Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([N:12]1[C:17]2([CH2:19][CH2:18]2)[CH2:16][N:15]([C:20]2[C:21]3[CH:28]=[CH:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:14][CH2:13]1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[CH2:48]O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(/N=N\C(=O)OC(C)C)=O)(C)C>C1COCC1.O>[CH2:36]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[CH2:48][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[S:9]([N:12]1[C:17]2([CH2:18][CH2:19]2)[CH2:16][N:15]([C:20]2[C:21]3[CH:28]=[CH:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:14][CH2:13]1)(=[O:11])=[O:10])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: OC[C@@H]1CCCN1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Agent: CC(C)OC(=O)/N=N\C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(C[C@@H]1CCCN1Cc1ccccc1)S(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Tert-butyl 4-[8-(tert-butoxycarbonylsulfamoyl)-5,8-diazaspiro[2.5]octan-5-yl]pyrrolo[2,3-d]pyrimidine-7-carboxylate (intermediate 47) (0.55 mmol) was dissolved in dry THF (3 mL) and added [(2S)-1-benzylpyrrolidin-2-yl]methanol (0.61 mmol) and triphenylphosphine (0.66 mmol). The reaction mixture was cooled to 0° C. and slowly added isopropyl (NZ)—N-isopropoxycarbonyliminocarbamate (0.66 mmol). The reaction mixture was allowed to warm up freely to rt and stirred at rt for 16 h. The crude mixture was treated with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with H2O (2×50 mL), brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=2)([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.OS(O)(=O)=O>>[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=3)([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)c(F)c1
Agent: O=S(=O)(O)O
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (0.6 g, 1.15 mmol) was cooled to 0° C., then conc. H2SO4 (2 mL) was added slowly. The reaction was stirred at RT for 2 hours. The mixture was then poured into ice and extracted with EtOAc. The organic phase was separated, dried over Na2SO4, filtered and solvent was removed under reduced pressure to yield a residue that was triturated with ethyl acetate/heptane and the precipitates were collected by filtration and washed with ether to yield the product rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.526 g, 98.1%) as a white solid. HRMS (ES+) m/z Calcd for C23H22Cl2F2N2O2S+H [(M+H)+]: 467.1099. found: 467.1097.
Reaction SMILES: [CH:1]([NH:5][C:6]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[O:7])([CH2:3][CH3:4])[CH3:2].Cl.[CH3:14]O>>[CH:1]([NH:5][C:6]([CH:8]=[CH:9][C:10]([O:12][CH3:14])=[O:11])=[O:7])([CH2:3][CH3:4])[CH3:2]
Reactant: CO
Reactant: CCC(C)NC(=O)C=CC(=O)O
Agent: Cl
Product: CCC(C)NC(=O)C=CC(=O)OC
Reaction time: 2 h

Procedure:
To 3-(sec butylcarbamoyl)acrylic acid (20 g, 117 mmol) at room temperature was added 150 mL 1.2M HCl in methanol. The resulting mixture was stirred for two hours. Solvents were removed in vacuo to give the desired ester, which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20]Cl)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]([NH2:25])=[S:24].CCOCC>O1CCOCC1>[ClH:19].[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:24][C:23](=[NH:22])[NH2:25])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(N)=S
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSC(=N)N)c2CC1
Product: Cl
Temperature: 95 °C
Reaction time: 1 h
Yield: 170.8 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.742 g, 2.247 mmol) in anhydrous dioxane (9.4 mL) add thiourea (0.17 g, 2.2 mmol) at room temperature. Heat the mixture at 95° C. overnight. Cool the mixture to room temperature and add anhydrous ether (25 mL). Stir the mixture for 1 h and filter the slurry. Wash the solid with ether (25 mL) and dry to afford the desired intermediate as a white solid (0.780 g, 85%). MS (ES+) m/z: 370.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[C:30](=[O:32])=[O:31]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:30]([OH:32])=[O:31])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)cc12
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)c(C(=O)O)c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-5-fluoro-1,2-benzisoxazole (0.30 g) in tetrahydrofuran (20 ml) was added lithium diisopropylamide (1.4 ml, 1.5M cyclohexane solution) dropwise at -70° C. under nitrogen atmosphere, and the reaction mixture was stirred at the same temperature for 15 minutes. Gaseous carbon dioxide was introduced for 10 minutes and the temperature was allowed to rise to 0° C. The reaction mixture was poured into ice water (40 ml) and washed with diethylether (40 ml each) twice. The aqueous layer was separated, and after the pH was adjusted to 4 with potassium dihydrogen phosphate, it was then extracted with ethyl acetate (each with 40 ml) twice. The combined extracts were dried over anhydrous magnesium sulphate, filtered and the solvent was evaporated under reduced pressure to give the title compound (0.31 g, 90% yield) as a colorless oil.
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]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2>CN(C=O)C>[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:25]2
Reactant: Fc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4ccc(F)cc4C3)c(F)cc2c1=O
Yield: 45.4 %

