Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[N:3]=1.[N:8]([O-])=[O:9].[Na+]>S(=O)(=O)(O)O.N([O-])=O.[Na+]>[CH3:7][C:4]1[N:3]=[C:2]([NH:1][N:8]=[O:9])[S:6][N:5]=1
Reactant: O=N[O-]
Reactant: Cc1nsc(N)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1nsc(NN=O)n1
Yield: 50831.3 %

Procedure:
First, 11.5 g (0.1 mol) of 5-amino-3-methyl-1,2,4-thiadiazole was dissolved in 100 mL of 2N sulfuric acid. While the mixture was stirred, an aqueous sodium nitrite solution (containing 8.0 g (0.116 mmol) of sodium nitrite in 20 mL of water) was added dropwise to the mixture at 0° C. or less. After completion of dropwise addition, the resultant solution was continuously stirred further for one hour at 0° C. The crystals precipitated were collected by filtration and washed with ice cold water. The crystals were dried in the air at room temperature overnight to obtain 8.5 g (56% in yield) of 3-methyl-5-nitrosoamino-1,2,4-thiadiazole. Next, 7.2 g (0.05 mol) of the obtained thiadiazole was dissolved in 50 mL of methanol at room temperature. While the resultant solution was stirred, 3 mL of concentrated sulfuric acid was added dropwise to the solution at 5° C. or less. After completion of dropwise addition, the solution was continuously stirred further at 5° C. or less for one hour or less and at 15 to 20° C. for 2 hours. The crystals precipitated were collected by filtration. The crystals were recrystallized from methanol to obtain 2.5 g (41% in yield) of triazene dissociative direct dye D-5.
Reaction SMILES: [CH3:1][C:2]1([C:26]([OH:28])=[O:27])[O:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH3:15])[CH2:4][O:3]1.[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:29]([O:27][C:26]([C:2]1([CH3:1])[O:3][CH2:4][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH3:15])[CH2:6][O:7]1)=[O:28])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CC(=NOCCCCC1COC(C)(C(=O)O)OC1)c1ccc2ccccc2c1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOC(=O)C1(C)OCC(CCCCON=C(C)c2ccc3ccccc3c2)CO1
Temperature: 60 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A mixture of 2-Methyl-5-[4-(1-naphthalen-2-yl-ethylideneaminooxy)-butyl]-[1,3]dioxane-2-carboxylic acid (prepared as per example 63) (0.9 g), n-octyl bromide (0.6 mL) and potassium carbonate (0.64 g) in anhydrous dimethyl formamide (10 mL) was stirred at 60° C. for about 8 hours in an inert atmosphere. The reaction mixture was cooled to ambient temperature, poured into ice cold water and extracted with ethyl acetate. The combined organic extract was washed with water, brine solution, dried over sodium sulphate and evaporated under reduced pressure. Crude product was flash chromatographed over silica gel 8% ethyl acetate in petroleum ether as eluent to obtain 1 g of pure product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.I[CH2:25][CH2:26][CH3:27]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]([CH2:25][CH2:26][CH3:27])[N:13]=[C:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]([F:23])([F:22])[F:21]
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(OC)c1
Reactant: CCCI
Product: CCCn1nc2c(C(F)(F)F)cccc2c1-c1ccc(OC)cc1OC

Procedure:
Prepared according to Example 101 from 3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole and 1-iodopropane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([CH:13]=[CH:14][C:15]([N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:16])=[C:9]([O:25]C)[C:8](=[O:27])[NH:7][C:6]=2[CH:28]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](/[CH:13]=[CH:14]/[C:15]([N:17]([CH3:18])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])=[C:9]([OH:25])[C:8](=[O:27])[NH:7][C:6]=2[CH:28]=1
Reactant: COc1c(C=CC(=O)N(C)c2ccccc2)c(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CN(C(=O)/C=C/c1c(O)c(=O)[nH]c2cc(Cl)ccc2c1=O)c1ccccc1
Reaction time: 1 h
Yield: 58.1 %

