Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH3:25])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17](=[O:23])[C:16]=2[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH2:40][CH:27]1[CH2:28][O:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([NH:36][CH3:37])=[O:35])=[CH:32][CH:31]=1>C(O)(C)C>[CH3:21][C:19]1([CH3:22])[NH:18][C:17](=[O:23])[C:16]2[CH:24]=[C:12]([O:11][CH2:10][CH:9]([N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:40][CH:27]([OH:26])[CH2:28][O:29][C:30]3[CH:39]=[CH:38][C:33]([C:34](=[O:35])[NH:36][CH3:37])=[CH:32][CH:31]=3)[CH3:25])[CH:13]=[CH:14][C:15]=2[O:20]1
Reactant: CC(COc1ccc2c(c1)C(=O)NC(C)(C)O2)NCc1ccccc1
Reactant: CNC(=O)c1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: CNC(=O)c1ccc(OCC(O)CN(Cc2ccccc2)C(C)COc2ccc3c(c2)C(=O)NC(C)(C)O3)cc1

Procedure:
A solution of 13.6 g of 6-(2-benzylaminopropoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one and 10.4 g of 4-(2,3-epoxypropoxy)-N-methylbenzamide in 80 ml of isopropanol is refluxed for 30 hours. The residue remaining after the solvent has been evaporated off is divided between ether and 2N hydrochloric acid. The acidic, aqueous phase is separated off, and, whilst cooling with ice, rendered alkaline with approximately 10% aqueous ammonia solution and extracted with ethyl acetate. By separating off, drying (MgSO4) and concentrating the ethyl acetate extract by evaporation, the crude 1-[N-[2-(2,3-dihydro-2,2-dimethyl-4-oxo-4H-1,3-benzoxazin-6-yloxy)-1-methylethyl]benzylamino]-3-(4-methylcarbamoylphenoxy)propan-2-ol is obtained as an oil which may be used without further purification for catalytic debenzylation.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([NH2:7])=O.CCN(CC)CC.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]#[N:7]
Reactant: NC(=O)c1c(F)ccc(Br)c1Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1c(F)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromo-2-chloro-6-fluorobenzamide (3.56 mmol) in 50 mL DCM were added 1.5 mL Et3N followed by trifluoromethanesulfonic acid anhydride (7.11 mmol) at 0° C. The ice bath was removed and the reaction mixture was stirred at RT. After 30 min, water was added and the mixture was extracted with DCM (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo to obtain the desired compound as brown solid.
Reaction SMILES: [Na].[CH:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:9](Cl)(=[O:12])[CH2:10][CH3:11]>COCCOCCOC.C(OCC)C>[CH3:11][CH2:10][C:9](=[O:12])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCC(=O)Cl
Reactant: C#CCCCCC
Agent: [Na]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: CCCCCC#CC(=O)CC
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
A 1-liter reactor was loaded with 345 mL of diglyme (RN 111-96-6) and 17.2 g (748 mmoles) of sodium (RN 7440-23-5) cut into pieces. After heating to a temperature slightly above the melting point of sodium accompanied by thorough stirring, 71.7 g (745 mmoles) i.e. 97.5 mL of 1-heptyne (RN 628-71-7) in solution in 100 mL of diglyme is then added four times at hourly intervals. The medium thickens to form a beige suspension. Stirring is continued for another 2 hours 30 minutes at the same temperature. The mixture is cooled down to 25-30° C. and poured slowly into a stirred solution of 64.8 g (700 mmoles) i.e. 61.0 mL of propionyl chloride (RN 79-03-8) in 600 mL of ethyl ether. An exothermic reaction takes place followed by stirring for 1 hour at no particular temperature.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]1)#[N:2].N.[H][H]>CO.O>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC2(CCCCC2)O1
Reactant: [H][H]
Agent: N
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC2(CCCCC2)O1
Reaction time: 22 h
Yield: 97.9 %

