Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].S([O-])([O-])(=O)=O.[Mg+2].[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][O:25][C:26]2=[O:31]>C(#N)C>[CH2:1]([N:3]([CH2:6][C:7]1[CH:14]=[CH:13][C:10](/[CH:11]=[N:21]/[C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH2:24][O:25][C:26]3=[O:31])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1ccc(C=O)cc1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: CCN(CC)Cc1ccc(/C=N/c2cccc3c2COC3=O)cc1
Yield: 33.6 %

Procedure:
To a stirred mixture of 4-((diethylamino)methyl)benzaldehyde (3.7 g, 19.4 mmol) and anhydrous magnesium sulfate (11.6 g, 96.8 mmol) in anhydrous acetonitrile (100 mL) was added 4-aminoisobenzofuran-1(3H)-one (2.89 g, 19.4 mmol) at 0° C. After the addition the mixture was stirred refluxed for 3 days. The mixture was filtered and the cake was washed with ethyl acetate (50 mL×3). The filtrate was concentrated to give crude product, which was re-crystallized from isopropanol to give the title compound (2.1 g, yield: 32%). LC-MS (ESI) m/z: 323 (M+1)+.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[S:18])=[CH:12][CH:11]=1>ClCCl>[CH3:22][C:21]([CH3:24])([CH3:23])[CH2:20][N:19]1[C:2](=[O:8])[C:3](=[O:5])[N:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[C:17]1=[S:18]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)(C)CNC(=S)Nc1ccc(F)cc1
Solvent: ClCCl
Product: CC(C)(C)CN1C(=O)C(=O)N(c2ccc(F)cc2)C1=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
Ethyl chlorooxoacetate (0.60 mL, 5.41 mmol) was added to a stirring solution of the above thiourea (1.00 g, 4.16 mmol) in dichloromethane (20 mL) and the resulting mixture was stirred overnight at room temperature. Concentration, trituration of the residue with diethyl ether, and recrystallization from boiling methanol afforded 0.77 g (62%) 1-(2,2-dimethyl-propyl)-3-(4-fluoro-phenyl)-2-thioxo-imidazolidine-4,5-dione as an orange-yellow solid: mp 165.2–166.3° C.; 1H NMR (DMSO-d6): δ 7.40 (m, 4H), 3.73 (s, 2H), 0.98 (s, 9H); IR (KBr): 3500, 2980, 1770 cm1; MS (m/z) 294 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][N:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][N:16]=2)[C:8]2[CH:7]=[C:6]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ncc(C)s2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc(C2=CCC(C)(C)c3ccc(CCc4ccc(C(=O)O)cc4)cc32)s1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[5,6-dihydro-5,5-dimethyl-8-(5-methylthiazol-2-yl)-2-naphthalenyl)ethynylbenzoate (Compound 15) (100 mg, 0.23 mmol) and 4 ml of EtOH at room temperature was added aqueous NaOH (1 ml, 1M, 1 mmol). The resulting solution was warmed to 50° C. for 1 hour and concentrated in vacuo. The residue was suspended in a solution of CH2Cl2 and ether (5:1) and acidified to pH 5 with 1M aqueous HCl. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered and the solvents removed under reduced pressure to give the title compound as a white solid. 1H NMR (d6-DMSO): δ 7.96 (1H, d, J=1.7 Hz), 7.95 (2H, d, J=8.0 Hz), 7.65 (2H, d, J=8.0 Hz), 7.64 (1H, s), 7.53 (1H, dd, J=1.7, 8.0 Hz), 7.46 (1H, d, J=8.0 Hz), 6.59 (1H, t, J=4.5 Hz), 2.50 (3H, s), 2.39 (2H, d, J=4.5 Hz), 1.27 (6H, s).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][NH:8][C:9](=[S:11])[S-:10])(=[O:4])=[O:3].C([NH+](CC)CC)C.[CH2:19]([OH:21])[CH3:20].BrCC(OCC)=O>O>[CH3:1][S:2]([NH:5][CH2:6][CH2:7][N:8]1[C:19](=[O:21])[CH2:20][S:11][C:9]1=[S:10])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)NCCNC(=S)[S-]
Reactant: CCO
Agent: CCOC(=O)CBr
Agent: CC[NH+](CC)CC
Solvent: O
Product: CS(=O)(=O)NCCN1C(=O)CSC1=S
Temperature: 20 °C
Yield: 100 %

