Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][O:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][O:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)OCc3ccccc34)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)OCc3ccccc34)cnc12
Yield: 33.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(3H-spiro[isobenzofuran-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.130 g, 0.269 mmol) obtained in step 2 and methanesulfonamide (0.127 g, 1.34 mmol), the title compound (0.050 g, 33%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[C:16]([CH3:22])=[CH:15][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10].[C:23](O)(=[O:25])[CH3:24]>[Fe]>[C:23]([NH:19][C:17]1[C:16]([CH3:22])=[CH:15][C:3]([O:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([CH3:1])[CH:18]=1)(=[O:25])[CH3:24]
Reactant: COC(=O)C(C)(C)CCCOc1cc(C)c([N+](=O)[O-])cc1C
Reactant: CC(=O)O
Agent: [Fe]
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(NC(C)=O)cc1C
Temperature: 0 °C

Procedure:
A mixture of 3.1 g (10 mmol) of the 5-(2,5-dimethyl-4-nitrophenoxy)-2,2-dimethylpentanoic acid, methyl ester (Example 1) and 2.0 g (3.5×10 mg-atom) of iron powder (40 mesh) in 35 mL of glacial acetic acid is stirred at reflux for 1.5 hours and poured into an ice-water mixture (300 mL). After scratching the oil crystallizes and the solid is collected on a filter, washed with water, and dried in vacuo at 40° C. The filtrate is extracted with dichloromethane. The extracts are washed with water, dried (magnesium sulfate), filtered, and evaporated leaving a medium brown oil which partially crystallizes. Recrystallization from 75 mL of isopropyl ether in the presence of charcoal affords 1.0 g of the title compound; mp 99°-100° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:53]=[CH:52][C:49]([C:50]#[N:51])=[CH:48][CH:47]=2)[CH2:42][CH2:41]1>CN(C)C=O.CCN(C(C)C)C(C)C>[CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[CH:8][C:4]=1[C:5]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:53]=[CH:52][C:49]([C:50]#[N:51])=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=[O:7])[CH3:2]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: CCc1cc(C)c(C=O)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C)c(C=O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a round-bottom flask was added a solution of 2-ethyl-5-formyl-4-methylbenzoic acid (compound 211.4, 450 mg, 2.34 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL). DIEA (907 mg, 7.02 mmol, 3.00 equiv) and HBTU (1.30 g, 3.43 mmol, 1.50 equiv) were added to the reaction mixture. The resulting solution was stirred for 30 min at 25° C. A solution of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 624 mg, 2.80 mmol, 1.20 equiv) in DIEA (2 mL) was added dropwise. The resulting solution was stirred for 30 min at 25° C., then quenched with 20 mL of water. The aqueous phase was extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with 1×50 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (5:1) as eluent to furnish 720 mg (85%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1>C1(C)C=CC=CC=1.CCOCC>[Br:1][C:2]1[C:3]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(OC)ncc1Br
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)CCc1cc(OC)ncc1Br
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To solution of ethyl (2E)-3-(5-bromo-2-methoxypyridin-4-yl)acrylate (1 eq.) from step 2 in Toluene (0.23M) at 110° C. was added benzenesulfonyl hydrazide (3 eq.). The reaction mixture was stirred at 110° C. for 3 h, cooled to room temperature and diluted with Et2O. The organic phase was washed with saturated NaOH (1N), brine, dried over MgSO4, filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 50% in 30 min) afforded the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CC1(C)[O:25][C:24](=O)[C:21]2([CH2:23][CH2:22]2)[C:20](=[O:27])[O:19]1>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][CH:21]([C:20]([OH:27])=[O:19])[C:24]3=[O:25])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1ccc(OCc2ccc(F)cc2)cc1
Product: O=C(O)C1CCN(c2ccc(OCc3ccc(F)cc3)cc2)C1=O

