Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)(=[O:13])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=1.[ClH:29].C(=O)([O-])[O-].[NH4+:34].[NH4+]>C(O)C>[ClH:29].[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)(=[O:12])=[O:13])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[NH:34])[NH2:28])[CH:22]=1
Reactant: [NH4+]
Reactant: Cn1c(COc2cccc(C#N)c2)nc2cc(S(=O)(=O)N3CCCC3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(COc2cccc(C(=N)N)c2)nc2cc(S(=O)(=O)N3CCCC3)ccc21

Procedure:
Prepared analogously to Example 32 from 1-methyl-2-[(3-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-pyrrolidide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: C([N:8]1[CH2:28][CH2:27][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[F:26][C:23]([F:24])([F:25])[C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:15]2[C:10]3[CH2:9][NH:8][CH2:28][CH2:27][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cc1
Reaction time: 72 h
Yield: 87.1 %

Procedure:
6-Benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (1.5 g, 3.9 mmol) was dissolved in methanol (25 mL) and palladium hydroxide was added (1.5 g, 20% wt). The mixture was shaken on a Parr Shaker under H2(g) atmosphere (60 PSI) for 3 days. The mixture was filtered through celite and evaporated to give 1.0 g of material as a yellow solid (87%), which was used as such for the next step.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12](O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C(=O)([O-])O.[Na+]>O1CCCC1.B.O1CCCC1>[C:1]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][OH:13])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(-c2ccccc2)on1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
To a solution of 5-phenylisoxazol-3-carboxylic acid (551 mg) in tetrahydrofuran (15 ml), 3.7 ml of borane-tetrahydrofuran complex (1.17M tetrahydrofuran solution) was added, and the reaction solution was stirred at 80° C. for 10 hours. Water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (10:90-50:50)) to afford the title compound as a white solid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([C:23](=[O:25])[NH2:24])=[CH:19][C:18]=4[CH3:26])[C:15]([CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O[Li].O>C1COCC1.O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([C:23](=[O:25])[NH2:24])=[CH:19][C:18]=4[CH3:26])[C:15]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1cc(C(N)=O)ccc1-n1c(CCC(=O)[O-])ccc1-c1ccc(-n2ccnc2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(N)=O)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.7 %

Procedure:
To a solution of compound 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (22.0 g, 48.3 mmol) in THF/H2O (v/v=1/1, 220 mL) was added LiOH.H2O (4.15 g, 96.6 mmol). The reaction solution was stirred at room temperature for 5 h. The THF was removed under reduced pressure and the aqueous solution was acidified with 10% HCl to pH=5. The solid was filtered and recrystallized from THF and water [1:1 (v/v)] to afford 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid as a yellow solid (11.35 g, 55%).
Reaction SMILES: [C:1]([C:3]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[N:21](COCC[Si](C)(C)C)[CH:22]=[C:23]([C:25]#[N:26])[N:24]=3)=[O:19])=[C:13]([C:35]3[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[CH2:37][CH:36]=3)[CH:12]=2)[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[CH2:5][CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.CCO>C(Cl)Cl>[C:1]([C:3]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=3)=[O:19])=[C:13]([C:35]3[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[CH2:37][CH:36]=3)[CH:12]=2)[CH2:4][CH2:5][S:6](=[O:9])(=[O:10])[CH2:7][CH2:8]1)#[N:2]
Reactant: CC1(C)CC=C(c2cc(C3(C#N)CCS(=O)(=O)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC=C(c2cc(C3(C#N)CCS(=O)(=O)CC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-(4-cyano-1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (193 mg, 0.318 mmol, as prepared in the previous step) in CH2Cl2 (10 mL) was treated with TFA (2 mL) and stirred at RT for 3 h. EtOH (5 mL) was added, and the mixture was concentrated to dryness. The residue was taken up in CH2Cl2 and carefully washed with satd aq NaHCO3 (1×). The aqueous layer was extracted with CH2Cl2 (1×), and the combined aqueous layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue on a 20-g Isolute SPE column (FlashMaster system) with 25-50% EtOAc-hexane afforded the title compound (50.4 mg, 33%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.39 (d, 1H, J=8.8 Hz), 8.01 (s, 1H), 7.53 (dd, 1H, J=8.8, 2.0 Hz), 7.42 (d, 1H, J=2.0 Hz), 5.85-5.80 (m, 1H), 3.59-3.46 (m, 2H), 2.81-2.69 (m, 2H), 2.62-2.52 (m, 2H), 2.39-2.32 (m, 2H), 2.17-2.10 (m, 2H), 1.68-1.58 (m, 4H), 1.13 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C25H27N5O3S, 478.2 (M+H). found 478.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=O)[CH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)[CH:7]=[CH:6]2.[CH3:25][NH2:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:26]([CH3:25])[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:14]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(=O)CCC(=O)c3ccccc3)ccc2c1
Reactant: CN
Product: COc1ccc2cc(-c3ccc(-c4ccccc4)n3C)ccc2c1
Yield: 84.7 %

