Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]([CH3:29])[CH2:6][C:7]1[CH:8]=[C:9]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:10]=[C:11]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=1)=[O:4].[OH-].[Na+]>O1CCOCC1>[C:3]([CH:5]([CH3:29])[CH2:6][C:7]1[CH:8]=[C:9]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:10]=[C:11]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=1)([OH:4])=[O:2]
Reactant: COC(=O)C(C)Cc1cc(CCC(=O)OC(C)(C)C)cc(Cc2cccnc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(Cc1cc(CCC(=O)OC(C)(C)C)cc(Cc2cccnc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
A mixture of t-butyl 3-[3-(2-methoxycarbonyl-1-propyl)-5-(3-pyridylmethyl)phenyl]propanoate (Preparation 28; 2.84 g), 2N aqueous sodium hydroxide solution (4.3 ml) and 1,4-dioxane (13 ml) was stirred at room temperature for 2 hours, heated at 100° C. for 1.5 hours and then allowed to stand at room temperature for a further 18 hours. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate and water. The aqueous phase was separated, acidified with glacial acetic acid and extracted twice with dichloromethane, then the combined organic solutions dried (MgSO4) and evaporated under vacuum. The residue was chromatographed on silica gel using a dichloromethane in methanol elution gradient (0 to 7% methanol), and the product fractions combined and evaporated under vacuum to give the title compound as a gum (1.88 g); Rf 0.60 (SS 7). Found: C,71.72; H,7.60; N,3.75. C23H29NO4 requires C,72.03; H,7.62; N,3.65%.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[C:23]([CH3:38])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[CH3:38][C:23]1[C:22]([CH2:21][O:19][C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)=[C:4]([CH3:3])[CH:5]=2)=[CH:27][CH:26]=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=2)[N:24]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
36 mg (0.90 mmol) of 95% sodium hydride were added to at 0° C. to a solution of 173 mg (0.75 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 4.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 214 mg (0.75 mmol) 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (WO 2005/049573) were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 8 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, and ether. The residue was purified by chromatography on silica (eluent: ethyl acetate) to yield 227 mg (63%) of the title compound as white crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH2:6].C(Cl)(Cl)Cl.Cl[C:18]([O:20][C:21]1([CH3:25])[CH2:24][CH2:23][CH2:22]1)=[O:19]>C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:12])[C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH:6][C:18]([O:20][C:21]1([CH3:25])[CH2:24][CH2:23][CH2:22]1)=[O:19]
Reactant: CC1(OC(=O)Cl)CCC1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](NC(=O)OC1(C)CCC1)C(=O)OC
Reaction time: 8 h

Procedure:
A suspension of 0.05 moles of aspartic acid dimethyl ester hydrochloride in 50 ml. of chloroform is cooled to 0°C. and the pH adjusted to 8 by addition of triethylamine. 1-Methylcyclobutyl chloroformate 0.10 moles prepared according to the procedure of Example 1 is added portion-wise at 0°C. and the pH of the reaction is maintained at 8 by addition of triethylamine. Upon completion of the addition, the reaction is stirred overnight at 20°-25°C. The reaction solution is washed successively with 10 ml. portions of a saturated sodium bicarbonate solution, 50% saturated solution of sodium chloride, 0.2 N sulfuric acid saturated with sodium sulfate, 50% saturated solution of sodium chloride (twice), and the chloroform solution is dried over sodium acetate. Removal of the chloroform affords N-(1-methylcyclobutyloxycarbonyl)-aspartic acid dimethyl ester. Saponification is accomplished by dissolving the ester in 50 ml. of methanol, water 50 ml. is added, and the pH is adjusted to 12 by addition of 2 N sodium hydroxide. After stirring overnight at 25°C., the pH is adjusted to 7 with 2N sulfuric acid. The methanol is removed in vacuo and saturated sodium bicarbonate solution is added to the water solution. The aqueous bicarbonate solution is washed two times with ether and then the pH is adjusted to 3 by addition of concentrated hydrochloric acid. The acidified solution is extracted three times with ethyl acetate and the organic extracts combined, washed twice with sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo to afford N-(1-methylcyclobutyloxycarbonyl) aspartic acid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1>C1COCC1>[CH3:13][C@:12]12[CH2:14][CH2:15][C@H:16]3[C@@H:7]([CH2:6][CH:5]=[C:4]4[C@:17]3([CH3:20])[CH2:18][CH2:19][C:2](=[O:1])[CH2:3]4)[C@@H:8]1[CH2:9][CH2:10][C:11]2=[O:21]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: C1CCOC1
Product: C[C@]12CCC(=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.2 %

