Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21]([OH:23])=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[NH2:26][C:27]([CH3:36])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:36][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([CH3:35])[NH:26][C:21](=[O:23])[CH2:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[NH:6][N:7]=[C:3]([C:2]([F:25])([F:1])[F:24])[CH:4]=3)=[CH:13][CH:12]=2)[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Reaction time: 4 h

Procedure:
To a 20 mL scintillation vial was added the product from Example 28 (30 mg, 0.085 mmol), tert-butyl 2-amino-2-methylpropanoate (15.0 mg, 0.088 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30 μL, 0.176 mmol). Following 4 hours of stirring, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.01-1.16 (m, 2 H), 1.26-1.31 (m, 6 H), 1.3-5 (s, 9 H), 1.40-1.53 (m, 2 H), 1.68-1.77 (m, 1 H), 1.77-1.90 (m, 4 H), 1.93-2.02 (m, 2 H), 8.01 (s, 1 H), 13.98 (s, 1 H): MS (ESI) min 494 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH2:17][CH3:18])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20].[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=1[Cl:36])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.N1C=CC=CC=1>C(O)(C)C>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:17][CH3:18])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:19]#[N:20])=[CH:31][C:30]=1[Cl:36])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1NC(C)=O
Agent: Cl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1NC(C)=O

Procedure:
A mixture of 4.17 g (0.0149 moles) of the N-(4-chloro-3-cyano-7-ethoxy-6-quinolinyl)acetamide, 4.04 g (0.0173 moles) of 4-benzyloxy-3-chloro-phenylamine (example 5), and 2.0 g (0.017 moles) of pyridine hydrochloride in 85 ml of isopropanol was stirred and refluxed in an oil bath for 30 minutes. The reaction was cooled in an ice bath, and the solid was collected by filtration and washed with isopropanol, and then with ether yielding 7.26 g of crude product as the hydrochloride salt. This material was purified by chromatography of the free base on silica gel by elution with 1:39 methanol-methylene chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:13][C:14](O)=[O:15])[C:8](=[O:9])[C:7]2=[CH:17][CH:18]=1)([O-:3])=[O:2].S(Cl)([Cl:21])=O>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:13][C:14]([Cl:21])=[O:15])[C:8](=[O:9])[C:7]2=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Product: O=C(Cl)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O

Procedure:
A mixture of (4-nitrophthalimido)acetic acid (2.17 g, 8.7 mmol) and thionyl chloride (5 mL) was refluxed for 80 minutes. The reaction mixture was cooled and, then, concentrated under reduced pressure to give a crude product of (4-nitrophthalimido)acetyl chloride. The crude product was dissolved, while heating, in 1,2-dichloroethane (10 mL). The solution was added (dropwise to a solution of (3aR*,10aS*)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]-diazepin-10(1H)-one (2.30 g, 7.9 mmol) in 1,2-dichloroethane (10 mL). The mixture was stirred for 5 minutes at room temperatures, to which was added a saturated aqueous solution of sodium hydrogen carbonate (25 mL). The aqueous layer was separated. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, which was dried over magnesium sulfate, and them subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was crystallized from chloroform-ethanol-hexane to give 1.91 g (yield 46%) of the titled compound, m.p. 196.5°-197.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=2)[CH:17]=1.[CH3:28][C:29]1([NH2:33])[CH2:32][O:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:33][C:29]3([CH3:28])[CH2:32][O:31][CH2:30]3)=[O:24])=[CH:20][N:19]=2)[CH:17]=1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: CC1(N)COC1
Product: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NC3(C)COC3)cn2)cn1
Yield: 74 %

Procedure:
As described for example 22, 6-(4-(4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (69 mg, 0.189 mmol) was converted, using 3-methyl-3-oxetaneamine instead of 4-aminotetrahydropyran, to the title compound (61 mg, 74%) which was obtained as a white foam after purification by chromatography (silica, 0 to 10% methanol in dichloromethane). MS: m/e=434.3 [M+H]+.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:33](Br)[CH:34]=[CH2:35]>O1CCCC1>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH:15]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[CH2:35][CH:34]=[CH2:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CC1CCCCC1)N1C(=O)OCC1Cc1ccccc1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(C(=O)N1C(=O)OCC1Cc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-benzyl-3-(2-cyclohexyl-acetyl)-oxazolidin-2-one (16.0 g, 53 mmol) in anhydrous tetrahydrofuran at −78° C. was added a 1.0 M solution of sodium bis(trimethylsilyl)amide (79.0 mL, 79 mmol), and the reaction mixture was stirred for 1 h. To the reaction mixture was then added allyl bromide (18.4 mL, 213 mmol), and the temperature was raised to −45° C. The reaction mixture was stirred at this temperature for 3 h. The reaction was quenched with aqueous saturated NH4Cl solution, and the resulting mixture was warmed to room temperature. The reaction mixture was extracted with ethyl acetate, and the combined extracts were washed with brine. The organic layers were dried (MgSO4) and concentrated in vacuo to yield a residue that was purified by silica gel column chromatography (5:1 hexanes:ethyl acetate) to yield (4-benzyl-3-(2-cyclohexyl-pent-4-enoyl)-oxazolidin-2-one) as a thick liquid that became a solid upon storage.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[CH:9][C:8]3[NH:14][C:15](=[O:28])[N:16]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:19][CH:18]=4)[C:7]=3[C:6]=2[CH:5]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[C:29]([N:14]1[C:8]2[CH:9]=[N:10][C:11]3[CH:12]=[CH:13][C:4]([Br:3])=[CH:5][C:6]=3[C:7]=2[N:16]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:27])[C:24]#[N:25])=[CH:19][CH:18]=2)[C:15]1=[O:28])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(C(=O)c3ccccc3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 0 °C