Procedure:
A solution of 1.19 g of (±)-cis-1,1-dimethylethyl 4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetate in 30 mL of methanol saturated with gaseous ammonia is treated with 0.3 g of Raney nickel #30 and hydrogen gas in a shaker at 60 pounds per square inch gage (psig) and 40° C. After 22 hours, thin layer chromatography indicates no starting nitrile present. The suspension is cooled, filtered through filter aid, and concentrated to an oil. This crude oil is purified by silica gel flash chromatography (30:20:1; ethyl acetate:methanol:ammonium hydroxide) to give 1.18 g of (±)-cis-1,1-dimethylethyl 4-(2-aminoethyl)- 1,5-dioxaspiro[5.5]undecane-2-acetate as a clear oil which solidifies upon standing.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([CH3:19])=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:20][C:21]1[N:25]([CH2:26][CH2:27][CH2:28][NH2:29])[CH:24]=[N:23][CH:22]=1>>[CH3:19][C:6]1[S:5][C:4]2[NH:1][C:2](=[S:3])[N:29]([CH2:28][CH2:27][CH2:26][N:25]3[C:21]([CH3:20])=[CH:22][N:23]=[CH:24]3)[C:9](=[O:11])[C:8]=2[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cncn1CCCN
Reactant: COC(=O)c1c(N=C=S)sc(C)c1-c1ccccc1
Product: Cc1sc2[nH]c(=S)n(CCCn3cncc3C)c(=O)c2c1-c1ccccc1

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanato-5-methyl-4-phenylthiophene-3-carboxylate (0.10 g, 0.35 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.048 g, 0.35 mmol) as described above.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:33])[N:12](COCC[Si](C)(C)C)[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(S)(S)C.O>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:33])[NH:12][N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cc(C(=O)NCc3ccc(Cl)cc3)c(=O)n(COCC[Si](C)(C)C)n2)ccc1O
Agent: CC(S)S
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cc(C(=O)NCc3ccc(Cl)cc3)c(=O)[nH]n2)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
70.7 mg of 6-(4-hydroxy-3-methoxy-phenyl)-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3-dihydro-pyridazine-4-carboxylic acid 4-chloro-benzyl amide and 60 μl ethandithiol and 60 μl water were dissolved in 750 μl TFA and stirred at room temperature for 3 h. Afterwards, the solvent was distilled off and the raw product purified by HPLC (column 125×25, PurospherStar RP18 endcapped, 5 μm; solvent: A: water (0.05% HCOOH), B: acetonitrile (0.05% HCOOH)).
Reaction SMILES: [C:1]1([C@H:7]([C@H:9]2[O:14][CH2:13][CH2:12][N:11]([C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([O:8][C@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:10]1)(=[O:35])=[O:34]
Reactant: C[C@H](c1ccccc1)N1CCO[C@H]([C@H](O)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1CCO[C@H]([C@H](OS(C)(=O)=O)c2ccccc2)C1
Reaction time: 6 h
Yield: 54.8 %

Procedure:
To a solution of 50 (0.05 g, 0.17 mmol) in dichloromethane (1 ml) at room temperature was added polymer supported Hünig's base ((Argonaut, 3.56 mmol/g, 0.089 g, 0.32 mmol, 1.9 eq) and methanesulphonyl chloride (0.02 g, 0.19 mmol). The mixture was stirred under nitrogen for 6 hours then filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (eluent: ethyl acetate/heptane 33/67 (v/v)) to give 51 as a colourless oil (0.035 g, 55%%); MW 375.49; C20H25NO4S 1H NMR (CDCl3) 7.20-7.35 (10H, m), 5.46 (1H, d), 3.79-3.88 (2H, m), 3.59 (1H,td), 3.4 (1H, q), 2.68-2.78 (2H, m), 2.68 (3H, s), 2.03-2.24 (2H, m), 1.34 (3H, d). m/z [M+H]+ 376.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]2=[N:10][C:11]([Br:15])=[C:12]([OH:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5].[H-].[Na+].[CH2:26](Br)[CH3:27]>>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:16]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:9]2=[N:10][C:11]([Br:15])=[C:12]([O:14][CH2:26][CH3:27])[CH:13]=[C:8]2[CH:7]=1)=[O:5]
Reactant: CCOC(=O)c1cc2cc(O)c(Br)nc2n1C(=O)OC(C)(C)C
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc2cc(OCC)c(Br)nc2n1C(=O)OC(C)(C)C

Procedure:
This compound was prepared in analogy to Example 1, intermediate d) from 6-bromo-5-hydroxy-pyrrolo [2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester, sodium hydride and ethyl bromide.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[H][H]>CO.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]
Reactant: CC(C)C[C@H](NC(=O)[C@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(N)=O
Yield: 90.2 %