Procedure:
A mixture of 3β-hydroxyandrost-5-en-17-one (13.0 g) and IBX (25.3 g) in THF (260 mL) was heated at reflux under stirring for 4 h. After cooling to room temperature, the mixture was filtered and the solid washed with EtOAc (3×50 mL). The filtrate was evaporated to dryness. The residue was taken up with CH2Cl2 and the suspension filtered. The filtrate was evaporated to dryness and the residue triturated with Et2O/MeOH 9/1 (65 mL). After filtration and drying under vacuum, 5-androstene-3,17-dione (8.68 g, 67%) was obtained. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 5.40 (m, 1H), 3.41 (m, 1H), 2.76-1.06 (m, 18H), 1.29 (s, 3H), 0.91 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[S:10][C:9]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=2[C:7]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[Na+]>CO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:8]2[C:7]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:22])=[O:2])[S:10][C:9]=2[CH:11]=1
Reactant: CCCCCc1c(/C=C/C(=O)OC)sc2cc(OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCc1c(/C=C/C(=O)O)sc2cc(OC)ccc12
Yield: 99.7 %

Procedure:
As in Example 112, (E)-3-(6-methoxy-3-pentylbenzo[b]thien-2-yl)-2-propenoic acid methyl ester (7.45 g) in methanol (40 mL) was treated with 2N sodium hydroxide solution (25 mL) at reflux for 15 minutes and the normal isolation procedure afforded 7.1 g of (E)-3-(6-methoxy-3-pentylbenzo[b]thien-2-yl)-2-propenoic acid. Crystallization of a sample from 2-propanol provided the analytical specimen, mp 209°-210° C. Anal. Calcd for C17H20O3S: C, 67.08; H, 6.62; S, 10.53 Found: C, 66.51; H, 6.49; S, 10.31
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:16]([N:17](C(C)=O)[C:18]([CH3:20])=[O:19])=[C:15]([C:24]#[N:25])[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O>C(O)C>[Cl:1][C:2]1[C:3]([N:12]2[C:16]([NH:17][C:18]([CH3:20])=[O:19])=[C:15]([C:24]#[N:25])[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: CC(=O)N(C(C)=O)c1c(C#N)cnn1-c1ncc(C(F)(F)F)cc1Cl
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1c(C#N)cnn1-c1ncc(C(F)(F)F)cc1Cl
Yield: 77.6 %

Procedure:
A stirred mixture of 0.32 gram (8.6×10-4 mole) of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-4-cyano-5-bis- (methylcarbonyl)aminopyrazole, 10 mL of water, and 10 mL of ethanol was heated at reflux for four hours. The mixture was cooled, and most of the ethanol was removed by distillation under reduced pressure. The aqueous pot residue, which contained a solid, was diluted with water, and the mixture was filtered. The filter cake was dried to yield 0.22 gram of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-4-cyano-5-methylcarbonylaminopyrazole. The rmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1.[Na+].[I-:16]>>[I:16][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: [I-]
Reactant: CCOC(=O)C1(CCCCCl)CCC1
Agent: [Na+]
Product: CCOC(=O)C1(CCCCI)CCC1
Yield: 99.4 %

Procedure:
Compound 105b was prepared, likewise the procedure described for 5a, starting from ethyl 1-(4-chlorobutyl)-1-cyclobutanecarboxylate (104b, 21.21 g, 97.0 mmol) and NaI (19.07 g, 127 mmol) to give 105b (29.91 g, 99%) as a slightly yellow oil. 1H NMR: δ 4.14 (q, J=7.1 Hz, 2H), 3.17 (t, J=6.9 Hz, 2H), 2.49-2.32 (m, 2H), 1.98-1.69 (m, 8H), 1.37-1.19 (m, 2H), 1.27 (t, J=7.1 Hz, 3H). 13C NMR: δ 176.5, 60.3, 47.5, 36.9, 33.7, 30.1 (2×), 26.0, 15.7, 14.5, 6.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[S:10](=[O:12])(=[O:11])[N:9]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:8][C:7]1=[O:23].O=S(Cl)[Cl:32]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[S:10](=[O:12])(=[O:11])[N:9]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([Cl:32])=[O:19])=[CH:16][CH:15]=2)[CH2:8][C:7]1=[O:23]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)O)cc3)S2(=O)=O)c(OC)c1
Solvent: Cc1ccccc1
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)Cl)cc3)S2(=O)=O)c(OC)c1