Procedure:
Sodium hydride (30 mg, 0.75 mmol) was added to dry DMF (5 ml) in a nitrogen atmosphere. The reaction flask was cooled in an ice-bath to 0° C., and 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 100 mg, 0.25 mmol) was added. After 15 minutes benzoyl chloride (42 mg, 0.29 mmol) was added, and the reaction mixture was heated at 50° C. for 24 hours. The reaction mixture was concentrated in vacuum. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 13 mg (10%); 1H NMR (DMSO-d6, 300 MHz): δ 9.410 (s, 1H), 7.998-8.028 (d, 1H, J=9 Hz), 7.939-7.963 (d, 2H, J=7.2 Hz), 7.848-7.876 (d, 2H, J=8.4 Hz), 7.764-7.792 (d, 3H, J=8.4 Hz), 7.644-7.669 (m, 1H), 7.48-7.56 (m, 2H), 6.865-6.872 (d, 1H, J=2.1 Hz), 1.78 (s, 6H); MS: m/z 511 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH:14]=[CH2:15])(=[O:11])[CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].Br[CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>C1COCC1>[C:20]1(=[O:29])[N:19]([CH2:18][CH2:17][CH:4]([C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[C:3]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: C=CCOC(=O)CC(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(=O)C(CCN1C(=O)c2ccccc2C1=O)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
A solution of sodium hydride (4.35 g, 0.18 mol) in freshly distilled THF (100 mL) was cooled to 0° C. and treated with diallyl malonate (35 g, 0.19 mol) over 40 min via a dropping funnel. After stirring at room temperature for 30 min, N-(2-bromoethyl)phthalimide (43.9 g, 0.17 mol) was added to the solution in one portion and the mixture was heated to reflux. After 48 h the solution was cooled to 0° C., quenched with 2N HCl and concentrated to about 20% of its original volume. The concentrate was diluted with ethyl acetate (300 mL) and washed successively with satd. aq. K2CO3 and NaCl. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography (5-25% ethyl acetate:hexanes) provided diallyl 2-phthalimidoethylmalonate (41.2 g, 67%) as a colorless oil. 1H NMR (300 MHz, CDCl3) d 7.82 (m, 2H), 7.72 (m, 2H), 5.85 (m, 2H), 5.30 (m, 2H), 5.22 (m, 2H), 4.60 (m, 4H), 3.80 (t, J=6.6 Hz, 2H), 3.46 (t, J=7.2 Hz, 1H), 2.30 (dd, J=13.8, 6.9 Hz, 2H). ##STR222## Step 3
Reaction SMILES: C([N:8]1[CH2:19][CH2:18][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[CH2:12]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.CCO>[OH-].[OH-].[Pd+2].C(O)(=O)C>[C:15]1(=[O:16])[C:11]2([CH2:10][CH2:9][NH:8][CH2:19][CH2:18]2)[CH2:12][C:13](=[O:17])[NH:14]1
Reactant: O=C1CC2(CCN(Cc3ccccc3)CC2)C(=O)N1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1CC2(CCNCC2)C(=O)N1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 8-benzyl-2,8-diaza-spiro[4.5]decane-1,3-dione (28.3 g, 0.11 mol) and Pd(OH)2 (8.5 g) in 2 l of flask, EtOH (438 ml) and acetic acid (5.5 ml) are added at ambient temperature. The reaction mixture is stirred under H2 at room temperature for 15 h. The catalysts are removed by filtration and EtOH is evaporated down to give 2,8-diaza-spiro[4.5]decane-1,3-dione in quantitative yield. To a suspension of 2,8-diaza-spiro[4.5]decane-1,3-dione (4.2 g, 25.2 mmol) in dichloromethane (60 ml), 1N NaOH (26 ml, 26 mmol) and di-t-butyldicarbonate (6.1 g, 27.7 mmol) in dichloromethane (20 ml) are added at ambient temperature. The reaction mixture is stirred for 15 h. 10% Citric acid is added to the reaction mixture and the pH of the mixture is adjusted to 5. The combined extracts are washed with brine, dried over magnesium sulfate and concentrated under vacuum to give solid product, which filtrated with diethyl ether.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:4]([C@@H:5]([OH:27])[CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:17])[CH2:13][CH2:14][CH:15]=[O:16])[CH2:3]1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1>[C:28]([O:1][C@@H:2]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:4]([C@@H:5]([O:27][C:5](=[O:27])[C:4]3[CH:22]=[CH:23][CH:24]=[CH:2][CH:3]=3)[CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:17])[CH2:13][CH2:14][CH:15]=[O:16])[CH2:3]1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](CCC=O)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: C[C@H](CCC=O)[C@H]1CC[C@H]2[C@@H]3C[C@H](OC(=O)c4ccccc4)[C@H]4C[C@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 5 h

