Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.Cl.[CH3:11][C:12](=O)CC(=O)C.C([O-])(O)=O.[Na+]>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:11]([CH3:12])=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1N
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2cc(F)ccc2[nH]1
Temperature: 50 °C

Procedure:
Under an N2 atmosphere, 4-fluorobenzene-1,2-diamine (5.00 g, 39.6 mmol) was suspended in EtOH (220 mL) and 5M HCl (160 mL) was added. The reaction was warmed to 50° C. and 2,4-pentandione (8.14 mL, 7.93 mmol) was added and the reaction was heated to reflux for 30 min. Upon cooling to room temperature, the reaction was neutralized with a saturated solution of NaHCO3(aq) and extracted with dichloromethane. The layers were separated and the aqueous layer was washed with additional dichloromethane (2×). The organics were then combined, dried (Na2SO4), filtered and concentrated in vacuo. The resulting solid was triturated with dichloromethane to afford the title compound. 1H NMR (400 MHz) (DMSO-d6) δ 7.43-7.19 (bm, 2H); 6.92 (bs, 1H); 2.44 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(O)(=[O:11])C.S(=O)(=O)(O)O.[Cl:18][CH2:19][C:20]#[N:21]>>[Cl:18][CH2:19][C:20]([NH:21][C:2]1([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)=[O:11]
Reactant: CC1(O)CCOCC1
Reactant: N#CCCl
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: CC1(NC(=O)CCl)CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-methyltetrahydro-2H-pyran-4-ol obtained in Example 7-1 in chloroacetonitrile (0.65 mL), was added a mixture of acetic acid and conc. sulfuric acid (1/1, 1.6 mL) dropwise with cooling on an ice bath. The reaction mixture was warmed to room temperature and stirred for 3 hrs.
Reaction SMILES: C[Al](C)C.[N:5]1([S:10]([CH:13]([S:15]([NH2:18])(=[O:17])=[O:16])[CH3:14])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29](=O)[O:30]C)[N:22]=1>C1(C)C=CC=CC=1.ClCCl>[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29](=[O:30])[NH:18][S:15]([CH:13]([S:10]([N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)(=[O:11])=[O:12])[CH3:14])(=[O:17])=[O:16])[N:22]=1
Reactant: COC(=O)Nc1nc(C)nc(OC)n1
Reactant: CC(S(N)(=O)=O)S(=O)(=O)N1CCCC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)C(C)S(=O)(=O)N2CCCC2)n1
Temperature: 0 °C

Procedure:
9 ml (0.018 mol) of a 2M solution of trimethylaluminum in toluene are added dropwise at room temperature to 3.6 g (0.015 mol) of 1-pyrrolidinosulfonylethanesulfonamide (Example 1a) in 150 ml of dichloromethane. When the evolution of gas has ceased, 3.6 g (0.018 mol) of methyl 4-methoxy-6-methyl-1,3,5-triazin-2-ylcarbamate in 30 ml of dichloromethane are added dropwise, and the resulting solution is refluxed for 24 hours. It is cooled and poured into 150 ml of ice-cold 1N hydrochloric acid. The organic phase is separated off, and the water phase is extracted twice with dichloromethane. The organic phase is dried and evaporated. After the crude product has been triturated with diethyl ether, 2.9 g (47% of theory) of 3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-1-(1-pyrrolidinosulfonylethylsulfonyl)urea of melting point 136°-137° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=2)([CH2:7][CH2:8][CH3:9])[O:5][C:4](=[O:20])[C:3]=1[O:21]CC1C=CC=CC=1.OC1C(=O)OC(C)(C2C=CC=CC=2)C=1O>>[OH:21][C:3]1[C:4](=[O:20])[O:5][C:6]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:14][CH:15]=2)([CH2:7][CH2:8][CH3:9])[C:2]=1[OH:1]
Reactant: CCCC1(c2ccc(CC(C)C)cc2)OC(=O)C(OCc2ccccc2)=C1O
Agent: CC1(c2ccccc2)OC(=O)C(O)=C1O
Product: CCCC1(c2ccc(CC(C)C)cc2)OC(=O)C(O)=C1O
Yield: 6.9 %

Procedure:
