Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]I)=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1.[CH3:29][O-:30].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][O:30][CH3:29])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CC(=O)Nc1cccc(-n2nc(CI)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1nn(-c2cccc(NC(C)=O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
According to Scheme 7 Step 7: To a cooled solution of 14(A) (220 mg, 0.43 mmol) in DMF (2 mL) under nitrogen atmosphere was added dropwise at 0° C. sodium methoxide 2M (in methanol, 215 μL, 0.43 mmol). The mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with water (100 mL) and the aqueous layer was extracted twice with DCM (100 mL). The organic layers were combined and successively dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 25 g C18) using water/CH3CN 6/4 as eluant to afford N-(3-(4-(4-chlorobenzyl)-6-(methoxymethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 14(B) (16 mg, 9%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>C(N(CC)CC)C.CN(C)C=O.O.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>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (6.96 g, crude from Preparation A1) in triethylamine (30 ml) and dimethylformamide (6 ml) at room temperature was added trimethylsilylacetylene (3 ml), cuprous iodide (150 mg) and bis(triphenylphosphine)palladium(II) chloride (300 mg). The mixture was heated at 50-60° C. for one hour, trimethylsilylacetylene (0.3 ml) was then added and stirring and heating continued for a further period of 30 minutes. The cooled reaction mixture was diluted with water (250 ml) extracted with ether (250 ml). The organic layer was separated (aided by the addition of brine). The aqueous layer was re-extracted with ether (250 ml). The combined ether extracts were dried (MgSO4) and evaporated to give the crude product as a gum (4.67 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[CH3:13][O:14][C:15](=[O:55])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=3)[N:27]([CH:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:26]=2[CH2:48][CH2:49][OH:50])=[CH:18][C:17]=1[O:51][CH:52]([CH3:54])[CH3:53]>ClCCl>[CH3:13][O:14][C:15](=[O:55])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=3)[N:27]([CH:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:26]=2[CH2:48][CH2:49][O:50][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:18][C:17]=1[O:51][CH:52]([CH3:53])[CH3:54]
Reactant: COC(=O)c1ccc(OCCc2c(CCO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCc2c(CCOS(C)(=O)=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Methane sulfonyl chloride (0.03 mL, 0.39 mmol) and Et3N (0.06 mL, 0.43 mmol) were added to a solution of the alcohol from Step 4 (0.10 g, 0.17 mmol) in dichloromethane (8 mL) at 0° C. Reaction was stirred at 0° C. for one hour and then warmed to room temperature and stirred an additional hour. Reaction solution was concentrated by rotary evaporation. Obtained 0.115 g of 4-{2-[1-Benzhydryl-5-chloro-2-(2-methanesulfonyloxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-isopropoxy-benzoic acid methyl ester in quantitative yield.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][S:10][C@@H:11]2[CH2:15][N:14]([CH3:16])[C@H:13]([C:17]([O:19]C)=[O:18])[CH2:12]2)=[CH:7][CH:6]=1.Cl>CO>[C:17]([C@@H:13]1[CH2:12][C@H:11]([S:10][CH2:9][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:22][CH:21]=2)[CH2:15][N:14]1[CH3:16])([OH:19])=[O:18]
Reactant: COC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.92 ml of a 1N aqueous solution of sodium hydroxide was added to a solution of 378 mg of (2S, 4S)-4-(4-methoxybenzylthio)-2-methoxycarbonyl-1-methylpyrrolidine [prepared as described in step (10) above] dissolved in 3.84 ml of methanol, and the mixture was stirred at room temperature for 3 hours. At the end of this time, the mixture was neutralized by the addition of 1.92 ml of 1N aqueous hydrochloric acid. The solvent was then removed by distillation under reduced pressure, and the residue was dried, to give crude (2S, 4S)-2-carboxy-4-(4-methoxybenzylthio)-1-methylpyrrolidine.
Reaction SMILES: C1([Mg]Cl)C=CC=CC=1.[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1I)([O-:11])=[O:10].[C:19]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[Cl-].[NH4+]>C1COCC1.CCCCCC.CCOC(C)=O>[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:19]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: O=C1CCCCC1
Agent: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1C1(O)CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
40.16 mL (80.32 mmol) of phenylmagnesium chloride (2 M in THF) is added dropwise at −50° C. to a solution of 20.0 g (80.32 mmol) of 2-nitroiodobenzene in absolute THF (150 mL) under a nitrogen atmosphere. After stirring for 15 minutes, 9.98 mL (96.30 mmol) of cyclohexanone is added quickly. The mixture is heated to RT and stirred for a further 2 hours. Saturated aqueous ammonium chloride solution is added and the aqueous phase is exhaustively extracted with EtOAc. The combined organic extracts are washed with saturated aqueous NaCl solution, dried with sodium sulfate, and evaporated down in vacuo. After column chromatography (silica gel, hexane/EtOAc 20:1), the product is obtained as a brownish oil. Yield: 5.20 g (29%); Rf=0.26 (silica gel, hexane/EtOAc 10:1); ESI-MS: [M+H—H2O]+=204.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](O)=[O:35])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][C:34]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:35])=[CH:30][CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Product: O=C(CCc1ccc(OCc2ccccc2)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and 3-(4-benzyloxy-phenyl)-propionic acid were processed to provide the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 1.83 (m, 2 H), 2.00 (m, 2 H), 2.66 (t, J=7.64 Hz, 2 H), 2.88 (t, J=7.49 Hz, 2 H), 3.05 (dd, J=10.45, 7.33 Hz, 2 H), 3.53 (m, 2 H), 3.69 (m, 2 H), 4.67 (t, J=6.24 Hz, 2 H), 5.06 (s, 2 H), 6.93 (m, 2 H), 7.07 (m, 1 H), 7.18 (m, 2 H), 7.32 (m, 1 H), 7.40 (m, 4 H), 7.70 (m, 1 H), 8.08 (m, 1 H), 8.28 (s, 1 H), 10.13 (s, 1 H); MS (DCI/NH3) m/z 469 (M+H)+;
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[CH2:5][C:4](=[O:17])[C:3]=1[C:18](=O)[CH2:19][CH2:20][CH3:21].Cl.[CH2:24]([O:26][NH2:27])[CH3:25].C([O-])(=O)C.[Na+].Cl>C(O)C>[CH2:24]([O:26][N:27]=[C:18]([C:3]1[C:4](=[O:17])[CH2:5][CH:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[CH2:7][C:2]=1[OH:1])[CH2:19][CH2:20][CH3:21])[CH3:25]
Reactant: CCCC(=O)C1=C(O)CC(c2cc3ccccc3o2)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCC(=NOCC)C1=C(O)CC(c2cc3ccccc3o2)CC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-hydroxy-5-(benzo[b]furan-2-yl)-2-butyryl cyclohex-2-en-1-one (1.0 g), ethoxyamine hydrochloride (0.36 g), sodium acetate (0.3 g) and ethanol (100 ml) were stirred at room temperature for 12 hr. The mixture was poured into a very dilute aqueous hydrochloric acid solution which was then extracted with ether. Evaporation of the dried (MgSO4) organic fraction and purification of the residue by column chromatography over silica with dichloromethane elution gave 2-[1-(ethoxyimino)butyl]-3-hydroxy-5-(benzo[b]furan-2-yl)cyclohex-2-en-1-one as a yellow solid, mp 70° C.
Reaction SMILES: Br[CH2:2][C:3]#[CH:4].[CH2:5]1N2CN3CN(C2)C[N:6]1[CH2:13]3.C(=O)([O-])[O-].[K+].[K+].[C:21]1(C)[CH:26]=CC=[CH:23][CH:22]=1>C(#N)C>[CH2:2]([N:6]1[CH2:13][CH2:23][CH2:22][CH2:21][CH2:26][CH2:5]1)[C:3]#[CH:4]
Reactant: Cc1ccccc1
Reactant: C#CCBr
Reactant: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCN1CCCCCC1
Temperature: 80 °C

