Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.[C:13]([O:21][CH2:22][C@@H:23]1[C@@H:29]([CH2:30][O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH:27]2[CH:25]([O:26]2)[CH2:24]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.P([O-])([O-])([O-])=O>CN(C=O)C.CO>[C:32]([O:31][CH2:30][C@@H:29]1[C@@H:23]([CH2:22][O:21][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:24][C@@H:25]([N:7]2[CH:8]=[N:9][C:10]3[C:6]2=[N:5][CH:4]=[N:3][C:11]=3[NH2:12])[C@H:27]([OH:26])[CH2:28]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(OC[C@H]1CC2OC2C[C@@H]1COC(=O)c1ccccc1)c1ccccc1
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@H](COC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C[C@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
In an atmosphere of argon gas, 60% sodium hydride (20 mg, 0.65 mole) was added to a suspension of adenine (202.5 mg, 1.34 mmoles) in anhydrous DMF (10 ml). After stirring the mixture at room temperature for one hour, (3S,4S)-3,4-bis(benzoyloxymethyl)-7-oxabicyclo-[4.1.0]heptane (245 mg, 0.67 mmole) was added and the resulting mixture was heated in an oil bath kept at 140° C. for 3 hours. After adding 0.2M phosphate buffer (pH 7.0) to the reaction mixture and stirring the mixture for a while, the mixture was subjected to extraction with ethyl acetate. After drying the extract solution on anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1, v/v) to obtain 9-[(1R,2R,4S,5S)-4,5-bis(benzoyloxymethyl)-2-hydroxycyclohexyl]-adenine (161 mg, Yield 48%).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][NH+:6]=[C:5]([CH2:9]Cl)[C:4]=1[O:11][CH3:12].[F:13][CH:14]([F:26])[O:15][C:16]1[CH:25]=[CH:24][C:19]2[NH:20][C:21]([SH:23])=[N:22][C:18]=2[CH:17]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>O>[OH2:11].[F:26][CH:14]([F:13])[O:15][C:16]1[CH:25]=[CH:24][C:19]2[NH:20][C:21]([S:23][CH2:9][C:5]3[C:4]([O:11][CH3:12])=[C:3]([Cl:2])[CH:8]=[CH:7][N:6]=3)=[N:22][C:18]=2[CH:17]=1
Reactant: COc1c(Cl)cc[nH+]c1CCl
Reactant: FC(F)Oc1ccc2[nH]c(S)nc2c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1c(Cl)ccnc1CSc1nc2cc(OC(F)F)ccc2[nH]1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 4.6 %

Procedure:
At 55-65° C., a solution of 4-chloro-2-chloromethyl-3-methoxypyridinium chloride (10.0 kg, 43.8 mol) in water (20 L) was added over 2-3 h to a mixture of 5-difluoromethoxy-1H-benzimidazole-2-thiol (8.84 kg, 40.9 mol), toluene (43 L), water (21 L) and 40% aqueous NaOH (10.3 kg, 103 mol). Stirring at 60° C. was continued for 2-3 h before the reaction mixture was cooled to 10-15° C. The precipitate was centrifuged off, washed with toluene (16 L) and re-pulped in water (122 L). Centrifugation followed by an aqueous rinse (32 L) and drying at 35° C. in vacuo gave 5-difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridinyl)methylthio]-1H-benzimidazole mono hydrate (KF=4.6%) as an off-white solid (m. p. 95-99° C.); yield 14.2 kg (92%).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[CH:7]1([CH2:10][NH2:11])[CH2:9][CH2:8]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH:7]1([CH2:10][NH:11][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:6])[CH2:9][CH2:8]1
Reactant: O=C(O)C1CC1
Reactant: NCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCC1CC1)C1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 41.7 %

Procedure:
To a solution of cyclopropane carboxylic acid (1.72 g, 20 mmol) and cyclopropylmethylamine (1.42 g, 20 mmol) in N,N-dimethylformamide (20 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.22 g, 22 mmol) and 1-hydroxybenzotriazole (4.05 mmol, 30 mmol), and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added ethyl acetate, and the mixture was washed with 1M hydrochloric acid and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, and then filtered and concentrated. The resulting residue was recrystallized (diethyl ether-n-hexane) to give the titled compound (1.16 g, 42%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:11])[C:5]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[F:11][C:6]1[C:5]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:4][CH:3]=[CH:2][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: [H][H]
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1cccc(C(=O)O)c1F

