Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH3:28][OH:29]>O>[OH:29][CH2:28][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][N:5]=1)[C:1]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccncc1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: COC(=O)c1ccnc(CO)c1
Temperature: 25 °C
Yield: 32 %

Procedure:
The reaction was performed in 2 separate 1000 mL round-bottomed flasks. To a solution of methyl isonicotinate (70 g, 510.44 mmol) and sulfuric acid (2.340 mL, 43.90 mmol) in MeOH (700 mL) under reflux, was added a solution of ammonium peroxydisulfate (210 g, 918.80 mmol) in water (350 mL) over 20 min. The reaction was refluxed for 20 min and was then allowed to cool to room temperature. The solid was filtered off and washed with MeOH. MeOH was removed from the filtrate under reduced pressure and then was neutralised by cautious stepwise addition of solid Na2CO3 under ice-cooling. The aqueous solution was extracted with ethyl acetate and the combined organic layers were dried with Na2SO4 and evaporated. The dark-brown residue was treated with cyclohexane (3×300 mL) and the cyclohexane phase was decanted. The remaining dark-brown residue was purified by automated flash chromatography on 2 Biotage® KP-SIL 340 g columns. A gradient from 25% to 100% of EtOAc in heptane over 10 CV was used as mobile phase. Methyl 2-(hydroxymethyl)isonicotinate (27.5 g, 32%) was isolated. 1H NMR (400 MHz, cdcl3) δ 3.90 (s, 3H), 4.78 (s, 2H), 7.57-7.90 (m, 2H), 8.64 (s, 1H). MS m/z 168 (M+H)+
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C@H:20]([CH3:24])[C:21]([OH:23])=[O:22])[CH:14]=[CH:13]2.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([CH:37]([CH3:41])[C:38]([OH:40])=[O:39])[CH:31]=[CH:30]2.[OH-].[Na+:43]>O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])[CH:14]=[CH:13]2.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C@H:37]([CH3:41])[C:38]([O-:40])=[O:39])[CH:31]=[CH:30]2.[Na+:43]
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2cc([C@H](C)C(=O)[O-])ccc2c1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
Using the apparatus of the above Comparative Example, a toluene solution of 2-(6-methoxy-2-naphthyl)propionic acid (580.68 grams, 18.11 wt % solids, 91.64% S-enantiomer) was prepared from a sample of high chiral purity (S)-2-(6-methoxy-2-naphthyl)propionic acid, and racemic 2-(6-methoxy-2-naphthyl)propionic acid. The solution was heated to 85° C. Totals of 27.59 grams of 49.22 wt % NaOH and 7.822 grams of water were added. Two clear liquid phases were obtained. Water was stripped to 94.0° C. in 285 minutes. The total amount of water collected during the strip was 21.36 grams and the amount of toluene removed was 1.83 grams. The batch was agitated at 93.6°-94.0° C. for 15 minutes and cooled to 75° C. in 82 minutes and agitated at 75° C. for 60 minutes. Solids in the slurry settled well at the end of the 60-minute 75° C. ride. The centrifuge cake (sodium (S)-2-(6-methoxy-2-naphthyl)propionate monohydrate) was washed with 149.94 grams of hot (75° C.) toluene. Totals of 483.77 and 127.61 grams of mother liquor and wash liquor were recovered, respectively. The wet centrifuge cake weighed 75.02 grams which after drying for 8 hours at 80°-90° C. and under full vacuum yielded 67.29 grams of anhydrous sodium (S)-2-(6-methoxy-2-naphthyl)propionate. Chiral purities for the product and the mother liquor were found by analysis to be 99.03% S-enantiomer and 80.28% S-enantiomer, respectively.
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:7]=[C:8](N)[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:15]=1.[BrH:17]>O>[Br:17][C:8]1[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:15]=[C:6]([F:5])[CH:7]=1
Reactant: Br
Reactant: Nc1cc(F)cc2c1OCCO2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1cc(Br)c2c(c1)OCCO2

