Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]4[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[C:16]([CH3:28])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:36]([CH3:38])[CH3:37].O>CN(C)C=O>[C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH:25]4[CH2:27][CH2:26]4)=[CH:23][CH:24]=3)=[C:16]([CH3:28])[N:15]([CH:36]([CH3:38])[CH3:37])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CC(C)I
Reactant: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cc2ccc(C3CC3)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C(C)C
Reaction time: 0.58 h

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-5-methyl-4-[(4-cyclopropylphenyl)methyl]-1H-pyrazole (56 mg) and cesium carbonate (23 mg) in N,N-dimethylformamide (1.5 mL) was added 2-iodopropane (0.043 mL) at 8° C., and the mixture was stirred for 35 minutes. To the reaction mixture was added water, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol). The obtained crude product was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloromethane/methanol=7/1) to give 3-(β-D-glucopyranosyloxy)-5-methyl-1-isopropyl-4-[(4-cyclopropylphenyl)methyl]-1H-pyrazole (45 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:21]3[CH:20]=[CH:19][C:18]4[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=4[C:16]=3[N:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]2[CH:29]=[CH:28][CH:27]=[CH:26][C:13]=23)[CH:5]=[CH:6][CH:7]=1.[C:30]1(B(O)O)[C:43]2[C:44]3=[C:45]4[C:40](=[CH:41][CH:42]=2)[CH:39]=[CH:38][CH:37]=[C:36]4[CH:35]=[CH:34][C:33]3=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C>[C:30]1([C:2]2[CH:3]=[C:4]([C:8]3[C:21]4[CH:20]=[CH:19][C:18]5[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=5[C:16]=4[N:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][C:12]3[CH:29]=[CH:28][CH:27]=[CH:26][C:13]=34)[CH:5]=[CH:6][CH:7]=2)[C:43]2[C:44]3=[C:45]4[C:40](=[CH:41][CH:42]=2)[CH:39]=[CH:38][CH:37]=[C:36]4[CH:35]=[CH:34][C:33]3=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Reactant: Brc1cccc(-c2c3ccc4ccccc4c3nc3c2ccc2ccccc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1cc(-c2c3ccc4ccccc4c3nc3c2ccc2ccccc23)cc(-c2ccc3ccc4cccc5ccc2c3c45)c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
10 (700 mg, 1.61 mmol), pyren-1-ylboronic acid (434 mg, 1.76 mmol), Palladium tetrakis triphenylphoshine (186 mg, 0.16 mmol) and potassium carbonate (1.34 g, 9.66 mmol) were introduced in a flask together with 17 mL toluene, 8.8 mL ethanol and 2.6 mL distilled water. This mixture is stirred at 80° C. during 24 hours before being filtered. The solid is then washed with hexane, water and some mL of chloroform before being dried.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[N-:23]=[C:24]=[O:25].[K+].O>C(O)(=O)C>[CH3:20][NH:19][C:15]1[N:14]=[C:13]([C:12]2[C:7]([O:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:24]([NH2:23])=[O:25])=[CH:3][CH:4]=3)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Reactant: [N-]=C=O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(N)=O)cc2)n1

Procedure:
Dissolved 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (75 mg, 0.26 mmol) in acetic acid (1.0 mL), then added potassium isocyanate (0.01 ml, 0.33 mmol), water (0.1 ml), and stirred at RT for 18 hours. Concentrated and purified by reverse phase HPLC (Gilson, acidic mobile phase), extracted into CH2Cl2 washed with NaHCO3 and H2O. Product began to crash out of CH2Cl2 layer, transfered to round bottom flask, concentrated to yield 1-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)urea as off-white solid. MS m/z=337 [M+1]+. Calc'd for C17H16N6O2: 336.35.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].[CH2:5]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([Si](C)(C)C)[CH2:12][CH2:11]1)=[O:9])[CH3:6]>C(OCC)C>[CH2:5]([O:7][C:8]([N:10]1[CH2:11][CH2:12][N:13]([C:1]([Cl:4])=[S:2])[CH2:14][CH2:15]1)=[O:9])[CH3:6]
Reactant: CCOC(=O)N1CCN([Si](C)(C)C)CC1
Reactant: S=C(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)N1CCN(C(=S)Cl)CC1
Temperature: 25 °C

