Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:3]([O:7][C:8]1[CH:12]=[C:11]([C:13](O)=O)[N:10]([CH3:16])[N:9]=1)[C:4]([OH:6])=[O:5])C.CCN=C=NCCCN(C)C.Cl.[CH2:29]([N:32]1[C:39]([NH2:40])=[C:38]([NH2:41])[C:36](=[O:37])[N:35]([CH2:42][CH:43]=[CH2:44])[C:33]1=[O:34])[CH:30]=[CH2:31]>CO>[CH2:42]([N:35]1[C:36](=[O:37])[C:38]2[NH:41][C:13]([C:11]3[N:10]([CH3:16])[N:9]=[C:8]([O:7][CH2:3][C:4]([OH:6])=[O:5])[CH:12]=3)=[N:40][C:39]=2[N:32]([CH2:29][CH2:30][CH3:31])[C:33]1=[O:34])[CH2:43][CH3:44]
Reactant: CCC(Oc1cc(C(=O)O)n(C)n1)C(=O)O
Reactant: C=CCn1c(N)c(N)c(=O)n(CC=C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetic acid (0.5 mmol) and EDCl (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-diallyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid.
Reaction SMILES: C([O:4][CH:5]([CH3:44])[C:6]([N:8]([CH2:38][CH2:39][O:40]C(=O)C)[C:9]1[C:10]([I:37])=[C:11]([C:17]([I:36])=[C:18]([N:21]([C:28](=[O:35])[CH:29]([O:31]C(=O)C)[CH3:30])[CH2:22][CH2:23][O:24]C(=O)C)[C:19]=1[I:20])CCC([O-])=O)=[O:7])(=O)C.[OH-:45].[Na+].Cl.[CH3:48]O>O>[OH:4][CH:5]([CH3:44])[C:6]([N:8]([CH2:38][CH2:39][OH:40])[C:9]1[C:10]([I:37])=[C:11]([C:17]([I:36])=[C:18]([N:21]([C:28](=[O:35])[CH:29]([OH:31])[CH3:30])[CH2:22][CH2:23][OH:24])[C:19]=1[I:20])[CH2:48][OH:45])=[O:7]
Reactant: CC(=O)OCCN(C(=O)C(C)OC(C)=O)c1c(I)c(CCC(=O)[O-])c(I)c(N(CCOC(C)=O)C(=O)C(C)OC(C)=O)c1I
Reactant: [OH-]
Reactant: CO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(O)C(=O)N(CCO)c1c(I)c(CO)c(I)c(N(CCO)C(=O)C(C)O)c1I
Reaction time: 3 h
Yield: 37 %

Procedure:
N,N'-Bis(2-acetoxypropionyl)-N,N'-bis(2-acetoxyethyl)-3,5-diamino-2,4,6-triiodobenzylacetate (175 mg, 0.18 mmol) was dissolved in a mixture of methanol (8 ml) and water (8 ml) and pH was adjusted to 12 with 1M aqueous NaOH. After stirring for 3 h, the solution was neutralized with aqueous HCl. Purification by preparative HPLC gave 50 mg (37%) of the pure product.
Reaction SMILES: [CH3:1][CH:2]([CH:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=1)[CH2:6][CH:7]=O)[CH:3]=O.[NH3:19].[H][H]>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([CH:5]2[CH2:6][CH2:7][NH:19][CH2:3][CH:2]2[CH3:1])=[CH:10][CH:11]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C=O)C(CC=O)c1ccc(C(C)(C)C)cc1
Reactant: [H][H]
Reactant: N
Product: CC1CNCCC1c1ccc(C(C)(C)C)cc1

