Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-])=O)[C:12]=1[OH:21])(=[O:10])=[O:9])([CH3:3])[CH3:2].[H][H]>[Pd]>[CH:1]([O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=1[OH:21])(=[O:10])=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)OCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)OCCNS(=O)(=O)c1c(Cl)ccc(N)c1O

Procedure:
Following the general hydrogenation procedure outlined in example 15, crude N-(2-isopropoxyethyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (1.17 g) was reduced with hydrogen and Pd/C (350 mg). The crude product (1.086 g) was carried on to the next step without purification. 1H NMR (MeOD-d4): δ 6.92 (d, 1H), 6.85 (d, 1H), 3.45 (m, 1H), 3.39 (t, 2H), 3.10 (t, 2H), 1.05 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]1(O)[CH2:32][CH2:31]CC[CH2:28][CH2:27][CH2:26]1>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:32][CH2:31][CH2:20]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: OC1CCCCCCC1
Agent: [Ti]
Solvent: CCO
Product: O=C(OC1CCCCCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 0.33 h

Procedure:
A mixture of 10.35 g (0.03 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1 carboxylate, 50 g of cyclooctanol and 2 g of tetraethyl orthotitanate is heated to 130° for 8 hours, a small amount of solvent being distilled off twice in vacuo. The mixture is subsequently evaporated in vacuo, the residue is taken up in chloroform and the solution is poured into about 20 percent hydrochloric acid. The mixture is stirred for 20 minutes, the chloroform phase is separated, washed successively with 1N hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. By chromatography on a silica gel column while eluting with ethyl acetate and subsequent crystallization from ethyl acetate/hexane there is obtained cyclooctyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 183°-184°.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH2:8][S:9][CH3:10])=[O:5].Br[CH2:12][CH2:13][N:14]1[CH:18]=[C:17]([NH:19][C:20]([C:22]2[CH:23]=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[N:27][C:26]=23)=[O:21])[C:16]([C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=2[O:38][CH:39]([F:41])[F:40])=[N:15]1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[NH4+]>CC#N.C(O)=O.O>[Cl:37][C:35]1[CH:34]=[CH:33][C:32]([O:38][CH:39]([F:41])[F:40])=[C:31]([C:16]2[C:17]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[N:27][C:26]=34)=[O:21])=[CH:18][N:14]([CH2:13][CH2:12][NH:2][CH2:3][C:4]([O:6][CH2:7][CH2:8][S:9][CH3:10])=[O:5])[N:15]=2)[CH:36]=1
Reactant: O=C(Nc1cn(CCBr)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: CSCCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Solvent: O=CO
Product: CSCCOC(=O)CNCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(methylsulfanyl)ethyl 2-aminoacetate HCl salt (792 mg, 3.57 mmol) in CH3CN was added N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (364 mg, 0.71 mmol) and DIEA (1.57 g, 12.15 mmol). The resulting solution was stirred at 75° C. overnight and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-Waters 2767-2 (HPLC-08)): Column, Xbridge Prep Phenyl, 5 um, 19×150 mm; mobile phase, Water with 50 mmol ammonium bicarbonate and acetonitrile (10.0% acetonitrile up to 33.0% in 2 min, up to 53.0% in 8 min, up to 100.0% in 1 min, down to 10.0% in 1 min); Detector, UV 220 nm. This resulted in 53.1 mg (2%) of the formic acid salt of 2-(methylsulfanyl)ethyl 2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)amino]acetate as light yellow oil. LCMS (Method 20): [M+H]+=580.15, RT=2.76 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.5, 6.9 Hz), 8.67 (dd, 1H, J=1.5, 4.2 Hz), 8.66 (s, 1H), 8.36 (s, 1H), 7.65-7.61 (m, 2H), 7.44 (d, 1H, J=9.3 Hz), 7.23 (dd, 1H, J=4.5, 7.2 Hz), 6.99 (t, 1H, J=73.5 Hz), 4.27-4.18 (m, 4H), 3.38 (s, 2H), 2.99 (t, 2H, J=6.0 Hz), 2.67 (t, 2H, J=6.6 Hz), 2.07 (s, 3H).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:16]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[N:1]1([CH2:10][CH2:11][CH2:12][C:13]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=2)=[O:15])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)CCCn1cnc2ccccc21
Product: CC(C)(C)c1ccc(NC(=O)CCCn2cnc3ccccc32)cc1

