Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([NH:7][C:8]([O:10][C@@H:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[O:9])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[OH:1][C@@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[NH:7][C:8](=[O:9])[O:10][C@@H:11]([CH3:16])[C:12]([F:13])([F:14])[F:15]
Reactant: C[C@H](OC(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C[C@H](OC(=O)N[C@@H]1CNC[C@H]1O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of tert-butyl (3R,4R)-3-hydroxy-4-[({[(2S)-1,1,1-trifluoropropan-2-yl]oxy}carbonyl)amino]pyrrolidine-1-carboxylate (100 mg) in CHCl3 (0.5 ml) was added TFA (0.5 ml). After stirring for 1 hour at room temperature, the mixture was poured into saturated aqueous solution of NaHCO3 and extracted with CHCl3. The extract was dried over Na2SO4 and concentrated to give (2S)-1,1,1-trifluoropropan-2-yl [(3R,4R)-4-hydroxypyrrolidin-3-yl]carbamate as a pale yellow foam.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:18]1[C:35]([CH:36]2[CH2:38][CH2:37]2)=[CH:34][C:21]2[C:22]([C:32]#[N:33])=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[O:24][C:20]=2[CH:19]=1)[S:14]([CH3:17])(=[O:16])=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:39][OH:40]>C(O)C>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[C:18]1[C:35]([CH:36]2[CH2:38][CH2:37]2)=[CH:34][C:21]2[C:22]([C:32](=[NH:33])[NH:39][OH:40])=[C:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[O:24][C:20]=2[CH:19]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)OCCCCN(c1cc2oc(-c3ccc(F)cc3)c(C#N)c2cc1C1CC1)S(C)(=O)=O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCCCN(c1cc2oc(-c3ccc(F)cc3)c(C(=N)NO)c2cc1C1CC1)S(C)(=O)=O
Temperature: 140 °C
Yield: 83.4 %

Procedure:
To a 20-mL microwave tube was added a solution of Example 11B (0.1346 g, 0.242 mmol) in ethanol (3 mL) followed by hydroxylamine (50 weight % in water, 3 mL, 50.9 mmol). The tube was sealed and the thick slurry was heated in a microwave reactor (Personal Chemistry (Biotage), Emrys Creator, 300 W maximum) for 30 minutes at 140° C. The reaction mixture was concentrated in vacuo to a cloudy solution that was taken up in ethyl acetate (60 mL), washed with 10% aqueous NaCl, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound as a foamy white solid (0.119 g, 84%).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][S:39]([CH:42]2[CH2:44][CH2:43]2)(=[O:41])=[O:40])=[CH:34][CH:33]=1>>[O:5]=[C:4]1[C:6]2([CH2:7][CH2:8][N:9]([S:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]([F:30])([F:29])[F:16])(=[O:27])=[O:26])[CH2:10][CH2:11]2)[CH2:12][CH2:13][N:31]1[C:32]1[CH:37]=[CH:36][C:35]([O:38][S:39]([CH:42]2[CH2:44][CH2:43]2)(=[O:41])=[O:40])=[CH:34][CH:33]=1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: Nc1ccc(OS(=O)(=O)C2CC2)cc1
Product: O=C1N(c2ccc(OS(=O)(=O)C3CC3)cc2)CCC12CCN(S(=O)(=O)c1ccccc1OC(F)(F)F)CC2

Procedure:
Light brown solid. MS (ESI): 575.11 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and cyclopropanesulfonic acid 4-amino-phenyl ester.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35](O)=[O:36])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl.[CH2:52]([NH2:54])[CH3:53].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:52]([NH:54][C:35](=[O:36])[C@@H:34]1[CH2:38][CH2:39][CH2:40][N:33]1[C:31](=[O:32])[C@H:23]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH:22][C:20](=[O:21])[CH2:19][NH:18][C:16](=[O:17])[C@@H:14]([CH3:15])[NH:13][C:11](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)[NH2:1])[CH3:53]
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1
Reaction time: 24 h

