Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[N:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[O:28][C:29]4[CH:35]=[C:34](C(Cl)=O)[CH:33]=[CH:32][C:30]=4[N:31]=3)[CH:22]=1)[C:14]2=[O:39])=[O:10])C1C=CC=CC=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[CH2:45][NH2:46]>>[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[CH2:45][NH:46][C:34]1[CH:33]=[CH:32][C:30]2[N:31]=[C:27]([C:23]3[CH:22]=[C:21]([N:15]4[C:14](=[O:39])[C:13]5[C:17](=[CH:18][CH:19]=[C:11]([C:9]([OH:8])=[O:10])[CH:12]=5)[C:16]4=[O:20])[CH:26]=[CH:25][CH:24]=3)[O:28][C:29]=2[CH:35]=1
Reactant: O=C(Cl)c1ccc2nc(-c3cccc(N4C(=O)c5ccc(C(=O)OCc6ccccc6)cc5C4=O)c3)oc2c1
Reactant: COc1ccc(CN)cc1OC
Product: COc1ccc(CNc2ccc3nc(-c4cccc(N5C(=O)c6ccc(C(=O)O)cc6C5=O)c4)oc3c2)cc1OC

Procedure:
Prepared by the method of Example 76 g), from 2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid benzyl ester (50 mg, 0.09 mmol) and 3,4-dimethoxybenzylamine (23 mg, 0.14 mmol) the title compound was obtained (17 mg, 33%). 1H NMR (DMSO) δ 9.14(t, 1H), 8.44(dd, 1H), 8.36(m, 2H), 8.29(m, 2H), 8.11(d, 1H), 7.99(dd, 1H), 7.91(d, 1H), 7.85–7.76(m, 2H), 6.97(d, 1H), 6.92–6.85(m, 2H), 4.45(d, 2H), 3.73(s, 3H), 3.71(s, 3H). MS 576.2 m/z (M−H)−.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[N:14]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:11]2=[N:12][CH:13]=1)=[O:7])#[N:2].N1C=CN=C1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].C(OCC)(=O)C>CN(C)C=O>[C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])=[CH:19][CH:18]=3)[N:14]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:11]2=[N:12][CH:13]=1)=[O:7])#[N:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#CCCNC(=O)c1cnc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(C(=O)NCCC#N)cnc3n2C2CCCCC2)cc1
Temperature: 35 °C
Reaction time: 20 h
Yield: 82.5 %

Procedure:
To a solution of intermediate 60 (1.5 g, 3.85 mmol) in dimethylformamide (5 mL) was added imidazole (0.917 g, 13.5 mmol) and tert-butyldimethylsilyl chloride (0.870 g, 5.77 mmol). The reaction mixture was stirred at 35° C. for 20 h, and then ethyl acetate (100 mL) was added. The resulting organic phase was washed with water (4×20 mL) and brine (1×) and then dried (Na2SO4). After concentrating on a rotary evaporator the resulting residue was purified by column chromatography (silica gel, 1:1 hexanes/ethyl acetate-3:7 hexanes/ethyl acetate) to afford intermediate 61 as a white solid (1.6 g, 83%). ESI-MS m/e 504.0 (M+1).
Reaction SMILES: Cl[C:2](Cl)([O:4][C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[OH:13][C:14](O)([CH3:20])[C:15](=O)[CH2:16]CC.C1COCC1>C(N(CC)CC)C>[C:14]([C:15]1([CH3:16])[CH2:7][O:6][C:5](=[O:11])[O:4][CH2:2]1)(=[O:13])[CH3:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCC(=O)C(C)(O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)C1(C)COC(=O)OC1
Temperature: -78 °C

