Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][CH2:16][O:15][CH2:14]2)(=O)=O)=CC=1.[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K]>CN(C)C=O>[O:15]1[CH2:16][CH2:17][CH:13]([CH2:12][N:22]2[C:18](=[O:28])[C:19]3[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:21]2=[O:23])[CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC1CCOC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of (tetrahydro-3-furanyl)methyl 4-methylbenzenesulfonate (i.e., the product of Step A) (11.0 g, 42.9 mmol) in N,N-dimethylformamide (160 mL) was added potassium phthalimide (7.9 g, 42.7 mmol) in one portion, and the resulting mixture was stirred at 80° C. for 6 h. Additional potassium phthalimide (5 g, 27 mmol) was added, and stirring was continued at 100° C. for 18 h. The cooled reaction mixture was partitioned between water and ethyl acetate and the aqueous layer was separated and extracted with ethyl acetate (5×75 mL). The combined extracts were dried over MgSO4 and filtered, and the solvent was removed under reduced pressure to give a residue which was chromatographed on silica gel (40 g) eluted with 5% to 100% ethyl acetate in hexanes to give 4.5 g of the title compound as a white solid, m.p. 114-118° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH-:12].[Na+].Cl>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([OH:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)cc1O
Temperature: 100 °C
Reaction time: 21 h

Procedure:
57.6 g (0.3 mol) of 2,4-dichloronitrobenzene were admixed with 10 g (0.014 mol) of dimethyldi(ethoxypolyoxypropyl)ammonium chloride and 150 ml of 20% by weight strength NaOH at 60° C. The two-phase reaction mixture was stirred for 21 hours at 100° C. and subsequently brought to pH 1 using HCl. Amount of 5-chloro-2-nitrophenol formed: after 21 hours: 40 GC area-%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH-:12].[Na+].Cl>CS(C)=O.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([OH:12])[CH:7]=1
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Cl)cc1O
Temperature: 60 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of 2,4-dichloro-1-nitrobenzene (100 g, 0.52 mol) in DMSO (200 mL), aqueous solution of NaOH (41.6 g, 1.04 mol) in water (42 mL) was added and the resulting mixture was stirred 60° C. for 16 h. The mixture was allowed to cool to room temperature, poured to ice water, and then acidified with aqueous HCl (1M) to adjusted the pH to 3-4. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was used directly in the next step (80 g, 88% yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[OH:12])=[CH:4][CH:3]=1
Reactant: O=C1CCCc2ccc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCCc2ccc(Br)cc21
Reaction time: 0.5 h