Procedure:
4.48 g (9.5 mmoles) of Z-D-Glp-Leu-Pro-NH2 are dissolved in 200 ml of methanol, 0.9 g of a 10% palladium-on-carbon catalyst are added to the solution, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is evaporated, and the amorphous residue is triturated with ether. The resulting 3.07 g of crude product are dissolved in water, the solution is decolourized, filtered, and the clear filtrate is freeze-dried. 2.90 g (90.5%) of D-Glp-Leu-Pro-NH2 are obtained; Rf5 =0.40, [α]D25 =-23.6° (c=1%, in acetic acid).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10](C(C)(C)C)[CH2:9][C@:8]1(O[SiH](C)C)[CH2:16][N:17]1[C:24]2[N:20]([N:21]=[CH:22][CH:23]=2)[CH:19]=[CH:18]1)=[O:6])[CH:2]=[CH2:3].Cl.C[O-:31].[Na+]>CO>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:31])[CH2:9][C@H:8]1[CH2:16][N:17]1[C:24]2[N:20]([N:21]=[CH:22][CH:23]=2)[CH:19]=[CH:18]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C[O-]
Reactant: C=CCOC(=O)N1C[C@@H](C(C)(C)C)C[C@@]1(Cn1ccn2nccc12)O[SiH](C)C
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cn1ccn2nccc12

Procedure:
A solution of (2S,4R)-1-allyloxycarbonyl-4-tertbutyldimethylsilyloxy-2-(imidazo[1,2-b]pyrazol-1-yl)methylpyrrolidine (4.23 g) and conc. hydrochloric acid (2.61 ml) in methanol (40 ml) was stirred at ambient temperature for 5 hours. The reaction mixture was adjusted to pH 8-9 with 28% sodium methoxide in methanol solution and the mixture was concentrated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (2:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-(imidazo [1,2-b]pyrazol-1-yl)methylpyrrolidine (3.18 g).
Reaction SMILES: [OH-:1].[Na+].O.[C:4]([S:8][CH2:9][C:10]1([CH3:17])[NH:14][C:13](=[O:15])[NH:12][C:11]1=[O:16])([CH3:7])([CH3:6])[CH3:5]>C(#N)C>[C:13]([NH:14][C@:10]([CH3:17])([C:11]([OH:1])=[O:16])[CH2:9][S:8][C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:15])[NH2:12]
Reactant: CC(C)(C)SCC1(C)NC(=O)NC1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)SC[C@](C)(NC(N)=O)C(=O)O

Procedure:
First, sodium hydroxide and water were added to 5-tert-butylthiomethyl-5-methylhydantoin, and the resultant mixture was heated to a predetermined temperature and stirred. The reaction solution was analyzed by HPLC (column: COSMOSIL 5C18-AR (produced by Nacalai Tesque Inc.), mobile phase: acetonitrile/10 mM aqueous potassium dihydrogen phosphate solution=30/70, flow rate: 1.0 ml/min, detection wavelength: 210 nm, column temperature: 40° C.) to determine the yield of the title compound. The results are shown in Table 1.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.O[CH2:13][CH2:14]/[CH:15]=[CH:16]/[P:17](=[O:26])([O:22][CH:23]([CH3:25])[CH3:24])[O:18][CH:19]([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:13][CH2:14]/[CH:15]=[CH:16]/[P:17]([O:22][CH:23]([CH3:24])[CH3:25])([O:18][CH:19]([CH3:20])[CH3:21])=[O:26])=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(C)OP(=O)(/C=C/CCO)OC(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)OP(=O)(/C=C/CCn1cnc2c(Cl)nc(N)nc21)OC(C)C
Temperature: 0 °C
Yield: 35.2 %

