Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:13]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][C:4]=2[S:3]1.[CH3:24][CH:25]([NH2:27])[CH3:26]>>[CH:25]([NH:27][C:21]([C:20]1[C:13]2[C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:5]4[NH:6][C:2](=[O:1])[S:3][C:4]=4[CH:10]=3)=[N:17][CH:16]=[N:15][C:14]=2[NH:18][CH:19]=1)=[O:22])([CH3:26])[CH3:24]
Reactant: CC(C)N
Reactant: O=C(O)c1c[nH]c2ncnc(Nc3ccc4[nH]c(=O)sc4c3)c12
Product: CC(C)NC(=O)c1c[nH]c2ncnc(Nc3ccc4[nH]c(=O)sc4c3)c12

Procedure:
18.7 mg (57 μmol) 4-[(2-Oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (prepared according to example 3) were transformed in analogy to example 4 using propan-2-amine to give after working up and purification 3.2 mg (14%) of the title compound.
Reaction SMILES: [N:1]1([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:46][CH2:45][CH2:44][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:43][CH2:42][CH2:41][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38](O)=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4].[NH2:54][C@H:55]([C@H:60]([CH2:62][C:63]([NH:65][C@H:66]([C:70]([NH:72][C@H:73]([C:82]([NH:84][C@H:85]([C:98]([O:100][CH3:101])=[O:99])[CH2:86][CH2:87][CH2:88][CH2:89][NH:90][C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])=[O:83])[CH2:74][C:75]1[CH:80]=[CH:79][C:78]([OH:81])=[CH:77][CH:76]=1)=[O:71])[CH:67]([CH3:69])[CH3:68])=[O:64])[OH:61])[CH2:56][CH:57]([CH3:59])[CH3:58].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[N:1]1([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:46][CH2:45][CH2:44][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:43][CH2:42][CH2:41][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38]([NH:54][C@H:55]([C@H:60]([CH2:62][C:63]([NH:65][C@H:66]([C:70]([NH:72][C@H:73]([C:82]([NH:84][C@H:85]([C:98]([O:100][CH3:101])=[O:99])[CH2:86][CH2:87][CH2:88][CH2:89][NH:90][C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])=[O:83])[CH2:74][C:75]1[CH:80]=[CH:79][C:78]([OH:81])=[CH:77][CH:76]=1)=[O:71])[CH:67]([CH3:68])[CH3:69])=[O:64])[OH:61])[CH2:56][CH:57]([CH3:59])[CH3:58])=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)C[C@H](O)[C@@H](N)CC(C)C)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(C)C
Reaction time: 24 h

