Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:18]([F:21])([F:20])[F:19])=[CH:11][C:12]=2[S:13][C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:27]Br>C(O)(=O)C.C(OCC)(=O)C.O>[Br:27][C:11]1[C:12]([S:13][C:14]([F:16])([F:17])[F:15])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:9][C:10]=1[C:18]([F:21])([F:19])[F:20]
Reactant: FC(F)(F)Sc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)Sc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(p-chlorophenyl)-5-(trifluoromethyl)-3-[(trifluoromethyl)thio]pyrrole (1.03 g, 3.0 mmol) and sodium acetate (0.3 g, 3.6 mmol) in acetic acid is treated with bromine (0.58 g, 3.6 mmol), stirred for 30 minutes at room temperature and diluted with an ethyl acetate/water mixture. The organic phase is separated, washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a semi-solid. Chromatography of the semi-solid using silica gel and hexanes gives the title product as a white solid (mp 87.0°-88.5° C.) which is identified by 1HNMR, 19FNMR and 13CNMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.C(O)C.C(=O)(O)[O-].[Na+]>O>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[OH:15])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2
Reactant: O=[N+]([O-])c1cnc2cc(Cl)ccc2c1O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cnc2cc(Cl)ccc2c1O
Temperature: 25 °C
Yield: 46.2 %

Procedure:
7-Chloro-3-nitro-4-hydroxyquinoline (4.48 g, 20 mmol), tin (II) chloride dihydrate (22.6 g, 100 mmol) and ethanol (200 mL) were combined and then heated at reflux for 4 hours. The reaction mixture was cooled to ambient temperature and then poured into water (250 mL). The mixture was brought to neutral pH by the addition of saturated sodium bicarbonate and then filtered to remove tin salts. The filtrate was extracted with ethyl acetate. The combined organic fractions were dried over magnesium sulfate, filtered and then concentrated under vacuum to provide 1.8 g of 3-amino-7-chloro-4-hydroxyquinoline as a green powder.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[C:6]2[CH:7]=[C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:9]=[CH:10][C:5]=2[CH:4]=[CH:3]1.[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[O:20]=[S:2]1(=[O:1])[C:6]2[CH:7]=[C:8]([NH:11][C:12]([N:35]3[CH2:36][CH2:37][N:32]([C:30]4[S:29][N:28]=[C:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:31]=4)[CH2:33][CH2:34]3)=[O:19])[CH:9]=[CH:10][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(Nc1ccc2c(c1)S(=O)(=O)C=C2)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1ccc2c(c1)S(=O)(=O)C=C2)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 31.7 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl (1,1-dioxido-1-benzothien-6-yl)carbamate (263 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.811 mmol) and diisopropylethylamine (0.129 ml, 0.811 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 106 mg (31.7%) of the desired product as a solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:15]([O:13][C:12](=[O:14])[C@H:9]([CH2:10][OH:11])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
In a round-bottomed flask were placed N-BocSerine (20.0 g, 89.605 mmol, 1 eq.), benzyl bromide (10.76 ml, 90.50 mmol, 1.01 eq.) and cesium carbonate (56.64 g, 173.84 mmol, 1.94 eq.) in DMF (180 mL). The suspension was stirred under nitrogen at room temperature for 2 hrs to overnight. The mixture was partitioned between water and ethyl acetate (1:1, 1000 ml) and aqueous layer was re-extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (2×500 mL), saturated sodium chloride, and dried over sodium sulfate. The solvents were removed in vacuo and the crude material purified on silica gel to get N-Boc-serine benzyl ester.
Reaction SMILES: ClC1C=CC=CC=1C1C(C[N:20]2[C:24]3=NC=NC(N)=[C:23]3[C:22](I)=[N:21]2)=NC2C(N=1)=CC=CC=2C.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[C:39]([CH2:49][N:50]2[C:54]3=[N:55][CH:56]=[N:57][C:58]([NH2:59])=[C:53]3[C:52](I)=[N:51]2)=[N:40][C:41]2[C:46]([N:47]=1)=[C:45]([CH3:48])[CH:44]=[CH:43][CH:42]=2.N1C=C(B2OC(C)(C)C(C)(C)O2)C=N1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[C:39]([CH2:49][N:50]2[C:54]3=[N:55][CH:56]=[N:57][C:58]([NH2:59])=[C:53]3[C:52]([C:23]3[CH:24]=[N:20][NH:21][CH:22]=3)=[N:51]2)=[N:40][C:41]2[C:46]([N:47]=1)=[C:45]([CH3:48])[CH:44]=[CH:43][CH:42]=2
Reactant: Cc1cccc2nc(Cn3nc(I)c4c(N)ncnc43)c(-c3ccccc3Cl)nc12
Reactant: Cc1cccc2nc(-c3ccccc3Cl)c(Cn3nc(I)c4c(N)ncnc43)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(Cn3nc(-c4cn[nH]c4)c4c(N)ncnc43)c(-c3ccccc3Cl)nc12

