Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][C:37]([N+:41]([O-:43])=[O:42])=[C:38]([OH:40])[CH:39]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([N+:41]([O-:43])=[O:42])=[C:38]([OH:40])[CH:39]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: NCCc1ccc([N+](=O)[O-])c(O)c1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc([N+](=O)[O-])c(O)c3)n2)c1

Procedure:
Intermediate 4 was coupled with 5-(2-amino-ethyl)-2-nitro-phenol and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 501. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.4 (d, 1H) 8.1 (m, 2H) 7.8 (m, 4H) 7.6 (s, 1H) 7.3 (m, 1H) 7.1 (s, 1H) 6.9 (d, 1H) 4.4 (s, 2H) 3.7 (m, 2H) 3.6 (s, 1H) 3.2 (m, 2H) 3.0 (s, 3H) 2.9 (m, 2H) 2.7 (m, 2H) 1.7 (m, 2H).
Reaction SMILES: C(#N)C.Cl[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[Cl:29])[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:13])=[O:12])=[CH:7][N:6]=1.[F-:30].[K+]>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl>[Cl:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[CH:14]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[S:11]([C:8]1[CH:9]=[CH:10][C:5]([F:30])=[N:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(c1ccc(Cl)nc1)C(c1cc(F)ccc1F)c1ccncc1Cl
Reactant: [F-]
Agent: [Br-]
Agent: [K+]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: O=S(=O)(c1ccc(F)nc1)C(c1cc(F)ccc1F)c1ccncc1Cl
Temperature: 25 °C
Yield: 6.9 %

Procedure:
To an acetonitrile (2 ml) solution of 2-chloro-5-[(3-chloropyridin-4-yl)(2,5-difluorophenyl)methylsulfonyl]pyridine (66 mg, 0.16 mmol) were added potassium fluoride (94 mg, 1.60 mmol) and tetraphenylphosphonium bromide (134 mg, 0.32 mmol). The resulting mixture was heated under reflux for 16 hours. After the reaction mixture was cooled to room temperature, dichloromethane was added thereto. The resulting mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=17:3 eluate is concentrated under reduced pressure to give the title compound (4.5 mg, 0.011 mmol, 7%) as a white solid.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:6][C:7]1=[N:8][C:9](=[O:19])[S:10]/[C:11]/1=[CH:12]\[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:4]#[CH:5].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:53]1[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[CH:55]=[C:54]1[C:62](O)=[O:63]>CN(C=O)C.O>[O:53]1[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[CH:55]=[C:54]1[C:62]([N:16]1[CH2:17][CH2:18][CH:13](/[CH:12]=[C:11]2/[C:7]([NH:6][CH2:3][C:4]#[CH:5])=[N:8][C:9](=[O:19])[S:10]/2)[CH2:14][CH2:15]1)=[O:63]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(C(=O)c2cc3ccccc3o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a solution of (5Z)-4-(prop-2-yn-1-ylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added N-ethyl-N-(1-methylethyl)propan-2-amine (0.56 mL), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (283 mg), and benzofuran-2-carboxylic acid (124 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/heptane to give the title compound (167 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@H:7]2[C@H:11]([OH:12])[CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)=[CH:4][C:3]=1[F:22].I(C1C=CC=CC=1C(O)=O)(=O)=O>CCOC(C)=O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[C:11](=[O:12])[CH2:10][N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:8]2)=[CH:4][C:3]=1[F:22]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](Oc2ccc(Cl)c(F)c2)C1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)C(Oc2ccc(Cl)c(F)c2)C1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To a solution of 414 (0.200 g, 0.603 mmol) and EtOAc (20 mL) was added 2-iodoxybenzoic acid (0.675 g, 2.41 mmol) and the resulting solution heated at reflux overnight. The reaction was cooled to RT and the white solid was filtered off and the filtrated was concentrated in vacuo to afford 0.16 g (80%) of tert-butyl 3-(4-chloro-3-fluorophenoxy)-4-oxo-pyrrolidine-1-carboxylate (416): LC-MS (ESI) m/z 274 (M+H-56).
Reaction SMILES: S(O[CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[C:9]1[CH2:17][C:18]([O:20][CH3:21])=[O:19])(C)(=O)=O.[I-:22].[Na+]>C(#N)C>[I:22][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[C:9]1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)Cc1c(C(=O)OC)ccn1CCOS(C)(=O)=O
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)Cc1c(C(=O)OC)ccn1CCI
Yield: 97.3 %