Procedure:
170 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 247 mg of 5- fluoroisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 109 mg of the target compound.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[NH3:40]>C(Cl)(Cl)Cl>[NH2:40][CH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:38][CH:39]=1
Reactant: N
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(CCN)cc2)c1

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (31 mg) and a saturated ammonia solution in chloroform (0.1 ml) according to an analogous synthetic method to Example 806, the title compound (0.7 mg) was obtained.
Reaction SMILES: C(N1C[C@H](OCC)[C@H](NC2C(CC)=NC(C3C=CC(Cl)=CC=3Cl)=C(CC)N=2)C1)(=O)C.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[N:40]=[C:41]([CH2:57][CH3:58])[C:42]([NH:47][C@H:48]2[C@@H:52]([O:53][CH2:54][CH2:55][F:56])[CH2:51][NH:50][CH2:49]2)=[N:43][C:44]=1[CH2:45][CH3:46].Cl[C:60]([O:62][CH3:63])=[O:61]>>[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[N:40]=[C:41]([CH2:57][CH3:58])[C:42]([NH:47][C@H:48]2[C@@H:52]([O:53][CH2:54][CH2:55][F:56])[CH2:51][N:50]([C:60]([O:62][CH3:63])=[O:61])[CH2:49]2)=[N:43][C:44]=1[CH2:45][CH3:46]
Reactant: COC(=O)Cl
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CNC[C@@H]1OCCF
Agent: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OC)C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting 5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(3R,4S)-4-(2-fluoroethoxy)pyrrolidin-3-yl]pyrazin-2-amine and methyl chloroformate, and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, DMSO-d6) δ) 7.71, 7.50, 7.41, 6.04, 4.61, 4.54, 4.42, 4.25, 3.78-3.70, 3.60, 3.54, 3.37, 2.65, 2.37, 1.15, 1.08; IR (diffuse reflectance) 2970, 2934, 2350 (w), 2341 (w), 2039 (w), 1940 (w), 1921 (w), 1710 (s), 1569, 1551, 1499, 1466 (s), 1452 (s), 1393 (s), 1373, cm−1; HRMS (FAB) calcd for C22H27Cl2FN4O3+H 485.1522, found 485.1541. Anal. Calcd for C22H27Cl2FN4O3: C, 54.44; H, 5.61; N, 11.54. Found: C, 54.73; H, 5.76; N, 11.46.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][N:3]=1.[Cl:12][S:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])(=[O:15])=[O:14]>>[CH:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]([C:19]([C:18]2[CH:17]=[C:16]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:24]=[CH:23][CH:22]=2)=[O:20])[C:19]([C:18]2[CH:17]=[C:16]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:24]=[CH:23][CH:22]=2)=[O:20])=[N:3][CH:4]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(N)nc1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Product: CC(C)Oc1ccc(N(C(=O)c2cccc(S(=O)(=O)Cl)c2)C(=O)c2cccc(S(=O)(=O)Cl)c2)nc1

Procedure:
The entitled compound was produced according to the method of Reference Example 5 but using 2-amino-5-isopropoxypyridine and 3-(chlorosulfonyl)benzoyl chloride as the starting materials.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]1[CH:37]=[CH:36][C:14]([CH2:15][C:16]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(C(OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>COCCO.O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][CH:16]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:36][CH:37]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(CCCc1ccccc1)(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: CCOC(=O)C(CCCc1ccccc1)Cc1ccc(OCc2ccccc2)cc1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
Potassium hydroxide (2.00 g) was added to a solution of diethyl 2-(4-benzyloxybenzyl)-2-(3-phenylpropyl)malonate (3.91 g) in a mixture of 2-methoxyethanol (30 ml) and water (3 ml). The mixture was stirred at 130° C. in an oil bath for 1.5 hours. At the end of this time the reaction mixture was partitioned between ethyl acetate and water and the mixture was acidified with aqueous hydrogen chloride solution (6N). The ethyl acetate layer was separated and washed with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated. A solution of the residual syrup in xylene (20 ml) was stirred for 1 hour and then concentrated. Concentrated sulfuric acid (1 ml) was added to a solution of the syrup residue of 2-(4-benzyloxybenzyl)-5-phenylvaleric acid in ethanol (40 ml). The mixture was stirred at 80° C. for 3 hours and allowed to stand at ambient temperature for 16 hours. At the end of this time the reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and concentrated to dryness to afford the desired compound (3.32 g) as a syrup.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11]([CH2:22][C:23](O)=[O:24])=[N:12][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:15])[C:3]1=2.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11]([CH2:22][C:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:24])=[N:12][N:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14](=[O:15])[C:3]1=2
Reactant: C1CCNC1
Reactant: Cn1c2ccccc2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21
Product: Cn1c2ccccc2c2c(CC(=O)N3CCCC3)nn(-c3ccccc3)c(=O)c21

