Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(O[O-])=O.[Na+].C(OC(=O)C)(=[O:8])C.CO.[CH3:15][O:16][C:17]1[CH:37]=[CH:36][C:20]2[NH:21][C:22]([S:24][CH2:25][C:26]3[C:31]([CH3:32])=[C:30]([O:33][CH3:34])[C:29]([CH3:35])=[CH:28][N:27]=3)=[N:23][C:19]=2[CH:18]=1>O.C1(C)C=CC=CC=1.CO>[CH3:15][O:16][C:17]1[CH:37]=[CH:36][C:20]2[NH:21][C:22]([S:24]([CH2:25][C:26]3[C:31]([CH3:32])=[C:30]([O:33][CH3:34])[C:29]([CH3:35])=[CH:28][N:27]=3)=[O:8])=[N:23][C:19]=2[CH:18]=1
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Reactant: CC(=O)OC(C)=O
Agent: O=BO[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Reaction time: 0.22 h
Yield: 84.8 %

Procedure:
Sodium perborate 4H2O (11.2 g, 73.0 mmol) was suspended in water (50 ml), followed by the dropwise addition of a solution of acetic anhydride (6.87 ml, 73.0 mmol)/methanol (5.75 ml) at 15.4° C. over 6 minutes and then, the mixture was stirred for about 13 min to prepare a homogenous solution (bulk temperature; 15.4° C. to 19.4° C.). The resulting solution was added dropwise to a solution (220 ml) of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-1H-benzimidazole (20.0 g, 60.8 mmol) in toluene/methanol (10:1) at −20° C. over 2 hr. The resulting mixture was further stirred at the same temperature for 1 hr. The resulting crystals were collected by filtration, washed for three times with water (20 ml) and washed twice with tert-butyl methyl ether (20 ml). The resulting crystals were dried, to give the title compound (17.8 g, yield; 85.0%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([NH:15][NH2:16])=[O:14])=[CH:7][CH:6]=2.[N:17]#[C:18]Br>CO.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[O:14][C:18]([NH2:17])=[N:16][N:15]=1)=[CH:7][CH:6]=2
Reactant: N#CBr
Reactant: NNC(=O)Cc1ccc2ncc(Br)cc2c1
Solvent: CO
Solvent: O
Product: Nc1nnc(Cc2ccc3ncc(Br)cc3c2)o1

Procedure:
A mixture of (3-bromo-quinolin-6-yl)-acetic acid hydrazide (prepared according to procedure described herein) (4.12 g, 14.7 mmol), cyanogen bromide (1.1 eq., 16.2 mmol, 1.7 g) and KHCO3 (1.25 eq., 18.3 mmol, 1.83 g) was stirred in methanol (30 mL) at ambient temperature for 18 hours. The was then diluted with water (40 mL) and the solid was collected via filtration and washed with cold methanol and dried to return the title compound as an off white solid (4.02 g, 13.2 mmol, 90%). 1H NMR (DMSO-d6): δ 4.27 (2H, s), 6.94 (s, 2H), 7.71 (dd, 1H), 7.86 (d, 1H), 8.02 (d, 1H), 8.73 (d, 1H); 8.93 (d, 1H); MS (m/z) 305 [M+H+]+.
Reaction SMILES: I[C:2]([Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:3]1[C:12](=[C:13](I)[Si:14]([CH3:17])([CH3:16])[CH3:15])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C([Li])(C)(C)C.CN1C(=O)N(C)CCC1.I[C:38]1[C:47](I)=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=1>C1COCC1.Cl[Cu]>[CH3:20][Si:19]([CH3:22])([CH3:21])[C:2]1[C:47]2[C:38](=[CH:39][C:40]3[C:45]([CH:46]=2)=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:13]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:12]2[C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[CH2:11]2
Reactant: Ic1cc2ccccc2cc1I
Reactant: C[Si](C)(C)C(I)=C1Cc2ccccc2CC1=C(I)[Si](C)(C)C
Agent: Cl[Cu]
Agent: [Li]C(C)(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c2c(c([Si](C)(C)C)c3cc4ccccc4cc13)Cc1ccccc1C2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39.8 %

