Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][O:7][C:8](=[O:45])[CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][C@@H:15]1[C@@H:19](/[CH:20]=[CH:21]/[C@@H:22]([O:30]C2CCCCO2)[C:23]([CH3:29])([CH3:28])[CH2:24][CH2:25][CH2:26][CH3:27])[C@H:18]([O:37]C2CCCCO2)[CH2:17][C@@H:16]1O.C(O)(=O)C.O.O1CCCC1>N1C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:6][O:7][C:8](=[O:45])[CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][C@@H:15]1[C@@H:19](/[CH:20]=[CH:21]/[C@@H:22]([OH:30])[C:23]([CH3:29])([CH3:28])[CH2:24][CH2:25][CH2:26][CH3:27])[C@H:18]([OH:37])[CH2:17][C@H:16]1[Cl:5]
Reactant: CCCCC(C)(C)[C@@H](/C=C/[C@@H]1[C@@H](CC/C=C\CCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Reactant: CS(=O)(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@@H](CC/C=C\CCC(=O)OC)[C@H](Cl)C[C@H]1O
Temperature: 20 °C
Reaction time: 4 h
Yield: 44.4 %

Procedure:
319 mg of methane sulfonic acid chloride is added at 0° C. to a solution of 1.00 g of (4Z,13E)-(9S,11R,15R)-9-hydroxy-16,16-dimethyl-11,15-bis-(tetrahydropyran-2-yloxy)-4,13-prostadienoic acid methyl ester in 10 ml of pyridine. It is stirred for 4 hours at 20° C. and the solution is added to a suspension of 9.99 g of tetrabutylammonium chloride in 10 ml of toluene. After 15-hours stirring at 0° C., it is stirred for another 7 hours at 40° C. Then it is added to 100 ml of ice water and extracted three times with 50 ml each of ether. After the organic phase is washed twice with 20 ml of brine, dried over MgSO4 and is concentrated by evaporation in a vacuum a-residue is obtained which is chromatographed on silica gel with hexane/0-40% ether. 839 mg of oily (4Z,13E)-(9R,11R,15R)-9-chioro-16,16-dimethyl-11,15-bis(tetrahydropyran-2-yloxy)-4,13-prostaqienoic acid methyl ester is obtained. For cleavage of the protecting groups, the resulting ester is stirred with 31 ml of a mixture of acetic acid/water/ tetrahydrofuran (65/35/10) for 24 hours at 20° C. After addition of toluene and concentration of the solution by evaporation in a vacuum the residue is chromatographed on silica gel. With toluene/0-10% isopropanol as eluant, 326 mg of the title compound is obtained as colorless oil.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[OH-].[Na+]>CN(C=O)C>[CH3:6][N:5]([CH3:7])[CH2:4][CH2:3][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH2:8])=[CH:10][CH:11]=1
Reactant: Nc1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 90.9 %