Procedure:
The preparation is carried out as in Example 3.2, from 1 g (3 mmol) of 5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid and from excess pyrrolidine. The product is recrystallized from propan-2-ol. 0.5 g (1.3 mmol) of solid is obtained.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:19]1([C:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=3)[N:27]([CH2:38][C:39]#[CH:40])[C:26]=2[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH2:47][O:48][Si](C(C)C)(C(C)C)C(C)C)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1.CCOC(C)=O>[CH:19]1([C:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=3)[N:27]([CH2:38][C:39]#[CH:40])[C:26]=2[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH2:47][OH:48])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: C#CCn1c(-c2ccccc2CO[Si](C(C)C)(C(C)C)C(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CCn1c(-c2ccccc2CO)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Tetrabutylammonium fluoride (1.3 eq., 1M solution in THF) was added dropwise to an ice cooled solution of methyl 3-cyclohexyl-1-prop-2-yn-1-yl-2-(2-{[(triisopropylsilyl)oxy]methyl}phenyl)-1H-indole-6-carboxylate in THF (0.036M). The mixture was stirred at 0° C. for 1 h then diluted with EtOAc, washed with saturated aq. NH4Cl, water and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was subjected to flash chromatography (PE:EtOAc, 3:1). After evaporation of the solvents the product was obtained as white solid (63%). MS (ES+): 402.6 (M+H+).
Reaction SMILES: [NH:1]=[C:2]([NH:10][OH:11])[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1.[C:12](OC(=O)C)(=O)[CH3:13]>>[CH3:12][C:13]1[O:11][N:10]=[C:2]([C:3]2[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=2)[N:1]=1
Reactant: N=C(NO)c1ccc(Br)cn1
Reactant: CC(=O)OC(C)=O
Product: Cc1nc(-c2ccc(Br)cn2)no1

Procedure:
In 250 ml of acetic anhydride was dissolved 8.6 g of 2-(imino-N-hydroxyaminomethyl)-5-bromopyridine and the solution was refluxed for one day. After completion of the reaction, the same post-treatment as in Preparation Example. 13 was conducted to give the title compound. 2.8 g.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1.Br[CH2:20][C:21]([O:23]C)=[O:22]>>[CH3:17][C:16]1[C:11]([S:8]([N:7]([CH2:20][C:21]([OH:23])=[O:22])[C:4]2[CH:3]=[CH:2][C:1]([CH3:18])=[CH:6][CH:5]=2)(=[O:10])=[O:9])=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc(NS(=O)(=O)c2ncccc2C)cc1
Reactant: COC(=O)CBr
Product: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)cc1

Procedure:
prepared by reaction of 3-methyl-pyridine-2-sulfonic acid p-tolylamide with methyl bromoacetate
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)[NH:12][C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ccco2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ccco2)=NC1c1ccc(F)cc1Br
Yield: 37.8 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(furan-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.74 g, 1.53 mmol) (The compound was synthesized according to the procedure as described in WO2010069147) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.31 g, 38%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:14]1([C:26]2[C:27](=[O:42])[NH:28][C:29](=[O:41])[C:30]=2[C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37](Br)[CH:38]=3)[NH:33][CH:32]=2)[C:24]2=[C:25]3[C:20](=[CH:21][CH:22]=[CH:23]2)[CH2:19][CH2:18][CH2:17][N:16]3[CH:15]=1.O>C1(C)C=CC=CC=1.C(O)C.C([O-])(O)=O.[Na+]>[C:14]1([C:26]2[C:27](=[O:42])[NH:28][C:29](=[O:41])[C:30]=2[C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)[CH:38]=3)[NH:33][CH:32]=2)[C:24]2=[C:25]3[C:20](=[CH:21][CH:22]=[CH:23]2)[CH2:19][CH2:18][CH2:17][N:16]3[CH:15]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccc(Br)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccc(-c3cccc4ccccc34)cc12
Temperature: 100 °C
Yield: 70.9 %