Procedure:
To a solution of 4.66 ml of 85% thiophosgene in 200 ml of ethyl ether, cooled to -76° was added, while stirring and under nitrogen, a solution of 7 g of 1-ethoxycarbonyl-4-trimethylsilylpiperazine in 35 ml of ethyl ether over a period of 20 minutes. The mixture was allowed to warm up to room temperature overnight. The suspension was filtered and the filtrate was evaporated to dryness. The residue was crystallized from methylene chloride-hexane to give 4-ethoxycarbonyl-1-piperazinylthiocarbonyl chloride, m.p. 107°-111°.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[CH:7]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[C:12](=[CH:22][C:23]([OH:25])=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1>C1C=CC=CC=1>[CH3:1][O:24][C:23](=[O:25])[CH:22]=[C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:17]=2[CH:16]=[CH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]1=2
Reactant: O=C(O)C=C1c2ccccc2C=Cc2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: COC(=O)C=C1c2ccccc2C=Cc2ccccc21

Procedure:
Oxalyl chloride (2.665 g., 1.79 ml., 0.021 mole) is added to a suspension of (5H-dibenzo[a,d]cyclohepten-5-ylidene)acetic acid (5.000 g., 0.020 mole) in dry benzene (70 ml.). An exothermic reaction occurs and the solid gradually dissolves. After solution is complete, the mixture is refluxed for one hour, then concentrated in vacuo to give an amber oil which crystallizes on storage at ambient temperature. The yield of crude ester melting at 83.5°-84.5° C. (uncorr.) is 5.210 g. (99.31%). Recrystallization of the material from methanol affords colorless rods melting at 86.0°-86.5° C. (uncorr.) in a yield of 3.508 g. (66.86%).
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=[O:10])[C:7](Cl)=O.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1C=[CH:17][NH:18]2>ClC(Cl)C>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:7]([CH:6]=[O:10])=[CH:17][NH:18]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc2[nH]ccc12
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cccc2[nH]cc(C=O)c12
Yield: 96.3 %

Procedure:
A solution of dry DMF (0.75 g) in 50 ml dichloroethane was cooled to 0° C. and placed under nitrogen. Oxalyl chloride (1.03 g) dissolved in dichloroethane (5 ml) was added dropwise with stirring. The solution was stirred until no more bubbling was observed (about 15-20 m). 4-Methoxyindole (1.0 g, 6.7 mmole) was added to the solution as a solid and the reaction mixture was stirred at room temperature for four hours. The reaction was quenched by careful addition of 10% sodium carbonate solution. The two phase mixture was stirred at room temperature for 2 hours. The layers were separated and the aqueous layer was extracted with methylene chloride, and the combined organic extracts were dried and evaporated to dryness. The crude residue was passed through a short silica gel column, eluting with 3:7 ethyl acetate:hexane to 1:1 ethyl acetate:hexane to yield 1.13 g (95%) of 4-methoxy-1H-indole-3-carbaldehyde.
Reaction SMILES: [OH: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][CH:3]=1.[CH2:15](O)[CH:16]=[CH:17][CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1C=CC=CC=1>[C:9]([O:8][C:6]([C:5]1[CH:13]=[CH:14][C:2]([O:1][CH2:15]/[CH:16]=[CH:17]/[CH3:18])=[CH:3][CH:4]=1)=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC=CCO
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C/C=C/COc1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 3 h
Yield: 0.1 %

Procedure:
A solution of 1,1-dimethylethyl 4-hydroxybenzoate (3.68 g, 18.9 mol) and 2-buten-1-ol (1.37 g, 18.9 mol) in dry benzene (100 ml) at 22° C. was treated with triphenylphosphine (5.48 g, 20.9 mmol) followed by a solution of diisopropyl azodicarboxylate (4.22 g, 20.9 mmol) in dry benzene (10 ml) added dropwise over 7 minutes. After 3 hours at 22° C., the solvent was concentrated under reduced pressure and the residue was chromatographed on silica gel. Elution with a mixture of toluene and ethyl acetate (99:1) gave 3.70 g (79%) of the title material as a clear oil: bp 85-90° C./0.1 torr (bulb to bulb, air bath temperature).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[C:13]([F:23])[C:8]2=[N:9][O:10][C:11]([CH3:12])=[C:7]2[CH:6]=1)=[O:4].C1COCC1.[Li+].[OH-].Cl>O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:14]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]2[C:8]([C:13]=1[F:23])=[N:9][O:10][C:11]=2[CH3:12]
Reactant: COC(=O)c1cc2c(C)onc2c(F)c1Nc1ccccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc2c(F)c(Nc3ccccc3Cl)c(C(=O)O)cc12
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of 6-(2-chlorophenylamino)-7-fluoro-3-methyl-benzo[c]-isoxazole-5-carboxylic acid methyl ester (55) (100 mg, 0.299 mmol) in 6:1 THF:water (3.5 mL) was added LiOH (0.60 ml of a 1 M solution in water). After 1 hour, the reaction was acidified to pH 1 with 1 N HCl, diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, dried (MgSO4) and concentrated to give the desired product (56) (87 mg, 91%). MS APCI (−) m/z 319, 321 (M+, Cl pattern) detected: 1H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 7.38 (dd, 1H), 7.20 (m, 1H), 6.91 (m, 2H), 2.88 (s, 3H): 19F NMR (376 MHz, CD3OD) −136.40 (s, 1F).
Reaction SMILES: [Na].CS(C)=O.[OH:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1.Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CO>[CH2:27]([O:26][C:24]([CH:23]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[N:8]=1)[CH3:29])=[O:25])[CH3:28]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ncn(-c2cccc(C(F)(F)F)c2)n1
Agent: [Na]
Solvent: CO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2cccc(C(F)(F)F)c2)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
A 1.7 g portion of sodium was dissolved in 30 ml of methanol, and the solution was added to 150 ml of dimethylsulfoxide. To it was added 17 g of 3-hydroxy-1-(3-trifluoromethylphenyl)-1,2,4-1H-triazole, and the solution was heated on the steam bath for 90 minutes. To it was then added 13.4 g of ethyl 2-bromopropionate, and heating was continued for 90 minutes more. The mixture was then cooled and poured over ice-water. The solid was collected, dried and recrystallized from ethanol to obtain 20.5 g of the desired product, m.p. 100°-102°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:24]=3[F:32])[CH:14]=2)=[N:11][CH:12]=1.[Cl-].[NH4+]>CCO.O.[Fe]>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=3[F:32])[CH:14]=2)=[N:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Yield: 103 %