Procedure:
18.8 ml of a 3-bromopropyne solution at 80% in toluene are added dropwise to 20.8 ml of hexamethyleneamine and 27.9 g of potassium carbonate in 300 ml of acetonitrile. The reaction mixture is heated at 50° C. for 12 hours and 6 hours at 80° C. The reaction mixture is filtered, and the solvents are evaporated off under reduced pressure. Compound 4.1 is purified by distillation; b.p.=61° C. under a pressure of 26.7 Pa.
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[CH2:3][C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:5].C(NC1C=CC(S([N:40]=[N+:41]=[N-])(=O)=O)=CC=1)(=O)C.C(#N)C>C(N(CC)CC)C>[N+:40](=[C:3]([C:2](=[O:1])[C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:5])=[N-:41]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COc1cccc(OC(=O)CC(=O)c2cc(OC)c(OC)c(OC)c2)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cccc(OC(=O)C(=[N+]=[N-])C(=O)c2cc(OC)c(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
The procedure of Baumm et al, Synthetic Communication 1987, 17(14), 1709-1716, was used. To a stirred solution of 0.0561 g (0.156 mmol) of the product of Step 2 and 0.041 g (0.171 mmol) of 4-acetamidobenzenesulfonyl azide in 2 ml of anhydrous acetonitrile 0.065 ml (0.47 mmol) of triethylamine was added at 0° C. After stirring for 3 hours at room temperature the solvent was evaporated to dryness under reduced pressure and the residue was purified by flash column chromatography (silica gel, methylene chloride) to give 0.059 g (98% yield) of 3-methoxyphenyl 2-diazo-3-oxo-3-(3,4,5-trimethoxyphenyl)propanoate. This was dissolved in 2 ml of anhydrous methylene chloride and 3.5 mg (7.9 μmol) of rhodium (III) acetate was added at room temperature under nitrogen atmosphere. The resulting mixture turned deep green after 1 h of stirring at room temperature. After filtration through Celite and washing with fresh methylene chloride, the filtrate was evaporated to dryness under reduced pressure to give the title compound as an deep yellow crystals (0.049 g, 91%); 1H NMR (CDCl3) δ 3.8 (s, 3H, OMe); 3.9 (s, 6H, OMe); 3.94 (s, 3H, OMe); 6.58 (dd, 1H, CH aromatic, J=2.4 Hz; 8.6 Hz); 6.76 (d, 1H CH aromatic; J=2.4 Hz); 7.04 (s, 2H, CH aromatic); 7.25 (d, 1H, CH aromatic, J=8.6 Hz).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16](Cl)(=[O:18])[CH3:17].Cl>C(Cl)Cl>[CH3:5][O:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1
Reactant: CC(=O)Cl
Reactant: COCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COCCCc1ccc(C(C)=O)cc1