Procedure:
NaNO2 (2.69 g, 39.9 mmol) in water (20 mL) was added slowly at 0° C. to a solution of 7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-amine (4.5 g, 26 mmol) in aq.47% HBr (20 mL) and continued stirring at same temperature for 30 min. The above diazonium salt solution was added slowly to a solution of CuBr (5.7 g, 39.9 mmol) in aq.47% HBr (25 mL) at 0° C. and stirred at 25° C. for 30 min. Reaction mixture was quenched with ice water, extracted with ethyl acetate (3×50 mL), washed it with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude. The crude was purified by column purification (using silica gel and 0-5% ethyl acetate in Hexane as eluent) to afford 5-bromo-7-fluoro-2,3-dihydrobenzo[b][1,4]dioxine (Int-53) (5.9 g). 1H NMR (300 MHz, CDCl3) δ ppm 6.9-6.84 (1H, dd), 6.6-6.5 (1H, dd), 4.3-4.3 (4H, m).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C(OC([N:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[C:40]1B(O)O)=O)(C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[C:40]1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:13])=[O:14])[CH:9]=2)[NH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Yield: 40.8 %

Procedure:
N-[3-(1H-Indol-2-yl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 1 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 900 mg 1-(tert-butyloxycarbonyl)indole-2-boronic acid, 40 ml of dimethylformamide, 3.2 ml of saturated aqueous sodium hydrogencarbonate solution and 50 mg of tetrakis(triphenylphosphine)palladium[0]. 330 mg of N-[3-(1H-indol-2-yl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting above 260° C. (analysis C22H18N4O4S2% calculated C, 56.63; H, 3.89; N, 12.01; O, 13.72; S, 13.75. % found C, 56.87H, 4.10: N, 13.81; S, 12.65).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)=[CH:6][C:5]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[O:18])=[CH:4][CH:3]=1.C(O)(=O)C>C(O)C.[Fe]>[NH2:14][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)=[O:18])[CH:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1cccc(N)c1

Procedure:
To 6-methyl-3′-nitro-N-[3-(trifluoromethyl)phenyl]biphenyl-3-carboxamide (0.90 g, 2.2 mmol) in ethanol (22 mL) was added acetic acid (2 mL) and iron (0.90 g, 16 mmol) and the resulting mixture was heated to reflux for 1 hour. Solvent was removed in vacuo. Ethyl acetate was added and solids were removed by filtration. The filtrate was washed sequentially with saturated sodium bicarbonate and brine, dried (Na2SO4) and then concentrated. The product was used without further purification (850 mg, 95%).
Reaction SMILES: C([O:4][CH:5](OC(=O)C)[C:6]1[O:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)(=O)C.OS(O)(=O)=O>O>[N+:11]([C:8]1[O:7][C:6]([CH2:5][OH:4])=[CH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: CC(=O)OC(OC(C)=O)c1ccc([N+](=O)[O-])o1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(CO)o1

Procedure:
2-(Diacetoxymethyl)-5-nitro-furane (48.6 pts. by wt.) are boiled in a mixture of water (216 pts. by vol.) and concentrated H2SO4 (108 pts. by wt.) for 15 minutes under N2, the mixture is then cooled and the 5-nitro-furfurol formed is taken up in ether and, after removing the ether, dissolved in 100 pts. by vol. of methanol. A solution of 1-amino-2-oxo-imidazolidine hydrochloride (27.5 pts. by wt.) in water (100 pts. by vol.) is added to this solution. After 4.5 hrs., the product which has separated out is filtered off, washed with water and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1

