Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCl.IC1N=C(N)C2N=CN(C=2N=1)[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1[OH:13].[Cl:23][C:24]1[N:25]=[C:26]([NH2:42])[C:27]2[N:28]=[CH:29][N:30]([C:40]=2[N:41]=1)[C@@H:31]1[O:39][C@H:36]([CH2:37]Cl)[C@@H:34]([OH:35])[C@H:32]1[OH:33]>>[Cl:23][C:24]1[N:25]=[C:26]([NH2:42])[C:27]2[N:28]=[CH:29][N:30]([C:40]=2[N:41]=1)[C@@H:31]1[O:39][C@H:36]([CH2:37][OH:13])[C@@H:34]([OH:35])[C@H:32]1[OH:33]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Agent: ClCl
Product: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
In yet another route the 5′-substituent was introduced prior to C2-substitution to circumvent all problems met in the previous routes. The method of Robins20 yielded 5′-deoxy-2-iodo-5′-chloroadenosine from 2-iodoadenosine (1). However, besides the 5′-hydroxyl group, also the 2-iodo group of 1 was replaced by chlorine to some extent, and a mixture of 5′-deoxy-2-iodo-5′-chloroadenosine with 2,5′-dichloro-5′-deoxyadenosine was obtained. Separation of the two products by column chromatography proved impossible. Thus, it was necessary to go further back in the synthesis route, since pure 2,5′-dichloro-5′-deoxyadenosine, obtained by chlorination of 2-chloroadenosine, failed to react with ethanethiol under different conditions (either with KOtBu in MeOH at different temperatures that all regained starting material, or in 2 M NaOH at elevated temperatures yielding the 2,5′-diethylthio substituted derivatives). Finally, in Scheme 1 the successful synthesis of the desired compounds is depicted. The 5′-substituents were introduced at guanosine, which is also the precursor of 2-iodoadenosine (1). Although more laborious, this route starts with the introduction of the 5′-alkylthio substituents at guanosine to circumvent all described problems. Chlorination20 of guanosine gave 5′-chloro-5′-deoxy-guanosine (16) in 93% yield. Compound 16 was reacted with the appropriate thiol in 2 M NaOH1,5 and the 2′- and 3′-hydroxyl groups of compounds 17–20 were subsequently protected to yield the 2′,3′-O-acetyl-5′-(alkylthio)-substituted derivatives 21–24. Several laboratories have described chlorination on the 6-position of purine nucleosides with phosphoryl chloride (POCl3).18,21 To prevent decomposition of the starting materials, the as chemicals used were either properly dried or freshly distilled, and compounds 25–28 were obtained in reasonable to good yields (40%–74%). Subsequently, the 2-amino group of compounds 25–28 was replaced by iodine. The method used26 was a variation of the originally diazotization-iodine substitution procedure.22 With this efficient method 29–32 were obtained in good yields (71–82%). Stirring 29–32 in ethanol freshly saturated with NH3 readily removed the protecting groups and slowly aminated the 6-position to give the intermediates 33–36. NMR showed that amination at the 6-position needed stirring at room temperature for at least two days. Subsequent introduction of the C2-substituents was done as described above,7,8 and compounds 37–40 and 45–48 were obtained in good yields.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][C@H:13]([C:41]1[CH:46]=[CH:45][C:44]2[O:47][CH2:48][O:49][C:43]=2[CH:42]=1)[C@H:14]([N:16]([CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C:17]([C@@H:19]1[C@@H:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][C:21](=[O:29])[O:20]1)=[O:18])[CH3:15].[OH-:50].[Na+:51]>O1CCCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][C@H:13]([C:41]1[CH:46]=[CH:45][C:44]2[O:47][CH2:48][O:49][C:43]=2[CH:42]=1)[C@H:14]([N:16]([CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C:17]([C@@H:19]([OH:50])[C@@H:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][C:21]([O-:20])=[O:29])=[O:18])[CH3:15].[Na+:51]
Reactant: CCOC(=O)[C@H]1CC(=O)O[C@@H]1C(=O)N(Cc1ccc2ccccc2c1)[C@H](C)[C@H](C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](CC(=O)[O-])[C@H](O)C(=O)N(Cc1ccc2ccccc2c1)[C@H](C)[C@H](C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
120 mg of ethyl (2S,3S)-2-[N-{(1R,2R,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-5-oxotetrahydrofuran-3-carboxylate was dissolved in a mixed solution of 5 ml of tetrahydrofuran and 2 ml of water, and 182 μl of a 1N sodium hydroxide aqueous solution was added thereto, followed by stirring at room temperature overnight. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform/methanol=20/1→10/1) to obtain 33.0 mg (yield: 26%) of the above-identified compound as a colorless foam.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:25]([C:32]2[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=2)=[CH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:27]1([CH:26]=[C:25]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH2:20][CH2:21][N:22]([CH3:23])[CH3:24])[CH:18]=[C:13]3[CH:12]=2)[C:32]2[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CN(C)CCOc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)CCOc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 74.7 %

