Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:20])=[C:6]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C:7]([CH3:10])=[N:8][CH:9]=1)(O)=O.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([O:11][C:6]2[C:7]([CH3:10])=[N:8][CH:9]=[C:4]([CH2:1][NH:21][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[C:5]=2[CH3:20])=[CH:13][CH:14]=1)#[N:17]
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1ncc(C(=O)O)c(C)c1Oc1ccc(C#N)cc1
Product: Cc1ncc(CNc2ccc(C#N)cc2)c(C)c1Oc1ccc(C#N)cc1
Yield: 45.1 %

Procedure:
The reductive amination of 4-(5-carboxy-2,4-dimethyl-pyridin-3-yloxy)-benzonitrile (189 mg, 0.75 mmol) and 4-aminobenzonitrile (400 mg, 3.38 mmol), as described in Example 21, gave 4-{[3-(4-cyano-phenoxy)-2,4-dimethyl-pyridin-5-ylmethyl]-amino}-benzonitrile (91) (120 mg, 45% yield) as a brown oil.
Reaction SMILES: [CH2:1](OCC1C=CC=CC=1)C1C=CC=CC=1.[NH2:16][CH2:17][CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([N:28]3[C:32]([C:33]4[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[C:36]([O:42]CC5C=CC=CC=5)=[CH:35][C:34]=4[O:50]CC4C=CC=CC=4)=[N:31][N:30]=[C:29]3[OH:58])=[CH:25][CH:26]=2)[CH:21]=[CH:20]1>>[OH:58][C:29]1[N:28]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:19]([CH2:18][CH2:17][NH:16][CH3:1])[CH:20]=[CH:21]3)[C:32]([C:33]2[CH:38]=[C:37]([CH:39]([CH3:40])[CH3:41])[C:36]([OH:42])=[CH:35][C:34]=2[OH:50])=[N:31][N:30]=1
Reactant: CC(C)c1cc(-c2nnc(O)n2-c2ccc3c(ccn3CCN)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: c1ccc(COCc2ccccc2)cc1
Product: CNCCn1ccc2cc(-n3c(O)nnc3-c3cc(C(C)C)c(O)cc3O)ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The benzylether[4-(1-(2-aminoethyl)-1H-indol-5-yl)-5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4H-1,2,4-triazol-3-ol; 188 mg, 0.33 mmol) was dissolved in 6 ml degassed THF/methanol (1:1). 50 mg Pd/C (10%) was added and the mixture stirred under hydrogen (balloon) at rt for 5 h. After filtration the solvent was removed and the crude purified by chromatography on silica with DCM/MeOH (5-20%)/NH4OH (0.5%) to yield 71 mg (0.18 mmol) 4-(5-hydroxy-4-(1-(2-(methylamino)ethyl)-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol. This amine (50 mg, 0.125) was added to 4-(2,5-dioxopyrrolidin-1-yl)butanoic acid (26 mg, 0.14 mmol), EDC (38 mg, 0.2 mmol) and HOBt (27 mg, 0.2 mmol) in 1.5 ml DMF at rt. The mixture was stirred for 12 h and then ethyl acetate and water added. The aq. Phase was extracted twice with ethyl acetate and the combined organic extracts washed with brine and dried over MgSO4. The crude was purified by chromatography on silica with DCM/MeOH (3-10%) to yield 34 mg (0.061 mmol) product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][N:30]3[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Reactant: O=C(O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCN5CC(C(=O)O)C5)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 3 h
Yield: 29.8 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (50 mg), 3-azetidinecarboxylic acid (25 mg) and acetic acid (0.1 mL) in DCM (10 mL) was added sodium triacetoxyborohydride (78 mg). The reaction was stirred at 20° C. for 3 h. The mixture was concentrated and the residue was partitioned between ethyl acetate (25 mL) and aqueous HCl (2 M, 25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford 1-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}-3-azetidinecarboxylic acid (E67) (18 mg, TFA salt). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 3.00 (2H, t), 3.47 (2H, t), 3.60 (1H, m), 3.65 (3H, s), 4.22 (4H, m), 4.88 (1H, m), 7.22 (1H, t), 7.31 (1H, s), 7.47 (2H, m), 7.87 (1H, dd), 8.12 (1H, dd), 8.19 (1H, d). MS (ES): C26H27ClN4O4 requires 494; found 495.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]([CH2:10][O:11][CH3:12])=[CH:8][CH:7]=[C:6]([N+:13]([O-])=O)[C:5]=1[OH:16].[C:17](=S)(OCC)[S-:18].[K+]>C(O)C>[CH3:12][O:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]2[N:13]=[C:17]([SH:18])[O:16][C:5]=2[C:4]=1[CH2:3][O:2][CH3:1]