Procedure:
To a mixture of 2-amino-6-chloropurine (0.6 g, 3.81 mmol) , diisopropyl (E)-4-hydroxybut-1-enylphosphonate (0.90 g, 3.81 mmol) and triphenyl phosphine (2.00 g, 7.62 mmol) in dry N,N-dimethylformamide (30 ml) stirred at 0° C. under dry nitrogen was added diethyl azodicarboxylate (1.33 g, 7.62 mmol). The mixture was allowed to warm to room temperature and stirred for 1.3 hr. The solvent was removed and the residue was purified by column chromatography on silica gel eluting with dichloromethane-methanol (9:1) to afford (E)-2-amino-6-chloro-9-[4-(diisopropoxyphosphoryl)but-3-enyl]purine as a light brown gum (0.52 g, 35%), m.p. 150° C.; λmax (EtOH) 311 (6,760), 249 (5,420) and 224 (24,320)nm; υmax (KBr) 3385, 3320, 3208, 1635, 1615, 1560, 1520, 1410 and 1240 cm-1 ; δH [(CD3) 2 SO] 1.08 (6H, d, J 6 Hz, CH(CH3)2), 1.16 (6H, d, J 6 Hz, CH(CH3)2), 2.77 (2H, m, CH2), 4.27 (4H, m, CH2N and CH(CH3)2), 5.69 (1H, dd, J 17 Hz and 21Hz, PCH=CH), 6.52 (1H, ddt, J 6 Hz, 17 Hz and 22 Hz PCH=CH), 6.89 (2H, br.s, D2O exchangeable, NH2), 8.11 (1H, s, H-8) (Found: MH+ 388.1288. C15H23ClN5O3P requires MH+ 388.1305).
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]2[C:10](=[O:11])[O:9][C:7](=[O:8])[C:6]2=[CH:12][CH:13]=1.CN(C)[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:25])[CH3:24])[CH:18]=1>[Cl-].[Zn+2].[Cl-].ClC1C=CC=CC=1>[CH2:7]([O:8][C:17]1[CH:18]=[C:19]([N:23]([CH3:25])[CH3:24])[CH:20]=[CH:21][C:22]=1[C:10]([C:5]1[CH:4]=[CH:3][CH:13]=[CH:12][C:6]=1[C:7]([OH:9])=[O:8])=[O:11])[CH:6]([CH3:12])[CH3:5]
Reactant: CN(C)c1ccc2c(c1)C(=O)OC2=O
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CC(C)COc1cc(N(C)C)ccc1C(=O)c1ccccc1C(=O)O

Procedure:
In a manner similar to that of part A of Example 3 condensation of 4-(dimethylamino)phthalic anhydride (1.91 g.) and N,N,N',N'-tetramethyl-m-phenylenediamine (1.64 g.) in contact with zinc chloride (2.70 g.) and with chlorobenzene (50 ml.) as diluent afforded 2-(2,4-bis(dimethylamino)benzoyl)-4-(dimethylamino)benzoic acid (II: Y'2 = Y'4 = Z'5 = (CH3)2N, Z4 = Z'6 = Z7 = H) (m.p. 216°-222° C.) or the 5-(dimethylamino) isomer thereof.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:43]1[N:44]=[C:45]([NH2:48])[S:46][CH:47]=1)[C:12]([NH:14][CH:15]1[C:41](=[O:42])[N:17]2[C:18]([C:25]([O:27]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:26])=[C:19](/[CH:22]=[CH:23]/[Cl:24])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(OC(C)C)(C)C>[C:6]([CH2:8][O:9][N:10]=[C:11]([C:43]1[N:44]=[C:45]([NH2:48])[S:46][CH:47]=1)[C:12]([NH:14][CH:15]1[C:41](=[O:42])[N:17]2[C:18]([C:25]([OH:27])=[O:26])=[C:19](/[CH:22]=[CH:23]/[Cl:24])[CH2:20][S:21][C@H:16]12)=[O:13])([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12)c1csc(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: Nc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)O)=C(/C=C/Cl)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a mixture of benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (syn isomer) (2.2 g) and anisole (2.2 ml) was added trifluoroacetic acid (9.0 ml) in an ice-bath. The mixture was stirred for two hours at room temperature and poured into diisopropyl ether (180 ml). The resulting precipitates were collected by filtration and washed with diisopropyl ether. The precipitates were dissolved in an aqueous solution of sodium bicarbonate and washed with ethyl acetate. The aqueous layer was concentrated to remove organic solvent under reduced pressure, cooled to 5° C. and adjusted to pH 2.2 with diluted hydrochloric acid. The resulting precipitates were collected by filtration, washed with water and dried in vacuo to give 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylic acid (syn isomer) (1.07 g).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[N:7]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:6]1)(=O)C.C[O-].[Na+]>CO>[CH2:27]([O:26][C:24]([N:7]1[C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@@H:5]([OH:4])[CH2:6]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)OC[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)CN1C(=O)OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(OCc1ccccc1)N1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
Compound (2) (9.13 g) was dissolved in methanol (100 ml). To this solution, sodium methoxide was added at 0° C. until the pH became almost 12, followed by stirring at 0° C. for 1 hour. After completion of the reaction, the solution was neutralized with ion exchange resin Amberlite IR-120 (H+). The resin was filtered out and washed with methanol. The filtrate was combined with washings, followed by concentration under reduced pressure. The resulting residue was subjected to column chromatography (Wako Gel C-200, dichloromethane/methanol=50/1 ) to yield compound (3) (4.96 g, 85.1%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].O>C(N(CC)CC)C.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.[Cu]I>[CH3:11][Si:12]([CH3:14])([CH3:13])[C:15]#[C:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.8 %