Procedure:
6-Chloro-2-fluoro-3-(propylsulfonamido)benzoic acid (0.5 g, 1.69 mmol) was dissolved in methanol (15 mL), and Pearlman's catalyst (one weight equivalent, 0.5 g, 20% Pd(OH)2 on carbon, 50% by weight water) was added. This mixture was subjected to a balloon of hydrogen for 3 hours and then filtered through GF/F filter paper. The filtrate was concentrated to 2-fluoro-3-(propylsulfonamido)benzoic acid (396 mg, 90%) as a solid. MS (M−H+) 262. NMR (DMSO-d6, 400 MHz) δ 13.36 (s, 1H), 9.76 (s, 1H), 7.58-7.70 (m, 2H), 7.26 (t, 1H, J=8), 3.10 (t, 2H, J=8), 1.69-1.80 (m, 2H), 0.98 (t, 3H, J=8).
Reaction SMILES: P(Br)(Br)[Br:2].O[CH:6]([CH3:17])[CH2:7][NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16].O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:2][CH:6]([CH3:17])[CH2:7][NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16]
Reactant: Cc1cccc(C)c1NCC(C)O
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cccc(C)c1NCC(C)Br
Reaction time: 6 h
Yield: 87.5 %

Procedure:
A mixture of 250 ml (712 g, 2.63 moles) of phosphorous tribromide and 250 ml of dry chloroform is added dropwise to a solution of 100 g (0.558 moles) of N-(β-hydroxypropyl)-2,6-dimethyl-aniline in 500 ml of dry chloroform. During the addition the temperature of the mixture is maintained below +25° C. by cooling with icy water. The resulting mixture is boiled for 6 hours, thereafter it is cooled on salted ice, and 100 ml of water are added dropwise. The pH of the resulting mixture is adjusted to 9 with 10 n aqueous sodium hydroxide solutions. The phases are separated from each other, and the aqueous phase is extracted thrice with 300 ml of chloroform each. The organic solutions are combined, washed four times with 500 ml of water each, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. 118.2 g (87.5%) of N-(β-bromopropyl)-2,6-dimethyl-aniline are obtained as a colourless oily residue. This product is sufficiently pure to be applied directly in the next step. When distilling the oil at 0.3 mm Hg it boils at 102°-106° C.
Reaction SMILES: [Ti:1](Cl)(Cl)(Cl)Cl.[C:6]1([N-:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li+].[C:20]1([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:13]1([N-:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[C:27]1([N-:26][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1.[C:13]1([N-:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[C:13]1([N-:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[Ti+4:1]
Reactant: Cl[Ti](Cl)(Cl)Cl
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Li+]
Agent: c1ccc([N-]c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [Ti+4]
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
The same apparatus described in Step (1) of Example 1-E is used in this procedure. The 250 ml dropping funnel is charged with toluene, 50 ml, and titanium tetrachloride, 2.4 ml (0.022 mole). This is added dropwise to the flask containing lithium diphenylamide which is maintained at -20° C. during the addition while stirring magnetically. Total addition time is 30 minutes. The mixture is warmed to room temperature and then refluxed for 2 hours. All volatiles are removed under vacuum to give a deep red oily residue. Unreacted diphenylamine is sublimed from the oil under reduced pressure at 120° C. to give a red solid. Extraction of the solid with hexane, 50 ml, followed by solvent volume reduction under vacuum then cooling to -30° C. yields red crystals of titanium tetrakis(diphenylamide).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]([CH3:12])[C:8](=[O:11])[NH:9][N:10]=1.Cl[C:14]1C=CC(C2N(CC)C(=O)NN=2)=CC=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]([CH3:12])[C:8](=[O:11])[N:9]([CH3:14])[N:10]=1
Reactant: CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Reactant: Cn1c(-c2cccs2)n[nH]c1=O
Product: Cn1nc(-c2cccs2)n(C)c1=O

