Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]([C:12]([OH:14])=[O:13])[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:15]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.C(O)(=O)C>[CH:15]1([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:12]([OH:14])=[O:13])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)C(C[C@H](N)C(=O)O)C(=O)O
Reactant: O=C1CCCCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)C(C[C@H](NC1CCCCCCC1)C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a stirred suspension of γ-tert-butyl-L-glutamic acid (4.06 g, 20.0 mmol) and cyclooctanone (3.15 g, 25 mmol) in N,N-dimethylformamide/acetic acid (99:1, v/v, 50 mL) was added sodium triacetoxyborohydride (6.36 g, 30.0 mmol) in small portions and the mixture was stirred overnight. After evaporation of the solvent, the residue was dissolved in water (50 mL). The pH was adjusted to 9 with 2 N sodium hydroxide solution, followed by extraction with diethylether (50 mL). Subsequently, the pH of the aqueous layer was carefully adjusted to 2.5 using 1.0 N hydrochloric acid. Extraction with dichloromethane afforded an organic layer, which was dried (magnesium sulphate) and concentrated under reduced pressure, yielding 4.82 g (77%) of the title compound as a white solid. ESI-MS: 314.2 (M+H)+, 336.2 (M+Na)+. Rf (silica gel; ethyl acetate/pyridine/acetic acid/water 63:20:6:11, v/v): 0.80.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([N:18]2[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19]2)[CH2:14][CH2:13]1)=[O:10].[NH2:25][OH:26]>CCO.CCOC(C)=O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([N:18]2[CH:22]=[CH:21][C:20](/[CH:23]=[N:25]/[OH:26])=[CH:19]2)[CH2:14][CH2:13]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(n3ccc(C=O)c3)CC2)c(Cl)c1Cl
Reactant: NO
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1[nH]c(C(=O)NC2CCN(n3ccc(/C=N/O)c3)CC2)c(Cl)c1Cl

Procedure:
A solution of 3,4-dichloro-N-[1-(3-formyl-1H-pyrrol-1-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 259, 151 mg, 0.41 mmol) and 50% aqueous hydroxylamine (55 μl, 0.83 mmol) in 5 ml EtOH was heated at 80° C. for 30 min. The mixture was diluted with EtOAc and washed with brine. Drying (MgSO4) and removal of solvent gave a solid that was purified by reverse phase HPLC (30-55% gradient CH3CN in water with 0.1% TFA) to give product as a mixture of geometrical isomers.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:17]([OH:19])=[O:18])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16])(=[O:3])[CH3:2].[OH-].[NH4+]>O>[C:1]([NH:4][C@@H:5]([C:17]([OH:19])=[O:18])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(Cc1c(C)[nH]c2ccccc12)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@H](Cc1c(C)[nH]c2ccccc12)C(=O)O
Reaction time: 24 h

Procedure:
Nα -Acetyl-2-methyl-D,L-tryptophan [Y. Yabe et al. Chem. Pharm. Bull. 27(8) 1907-1911 (1979)] 1.3 g (5 mmol), was suspended in 50 ml of water and dissolved by adding concentrated ammonium hydroxide to a pH of 7.5. 5 mg of acylase (from porcine kidney, Sigma Grade III lyophilized) was added and the mixture kept at 40° C. for 24 hours. The insoluble material was separated by filtration and the filtrate was lyophilized to dryness. The residue was dissolved in the upper phase (10 ml) of n-BuOH-AcOH-H2O (16:1:20) and chromatographed on a 3.5×50 cm column of Sephadex G-25 (Pharmacia, Fluka) collecting 10 ml fractions. The less polar fractions (N° 16-25) were pooled to give mainly undigested Nα -acetyl-2-methyl-D-tryptophan which, without purification, was hydrolyzed under N2 with a solution of 1 g KOH in 25 ml of water at 100° F. for 24 hours. Acetic acid (2 ml) and water (10 ml) were added to the hot solution and placed in the refrigerator for 12 hours. The crude resulting 2-methyl-D-tryptophan was filtered, washed and dried and recrystallized from hot water (charcoal) to yield the title compound, m.p. 244-246°,[α]D20 +18.6, [c0.26(H2O)].
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].CN(C)C=O.[N-:16]=[N+:17]=[N-:18].[Na+]>O>[CH:1]([CH:3]([N:16]=[N+:17]=[N-:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: C=CC(Cl)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(N=[N+]=[N-])c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100 ml round bottom flask equipped with a stir bar, 4.0 g (26.2 mm) of vinylbenzyl chloride, and 10 ml of dimethylformamide (DMF) were added. To this solution 3.40 g (52.4 mm) of sodium azide was added and the reaction mixture was stirred at room temperature overnight, after which time 50 ml of deionized water were added to the solution. The resulting 4-vinyl benzyl azide was extracted from the reaction solution with ethyl ether. The product was confirmed by 1H NMR.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]Cl.[Mg].[Cl:9][CH2:10][Si:11](Cl)(Cl)[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1>>[Cl:9][CH2:10][Si:11]1([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCCCCCCl
Reactant: Fc1ccc([Si](Cl)(Cl)CCl)cc1
Agent: [Mg]
Product: Fc1ccc([Si]2(CCl)CCCCC2)cc1
Yield: 48.1 %

