Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27]N)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N[C@@H:40]([C:48]([NH:50][C@H:51]([C:56]([NH:58][C@H:59]([C:64]([NH2:66])=[O:65])[CH2:60][CH2:61][S:62][CH3:63])=[O:57])[CH2:52][CH:53]([CH3:55])[CH3:54])=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.Cl>>[N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][C@@H:40]([C:48]([NH:50][C@H:51]([C:56]([NH:58][C@H:59]([C:64]([NH2:66])=[O:65])[CH2:60][CH2:61][S:62][CH3:63])=[O:57])[CH2:52][CH:53]([CH3:54])[CH3:55])=[O:49])[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1ccccc1)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Agent: Cl
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 91 %

Procedure:
Condensation of BocPro-DPhe-PheNHNH2 (2.09 g.) and HDPhe-Leu-MetNH2 hydrochloride salt (1.78 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-DPhe-Phe-DPhe-Leu-MetNH2 in 91% yield. De-t-butoxycarbonylation of BocPro-DPhe-Phe-DPhe-Leu-MetNH2 (2.32 g.) using hydrogen chloride in ethyl acetate gave HPro-DPhe-Phe-DPhe-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt dihydrate in 44% yield.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[OH:24][CH:25]1[CH2:28][NH:27][CH2:26]1.C(N(CC)CC)C.CS(C)=O>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH:25]([OH:24])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: OC1CNC1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(O)C3)c(F)cc2c1=O
Yield: 98 %

Procedure:
A solution of 1.22 g (3.92 mmoles) of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 0.86 g (7.85 mmoles) of 3hydroxyazetidine hydrochloride, 2 g (19.8 mmoles) of triethylamine and 20 ml of dimethyl sulphoxide (DMSO) is heated for 4 hours at 80° C. The solution is allowed to cool and is added to a mixture of ice and water, giving a precipitate which is filtered and washed with water. The solid is dried under vacuum yielding 1.40 g (97%) of ethyl 1-cyclopropyl-6,8-difluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate melting at 260°-270° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:23]3[C:14](=[CH:15][C:16]4[O:21][CH2:20][CH2:19][O:18][C:17]=4[CH:22]=3)[O:13][CH2:12]1)[C:5](=[O:11])[NH:6]2.Cl.Cl[CH2:26][C:27]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:23]3[C:14](=[CH:15][C:16]4[O:21][CH2:20][CH2:19][O:18][C:17]=4[CH:22]=3)[O:13][CH2:12]1)[C:5](=[O:11])[N:6]2[CH2:26][C:27]1[C:32]([C:33]([F:35])([F:34])[F:36])=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: FC(F)(F)c1cccnc1CCl
Reactant: O=C1Nc2cccc(F)c2C12COc1cc3c(cc12)OCCO3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1N(Cc2ncccc2C(F)(F)F)c2cccc(F)c2C12COc1cc3c(cc12)OCCO3
Temperature: 60 °C
Yield: 82.6 %