Procedure:
When, in the procedure of Example 7, 5-(2-thienyl)-2,4-dihydro -4-methyl-3H-1,2,4-triazol-3-one is substituted for 5-(4-chlorophenyl)-2,4-dihydro-4-ethyl-3H-1,2,4-triazol-3-one, the title compound is obtained. Mp 108°-110° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C:3]2([CH2:10][CH:9]3[CH2:11][N:6]2[CH2:7][CH2:8]3)[CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].Br[C:65]1[CH:66]=[C:67]([O:71][CH2:72][CH3:73])[CH:68]=[N:69][CH:70]=1>C1(C)C=CC=CC=1>[CH2:72]([O:71][C:67]1[CH:66]=[C:65]([N:1]2[CH2:5][CH2:4][C:3]3([CH2:10][CH:9]4[CH2:11][N:6]3[CH2:7][CH2:8]4)[CH2:2]2)[CH:70]=[N:69][CH:68]=1)[CH3:73]
Reactant: CCOc1cncc(Br)c1
Reactant: C1CC2(CN1)CC1CCN2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOc1cncc(N2CCC3(CC4CCN3C4)C2)c1
Temperature: 160 °C
Yield: 34.1 %

Procedure:
A mixture of spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] (50 mg, 0.3 mmol) tris(dibenzylideneacetone)dipalladium(0) (9 mg, 0.009 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (12 mg, 0.018 mmol), potassium tert-butoxide (147 mg, 1.2 mmol), and 5-bromo-3-ethoxypyridine (73 mg, 0.36 mmol) in dry toluene (5 mL) was placed in a sealed tube under argon and heated at 160° C. for 17 h. The reaction was cooled to 0° C. and the contents transferred to a 100 mL round bottom flask. The solvent was removed by rotary evaporation and the residue was dissolved in a saturated solution of NaHCO3 (10 mL) and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (K2CO3), filtered and concentrated by rotary evaporation to give a dark colored syrup. This was purified by column chromatography, using MeOH:CHCl3:NH4OH (8:2:0.01, v/v) as the eluent, to give 28 mg (27%) of 1′-(5-ethoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] as a viscous brown oil.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[C:12](=O)(OC(Cl)(Cl)Cl)[O:13]C(Cl)(Cl)Cl>C1COCC1>[I:1][C:2]1[CH:10]=[C:6]2[C:7]([O:9][C:12](=[O:13])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(I)cc2c(=O)o1
Temperature: 50 °C
Reaction time: 2 h
Yield: 212.5 %

Procedure:
10 g (0.038 mol) of 5-iodoanthranilic acid were dissolved in 180 ml of THF, and 3.76 g (0.0127 mol) of bis(trichloromethyl) carbonate dissolved in 20 ml of THF were added. The mixture was then stirred at room temperature for 1 h and at 50° C. for 2 h. After cooling, the precipitate was filtered off with suction and dried. 7.8 g (71%) of 5-iodoisatoic anhydride were obtained as white crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].C(=O)([O-])O.[Na+]>ClCCl>[C:11]([O:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1csc2cncn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCc1csc2cncn12
Yield: 95 %

Procedure:
0.15 g of the 3-hydroxymethylimidazo[5,1-b]thiazole prepared in Preparation 55 was dissolved in 4 ml of dichloromethane, and the solution was stirred. To this was added 0.1 ml of acetic anhydride, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added 5 ml of a saturated aqueous solution of sodium hydrogencarbonate, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (5 ml×2). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 0.181 g (yield 95%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:6]([CH:7]=[CH:8][C:9]3[NH:19][CH2:18][CH:17]=[C:11]4[NH:12][C:13](=[O:16])[C:14]=2[C:10]=34)=[C:5]([CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:4]=[CH:3]1.O=[C:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.ClC(Cl)C.C(O)(=O)C.[Na]>>[CH3:1][N:2]1[C:15]2[C:6]([CH:7]=[CH:8][C:9]3[N:19]([CH:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)[CH2:18][CH:17]=[C:11]4[NH:12][C:13](=[O:16])[C:14]=2[C:10]=34)=[C:5]([CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:4]=[CH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CN1C=CC(CS(C)(=O)=O)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3
Agent: [Na]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CN1C=CC(CS(C)(=O)=O)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 83.7 %

