Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OC)=O.CCCCCC.[C:45]([O:48]CC)(=[O:47])[CH3:46]>C(Cl)Cl>[C:45]([OH:48])(=[O:47])/[CH:46]=[CH:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCC/C=C/C=O
Reactant: CCOC(C)=O
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCCCCCC/C=C/C=C/C(=O)O
Reaction time: 2 h

Procedure:
To the trans-2-tridecenal (1.7 g) dissolved in methylene chloride (80 ml) was added (carbomethoxymethylene)triphenyl phosphorane (4.0 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-pentadecadienoic acid (2.1 g). Potassium hydroxide (2.0 g) was dissolved in a mixed solvent of ethanol-water (1:1), and the methyl ester of trans,trans-2,4-pentadecadienoic acid (2.1 g). After the mixture was stirred at 60° C. for 40 minutes, it was cooled, adjusted to a weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans,trans-2,4-pentadecadienoic acid (1.9 g). The product was dissolved in N,N-dimethylformamide (DMF, 50 ml), and para-nitrophenol (1.2 g) and N,N'-dicyclohexylcarbodiimide (1.7 g) were added. The mixture was stirred for 12 hours. After the reaction, precipitates produced were removed by filtration, DMF was removed by distillation, and the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-pentadecadienoic acid (1.3 g). To the active ester (600 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (750 mg) and triethylamine (1.2 ml). The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK285 in the yield of 530 mg.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9](CC3C=CC(OC)=CC=3OC)[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31]C(=O)OC(C)(C)C)[N:3]=1.CC1(C)C(C)(C)OB([C:47]2[S:48][CH:49]=[CH:50][CH:51]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[NH2:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:4]1[N:3]=[C:2]([C:47]2[S:48][CH:49]=[CH:50][CH:51]=2)[C:7]2[C:8](=[O:22])[NH:9][CH2:10][C:6]=2[C:5]=1[F:23]
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N[C@H]1CCCC[C@H]1Nc1nc(-c2cccs2)c2c(c1F)CNC2=O
Temperature: 80 °C
Yield: 43.9 %

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (300 mg, 0.546 mmol), 4,4,5,5-tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane (172 mg, 0.820 mmol), and trans-dichloro-bis(triphenylphosphine)palladium-II (38.4 mg, 0.055 mmol) were dissolved in dioxane (5 mL). An aqueous solution of 2N Na2CO3 (0.5 mL) was added, the cap was sealed, and the mixture was allowed to react at 85° C. for 3 h. The reaction mixture was subsequently diluted with water (5 mL) and extracted into EtOAc (2×30 mL). The organic layer was dried over sodium sulfate and evaporated. The resulting residue was treated with TFA (4 mL) and heated at 80° C. for 1 h to remove the protecting groups. Next, TFA was evaporated from the reaction mixture. The product was reconstituted in DMSO (8 mL) and was then purified via preparative HPLC eluting with water (0.05% TFA) and ACN (15-45% gradient, 0.035% TFA). The pure fractions were combined and evaporated to a minimal volume. Saturated aq NaHCO3 (10 mL) was added and the mixture was extracted with EtOAc (3×25 mL). The organic layers were combined, dried over sodium sulfate, and evaporated to give the title compound as a pale yellow solid (83 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.80 (m, 8 H), 3.18 (br s, 1 H), 3.86-4.11 (m, 1 H), 4.39 (s, 2 H), 6.60 (d, J=6.57 Hz, 1 H), 7.13 (dd, J=5.05, 3.79 Hz, 1 H), 7.60 (dd, J=5.18, 1.14 Hz, 1 H), 8.39 (s, 1 H), 9.00 (dd, J=3.79, 1.01 Hz, 1 H). [M+H] calc'd for C17H19FN4OS, 347; found, 347.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Br:9][C:10]1[S:14][C:13]([N:15]=[C:16]=[O:17])=[CH:12][CH:11]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[Br:9][C:10]1[S:14][C:13]([NH:15][C:16]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:17])=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccc(Br)s1
Reactant: CN1CC(=O)N=C1N
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccc(Br)s1
Temperature: 75 °C
Yield: 29.6 %