Reactant: COCc1ccc([N+](=O)[O-])c(O)c1COC
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Product: COCc1ccc2nc(S)oc2c1COC
Yield: 59 %

Procedure:
Thus, the aminophenol (276 mg, 1.29 mmol) was dissolved in ethanol (10 ml) and potassium O-ethyl dithiocarbonate (228 mg, 1.42 mmol) was added thereto followed by heating to reflux for 16 hours. After cooling, the solvent was evaporated therefrom in vacuo. The residue was acidified by adding 2N hydrochloric acid thereto and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom. The residue was purified by a preparative thin layer chromatography (developing solvent, hexane:acetone=5:3) to provide 182 mg (yield 59%) of 6,7-bis(methoxymethyl)-2-mercaptobenzooxazole as pale brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]S)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](C1C=C([N+]([O-])=O)C=CC=1CS)([O-])=O.[N+](C1C=CC(CCl)=CC=1)([O-])=O.[C:37]([OH:40])(=[S:39])[CH3:38]>C1COCC1.N1C=CC=CC=1>[C:37]([O:40][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[S:39])[CH3:38]
Reactant: O=[N+]([O-])c1ccc(CS)cc1
Reactant: CC(O)=S
Agent: O=[N+]([O-])c1ccc(CCl)cc1
Agent: O=[N+]([O-])c1ccc(CS)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=S)OCc1ccc([N+](=O)[O-])cc1
Yield: 77 %

Procedure:
The two step procedure for the preparation of 4-nitrobenzyl, (see, for example, Horn, W. J., J. Am. Chem. Soc., 43, 2603, 1921), and 2,4-dinitrobenzyl, (see, for example, Zhao Zhengyun, Ph.D. Thesis, London University, 181-182, 1993), mercaptans (17a and 17b, respectively) is indicated in outline in Scheme 3(a). Thus, when 4-nitrobenzyl chloride 15a was treated with an excess both of thioacetic acid and pyridine in THF solution at 50° C., 4-nitrobenzyl thioacetate 16a was obtained in 77% yield. When the latter compound 16a was heated, under reflux, in sulfuric acid--water (1:1 v/v), 4-nitrobenzyl mercaptan 17a was obtained in almost quantitative yield. 2,4-dinitrobenzyl mercaptan, (see, for example, Zhao, loc cit), 17b was similarly prepared from 2,4-dinitrobenzyl chloride, (see, for example, Cohn, P., and Friedlander, P., Ber., 35, 1265, 1902) 15b in 73% overall yield. N-(4-nitrobenzylmercapto)succinimide 18 was prepared [Scheme 3(b) and Experimental below] in 65 % yield by heating a suspension of the lead(II) salt, (see, for example, Pant, B.C., and Noltes, J. G., Inorg. Nucl. Chem. Lett., 7, 63, 1971), of the mercaptan 17a with N-bromosuccinimide (NBS) in benzene. Preliminary attempts to convert 2,4-dinitrobenzyl mercaptan 17b into the corresponding succinimide and phthalimide derivatives (13 and 14, R=2,4-(O2 N)2C6H3) were unsuccessful. However, di-(2,4-dinitrobenzyl) disulfide 19, (see, for example, Zhao, loc cit), which was easily prepared in good yield by the iodine-promoted oxidation [Scheme 3(c) and Experimental below] of the mercaptan 17b, proved (see below) to be an equally effective reagent for the required purpose. Finally, 2-cyanoethyl mercaptan 20, (see, for example, Bauer, L., and Welsh, T. L., J. Org. Chem., 26, 1443, 1961) was converted (see, for example, Behforouz, M., and Kerwood, J. E., J. Org. Chem., 34, 51, 1969), [Scheme 3(d) and Experimental below] via a putative intermediate sulfenyl chloride into N-(2-cyanoethylmercapto)phthalimide 21 which was isolated without chromatography as a crystalline solid in 58% yield. ##STR10## Scheme 4 Reagents and conditions: i, a, PCl3, 1,2,4-1H-triazole, Et3N, THF, -35° C., b, Et3N, H2O, RT; ii, for 24a: 18, Me3SiCl, Et3N, CH2Cl2, RT, for 24b: 19, Me3SiCl,4-methylmorpholine, CH2Cl2, RT, for 24c: 21, Me3SiCl, 4-methylmoxpholine, CH2Cl2, RT; iii, aq. Et NH+ HCO3 --.