Procedure:
In a one liter three neck flask equipped with a mechanical stirrer and under nitrogen were added triphosgene (37.0 g), 3,3 dihydroxyethyl-2-butanone (50 g) and THF (300 mL). The resulting mixture was stirred until a homogeneous solution resulted. This homogeneous solution was cooled to −78° C. Triethylamine (75.0 g) was added to the this solution over 30 min. The cold bath was removed and the reaction allowed to warm to room temperature. After stirring for one hour at room temperature the triethylamine/HCl salt was removed by filtration and the filtrate pass through a silica gel plug. The solvent was removed under reduced pressure resulting in an off white product. This product was then washed with hot ether giving a white solid. NMR analysis indicated that the product contained a small amount of triethylamine/HCl salt, thus the material was dissolved in dichloromethane and washed with water affording 15.02 g of material. 1H NMR (CDCl3) ppm: 4.70 (ab doublet, 2H), 4.20 (ab doublet, 2H), 2.3 (S, 3H), 1.25 (S, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)[CH:3]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(Br)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 5′-bromo-6-methyl-4-(4-trifluoromethylphenyl)-[2,3′]bipyridinyl (example E.24) (0.15 g, 0.38 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.093 g, 0.42 mmol) according to the general procedure VI. Obtained as a white solid (0.035 g, 22%). MS (ISP) 408.3 [(M+H)+]; mp 248-252° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]([Mg]Br)=[CH2:12]>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[NH:8][CH:12]=[CH:11]2
Reactant: O=[N+]([O-])c1cccnc1Br
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: Brc1nccc2cc[nH]c12

Procedure:
The route shown in Scheme 1 below exemplifies synthesis of certain 7-aryl(heteroaryl) and 7-anilino-6-azaindole-1-sulfonamide compounds of the present invention. 2-Bromo-3-nitropyridine (1) reacts with vinylmagnesium bromide in THF, at −40-50° C. to afford 7-Bromo-6-azaindole (2), which reacts with 4-methoxyphenylsulfonyl chloride to provide 7-bromo-1-(4-methoxyphenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine (3). The sulfonamide (3), is then either treated with a substituted or unsubstituted phenylboronic acid, Pd(PPh3)4, and K2CO3 in toluene/EtOH to afford final compound (4) or treated with a substituted or unsubstituted aniline in pyridine to yield final compound (5).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[O:11][CH2:12][C:13](=[O:20])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:5]1)(=[O:3])[NH2:2].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCCCC1>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([N:6]3[CH2:7][CH2:8][CH2:9][CH:4]([C:1](=[O:3])[NH2:2])[CH2:5]3)=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: CCOC(=O)C1=C(N2CCCC(C(N)=O)C2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
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: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C[OH:29]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([O:24][CH2:25][CH2:26][OH:29])=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reactant: OCCO
Product: O=C(OCCO)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1

Procedure:
200 mg (0.6 mmol) of 1-benzyl-3-(5-ethoxycarbonyl-2-furyl)indazole were dissolved in ethylene glycol and heated under reflux for 1.5 h. For work-up, the mixture was concentrated using a rotary evaporator and the crude product was chromatographed over silica gel using hexane/ethyl acetate (1:1). This gave 68 mg (31%) of the title compound. 1H-NMR (D6-DMSO): δ=3.72 (q, 2H, CH2—OH), 4.31 (t, 2H, CH2—C —OH), 4.93 (t, 1H, OH), 6.78 (s, 2H, CH2-phenyl), 7.23 (d, 1H, H-3′), 7.23-7.40 (m, 6H, phenyl-H, H-5), 7.50 (d, 1H, H-4′), 7.50 (t, 1H, H-6), 7.83 (d, 1H, H-7), 8.16 (d, 1H, H-4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:24])=[CH:12][C:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH2:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH3:28]>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:24][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([CH2:27][CH3:28])=[CH:30][CH:31]=3)=[CH:12][C:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:19])[CH3:18])=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(C(=O)Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2N)cc1
Product: CCc1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2ccc(OC)cc2)cc1
Yield: 88.1 %

Procedure:
Using the procedure described in Example 68, Part A, N1-(4-methoxybenzoyl)-4-(tert-butyldimethylsilyloxy)-1,2-benzenediamine (300 mg, 0.81 mmol) was reacted with 4-ethylbenzoyl chloride (0.13 mL, 0.89 mmol) to yield 360 mg (88%) of the title compound as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]([CH:12]([O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:13][CH:14]([CH3:16])[CH3:15])(O)=[O:10].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C(N(CC)CC)C>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][NH:2][C:9]([CH:12]([O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH3:8]
Reactant: CCOC(=O)CN
Reactant: CC(C)CC(OC[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)C(CC(C)C)OC[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 14 h

