Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:17]4[C:8](=[CH:9][CH:10]=[CH:11][C:12]=4[C:13]=2[CH2:14][CH2:15][CH:16]=1)[CH2:7][CH2:6]3>O1CCOCC1.C(OCC)(=O)C.O>[CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:3]=1[CH:4]=[C:5]1[C:17]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]2=3)[CH:7]=[CH:6]1
Reactant: CC1=CCCc2c1cc1c3c(cccc23)CC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cccc2c1cc1c3c(cccc32)C=C1
Yield: 54.9 %

Procedure:
A solution of 7-methyl-9,10-dihydroacephenanthrene (0.13 g, 0.59 mmol) and dichlorodicyanoquinone (0.27 g, 1.18 mmol) in dioxane (10 ml) was heated at reflux for 0.5 h. The reaction mixture was allowed to cool and was diluted with ethyl acetate (50 mL) and water (20 mL). The organic layer was separated, washed with water (3×20 mL) and brine solution (3×20 mL), dried (MgSO4), and concentrated under reduced pressure. The resulting solid was purified by flash chromatography to give 0.07 g (57%) of the product: 1H NMR (CDCl3, 300 MHz) δ 8.54 (d, 1H, J=8.0 Hz), 8.40 (dd, 1H, J=7.3, 6.9 Hz), 8.24 (s, 1H), 7.66 (m, 2H), 7.58 (dd, 1H, J=8.4, 7.3 Hz), 7.46 (d, 1H, J=7.3 Hz), 7.20 (d, 1H, J= 5.1 Hz), 7.16 (d, 1H, J=5.4 Hz), 2.82 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:15]
Reactant: NCCNCc1cnccn1
Reactant: CN=C=O
Product: CNC(=O)NCCNCc1cnccn1

Procedure:
Reacting N-(2-pyrazinylmethyl)ethylenediamine with methyl isocyanate by the procedure of Example 24, then concentrating and separating the residue by column chromatography gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:13]=[N+:14]=[N-].[Na+]>Cl.O>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(N=[N+]=[N-])cc1
Reaction time: 0.33 h

Procedure:
p-Toluidine (9.3 mM) was dissolved in hydrochloric acid (5M; 10 ml), and the mixture cooled to <0° C. Sodium nitrite (10.28 mM) was dissolved in a minimum amount of water, and this solution was added dropwise to the reaction over 30 minutes. The solution was stirred for 20 minutes, then the presence of the oxidising agent was tested for using starch/iodide paper. Sodium azide (37.38 mM) was then added slowly to the reaction mixture over a period of 1 hour (due to vigorous effervescing). The reaction was quenched, once all the sodium azide had been added, in water (50 ml), and quantitatively transferred to a conical flask with water (50 ml). The mixture was neutralised with sodium carbonate, until pH=6. The organics were extracted into dichloromethane (3×30 ml), washed with water (2×20 ml), dried over magnesium sulphate, and excess solvent removed under vacuum. The p-azidotoluene thus obtained was an oil and was isolated via chromatography (100% petroleum/ether 40-60).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([N:22]=[C:23]=[O:24])[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].N1C=CC=CC=1>ClCCl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:22][C:23]([N:6]2[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]2=[O:8])=[O:24])[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19]
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(NC(=O)n2cc(F)c(=O)[nH]c2=O)cc(OC)c1OC
Temperature: 90 °C
Yield: 47.2 %

Procedure:
A mixture of 3.9 g of 5-fluorouracil, 6.27 g of 3, 4, 5-trimethoxyphenylisocyanate and 15 ml of pyridine was heated at 90° C. for 2 hr and, after evaporating pyridine, 100 ml of dichloromethane and 200 ml of hydrochloric acid water were added to it. The insoluble substance produced was combined with the substance dissolved in the dichloromethane. The combined substances were washed with water and then with ethanol, and 4.8 g of 1-(3, 4, 5-trimethoxyphenylcarbamoy)-5-fluorouracil (melting point: 168°-170° C.) was obtained (Compound No. 6). NMR: 3.76 (3H s OCH3) 3.84 (6H s OCH3) 6.64-7.0 (2H b C6H2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([N:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[NH:30][C:29]2=[O:37])[CH2:24][CH2:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH2:13][CH2:12][CH:11]([N:22]3[CH2:23][CH2:24][CH:25]([N:28]4[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[NH:30][C:29]4=[O:37])[CH2:26][CH2:27]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)CC1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=c1[nH]c2ccccc2n1C1CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1