Procedure:
In a similar manner as described in step 4 of Example 1, the title compound was prepared from 1-(6-methoxy-2-naphthyl)-4-phenylbutane-1,4-dione (3.00 g, 9.42 mmol), prepared in step 3 of Example 1, and methyl amine (8 M solution in EtOH, 100 mL, 800 mmol). Isolation of the solids by vacuum filtration gave 2-(6-methoxy-2-naphthyl)-1-methyl-5-phenyl-1H-pyrrole as a white solid (2.5 g, 85%), mp 197–198° C. Elemental Analysis for C22H19NO Calc'd: C, 84.31; H, 6.11; N, 4.47. Found: C, 84.47; H, 6.08; N, 4.41.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Product: OCc1cccc(Cl)c1Cl
Reaction time: 1.5 h

Procedure:
To a solution of 2,3-dichlorobenzaldehyde (Aldrich, 50 gms) in alcohol (800 mL) at room temperature was added NaBH4 (8.54 gms) and the resulting mixture stirred for 1.5 hours. The reaction was quenched with water and the solvent evaporated in vacuo before partitioning the residue between CHCl3 and saturated NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and the solvent evaporated in vacuo to leave a white solid, 48.38 gms, mp. 87°-87.5° C.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[N:15]=[C:16](OC)[NH:17][C:18]=2[CH3:19])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[NH4+:39].[NH4+].C([O-])(=O)C.[NH4+]>C(O)C.C(OCC)(=O)C>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[N:15]=[C:16]([NH2:39])[NH:17][C:18]=2[CH3:19])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC1=NC(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(C)N1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)N=C(N)N1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
111 mg (0.234 mmol) of 4-(3-chlorophenyl)-2-methoxyl-6-methyl-1,4-dihydropyrimidine-5-carboxylic acid (3,3-diphenylpropyl)amide was dissolved in 5 ml of ethanol. 67.4 mg (0.702 mmol) of ammonium carbonate and 11.8 mg (0.187 mmol) of ammonium acetate were added to the obtained solution, and they were stirred at 80° C. for 2 days. The reaction mixture was diluted with ethyl acetate. An insoluble matter thus formed was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by the basic silica gel chromatography (100% dichloromethane) to obtain the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].O.[O:11]1[CH2:15][CH2:14][CH:13]([O:16][C:17](=O)[O:18]C2C=CC([N+]([O-])=O)=CC=2)[CH2:12]1.CCN(C(C)C)C(C)C>CC#N.CO>[CH3:7][C:6]([CH3:9])([CH3:8])[CH:2]([NH:1][C:17]([O:16][CH:13]1[CH2:14][CH2:15][O:11][CH2:12]1)=[O:18])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)C(N)C(=O)O
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCOC1
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(NC(=O)OC1CCOC1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
2-Amino-3,3-dimethyl-butyric acid (551 mg, 4.2 mmol) was dissolved in CH3CN (15 mL), H2O (3 mL) and MeOH (3 mL). Carbonic acid 4-nitro-phenyl ester tetrahydro-furan-3-yl ester (1.6 g, 6.3 mmol) and DIEA (1.46 mL, 8.4 mmol) were added. This reaction mixture was allowed to stir at room temperature for 16 h. After concentrated, diluted with EtOAc, washed with brine and H2O, dried over Na2SO4, the crude product was purified on silica (12 g, 25-75% EtOAc/hexanes) to give intermediate 3,3-dimethyl-2-(tetrahydro-furan-3-yloxycarbonylamino)-butyric acid as a white solid (670 mg, 65%).
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]3[CH2:17][CH2:16][C:15]([CH2:23][CH2:24][CH2:25][N:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=5)[CH:29]=[CH:28][C:27]4=[O:38])([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]3[CH2:17][CH2:16][C:15]([CH2:23][CH2:24][CH2:25][N:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=5)[CH:29]=[CH:28][C:27]4=[O:38])([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(Cc2cc3c(cn2)OCCO3)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2ccc(=O)n(CCCC3(C(=O)O)CCN(Cc4cc5c(cn4)OCCO5)CC3)c2c1
Reaction time: 8 h
Yield: 14.5 %