Procedure:
11.28 g (33.04 mmol) benzyl 4-(4-nitro-phenyl)-piperazine-1-carboxylate are dissolved in 500 mL methanol and combined with 1 g Raney nickel. The mixture is hydrogenated for 18 h at 5 bar hydrogen pressure. Then the catalyst is filtered off and the residue is combined with 70 mL of aqueous 1 N hydrochloric acid and the solvent is eliminated in vacuo.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:13][O:12][C:11](=[O:14])[C:10]2[C:15]([CH3:35])=[C:16]([O:27][Si](C(C)(C)C)(C)C)[CH:17]=[C:18]([O:19][Si](C(C)(C)C)(C)C)[C:9]=2[CH2:8][S:7][CH2:6][C@@H:5]([C:36]([O:38][CH3:39])=[O:37])[NH:4][C:3]1=[O:40].[C:41]([O:45][C:46]([NH:48][C@H:49]([C:52](O)=[O:53])[CH2:50][OH:51])=[O:47])([CH3:44])([CH3:43])[CH3:42].Cl.CN(CCCN=C=NCC)C>C(#N)C.C(OCC)(=O)C>[C:41]([O:45][C:46]([NH:48][C@@H:49]([CH2:52][OH:53])[C:50]([NH:1][C@H:2]1[CH2:13][O:12][C:11](=[O:14])[C:10]2[C:15]([CH3:35])=[C:16]([OH:27])[CH:17]=[C:18]([OH:19])[C:9]=2[CH2:8][S:7][CH2:6][C@@H:5]([C:36]([O:38][CH3:39])=[O:37])[NH:4][C:3]1=[O:40])=[O:51])=[O:47])([CH3:44])([CH3:43])[CH3:42]
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c(C)c2C(=O)OC[C@H](N)C(=O)N1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)[C@@H]1CSCc2c(O)cc(O)c(C)c2C(=O)OC[C@H](NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)N1
Temperature: 0 °C
Reaction time: 4 h
Yield: 38.7 %

Procedure:
To a solution of 61 mg of methyl (4R, 7S)-7-amino-12,14-bis(tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4-carboxylate and 21 mg N-(tert-butoxycarbonyl)-L-serine in 2 ml of acetonitrile, cooled to 0° C., were added 20 mg of N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride. The mixture was stirred at 0° C. for 4 hours, then diluted with 30 ml of ethyl acetate, and washed successively with 0.5N hydrochloric acid, water, 5% sodium bicarbonate solution, and with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in 2 ml of methanol, 20 mg of ammonium fluoride were added, and the mixture was stirred for 30 minutes at room temperature. The mixture was diluted with 40 ml of ethyl acetate and washed with 30 ml of water. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. The solid residue was triturated with 2 ml of ether, then hexane was added, and the white solid was isolated by filtration to give 22 mg of methyl (4R, 7S)-7-[(S)-2-(1-tert-butoxyformamido)-3-hydroxypropionylamino]-1,3,4,5,6,7,8,10-octahydro-12,14-dihydroxy-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4-carboxylate.
Reaction SMILES: [CH:1]1([C:8]2[N:13]3[N:14]=[CH:15][N:16]=[C:12]3[N:11]=[C:10](O)[C:9]=2[C:18]2[C:23]([F:24])=[CH:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)=[CH:20][C:19]=2[F:39])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:42])=O.C(N(CC)C1C=CC=CC=1)C>>[Cl:42][C:10]1[C:9]([C:18]2[C:19]([F:39])=[CH:20][C:21]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)=[CH:22][C:23]=2[F:24])=[C:8]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[N:13]2[N:14]=[CH:15][N:16]=[C:12]2[N:11]=1
Reactant: COc1ccc(COCCCOc2cc(F)c(-c3c(O)nc4ncnn4c3C3CCCCCC3)c(F)c2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: COc1ccc(COCCCOc2cc(F)c(-c3c(Cl)nc4ncnn4c3C3CCCCCC3)c(F)c2)cc1