Procedure:
A mixture of 4′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.31 g, 1.00 mmol), 2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride (0.29 g, 1.50 mmol) and cesium carbonate (0.98 g, 3.00 mmol) in N,N′ dimethylformamide (10 mL) was heated at 60° C. for 2 h and was filtered while hot. The filtrate was allowed to cool to ambient temperature and water was added, causing a precipitate to be deposited. The solid was collected by filtration, washed with water (50 mL) and dried under vacuum. The residue was recrystallized from N,N′ dimethylformamide/water to afford 4′-fluoro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.39 g, 82%) as a beige solid: mp 245-247° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.68 (d, J=4.5 Hz, 1H), 8.27 (d, J=7.65 Hz, 1H), 7.59 (dd, J=7.8, 4.9 Hz, 1H), 7.30 (ddd, J=8.2, 8.2, 5.8 Hz, 1H), 6.86 (d, J=9.0 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.54 (s, 1H), 6.49 (s, 1H), 5.25 (ABq, J=17.4 Hz, 2H), 4.79 (q, J=9.4 Hz, 2H), 4.22-4.10 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.5, 157.9 (d, 1JC-F=247 Hz), 154.6, 152.3, 152.1 (d, 5JC-F=1.2 Hz), 144.9 (d, 4JC-F=8.9 Hz), 144.3, 137.6, 135.1 (q, 4JC-F=4.9 Hz), 130.8 (d, 4JC-F=8.6 Hz), 125.6 (q, 1JC-F=274 Hz), 123.0, 122.9 (d, 2JC-F=32.3 Hz), 119.4, 117.1 (d, 3JC-F=19.3 Hz), 111.5, 109.9 (d, 3JC-F=19.9 Hz), 105.7 (d, 5JC-F=2.9 Hz), 98.4, 77.4, 64.1, 63.5, 56.0 (d, 5JC-F=1.7 Hz), 42.3 (q, 5JC-F=3.3 Hz); MS (ES+) m/z 460.9 (M+1).
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[C:12]=2[O:21][CH3:22])[CH2:7][CH2:6]1)=[O:3].CCN=C=NCCCN(C)C.[C:38]([C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][C:49](O)=[O:50])=[CH:43][CH:42]=1)([OH:40])=[O:39]>CN(C1C=CN=CC=1)C>[C:2]([NH:4][C@@H:5]1[C:15]2[CH:16]=[C:17]([O:20][C:49](=[O:50])[CH2:48][CH2:47][C:44]3[CH:45]=[CH:46][C:41]([C:38]([OH:40])=[O:39])=[CH:42][CH:43]=3)[CH:18]=[CH:19][C:14]=2[C:13]2[C:12]([O:21][CH3:22])=[C:11]([O:23][CH3:24])[C:10]([O:25][CH3:26])=[CH:9][C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:1]
Reactant: O=C(O)CCc1ccc(C(=O)O)cc1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCc3ccc(C(=O)O)cc3)cc1[C@@H](NC(C)=O)CC2
Yield: 70 %

Procedure:
A solution of N-acetyl-colchicinol (0.357 g; 1 mmol), EDCI (0.23 g; 1.2 mmol), DMAP (0.025 g; 0.2 mmol) and 3-(4-carboxyphenyl)propionic acid (0.233 g; 1.2 mmol) was stirred at ambient temperature overnight. After removal of the solvent by evaporation, the residue was purified by preparative HPLC on reverse phase silica eluting with methanol/ammonium carbonate buffer (2 g/l pH7) (50/50) to give 4-(3-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxy-3-oxopropyl)benzoic acid.
Reaction SMILES: B.CSC.[CH3:5][O:6][C:7]([C:9]1([C:22]([O:24][CH3:25])=[O:23])[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[NH:11][C:10]1=O)=[O:8].CO.Cl>C1COCC1.O>[CH3:25][O:24][C:22]([C:9]1([C:7]([O:6][CH3:5])=[O:8])[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[NH:11][CH2:10]1)=[O:23]
Reactant: COC(=O)C1(C(=O)OC)C(=O)Nc2cc([N+](=O)[O-])ccc21
Agent: B
Agent: Cl
Solvent: O
Solvent: CSC
Solvent: CO
Product: COC(=O)C1(C(=O)OC)CNc2cc([N+](=O)[O-])ccc21
Yield: 51.8 %