Procedure:
A mixture of 10 g of 4,4-bis(p-fluorophenyl)cyclohexanone, 6.6 g of 1-(4-piperidyl)-2-benzimidazolinone, 0.2 g of p-toluenesulfonic acid and 80 ml of xylene is stirred under reflux for 34 hours, the water formed being removed. The xylene is then removed under reduced pressure, and to the residue is added 200 ml of methanol and 10 ml of water. To the resulting mixture is added dropwise 15 g of sodium borohydride at about 20° C with cooling. After the addition is complete, the mixture is stirred under reflux for 3 hours. The reaction mixture is concentrated completely under reduced pressure, water is added to the residue, and the aqueous mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The residual viscous oil is purified by column chromatography using methylene chloride and then a mixture of methylene chloride and methanol (9:1) as an eluent. Thus is obtained 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]- 2-benzimidazolinone as colorless crystals, melting at 235°-238° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][C:60]1[S:61][C:62]([CH2:66]O)=[C:63]([CH3:65])[N:64]=1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:66][C:62]2[S:61][C:60]([CH3:59])=[N:64][C:63]=2[CH3:65])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1nc(C)c(CO)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2sc(C)nc2C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (2,4-dimethyl-1,3-thiazol-5-yl)methanol (0.6 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.33 g, 99%).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.[CH3:33][N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN>CN(C=O)C.C1COCC1>[CH3:33][NH:34][C:6]([CH:4]1[CH2:5][C:2]([OH:1])([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:22])([F:23])[F:21])[O:17][N:16]=3)=[CH:13][CH:14]=2)[CH2:3]1)=[O:8]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 29.2 %

Procedure:
To a stirred solution of 3-hydroxy-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 4, 0.060 g, 0.118 mmol) in dry DMF (1 mL) was added HATU (0.067 g, 0.177 mmol), HOBt (0.0175 g, 0.129 mmol), DIPEA (0.03 g, 0.236 mmol) and saturated solution of methyl amine in THF (2 mL) at 0° C. Resulting reaction mixture was stirred 0° C. for 2 hours and at room temperature for 18 hours. After complete consumption of starting material, reaction mixture was quenched with water (5 mL), extracted with EtOAc (10 mL). Organic layer was washed with saturated solution of lithium chloride (2×20 mL), water (2×20 mL), dried over sodium sulphate and evaporated in vacuo to get brown crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 1.2% methanol in DCM to afford sticky mass, which was crystallized by chloroform:pentane (1:9) to afford white solid (0.018 g, 29%). 1H-NMR (400 MHz, CDCl3) δ: 2.49-2.52 (m, 2H), 2.81-2.83 (m, 2H), 2.84-2.86 (m, 1H), 2.88 (d, 3H, J=4.88 Hz), 3.67 (d, 1H, J=17.08 Hz), 4.07 (d, 1H, J=17.16 Hz), 5.67 (bs, 1H), 5.81 (s, 1H), 7.55 (d, 2H, J=8.4 Hz), 7.62-7.64 (m, 4H). LC-MS (m/z): [M−H] 518.80. HPLC purity: 98.48%.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:21])[CH3:20])=[CH:10][CH:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl>CO.[B-](F)(F)(F)F.COC1C([P@](CC[P@](C2C=CC=CC=2)C2C(OC)=CC=CC=2)C2C=CC=CC=2)=CC=CC=1.C1CC=CCCC=C1.[Rh]>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:21])[CH3:20])[CH2:10][CH:9]1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N(C1=CC(C)N(Cc2ccccc2)c2ccccc21)c1ccccc1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: COc1ccccc1[P@](CC[P@](c1ccccc1)c1ccccc1OC)c1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: C1=CCCC=CCC1
Product: CC(=O)N(c1ccccc1)C1CC(C)N(Cc2ccccc2)c2ccccc21
Yield: 79.6 %