Procedure:
To a stirred suspension of 3.0 g (26 mM) of creatinine in 30 ml of anhydrous DMF was added a solution of 5.0 g (26.5 mM) of 5-bromo-2-thienyl isocyanate in 15 ml of toluene. The resulting mixture was heated at 75° C. for 3 hrs., cooled, and poured into 200 ml of water. The precipitate was collected, washed with ethanol and ether, and air-dried. The solid was dissolved in 250 ml hot acetone, treated with charcoal, filtered, and the filtrate diluted with water (250 ml). The resulting precipitate was collected, washed with acetone and then ether. Air-drying gave 2.3 g of the above urea as a buff powder, m.p. 192°-193° C. (dec.).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7](=O)[C:6]2[CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1.[BH4-].[Na+].Cl>CO.O>[CH3:1][CH:2]1[CH:8]=[CH:7][C:6]2[CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1
Reactant: CC1CCc2ccc(CC(=O)O)cc2C(=O)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1C=Cc2cc(CC(=O)O)ccc2CC1
Temperature: 25 °C

Procedure:
6,7,8,9-tetrahydro-7-methyl-9-oxo-5H-benzocycloheptene-2-acetic acid (6.3 g) is dissolved in 90 cc of methanol, and 4.1 g of sodium borohydride are added in small portions within 10 minutes while stirring at room temperature. The solution is stirred for a further 30 minutes, is diluted with water, acidified with 1 N hydrochloric acid, and the crude 6,7,8,9-tetrahydro-9-hydroxy-7-methyl-5H-benzocycloheptene-2-acetic acid is filtered off. The crude product has a M.P. of 161°-163°.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1>O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[Na+].C(C(CC)=O)C>[CH2:3]([C:2]1([CH2:11][CH3:10])[NH:12][C:10]2[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1]1)[CH3:4]
Reactant: Nc1cccc2cccc(N)c12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: CCC(=O)CC
Product: CCC1(CC)Nc2cccc3cccc(c23)N1
Reaction time: 5 h
Yield: 1769.7 %

Procedure:
With 1.58 g of 1,8-diaminonaphthalene, 10.8 g of diethyl ketone and 25 mg of sodium p-toluenesulfonate monohydrate were mixed. The mixture was heated and stirred for 5 hours in a steam bath. The resulting mixture was extracted with 100 ml of ethyl acetate and 50 ml of a saturated aqueous solution of sodium hydrogencarbonate. The solvent was distilled out to obtain 20 g of 2,2-diethyl-2,3-dihydroperimidine.
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:10](=[O:11])[C:9]2[S:12][CH:13]=[CH:14][C:8]=2[NH:7][C:6]1=[O:15])[CH:2]=[CH2:3].Br[CH2:17][CH2:18][OH:19].[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH2:1]([O:4][N:5]1[C:10](=[O:11])[C:9]2[S:12][CH:13]=[CH:14][C:8]=2[N:7]([CH2:17][CH2:18][O:19][S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:6]1=[O:15])[CH:2]=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCBr
Reactant: C=CCOn1c(=O)[nH]c2ccsc2c1=O
Solvent: c1ccncc1
Product: C=CCOn1c(=O)c2sccc2n(CCOS(=O)(=O)c2ccc(C)cc2)c1=O
Reaction time: 4 h