Procedure:
To a suspension of 30 (10 g, 22.05 mmol) in EtOH (216 ml) and water (108 ml) was added iron powder (10.47 g, 187 mmol) and ammonium chloride (1.015 g, 18.97 mmol). The mixture was heated to reflux for 30 min, filtered while hot and the solids were washed with ether (200 mL). The filtrate and washings were combined and concentrated to afford intermediate 31 (9.62 g, 99% yield) as a beige solid. This material was used in the next step (Scheme 9) without additional purification. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.64 (d, J=2.0 Hz, 1H), 8.51 (dd, J=5.6, 2.0 Hz, 1H), 8.34 (s, 1H), 8.28 (dd, J=8.0, 0.8 Hz, 1H), 7.93 (dd, J=8.4, 2.0 Hz, 1H), 7.13 (t, J=9.0 Hz, 1H), 6.61 (dd, J=5.4, 0.6 Hz, 1H), 6.54 (dd, J=13.2, 2.4 Hz, 1H), 6.46 (ddd, J=8.8, 2.8, 0.6 Hz, 1H), 5.67 (s, 1H), 5.56 (s, 2H), 4.19 (dd, J=10.6, 5.0 Hz, 2H), 3.98 (td, J=12.0, 2.5 Hz, 2H), 2.09-1.99 (m, 1H), 1.49 (dt, J=13.2, 1.3 Hz, 1H). MS (m/z): 424.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21](O)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:24]CCl.C(Cl)(C(Cl)=O)=O>CN(C)C=O>[Cl:24][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[N:22]=1
Reactant: COc1cc(-c2nc(O)c3ccccc3n2)cc(OC)c1OC
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1cc(-c2nc(Cl)c3ccccc3n2)cc(OC)c1OC
Temperature: 0 °C

Procedure:
Into a 1-L 3-necked round-bottom flask, was placed 2-(3,4,5-trimethoxyphenyl)quinazolin-4-ol (12 g, 38.5 mmol, 1.00 equiv), dichloromethane (500 mL) and N,N-dimethylformamide (0.5 mL). This was followed by the addition of (COCl)2 (15 g) dropwise with stirring at 0° C. The resulting solution was heated to reflux for 1 h in an oil bath. The reaction was then quenched by the addition of 50 mL of sodium bicarbonate (sat.). The resulting solution was extracted with 2×100 mL of dichloromethane and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:dichloromethane:petroleum ether (1:1:4). This resulted in 10 g (78.7%) of 4-chloro-2-(3,4,5-trimethoxyphenyl)quinazoline as a white solid. MS (ESI) m/z 332 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:31]=[CH:30][C:19]([CH2:20][CH:21]([C:26]([O:28]C)=[O:27])[C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:25][O:24][C:22]([CH:21]([CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:31][CH:30]=1)[C:26]([OH:28])=[O:27])=[O:23]
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 6.6 %