Procedure:
840 mg of Boc-Pro-His-Pro-Phe-His-OH, 600 mg of H-Sta-Val-Tyr-Lys(Boc)-OMe (from stage 1.5) and 250 mg of HONB are dissolved in 6 ml of DMF, cooled to 0°, and 290 mg of DCCI are added. The whole is stirred for 6 hours at 0° and for 24 hours at 25° the DCH is filtered off, and the filtrate is concentrated to dryness by evaporation. The residue is dissolved in 18.8 ml of MeOH, 0.6 ml of glacial acetic acid and 0.6 ml of H2O, heated for 1 hour at 60°, concentrated to approximately 3 ml, and the peptide is precipitated in the form of greasy material with 20 ml of diisopropyl ether. It is purified by Craig partitioning in the system MeOH/0.1N AcOH/ethylene chloride/chloroform (10:3:8:4) over 750 stages; K=0.75. The chromatographically pure middle fraction is isolated by strong concentration and lyophilisation, yielding Boc-Pro-His-Pro-Phe-His-Sta-Val-Tyr-Lys(Boc)-OMe in the form of an amorphous powder; Rfn (B)=0.38; Rf (I)=0.46; Rf (C)=0.64.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl.C(O[CH:14](O)[C:15]([CH3:17])=[CH2:16])(=O)C.CC(=C)C(O)O>O1CCOCC1.O>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[N:6]=[CH:16][C:15]([CH3:17])=[CH:14]2
Reactant: C=C(C)C(O)OC(C)=O
Reactant: Nc1ccc(Cl)cc1
Agent: C=C(C)C(O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc2ccc(Cl)cc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
To a solution of 4-chloroaniline (9.59 g, 75.2 mmol) in dioxane (112 mL) was added a 6 M aqueous solution of HCl (180 mL). The reaction mixture was heated to 100° C. and a solution of 2-methyl-2-propene-1,1-diol acetate (15.5 g, 90.3 mmol) in dioxane (20 mL) was added dropwise during 1 h under an argon atmosphere. The reaction mixture was stirred for 2 h at 120° C. after which an aliquot was taken and analyzed by HPLC. Since some starting material was still left, the reaction mixture was cooled down to 100° C. and another portion of 2-methyl-2-propene-1,1-diol actetate (5.2 g, 30 mmol) was added during 1 h. After heating for 2 h at 120° C., the reaction mixture was cooled down again to 100° C. and a final portion of 2-methyl-2-propene-1,1-diol actetate (5.2 g, 30 mmol) was added during 1 h at 100° C. Heating was continued for 30 min. at 120° C. After cooling to ambient temperature the reaction mixture was diluted with water (100 mL) and extracted with 2-methoxy-2-methylpropane (2×200 mL). The combined organic phases were extracted with a 4 M HCl solution (100 mL). The combined aqueous phases were basified to pH 9 with a 4 M NaOH solution and extracted with TBME (3×200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated at reduced pressure to afford a brown oil. The crude product was purified by flash column chromatography (silica gel, cyclohexane/EtOAc 95:5) to afford 6-chloro-3-methylquinoline as a pale brown crystalline solid (6.32 g, 35.6 mmol, 47%). 1H NMR (400 MHz, CDCl3, 298 K): δ=8.78 (d, J=2.2 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.86 (bs, 1H), 7.75 (d, J=2.2 Hz, 1H), 7.60 (dd, J=8.8 Hz, 2.2 Hz, 1H), 2.55 (s, 3H). MS (ES+): 178 (M(C10H835ClN)+H)+.
Reaction SMILES: [C:1]1([C@H:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](OC([O-])=O)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:21][C:20]([O:19][C:17]([N:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:18])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A 10.00 g portion of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 10.41 g of tert-butyl dicarbonate were added to a mixture of 50 ml of toluene, 6.95 g of potassium carbonate and 30 ml of water and stirred at 20° C. overnight, and then the organic layer was washed with 30 ml of water. The thus obtained organic layer was concentrated under a reduced pressure and then dried to obtain 14.59 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 2-methylpropan-2-yl ester (1H-NMR (DMSO-d6, tetramethylsilane internal standard, 80° C.): δ 1.39 (9H, s), 2.72-2.91 (2H, m), 3.28-3.32 (1H, m), 3.80-3.89 (1H, m), 6.18 (1H, s), 7.07-7.33 (9H, m), mass spectrum: m/z=310 [M +H]+ (FAB)).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([Si:16]([CH3:28])([CH3:27])[O:17][CH:18]1[CH2:25][CH2:24][CH2:23][CH:22]([NH2:26])[CH2:21][CH2:20][CH2:19]1)([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:5]([O:4][C:2](=[O:3])[NH:26][CH:22]1[CH2:23][CH2:24][CH2:25][CH:18]([O:17][Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:27])[CH3:28])[CH2:19][CH2:20][CH2:21]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(N)CCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCCC(NC(=O)OCc2ccccc2)CCC1
Temperature: 25 °C

