cccnc2)c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a mixture of 3-bromopyridine (2.6 ml) and tetrakis(triphenylphosphine)palladium(0) (0.93 g) in toluene (50 ml) was added 2M aqueous solution of sodium bicarbonate (27 ml) and a solution of dihydroxy(3-nitrophenyl)borane (5.0 g) in methanol (12 ml). The mixture was stirred at 80° C. for 6 hours and cooled. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate (3:7)) to give 3-(3-nitrophenyl)pyridine (3.57 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][S:7](Cl)(=[O:9])=[O:8].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CC#N>[CH3:6][S:7]([CH:4]([OH:5])[CH2:3][CH2:2][Cl:1])(=[O:9])=[O:8]
Reactant: OCCCCl
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)C(O)CCCl
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.5 %

Procedure:
To 3-chloro-1-propanol (5.02 mL, 60 mmole) in CH3CN (200 mL) was added methanesulfonyl chloride (10.4 g, 90 mmole) and triethyl amine (13 mL, 90 mmole). The reaction mixture was stirred at room temperature for 12 hours under an argon atmosphere. 200 mL of saturated NaHCO3 (aq) was added and the stirring was continued for 15 minutes. The mixture was extracted several times with ether. The combined ether layers were dried over Na2SO4, the Na2SO4 was filtered and the filtrate was evaporated to give 10 g (96.6%) of the title compound: TLC (Rf: 0.3; 20% EtOAc/Hexane), 1H NMR (CDCl3) δ 2.2 (m, 2 H, CH2), 3.0 (s, 3 H, CH3), 3.6 (t, 2 H, CH2), 4.4 (t, 2 H, CH2). 13C NMR (CDCl3): δ 31.5 (CH2), 37.0 (CH3), 40.2 (CH2), 66.3 (CH2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[Li]CCCC.CCCCCC.CON(C)[C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]>C1COCC1>[Cl:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]
Reactant: Clc1cccc(Br)c1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 1-bromo-3-chlorobenzene (15 g, 78.3 mmol) in anhydrous THF (150 mL) cooled to −78° C. was added dropwise a solution of 2.5 M n-BuLi in hexane (31.3 mL, 78.34 mmol). The reaction mixture was stirred at −78° C. for 1 h and a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (17.8 g, 65.3 mmol) in anhydrous THF (50 mL) was added dropwise. After addition, the mixture was allowed to warm to rt and stirred for 2 h. The mixture was quenched with saturated NH4Cl (250 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (PE/EtOAc 5:95) to give (R)-tert-butyl 3-(3-chlorobenzoyl)piperidine-1-carboxylate (12.9 g, 51%). 1H NMR (400 MHz, CDCl3): 1.45 (s, 9H), 1.54-1.73 (m, 2H), 1.75 (m, 1H), 2.00 (m, 1H), 2.71-2.78 (m, 1H), 2.93 (m, 2H), 3.30-3.35 (m, 1H), 4.22 (m, 1H), 7.39-7.42 (t, 1H), 7.52 (d, 1H), 7.89 (d, 1H), 7.90 (m, 1H). MS (E/Z): 324 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>O1CCCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCOCC2)nc1
Temperature: 25 °C

Procedure:
To a solution of 20 g (126 mmol) of 2-chloro-5-nitropyridine in 150 ml tetrahydrofuran were added dropwise 27 ml (315 mmol) morpholine within 10 min. The reaction mixture was refluxed for additional 2 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was re-dissolved in 200 ml ethyl acetate. The organic phase was washed with 200 ml 1 N sodium bicarbonate solution, dried (magnesium sulfate) and evaporated to give 27.3 g (quantitative) of the title compound as a yellow solid. M.p. 142-143° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[C:18]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4)nc23)CC1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
To a solution of 0.100 gm (0.43 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine in 3 mL 50% aqueous tetrahydrofuran were added 0.43 mL (0.86 mMol) benzoyl chloride and the resulting mixture was stirred at room temperature. After about 4 hours the reaction mixture was partitioned between dichloromethane and 2N sodium hydroxide. The phases were separated and the aqueous phase extracted well with dichloromethane. The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of dichloromethane (2-10% methanol) containing 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 0.095 gm (66%) of the title compound. A portion was recrystallized from ethanol/water to provide an analytical sample.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[NH4+:11].C1COCC1>O>[Br:1][C:2]1[C:3]([NH2:11])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 100 mL round bottom flask was charged with 5-bromo-2,4-dichloropyrimidine (10.0 g, 44 mmol), concentrated ammonium hydroxide (100 mL) and THF (150 mL). The resulting mixture was magnetically stirred at room temperature for 12 h. Work-up: the reaction mixture was diluted with water (100 mL) and then extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford 11 g (quantitative) of the product as a white solid. MS m/z: 208 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([OH:9])=[O:8])[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]1.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[CH2:13]([O:8][C:7]([CH:5]1[CH:4]([C:10]([OH:12])=[O:11])[CH2:3][C:2](=[O:1])[O:6]1)=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=C1CC(C(=O)O)C(C(=O)O)O1
Solvent: CC(C)=O
Product: O=C1CC(C(=O)O)C(C(=O)OCc2ccccc2)O1
Reaction time: 12 h

