Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CCCCCC.[CH2:20]1[O:22][CH2:21]1.CCOCC>C1COCC1>[CH:1]1[C:13]2[CH:12]([CH2:20][CH2:21][OH:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C1CO1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: OCCC1c2ccccc2-c2ccccc21
Reaction time: 5 h

Procedure:
2-(9-Fluorenyl) ethanol was prepared from a solution of fluorene (116.35 g, 0.7 mmol) in 800 ml of dry THF at -20° C. which was added n-Buli in hexane (0.7 mol) keeping the temperature below -10° C. To the clear solution was rapidly added 357 ml of 1.4M ethylene oxide in ether (0.5 mol) keeping the temperature below 5° C. The reaction mixture was stirred for 5 hours, then quenched with 50 ml of saturated ammonium chloride solution. The THF was removed at a rotary evaporator. The residue was partitioned between water and ethyl acetate. The organic layer was separated, dried with MgSO4 and concentrated in vacuo until crystallization began. The solution was allowed to stand overnight and the crystals were collected and dried (mp 97° C.) (85.5 g, (81%)).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH2:44]([NH:46][CH2:47][C:48]([CH2:54][NH:55][C:56]1[CH:64]=[C:63]([CH3:65])[CH:62]=[C:61]2[C:57]=1[CH:58]=[N:59][N:60]2[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([OH:53])[C:49]([F:52])([F:51])[F:50])[CH3:45]>CN(C)C=O>[CH2:44]([N:46]([CH2:47][C:48]([OH:53])([CH2:54][NH:55][C:56]1[CH:64]=[C:63]([CH3:65])[CH:62]=[C:61]2[C:57]=1[CH:58]=[N:59][N:60]2[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:49]([F:52])([F:51])[F:50])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[CH3:45]
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: Cc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To a solution of 2-methylbenzoic acid (12.7 mg, 0.09 mmol) in N,N-dimethylformamide (100 μl) was added a solution of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (34 mg, 0.09 mmol) in dimethylformamide (150 μl) followed by N,N-diisopropylethylamine (36 μl, 0.21 mmol). The mixture was shaken for 5 minutes and then a solution of 3-(ethylamino)-1,1,1-trifluoro-2-{[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol (27 mg, 0.07 mmol) in N,N-dimethylformamide (150 μl) was added. The mixture was again shaken for 5 minutes and then left to stand at room temperature for 18 hours. The crude reaction was purified by mass-directed autopreparation (System A) to give the title compound (21.1 mg).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:1]([O:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(OC(=O)c1ccccc1)c1ccccc1

Procedure:
Moreover, in the case of benzoyl chloride, the resulting mixed anhydride is more reactive than benzoyl chloride. Thus, the carboxylate ion of acrylic acid preferentially reacts with the mixed anhydride to give acrylic anhydride and the benzoate ion, which subsequently reacts with unreacted benzoyl chloride to give benzoic anhydride, according to reaction scheme I.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][C:9]1=2)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C.CCOC(C)=O>[N:29]([CH2:6][CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][C:9]1=2)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCOS(C)(=O)=O)c3ccccc23)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCN=[N+]=[N-])c3ccccc23)CC1
Temperature: 60 °C
Reaction time: 14.5 h
Yield: 94.3 %

Procedure:
tert-Butyl 6-{2-[(methylsulfonyl)oxy]ethyl }-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.224 g, 0.549 mmol) and NaN3 (0.357 g, 5.49 mmol, 10.0 equiv.) were dissolved in DMF (2.5 mL) and the solution was stirred at 60° C. under N2 for 14.5 h. The reaction mixture was taken up in EtOAc and washed with water (2×15 mL). The aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and concentrated. The crude product (0.214 g) was chromatographed (SiO2 25 g, eluted with 3:1 hexane:EtOAc) to give tert-butyl 6-(2-azidoethyl)-1,4,5, 6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.184 g) in 94% yield. 1H NMR (300 MHz, CDCl3) δ 1.51, 2.99-3.10, 3.60, 3.66-3.84, 4.26, 7.14, 7.21, 7.27, 7.51; MS (ESI+) for Cl9H25N5O2 m/z 356.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[C:12]2[CH2:17][CH2:16][N:15]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:27]
Reactant: BrCc1ccccc1
Reactant: CCN(CC)C(=O)c1ccc(C(=C2CCNCC2)c2ccc(Cl)cc2)cc1
Product: CCN(CC)C(=O)c1ccc(C(=C2CCN(Cc3ccccc3)CC2)c2ccc(Cl)cc2)cc1
Yield: 92.8 %