Procedure:
Next, 195 g of AlCl3 and 100 g of 3-methoxypropylbenzene were poured into 1.5 liters of CH2Cl2, and the resulting mixture was cooled with ice under stirring. Thereto was gradually added dropwise 79 g of acetyl chloride (CH3COCl), and the thus obtained mixture was stirred under ice-cooling continuously for 6 hours. After the termination of the evolution of hydrogen chloride (HCl) gas was ascertained, the reaction solution was poured into 1 liter of dilute hydrochloric acid, and the CH2Cl2 layer was separated, after which the CH2Cl2 was distilled off, and the residue was distilled under reduced pressure to obtain p-(3-methoxypropyl)acetophenone. The boiling point of this compound was 94°-95° C./0.3 mmHg.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[CH3:30])[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:20][C:18]1[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH3:31])[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[CH3:30])[CH:19]=1
Reactant: Cc1cc(Cl)ccc1C1c2c(cc(Br)n2C(C)C)C(=O)N1c1cc(Cl)c(=O)n(C)c1
Reactant: COc1ccccc1B(O)O
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1C)N(c1cc(Cl)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate N) and 2-methoxyphenylboronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a light yellow solid. tR: 7.25 min (HPLC 2); ESI-MS: tR=1.21 min, [M+H]+ 536/538 (LC-MS 1); TLC: Rf=0.20 (EtOAc).
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:14][CH2:15][C@H:16]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=2)([CH3:13])[CH3:12])[CH:5]=1.[OH-].[Na+].O>O1CCOCC1>[Si:27]([O:26][C@H:16]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=1)[CH2:15][NH:14][C:11]([CH3:13])([CH3:12])[CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:34])=[O:2])([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:29])[CH3:28]
Reactant: COC(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(CO)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Yield: 87.7 %