Hydrogenolysis of 4-hydroxy-5-(4-isobutylphenyl)-3-phenylmethoxy-5-(1 -propyl)-2(5H)-furanone was performed in a similar manner as described in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provide 200 mg (6.9% yield) of 3,4-dihydroxy-5-(4-isobutylphenyl)-5-(1-propyl)-2(5H)-furanone as an oil, which was purified by preparative TLC using hexanes/acetone/acetic acid (70/29/1) as eluant: 1H NMR (acetone-d6) δ 7.48-7.13 (m, 4H), 2.47 (d, J=10.3 Hz, 2H), 2.10-1.66 (m, 1H), 1.29-0.85 (m, 13H). 13C NMR (acetone-d6) δ 169.20, 155.54, 141.58, 137.91, 129.24, 125.32, 118.25, 83.37, 45.02, 39.60, 30.26, 22.03, 16.84, 13.63. Anal Calcd for C17H22O4 : C, 70.32; H, 7.64. Found: C, 70.01; H, 7.61.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COC1C=CC(C(C2C=CC=CC=2)(C2C=CC=CC=2)[O:20][CH2:21][CH:22]([OH:41])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])=CC=1.O>CN(C)C=O>[C:4]1([CH2:3][O:41][CH:22]([CH2:21][OH:20])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COCCOCCOCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCOCCCCCCCCOCC(CO)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a stirred suspension of 3.26 g of unwashed 50% sodium hydride and 10.9 g of benzyl bromide in 40 ml of dimethylformamide, under argon, was added a solution of 27.14 g of 20-[(4-methoxyphenyl)diphenylmethoxy]-2,5,8,17-tetraoxaeicosan-19-ol in 50 ml of dimethylformamide over 1/2hour. This mixture was stirred overnight, water was then added and the mixture extracted with ether. The ether extract was washed with water, dried and the solvent removed. The residue was dissolved in hot methanol and stirred with 10 g of a strongly acidic ion exchange resin. This mixture was filtered and the solvent removed. The residue was purified by HPLC, eluting with hexane:ethyl acetate (65:35) giving the desired compound as 12.9 g of a light yellow oil.
Reaction SMILES: [CH3:1][O-].[Na+].[N:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[N:6][CH:5]=1>CN(C=O)C.CO>[CH3:1][N:14]1[CH:15]=[C:10]([C:7]2[CH:8]=[CH:9][N:4]=[CH:5][N:6]=2)[CH:11]=[CH:12][C:13]1=[O:16]
Reactant: C[O-]
Reactant: O=c1ccc(-c2ccncn2)c[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1cc(-c2ccncn2)ccc1=O
Temperature: 60 °C

Procedure:
A solution of 4.8 g of sodium methoxide in 300 ml of dry DMF and 15 ml of methanol is added to a suspension of 5-(4-pyrimidinyl)-2(1H)-pyridone (2 g) in 200 ml DMF. The reaction mixture is filtered and 5.5 ml of methyl iodide added to the filtrate. The reaction mixture is heated to 60° C. for 2 hours, cooled to RT, and the solvent evaporated in vacuo leaving a liquid residue that crystallizes upon the addition of distilled H2O. The crystalline solid is stirred with 400 ml of distilled H2O, filtered, washed with H2O, isopropyl alcohol, and ether and then air dried to yield the desired 1-methyl-5-(4-pyrimidyl)-2-pyridone, M.P. 147°-149° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]1([C:11]([CH:13](Br)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[O:12])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:8]1([C:11]([CH:13]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[O:12])[CH2:10][CH2:9]1
Reactant: OC1CCNCC1
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(C1CC1)C(c1ccccc1F)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
3.13 g (31 mmol) of 4-hydroxypiperidine were dissolved in 30 ml of dimethylformamide (DMF), followed by the addition of 7.94 g (31 mmol) of α-cyclopropylcarbonyl-2-fluorobenzyl bromide and 4.7 g (34 mmol) of potassium carbonate. The resulting mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the resulting mixture was extracted with toluene. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (eluting solvent: chloroform/methanol=19/1), whereby 8.00 g of the title compound were obtained as a brown oil (yield: 93%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.Cl[CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[F:22].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:22][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[C:15]1[O:1][C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=1