Procedure:
In the same apparatus and procedures as Example 1-i) were reacted 6.2 g of 1,5-dichloropentane (0.044 mol) and 2.8 g of magnesium species (0.11 mol), and then followed by coupling with 5.6 g (0.03 mol) of (chloromethyl)dichloro (4-fluorophenyl)silane prepared from the above procedure i) to give 3.5 g of 1-(chloromethyl)-1-(4-fluorophenyl)-1-silacyclohexane (74° C./0.2 mmHg).
Reaction SMILES: [NH3:1].[N:2]1([C@@H:7]([CH2:12][CH3:13])[C:8](OC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1>O>[N:2]1([C@@H:7]([CH2:12][CH3:13])[C:8]([NH2:1])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N
Reactant: CC[C@@H](C(=O)OC)N1CCCC1
Solvent: O
Product: CC[C@@H](C(N)=O)N1CCCC1
Temperature: 5 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
11.3 g of ammonia gas was condensed in 13.2 ml of water at approximately 0° C. and the temperature was maintained at 0–5° C. Then 20 g of (S)-PBM (26) was added dropwise over a period of 10 min and reaction mixture was maintained at 5° C. and stirred for minimum 8 hrs (reaction was complete as indicated by TLC). The reaction mixture was then evaporated to dryness under vacuum and dried by means of toluene (2×50 ml) to give minimum 17 g (92%) of crude (S)-pyrrolidinobutyramide (crude Levetiracetam) as an off-white to beige solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:25])[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:5]([CH3:16])=[CH:6][C:7]=1[C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H][H]>CCOC(C)=O.CCO.O=[Pt]=O>[Br:1][C:2]1[C:3](=[O:25])[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:5]([CH3:16])=[CH:6][C:7]=1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [H][H]
Reactant: Cc1cc(C#Cc2ccccc2)c(Br)c(=O)n1Cc1cccc(F)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(CCc2ccccc2)c(Br)c(=O)n1Cc1cccc(F)c1

Procedure:
To a solution of 3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(phenylethynyl)pyridin-2(1H)-one (0.55 g, 0.0014 mol) in EtOAc (10.0 mL) and EtOH (10.0 mL) was added PtO2 (0.05 g) and stirred in an atmosphere of hydrogen gas at 15 psi for 30 min. The catalyst was removed by filtration, the filtrate was concentrated and the residue was purified by silica gel flash chromatography using 25% EtOAc in hexane as the eluent.
Reaction SMILES: C1(C)C=CC=CC=1.S(Cl)([Cl:10])=O.[O:12]=[C:13]1[C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=[C:15]([C:22]([F:25])([F:24])[F:23])[N:14]1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[O:12]=[C:13]1[C:18]([C:19]([Cl:10])=[O:20])=[CH:17][CH:16]=[C:15]([C:22]([F:25])([F:24])[F:23])[N:14]1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)n(Cc2ccccc2)c1=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(C(F)(F)F)n(Cc2ccccc2)c1=O

Procedure:
Toluene (20 mL), thionyl chloride (1.3 g, 10.7 mmol) and a catalytic amount of N,N′-dimethylformamide were added to 1,2-dihydro-2-oxo-1-phenylmethyl-6-(trifluoromethyl)pyri-dine-3-carboxylic acid (2.0 g, 7.2 mmol), and the mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 1,2-dihydro-2-oxo-1-phenylmethyl-6-(trifluoromethyl)pyridine-3-carbonyl chloride. The obtained acid chloride was dissolved in acetonitrile (30 mL), and 1,3-cyclohexanedione (0.9 g, 7.9 mmol) and sodium cyanide (0.8 g, 15.8 mmol) were added thereto. This mixture was stirred for a day at room temperature. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After separating the inorganic substance by filtration, the solvent was distilled off under reduced pressure and thus obtained concentrated solution was purified by column chromatography, to obtain 1.5 g of a desired product (yield: 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[CH2:18]([O:25][CH2:26][C@H:27]([OH:30])[CH2:28]O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:28][C@H:27]([OH:30])[CH2:26][O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: OC[C@@H](O)COCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OC[C@H](O)COCc3ccccc3)ccc2c1