Procedure:
A mixture of 1-naphthyl boronic acid (41 mg, 0.24 mmol), 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(5-bromo-1H-indol-3-yl)pyrrole-2,5-dione (88 mg, 0.2 mmol) (prepared as in Example 24), tetrakistriphenylphosphine palladium (5 mol %) in toluene (4 ml), ethanol (4 ml), saturated NaHCO3 (1 ml), and water (2 ml) was heated at 100° C. under nitrogen for 5 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (3×15 ml) and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate/hexanes (1:4) to afford 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(5-1-naphthyl-1H-indol-3-yl)pyrrole-2,5-dione as a bright red solid (70 mg, 71%). 1H NMR (CD3OD) δ: 1.80-1.92 (m, 2H), 2.72-2.80 (t, J=6.0 Hz, 2H), 3.94-3.99 (t, J=6.0 Hz, 2H), 6.50-6.58 (m, 3H), 6.66 (s, 1H), 6.72 (m, 1H), 6.98 (dd, J=8.4 Hz, J′=2.0 Hz, 1H), 7.00-7.50 (m, 2H), 7.28 (dd, J=6.8 Hz, J′=8.4 Hz, 1H), 7.38-7.43 (m, 2H), 7.61 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.97 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[S:30][CH:31]=[CH:32][N:33]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[S:30][CH:31]=[CH:32][N:33]=1)=[O:28]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1nccs1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2nccs2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 8 (Method A) from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetylthiazole hydrobromide (A. Dondoni, A. Marra, and P. Merino, J. Am. Chem. Soc., 1994, 116, 3324).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:2]([CH3:1])[CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CNCc1ccncc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N(C)Cc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.3 %

Procedure:
To a solution of N-methyl-N-(4-picolyl)amine (0.40 g, 3.3 mmol) and triethylamine (1.5 mL, 10.8 mmol) in CH2Cl2 (15 mL) was added 4-methoxybenzoyl chloride (1.2 g, 7.3 mmol). The resulting mixture was stirred at rt for 15 min, and then partitioned between 2.5N NaOH and Et2O. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with a solvent gradient of 2-4% MeOH/CHCl3. The material that was isolated was triturated with Et2O to provide the title compound as a light yellow solid (0.18 g, 21%): 1H NMR (CDCl3): δ8.60 (d, 2H); 7.43 (br d, 2H); 7.20 (br s, 2H); 6.90 (br d, 2H); 4.66 (br s, 2H); 3.80 (s, 3H); 3.00 (s, 3H).
Reaction SMILES: C[Mg]Cl.[S:4]([N:14]1[C:18]2=[N:19][CH:20]=[C:21]([CH:23]=[O:24])[N:22]=[C:17]2[CH:16]=[CH:15]1)([C:7]1[CH:13]=[CH:12][C:10]([CH3:11])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[NH4+].[Cl-].[CH3:27]COC(C)=O>C1COCC1.C(Cl)Cl>[S:4]([N:14]1[C:18]2=[N:19][CH:20]=[C:21]([CH:23]([OH:24])[CH3:27])[N:22]=[C:17]2[CH:16]=[CH:15]1)([C:7]1[CH:8]=[CH:9][C:10]([CH3:11])=[CH:12][CH:13]=1)(=[O:5])=[O:6]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C=O)cnc32)cc1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(C)O)cnc32)cc1
Temperature: 25 °C
Yield: 23 %

Procedure:
To a solution of methylmagnesium chloride (0.232 mL, 0.697 mmol) in THF (10 mL) at about −78° C. was added a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (0.210 g, 0.697 mmol, Example #10, Step B) in DCM (10.0 mL). After about 10 min saturated aqueous NH4Cl was added to the reaction mixture. After warming to room temperature, EtOAc (30 mL) was added to the reaction mixture and the organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 20-80% EtOAc/heptane to provide 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanol (0.050 g, 23%) as a yellow oil. LC/MS (Table 2, Method a) Rt=2.04 min; MS m/z: 318 (M+H)+.