Procedure:
30 g (2.1×10-1 mols) of 2-methanesulfonylaminoethylamine and 18.1 g (2.3×10-1 mols) of carbon bisulfide were dispersed into 10 ml of ethyl acetate. 32.8 g (2.3×10-1 mols) of triethylamine was added dropwise to the dispersion while stirring at room temperature. The admixture was allowed to react for about 4 hours while the internal temperature thereof was maintained at 40° C. 70 ml of ethanol was added to the reaction system. The resulting crystal was filtered off and then washed with 30 ml of ethanol to obtain 54.0 g of triethylammonium N-(2-methanesulfonylaminoethyl)dithiocarbamate as an intermediate product. 54.0 g (1.7×10-1 mols) of the thus-obtained triethylammonium N-(2-methanesulfonylaminoethyl)dithiocarbamate was dispersed into 75 ml of ethanol. The dispersion was stirred while the internal temperature thereof was maintained at 7° to 8° C. under ice cooling. 28.6 g (1.7×10-1 mols) of ethyl bromoacetate was added dropwise to the dispersion. The dispersion was stirred for about 1 hour while the internal temperature was maintained at 20° C. by suppressing heat generation under ice cooling. The dispersion was further stirred for about 1 hour at room temperature. The resulting reaction product was put into 300 ml of water. The aqueous mixture was extracted with 500 ml of ethyl acetate. The mixture was then washed with water. The resulting ethyl acetate layer was dried over anhydrous sodium sulfate. The ethyl acetate solution was filtered, and the filtrate was concentrated to obtain 43.7 g of 3-(2-methanesulfonylaminoethyl)rhodanine (yield: 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:24].[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:29][CH2:30][N:26]([CH3:25])[C:27]4=[O:31])=[C:3]([F:24])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)c(F)c3)CC2)c(C)c1
Yield: 65.6 %

Procedure:
Using (4-bromo-3-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (353 mg) described in Preparation Example 125 and 1-methylimidazolidin-2-one (108 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (243 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:29][NH:30][S:31]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)(=[O:33])=[O:32]>>[ClH:1].[CH3:29][NH:30][S:31]([CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:2]2[N:7]=[C:6]([N:8]([C:9]3[CH:27]=[CH:26][C:12]4[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]5[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=5)=[N:15][C:11]=4[CH:10]=3)[CH3:28])[CH:5]=[CH:4][N:3]=2)=[CH:40][CH:41]=1)(=[O:32])=[O:33]
Reactant: CNS(=O)(=O)CCc1ccc(N)cc1
Reactant: CN(c1ccc2c(c1)nc(NCc1ccc(F)cc1)n2C)c1ccnc(Cl)n1
Product: CNS(=O)(=O)CCc1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(NCc3ccc(F)cc3)n4C)n2)cc1
Product: Cl
Yield: 58.9 %

Procedure:
The title compound was prepared following the procedure of example two with N5-(2-chloro-pyrimidin-4-yl)-N2-(4-fluoro-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (99 mg, 0.25 mmol) and 2-(4-amino-phenyl)-ethanesulfonic acid methylamide (54 mg, 0.25 mmol) to give the desired product as a white solid (90 mg, 59%). 1H NMR (300 MHz, d6-DMSO) δ 9.04 (s, 1H), 7.68-7.75 (m, 3H), 7.41-7.46 (m, 3H), 7.23 (d, J=8.1 Hz, 1H), 7.08-7.17 (m, 4H), 6.94 (q, J=5.1 Hz, 1H), 6.83 (dd, J=8.1 and 1.5 Hz, 1H), 5.59 (d, J=6.0 Hz, 1H), 4.57 (d, J=5.4 Hz, 2H), 3.56 (s, 3H), 3.41 (s, 3H), 3.20-3.26 (m, 2H), 2.83-2.88 (m, 2H), 2.59 (d, J=5.1 Hz, 3H). MS (ESI) m/z=575 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1F.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[N:19]([CH2:20][CH3:21])[CH2:17][CH3:18]
Reactant: CNc1cc(F)c(C(=O)OC)cc1[N+](=O)[O-]
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)c1cc(NC)c([N+](=O)[O-])cc1C(=O)OC

Procedure:
2-Diethylamino-4-methylamino-5-nitro-benzoic acid methyl ester (1.2 g) was prepared by following General Procedure A starting from 2-fluoro-4-methylamino-5-nitro-benzoic acid methyl ester (1.0 g) and diethylamine (683 uL) in DMF.
Reaction SMILES: Cl[C:2]1[C:7]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]3[N:14]=2)=[CH:6][C:5]([F:27])=[CH:4][N:3]=1.[CH2:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]#[CH:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(C)C)(C)C>CN(C=O)C.[Cu]I>[C:34]([O:33][C:32]([NH:31][CH2:28][C:29]#[C:30][C:2]1[C:7]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]3[N:14]=2)=[CH:6][C:5]([F:27])=[CH:4][N:3]=1)=[O:38])([CH3:37])([CH3:36])[CH3:35]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3Cl)nc12
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3C#CCNC(=O)OC(C)(C)C)nc12
Temperature: 95 °C