Procedure:
0.7 g. (1 mmoles) of Z-Tyr-D-Ala-Gly-Phe-Pro-OH (3rd step of Example 5) are dissolved in 2 ml. of dimethyl formamide, then 0.1 g. (1.24 mmoles) of ethylamine hydrochloride, 0.17 ml. (1.24 mmoles) of triethylamine and 0.21 g. (1 mmole) of dicyclohexyl-carbodiimide are added. The reaction mixture is allowed to stand for one day, filtered and diluted with 30 ml. of ethyl acetate. The solution is washed with 0.5N sulphuric acid, water, 5% solution of sodium hydrogen carbonate and water, then dried and evaporated. The residue on evaporation (Rf2 0.80-0.85) is dissolved in 30 ml. of methanol and hydrogenated in the presence of palladium as catalyst. At the end of the reaction the catalyst is filtered off, the solution evaporated, rubbed with ether, filtered, washed with ether and dried. Yield: 0.43 g. (75%) of the named pentapeptide; Rf4 0.34-0.44.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:18][CH3:19])=[C:9]2[C:14](=O)[C:13]([CH3:17])([CH3:16])[CH2:12][CH2:11][C:10]=12)=[O:5])[CH3:2]>C(Cl)Cl.C(OCC)C.[Zn+2].[I-].[I-]>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:18][CH3:19])=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:17])[CH2:12][CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(C)(C)C2=O
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1sc(SC)c2c1CCC(C)(C)C2

Procedure:
To a suspension of anhydrous ZnI2 (647 mg, 2.03 mmol) and Na(BH3CN) (117 mg, 1.86 mmol) in DCM (5 mL), a solution of 5,5-dimethyl-3-methylsulfanyl-4-oxo-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid ethyl ester (539 mg, 1.81 mmol) in DCM (5 mL) is added. The yellow suspension is refluxed over night before another portion of ZnI2 (100 mg, 0.314 mmol) and Na(BH3CN) (26 mg, 0.419 mmol) is added. The reaction mixture is refluxed for further 24 h. The mixture is diluted with diethyl ether and washed with sat. aq. NaHCO3 solution and brine. The organic layer is separated, dried over Na2SO4 and the solvent is removed under reduced pressure to give 5,5-dimethyl-3-methylsulfanyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid ethyl ester as a beige resin; LC-MS: tR=1.15 min, [M+1]=285.2; 1H NMR (CDCl3): δ 4.30 (q, J=7.0 Hz, 2H), 3.00 (t, J=7.0 Hz, 2H), 2.50 (s, 3H), 2.33 (s, 3H), 1.54 (t, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H), 0.97 (s, 6H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(Cl)(Cl)Cl.[CH:16]1[C:25]2[CH2:24][CH2:23][CH:22]=[CH:21][C:20]=2[CH:19]=[CH:18][C:17]=1[NH:26][C:27](=[O:29])[CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:27]([NH:26][C:17]1[CH:16]=[C:25]2[C:20](=[CH:19][CH:18]=1)[CH2:21][C:22](=[O:9])[CH2:23][CH2:24]2)(=[O:29])[CH3:28]
Reactant: CC(=O)Nc1ccc2c(c1)CCC=C2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2c(c1)CCC(=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.1 %