Procedure:
To 1 mL of an ethanol solution containing 80 mg of ethyl 1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 0.25 mL of 20% aqueous sodium hydroxide solution was added and refluxed with heating for 7.5 hours. Further, 0.30 mL of 20% aqueous sodium hydroxide solution was added and left to stand at room temperature overnight. The solvent was removed under reduced pressure, water was added, and adjusted to pH 6.5 with 6.0 mol/L hydrochloric acid. The resulting solid was filtered to give 11 mg of 1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylic acid as a white solid. Also, the filtrate was removed under reduced pressure, and the residue thus obtained was purified by reversed-phase silica gel column chromatography [eluent; acetonitrile: water=2:8] to give 31 mg of 1-(2,3-dihydro(1,4)dioxino (2,3-c)pyridin-7-ylmethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl) propyl)piperidine-4-carboxylic acid.
Reaction SMILES: C(O[C@H:5]1[C@H:9]([O:10]C(=O)C2C=CC=CC=2)[C@H:8]([CH2:19][O:20]C(=O)C2C=CC=CC=2)[O:7][C@@H:6]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][CH:32]=[N:33][C:34]=2[NH2:38])(=O)C>C(O)(=O)C>[CH2:5]1[C@@H:6]([N:29]2[C:30]3[N:31]=[CH:32][N:33]=[C:34]([NH2:38])[C:35]=3[N:36]=[CH:37]2)[O:7][C@@H:8]([CH2:19][OH:20])[C@@H:9]1[OH:10]
Reactant: CC(=O)O[C@H]1[C@H](OC(=O)c2ccccc2)[C@H](COC(=O)c2ccccc2)O[C@@H]1n1cnc2c(N)ncnc21
Solvent: CC(=O)O
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@@H](O)[C@H](CO)O1
Yield: 85.3 %

Procedure:
Compound 2 (0.44 g, 0.56 mmol) was treated with an aqueous solution of acetic acid 80% (17 mL) at room temperature for 5 h. The mixture was concentrated to dryness, the residue was dissolved in water (20 mL) and washed with diethyl ether (2×15 mL). The aqueous layer was concentrated and co-evaporated with toluene and methanol. The desired 2′-deoxy-β-L-adenosine (β-L-dA) (0.12 g, 83%) was obtained after purification by silica gel column chromatography (0-12% MeOH in dichloromethane) and filtration through a Millex HV-4 unit (0.45μ, Millipore): mp 193-194° C. (crystallized from water) (Lit. 184-185° C. for L-enantiomer [Ref.: Robins, M. J.; Khwaja, T. A.; Robins, R. K. J Org Chem 1970, 35, 636-639] and 187-189° C. for D-enantiomer [Ref.: Ness, R. K. in Synthetic Procedures in Nucleic Acid Chemistry; Zorbach, W. W., Tipson, R. S., Eds.; J. Wiley and sons: New York, 1968; Vol 1, 183-187]; 1H NMR (DMSO-d6): δ2.2-2.3 and 2.6-2.7 (2m, 2H, H-2′ and H-2″), 3.4-3.6 (2m, 2H, H-5′ and H-5″), 3.86 (pq, 1H, H-4′), 4.3-4.4 (m, 1H, H-3′), 5.24 (t, 1H, OH-5′, JH,OH=5.8 Hz), 5.30 (d, 1H, OH-3′, JH,OH=4.0 Hz), 6.32 (dd, 1H, H-1′, J1′2′=6.2 Hz, J1′,2″=7.8 Hz), 7.3 (br s, 2H, NH2-6), 8.11 and 8.32 (2s, 2H, H-2 and H-8); ms: matrix G/T, (FAB+) m/z 252 [M+H]+, 136 [BH2]+, (FAB−) m/z 250 [M−H]−, 134 [B]−; UV (95% ethanol): λmax 258 nm (ε14300), λmin 226 nm (ε2100); [α]D20=+25 (c 1.03, H2O), (Lit. [α]D20=+23 (c 1.0, H2O) for L-enantiomer [Ref.: Robins, M. J.; Khwaja, T. A.; Robins, R. K. J Org Chem, 1970, 35, 636-639] and [α]D20=−25 (c 0.47, H2O) for D-enantiomer [Ref.: Ness, R. K. in Synthetic Procedures in Nucleic Acid Chemistry; Zorbach, W. W., Tipson, R. S., Eds.; J. Wiley and sons: New York, 1968; Vol 1, 183-187]). Anal. Calcd for C10H13N5O3+1.5 H2O (M=278.28): C, 43.16; H, 5.80; N, 25.17. Found: C, 43.63; H, 5.45; N, 25.33.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:22])=[CH:26][CH:25]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4ccc(F)cc4)cc3)c2)o1