Procedure:
Benzyl chloroformate (4 mL, 28.02 mmol) was added to a stirred and cooled (0° C.) solution of the product of Example 5C (14.01 mmol) and diisopropylethyl amine (7.5 mL, 42.03 mmol) in dry dichloromethane (50 mL). After the addition, the solution was warmed to room temperature and stirred for another three hours. It was quenched with NaHCO3 solution. The phases were separated and the organic phase was washed with NaHSO4 solution brine, dried (Na2SO4), filtered, and evaporated. The crude [5-(tert-Butyl-dimethyl-silanyloxy)-cyclooctyl]-carbamic acid benzyl ester was isolated as an oil and was used without further purification. Tetrabutyl ammonium fluoride (42 mL, 1 M in tetrahydrofuran, 42.03 mmol) was added to a solution of crude [5-(tert-Butyl-dimethyl-silanyloxy)-cyclooctyl]-carbamic acid benzyl ester (about 14.01 mmol) in tetrahydrofuran (35 mL). The resulting solution was stirred for two hours at 23° C. before it was partitioned with diethyl ether and water. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. The residue was purified over silica gel using 5-50% ethyl acetate in hexanes to give (5-Hydroxy-cyclooctyl)-carbamic acid benzyl ester as an oil. (5-Hydroxy-cyclooctyl)-carbamic acid benzyl ester (2.68 g, 9.66 mmol) was stirred in the presence of Pd(OH)2/C (0.5 g) in methanol under H2 (balloon) for two hours at 23° C. before it was filtered through a pad of Celite and the solvent was evaporated. The title compound was isolated as an oil and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].[Cl-].[Mg+2].[Cl-].[CH2:14]=[O:15].Cl>ClCCCl.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH:14]=[O:15]
Reactant: C=O
Reactant: COc1cccc(O)c1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C=O)c(O)c1Cl
Temperature: 70 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
To a solution of 2-chloro-3-methoxyphenol (19.3 g) in 1,2-dichloroethane (150 mL) were added triethylamine (73.7 g), magnesium chloride (57.8 g) and paraformaldehyde (36.5 g), and the mixture was stirred at 70° C. for 4 hr under nitrogen atmosphere. The reaction mixture was poured into 1N hydrochloric acid, and the precipitate was removed by filtration, and washed with dichloromethane. The organic layer was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (21.5 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:32])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][C:5]2=O.Cl.[CH3:34][O:35][NH2:36].CO.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[OH:1][C:2]1[C:3]([CH3:32])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=1)([CH3:14])[CH2:6]/[C:5]/2=[N:36]\[O:35][CH3:34]
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CO/N=C1\CC(C)(COc2ccc(CC3SC(=O)NC3=O)cc2)Oc2c(C)c(C)c(O)c(C)c21
Reaction time: 240 h

Procedure:
A mixture of 1 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Example 22 of copending U.S. Ser. No. 644,996), 0.6 g of methoxyamine hydrochloride and 5 g of methanol was allowed to stand for 10 days at room temperature. At the end of this time, ethyl acetate and an aqueous solution of potassium carbonate were added. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography eluted with a 3:1 by volume mixture of hexane and ethyl acetate, to give the title compound softening at 72°-76° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[CH3:1][C:2]1[C:10]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:30][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCc1ccccc1
Reactant: Cc1c(Oc2ccc(C(N)=O)cn2)ccc2c1CCC2=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: Cc1c(Oc2ccc(C(N)=O)cn2)ccc2c1CCC2NCCc1ccccc1
Yield: 81.7 %