Procedure:
m-Chloroperbenzoic acid (5.13 g, 20.8 mmol) was added to a chloroform solution (80 ml) of N-(7,8-dihydro-2-naphthalenyl)acetamide (3.00 g, 16.0 mmol) obtained in 1) under ice-cooling, which was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, which was washed with saturated sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was purified by alumina B column chromatography (development solvent; hexane:ethyl acetate=1:1). 1N Sodium hydroxide solution (10.7 ml) was added to a methanol solution (100 ml) of the obtained oily substance (3.20 g, 8.89 mmol) under ice-cooling, which was stirred at room temperature for 30 minutes. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was purified by alumina B column chromatography (development solvent; ethyl acetate: methanol=10:1). p-Toluenesulfonic acid (50 mg, 0.262 mmol) and toluene (26 ml) were added to the obtained diol (596 mg, 2.62 mmol), which was stirred at 120° C. for 3 hours. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was purified by silica gel column chromatography (development solvent; hexane:ethyl acetate=1:3), and powdered with diisopropyl ether, to give the titled compound (231 mg).
Reaction SMILES: [C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].C([O-])(O)=O.[Na+].[C:18](=[O:25])([O:22][CH2:23]I)[S:19][CH2:20][CH3:21]>O.C(Cl)Cl>[C:18](=[O:25])([S:19][CH2:20][CH3:21])[O:22][CH2:23][O:5][C:4](=[O:6])[CH2:3][CH2:2][C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)CCC(=O)[O-]
Reactant: CCSC(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCSC(=O)OCOC(=O)CCC(=O)OC(C)(C)C
Reaction time: 0.42 h
Yield: 82 %

Procedure:
To a mixture of acid 1 (1.0 g, 5.74 mmol) in H2O (14.5 mL), and CH2Cl2 (14.5 mL) was added NaHCO3 (1.00 g, 11.9 mmol) and TBAHSO4 (1.95 g, 5.74 mmol). After stirring for 25 min, S-ethyl O-iodomethyl carbonothioate (1.10 g, 4.42 mmol, prepared according to Synthesis 1990, 1159) in CH2Cl2 (5 mL) was added. The biphasic reaction was stirred vigorously for 2 h 35 min and was diluted with water and CH2Cl2. The layers were separated, the organic layer was washed with water, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over Na2SO4, filtered and concentrated to dryness. The crude product was triturated with Et2O and the solids were removed by filtration and rinsed with small portions of Et2O. After concentration, the combined filtrates were purified by flash chromatography on silica gel, using 20% EtOAc in hexanes as eluent to furnish compound 2 (1.06 g, 82%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.33 (t, J=7.4 Hz, 3H), 1.44 (s, 9H), 2.54-2.58 (m, 2H), 2.63-2.66 (m, 2H), 2.89 (q, J=7.4 Hz, 2H), 5.62 (s, 2H).
Reaction SMILES: [Na].[CH2:2]([S:5][C:6]1[N:7]=[N:8][NH:9][CH:10]=1)[CH2:3][CH3:4].S(OS([O-])=O)([O-])=[O:12].[Na+].[Na+].[OH2:20]>C(O)(=O)C>[CH2:2]([S:5]([C:6]1[N:7]=[N:8][NH:9][CH:10]=1)(=[O:12])=[O:20])[CH2:3][CH3:4]
Reactant: O=S([O-])OS(=O)[O-]
Reactant: CCCSc1c[nH]nn1
Reactant: O
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Product: CCCS(=O)(=O)c1c[nH]nn1
Temperature: 45 °C
Reaction time: 0.17 h

Procedure:
170.5 g (1.08 mole) of sodium permangamate are added batchwise within a period of 30 minutes at 45° to 55° C. to a solution of 103.2 g (0.72 mole) of 4-propylthio-1,2,3-triazole in 320 ml acetic acid and 420 ml water. The solution is then stirred for 10 minutes at 45° C. and reacted at 20° C. with a solution of 159.8 g (0.84 mole) of sodium disulfite in 500 ml water up to complete decolorization. Thereupon extraction is effected four times with 250 ml of acetic acid ester. The organic phase is then dried on magnesium sulfate, filtered and concentrated in a vacuum.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:13][N:14]([CH2:16][CH2:17][CH2:18][NH2:19])[CH3:15]>C(OCC)(=O)C.CCCCCC>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH:16]([N:14]([CH3:15])[CH3:13])[CH2:17][CH2:18][NH2:19])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CN(C)CCCN
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(C)C(CCN)c1ccnc2cc(Cl)ccc12