Procedure:
One gram of 3α,6α-bis(hydroxy)-5α-cholane-24-al is dissolved in 5 ml of pyridine. With external cooling, 1 ml of benzoyl chloride is added dropwise with stirring. The mixture is kept at room temperature for five hours, then stirred with ice water. By extraction with methylene chloride, the reaction product is removed. The methylene chloride solution is repeatedly washed with dilute hydrochloric acid, then with water. After drying, the solvent is evaporated. The residue is 3α,6α-bis(benzoyloxy)-5α-cholane-24-al.
Reaction SMILES: [BrH:1].[CH2:2]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH2:10]O)[CH2:5]1)[CH3:3].O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:1][CH2:10][CH:6]1[CH2:7][CH2:8][CH2:9][N:4]([CH2:2][CH3:3])[CH2:5]1
Reactant: CCN1CCCC(CO)C1
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCN1CCCC(CBr)C1

Procedure:
48% Aqueous hydrogen bromide (16 ml) was added to N-ethyl-3-piperidinemethanol (1.53 g) and the stirring mixture refluxed for 6 hours. After cooling, the solvent was stripped, the residue treated with water and made basic by addition of 1M aq. potassium carbonate. The mixture was shaken with dichloromethane, filtered to remove unwanted solid, and the filtrate separated. The aqueous layer was further extracted with dichloromethane and the combined extracts washed with dilute brine, dried by passing through a phase separation cartridge and stripped to give the title compound as a pale oil (1.4 g).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:28])[CH2:9][CH:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.Cl>[C:30]1([CH2:29][N:13]2[C:12]3[CH2:11][CH:10]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[CH2:9][C:8](=[O:28])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(c1ccc(C(F)(F)F)cc1)C3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2)CC(c2ccc(C(F)(F)F)cc2)CC1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 96 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-2-(4-trifluoromethylphenyl)-9H-carbazol-4(3H)-one (1.57 g, 4.05 mM), benzyl bromide (0.49 ml, 4.13 mM), and potassium carbonate (1.12 g, 8.10 mM) in 20 mL DMF was stirred at room temperature for 22 hours. The mixture was diluted with EtOAc and 1N HCl. The layers were separated and the aqueous extracted with EtOAc. The combined EtOAc layers were extracted with 1N HCl, water, then brine. After drying (NaSO4), evaporation in vacuo afforded 1.87 g (96%) of the 9-[(phenyl)methyl]-5-carbomethoxy-2-(4-trifluoromethylphenyl)-1,2-dihydrocarbazol-4(3H)-one. 1H NMR (CDCl3) δ7.6 (d, J=8 Hz, 2H), 7.45-7.25 (m, 8H), 6.95 (m, 2H), 5.35 (s, 2H), 4.05 (s, 3H), 3.65 (m, 1H), 3.2 (dd, J=16 and 5 Hz, 1H), 3.0 (dd, J=16 and 10 Hz, 1H), 2.8 (m, 2H). MS (ES) m/e 478.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)#[N:2]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1
Reactant: N#Cc1ccccc1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1ccccc1-c1ccc(N)cc1
Reaction time: 2.5 h

Procedure:
6.0 g (26.8 mmol) of 2'-cyano-4-nitrobiphenyl (prepared according to B. Sain, J. S. Sandhu, J. Org. Chem. 1990, 55, 2545) were dissolved in a mixture of 60 ml ethanol and 60 ml ethyl acetate, and the solution was filled into an autoclave. After addition of 660 mg 10% Pd on charcoal the mixture was set under an atmosphere of hydrogen (2-3 bar). The reduction was carried out at room temperature, the course of the reaction monitored by thin layer chromatography, and it had completed after 2.5 h. The catalyst was filtered and the solvent distilled off in vacuo. The title amine was obtained by crystallization from hexane as a white powder,
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][O:3][CH2:2]1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C(C)=CC=CC=1>[CH2:9]([N:16]1[C:5](=[O:6])[CH2:4][O:3][CH:2]([C:1]([OH:7])=[O:8])[CH:9]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1COCC(=O)O1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(O)C1OCC(=O)N(Cc2ccccc2)C1c1ccccc1
Temperature: 0 °C
Yield: 43 %