Procedure:
The title compound is prepared in analogy to Example 3c) from 4-(4-fluoro-benzyloxy)-phenylamine and 6,6-dimethyl-5,7-dioxa-spiro[2,5]octane-4,8-dione. Yield: 56% of a colorless solid. MS: m/e=284.1 (M−CO2).
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].[CH3:6][C:7](=[CH:9][CH2:10][CH2:11][CH:12]([CH2:14][CH:15]=[O:16])[CH3:13])[CH3:8]>ClCCl>[CH3:13][CH:12]([CH2:11][CH2:10][CH:9]=[C:7]([CH3:8])[CH3:6])[CH2:14][CH:15]([OH:16])[CH:4]([N+:1]([O-:3])=[O:2])[CH3:5]
Reactant: CC(C)=CCCC(C)CC=O
Reactant: CC[N+](=O)[O-]
Solvent: ClCCl
Product: CC(C)=CCCC(C)CC(O)C(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Nitroethane (7.5 g) was added to a stirred solution of 13.82 g of citronellal in dichloromethane. Approximately 12-14 g of Amberlyst A-21 ion exchange resin was added, and the mixture was stirred at room temperature overnight. After filtration, the resin was rinsed 4 times with 75 mL of dichloromethane. The filtrate was dried over anhydrous MgSO4 and the solvent was removed by rotary evaporation, affording 20.1 g (95%) of a mixture of stereoisomers of the desired nitro alcohol 6. 1H NMR δ (ppm) 5.2 (t, C═CH), 4.4 (m, CH3CHNO2), 2.5 (broad s, CHOH), 2.0 (br m, ═CHCH2), 1.60 and 1.65 (both s, CH3C(CH3)═), 1.5 (d, CH3CHNO2), 1.2-1.5 (m, CH2CH(CH3)CH2), 0.95 (d, CH2CH(CH3)CH2).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[N:19]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[CH2:18]3)=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9])#[N:2].Cl.[H][H]>C(O)(C)C.C(O)(=O)C.[Pt]=O>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[N:19]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[CH2:18]3)=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1C#N
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CC(C)O
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1CN

Procedure:
A mixture of 1-(3-cyano-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea (0.54 g, 1.0 mmol), platinum oxide (0.1 g), and 5-6M HCl in isopropanol (2 mL) in acetic acid (15 mL) is hydrogenated under 50 psi hydrogen for 48 hrs. The mixture is filtered through Celite, the filtrate is evaporated under vacuum, and the residue is purified by preparative HPLC to provide the product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:3]=12.[NH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([NH:22][CH3:23])=[O:21]>>[CH3:23][NH:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=1[NH:17][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:3]=12
Reactant: Clc1ccnc2cc(-c3ccccc3)oc12
Reactant: CNC(=O)c1ccccc1N
Product: CNC(=O)c1ccccc1Nc1ccnc2cc(-c3ccccc3)oc12

Procedure:
The title compound was prepared by procedure D using 7-chloro-2-phenylfuro[3,2-b]pyridine (50.00 mg; 0.22 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and using 2-amino-N-methylbenzamide(39.23 mg; 0.26 mmol; 1.20 eq.) instead of N-(3-aminomethyl-pyridin-2-yl)-N-methyl-methanesulfonamide and was obtained as a white solid (50 mg, 67%). (HPLC (method F): 92%, RT: 3.37 min); MS (m/z) 344 [M+H]+, RT: 2.5 min.
Reaction SMILES: C(OC([NH:8][CH:9]([C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[CH3:10])=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:8][CH:9]([C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[CH3:10]
Reactant: COC(=O)c1cccc(C(C)NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(C(C)N)c1
Yield: 100.7 %

Procedure:
A solution of methyl 3-{1-[(tert-butoxycarbonyl)amino]ethyl}benzoate (200 mg, 0.72 mmol) in 20% trifluoroacetic acid in dichloromethane (10 mL) was stirred at room temperature for 1.5 hours. After this time the mixture was concentrated under reduced pressure and the residue was dissolved in water and basified to pH 11 with aqueous ammonia. The mixture was extracted with ethyl acetate (2×15 mL) and the extracts were washed with brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure to give methyl 3-(1-aminoethyl)benzoate (130 mg, 100%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=1)[C:10]([O:12][CH3:13])=[O:11]>[Pt](=O)=O.C(O)(=O)C>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][CH:7]1[CH2:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:14][CH2:15][NH:16]1
Reactant: COC(=O)c1ccnc(Cc2cccc(C(F)(F)F)c2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(Cc2cccc(C(F)(F)F)c2)C1
Reaction time: 6 h
Yield: 110 %

Procedure:
Methyl 2-(3-(trifluoromethyl)benzyl)isonicotinate (12.83 g, 43.45 mmol) and platinum(IV) oxide (0.197 g, 0.87 mmol) were added to acetic acid (150 mL). The reaction mixture was hydrogenated in a Büchi hydrogenator for 6 h at room temperature and 5 bar. The catalyst was filtered off and fresh platinum(IV) oxide (0.26 g) was added. Hydrogenation was continued overnight at 6 bar. The catalyst was filtered off and the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with Na2CO3 (aq). The organic layer was isolated, dried over MgSO4, filtered through celite and the solvent evaporated. Crude methyl 2-(3-(trifluoromethyl)benzyl)piperidine-4-carboxylate (14.4 g, 110%) was isolated.
Reaction SMILES: [CH:1]([CH:3]1[O:7][CH:6]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)=[O:2].C(=O)([O-])[O-:18].[K+].[K+].OO>>[CH:1]([C:3]1[O:7][C:6]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]([NH2:14])=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: N#Cc1ccc(OC2CCC(C=O)O2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Product: NC(=O)c1ccc(Oc2ccc(C=O)o2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.1 %