Procedure:
8-Chloro-4-[2-(phenyl-N-methylaminocarbonyl)ethenyl]-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.150 g) was suspended in methylene chloride (10 mL) under nitrogen. This suspension was treated in one portion with boron tribromide (285 mg, 1.07 μL) via syringe at ambient temperature. The mixture immediately went from a buff suspension to a rust red mixture. Stirring was continued for one hour. The mixture was then treated with saturated aqueous sodium bicarbonate (10 mL) and the pH of the mixture was then adjusted to pH 3 with concentrated hydrochloric acid and the resulting buff colored suspension was stirred for an additional hour. The solid product was filtered off and washed with cold water and dried. The crude product was dissolved in warm ethyl acetate (15 mL) and hexane was added gradually to precipitate the product. The product was filtered off and dried under vaccum to afford the desired product 84 mg. Yield 58%; 1H NMR (d6 -DMSO) 7.63 (d,1, J=16), 6.80 (d,1, J=16) trans olefin protons; MS: m/z=383 (M+1). Analysis for C20H15ClN2O4 : Calculated: C, 62.75; H, 3.95; N, 7.32; Found: C, 62.45; H, 3.94; N, 7.08.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18](Cl)[N:17]=[C:16]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH3:36][O:37][CH2:38][C:39]#[C:40][CH2:41][OH:42].C(O)C#CCO.COS(OC)(=O)=O.[H-].[Na+]>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:42][CH2:41][C:40]#[C:39][CH2:38][O:37][CH3:36])[N:17]=[C:16]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COCC#CCO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: OCC#CCO
Agent: [H-]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COCC#CCOc1nc(-c2ccncc2)nc(NS(=O)(=O)c2ccc(C(C)C)cn2)c1Oc1ccccc1OC
Reaction time: 24 h
Yield: 45.7 %

Procedure:
To a solution of 300 mg of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)4-pyrimidinyl]-2-pyridine sulfonamide (Example 1f) and 1.47 g of 4-methoxy-2-butynol (prepared starting from 2-butyn-1,4-diol and dimethylsulfate following the procedure given in Bull. Chem. Soc. Japan 28 (1955), 80-83) in 15 ml of DMF was carefully added 234 mg of 55% NaH in mineral oil. The brown solution stirred for 24 h at room temperature before further 120 mg of 55% NaH in mineral oil was added. Stirring was continued for 24 h. The mixture was diluted with 100 ml of 10% aqueous citric acid and extracted four times with 50 ml of ethyl acetate. The combined organic phases were washed twice with 50 ml of water, dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate to give 154 mg of 5-isopropyl-N-[6-(4-methoxy-but-2-ynyloxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-2-pyridine sulfonamide as a yellow solid. LC-MS: tR=4.84 min, [M+1]+=576.42, [M−1]−=574.37.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1.O>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=2)=[N:16][CH:17]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Br)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of 4-methanesulfonylbenzoic acid (100 mg, 0.50 mmol) and 2-amino-5-bromopyridine (104 mg, 0.60 mmol) in dry dichloromethane (10 mL) was added 4-(dimethylamino)pyridine (67 mg, 0.55 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (105 mg, 0.55 mmol). The mixture was stirred at room temperature overnight under N2, diluted with water (10 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate=3/1) to give the title compound as a white crystal (56 mg, yield 32%).
Reaction SMILES: [OH:1][C:2]1([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[N:17]=2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[S:24]1[CH:25]=[CH:26][N:27]=[C:23]1[NH:22][C:18]1[N:17]=[C:16]([CH2:15][C:2]2([OH:1])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cc2cccc(Nc3nccs3)n2)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: OC1(Cc2cccc(Nc3nccs3)n2)CCNCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5.9 mg of tert-butyl 4-hydroxy-4-((6-(1,3-thiazol-2-ylamino)pyridin-2-yl)methyl)piperidine-1-carboxylate in 1 ml of chloroform was added 0.5 ml of trifluoroacetic acid at 0° C., followed by stirring the reaction mixture at 0° C. for 2 hours. The reaction mixture was concentrated in vacuo, basified with saturated aqueous sodium bicarbonate solution, and extracted with chloroform. The resulting chloroform layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to give the title compound as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([O:21][CH2:22][C:23]([OH:25])=O)[CH:18]=[CH:19][CH:20]=3)[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:26].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCC[N+](C)(C)C.[I-]>ClC(Cl)C.CN(C)C=O>[CH2:27]([NH:34][C:23](=[O:25])[CH2:22][O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:10]2[NH:11][C:12](=[O:14])[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([CH3:26])[CH:4]=3)[CH:9]=2)[CH:16]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cc(-c2cc(-c3cccc(OCC(=O)O)c3)[nH]c(=O)n2)ccc1O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(-c3cccc(OCC(=O)NCc4ccccc4)c3)[nH]c(=O)n2)ccc1O
Yield: 25.5 %