Procedure:
1.66 g (3.47 mmols) of the title A compound, 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid and 2.5 mL (34 mmol) of SOCl2 in 40 mL toluene are heated at 110° C. until only a small amount of dark solid remained undissolved. The solution is filtered and the solvent is removed on a rotary evaporator and the residual dark purple solid is dried in a vacuum oven overnight to give 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoyl chloride which is used as such without further purification.
Reaction SMILES: CN(C)NC(C1SC2C(=NC=CC=2O[C:16]2[CH:21]=[CH:20][C:19]([N:22]([C:29]3C=CC=CC=3OC)[C:23](=[O:28])[CH2:24][C:25](N)=[O:26])=[CH:18][C:17]=2F)C=1)=O.[NH2:39][C:40]1[CH:62]=[CH:61][C:43]([O:44][C:45]2[CH:50]=[CH:49][N:48]=[C:47]3[CH:51]=[C:52]([C:54]([N:56]([CH3:60])[N:57]([CH3:59])[CH3:58])=[O:55])[S:53][C:46]=23)=[C:42]([F:63])[CH:41]=1>>[F:63][C:42]1[CH:41]=[C:40]([NH:39][C:25](=[O:26])[CH2:24][C:23]([N:22]([CH3:29])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:21][CH:20]=2)=[O:28])[CH:62]=[CH:61][C:43]=1[O:44][C:45]1[CH:50]=[CH:49][N:48]=[C:47]2[CH:51]=[C:52]([C:54]([N:56]([CH3:60])[N:57]([CH3:58])[CH3:59])=[O:55])[S:53][C:46]=12
Reactant: COc1ccccc1N(C(=O)CC(N)=O)c1ccc(Oc2ccnc3cc(C(=O)NN(C)C)sc23)c(F)c1
Reactant: CN(C)N(C)C(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Product: CN(C(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N(C)N(C)C)sc23)c(F)c1)c1ccccc1
Yield: 43 %

Procedure:
Following the procedure described above for compound 236 (step 4, example 95, scheme 63) but replacing amine 239 with 7-(4-amino-2-fluorophenoxy)-N,N′,N′-trimethylthieno[3,2-b]pyridine-2-carbohydrazide (244), title compound 241 was obtained in 43% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.45 (s, 1H), 8.45 (d, J=5.4 Hz, 1H), 7.79 (d, J=13.3 Hz, 1H), 7.67 (s, 1H), 7.62-7.31 (m, 7H), 6.62 (d, J=5.4 Hz, 1H), 3.40 (s, 9H), 3.23 (s, 2H), 3.21 (s, 3H). MS (m/z): (M+1) 536.2 (100%).
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=2)[CH3:12])(=O)=O)=CC=1.[CH3:25][NH2:26]>C(O)C>[CH3:25][NH:26][CH:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[CH3:12]
Reactant: COc1cncc(/C=C/CC(C)OS(=O)(=O)c2ccc(C)cc2)c1
Reactant: CN
Solvent: CCO
Product: CNC(C)C/C=C/c1cncc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.8 %