Procedure:
5.2 g of (2RS,3SR)-5-oxotetrahydrofuran-2,3-dicarboxylic acid in 88 ml of acetone was stirred with 6.5 g of 1,1'-dicyclohexylcarboriimide at room temperature for 2 hours. After addition of 3.26 ml of benzyl alcohol, the reaction solution was stirred at the same temperature for 12 hours. The insolubles were filtered off, and the filtrated was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=4/1→chloroform/methanol=50/1] to give 7.93 g of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][NH2:6])[CH3:2].[Cl:8][CH2:9][C:10](Cl)=[O:11]>>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][NH:6][C:10](=[O:11])[CH2:9][Cl:8])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)CN
Product: CCOC(=O)CNC(=O)CCl

Procedure:
The ester prepared in step 1 is reacted with chloroacetylchloride at a temperature of from about -10° to +10° C. in a suitable solvent in the presence of a suitable base to produce chloroacetylglycine ethyl ester. Solvents useful in this reaction include water, dichloromethane, and dichloroethane. Suitable bases include sodium bicarbonate, sodium carbonate, potassium carbonate, and sodium hydroxide. If the aminoacid is used in the form of its hydrochloride, a two-fold excess of base must be used.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[C:15](Cl)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CC(C)=O>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(C=Cc1ccccc1)Nc1ccccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
To a solution of 2-fluoroaniline (25.0 g, 225 mmol) and potassium carbonate (47 g, 337 mmol) in water (112 mL) and acetone (45 mL) at 0° C. was added cinnamoyl chloride (37.0 g, 225 mmol, 1 eq) in acetone (45 mL) over 2 h. The reaction was stirred for 1 h at 0° C., and quenched into 200 mL of ice-water. The white crystalline solid was filtered and washed with water. The solid was air dried for 2 h, then washed with 400 mL of hexanes. The solid was dried under vacuum overnight to afford N-(2-fluorophenyl)cinnamamide (56 g, 103% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.49 (br t, J=7.8 Hz, 1H), 7.80 (d, J=15.3 Hz, 1H), 7.57 (m, 3H), 7.41 (m, 3H), 7.17 (m, 3H), 6.61 (d, J=15.6 Hz, 1H). Mass Spectrum (ESI) m/e=242.1 (M+1).
Reaction SMILES: [C:1]1(=[O:44])[N:5]([CH:6]2[C:37](=[O:38])[N:8]3[C:9]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:10]([CH2:13][S:14][C:15]4[S:16][C:17]([CH3:20])=[N:18][N:19]=4)[CH2:11][S:12][C@H:7]23)[C:4](=[O:39])[C:3]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:2]12.C1C[O:48]CC1.[S-2].[Na+].[Na+].S(=O)(=O)(O)O>C(OCC)(=O)C.O>[C:1]([C:2]1[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=1[C:4]([NH:5][CH:6]1[C:37](=[O:38])[N:8]2[C:9]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH3:20])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[O:39])([OH:48])=[O:44]
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N4C(=O)c5ccccc5C4=O)[C@H]3SC2)s1
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [S-2]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)c4ccccc4C(=O)O)[C@H]3SC2)s1
Reaction time: 0.25 h