Procedure:
3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid methyl ester (Preparation 36) (1.50 g, 3.08 mmol), aqueous sodium hydroxide solution (5M, 3.07 ml, 15.0 mmol), water (2 ml) and dioxane (20 ml) were stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue dissolved in water (30 ml) and acidified with aqueous hydrochloric acid (1N, 15.38 ml). The resulting white precipitate was filtered off and dried in vacuo for 72 hours to furnish the title compound as a white solid (1.28 g). 1H NMR (400 MHz, CD3OD) δ=7.88 (1H, d), 7.81 (1H, bs), 7.38-7.28 (3H, m), 7.10 (1H, dd), 6.77 (1H, d), 4.92 (1H, m, partially under solvent peak), 4.61 (2H, dd), 3.23-3.12 (2H, m), 2.95 (2H, dd), 1.08 (6H, s), 0.81 (9H, s), −0.04 (3H, s), −0.15 (3H, s). LRMS (electrospray) m/z 474 [M+H]+
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([CH2:11][C:12]([O:14]CC)=[O:13])#[N:10].N1CCCCC1.C(O)(=O)C>CCCCC>[C:9]([C:11](=[CH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:12]([OH:14])=[O:13])#[N:10]
Reactant: O=CC1CCCCC1
Reactant: CCOC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CCCCC
Product: N#CC(=CC1CCCCC1)C(=O)O

Procedure:
A mixture of 56 g of cyclohexanecarboxaldehyde, 56.5 g of ethyl cyanoacetate, 1 g of piperidine and 100 ml of acetic acid was heated on a steam bath for 30 minutes. The acetic acid was stripped under reduced pressure. The residue was dissolved in 500 ml of pentane. The solution was extracted, successively, with water, sodium bicarbonate solution, and water. The pentane was evaporated under reduced pressure and the residue was distilled to give the ethyl ester of 2-cyano-3-cyclohexyl-2-propenoic acid (4A), bp: 120°-121° C. at 0.01 Torr.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH2:13]O.S(Cl)([Cl:17])=O>C(Cl)Cl>[Cl:17][CH2:13][C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)c(F)cc1[N+](=O)[O-]
Solvent: ClCCl
Product: COc1cc(CCl)c(F)cc1[N+](=O)[O-]

Procedure:
A solution of (2-fluoro-5-methoxy-4-nitrophenyl)methanol (Compound 130D, 1.45 g, 7.21 mmol) in anhydrous DCM (17.0 mL) was charged with Thionyl chloride (1.055 mL, 14.5 mmol). and stirred while refluxing for 16 h. The reaction mixture was concentrated under reduced pressure to yield a brown solid. This material was used without any further purification. 1H NMR (CDCl3, 400 MHz): δ=3.99 (s, 3H), 4.65 (d, J=1.01 Hz, 2H), 7.19 (d, J=5.81 Hz, 1H), 7.65 (d, J=8.84 Hz, 1H).
Reaction SMILES: Br[C:2]([CH:5]1[CH2:10][CH2:9][CH:8]([CH3:11])[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[OH:12]/[N:13]=[C:14](/[C:20](=[O:22])[CH3:21])\[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(Cl)Cl>O1CCOCC1.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:2]([CH3:4])([O:12]/[N:13]=[C:14](/[C:20](=[O:22])[CH3:21])\[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:3])[CH2:6][CH2:7]1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Reactant: CC1CCC(C(C)(C)Br)CC1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)/C(=N\OC(C)(C)[C@H]1CC[C@H](C)CC1)C(C)=O