Procedure:
Method as described for Example 4, using compound 23 (96 mg) and benzyl bromide (43 mg) provided N,N-diethyl-4-(4-chlorophenyl-N-benzyl-piperidin-4-ylidene-methyl)-benzamide (110 mg, 93%):
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C)(=O)=O)=[CH:13][CH:12]=[N:11][C:10]=2[CH:21]([CH3:23])[CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:24][C:25]1[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=1>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])=[CH:13][CH:12]=[N:11][C:10]=2[CH:21]([CH3:23])[CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)c1cnc2c(C(C)C)nccc2c1OS(C)(=O)=O
Product: CCCC(=O)c1cnc2c(C(C)C)nccc2c1Nc1ccccc1C
Yield: 58 %

Procedure:
By following a similar procedure described in Example 33(B) using 3-Butyryl-8-isopropyl-4-methanesulfonyloxy-1,7-naphthyridine (282 mg) and o-toluidine (0.17 ml) to give the titled compound (168 mg, 58%).
Reaction SMILES: O.NC1C(C(N=CNNC(NCC(OC(C)(C)C)=O)=O)=[O:12])=NC([Cl:10])=C(N)N=1.[NH2:28][C:29]1[C:30]([C:37]([N:39]=[CH:40][NH:41][NH:42][C:43]([NH:45][CH2:46][C:47]([O:49]C(C)(C)C)=[O:48])=[O:44])=[O:38])=[N:31][C:32]([Cl:36])=[C:33]([NH2:35])[N:34]=1.CC(=C)C>Cl>[OH2:12].[ClH:10].[ClH:36].[NH2:28][C:29]1[C:30]([C:37]([N:39]=[CH:40][NH:41][NH:42][C:43]([NH:45][CH2:46][C:47]([OH:49])=[O:48])=[O:44])=[O:38])=[N:31][C:32]([Cl:36])=[C:33]([NH2:35])[N:34]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)NNC=NC(=O)c1nc(Cl)c(N)nc1N
Agent: C=C(C)C
Agent: Cl
Solvent: O
Product: Nc1nc(N)c(C(=O)N=CNNC(=O)NCC(=O)O)nc1Cl

Procedure:
Concentrated hydrochloric acid (100 ml) and 3,5-diamino-6-chloro-N-{[(tert-butoxycarbonylmethylaminocarbonyl)amino]aminomethylene}-2-pyrazinecarboxamide hemihydrate (2 g.) are united in a 500 ml. round bottomed flask and heated with stirring on a steam bath for 10 minutes during which time the evolution of isobutylene is observed. The hot reaction mixture is filtered. The 3,5-diamino-6-chloro-N{[(carboxymethylaminocarbonyl)amino]aminomethylene}-2-pyrazinecarboxamide dihydrochloride hydrate which is collected and dried in a steam cabinet melts at 252° C (dec.).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:35]1[C:39]2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.Cl.CN>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:35][CH3:39])=[O:28])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: On1nnc2ccccc21
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(=O)NC)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To a mixture of 0.0704 g (0.153 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) and 4 mL of dimethylformamide was added 0.03338 g (0.250 mmole) of 1-hydroxybenzotriazole, 0.0904 g (0.238 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1632 g (1.265 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0229 g (0.337 mmole) of methylamine hydrochloride was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0562 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-N-methyl-benzamide (I-220) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[OH:13])=[O:5].I[CH2:20]I>CN(C)C=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:2]2[O:1][CH2:20][O:13][C:7]3[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=3[C:4](=[O:5])[C:3]=2[CH:14]=1
Reactant: ICI
Reactant: O=C(c1cc(Cl)ccc1O)c1cc(Cl)ccc1O
Solvent: CN(C)C=O
Product: O=C1c2cc(Cl)ccc2OCOc2ccc(Cl)cc21
Temperature: 105 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
2,2'-Dihydroxy-5,5'-dichlorobenzophenone (12.1 g, 0.042 mol, prepared similarly as described in Journal of the American Chemical Society 77, 543 (1955)) and diiodomethane (11.9 g, 0.044 mol) were dissolved in dry N,N-dimethylformamide (226 ml). Dried and powdered potassium carbonate (8.3 g) was added and the mixture was heated at 105° C. for 5 h and left overnight at room temperature. The reaction mixture was poured on ice (220 g). The precipitate was collected by filtration after 0.5 h and dissolved in diethyl ether (500 ml). The organic layer was washed with 5% sodium hydroxide (50 ml), dried over MgSO4 and evaporated in vacuo, affording 12 g (96%) of 2, 10-dichloro-12H-dibenzo[d,g][1,3]-dioxocin-12-one as a solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH:9][CH:10]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])[C:3]=1[O:20][CH2:21][CH:22](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:23].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[F:8][C:7]1[CH:6]=[CH:5][C:4]2[N:9]([CH:10]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])[CH:22]([CH3:23])[CH2:21][O:20][C:3]=2[C:2]=1[F:1]
Reactant: COC(=O)C(=CNc1ccc(F)c(F)c1OCC(C)OS(=O)(=O)c1ccc(C)cc1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)C(=CN1c2ccc(F)c(F)c2OCC1C)C(=O)OC
Temperature: 80 °C
Yield: 92.7 %