Procedure:
A solution of 785 mg of methyl N-(2-mesyloxyethyl)-3-carbomethoxypyrrole-2-acetate and 1.83 g of sodium iodide in 10 ml of acetonitrile is refluxed for 1 hour. The cooled reaction mixture is evaporated to dryness under reduced pressure and the residue is triturated with water. The insoluble material is separated by filtration and is air dried, thus obtaining 840 mg (97%) of methyl N-(2-iodoethyl)-3-carbomethoxypyrrole-2-acetate (VI, R=H), m.p. 137°-138° C.
Reaction SMILES: Cl[C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[CH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:20][CH3:21])=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=2)[C:6]1=[O:22].[Li]CCCC.[F:36][C:37]([F:45])([F:44])[C:38]([C:40]([F:43])([F:42])[F:41])=[O:39]>C1COCC1>[F:36][C:37]([F:45])([F:44])[C:38]([C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[CH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:20][CH3:21])=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=2)[C:6]1=[O:22])([OH:39])[C:40]([F:43])([F:42])[F:41]
Reactant: COc1cc2c(cc1N1CCOCC1)CC(Cc1cc(C(F)(F)F)ccc1Cl)C2=O
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1cc(C(F)(F)F)ccc1C(O)(C(F)(F)F)C(F)(F)F)C2=O
Reaction time: 0.17 h
Yield: 15.5 %

Procedure:
To a stirred solution of 2-(2-chloro-5-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 269 (0.1 g, 0.226 mmol) in dry THF, cooled to 0° C., n-BuLi (0.021 g, 0.339 mmol) was added drop wise and the solution stirred for 10 min. Then hexafluoroacetone 244 (0.10 g, 0.453 mmol) was added to the reaction and stirred for another 2 h. After completion of the reaction, it was quenched with saturated ammonium chloride solution. The organic layer was separated and aqueous phase was extracted again with diethyl ether, the combined organic layer was dried over sodium sulphate and concentrated to get the crude 270, which was purified through 100-200 mesh silica gel by eluting with 15% ethyl acetate in hexane to give 20 mg of compound 2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-5-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 270.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]([CH3:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:28])=[CH:4][N:3]=1.[CH3:29][N:30]([CH3:39])[C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:28][C:5]1[C:6]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C:18]([N:20]([CH3:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:19])[CH2:15][CH2:16]2)=[C:7]2[N:8]=[C:35]([C:34]3[CH:37]=[CH:38][C:31]([N:30]([CH3:39])[CH3:29])=[CH:32][CH:33]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C(=O)CN1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1)c1ccccc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CC(=O)N(C)c5ccccc5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-methyl-N-phenyl-acetamide (0.037 g, 0.09 mmol), ethanol (3 ml), and 4-dimethylamino-benzaldehyde (0.019 g, 0.13 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.4 ml, 0.4 mmol). The reaction mixture was heated at 70° C. for 6 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted first with ethyl acetate/dichloromethane (v/v; 1:1), and then 1-2% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained after trituration with diethyl ether as a pale yellow solid (0.008 g, 18%); 1H-NMR (500 Mz, DMSO-d6) 2.58 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.21 (s, 3H, NCH3), 3.61 (br s, 4H, piperazine N(CH2)2), 6.82 (d, J=9.87 Hz, 2H, 3,5-C6H4—NMe2 or 2,6-C6H4—NMe2), 7.30-7.50 (m, 5H, N-Ph), 8.00 (m, 3H, 3,5-C6H4—NMe2 or 2,6-C6H4—NMe2 and imidazo[4,5-b]pyridine 5-H); 13.09 (s, 1H, imidazo[4,5-b]pyridine N—H); LC-MS (ESI, m/z) 5.10 min—504, 506 [(M+H)+, Cl isotopic pattern]; ESI-HRMS Found: 504.2278, calculated for C27H31N7ClO (M+H)+: 504.2279.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8](Br)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].[N-:21]=[N+:22]=[N-:23].[Na+]>CO.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:21]=[N+:22]=[N-:23])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1nc2c(s1)C(Br)COc1ccc(Br)cc1-2
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1nc2c(s1)C(N=[N+]=[N-])COc1ccc(Br)cc1-2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 110.5 %