Procedure:
To 9.5 g of 7-bromo-3,4-dihydronaphthalen-1(2H)-one (42 mmol), prepared according to the method described in Synth. Comm. 1994, 2777, dissolved in 100 ml of ethanol, there are added, at 0° C. and in two portions,0.8 g of sodium borohydride (21 mmol). The reaction mixture is then allowed to come back up to ambient temperature over 30 minutes, and then the ethanol is evaporated off. The residue is taken up in 100 ml of toluene and 100 ml of water. After separation, the aqueous phase is extracted with 50 ml of toluene. The toluene phases are combined, washed with a saturated aqueous solution of sodium chloride and are then evaporated to yield 7-bromo-1,2,3,4-tetrahydronaphth-1-ol in the form of an oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[O:8]=[C:5]1[CH2:6][CH2:7][N:2]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:3][CH2:4]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of piperidin-4-one hydrochloride (1567 g, 11.56 mol) and triethylamine (1400 g, 13.87 mol) in dichloromethane (12 L) was added benzyl chloroformate (1965 g, 11.55 mol) dropwise at 0° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. TLC (EtOAc/petroleum ether=1:5) showed the reaction was complete. The mixture was washed with water (3 L) and brine (1 L), dried over sodium sulfate and concentrated to afford benzyl 4-oxopiperidine-1-carboxylate as a colorless oil.
Reaction SMILES: [CH2:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:13]N1C(=O)C2=CC=CC=C2C1=O.N(OC(C)(C)C)=O.C1(=NO)CCCCCCCCCCC1.N(C1CCCCCCCCCCC1)=O.[N+](C1CCCCCCCCCCC1)([O-])=O>C(O)(=O)C>[C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCCCCCCCCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)(C)ON=O
Agent: O=NC1CCCCCCCCCCC1
Agent: O=[N+]([O-])C1CCCCCCCCCCC1
Solvent: CC(=O)O
Product: O=C1CCCCCCCCCCC1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
Cyclododecane (3.32 g; 19.8 mmol), N-hydroxyphthalimide (0.8 mmol), and acetic acid (4 ml) were placed in a flask, t-butyl nitrite (4 mmol) was added to the mixture in four installments of 1 mmol each once every 30 minutes with stirring at 70° C. in an atmosphere of argon gas for a total of 2.5 hours. The reaction mixture was analyzed to find that cyclododecanone oxime, nitrosocyclododecane dimer, nitrocyclododecane, and cyclododecanone were formed in yields of 11%, 60%, 1%, and 1%, respectively.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[H][H]>[Pt].C(OC(C)C)(=O)C>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)OC(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
20 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid (2-a, R1=Boc, R2=H, R3=CO2H) is added to isopropyl acetate (400 μl). 10% Platinum on carbon (2 mg) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with isopropyl acetate (2×0.5 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-b, R1=Boc, R2=H, R3=CO2H). Spectroscopic data as in Example 40, Method 1.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[H][H]>C(OC(C)C)(=O)C>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Solvent: CC(=O)OC(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
20 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid (2-a, R1=Boc, R2=H, R3=CO2H) is added to isopropyl acetate (400 μl). 10% Platinium on carbon (2 mg) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with isopropyl acetate (2×0.5 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-b, R1=Boc, R2=H, R3=CO2H). Spectroscopic data as in Example 40, Method 1.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[H][H]>[Pd].C(OC(C)C)(=O)C>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)OC(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
20 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid (2-a, R1=Boc, R2=H, R3=CO2H) is added to isopropyl acetate (400 μl). 10% Palladium on carbon (2 mg, 50% water wet, Degussa type E101 NE/W) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with isopropyl acetate (2×0.5 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-b, R1=Boc, R2=H, R3=CO2H). Spectroscopic data as in Example 40, Method 1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.ClCCl.BrN1C(=O)CCC1=O.[CH3:41][C:42]([CH3:47])([CH3:46])[C:43](=[S:45])[NH2:44]>C(OCC)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:45][C:43]([C:42]([CH3:47])([CH3:46])[CH3:41])=[N:44][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)C(N)=S
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Temperature: 10 °C
Reaction time: 0.21 h
Yield: 481.8 %

Procedure:
To a reactor vessel was charged N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 mL). The reaction slurry was cooled to ˜10° C. and N-bromosuccinimide (“NBS”) (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ˜20° C. and stirred for 45 min. Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to ˜120 mL. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to ˜120 mL. Dimethylacetamide (270 mL) was then added to the reaction mixture and cooled to ˜10° C. 2,2-Dimethylpropanethioamide (1.3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ˜5 minutes between additions. The reaction was warmed to 20-25° C. After 45 min, the vessel contents were heated to 75° C. and held for 1.75 hours. The reaction mixture was then cooled to 5° C. and water (270 ml) was slowly charged keeping the temperature below 30° C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25° C. The organic layers were then concentrated under heat and vacuum to 120 mL. The vessel contents were then heated to 50° C. and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0° C. and held for ˜2 hrs. The solids were filtered and rinsed with heptanes (2×2 vol). The solid product was then dried under vacuum at 30° C. to obtain N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (28.8 g, 80%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[OH:20].[OH-].[Na+].S(=O)(=O)(O)O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[O:20][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: OCCCBr
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: [I-]
Solvent: O
Solvent: Cc1ccccc1
Product: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 6 h
Yield: 91.5 %