Procedure:
3-Allyloxy-1H-thieno[3,2-d]pyrimidine-2,4-dione (from previous example) was alkylated with 2-bromoethanol via general procedure B1. The intermediate alcohol was treated with tosyl chloride (3 eq) in pyridine (0.2 M). After 4 hours, the reaction mixture was partitioned between EtOAc and water. The organic layer was dried over MgSO4 and concentrated to give toluene-4-sulfonic acid 2-(3-allyloxy-2,4-dioxo-3,4-dihydro-2H-thieno[3,2-d]pyrimidin-1-yl)-ethyl ester. This material could be used crude or could be further purified by chromatography in 1:1 EtOAc/hexanes. The tosylate was treated with pyrrolidine (1.5 eq) and Et3N (1.5 eq) in CHCl3. The reaction was heated to 55° C. for 2 hours. Additional pyrrolidine (2 eq) was added and the reaction was stirred overnight at 55° C. The reaction was cooled, washed with water, and concentrated. The crude intermediate was deprotected via general procedure D2 to give the title compound which was purified by mass-triggered preparative HPLC. 1H NMR (DMSO-d6) δ 8.14 (d, 1H, J=5.4 Hz), 7.32 (d, 1H, J=5.4 Hz), 4.14 (t, 2H, J=6.9 Hz), 3.60-3.30 (m, 4H), 2.67 (t, 2H, J=6.9 Hz), 1.69-1.60 (m, 4H); Electrospray MS: 322 (M+H); retention time: 1.24 min.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:20]([C:23]1[CH:54]=[CH:53][C:26]([CH2:27][O:28][C:29](=[O:52])[CH:30]([N:32]2[C@H:35]([S:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][C:41](=[O:50])[CH2:42][O:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:33]2=[O:51])Cl)=[CH:25][CH:24]=1)([O-:22])=[O:21]>O1CCOCC1>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][O:28][C:29](=[O:52])[C:30]([N:32]2[C@H:35]([S:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][C:41](=[O:50])[CH2:42][O:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:33]2=[O:51])=[P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:53][CH:54]=1)([O-:22])=[O:21]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)S[C@@H]1[C@@H](OC(=O)COc2ccccc2)C(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1COCCO1
Product: CC(=O)S[C@@H]1[C@@H](OC(=O)COc2ccccc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
786 mg of triphenylphosphine and 3 g of poly-Hunig base are added to a solution of 960 mg of 2-[(3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester in 40 ml of dioxan and the mixture is stirred overnight at 50° under nitrogen. The poly-Hunig base is removed by filtration and the filtrate is concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (9:1, 4:1 and 1:1) and yields the title compound. IR spectrum (in methylene chloride): characteristic absorption bands at 5.7, 5.9, 6.17, 6.55 and 7.45 μ.
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:9]=[CH:8][N:7]=1)O)[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C.O>[N:21]([CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:9]=[CH:8][N:7]=1)[CH:3]([CH2:19][CH3:20])[CH2:1][CH3:2])=[N+:22]=[N-:23]
Reactant: CCC(CC)C(O)c1ncnn1Cc1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)C(N=[N+]=[N-])c1ncnn1Cc1ccc(F)cc1
Yield: 67 %