Procedure:
From 4,7-dichloroquinoline and 3-(N,N-dimethylamino)-propylamine; colourless crystals from ethyl acetate-hexane, m.p.: 111°-113° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.CO.[C].[Pd]>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2c(-c3nc(/C=C/C(=O)O)cs3)cnn2C(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3nc(CCC(=O)O)cs3)cnn2C(C)(C)C)cc1
Yield: 89.4 %

Procedure:
A mixed solution of (E)-3-(2-(1-(tert-butyl)-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acrylic acid (70 mg, 0.18 mmol) and 10% palladium carbon (19.43 mg, 0.18 mmol) in THF (2 mL) and methanol (2 mL) was stirred under 1 atm hydrogen atmosphere at room temperature for 14 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was crystallized from diethyl ether to give 3-(2-(1-(tert-butyl)-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)thiazol-4-yl)propanoic acid (62.0 mg, 0.161 mmol, 88%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][O:14][C:15]([CH3:23])([C:19]([F:22])([F:21])[F:20])[C:16]([OH:18])=[O:17])[CH:7]=[CH:6]2.[N+](=[CH2:26])=[N-]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][O:14][C:15]([CH3:23])([C:19]([F:20])([F:21])[F:22])[C:16]([O:18][CH3:26])=[O:17])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(COC(C)(C(=O)O)C(F)(F)F)ccc2c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C(C)(OCc1ccc2cc(OC)ccc2c1)C(F)(F)F

Procedure:
A solution of (±)-2-(6-methoxy-2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionic acid (1.0 g.) in ether is treated with diazomethane by the process described in Example 18 to give (±)-methyl 2-(6-methoxy-2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate (0.8 g.) m.p. 60°-62° C. (from methanol at -50° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH:13]=[CH:12][CH2:11][C@@H:10]2[N+:15]([O-])=O)=[CH:5][C:4]=1[O:18][CH3:19].C(O)(=O)C>C(O)C.[Zn]>[CH3:19][O:18][C:4]1[CH:5]=[C:6]([C@@H:9]2[C@H:10]([NH2:15])[CH2:11][CH:12]=[CH:13][CH2:14]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])cc1OC
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc([C@H]2CC=CC[C@H]2N)cc1OC
Yield: 32.4 %

Procedure:
40 g of (±)-cis-1,2-dimethoxy-4-(2-nitrocyclohex-4-enyl)benzene (compound I7) are dissolved in 400 ml of ethanol and 40 g of zinc powder are added. After heating to boiling temperature, 65 ml of glacial acetic acid are added dropwise. Afterwards, the reaction mixture is filtrated and concentrated. The residue is redissolved in diluted hydrochloric acid and extracted with toluene. The aqueous layer is alkalized using 6 N solution of sodium hydroxide and extracted several times with toluene. The combined organic phases of the alkalic extraction are dried using sodium sulfate and concentrated. The residue is chromatographed on silica gel. 11.5 g of the title compound are obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][C@H:10]2[C:12]([O:14]C)=[O:13])=[CH:5][CH:4]=1.Cl>C1COCC1.O>[F:16][C:2]([F:1])([F:17])[C:3]1[N:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][C@H:10]2[C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1
Reactant: COC(=O)[C@@H]1C[C@H]1c1ccc(C(F)(F)F)nc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(C(F)(F)F)nc1
Reaction time: 14 h
Yield: 76.9 %

