Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[CH:13]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:14]([CH:17]([O:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:15][S:16][C@H:11]12)=[O:8].ClC1C=CC=C(C(OO)=[O:49])C=1>C(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[C:13]([C:23]([O:25][CH:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:24])=[C:14]([CH:17]([O:19][C:20](=[O:22])[CH3:21])[CH3:18])[CH2:15][S:16](=[O:49])[C@H:11]12)=[O:8]
Reactant: CC(=O)OC(C)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC(C)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S(=O)C1
Temperature: 5 °C

Procedure:
To a cooled (5° C.), stirred solution of 0.897 g. of benzhydryl 7-(2-thienylacetamido)-3-(1-acetoxyethyl)-2-cephem-4-carboxylate in 80 ml. of chloroform was added a solution of 0.348 g. of 85 percent m-chloroperbenzoic acid in 3 ml. of chloroform. The reaction mixture was allowed to stir with cooling for 30 minutes after which time it was transferred to a separatory funnel with the aid of additional chloroform and washed successively with sodium bicarbonate solution (2X), and brine (2X) and dried over anhydrous sodium sulfate. The residue obtained by evaporation in vacuo to a froth which was chromatographed on a silica gel column using a toluene-ethyl acetate gradient to give 0.243 g. (26 percent) of what was labeled diastereoisomer I and 0.514 g. (55 percent) of what was labeled diastereoisomer II of the title product; isomer I coming off the column first.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:34])[C@H:21]([CH2:23][C:24](OCC1C=CC=CC=1)=[O:25])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C([Mg]Cl)(C)(C)C.C(Cl)Cl>C(OCC)C>[CH2:12]([O:19][C:20]([C@H:21]1[NH:22][C:24](=[O:25])[CH2:23]1)=[O:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CC(C)(C)[Mg]Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C1C[C@@H](C(=O)OCc2ccccc2)N1
Temperature: 0 °C
Reaction time: 12 h
Yield: 57.2 %

Procedure:
1 was synthesized according to a procedure similar to that reported by Salzmann.20 A modified procedure31 was adopted to achieve higher yields of 1. Commercially available L-aspartic acid dibenzyl ester p-toluenesulfonate salt (25 g 0.052 mol) was charged to a dry schlenk flask. The substrate in the flask was dried under high vacuum for 2 h. Dry CH2Cl2 (450 mL) was transferred to the flask under N2 and then the solution was cooled to 0° C. using an ice bath. Triethyl amine (15.8 mL, 0.1133 mol, 2.2 eq) was added and followed by addition of TMSCI (6.588 mL, 0.052 mol). The solution was slowly warmed to room temperature and stirred for an additional 12 h. The solution was then cooled again to 0° C. and tert-BuMgCl (77 mL of a 2.0 M solution in diethyl ether, 3.0 eq) was slowly added to the mixture. The solution was kept at 0° C. for 2 h and then slowly warmed to room temperature. The reaction was stopped 10 h later by addition of 200 mL wet CH2Cl2. The organic phase was washed with 1 N HCl (2×400 mL), saturated NaHCO3 (2×400 mL) and brine (2×400 mL). The organic phase was dried over MgSO4. After the solvent was removed, a yellow solid was obtained. The solid was purified by crystallization from CH3OH and then sublimation at 110° C. under high vacuum to give 1 as white crystals (6.1 g, 55%). FTIR (THF): 1779 cm−1 (νCO, lactam, s), 1747 cm−1 (νCO, ester, s). 1H NMR (CDCl3, 500 MHz) δ 7.25 (s, 5H, CH2C(O)NHCH(CO2CH2C6H5)), 6.0 (br, 1H, CH2C(O)NHCH(CO2CH2C6H5)), 5.15 (s, 2H, CH2C(O)NHCH(CO2CH2C6H5)), 4.24 (dd, 1H, CH2C(O)NHCH(CO2CH2C6H5)), 3.36 (ddd, 1H, CH2C(O)NHCH(CO2CH2C6H5), 3.15 (ddd, 1H, CH2C(O)NHCH(CO2CH2C6H5)). 13C NMR (CDCl3, 200 MHz) δ 171.0, 166.5, 135.1, 128.9, 128.7, 67.7, 47.5, 43.8. FTIR, 1H NMR and 13C NMR spectra of this compound were identical to literature data for 1.12
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[C:27]([CH2:30][C:31]1[N:32]2[CH:38]=[N:37][CH:36]=[C:33]2[S:34][CH:35]=1)(=[O:29])[NH2:28]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:37]3[CH:36]=[C:33]4[S:34][CH:35]=[C:31]([CH2:30][C:27](=[O:29])[NH2:28])[N+:32]4=[CH:38]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: NC(=O)Cc1csc2cncn12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(CC(N)=O)[n+]4c3)[C@H](C)[C@H]12
Yield: 3.9 %

