Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2].[H-].[Na+].Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH:35]2[CH2:39][C:38]3[CH:40]=[C:41]([Cl:44])[CH:42]=[CH:43][C:37]=3[O:36]2)[CH2:30][CH2:29]1)=[O:27]>O1CCCC1.CN(C)C=O>[Cl:44][C:41]1[CH:42]=[CH:43][C:37]2[O:36][CH:35]([CH2:34][N:31]3[CH2:30][CH2:29][N:28]([C:26](=[O:27])[CH2:25][O:17][CH:14]4[CH2:15][CH2:16][CH:11]([NH:10][C:7]5[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:18]([F:19])([F:20])[F:21])[CH:6]=5)[CH2:12][CH2:13]4)[CH2:33][CH2:32]3)[CH2:39][C:38]=2[CH:40]=1
Reactant: O=[N+]([O-])c1ccc(NC2CCC(O)CC2)cc1C(F)(F)F
Reactant: O=C(CCl)N1CCN(CC2Cc3cc(Cl)ccc3O2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(CC2Cc3cc(Cl)ccc3O2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
To a solution of 4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexan-1-ol (40 mg, 0.13 mmol) in tetrahydrofuran (1 ml) and N,N-dimethylformamide (0.3 ml) was added sodium hydride (26 mg, 1.08 mmol, 8 eq) with stirring for 30 minutes at 0° C. Then 2-chloro-1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]ethan-1-one (90 mg, 0.27 mmol, 2 eq) in tetrahydrofuran (0.5 ml) was added with stirring for 5 hours at room temperature. The reaction mixture was quenched by water (20 ml) and extracted with ethyl acetate (3×30 ml). The organic layers were combined and dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified by Pre-TLC using 50% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (29.8 mg, 38%); (ES, m/z): [M+H]+ 597.35; 1H NMR (300 MHz, CDCl3): δ 8.02 (d, J=7.2 Hz, 1H), 7.04-7.12 (m, 2H), 6.84 (d, J=2.4 Hz, 1H), 6.61-6.71 (m, 2H), 5.01 (broad s, 1H), 4.46 (d, J=7.8 Hz, 1H), 4.19 (s, 2H), 3.60-3.73 (m, 3H), 3.40-3.47 (m, 2H), 3.23-3.32 (dd, J=9.3 Hz, 15.9 Hz, 1H), 2.92-2.99 (dd, J=7.8 Hz, 15.9 Hz, 1H), 2.77-2.84 (m, 1H), 2.62-2.77 (m, 4H), 2.12-2.16 (m, 4H), 1.41-1.52 (m, 3H), 1.22-1.30 (m, 3H).
Reaction SMILES: [O:1]=[C:2]([NH:8][C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[C:15]([O:17]CC)=O)[CH2:3][C:4]([O:6][CH3:7])=[O:5].O=C(NC1CCCCC=1C(OC)=O)CC(OC)=O>>[OH:17][C:15]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[NH:8][C:2](=[O:1])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCOC(=O)C1=C(NC(=O)CC(=O)OC)CCCC1
Agent: COC(=O)CC(=O)NC1=C(C(=O)OC)CCCC1
Product: COC(=O)c1c(O)c2c([nH]c1=O)CCCC2

Procedure:
Using the general method of Example 1 Part D, a mixture of methyl 3-oxo-3-[(2-ethoxycarbonylcyclohexen-1-yl)amino]propanoate and methyl 3-oxo-3-[(2-methoxycarbonylcyclohexen-1-yl)amino]propanoate (43.2 g, 0.16 mole) was cyclized to provide 35.5 g of methyl 1,2,5,6,7,8-hexahydro-4-hydroxy-2-oxoquinoline-3-carboxylate as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][CH2:35][O:36]C2CCCCO2)=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][CH2:35][OH:36])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/CCOC4CCCCO4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1cc(-c2csc3c(/C=C/CCO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.5 %

