Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.CN1CCOCC1.[O:18]=[C:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:24][C:25](O)=[O:26].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:25](=[O:26])[CH2:24][N:20]1[CH2:21][CH2:22][CH2:23][C:19]1=[O:18]
Reactant: O=C(O)CN1CCCC1=O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1CCCN1C(=O)CN1CCCC1=O
Temperature: -25 °C
Reaction time: 16 h
Yield: 101.9 %

Procedure:
To a solution of L-proline methyl ester hydrochloride (8.28 g) in DMF (100 ml) were added N-methylmorpholine (5.50 ml), 2-oxo-1-pyrrolidine acetic acid (7.15 g) and HOBt (10.12 g) under ice-cooling. The mixture was cooled to -25° C., added with DCC (10.32 g), and stirred at room temperature for 16 hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 12.94 g of N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-proline methyl ester.
Reaction SMILES: [CH2:1](Cl)[CH3:2].[N:4]1([CH2:10][CH2:11][CH2:12][O:13][C:14]([N:16]2[N:21]=[C:20]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32](=[O:43])[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=3)[CH2:27][CH2:26][CH2:25]4)[CH:19]([CH3:44])[S:18][C:17]2=[O:45])=[O:15])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([N:7]1[CH2:6][CH2:5][N:4]([CH2:10][CH2:11][CH2:12][O:13][C:14]([N:16]2[N:21]=[C:20]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32](=[O:43])[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=3)[CH2:27][CH2:26][CH2:25]4)[CH:19]([CH3:44])[S:18][C:17]2=[O:45])=[O:15])[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCCl
Reactant: COc1ccc(C(=O)N2CCCc3cc(C4=NN(C(=O)OCCCN5CCNCC5)C(=O)SC4C)ccc32)cc1OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN1CCN(CCCOC(=O)N2N=C(c3ccc4c(c3)CCCN4C(=O)c3ccc(OC)c(OC)c3)C(C)SC2=O)CC1

Procedure:
1.3 g of ethyl chloride dissolved in 10 ml of toluene are added dropwise with stirring to a solution of 10 g of 3-(3-piperazinopropoxycarbonyl)-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one and 1.8 g of triethylamine in 100 ml of toluene, and the mixture is stirred with heating for one hour. The solvent is removed and the mixture is worked up in the conventional manner to give 3-[3-(1-ethyl-4-piperazinyl)-propoxycarbonyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one.
Reaction SMILES: [CH:1]([S:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])(=[O:6])=[O:5])([CH3:3])[CH3:2].O1CCCC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl-].[Na+]>O>[CH:1]([S:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)Nc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)Nc1cc(C(=O)c2ccccc2)ccc1N

Procedure:
A solution of 3.91 g. (0.0112 m.) of 3-(isopropylsulfonyl)amino-4-nitrobenzophenone in 60 ml. of tetrahydrofuran (THF) was added dropwise over a period of 30 minutes to a stirred solution of 23.7 g. of sodium hydrosulfite in 200 ml. of water. After 60 minutes of additional stirring, solid sodium chloride was added and the layers were separated. The aqueous layer was extracted with THF, and the combined THF extracts were washed with a saturated solution of sodium chloride. Evaporation of the THF gave crude 3-(isopropylsulfonyl)amino-4-aminobenzophenone which was used without further purification in the subsequent cyclization. A small sample was crystallized from isopropanol several times to give the pure compound as colorless blocks, m.p. about 143°-145° C.
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([CH3:3])[CH3:2].O.N.[CH2:14](O)[CH3:15]>S(=O)(=O)(O)O>[CH2:14]([O:10][C:9]([C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[NH:8][N:7]=1)=[O:11])[CH3:15]
Reactant: CC(C)c1cc(C(=O)O)n[nH]1
Reactant: CCO
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1cc(C(C)C)[nH]n1