Procedure:
To a stirring solution of 26B (22 mg, 0.09 mmol) in THF (1 mL) at ambient temperature was added LiOH monohydrate (11 mg, 0.26 mmol) as a slurry in H2O (0.500 mL). The reaction was left to stir for 14 h, acidified to pH 4 via 1N HCl (aq), and then extracted with EtOAc (3×10 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to give 16 mg 26C (79% yield). m/z (ES+) M+1=232.0; HPLC tR=1.86 min. 1H NMR (500 MHz, MeOH-d4) δ 8.56 (d, J=2.1 Hz, 1H), 7.78-7.65 (m, 2H), 2.62-2.47 (m, 1H), 1.97 (ddd, J=9.0, 4.7, 4.6 Hz, 1H), 1.63 (ddd, J=9.4, 5.0, 4.8 Hz, 1H), 1.49-1.39 (m, 1H).
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:24])[C@H:12]2[C@@H:15](OS(OCC)(=O)=O)[CH3:16])[C:9]=1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])(=[O:3])[CH3:2].[C:35]([NH:38]/[CH:39]=[CH:40]/[S:41][C:42]1[CH2:48][C@H:47]2[N:44]([C:45](=[O:56])[C@H:46]2[C@@H:49](OS([O-])(=O)=O)[CH3:50])[C:43]=1[C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])(=[O:37])[CH3:36].[Na+].N12CCCCC1C=NCCC2>>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:24])/[C:12]/2=[CH:15]/[CH3:16])[C:9]=1[C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])(=[O:3])[CH3:2].[C:35]([NH:38]/[CH:39]=[CH:40]/[S:41][C:42]1[CH2:48][C@H:47]2[N:44]([C:45](=[O:56])/[C:46]/2=[CH:49]\[CH3:50])[C:43]=1[C:57]([O:59][CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)=[O:58])(=[O:37])[CH3:36]
Reactant: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccccc2)N2C(=O)[C@@H]([C@H](C)OS(=O)(=O)[O-])[C@H]2C1
Reactant: CCOS(=O)(=O)O[C@@H](C)[C@@H]1C(=O)N2C(C(=O)OCc3ccccc3)=C(S/C=C/NC(C)=O)C[C@H]12
Agent: C1=NCCCN2CCCCC12
Agent: [Na+]
Product: C/C=C1/C(=O)N2C(C(=O)OCc3ccccc3)=C(S/C=C/NC(C)=O)C[C@H]12
Product: C/C=C1\C(=O)N2C(C(=O)OCc3ccccc3)=C(S/C=C/NC(C)=O)C[C@H]12

