Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:54]=[CH:53][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])[C:24](=[O:44])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:43])[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([O:41][CH3:42])[CH:35]=4)=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:45][C:46]([OH:48])=[O:47])[C:24](=[O:44])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:43])[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([O:41][CH3:42])[CH:35]=4)=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:53][CH:54]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(C)c(OC)c4)cc3)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)O)C(=O)c3ccc(NC(=O)Cc4ccc(C)c(OC)c4)cc3)cc2)cc1
Temperature: 30 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
Prepared using General Procedures 6 and 8: To 2-(3-methoxy-4-methylphenyl)acetic acid (14.1 mg, 0.08 mmol) were added HOBT (12.0 mg, 0.08 mmol) in DMF (0.1 mL) and EDC (15.0 mg, 0.08 mmol) in DMF (0.1 mL). After stirring at room temperature for 30 min, 4-((4-amino-N-(2-(tert-butoxy)-2-oxoethyl)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-4 (30 mg, 0.05 mmol) and TEA (0.019 mL, 0.10 mmol) in DMF (0.3 mL) were added. The reaction was stirred for 18 h then purified by preparative HPLC to provide 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(3-methoxy-4-methylphenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate. To 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(3-methoxy-4-methylphenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate in DCM (1.0 mL) was added TFA (0.2 mL). The reaction was stirred at 30° C. for 6 h. The reaction was concentrated to afford 22.3 mg (65%) of 2-(N-(4-((4-(heptyloxy)benzoyl)oxy)benzyl)-4-(2-(3-methoxy-4-methylphenyl)acetamido)benzamido)acetic acid 4. LCMS-ESI (m/z) calculated for C40H44N2O8: 680; no m/z observed, tR=11.45 min (Method 2). 1H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 8.06 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.43 (d, J=7.2 Hz, 1H), 7.40-7.28 (m, 3H), 7.24 (d, J=8.5 Hz, 2H), 7.17-7.02 (m, 3H), 6.91 (s, 1H), 6.79 (d, J=7.5 Hz, 1H), 4.62 (d, J=36.2 Hz, 2H), 4.08 (t, J=6.5 Hz, 2H), 3.95 (d, J=28.6 Hz, 2H), 3.77 (s, 3H), 3.60 (s, 2H), 2.10 (s, 3H), 1.74 (dd, J=9.8, 4.8 Hz, 2H), 1.48-1.24 (m, 8H), 0.86 (d, J=7.0 Hz, 3H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[C:19]3=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]3[CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:26][N:15]1[CH2:16][CH2:17][N:18]2[C:19](=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23]2)[C@@H:14]1[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: O=S1(=O)CCN2CCN[C@@H](c3ccc(Oc4ccccc4)cc3)C2=N1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCN2CCS(=O)(=O)N=C2[C@@H]1c1ccc(Oc2ccccc2)cc1
Reaction time: 20 h
Yield: 13.4 %

Procedure:
A mixture of (9S)-9-(4-phenoxyphenyl)-3,4,6,7,8,9-hexahydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide (129 mg), potassium carbonate (100 mg) and iodomethane (0.022 mL) in DMF (4 mL) was stirred at 0° C. to room temperature for 20 hr. The reaction mixture was added with NH silica gel, evaporated, and purified by column chromatography (NH silica gel, eluted with EtOAc in hexane then 20% MeOH in EtOAc) then preparative HPLC (C18, MeCN in H2O with 0.1% TFA). The combined collected fractions were concentrated in vacuo. The resulting aqueous solution was added with NaHCO3 and NaCl, then extracted with EtOAc (2×100 mL). The organic layer was combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from EtOAc-IPE to give the title compound (18 mg) as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]([OH:23])([CH3:22])[CH2:20][CH3:21])=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:58][C:59]1[S:60][CH:61]=[CH:62][N:63]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]([OH:23])([CH3:22])[CH2:20][CH3:21])=[CH:13][CH:12]=2)[C:8]([NH:58][C:59]2[S:60][CH:61]=[CH:62][N:63]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCC(C)(O)C#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)(O)C#Cc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Yield: 57 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-hydroxy-3-methyl-pent-1-ynyl)-phenyl]-propionic acid (157 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (86 mg, 0.75 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 2 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a half-saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(3-hydroxy-3-methyl-pent-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (113 mg, 57.1%) as a white solid: mp 172-174° C.; EI-HRMS m/e calcd for C23H28N2O2S (M+) 396.1871, found 396.1866.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[N:8]=2)[CH:6]=1.[S:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:4]2[N:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C@H:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:15])[N:8]=3)[CH:6]=[C:2]([C:31]3[CH:32]=[CH:33][S:29][CH:30]=3)[N:3]=2)=[CH:23][CH:24]=1
Reactant: C[C@H](Nc1nccc(-n2cc(Br)nc2-c2ccc(F)cc2)n1)c1ccccc1
Reactant: OB(O)c1ccsc1
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: C1COCCO1
Product: C[C@H](Nc1nccc(-n2cc(-c3ccsc3)nc2-c2ccc(F)cc2)n1)c1ccccc1
Yield: 56.2 %