Procedure:
5-Isopropyl-1H-pyrazole-3-carboxylic acid (WO 03/035065, page. 485, example 17b) (1.00 g, 6.49 mmol) was dissolved in a mixture of concentrated sulphuric acid (1.5 mL) and ethanol (25 mL) and the reaction mixture heated at reflux for 3 hours. The reaction mixture was cooled, poured into water, basified with 0.88 ammonia then extracted with ethyl acetate. The ethyl acetate was washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield the title product, 514 mg (43%).
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][C@H:10]([CH3:12])[CH2:9][N:8]2[C:13]([O:15]C(C)(C)C)=O)=[N:4][CH:3]=1.[CH3:20][O:21][C:22]([NH:24][C@@H:25]([C@@H:29]([CH3:32])[CH2:30][CH3:31])C(O)=O)=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>Cl.CCO.CN(C=O)C>[Br:1][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][C@H:10]([CH3:12])[CH2:9][N:8]2[C:13](=[O:15])[C@@H:25]([NH:24][C:22](=[O:23])[O:21][CH3:20])[C@@H:29]([CH3:32])[CH2:30][CH3:31])=[N:4][CH:3]=1
Reactant: C[C@H]1C[C@@H](c2ncc(Br)[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1C[C@@H](C)C[C@H]1c1ncc(Br)[nH]1
Reaction time: 2 h
Yield: 1786.5 %

Procedure:
(2S,4S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (100 mg, 0.13 mmol) in 1.25 N HCl in EtOH (15 mL) was heated to 50° C. for 3 h and then concentrated under reduced pressure. The crude residue was treated with (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid (625 mg, 3.30 mmol), HATU (1.05 g, 2.77 mmol) and DMF (10 mL), then DIPEA (1.33 mL, 7.62 mmol) was added dropwise. After 2 h, the mixture was poured into saturated aqueous NaHCO3 and then extracted with EtOAc. The organic phase was washed with successively with 5% aqueous LiCl and Brine. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (30 to 90% of 10% MeOH/EtoAc to Hexanes) afforded methyl (2S,3S)-1-((2S,4S)-2-(5-bromo-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-ylcarbamate (932 mg, 81%).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9]O>>[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[C:3]1([O:4][CH3:9])[C:1](=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:2]
Reactant: CO
Agent: Oc1ccccc1O
Product: COc1ccccc1O
Reaction time: 14 h

Procedure:
The catalyst stratum was heated and when the temperature of the catalyst stratum reached 280° C., a starting compound mixture gas consisting of catechol and methyl alcohol in a molar mixing ratio of 1:3.44 and evaporated in an evaporator was fed, at a feeding rate of 10.5 g/min, together with nitrogen gas, into the reaction tube for 14 hours, to cause a catalytic dehydration (etherification) reaction of catechol with methyl alcohol and provide monoalkyl ester of catechol, i.e., guaiacol.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH2:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4]1)[CH3:2]>CO.[Pd]>[CH2:1]([CH:3]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1)[CH3:2]
Reactant: CCC1C=C(C(=O)OC)CC1
Agent: [Pd]
Solvent: CO
Product: CCC1CCC(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl 3-ethylcyclopent-1-enecarboxylate (1.60 g, 10.3 mmol) in methanol (15 mL) was added 10% Pd/C (100 mg), and the mixture was purged with hydrogen for 10 minutes. Then reaction mixture was then stirred at room temperature for 16 hours under a hydrogen atmosphere (balloon). The reaction mixture was then filtered through a pad of celite, and the filtrate was concentrated to dryness to afford methyl 3-ethylcyclopentanecarboxylate as a mixture of cis and trans isomers.
Reaction SMILES: [OH:1][C@@H:2]([CH2:14][N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1.[K+].[Br-].C=O.N1CCNCC1>C(OCC)(=O)C.[OH-].[OH-].[Pd+2].C(Cl)(Cl)Cl>[NH2:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][CH2:3][C@@H:2]([OH:1])[CH2:14][N:15]1[CH2:16][CH2:17][N:18]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:19][CH2:20]1
Reactant: COc1ccc(S(=O)(=O)N2CCN(C[C@H](O)COc3cccc([N+](=O)[O-])c3)CC2)cc1
Agent: [Pd+2]
Agent: C1CNCCN1
Agent: C=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)N2CCN(C[C@H](O)COc3cccc(N)c3)CC2)cc1