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 3.70 g, 16.1 mmol), (R)-(+)-3-benzyloxy-1,2-propanediol (2.92 g, 19.0 mmol), N,N-dimethylaminopyridine (DMAP, 0.40 g, 3.3 mmol) and 1,3-dicyclohexylcarbodiimide (3.61 g, 17.5 mmol) in CH2Cl2 (120 mL) was stirred at ambient temperature overnight. The byproduct, dicyclohexyl urea, was removed by filtration. The reaction mixture was partitioned between HCl (3N, 50 mL) and CH2Cl2 (50 mL×2). The combined organic extracts were back washed with water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with EtOAc:hexane (1:2, Rf=0.23) to give a mixture of the 1- and 2-glycerol ester isomers (88:12, 3.87 g). 1H NMR (300 MHz, CDCl3) δ 7.69-7.64 (m, 3H), 7.40-7.03 (m, 8H), 5.34 (s, 2H), 4.17-4.14 (m, 2H), 3.88 (s, 3H), 3.9-3.85 (m, 2H), 3.33-3.28 (m, 2H), 2.45 (br. d, 1H), 1.56 (d, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.6, 157.6, 137.6, 135.4, 133.6, 129.6, 129.2, 128.8, 128.3, 127.7, 127.61, 127.55, 127.1, 126.1, 125.9, 119.0, 105.5, 73.3, 70.6, 68.8, 65.5, 62.2, 55.2, 45.3, 18.3. Mass spectrum (API-TIS) m/z 412 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[ClH:18].Cl.[NH2:20][CH2:21][CH2:22][O:23][NH2:24].N1C=CC=CC=1>C(O)C>[ClH:1].[ClH:18].[NH2:20][CH2:21][CH2:22][O:23][N:24]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: NCCON
Reactant: O=C(CCCn1ccnc1)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: NCCON=C(CCCn1ccnc1)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 77.4 %

Procedure:
A mixture of 1-(4-chlorophenyl)-4-(1-(1H)-imidazolyl)-1-butanone (2.20 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.58 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for two hrs. The reaction mixture was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 1.3 g (39%) of product, mp 205°-207° C. (dec).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:10][CH2:11]C1C=CC=C(C=1)C=O.C=O.Cl>>[Cl:10][CH2:11][C:7]1[CH:6]=[CH:5][C:3]([OH:4])=[C:2]([CH:8]=1)[CH:1]=[O:9]
Reactant: O=Cc1cccc(CCl)c1
Reactant: O=Cc1ccccc1O
Agent: C=O
Agent: Cl
Product: O=Cc1cc(CCl)ccc1O

Procedure:
The salicylaldehyde is convened to the 5-chloromethylbenzaldehyde by combining the aldehyde with aqueous formaldehyde (37%) and concentrated hydrochloric acid, at a reduced temperature in the range of -10° to +10° C. or thereabouts. Gaseous HCl is then bubbled through the solution to saturate with HCl after which the solution is stirred for a period sufficient to effect the reaction at a reduced temperature, one which is about that of the temperature at which the reactants were combined initially. The product, the 5-(chloromethyl)-2-hydroxybenzaldehyde, should be formed as a white precipitate which can be recovered by conventional means.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:17]1(B2OC(C)(C)C(C)(C)O2)[CH2:21][CH2:20][CH2:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:17]1([C:2]2[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: O=[N+]([O-])c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnc(OCC(F)(F)F)c(C2=CCCC2)c1
Temperature: 80 °C
Yield: 43.6 %

