Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1CCC(N=C=NC2CCCCC2)CC1.[O:16]=[C:17]1[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]1.CO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:16]=[C:17]1[CH2:20][CH:19]([C:21]([O:23][CH3:1])=[O:22])[CH2:18]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CC(C(=O)O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.7 %

Procedure:
To a solution of DCC (5.96 g, 28.95 mmol) in DCM (20 ml) was added dropwise a mixture of 3-oxocyclobutanecarboxylic acid (3.0 g, 26.31 mmol), MeOH (1.68 g, 52.62 mmol) and DMAP (2.57 g, 21.05 mmol) in DCM (30 ml). The reaction mixture was stirred at RT overnight. The mixture was filtrated. The filtrate was washed with 0.5 M HCl solution (50 ml). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by SGC (PE:EA=5:1) to obtain the title compound (4.0 g). 1H N.R (500 MHz, CDCl3): δ 3.77 (s, 3H), 3.42-3.26 (m, 5H) ppm.
Reaction SMILES: C1([C:7]2O[N:10]=[C:9]([NH2:12])[N:8]=2)C=CC=CC=1.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([N:18]2[CH:7]=[N:8][C:9]([NH2:12])=[N:10]2)=[CH:16][CH:15]=1
Reactant: Nc1noc(-c2ccccc2)n1
Reactant: Nc1ccc(Cl)cc1
Product: Nc1ncn(-c2ccc(Cl)cc2)n1

Procedure:
Prepared in analogy to example 18a), starting with 5-phenyl-[1,2,4]oxadiazol-3-ylamine and 4-chloroaniline. The title compound was obtained as brownish solid (Yield=54%). MS ISP (m/e): 195.1 (100) [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:27][OH:28])[CH:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:16]=3[N:15]=2)=[CH:10][CH:9]=1.[Mn]([O-])(=O)(=O)=[O:30].[K+]>N1C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[NH:18][C:17]4[CH:19]=[C:20]([C:23]([F:25])([F:26])[F:24])[CH:21]=[CH:22][C:16]=4[N:15]=3)=[CH:10][CH:9]=2)=[N:6][CH:5]=[C:4]([CH:3]=1)[C:27]([OH:30])=[O:28]
Reactant: OCc1cnc(-c2ccc(-c3nc4ccc(C(F)(F)F)cc4[nH]3)cc2)c(Cl)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1cnc(-c2ccc(-c3nc4ccc(C(F)(F)F)cc4[nH]3)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
0.40 g of {5-chloro-6-[4-(6-trifluoromethyl-1H-benzoimidazol-2-yl)-phenyl]-pyridin-3-yl}-methanol (28) (0.99 mmol) prepared in Example 16 was dissolved in 4 mL of pyridine and 2 mL of distilled water. 0.59 g of potassium permanganate (3.71 mmol) was added thereto, and reacted at 110° C. for 4 hours. Then, 0.59 g of potassium permanganate (3.71 mmol) and 2 mL of distilled water were added thereto, and reacted at 110° C. for 18 hours. The resultant was cooled to room temperature, and concentrated under reduced pressure. The aqueous layer was washed with ethyl acetate, pH 1 was adjusted with concentrated hydrochloric acid, and extracted with ethyl acetate several times. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/1) to obtain 0.32 g of 5-chloro-6-[4-(6-trifluoromethyl-1H-benzoimidazol-2-yl)-phenyl]-nicotinic acid (yield 77%).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:16]=[CH:15][C:11]2[CH:12]=[N:13][S:14][C:10]=2[C:9]=1[F:17])=[O:7])(C)(C)C.O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:17][C:9]1[C:10]2[S:14][N:13]=[CH:12][C:11]=2[CH:15]=[CH:16][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc2cnsc2c1F
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc2cnsc2c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 7-fluoro-benzo[d]isothiazole-6-carboxylic acid tert-butyl ester (1.0 g, 4.0 mmol) in DCM (10 mL) was added water (0.2 mL) and TFA (10 mL). There reaction mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was azeotroped with toluene to give the title compound as a yellow solid (788 mg, 100%). LCMS (method B): RT=2.86 min, [M−H]−=196.
Reaction SMILES: [CH2:1](N(CC)CC)C.O[C:9]1([CH3:17])[CH2:14]S[C:12]([OH:16])([CH3:15])[CH2:11][S:10]1.Cl[C:19]1[C:28]2[C:23](=C[CH:25]=[CH:26][CH:27]=2)C[CH2:21][C:20]=1[CH:29]=O.[OH-].[Na+]>O.C(O)C>[C:12]([C:11]1[S:10][C:9]2[C:17]3[C:27]([CH2:26][CH2:25][C:14]=2[CH:1]=1)=[C:28]([CH3:23])[CH:19]=[C:20]([CH3:29])[CH:21]=3)(=[O:16])[CH3:15]
Reactant: CC1(O)CSC(C)(O)CS1
Reactant: CCN(CC)CC
Reactant: O=CC1=C(Cl)c2ccccc2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)c1cc2c(s1)-c1cc(C)cc(C)c1CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Next, 1.4 mL of triethylamine was added dropwise to a 10 mL ethanol solution of 0.9 g of 2,5-dihydroxy-2,5-dimethyl-1,4-dithiane, and the system was stirred for 30 minutes at room temperature. To this was added at room temperature a 10 mL ethanol solution of the 1-chloro-2-formyl-3,4-dihydronaphthalene obtained previously, and the system was refluxed under heating overnight. After the reaction, reduced-pressure solvent distillation was performed, first water and then 2M a sodium hydroxide aqueous solution were added under ice cooling, and extraction was performed with ethyl acetate. The organic layer was washed first with a saturated ammonium chloride aqueous solution and then with saturated brine, dried with magnesium sulfate, and subjected to reduced-pressure solvent distillation, and the residue was refined by silica gel column chromatography (20% ethyl acetate/hexane) and then recrystallized with ethanol to obtain 1.6 g of 2-acetyl-4,5-dihydro-6,8-dimethylnaphtho[1,2-b]thiophene (Table 6-1) in the form of yellow crystals.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C@@H:22]([OH:25])[CH2:23][OH:24])[C:16](=[O:26])[CH:15]2[CH3:27])[CH:10]=[CH:11][C:12]=1[Cl:13].CC1C=C(C)C=C(C)N=1>CC(N(C)C)=O>[Cl:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C@@H:22]([OH:25])[CH2:23][O:24][S:2]([CH3:1])(=[O:4])=[O:3])[C:16](=[O:26])[CH:15]2[CH3:27])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CC1C(=O)N(CC[C@@H](O)CO)CCN1c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC(=O)N(C)C
Product: CC1C(=O)N(CC[C@@H](O)COS(C)(=O)=O)CCN1c1ccc(Cl)c(Cl)c1
Yield: 129.8 %