Procedure:
Using a method similar to Example 14, using 6-(4-methyl-1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 12, 100 mg, 0.354 mmol), phenethylamine (52 mg, 0.425 mmol), Ti(iPrO)4 (201 mg, 0.708 mmol), TiCl4 (1.0M/DCM, 0.708 ml, 0.708 mmol), and NaBH3CN (44 mg, 0.708 mmol) gives the title compound (112 mg) as a white solid. Mass spectrum (ion spray): m/z=388 (M+1); 1HNMR (CDCl3): 8.57 (s, 1H), 8.14 (d, 1H), 7.32-7.19 (m, 5H), 7.14 (d, 1H), 6.91-6.87 (m, 2H), 6.03 (br. s, 2H), 4.28 (t, 1H), 3.01 (t, 2H), 2.94 (m, 1H), 2.85 (m, 2H), 2.74 (m, 1H), 2.44 (m, 1H), 2.02 (s, 3H), 1.86 (m, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[OH:12][CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[NH2:7][C:6]1[CH:8]=[C:2]([CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[O:12][CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15]
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COc1ccc([N+](=O)[O-])c(N)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a solution of 5-fluoro-2-nitroaniline (2.00 g) and tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (2.25 g) in DMF (50 mL) was added sodium hydride (60% in oil, 0.564 g), and the mixture was stirred at room temperature for 10 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.75 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[N:18]([CH3:25])[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[C:14]3[C:26](=[O:29])[NH:27][CH2:28][C:13]=3[C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)#[N:2].[C:30](O)(=[O:32])C>CO>[C:1]([CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[N:18]([CH3:25])[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[C:14]3[C:26](=[O:29])[NH:27][CH:28]([O:32][CH3:30])[C:13]=3[C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)#[N:2]
Reactant: Cn1c2ccccc2c2c3c(c4c5ccccc5n(CCC#N)c4c21)CNC3=O
Reactant: CC(=O)O
Solvent: CO
Product: COC1NC(=O)c2c1c1c3ccccc3n(CCC#N)c1c1c2c2ccccc2n1C

Procedure:
356 mg (0.94 mmole) 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3a]pyrrolo[3,4-c]carbazole (Example 2) are stirred for 16 hours at 20° C. in 50 mL glacial acetic acid and 1 mL methanol. The further preparation is carried out in Example 4 and the crude product is chromatographed on silica gel with dichloromethane/methanol 199:1 (v/v). The fraction with an Rf of 0.25 in toluene/ethyl acetate 4:1 (v/v) is isolated. 12-(2-Cyanoethyl)-6,7,12,13-tetrahydro-7-methoxy-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of beige crystals which decompose above about 200° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[C:23](Cl)([O:25][CH2:26][CH:27]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24].Cl>O.O1CCOCC1.O1CCOCC1>[C:23]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)([O:25][CH2:26][CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[C:39]1=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:24]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1cccc(-c2ccc(C(=O)O)cc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2ccc(C(=O)O)cc2)c1)OCC1c2ccccc2-c2ccccc21
Temperature: 3 °C
Reaction time: 3 h

Procedure:
Dissolve 3′-aminobiphenyl-4-carboxylic acid (Preparation B, Step 3) (1.07 g, 5 mmol) and Na2CO3 (1.33 g, 12.5 mmol ) in H2O-dioxane (2:1, 45 mL), and cool the solution to ˜3° C. Add Fmoc-Cl (1.3 g) in dioxane (10 ml); stir at ice bath temperature for 3 hours, allow to warm to room temperature and stir for another 4 hours. Pour into ice water and acidify with aqueous HCl. Extract with EtOAc. Dry extracts over MgSO4, and strip solvent in vacuo. Recrystallize residue from CH3CN to give the title compound. HPLC Retention Time, 22.6 minutes (condition (b)).
Reaction SMILES: [F-:1].[K+].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@@H:15](O)[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)CO>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([F:1])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Reactant: [F-]
Agent: [K+]
Solvent: OCCO
Product: O=C(OCc1ccccc1)N1CC[C@H](F)C1

Procedure:
A stirred mixture of 20.85 g (0.360 moles) of potassium fluoride spray-dried and 18.0 g (0.048 moles) of (3R)-N- benzyloxycarbonyl-3-hydroxypyrrolidine in 160 ml of freshly distilled ethylene glycol was kept at 85° C. for 15 h under nitrogen atmosphere.
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: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(N2CCCC(C(N)=O)C2)OCC1=O
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: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[C:18]3[N:17]=[C:16]([CH3:19])[N:15]=[C:14]([NH:20][CH2:21]CCC(N)=O)[C:13]=3[N:12]([CH3:27])[CH:11]=2)=[C:5]([CH3:28])[CH:4]=1.B.CSC>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:10][CH2:11][NH:12][CH2:13][CH2:21][NH:20][C:14]2[C:13]3[N:12]([CH3:27])[CH:11]=[C:10]([C:6]4[C:5]([CH3:28])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])[C:18]=3[N:17]=[C:16]([CH3:19])[N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1cc(C)c(-c2cn(C)c3c(NCCCC(N)=O)nc(C)nc23)c(C)c1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: COc1ccc(CCNCCNc2nc(C)nc3c(-c4c(C)cc(OC)cc4C)cn(C)c23)cc1

