Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1.[C:19](Cl)(=[O:23])[O:20][CH2:21][CH3:22]>C(OCC)(=O)C>[C:19](=[O:23])([O:20][CH2:21][CH3:22])[O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:12]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)OCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.5 %

Procedure:
To a mixture of tert-butyl 3-hydroxypropylcarbamate (8.00 g) obtained in Reference Example 40 and ethyl acetate (50 mL) were-added pyridine (4.06 mL) and ethyl chlorocarbonate (5.95 g) under ice-cooling, and the mixture was stirred at room temperature for 24 hrs. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), an aqueous copper sulfate solution (30 mL), water (30 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (9.31 g) as a colorless oil.
Reaction SMILES: N[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N:12]1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].O>O1CCCC1>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]([NH:12][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[CH:2][N:3]=1
Reactant: c1ccncc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cc2ccccc2cn1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cncc2ccccc12)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 3-aminoisoquinoline (1.00 g, 6.94 mmol) and pyridine (0.660 ml, 8.32 mmol) in tetrahydrofuran (23 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.15 ml, 8.32 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 2.03 g (91.7%) of the desired product as a solid was separated by filtration.
Reaction SMILES: N#N.[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:5])[CH3:4].OS(O)(=O)=O.[C:18]([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CO>[CH3:18][O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][C:3](=[O:5])[CH3:4]
Reactant: CC(=O)CCCCC(=O)O
Reactant: O=C([O-])[O-]
Agent: N#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCCC(C)=O
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask under inert atmosphere (N2), a solution of 5-acetylvaleric acid (7.54 g, 50.21 mmol) in a mixture of CH2Cl2 (35 mL) and MeOH (14 mL) was treated with conc. H2SO4 (0.14 mL, 2.51 mmol) and the reaction mixture was stirred at reflux for 24 h. The mixture was cooled to rt and sat. aq. Na2CO3 was added. The aq. layer was extracted with CH2Cl2 and the combined organic layers were washed with water, dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:1→1:2 hept-EA) gave the title compound as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[CH:12][CH:11]=1.OO.[O-:32]S([O-])=O.[Na+].[Na+].CCOC(C)=O.FC(F)(F)[CH:46]([OH:51])[C:47]([F:50])([F:49])[F:48]>>[C:46]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:16].[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:9])=[O:32])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[CH:12][CH:11]=1
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: O=S([O-])[O-]
Reactant: CSc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cn2)c(F)c1
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)=O)cc3F)nc2)CC1
Product: O=C(O)C(F)(F)F
Reaction time: 2 h
Yield: 48 %
Yield: 0.1 %