Procedure:
A solution of methanesulfonyl chloride (53 mg, 0.46 mmol) in DMA (0.5 mL) was added at 0° C. to a solution of 4-(3,4-dichloro-phenyl)-1-((R)-3,4-dihydroxy-butyl)-3-methyl-piperazin-2-one (160 mg, 0.46 mmol) and 2,4,6-trimethylpyridine (279 mg, 2.30 mmol) in DMA (2 mL), then after 2½ h the reaction mixture was partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford crude methanesulfonic acid (R)-4-[4-(3,4-dichloro-phenyl)-3-methyl-2-oxo-piperazin-1-yl]-2-hydroxy-butyl ester (254 mg) as a light yellow gum. This was dissolved in DMA (2 mL), cooled to 0° C., and treated with NaH (55% dispersion in mineral oil, 41 mg, 0.94 mmol). After 15 min, as the methanesulfonate intermediate had disappeared, with mass spectrometry confirming the formation of the epoxide intermediate, 4-(3,4-dichloro-phenyl)-3-methyl-1-((R)-2-oxiranyl-ethyl)-piperazin-2-one [m/e=329, (M+H)+)], cesium carbonate (184 mg, 0.56 mmol) and a solution of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 77 mg, 0.47 mmol) and N,N-diisopropylethylamine (152 mg, 1.2 mmol) in DMA (1 mL) were added. The reaction mixture was heated at 80° C. for 20 h, then diluted with EtOAc/MeOH 4:1 and filtered through diatomaceous earth. The filtrate was chromatographed (IST Isolute® Flash NH2; EtOAc/MeOH gradient) to produce the title compound (101 mg, 47%). Light yellow foam, MS: 456.2 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CC(C)=O.C(=O)=O.[NH3:19]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH2:19])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: N
Agent: O=C=O
Solvent: CC(C)=O
Product: Nc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 7 h