Procedure:
Dissolve 2-(4-methoxyphenyl)-N-(2-{[7-(4-methoxy-2,6-dimethylphenyl)-2,5-dimethylpyrrolo[2,3-e]pyrimidin-4-yl]aminoethyl)acetamide in anhydrous THF (5 mL) and stir under N2. Add borane-dimethylsulfide complex (0.2 mL, 10.0 M in THF) and heat to reflux for 14 h. Quench by addition of N,N′-dimethyl-1,2-ethylenediamine (0.21 mL) in MeOH (5 mL) and stir for 1 h at ambient temperature. Concentrate under reduced pressure and purify the residue by preparative TLC, eluting with 10% MeOH in CH2Cl2. Dissolve the residue in a minimum amount of MeOH then add HCl in EtOAc (2 mL) and triturate with Et2O to obtain the title compound as a solid (HCl salt).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[C:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[OH:23][C:24]1[C:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Reactant: CCCCCCc1cccc(B(O)O)c1O
Product: CCCCCCc1cccc(-c2cccc(-c3cccc(-c4cccc(OC)c4O)n3)n2)c1O
Yield: 68 %

Procedure:
6-(2-Hydroxy-3-hexylphenyl)-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-3-hexylphenylboronic acid in 68% yield using method F; δH [2H6]-DMSO 13.23,(1H, s), 8.35,(2H, t), 8.27,(2H, m), 8.17,(1H, d), 8.10,(1H, d), 7.97,(1H, d), 7.72,(1H, d), 7.26,(1H, d), 7.09,(1H, d), 6.93,(2H, m), 3.84,(3H, s), 2.68,(2H, t), 1.62,(2H, m), 1.42-1.25(6H, m), 0.88(3H, t); MS 455 (MH)+; HPLC retention time (system 1) 4.94 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:22](Br)[C:23]#[CH:24].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC.C([O-])C.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:24][C:23]#[CH:22])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C#CCBr
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: CC[O-]
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: [Na+]
Product: C#CCN1N=C(c2ccc(OC)c(OC)c2)[C@@H]2CCCC[C@@H]2C1=O

Procedure:
Prepared from compound 1 and propargylbromide as described for compound 8, using sodium ethanolate instead of sodium hydride. Purified by chromatography (dichloromethane). Crystallized from methanol. M.p. 118-121° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][N:18]=[C:17]([C@@H:20]3[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]3[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH:16]=2)=[CH:11][CH:10]=1.[F:33][C:34]([F:47])([F:46])[O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>N1C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][N:18]=[C:17]([CH:20]3[CH2:25][CH2:24][N:23]([S:42]([C:39]4[CH:38]=[CH:37][C:36]([O:35][C:34]([F:33])([F:46])[F:47])=[CH:41][CH:40]=4)(=[O:44])=[O:43])[CH2:22][CH:21]3[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Fc1ccc([C@@H]2CNCC[C@H]2c2cc(-c3ccc(Cl)cc3)[nH]n2)cc1
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCC(c2cc(-c3ccc(Cl)cc3)[nH]n2)C(c2ccc(F)cc2)C1
Temperature: 60 °C

Procedure:
The product from Example 8 (23 mg, 0.049 mmol) in pyridine (1.0 ml) was treated with 4-trifluoromethoxybenzenesulfonyl chloride (63.8 mg, 0.245 mmol). The reaction mixture was heated to 60° C. for 12 h. The mixture was then concentrated and purified by RP-HPLC(C18, acetonitrile, water, 0.05% TFA) to afford the title compound. HPLC/MS: 580.0, 582.1; Rt=2.33 min (LC-4 HPLC conditions).