Procedure:
Triethylamine, 1.15 g (0.0114 mol), is added to 1.59 g (0.0114 mol of ethyl glycinate hydrochloride in 200 ml of dichloromethane at 0°. To the previous suspension at 0° C. is added 4 g (0.0114 mol) of (2S)-phenylmethyl 2-[(1-carboxy-3-methylbutoxy)methyl]-1-pyrrolidinecarboxylate (center on side chain is R,S mixture), 1.74 g (0.0114 mol) of 1-hydroxybenzotriazole and 2.35 g (0.0114 mol) of dicyclohexylcarbodiimide. The mixture is allowed to reach room temperature and stirred 14 hours, filtered, the solvent evaporated in vacuo and the residue dissolved in 200 ml of dichloromethane and washed successively with a 5% aqueous solution of sodium carbonate, 2×200 ml, 10% aqueous solution of citric acid, 2×200 ml, and a saturated aqueous solution of sodium chloride, 2×200 ml. The dichloromethane layer is separated, dried over sodium sulfate, evaporated in vacuo, and the residue purified by chromatography using silica gel and eluting with dichloromethanemethanol (98:2) to give (2S)-phenylmethyl 2-[[1-[[(2-ethoxy-2-oxoethyl)amino]carbonyl]-3-methylbutoxy]methyl]-1-pyrrolidinecarboxylate (center on side chain is R,S mixture), 4 g; [α]D25 -72.7° (c 0.33, methanol).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C1N2CN3CN(C2)CN1C3.[C:20](O)(=[O:22])C>O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:20]=[O:22])=[CH:2]1
Reactant: CC(=O)O
Reactant: c1cnc2[nH]ccc2c1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2ncccc12
Reaction time: 4 h

Procedure:
Into a 250 mL round bottom flask was placed 1H-pyrrolo[2,3-b]pyridine (10 g, 84.75 mmol). To this was added HMTA (hexamethylenetetramine) (17.8 g, 126.99 mmol). Addition of acetic acid (36 mL) was next. To the mixture was added H2O (70 mL). The resulting solution was allowed to react, with stirring, for 4 hours while the temperature was maintained at reflux in a bath of oil. The resulting solution was diluted with 200 mL of H2O. The reaction mixture was cooled. A filtration was performed and the filtrate cake was washed with H2O. This resulted in 7.5 g (61%) of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde as a white solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH2:29]([O:31][C:32](=[O:37])[CH:33](Br)[CH2:34]Br)[CH3:30]>C1(C)C=CC=CC=1>[CH2:29]([O:31][C:32]([CH:33]1[CH2:34][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][N:11]1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH3:19])=[O:37])[CH3:30]
Reactant: Cc1cc(F)ccc1NCCNCc1ccccc1
Reactant: CCOC(=O)C(Br)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1c1ccc(F)cc1C
Temperature: 135 °C

Procedure:
To N-benzyl-N′-(4-fluoro-2-methyl-phenyl)-ethane-1,2-diamine (15.1 g) in toluene (150 mL) was added N,N-diisopropylethylamine (33.8 mL) and 2,3-dibromopropionic acid ethyl ester (25.61 mL) in toluene (350 mL). The reaction mixture was heated to 135° C. for 18 h, cooled to room temperature, and the precipitated solid was removed by filtration. The solution was concentrated, and the crude material was redissolved in TBME and washed with an aqueous 2M solution of Na2CO3 and brine, dried (Na2SO4), filtered and evaporated. Chromatography (SiO2, n-heptane/ethyl acetate 97:3) gave 4-benzyl-1-(4-fluoro-2-methyl-phenyl)-piperazine-2-carboxylic acid ethyl ester (5.5 g) as yellow oil, MS: 357.3 ([M+H]+) and 1-benzyl-4-(4-fluoro-2-methyl-phenyl)-piperazine-2-carboxylic acid ethyl ester (3.3 g) as yellow oil, MS: 357.1 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:14]2[CH:13]=[C:12](B(O)O)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:1][C:2]1([CH3:18])[C:14]2[CH:13]=[C:12]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][N:21]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: Clc1nccc2ccccc12
Reactant: CC1(C)c2ccccc2-c2ccc(B(O)O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)c2ccccc2-c2ccc(-c3nccc4ccccc34)cc21
Reaction time: 5 h
Yield: 54.3 %