Procedure:
2-Methyl-3-(p-tert.-butylphenyl)-1,5-pentanedial (VI) can be hydrogenated with ammonia and hydrogen in the presence of a hydrogenation catalyst to give 4-(p-tert.-butylphenyl)-3-methylpiperidine (VII). ##STR8##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[C:6]([CH2:8][NH2:9])[CH:7]=1.CCN(C(C)C)C(C)C.[Br:24][CH2:25][C:26](Br)=[O:27]>C1COCC1.CCOC(C)=O>[Br:24][CH2:25][C:26]([NH:9][CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:10]1[CH:14]=[N:13][N:12]=[N:11]1)=[O:27]
Reactant: NCc1cc(Cl)ccc1-n1cnnn1
Reactant: O=C(Br)CBr
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CBr)NCc1cc(Cl)ccc1-n1cnnn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1-[5-chloro-2-(1H-tetraazol-1-yl)phenyl]methanamine (150 mg, 0.72 mmol) and Hünig's base (137 μL, 0.79 mmol) in anhydrous THF (3.3 mL) at 0° C. was added dropwise bromoacetyl bromide (69 μL, 0.79 mmol). The resulting orange-yellow suspension was stirred under N2 atmosphere at 0° C. for 20 min. The mixture was diluted with EtOAc and washed twice with H2O, twice with saturated aqueous NaHCO3 and once with brine. The organic layer was dried (anhydrous Na2SO4), filtered and concentrated to a brown oil. Silica gel chromatography (70% EtOAc-hexanes) afforded the title compound as a yellow oil which slowly formed a tan foam after drying in vacuo. 1H NMR (400 MHz, CDCl3): δ 8.95 (s, 1 H), 7.70 (d, J=2.2 Hz, 1 H), 7.50 (dd, J=2.0, 8.4 Hz, 1 H), 7.30 (d, J=8.4 Hz, 1 H), 7.21 (br s, 1 H), 4.29 (d, J=6.4 Hz, 2 H), 3.88 (s, 2 H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[N:4][C:5]2[N:6]([N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[CH:11]=2)[C:7]=1Cl.[F:20][C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1.CCOCC.[Li+].[Cl-].C1COCC1.Cl[C:42](=[O:47])[C:43]([O:45][CH3:46])=[O:44]>C1COCC1.CCOCC.[Cu]Br>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[CH:11]=[C:5]3[N:4]=[C:3]([CH3:19])[C:2]([C:42](=[O:47])[C:43]([O:45][CH3:46])=[O:44])=[C:7]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[N:6]3[N:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: Cc1nc2cc(-c3cccc(Cl)c3)nn2c(Cl)c1Br
Reactant: COC(=O)C(=O)Cl
Agent: [Cu]Br
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1-c1ccc(F)cc1
Reaction time: 2 h
Yield: 30.4 %

Procedure:
To a stirred mixture of 6-bromo-7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine (0.179 g, 0.5 mmol) and copper(I) bromide (0.072 g, 0.500 mmol) in THF (3 mL) was added dropwise a pre-mixed solution of 2M 4-fluorophenylmagnesium bromide/ether (3.00 ml, 6.00 mmol) and 0.5M LiCl/THF (6.00 ml, 3.00 mmol) over 15 min. After 2 h, added at once methyl 2-chloro-2-oxoacetate (0.368 ml, 4.00 mmol) to the dark solution. After 1 h, the reaction was diluted with Et2O (50 mL), quenched with Na2CO3 (1 mL), washed with 10 mL each water and brine, dried (Na2SO4), filtered and concentrated to give orange paste which was purified by prep-HPLC to afford methyl 2-(2-(3-chlorophenyl)-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (0.0644 g, 0.152 mmol, 30.4% yield) as yellow solid contaminated with some impurity. 1H NMR (500 MHz, CDCl3) δ: 7.88 (s, 1H), 7.81-7.74 (m, 1H), 7.73-7.67 (m, 2H), 7.35 (d, J=5.2 Hz, 2H), 7.31-7.24 (m, 2H), 6.97 (s, 1H), 3.44 (s, 3H), 2.67 (s, 3H). LCMS (M+H) calcd for C22H16ClFN3O3: 424.09. found: 424.3. LCMS (M+H) calcd for C22H16ClFN3O3: 424.09. found: 424.3.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH2:26][CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30]>>[OH:31][C@@H:28]([CH2:29][OH:30])[CH2:27][NH:26][C:22]([C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:25])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:16])([CH3:17])[C:10]=2[CH:18]=1)=[O:23]
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: NC[C@@H](O)CO
Product: CC1(C)c2cc(C(=O)NC[C@@H](O)CO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and (R)-(+)-3-amino-1,2-propanediol.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[C:7]([O:19]C)=[CH:8][C:9]([CH3:18])=[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=1>ClCCl>[Cl:5][C:6]1[C:7]([OH:19])=[CH:8][C:9]([CH3:18])=[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(OC)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(Cl)c(O)cc1C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 72.1 %