Procedure:
Pd(OH)2/C at 20% [1.54 g, 2.2 mM Pd(OH)2] is suspended in a solution of (S)-2-hydroxy-3-[4-(4-methoxyphenylsulfonyl)piperazin-1-yl)-1-(3-nitrophenoxy)propane (3.30 g, 7.73 mM) (Example 27) in ethyl acetate (43 ml). The mixture is maintained in agitation in atmosphere of H2 (10 atm) for 30 hours. The catalyst is then removed by filtering the reaction mixture on Celite, and the solvent is distilled under vacuum. A white solid is obtained (97% of yield). Pf 138.5-139.6° Cs. [α]D=−10.7 (c 1.06, CHCl3). FT-IR (KBr): 3456, 3371, 3100, 3063, 2945, 2916, 2853, 1597, 1576, 1497, 1456, 1343, 1328, 1302, 1263, 1195, 1161, 1096, 948, 839, 809, 773, 737, 694, 660 cm −1. 1NMRs (300 MHz CDCl3, δ): 7.71-7.67 (m, 2H, aromatic protons); 7.05-6.98 (m, 3H, aromatic protons); 6.30-6.29 (d, 1H, J=2.2 Hz, aromatic proton); 6.27-6.26 (m, 1H, aromatic proton); 6.23-6.22 (t, J=2.2 Hz, 1H, aromatic proton); 4.05-3.97 (m, 1H, CHOH); 3.89-3.88 (m, 5H, CH2O and OCH3), 3.70-3.10 (bs, 2H, NH2); 3.10-2.85 (bs, 5H, 2 CH2N of piperazine and OH); 2.79-2.69 (m, 2H, CH2N of piperazine); 2.58-2.45 (m, 4H, CH2N of piperazine and CHOHCH2N). 13C NMRs (75 MHz CD3OD, δ): 163.39, 159.95, 148.03, 130.35, 130.16, 127.15, 114.51, 108.55, 104.67, 101.90, 70.09, 66.07, 60.46, 55.87, 52.69, 46.28. MS-ESI m/z (%): 444 [M+Na]+ (100). Anal. Calc. for C20H27N3O5S: C, 56.99; H, 6.46; N, 9.97. Found: C, 56.91; H, 6.41; N, 9.69.
Reaction SMILES: [CH:1]([N:3]1[C:7](=[O:8])[CH2:6][CH2:5][C:4]1=[O:9])=[CH2:2].C(Cl)(Cl)(Cl)[Cl:11]>>[Cl:11][CH:1]([N:3]1[C:7](=[O:8])[CH2:6][CH2:5][C:4]1=[O:9])[CH3:2]
Reactant: C=CN1C(=O)CCC1=O
Reactant: ClC(Cl)(Cl)Cl
Product: CC(Cl)N1C(=O)CCC1=O
Reaction time: 24 h

Procedure:
N-vinylsuccinimide, 50.0 g. (0.40 mole) is dissolved in 1000 ml. carbon tetrachloride, 5.20 g. (0.020 mole) of stannic chloride is added and the mixture is stirred while saturating with hydrogen chloride for 6 hours at 20-30° C. After 24 hours, the mixture is resaturated with hydrogen chloride for 1.5 hours. At the end of 48 hours, the solution is decanted and the gummy residue is washed with ten 100 ml. portions of carbon tetrachloride. The combined extracts are slurried with 10 g. of diatomaceous earth, filtered an the filtrate concentrated under reduced pressure to approximately 400 ml. The N-(1-chloro-ethyl)-succinimide is filtered and dried at 20°-30° C. under reduced pressure to yield 38.4 g. (59%) of white solid melting at 83.5°-84.5° C.
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11]CC)=[O:10])[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)=O)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)c1cc(C(=O)O)n[nH]1
Yield: 87.6 %