Procedure:
N-(4-Fluorophenyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-fluorophenylamine using method 1. LCMS; retention time 3.55 min, MH+ 388.
Reaction SMILES: [C:1]([C:3]1([O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[Li]CCCC.CON(C)[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C1COCC1>[N:25]1[CH:26]=[CH:27][C:22]([C:21](=[O:28])[C:2]#[C:1][C:3]2([O:8][Si:9]([CH3:10])([CH3:12])[CH3:11])[CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:23][CH:24]=1
Reactant: CON(C)C(=O)c1ccncc1
Reactant: C#CC1(O[Si](C)(C)C)CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)OC1(C#CC(=O)c2ccncc2)CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
To a stirred solution of (1-ethynylcyclopentyloxy)trimethylsilane (2.0 g, 11.0 mmol) in dry THF (50 mL) was added n-BuLi (20.0 mL, 20.0 mmol, 1.6 M in hexane) drop wise at −78° C. under an inert atmosphere for a period of 10 min. After being stirred for 30 min at −78° C., a solution of compound N-methoxy-N-methylisonicotinamide (2.1 g, 13.2 mmol) in dry THF (10 mL) was added to the reaction mixture and stirring was continued for an additional 2 h at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×60 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 5% EtOAc in Hexane to afford 1-(pyridin-4-yl)-3-(1-(trimethylsilyloxy)cyclopentyl) prop-2-yn-1-one (1.0 g, 32%) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][C:5]=1[C:18]([F:21])([F:20])[F:19])([O-])=O>CO.[C].[Pd]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][C:5]=1[C:18]([F:21])([F:19])[F:20]
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)ccn1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(Oc2ccc(N)c(C(F)(F)F)c2)ccn1
Temperature: 25 °C
Reaction time: 10 h
Yield: 55.7 %

Procedure:
To a solution of 4-(4-nitro-3-trifluoromethylphenoxy)pyridin-2-ylamin (400 mg, 1.34 mmol) in methanol (20 ml) was added 10% palladium carbon (146 mg), followed by stirring under a hydrogen atmosphere at room temperature for 10 hrs. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate) to provide the titled compound (201 mg, 55.4%) as a brown oil.
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]2[N:15]=[C:14]([C@H:16]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)=[N:20][NH:19][C:18](=[O:32])[CH2:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(#N)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18]([OH:32])[N:19]=[N:20][C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(Nc1nccc([C@@H]2CC(=O)NN=C2c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC#N
Product: C[C@H](Nc1nccc(-c2cc(O)nnc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 8 (4.24 g, 9.66 mmol), 2,3-dichloro-5,6-dicyano-4-benzoquinone (4.38 g, 19.3 mmol), and acetonitrile (100 mL) were combined and stirred at room temperature under argon for 24 h. The solvent was removed in vacuo and 5% ammonium hydroxide was added. The solution was extracted exhaustively with methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give a solid. Trituration with hexane-ether gave Compound 9 as a solid: 3.5 g (8.0 mmol, 82%)
Reaction SMILES: Br[C:2]1[N:3]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[CH:6][N:5]=2.[SH-:19].[Na+]>C(O)C>[CH2:12]([N:3]1[C:2]([SH:19])=[N:10][C:9]2[C:4]1=[N:5][CH:6]=[N:7][C:8]=2[NH2:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [SH-]
Reactant: Nc1ncnc2c1nc(Br)n2Cc1ccccc1
Agent: [Na+]
Solvent: CCO
Product: Nc1ncnc2c1nc(S)n2Cc1ccccc1
Yield: 99 %