Procedure:
Part C. The title compound was synthesized according to a procedure described in Example 98 starting from 4-benzoimidazol-1-yl-butyric acid and 4-tert-butyl-aniline. Calculated for C16H23N3O m/z: 335.20, found 336.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=1[CH:25]([CH3:27])[CH3:26]>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH:25]([CH3:26])[CH3:27])=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Br)cc21
Reactant: Cc1cc(C(C)C)c(CN)c(=O)[nH]1
Product: Cc1cc(C(C)C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as example 101 from 6-Bromo-1-(1-methylethyl)-1H-indazole-4-carboxylic acid and 3-(aminomethyl)-6-methyl-4-(1-methylethyl)2(1H)-pyridinone. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (s, 1H) 8.63 (t, J=4.80 Hz, 1H) 8.37 (s, 1H) 8.20 (s, 1H) 7.69 (d, J=1.26 Hz, 1H) 6.02 (s, 1H) 5.05 (quin, J=6.57 Hz, 1H) 4.41 (d, J=4.80 Hz, 2H) 3.21 (quin, J=6.76 Hz, 1H) 2.16 (s, 3H) 1.47 (s, 3H) 1.45 (s, 3H) 1.11 (s, 3H) 1.09 (s, 3H); MS (ES) [M+H]+ 445.1, 446.9.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][C:6](=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([O:11]CC)=[O:10])[CH3:7])=[O:4].S(=O)(O)[O-].[Na+]>[I-].C[SiH](C)C>[F:1][C:2]([F:20])([F:21])[C:3]([NH:5][C:6](=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([OH:11])=[O:10])[CH3:7])=[O:4]
Reactant: CCOC(=O)C(=C(C)NC(=O)C(F)(F)F)c1ccccc1
Agent: C[SiH](C)C
Agent: O=S([O-])O
Agent: [I-]
Product: CC(NC(=O)C(F)(F)F)=C(C(=O)O)c1ccccc1
Yield: 78.2 %

Procedure:
16.5 g of the product of Step A were dissolved in 15.6 ml of trimethylsilane iodide and after 16 hours of reflux, the solution was poured into 200 ml of a solution of sodium bisulfite and then was extracted with ether. The extracts were washed with water, dried and concentrated to dryness under reduced pressure to obtain 11.7 g of the expected product which after crystallization from heptane melted at 174° C.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH2:23])[CH2:16][CH2:15][CH2:14]1>O1CCCC1>[NH:23]1[C:21]2=[C:22]3[C:17](=[CH:18][CH:19]=[CH:20]2)[CH2:16][CH2:15][CH2:14][N:13]3[C:1]1=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc2c1NCCC2
Solvent: C1CCOC1
Product: O=c1[nH]c2cccc3c2n1CCC3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 1,1′-carbonyldiimidazole in tetrahydrofuran was added to a solution of 1,2,3,4-tetrahydro-8-quinolineamine (10 g) obtained in Reference Example 130 in tetrahydrofuran (100 ml), and the mixture was stirred at room temperature at 4 hours. The reaction mixture was concentrated to give a brown solid (11 g). Further recrystallization from water-ethyl estate afforded the title compound as colorless crystals (10 g).
Reaction SMILES: [Si](OCC[N:11]1[C:23]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:16]([O-])=[CH:15][C:14]=2[N:13]=[C:12]1[CH2:25][O:26][CH2:27][CH3:28])(C(C)(C)C)(C)C.[NH4+:29].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[CH2:27]([O:26][CH2:25][C:12]1[NH:11][C:23]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:29])[C:14]=2[N:13]=1)[CH3:28]
Reactant: [NH4+]
Reactant: CCOCc1nc2c[n+]([O-])c3cccnc3c2n1CCO[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cccnc3c2[nH]1
Reaction time: 1.5 h