Procedure:
Compound 2 obtained in step 1 (552 mg, 1.0 mmol) was dissolved in THF (15 ml). To this solution, t-butyllithium (1.76 M in n-pentane, 2.27 mL, 4.0 mmol) was slowly added at −78° C., and this mixture was stirred for 15 minutes. The resulting solution was kept at −40° C. for 30 minutes and then cooled again to −78° C. After 15 minutes passed, this solution was mixed with CuCl (198 mg, 2.0 mmol) and DMPU (0.36 mL, 3.0 mmol), followed by stirring at 0° C. for 0.5 hours. Then, to this reaction mixture, 2,3-diiodonaphthalene (760 mg, 2.0 mmol) was added and heated at 50° C. for 12 hours. The reaction mixture was cooled to 0° C. and then quenched with 3 N HCl, and the reaction product was extracted with hexane. The organic layer was washed with saturated aqueous sodium bicarbonate and aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate:triethylamine=50:1:1) to give the titled compound (compound 3) as a yellow solid (169 mg, yield: 40%).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1)[CH2:9][CH3:10].[S:21]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[CH:22]1.NC1C=C(C=CC=1)CN>>[CH3:20][C:2]([CH3:19])([CH3:1])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)[CH:27]=2)[CH:13]=1)[CH2:9][CH3:10]
Reactant: O=Cc1cccc(-c2ccsc2)c1
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(N)c1
Agent: NCc1cccc(N)c1
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(NCc2cccc(-c3ccsc3)c2)c1

Procedure:
Compounds of Examples 175 to 180 were obtained by performing the same reaction as in Example 174 except that instead of the starting compound (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-aminobenzylamine and/or 3-(3-thienyl)benzaldehyde, the corresponding 3-aminobenzylamine derivatives and/or 3-substituted benzaldehyde derivatives were used.
Reaction SMILES: [S:1](=[O:22])(=[O:21])([O:3][CH2:4][C@@H:5]1[C@@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[O:8][C:7](C)(C)[O:6]1)[NH2:2].Cl.C1N=CN(C(N2C=NC=C2)=[O:30])C=1>CCOC(C)=O>[S:1](=[O:22])(=[O:21])([O:3][CH2:4][C@@H:5]1[C@@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[O:8][C:7](=[O:30])[O:6]1)[NH2:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)O[C@H](c2ccccc2[N+](=O)[O-])[C@@H](COS(N)(=O)=O)O1
Agent: Cl
Solvent: CCOC(C)=O
Product: NS(=O)(=O)OC[C@H]1OC(=O)O[C@@H]1c1ccccc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 51.1 %