Procedure:
Benzyl (5R,6R)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-ethoxysulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e24) prepared from sodium (5R,6R)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-sulphonatooxyethyl]-7-oxo-2-benzyloxycarbonyl-1-azabicyclo[3.2.0]hept-2-ene (e23) (100 mg) as described in Example 13 was treated with 1,5-diazabicyclo[5.4.0]-undec-5-ene (35 mg) in an analogous manner to that described in Example 19 to give benzyl (5R,6E)-3-[(E)-2-acetamidoethenylthio]-6-ethylidene-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate and benzyl (5R,6Z)-3-[(E)-2-acetamidoethenylthio]-6-ethylidene-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e45 and e37) (30 mg). The n.m.r. spectrum [CDCl3 +(CD3)2SO]indicated that the ethylidene group was largely in the E-form (e45) but that some Z-form (e37) was also present.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][CH2:12][CH:13]([OH:15])[CH3:14].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>ClCCl.C(Cl)(Cl)Cl>[OH:15][CH:13]([CH3:14])[CH2:12][NH:11][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=1
Reactant: O=C(O)c1cccc(I)c1
Reactant: CC(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(O)CNC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
3-Iodobenzoic acid (2.00 g, 8.06 mmol) was dissolved in dichloromethane (80 mL), and the mixture was stirred at room temperature for 2 hours after adding 1-amino-2-propanol (1.25 mL, 16.1 mmol), 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (1.86 g, 9.67 mmol), and 1-hydroxybenzotriazole.monohydrate (1.23 g, 8.06 mmol). The mixture was diluted with chloroform, and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and crystallized from diethyl ether to give N-(2-hydroxypropyl)-3-iodobenzamide (1.71 g, 70%).
Reaction SMILES: Cl.[CH2:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][C:6]1=[O:11])[CH:3]=[CH2:4].C(N(C(C)C)CC)(C)C.[CH3:21][CH:22]([N:24]=[C:25]=[O:26])[CH3:23].O>ClCCl>[CH2:2]([N:5]1[CH2:10][CH2:9][N:8]([C:25](=[O:26])[NH:24][CH:22]([CH3:23])[CH3:21])[CH2:7][C:6]1=[O:11])[CH:3]=[CH2:4]
Reactant: CC(C)N=C=O
Reactant: C=CCN1CCNCC1=O
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN1CCN(C(=O)NC(C)C)CC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(2-propenyl)-2-piperazinone hydrochloride (7.9 g, 44 mmol) and diisopropylethylamine (8 mL, 46 mmol) in dichloromethane (100 mL) was added 2-propylisocyanate (5.6 g, 66 mmol). The mixture was stirred at ambient temperature for 18 h. Water (75 mL) was added, and the organic layer was collected, dried (MgSO4), filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography using a gradient elution of 2%, 3%, 4% MeOH in CH2Cl2. Product-containing fractions were combined and concentrated in vacuo to yield 1-(2-propenyl)-4-(N-2-propylcarbamoyl)-2-piperazinone as a solid. HPLC RT=2.17 min (Mehtos A); ES MS (M+H)=226; 1H NMR (400 MHz, CDCl3) δ 5.75 (ddt, 1H), 5.2 (overlapping doublets, 2H), 4.32 (b rd, 1H), 4.04 (d, J=6 Hz, 2H), 3.97 (s, 2H), 3.67 (t, J=7 Hz, 2H), 3.33 (t, J=7 hz, 2H), 1.16 (d, J=7 Hz, 6H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:48][CH:49]1[C@H:53]2[C@H:54](OC3CCCCO3)[N:55](C(OC(C)(C)C)=O)[C:56]3[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[CH:60][C:57]=3[C:58](=[O:59])[N:52]2[CH2:51][CH2:50]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH:17]1[C@H:21]2[C@H:22](OC3CCCCO3)[N:23](C(OC(C)(C)C)=O)[C:24]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:25]=3[C:26](=[O:27])[N:20]2[CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:48][CH:49]1[C@@H:53]2[CH:54]=[N:55][C:56]3[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[CH:60][C:57]=3[C:58](=[O:59])[N:52]2[CH2:51][CH2:50]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH:17]1[C@@H:21]2[CH:22]=[N:23][C:24]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:25]=3[C:26](=[O:27])[N:20]2[CH2:19][CH2:18]1
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)[C@@H](OC1CCCCO1)[C@@H]1C(OCCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)CCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)N=C[C@H]1C(OCCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N=C[C@@H]34)CCN1C2=O
Reaction time: 1 h
Yield: 94.4 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 8f (191 mg, 0.18 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9f (106 mg, 0.17 mmol, 97%) as a solid: [α]20D=+467° (c=0.14, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.34-1.53 (m, 8H, 14-H, 14′-H, 15-H, 15′-H), 1.78-1.91 (m, 4H, 13-H, 13′-H), 1.96-2.10 (m, 4H, 2-H, 2′-H), 2.25-2.38 (m, 4H, 1-H, 1′-H), 3.54-3.63 (m, 2H, 3-H, 3′-H), 3.70-3.76 (m, 2H, 11a-H, 11a′-H), 3.77-3.88 (m, 2H, 3-H, 3′-H), 3.90 (s, 6H, 7-OMe, 7′-OMe), 4.04-4.17 (m, 4H, 12-H, 12′-H), 6.81 (s, 2H, 9-H, 9′-H), 7.52 (s, 2H, 6-H, 6′-H), 7.67 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.8, 29.0, 29.1, 29.6, 46.6, 53.7, 56.0, 69.0, 109.6, 112.5, 120.2, 140.5, 147.1, 151.6, 162.3, 164.6; IR (neat): 3326, 2937, 1599, 1506, 1448, 1387, 1262, 1217, 1092, 1023 cm−1; MS (FAB) m/z (relative intensity) 667 ([M+2×MeOH]+., 7), 635 ([M+MeOH]+., 15), 603 (M+., 100).