Procedure:
1-Chloro-2-dimethylaminoethane hydrochloride (2 g, 21.9 mmol, 1.2 equiv) was added in one portion to a mixture of 4-aminophenol (2 g, 18.3 mmol) and finely powdered sodium hydroxide (1.8 g, 45.8 mmol, 2.5 equiv) in DMF (27 mL), under an argon atmosphere. The reaction mixture was stirred for 17 h at rt. The resulting dark suspension was filtered. The filtrate was diluted with DCM (200 ml) and washed with brine (2×50 mL). The organic phase was dried (Na2SO4), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH, 7:3) provided 3 g of the title compound as a brown solid: API-MS: 181.2 [M+H]+; TLC: Rf=0.18 (DCM/MeOH, 7:3).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH:16]([NH:19][CH2:20][CH2:21][NH2:22])([CH3:18])[CH3:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:22][CH2:21][CH2:20][NH:19][CH:16]([CH3:18])[CH3:17])(=[O:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NCCNS(=O)(=O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
4-methylsulfonamidobenzenesulfonyl chloride (2.70 g) was added portionwise to a 0.01 mole portion of N-isopropylethylenediamine and triethylamine (0.01 mole) in methylene chloride (250 ml) to obtain a white solid which precipitated from the methylene chloride reaction mixture 2.62 g, m.r. 180°-182° C. This solid was washed well with methylene chloride, dissolved in isopropanol/HCl/methanol and the methanol boiled away. The product was precipitated and filtered to yield 1.65 g, m.r. 158°-160° C.(d).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[C:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([OH:29])=[O:28].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[CH3:18][N:16]1[C:15](=[O:19])[CH:14]=[CH:13][C:12]([C:10](=[O:11])[CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:33]3[CH:34]=[CH:35][C:30]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)=[CH:7][CH:6]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[CH:17]1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one (50 mg, example 162, step 3) and 4-carboxyphenylboronic acid (32 mg) in 1,4-dioxane (0.4 ml) under argon were added dichloro(1,1′-bis(diphenylphosphino)ferrocene)-palladium(II) dichloromethane adduct (4.5 mg), water (0.3 ml) and 2 M aqueous sodium carbonate solution (0.18 ml). The mixture was stirred at 80° C. for 2 h. After cooling to room temperature, the mixture was filtered. The filter cake was washed with ethyl acetate and with a saturated KHSO4 solution. The combined filtrate was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, dichloromethane/methanol 1:0 to 9:1) to give the title compound (75 mg, not totally pure) as a colorless solid, MS (ESI−): m/z=450.2 [M−H]−.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@H:23]4[C@H:19]([O:20]C(C)(C)[O:22]4)[C@@H:18]([CH2:26][N:27]([CH3:48])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]5[NH:38][C:37]6[CH:39]=[CH:40][C:41]([C:43]7([CH3:47])[CH2:46][CH2:45][CH2:44]7)=[CH:42][C:36]=6[N:35]=5)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.FC(F)(F)C(O)=O.O.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@@H:16]3[CH2:17][C@H:18]([CH2:26][N:27]([CH3:48])[CH:28]4[CH2:29][CH:30]([CH2:32][CH2:33][C:34]5[NH:38][C:37]6[CH:39]=[CH:40][C:41]([C:43]7([CH3:47])[CH2:44][CH2:45][CH2:46]7)=[CH:42][C:36]=6[N:35]=5)[CH2:31]4)[C@@H:19]([OH:20])[C@H:23]3[OH:22])[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(C6(C)CCC6)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C4(C)CCC4)ccc3[nH]2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 3.1 %

Procedure:
N-(2,4-dimethoxybenzyl)-7-((3aS,4R,6R,6aR)-2,2-dimethyl-6-((methyl(3-(2-(5-(1-methylcyclobutyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (128 mg, 0.17 4 mmol) was dissolved in a mixture of Trifluoroacetic Acid (3.60 ml, 46.7 mmol) and Water (0.4 ml, 20 mmol) which had been pre-cooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, then the ice bath was removed and the mixture was warmed to RT at which this temperature was maintained for a further 2.5 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in 3 ml MeOH and concentrated and the process was repeated twice. The resultant white residue was placed on high vacuum. The crude residue was combined with another batch of crude material (prepared identically, ˜⅓ of the amount used in this reaction), diluted with 5 mL MeOH, treated with 140 mg K2CO3, 10 drops of H2O and allowed to stir at RT till the solution was basic by pH paper. The mixture was filtered and the solids were washed with 15 ml MeOH. The solution was concentrated to an oil that was placed on high vacuum. The crude material was purified by flash chromatography (SiO2, eluting with 10-15% 7N NH3 in CH3OH/CH2Cl2 to yield the desired product as glass/stiff foam (68 mg). 1H NMR (400 MHz, MeOD) δH ppm 8 06 (s, 1H), 7.39 (d, J=7.88 Hz, 1H), 7.23 (s, 1H), 7.21 (dd, J=3.63, 1.76 Hz, 1H), 6.99 (m, 1H), 6.60 (d, J=3.52 Hz, 1H), 4.93 (m, 1H), 4.32 (m, 1H), 3.89 (m, 1H), 3.03 (m, 1H), 2.83 (m, 2H), 2.70 (q, J=8.15 Hz, 1H), 2.52 (m, 1H), 2.40 (m, 4H), 2.27 (m, 2H), 2.18 (d, J=6.22 Hz, 3H), 2.11 (m, 4H), 2.03 (m, 1H), 1.86 (m, 4H), 1.62 (m, 1H), 1.51 (m, 1H), 1.47 (s, 3H).
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:11])[C:5]([CH2:7][CH:8]([CH3:10])[CH3:9])=[CH2:6].[P:12]([S-:25])([SH:24])([S:14][CH2:15][CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=S>>[CH2:22]([O:21][CH:17]([O:18][CH2:19][CH3:20])[CH2:16][CH2:15][S:14][PH:12]([S:25][CH2:2][NH:3][C:4](=[O:11])[CH:5]([CH2:6][S:25][PH:12]([S:14][CH2:15][CH2:16][CH:17]([O:18][CH2:19][CH3:20])[O:21][CH2:22][CH3:23])=[S:24])[CH2:7][CH:8]([CH3:10])[CH3:9])=[S:24])[CH3:23]
Reactant: C=C(CC(C)C)C(=O)NCO
Reactant: CCOC(CCSP(=S)([S-])S)OCC
Product: CCOC(CCS[PH](=S)SCNC(=O)C(CS[PH](=S)SCCC(OCC)OCC)CC(C)C)OCC