Procedure:
9.86 g (0.085 mole) of diglycolic anhydride and 16.5 g of Schiff base (0.085 mole), prepared from benzyldehyde and benzylamine, are refluxed at 140° C. in 220 ml of xylene for 6 hr. After cooling to 0° C. the solid is collected and washed with ether: 14.5 g (54%) mp 170°-9° C. Recrystallization from methylene-chloride (little) and ether gave 11.3 g (43%) of title compound mp 177°-81° C.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:33])[NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:29][C:30](=[O:32])[CH3:31])[C:12](=[O:28])[NH:13][CH2:14][CH2:15][N:16]([C:18](OCC1C=CC=CC=1)=O)C)([CH3:3])[CH3:2].[CH3:34]O>[Pd]>[C:1]([O:4][C:5](=[O:33])[NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:29][C:30](=[O:32])[CH3:31])[C:12](=[O:28])[NH:13][CH2:14][CH2:15][NH:16][CH3:18])([CH3:2])([CH3:3])[CH3:34]
Reactant: CO
Reactant: CC(=O)N[C@@H](CCCCNC(=O)OC(C)C)C(=O)NCCN(C)C(=O)OCc1ccccc1
Agent: [Pd]
Product: CNCCNC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(C)=O
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of compound I (1.4 g, 3.00 mmol) in MeOH (40 mL) was added 5% Pd/C (300 mg). This reaction mixture was subjected to hydrogenation at 70 psi for 2 h. Next, the reaction mixture was filtered through a celite pad, MeOH was removed in a rotary evaporator to afford compound J (1.02 g, 98%). LC-MS [M+H] 344.9 (C16H32N4O4+H, calc: 345.4).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][C@@H:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][OH:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[CH2:7]([O:14][C@@H:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH:17]=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCC[C@@H](CCO)OCc1ccccc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC[C@@H](CC=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Chromium trioxide (6.0 g., 0.06 mole) is added to a mechanically-stirred solution of dry pyridine (9.49 g., 0.12 mole) in methylene chloride (150 ml.) maintained at 0°-5° C. under a nitrogen atmosphere. The resulting reaction mixture is warmed to 25° C., stirred at 25° C. for 1/3 hour, and treated with a solution of 3(S)-benzyloxy-1-octanol (2.37 g., 0.01 mole) in methylene chloride (2 ml.) which initiates precipitation of a black, intractable precipitate. After stirring at 25° C. for 1/4 hour, the solution is decanted, and the insoluble precipitate washed with ether (200 ml.). The combined decantates are washed successively with 5% sodium hydroxide (3 × 100 ml.), 5% hydrochloric acid (100 ml.), and 5% aqueous sodium bicarbonate (100 ml.); dried over magnesium sulfate; and filtered. In vacuo evaporation of the filtrate affords the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[OH:45].N12CCCN=C1CCCCC2>CS(C)=O>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][NH:23][C:4]2[N:3]=[C:2]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[OH:45])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[O:17][C@H:16]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: Nc1ccccc1O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Nc4ccccc4O)nc32)[C@H](O)[C@@H]1O
Reaction time: 8 h
Yield: 8 %

Procedure:
A mixture of 1-[2-chloro6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-1-deoxy-N-ethyl-β-D-ribofuranuronamide (0.20 g, 0.38 mmol), 2-aminophenol (0.20 g, 1.83 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.052 ml, DBU) and dimethylsulphoxide (1 ml) was stirred and heated at 140° C. under nitrogen for 6h, and then left at 21° C. overnight. The mixture was partitioned between ethyl acetate (200 ml) and water (40 ml). The aqueous layer was extracted with more ethyl acetate (50 ml) and the total organic solution was washed (water, 20 ml), dried (Na2SO4) and evaporated. The residue was purified on flash silica eluting with dichloromethane:methanol (19:1), and then by preparative TLC (20×20 cm plate with 2 mm layer of Kieselgel 60 F254 ; Art 5717) in dichloromethane:ethyl acetate:ethanol 9:9:2, and then by preparative HPLC (30 to 70% acetonitrile) to give the title compound (0.018 g) as a cream foam, MH+ =596. Analysis found: C,52.2, H,4.3, N,11.8; C32H33N7O5.2CF3CO2H requires C,52.5, H,4.3, N,11.9%.