Procedure:
Ethyl 5-acetyl-1H-pyrazole-3-carboxylate (0.050 g, 0.274 mmol) was dissolved in EtOH (5 mL) and treated with a 2 M solution of NaOH (0.5 mL, 1 eq.) at reflux temperature for 3 h. Solvent was evaporated to dryness and the residue dissolved in H2O. After treatment with 2M HCl the resulting precipitate was extracted with DCM. The organic phase was dried on Na2SO4 and concentrated to dryness to give the title compound (37 mg, 87% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][C:9]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.Br[CH2:48]COCC.BrCCOC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][C:9]([O:40][CH2:41][CH2:42][O:43][CH2:44][CH3:48])=[CH:8][CH:7]=2)=[CH:45][CH:46]=1
Reactant: COCCOc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: CCOCCBr
Agent: COCCBr
Product: CCOCCOc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1

Procedure:
The title compound was synthesized as described for Compound 475, except 1-bromo-2-ethoxy ethane was used for alkylation instead of 1-bromo-2-methoxy ethane.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@:11]([CH3:15])([OH:14])[C@H:10]([OH:16])[CH2:9]1)C1C=CC=CC=1.C([N+]([O-])=O)CCCCC>>[CH3:15][C@:11]1([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[OH:16]
Reactant: C[C@]1(O)CCN(Cc2ccccc2)C[C@H]1O
Agent: CCCCCC[N+](=O)[O-]
Product: C[C@]1(O)CCNC[C@H]1O

Procedure:
The product was obtained analogously to IP 5d starting from 1.23 g (5.57 mmol) of (3R,4S)-1-benzyl-4-methylpiperidin-3,4-diol. Yield: 730 mg (quant. yield); C6H13NO2 (M=131.173); calc.: molpeak (M+H)+: 132; found: molpeak (M+H)+: 132; HPLC-MS: 0.93 minutes (method C).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]3[N:23]=[C:24]([OH:26])[CH:25]=[C:19]3[C:18]2=[O:27])=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:26][C:24]1[CH:25]=[C:19]2[C:18](=[O:27])[N:17]([C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=3)[CH2:22][CH2:21][N:20]2[N:23]=1
Reactant: Fc1ccccc1CBr
Reactant: O=C1c2cc(O)nn2CCN1c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C1c2cc(OCc3ccccc3F)nn2CCN1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
2-Fluorobenzyl bromide (0.049 mL, 0.39 mmol) was added to a stirred suspension of 5-(4-fluorophenyl)-2-hydroxy-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.092 g, 0.36 mmol) and Cs2CO3 (0.234 g, 0.72 mmol) in ACN (1.85 mL). The mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo. The residue was diluted with water and extracted with AcOEt. The organic layer was separated, washed with a saturated solution of NaCl, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield 2[(2-fluorobenzyl)oxy]-5-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.109 g, 85% yield) as a white solid. C19H15F2N3O2. 1H NMR (500 MHz, CDCl3) δ ppm 4.14 (dd, J=6.8, 5.1 Hz, 2H), 4.37 (dd, J=6.9, 5.2 Hz, 2H), 5.30 (s, 2H), 6.37 (s, 1H), 7.04-7.15 (m, 3H), 7.17 (td, J=7.5, 0.9 Hz, 1H), 7.28-7.36 (m, 3H), 7.53 (td, J=7.4, 1.4 Hz, 1H).
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].C=O>O1CCCC1>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 45 °C