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:16]1[CH:21]=[C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([NH:26][C:27]([C:29]3[C:38]([OH:39])=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)=[O:28])[C:19]2=[CH:18][CH:17]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[C:25]1([NH:26][C:27]([C:29]2[C:38]([O:39][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:28])[C:19]2[C:20](=[CH:21][CH:16]=[CH:17][CH:18]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Nc1cccc2ccccc12)c1cc2ccccc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4cc3C(=O)Nc3cccc4ccccc34)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 17.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), naphthol AS-BO (626 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (43 mg, yield 17%).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:22][C@@:21]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:20]2[C:19](=[N:24]O)[CH2:18][C@@:17]2([CH3:26])[C@H:11]3[CH2:12][CH2:13]/[C:14]/2=[CH:15]/[CH3:16])[CH2:6][C@@H:5]1[OH:27])[CH3:2].O>C(O)CC>[NH2:24][C@@H:19]1[CH2:18][C@@:17]2([CH3:26])[C@@H:11]([CH2:12][CH2:13]/[C:14]/2=[CH:15]/[CH3:16])[C@H:10]2[C@H:20]1[C@:21]1([CH3:23])[C@@H:7]([CH2:8][CH2:9]2)[CH2:6][C@H:5]([OH:27])[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:22]1
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3C(=NO)C[C@]12C
Solvent: O
Solvent: CCCO
Product: C/C=C1/CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3[C@H](N)C[C@]12C

Procedure:
A refluxing solution (under nitrogen) of (Z)-2β-ethoxy-3α-hydroxy-5α-pregn-17(20)-en-11-one 11-oxime (450 mg) in propan-1-ol (15 ml) was treated with pieces of Na (450 mg). When there was no trace of Na left the mixture was added to chilled water to give a fine precipitate which was collected by filtration.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]([CH3:21])([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=O)[C:7]([NH2:9])=[O:8])([CH3:5])[CH3:4]>>[CH:3]([C:6]1([CH3:21])[N:10]2[C:18](=[O:19])[C:17]3[C:12]([C:11]2=[N:9][C:7]1=[O:8])=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH3:5])[CH3:4]
Reactant: CC(C)C(C)(C(N)=O)N1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21

Procedure:
Following the procedure described in Example 1 and sodium hydride as the base, but substituting (-)-α-isopropyl-α-methyl-1,3-dioxo-2-isoindolineacetamide for the racemic compound, the product (+)-3-isopropyl-3-methyl-5H-imidazo-[2,1-a]isoindole-2(3H),5-dione is obtained, melting point 137.5°-139° C, [α]D25 +64.54 (THF, C 0.097).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][C@@H:17]([CH2:24][C@H:25]([CH3:32])[CH2:26]OS(C)(=O)=O)[CH2:18]OS(C)(=O)=O)=[O:15])([CH3:12])([CH3:11])[CH3:10]>COCCOC>[C:9]([O:13][C:14](=[O:15])[NH:16][C@H:17]1[CH2:24][C@H:25]([CH3:32])[CH2:26][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18]1)([CH3:10])([CH3:11])[CH3:12]
Reactant: NCc1ccccc1
Reactant: C[C@H](COS(C)(=O)=O)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Solvent: COCCOC
Product: C[C@H]1C[C@H](NC(=O)OC(C)(C)C)CN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A 50 L reactor is charged with 9.1 Kg of neat benzylamine. The reactor is brought to 55° C. and a solution of intermediate (6) (8.2 Kg) in 1,2-dimethoxyethane (DME) (14.1 Kg) is added to the reactor while maintaining a temperature of 60° C.±5° C. After complete addition of this solution, the reaction is stirred at 60° C.±5° C. for several hours and monitored for completion by TLC or HPLC. The reaction is cooled to ambient temperature and volatiles (DME) are removed by rotary evaporation under vacuum. The residue is diluted with 11.7 Kg of 15% (v/v) ethyl acetate/hexanes solution and treated, while agitating, with 18.7 Kg of 20% (wt) aqueous potassium carbonate solution. A triphasic mixture is obtained upon settling. The bottom aqueous phase is removed and the middle phase is set aside. The upper organic phase is collected and held for combination with extracts from additional extractions. The isolated middle phase is extracted twice again with 11.7 Kg portions of 15% (v/v) ethyl acetate/hexanes solution, each time combining the extracts with original organic phase. The combined organic extracts are transferred into a rotary evaporator and solvent is removed under vacuum until an oily residue remains. The residue is then purified via large-scale preparative chromatography to afford purified intermediate (7) as an oil.