Procedure:
To a stirred mixture of 4,9-Dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (400 mg, 0.95 mmol) in MeOH (20 mL) was added a solution of NaN3 (93.1 mg, 1.43 mmol) in water (2 mL) dropwise at room temperature. The mixture was heated to 60° C. overnight. The mixture was cooled to room temperature, and then 20 mL of water was added. The mixture was stirred for 0.5 h and then filtered to afford 4-Azido-9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (400 mg, 28%). 1H NMR (400 MHz, DMSO-d6): δ 8.50 (d, J=2.5 Hz, 1H), 7.56 (dd, J=8.7 Hz, J2=2.6 Hz, 1H), 7.16 (d, J=8.6 Hz, 1H), 5.35 (m, 1H), 4.75 (m, 1H), 4.33 (m, 1H), 3.98 (s, 3H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:28])([F:27])[CH2:6][N:7]([C:17]1[C:22]([N+:23]([O-])=O)=[CH:21][N:20]=[C:19]([Cl:26])[N:18]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C>C(O)(=O)C.[Fe]>[Cl:26][C:19]1[N:20]=[CH:21][C:22]2[NH:23][C:4](=[O:3])[C:5]([F:28])([F:27])[CH2:6][N:7]([CH2:8][CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[N:18]=1
Reactant: CCOC(=O)C(F)(F)CN(CCCc1ccccc1)c1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N(CCCc2ccccc2)CC1(F)F
Reaction time: 0.17 h
Yield: 81.3 %

Procedure:
To a solution of 1.61 g (0.0038 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(3-phenyl-propyl)-amino]-2,2-difluoro-propionic acid ethyl ester (IV-281) in 25 mL of acetic acid was added 1.6 g (0.029 g-atom) of iron powder. The mixture was heated to 80 degrees for 2 hours and then filtered while hot. Water and ethyl acetate were added to the filtrate and the mixture was stirred for 10 minutes and then filtered. The layers were separated. The organic layer was washed successively with ammonium hydroxide and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 1.09 g of 2-chloro-7,7-difluoro-9-(3-phenyl-propyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-281) as a yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH:19]=2)[OH:18])[CH3:12])=[CH:4][CH:3]=1.[C:21]([CH:24]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:25](OCC)=[O:26])(=O)[CH3:22].P(Cl)(Cl)(Cl)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:14]=[C:15]3[C:16]([C:21]([CH3:22])=[C:24]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:25](=[O:26])[O:20]3)=[C:17]([OH:18])[CH:19]=2)[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)cc(O)c1
Reactant: CCOC(=O)CCC(C(C)=O)C(=O)OCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CCc1c(C)c2c(O)cc(C(C)CCCc3ccc(F)cc3)cc2oc1=O

Procedure:
Ethyl 7-[5-(p-fluorophenyl)-2-pentyl]-5-hydroxy-4-methylcoumarin-3-propionate is prepared by reaction of 5-[5-(p-fluorophenyl)-2-pentyl]resorcinol, diethyl α-acetylglutarate, and phosphorus oxychloride according to the method of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCN1CCC(O[C@@H](c2ccc(Cl)cc2)c2ccccn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCN1CCC(O[C@@H](c2ccc(Cl)cc2)c2ccccn2)CC1
Reaction time: 8 h