Procedure:
A suspension of N-(4-{4-amino-7-[(1E)-4-(tetrahydro-2H-pyran-2-yloxy)but-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.05 g, 0.09 mmol) in methanol (3 mL) was treated with p-toluene sulfonic acid monohydrate (0.002 g, 0.0095 mmol). The reaction mixture was stirred for 15 hours at room temperature. Solvent was removed under reduced pressure. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane to give 0.033 g (77%) of the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (s, 1H), 8.00-7.98 (m, 1H), 7.93 (s, 1H), 7.71-7.69 (m, 1H), 7.61-7.58 (m, 2H), 7.35-7.33 (m, 2H), 7.20 (m, 1H), 7.15-7.15 (m, 1H), 709-7.07 (m, 1H), 6.59-6.55 (m, 1H), 6.35-6.20 (m, 1H), 5.58 (brs, 2H), 4.65 (m, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 3.57-3.54 (m, 2H), 2.42 (m, 2H); LCMS (conditions a) Rt 3.42 min (96%), M+ 499.3.
Reaction SMILES: O.[OH-].[Li+].OO.C([C@@H]1COC(=O)N1[C:19]([CH:21]1[C:25]2([CH2:27][CH2:26]2)[C:24](=[O:28])[N:23]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=2[O:38][CH3:39])[CH2:22]1)=[O:20])C1C=CC=CC=1.S([O-])(O)=[O:41].[Na+]>O.O1CCCC1>[CH3:39][O:38][C:31]1[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:30]=1[CH2:29][N:23]1[CH2:22][CH:21]([C:19]([OH:20])=[O:41])[C:25]2([CH2:26][CH2:27]2)[C:24]1=[O:28]
Reactant: COc1ccc(CN2CC(C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)C3(CC3)C2=O)c(OC)c1
Reactant: O=S([O-])O
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2CC(C(=O)O)C3(CC3)C2=O)c(OC)c1
Reaction time: 0.25 h
Yield: 40.7 %

Procedure:
To a solution of lithium hydroxide monohydrate (142 mg) in water (5 ml) was added 30 wt % aqueous solution of hydrogen peroxide (0.8 ml) at −5° C., and the mixture was stirred for 15 minutes. To this reaction mixture were sequentially added tetrahydrofuran (5 ml) and a solution of an optically active compound of 7-((R)-4-benzyl-2-oxooxazolidine-3-carbonyl)-5-(2,4-dimethoxybenzyl)-5-azaspiro[2.4]heptan-4-one (1.39 g) in tetrahydrofuran (10 ml), and the mixture was stirred for additional 1 hour. To this reaction mixture was added a solution of sodium hydrogen sulfite (815 mg) in water (5 ml), and the mixture was stirred at room temperature for 1 hour, and then extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate only). To the resulting solid was added diisopropyl ether/ethyl acetate/n-hexane (10/1/5, 10 ml), and the mixture was stirred. A solid was collected from this suspension by filtration, and dried under reduced pressure to give the titled compound (372 mg).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:53][Si:54]([C:57]#[CH:58])([CH3:56])[CH3:55]>CN(C)C=O.N1CCCCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:58]#[C:57][Si:54]([CH3:56])([CH3:55])[CH3:53])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C#C[Si](C)(C)C)c(OCc1ccccc1)c2=O
Temperature: 50 °C
Yield: 62.7 %

Procedure:
A solution of intermediate 174, N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.277 g, 0.49 mmol) in a mixture of N,N-dimethylformamide (3 ml) and piperidine (1.2 ml) was treated under argon with dichlorobis(triphenylphosphine)palladium(II) (0.020 g), triphenylphosphine (0.010 g), copper(1) iodide (0.010 g) followed by (trimethylsilyl)acetylene (0.21 ml, 1.47 mmol). The resulting mixture was sealed and heated at 50° C. for one hour. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.164 g (63% yield) of the title material as a light yellow solid. 1HNMR 400 MHz (CDCl3) δ ppm: 0.27 (9H, s, SiCH3), 1.64 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2), 4.71 (2H, d, J=6.1 Hz=NCH2), 5.32 (2H, s, OCH2), 6.99 (1H, m, aromatic), 7.19 (1H, dd, J=2.6 Hz and J=9.1 Hz, aromatic), 7.3–7.37 (4H, m, aromatics), 7.48–7.51 (2H, m, aromatics), 7.75 (1H, broad t, NH). HRMS (ESI+) calculated for C29H33FN3O4Si [M+H+]: 534.2224. Found: 534.2229.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([O:9]CC)[N:3]=1.[Cl-].[Cl-].[Cl-].[Al+3]>C1(C)C=CC=CC=1>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[NH:3][C:4](=[O:9])[CH:5]=1
Reactant: CCOc1cc(N)cc(Cl)n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Nc1cc(Cl)[nH]c(=O)c1
Temperature: 25 °C