Procedure:
To the above 7-cycloheptyl-6-(2,6-difluoro-4-{3-[(4-methoxybenzyl)oxy]propoxy}phenyl)[1,2,4]triazolo[1,5-a]pyrimidin-5-ol (820 mg) is added 5 mL of phosphorous oxychloride and 2 mL of N,N-diethylaniline, and the mixture is heated at reflux for 1 h. The excess phosphorous oxychloride is removed in vaccuo, and the resulting residue is partitioned between methylene chloride and 1 N hydrochloric acid. The organic layer is washed with saturated sodium chloride, dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of hexanes to 20% ethyl acetate in hexanes. Concentration provides 5-chloro-7-cycloheptyl-6-(2,6-difluoro-4-{3-[(4-methoxybenzyl)oxy]propoxy}phenyl)[1,2,4]triazolo[1,5-a]pyrimidine as a yellow oil (180 mg). MS: m/z 557.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21]Cl)[C:9]2=[O:23])[CH:7]=1.[CH2:27]([O:34][C@@H:35]1[C@@H:41]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@H:40]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@@H:39]([CH2:58][O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[O:38][CH:36]1[OH:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=3)[N:10]([CH2:21][O:37][CH:36]3[C@H:35]([O:34][CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C@@H:41]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C@@H:40]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C@@H:39]([CH2:58][O:59][CH2:60][C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)[O:38]3)[C:9]2=[O:23])[CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CCl)c2cc(C(F)(F)F)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC2O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a round bottom flask containing a solution of (S)-3-(5-Chloro-2-methoxy-phenyl)-1-chloromethyl-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one (S)-IV) (0.486 g, 1.2 mmol) in anhydrous acetonitrile (9 mL) was added 2,3,4,6-tetra-O-benzyl-D-glucopyranose (V; 0.648 g, 1.2 mmol) and cesium carbonate (0.390 g, 1.2 mmol). The reaction mixture was allowed to stir at room temperature overnight. The solvent was then removed, and the crude product was purified via flash chromatography (silica gel, 5:1 hexanes:ethyl acetate) to give a 1:1 mixture of α and β anomers of the title compound (0.768 g, 71%). 1H NMR (CDCl3, 400 MHz): δ 7.79 (dd, 2H, J=5.1 Hz, 1.8 Hz), 7.37-7.12 (m, 48H), 6.66 (m, 2H), 5.66 (d, 1H, J=11.0 Hz), 5.34 (m, 2H), 5.08 (d, 1H, J=3.7 Hz), 4.89-4.73 (m, 9H), 4.66-4.44 (m, 9H), 3.79 (m, 3H), 3.73-3.59 (m, 6H), 3.55-3.49 (m, 3H), 3.38 (d, 6H, J=4.1 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:37]=[CH:36][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:27]([N:29]([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])=[O:28])=[C:18]([CH:26]=2)[O:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:39][OH:40].[O-]CC.[Na+:44]>C(O)C>[Na+:44].[NH2:2][C:1](=[N:39][OH:40])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:27]([N:29]([CH:30]([CH3:32])[CH3:31])[CH:33]([CH3:35])[CH3:34])=[O:28])=[C:18]([CH:26]=2)[O:19][C:20]([CH3:25])([CH3:24])[C:21]([O-:23])=[O:22])=[CH:36][CH:37]=1
Reactant: NO
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1OC(C)(C)C(=O)O)C(C)C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C(N)=NO)cc2)cc1OC(C)(C)C(=O)[O-])C(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A stirred solution of 2-[5-[5-(4-cyanophenoxy)pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]-2-methylpropionic acid (1.4 g, 2.8 mmol) in 30 mL of anhydrous ethanol is treated with hydroxylamine hydrochloride (590 mg, 8.4 mmol) and 21% sodium ethoxide solution in ethanol (3.1 mL, 5.7 mmol) and stirred at 50° C. overnight. The reaction is concentrated in vacuo and purified by chromatography on silica gel (20 g) with 80-100% ethyl acetate/hexane followed by 0-10% methanol/ethyl acetate as the eluent to afford 2-[5-[5-[4-[amino(hydroxyimino)methyl]phenoxy]pentyloxy]2-[N,N-bis(1-methylethyl) -aminocarbonyl]phenoxy]-2-methylpropanoic acid sodium salt as a colorless foam;
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([C:19]([CH2:21][C:22](OCC)=[O:23])=O)([F:18])([F:17])[F:16].CS(O)(=O)=O>>[CH2:1]([C:8]1[CH:13]=[C:12]2[C:11](=[CH:10][CH:9]=1)[O:14][C:22](=[O:23])[CH:21]=[C:19]2[C:15]([F:18])([F:17])[F:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Oc1ccc(Cc2ccccc2)cc1
Agent: CS(=O)(=O)O
Product: O=c1cc(C(F)(F)F)c2cc(Cc3ccccc3)ccc2o1
Temperature: 65 °C
Yield: 44.3 %