Procedure:
Combine 4-(5-Formyl-tetrahydro-furan-2-yloxy)-benzonitrile (1.0 g, 4.69 mmol), dimethylsufoxide (100 mL), potassium carbonate (0.32 g, 2.35 mmol), and 1 mL of 30% hydrogen peroxide solution. Stir 18 hours at ambient temperature. Dilute with 300 mL of ice/water, extract with ethyl acetate (3×150 mL). Wash the organic phase with 100 mL of water, and 100 mL of brine. Dry the organic phase over sodium sulfate, filter, and concentrate under vacuum. Purify via ISCO™ 100 c system using a gradient of 75:25 hexane/ethyl acetate to 25:75 hexane/ethyl acetate as eluting solvent to give 0.18 g (18%) of the title compound: 1H NMR (DMSO-d6): 9.38 (s, 1H), 7.6 (d, 1H, J=3.8 Hz), 7.30-7.40 (m, 3H), 6.0 (d, 2H, J=3.7 Hz).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:4].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37](=[O:38])[CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]([CH3:43])[C:33]2=[O:44])=[CH:28][C:27]=1[CH:45]=O>CO>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37](=[O:38])[CH:36]=[C:35]([C:39]([F:41])([F:42])[F:40])[N:34]([CH3:43])[C:33]2=[O:44])=[CH:28][C:27]=1[CH:45]=[CH:5][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=O)c2)c1=O
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CCl
Solvent: CO
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=CC(=O)CCl)c2)c1=O
Reaction time: 10 h

Procedure:
4.6 g of chloroacetylmethylenetriphenylphosphorane were added to a solution of 3.3 g of 3-[4-chloro-3-formylphenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine in 100 ml of methanol, and stirring was carried out for 10 hours at room temperature. The precipitate which had separated out was isolated, washed with petroleum ether and dried.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[C:8]([OH:10])[C:7]([Br:11])=[CH:6][C:5]=1[OH:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CS(C)=O>[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]([Br:11])=[CH:6][C:5]=1[O:12][CH2:8][CH2:9][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Oc1cc(Br)c(O)cc1Br
Reactant: CCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCOc1cc(Br)c(OCCCCCC)cc1Br
Reaction time: 1 h

Procedure:
A suspension of KOH powder (10.47 g, 186.6 mmol) in dried DMSO (360 mL) was degassed under vigorous stirring for 1 h. 2,5-dibromo-1,4-dihydroxybenzene (5 g, 18.66 mol) and 1-bromohexane (5.8 mL, 41.06 mmol) were added and stirred for 12 h. The solution was concentrated and precipitated in water, filtered, washed with methanol. The product was recrystallized in ethanol, dried in vacuo (4.518 g, 55.5%). 1H NMR(300 MHz, CDCl3): δ 7.08 (s, 2H), 3.95 (t, 4H), 1.8 (m, 4H), 1.49 (m, 4H). 1.37 (m, 8H), 0.9 (t, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].[S:23]1[C:27]([CH:28]=O)=[CH:26][N:25]=[CH:24]1.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:28][C:27]1[S:23][CH:24]=[N:25][CH:26]=1)[CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2]
Reactant: O=Cc1cncs1
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2Cc1cncs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.8 %

Procedure:
To a solution of 1G (94 mg, 0.3 mmol) and thiazole-5-carbaldehyde (67.9 mg, 0.6 mmol) (prepared following the procedures described in Alessandro Dondoni, et al, Synthesis, 11, 998-1001, (1987)) in a mixed solvents of TFA (0.75 mL) and CH2Cl2 (0.75 mL) was added Et3SiH (0.096 mL, 0.6 mmol). The resulting mixture was stirred at RT under argon for 18 h, then concentrated under reduced pressure. The residue was diluted with saturated aqueous NaHCO3, then extracted with EtOAc (3×20 mL). The combined EtOAc extracts were washed with brine, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (50-90%) in hexane to give the title compound as an off-white solid (70 mg, 57%). HPLC: 99% at 5.43 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4), Flow rate at 2.5 mL/min, UV detection at 220 nm). MS (ES): m/z 411 [M+H]+; Chiral HPLC 100% e.e.; retention time=32.9 min; Conditions: AD (4.6×250 mm); Eluted with 40% isopropanol in hexane for 50 min at 1 mL/min.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([O:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:45]([O:51][CH2:52]I)(=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47].O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([O:30][CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH2:52][O:51][C:45](=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (4.1 g) in N,N-dimethylformamide (41 ml) was added iodomethyl pivalate (1.55 g) at 0° C., and the mixture was stirred for 15 minutes at same temperature. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate (200 ml). The extract was washed with a saturated aqueous sodium bicarbonate and water, followed by drying over magnesium sulfate. The solution was evaporated in vacuo to give pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3.75 g).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24](=[O:29])[NH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br[CH2:31][CH2:32][O:33][CH3:34].[F-].[Cs+]>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24](=[O:29])[N:25]([CH2:31][CH2:32][O:33][CH3:34])[CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc[nH]c3=O)cc1-2
Reactant: COCCBr
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COCCn1cccc(-c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)sc2CCO3)c1=O
Temperature: 80 °C
Yield: 25.2 %