Procedure:
In 760 ml of ethanol was dissolved 126.0 g (0.302 mol) of ethyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]-piperidino]butanoate obtained according to Reference example 3(1), and then 120.8 ml of a 5N aqueous sodium hydroxide solution was added to the mixture and the mixture was allowed to stand at room temperature overnight. After confirming disappearance of the starting materials, the mixture was neutralized by adding 121.1 ml of a 5N hydrochloric acid. After the precipitated crystals were removed by filtration, the reaction mixture was concentrated under reduced pressure. To the residue was added 600 ml of methyl acetate, and the solution was again concentrated under reduced pressure. The residue was dissolved in 600 ml of dichloromethane and dried over anhydrous magnesium sulfate sufficiently. Insolubles were removed by filtration, the filtrate was concentrated to afford the desired compound as an orange syrupy product (125.3 g). When the syrupy product was further dried under reduced pressure, it became a foamy product (120.2 g).
Reaction SMILES: Cl[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CO>[CH:14]1([CH2:13][N:10]2[CH2:11][CH2:12][CH:7]([N:6]3[C:5]4[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=4[N:3]=[C:2]3[N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[CH2:8][CH2:9]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: Clc1nc2ccccc2n1C1CCN(CC2CCCC2)CC1
Solvent: CO
Product: CN1CCN(c2nc3ccccc3n2C2CCN(CC3CCCC3)CC2)CC1
Temperature: 120 °C

Procedure:
The mixture of 1-(1-cyclopentylmethyl-4-piperidinyl)-1,3-dihydro-2H-benzimidazole-2-one(202 mg) and POCl3(5 ml) was heated at 120° C. for 2 h. After cooling down to room temperature, the reaction mixture was poured into NH4OH solution, and extracted with CH2Cl2. The extracts combined were washed with water, and dried (Na2SO4). After filtration, the filtrate was concentrated to give oil, which was purified by preparative TLC (1 mm thick plate×2, CH2Cl2/MeOH:15/1) to give 148 mg (69%) of 2-chloro-1-(1-cyclopentylmethyl-4-peridinyl)-1H-benzimidazole as colorless amorphous solid. To a solution of 2-chloro-1-(1-cyclopentylmethyl-4-piperidinyl)-1H-benzimidazole(148 mg, 0.466 mmol) in MeOH(5 ml) was added N-methylpiperazine(1 ml) and the resulting mixture was heated at 120° C. in a sealed tube for 2 days. After concentration, the residue was purified by preparative TLC (1 mm thick plate×2, CH2Cl2/MeOH:12/1, 2 developed) to give 161 mg of colorless amorphous solid. This was purified again by column chromatography(basic silica gel: 50 g; CH2Cl2/MeOH:200/1 to 50/1) to afford 52 mg (29%) of title compound as colorless amorphous solid.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[O:11][CH2:12][C:13](=[O:20])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:5]1)(=[O:3])[NH2:2].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCCCC1>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([N:6]3[CH2:7][CH2:8][CH2:9][CH:4]([C:1](=[O:3])[NH2:2])[CH2:5]3)=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: CCOC(=O)C1=C(N2CCCC(C(N)=O)C2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(N2CCCC(C(N)=O)C2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 8.3 %