Procedure:
To a mixture of Example 6a (0.015 g, 0.044 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (0.017 g, 0.087 mmol) was added dichloroethane (1 mL) and acetic acid (0.03 mL, 0.524 mmol). The reaction mixture was heated at 50° C. for 2 hours, treated with sodium triacetoxyhydroborate (0.028 g, 0.131 mmol) and heated overnight at 50° C. Additional tert-butyl 4-oxopiperidine-1-carboxylate (0.017 g, 0.087 mmol) was added and the mixture was heated for 1 hour. Additional sodium triacetoxyhydroborate (0.028 g, 0.131 mmol) was added and the mixture was heated over a second night at 50° C. The reaction mixture was cooled to ambient temperature, partitioned between ethyl acetate and water, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-6% methanol in dichloromethane) to give 0.0194 g (84%) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ 10.71 (d, J=5.49 Hz, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.13 (s, 1H), 6.79 (d, J=5.49 Hz, 1H), 4.40 (m, 2H), 4.11 (s, 3H), 3.87 (m, 2H), 3.73 (m, 1H), 3.63 (m, 1H), 3.19 (m, 1H), 2.91 (s, 3H), 2.66 (m, 2H), 1.67 (m, 1H), 1.58 (m, 1H), 1.45 (m, 2H), 1.38 (s, 9H), 1.23 (m, 1H). MS (ESI+) m/z 526.8 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH:28]C=O)[CH:6]=[C:7]([CH:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:26])[CH2:21][CH2:20]1)[CH2:8][P:9]([O:15]C(C)C)([O:11]C(C)C)=[O:10])[CH3:2].C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH2:28])[CH:6]=[C:7]([CH:19]1[CH2:20][CH2:21][N:22]([C:25](=[O:27])[CH3:26])[CH2:23][CH2:24]1)[CH2:8][P:9]([OH:15])([OH:11])=[O:10])[CH3:2]
Reactant: CCOC(=O)C(C=C(CP(=O)(OC(C)C)OC(C)C)C1CCN(C(C)=O)CC1)NC=O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(N)C=C(CP(=O)(O)O)C1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.15 g (6.84 mmol) of 4-(1-acetylpiperidin-4-yl)-5-diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester are dissolved in 17 ml of dichloromethane, and 3.54 ml (27.3 mmol) of trimethylbromossilane are added dropwise at room temperature. The mixture is left to stand room at temperature for 16 hours, 17 ml of ethanol are added dropwise, the mixture is left to stand for a further 18 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 12 ml of ethanol, and a mixture of 3 ml of propylene oxide and 3 ml of ethanol is added. A suspension forms, which is stirred for a further 2 hours at room temperature and for 2 hours with ice cooling and is then filtered with suction. 2-amino-4-(1-acetylpiperidin-4-yl)-5-phosphono-pent-3-enoic acid ethyl ester having a melting point of 225° (decomp.) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=[CH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][C:6]([OH:8])=[O:7].[H][H]>CO>[CH3:1][O:2][C:3](=[O:16])[CH:4]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(=CC1CCCCC1)CC(=O)O
Reactant: [H][H]
Solvent: CO
Product: COC(=O)C(CC(=O)O)CC1CCCCC1
Temperature: 45 °C
Reaction time: 18 h

Procedure:
2-Cyclohexylmethylidenesuccinic acid 1-methyl ester (0.22 g, 1.0 mmol) and each metal complex catalyst (0.005 mmol) were weighed in a Pyrex (registered trade name) test tube for autoclaving and the tube was put into a 50 mL-autoclave together with a stirrer in the tube, and then the atmosphere in the autoclave was substituted with nitrogen. The mixture was added with 2 mL of deoxygenized methanol, and after the atmosphere in the autoclave was sufficiently substituted with hydrogen, and then pressurized with 0.5 MPa of hydrogen, the mixture was stirred at 45° C. for 18 hours. After 18 hours, the atmosphere of the autoclave was returned to ordinary pressure, and the reaction mixture was concentrated in an evaporator. The concentrated residue was added with 5 mL of 2 M aqueous sodium hydroxide for dissolution, and the solution was washed with 5 mL of ethyl acetate. The aqueous layer was separated, and added with diluted hydrochloric acid until pH of the aqueous layer became lower than 2, and the produced oil was extracted with 10 mL of ethyl acetate. The organic layer was concentrated in an evaporator to quantitatively obtain optically active cyclohexylmethylsuccinic acid 1-methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[N:18][C:19](=[O:30])[N:20]([CH2:22][CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[CH:21]=4)[S:15][C:8]=23)=[C:4]([F:33])[CH:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43](=[O:48])[CH2:44][C:45](O)=[O:46].C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C.C(Cl)CCl>[F:33][C:4]1[CH:3]=[C:2]([NH:1][C:45](=[O:46])[CH2:44][C:43]([NH:42][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][CH3:34])=[O:48])[CH:32]=[CH:31][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[N:18][C:19](=[O:30])[N:20]([CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[CH:21]=3)[S:15][C:8]=12
Reactant: Nc1ccc(Oc2ccnc3cc(-c4cnc(=O)n(CCN5CCOCC5)c4)sc23)c(F)c1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cnc(=O)n(CCN5CCOCC5)c4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.3 %