Procedure:
Boron tribromide (1.068 mL, 11.30 mmol) was added dropwise to ethyl 2-(5-chloro-4-methoxy-2-methylphenyl)acetate (Intermediate 3-4; 456 mg, 1.88 mmol) in dichloromethane (10 mL) at ambient temperature under nitrogen. The resulting orange red solution was stirred at 0° C. for 45 minutes. The reaction mixture was carefully quenched with water (25 mL), extracted with EtOAc (2×100 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford crude product as a yellow gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford ethyl 2-(5-chloro-4-hydroxy-2-methylphenyl)acetate (310 mg, 72.2%) as a colourless oil which solidified on standing.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[CH2:15][CH2:14]1)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd]>[C:1]([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)[CH2:15][CH2:14]1)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Reactant: [H][H]
Agent: [Pd]
Product: Nc1cccc(CN2CCC(NC(=O)NC(=O)c3ccccc3)CC2)c1
Yield: 46.1 %

Procedure:
1-Benzoyl-3-[1-(3-nitrobenzyl)piperid-4-yl]urea 4.47 g (from Example 13) was hydrogenated with 5% Pd/C (0.5 g) at atmospheric pressure and room temperature until no more hydrogen was taken up. The catalyst was filtered and the filtrate evaporated. The residue was dissolved in water and basified with 0.880 ammonia. The precipitated solid was filtered, washed well with water, dried, treated with charcoal, and evaporated to give the title compound, (1.9 gms). This was recrystallised from ethanolic HCl to give the dihydrochloride salt, monohydrate, m.p. 194°-195° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.C(C1C=C([N+:18]([O-:20])=[O:19])C=CC=1SBr)=O.N>>[N+:18]([C:8]1[CH:7]=[CH:6][C:5]2[S:1][N:2]=[CH:3][C:4]=2[CH:9]=1)([O-:20])=[O:19]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1SBr
Reactant: c1ccc2sncc2c1
Agent: N
Product: O=[N+]([O-])c1ccc2sncc2c1