Procedure:
A mixture of (4E)-5-(5-methoxy-3-pyridyl)-4-penten-2-ol p-toluenesulfonate (5.00 g, 14.41 mmol), methylamine (150 mL, 40% solution in water), and ethyl alcohol (10 mL) was stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-methanol (7:3, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing an oil. Further purification by vacuum distillation furnished 1.25 g (41.8%) of a colorless oil, bp 90–100° C. at 0.5 mm Hg.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][C:8]=1[CH3:16])(=O)=O.[CH3:19][C:20]([CH3:37])([CH3:36])[CH2:21][N:22]1[C:30]2[C:25](=[N:26][C:27](B(O)O)=[CH:28][CH:29]=2)[N:24]([CH3:34])[C:23]1=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CO.Cl[Cu].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:27]2[N:26]=[C:25]3[N:24]([CH3:34])[C:23](=[O:35])[N:22]([CH2:21][C:20]([CH3:19])([CH3:37])[CH3:36])[C:30]3=[CH:29][CH:28]=2)=[C:8]([CH3:16])[CH:9]=1)(=[O:15])[CH3:14]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(B(O)O)nc21
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Agent: Cl[Cu]
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)c1ccc(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c(C)c1
Temperature: 100 °C

Procedure:
To a microwave vial, 4-acetyl-2-methylphenyl trifluoromethanesulfonate (34-1) (40 mg, 0.14 mmol), [1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]boronic acid (14-1) (56 mg, 0.22 mmol), cesium carbonate (92 mg, 0.28 mmol), CuCl (14 mg, 0.14 mmol), and Bis(diphenylphosphino)ferrocene dicholoropalladium (8 mg, 0.015 mmol) was added under nitrogen and dissolved in DMF (0.7 ml). The suspension was heated overnight at 100° C. The reaction was cooled to room temperature, diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 5-(4-acetyl-2-methylphenyl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (34-2). MS (M+H)+: observed=352.3, calculated=352.4.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]=1[C:15]([OH:17])=O.Cl.[NH2:19][CH:20]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22][C:21]1=[O:27]>N1C=CC=CC=1>[O:27]=[C:21]1[CH:20]([N:19]2[C:15](=[O:17])[C:7]3[C:8](=[CH:12][CH:13]=[CH:14][C:6]=3[NH:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]2=[O:11])[CH2:25][CH2:24][C:23](=[O:26])[NH:22]1
Reactant: COCCNc1cccc(C(=O)O)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 61.6 %

Procedure:
To a stirred solution of 3-(2-methoxy-ethylamino)-phthalic acid (8.38 mmol) in pyridine (40 ml) was added 3-amino-piperidine-2,6-dione hydrochloride (1.39 g, 8.42 mmol). The reaction mixture was heated to reflux for 5 hours. The solvent was evaporated in vacuo and the residue dissolved in methylene chloride (125 ml). The methylene chloride mixture was treated with Norit (2 g), washed with water (2×100 ml), 0.1N HCl (1×100 ml), brine (1×100 ml), and dried (MgSO4). The solvent was evaporated in vacuo and the residue (oil) crystallized from a minimal amount of ethanol to give a yellow solid that was purified by preparative HPLC to give 1.71 g (64%) of product as a yellow solid: mp 182-1184° C.; 1H NMR (DMSO-d6) d 11.12 (s, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.04 (d, J=6-9 Hz, 1H), 6.59 (bs, 1H), 5.07 (dd, J=4.7 and 12.1 Hz, 1H), 3.54-3.30 (m, 7H), 2.95-2.85 (m, 1H), 2.64-2.52 (m, 2H), 2.07-2.02 (m, 1H); 3C NMR (DMSO-d6) d 172.79, 170.06, 168.98, 167.27, 146.38, 136.21, 132.07, 117.33, 110.67, 109.24, 70.39, 58.12, 48.58, 41.50, 30.99, 22.15; Anal. Calcd. For C16H17N3O5: C, 58.00; H, 5.17; N, 12.68. Found: C, 58.06; H, 5.12; N, 12.76.
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(N)CCCCC1>CN(C)C=O>[ClH:1].[CH:3]1([NH:2][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: NC1CCCCC1
Product: Cc1cc(NC2CCCCC2)c2c(ccc3nc[nH]c32)n1

Procedure:
A solution of 22 g. (0.1 m.) of the compound of Example I, C., and 10 g. (0.1 m.) cyclohexylamine in 200 ml. of dimethylformamide was heated under reflux for 18 hours and filtered hot. The crystalline product which separated on cooling was filtered, washed with a little cold dimethylformamide then ether and air-dried to give 17 g. Recrystallization from 300 ml. of ethanol and 300 ml. of ether gave an analytical sample as white needles, m.p. 174°-178°.
Reaction SMILES: C(N(CC)CC)C.B(F)(F)F.[C:12]([C:15]1[S:16][C:17]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:18]=2[CH:19]=1)(=O)[CH3:13].[Cl-].[Na+]>ClCCl>[CH2:12]([C:15]1[S:16][C:17]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:18]=2[CH:19]=1)[CH3:13]
Reactant: CC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: FB(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc2cc([N+](=O)[O-])ccc2s1
Temperature: 0 °C
Yield: 123.2 %