Procedure:
To a stirred solution of ((4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl sulfamate (Example 77, 5.2 g, 16 mmol) in EtOAc (50 mL) was added 3N HCl (24.6 mL, 80.0 mmol) at room temperature. The mixture was stirred for 5 h. The resulting mixture was diluted with EtOAc, washed with sat. NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product stirred in THF (35 mL) was added CDI (2.91 g, 17.9 mmol) at room temperature. The mixture was stirred for 1 h. The resulting mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 gel column chromatography to produce the title compound (2.6 g, 60˜80%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@@H:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([O:29]C)=[O:28])[C:22]3[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=3[O:20][C@@H:19]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[OH-].[Li+].CO.Cl>C1COCC1.O>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@@H:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([OH:29])=[O:28])[C:22]3[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=3[O:20][C@@H:19]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:16])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)[C@@H](c2ccccc2)Oc2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)N(CC(=O)O)c2ccccc2O[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a stirred solution of methyl [(2R,3S)-3-({N-[(3,5-difluorophenyl)acetyl]-L-alanyl}amino)-4-oxo-2-phenyl-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate (70) (133 mg, 0.241 mmol) in THF (4 mL) was added a solution of lithium hydroxide (11 mg, 0.262 mmol) in water (1 mL). Several small drops of methanol were then added until a clear homogeneous solution was achieved. The mixture was stirred for 1 h at ambient temperature then acidified with 1N aqueous HCl and extracted with ethyl acetate. The organic solution was dried, filtered and evaporated. The glass-like solid residue was dissolved in dichloromethane (2 mL) then precipitated by addition of hexanes to afford the title compound (124 mg, 96%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ1.08 (d, 3H, J=7.0 Hz), 3.41 and 3.48 (AB quartet, 2H, J=14.5 Hz), 4.21 (m, 1H), 4.58 (s, 2H), 5.02 (t, 1H, J=7.0 Hz), 5.55 (d, 1H, J=7.0 Hz), 6.94 (m, 2H), 7.08 (m, 1H), 7.24-7.49 (m, 10H), 8.33 (d, 1H, J=7.0 Hz), 12.94 (br, 1H). MS APCI, m/z=538 (M+1). LC/MS: 2.27 min.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](N1C=CN=C1)([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16].O>ClCCl>[CH:1]([NH:14][C:15]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C(NC(c1ccccc1)c1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzhydrylamine (1.83 g) was dissolved in dichloromethane (3.0 ml). Carbonyldiimidazole (1.78 g) was added to the solution. The mixture was stirred at room temperature overnight. Water and dichloromethane were added thereto. The mixture was stirred, and then extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation is to give imidazole-1-carboxylic acid benzhydrylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[CH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:4][CH:3]=1.[C:17]([CH2:19][C:20](OCC)=[O:21])#[N:18].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:19]([C:17]#[N:18])=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(C=NNc1ccc(Cl)cc1)C(F)(F)F
Reactant: CCOC(=O)CC#N
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1c(C(F)(F)F)cnn(-c2ccc(Cl)cc2)c1=O
Temperature: 110 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
After 0.281 g of 3, 3, 3-trifluoro-2-oxopropanal 1-(4-chlorophenylhydrazone) was dissolved in 5 mL of pyridine, 0.304 g of ethyl cyanoacetate was added to the pyridine solution, which was followed by stirring for 5 hours at 110° C. After cooling to room temperature, the reaction mixture was poured into 3N-hydrochloric acid and extracted with diethyl ether. After the organic layer was washed with aqueous saturated sodium bicarbonate and concentrated, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate/hexane =1/9), and furthermore recrystallized from a solvent mixture (toluene/hexane =1/3) to afford 0.234 g of 2-(4-chlorophenyl)-4-cyano-5-trifluoromethylpyridazin-3-one (The present compound 1-15). 1H-NMR (300 MHz, CDCl3)δ(ppm): 7.49(2H, d, J=8.8 Hz), 7.61 (2H, d, J=8.8 Hz), 8.19 (1H,s)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.O.C(OCC)(=O)C>[CH3:19][Si:20]([CH3:22])([CH3:21])[C:23]#[C:24][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: COCOc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5.74 g (21.7 mmol) of 1-iodo-4-methoxymethoxybenzene, 100 ml of triethylamine and a mixture of 1.53 g (2.18 mmol) of dichlorobis(triphenylphosphine)palladium and 831 mg (4.37 mmol) of copper iodide are introduced into a three-necked flask. 6.14 ml (43.5 mmol) of trimethylsilylacetylene are then added and the medium is stirred for 48 h at room temperature. It is then poured into a water/ethyl acetate mixture. The organic phase is washed twice with water and, after separation of the phases by settling, it is washed with magnesium sulphate and concentrated.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1
Reactant: COc1ccccc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1C1=CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
1-t-Butoxycarbonyl-4-hydroxy-4-(2-methoxyphenyl)piperidine (240 mg, 0.78 mmol) was dissolved in methylene chloride (4 ml). Thereto was added trifluoroacetic acid (4 ml) and the resulting solution was stirred at room temperature for 1 hour. The solvent was evaporated under a reduced pressure, and ethyl acetate was added to the thus obtained residue. This was washed with 1 N sodium hydroxide aqueous solution and saturated brine in that order, and then the solvent was evaporated under a reduced pressure to obtain 150 mg of the aforementioned compound of interest (0.78 mmol, 100% in yield).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][NH:10][S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.C(Cl)CCl.[CH2:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH:29]1[C:38](O)=[O:39]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([NH:10][CH2:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([CH2:2][NH:1][C:38]([CH:29]2[CH2:30][CH2:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28]2)=[O:39])[CH2:4][CH2:5]1)(=[O:13])=[O:12]
Reactant: O=C(O)C1CCc2ccccc2C1
Reactant: NC[C@H]1CC[C@H](CNS(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NC[C@H]1CC[C@H](CNS(=O)(=O)c2ccc3ccccc3c2)CC1)C1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of naphthalene-2-sulfonic acid-(4-aminomethyl-trans-cyclohexylmethyl)amide (0.5 g, 1.4 mmol), EDC (0.54 g, 2.8 mmol), and DMAP (0.34 g, 2.8 mmol) in methylene chloride (30 mL) was stirred at room temperature for 0.5 h. 1,2,3,4-tetrahydronaphthalen-2-carboxylic acid (0.24 g, 1.4 mmol) was added to the reaction mixture and stirred at room temperature till the completion of the reaction (by TLC). The reaction mixture was washed with saturated ammonium chloride (3×30 mL), dried over sodium sulfate and concentrated in vacuo. The residue was flash chromatographed over silica gel to afford white solid (0.66 g, 99%); mp 225-6° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[C:11]2[C:13]3[N:20]([CH3:21])[N:19]=[C:18]([C:22](=[O:27])[N:23]([O:25][CH3:26])[CH3:24])[C:14]=3[CH2:15][CH2:16][CH2:17][C:10]2=[CH:9][N:8]=1)(=O)=O.[Br:30][C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][CH:32]=1>C1COCC1>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][C:7]2[N:12]=[C:11]3[C:13]4[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:23]([O:25][CH3:26])[CH3:24])=[O:27])[C:14]=4[CH2:15][CH2:16][CH2:17][C:10]3=[CH:9][N:8]=2)=[CH:33][CH:32]=1
Reactant: CON(C)C(=O)c1nn(C)c2c1CCCc1cnc(OS(=O)(=O)C(F)(F)F)nc1-2
Reactant: Sc1ccc(Br)cc1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1nn(C)c2c1CCCc1cnc(Sc3ccc(Br)cc3)nc1-2
Temperature: 60 °C
Reaction time: 48 h
Yield: 2 %