Procedure:
2,4-Difluoronitrobenzene (1.0 eq) was placed in a dry round-bottomed flask equipped with a dry ice condenser charged with acetone/dry ice. Ammonia was condensed into the flask and the resulting solution was stirred at reflux for 7 hours. A yellow precipitate was formed within 1 hours. After 7 hours, the condenser was removed and the liquid ammonia was allowed to evaporate over several hours. The crude product was purified by flash chromatography on silica gel (85:15 hexanes:EtOAc, product at R=0.32, contaminant at Rf=0.51). GC/MS m/z 156.1 (M+), Rf 11.16 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:10]1[CH2:20][C:18](=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1>C1COCC1.CCOCC>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:18][CH2:20][CH:10]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCCc2ccccc21
Reactant: COc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(C2=CCCc3ccccc32)c1
Reaction time: 8 h

Procedure:
A solution of the Grignard reagent derived from 50 g (0.27 mol) of 3-bromoanisole in 200 ml of dry THF was treated with a solution of alpha-tetralone in 100 ml of THF added over 1 hour while maintaining the internal temperature at 15°-25° C. After stirring overnight, the mixture was diluted with 500 ml of ether and quenched with 200 ml of 20% aqueous ammonium chloride. The aqueous layer was extracted with 200 ml of ether. The combined organic layers were dried over MgSO4 and evaporated to 66.5 g of the oily alcohol. This was dissolved in 450 ml of dry toluene containing 0.020 g of p-toluenesulfonic acid and refluxed overnight in a Dean-Stark apparatus. After cooling, the mixture was washed with 100 ml of 5% sodium bicarbonate, with 100 ml of water, and then with 100 ml of brine. The mixture was dried over MgSO4 and evaporated. The residue was distilled under reduced pressure to give the title compound, b.p. (0.5 mm) 158°-162° C.
Reaction SMILES: [N+](C(OC(C)C)=O)(C(OC(C)C)=O)=[N-].[O:15]=[C:16]1[NH:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])[CH:18]=[CH:17]1.[CH3:30][C:31]1[CH:32]=[N:33][C:34]([C:37]2[CH:38]=[C:39]([CH2:43]O)[CH:40]=[CH:41][CH:42]=2)=[N:35][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:30][C:31]1[CH:36]=[N:35][C:34]([C:37]2[CH:38]=[C:39]([CH:40]=[CH:41][CH:42]=2)[CH2:43][N:21]2[C:16](=[O:15])[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])=[N:20]2)=[N:33][CH:32]=1
Reactant: N#Cc1cccc(-c2ccc(=O)[nH]n2)c1
Reactant: Cc1cnc(-c2cccc(CO)c2)nc1
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cnc(-c2cccc(Cn3nc(-c4cccc(C#N)c4)ccc3=O)c2)nc1

Procedure:
8.3 147 μl (0.75 mmol) of diisopropyl diazodicarboxylate are added dropwise to a suspension of 98.6 mg (0.50 mmol) of 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 100 mg (0.50 mmol) of [3-(5-methylpyrimidin-2-yl)phenyl]methanol and 197 mg (0.75 mmol) of triphenylphosphine in 3 ml of THF, and the resultant solution is stirred at room temperature for 18 hours. The reaction mixture is evaporated in vacuo, and 2-propanol is added to the residue. The resultant precipitate is filtered off with suction and chromatographed on a silica gel column with dichloromethane/methanol as eluent: 3-{1-[3-(5-methylpyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile (“A15”) as yellowish solid; ESI 380;
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].Cl[C:6]1[CH:11]=[C:10](Cl)[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14].[CH3:16][OH:17]>>[CH3:1][O:2][C:6]1[CH:11]=[C:10]([O:17][CH3:16])[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: CO
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Product: COc1ccc([N+](=O)[O-])c(OC)c1