Procedure:
A mixture of 749 mg of the compound obtained in Example 7, 207 mg of potassium carbonate and 5 ml of anhydrous DXF was heated at 80° C. for 8 hours. The mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield 455 mg of the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:16]Br)=[C:4]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:5]([O:7]C)=O.Cl.[NH2:19][CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:4]2[C:3]=1[CH2:16][N:19]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1)[C:5]2=[O:7]
Reactant: COC(=O)c1cc(OC)c(OC)c(Br)c1CBr
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2Cc3c(cc(OC)c(OC)c3Br)C2=O)cc1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
Methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate (1.5 g, 4.1 mmol) and methyl 4-(aminomethyl)benzoate hydrochloride (1.6 g, 2 equiv.) in the step 1 were dissolved in a mixture of THF and distilled water (mixture ratio=4:1 (v/v), 10 mL). Triethyl amine (1.7 mL, 3 equiv.) was added thereto and stirred at room temperature for 1 night. The reaction proceeded until no methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate was detectable by thin-layer chromatography (TLC). The resulting mixture thus obtained was distilled under a reduced pressure to remove THF. The resulting material was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and the distilled water. The isolated organic layer was collected, dried over anhydrous MgSO4, and distilled under a reduced pressure to remove solvent. The resulting residue was subjected to a silica gel column chromatography (EtOAc/hexane=1:1) to obtain the title compound (1.6 g, 93%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:12]=2[CH:32]=1.O>O1CCCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[CH:18]=[C:19]([CH2:21][OH:22])[N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:12]=2[CH:32]=1
Reactant: CCOC(=O)c1cn2c(n1)CN=C(c1ccccn1)c1cc(Br)ccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cn2c(n1)CN=C(c1ccccn1)c1cc(Br)ccc1-2
Temperature: -35 °C
Yield: 43.3 %

Procedure:
0.38 g of lithium aluminium hydride was added portionwise to a suspension of 2.06 g of ethyl 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylate in 250 ml of tetrahydrofuran at −40° C. while stirring vigorously. A dark green solution thereby formed and this was stirred at −7 to −10° C. for 45 min. Then, the mixture was cooled to −35° C. and treated dropwise with 2 ml of water. After stirring at room temperature for 2 h. a further 6.0 ml of water were added slowly. The reaction mixture was filtered clear over Dicalite and the filtrate was evaporated in a vacuum. The residue was partitioned between 100 ml of chloroform and 50 ml of saturated aqueous sodium hydrogen carbonate solution. The chloroform phase was separated, dried over sodium sulphate and evaporated in a vacuum. The residue (1.9 g) was dissolved in 100 ml of tert-butanol and 50 ml of pyridine, treated with 1.0 g of selenium dioxide and stirred at 65° C. for 30 min. The mixture was evaporated in a vacuum, the residue was dissolved in chloroform, with a small amount of insoluble impurity being filtered off. The solution was chromatographed over 250 g of aluminium oxide (activity 1). A small amount of impurity was eluted with dichloromethane/etanol 98:2, then 0.95 g of the desired 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol was eluted with dichloromethane/ethanol 95:5, 90:10 and 80:20. After recrystallization from ethyl acetate there was obtained 0.80 g of 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 176-178° C. which was converted into the hydrochloride (m.p. above 300° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=1.Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[NH:24][CH:23]=[CH:22][N:21]=2)=[CH:8][N:7]=[C:6]([CH2:5][NH:4][CH2:3][CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)[N:11]=1
Reactant: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(NCCNCc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
Using the procedure described above in Example 139, reaction of (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methylamine and 2-chloro-5-cyanopyridine were reacted to afford [4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methyl {2-[(5-cyano(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])NC2=CSC=C2C=1Cl)=[O:5])[CH3:2].Cl.[CH3:18][O:19][C:20]([C:22]1[C:26]([NH2:27])=[CH:25][S:24][CH:23]=1)=[O:21].C(C(C(Cl)=O)C(Cl)=O)C>>[CH3:18][O:19][C:20]([C:22]1[C:26]([NH:27][C:11](=[O:12])[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:25][S:24][CH:23]=1)=[O:21]
Reactant: CCOC(=O)c1c(Cl)c2cscc2[nH]c1=O
Reactant: COC(=O)c1cscc1N
Agent: CCC(C(=O)Cl)C(=O)Cl
Agent: Cl
Product: CCOC(=O)CC(=O)Nc1cscc1C(=O)OC