Procedure:
2-Chloro-6-ethoxypyridin-4-amine (10.0 g, prepared according to the reported preparation in J. Med. Chem., (2006), 49 (12), 3563-3580) and aluminum trichloride (19.3 g) were suspended in toluene (300 mL) and heated at reflux under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and partitioned between saturated aqueous Rochelle's salt and ethyl acetate and vigorously stirred overnight. The biphasic mixture was filtered. The aqueous was repeatedly extracted with ethyl acetate. The combined organics were dried, magnesium sulfate and concentrated under reduced pressure to furnish the title compound (4.23 g), which was used without further purification, possessing the following physical data.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:25]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][O:23][N:22]=2)=[CH:17][CH:16]=1)(C)(C)C>>[CH2:26]([C:25]1[C:21]([C:18]2[CH:17]=[CH:16][C:15]([NH2:14])=[CH:20][CH:19]=2)=[N:22][O:23][CH:24]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2nocc2Cc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2nocc2Cc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Trifluoroacetic acid (0.5 mL) is added to [4-(4-benzylisoxazol-3-yl)phenyl]carbamic acid tert-butyl ester (0.3 g) and stirred for 30 minutes. The reaction mixture is concentrated under reduced pressure and the concentrate is partitioned between ethyl acetate and 1N sodium hydroxide solution. The organic layer is washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and chromatographed on silica gel (ethyl acetate/hexane as eluant) to give 0.15 g product as a white solid. MS: m/z 251 (M+H)+.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=4)=[C:3]([CH3:23])[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c3c2C)c1
Temperature: 100 °C
Yield: 34.6 %

Procedure:
To a solution of N-(2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 77) (100 mg, 0.232 mmol) in water (1 mL) and 1,4-dioxane (2 mL) was added [3-(methyloxy)phenyl]boronic acid (52.8 mg, 0.347 mmol), bis(triphenylphosphine)palladium(II) chloride (16.26 mg, 0.023 mmol), potassium carbonate (96 mg, 0.695 mmol) and the mixture heated to 100° C. for 15 min using a microwave reactor. The mixture was then filtered through celite, washing with ethyl acetate (30 mL) and DCM (20 mL). The organics were then combined, dried (phase separation cartridge) and concentrated. The residue was then purified by MDAP (basic conditions), to afford the title compound (36.8 mg). LCMS (A) m/z: 459 [M+1]+, Rt 1.32 min (acidic).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[C:11]([O:15][OH:16])([CH3:14])([CH3:13])[CH3:12].S(=O)(=O)(O)O>CCCCC>[CH3:10][C:4]1([O:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH2:3]1
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: CC(C)(C)OO
Agent: O=S(=O)(O)O
Solvent: CCCCC
Product: CC1(C)CC(=O)CC(C)(OOC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A reaction mixture of 6.9 g. (0.05 mole) of isophorone, 23.20 g. (0.2 mole) of dry 81% t-butyl hydroperoxide and 25 ml. of pentane was cooled to 10° C. and 5.70 g. of 77% sulfuric acid added slowly over 45 minutes. The reaction mixture was allowed to warm to 25° C. and stirred at 25° C. for five hours. The pentane solution of the product was washed with water, and sodium bisulfite solution and then dried over anhydrous magnesium sulfate. The product weighing 9.35 g., was obtained by stripping under reduced pressure (60.4% recovery). The infrared spectrum had a strong absorption in the 880 cm-1 region usually associated with t-butylperoxy groups. Iodometric assay showed the presence of active oxygen and the GLC scan of the product showed a large peak for the expected product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:22])=[O:21]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccccc2Br)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-bromobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (41.9 mg) with purity >90%. MS (pos) m/z 405.1, 407.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]([CH2:18][CH2:19][CH:20]([C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)[C:21]([O:23]C)=[O:22])[C:14]([O:16]C)=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[K+].O.Cl>C(O)C>[CH3:32][O:31][C:29]1[CH:30]=[C:25]([CH:20]([CH2:19][CH2:18][CH:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:14]([OH:16])=[O:15])[C:21]([OH:23])=[O:22])[CH:26]=[C:27]([O:35][CH3:36])[C:28]=1[O:33][CH3:34]
Reactant: COC(=O)C(CCC(C(=O)OC)c1cc(OC)c(OC)c(OC)c1)c1cc(OC)c(OC)c(OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C(CCC(C(=O)O)c2cc(OC)c(OC)c(OC)c2)C(=O)O)cc(OC)c1OC
Yield: 97 %