Procedure:
To a solution of sodium methoxide in methanol (freshly prepared by adding 50.0 g (2.17 mol) of sodium, in portions, to 1.5 l of methanol at 0° C.) was added 2,4-dichloro-nitrobenzene (95.0 g, 0.495 mol) in methanol (100 ml). After refluxing for 3 days, the reaction mixture was cooled in an ice bath and filtered, the precipitate was washed with water and dried (Na2SO4). The title compound was collected as a yellow solid (83.0 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[CH:5][NH:6]2.[NH:18]1[C:26]2[C:21](=[C:22]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:30]3[CH2:31][CH2:32][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[C:26]5[C:21]=4[CH:20]=[CH:19][NH:18]5)[CH2:28][CH2:29]3)[CH2:13][CH2:12]1)=[CH:5][NH:6]2
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: O=C1CCC(c2c[nH]c3cccc(F)c23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Fc1cccc2[nH]cc([C@H]3CC[C@@H](N4CCN(c5cccc6[nH]ccc56)CC4)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
A solution of 4-(4-fluoro-1H-indol-3-yl)-cyclohexanone (0.88 g, 3.8 mmol), 1-(indol-4-yl)piperazine (0.7 g, 3.5 mmol), sodium triacetoxyborohydride (1.1 g, 5.2 mmol) and acetic acid (0.4 ml, 7 mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×60 ml), and washed with brine (3×60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (5-7% methanol-ethyl acetate) afforded 1.14 g (79%) of product as a white foam.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1.[O-]S([O-])=O.[Na+].[Na+]>CN(C)C=O.O>[Br:1][C:8]1[CH:9]=[C:4]([F:3])[C:5]([OH:10])=[N:6][CH:7]=1
Reactant: BrBr
Reactant: Oc1ncccc1F
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
32.0 ml (620.0 mmol) of bromine are added dropwise at 0° C. to 63.7 g (563.2 mmol) of 3-fluoro-2-hydroxypyridine in 700 ml of dimethylformamide. After the mixture has been stirred at room temperature for a further two hours, 800 ml of water are added, and 78 g of Na2SO3 in 350 ml of water are added dropwise. The mixture is then extracted three times with 400 ml of dichloromethane in each case, and the organic phase is dried over Na2SO4 and evaporated to dryness, giving 97.6 g of 5-bromo-3-fluoro-2-hydroxypyridine. ##STR21##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:33]2[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:32])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH:28]([CH3:31])[CH2:29][OH:30])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[CH3:41]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:33]2[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:32])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH:28]([CH:29]3[CH2:41][O:30]3)[CH3:31])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)CO)CC2)c2ncnn12
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C3CO3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3′-fluoro-4′-({4-[trans-4-(2-hydroxy-1-methylethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.81 g), Dess-Martin periodinane (1.2 g) and acetonitrile (10 mL) was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution were added to the reaction mixture. After evaporation of the solvent under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was added to a mixture of trimethylsulfoxonium iodide (0.39 g), sodium hydride (0.072 g) and dimethyl sulfoxide (10 mL) stirred at room temperature for 1 hr in advance, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.15 g, 18%).
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:18][OH:19])[O:4][C@H:5]2[N:9]1[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]1=[O:11].[C:20](OC(=O)C)(=[O:22])[CH3:21].[CH2:27]([OH:29])[CH3:28]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:20]([O:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@@:3]1([CH2:18][O:19][C:27](=[O:29])[CH3:28])[O:4][C@H:5]2[N:9]1[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]1=[O:11])(=[O:22])[CH3:21]
Reactant: Cc1cn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)[nH]c1=O
Reactant: CC(=O)OC(C)=O
Reactant: CCO
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@]12CO[C@@H]([C@H](n3cc(C)c(=O)[nH]c3=O)O1)[C@@H]2OC(C)=O
Reaction time: 2 h

Procedure:
To a stirred solution of nucleoside 37 (209.8 mg, 0.78 mmol) in anhydrous pyridine (2.5 cm3) was added acetic anhydride (0.3 cm3, 3.23 mmol) and a catalytic amount of DMAP (5 mg). After stirring for 2 h, ethanol was added (4 cm3) and the mixture was evaporated under reduced pressure. The residue was redissolved in dichloromethane and washed with a saturated aqueous solution of sodium hydrogencarbonate (7 cm3). The organic phase was dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (97:3, v/v) as eluent affording 64 as a white solid material (249 mg, 90%). δC (CDCl3) 169.59, 163.20, 149.50, 133.55, 110.64, 87.05, 85.38, 77.84, 71.70, 71.02, 58.60, 20.62, 20.53, 12.78. FAB-MS m/z 355 [M+H]+.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([C:23]2[S:24][CH:25]=[C:26]([CH2:28]OS(C)(=O)=O)[N:27]=2)[CH2:6]1)(=[O:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C)C=O>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@H:7]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][N:34]=[N+:35]=[N-:36])[N:27]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)S[C@H]1C[C@@H](c2nc(COS(C)(=O)=O)cs2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](c2nc(CN=[N+]=[N-])cs2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-2-[4-(methanesulfonyloxymethyl) thiazol-2-yl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.5 g) in dimethylformamide (20 ml) was added sodium azide (0.15 g) at ambient temperature. After stirring at 70° C. for 2 hours, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine successively, dried over magnesium sulfate and concentrated to give a syrup. The syrup was subjected to a column chromatography on silica gel and eluted with a mixture of acetone and dichloromethane (1:9, V/V) to give (2S, 4S)-4-acetylthio-2-(4-azidomethylthiazol-2-yl) -1-(4-nitrobenzyloxycarbonyl)pyrrolidine (500 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:8][C:9]([O:11][CH2:21][CH3:22])=[O:10])=[CH:12][CH:13]=1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)cc1
Yield: 95 %