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH:9]([OH:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CO[C:21](OC)([CH3:23])[CH3:22].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CO>C(Cl)Cl>[CH2:6]([O:5][C:3]([CH:2]1[CH2:8][CH:9]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[O:18][C:21]([CH3:23])([CH3:22])[O:1]1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(O)CC(O)CC(=O)OC(C)(C)C
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C1CC(CC(=O)OC(C)(C)C)OC(C)(C)O1
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of 1-ethyl 6-tert.-butyl 2,4-dihydroxyadipate (1.6 g, 6.1 mmol) in methylene chloride (60 ml), dimethoxypropane (1.672 ml, 78 mmol) and pyridinium p-toluenesulfonate (251 mg, 1 mmol) were added and stirred under reflux conditions for one hour, followed by further stirring at 50° C for one hour while azeotropically removing methanol with methylene chloride. To the mixture, methylene chloride (60 ml) was added and stirred at 50° C. for one hour to remove methylene chloride. After adding water, the mixture was extracted with methylene chloride. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:acetone=7:1) to give pure 2-ethoxycarbonyl-4-tert.-butoxycarbonylmethyl-6,6-dimethyl-1,5-dioxane (1.23 g, 4.06 mmol). Yield, 67%.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[H-].[Na+].[CH2:11](Br)[CH3:12]>O1CCCC1>[CH2:11]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH3:12]
Reactant: Oc1ccc(O)cc1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(O)cc1

Procedure:
Hydroquinone can be added to a solution of sodium hydride (NaH) dissolved in tetrahydrofuran (THF) and combined with ethyl bromide yielding para-ethoxyphenol. The para-ethoxyphenol can be extracted and added to a solution of tosyl chloride (TsCl) dissolved in pyridine and tetrahydrofuran (THF) at room temperature, yielding para-ethoxytosyloxybenzene. The para-ethoxytosyloxybenzene can be extracted and added to a solution of diatomic iodine (I2) and potassium iodide trioxide (KIO3) dissolved in sulfuric acid (H2SO4) and acetic acid (CH3COOH) yielding 4-ethoxy-3-iodo-1-tosyloxybenzene. The 4-ethoxy-3-iodo-1-tosyloxybenzene is extracted and added to a solution of aqueous sodium hydroxide (NaOH) and tert-butanol, removing the tosylate protecting group and yielding 4-ethoxy-3-iodophenol. The 4-ethoxy-3-iodophenol can be extracted and exposed to resin-bound triphenylphosphine (PPh3) in a solution of azopyridine and methanol (CH3OH) in a salt bath at 0° C., yielding 4-ethoxy-3-iodomethoxybenzene. The 4-ethoxy-3-iodomethoxybenzene can be extracted and added to a solution of titanium tetrachloride (TiCl4) and 1,1-dichlorodimethylether (CHCl2OCH3) dissolved in dichloromethane (CH2Cl2) in a salt bath at −10° C., yielding 2-methoxy-4-iodo-5-ethoxybenzaldehyde. The 2-methoxy-4-iodo-5-ethoxybenzaldehyde can be extracted and half of the yield can be added to tri-iso-propylsilylacetylene (TIPS-acetylene) in an amine solvent such as triethylamine, diethylamine, piperidine, or di-iso-propylethylamine. This mixture can be passed over a palladium (Pd) catalyst bed, yielding 2-methoxy-5-ethoxy-4-((tri-iso-propylsilyl)ethynyebenzaldehyde.