Procedure:
4-Bromo-2-(4-fluorophenyl)-1-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)imidazole (109 mg, 0.25 mmol), thiophene-3-boronic acid (35 mg; 0.27 mmol) and Pd(PPh3)4 (14 mg, 0.0125 mmol) are dissolved in dioxane (1.25 ml) and saturated Na2CO3 solution (0.33 ml, 0.5 mmol) and heated to 80 C for 18 h. The reaction mixture is poured on saturated Na2CO3 solution and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated and purified via preparative HPLC on LiChrospher RP-18 (Gilson HPLC-system; column tube: 125 mm×25 mm ID) with MeCN/water as elution system, 40:60 to 100:0 as gradient and a flow rate of 10 ml/min to yield the title product as colorless crystals (62 mg, 60%).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)=O)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2].[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:18]([F:17])[CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2]
Reactant: CCn1c(=O)ccc2cnc(S(C)=O)nc21
Reactant: Nc1cccc(F)c1
Product: CCn1c(=O)ccc2cnc(Nc3cccc(F)c3)nc21
Temperature: 175 °C
Yield: 25 %

Procedure:
A mixture of 8-ethyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (112 mg, 0.47 mmol) and 500 μL of 3-fluoroaniline was heated at 175° C. for 10 minutes. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate. Recrystallization from chloroform and hexane provided 33 mg (25%) of 8-ethyl-2-(3-fluorophenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, mp 210-212° C.
Reaction SMILES: [CH:1]1[C:18]2[C:5](=[C:6]3[C:15](=[CH:16][CH:17]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[S:8](=[O:20])(=[O:19])[NH:7]3)[N:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:23]I>C1COCC1>[CH3:23][N:7]1[S:8](=[O:19])(=[O:20])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]2[C:6]1=[C:5]1[C:18](=[CH:17][CH:16]=2)[CH:1]=[CH:2][CH:3]=[N:4]1
Reactant: O=S1(=O)Nc2c(ccc3cccnc23)-c2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1c2c(ccc3cccnc23)-c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
5H-6-Thia-4,5-diaza-chrysene 6,6-dioxide (Example Compound 2) (50 mg, 0.18 mmol) was added to solution of NaH (60% dispersion in mineral oil; 11 mg, 0.27 mmol) dissolved in dry THF (3 ml), under argon, at 0° C., and the mixture was stirred for 15 min. Methyliodide (29 mg, 0.22 mmol) was added and the reaction was allowed to warm to room temperature and stirring continued for 12 h. After completion of the reaction (monitored by TLC), the solvent was removed in vacuo. The residue was dissolved in EtOAc, washed with water and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAc (3:1) as the eluent to give the title compound (27 mg, 52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=O)[CH2:11][CH3:12].C(O)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH2:11][CH3:12])=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COc1ccccc1N
Reactant: CCOC(=O)CC(=O)CC
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C=C(CC)Nc1ccccc1OC
Yield: 49.4 %