Procedure:
A mixture of 0.53 g of 3-bromopropanol, 5.0 g of toluene and 0.06 g of tetra-n-butylammonium iodide was heated to 60° C. Thereto was added dropwise a mixed solution of 1.0 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 5.0 g of water and 0.51 g of a 27% aqueous sodium hydroxide solution with stirring over 6 hours. After completion of the addition, the mixture was further stirred at 60° C. for 10 hours. The reaction mixture was then cooled to 20° C. After 2.0 g of a 20% aqueous sulfuric acid solution was added thereto, the mixture was stirred and then separated. The obtained organic layer was washed with 5.0 g of water and concentrated under reduced pressure to give 1.1 g of 3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-1-propyl alcohol (purity: 94%, yield: 86%).
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:25]1[CH:26]=[N:27][CH:28]=[C:29]([C:31]#[N:32])[CH:30]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:31]([C:29]1[CH:30]=[C:25]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]3)[CH:26]=[N:27][CH:28]=1)#[N:32]
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Reactant: N#Cc1cncc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1cncc(N2C[C@H]3CN(C(=O)OCc4ccccc4)C[C@H]32)c1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
The product of Example 52D (830 mg, 3.58 mmol) in toluene (20 mL) was treated with Pd2(dba)3 (71.0 mg, 0.072 mmol), BINAP (134 mg, 0.214 mmol), Cs2CO3 (2.32 g, 7.16 mmol) and 3-bromo-5-cyanopyridine (0.98 g, 5.37 mmol). The mixture was heated at 100° C. under N2 for 10 hours and then allowed to cool to room temperature and diluted with ethyl acetate (100 mL). The brown solution was washed with water (2×10 mL) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, EtOAc:hexane, 50:50, Rf 0.3) to provide the title compound (770 mg, 64% yield). 1H NMR (MeOH-d4, 300 MHz) δ 3.2(dd, J=12.9, 4. Hz, 1H), 3.30-3.4 (m, 2H), 3.6 (dd, J=8.2, 3. Hz, 1H), 3.96-4.10 (m, 3H), 4.74 (dd, J=6.1, 4.0 Hz, 1H), 5.10 (m, 2H), 7.15 (dd, J=2.7, 1.7 Hz, 1H), 7.25 (m, 3H), 7.35 (m, 2H), 7.96 (d, J=2.7 Hz, 1H), 8.15 (d, J=1.7 Hz, 1H); MS (DCI/NH3) m/z 335 (M+H)+.
Reaction SMILES: C(OC)(OC)(OC)C.[C@@H:9]1([N:18]2[C:27]3[N:26]=[CH:25][N:24]=[C:22]([OH:23])[C:21]=3[N:20]=[CH:19]2)[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12](O)[C@H:10]1O.C(Br)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+].[H][H]>C(O)(=O)C.[C].[Pd].C(#N)C>[C@@H:9]1([N:18]2[C:27]3[N:26]=[CH:25][N:24]=[C:22]([OH:23])[C:21]=3[N:20]=[CH:19]2)[O:17][C@H:14]([CH2:15][OH:16])[CH2:12][CH2:10]1
Reactant: [H][H]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Agent: [Pd]
Agent: CC(=O)Br
Agent: COC(C)(OC)OC
Solvent: CC(=O)O
Solvent: CC#N
Product: OC[C@@H]1CC[C@H](n2cnc3c(O)ncnc32)O1
Temperature: 25 °C
Reaction time: 10 h
Yield: 45.9 %

Procedure:
Trimethyl orthoacetate (6.49 ml, 51.0 mmols) was added to 10 g (37.2 mmols of inosine suspended in 20 ml of acetic acid. The mixture was stirred at 25° C. for 10 hours. The reaction solution was concentrated to 26.7 g. After 35 ml of acetonitrile was added to the concentrate, 6.9 ml (93.4 mmols) of acetyl bromide was slowly added to the mixture with stirring while keeping the temperature at -5° C. to 0° C. After completion of the addition, the mixture was stirred at -5° C. to 0° C. for about an hour. The reaction solution was neutralized with 20% sodium carbonate aqueous solution. A small amount of the solution was taken out and analyzed by HPLC. The desired Br--AcO--Hx was contained in 10.9 g (70.6% yield based on inosine). After 15 ml of acetonitrile and 2.1 g of 10% palladium carbon were added were added to the neutralized reaction solution, pH was adjusted to 8.5 with 25% NaOH and hydrogen gas was passed at 7° to 8° C. in a flow amount of 30 ml/min for 10 hours. During the procedure, the pH was maintained between 8.0 and 8.5, using 25% NaOH. Palladium carbon was filtered off. The filtrate was concentrated under reduced pressure and acetonitrile was distilled off. After about 25 ml of 25% NaOH was added to the residue, the mixture was stirred at 50° C. for 30 minutes to give 4.03 g (yield of 45.9% based on inosine) of 2',3'-dideoxyinosine A 300 MHz nuclear magnetic resonance absorption spectrum of the isolated 2',3'-dideoxyinosine supported the structure of this product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]([OH:15])=O)[CH2:9][CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]12([NH2:26])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:16]12([NH:26][C:13](=[O:15])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10][CH3:11])[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: CCCN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC(=O)NC12CC3CC(CC(C3)C1)C2)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Next, methylene chloride (208 ml) was added to a mixture of 2-[N-(t-butoxycarbonyl)-N-propylamino]acetic acid (4.52 g, 20.8 mmol) and 1-adamantaneamine (3.46 g, 22.9 mmol), and the whole was stirred at room temperature. N,N-Diisopropylethylamine (7.25 ml, 41.6 mmol) and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate (8.71 g, 22.9 mmol) were added thereto, and the whole was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 7.88 g (quantitatively) of 2-[N-(t-butoxycarbonyl)-N-propylamino]acetic acid N-(1-adamantyl)amide as a colorless oily matter. The obtained oily matter solidified at room temperature.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6]1[O:14][CH:7]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCO.N1C=CC=CC=1>[N:1]1([CH2:6][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[OH:14])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: c1ccc(C2CO2)cc1
Solvent: c1ccncc1
Solvent: CCO
Product: OC(Cn1ccnc1)c1ccccc1
Yield: 35.2 %