Procedure:
Dimethyl 2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]malonate (8.46 g, 20 mmol) synthesized according to the method described in WO95/18125 was dissolved in a mixture of methanol (80 ml) and tetrahydrofuran (40 ml), and 2N aqueous sodium hydroxide solution (11 ml, 22 mmol) was added at 0° C. The mixture was stirred for 1.5 hr at room temperature and the solvent was evaporated. A saturated aqueous solution (5 ml) of sodium hydrogencarbonate was added and the aqueous layer was washed with ethyl acetate. To the obtained aqueous layer was added sodium chloride to saturate the solution, and the mixture was acidified with 1N hydrochloric acid and washed three times with ethyl acetate (50 ml). The extracted organic layers were combined, washed with brine, dried over sodium sulfate and dried to solidness to give a crude title compound (8.2 g, yield 100%). The obtained crude compound (750 mg) was recrystallized from a mixed solvent of ethyl acetate-hexane (1:2) to give the title compound (540 mg) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:11][CH:10]([CH2:12][CH2:13][OH:14])[CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.C(OCC)(=O)C>[Br:34][C:35]1[CH:40]=[CH:39][C:38]([O:14][CH2:13][CH2:12][CH:10]2[CH2:9][CH:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH2:11]2)=[CH:37][CH:36]=1
Reactant: OCCC1CC(OC2CCCCO2)C1
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1ccc(OCCC2CC(OC3CCCCO3)C2)cc1
Temperature: 25 °C
Yield: 32.5 %

Procedure:
2-[3-(Tetrahydro-2H-pyran-2-yloxy)cyclobutyl]ethanol (1.08 g, 5.39 mmol) was dissolved in tetrahydrofuran (20 mL) and was cooled in an ice bath. Triphenylphosphine (2.12 g, 8.09 mmol) and 4-bromo-phenol (1.12 g, 6.47 mmol) were added and the reaction was stirred until dissolved. Diethylazodicarboxylate (1.45 g, 8.09 mmol) was added dropwise to the reaction and the reaction was then warmed to room temperature and stirred for 48 hours. The reaction was diluted with ethyl acetate and washed with 1 N aqueous sodium hydroxide. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give a clear oil. Purification on silica gel with heptane-ethyl acetate (15% ethyl acetate) gave 2-({3-[2-(4-bromophenoxy)ethyl]cyclobutyl}oxy)tetrahydro-2H-pyran (622 mg, 32.4%) as a clear oil. Partial 1H NMR indicated a −4:1 mix of unknown cis-trans isomers. (CDCl3, δ ppm, key peaks are 4.08 (m, 0.80H), 4.38 (m, 0.20H), 6.74 (d, J=8.98, 2H), 7.34 (d, J=9.18, 2H).
Reaction SMILES: [CH:1]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[N:3]([CH2:9][C@H:10]([O:13][CH2:14][P:15]([OH:18])([OH:17])=[O:16])[CH2:11][OH:12])[CH:2]=1.[CH3:19][CH2:20][N:21]([CH:25]([CH3:27])C)[CH:22](C)[CH3:23]>CN(C=O)C>[CH:1]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[N:3]([CH2:9][C@H:10]([O:13][CH2:14][P:15]([OH:18])([OH:17])=[O:16])[CH2:11][OH:12])[CH:2]=1.[CH3:19][CH2:20][N:21]([CH2:25][CH2:27][OH:5])[CH2:22][CH3:23]
Reactant: CCN(C(C)C)C(C)C
Agent: Nc1ccn(C[C@@H](CO)OCP(=O)(O)O)c(=O)n1
Solvent: CN(C)C=O
Product: CCN(CC)CCO