Procedure:
To a stirred solution of 2-ethyl-1-[1-(4-fluorobenzyl)-1H-1,2,4-triazol-5-yl]butan-1-ol (0.459 g, 1.42 mmol) in DMF (10 mL) was added sodium azide (0.277 g, 4.26 mmol) and the mixture was heated to reflux for 3 h. After cooling, the reaction mixture was diluted with H2O and extracted with EtOAc twice. The organic extracts were dried (MgSO4), filtered, concentrated in vacuo and purified by column chromatography (SiO2, EtOAc/hexane, 1:9) to yield a clear oil in 67% yield.
Reaction SMILES: NC1[N:11]=[C:10]([O:12]C)C2C(=NC=CN=2)N=1.[F:14][C:15]([F:29])([F:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=C=O)(=[O:24])=[O:23]>C(Cl)Cl>[F:29][C:15]([F:14])([F:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH:25][C:10](=[O:12])[NH2:11])(=[O:24])=[O:23]
Reactant: O=C=NS(=O)(=O)c1ccccc1C(F)(F)F
Reactant: COc1nc(N)nc2nccnc12
Solvent: ClCCl
Product: NC(=O)NS(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
0.88 g (0.005 mol) of 2-amino-4-methoxypteridine and 1.30 g (0.0052 mol) of 2-trifluoromethylphenylsulfonyl isocyanate were reacted in 40 ml of methylene chloride according to Example 4 to obtain 2.0 g (94% of theory) of N-4-methoxypteridin-2-yl)-N'-(2-trifluoromethylphenylsulfonyl)-urea in the form of light yellow crystals melting at 187° C.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:14][C@@H:13]([F:15])[CH2:12][NH:11][CH2:10]1)(C(C)(C)C)(C)C.Cl.[CH:17]([OH:20])([CH3:19])C.[CH3:21][OH:22]>>[F:15][C@@H:13]1[CH2:14][C@@H:9]([OH:8])[CH2:10][N:11]([C:21]([O:20][CH2:17][C:19]2[CH:10]=[CH:9][CH:14]=[CH:13][CH:12]=2)=[O:22])[CH2:12]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CNC[C@H](F)C1
Reactant: CC(C)O
Reactant: CO
Agent: Cl
Product: O=C(OCc1ccccc1)N1C[C@H](O)C[C@@H](F)C1
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of (3R,5R)-3-(tert-butyldimethylsilyloxy)-5-fluoropiperidine (1 eq) in 30 mL of methanol was added 3.8M HCl in isopropanol (4 eq). The reaction mixture was allowed to stand at room temperature for 3 hours at which point it was concentrated under reduced pressure. The resulting residue was diluted with 120 mL of EtOAc, washed with sat. aq. sodium bicarbonate, brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=2:1) to give (3R,5R)-benzyl 3-fluoro-5-hydroxypiperidine-1-carboxylate, (94%). LC/MS (m/z): 254.2 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].O>ClCCl>[CH3:1][N:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)[S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)S(C)(=O)=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in dichloromethane (10 ml) is added triethylamine (0.24 ml). Subsequently, thereto is added methanesulfonyl chloride (0.14 ml) under ice-cooling, and then, the mixture is warmed to room temperature and stirred overnight. Water is added to the reaction solution, extracted three times with dichloromethane. The extract is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1), and recrystallized from ethanol to give 5-(N-methyl-N-methanesulfonylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.48 g) as colorless scales, m.p. 197°-198° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1([C:21]([NH2:23])=[O:22])[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=2)[CH2:10]1.[CH3:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27].C(N(CC)CC)C.[NH4+].[Cl-]>C1COCC1>[CH3:24][C:25]([CH3:30])([CH3:29])[C:26]([NH:8][C:9]1([C:21]([NH2:23])=[O:22])[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=2)[CH2:10]1)=[O:27]
Reactant: NC(=O)C1(N)Cc2ccc([N+](=O)[O-])cc2C1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NC1(C(N)=O)Cc2ccc([N+](=O)[O-])cc2C1

Procedure:
A solution of (±)-2-amino-5-nitroindane-2-carboxamide, trifluoroacetate salt (described in Intermediate 3, 25.0 mg, 0.075 mmol), 2,2-dimethylpropanoyl chloride (0.011 mL, 0.089 mmol), and triethylamine (0.026 mL, 0.186 mmol) in THF (5 mL) was stirred at ambient temperature for 16 h. The reaction mixture was poured onto saturated NH4Cl (10 mL) and extracted with CH2Cl2 (3×10 mL). A solid precipitate was filtered and collected, then dissolved in MeOH and combined with the organic layers. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=306 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCCCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, piperidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.65 minutes; C21H20Cl2N4O2 (431.32); mass spectrum: (M+H)+=431.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1.[O:18]([C:20]#[N:21])[Na]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:20]([NH2:21])=[O:18])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1
Reactant: N#CO[Na]
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Solvent: CC(=O)O
Product: COC1=Cc2ccccc2N(C(N)=O)c2ccccc21
Reaction time: 7 h