Procedure:
Borane-dimethylsulfide (6.35 mL, 63 mmol) was added to a suspension of 3,3-di(methoxycarbonyl)-6-nitro-2-indolone (10.38 g, 35.2 mmol) in THF (350 mL) under nitrogen, and the mixture stirred at reflux for 1 h. The pale yellow solution was cooled, MeOH (10 mL), then H2O (10 mL), then aq. HCl (2 N, 50 mL) added, and the mixture stirred at 20° C. for a few minutes. The THF was evaporated and the aqueous residue extracted with EtOAc (×2). The extracts were dried (Na2SO4) and evaporated, and the resulting orange solid triturated with CH2Cl2 (2×100 mL) at 20° C. and filtered to remove most of the 3-(methoxycarbonyl)-6-nitroindole impurity. The CH2Cl2 solution was filtered through a short column of silica, eluting with more CH2Cl2, the solvent evaporated, and the resulting yellow solid recrystallised from MeOH to give title compound as a yellow crystalline solid (5.11 g, 52%), mp 139.5-140.5° C. 1H NMR (CDCl3) δ7.64 (dd, J=8.3, 2.1 Hz, 1H, H-5), 7.56 (d, J=8.3 Hz, 1H, H-4), 7.41 (d, J=2.1 Hz, 1H, H-7), 4.24 (d, J=1.9 Hz, 2H, NHCH2), 4.16 (br s, 1H, NH), 3.82 (s, 6H, CO2Me); 13C NMR δ168.7 (CO2Me), 151.7, 149.8, 130.8 (C-6,8,9), 127.2, 114.2, 104.2 (C-4,5,7), 62.7 (C-3), 54.1 (C-2), 53.6 (OMe); IR (KBr) 3351 (NH), 1732 (CO2Me), 1535 (NO2), 1351 (NO2), 1279 cm-1. Anal. Calculated for C12H12N2O6 : C, 51.4; H, 4.3; N, 10.0. Found: C, 51.4; H, 4.4; N, 10.0%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[N:18]=2)[CH:14]=[CH:13][S:12]3)[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:37]>C(OCC)(=O)C>[ClH:37].[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]4)[N:18]=2)[CH:14]=[CH:13][S:12]3)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nccc(-c3c(-c4cccc(C#N)c4)nc4sccn34)n2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)c1