Procedure:
Following the procedure of Example 1, 0.4 mole of N-hydroxymethyl-2-isobutylacrylamide is reacted with 0.8 mole of diethoxypropyl hydrogen phosphorotetrathioate to yield N-(diethoxypropylthiophosphinothioylthiomethyl) 2-(diethoxypropylthiophosphinothioylthiomethyl)-4-methylvaleramide.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8](O)[CH2:9][CH2:10][OH:11].C(OCC)(OCC)OCC.[OH-].[Na+]>ClCCl.[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[CH2:10]1[O:11][C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:7][CH2:8][CH2:9]1
Reactant: O=C1CCCCC1
Reactant: OCCCO
Agent: [Zr+4]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(OCC)OCC
Product: C1CCC2(CC1)OCCCO2
Yield: 55.3 %

Procedure:
To a solution of cyclohexanone (32 ml, 0.31 mol) in dry dichloromethane (950 ml) were added successively 1,3-propanediol (33.5 ml, 0.46 mol), triethyl orthoformate (51.5 ml, 0.31 mol) and zirconium chloride (1.44 g, 6.18 mmol) with stirring, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After stirring, ice-chilled 1N aqueous sodium hydroxide solution (1.5 l) was added to the reaction mixture with stirring, and the resulting mixture was extracted with dichloromethane. The extract was washed with water and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by reduced-pressure distillation to afford cyclohexanone trimethylene ketal (26.8 g, yield: 55%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:13])([CH3:12])[C:9]([NH2:11])=[O:10].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[CH2:32]([Si:34]([C:39]#[CH:40])([CH2:37][CH3:38])[CH2:35][CH3:36])[CH3:33]>CN(C=O)C.[Cu]I.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>[CH3:12][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:33]#[C:32][Si:34]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:35][CH3:36])([CH3:13])[C:9]([NH2:11])=[O:10]
Reactant: CC(C)(C(N)=O)c1ccccc1Br
Reactant: C#C[Si](CC)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Product: CC[Si](C#Cc1ccccc1C(C)(C)C(N)=O)(CC)CC
Temperature: 65 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(2-bromophenyl)-2-methylpropanamide A34 (0.196 g, 0.810 mmol), CuI (0.008 g, 0.040 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.012 g, 0.040 mmol), PdCl2(PPh3)2 (0.028 g, 0.040 mmol) and (triethylsilyl)acetylene (0.174 mL, 0.971 mmol) in DMF (5 mL) was bubbled with N2 for 10 minutes. Et3N (5 mL) was added and the mixture was stirred under nitrogen at 65° C. for 4 hours. The mixture was cooled and the volatiles were removed in vacuo. The dark brown residue was adsorbed onto silica and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A35 as a brown solid (0.116 g, 48%). LCMS-D: rt 3.84 min; m/z 302 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]([F:13])[F:12])[CH:3]=1.[Li+].[Cl-].[CH2:16]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH2:18]>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH2:18]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]([F:13])[F:12])[CH:3]=1)[CH:17]=[CH2:16]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccc(Br)cc1OC(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc(C#N)c(OC(F)F)c1

Procedure:
To a solution of 4-bromo-2-(difluoromethoxy)benzonitrile (620 mg, 2.5 mmol) in 30 ml of toluene was added LiCl (322 mg, 7.5 mmol), Pd(PPh3)4 (60 mg), Allyl tributyltin (990 mg, 3.0 mmol), and then the mixture was heated to reflux overnight. After the reaction was completed, the reaction solution was diluted with EtOAc and filtered. The filtrate was concentrated and purified with silica gel column chromatograph to give crude 4-allyl-2-(difluoromethoxy)benzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[K+].[I:13]N1C(=O)CCC1=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[I:13][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Brc1cnc2[nH]ccc2c1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Product: Brc1cnc2[nH]cc(I)c2c1
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-1H-pyrrolo[2,3-b]-pyridine (commercial product, 1 g, 5.10 mmol) in 200 ml of CH2Cl2 is added KOH (145 mg, 2.55 mmol) at room temperature. After 30 minutes, N-iodosuccinimide (1.2 g, 5.10 mmol) is added and the solution is stirred for 15 hours, neutralized with saturated Na2S2O3 solution and extracted several times with CH2Cl2. The organic phases are combined, dried on MgSO4 and concentrated under reduced pressure. The expected product is obtained with a quantitative yield and used in the following step without additional purification.
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:33])[CH:21]([NH:22][C:23](=[O:32])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C@H:8]2[S:7]1>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:33])[CH:21]([NH:22][C:23](=[O:32])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3cccc(Cl)c3)[C@H]2S1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccc(Cl)c3)[C@H]2S1
Yield: 73.1 %