Procedure:
To a solution of ({3-[6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl]phenyl}oxy)acetic acid (16.9 mg, 48 μmol) and benzylamine (4.3 mg, 40 umol) in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL) was added 1-hydroxybenzotriazole (6.8 mg, 50 μmol) followed by 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 μmol). The resultant mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo. Purification of the residue by HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) followed by concentration in vacuo gave the title compound N-benzyl-2-(3-(6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl)phenoxy)acetamide (4.5 mg, 25%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1B(O)O>C1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>[CH:23]1[C:24]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:22]=1[C:2]1[N:3]=[CH:4][N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: C[Si](C)(C)CCOCn1cnc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C[Si](C)(C)CCOCn1cnc(-c2ccc3ccccc3c2)c1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a solution of E1 (1.0 eq.) in benzene (0.1 M solution), 2-naphthylboronic acid (1.5 eq.) and sat. aq. Na2CO3 solution under argon was added PdCl2((PPh)3)2. The mixture was stirred for 72 hr at 60° C., then cooled and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel eluting with 20-50% EtOAc/petroleum ether to obtain E2 as yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.31 (1H, s), 7.88-7.70 (5H, m), 7.48-7.39 (3H, m), 5.28 (2H, s), 3.54 (2H, t, J=8.2 Hz), 0.94 (2H, t, J=8.2 Hz), 0.00 (9H, s). MS (ES) C19H24N2OSi requires: 324, found: 325 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[N:37][CH:38]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([NH:42][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:4]3[C:5]([CH3:13])=[C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:2]([CH3:1])=[N:3]3)=[CH:19][CH:18]=2)=[O:24])(=[O:40])=[O:41])=[N:37][CH:38]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1ccc(Cl)cn1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(Cl)cn3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 5-chloro-2-pyridinesulfonamide (DK Patent 107422): 1H-NMR (CDCl3) δ 8.59 (1H, d, J=1.8 Hz), 8.00-7.90 (2H, m), 7.46-7.22 (9H, m), 6.52 (1H, br.s), 3.48-3.41 (2H, m), 2.85-2.80 (2H, m), 2.33 (3H, s), 2.24 (3H, s).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12]2[C:17]([N:18]=1)=[C:16]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]1)[N:15]=[C:14]([CH3:27])[N:13]=2.[CH3:28][O:29][CH2:30]Br>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]([CH2:28][O:29][CH3:30])[C:12]2[C:17]([N:18]=1)=[C:16]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]1)[N:15]=[C:14]([CH3:27])[N:13]=2
Reactant: COCBr
Reactant: CCN1CCN(c2nc(C)nc3[nH]c(-c4ccccc4Cl)nc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCN(c2nc(C)nc3c2nc(-c2ccccc2Cl)n3COC)CC1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 11.1 %