Procedure:
A solution of 22.6 g (0.195 mole) of triethylamine in 50 ml of dichloromethane is cooled to 0° C. by means of an ice-sodium chloride bath. Boron trifluoride is then added to saturate the solution (about 25 g). A solution of 14.4 g (0.065 mole) of 2-acetyl 5-nitro benzothiophene in 50 ml of dichloromethane is added while the temperature is maintained at 0° C. Stirring is continued at 0° C. for 0.5 h while a very gentle stream of boron trifluoride is introduced. The complex formed is decomposed with a saturated solution of sodium chloride, the organic fraction is washed three times with a solution of sodium chloride and dried over anhydrous sodium sulfate. It is filtered and the solvent is evaporated at a rotary evaporator. In this manner, 16.6 g of 2-ethyl 5-nitro benzothiophene are obtained in the form of a yellow solid which is purified by chromatography on a column of silica (eluant: heptane/ethyl acetate 9/1).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[NH:8][C:7](=[O:12])[C:6]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[N:30](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4].Cl.C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.[OH-].[Na+]>CO.C(O)(=O)C>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[NH:8][C:7](=[O:12])[C:6]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 0.33 h

Procedure:
The title compound may be prepared by dissolving 6-butyl-2-methyl-5-[(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl]pyrimidin-4(3H)-one in methanol and adding excess concentrated HCl and stirring for 10-30 minutes. An indicator quantity of phenolphthalein is added followed by 10% NaOH solution until pink. Excess acetic acid is added and the mixture is extracted three times with ether. The combined organic material is dried over MgSO4, stripped of solvent in vacuo, and MPLC'd to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:24]([O-])=O)=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]2)[CH:7]=1>[Pd]>[NH2:24][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:10]1
Reactant: CC(C)(C)C(=O)OCCN1CCC[C@@H](Nc2cc(F)ccc2[N+](=O)[O-])C1
Agent: [Pd]
Product: CC(C)(C)C(=O)OCCN1CCC[C@@H](Nc2cc(F)ccc2N)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.4 %

Procedure:
To a solution of 2,2-dimethylpropionic acid 2-[(R)-3-(5-fluoro-2-nitrophenylamino)piperidin-1-yl]ethyl ester (2.53 g, 6.88 mmol) in EtOAC (100 mL) was added a slurry of 10% Pd/C (200 mg) in IMS (20 mL) and the reaction mixture stirred at RT under a hydrogen atmosphere for 18 h. The suspension was filtered through a pad of Celite® and the filtrate concentrated in vacuo affording the title compound as a purple oil (2.33 g, 100%). LCMS (Method J): RT 1.75 min [M+H]+ 338.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])[CH:2]([CH3:4])[OH:3]>C(Cl)Cl>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])[C:2]([CH3:4])=[O:3]
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(C(=O)C(C)O)cc2)CC1
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](c2ccc(C(=O)C(C)=O)cc2)CC1
Reaction time: 1 h

Procedure:
1,1,1-tris(Acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (5.14 g, 12.12 mmol) was added to a stirred solution of methyl trans-4-(4-lactoylphenyl)cyclohexanecarboxylate (Intermediate 65-3, 1.758 g, 6.06 mmol) in DCM (25 mL). The mixture was stirred for 1 h, hexanes (50 mL) was added and the mixture was filtered through a pad of diatomaceous earth. Volatile material was removed by evaporation to give the title compound (1.55 g, 88%) as a solid that was used without further purification; 1H NMR δ 7.88 (2H, d), 7.45 (2H, d), 3.63 (3H, s), 2.70-2.57 (1H, m), 2.50 (3H, s), 2.48-2.36 (1H, m), 2.08-1.94 (2H, m), 1.90-1.80 (2H, m), 1.60-1.40 (4H, m); MS 311 (M+Na)+.