Procedure:
A preferred intermediate in the preparation of a compound of formula (II) is 4-chloro-1,2-dihydro-2-oxo-thieno[3,4-b]pyridine-3-carboxylic acid ethyl ester, depicted by formula (25) below. To prepare this intermediate, 4-amino-thiophene-3-carboxylic acid methyl ester hydrochloride, depicted by formula (21), was reacted with ethylmalonyl chloride to yield intermediate 4-(2-ethoxycarbonyl-acetylamino)-thiophene-3-carboxylic acid methyl ester, depicted by formula (22). This intermediate was converted to 7-hydroxy-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester, depicted by formula (23) by reacting with sodium ethoxide, and was then converted into 5,7-dihloro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester, depicted by formula (24). Hydrolysis 5,7-dihloro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester, depicted by formula (24), yielded 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-indene-3-carboxylic acid ethyl ester, depicted by formula (25), as shown in Scheme 11.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)[CH3:7].[Li].C(C1C=CC(C2C=CC(C(C)(C)C)=CC=2)=CC=1)(C)(C)C>C1COCC1>[F:14][C:10]1[CH:9]=[C:8]([C:6]2([CH3:7])[CH2:2][CH2:3][CH2:4][NH:5]2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(=NCCCCl)c1cccc(F)c1
Agent: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Agent: [Li]
Solvent: C1CCOC1
Product: CC1(c2cccc(F)c2)CCCN1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
In step 8-2, 3-chloro-N-(1-(3-fluorophenyl)ethylidene)propan-1-amine (8-1) (4.7 g, 22 mmol) was added at −78° C. to a solution of lithium granules (0.8 g, 110 mmol) and 4,4′-di-tert-butylbiphenyl (0.6 g, 2.2 mmol) in THF (40 mL) cooled to −78° C. The resulting solution was stirred at −78° C. for 2 hours then quenched with water and the temperature was allowed to increase to 20° C. Solids were then removed by filtration, the mother liquor was reduced using a rotary evaporator and the resulting residue was reconstituted in ethyl acetate. The organic was washed with 1N HCl (3×25 mL) and the aqueous layer extracted with ethyl acetate. The aqueous layer was neutralized with 1N NaOH solution and extracted with ethyl acetate (3×100 mL). The organic layer was dried with sodium sulfate and the solvent removed to yield 2-(3-fluorophenyl)-2-methylpyrrolidine (8-2) as a light yellow oil. m/z=180.3 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[C:15]([C:21]([OH:23])=O)[NH:16]4)[C:6]=2[CH:24]=1.Cl.Cl.Cl.[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1>>[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH:45][C:21]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[C:12]([O:11][CH2:10][C:7]3[C:6]5[CH:24]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=5[O:9][CH:8]=3)[CH:20]=[CH:19][CH:18]=4)=[O:23])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Reactant: O=C(O)c1cc2c(OCc3coc4ccc(F)cc34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(F)cc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(5-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (113) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:32])[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:20]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:20]=3)[CH2:17][C:16](=[O:32])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2ccc(Cl)cc2N1

Procedure:
The title compound was prepared from {4-chloro-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M25) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (84 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[C:26]([C:27]([O:29]C)=[O:28])[C:20]=4[N:19]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[C:26]([C:27]([OH:29])=[O:28])[C:20]=4[N:19]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc4c(C(=O)OC)cccc4[nH]3)C[C@H]2OC)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc4c(C(=O)O)cccc4[nH]3)C[C@H]2OC)nc1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Methyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1H-benzimidazole-4-carboxylate obtained in Example (187d) (190 mg, 0.41 mmol) was dissolved in methanol (5 ml) and THF (5 ml). A 2 N aqueous lithium hydroxide solution (5 ml) was added, and the mixture was stirred at 50 to 70° C. for one hour. The organic solvent was evaporated under reduced pressure, followed by neutralization with 1 N hydrochloric acid. The resulting solid was collected by filtration, washed with distilled water, and dried under reduced pressure at 45° C. to obtain the title compound as a solid.