Procedure:
To prepare compound 5 of FIG. 2, 135 mg (0.428 mmol) cidofovir was exposed to 135 mg (1.04 mmol) DIEA and dissolved in 4 mL DMF. A HPMPC-DEEA salt was obtained after solvent was removed under vacuum. 650 mg (1.8 mmol) dipeptide (t-BOC-Val-Ser-t-butyl described above) was added to a reaction flask containing the HPMPC-DIEA salt and 4 mL dry DMF. 660 mg (1.27 mmol) PyBOP and 425 μL (2.44 mmol) DIEA were added, and the reaction took place stirring under N2 (g) at 40° C. for 1 h. An additional 330 mg (0.635 mmol) PyBOP was added and left for 3 additional hours. Solvents were removed under vacuum, and a silica gel column chromatography purification was performed [eluent; CH2Cl2: acetone:methanol, 20:10:1.]. Solvent was removed and deprotection of the t-BOC and t-butoxy groups was performed in 4 mL of CH2Cl2 in the presence of 2 mL of 99% TFA for 3 h at room temperature. Solvents were removed under vacuum and ether was added to precipitate the final compound, 5, which was filtered by methanol on a funnel containing a silica gel layer. Preparative HPLC purification on a C-18 column (5 μm, 100 Å 21.4×250 mm by Varian) was obtained using a mobile phase containing 0.1 M TEA and 3.5% acetonitrile at pH 6.7 adjusted with acetic acid. A fraction of the sample was purified by preparative HPLC methods and evaluated by NMR and HR-MS techniques. 1H NMR (CD3OD); δ 0.94 (6H, m), 2.10 (1H, m), 2.94-5.73 (10H, m), 5.73 (1H, m), 7.40 (1H, m). 31P NMR (CD3OD): δ 14.3 and 15.6 (1P, 2s). Exact mass (C16H26N5O8P); 447.1519 m/z.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]([N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=2)[C:33]([C:42]([OH:44])=O)=[CH:32]1)([CH3:30])[CH3:29].[NH2:45][C:46]1[S:47][CH:48]=[CH:49][N:50]=1>C(Cl)Cl>[S:47]1[CH:48]=[CH:49][N:50]=[C:46]1[NH:45][C:42]([C:33]1[C:34]2[C:39](=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[N:31]([CH:28]([CH3:29])[CH3:30])[CH:32]=1)=[O:44]
Reactant: COc1ccc2c(C(=O)O)cn(C(C)C)c2c1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2c(C(=O)Nc3nccs3)cn(C(C)C)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
A solution of triphenylphosphine (219 mg, 0.84 mmol) in methylene chloride (3 mL) cooled to 0° C. was treated with N-bromosuccinimide (149 mg, 0.84 mmol). The reaction was stirred at 0° C. for 15 min. At this time, the reaction was treated with 1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid (150 mg, 0.64 mmol). The reaction was stirred at 0° C. for 5 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 2-aminothiazole (148 mg, 1.48 mmol) and stirred at 25° C. for 24 h. At this time, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL) and treated with a 1N aqueous hydrochloric acid solution (25 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL) and a saturated aqueous sodium chloride solution (1×25 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid thiazol-2-ylamide (101 mg, 50%) as tan solid: mp 182-185° C.; EI-HRMS m/e calcd for C16H17N3O2S (M+) 315.1041, found 315.1039.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([Li])CCC.[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br)([O-:16])=[O:15]>O1CCCC1.C(OCC)C>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: Nc1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccccc1CNc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A solution of 2-fluoroaniline (6.8 mL, 70 mmol) in tetrahydrofuran (200 mL) was cooled to −78° C. and treated with n-butyllithium (31 mL of a 2.5 M solution in hexanes, 77 mmol). After 1 h, the reaction mixture was treated with a solution of 2-nitrobenzylbromide (15.1 g, 70 mL) in tetrahydrofuran (50 mL), and warmed to room temperature and stirred for 16 h. The reaction mixture was diluted with ethyl ether (500 mL), and washed with H2O (500 mL), and evaporated. Flash chromatography (SiO2, 5-20% ethyl acetate/hexanes) provided 2-fluoro-N-(2-nitrobenzyl)aniline (13.4 g) as a yellow solid:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[CH2:8])[CH3:7])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:1]([O:4][CH2:5][C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:7])[CH3:8])(=[O:3])[CH3:2]
Reactant: C=C(C)COC(C)=O
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)OCC(C)(C)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Mix methallyl acetate (228 g, 2.0 mol) and benzene (1L) and cool to 5° C. Add aluminum chloride (266 g, 2.0 mol) over approximately 30 minutes while maintaining the temperature below 10° C. Add, in portions of 50 mL to 80 mL each, to a 5° C. mixture of aluminum chloride (15 g) in benzene (600 mL). After addition is complete, stir at 0-3° C. for ½ hour, pour onto ice (2 kg) and separate the organic layer. Wash with water (2×300 mL), dry (Na2SO4), and distill to give neophyl acetate.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][O:7][C:8]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:22][C:23]#[N:24].[C:25](=O)([O:29]CC)[O:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1.C(O)C>[C:23]([CH:22]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:8]=1[O:7][CH3:6])[C:25]([O:26][CH2:27][CH3:28])=[O:29])#[N:24]
Reactant: COc1c(CC#N)cccc1Oc1ccccc1C
Reactant: CCOC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2C)c1OC
Yield: 96.5 %

Procedure:
A mixture of sodium ethoxide prepared from ethanol (20 ml) and sodium metal (480 mg), 2-[2-methoxy-3-(o-tolyloxy)phenyl]acetonitrile (5 g) and diethyl carbonate (9.4 g) in toluene (50 ml) was treated in a similar manner to that of Example 10-(4) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]acetate (6.2 g).