Procedure:
A mixture of 1-methylethyl 4-[({6-[2-fluoro-4-(methylthio)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (50 mg, 0.12 mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (2 mL) was treated with 30% aqueous H2O2 (0.027 mL, 0.24 mmol) at ambient temperature. After 2 h, saturated aqueous Na2SO3 (5 mL) was added carefully and the mixture was stirred for 10 min. EtOAc (3 mL) was added, the organic layer was separated and dried over Na2SO4 and the solvent evaporated off. The crude product was purified by reverse-phase preparative HPLC using a CH3CN:H2O gradient (10:90 to 100:0) with 0.1% TFA as a modifier to give 25 mg (48%) of the title compound as a white solid. 1HNMR (400 MHz, CDCl3): δ 8.41 (d, 1H, J=2.7 Hz), 8.14 (t, 1H, J=7.8 Hz), 7.78 (dd, 1H, Ja=8.7 Hz, Jb=1.5 Hz), 7.51 (dd, 1H, Ja=10.5 Hz, Jb=1.4 Hz), 7.44 (dd, 1H, Ja=8.2 Hz, Jb=1.5 Hz), 7.30-7.23 (m, 1H), 4.92 (septet, 1H, J=6.2 Hz), 4.30-4.15 (m, 2H), 3.90 (d, 2H, J=6.4 Hz), 2.85-2.74 (m, 2H), 2.76 (s, 3H), 2.06-1.96 (m, 1H), 1.85 (m, 2H), 1.88-1.22 (m, 2H), 1.24 (d, 6H, J=6.4 Hz); LRMS (ESI), m/z 435 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.O[C@H:32]([C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH3:33].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:19])([CH3:18])[CH3:20])[C:12]([O:14][C@@H:32]([CH3:33])[C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[O:13])(=[O:7])=[O:6]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: CC(C)C(=O)[C@H](C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)[C@H](C)OC(=O)[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCCl
Yield: 35.9 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(1,1,2,2-tetramethyl-1-silapropoxy)butanoic acid (15) (2.0 g, 5.0 mmol) dissolved in 25 mL of anhydrous dichloromethane (DCM) was reacted with 0.90 mL (1.31 g, 10 mmol) of oxalyl chloride. Upon completion of the reaction, a solution of 2 mL (1.2 g, 10.0 mmol) of (2S)-2-hydroxy-4-methylpentan-3-one (synthesized following procedures according to Gallop et al., U.S. Pat. No. 6,927,036) and 0.85 mL of pyridine (0.79 g, 10.0 mmol) in 20 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:9) as eluent to provide 0.9 g (36% yield) of the title compound (30a) as a colorless oil. Rf=0.39 (EtOAc/Hxn=1:4). 1H NMR (400 MHz, CDCl3): δ=0.05 (s, 3H), 0.10 (s, 3H), 0.94 (s, 9H), 1.09 (s, 6H), 1.12 (d, J=7.2 Hz, 3H), 1.19 (d, J=7.2 Hz, 3H), 1.46 (d, J=7.2 Hz, 3H), 2.32-2.39 (m, 2H), 2.83 (sept., J=7.2 Hz, 1H), 3.31-3.35 (m, 2H), 3.69-3.72 (m, 2H), 4.10-4.13 (m, 3H), 5.24 (q, J=7.2 Hz, 1H) ppm. MS (ESI) m/z 501.09 (M+H)+, 523.03 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH3:1][OH:2].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][CH2:9][NH:10][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:12](N)=[O:13]>S(=O)(=O)(O)O>[ClH:21].[CH3:1][O:2][C:12](=[O:13])[CH:11]([NH:10][CH2:9][CH2:8][C:4]1[S:3][CH:7]=[CH:6][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21]
Reactant: NC(=O)C(NCCc1cccs1)c1ccccc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(NCCc1cccs1)c1ccccc1Cl
Product: Cl
Temperature: 130 °C
Reaction time: 5 h