Procedure:
A solution of (2-{1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-ethyl)-dimethyl-amine (350 mg, 0.59 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 4 mL, 4 mmol) was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL), and washed with a saturated aqueous ammonium chloride solution, brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford (2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-ethyl)-dimethyl-amine (200 mg, 75%) as a white solid: LC/MS m/e calcd for C25H31N3O3S [M+H]+ 454.61, observed 454.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=3)=[CH:28][CH:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(COc2ccc(-c3ccc(Cl)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
1-(tert-Butoxycarbonyl)piperidin-3-ylmethanol (323 mg, 1.50 mmol) and 4′-chloro-4-hydroxybiphenyl (307 mg, 1.50 mmol) were suspended in tetrahydrofuran (15 mL). To this suspension, triphenylphosphine (608 mg, 2.25 mmol) was added and the mixture was stirred at room temperature for 10 min. A 40% diethylazodicarboxylate/toluene solution (1.36 mL, 3.00 mmol) was then added and the mixture was stirred at room temperature for 16 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=50:1->10:1) gave 401 mg (67%) of the desired compound as a colorless powder.
Reaction SMILES: [CH:1](=[N:8]/[CH2:9][CH2:10][CH:11]=[CH2:12])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(Cl)Cl>CCO>[CH2:1]([NH:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC/N=C/c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: C=CCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of (E)-N-benzylidenebut-3-en-1-amine (1.298 gm, 8.15 mmol) in EtOH (25 mL) cooled to 0° C. was added NaBH4 (0.324 g, 8.56 mmol) portionwise over 40 min. After addition, the reaction mixture was stirred at rt for 3 hr. The reaction mixture was filtered and the filtrate was concentrated to give a white semi-solid residue. To the residue 50 mL of DCM was added. The resulting milky solution was stirred for 15 min and then was filtered. The obtained clear filtrate was concentrated to give N-benzylbut-3-en-1-amine (1.30 g, 6.85 mmol, 84% yield) as a pale yellow oil. Anal. Calcd. for C11H15N m/z 161.2. found: 162.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.42-7.21 (m, 5H), 5.79 (ddt, J=17.1, 10.2, 6.9 Hz, 1H), 5.13-4.99 (m, 2H), 3.80 (d, J=6.8 Hz, 2H), 3.29 (q, J=6.8 Hz, 1H), 2.71 (q, J=6.9 Hz, 1H), 2.29 (q, J=6.8 Hz, 1H), 1.25 (dt, J=9.1, 7.1 Hz, 1H), 1.12-1.03 (m, 1H).
Reaction SMILES: [OH:1][C@H:2]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=O)[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.COC1C=CC(P2(=S)CP(=S)(C3C=CC(OC)=CC=3)S2)=CC=1>COCCOC>[OH:1][C@H:2]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[S:30])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1cccs1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: COc1ccc(P2(=S)CP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: CN1C(=S)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1cccs1
Temperature: 65 °C
Yield: 15 %

Procedure:
(±)-(4R*,5R*)-5-((1S*)-Hydroxy-2-thienylmethyl)-1-methyl-4-phenyl-pyrrolidin-2-one (Example 5, 0.30 g, 1.06 mmol) and Lawesson's Reagent ([2,4-bis(4-methoxyphenyl)-1,2-dithia-2,4-diphosphetane-2,4-disulfide; 0.22 g, 0.53 mmol) were mixed in DME (3 mL) at rt for 18 h then heated to 65° C. for another 18 h. The reaction was cooled to rt and the solvent was concentrated under reduced pressure to give a dark oil. The crude product was purified by flash chromatography (1% MeOH/99% CH2Cl2) to give (±)-(4R*,5R*)-5-((1S*)-hydroxy-2-thienylmethyl)-1-methyl-4-phenylpyrrolidin-2-thione (46 mg, 15% yield) as a yellow solid; TLC (75% EtOAc/25% hexanes) Rf 0.36; HPLC ES-MZ m/z (rel abundance) 304 ([MH]+, 100%) AT 4.8 min.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1>O.C(O)(C)C>[S:11]([N:1]=[N+:2]=[N-:3])([C:8]1[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reaction time: 1 h
Yield: 77.1 %