Procedure:
A solution of N-(1-benzyl-2-methyl-1,2-dihydroquinolin-4-yl)-N-phenylacetamide (100 mg) and (R,R)-(−)-1,2-bis[(o-methoxyphenyl)(phenyl)phosphino]ethane(1,5-cyclooctadiene)rhodium (I) tetrafluoroborate (20 mg) in methanol (6 ml) was stirred under 20 bars of hydrogene overnight. Dichloromethane was added and the organic layer was washed by water and dried over sodium sulfate. The solvent was removed and the mixture was purified by chromatography on silica gel (dichloromethane/ethanol (99:1)) to afford N-(1-benzyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenylacetamide (80 mg).
Reaction SMILES: [C:1]1([C:10](OCC)=[O:11])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3][CH2:2]1>C1COCC1>[OH:11][CH2:10][C:1]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCC1
Solvent: C1CCOC1
Product: CCOC(=O)C1(CO)CCC1

Procedure:
Diethyl cyclobutane-1,1-dicarboxylate (7.17 mL) was added to a THF (150 mL) suspension of LiAH(OtBu)3 (22.08 g) at room temperature, and the suspension was refluxed for 7 h. The THF was stripped off and the mixture was quenched with water, neutralized with HCl (3 M) and extracted with dichloromethane and ethylacetate. The combined organic phases were washed with brine, dried and evaporated. The crude residue was put on a column and eluted with DCM : EtOAc; 5:1 to give ethyl 1-(hydroxymethyl)-cyclobutanecarboxylate (4.08 g) as a clear oil. 1H-NMR (300 MHz, CDCl3), δ=4.3372-4.1188 (q, 2H); 3.9337-3.7479 (d, 2H); 2.5485-2.322 (m, 3H); 2.1117-1.9015 (m, 4H); 1.3963-1.2174 (t, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C[C@@H](OC)[C@H](F)[C@H]1C(O)=O)=O)(C)(C)C.[CH3:37][C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH2:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16](=[O:18])[NH:41][CH2:40][CH2:39][C:38]([CH3:43])([CH3:42])[CH3:37])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CO[C@H]1[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C[C@@H]1F
Reactant: CC(C)(C)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CO[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)[C@H]1F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CO[C@H]1[C@@H](C(=O)NCCC(C)(C)C)N(C(=O)OC(C)(C)C)C[C@@H]1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (300 mg, 1.14 mmol), 3,3-dimethylbutylamine (115 mg, 1.14 mmol) and HBTU (648 mg, 1.71 mmol) in CH2Cl2 (7 mL) was added DIPEA (0.60 mL, 3.42 mmol). The reaction mixture was stirred at RT under nitrogen atmosphere overnight and concentrated. The crude residue was taken-up in EtOAc, washed with 0.1 N HCl (×2), dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 6:4 in 40 min) to give (2S,3S,4S)-2-(3,3-dimethyl-butylcarbamoyl)-4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: Rf, TLC (EtOAc)=0.5; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.92 (m, 1H), 5.16 (dq, 1H), 4.29-4.37 (m, 1H), 4.15 (m, 1H), 3.72 (m, 1H), 3.39 (m, 1H), 3.35 (s, 3H), 3.08 (m, 2H), 1.32-1.40 (m, 11H), 0.90 (s, 9H) and (2R,3R,4R)-2-(3,3-dimethyl-butylcarbamoyl)-3-fluoro-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: Rf, TLC (EtOAc)=0.6; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.90 (m, 1H), 5.05 (m, 1H), 4.20 (t, 1H), 4.02 (m, 1H), 3.70 (m, 1H), 3.39 (m, 1H), 3.33 (overlap with DMSO, m, 1H); 3.27 (s, 3H), 3.06 (m, 2H), 1.36-1.43 (m, 11H), 0.89 (s, 9H)
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[O:22][C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:20][N:19]=4)=[CH:14][CH:13]=3)=[N:9][CH:8]=2)=[CH:3][CH:2]=1.[S:29](=[O:33])(=[O:32])([OH:31])O>>[C:12]1([C:10]2[O:11][C:7]([C:4]3[CH:3]=[CH:2][C:1]([S:29]([OH:33])(=[O:32])=[O:31])=[CH:6][CH:5]=3)=[CH:8][N:9]=2)[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([OH:31])(=[O:33])=[O:32])=[CH:25][CH:24]=3)=[CH:20][N:19]=2)=[CH:14][CH:13]=1
Reactant: c1ccc(-c2cnc(-c3ccc(-c4ncc(-c5ccccc5)o4)cc3)o2)cc1
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1ccc(-c2cnc(-c3ccc(-c4ncc(-c5ccc(S(=O)(=O)O)cc5)o4)cc3)o2)cc1
Reaction time: 8 h