Procedure:
To a solution of ethyl 2-(3-carbamoylpiperidino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.15 g, 0.53 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.078 g, 0.53 mmol) in ethanol (10 mL), piperidine (0.020 mL, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound as solid (0.018 g, y. 9%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH:9]=[CH:8][N:7]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)=O)C.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[C:6]1([CH:4]=[O:3])[C:11]2[NH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: CCOC(=O)c1nccc2c1[nH]c1ccccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=Cc1nccc2c1[nH]c1ccccc12
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To a stirred solution of ethyl-9H-pyrido[3,4-b]indole-1-carboxylate, 1, (1.26 g, 5.24 mmol) in CH2Cl2 (50 mL) was added a DIBAL-H solution (1.0 M in toluene; 36.0 mL, 36.71 mmol) at −50° C. The mixture was stirred at −50° C. for 10 min and quenched by sequential addition of methanol (14.0 mL) and 10% NaOH (10 mL) at −50° C. Then the mixture was stirred at ambient temperature for an additional 1 h. The precipitates were removed by filtration through Celite and washed with CHCl3-methanol (10:1). The combined filtrates were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The product was purified by chromatography on silica gel (2-20% methanol/CH2Cl2) to afford 0.46 g (45% yield) of β-carboline-1-carbaldehyde, 2: 1H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 10.04 (bs, 1H), 8.63 (d, J=5.2 Hz, 1H), 8.18-8.15 (m, 2H), 7.64-7.57 (m, 2H), 7.35 (dt, J=1.6, 7.6 Hz, 1H); ESI+ MS: m/z (rel intensity) 197.0 (100, [M+H]+).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[CH:13]=1)[CH3:4].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](O)=[O:38])=[CH:32][N:31]=1>>[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([C:37](=[O:38])[CH2:36][C:33]2[CH:32]=[N:31][C:30]([Cl:29])=[CH:35][CH:34]=2)[CH2:26][CH3:27])[CH:13]=1)[CH3:4]
Reactant: O=C(O)Cc1ccc(Cl)nc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Agent: Cl
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)Cc2ccc(Cl)nc2)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester, dihydrochloride and 2-chloropyridine-5-acetic acid were reacted as described in Example 8, Step 6 to provide {5-[2-({N-[2-(6-chloro-pyridin-3-yl)-acetyl]-N-ethyl-amino}-methyl)-4-trifluoromethyl-phenyl]-pyridin-3-yl}-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[O:40][C@H:41]1[C@H:50]([OH:51])[C@@H:49]([CH2:52][OH:53])[O:48][C@H:43]([O:44][CH2:45][CH:46]=[CH2:47])[C@@H:42]1[O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:62][O:63][C:64]1[CH:69]=[CH:68][C:67](O)=[CH:66][CH:65]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[O:40][C@H:41]1[C@H:50]([OH:51])[C@@H:49]([CH2:52][O:53][C:67]2[CH:68]=[CH:69][C:64]([O:63][CH3:62])=[CH:65][CH:66]=2)[O:48][C@H:43]([O:44][CH2:45][CH:46]=[CH2:47])[C@@H:42]1[O:54][CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(O)cc1
Reactant: C=CCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O[C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=CCO[C@H]1O[C@H](COc2ccc(OC)cc2)[C@@H](O)[C@H](O[C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 68.7 %

Procedure:
Allyl 3-O-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-2-O-benzyl-α-D-glucopyranoside 14 (10.1 g, 12.1 mmol), 4-methoxyphenol (3.76 g, 30.3 mmol), and triphenylphosphine (4,77 g, 18.2 mmol) were combined in a flask, cooled to 0° C. before adding anhydrous CH2Cl2 (100 mL). This solution was stirred for 40 minutes and then a solution of diethylazodicarboxylate (DEAD) in toluene (40% by weight, 8.84 mL, 19.4 mmol) was added. The reaction mixture was stirred at 0° C. for 45 minutes, and then allowed to warm to room temperature overnight. The reaction mixture was diluted with CH2Cl2, washed with 1N NaOH (200 mL, 100 mL), 1 N HCl (200 mL), saturated NaHCO3 (200 mL), and brine, dried over Na2SO4, filtered and concentrated. The residue was purified on a silica gel column eluted using an ethyl acetate:heptane step gradient (1:10→1:5→1:3) to give allyl 3-O-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-2-O-benzyl-6-O-(4-methoxyphenyl)-α-D-glucopyranoside 14 (7.81 g, 69%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:12][CH2:11]2)[N:7]=[C:6]([CH3:13])[C:5]=1[OH:14].Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:12][CH2:11]2)[N:7]=[C:6]([CH3:13])[C:5]=1[O:14][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1
Reactant: COC(=O)c1cc(C2CC2)nc(C)c1O
Reactant: N#Cc1cccc(CBr)c1
Product: COC(=O)c1cc(C2CC2)nc(C)c1OCc1cccc(C#N)c1
Yield: 64.2 %

Procedure:
The coupling of 6-cyclopropyl-3-hydroxy-2-methyl-isonicotinic acid methyl ester (182) (614 mg, 2.9 mmol) and α-bromo-m-tolunitrile (638 mg, 3.26 mmol), as described in Example 1, gave 3-(3-cyano-benzyloxy)-6-cyclopropyl-2-methyl-isonicotinic acid methyl ester (188) (600 mg, 63% yield).