Procedure:
To 330 (0.075 g, 0.18 mmol) in DMF (2 mL) was added 1-bromo-2-methoxyethane (0.1 mL, 0.55 mmol) and cesium fluoride (0.084 g, 0.55 mmol). The reaction mixture was allowed to stir and heat at 80° C. for 2 days while monitoring by LCMS. To the reaction mixture was added bromo-2-methoxyethane (1 mL, 7.2 mmol) and cesium fluoride (1.0 g, 6.6 mmol). The reaction mixture was allowed to stir and heat at 80° C. for 2 days before cooling, concentrating under reduced pressure, and diluting with EtOAc. The solution was washed sequentially with water, and brine, before drying over MgSO4 and concentrating under reduced pressure. The crude material was dissolved in DMF and purified by reverse phase HPLC to provide 477 (21 mg, 24%). 1H NMR (400 MHz, DMSO) δ 9.08 (d, J=2.3, 1H), 8.10 (s, 1H), 7.73-7.55 (m, 3H), 7.08 (d, J=8.4, 1H), 6.34 (t, J=6.9, 1H), 5.95 (dt, J=13.1, 6.5, 1H), 4.40 (t, J=4.9, 2H), 4.16 (t, J=5.3, 2H), 3.66 (t, J=5.3, 2H), 3.46 (t, J=5.0, 2H), 3.27 (s, 3H), 1.55 (d, J=6.6, 6H). MS (ESI(+)): m/z 464.1 (M+H)
Reaction SMILES: C([C:3]([CH2:14][CH3:15])(P(=O)=O)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])C.[H-].[Na+].O=C1C[CH2:23][CH:22]([C:25]2[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>CN(C)C=O>[C:7]([O:6][C:4]([CH:3]=[C:14]1[CH2:15][CH2:23][CH:22]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:34][CH:35]=2)[CH2:21][CH2:20]1)=[O:5])([CH3:8])([CH3:9])[CH3:10]
Reactant: CCOC(=O)c1ccc(C2CCC(=O)CC2)cc1
Reactant: CCC(CC)(C(=O)OC(C)(C)C)P(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C2CCC(=CC(=O)OC(C)(C)C)CC2)cc1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
5.63 g of tert-butyl diethylphosphoacetate (20.3 mmol, 1 eq.) are placed in 20 mL of dimethylformamide with stirring. The solution is cooled to a temperature of 4° C. by placing it in an ice bath, and 0.536 g of sodium hydride (22.33 mmol, 1.1 eq.) is then added portionwise. After 30 minutes, 5 g of ethyl 4-(4-oxo-cyclohexyl)benzoate (20.3 mmol, 1 eq.) are added and the ice bath is removed. After stirring for 1 hour, the flask is placed in an ice bath to cool the reaction medium to a temperature of 4° C., and 0.049 g of sodium hydride (2.04 mmol, 0.1 eq.) is added. The ice bath is removed and, after 30 minutes, the mixture is poured into 200 mL of 1N potassium hydrogen sulfate and extracted with 300 mL of ethyl ether. The organic phase is washed 4 times with brine. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane ranging from 0% to 5%. 5.04 g of ethyl 4-(4-tert-butoxycarbonylmethylenecyclohexyl)benzoate are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].[CH2:38]([N:46]=[C:47]=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN1C(=O)CCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:47]([NH:46][CH2:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:48])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)=[O:37])(=[O:21])=[O:22])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: O=C=NCCc1ccccc1
Reactant: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(N2CCNCC2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(N2CCN(C(=O)NCCc3ccccc3)CC2)cc1
Reaction time: 18 h

Procedure:
A solution of Example 173A (54.1 mg, 0.1 mmol) in NMP (2 mL) at room temperature was treated with phenethylisocyanate (0.2 mmol), stirred for 18 hours, diluted with water, and centrifuged. The solid was purified by flash column chromatography on silica gel with 0-5% methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e 687 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ8.75 (t, 1H), 8.58 (d, 1H), 7.90 (dd, 1H), 7.75 (d, 2H), 7.39-7.34 (m, 2H), 7.31-7.14 (m, 9H), 6.94 (d, 2H), 6.71 (t, 1H), 3.66 (q, 2H), 3.42-3.39 (m, 4H), 3.30-3.21 (m, 8H), 2.72 (dd, 2H).