Procedure:
A mixture of o-anisidine (15.11 g), ethyl propionylacetate (17.69 g) and acetic acid (0.5 ml) in benzene (30 ml) was refluxed removing water for 24 hours. The solvent was removed in vacuo, and the residue was dissolved in toluene (30 ml). The reaction mixture was refluxed for an additional 8 hours. The solvent was removed in vacuo. The residue was purified by column chromatography (hexane--ethyl acetate) to give ethyl 3-(2-methoxyanilino)-2-pentenoate (15.11 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[O:11].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:39][NH:40][CH2:41][CH3:42])[C:29]([O:31][CH2:32][CH3:33])=[O:30].CCN(CC)CC>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:39][NH:40][CH2:41][CH2:42][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Reactant: CCNCCOc1ccc(C(=O)OCC)cc1OC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(OCCNCCC(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)c(OC)c1
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a stirred solution of pentafluorophenyl ester of 3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetic acid (135 mg, 0.28 mmol) and ethyl 3-methoxy-4-(2-ethylaminoethoxy)benzoate (78 mg, 0.29 mmol) was added Et3N (0.1 mL, 0.72 mmol), and the resulting mixture was stirred overnight. The mixture was diluted with EtoAc, washed successively with 0.5N HCl, brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3—MeOH (50:1, v/v) as eluent to give 160 mg (q.y.) ethyl 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoate as an oil. 1H-NMR (CDCl3) d 1.13-1.23 (m, 3 H), 1.37-1.40 (m, 3 H), 2.90-3.89 (m, 12 H), 4.09-4.28 (m, 2 H), 4.33-4.39 (m, 2 H), 6.70-8.21 (series of m, total 12 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[CH2:22][CH2:23][O:24][C:25]4[CH:31]=[CH:30][C:29]([C:32]5[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=5)=[CH:28][C:26]=4[CH:27]=3)=[O:20])=[CH:14][CH:13]=2)=[N:7][CH:8]=[CH:9][CH:10]=1.ClC1C=CC=C(C(OO)=[O:47])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:47][N+:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]2[CH2:22][CH2:23][O:24][C:25]3[CH:31]=[CH:30][C:29]([C:32]4[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=4)=[CH:28][C:26]=3[CH:27]=2)=[O:20])=[CH:16][CH:17]=1
Reactant: COCOc1cccnc1Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc[n+]([O-])c1Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.6 %

Procedure:
To a solution of N-[4-(3-methoxymethoxypyridin-2-ylmethyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (300 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.22 g) at 0° C., and the mixture was stirred at room temperature for 18 hours. To the mixture was added sodium thiosulfate, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:15→1:10), and recrystallized from ethanol to give N-[4-(1-oxido-3-methoxymethoxypyridin-2-ylmethyl)phenyl]-7-(4-methyl-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 173) (203 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.Br.[Br:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[BrH:13].[N:1]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: BrCCNCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1Cc2cc(N3CCNCC3)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A mixture of 5-aminooxindol (14 g), 29 g of bis(β-bromoethyl)amine.hydrobromide in 250 ml of ethanol was stirred under reflux for 8 hours and allowed to stand overnight at room temperature. To the mixture was added sodium carbonate (10.1 g) and the mixture was stirred further for 8 hours under reflux. After cooling to room temperature, crystals which precipitated were collected by filtration and recrystallized from a mixture of water and ethanol to give 16 g of 5-(1-piperazinyl)oxindol.hydrobromide.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])C.[F:42][C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][C:48]=1[CH3:49]>>[C:36]([CH2:35][CH2:34][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:45]3[CH:46]=[CH:47][C:48]([CH3:49])=[C:43]([F:42])[CH:44]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])([OH:38])=[O:37]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Reactant: Cc1ccc(B(O)O)cc1F
Product: Cc1ccc(-c2cc(OCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)cc(C(=O)N(C)C)c2)cc1F
Yield: 30 %

Procedure:
The title compound was prepared according to the general procedure described in Steps 3 and 4 of Method F starting from 4-[3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester and 3-fluoro-4-methylphenylboronic acid. LC/MS indicated a purity of 100% as measured by UV 214 nM. Yield: 30% (after two steps)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:30](=[O:31])[CH2:29][C:28](=[O:32])[NH:27][C:26]3[C:33]4[C:38]([CH:39]=[CH:40][C:25]2=3)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][CH:19]=1>>[CH3:12][C:7]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[C:3]=1[C:4]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:30](=[O:31])[CH2:29][C:28](=[O:32])[NH:27][C:26]3[C:33]4[C:38]([CH:39]=[CH:40][C:25]2=3)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][CH:19]=1)=[O:6]
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C)c(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c(C)c1
Yield: 12.9 %

Procedure:
2,4,6-Trimethylbenzoic acid (25 mg, 0.15 mmol) was treated with thionyl chloride in the same manner as that of Example 13, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), the title compound (6 mg, yield 13%) was obtained as slightly brown crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:24]=[CH:25][C:26]([Br:33])=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:24]=[CH:25][C:26]([Br:33])=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)(=[O:3])[CH3:2]
Reactant: Nc1ccc(Br)c2cccnc12
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ccc(Br)c3cccnc23)c1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 24.8 %