Procedure:
A stirred suspension of 4-benzylphenol (4.67 g, 25.4 mmol), CF3COCH2CO2Et (7.00 g, 38.0 mmol), & MeSO3H (8.5 mL, 130.9 mmol) was heated at 65° C. for 9 h. On cooling, the mixture was partitioned between Et2O (200 mL) & H2O (50 mL), then the aqueous phase was basicified with 2 M NaOH. The organic layer was separated & washed with H2O & brine, before being dried (MgSO4). Filtration, solvent evaporation, & column chromatography (4:1 PE-Et2O) furnished 6-benzyl4-trifluoromethylchromen-2-one (3.42 g, 44%): δH (CDCl3)=4.10 (s, 2H), 6.85 (s, 1H), 7.20–7.40 (m, 5H), 7.45 (dd, 1H), 7.60 (d, 1H). This compound (2.00 g, 6.6 mmol) was dissolved in H2SO4 (20 mL), then the whole was stirred for 15 min. The mixture was carefully treated with crushed ice (80 g), then the resulting white precipitate was collected by filtration. The precipitate was air-dried, before being treated with hot THF (100 mL). After filtration, the filtrate was concentrated to yield 4-(2-oxo-4-trifluoromethyl-2H-chromen-6-ylmethyl)benzenesulfonic acid (2.20 g, 87%): δH ((CD3)2SO)=4.05 (s, 2H), 7.00 (s, 1H), 7.20 (d, 2H), 7.45 (d, 1H), 7.50–7.60 (m, 4H). This compound was reacted with (COCl)2, as described above in Preparation 1, to give a solid which was dissolved in EtOAc, before being filtered & concentrated to produce the title compound (2.30 g, 87%): Rf (2:1 PE-EtOAc)=0.60.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:35]([CH2:54]O)[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:35]([CH2:54][O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CO[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO[C@H]1O[C@H](COS(=O)(=O)C(F)(F)F)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of dry pyridine (0.46 ml) in methylene chloride (17.5 ml) cooled to -15° C. was added trifluoromethanesulfonic anhydride (0.87 ml). The mixture was stirred during 15 min at -10° C. then methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (1.2 g, 2.58 mmol) in methylene chloride (5 ml) was added (P. Kovac, V. Sklenar and C. Glaudemans, Carbohydr. Res., 175, 201 (1988)). The mixture was stirred during 1.5 h at -10° C. The reaction mixture was washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 7:3 mixture of hexane and ethyl acetate afforded the expected compound methyl 2,3,4-tri-O-benzyl-6-O-trifluoromethylsulfonyl-α-D-glucopyranoside which was crystallized from hexane (1.43 g, 93%); m.p. 44°-45° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[I:17][C:18]1[N:19]=[C:20]([C:24](O)=[O:25])[NH:21][C:22]=1[I:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[I:17][C:18]1[N:19]=[C:20]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])[NH:21][C:22]=1[I:23]
Reactant: O=C(O)c1nc(I)c(I)[nH]1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(I)c(I)[nH]1
Yield: 43 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (170 mg, 0.74 mmol), 4,5-diiodoimidazole-2-carboxylic acid obtained in Example (71b) (about 0.34 mmol), WSC hydrochloride (195 mg, 1.02 mmol) and HOBT (46 mg, 0.34 mmol), to obtain 83.1 mg of the title compound as a white solid (43%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][NH:7][C:8](=[O:40])[C@@H:9]([CH3:39])[NH:10][C:11](=[O:38])[C@H:12]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=1[CH2:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:37])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Cl>CC(C)=O>[C:17]([O:16][C:14]([NH:13][C@H:12]([C:11]([NH:10][C@@H:9]([C:8]([NH:7][CH2:6][C:5]([OH:41])=[O:4])=[O:40])[CH3:39])=[O:38])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=1[CH2:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:37])=[O:15])([CH3:18])([CH3:19])[CH3:20]
Reactant: COC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1Cc1c(Cl)cccc1Cl)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1Cc1c(Cl)cccc1Cl)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O

Procedure:
Aqueous 1N sodium hydroxide (12 ml.) is added to a suspension of t-butoxycarbonyl-0-(2,6-dichlorobenzyl)-L-tyrosyl-D-alanylglycine methyl ester (Step 2, 4.7 g.) in acetone (25 ml.) stirred with a magnetic stirrer. After 4 1/2 hours the solution is acidified to pH 2 with 4N hydrochloric acid. After an hour a white precipitate is removed by filtration and dried under vacuum to give t-butoxycarbonyl-0-(2,6-dichlorobenzyl)-L-tyrosyl-D-alanylglycine.