Procedure:
The same procedure as in Example 1 was repeated except that 95 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 70 mg of 3-carbamoylmethylimidazo[5,1-b]thiazole were used, thereby obtaining 4.1 mg of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[NH2:20].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:27][O:26][C:22]1[CH:21]=[C:19]([NH:20][C:12]([CH:10]2[CH2:9][S:8][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:11]2)=[O:14])[CH:18]=[C:17]([O:16][CH3:15])[C:23]=1[O:24][CH3:25]
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Reactant: COc1cc(N)cc(OC)c1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)C2CSC(c3cccnc3)N2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
A mixture of 630 mg of 2-(3-pyridyl)thiazolidine-4-carboxylic acid, 520 mg of 3,4,5-trimethoxyaniline, 650 mg of dicyclohexylcarbodiimide and 430 mg of 1-hydroxybenzotriazole in 8 ml of N,N-dimethylformamide was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed in sequence with aqueous sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (eluent: ethyl acetate) gave 370 mg of N-(3,4,5-trimethoxyphenyl)-2-(3-pyridyl)thiazolidine-4-carboxamide. This compound was dissolved in 10 ml of ethyl acetate, and 2 ml of 2N hydrogen chloride solution in dioxane was added. The resultant solid was collected by filtration, washed with ethyl acetate and dried to give mg of N-(3,4,5-trimethoxyphenyl)-2-(3-pyridyl)thiazolidine-4-carboxamide dihydrochloride. Melting point 130°-132° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:9]2)C=CC=CC=1.[ClH:24]>[OH-].[Pd+2].[OH-].C(O)C>[ClH:24].[ClH:24].[O:15]1[CH2:16][CH2:17][N:12]([CH:10]2[CH2:11][NH:8][CH2:9]2)[CH2:13][CH2:14]1
Reactant: c1ccc(C(c2ccccc2)N2CC(N3CCOCC3)C2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: C1CN(C2CNC2)CCO1
Reaction time: 72 h