Procedure:
A solution of 17.6 g (0.258 mol) of imidazole in 100 mL of absolute EtOH was treated with 0.6 mL (4.0 mmol) of pyridine and refluxed for 25 minutes. This was then treated dropwise with a solution of 31.06 g (0.258 mol) of styrene oxide and the solution heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in Et2O and washed with H2O. A solid separated which was collected and dissolved in warm CHCl3 /EtOAc. The organic phase was washed with saturated NaCl and dried over MgSO4. Treatment of the filtrate with charcoal, filtering, and concentrating to 1/3 volume caused a solid to separate. There was collected 17.09 g (35% yield) of the product as a white solid, mp 146-148° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 189 (M+H+).
Reaction SMILES: [C:1]([C@:9]([C:24]([OH:26])=[O:25])([OH:23])[C@:10]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:14])[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N+:35]([CH2:38][CH2:39][O:40][C:41]([CH:43]([C:45]1[CH:50]=[CH:49][C:48]([CH2:51][CH:52]([CH3:54])[CH3:53])=[CH:47][CH:46]=1)[CH3:44])=[O:42])([CH3:37])[CH3:36].[Br-:55]>C1(C)C=CC=CC=1>[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N+:35]([CH2:38][CH2:39][O:40][C:41]([CH:43]([C:45]1[CH:50]=[CH:49][C:48]([CH2:51][CH:52]([CH3:53])[CH3:54])=[CH:47][CH:46]=1)[CH3:44])=[O:42])([CH3:37])[CH3:36].[Br-:55].[C:15]([C@:10]([C:11]([O-:13])=[O:12])([OH:14])[C@:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:23])[C:24]([O-:26])=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Agent: CCCCCCCC[N+](C)(C)CCOC(=O)C(C)c1ccc(CC(C)C)cc1
Agent: [Br-]
Solvent: Cc1ccccc1
Product: O=C([O-])[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)[O-])C(=O)c1ccccc1
Yield: 80 %

Procedure:
A hot solution of dibenzoyl-D-tartaric acid (5.4 g., 15 mmole) in 500 ml. toluene was added while stirring to AF150 (5.5 g., 32 mmole) dissolved in 200 ml. dry toluene. The precipitate was allowed to settle and the supernatant liquid was decanted off. The residual solid was washed with 3×100 ml. dry toluene and dried under reduced pressure to afford 8.4 g. (80% yield) of a white slightly hygroscopic solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](Cl)([Cl:10])[Cl:9])[N:3]=1.[OH-].[Na+].P([O-])(OC)OC.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([Cl:10])[Cl:9])[N:3]=1
Reactant: Clc1cccc(C(Cl)(Cl)Cl)n1
Agent: COP([O-])OC
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1cccc(C(Cl)Cl)n1
Reaction time: 0.08 h
Yield: 71.3 %

Procedure:
In a reaction vessel fitted with a magnetic stirrer, 2.31 grams (10 mmole) of 2-chloro-6-(trichloromethyl)pyridine was dissolved in 25 ml of N-methylpyrrolidone. To this mixture was added 2.0 grams of 50% aqueous sodium hydroxide and 1.29 grams (10.2 mmole) of dimethyl phosphite. Within five minutes the temperature rose from 24° C. to 55° C. Analysis by glc indicated a ratio of 97.6/1.7 for reduced product to starting material. The reaction mixture was poured into 100 ml of water and the oil which separated was crystallized to form 1.4 grams of 2-chloro-6-(dichloromethyl)pyridine (mp 50°-53° C.). The yield was calculated to be 71% of theoretical.