Procedure:
4 g (20 mmol) of ortho-bromonitrobenzene, 842 mg (1.2 mmol) of bis(triphenyl-phosphine)palladium(II) chloride and 230 mg (1.2 mmol) of copper(I) iodide were, under argon, initially charged in 40 ml of triethylamine. At room temperature, 2.95 g (30 mmol) of trimethylsilylacetylene were then added dropwise over a period of 10 min, and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into 50 ml of water and extracted three times with in each case 50 ml of diethyl ether, and the extracts were dried over sodium sulphate and concentrated. Column-chromatographic purification on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 3:1) gave 4.2 g (96% of theory) of trimethyl-(2-nitrophenyl-ethynyl)silane [log P (pH 2.3)=4.12].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:24]1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.N>CN(C)C=O>[NH2:24][C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(N)=O)cc2)CC1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 21.4 g of 1-tert.butyloxycarbonyl-4-(4-carboxyphenyl)-piperidine in 250 ml of anhydrous dimethylformamide are added, at -10° C., 9.5 g of 1-hydroxy-(1H)-benzotriazole and 17.3 g of N,N'-dicyclohexylcarbodiimide. The mixture is stirred for 15 minutes at -10° C. and the temperature is allowed to come up to ambient temperature within 1 hour. Then at -10° C. 20 ml of conc. ammonia are added dropwise with vigorous stirring. The mixture is stirred for 1 hour at -10° C. and for a further 2 hours at ambient temperature. The solvent is removed under reduced pressure. The residue remaining is suspended in water and the aqueous phase is extracted four times with ethyl acetate. The combined ethyl acetate phases are filtered, the filtrate is dried over sodium sulphate and the solvent is removed under reduced pressure. The residue remaining is chromatographed over silica gel. Yield: 17.5 g (82% of theory), Melting point: 188°-191° C. Rf value: 0.36 (silica gel; ethyl acetate/cyclohexane=4:1)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:35])[C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([S:19][C:20]3[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:4].Br[CH2:37][CH2:38][CH2:39][OH:40].C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:35])[C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([S:19][C:20]3[CH:25]=[C:24]([C:26]([CH3:27])([CH3:28])[CH3:29])[C:23]([O:30][CH2:37][CH2:38][CH2:39][OH:40])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=3)[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)n1C
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(OCCCO)c(C(C)(C)C)c3)CC2)n1C
Temperature: 75 °C
Yield: 42.1 %

Procedure:
To 5-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (Ex. 4a, 436 mg, 0.83 mmol) in 3 mL of DMF was added 3-bromo-propan-1-ol (127 mg, 0.91 mmol) and K2CO3 (343 mg, 2.5 mmol). The mixture was heated to 75° C. for 16 h. Upon cooling to room temperature it was poured into saturated NH4Cl (30 mL). The mixture was extracted with Ethyl acetate (3×30 mL) and the organic extracts were dried over Na2SO4 and concentrated under reduced pressure. Chromatography (3-40% Ethyl acetate/hexanes) gave 5-{4-[3,5-di-tert-butyl-4-(3-hydroxy-propoxy)-phenylsulfanyl]-piperidine-1-sulfonyl}-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester as a pale-yellow thick oil (203 mg). ESI/CI-MS m/z 581 ([M+H]+).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([N:23]2[CH2:27][CH2:26][N:25]([CH2:15][C:12]3[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:14][N:13]=3)[C:24]2=[O:28])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Reactant: O=C1NCCN1c1ccccc1
Product: O=C1N(Cc2ccc(C#Cc3ccccc3)cn2)CCN1c1ccccc1

Procedure:
The title compound, light yellow solid, MS: m/e=354.3 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and 1-phenyl-imidazolidin-2-one.