Procedure:
To a solution of the amine 416 (0.16 mmol) in DMF (1 mL) was added acid 27 (38 mg, 0.18 mmol), HOBT (24 mg, 0.18 mmol) and EDC×HCl (46 mg, 0.24 mmol). The mixture was stirred at room temperature for 16 h. The solvent was evaporated, then the residue was purified by flash chromatography with gradient of methanol (0-5%) in dichloromethane, followed by preparative HPLC purification with gradient of methanol (20-100%) in water to give title compound 412 (14 mg, 13% yield). MS (m/z): 659.1 (M+H). 1H NMR (DMSO-d6) δ (ppm): 10.59 (s, 1H), 9.64 (s, 1H), 9.16 (d, J=3.3 Hz, 1H), 8.69 (d, J=3.3 Hz, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.07 (d, J=7.4 Hz, 1H), 7.98 (s, 1H), 7.88 (dd, J=13.2.3 Hz, 1H), 7.51 (t, J=9.0 Hz, 1H), 7.43 (dd, J=8.8, 1.6 Hz, 1H), 7.11-7.05 (m, 2H), 6.94-6.90 (m, 1H), 6.67 (d, J=4.7 Hz, 1H), 4.05 (t, J=6.5 Hz, 2H), 3.86 (s, 3H), 3.64 (s, 2H), 3.55-3.50 (m, 4H), 2.63 (t, J=5.5 Hz, 2H), 2.46-2.42 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:3]=1.[Cl:17][C:18]1[C:19](B(O)O)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.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>[Cl:17][C:18]1[C:19]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[N:3]=2)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: Fc1cccc(COc2cccc(Br)n2)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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Fc1cccc(COc2cccc(-c3cc(F)ncc3Cl)n2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
A mixture of 2-bromo-6-(3-fluorobenzyloxy)pyridine (145 mg, 0.514 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (144 mg, 0.822 mmol), PalladiumTetrakis (71.3 mg, 0.062 mmol), DME (3 ml), and t 2M sodium carbonate (1.028 ml, 2.056 mmol) was reaction mixture was stirred at 100° C. for 3 hr, followed by LCMS. The reaction mixture was cooled, diluted with 10 ml of ethyl acetate, filtered and concentrated to yield a crude product, which was purified by silica gel chromatography using a 12 g column eluting from 0%-20% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 100 mg of titled compound as a free base. LCMS (m/z): 333.1 (MH+), retention time=1.26 min.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH2:19][CH2:20][CH2:21][C:22]1[N:30]=[C:29]2[C:25]([N:26]=[CH:27][N:28]2[C@H:31]2[C@H:35]([OH:36])[C@H:34]([OH:37])[C@@H:33]([CH2:38][O:39][CH3:40])[O:32]2)=[C:24]([NH:41][CH2:42][CH:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:23]=1.[C:56]1(=O)[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>ClCCl>[CH:56]1([NH:19][CH2:20][CH2:21][C:22]2[N:30]=[C:29]3[C:25]([N:26]=[CH:27][N:28]3[C@H:31]3[C@H:35]([OH:36])[C@H:34]([OH:37])[C@@H:33]([CH2:38][O:39][CH3:40])[O:32]3)=[C:24]([NH:41][CH2:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:23]=2)[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: O=C1CCCCC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNC4CCCCC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.6 %

Procedure:
Sodium triacetoxyborohydride (75 mg, 0.35 mmol) and acetic acid (16 mg, 0.27 mmol) were added sequentially to a stirred solution of (2R,3R,4S,5R)-2-{2-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 11) (120 mg, 0.24 mmol) and cyclohexanone (23 mg, 0.235 mmol) in dichloromethane (15 ml). The resulting mixture was stirred at room temperature for 24 hr, diluted with dichloromethane and washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate, water and brine. The organic phase was dried with anhydrous sodium sulfate, the solvent removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:ammonia (95:5:0.5) changing to dichloromethane:methanol:ammonia (90:10:1) to afford the title compound as a solid (78 mg). MS: 587 (MH+).