Procedure:
In a 100 ml-three-necked flask, 2.91 g (12.2 mmole) of 9,9-dimethylfluorene-2-boronic acid, 2.00 g (12.2 mmole) of 1-chloroisoquinoline, 10 ml of toluene, 5 ml of ethanol and 10 ml of 2M-sodium carbonate aqueous solution were placed and stirred at room temperature under nitrogen stream, and 0.44 g (0.38 mmole) of tetrakis(triphenylphosphine)palladium (0) was added thereto. Thereafter, reflux under stirring was performed for 5 hours under nitrogen stream. After completion of the reaction, the reaction product was cooled and extracted by addition of cold water and toluene. The organic layer was washed with saline water and dried on magnesium sulfate, followed by removal of the solvent under a reduced pressure to provide dry solid. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=50/1) to obtain 2.13 g (yield=54.2%) of 1-(9,9-dimethylfluorene-2-yl)isoquinoline.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:4][CH2:3]1.[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.[OH-].[Na+]>[C:15]1([CH2:14][O:21][C:22]([N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:4][CH2:3]2)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)CCCC1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 5 °C

Procedure:
Either solid 4-(4-piperidyl) butyric acid hydrochloride (124 kg) is dissolved in water (600 kg), or the 16% aqueous solution of 4-(4-piperidyl)butyric acid hydrochloride prepared in step 3 (777 kg), is diluted with aqueous sodium hydroxide (289 kg) in a 1600 liter glass lined reactor cooled at 5° C. Benzylchloroformate (112 kg) is added over a period of 2-3 hours and the solution is heated to about 25° C. The reaction mixture is extracted with methyl tert-butyl ether (476 kg). The aqueous layer is then acidified with hydrochloric acid (187 kg) and extracted with toluene (450 kg). The organic layer is washed with water (240 kg) and dried by azeotropic distillation at atmospheric pressure under nitrogen. The resulting solution of 1-[(phenylmethoxy)carbonyl]-4-piperidinebutanoic acid in toluene is used as is in step 5. Weight of the product in solution: 179 kg. Quality: about 35% w/w in toluene.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1.[OH-:14].[K+].C>O>[Br:13][C:9]1[N:10]=[C:11]([OH:14])[C:6]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[N:7][CH:8]=1
Reactant: Brc1cnc(NC2CCC2)c(Br)n1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: Oc1nc(Br)cnc1NC1CCC1
Yield: 80 %