Procedure:
To a solution of (S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-but-1-enyl)-pyrrolidin-2-one (4a, R1=1-butenyl, R4=phenyl) (5.5 g, 13.2 mmol) in 25 mL of tetrahydrofuran is added 1 M K2CO3 aqueous solution (26.4 mL, 26.4 mmol), 37% CH2O aqueous solution (2.2 mL, 26.4 mmol) and n-Bu4NOH (0.4 mL, 0.7 mmol), heat to 45° C. under N2 for 2 h, cool to room temperature, extract with toluene, the combined organic layer are washed with 5% HCl(aq), saturated Na2CO3 aqueous solution and brine, dry over anhydrous Na2SO4, evaporate the solvent, the residue is purified by column chromatography to obtain (R)-5-Biphenyl-4-ylmethyl-1-((E)-but-1-enyl)-3-methylene-pyrrolidin-2-one (1a, R1=1-butenyl). Spectroscopic data as Example 24, Method 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][N+:8]([O-:10])=[O:9].[CH3:16][N:17]([CH3:21])[C:18](=[S:20])[S-:19].C[NH2+]C>C(=S)=S>[CH3:16][N:17]([CH3:21])[C:18](=[S:19])[S:20][CH:6]([CH2:7][N+:8]([O-:10])=[O:9])[C:5]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1OC
Reactant: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: S=C=S
Product: COc1ccc(C(C[N+](=O)[O-])SC(=S)N(C)C)cc1OC

Procedure:
As in Example 17, reaction of 3,4-dimethoxy-β-nitrostyrene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave 3,4-dimethoxy-α-(nitromethyl)-benzyl dimethyldithiocarbamate melting at 108° C.-110° C. after recrystallization without heating from acetone-methanol solution.
Reaction SMILES: C([O:4][C@H:5]([CH2:10]Br)[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[OH-].[Ca+2:13].[OH-]>O>[Ca+2:13].[O:4]1[CH2:10][C@@H:5]1[CH2:6][C:7]([O-:9])=[O:8].[O:4]1[CH2:10][C@@H:5]1[CH2:6][C:7]([O-:9])=[O:8]
Reactant: CC(=O)O[C@H](CBr)CC(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C[C@H]1CO1
Reaction time: 2 h

Procedure:
A solution of distilled water (10 ml), (S)-3-acetoxy-4-bromobutyric acid (0.9 g, 0.004 mol) and calcium hydroxide (0.45 g, 0.006 mol) was charged to 100 ml flask equipped with a thermometer, pH meter and agitator, and stirred at 0˜5° C. for 2 hours to give (S)-3,4-epoxybutyric acid calcium salt. It was confirmed by a NMR analysis that more than 99% (S)-3,4-epoxybutyric acid calcium salt was converted.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)[C:6]([OH:8])=[O:7]>C(O)C>[NH2:12][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: CCO
Product: COc1cc(N)cc(C(=O)O)c1
Yield: 111 %

Procedure:
3-Methoxy-5-nitrobenzoic acid (510 mg) was dissolved in 5 ml of ethanol and 10% Pd(C) (50 mg) was added. The resulting suspension was stirred under a hydrogen-filled balloon for 2 hours. Then the reaction mixture was filtered and concentrated to dryness. Isolated dark brown solid (480 mg) was used without further purification in the next step.
Reaction SMILES: [CH:1]1[N:5]([CH:6]2[O:10][CH:9]([CH2:11][OH:12])[CH:8]([OH:13])[CH:7]2[OH:14])[C:4]2[N:15]=[C:16]([NH2:20])[N:17]=[C:18](Cl)[C:3]=2[N:2]=1.Cl.[I:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27].C(N(CC)CC)C>C(O)C>[NH2:20][C:16]1[N:15]=[C:4]2[C:3]([N:2]=[CH:1][N:5]2[C@@H:6]2[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]2[OH:14])=[C:18]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([I:22])[CH:24]=2)[N:17]=1
Reactant: NCc1cccc(I)c1
Reactant: Nc1nc(Cl)c2ncn(C3OC(CO)C(O)C3O)c2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(NCc2cccc(I)c2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 80 °C
Yield: 76.4 %