Procedure:
Add sodium hydride (0.031 g, 0.0013 mol) to a solution of 8-(2-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-methyl-9H-purine (0.233 g, 0.00065 mol) in dry tetrahydrofuran (20 mL) at 0° C. Stir the reaction mixture for 15 min, then cool to −30° C. and add bromomethyl methyl ether (0.081 g, 0.00065 mol). Warm the reaction mixture to room temperature and stir for one hour. Quench the reaction mixture with water, remove the tetrahydrofuran by evaporation and then extract the reaction mixture with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give the residue. Purify the residue through preparative reverse phase HPLC (X-Bridge column, 5 mM NH4OAc/acetonitrile) to give the title compound (0.029 g). ES/MS m/z 401 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[N:3]=1.[F:16][C@@H:17]1[C@@H:21]([CH2:22][OH:23])[O:20][C@@H:19](N2C=CC(=O)NC2=O)[CH2:18]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:19]2[O:20][C@H:21]([CH2:22][OH:23])[C@@H:17]([F:16])[CH2:18]2)=[C:4]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[N:3]=1
Reactant: CCN(CC)c1nc(N)nc2[nH]cnc12
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCN(CC)c1nc(N)nc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 45 °C
Reaction time: 336 h

Procedure:
2-Amino-6-diethylamino-9H-purine (0.47 g 2.3 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.41 g, 1.8 mmoles) were suspended in potassium phosphate buffer (10 mM) 50 ml), pH 6.8, containing 0.04% potassium azide. Purified purine nucleoside phosphorylase (5350 units) and thymidine phosphorylase (2000 unit (Krenitsky et al., Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) were added to the reaction mixture and the suspension stirred at 45° C. After 14 days, additional purine nucleoside phosphorylase (15,700 units) and thymidine phosphorylase (4000 units) were added to the reaction mixture. After a total reaction time of 123 days, denatured protein was removed by filtration and the filtrate was applied to a column of AG1-X2 (2.5×10 cm, OH- form). After the column was washed with methanol, fractions containing product were pooled, evaporated and chromatographed on silica gel (2.5×20 cm) using dichloromethane:methanol (97:3). Solvent was removed and lyophilization yielded 2-amino-6-diethylamino-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-9H-purine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:10][CH2:11][C@@:12]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([C:23]([O:25]CC1C=CC=CC=1)=[O:24])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:12]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH2:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[C:23]([OH:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC[C@](Cc1ccc([N+](=O)[O-])cc1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(N)cc1)(C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
4-benzyl 1,4-di-tert-butyl (1S,4S)-1-[(tert-butoxycarbonyl)amino]-5-(4-nitrophenyl)-pentane-1,4,4-tricarboxylate (1.04 g, 1.618 mmol) were dissolved in methanol (20 ml). Palladium (10% on charcoal) (52 mg) was added and the suspension was shaken under a hydrogen atmosphere for 12 h. The catalyst was filtered off, the residue was concentrated in vacuo, and the product was obtained as white foam (864 mg, quant.).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7]C2)[O:4][CH2:3][CH2:2]1.O1C2(CCC(C(OCC)=O)C2)OCC1.O1C2(CCC(C(OCC)=O)CC2)OCC1>>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C(O)C1CCC2(CC1)OCCO2
Agent: CCOC(=O)C1CCC2(C1)OCCO2
Agent: CCOC(=O)C1CCC2(CC1)OCCO2
Product: O=C(O)C1CCC2(C1)OCCO2

Procedure:
1,4-dioxaspiro[4.4]nonane-7-carboxylic acid was synthesized in a manner similar to the synthesis of 1,4-dioxaspiro[4.5]decane-8-carboxylic acid, but with ethyl 1,4-dioxaspiro[4.4]nonane-7-carboxylate substituted for ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H][H]>CC(O)C>[C:4]1([C@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(=O)c1ccccc1
Agent: *C(F)(F)C(*)(F)F
Solvent: CC(C)O
Product: C[C@@H](O)c1ccccc1
Reaction time: 12 h
Yield: 95 %