Reactant: Fc1cnccc1CCl
Reactant: O=Cc1cc(C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Temperature: 150 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A mixture of 1.59 g of 2-hydroxy-5-(trifluoromethyl)benzaldehyde, 1.22 g of 4-(chloromethyl)-3-fluoropyridine, 3.48 g of potassium carbonate and 7 ml of DMF was stirred at 80° C. for 1 hour and subsequently at 150° C. for 2 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.27 g of 3-fluoro-4-[5-(trifluoromethyl)benzofuran-2-yl]-pyridine (hereinafter, referred to as “Present Active Compound 8”).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[C:6]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7]1.CS(C)=[O:16]>>[C:10]([OH:12])(=[O:11])[CH2:9][CH2:8][CH2:2][C:1]([OH:4])=[O:3].[C:6]([OH:12])(=[O:13])[CH2:7][CH2:8][CH2:9][C:10]([OH:16])=[O:11].[C:10]([OH:12])(=[O:11])[CH2:9][CH2:8][CH2:2][C:1]([OH:4])=[O:3].[C:10]([OH:12])(=[O:11])[CH2:9][CH2:8][CH2:2][C:1]([OH:4])=[O:3].[C:10]([OH:12])(=[O:11])[CH2:9][CH2:8][CH2:2][C:1]([OH:4])=[O:3].[C:10]([OH:12])(=[O:11])[CH2:9][CH2:8][CH2:2][C:1]([OH:4])=[O:3].[C:10]([OH:12])(=[O:11])[CH2:9][CH2:8][CH2:2][C:1]([OH:4])=[O:3].[C:10]([OH:12])(=[O:11])[CH2:9][CH2:8][CH2:2][C:1]([OH:4])=[O:3].[C:10]([OH:12])(=[O:11])[CH2:9][CH2:8][CH2:2][C:1]([OH:4])=[O:3].[OH:11][CH2:10][CH:2]([CH2:1][OH:4])[OH:16].[OH:11][CH2:10][CH:2]([CH2:1][OH:4])[OH:16].[OH:11][CH2:10][CH:2]([CH2:1][OH:4])[OH:16].[OH:11][CH2:10][CH:2]([CH2:1][OH:4])[OH:16].[OH:11][CH2:10][CH:2]([CH2:1][OH:4])[OH:16].[OH:11][CH2:10][CH:2]([CH2:1][OH:4])[OH:16].[OH:11][CH2:10][CH:2]([CH2:1][OH:4])[OH:16].[OH:11][CH2:10][CH:2]([CH2:1][OH:4])[OH:16]
Reactant: CS(C)=O
Reactant: CC(=O)[O-]
Reactant: O=C1CCCC(=O)O1
Agent: [Na+]
Product: O=C(O)CCCC(=O)O
Product: OCC(O)CO
Temperature: 70 °C

Procedure:
Octaglycerin (6.1 g, 0.01 mol) was dispersed in dimethyl sulfoxide (50 mL), added with 9.0 g (0.11 mol) of sodium acetate, warmed to 70° C., and then added with 11.4 g (0.1 mol) of glutaric anhydride and reacted for 12 hours. After completion of the reaction, sodium acetate was removed by filtration, and dimethyl sulfoxide was evaporated under reduced pressure by using an evaporator to obtain 15.9 g of octaglycerol nonaglutarate.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.[H-].[Na+].Br[CH2:14][C:15]1[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[C:17](=[O:26])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25]>CN(C=O)C>[NH2:10][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[N:7]=[CH:6][N:5]2[CH2:14][C:15]1[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[C:17](=[O:26])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25]
Reactant: Cc1ccccc1-n1c(CBr)cc2cccc(C)c2c1=O
Reactant: Nc1ncnc2[nH]cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1c(Cn2cnc3c(N)ncnc32)cc2cccc(C)c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
9H-Purin-6-amine (1901) (540 mg, 4.0 mmol) was dissolved in anhydrous DMF (20 mL). NaH (60% in mineral oil, 160 mg, 4.0 mmol) was added and the resulting mixture was stirred at RT for 30 min. 3-(Bromomethyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1610) (1.37 g, 4.0 mmol) was added. The reaction mixture was stirred at RT for 30 min, poured into ice-water (30 mL) and then extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (25 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (2-20% MeOH/DCM) to afford the desired product, 3-((6-amino-9H-purin-9-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1902, compound 5 of Table 4) (1.1 g, 70% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[N:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>C(Cl)Cl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32]([NH:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=4)=[O:33])=[CH:3][CH:4]=3)[C:16]=12