Procedure:
Acetic acid (150 mL) is added dropwise to a stirred mixture of 10-methoxy-5H-dibenzo[b,f]azepine (25.0 g, 112 mmol) and NaOCN (9.25 g, 142 mmol) under a nitrogen atmosphere at room temperature. After stirring for 7 hours the resulting yellow suspension of the title compound (>95% area of the compound by HPLC) is used for synthesis of 10-oxo-10,11-dihydro-dibenzo[b,f]azepine-S-carboxylic acid amide. The title compound can be isolated by adding 1N NaOH to a pH of ≧8 followed by extraction with toluene. Drying of the combined organic layers and concentration in vacuo yields the title compound as a light yellow solid (yield≧75%).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:29])=[C:7]([C:10]2[O:14][C:13]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22]O)=[C:17]([CH3:28])[CH:16]=3)=[N:12][N:11]=2)[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].CC[N:32](CC)CC.CS(Cl)(=O)=O.N>C1COCC1.CO>[NH2:32][CH2:22][CH:21]([OH:24])[CH2:20][O:19][C:18]1[C:25]([CH3:27])=[CH:26][C:15]([C:13]2[O:14][C:10]([C:7]3[S:8][CH:9]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]=3[CH3:29])=[N:11][N:12]=2)=[CH:16][C:17]=1[CH3:28]
Reactant: Cc1cc(-c2nnc(-c3scc(CC(C)C)c3C)o2)cc(C)c1OCC(O)CO
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2nnc(-c3scc(CC(C)C)c3C)o2)cc(C)c1OCC(O)CN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol (90 mg, 0.22 mmol) in THF (4 mL) are added NEt3 (0.14 mL) and, subsequently, methanesulfonlychloride (0.02 mL, 0.26 mmol). The mixture is stirred at rt for 3 h. A solution of NH3 in MeOH (7M, 4 mL) is added and the mixture is heated at 60° C. for 15 h. The mixture is evaporated, 1M aq. NaOH (3 mL) is added and the mixture is extracted with EA (2×20 mL). The organic extracts are dried (Na2SO4), filtered and evaporated to give crude 1-amino-3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}-propan-2-ol; LC-MS: tR=0.86 min, [M+1]+=416.32.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[O:20])[CH2:14][CH2:13]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH3:40][S:41]([NH:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[O:20])[CH2:14][CH2:13]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN)CCCCC3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCNS(C)(=O)=O)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of N-[1-[2-[1-(2-aminoethyl) cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide (synthesized in Example 18) (260 mg) in dichloromethane (3 mL) were added triethylamine (0.15 mL) and methanesulfonyl chloride (56 μL) successively. The solution was stirred at room temperature for 6 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (7:3 to 1:1 to 1:2] to give the title compound (214 mg).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[O:21][CH2:22]OC)=[CH:8][CH:9]=[C:10]([NH2:12])[CH:11]=1)=[O:5].[C:26]1([Li])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1C[O:36][CH2:35]C1>>[NH2:12][C:10]1[CH:9]=[CH:8][C:7]([C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[O:21][CH2:22][O:36][CH3:35])=[C:6]([C:4](=[O:5])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:11]=1
Reactant: [Li]c1ccccc1
Reactant: C1CCOC1
Reactant: COCOc1cccc(OC)c1-c1ccc(N)cc1C(=O)N(C)OC
Product: COCOc1cccc(OC)c1-c1ccc(N)cc1C(=O)c1ccccc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of Example 5C (5.44 g., 15.72 mmole) in THF (70 mL) and cooled to −5° C. was treated with of 1.8M phenyllithium in ether-cyclohexane (52.4 mL, 94.33 mmol). The mixture was stirred at −5° C. for 1 hour, cooled to −78° and a solution of aqueous KHCO3 was added rapidly. The mixture was extracted with ether, which was combined, dried (Na2SO4), filtered, concentrated under reduced pressure and purified on silica gel eluting with 8% ethyl acetate in CH2Cl2 to provide the titled compound (4.84 g, 85% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.[CH2:18]([S:25](Cl)(=[O:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:18]([S:25]([NH:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1)(=[O:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Yield: 53.9 %

Procedure:
To a solution of tert-butyl 2-[3-amino-6-methyl-2-oxo-1(2H)-pyridinyl]acetate (3.04 g, 12.1 mmol) in pyridine (30 mL) cooled to 0° C. was added benzylsulfonylchloride (2.67 g, 15.1 mmol). While stirring of the reaction mixture the precipitate formed. After one hour the solvent was evaporated under reduced pressure and the product was partitioned between dichloromethane and 10% KHSO4 solution. The aqueous phase was extracted with dichloromethane twice. The combined organic phases were dried over a drying agent and the solvent was evaporated under reduced pressure. A brown-reddish product obtained was suspended in ethyl acetate and heated to reflux, then cooled and filtered to give 2.56 g (6.52 mmol) of a pink product.