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:27][OH:28])[O:4][C@H:5]2[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:29][O:30][C:31]1[CH:52]=[CH:51][C:34]([C:35](Cl)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:27][O:28][C:35]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)[C:34]1[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:52][CH:51]=1)[O:4][C@H:5]2[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:27][OH:28])[O:4][C@H:5]2[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:18]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4cnc5c(NC(=O)c6ccccc6)ncnc54)O2)[C@@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of compound 61B (0.50 g) in anhydrous pyridine (20 cm3) was added 4,4′-dimethoxytrityl chloride (0.71 g, 2.09 mmol) and 4-N,N-dimethylaminopyridine (DMAP) (0.1 g). After stirring for 2 h at room temperature and for 1 h at 50° C., the reaction mixture was cooled to 0° C. and a saturated aqueous solution of sodium hydrogencarbonate (100 cm3) was added. After extraction using dichloromethane (3×50 cm3), the combined organic phase was dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol/pyridine (98.0:1.5:0.5) to give nucleoside 61C as a white solid material (0.36 g, ˜50% from 61A). δH (C5D5N) 12.52 (NHCO), 9.10 (2H, d, J 7.7, Bz), 8.88 (1H, s, 8-H), 8.50-7.11 (17H, m, DMT, Bz, 2-H), 6.65 (1H, s, H-1′), 5.25 (2H, s, H-2′, H-3′), 4.71 (1H, d, J 7.8, 1″-Ha), 4.56 (1H, d, J 7.8, 1″-Hb), 4.20 (1H, d, J 10.8, 5′-Ha), 4.07 (1H, d, J 10.8, 5′-Hb), 3.82, 3.81 (2×3H, 2×s, 2×OCH3). δC (C5D5N) 167.56 (NHCO), 159.24 (C-6), 152.50, 152.08, 151.81, 145.84, 141.45, 136.52, 136.28, 132.55, 130.76, 130.70, 129.32, 128.85, 128.76, 128.46, 127.38, 126.33 (DMT, Bz, C-2, C-4, C-8), 113.84 (C-5), 88.64, 87.20, 86.85, 80.52, 73.13, 72.16, 60.86 (C-1′, C-4′, DMT, C-2′, C-3′, C-1″, C-5′), 55.24 (OCH3). FAB-MS m/z 686 [M+H]+. Found: C, 68.3; H, 5.0; N, 9.7; C39H35N5O7 requires C, 68.3; H, 5.1; N, 10.2%).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=1[O:35][CH:36]([CH3:38])[CH3:37]>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:22][CH2:23][N:24]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[O:35][CH:36]([CH3:38])[CH3:37])[CH2:25][CH2:26]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)Oc1c(N)ncnc1Cl
Reactant: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Product: CC(C)Oc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(C)C)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “1” by using 4-[1-(2-azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-isopropyl-pyridine and 6-chloro-5-isopropoxy-pyrimidin-4-ylamine as the starting materials. LC-MS (M+H=505, obsd=505).
Reaction SMILES: [C:1]([C:5]1[N:6]([CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:7]=[C:8]([C:10]2[CH:11]=C([CH:15]=[CH:16][CH:17]=2)C#N)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:25].[Na+].[CH2:27]([OH:29])[CH3:28]>>[C:1]([C:5]1[N:6]([CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:7]=[C:8]([C:10]2[CH:11]=[C:28]([CH:15]=[CH:16][CH:17]=2)[C:27]([OH:25])=[O:29])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCO
Reactant: [OH-]
Reactant: CC(C)(C)c1nc(-c2cccc(C#N)c2)cn1CC1CCCCC1
Agent: [Na+]
Product: CC(C)(C)c1nc(-c2cccc(C(=O)O)c2)cn1CC1CCCCC1
Temperature: 25 °C
Yield: 98 %

Procedure:
Compound 1 (0.17 g, 0.53 mmol) obtained in Example 1 was dissolved in ethanol (60 mL), and a 2 mol/L aqueous sodium hydroxide solution (60 mL, 120 mmol) was added thereto, and then, the mixture was refluxed overnight. After the mixture was left to cool to room temperature, the solvent was evaporated under reduced pressure. To the residue, 2 mol/L hydrochloric acid was added to adjust the pH of the mixture to 4. Then, the mixture was extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure to give the title compound a (178 mg, 0.52 mmol, yield: 98%).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=1>>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:2]([CH3:5])([CH3:4])[CH3:3])[CH:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: Clc1cccc(Br)c1
Product: C[Si](C)(C)c1cccc(Cl)c1

Procedure:
1-Chloro-3-trimethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing chlorotrimethylsilane and 1-chloro-3-bromobenzene as the dihalo compound of formula (II).