Procedure:
The tert-butyl (3R)-3-({4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate (2.90 g, 5.79 mmol) was dissolved in 20 mL of ethyl acetate and treated with 30 mL of 3.0 M HCl in ethyl acetate at room temperature (RT) overnight. Solid product was filtered, washed with ethyl acetate and dried under vacuum overnight to provide the title compound as a yellow solid. It was used without further purification. LCMS: 402 [M+H].
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]=[C:3]1[C:8]([O:10][CH3:11])=[O:9].[H-].[Na+].C(O[CH:18]1[CH2:22][CH:21]([CH2:23][O:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=[CH:19]1)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CN(C)C=O.O1CCCC1.C(OCC)(=O)C.O>[O:1]=[C:2]1[N:7]([CH:18]2[CH2:22][CH:21]([CH2:23][O:24][C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:20]=[CH:19]2)[CH:6]=[CH:5][N:4]=[C:3]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(=O)OC1C=CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: COC(=O)c1ncc[nH]c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nccn(C2C=CC(COC(c3ccccc3)(c3ccccc3)c3ccccc3)C2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
In 4.0 mL of N,N-dimethylformamide was dissolved 0.39 g of methyl 3-oxo-3,4-dihydro-2-pyrazinecarboxylate. In an atmosphere of nitrogen gas, 90 mg of sodium hydride was added and stirred at room temperature for 2 hours. Then, a suspension of 0.50 g of 4-[(trityloxy)methyl]-2-cyclopenten-1-yl acetate, 0.62 g of tetrakis-triphenylphosphine palladium and 50 mg of triphenylphosphine in 4 mL of tetrahydrofuran was added, and the mixture thus obtained was stirred at room temperature for one hour and thereafter at 60° C. for 4 hours. The reaction mixture was allowed to cool, diluted with 30 mL of ethyl acetate and 20 mL of water, adjusted to pH 4 with 1 mol/L hydrochloric acid, and separated into layers. The organic layer was washed successively with saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent: hexane:ethyl acetate=1:1] to obtain 0.23 g of methyl 3-oxo-4-{4-[(trityloxy)methyl]-2-cyclopenten-1-yl}-3,4-dihydro-2-pyrazinecarboxylate as a light yellow oily product.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[CH:12][C:13]([NH:15][C@H:16]([C:28]([O:30]C)=[O:29])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH3:27])[CH:19]=1)=[O:14])(=O)C.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[CH:12][C:13]([NH:15][C@H:16]([C:28]([OH:30])=[O:29])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH3:27])[CH:19]=1)=[O:14]
Reactant: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1ccccc1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(C[C@H](NC(=O)C=Cc2ccccc2O)C(=O)O)c2ccccc21
Yield: 62.1 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 21 (3.9 g), 1 mol/L of an aqueous sodium hydroxide solution (28 mL), and methanol (140 mL), to give the captioned compound (2.1 g, 62%) as crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[CH3:44][O:45][C:46]1[CH:58]=[CH:57][C:49]2[C:50]([CH2:53][C:54](O)=[O:55])=[CH:51][O:52][C:48]=2[CH:47]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:54](=[O:55])[CH2:53][C:50]3[C:49]4[CH:57]=[CH:58][C:46]([O:45][CH3:44])=[CH:47][C:48]=4[O:52][CH:51]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: COc1ccc2c(CC(=O)O)coc2c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1ccc2c(CC(=O)NCc3cccc4c3C(=O)N(C3CCC(=O)NC3=O)C4=O)coc2c1
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 2-(6-methoxy-1-benzofuran-3-yl)-acetic acid were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). After stirring at room temperature overnight, the mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]2-(6-methoxy-benzofuran-3-yl)-acetamide (0.76 g, 73%) as a white solid: mp 143-145° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.41 min. (98%); 1H NMR (DMSO-d6) δ 2.03-2.07 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.91 (m, 1H), 3.60 (s, 2H), 3.79 (s, 3H), 4.74 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.8 Hz, 1H), 6.85-6.89 (dd, J=2.2 and 8.6 Hz, 1H), 7.15 (d, J=2.2 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.64-7.81 (m, 4H), 8.69 (t, J=5.9 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.51, 30.90, 37.91, 48.83, 55.53, 95.93, 111.42, 114.55, 120.21, 120.91, 121.90, 127.12, 131.49, 133.29, 134.63, 139.06, 142.19, 155.57, 157.68, 166.90, 167.43, 169.78, 172.63, 172.73; Anal. Calcd. for C25H21N3O7: C, 63.16; H, 4.45; N, 8.84. Found: C, 62.90; H, 4.44; N, 8.74.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([N:18]([CH2:36][CH2:37][CH2:38][CH3:39])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]2[S:31][C:30]([CH:32]=O)=[CH:29][CH:28]=2)=[C:21]([O:34][CH3:35])[CH:20]=1)[CH2:15][CH2:16][CH3:17].O>O1CCCC1>[CH2:14]([N:18]([CH2:36][CH2:37][CH2:38][CH3:39])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]2[S:31][C:30]([CH:32]=[CH:5][C:3]#[N:4])=[CH:29][CH:28]=2)=[C:21]([O:34][CH3:35])[CH:20]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OC)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC#N)s2)c(OC)c1
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To 111 mg (4.63 mmol) of sodium hydride, 8 ml of tetrahydrofuran was added. To this mixture, 820 mg (4.63 mmol) of diethyl cyanomethylphosphonate was added dropwise under ice cooling, and the mixture was stirred for 30 minutes. Next, 860 mg (2.31 mmol) of 5-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]thiophene-2-carboaldehyde in tetrahydrofuran was added dropwise, and the mixture was stirred for 1 hour. The reaction mixture was poured into water and subjected to extraction with ethyl acetate. The extract was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 828 mg of a deep red oily matter (yield: 90.7%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:6]([CH:9]=1)[CH2:7][OH:8].N1C=CN=C1.[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:6]([CH:9]=1)[CH2:7][O:8][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30]
Reactant: CCCCCCCCOc1ccc(Br)cc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(Br)cc1CO[Si](C)(C)C(C)(C)C
Reaction time: 0.33 h
Yield: 102.5 %

Procedure:
To a solution of compound 35-2 (7.95 g) and imidazole (4.19 g) in N,N-dimethylformamide (35 ml) was added t-butyldimethylchlorosilane (4.45 g) under ice-cooling, and the mixture was stirred for 20 min under ice-cooling, and further at room temperature for 18 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (11.1 g) as a pale-brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[I:8][C:5]1[CH:4]=[N:3][C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:6]=1
Reactant: C1COCCN1
Reactant: Clc1ncc(I)cn1
Product: Ic1cnc(N2CCOCC2)nc1