Procedure:
In 150 ml of methanol 8.5 ml (0.15 mol) of 96% sulfuric acid is dissolved under cooling and the solution is then heated under reflux conditions for ½ hour. After cooling to room temperature 20 g (0.0678 mol) of [2-(2-thienyl)ethylamino](2-chlorophenyl)acetamide, falling under general formula (VII) and prepared as described in Example 7, is added to the solution, the mixture is placed into a closed apparatus (autoclave) and stirred at 130° C.—on for 5 hours, while the inner pressure elevates to 13 bar. The reaction mixture is then cooled to room temperature (remaining pressure 1-2 bar), the methanol is distilled off in vacuo and to the residue 100 ml of isopropyl acetate and 100 ml of water are added and the pH of the mixture is adjusted to 7.5 by dropwise addition of 60 ml of 10% sodium hydroxide solution, under cooling and stirring, while keeping the mixture at room temperature. The phases are separated, the organic phase is stirred with 60 ml of 3% aqueous maleic acid solution at 40-50° C. for 10 minutes, the two phases are then separated. After re-extracting the aqueous maleic acid solution with 30 ml so isopropyl acetate the organic layers are combined, dried over anhydrous sodium sulfate and concentrated to the half of its volume. On addition of 5 ml of conc. hydrochloric acid solution the product precipitates as an oil which crystallizes within a few minutes. It is cooled to 0-(+5)° C. and after 2 hours the crystals are collected by filtration, washed with a small amount of isopropyl acetate and dried. Weight: 19.4 g (82.5%) mp.: 177-178° C. The quality of the product is similar to that of the material obtained in Example 9.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[NH:11][CH:12]=[N:13][C:14]#[N:15].CN(C)C=O.[K].[CH3:23][C:24]([OH:27])(C)[CH3:25].BrCC(=O)C>O>[NH2:15][C:14]1[N:13]=[CH:12][N:11]([CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][C:2]2([CH3:16])[CH3:1])[C:23]=1[C:24](=[O:27])[CH3:25]
Reactant: CC1(C)Cc2ccccc2C1NC=NC#N
Reactant: CC(C)(C)O
Agent: CC(=O)CBr
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(N)ncn1C1c2ccccc2CC1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
316 Parts of N-(2,3-dihydro-2,2-dimethyl-1H-inden-1-yl)-N'-cyanoformamidine were suspended in 282 parts of N,N-dimethylformamide. To this suspension were added slowly 163 parts of 2-methyl-2-propanol potassium salt and after stirring at room temperature for 4 hours there were added dropwise 194 parts of bromopropanone. After 48 hours, the reaction mixture was poured into water and extracted with 1,1'-oxybisethane. The separated organic layers were evaporated and the residue was crystallized first from a mixture of 1,1'-oxybisethane and petroleum ether. The precipitate was filtered off and dried and then recrystallized from methylbenzene. The product was filtered off and dried, yielding 93 parts (23%) of [4-amino-1-(2,3-dihydro-2,2-dimethyl-1H-inden-1-yl)-1H-imidazol-5-yl]ethanone; mp. 174°-175° C.
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH3:17])[CH:9]=1)[CH3:7])(=O)=O.[F:18][C:19]([F:33])([C:24]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[NH:26][N:25]=1)[C:20]([F:23])([F:22])[F:21].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.O>[CH3:17][C:10]1[CH:9]=[C:8]([CH:6]([N:25]2[C:24]([C:19]([F:18])([F:33])[C:20]([F:23])([F:22])[F:21])=[N:28][C:27]([C:29]([F:30])([F:31])[F:32])=[N:26]2)[CH3:7])[CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15].[CH3:17][C:10]1[CH:9]=[C:8]([CH:6]([N:26]2[C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:24]([C:19]([F:18])([F:33])[C:20]([F:21])([F:22])[F:23])=[N:25]2)[CH3:7])[CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1cc(C(C)OS(C)(=O)=O)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)c1nc(C(F)(F)C(F)(F)F)n[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C(C)n2nc(C(F)(F)C(F)(F)F)nc2C(F)(F)F)ccc1[N+](=O)[O-]
Product: Cc1cc(C(C)n2nc(C(F)(F)F)nc2C(F)(F)C(F)(F)F)ccc1[N+](=O)[O-]

Procedure:
1-(3-Methyl-4-nitrophenyl)-ethyl methanesulfonate (2.5 g), 3-pentafluoroethyl-5-trifluoromethyl-1H-(1,2,4)-triazole (2.2 g), potassium carbonate (1.6 g) and 18-crown-6 (0.26 g) were refluxed in acetonitrile (100 ml) for 6 hours. After finishing the reaction, water (100 ml) was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride (100 ml) and then dried with anhydrous sodium sulfate. After distilling off the solvent, the obtained residue was purified by silica gel column chromatography (mixed solvent of n-hexane and ethyl acetate) to obtain (IX-11) 1-([1-(3-methyl-4-nitro-phenyl)-ethyl]-5-pentafluoroethyl-3-trifluoromethyl-1H-(1,2,4)-triazole (0.95 g) as the first elution portion and (IX-12) 1-([1-(3-methyl-4-nitro-phenyl)-ethyl]-3-pentafluoroethyl-5-trifluoromethyl-1H-(1,2,4)-triazole (1.35 g) as the second elution portion.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[NH:16][N:15]=[C:14]([C:17]2[S:21][C:20]([CH2:22][N:23]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[N:13]=1>CN(C)C=O>[NH2:11][C:12]1[N:16]([C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[N:15]=[C:14]([C:17]2[S:21][C:20]([CH2:22][N:23]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[N:13]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1nc(-c2ccc(CN3CCCCCC3)s2)n[nH]1
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccc(CN3CCCCCC3)s2)nn1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
5 ml of N,N-dimethylformamide solution containing 331 mg (2.49 mmol) of benzyl isocyanate was added to 75 ml of N,N-dimethylformamide solution containing 690 mg (2.49 mmol) of the compound of Example 38, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the resulting residue was dissolved in chloroform, washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was subjected to a silica gel column chromatography, which was eluted with chloroform-methanol (75:1) to give 1.07 g of the title compound. This was crystallized by adding an appropriate amount of diethyl ether and then recrystallized from ethyl acetate-n-hexane to give 564 mg of the compound of interest.
Reaction SMILES: [CH2:1]1[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8]([NH2:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18]>C(O)(C)C>[CH2:17]([NH:18][CH2:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:19][CH2:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NCCCCCCCCCCN
Reactant: CCCCC1CO1
Solvent: CC(C)O
Product: CCCCC(O)CNCCCCCCCCCCNCC(O)CCCC
Yield: 13.7 %