Procedure:
Acetic acid (4.1 ml) and zinc powder (3.4 g) were added under stirring and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-(3-chlorophenyl)-acetamido]-3-cephem-4-carboxylate (2.6 g) in anhydrous dimethylformamide (30 ml), and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, zinc powder was filtered off, and the filtrate was poured into a mixture of 5% hydrochloric acid (150 ml) and ethyl acetate (75 ml), and then extracted. The extract was washed with water and dried. After the solvent was distilled off, the residue was crystallized by adding acetonitrile. The crystals were collected by filtration, washed with ether and dried to give colorless crystals of 2-methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid (1.4 g), mp 173° to 174° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[C:17]1([CH2:23][CH2:24]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O.O>[CH2:24]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:5][CH2:6]1)[CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCc1ccccc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1[nH]c2ccccc2n1C1CCN(CCc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 1-piperidin-4-yl-1,3-dihydro-benzimidazol-2-one (0.5 g, 2.3 mmol), 2-phenyl-ethylbromid (0.34 ml, 2.5 mmol), triethylamine (0.35 ml, 2.5 mmol) and sodium iodide (0.01 g, 0.67 mmol) in dry N,N-dimethyl foramide (5 ml) was stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, and then poured into water (20 ml). The product precipitated upon stirring on a ice/water bath and was isolated by filtration. Yield 0.45 g (1.4 mmol, 61%). M.p. 181-185° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[F:32][C:33]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:34]=1[C:35](=[S:38])[NH:36][NH2:37]>C(Cl)Cl>[Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:37][N:36]=[C:35]([C:34]2[CH:39]=[C:40]([F:43])[CH:41]=[CH:42][C:33]=2[F:32])[S:38]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OCCC(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NNC(=S)c1cc(F)ccc1F
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1)(c1ccccc1)c1ccccc1
Reaction time: 48 h

Procedure:
To a solution of 3-(tert-butyldiphenylsilyloxy)-1-phenylpropan-1-one (1.98 g, 5.10 mmol) in 20 mL of a 3:1 mixture of EtOH:DCM was added 2,5-difluorobenzothiohydrazide (0.800 g, 4.25 mmol). The mixture was allowed to stir capped, at room temperature for 60 hours, then uncapped for 48 hours and then concentrated in vacuo. The residue was purified by flash column chromatography (Hexanes) to afford the desired product as an orange oil, 2.19 g, 92% which was contaminated with 3-(tert-butyldiphenylsilyloxy)-1-phenylpropan-1-one. The compound was carried forward to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[C:15]([CH2:17][C:18]([NH2:20])=[O:19])#[N:16].N1CCCCC1>N1C=CC=CC=1>[C:15]([C:17](=[CH:6][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=1)[C:18]([NH2:20])=[O:19])#[N:16]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: N#CCC(N)=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1cc(C=C(C#N)C(N)=O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
100 g of 3,4,5-trimethoxy-benzaldehyde and 44 g of α-cyano-acetamide were dissolved in 300 cc of dry pyridine at 50°. To this solution 10 cc of piperidine were added and the mixture was heated at 50° with stirring for 2 hours. The reaction mixture was cooled at room temperature, filtered off and the precipitate was washed on the filter with 50 cc of cold isopropanol. The product was dried at 80° to yield 123.6 g (92.5%) of α-cyano-3,4,5-trimethoxy-cinnamamide; m.p. 192°-194°. This product was used for the hydrogenation step without further purification. A pure sample, recrystallized from isopropanol, melted at 193°-195°.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH:15]([CH3:17])[CH3:16])[C:7](=[O:18])[CH2:6][C:5]1=[O:19])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:48]=[N+:49]=[N-:50])(=O)=O)(C)C.C(O)(=O)C.C(=O)([O-])O.[Na+].[N-]=[N+]=[N-]>O1CCCC1>[N:48]([CH:6]1[C:5](=[O:19])[N:4]([CH:2]([CH3:1])[CH3:3])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH:15]([CH3:17])[CH3:16])[C:7]1=[O:18])=[N+:49]=[N-:50]
Reactant: CC(C)N1C(=O)CC(=O)N(C(C)C)c2ccccc21
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N1C(=O)C(N=[N+]=[N-])C(=O)N(C(C)C)c2ccccc21
Temperature: 25 °C