Procedure:
A mixture of 1-diphenylmethyl-3-morpholinoazetidine (see Preparation 55) (18.6 g, 60.4 mmol), palladium hydroxide (2 g), ethanol (200 ml) and 1 N aqueous hydrochloric acid solution (52 ml) was stirred under an atmosphere of hydrogen at 345 kPa (50 p.s.i.) for three days. The catalyst was then removed by filtration and the filtrate evaporated to dryness. Addition of dichloromethane (100 ml) to the residue and trituration yielded a solid which was recrystallised from methanol to give the title compound (10.2 g) as a crystalline solid. LRMS m/z=179(m+1)+. (N.B. The monohydrochloride, used instead of the dihydrochloride in some reactions, can be similarly prepared using one molar equivalent of hydrogen chloride.
Reaction SMILES: C#C.[CH3:3][C:4]([O-])(C)C.[K+].[F:9][C:10]1[CH:28]=[CH:27][C:13]([O:14][CH:15]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:12][CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[F:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH:15]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[C:16]([OH:21])([C:17]([CH3:19])([CH3:20])[CH3:18])[C:3]#[CH:4])=[CH:27][CH:28]=1
Reactant: CC(C)(C)C(=O)C(Oc1ccc(F)cc1)n1cncn1
Reactant: CC(C)(C)[O-]
Agent: C#C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: C#CC(O)(C(Oc1ccc(F)cc1)n1cncn1)C(C)(C)C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
Acetylene was passed into a suspension of 31.4 g (0.28 mol) of potassium tert-butylate in 300 ml of tetrahydrofuran for 30 minutes at 15° C., while stirring. A solution of 55.5 g (0.2 mol) of 1-(4-fluorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)-butan-2-one in 150 ml of tetrahydrofuran was then added dropwise in the course of one hour, while acetylene was further passed through the mixture. After a further two hours, the solution was adjusted to a pH value of 8 by the addition of 175 ml of a 23% strength aqueous ammonium chloride solution. The mixture was extracted with twice 200 ml of ethyl acetate, the extracts were washed with water, and the solution was concentrated under reduced pressure. The remaining solid residue was triturated with petroleum ether. 27.2 g (44.8% of theory) of 3-((4-fluorophenoxy)-(1H-1,2,4-triazol-1-yl)-methyl)-4,4-dimethyl-pent-1-yn-3-ol of melting point 155° to 161° C. were thus obtained. By cooling and triturating, a further 3.2 g (5.3% of theory) of a pure diastereomeric form A of melting point 134° to 135° C. were obtained from the petroleum ether phase.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([NH:20][C:21]([C@@H:23]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)=[O:22])[CH2:16][CH2:15]1)([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.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([NH:20][C:21]([C@@H:23]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH2:25][NH:24]2)=[O:22])[CH2:16][CH2:15]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)[C@H]1C(=O)NN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NN1CCN(C(c2ccccc2)c2ccccc2)CC1)[C@H]1NCCC1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(tert-Butoxycarbonyl)-3-phenyl-[(2S)-2-pyrrolidinecarboxylic acid] (4-benzhydrylpiperazine-1-yl) amide (15) (2.70 g; 5.14 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 2 hours at ambient temperature. The reaction mixture is cooled in an ice-bath and the pH adjusted to 9 with saturated potassium carbonate solution. The mixture is poured onto water (30 mL) and extracted with methylene chloride (1×60 mL, 2×20 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product. CIMS: MH+ 426
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:3]=1[NH2:4].I[C:19]1[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[Cl:1][C:2]1[CH:8]=[C:7]([C:19]2[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=2)[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: CC1(C)OB(c2ccc(N)c(Cl)c2)OC1(C)C
Reactant: Cn1ccc(I)n1
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: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1ccc(-c2ccc(N)c(Cl)c2)n1
Temperature: 135 °C
Yield: 73.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.046 g, 0.039 mmol) was added to a solution of 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.1 g, 0.394 mmol), 3-iodo-1-methyl-1H-pyrazole (0.123 g, 0.592 mmol) and sodium carbonate (0.125 g, 1.183 mmol) in DME/H2O 3/1 (2.00 mL). The reaction mixture was heated for 1 hour at 135° C. under microwave irradiation before being diluted with EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude mixture was purified via Biotage silica gel column chromatography eluting with (Cyclohexane/EtOAc 80/20 to 60/40) to afford the title product as a yellow solid (60 mg, 73%). 1H NMR (500 MHz, CDCl3): δ 3.93 (s, 3H), 4.09 (br s, 2H), 6.42 (d, J=2.3 Hz, 1H), 6.79 (d, J=8.3 Hz, 1H), 7.34 (d, J=2.3 Hz, 1H), 7.50 (dd, J=8.3, 2.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H). LC (Method B)-MS (ESI, m/z) tR 2.35 min, 208 [(M+H+), 100%].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:11]=O)[S:10][C:3]=12.[NH2:13][OH:14].Cl>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:11]=[N:13][OH:14])[S:10][C:3]=12
Reactant: NO
Reactant: O=Cc1cc2nccc(Cl)c2s1
Agent: Cl
Solvent: O
Solvent: CO
Product: ON=Cc1cc2nccc(Cl)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of aldehyde 14 (scheme 3) in MeOH was added NH2OH×HCl (227 mg, 3.26 mmol) in water (0.5 mL) and the mixture was stirred at room temperature for 0.5 h. The solvents were removed by under reduced pressure and the residue was partitioned between EtOAc and water. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to afford the title compound 125 (458 mg, 85% yield) as a white solid. MS (m/z) 213.1/215.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:30][C:31]1[CH:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=1.CO>O1CCOCC1>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:35]4[N:34]=[CH:33][N:32]=[C:31]([NH2:30])[CH:36]=4)=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Reactant: Nc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4cccc(C(F)(F)F)c4)[nH]3)cc2)ncn1
Yield: 59.8 %