Procedure:
In a manner similar to that of Example 1, condensation of 1-hexene oxide (34.8 g.) and 1,10-decanediamine (30 g.) and recrystallization of the resulting product from isopropyl alcohol gave N,N'-(1,10-decylene)-bis[2-hydroxyhexylamine] (I: R= CH3 (CH2)3R' = H, X= (CH2)10, Z= H) (8.9 g., m.p. 127.0°-137.0° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[CH:6][C:5]=1[OH:12].C(Cl)Cl.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:17](=[O:20])[CH:18]=[CH2:19])=[CH:6][C:5]=1[OH:12]
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(O)c(C(=O)OC)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester, was added DCM and triethylamine. This mixture was cooled to 0° C. and acryloyl chloride was added dropwise with stirring. After approximately 2 hours, the reaction was quenched by adding MeOH at 0° C. and the resulting mixture was stirred at room temperature for about 15 min and then concentrated in vacuo. DCM and water were added to the residue and this mixture was mixed thoroughly. The layers were separated and the aqueous layer was extracted with DCM. The organic layers were combined, dried (Na2SO4), filtered and the solvent was removed in vacuo to give 4-acryloylamino-5-chloro-2-hydroxybenzoic acid methyl ester. This ester was then combined with Preparation 1, followed by the addition of a THF-MeOH solvent. The mixture was heated and stirred for about 16 hours to provide biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-3-hydroxyphenylcarbamoyl)ethyl]piperidin-4-yl ester was made. Using this ester, and following the procedure described in Example 2 and substituting the appropriate amine, the title compound was prepared. MS m/z [M+H+] calcd for C35H38N4O5, 595.7; found, 595.2.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI>O1CCCC1>[C:1]([O:5][C:6]([CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(C(=O)OC(C)(C)C)CC3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 3-(4-(tert-butoxycarbonyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (700 mg, 1.52 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). Then sodium hydride (300 mg, 12.50 mmol, 8.25 equiv) was added. The resulting mixture was stirred for 1 h at room temperature. To this was added CH3I (0.5 mL) at 0° C. The resulting solution was stirred 3 h at room temperature. The reaction was then quenched by the addition of icewater. The resulting mixture was concentrated under vacuum. This resulted in 0.65 g (93%) of 3-(4-(tert-butoxycarbonyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as yellow oil.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:3]=1.CCO.[NH4+].[Cl-]>[Fe].O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:3]=1
Reactant: COc1ccc(Cn2nc(I)c3cc([N+](=O)[O-])cnc32)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2nc(I)c3cc(N)cnc32)cc1
Temperature: 80 °C
Yield: 83.6 %

Procedure:
3-Iodo-1-(4-methoxybenzyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (3.5 g, 8.5 mmol), EtOH (70 mL), water (30 mL), Fe (0) (1.9 g, 34 mmol), and NH4Cl (4.6 g, 85 mmol) were charged to a 250 mL round-bottomed flask. This mixture was warmed to 80° C. for 4 hours, and then allowed to cool to room temperature. The mixture was filtered through GF/F filter paper and concentrated to remove EtOH. The organic layers were extracted with EtOAc (2×100 mL), dried over Na2SO4, and concentrated to get 3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-amine (2.7 g, 74%) of crude product as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:5][C:6](=O)[C:7]=1[Cl:8])=[O:4].[NH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=O)[C:12]=1[C:20]([OH:22])=[O:21]>O1CCOCC1>[Cl:1][C:2]1[C:3]([N:10]([C:11]2[CH:19]=[CH:18][CH:17]=[C:13]3[C:14]([O:22][C:20](=[O:21])[C:12]=23)=[O:16])[C:6](=[O:5])[C:7]=1[Cl:8])=[O:4]
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: Nc1cccc(C(=O)O)c1C(=O)O
Solvent: C1COCCO1
Product: O=C1OC(=O)c2c1cccc2N1C(=O)C(Cl)=C(Cl)C1=O
Temperature: 130 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
20 g (0.12 mol) of 2,3-dichloromaleic anhydride are added to a solution of 18.1 g (0.1 mol) of 3-aminophthalic acid in 90 ml of dioxane. The reaction mixture is stirred at 20°-30°C, whereupon a clear solution is produced over the course of approx. 30 minutes. The dioxane is then distilled off in vacuo (20 mm Hg) and the oil which remains is warmed to 130°C. After 3 hours, the crystalline mass is cooled to 50°C and mixed with 100 ml of ethyl acetate. The reaction product is filtered off at 10°C and dried in vacuo at 80°C. 18.1 g (58% of theory) of crystalline 3-(2',3'-dichloromaleinimidyl)-phthalic anhydride are obtained, melting at 229°-230°C after recyrstallisation from anhydrous acetic acid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:22][C@H:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH3:21])[N:11]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Cl)nc1N[C@@H](C)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 37.8 %