Procedure:
The mixture of 2-chloro-5-iodopyrimidine (0.200 g, 0.836 mmol) in morpholine (3.0 mL) was refluxed for 2-3 h. The reaction mass was quenched in water and the solid obtained was filtered off. The obtained solid was dried to afford 0.180 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.63 (s, 8H), 8.52 (s, 2H); MS (m/z): 292.25 (M+H)+.
Reaction SMILES: O[N:2]=[C:3]1[CH:7]([CH3:8])[S:6][CH:5]([CH3:9])[CH:4]1[C:10]([O:12][CH3:13])=[O:11].Cl>C(OCC)C>[NH2:2][C:3]1[C:4]([C:10]([O:12][CH3:13])=[O:11])=[C:5]([CH3:9])[S:6][C:7]=1[CH3:8]
Reactant: COC(=O)C1C(=NO)C(C)SC1C
Agent: Cl
Solvent: CCOCC
Product: COC(=O)c1c(C)sc(C)c1N
Yield: 47.1 %

Procedure:
A cooled solution of 80 g (0.39 mol) of tetrahydro-4-(hydroxyimino)-2,5-dimethyl-3-thiophenecarboxylic acid, methyl ester (Example D) in 1 L of anhydrous diethyl ether is saturated with dry hydrogen chloride over a period of one hour. The solution is stirred and allowed to reach room temperature over fourteen hours. The resulting precipitate is filtered, dissolved in 200 ml of water, neutralized with concentrated ammonium hydroxide and the aqueous solution is extracted with 200 ml of diethyl ether. The diethyl ether solution is washed with 100 ml of water. The diethyl ether layer is separated, dried over anhydrous Na2SO4 and evaporated to give 34 g of 4-amino-2,5-dimethyl-3-thiophenecarboxylic acid, methyl ester; mp 75°-77° C. after recrystallization from hexane.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cnc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
1H-Benzimidazole (300 mg) was dissolved in N,N-dimethylformamide (6 ml), added with sodium hydride (60%, in oil, 122 mg) and stirred at room temperature for 1 hour. Subsequently, the reaction mixture was added with 1-(tert-butoxycarbonyl)-4-(p-toluenesulfonyloxy)piperidine (1.08 g) and further stirred at room temperature for 23 hours and at 60° C. for 2 hours. The reaction mixture was added with water (10 ml) and extracted twice with ethyl acetate (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 192 mg of the title compound. Yield: 25%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:14](O)=O)=[CH:11][NH:12][CH:13]=1.[NH3:17]>C(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:14]#[N:17])=[CH:11][NH:12][CH:13]=1
Reactant: O=C(O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Reactant: N
Solvent: CCO
Product: N#Cc1c[nH]cc1-c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2.1 g of the free 4-(2,3-dichlorophenyl)pyrrole-3-carboxylic acid obtained in (b) are dissolved in 30 ml of ethanol. The solution is made alkaline with concentrated ammonia and then evaporated to dryness. The residue is dissolved in 50 ml of ethanol. NH3 gas is added (20 atm) to this solution at room temperature in an autoclave and the reaction mixture is kept for 15 hours at 220° C. The reaction mixture, which has cooled to room temperature, is poured into ice/HCl, the precipitate is isolated by filtration and dried at 60° C. The resultant powder is heated with 17 g of polyphosphoric acid in an open vessel at 180° C., the hot mixture is dropped onto ice, made alkaline with NaOH and extracted with ethyl acetate. The combined extracts are concentrated by evaporation and the residue is purified by column chromatography (silica gel; elution with a 4:1 mixture of toluene/ethyl acetate), affording 4-(2,3-dichlorophenyl)-3-cyanopyrrole of m.p. 148°-150° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[CH2:22][C:23]([OH:25])=[O:24].CCN(CC)CC>C(Cl)Cl>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][N:17]([CH2:22][C:23]([OH:25])=[O:24])[CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C1N(c2ccc(C3CC3)cc2)CCC12CCNCC2
Reactant: O=C(O)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CN1CCC2(CC1)CCN(c1ccc(C3CC3)cc1)C2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.4 g (1.47 mmol) 2-(4-Cyclopropyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, 0.226 g (1.63 mmol) bromoacetic acid and 0.299 g (2.96 mmol) NEt3 in 50 mL DCM was stirred at room temperature for 16 h. The mixture was concentrated and used without further purification in the consecutive step. MS m/e: 329.3 [M+H]+.