Procedure:
4-(5-{[3-(trifluoromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (101.7 mg, 0.31 mmol) was added, followed by 4-amino-6-chloro-pyrimidine (48.5 mg, 0.37 mmol). The vial was capped and microwaved at 200° C. for 5 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension. The resulting reddish-brown solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water system with 0.01% of TFA. The fractions, containing the product, were collected and partitioned between EtOAc and saturated aqueous NaHCO3. Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a white solid (76.6 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH2:27][C:28]([OH:30])=[O:29])/[C:8]([NH:10][C@H:11]2[C@@H:14]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[N:13]([S:20]([OH:23])(=[O:22])=[O:21])[C:12]2=[O:24])=[O:9])[N:6]=1.C(N(CC)CC)C.C(C(CCCC)C([O-])=O)C.[Na+:48]>CO.C(OCC)(=O)C.CC(C)=O>[Na+:48].[Na+:48].[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH2:27][C:28]([OH:30])=[O:29])/[C:8]([NH:10][C@H:11]2[C@@H:14]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[N:13]([S:20]([O-:23])(=[O:21])=[O:22])[C:12]2=[O:24])=[O:9])[N:6]=1.[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH2:27][C:28]([OH:30])=[O:29])/[C:8]([NH:10][C@H:11]2[C@@H:14]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[N:13]([S:20]([O-:23])(=[O:21])=[O:22])[C:12]2=[O:24])=[O:9])[N:6]=1
Reactant: NC(=O)OC[C@@H]1[C@H](NC(=O)/C(=N\OCC(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: NC(=O)OC[C@@H]1[C@H](NC(=O)/C(=N\OCC(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]
Reaction time: 0.17 h
Yield: 90.5 %

Procedure:
110 g (0.235 mol) of crude (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid (obtained according to Example 41) are dispersed in 4.7 l of methanol and treated with 72.3 ml (0.518 mol) of triethylamine and 282.9 ml (0.566 mol) of a 2N solution of sodium 2-ethylcaproate in ethyl acetate. The solution obtained is stirred for 10 minutes, diluted with 9 l of acetone and concentrated to 3 l. The residual suspension is diluted with 3 l of acetone, filtered and the crystalline salt is washed with ether and dried. 108.59 g (90.5%) of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid disodium salt are obtained. This crude salt is dissolved in 420 ml of water. 1050 ml of ethanol are added thereto and subsequently (after a few minutes) a further 210 ml of ethanol are added. The solution is turbid and is stirred for 1 hour. 1770 ml of ethanol are now added dropwise thereto within 2 hours. After stirring for a further 1 hour and cooling to 0° C., the precipitate is filtered off and washed with ethanol. The crystals obtained are dispersed in 170 ml of ethanol and 680 ml of ether, filtered off and washed with ether. After drying under greatly reduced pressure at 40° C., there obtained 102.9 g (85.5%) of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid disodium salt.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]1)=[O:26])=[CH:19]2
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2cc3cc(F)ccc3[nH]2)CC1
Reaction time: 24 h