Procedure:
A mixture of dimethyl α,α'-bis(3,4,5-trimethoxyphenyl)adipate (11.0 g, 21.7 mmoles), potassium hydroxide (13.0 g, 202 mmoles), water (163 ml), and ethanol (65 ml) was heated at 90° in a nitrogen atmosphere for 3 hours. After cooling the clear solution was added slowly to 250 ml of 1N hydrochloric acid with vigorous stirring. The slurry was stirred and warmed to 50° for several minutes. After cooling in an ice bath the solid was filtered, washed with water (4 times) and dried to give 10.07 g (97%) of α,α'-bis(3,4,5-trimethoxyphenyl)adipic acid, m.p. 226°-223°. NMR (DMSO-d6) indicates a 9:1 mixture of meso and racemic isomers.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:31][C:32]1[C:33]([C:39]([C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)=[O:40])=[N:34][C:35](Br)=[CH:36][N:37]=1.B(O)(O)[C:48]1[NH:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.C([O-])(O)=O.[Na+].C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.C(O)C>[NH2:31][C:32]1[C:33]([C:39]([C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)=[O:40])=[N:34][C:35]([C:52]2[CH:51]=[C:50]3[C:55](=[CH:54][CH:53]=2)[NH:56][CH:48]=[CH:49]3)=[CH:36][N:37]=1
Reactant: Nc1ncc(Br)nc1C(=O)c1cccnc1
Reactant: OB(O)c1cc2ccccc2[nH]1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: N#Cc1ccccc1
Product: Nc1ncc(-c2ccc3[nH]ccc3c2)nc1C(=O)c1cccnc1

Procedure:
Bis(benzonitrile)palladium(II)chloride (5.2 mg, 0.013 mmol) and 1,4-bis(diphenylphosphino)butane (6.7 mg, 0.015 mmol) in toleune (0.6 ml) are stirred for 20 minutes. (3-Amino-6-bromo-pyrazin-2-yl)-pyridin-3-yl-methanone (Intermediate AA) (0.075 g, 0.27 mmol), 5-indoylboronic acid (0.056 g, 0.35 mmol), ethanol (0.36 ml) and 1M Na2CO3 (0.65 ml) are added and the reaction is heated using microwave radiation at 140° C. for 20 minutes. The mixture is diluted with EtOAc and sat. aq. NaHCO3. The layers are separated and the aqueous layer is extracted with EtOAc. The combined organic extracts are dried (MgSO4), and purified by preperative HPLC (0-100% MeCN in water −0.1% TFA) to yield the title compound as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ11.27 (1H, s), 9.21 (1H, s), 9.09 (1H, s), 8.86 (1H, dd), 8.39-8.41 (1H, dt), 8.19 (1H, s), 7.99 (2H, s), 7.65-7.73 (2H, m), 7.5 (1H, d), 7.44 (1H, t), 6.53 (1H, s). MS ink 316 [M+H]+
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]#[N:21])=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26]Br.O>CCCCCC>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2([C:20]#[N:21])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrCCCCBr
Reactant: N#CCc1cn(Cc2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: N#CC1(c2cn(Cc3ccccc3)c3ccccc23)CCCC1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (60%, 2.26 g, 56 mmol) was added a solution of 1-benzyl-1H-indol-3-ylacetonitrile (5.7 g, 22 mmol) and 1,4-dibrombutane (2.6 ml) in DMSO-ether (10 ml: 80 mL) dropwise and the mixture was stirred for 5 hours at 20° C. Water and hexane were added. Solid was collected by filtration and washed with water and hexane to give 1-(1-benzyl-1H-indol-3-yl)cyclopentanecarbonitrile (5.3 g). MS (ES): 301 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([O:33]C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=3)[C:3]=12.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH2:40]>>[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH:40][C:31](=[O:33])[CH2:30][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=2)=[N:9]1
Reactant: COC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Reactant: CN(C)CCCN
Product: CN(C)CCCNC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21