Procedure:
2-Bromo-2-(4-methylcyclohex-1-yl)propane (1.99 g, 9.06 mmol), ethyl (Z)-2-hydroxyimino-3-oxobutyrate (1.44 g, 9.06 mmol) and silver trifluoromethanesulphonate (2.33 g) were reacted together in dry dioxane (8 ml) using a similar method to Example 9a. The title compound was obtained as an oil (1.31 g, 51%), νmax (CH2Cl2) 2920, 2860, 1740, 1685, 1370, 1320, 1235, 1070, and 1000 cm-1. δ13C (100 MHz, CDCl3) 14.14 (CH3), 22.55 (CH3), 23.24 (2×CH3), 25.11 (CH3), 26.8 (2×CH2), 32.76 (CH), 35.36 (2×CH2), 46.25 (CH), 61.7 (CH2) 87.6, 149.7, 161.6 (C=O), 193.1 (C=O); δH (400 MHz, CDCl3), 0.86 (3H, d, J 6.5 Hz), 0.8-0.95 (2H, m), 0.95-1.15 (2H, m), 1.29 (6H, s), 1.32 (3H, t, J 7.1 Hz), 1.2-1.35 (1H, m), 1.45-1.65 (2H, m), 1.65-1.80 (3H, m), 2.40 (3H, s), and 4.34 (2H, q, J 7.1 Hz).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:34]1[N:35]=[C:36]([NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])[S:37][CH:38]=1)[C:5]([NH:7][CH:8]1[C:32](=[O:33])[N:10]2[C:11]([C:19]([O:21]CC3C=CC([N+]([O-])=O)=CC=3)=[O:20])=[C:12]([CH2:15][S:16][CH:17]=[CH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].[H][H].C(O)C.P([O-])([O-])([O-])=O>[Pd].O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:34]1[N:35]=[C:36]([NH:39][C:40](=[O:45])[C:41]([F:43])([F:42])[F:44])[S:37][CH:38]=1)[C:5]([NH:7][CH:8]1[C:32](=[O:33])[N:10]2[C:11]([C:19]([OH:21])=[O:20])=[C:12]([CH2:15][S:16][CH:17]=[CH2:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C=CSCC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCO
Product: C=CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Yield: 37.3 %

Procedure:
p-Nitrobenzyl 7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-vinylthiomethyl-3-cephem-4-carboxylate (syn isomer) (100 mg) was hydrogenated in the presence of 5% palladium on carbon under an atmospheric pressure of hydrogen in a mixture of tetrahydrofuran (6 ml), ethanol (0.6 ml) and 0.025M phosphate buffer solution (pH 6.85, 6.4 ml) at ambient temperature for 1.5 hours. The catalyst was filtered off and washed with ethyl acetate and a saturated aqueous solution of sodium bicarbonate successively. The filtrate and washings were combined and adjusted to pH 8 with diluted hydrochloric acid. The aqueous layer was separated, adjusted to pH 6 with diluted hydrochloric acid, washed with ethyl acetate, adjusted to pH 2.4 with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated in vacuo and triturated with diethyl ether to give 7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-vinylthiomethyl-3-cephem-4-carboxylic acid (syn isomer) (30.0 mg).
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10]>C(Cl)(Cl)Cl>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([N:1]2[CH2:3][CH2:2]2)(=[O:20])=[O:19])=[CH:16][CH:17]=1)([O-:11])=[O:10]
Reactant: C1CN1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC2)cc1
Reaction time: 0.17 h

Procedure:
To a 25 mL round-bottom flask was added aziridine (10 mg, 234 μmol), sodium bicarbonate (20 mg, 234 μmol), 4-nitrobenzene-1-sulfonyl chloride (45 mg, 234 μmol) and 2 mL chloroform. After 10 minutes, LC-MS showed the desired product was formed. The reaction mixture was concentrated under reduced pressure to give the crude product of the title compound, that was used directly for the next step. MS m/z: 229 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:12]=[N:11][CH:10]=1.[OH-].[Na+]>ClCCl>[Cl:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[CH:12]=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cncc(N2CCNCC2)n1
Reaction time: 1 h

Procedure:
A solution of trifluoroacetic acid (TFA; 6 mL) in dichloromethane (24 mL) was added to a stirred solution of the product of step 1 above (5.79 g, 19.4 mmol) in dichloromethane (20 mL) at 0° C. After 1 h and 1.5 h of stirring, additional portions (10 mL and 5 mL) of TFA were added. Crushed ice and 5 M aqueous NaOH were added and the mixture was extracted with dichloromethnae (12×200 mL). The combined organic layers were dried (K2CO3), filtered and concentrated in vacuo. This furnished 3.48 g (90%) of the title compound as a light yellow solid.