Procedure:
1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridine 5-oxide (2.40 g, 5.97 mmol) was dissolved in 60 mL of CH2Cl2 and treated with 6 mL of concentrated aqueous NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (1.19 g, 6.27 mmol) was carefully added. Rapid stirring was continued for 1.5 hours. The reaction mixture was then treated with 50 mL of CH2Cl2 and 25 mL of H2O. The layers were separated and the organic portion was washed successively with 2% Na2CO3 solution (2×25 mL), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10-15% CMA/CHCl3) gave 1-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (1.93 g) as a light-brown foam.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[C:17]([CH:18]=[C:19]4[C:24]=2[CH:23]=[CH:22][CH:21]=[CH:20]4)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:25]Br.C(Cl)(Cl)(Cl)Cl>O>[Br:25][C:18]1[C:19]2[C:24]([C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: CC(C)(C)c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)c1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixed solution of 13.3 g of the above-mentioned 9-(4-tert-butylphenyl)anthracene, 7.52 g of bromine and 300 ml of carbon tetrachloride was heated to reflux under nitrogen atmosphere for 1 hour. After cooling the mixed solution to room temperature, 200 ml of water was injected thereto to extract 200 ml of dichloromethane therefrom. The organic layer was washed twice in 200 ml of water, dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was washed twice in 100 ml of hexane and vacuum dried to thereafter obtain 16.09 g of 9-bromo-10-(4-tert-butylphenyl)anthracene.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]=1.[Cl:8][SiH:9]([Cl:11])[Cl:10].N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>>[CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]1[Si:9]([Cl:11])([Cl:10])[Cl:8]
Reactant: CC1=CC(C)CC1
Reactant: Cl[SiH](Cl)Cl
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Product: CC1CCC(C)C1[Si](Cl)(Cl)Cl
Yield: 72.5 %

Procedure:
A one-liter autoclave equipped with a stirrer was charged in a nitrogen atmosphere with 49 grams (0.51 mol) of 1,3-dimethylcyclopentene, 138 grams (1.0 mol) of trichlorosilane and 24 grams (0.1 mol) of 1,1'-azobis(cyclohexane-1-carbonitrile) and the mixture was reacted at a temperature of 130° C. for 3 days. The resulting reaction mixture was purified by distillation thereby obtaining 85 grams (0.37 mol) of 2,5-dimethylcyclopentyltrichlorosilane. The structure of the resulting product was identified by 1H-NMR analysis.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][S:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29](Cl)=[O:30])[CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19].Cl>O1CCCC1.O>[OH:3][NH:2][C:29](=[O:30])[CH:28]=[CH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:18](=[O:20])(=[O:19])[NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[CH:22]=1
Reactant: COc1ccccc1NS(=O)(=O)c1cccc(C=CC(=O)Cl)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1NS(=O)(=O)c1cccc(C=CC(=O)NO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.36 g, 5.20 mmol) in tetrahydrofuran (6 ml) a saturated NaHCO3 solution (4.5 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-[3-(2-methoxy-phenylsulfamoyl)-phenyl]-acryloyl chloride (16c) (0.37 g, 1.05 mmol) in tetrahydrofuran (5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was poured into water, the obtained solution was acidified with 2N HCl and extracted with ethyl acetate. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from ethyl acetate and washed with diethyl ether affording the title compound (0.23 g, 64%). M.p. 181° C. 1H NMR (DMSO-d6, HMDSO) δ: 3.45 (3H, s); 6.49 (1H, d, J=16.0 Hz); 6.76-7.96 (9H, m); 9.09 (1H, br s); 9.54 (1H, s); 10.78 (1H, br s). HPLC analysis on Symmetry C8 column: impurities 1.3% (column size 3.9×150 mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5), 35:65; sample concentration 0.15 mg/ml; flow rate 1.2 ml/min; detector UV 230 nm). Anal. Calcd for C16H16N2O5S, %: C, 55.16; H, 4.63; N, 8.04. Found %: C, 55.14; H, 4.52; N, 7.99.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:11].[NH3:13]>CO>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:2]([CH3:12])([CH3:1])[C:3]([NH2:13])=[O:11]
Reactant: CC1(C)C(=O)Oc2ccccc21
Reactant: N
Solvent: CO
Product: CC(C)(C(N)=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3,3-Dimethylbenzofuran-2(3H)-one (Example 198a, 19.7 g) was dissolved in 7N ammonia in methanol (50 mL) under nitrogen. The resulting solution was stirred at 25° C. for 16 h. The reaction mixture was evaporated to afford crude product. The solid was triturated with diethyl ether and filtered to give the subtitle compound (15.34 g).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.FC1C=CC(O)=CC=1.C([O:29][C@@H:30]1[C@H:34]([O:35]C(=O)C2C=CC=CC=2)[C@@H:33]([CH2:44][O:45]C(=O)C2C=CC=CC=2)[O:32][C@H:31]1[N:54]1[CH:62]=[N:61][C:60]2[C:55]1=[N:56][C:57]([Cl:64])=[N:58][C:59]=2Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C>O1CCOCC1>[Cl:64][C:57]1[N:58]=[C:59]([NH:10][C@H:8]([CH3:9])[CH2:7][O:6][C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=2)[C:60]2[N:61]=[CH:62][N:54]([C:55]=2[N:56]=1)[C@@H:31]1[O:32][C@H:33]([CH2:44][OH:45])[C@@H:34]([OH:35])[C@H:30]1[OH:29]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: C[C@@H](N)COc1ccc(F)cc1
Agent: Oc1ccc(F)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@H](COc1ccc(F)cc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.1 %