Procedure:
A suspension of 2-(N-cyclobutylamino)-3,5-dibromopyrazine (EX-15B) (25.03 g, 81.53 mmol) in 500.0 mL water (0.16 M) was added potassium hydroxide (22.90 g, 408.1 mmol) in 480.0 mL water. The resulting suspension was heated to reflux for approximately 18 hours. The reaction mixture was then added charcoal and refluxed for an additional 15 minutes. The mixture was then allowed to cool for 5 minutes and was filtered through Celite 545. The filtrate was cooled in an ice bath and was acidified to a pH of approximately 5 (litmus paper) upon which a white precipitate forms. The precipitate was collected by filtration, washed twice with water, and dried under vacuum to afford pure 5-bromo-2-(N-cyclobutylamino)-3-hydroxypyrazine (EX-115C) in 80% yield: 1H NMR (400 MHz, DMSO) δ 12.43 (s, 1H), 7.18 (br d, J=5.1 Hz, 1H), 6.87 (s, 1H), 4.29-4.19 (m, 1H), 2.16-2.09 (m, 2H), 2.03-1.93 (m, 2H), 1.63-1.51 (m, 2H); 13C NMR (100 MHz, DMSO) δ 147.0, 144.2, 119.9, 41.3, 26.0, 10.8; HRMS (EI) calcd for C8H11BrN3O 244.0085, found 244.0086.
Reaction SMILES: [OH-].[NH4+:2].[C:3]([N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[N:18][C:19]([NH2:22])=[N:20][CH:21]=3)=[CH:15][C:10]=2[N:9]=[C:8]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:33]=[C:32](C(Cl)(Cl)Cl)[O:31][N:30]=1)([CH3:6])([CH3:5])[CH3:4].O>CN(C=O)C>[NH2:2][C:32]1[O:31][N:30]=[C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:8]2[N:7]([C:3]([CH3:5])([CH3:6])[CH3:4])[C:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:17]=[N:18][C:19]([NH2:22])=[N:20][CH:21]=4)=[CH:15][C:10]=3[N:9]=2)[N:33]=1
Reactant: CC(C)(C)n1c(-c2ccccc2-c2noc(C(Cl)(Cl)Cl)n2)nc2cc(-c3cnc(N)nc3)ccc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1c(-c2ccccc2-c2noc(N)n2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
To a stirred solution of ammonium hydroxide (0.02 mL, 0.39 mmol) in DMF (2 mL) at room temperature is added 5-{1-tert-butyl-2-[2-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-phenyl]-1H-benzimidazol-5-yl}-pyrimidin-2-ylamine (395 mg, 0.26 mmol). The reaction mixture is stirred at room temperature for 0.5 hours. Water is added to the reaction mixture and the product is extracted into EtOAc (3×) and the combined organics are then dried (Na2SO4), filtered, and concentrated. Purification via flash chromatography (10 g silica gel, 3-6% MeOH/CH2Cl2) affords the title compound (20.6 mg, 17%). LCMS (ESMS): m/z 427.29 (M++1)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[N:6][C:5]2=[O:12].[H-].[Na+].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.O>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:5]2=[O:12]
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1nc[nH]c2ccc(I)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2cnc3ccc(I)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
6-Iodo-1H-quinazolin-4-one (0.50 g, 1.84 mmol) was added to a solution of sodium hydride (0.110 g, 2.76 mmol) in THF (10 mL) and stirred at room temperature for one hour. 1-Chloromethyl-4-methoxy-benzene (0.345 g, 2.21 mmol) was added and the reaction was stirred for several hours. Water was added and the crude product was extracted from ethyl acetate and evaporated in vacuo. The product was purified via silica gel column chromatography in hexane:ethyl acetate (4:1) to give 0.69 g (96%) of 6-iodo-3-(4-methoxy-benzyl)-3H-quinazolin-4-one. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, 1H, J=2.0 Hz), 8.01 (s, 1H), 7.90 (dd, 1H, J=2.0, 8.8 Hz), 7.33 (d, 1H, J=8.8 Hz), 7.22 (d, 2H, J=8.0 Hz), 6.80 (d, 2H, J=8.8 Hz), 5.03 (s, 2H), 3.70 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:14](=[O:52])[CH2:15][N:16]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:19](=[O:33])[CH:18]([CH2:34][C:35]4[C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:37](C(OC(C)(C)C)=O)[N:36]=4)[C:17]3=[O:51])[C:7]=2[CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:35]([CH2:34][CH:18]2[C:17](=[O:51])[N:16]([CH2:15][C:14]([N:13]3[C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:52])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:19]2=[O:33])=[N:36]1
Reactant: COc1cccc2c1CCCCN2C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1CCCCN2C(=O)CN1C(=O)C(Cc2n[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21
Reaction time: 8 h
Yield: 19.7 %

Procedure:
A solution of tert-butyl 3-({1-[2-(6-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-2-oxoethyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl}methyl)-1H-indazole-1-carboxylate (83 mg) in methylene chloride (10 mL) was treated with trifluoroacetic acid (1 mL). The reaction was stirred overnight then concentrated to dryness. The residue was chromatographed on silica gel (Hexane:Ethyl Acetate. The residue was triturated with Ethyl Ether and filtered to yield the title compound as a white powder (14 mg).
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH:7](=O)[CH2:8][CH3:9].O.C(O)(=O)C.[CH2:16]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:17]([CH3:19])[CH3:18]>>[CH3:18][CH:17]([CH3:19])[CH2:16][N:20]([CH:7]=[CH:8][CH3:9])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CCC=O
Reactant: CC(C)CNCC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: O
Product: CC=CN(CC(C)C)CC(C)C
Temperature: 12.5 °C
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
To a suspension of magnesium sulfate (10.1 g) in diisobutylamine (72.2 g) was added dropwise propionaldehyde (16.4 g) at 0-10° C. under a nitrogen atmosphere, and it was stirred at 10-15° C. for 1.5 hours. After ice-cooling, water (60 ml) was added and it was stirred to dissolve the magnesium sulfate. After the removal of the aqueous layer, to the organic layer obtained was added a 9% (w/v) aqueous acetic acid solution (200 ml) at 0-5° C. and then stirred for 10 minutes. The aqueous layer was, then, removed again, a 0.5% (w/v) aqueous sodium hydroxide solution (60 ml) was added to the organic layer at 0-5° C., and stirred for 5 minutes. After stirring, the aqueous layer was removed to afford the title compound (42.5 g, yield: 81%, purity: 95.3%) as a colorless oil.