Procedure:
(R)-ethyl 5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Example 12, Step C; 153 mg, 0.392 mmol) in DMF (2 mL) was added tert-butyl prop-2-ynylcarbamate (122 mg, 0.785 mmol), copper(I) iodide (11 mg, 0.0578 mmol), triphenylphosphine (82.4 mg, 0.314 mmol), di-triphenylphosphine palladium(II) chloride (116 mg, 0.165 mmol), and diisopropylamine (99.3 mg, 0.981 mmol). The reaction mixture was sealed and heated to 95° C. for 8 hours, then cooled to ambient temperature and concentrated under reduced pressure The residue was purified by silica column chromatography, eluting with 33% EtOAc/Hexanes to afford the final product mixed with Ph3P (160 mg, 80.2% yield). MS (apci) m/z=508.9 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH2:15](Br)[CH:16]([CH3:18])[CH3:17].[H-].[Na+]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)CBr
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)CN(c1ccc(I)cc1)c1ncccn1
Yield: 93.6 %

Procedure:
In the same manner as in Reference Example 13, N-(4-iodophenyl)pyrimidin-2-amine (150 mg) and isobutyl bromide (83 mg) were reacted in the presence of sodium hydride to obtain N-(4-iodophenyl)-N-isobutylpyrimidin-2-amine (167 mg).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:55]=[C:54]([CH3:56])[CH:53]=[CH:52][C:49]=1[CH2:50][NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:51][CH2:50][C:49]4[CH:52]=[CH:53][C:54]([CH3:56])=[CH:55][C:48]=4[F:47])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(CN)c(F)c1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2ccc(C)cc2F)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2-fluoro-4-methylbenzylamine (Jrd-Fluoro) to give the title product. LC-MS (ES+) 786 [(M+H)+].
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@@H:19]2[S:23][CH3:24])[C@H:15]2[C@@:6]1([F:27])[C@:7]1([CH3:26])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:25])[CH:9]=[CH:8]1)(=O)C>CO.O1CCCC1>[F:27][C@:6]12[C@@H:5]([OH:4])[CH2:22][C@@:20]3([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@@H:19]3[S:23][CH3:24])[C@@H:15]1[CH2:14][CH2:13][C:12]1[C@:7]2([CH3:26])[CH:8]=[CH:9][C:10](=[O:25])[CH:11]=1
Reactant: CS[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@]12C
Solvent: C1CCOC1
Solvent: CO
Product: CS[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of (11β,17β)-11-(acetyloxy)-9-fluoro-17-(methylthio)androsta-1,4-dien-3-one (2.0 g; 5.09 mmole) in a mixture of methanol (15 ml) and tetrahydrofuran (15 ml) was flushed well with nitrogen, 3M aqueous sodium hydroxide (2.0 ml) was added and the mixture was stirred at room temperature for 45 minutes. A moderate excess of acetic acid was added, the mixture was concentrated in vacuo and was diluted with water. The steroid that separated was isolated by filtration, washed with water, dried, crystallized from ethyl acetate-hexane and dried (100° C., 0.3 mm of Hg, 10 hours) to afford the homogeneous (tlc) analytical specimen of the title commpound (1.4 g), melting point 269°-270° C. with consistent spectral data.
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](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[NH2:41][CH:42]1[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]1>CN(C)C=O>[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]([NH:41][CH:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a mixture of 0.11 g (0.24 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-fluoro-benzoic acid (I-182), 0.17 mL (0.96 mmole) of ethyldiisopropyl amine, 0.030 g (0.26 mmole) of 4-amino-1-methyl-piperidine and 3.0 mL of dimethylformamide was added 0.11 g (0.26 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-80:20) gave 0.065 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-fluoro-N-(1-methyl-piperidin-4-yl)-benzamide (I-183) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C[Al](C)C.[F:27][C:28]([F:47])([F:46])[C:29]([NH:31][C:32]1[C:40]2[C:35](=[N:36][CH:37]=[CH:38][N:39]=2)[S:34][C:33]=1[C:41](OCC)=[O:42])=[O:30]>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:20]([C:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:10]([NH:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:41]([C:33]2[S:34][C:35]3=[N:36][CH:37]=[CH:38][N:39]=[C:40]3[C:32]=2[NH:31][C:29](=[O:30])[C:28]([F:27])([F:47])[F:46])=[O:42])[CH:3]=1)=[O:22])([CH3:19])[CH3:18])#[N:21]
Reactant: CCOC(=O)c1sc2nccnc2c1NC(=O)C(F)(F)F
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2nccnc2c1NC(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
A solution of N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 5 (25 mg, 0.085 mmol) and trimethylaluminum (0.170 mL, 0.341 mmol) in toluene (1 mL) was stirred for 30 min. Ethyl 7-(2,2,2-trifluoroacetamido)thieno[2,3-b]pyrazine-6-carboxylate 10 (27.2 mg, 0.085 mmol) in toluene (1 mL) was added and stirred overnight at 60° C. Poured in NaHCO3 solution and extracted with EtOAc. Organic layer was washed with brine, dried and evaporated. Purification by chromatography (20->80 ethylacetate in CH2Cl2) gave the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-7-(2,2,2-trifluoroacetamido)thieno[2,3-b]pyrazine-6-carboxamide 44 (10 mg, 20%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.26 (s, 3H), 7.29 (d, J=8.2 Hz, 1H), 7.58-7.66 (m, 2H), 7.76 (d, J=8.2 Hz, 1H), 7.91-7.98 (m, 2H), 8.05 (s, 1H), 8.85 (s, 1H), 8.94 (s, 1H), 10.20 (br s, 1H), 10.38 (s, 1H), 11.80 (br s, 1H). (m/z)=567 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=1>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:31]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)(=[O:33])=[O:32])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3cccnc3)cc2)c2ccc3ccccc3c2N1
Yield: 91.8 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 3-pyridinesulfonyl chloride (20 mg, 0.11 mmol) were treated by heating in pyridine (3 mL). A post-treatment was performed in a conventional manner to give N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-pyridinesulfonamide (40 mg).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[Br:13][C:14]1[N:19]=[C:18]([CH:20]=[CH:21][C:22](N(OC)C)=[O:23])[CH:17]=[CH:16][CH:15]=1>>[Br:13][C:14]1[N:19]=[C:18]([CH:20]=[CH:21][C:22](=[O:23])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])[CH:17]=[CH:16][CH:15]=1
Reactant: CON(C)C(=O)C=Cc1cccc(Br)n1
Reactant: FC(F)(F)C(F)(F)I
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1cccc(Br)n1)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 61.6 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (42.1 mL, 35.3 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (23.6 mL, 35.3 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of 3-(6-bromo-pyridin-2-yl)-N-methoxy-N-methyl-acrylamide (3.2 g, 11.8 mmol, in tetrahydrofuran 30.0 mL) prepared in Step 2 was slowly added at −78° C. The reaction mixture was stirred at room temperature, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 2.4 g of the titled compound as a yellow liquid.
Reaction SMILES: [N:1]([CH2:8][CH2:9][OH:10])([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:21]1([NH:24][C:25]([C:27]2[S:40][C:30]3=[N:31][C:32](S(C)=O)=[C:33]([Cl:36])[C:34]([CH3:35])=[C:29]3[C:28]=2[NH2:41])=[O:26])[CH2:23][CH2:22]1>C1COCC1>[CH:21]1([NH:24][C:25]([C:27]2[S:40][C:30]3=[N:31][C:32]([O:4][CH2:3][CH2:2][N:1]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7])=[C:33]([Cl:36])[C:34]([CH3:35])=[C:29]3[C:28]=2[NH2:41])=[O:26])[CH2:23][CH2:22]1
Reactant: OCCN(CCO)CCO
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCN(CCO)CCO)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 41.7 %