Procedure:
To a stirred solution of 40 mg (0.139 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 8-amino-5-bromoquinoline (47 mg, 0.209 mmol) was added. The resulting mixture was stirred at room temperature for five days and heated at 50° C. during four days. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyl acetate 4:1) to yield the title compound (16 mg, 25% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:36]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](O)=[O:43])=[CH:37]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1.C(Cl)Cl>[CH3:34][N:33]([CH3:35])[CH2:32][CH2:31][O:30][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:42](=[O:43])[CH2:41][C:38]5[CH:39]=[CH:40][S:36][CH:37]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)Cc1ccsc1
Reactant: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5ccsc5)c4)nn4ccccc34)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-2-pyrimidinamine (140 mg, 0.3 mmol) in THF were added 3-thienylacetic acid (51 mg, 0.36 mmol), TEA (125 μL, 0.9 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (136 mg, 0.36 mmol). The reaction was stirred overnight at rt, after which the reaction mixture was diluted with DCM, washed with 5% aqueous Na2CO3, dried over Na2SO4, and adsorbed onto silica gel. The crude product was purified by column chromatography and lyophilized to generate the title compound in 72% yield. 1H NMR (400 MHz, d6-DMSO) δ 10.27 (s, 1H), 9.55 (s, 1H), 8.83 (d, J=6.7 Hz, 1H), 8.51 (d, J=8.8 Hz, 1H), 8.26 (d, J=5.1 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.40-7.53 (m, 4H), 7.26-7.31 (m, 3H), 7.08-7.18 (m, 3H), 6.53 (d, J=8.2 Hz, 1H), 6.48 (d, J=5.3 Hz, 1H), 3.99 (t, J=5.7 Hz, 2H), 3.66 (s, 2H), 2.58 (t, J=5.9 Hz, 2H), 2.18 (s, 6H). ES-LC/MS m/z=588 [M+H]+.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24]([OH:26])=[O:25])=[C:13]2[CH3:27])=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.[C:29]1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24]([O:26][CH3:29])=[O:25])=[C:13]2[CH3:27])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)CC1=C(C)C(=Cc2ccc(S(N)(=O)=O)cc2)c2ccc(OC)cc21
Yield: 202.4 %

Procedure:
A solution of the E acid 3a (950 mg) and toluenesulfonic acid monohydrate (200 mg) in methanol (60 ml) was refluxed for 1-2 hours. The solution was filtered and the filtrate was concentrated to 30 ml. After cooling at 0° to 5° for 1 hour, the crystals were collected and dried. The crude ester was recrystallized from acetonitrile to give the pure E methyl 1-(4-aminosulfonylphenyl)methylene-5-methoxy-2-methyl-1H-3-indenylacetate 5a (850 mg, 86%): m.p. 169.5°-171.0° C.
Reaction SMILES: [F:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([C:14]#[C:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO>[F:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([C:14]#[C:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C#CC(C)(C)C)c(OC)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C#CC(C)(C)C)ccc(C(=O)O)c1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 112.5 %

Procedure:
Methyl 2-fluoro-3-methoxy-4-(3,3-dimethylbut-1-ynyl)benzoate (760 mg, 2.7 mmol) was dissolved in MeOH (10 mL), NaOH (in 10 mL water) was added and stirred at 50° C. for 1 h. Solvent was removed, more water was added, neutralized by HCl till pH˜2, white solid thus formed was filtered out, dried in vacuum oven (at 65° C.). Product was obtained as a white solid (760 mg, 93%).
Reaction SMILES: C(OC(=O)[CH2:5][C:6]([CH:8]=[CH:9][NH:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[CH:12]=1)=[O:7])C.[C:18]1([O:24]C2C=CC=CC=2)C=CC=CC=1>>[C:6]([C:8]1[C:18]([OH:24])=[C:12]2[C:13]([CH3:16])=[N:14][O:15][C:11]2=[N:10][CH:9]=1)(=[O:7])[CH3:5]
Reactant: CCOC(=O)CC(=O)C=CNc1cc(C)no1
Reactant: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)c1cnc2onc(C)c2c1O
Reaction time: 0.08 h

Procedure:
23.8 g. of (3-methyl-5-isoxazolyl)aminomethyleneacetoacetic acid ethyl ester (0.1 mol.) are quickly added to 100 ml. of vigorously refluxing diphenyl ether. After 5 minutes, the reaction mixture is cooled, as rapidly as possible. After addition of 100 ml. diethyl ether, 5-acetyl-4-hydroxy-3-methylisoxazolo[5,4-b]pyridine crystallizes and is filtered off. Recrystallization from methanol yields 9.5 g. (49.5%) of pure product, m.p. 162°.