Reactant: Nc1ccc(-c2nn([C@H]3CCOC3)c3ncnc(N)c23)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc1)nn2[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-(4-aminophenyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.1 g, 0.34 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)phenyl isocyanate (0.047 mL, 0.34 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 12 hours. Reaction completion was judged by TLC and LC-MS. The reaction mixture was filtered, dried onto silica, and purified using silica gel column chromatography (50% EtOAc:Hexanes to 100% EtOAc gradient) to afford final compound AD66. ESI-MS m/z [M+H]+ found 484.4, calculated 484.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH:14](O)[CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([CH:20]([CH3:22])[CH3:21])=[N:10]2)=[CH:5][CH:4]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH:14]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([CH:20]([CH3:22])[CH3:21])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2cc(C(O)CC(C)C)c(C(C)C)n2)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: COc1ccc(-n2cc(C(CC(C)C)Nc3ccc(C(=O)NCCC(=O)O)cc3)c(C(C)C)n2)cc1
Yield: 3 %

Procedure:
Using 1-[1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]-3-methylbutan-1-ol (0.57 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.45 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (28.0 mg, 3%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([O:14][CH3:15])[CH:3]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)=[O:13])=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: COc1cc(Cl)c(I)cc1NCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(I)cc1NCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of 2-(4-chloro-5-iodo-2-methoxyphenylamino)acetic acid (280 mg, 0.83 mmol) and tert-butyl piperazine-1-carboxylate (185 mg, 0.99 mmol) in DMF (10 mL) at room temperature, BOP (550 mg, 1.25 mmol) and DIEA (321 mg, 2.4 9 mmol) were added and the resulting mixture was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=3:1) to afford the desired product (350 mg, 68.7% yield). ESI-MS m/z: 510.3[M+1]+.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=2[Cl:23])[N:13]=[C:12]([C:24]#[N:25])[CH:11]=1>C(#N)C.ClCCl>[NH2:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=2[Cl:23])[N:13]=[C:12]([C:24]#[N:25])[C:11]=1[I:1]
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(Cl)cc2Cl)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1I

Procedure:
N-Iodosuccinimide (17.67 g) was added portionwise to a stirred solution of 5-amino-3-cyano-1-(2,4,6-trichlorophenyl)pyrazole (U.S. Pat. No. 5,232,940; 22.5 g) in acetonitrile (300 ml) and the resulting mixture stirred at room temperature for 1 hour, then evaporated under reduced pressure. The residue was partially purified by chromatography on silica gel (800 g), using an elution gradient of dichloromethane:ethyl acetate (100:0 to 0:100), to produce a pale brown solid which was further purified as follows. Trituration with hexane (25 ml) provided a residue which was dissolved in dichloromethane (500 ml). This solution was washed with water (500 ml), the aqueous washing back-washed with ethyl acetate (500 ml) and the combined organic solutions dried (Na2SO4) and evaporated under reduced pressure to furnish the title compound as a pale brown solid. δ (DMSOd6): 6.28 (br.s,2H), 7.98 (s,2H). MS (thermospray): M/Z [M+H] 413.0; C10H4Cl3IN4 +H requires 412.9.