Procedure:
Tosyl azide was prepared as follows. A solution of sodium azide (58.5 g, 0.90 tool) in distilled water (170 mL) was quickly added to a stirred suspension (partly in solution) of p-toluenesulfonyl chloride (143.0 g, 0.75 tool) in isopropanol (850 mL) contained in a beaker at room temperature. The mixture was stirred for one hour, then poured into 3 L of distilled water and stirred for one more hour. The separated oily tosyl azide was washed three times with water, dried over anhydrous magnesium sulfate, then dried by stirring under vacuum. It is important for its use as a reagent in the lithiation reaction that tosyl azide is substantially pure (free of impurities) and contains a negligible amount of water (measured by proton NMR). 114 g of colourless tosyl azide oil was obtained (yield 77%). A 95% yield could be obtained by extracting the drying agent with chloroform. 1HNMR: δ=7.84 H-ortho-sulfonyl (2H d, J≈8.3); δ=7.41 H-orthomethyl (2H d, J≈8.3); δ=2.49 Me (3H s).
Reaction SMILES: [CH2:1]([N:8]1[C:14]([CH3:16])([CH3:15])[C:12](=[O:13])[N:11]([CH2:17][C:18]#[CH:19])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:20]N1C(=O)CCC1=O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([N:8]1[C:14]([CH3:15])([CH3:16])[C:12](=[O:13])[N:11]([CH2:17][C:18]#[C:19][I:20])[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCN1C(=O)N(Cc2ccccc2)C(C)(C)C1=O
Reactant: O=C1CCC(=O)N1I
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: CC1(C)C(=O)N(CC#CI)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.3 %

Procedure:
To a stirred solution of 1-benzyl-3-propargyl-5,5-dimethylhydantoin (1.2 g, 4.6 mmole) in acetone (50 mL) at room temperature was added finely ground silver nitrate (0.15 g. 0.8 mmole), followed by N-iodosuccinimide (1.16 g, 5.2 mmole). The reaction mixture was stirred at room temperature for 5 hr. The reaction mixture was then passed through Celite by suction filtration and washed with acetone. The titrate was concentrated on a rotary evaporator and diluted with ethyl acetate. The solution was washed with water and brine and dried over sodium sulfate. The solvent was evaporated on a rotary evaporator to give 1.5 g of 1-benzyl-3-(3-iodo-2-propynyl)-5,5-dimethylhydantoin as a solid, mp=109°-112° C. An NMR spectrum also showed the desired structure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](N2C(C(F)(F)F)=C(C(OCC)=O)C=N2)[CH:5]=[CH:4][N:3]=1.C[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.B(Br)(Br)Br>>[N:7]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[OH:23]
Reactant: CCOC(=O)c1cnn(-c2ccnc(Cl)n2)c1C(F)(F)F
Reactant: COc1ccccc1B(O)O
Agent: BrB(Br)Br
Product: Oc1ccccc1-c1ncccn1

Procedure:
Suzuki coupling of the title compound from Example 18 Step A with 2-methoxyphenylboronic acid, followed by treatment with BBr3 (according to Example 8 Steps A and B) gave a pyrimidinyl phenol which was processed to the title compound according to Example 1 Steps C and D: LCMS m/z 545.3 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 9.20 (d, J=5.5 Hz, 1H), 8.42 (s, 1H), 7.88 (d, J=5.5 Hz, 1H), 7.69 (dd, J=8.0, 2.0 Hz, 1H), 7.50-7.47 (m, 1H), 7.27-2.08 (m, 11H), 5.13 (s, 2H), 2.82 (s, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([O-:11])=[O:10].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:18][C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Nc1cc(Cl)ccn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Temperature: 150 °C
Reaction time: 72 h
Yield: 21.2 %