Procedure:
tert-Butyl 1,4-diazepane-1-carboxylate (2.0 g, 10 mmol, Aldrich), 5-fluoro-1H-indole-2-carboxylic acid (1.79 g, 10 mmol, Aldrich), and EDCI (1.92 g, 10 mmol) were combined in CH2Cl2 (30 mL) at room temperature and stirred for 24 hours. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (5% MeOH/CH2Cl2) to provide the title compound. 1H NMR (CD3OD, 300 MHz) δ 1.46 (s, 9H), 1.86-2.14 (m, 2H), 3.40-3.58 (m, 2H), 3.62-3.72 (m, 2H), 3.75-4.05 (m, 4H), 6.78 (s, 1H), 6.99-7.09 (m, 1H), 7.28-7.35 (m, 2H); MS (DCI/NH3) m/z 362 (M+H)+.
Reaction SMILES: O[N:2]=[C:3]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[NH:12][CH:11]=1)[C:4]([O:6]CC)=[O:5].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[Cl:19][C:17]1[CH:16]=[C:15]([Cl:20])[CH:14]=[C:13]2[C:18]=1[C:10]([CH2:9][C@@H:3]([C:4]([OH:6])=[O:5])[NH2:2])=[CH:11][NH:12]2
Reactant: CCOC(=O)C(Cc1c[nH]c2cc(Cl)cc(Cl)c12)=NO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N[C@@H](Cc1c[nH]c2cc(Cl)cc(Cl)c12)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 102.3 %

Procedure:
Dissolve ethyl 2-(hydroxyimino)-3-(4,6-dichloro-3-indolyl)propanoate (1.10g, 3.65mmol ) in acetic acid (200mL) and add activated zinc dust (1.25g, 19.2mmol). Stir at room temperature for 72 hours. Evaporate the acetic acid in vacuo to give a white oil. Take the white oil up in ethyl acetate (200mL) and treat with saturated sodium hydrogen carbonate (500mL). Filter t he resulting white precipitate and separate the organic phase. Wash with saturated sodium hydrogen carbonate (100mL) a nd brine (100mL). Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound as an amber oil (1.02g, 98%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.C(O)C>[Pd].C(N(CC)CC)C>[C:5]1([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[NH:11][CH:12]=2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(-c2ccccc2)c[nH]1
Reaction time: 3 h
Yield: 78.9 %

Procedure:
4-(4-Chlorophenyl)pyrrole-2-carboxylic acid (0.6 g.) was hydrogenated over 200 mg. of 5% Pd/C in 50 ml. of ethanol for approximately 16 hours at 50 p.s.i. An additional 200 ml. of catalyst and 1 ml. of triethylamine was added and hydrogenation continued for 3 hours at 50 p.s.i. The catalyst was recovered by filtration, and the mother liquor concentrated to dryness to yield 4-phenylpyrrole-2-carboxylic acid [400 mg., m.p. 226°-228° C. (dec.), m/e 187]. For analysis, the product was recrystallized from acetone/hexane [240 mg., m.p. 227°-229° C. (dec.)].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[CH:24]=[C:23]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCOC(C)=O.CCCCCCC>O1CCCC1>[CH2:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[CH:24]=[C:23]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3ccc(-c4ccccc4)cc3c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCc3[nH]c4ccc(-c5ccccc5)cc4c3CC2)cc1
Yield: 69.7 %

Procedure:
A solution of lithium aluminum hydride (0.17 g, 4.45 mmol) in tetrahydrofuran (3.0 mL) and a solution of 3-benzoyl-9-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.17 g, 0.46 mmol) in tetrahydrofuran (5.0 mL) at 0° C. were reacted in a manner similar to Example 1 to give an oil. Column chromatography (silica gel, 10-50% EtOAc/heptane) afforded 0.113 g (71%) of the title compound as an oil. 1H NMR (300 MHz, CDCl3) δ 8.05, 7.66-7.57, 7.49, 7.45-7.30, 7.13-7.04, 3.98, 3.18-2.97; MS (EI) m/z 366 (M+); HRMS (FAB) calcd for C25H24N2+H: 353.2018, found: 353.2021.