Procedure:
To a stirred solution of 3-bromo-5-nitro-2-(2,2,2-trifluoro-ethoxy)-pyridine (Example 1a) (6 g, 19.9 mmol) in DMF (30 mL) was added 2-(1-cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 287944-10-9) (4.64 g, 23.9 mmol) and K2CO3 (8.2 g, 59.8 mmol) at 25° C. and the reaction mixture was degassed with argon over 30 min. To this was added PdCl2 (dppf)2 dichloromethane complex (814 mg, 1.1 mmol) and the reaction mixture was heated to 80° C. for 20 h. The reaction mixture cooled to 25° C., water (50 mL) was added, the mixture was extracted with ethyl acetate (4×50 mL), washed with water (200 mL), brine, dried with Na2SO4 and concentrated. The crude material was purified by column chromatography (Combi-Flash, 40 g, 2% dichloromethane/hexane) to get the title compound (2.5 g, 43.51%) as pale white solid; NMR complies.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Br.C(N(CC)CC)C>CN(C)C=O>[F:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: OC1CCNCC1
Reactant: Fc1ccccc1CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1CCN(Cc2ccccc2F)CC1
Reaction time: 16 h
Yield: 66.2 %

Procedure:
1.28 g (0.0127 mol) of 4-hydroxypiperidine were dissolved in 60 ml of dimethylformamide and cooled to 0°. 3.0 g (0.0159 mol) of 2-fluoro-benzyl bromide and 5.0 ml (0.0349 mol) of triethylamine were added under argon and the mixture was left to come to room temperature. It was stirred for 16 hrs., the solvent was distilled off and the residue was chromatographed on silica gel with dichloromethane/methanol (19:1) as the eluent. 1.76 g (53%) of 2-fluoro-benzyl-piperidin-4-ol were obtained as a yellow oil. MS: me/e=210 (C12H17FNO+).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].C([O:13][CH2:14][CH3:15])(=O)C>>[C:14]([O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5])(=[O:13])[C:15]1[CH:7]=[CH:6][CH:2]=[CH:3][CH:4]=1
Reactant: CCOC(C)=O
Reactant: C#CCC(O)CCCC
Product: C#CCC(CCCC)OC(=O)c1ccccc1

Procedure:
From fractions 13-20 is obtained 75 mg of colorless oil, identical to 4-hydroxy-1-octyne, [α]D25 = -17 ± 1.0° (C=0.77, ethyl acetate). This compound has the (R)-configuration.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32][CH2:33][CH2:34][OH:35])=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O[C:37]1[C:45]2[C:41](=[N:42][S:43][N:44]=2)[CH:40]=[CH:39][CH:38]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[N:42]1[S:43][N:44]=[C:45]2[C:37]([O:35][CH2:34][CH2:33][O:32][C:27]3[C:26]([N:23]4[CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:21][CH2:22]4)=[N:31][CH:30]=[CH:29][N:28]=3)=[CH:38][CH:39]=[CH:40][C:41]=12
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: Oc1cccc2nsnc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2cccc3nsnc23)CC1
Yield: 12 %

Procedure:
DEAD (0.52 mL, 3.3 mmol) was added to a slurry of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol; prepared in Example 52, Step 2), 4-hydroxy-2,1,3-benzothiadiazole* (0.46 g, 3.0 mmol) and resin bound PPh3 (1.1 g, 3.3 mmol) and shaken until HPLC showed no starting material. The mixture was filtered to remove the resin, concentrated and purified by column chromatography on silica to give 0.163 g (12%) of the title compound. Pos-EI-MS shows M+ and 11 ions supporting the stated structure. HRMS m/z calcd for C21H26N6O4S (M)+ 458.1736, found 458.1716.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:7].[CH:8]1[N:13]=[C:12](Cl)[C:11]2[N:15]=[CH:16][N:17]([C@@H:18]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:20]([OH:25])[C@H:19]3[OH:26])[C:10]=2[N:9]=1.C(N(CC)CC)C>O1CCOCC1>[OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:12]1[C:11]2[N:15]=[CH:16][N:17]([C:10]=2[N:9]=[CH:8][N:13]=1)[C@@H:18]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:20]([OH:25])[C@H:19]1[OH:26]
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@H](O)[C@@H]1O
Temperature: 100 °C
Yield: 18.4 %