Procedure:
Angewandte Chemie, 36 (1923), 159, and Berichte der deutschen Chemischen Gesellschaft, 58 (1925), 2,095, disclose the reaction of thionaphthene-2,3-dione with ammonia and hydrogen peroxide to give 3-carbamyl-1,2-benzisothiazole and the conversion of the latter to 1,2-benzisothiazole by hydrolysis and decarboxylation. Berichte der deutschen Chemischen Gesellschaft, 56 (1923), 1,630, and Liebigs Annalen der Chemie, 454 (1927), 264, disclose the reaction of 2-formyl-4-nitrophenylsulfenyl bromide with ammonia to give 5-nitro-1,2-benzisothiazole. Benzisothiazoles can also be synthesized by cyclizing o-mercapto-phenyl-carbonyl compounds in the presence of polyphosphoric acid (Annali di Chimica, 53 (1963), No. 5, 577-587). German Laid-Open Application DOS No. 1,670,196 discloses the reaction of dihalomethylaryl compounds with ammonia and sulfur to give benzisothiazoles.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.[CH3:28][O:29]C(Cl)Cl>ClCCCl.ClCCl>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([O:11][C:12]2[CH:21]=[C:20]3[C:15](=[C:14]([CH3:22])[CH:13]=2)[CH:16]=[C:17]([CH:28]=[O:29])[CH:18]=[CH:19]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(Cl)Cl
Reactant: Cc1cc(OC2CCC(C(C)(C)C)CC2)cc2ccccc12
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(OC2CCC(C(C)(C)C)CC2)cc2ccc(C=O)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a mixture of 3-(4-tert-butyl-cyclohexyloxy)-1-methyl-naphthalene (450 mg, 1.5 mmol) in 1,2-dichloroethane (9 mL) was added tin tetrachloride (236 uL, 2 mmol) at 0° C. After stirred at 0° C. for 1 hr, dichloromethyl methyl ether (183 uL, 2 mmol) was added. The solution was stirred at 0° C. for 1 hr and then warmed to room temperature. The mixture was added ice water and stirred for 1 hr, then the dark solution was diluted with dichloromethane and washed with water. The organic phase was washed with sodium bicarbonate aqueous, and dried over MgSO4. The driving agent was filtered off and the solvent was concentrated to dryness to give dark solid product (0.48 g, yield: 97%). ESI-MS: 325.20 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19].O>C(Cl)Cl>[C:18]([O:21][CH2:22][C:23]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5])=[O:24])(=[O:20])[CH3:19]
Reactant: CNc1cccc(N)c1C#N
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CNc1cccc(NC(=O)COC(C)=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(methylamino)benzonitrile (4.4 g) in methylene chloride (50 ml) is added pyridine (4.9 ml), and thereto is added dropwise acetoxyacetyl chloride (6.5 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethyl acetate-hexane to give the title compound (5.1 g) having the following physical properties.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11]1[CH2:15][CH:14]=[CH:13][CH:12]=1)[CH2:8]2.[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[O-].[Na+]>C(O)C>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[C:11]1[CH:15]=[CH:14][C:13](=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:12]=1)[CH2:10]2
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: C1=CCC(C2C3CC4CC(C3)CC2C4)=C1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: C1=CC(=C(c2ccccc2)c2ccccc2)C=C1C1C2CC3CC(C2)CC1C3
Reaction time: 120 h
Yield: 71.5 %

Procedure:
A 250 mL round bottom flask was charged with 2-adamantylcyclopentadiene (10.24 g, 51.13 mmol), benzophenone (9.32 g, 51.13 mmol) and 100 mL absolute ethanol. Once the solids had dissolved, sodium methoxide (5.00 g, 92.6 mmol) was added and the reaction was stirred for five days. The orange precipitate was collected by suction filtration and washed with 50 mL ethanol. The air dried product was stirred in 100 methanol overnight and the solid was collected by suction filtration and washed with 50 mL methanol. Drying in vacuo for several hours provided 13.32 grams of desired product (71.5 %).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21](C)[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:24])(C(C)(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[C:49]1(=[O:50])[N:45]([O:8][CH2:9][C@H:10]2[O:14][C@@H:13]([N:15]3[CH:23]=[CH:21][C:19](=[O:20])[NH:18][C:16]3=[O:17])[CH2:12][C@@H:11]2[OH:24])[C:46](=[O:55])[C:47]2=[CH:54][CH:53]=[CH:52][CH:51]=[C:48]12
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Temperature: 0 °C
Yield: 62 %

Procedure:
To a solution of 5'-O-t-butyldimethylsilylthymidine [1, 21.36 g, 60 mmol, prepared according to the procedure of Nair, et al., Org. Prep. Procedures Int. 1990, 22, 57 in dry THF (750 ml)], triphenylphosphine (17.28 g, 66 mmol) and N-hydroxyphthalimide (10.74 g, 66 mmol) were added. The solution was cooled to 0° C. and diisopropylazodicarboxylate (15.15 g, 75 mmol) was added dropwise over a period of 3 hr while stirring under nitrogen. The reaction mixture was then stirred at room temperature for 12 hr. The solution was evaporated and the residue was dissolved in CH2Cl2 (750 ml), extracted with sat. NaHCO3 (200 ml), and water (200 ml), dried (MgSO4), filtered and concentrated to furnish yellow oily residue. Silica gel column chromatography (100% hexanes, and the hexanes:Et2O gradient to 90% Et2O) of the residue gave compound 2 as a colorless glass (18.68 g, 62%); 1H NMR (CDCl3) δ [2s, 6, (CH3)2 ], 0.91 [s, 9, (CH3)3 ], 2.0 (s, 3, CH3), 2.5-2.65 (m, 2, 2'CH2), 4.05-4.2 (m, 2, 5'CH2), 4.25-4.35 (m, 1, 4'H), 5.0 (m, 1, 3'H), 6.15 (m, 1, 1'H), 8.6 (br s, 1, NH), and aromatic protons. Anal. Calcd. for C24H31N3O7Si; C, 57.46; H, 6.23; N, 8.37. found: C, 57.20; H, 6.26; N, 8.27.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:6]([CH2:16][OH:17])=[CH:5][C:4]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C-:25]#[N:26].[Na+].O>CN(C=O)C>[CH2:19]([O:18][C:4]1[CH:5]=[C:6]([CH2:16][OH:17])[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][C:3]=1[CH2:2][C:25]#[N:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: [C-]#N
Reactant: CCCCCCOc1cc(CCl)c(OCCCCCC)cc1CO
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOc1cc(CC#N)c(OCCCCCC)cc1CO
Yield: 88.5 %

Procedure:
A solution of the chloride (31) (1.52 g) and sodium cyanide (0.22 g) in DMF (50 ml) was stirred at 60° C. for 3 h. It was poured into water (100ml), and extracted with ether -hexane (1:1, 150 ml ). The organic fraction was washed with water, dried (MgSO4) and the solvent evaporated to give an oil, which was crystallised from hexane (80 ml) to give (32), (1.31 g, 88%), as needles, m.p 63°-66° C., Found C. 73.0, 9.7, N 3.8, C21H33NO3 requires C 72.6, 9.6, N 4.0%!; vmax (KBr)/cm-1 3334 m, 2250 m, 1511 s, 1425 s, 1395 s, 1216 s, 1192 s, 1034 s, 998 s, 871 m, 724 m; δH (250.1 MHZ; CDCl3) 0.9-1.9 (22H, m), 4.36 (4H, m), 2.42 (1H, t, J=5), 3.68 (2H, s), 4.66 (2H, d, J=5), 6.84 (1H, s), 6.89 (1H, s); δC (62.9 MHz; CDCl3) 14.1, 18.7, 22.7, 25.9, 29.4, 31.7, 62.0, 69.1, 112.4, 112.7, 118.3, 130.2, 150.2, 150.7, m/z (CI) 347 (M+, 43), 330 (100), 263 (5).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:28])[N:4]([CH2:14][C:15]([NH:17][CH:18]([CH:25]([CH3:27])[CH3:26])[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])=[O:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.ClS([N:33]=[C:34]=[O:35])(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[O:28]=[C:3]1[C:2]([NH:1][C:34]([NH2:33])=[O:35])=[CH:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]1[CH2:14][C:15]([NH:17][CH:18]([CH:25]([CH3:26])[CH3:27])[C:19](=[O:24])[C:20]([F:22])([F:23])[F:21])=[O:16]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O)C(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(N)=O)c1=O)C(=O)C(F)(F)F
Reaction time: 0.17 h
Yield: 69.1 %

Procedure:
To a solution of 2-(3-amino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.30 g) in tetrahydrofuran (5 mL), cooled to 0° C., was added, dropwise, chlorosulfonyl isocyanate (0.12 g). The reaction mixture was stirred for 10 min, neutralized with saturated aqueous sodium bicarbonate solution (1 mL), diluted with ethyl acetate (10 mL), and the organic phase washed (water, brine), dried (MgSO4) and evaporated. Purification by chromatography, using an eluant of methylene chloride:methanol (30:1), followed by overnight vacuum-drying (50° C. at 27 Pa), yielded the title product as a white solid (0.23 g); mp 227°-230° C. (dec); TLC: Rf =0.16, dichloromethane:methanol (20:1); 300 MHz NMR: 0.88 (2d,6), 2.15 (m,1), 4.50 (q,2), 4.65 (d,1), 6.18 (d,1), 6.40 (broad s,2), 7.40 (m,5), 8.08 (d,1), 8.35 (s,1), 8.75 (d,1); IR(KBr): 3470 (broad), 3360, 2980, 1760, 1700, 1535, 1490, 1210, 1160, 1020 cm-1 ; MS: m/z=439(M+1).
Reaction SMILES: [CH:1]([O:4][C:5]([CH:7]([NH2:17])[CH:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C>O.C(O)(C)C>[CH:1]([O:4][C:5]([CH:7]([NH2:17])[C@@H:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)CC(CC(=O)O)C(N)C(=O)OC(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)O
Product: CC(C)C[C@@H](CC(=O)O)C(N)C(=O)OC(C)C
Temperature: 57.5 °C
Yield: 61.1 %

Procedure:
A 500 ml three-necked round-bottom flask, under nitrogen atmosphere, is added with raceme 3-(isopropoxycarbonyl-amino-methyl)-5-methyl-hexanoic acid (44.2 g, 0.180 moles), triethylamine (8.20 g, 0.081 moles) and (S)-(−)-phenyl-ethylamine (12.00 g; 0.099 moles) in a 95:5 water/isopropanol mixture (200 ml) heated at 55-60° C. The mixture is spontaneously left to cool to room temperature, then it is cooled to 0-5° C. for at least 1 h. The solid is filtered off and washed with cool water (2×20 ml) and then with cool toluene (4×20 ml), it is dried in oven at 55-60° C. for 16-18 h. 27.0 g of white solid are obtained with an enantiomer ratio of 99:1.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][C@@H:9]2[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]3[CH:23]=[C:22]([F:24])[C:20](=[O:21])[NH:19][C:17]3=[O:18])[CH2:10]2)=[CH:4][CH:3]=1.Cl.[CH2:26]([N:28]([CH2:34][CH3:35])[CH2:29][CH2:30][C:31](O)=[O:32])[CH3:27].[CH:36]([C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[C:41]([CH:49]([CH3:51])[CH3:50])[C:40]=1C(C)C)([CH3:38])[CH3:37]>N1C=CC=CC=1>[CH:49]([C:41]1[CH:40]=[C:39]([CH:36]([CH3:37])[CH3:38])[CH:44]=[C:43]([CH:30]([CH3:29])[CH3:31])[C:42]=1[S:45]([OH:46])(=[O:47])=[O:8])([CH3:50])[CH3:51].[Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][C@@H:9]2[C@@H:13]([CH2:14][O:15][C:31](=[O:32])[CH2:30][CH2:29][N:28]([CH2:34][CH3:35])[CH2:26][CH3:27])[O:12][C@@H:11]([N:16]3[CH:23]=[C:22]([F:24])[C:20](=[O:21])[NH:19][C:17]3=[O:18])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccc(Cl)s3)[C@@H](CO)O2)cc1F
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)c(C(C)C)c1C(C)C
Reactant: CCN(CC)CCC(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)O)c(C(C)C)c1
Product: CCN(CC)CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
To a solution of 1.00 g of 3'-O-(5-chloro-2- thenyl)-2'-deoxy-5-fluorouridine in 50 ml of pyridine were added 0.72 g of N,N-diethyl-β-alanine hydrochloride and 1.61 g of triisopropylbenzenesulfonyl chloride, and the mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure, and the residue was placed on silica gel column and eluted with 2% methanol-chloroform for purification, thereby giving 0.97 g of 3'-O-(5-chloro-2-thenyl)-2'-deoxy-5'-O- [3-(diethylamino)propanoyl]-5-fluorouridine 2,4,6-triisopropylbenzenesulfonate.