Procedure:
One hundred milliliters of 20% fuming sulfuric acid (oleum) is charged into a 500 mL flask. Stirring is begun, and 50.0 g of POPOP is added in small portions. The reaction is exothermic. After the addition is complete, the reaction mixture is heated at about 90°-100°C. with stirring for two hours. The reaction is then quenched by pouring the reaction mixture onto 500 g of crushed ice with stirring. A bright-yellow product precipitates as a very fine powder. The resulting suspension is allowed to stand overnight. The product is then collected on a medium-porosity fritted-glass Buchner funnel. It should not be washed at this point, nor should the filter cake be disturbed. As much liquid is removed from the filter cake as possible. The pasty filter cake is then washed by stirring it in 200 mL of 2/1 (v/v) water/methanol or 1/20/10 concentrated hydrochloric acid/water/methanol. Water alone should not be used, as a very thick paste will form. Stirring is continued until the product is finely dispersed. The suspension is then allowed to settle briefly, and the solid is collected by vacuum filtration. The washing process should be repeated once. The product is then dried in a vacuum oven at 60°-70° C. Typical yields are 67-73 g (90-94%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:7][CH:6]=1)C.[NH3:17]>CO>[CH2:12]([C:8]1[C:9]([CH3:11])=[CH:10][C:5]([C:4]([NH2:17])=[O:3])=[CH:6][N:7]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: N
Reactant: CCOC(=O)c1cnc(CC(C)C)c(C)c1
Solvent: CO
Product: Cc1cc(C(N)=O)cnc1CC(C)C

Procedure:
A solution of 6-isobutyl-5-methyl-nicotinic acid ethyl ester (2.86 g, 12.9 mmol) in 7 N NH3 in MeOH (80 mL) is stirred at 60° C. for 20 h before the solvent is removed in vacuo. The residue is dried to give 6-isobutyl-5-methyl-nicotinamide (1.89 g) as a yellow oil; LC-MS: tR=0.66 min, [M+1]+=193.29; 1H NMR (D6-DMSO): δ 0.91 (d, J=6.5 Hz, 6H), 2.08-2.20 (m, 1H), 2.32 (s, 3H), 2.65 (d, J=7.3 Hz, 2H), 7.43 (s, 1H), 7.95 (s, 1H), 8.01 (m, 1H), 8.78 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH3:15])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:18]I>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:14][CH3:15])[C:10](=[O:13])[N:11]([CH3:18])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(-c2ccc(Cl)cc2)nn(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, room temperature solution of 5-(4-chlorophenyl) -2,4-dihydro-4-ethyl-3H-1,2,4-triazol-3-one (6.00 g, 2.68×10-2 mole) and 1 molar aqueous NaOH (30.0 ml, 3.00×10-2 mole) was added a solution of methyl iodide (2.5 ml, 4.0×10-2 mole) and ethanol (10 ml). After stirring overnight at room temperature, the reaction mixture was transferred to a separatory funnel where it was extracted three times with EtOAc. The EtOAc extracts were combined, washed with saturated aqueous NaCl, and dried over Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving an oil which slowly solidified. Chromatography and crystallization from cyclohexane gave small colorless needles: 3.4 g (53%), Mp 73°-75° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4](Cl)[N:3]=1.C(N(C(C)C)C(C)C)C.[C:27]1([CH:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:34][NH2:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH:35][CH2:34][CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:3]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Yield: 104.1 %