Reaction SMILES: [O:1]=[C:2]([CH2:49][CH2:50][CH2:51][C:52](=[O:72])[NH:53][C:54]1[CH:55]=[N:56][C:57]([C:60]2[N:61]=[N:62][C:63]([C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][N:67]=3)=[N:64][N:65]=2)=[CH:58][CH:59]=1)[NH:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][C:42]([O:44]C(C)(C)C)=[O:43].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]([CH2:49][CH2:50][CH2:51][C:52](=[O:72])[NH:53][C:54]1[CH:55]=[N:56][C:57]([C:60]2[N:61]=[N:62][C:63]([C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][N:67]=3)=[N:64][N:65]=2)=[CH:58][CH:59]=1)[NH:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCCC(=O)Nc1ccc(-c2nnc(-c3ccccn3)nn2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCCC(=O)Nc1ccc(-c2nnc(-c3ccccn3)nn2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3 (160 mg, 0.157 mmol) in anhydrous DCM (2 mL) under nitrogen atmosphere was added TFA (2 mL). The reaction mixture was stirred for 2 hours at room temperature and evaporated to dryness. The residue was redissolved in dry DCM (2 ml) and again treated with TFA (2 mL) for 2 hours. This process was repeated once more. Finally, the reaction mixture was evaporated to dryness and co-evaporated twice with DCM furnishing the deprotected product 4 in quantitative yield.
Reaction SMILES: [H-].[Na+].[N:3]([C@@H:6]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C@H:12]([OH:24])[C@@H:11]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:10][C@H:7]1[S:8][CH3:9])=[N+:4]=[N-:5].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CO>CN(C=O)C>[N:3]([C@@H:6]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C@H:12]([O:24][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:11]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:10][C@H:7]1[S:8][CH3:9])=[N+:4]=[N-:5]
Reactant: BrCc1ccccc1
Reactant: COc1ccc(CO[C@H]2[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H]2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A suspension of sodium hydride (196 mg, 5.1 mmol) in dry DMF (10 mL) was cooled to 0° C., and a solution of methyl 2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D glucopyranoside (10) (2.53 g, 4.3 mmol) in dry DMF (20 mL) was added dropwise in 30 minutes. The resulting solution was stirred at room temperature for 30 minutes and benzyl bromide (880 mg, 5.1 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature overnight, cooled to 0° C. and dry methanol (1 mL) was added dropwise. The reaction mixture was concentrated under reduced pressure, then xylene (20 mL) was co-evaporated from the residue. The residue was taken up in CHCl3 (100 mL) washed with H2O (100 ml), saturated NaHCO2 solution (100 mL) dried over MgSO4 and evaporated to dryness. The residue was purified by chromatography using EtOAc—Hexane 1:9 as the mobile phase to give methyl 2-azido-4-O-benzyl-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (32) (2.0 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOC(=O)c1ccc(OC)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
16.7 g (0.1 mol) of 3-amino-4-methoxybenzoic acid was added to 50 ml of N,N-dimethylformamide. Then 13.8 g (0.1 mol) of potassium carbonate was added to the solution obtained above, and the resulting mixture was stirred in the temperature range of from 20 to 30° C. for 30 min. 30.5 g (0.11 mol) of tetradecyl bromide was poured into the solution thus obtained, and the resulting solution was heated to 80° C., and allowed to react at the temperature for 1 hour. After completing the reaction, 50 ml of ethyl acetate, and 50 ml of water were added to the reaction mixture, and the organic layer obtained was separated, concentrated, diluted with 100 ml of methanol, and then cooled to precipitate crystals. The crystals were separated by filtration, and then dried to obtain 33.1 g (yield 91%) of the desired product. Purity 98% or higher. Melting point 54.0-56.0° C. A result of the elemental analysis of this sample was as follows: