Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=[O:7].[CH2:11]([C:13]1([CH2:28][CH2:29][OH:30])[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16][CH2:15][O:14]1)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:26][CH3:27])[CH3:12]>C(Cl)Cl.[NH4+].[Cl-]>[CH2:11]([C:13]1([CH2:28][CH:29]([OH:7])[OH:30])[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16][CH2:15][O:14]1)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:26][CH3:27])[CH3:12]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Reactant: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(O)O)OCC3
Yield: 31.8 %

Procedure:
Dry DMSO (71 μL, 1.0 mmol, 2.0 eq) was added dropwise to a solution of oxalyl chloride (66 μL, 0.75 mmol, 1.5 eq) in CH2Cl2 (1 mL) at −78° C. After stirring for ten minutes, a solution of compound 1 (136 μL, 0.5 mmol) in CH2Cl2 (4 mL) was added dropwise, and the reaction was stirred for an additional thirty minutes at −78° C. before the addition of TEA (2.79 μL, 2.0 mmol, 4.0 eq). The reaction mixture was then allowed to warn slowly to 0° C., diluted with saturated NH4Cl, and extracted twice with Et2O. The combined organic phases were washed with water and brine, dried with Na2SO4, concentrated, and purified by column chromatography using a gradient of 50:50:EtOAc:Hexane to 100% EtOAc to give a white solid (46 mg, 32%): mp 158-159° C. 1HNMR (CDCl3, δ TMS): 0.50 (t, 3H), 1.25 (t, 3H), 1.50 (m, 1H), 1.82 (m, 1H), 2.04 (m, 1H), 2.17 (m, 1H), 2.33 (m, 1H), 2.58 (q, 2H), 2.88 (m, 2H), 3.77 (m, 1H), 3.91 (m, 1H), 4.19 (q, 1H), 4.33 (m, 1H), 7.02-7.15 (m, 3H, Ar—H), 7.66 (br, 1H, NH). MS−: m/z 288 ([M−H]−). Anal. (C17H23NO3): C, H, N.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.NC1C=CC(C(F)(F)F)=CC=1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1cc2ncnc(Nc3ccc(C(F)(F)F)cc3)c2cn1
Temperature: 180 °C
Reaction time: 0.03 h
Yield: 63.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (390 mg, 2.03 mmol), 4-aminobenzotrifluoride hydrochloride (0.40 g, 2.02 mmol) and 4-aminobenzotrifluoride (1.61 g, 10.0 mmol) is stirred at 180° C. for 2 min. The resulting product is neutralized with excess NaHCO3, dissolved in MeOH/CHCl3, dried onto alumina and chromatographed over alumina (4-7% MeOH/CH2Cl2) to give 7-amino-4-(4-trifluoromethylanilino)pyrido[4,3-d]pyrimidine (390 mg, 63) as a cream solid. Analytically pure material was obtained by further chromatography over silica gel (5% MeOH/CH2C2) to give pale yellow needles. 1H NMR (DMSO) δ 10.09 (1H, brs), 9.40 (1H, s), 8.48 (1H, s), 8.13 (2H, d, J 8.2 Hz), 7.74 (2H, d, J=8.7 Hz), 6.72 (2H, brs), 6.40 (1H, s).
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[CH:24]=[C:23]([N:25]2[CH2:30]C[CH:28]([C:31]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:32])[CH2:27][CH2:26]2)[CH:22]=[CH:21][C:20]=1[Cl:38])=[O:7])(C)(C)C.ClCCl.CO>Cl.CCOCC>[CH:6]([OH:7])=[O:5].[Cl:38][C:20]1[CH:21]=[CH:22][C:23]([N:25]2[CH2:30][CH:28]([C:31]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:32])[CH2:27][CH2:26]2)=[CH:24][C:19]=1[C:9]1[NH:8][C:12]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=2[N:10]=1
Reactant: COc1ccc2c(c1)nc(-c1cc(N3CCC(C(=O)N4CCCC4)CC3)ccc1Cl)n2C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2[nH]c(-c3cc(N4CCC(C(=O)N5CCCC5)C4)ccc3Cl)nc2c1
Product: O=CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
Method F—Step b To a mixture of 2-{2-Chloro-5-[4-(pyrrolidine-1-carbonyl)-piperidin-1-yl]-phenyl}-5-methoxy-benzoimidazole-1-carboxylic acid tert-butyl ester (0.10 g, 0.19 mmol) in 2M HCl in Et2O (2 mL), few drops of dichloromethane and methanol were added to improve the solubility of the starting material. The resulting mixture was stirred overnight at room temperature, Et2O was added (5 mL), the precipitate was filtered off and then purified by PrepHPLC to get 0.03 g of the title compound as hydrochloride salt, with quantitative yield.
Reaction SMILES: [CH:1]([C:4]1[O:8][N:7]=[C:6]([CH2:9][CH2:10][NH2:11])[N:5]=1)([CH3:3])[CH3:2].[CH2:12]([N:14](CC)CC)C.[C:19]([NH:22][C:23]1[S:24][C:25]([C:29]2[N:30]=[C:31]([C:34](NCC3CCCO3)=O)[S:32][CH:33]=2)=[C:26]([CH3:28])[N:27]=1)(=[O:21])C>CN(C=O)C>[C:12]([CH2:34][C:31]1[S:32][CH:33]=[C:29]([C:25]2[S:24][C:23]([NH:22][C:19]([NH:11][CH2:10][CH2:9][C:6]3[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[O:8][N:7]=3)=[O:21])=[N:27][C:26]=2[CH3:28])[N:30]=1)#[N:14]
Reactant: CCN(CC)CC
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)NCC3CCCO3)n2)s1
Reactant: CC(C)c1nc(CCN)no1
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)NCCc2noc(C(C)C)n2)sc1-c1csc(CC#N)n1
Reaction time: 0.5 h

Procedure:
2-(5-Isopropyl-1,2,4-oxadiazol-3-yl)ethanamine (Amine 16) (129.2 mg; 0.48 mmol; 2 eq) is dissolved in DMF (4 ml). Triethylamine (133 μl; 0.96 mmol; 4 eq) and N-[2-(cyanomethyl)-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl]-1H-imidazole-1-carboxamide (Intermediate 6) (79.3 mg; 0.24 mmol; 1 eq) are added. After less than 1 min the mixture becomes homogeneous, and after 30 min the reaction is complete. Solvents are evaporated and the resulting crude product is purified by preparative HPLC. The purified fractions are neutralized with NaHCO3 sat. solution and the desired product is extracted with DCM. The combined organic layers are dried over MgSO4, filtered and concentrated to Compound (82) as a white powder (29.6 mg; 30%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:32]([O:33]C(OC)=O)=[CH:31][C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]([F:38])[CH:5]=1.O.Cl>CO>[ClH:3].[Cl:3][C:4]1[C:32]([OH:33])=[CH:31][C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]([F:38])[CH:5]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCCCc4ccncc4)c(OC)cc23)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ncnc2cc1OCCCc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 150.4 %

Procedure:
2M Aqueous sodium hydroxide (1.5 ml, 3 mmol) was added to a solution of 4-(4-chloro-2-fluoro-5-methoxycarbonyloxyanilino)-6-methoxy-7-(3 -(4-pyridyl)propoxy)quinazoline (1.28 g, 2.5 mmol) in methanol (13 ml) and the mixture stirred for 2 hours at ambient temperature. Water was added and the mixture was adjusted to pH7 with 2M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried under vacuum. This solid was dissolved in methylene chloride (30 ml) and methanol (5 ml) and a solution of 5M hydrogen chloride in isopropanol (2.5 ml) was added. The solution was diluted with isopropanol and concentrated under vacuum to a total volume of 10 ml. The resulting solid was collected by filtration, washed with isopropanol and then ether and dried under vacuum to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline hydrochloride (924 mg, 70%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[O:20]1[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[CH2:22][CH2:21]1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.Cl>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:7]([NH:8][C:26]([CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)=[O:27])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: O=C(O)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of 2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl amine (0.1 g, 0.385 mmol) in DCM (3 mL) and DMF (1 mL), was added sequentially tetrahydro-2H-pyran-4-carboxlic acid (0.06 g, 0.461 mmol), N-methylmorpholine (0.127 mL, 1.16 mmol), 1-hydroxylbenzotriazole (HOBT) (0.068 g, 0.504 mmol), and EDCl.HCl (0.096 g, 0.504 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate (3 mL) and 15 mL of dichloromethane. The aqueous layer was extracted with dichloromethane (15 mL, 2×). The combined organic layers were washed with sodium bicarbonate (15 mL), brine (15 mL), dried over Na2SO4, and concentrated under vacuum. Purification by column chromatography on silica gel (0-10%) methanol in dichloromethane afforded 0.103 g (73%) of the title compound.
Reaction SMILES: [N:1]1O[C:3]([O-])=[C:4]2[N+:9]=1[CH2:8][CH2:7][O:6][CH2:5]2.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[C:12]#C>CC1C=CC=CC=1C>[N:1]1[N:9]2[C:4]([CH2:5][O:6][CH2:7][CH2:8]2)=[CH:3][C:12]=1[C:11]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: [O-]c1on[n+]2c1COCC2
Reactant: C#CC(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2n(n1)CCOC2
Temperature: 140 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a partial solution of 6,7-dihydro-4H-[1,2,3]oxadiazolo[4,3-c][1,4]oxazin-8-ium-3-olate (3.41 g, 24 mmol) in o-xylene (80 ml), was added ethyl propiolate (2.7 ml, 26 mmol). The mixture was stirred at 140° C. for 3 hr. An additional 2.0 ml (19 mmol) of ethyl propiolate was then added and the mixture was stirred at reflux for 18 hr. The final solution was evaporated under vacuum, and the residue was dissolved in a mixture of methylene chloride and hexanes (1:5). The solution was passed through a pad of silica gel and the filter pad was eluted with methylene chloride-hexanes, followed by ethyl acetate. The ethyl acetate eluent was evaporated and the residue washed with hexanes to give 4.10 g of a white solid; mp 63° C.; MS (ESI) m/z 197.1 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:10][C:11]([NH2:13])=[S:12].[I-:14].[K+].II>CO>[CH:6]1[CH:5]=[C:4]2[C:3]([S:12][C:11]([NH2:13])=[NH:10])=[CH:2][NH:1][C:9]2=[CH:8][CH:7]=1.[IH:14]
Reactant: c1ccc2[nH]ccc2c1
Reactant: NC(N)=S
Reactant: [I-]
Agent: II
Agent: [K+]
Solvent: CO
Product: I
Product: N=C(N)Sc1c[nH]c2ccccc12

Procedure:
To 240 parts of methanol is added 23.4 parts of indole, 15.2 parts of thiourea, and a sufficient amount of a 1 N aqueous solution of potassium iodide and iodine so that an equivalent of each is present for each equivalent of indole. The whole is stirred for sixteen hours, after which time the solvent is evaporated in vacuo to yield S[3-indolyl]isothiuronium iodide as colorless crystals; m.p. 214°-216°. Treatment of this product with an excess of a concentrated aqueous solution of sodium hydroxide under a nitrogen atmosphere at 80° for ten minutes, followed by cooling to room temperature yields a basic solution of 3-indolylthiol. Neutralization thereof with dilute hydrochloric acid yields as pure product, 3-indolylthiol; m.p. 100°-101°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][SH:9])=[CH:4][CH:3]=1.Cl[C:11]1[CH:21]=[C:15]2[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]2[C:13](=[O:22])[N:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9][C:11]2[CH:21]=[C:15]3[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]3[C:13](=[O:22])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: SCc1ccc(Cl)cc1
Product: CN1CCCn2c1cc(SCc1ccc(Cl)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E62 starting from (4-chlorophenyl)methanethiol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: CO[C:3](=[S:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[NH2:12][C@H:13]([C:18]([OH:20])=[O:19])[CH2:14][C:15]([OH:17])=[O:16].[OH-].[Na+]>CCOCC>[Cl:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([NH:12][C@H:13]([C:18]([OH:20])=[O:19])[CH2:14][C:15]([OH:17])=[O:16])=[S:11])=[CH:9][CH:8]=1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: COC(=S)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)C[C@H](NC(=S)c1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.6 %

Procedure:
A mixture of methyl-4-chlorothiobenzoate (2.11 g, 11.3 mmol), aspartic acid (2.7 g, 2.02 mmol), aq NaOH (3N, 8.8 ml), and Et2O (8 ml) were vigourously stirred at room temperature for 3 days. The aq. layer was separated, acidfied (dil.HCl), and extracted with Et2O (2×25 ml). The combined ether extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to yield N-p-chlorothiobenzoylaspartic acid (0.23 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH:14]=[C:15]2[C:21]3=[CH:22][CH:23]=[CH:24][NH:25][C:20]3=[CH:19][O:18][C:17]3[CH:26]=[CH:27][C:28]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:29][C:16]2=3)=[CH:4][CH:3]=1.[CH:34](=O)[CH3:35].[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:38].[Na+].C(O)(=O)C>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:34][CH3:35])[CH2:9][CH2:10][N:11]([CH2:37][CH3:38])[CH2:12][CH2:13][CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[N:25][C:20]=3[CH2:19][O:18][C:17]3[CH:26]=[CH:27][C:28]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:29][C:16]2=3)=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC=O
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCNCCNc1ccc(Cl)cc1)C1=CC=CNC1=CO2
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(CCC=C1c2cc(C(C)(C)O)ccc2OCc2ncccc21)CCN(CC)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-{3-[2-(4-chloro-phenylamino)-ethylamino]-propylidene}-5,1-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl)-propan-2-ol (0.13 g, 0.27 mmol) in dichloroethane (5.0 mL) was added acetaldehyde (0.045 mL, 0.81 mmol), sodium triacetoxy borohydride (0.17 g, 0.81 mmol) and catalytic acetic acid and stirred at room temperature overnight. The reaction mixture was concentrated and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified on silica using gradient elution from ethyl acetate (100%) to ethyl acetate/methanol (5%). 1H-NMR (CDCL3) δ: 0.90-1.20 (6H, 2×t), 1.60 (6H, s), 2.20-2.40 (2H, m), 2.45-2.65 (6H, m), 3.20-3.40 (4H, 2×q), 5.30 (2H, br, s), 6.10 (1H, t), 6.50 (2H, dd), 6.80 (1H, d), 7.10 (2H, dd) 7.20-7.35 (2H, m), 7.45 (1H, dd), 7.55 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 520 (M+1), UV retention time: 1.51 min.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][S:12][CH3:13])[CH:5]=1.[OH:14]O>C(O)(=O)C.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>[CH3:13][S:12]([CH2:11][O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH2:3][NH:2][CH3:1])=[O:14]
Reactant: OO
Reactant: CNCc1cccc(OCSC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNCc1cccc(OCS(C)=O)c1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Compound from step 3 (592 mg, 3.00 mmol) was dissolved in glacial acetic acid (4 mL) and cooled to 0° C. H2O2 (0.34 mL, 3.00 mmol) was added drop-wise. The mixture was allowed to stir for 6 h. The mixture was then diluted with CH2Cl2 and neutralized with K2CO3. The solids were filtered off. The filtrate was dried over Na2SO4 and concentrated in vacuo to give 640 mg (quant) of a yellow crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-:21].[Na+].[CH3:23]O>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:21][CH3:23])[N:6]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Product: COc1nc(N)c2nc(OC)n(Cc3ccccc3)c2n1
Yield: 78 %

Procedure:
To 6-amino-9-benzyl-8-bromo-2-methoxypurine (125 mg, 0.374 mmol) in 10 ml of methanol was added 10N aqueous sodium hydroxide (50 ml) and the solution was refluxed under heating for 2 hours. The reaction mixture was concentrated in vacuo to dryness and to the residue was added water. The mixture was extracted with chloroform and the organic layer was dried on sodium sulfate. After removal of the solvent the residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (83 mg, yield 78%).
Reaction SMILES: C(Cl)(=O)[C:2]1[CH:7]=[CH:6]C=CC=1.[N:10]1[CH:15]=[CH:14]C=[CH:12][CH:11]=1.Cl[CH2:17]Cl>CN(C1C=CN=CC=1)C>[CH3:14][CH2:15][N:10]([CH:7]([CH3:6])[CH3:2])[CH:11]([CH3:12])[CH3:17]
Reactant: ClCCl
Reactant: c1ccncc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Product: CCN(C(C)C)C(C)C

Procedure:
The following stages have been newly invented: using sodium azide in DMF, 29 was reacted to give the azide 30 and this was reduced with triphenylphosphine in pyridine to give the aminoethyluracil 31. The amino function in 31 was finally protected with N-ethoxycarbonylphtalimide (Scheme 2). Nucleosidation of ribose tetrabenzoate 33 with N-phtaloylaminoethyluracil 32 produced the ribose tribenzoate 34 in good yields. The anomeric centre of the pyranose ring is in the β configuration, as can be clearly seen from the coupling constants between H—C(1′) and H—C(2′) of J=9.5 Hz. Subsequent removal of the benzoate protective groups using NaOMe in MeOH yielded the linker triol 35. 35 was reacted with benzoyl chloride at −78° C. in pyridine/dichlormethane 1:10 in the presence of DMAP. In this process, in addition to the desired 2′-benzoate 36 (64%), 2′,4′-dibenzoylated product (22%) was also obtained, which was collected and converted into the triol 35 analogously to the methanolysis of 34 to 35. The 2′-benzoate 36 was tritylated with dimethoxytrityl chloride in the 4′-position in yields of greater than 90% in the presence of Hünig's base in dichloromethane. The rearrangement of 4′-DMT-2′-benzoate 37 to the 4′-DMT-3′-benzoate 38 was carried out in the presence of DMAP, p-nitrophenol and Hünig's base in n-propanol/pyridine 5:2. After chromatography, 38 is obtained. 4′-DMT-3′-benzoate 38 was finally reacted with ClP (OAll)N(iPr)2 to give the phosphoramidite 39 in the presence of Hu{umlaut over (n)}ig's base (Scheme 3). This can be employed for the automated oligonucleotide synthesis without alteration of the synthesis protocols.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[C:19](Br)[C:12]2=[N:11][C:10]=1[C:27]1[O:28][C:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:30][N:31]=1)C1C=CC=CC=1.[Si]([I:44])(C)(C)C.CO.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C>[F:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][C:29]2[O:28][C:27]([C:10]3[N:11]=[C:12]4[C:19]([I:44])=[CH:18][C:17]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:16][N:13]4[C:14](=[O:15])[C:9]=3[OH:8])=[N:31][CH:30]=2)=[CH:34][CH:35]=1
Reactant: C[Si](C)(C)I
Reactant: O=c1c(OCc2ccccc2)c(-c2ncc(Cc3ccc(F)cc3)o2)nc2c(Br)cc(N3CCOCC3)cn12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: O=c1c(O)c(-c2ncc(Cc3ccc(F)cc3)o2)nc2c(I)cc(N3CCOCC3)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of the product of example 3 (25 mg, 0.042 mmol) in acetonitrile (1 ml) was added idodotrimethylsilane (TMSI) (0.05 ml, 0.338 mmol) at room temperature. The mixture was stirred at room temperature for 8 hours, after which methanol (0.1 ml) was added to quench the reaction. Then saturated solution of Na2S2O3 was added drop-wise till a yellow solid was precipitated. The resulting solids were collected by filtration, washed with ethyl acetate to give the titled compound (13 mg, 60% yield).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=2)[O:4][C:3]1=[O:16].[H][H]>CO.C(Cl)(Cl)Cl.[Pd]>[NH2:13][C:9]1[CH:8]=[C:7]([C:5]2[O:4][C:3](=[O:16])[N:2]([CH3:1])[N:6]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Cn1nc(-c2cccc([N+](=O)[O-])c2)oc1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cn1nc(-c2cccc(N)c2)oc1=O
Yield: 79.6 %

Procedure:
3-Methyl-5-(3-nitrophenyl)-1,3,4-oxadiazol-2(3H)-one (2.17 g, 9.79 mmol) obtained in Step 2 was dissolved in methanol (60 mL) and chloroform (51 mL), and the mixture was stirred at room temperature for 4 hours under a stream of hydrogen after adding 10% palladium-on-carbon (217 mg, 0.102 mmol). The mixture was further stirred at room temperature for 4 hours under a stream of hydrogen after adding 10% palladium-on-carbon (217 mg, 0.102 mmol). Then, insolubles were separated by filtration through sellite, and the filtrate was concentrated under reduced pressure. The residue was triturated with diethyl ether, and the solid was filtered off and dried to give 5-(3-aminophenyl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (1.49 g, 80%).
Reaction SMILES: [N+:1]([C:4](=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)C(OCC)=O)([O-:3])=[O:2].[OH-].[Na+]>C(O)(=O)C>[N+:1]([CH:4]=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=C1NCCCS1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.3 g of (A) was added to 10 ml of 20% aqueous sodium hydroxide and the mixture was stirred at room temperature for 12 hours. The resulting solution was treated dropwise with 3.5 g of acetic acid. The addition was accompanied by vigorous gas evolution. The resulting mixture was extracted with methylene chloride and the extract was dried (magnesium sulfate) and concentrated under reduced pressure to give (B) as a pale yellow solid, m.p. 76°-78°.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:15].BrN1C(=O)CCC1=O.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1F
Reactant: NCc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(F)c(CNCc2ccccc2)c1
Yield: 60.9 %

Procedure:
According to the procedure of Preparation 4(b), except using tert-butyl 4-fluoro-3-methylbenzoate (6.25 g, 29.7 mmole), N-bromosuccinimide (5.75 g, 32.3 mmole), benzoyl peroxide (375 mg, 1.6 mmole), CCl4 (50 mL), and benzylamine (17 mL, 156 mmole), the title compound (5.70 g, 60%) was prepared as a yellow oil following flash chromatography on silica gel (20% EtOAc/hexanes): MS (ES) m/e 316.1 (M+H)+.