Procedure:
Chiral hydrogenation of acetophenone was carried out (generally-used procedures; see formula (6) below). The (S,SS)-ruthenium hydride complex (1.5 mg; 0.00125 mmol) synthesized in Example 2 was weighed and placed in a 100 mL glass autoclave equipped with a stirrer coated with polytetrafluoroethylene, and after depressurizing the interior of the vessel to eliminate air, argon was introduced. Acetophenone (600 mg; 5.0 mmol) (made by Nacalai Tesque, Inc.) and 2-propanol (2.5 mL), both of which had been deaerated by argon bubbling in advance, were then added into the vessel by means of a syringe and under an argon gas flow. The procedure of performing pressure reduction and argon introduction while stirring the solution obtained was then repeated 5 times for deaeration. A hydrogen tank was then connected to the autoclave using a hydrogen introduction tube and the replacement of the air inside the introduction tube with hydrogen at 2 atmospheres was performed 5 times. The pressure inside the autoclave was then adjusted to 5 atmospheres and then hydrogen was released carefully until the pressure dropped to 1 atmosphere. After repeating this procedure 10 times, the hydrogen pressure was adjusted to 8 atmospheres and vigorous stirring at 25° C. was performed for 12 hours. After completion of reaction, the solution obtained was concentrated by depressurization. The crude product was then subject to simple distillation under reduced pressure (1 mmHg) to obtain (R)-1-phenylethanol (582 mg; 4.75 mmol; yield: 95%) at an ee of 99% as a colorless oily substance. Both conversion rate and enantiomeric excess were 99% in accordance with GC analysis: GC (column: Chirasil-DEX CB; inner diameter (df): 0.25 mm; size: 0.32 mm×25 m; made by Chromopack, Inc.; column temperature: 105° C.; injection and detection temperature: 200° C.; helium pressure: 41 kPa; retention time (tR) of (R)-1-phenylethanol: 21.7 minutes (99.56%); tR of (S)-1-phenylethanol: 23.5 minutes (0.43%); tR of acetophenone: 9.5 minutes (0.01%)); 1HNMR (400 MHz, CDCl3)δ1.50 (d, 3, J=6.6 Hz, CH3), 4.90 (dq, 1, J=3.3 and 6.6 Hz, CHOH), 7.21-7.41 (m, 5, aromatics); [α]28D: +51.8° (c: 0.984; CH2Cl2); absolute structure: R; literature value: [α]23D+48.6° (c: 0.9-1.1; CH2Cl2), 96% ee (R).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2OC)c(C)c1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A suspension of methyl 4-bromo-3-methylbenzoate (4.9 g; 21.4 mmol; 1 eq.), 2-methoxyphenylboronic acid (Aldrich 44,523-1; 3.6 g; 23.5 mmol; 1.1 eq.), potassium carbonate (14.8 g; 107 mmol; 5 eq.) and Pd(PPh3)4 (2.47 g; 2.14 mmol; 0.1 eq.) in toluene (24.5 mL) and water (24.5 mL) was refluxed for 6 hours. The reaction mixture was cooled down to room temperature and filtered through a pad of CELITE which was further washed with toluene (500 mL). The filtrate was concentrated in vacuo and the residue taken up in ethyl acetate (500 mL). The organic layer was washed with sat. aq. NaHCO3 (200 mL), water (200 mL) and brine (200 mL) then dried over magnesium sulfate and concentrated in vacuo. The crude was purified by column chromatography (c-hexane/ethyl acetate, 90/10) to afford the title compound (4.38 g, 80%) as a colorless oil. HPLC (Method A): Rt 4.85 min (purity 98.9%). LC/MS: 257.0 (M+H)+.