Procedure:
To a solution of triethanolamine (1.044 g, 7.0 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. in a sealed tube for 1.5 hours, cooled to room temperature, and then quenched by the addition of water (10 ml). The reaction mixture is transferred to an erlenmeyer flask and diluted to 75 ml with water. The mixture is cooled to 0° C. and stirred. During this time, a yellow precipitate is formed. This solid is collected by filtration and slurried in a 2:1 EtOAc:hexane mixture. This slurry is stirred for 10 minutes, filtered, and the collected solid is placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.179 g, 41%). Mass (m/z): 429.2 (M++1), 427.2 (M+−1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([CH3:25])[CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[C:17]([CH3:25])[CH:16]=2)[CH:6]=1)=[O:4]
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(-c2cc(C)nc3ccccc23)c2ccccc12
Temperature: 80 °C
Reaction time: 60 h

Procedure:
1 mmol (175 mg) of 1H-indole-3-carboxylic acid methyl ester, 1.1 mmol (195 mg) of 4-chloro-2-methyl-quinoline and 1.2 mmol (390 mg) of Cs2CO3 are suspended in 3 ml of dry DMF. The mixture is stirred for 60 h at 80° C. under argon, allowed to cool to room temperature, and diluted with water (20 ml). Part of the product precipitates and is filtered off, the filtrate is extracted twice with ethyl acetate (20 ml portions). The combined extracts are dried over anhydrous Na2SO4 and evaporated. The residue is combined with the precipitate and purified by prep. HPLC to yield 1-(2-methyl-quinolin-4-yl)-1H-indole-3-carboxylic acid methyl ester (MS molpeak 316.12 (M+H, electrospray ionisation)) as an off-white foam after freeze-drying.