Procedure:
4-Trifluoromethylcinnamic acid (10.2 g), conc. sulfuric acid (1 ml) and ethanol (100 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(a) to obtain the title compound (10.9 g, 95%) as a colorless oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])(=[O:3])[CH3:2].[F-].[Na+].FN=C(F)[C:17]([F:20])([F:19])[F:18].[C:22](#[N:24])C>>[F:20][C:17]([N:24]=[C:22]1[N:4]([C:1](=[O:3])[CH3:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:11]1)([F:18])[F:19]
Reactant: CC#N
Reactant: FN=C(F)C(F)(F)F
Reactant: CC(=O)Nc1ccccc1O
Agent: [F-]
Agent: [Na+]
Product: CC(=O)n1c(=NC(F)(F)F)oc2ccccc21

Procedure:
15 g (0.1 mole) of 2-(N-acetylamino)-phenol in 100 ml of dry acetonitrile and 9 g (0.214 mole) of dry sodium fluoride were heated to 75°-80°C while stirring and 15 g (0.11 mole) of perfluoroazapropene were slowly passed into this suspension. After completion of the reaction, the mixture was filtered, the solvent was concentrated and the residue was recrystallized from chloroform. 15 g of 2-trifluoromethylimino-3-acetyl-benzoxazoline were obtained as pale yellow prisms of melting point 140°-143°C. The yield of pure material was 67% of theory.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]([NH:14][C@@:15]1([C:32]([O:34]CC)=[O:33])[CH2:20][C@@H:19]([S:21][C:22]2[NH:26][CH:25]=[N:24][N:23]=2)[C@@H:18]2[C@H:16]1[C@H:17]2[C:27]([O:29]CC)=[O:28])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.O>[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]([NH:14][C@@:15]1([C:32]([OH:34])=[O:33])[CH2:20][C@@H:19]([S:21][C:22]2[NH:26][CH:25]=[N:24][N:23]=2)[C@@H:18]2[C@H:16]1[C@H:17]2[C:27]([OH:29])=[O:28])=[O:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)CNC(=O)OC(C)(C)C)(C(=O)OCC)C[C@H]2Sc1nnc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@]1(C(=O)O)C[C@@H](Sc2nnc[nH]2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
Add 2M sodium hydroxide (4.5 mL, 9 mmol) to a stirred solution of diethyl (1R,2S,4R,5R,6R)-2-[[2-(tert-butoxycarbonylamino)acetyl]amino]-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate (1.4 g, 2.81 mmol) in tetrahydrofuran (8 mL) at room temperature. Stir the biphasic mixture for 2 hours, dilute the reaction mixture with water (50 mL) and wash with diethyl ether (50 mL). Cool the aqueous layer to 0-5° C., acidify to pH=2 with 2M hydrochloric acid and extract with ethyl acetate (2×60 mL). Combine the organics phases, dry on sodium sulfate and concentrate to give the title compound as a white solid (0.75 g, 1.69 mmol). 1H NMR (D2O) δ 1.18-1.27 (m, 1H), 1.32 (s, 9H), 1.44-1.49 (m, 1H), 2.0-2.6 (m, 1H), 2.12-2.19 (m, 1H), 2.65-2.75 (m, 2H), 3.57-3.68 (m, 2H), 4.12-4.21 (m, 1H), 8.23 (s, 1H) as well as some title compound in the remaining aqueous layer (approximately 1.12 mmol). MS (m/z): 442 (M+1), 464 (M+23).