Procedure:
A solution of 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Preparation 19) (30.9 g, 0.11 mol) in isopropyl alcohol (600 ml) was treated with N-ethyl-N-isopropyl-2-propanamine (47.5 ml, 0.27 mol) and 2,2-diphenylethylamine (24.8 g, 0.13 mol) and the resulting mixture was heated under reflux for 3 hours. The solvent was removed under reduced pressure and the residue was azeotroped with ethyl acetate. The residue was purified by column chromatography on silica gel eluting with a gradient system of ethyl acetate: hexane (40:60, by volume) gradually changing to ethyl acetate:hexane (60:40, by volume) to afford the title compound as a foam (49.7 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.C(N(C(C)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.[C:48]([O:52][C:53]([NH:55][C@@H:56]1[CH2:61][C@H:60]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:59][N:58]([C:70]2[CH:75]=[C:74]([NH:76][C:77]3[CH:82]=[CH:81][C:80]([NH2:83])=[CH:79][CH:78]=3)[CH:73]=[C:72]([N:84]3[CH2:89][C@@H:88]([NH:90][C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:87][C@@H:86]([NH:98][C:99]([O:101][C:102]([CH3:105])([CH3:104])[CH3:103])=[O:100])[CH2:85]3)[N:71]=2)[CH2:57]1)=[O:54])([CH3:51])([CH3:50])[CH3:49]>CN(C=O)C.CCOC(C)=O>[C:48]([O:52][C:53]([NH:55][C@@H:56]1[CH2:61][C@H:60]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:59][N:58]([C:70]2[CH:75]=[C:74]([NH:76][C:77]3[CH:82]=[CH:81][C:80]([NH:83][C:12]([C:3]4[CH:4]=[CH:5][C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]=4[OH:1])=[O:14])=[CH:79][CH:78]=3)[CH:73]=[C:72]([N:84]3[CH2:89][C@@H:88]([NH:90][C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:87][C@@H:86]([NH:98][C:99]([O:101][C:102]([CH3:105])([CH3:104])[CH3:103])=[O:100])[CH2:85]3)[N:71]=2)[CH2:57]1)=[O:54])([CH3:49])([CH3:50])[CH3:51]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2cc(Nc3ccc(N)cc3)cc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2cc(Nc3ccc(NC(=O)c4ccc5ccccc5c4O)cc3)cc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
1-Hydroxy-naphthalene-2-carboxylic acid (142) (0.028 g, 0.148 mmol) was dissolved in DMF (1 mL), iPr2EtN (0.222 mmol) was added followed by 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (HBTU) (0.062 g, 0.163 mmol) and the mixture was shaken in an 8 mL Teflon septum capped vial at room temperature for 20 minutes. N-(2,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-pyridin-4-yl)-benzene-1,4-diamine (141) (0.08 g, 0.0986 mmol) was added and the mixture was shaken at room temperature for 16 h. LC-MS indicated complete coupling at this point. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), NaHCO3 (aqueous sat., 15 mL) and brine (15 mL) via extraction, dried over MgSO4 and concentrated to give an orange/green oil. Purification by flash chromatography using a gradient of hexane and EtOAc (eluding with 15–100% EtOAc in hexane in 30 minutes) gave the desired product (143) as a greenish-white powder upon concentration (0.063 g, 0.064 mmol, 65% yield). LC-MS (ESI): (exact mass: 981.53) m/e=982.6 [M+1]+ (100%).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[B:26](OC)([O:29]C)[O:27]C>C1COCC1>[CH2:6]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([B:26]([OH:29])[OH:27])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COB(OC)OC
Reactant: CCCCCCCc1ccc(-c2ccc(Br)cc2)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCc1ccc(-c2ccc(B(O)O)cc2)nc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
9 ml of n-butyl lithium (1.68M hexane solution) was added dropwise to a solution of 5 g of 5-heptyl-2-(4-bromophenyl) pyridine prepared by the method described in Toku-Kai-Sho 60-163864 in 100 ml of THF with maintaining at -60° C. After stirring for 30 minutes with maintaining at -60° C., 3 g of trimethyl borate was added and stirred for further 1 hour. After the inner temperature was recovered gradually to the room temperature, 40 ml of 6N hydrochloric acid was added and then THF was distilled off. The formed solid was filtered and recrystallized, to obtain 3 g of 4-(5-heptylpyridin-2-yl)phenyl boronic acid. Melting point; 206-214° C.