Procedure:
Trans-2-hydroxycyclopentylamine (0.35 g, 3.46 mmol)(prepared by reaction of cyclopentene oxide with ammonia in a sealed vessel: see example 11) was reacted with 6-chloropurine riboside (i.e. 9-β-D-ribofuranosyl-9H-purine) (0.5 g, 1.7 mmol) in dioxan (30 ml) in the presence of triethylamine (0.93 g, 9 mmol). The reaction mixture was heated at 100° C. for 70 h, cooled and evaporated. The resultant residue was purified by flash chromatography eluting with a mixture of ethyl acetate and methanol (19:1). The fractions found to contain the highest amounts of N-[(1R, trans)-2-hydroxycyclopentyl]adenosine following HPLC examination, were combined and evaporated to a solid (0.17 g). Recrystallisation from methanol provided the pure N-[(1R, trans)-2-hydroxycyclopentyl]adenosine (0.11 g, 18%) mp 233°-235° C. 1H NMR (DMSO-d6)δ 1.43-2.12 (6H, 4m, --CH2CH2CH2 --), 3.52-3.59 (1H, m, H-5'a), 3.54-3.71 (1H, m, H-5'b), 3.97 (1H, q, H-4'), 4.07 (1H, br, --C HOH) 4.15 (1H, q, H-3'), 4.61 (1H, q, H-2'), 4.87, 5.21, 5.41-5.47 (4H, d & 3m, OH groups), 5.89 (1H, d, H-1'), 7.75 (1H, br d, --NH), 8.21 and 8.37 (H-2 and H-8).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7](OC=C)(=O)[CH3:8].[CH2:13]([C:15]1([CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]2)[CH2:18][O:17][CH2:16]1)[CH3:14]>C1(C)C=CC=CC=1>[CH2:13]([C:15]1([CH2:19][O:20][CH:21]2[CH2:22][CH2:23][CH:24]([O:27][CH:7]=[CH2:8])[CH2:25][CH2:26]2)[CH2:18][O:17][CH2:16]1)[CH3:14]
Reactant: CCC1(COC2CCC(O)CC2)COC1
Reactant: C=COC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=COC1CCC(OCC2(CC)COC2)CC1
Reaction time: 1 h
Yield: 92 %

Procedure:
A mixture (100 mL) of sodium carbonate (0.06 mol) and toluene was heated to 95° C. Maintaining the temperature of the reaction mixture, 4.2 g of vinyl acetate was added dropwise to the mixture, and fifteen minutes later, further the mixture was combined with di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (0.5 mmol). Next, 4-(3-ethyloxetan-3-yl-methoxy)cyclohexanol (0.05 mol) was added dropwise for two hours, and a reaction was then carried out in a nitrogen atmosphere while adding dropwise 12.6 g of vinyl acetate and holding the reaction temperature at 95° C. After the completion of dropwise addition, the mixture was stirred for one hour. As the result of gas chromatography analysis of the mixture, it is confirmed that there was produced 3-ethyl-3-(4-vinyloxycyclohexyloxymethyl) oxetane represented by following Formula (11) in a yield of 92%. In 1H-NMR (CDCl3) analysis, signals specific to vinyl group were observed at 6.5 ppm, 4.2 ppm, and 4.04 ppm as in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH2:61])=[N:58][C:57]=1[CH3:62])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:64](Cl)(=[O:67])[CH2:65][CH3:66]>>[CH3:1][O:2][C:3](=[O:63])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:64](=[O:67])[CH2:65][CH3:66])=[N:58][C:57]=1[CH3:62])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: CCC(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: CCC(=O)Nc1nc(C)c(S(=O)(=O)N2Cc3cc4c(cc3CC2C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(=O)OC)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)s1

Procedure:
(S)-2-({(S)-7-(2-Amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (30 mg) treated with propionyl chloride according to General Procedure F to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(4-methyl-2-propionylamino-thiazole-5-sulfonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino-[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester (19 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[O:21])[CH2:7][CH2:8][CH2:9][NH:10]C(OCC1C=CC=CC=1)=O.[ClH:22]>CO.[Pd]>[ClH:22].[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[O:21])[CH2:7][CH2:8][CH2:9][NH2:10]
Reactant: COCCNC(=O)CCCNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COCCNC(=O)CCCN

Procedure:
2.95 g of 4-benzyloxycarbonylaminobutyric acid N-(2-methoxyethyl)amide are hydrogenated in the presence of 0.24 g of 10% Pd/C in 150 ml of methanol and 100 ml of 0.1N hydrochloric acid for 2 hours at room temperature and under normal pressure. The reaction mixture is filtered and concentrated by evaporation. The crude title compound is obtained: 1H NMR (CD3OD), δ (ppm)=4.92 (4H, s), 3.53-3.20 (4H, m), 3.34 (3H, s), 2.96 (2H, t, J=12 Hz), 2.37 (2H, t, J=12 Hz), 1.93 (2H, m).