Procedure:
910 mg (3.0 mmol) of 8-bromo-9-benzyladenine and 1.08 g of sodium hydrosulfide were added to 50 ml of ethanol and heated for 12 hr under refluxing. After the solvent was removed by distillation, the reaction product was dissolved in distilled water and neutralized with 1 N hydrochloric acid. Deposited crystals were collected by filtration to thereby obtain the captioned compound (770 mg; yield: 99%).
Reaction SMILES: [C:1]([C:4]1[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]([OH:60])=[O:59].Cl>O.CO.CN(C)C=O>[O:18]=[C:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([NH:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]([OH:60])=[O:59])=[O:3])[C:17]=2[NH:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: O=C(O)c1cccc2c(=O)c3ccccc3[nH]c12
Reactant: NCCCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCNC(=O)c1cccc2c(=O)c3ccccc3[nH]c12
Reaction time: 2 h
Yield: 62.1 %

Procedure:
4-Carboxyacridone (2.15 g, 9 mmol), was mixed with N,N-dimethylformamide (15 ml) and N,N-diisopropylethylamine (1.6 ml, 9.2 mmol) and stirred under nitrogen to give a deep yellow solution. To this was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.5 g, 9 mmol) and stirring continued for 2 hrs. During this time a thick yellow precipitate formed. 6-Aminohexanoic acid (1.45 g, 11 mmol) was then added and stirring continued overnight. Reverse phase chromatographic analysis (C18) (methanol:water, 80:20) indicated two spots at Rf=0.75 and Rf=0.55. The reaction mixture was then poured into 0.25M aqueous HCl (200 ml) and the precipitated product collected by vacuum filtration, washing with more dilute HCl and water. The still-damp solid was recrystallized from ethanol/water and dried under vacuum over phosphorus pentoxide to give 6-(9-oxo-9H-acridin-4-carboxamido)hexanoic acid (1.97 g, 62%). λmax (EtOH)=408, 390, 256 nm. δH (300 MHz, DMSO-d6) 1.35-1.65 (6H, m), 2.24 (2H, t), 3.40 (2H, t), 7.26-7.39 (2H, m), 7.74-7.77 (2H, m), 8.21-8.28 (2H, m), 8.44 (2H, app.d), 9.00 (1H, broad t, amide), 12.02 (broad s, D20 exch.) and 12.49 (broad s, D20 exch.). Mass spectrum: MALDI-TOF, m/z=353.15, M=353.15 for C20H21N2O4. Melting Point=218° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.[CH2:39](Br)[CH:40]=[CH2:41].C(O)C>CN(C=O)C>[CH2:41]([N:34]1[CH2:35][CH2:36][C:31]2([C:28]3[C:27](=[CH:26][C:25]4[CH2:24][CH2:23][N:22]([C:20]([C:17]5[CH:18]=[CH:19][C:14]([C:3]6[CH:4]=[CH:5][C:6]([N:8]7[CH2:12][CH2:11][CH2:10][C:9]7=[O:13])=[CH:7][C:2]=6[CH3:1])=[CH:15][CH:16]=5)=[O:21])[C:30]=4[CH:29]=3)[O:38][CH2:37]2)[CH2:32][CH2:33]1)[CH:40]=[CH2:39]
Reactant: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCNCC2)CO4)cc1
Reactant: C=CCBr
Solvent: CN(C)C=O
Solvent: CCO
Product: C=CCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(N4CCCC4=O)cc2C)cc1)CC3
Yield: 11 %

Procedure:
This was prepared from 5-[2'-methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E18) and allyl bromide using a similar procedure to Example 19, except that DMF was used as solvent in place of ethanol. This gave the title compound as a white foam (11%) which was converted to its hydrochloride salt, crystallising from acetone as a white solid.