Procedure:
A mixture of 2-amino-6-chloropurine riboside (purchased from Aldrich Chemical Co., 80 mg, 0.26 mmol), 3-iodobenzylamine hydrochloride (71.5 mg, 0.265 mmol), and triethylamine (0.11 ml, 0.79 mmol) in ethanol (1.6 ml) was heated for 24 h at 80° C. After the reaction mixture was concentrated to dryness the residue was purified on a silica gel column chromatography (CHCl3 --MeOH, 20:1→10:1) to yield 2-amino-N6 -(3-iodobenzyl)-9-[β-D-ribofuranosyl]-adenine (99 mg, 75%) as a colorless solid: m.p. 152°-154° C.; 1H NMR (DMSO-d6) d 3.52 (m, 1H, H-5'a), 3.63 (m, 1H, H-5'b), 3.89 (m, 1H, H-4'), 4.10 (m, 1H, H-3'), 4.50 (m, 1H, H-2'), 4.60 (br s, 2H, CH2), 5.08 (d, J=4.6 Hz, 1H, exchangeable with D2O, 3'-OH), 5.35 (m, 2H, exchangeable with D2O, 5'- and 2'-OH), 5.73 (d, J=6.2 Hz, 1H, H-1'), 5.83 (br s, 2H, exchangeable with D2O, NH2), 7.11 (pseudo t, J=7.9 and 7.8 Hz, 1H, H-5"), 7.36 (d, J=7.8 Hz, 1H, H-4" or -6"), 7.58 (d, J=7.8 Hz, 1H, H-4" or -6"), 7.70 (s, 1H, H-2"), 7.94 (s, 1H, H-8).
Reaction SMILES: [CH2:1]1[CH2:6][O:5][CH:4]=[CH:3][CH2:2]1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[Br:22][C:23]1[C:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:39][OH:40].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:22][C:23]1[C:28]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:39][O:40][CH:4]1[CH2:3][CH2:2][CH2:1][CH2:6][O:5]1
Reactant: COc1ccc(COc2cccc(CO)c2Br)cc1
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(COc2cccc(COC3CCCCO3)c2Br)cc1
Temperature: 25 °C

Procedure:
DHP (0.67 mL, 7.4 mmol) and CSA (30 mg, 0.12 mmol) were added to a solution of [2-bromo-3-(4-methoxy-benzyloxy)-phenyl]-methanol (2.0 g, 6.1 mmol) in CH2Cl2 (15 mL). The resulting mixture was stirred at rt O/N. 4 Å Molecular sieves (1.0 g) was added and mixture was stirred for 1 h. Sat. NaHCO3 was added and mixture was extracted with CHCl3 (2×50 mL). The organic fractions were washed with H2O (2×25 mL) then brine (50 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (25% EtOAc in hexane) to give the title compound as yellow oil: yield 1.30 g (96%).
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][C:28]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[N:27][CH:26]=1)[CH:20]([NH:36][C:37](=[O:67])[C:38](=[N:64][O:65][CH3:66])[C:39]1[N:40]=[C:41]([NH:44]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:42][CH:43]=1)[C:19]2=[O:68])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1>C(O)=O>[NH2:44][C:41]1[S:42][CH:43]=[C:39]([C:38](=[N:64][O:65][CH3:66])[C:37]([NH:36][CH:20]2[C:19](=[O:68])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([C:25]2[S:29][C:28]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[N:27][CH:26]=2)=[C:17]3[C:15]([OH:16])=[O:14])=[O:67])[N:40]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4cccnc4)s3)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Solvent: COc1ccccc1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(c3cnc(-c4cccnc4)s3)CSC12)c1csc(N)n1
Yield: 89.2 %

Procedure:
The syn isomer of 2-benzhydryloxycarbonyl-7[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-3-[2-(pyridin-3-yl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.1 g) is treated with formic acid (20 cc) containing anisole (2 cc) for 30 minutes at 50° C. and the reaction mixture is then concentrated to dryness under reduced pressure (1 mm Hg; 0.13 kPa) at 40° C. The residue is taken up in ethanol (20 cc), which is evaporated off under reduced pressure (30 mm Hg; 4 kPa) at 40° C.; this operation is repeated a further 2 times. The residue is solidified with ethanol (150 cc). The solid is filtered off, washed with ethanol (2×5 cc) and ethyl ether (3×20 cc) and dried to give the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-2-carboxy-8-oxo-3-[2-(pyridin-3-yl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.56 g) in the form of a pale yellow solid.