Procedure:
5.0 g of methyl 2,6-dichloronicotinate was dissolved in ml of dimethylformamide, and 4.39 g of (S)-(−)-1-(4-fluorophenyl)ethylamine, 6.27 g of diisopropylethylamine and 150 mg of 4-dimethylaminopyridine were added thereto, and the mixture was stirred at 60° C. for 24 hours. The reaction solution was cooled, and then diluted with ethyl acetate, and washed in turn with water and brine, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 2.83 g of the objective compound as white powder.
Reaction SMILES: O1CCOCC1.Cl[CH2:8][C:9]([NH:11][C:12]1[C:13]([N+:30]([O-:32])=[O:31])=[CH:14][C:15]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=1)=[O:10].[CH2:33]([NH2:37])[CH2:34][CH2:35][CH3:36]>O>[CH2:33]([NH:37][CH2:8][C:9]([NH:11][C:12]1[C:13]([N+:30]([O-:32])=[O:31])=[CH:14][C:15]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=1)=[O:10])[CH2:34][CH2:35][CH3:36]
Reactant: CS(=O)(=O)Nc1cc(NC(=O)CCl)c([N+](=O)[O-])cc1Oc1ccccc1
Reactant: CCCCN
Solvent: C1COCCO1
Solvent: O
Product: CCCCNCC(=O)Nc1cc(NS(C)(=O)=O)c(Oc2ccccc2)cc1[N+](=O)[O-]
Yield: 72 %

Procedure:
To 7 ml of a dioxane solution containing 1.4 g of N-(5-chloroacetylamino-4-nitro-2-phenoxyphenyl)methanesulfonamide was added 0.77 g of n-butylamine at room temperature, followed by stirring for an hour. Water was added to the reaction solution, the precipitate was collected by filtration and recrystallized from ethanol to give 1.1 g of N-[5-(n-butylaminoacetylamino)4-nitro-2-phenoxyphenyl]methanesulfonamide as yellow needles.
Reaction SMILES: [NH2:1][O:2][C@@H:3]1[C@@H:7]([CH2:8][OH:9])[O:6][C@@:5]([Si](C(C)(C)C)(C)C)([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:4]1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C1COCC1>>[NH2:1][O:2][C@@H:3]1[C@@H:7]([CH2:8][OH:9])[O:6][C@@H:5]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:4]1
Reactant: Cc1cn([C@@]2([Si](C)(C)C(C)(C)C)C[C@H](ON)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cn([C@H]2C[C@H](ON)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 72 %

Procedure:
3'-O-Amino-(t-butyldimethylsilyl)thymidine was deblocked with (Bu)4NF/THF in standard way to furnish compound 4 (72%). Crystallized from ether/hexanes/ethanol as fine needles, mp 81° C. 1 h NMR (Me2SO-d6) δ 1.78 (s, 3, CH3), 2.17 and 2.45 (2m, 2, 2'CH2), 3.70 (m, 2, 5'CH2), 3.88 (m, 1, 4'H), 4.16 (m, 1, 3'H), 4.8 (br s, 1, 5'OH), 6.05 (dd, 1, 1'H), 6.2 (br s, 2 NH2), 7.48 (s, 1, C6H), and 11.24 (br s, 1NH). Anal. Calcd. for C10H15N3O5 : C, 46.69; H, 5.87; N, 16.33; found: C, 46.55; H, 5.91; N, 16.21.