Procedure:
2-Amino-4-chloropyridine (2.00 g) was dissolved in N-methylpyrrolidone (31.8 ml) under a nitrogen atmosphere, and 4-nitrophenol (6.51 g) and N,N-diisopropylethylamine (15.9 ml) were added, followed by stirring at 150° C. for 3 days. The reaction mixture was allowed to cool down to room temperature, and partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide (32 ml). The organic layer was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2 to 1:5). Fractions containing the target compound were concentrated under reduced pressure, and the residue was dried under reduced pressure to provide the titled compound as a brown solid (764 mg, 21.2%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([CH3:25])([CH2:22][CH:23]=[CH2:24])[C:17]([O:19]CC)=[O:18])=[N:2]1.[OH-].[K+].Cl>COCCO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([CH3:25])([CH2:22][CH:23]=[CH2:24])[C:17]([OH:19])=[O:18])=[N:2]1
Reactant: C=CCC(C)(C(=O)OCC)c1ccccc1-c1noc2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Product: C=CCC(C)(C(=O)O)c1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Yield: 75.7 %

Procedure:
To a solution of 0.75 g of ethyl 2-[2-(1,2-benzisoxazol-3-yl)-phenyl]-2-methyl-4-pentenoate in 10 ml of 2-methoxyethanol was added 5 ml of 10M potassium hydroxide solution. The solution was refluxed overnight then cooled to room temperature and poured onto ice. This aqueous solution was acidified with 5M hydrochloric acid and extracted with three 100 ml portions of ether. The extracts were evaporated and azeotroped with toluene. Flash chromatography of the residue, eluting with 0 to 10% methanol in methylene chloride, afforded 0.52 g of 2-[2-(1,2-benzisoxazol-3-yl)-phenyl]-2-methyl-4-pentenoic acid as a gum, 1H NMR (400 MHz; CDCl3) δH 1.52 (Me).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][C:3]=1[O:10][CH3:11].[CH:12]([O:17][CH3:18])([O:15][CH3:16])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[CH3:18][O:17][CH:12]([O:15][CH3:16])[C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[C:3]([O:10][CH3:11])[CH:4]=1
Reactant: COC(OC)OC
Reactant: COc1cc(C=O)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(OC)OC)ccc1Cl
Yield: 86 %

Procedure:
A heterogenous mixture of methanol (2 ml), CH2Cl2 (3 ml), 4-chloro-3-methoxybenzaldehyde (2 g, 11.7 mmol; prepared essentially as described by R. M. Riggs et al., J. Med. Chem., 30 1887, 1987.), trimethyl orthoformate (1.7 ml, 15.5 mmol) and a large crystal of p-toluenesulfonic acid was stirred at room temperature for one hour. Additional MeOH (1 ml) and a crystal of p-toluenesulfonic acid were added and the solution was warmed until homogenous. Upon completion of the reaction, the solution was stirred 5 min with excess solid NaHCO3 and rotory evaporated to remove solvents. The paste was dissolved in 40 ml EtOAC, partitioned against dilute NaHCO3 solution, and evaporated to yield a light brown oil. The reaction was repeated with another 2 g of 4-chloro-3-methoxybenzaldehyde and both product oils were combined to give 4.37 g (86%) of dimethyl acetal 3.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:44])([C:11]([O:13][C@@H:14]([CH3:43])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[C:27](/[N:29]=[C:30]1\[S:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[N:38]\1[CH2:39][CH2:40][CH2:41][CH3:42])=[O:28])=[O:12])[CH3:10])=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:44][C:9]([C:11]([O:13][C@@H:14]([CH3:43])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[C:27](/[N:29]=[C:30]1\[S:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[N:38]\1[CH2:39][CH2:40][CH2:41][CH3:42])=[O:28])=[O:12])([CH3:10])[NH2:8]
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@H](C)OC(=O)C(C)(C)NC(=O)OC(C)(C)C)sc2ccncc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@H](C)OC(=O)C(C)(C)N)sc2ccncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of Example 2A (265 mg, 0.415 mmol) in anhydrous dichloromethane (4 mL) was added trifluoroacetic acid (Aldrich, 0.320 mL, 4.15 mmol). The solution was stirred at room temperature overnight, then saturated sodium bicarbonate solution was added to adjust the pH to 9. The mixture was extracted with dichloromethane (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporator. Purification by flash chromatography (silica gel: 50-100% ethyl acetate in hexanes) afforded 202 mg (90%) of the title compound. 1H NMR (DMSO-d6) δ 0.94 (t, J=7.3 Hz, 3H), 1.08 (s, 3H), 1.10 (s, 3H), 1.30 (d, J=6.8 Hz, 3H), 1.34-1.46 (m, 3H), 1.77-1.87 (m, 3H), 4.19-4.32 (m, 2H), 4.53 (t, J=7.3 Hz, 2H), 5.08-5.18 (m, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.84 (dd, J=8.6, 2.2 Hz, 1H), 8.03 (d, J=4.4 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 9.03 (s, 1H). MS (ESI+) m/z 539 (M+H)+.
Reaction SMILES: C(=O)(O)O.[C:5]([OH:10])(=O)[C:6](O)=[O:7].C(O)(=O)C(CO)O.C(O)(=O)CO.C(O)(=O)C(C)O.[O:29]=[C:30](O)[C@@H:31]([C@@H:33]([CH2:35][OH:36])[OH:34])[OH:32]>>[O:29]=[CH:30][C@@H:31]([C@H:33]([C@@H:35]([C@@H:6]([CH2:5][OH:10])[OH:7])[OH:36])[OH:34])[OH:32]
Reactant: O=C(O)C(=O)O
Reactant: O=C(O)[C@H](O)[C@H](O)CO
Agent: CC(O)C(=O)O
Agent: O=C(O)C(O)CO
Agent: O=C(O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 25 %