Procedure:
To a solution of 3-[methoxy(methyl)carbamoyl]-1-methyl-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidin-9-yl trifluoromethanesulfonate (70 mg, 0.16 mmol) in THF (3 mL), 4-bromothiophenol was added in microwave vial flushed under argon. The reaction mixture was stirred at 60° C. for 48 h. The solvent was removed under reduced pressure, the crude was purified by preparative HPLC to give 2 mg (2% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].[CH2:15]([O:17][C:18]([C:20]1[C:21](Cl)=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=1)=[O:19])[CH3:16].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:15]([O:17][C:18]([C:20]1[C:21]([N:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCOC(=O)CCNC1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN(c1nc(SC)ncc1C(=O)OCC)C1CCCCC1
Reaction time: 16 h
Yield: 82.4 %

Procedure:
3-Cyclohexylamino-propionic acid ethyl ester (1.0 g, 5.0 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.17 g, 5.02 mmol) were combined in DCM (15 mL) and diisopropylethylamine (0.81 g, 6.3 mmol) was added. After 16 h, the solution was partitioned between water and DCM and the organic layer was dried (MgSO4) and concentrated. Chromatography (0-20% EtOAc/hexanes gradient) provided 1.63 g (84%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 8.39 (s, 1H) 5.30 (s, 1H), 4.30 (q, 2H, J=7.1 Hz), 4.14 (q, 1H, J=7.1 Hz), 3.76-3.80 (m, 2H), 2.65-2.69 (m, 2H), 2.49 (s, 3H), 1.81-1.84 (m, 2H), 1.34-1.40 (m, 7H), 1.12-1.27 (m, 7H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]([CH3:18])([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH3:8])=[N:5][N:6]=1>CCOC(C)=O.[Pd]>[CH3:1][C:2]1[O:3][C:4]([C:7]([CH3:18])([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH3:8])=[N:5][N:6]=1
Reactant: Cc1nnc(C(C)(C)c2ccc([N+](=O)[O-])cc2)o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nnc(C(C)(C)c2ccc(N)cc2)o1
Reaction time: 16 h

Procedure:
A mixture of 2-methyl-5-[1-methyl-1-(4-nitro-phenyl)-ethyl]-[1,3,4]oxadiazole (1.36 g, 5.5 mmol) and Pd/C (68 mg) in EtOAc (50 mL) was stirred under 1 atm of H2 for 16 h. The resulting slurry was filtered over Celite®, and the filtrate was concentrated to give the titled compound as a pale yellow crystalline solid. MS: (ES+) 218 (M+H). Calc'd for C12H16N3O—218.12.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16](N5CCNCC5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:27][CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1>>[OH:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:29]1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Reactant: OC1CCCNC1
Product: O=c1c2c[nH]c3ccc(N4CCCC(O)C4)nc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described for 6a using 3-hydroxypiperidine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 1.40 (2H, m), 1.75 (1H, m), 1.80 (1H, m), 2.92 (1H, dd, J=12.64, 8.79 Hz), 3.51 (1H, m), 4.10 (1H, m), 4.33 (1H, dd, J=12.63, 3.84 Hz), 4.91 (1H, d, J=4.40 Hz), 7.15 (1H, tt, J=7.42, 1.09 Hz), 7.20 (1H, d, J=9.34 Hz), 7.42 (2H, dd, J=8.52, 7.42 Hz), 7.80 (1H, d, J=9.34 Hz), 8.21 (2H, dd, J=8.79, 1.38 Hz), 8.53 (1H, s). m/z 361.4 (MH+).
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:29])=[C:19]([C@@:21]2([CH3:28])[NH:26][C:25](=O)[CH2:24][O:23][CH2:22]2)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>O1CCOCC1>[C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:29])=[C:19]([C@@:21]2([CH3:28])[NH:26][C:25](=[S:39])[CH2:24][O:23][CH2:22]2)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@]1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)COCC(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)COCC(=S)N1
Temperature: 80 °C