Procedure:
(R)-1-(4-fluorophenoxy)-2-propylamine (0.29 g, 1.4 mmol)(prepared from 4-fluorophenol by the method desrcribed in example 2) was reacted with 9-(2',3',5'-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (0.89 g, 1.4 mmol) in dioxan (30 ml) in the presence of triethylamine (0.42 g, 3 mmol). The reaction mixture was stirred at room temperature for 18 h, and heated at 60° C. for 4 h. The reaction mixture was filtered and evaporated to a residue which was purified by flash chromatography. The resultant 2',3',5'-tri- O-benzoyl-2-chloro- N-[(R)-1-(4-fluorophenoxy)-2-propyl]adenosine was deprotected using methanolic ammonia to provide the title 2-chloro- N-[(R)-1-(4-fluorophenoxy)-2-propyl]adenosine (0.21 g, 40%)(after column chromatography), mp 172°-173° C.; 1H NMR (DMSO-d6)δ 1.29 (3H, d, --CH3), 3.52-3.60 (1H, m, H-5'a), 3.64-3.72 (1H, m, H-5'b), 3.92-4.00 (2H, m, H-4' and --C--H), 4.05-4.20 (2H, m, H-3' and --C--H), 4.53 (1H, m, H-2'), 4.65 (1H, m, --CH3C H--), 5.08, 5.24, 5.50 (3H, 3 br, 2', 3' and 5'-OH), 5.86 (1H, d, H-1'), 6.89-7.15 (4H, 2 m, Ar--H), 8.30-8.46 (2H, m, H-8 and N--H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][OH:37])[CH2:31][CH2:30]2)=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])=[O:7].Cl>CO>[OH:3][C:4]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][OH:37])[CH2:33][CH2:34]2)=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:18]=[C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])=[O:7]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(CCO)CC2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(C2CCN(CCO)CC2)ccc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
Methanol (1.0 mL) and a 2.0 mol/L aqueous solution of sodium hydroxide (0.37 mL) were added to the obtained methyl 2-(2-hydroxy-5-(1-(2-hydroxyethyl)piperidin-4-yl)benzamido)-4-phenylbenzoate (0.035 g), followed by stirring at 50° C. for 2 hours. After cooling the reaction mixture to room temperature and adjusting the pH to 6.0 with 2.0 mol/L hydrochloric acid, the solid substance was collected by filtration to obtain 0.030 g of 2-(2-hydroxy-5-(1-(2-hydroxyethyl)piperidin-4-yl)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].S([O-])([O-])(=O)=O.[Mg+2].[CH:12](=O)[CH:13]([CH3:15])[CH3:14]>CCOCC>[CH3:12][CH:13]([CH3:15])[CH:14]=[N:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C=O
Reactant: CC(C)(C)N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(C)C=NC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.9 %

Procedure:
To a stirred solution of t-butylamine (20.0 mL, 190 mmol) in anhydrous ether (200 mL) was added magnesium sulfate (20 g). A solution of isobutyraldehyde (17.3 mL, 190 mmol) in ether (50 mL) was then added dropwise over 30 minutes. After stirring at ambient temperature for 3 days, the reaction was filtered and the ether removed in vacuo (300 mm). The residual liquid was distilled to afford the title compound (14.0 g, 58%) as a colorless liquid; bp 52° C. (75 mm);
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:16]1[CH2:17][CH2:18][O:19][CH2:20][CH:21]=1)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:19]1[CH2:18][CH:17]=[C:16]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=2)[CH2:21][CH2:20]1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccnc(C2=CCOCC2)c1
Temperature: 100 °C
Yield: 23 %

Procedure:
To a stirred solution of 7.00 g (44.2 mmol) 2-chloro-4-nitropyridine in 150 ml N,N-dimethylformamide were added 16.8 g (45.0 mmol) tributyl-(3,6-dihydro-2H-pyran-4-yl)stannane, 3.72 g (5.30 mmol) bis(triphenylphosphine)palladium(II) chloride, 6.95 g (26.5 mmol) triphenylphosphine, 15.0 g (353 mmol) lithium chloride and 0.97 g (4.42 mmol) 2,6-di-tert-butyl-p-cresol. The mixture was heated at 100° C. for 4 h and then cooled to room temperature and concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 9/1 then ethyl acetate) afforded 2.10 g (23%) 2-(3,6-dihydro-2H-pyran-4-yl)-4-nitro-pyridine as an orange solid. ES-MS m/e (%): 207 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[C:15](=[O:17])=[O:16]>O1CCCC1.CCCCCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:15]([OH:17])=[O:16]
Reactant: Fc1cc(F)cc(F)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 10.0 grams (0.076 mole) of 1,3,5-trifluorobenzene in 150 ml of anhydrous tetrahydrofuran, under an argon atmosphere, was cooled to -78° and 4.8 grams (0.076 mole) of n-butyllithium (as 48.7 ml of a 1.55 molar solution in hexane) was added dropwise during a 30-minute period. Upon completion of addition the reaction mixture was stirred at -78° for eight hours. A quantity of fresh, crushed dry ice, sufficient to cause the reaction mixture to become a thick slurry, was added to the reaction vessel. The reaction mixture was allowed to warm to ambient temperature as it was stirred for 26 hours. The tetrahydrofuran was removed from the reaction mixture under reduced pressure. The residue was washed into a separatory funnel with 100 ml of aqueous 2N sodium hydroxide and 200 ml of diethyl ether. The aqueous base layer was separated and the organic layer extracted with two 100 ml portions of aqueous 2N sodium hydroxide. The organic layer was discarded and the combined aqueous base layer and extracts were washed with 100 ml of diethyl ether, cooled, and acidified with concentrated hydrochloric acid. The mixture was saturated with sodium chloride and extracted with three portions of 150 ml each of diethyl ether. The combined ether extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a solid residue. The residue was recrystallized from toluene to give 10.2 grams of 2,4,6-trifluorobenzoic acid; mp 225°-227°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])=[CH:5][CH:4]=1.[H][H]>CO.[Pd]>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[NH2:15])=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccc(CN)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)cc1-c1ccc(CN)cc1

Procedure:
A solution of 2-(4-aminomethylphenyl)-4-nitroanisole (4.50 g) in methanol (200 mL) was treated with 10% palladium on carbon (200 mg). The reaction mixture was stirred under one atmosphere of hydrogen for 2.5 hours. The reaction mixture filtered through Celite, and the filter cake was washed with methanol (3×25 mL). The filtrate was concentrated to dryness and the residue was purified by flash chromatography on silica gel (80 g) eluting with 0–6% methanol/0.5% triethylamine/dichloromethane. Pure fractions were combined and concentrated to give 3-(4-aminomethylphenyl)-4-methoxyaniline as an off white powder.