Procedure:
This type of alkaline oxidative degradation, which is 25 effective both on hemiacetal functions and on ketone functions, also entails the formation of by-products such as, in particular, carbonic acid, oxalic acid, glyceric acid, glycolic acid, lactic acid, erythronic acid and, of course, fornic acid, which are obtained in a molar yield of about 25% from glucose when the alkalinity conditions are such that they allow a 75% yield of arabinonate. Formic acid is always produced in yields close to 100% of the stoichiometry.
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:33]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[N:11]([CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:12]=1)=[O:7])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Reactant: BrCCCc1ccccc1
Product: CCCCN(CCCC)C(=O)c1cn(CCCc2ccccc2)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Yield: 76.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 271F, 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (200 mg, 0.4 mmol) and (3-bromopropyl)benzene (97 mg, 0.48 mmol) were converted the title compound (187 mg, 74%). 1H NMR (CDCl3) 8.65 (d, J=1.6 Hz, 1H), 8.20 (dd, J=8.0, 1.6 Hz, 1H), 7.53 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.33-7.30 (m, 4H), 7.24-7.14 (m, 4H), 6.94 (d, J=8.0 Hz, 2H), 5.13 (s, 2H), 4.00 (s, 3H), 3.99 (br s, 2H), 3.52 (t, J=7.6 Hz, 2H), 3.46 (br s, 2H), 2.39 (t, J=7.6 Hz, 2H), 1.82-1.78 (m, 2H), 1.55-1.50 (m, 4H), 1.26-1.22 (m, 4H), 0.96-0.83 (m, 6H); MS(ESI+) m/z 610.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=O)=[CH:7][CH:6]=1)=[O:4].Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=[N:24][OH:25])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)c2ccc(C(=O)OC)cc2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: COC(=O)c1ccc(C(=NO)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A mixture of 6 (2.33 g, 7.81 mmol), HCl-H2NOH (1.63 g, 23.4 mmol) and sodium acetate (1.92 g, 23.4 mmol) in Ethanol (80 ml) was heated for 24 h under reflux. The mixture was allowed to cool to RT, and half concentrated NaHCO3-solution (200 ml) was added. The aqueous phase was extracted with Et2O, the unified organic phases were washed with saturated solutions of NaHCO3 and NaCl, and dried over Na2SO4. The solvent was removed, and the crude product is crystallized from ethanol. 2.15 g (88%) of compound 7 are obtained as a colorless solid. Melting point 177-178° C.; IR (KBr) 3190, 2920, 1700, 1585 cm−1; 1H-NMR (CDCl3) δ 8.50 (sbr, 1H), 8.16 (d, 8.6 Hz, 2H), 8.00 (d, 8.6 Hz, 2H), 7.51 (d, 8.6 Hz, 2H), 7.47 (d, 8.6 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H); MS (EI) m/z 313 (M+). Anal. calc. for C17H15NO5: C, 65.17; H, 4.83; N, 4.47. Found C, 65.14; H, 4.78; N, 4.47.