Procedure:
A solution of (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholin-3-one 287 mg, 0.7 mmol) in dioxane (4 ml) was treated with Lawesson's reagent (181 mg, 0.5 mmol). After heating at 80° C. for 16 hours the reaction mixture was evaporated at reduced pressure. The residue was directly purified by chromatography on an Isolute flash NH2 column using a gradient of heptane and ethyl acetate=100/0 to 40/60 as the eluent. The title compound was obtained as yellow foam (181 mg, 61.5% of theory). Mass (calculated) C24H21FN2OS [404.507]; (found) [M+H]+=405.
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]([CH:21]2[C:30]3N=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:24][CH2:23][CH2:22]2)S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)=[C:5]([CH2:33][OH:34])[CH:4]=1)#[N:2].[C:35]([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1.N#N>CN(C=O)C>[OH:34][CH2:33][C:5]1[CH:4]=[C:3]([CH:32]=[CH:31][C:6]=1[CH2:7][NH:8][CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:35]=2)[CH2:24][CH2:23][CH2:22]1)[C:1]#[N:2]
Reactant: N#Cc1ccc(CN(C2CCCc3cccnc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])c(CO)c1
Reactant: O=C([O-])[O-]
Agent: N#N
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CNC2CCCc3ccccc32)c(CO)c1
Yield: 86 %

Procedure:
To a solution of N-(4-cyano-2-hydroxymethyl-benzyl)-2-nitro-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-benzenesulfonamide (2.32 g, 4.85 mmol) dissolved in DMF (50 mL) was added K2CO3 (3.35 g, 24.3 mmol) and thiophenol (1.49 mL, 14.6 mmol). The solution was stirred at room temperature under a positive pressure of N2 for 3 hours. The mixture was concentrated in vacuo and redissolved in CH2Cl2 (50 mL). The mixture was filtered through a sintered glass funnel containing celite. The solution was concentrated in vacuo to afford a yellow solid. Purification via column chromatography on silica gel (hexane:EtOAc, 1:1, v/v) afforded 3-hydroxymethyl-4-[(1,2,3,4-tetrahydro-naphthalen-1-ylamino)-methyl]-benzonitrile as a yellow solid (1.22 g, 86%). 1H NMR (CDCl3) δ 1.92 (m, 3H), 2.26 (m, 1H), 2.77 (m, 2H), 3.86 (m, 1H), 4.02 (d, 1H, J=13.3 Hz), 4.17 (d, 1H, J=12.3 Hz), 4.51 (d, 1H. J=12.3 Hz), 4.80 (d, 1H, J=11.4 Hz), 7.09 (dd, 1H, J=8.3, 5.3 Hz), 7.42 (d, 1H, J=6.6 Hz), 7.49 (d, 1H, J=7.9 Hz), 7.59 (m, 1H), 7.64 (s, 1H), 8.35 (d, 1H, J=4.8 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:6](N1C2C=CC=CC=2N=N1)=[O:7])[CH3:2].[Li+].CC([N-]C(C)C)C.[C:32]1(=[O:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C1COCC1>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C:6](=[O:7])[CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:32]1=[O:39])[CH3:2]
Reactant: CCOC(=O)C(C(=O)n1nnc2ccccc21)C1CCCCC1
Reactant: O=C1CCCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)C1CCCCCC1=O)C1CCCCC1

Procedure:
In analogy to the procedure described in example 1.2, 3-benzotriazol-1-yl-2-cyclohexyl-3-oxo-propionic acid ethyl ester (example 1.1) was treated with LDA and subsequently reacted with cycloheptanone (CAS Reg. No. 502-42-1) in THF to give the title compound as yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[O:14]1>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:16]1[C:17](=[O:19])[O:18][C:13]([CH3:21])([CH3:12])[O:14][C:15]1=[O:20])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)C(=Cc2cccc([N+](=O)[O-])c2)C(=O)O1

Procedure:
5-(3-Nitrobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione can be obtained in the following manner: a solution of 30.2 g of 3-nitrobenzaldehyde and 2,2-dimethyl-1,3-dioxane-4,6-dione in 400 cm3 of dimethylformamide is stirred for 18 hours at a temperature near to 20° C. The reaction mixture is diluted with 500 cm3 of ethyl acetate, washed five times with water, dried over magnesium sulphate, filtered and concentrated to dryness (1.2 kPa) to give an oil. This oil is crystallized in 100 cm3 of ethanol to give 26 g of 5-(3-nitrobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione in the form of a solid melting at 128° C.