Procedure:
A solution of benzhydryl 7-phthalimido-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (2 mmol.) in 25 ml. of THF and 8 ml. of water is cooled in an ice-water bath, and 660 mg. of Na2S.9H2O are then added. The mixture is stirred for 15 minutes, and 10 ml. of water and 40 ml. of ethyl acetate are added. The layers are separated, and a neutral material is obtained from the ethyl acetate layer. The aqueous layer is acidified to pH 4.3 with 1N sulfuric acid and is extracted twice with ethyl acetate. The ethyl acetate extract is washed, dried, and evaporated to give the title compound.
Reaction SMILES: [H-].[Na+].C[CH:4]([CH2:8][CH3:9])[CH2:5][CH:6]=[O:7]>CCCCCC.C(COC)OC.COCC>[CH3:4][CH:9]([CH2:5][CH3:6])[CH2:8][CH:4]=[CH:5][C:6]([O:7][CH2:9][CH3:8])=[O:7]
Reactant: CCC(C)CC=O
Agent: CCOC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Product: CCOC(=O)C=CCC(C)CC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 122 %

Procedure:
Sodium hydride (60% dispersion, 2.4 g, 65 mmol) was washed with hexane and suspended in dimethoxyethane 60 mL. While cooling in ice water bath triethyl phosphonoacetate was slowly added, calcd. 5 minutes. The reaction was stirred for 15 minutes at 0° C. and a solution of 3-methyl-1-pentanal 11 (6.5 g, 65 mmol) in methoxyethane 20 mL was added. After refluxing overnight, it was concentrated, water and hexane were added, the organic phase was separated, and the aqueous portion discarded. The solution was washed twice with brine and dried on magnesium sulfate. The solvent was evaporated to give 12 (6.75 g, 61%). 1H-NMR (CDCl3) δ 6.89 (m, 1H, —CH2CH:CHCOOEt), 5.77 (d, 1H, —CH2CH:CH:CHCOOEt), 4.16 (q, 2H, —COOCH2CH3), 2.15 and 1.98 (1H each and a multiplet, —CH2CH:CHCOOEt), 1.48 (m, 1H, C2H5(CH3)CHCH2), 1.30–1.10 (m), and 0.83.
Reaction SMILES: ClCCC1N=CC=CN=1.OCCN1C=CC=NC1.S(Cl)(Cl)=O.[NH2:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.[C:35]([NH:37][C:38](=[N:41][CH3:42])SC)#[N:36]>>[C:35]([NH:37][C:38]([NH:41][CH3:42])=[N:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][C:29]1[N:30]=[CH:31][CH:32]=[CH:33][N:34]=1)#[N:36]
Reactant: CN=C(NC#N)SC
Reactant: NCCSCCc1ncccn1
Agent: ClCCc1ncccn1
Agent: OCCN1C=CC=NC1
Solvent: O=S(Cl)Cl
Product: CNC(=NCCSCCc1ncccn1)NC#N

Procedure:
By the procedure of Example 17 using 2-(2-chloroethyl)pyrimidine, prepared by treating 3-(2-hydroxyethyl)pyrimidine with thionyl chloride, as the starting material, 2-[2-(2-aminoethyl)thioethyl]pyrimidine is prepared, which when treated with N-cyano-N',S-dimethylisothiourea by the procedure of Example 3(a) gives the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([C:6]([OH:8])=[O:7])[NH2:5].[C:9]([NH:12][C@@H:13]([C:21]([OH:23])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:11])[CH3:10]>CO.O>[C:9]([NH:12][C@@H:13]([C:21]([OH:23])=[O:22])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:11])[CH3:10].[CH3:1][O:2][CH2:3][C@H:4]([C:6]([OH:8])=[O:7])[NH2:5]
Reactant: COCC(N)C(=O)O
Agent: CC(=O)N[C@H](Cc1ccccc1)C(=O)O
Solvent: O
Solvent: CO
Product: COC[C@@H](N)C(=O)O
Temperature: 50 °C
Yield: 68 %

Procedure:
Into a 250 mL round-bottomed flask equipped with a stirrer, reflux condenser and thermometer was added O-methyl-D,L-serine (5 g) in 90:10 methanol/water (25 mL). N-Acetyl-D-phenylalanine (8.70 g) was added in one portion and the mixture heated to 50° C. overnight. The suspension was cooled to room temperature and filtered, and the solid was rinsed with 90:10 methanol/water (5 mL) and dried at 40° C. under vacuum for 3 h. The N-acetyl-D-phenylalanine salt of O-methyl-D-serine (3.4 g, 25%) was obtained as a white solid with a chiral purity >90%. Regeneration of the title compound could be effected by adjustment of the pH to 1-2 by treatment with HCl, followed by extraction into an organic solvent and subsequent adjustment of the pH to ˜7 with NaOH.