Procedure:
The representative procedure for amide formation was used in the reaction of methyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate (0.025 g, 0.048 mmol) with 3-(dimethylamino)propylamine (1 mL). Purification by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 6.7-7.3 min) afforded N1-[3-(dimethylamino)propyl]-2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetamide as an off-white powder (0.015 g, 0.025 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 8.20 (m, 1H), 7.96 (m, 1H), 7.76 (m, 1H), 7.43 (t, 1H), 7.30 (m, 2H), 4.93 (s, 2H), 3.12 (m, 2H), 2.82 (m, 2H), 2.50 (s, 6H), 1.73 (m, 2H); MS (M−H) 593.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][NH:18][C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[C:24](=[O:28])[N:23]([C@@H:29]([CH2:46][CH2:47][C:48]([O:50]CC)=[O:49])[C:30]([NH:32][C@H:33]([C:41]([O:43]CC)=[O:42])[CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:31])[CH2:22]5)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[Na+].Cl>CCO>[C:48]([CH2:47][CH2:46][C@H:29]([N:23]1[CH2:22][C:21]2[C:25](=[CH:26][CH:27]=[C:19]([NH:18][CH2:17][C:14]3[CH:15]=[CH:16][C:7]4[CH:6]=[CH:5][C:4]5[N:3]=[C:2]([CH3:1])[NH:11][C:10](=[O:12])[C:9]=5[C:8]=4[CH:13]=3)[CH:20]=2)[C:24]1=[O:28])[C:30]([NH:32][C@H:33]([C:41]([OH:43])=[O:42])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:31])([OH:50])=[O:49]
Reactant: CCOC(=O)CC[C@@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)OCC)N1Cc2cc(NCc3ccc4ccc5nc(C)[nH]c(=O)c5c4c3)ccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc3ccc(CNc4ccc5c(c4)CN([C@@H](CCC(=O)O)C(=O)N[C@@H](Cc4ccccc4)C(=O)O)C5=O)cc3c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.2 %

Procedure:
To a 100 mL 3-necked flask equipped with a magnetic stirrer and a nitrogen inlet were added 0.90 g of ethyl N-((S)-2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl)-4-(ethoxycarbonyl)butanoyl)-L-phenylalaninate, 3 mL of EtOH and 10 mL of 0.2N aqueous NaOH. The solution was stirred at RT under nitrogen for 2 h and was acidified to pH 3.0 by addition of 1N HCl. A white precipitate resulted which was separated by centrifugation. Analysis of this material by analytical HPLC (C18, 70:30:0.10 H2O:MeCN:TFA) indicated a major component at K'=1.93 (90%) and a minor component at k'=2.41. The crude product was purified by semi-preparative reverse phase HPLC (C18, 75:25:0.1 H2O:MeCN:TFA). Fractions containing pure product (k'=1.93 by analytical HPLC using above conditions) were combined and concentrated in vacuo to dryness. The residue was dissolved in 15 mL of 0.1N aqueous NaOH and the solution was adjusted to pH 3.0 by addition of 1N HCl. The resulting precipitate was collected by centrifugation, washed with four cycles of aqueous suspension-centrifugation-decantation, and lyophilized to afford 0.035 g (40%) of N-((S)-4-carboxy-2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl)butanoyl)-L-phenylalanine as a white powder, m.p. 180° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([Br:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:13][CH:12]=1.BrC1C=CC(O)=C([N+]([O-])=O)C=1C.[C:39](Cl)(=[O:44])[CH2:40][C:41](Cl)=[O:42]>C1COCC1>[Br:9][C:6]1[CH:5]=[CH:4][C:3]2[N:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][S:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:39](=[O:44])[CH2:40][C:41](=[O:42])[NH:1][C:2]=2[C:7]=1[CH3:8]
Reactant: O=C(Cl)CC(=O)Cl
Reactant: Cc1c(Br)ccc(Nc2ccc(NS(=O)(=O)c3ccccc3)cc2)c1N
Agent: Cc1c(Br)ccc(O)c1[N+](=O)[O-]
Solvent: C1CCOC1
Product: Cc1c(Br)ccc2c1NC(=O)CC(=O)N2c1ccc(NS(=O)(=O)c2ccccc2)cc1
Yield: 10.6 %

Procedure:
N-[4-(2-Amino-4-bromo-3-methylphenylamino)phenyl]benzenesulfonamide (100 mg, 0.231 mmol) synthesized by using 4-bromo-3-methyl-2-nitrophenol was treated with malonyl chloride (22 μL, 0.226 mmol) in THF to give the title compound (12 mg, yield 10%).