Procedure:
To a stirring solution of 1,5-bis-(2-propyl)-1,5-benzodiazepin-2,4-dione (500 mg, 1.92 mmole) in tetrahydrofuran (25 mL), which was cooled to -78° C. in a dry ice/acetone bath, was added dropwise potassium bis(trimethylsilyl) amide (0.5M in toluene, 4.6 mL, 2.3 mmole). After ten minutes, 2,4,6-triisopropylbenzenesulfonyl azide (708 mg, 2.0 mmole) in tetrahydrofuran (5 mL) was added dropwise. After ten minutes, acetic acid (0.44 mL, 7.7 mmole) in tetrahydrofuran (5 mL) was added in one portion and the reaction was warmed to room temperature over three hours. The reaction was poured into a solution of saturated sodium hydrogen carbonate (200 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1:3 ethyl acetate:hexane to give 315 mg of an isomer that is identified as the axial azide, and 120 mg of a lower rf isomer identified as the equatorial conformer. NMR dam for the major isomer is:
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=[O:8])=[O:5].[CH3:10][CH:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C(O)(=O)C>[C:12]1([CH:11]([N:18]=[C:4]([OH:5])/[C:3](/[Cl:9])=[C:2](/[Cl:1])\[C:7]([OH:6])=[O:8])[CH3:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: CC(N)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(N=C(O)/C(Cl)=C(/Cl)C(=O)O)c1ccccc1
Yield: 72.2 %

Procedure:
16.7 g (0.1 mol) of dichloromaleic anhydride and 12.0 g (0.1 mol) of α-methylbenzylamine are heated in 100 ml of glacial acetic acid at the boiling point for 4 hours. 100 ml of water are then added and the oil which has separated out is extracted with methylene chloride. The methylene chloride phase is separated off, washed with water, dried and evaporated. The oil which remains cystallizes. 20.8 g (77.3% of theory) of dichloromaleic acid N-1-phenylethylimide of melting point 62°-65° C. are obtained.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:8]([C:9](=[O:33])[NH:10][CH:11]([CH2:27][C:28]2[N:29]=[CH:30][NH:31][CH:32]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:19]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:15]([NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@@H:8]3[O:7][C@H:6]3[C:4]([OH:5])=[O:3])=[O:33])[CH2:27][C:28]3[N:29]=[CH:30][NH:31][CH:32]=3)[S:16][CH:17]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)[C@@H]1O[C@H]1C(=O)NC(Cc1c[nH]cn1)C(=O)Nc1nc(-c2ccc(F)cc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1nc(-c2ccc(F)cc2)cs1)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1O[C@H]1C(=O)O
Yield: 45.4 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 18d (200 mg, 0.42 mmol); LiOH (12 mg, 0.50 mmol); THF/MeOH/H2O (2.5 mL: 1.5 mL: 1.5 mL); yielded 30b as a white solid (85 mg, 45.2%). 1H NMR (DMSO-d6, 400 MHz): δ 12.52 (bs, 1H); 8.85-8.75 (dd, 2H, J=6.9 Hz; J=43.1 Hz); 7.94-7.91 (t, 2H); 7.80 (s, 1H); 7.62 (s, 1H); 7.28-7.24 (t, 2H); 6.93 (s, 1H): 4.80-4.76 (q, 1H); 3.65-3.64 (d, 1H, J=4.40 Hz); 3.46-3.42 (d, 1H, J=14.0 Hz); 3.09-2.96 (m, 2H). 13C NMR (DMSO-d6, 100 MHz): 169.5, 168.8, 165.9, 162.9, 160.5, 157.6, 147.8, 134.6, 132.1, 130.7, 127.6, 116.4, 115.5 (d, J=21.4 Hz), 108.0, 52.9, 52.7, 52.6, 51.9, 28.6. ESI-HRMS (m/z): [M+H+] calcd. for C19H16FN5O5S: 446.0928, observed: 446.0939; HPLC method 2: Rt=15.8 min, purity=97.2%.