Procedure:
Prepared according to Procedure J using a mixture of 1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.2737 g, 0.52 mmol, 1 eq), 4-pyrazoleboronic acid pinacol ester (0.20 g, 1.0 mmol, 2.0 eq), tetrakis(triphenylphosphine)palladium(0) (0.060 g, 0.052 mmol, 10 mol %), and sodium carbonate (2M aq. sol, 1.6 mL, 3.1 mmol, 6 eq) in DMF (3.1 mL). After purification, a mixture of 1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was obtained as tan solid. The tan solid (0.1566 g) was dissolved in DMSO (8 mL) and purified by semi-prep-HPLC on C18 column using 20-70% gradient of CH3CN (0.1% of TFA) in water (0.1% of TFA) over 40 min as eluent to provide 1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine [PI3Kδ IC50=18 nM] as white solid as a TFA salt and 1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine [PI3Kδ IC50=30 nM] as white solid as a TFA salt. 1H NMR (DMSO-d6) δ ppm 8.18 (1 H, s), 7.88-7.96 (3 H, m), 7.77-7.82 (1 H, m), 7.72-7.77 (1 H, m), 7.49 (1 H, d, J=7.8 Hz), 7.27-7.38 (3 H, m), 5.82 (2 H, d, J=18.4 Hz), 2.54 (3 H, s); Mass Spectrum (ESI) m/e=468.1 (M+1); HPLC: a peak at 6.522 min. 1H NMR (DMSO-d6) δ ppm 8.15 (1 H, s), 7.91-7.96 (1 H, m), 7.89 (2 H, s), 7.78-7.84 (1 H, m), 7.74-7.78 (1 H, m), 7.40-7.49 (1 H, m), 7.18-7.34 (3 H, m), 5.82 (2 H, d, J=27.4 Hz), 2.66 (3 H, s); Mass Spectrum (ESI) m/e=468.1 (M+1); HPLC: a peak at 6.700 min.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH2:36])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CC(O)C.C(Cl)Cl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:36][C@@H:32]4[CH2:33][CH2:34][CH2:35][N:30]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:31]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: N[C@@H]1CCCN(Cc2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCCN(Cc2ccccc2)C1
Temperature: 120 °C
Yield: 113.3 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (260 mg, 0.77 mmol), (R)-1-benzyl-3-aminopiperidine (175 mg, 0.92 mmol), diisopropylethylamine (197 μl, 1.16 mmol) in propan-2-ol (5 ml) was heated in a microwave reactor at 120° C. for 10 minutes. The mixture was diluted with DCM and then purified by column chromatography on silica gel (gradient: 0 to 40% ethyl acetate in cyclohexane) affording 429 mg of (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-((R)-1-benzyl-piperidin-3-yl)amine, which was used for the next step without further purification. LCMS (Method B, ESI): RT=3.58 min, m+H=492.5; 1H NMR (400 MHz, CDCl3) δ: 9.53 (br s, 1H), 9.10 (s, 1H), 8.19-8.15 (m, 2H), 7.69-7.33 (m, 9H), 6.68-6.61 (m, 1H), 4.24-4.15 (br m, 1H), 3.54 (s, 2H), 2.77-2.27 (br m, 4H), 1.88-1.74 (br m, 3H), 1.69-1.52 (br m, 1H).
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.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH: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)=[O:30]
Reactant: COc1ccccc1C(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: COc1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 45.7 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (100 mg, 0.315 mmol) obtained in Example 1, (3), and 2-methoxybenzoyl chloride (63 μL, 0.473 mmol), the title compound (65 mg, yield 46%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C:10]1([OH:15])[CH2:14][CH2:13][NH:12][CH2:11]1.Cl[C:17]1[N:25]2[C@@H:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:27][O:28][C:23]3=[C:24]2[C:19](=[CH:20][CH:21]=[C:22]3[C:35]2[C:36]([CH3:41])=[N:37][O:38][C:39]=2[CH3:40])[N:18]=1>CN1CCCC1=O.CO>[CH3:41][C:36]1[C:35]([C:22]2[C:23]3[O:28][CH2:27][C@H:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[N:25]4[C:17]([N:12]5[CH2:13][CH2:14][C:10]([CH3:9])([OH:15])[CH2:11]5)=[N:18][C:19]([C:24]=34)=[CH:20][CH:21]=2)=[C:39]([CH3:40])[O:38][N:37]=1
Reactant: Cc1noc(C)c1-c1ccc2nc(Cl)n3c2c1OC[C@@H]3c1ccccn1
Reactant: CC1(O)CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2nc(N3CCC(C)(O)C3)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 150 °C

Procedure:
Triethylamine (0.76 mL, 5.5 mmol) and 3-methylpyrrolidin-3-ol hydrochloride (563 mg, 4.09 mmol) were added to (4S)-2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (100 mg, 0.27 mmol) in N-methylpyrrolidinone (3 mL) and the resulting mixture was heated in a microwave at 150° C. for 20 min. The mixture was then diluted with methanol and purified by preparative LCMS at pH 2 buffer followed by preparative LCMC at pH 10 buffer to give the title compound as a mixture of diastereomers (47.1 mg, 40%). LCMS calc. for C24H26N5O3 (M+H)+: m/z=432.2. found: 432.2. The isomers were separated by prep chiral column chromatography: Column: phenomenex Lux Cellulose C-2 5 μm, 21, 2×250 mm, Mobile phase: 20% EtOH/Hexanes, gradient condition: isocratic at 18 mL/min, run time: 30 min, peak time: 23.0 and 25.7 min.
Reaction SMILES: Br[C:2]1[C:3]2[N:10]([CH2:11][CH3:12])[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].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>[NH2:18][C:14]1[C:13]([C:9]2[N:10]([CH2:11][CH3:12])[C:3]3[C:2]([C:25]4[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=4)=[CH:7][N:6]=[CH:5][C:4]=3[N:8]=2)=[N:17][O:16][N:15]=1
Reactant: CCn1c(-c2nonc2N)nc2cncc(Br)c21
Reactant: O=C(O)c1ccc(B(O)O)cc1
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: CCn1c(-c2nonc2N)nc2cncc(-c3ccc(C(=O)O)cc3)c21
Reaction time: 18 h
Yield: 35 %

Procedure:
To a solution of the product from Example 100 (1.5 g, 4.85 mmol) in 1,4-Dioxane (50 ml) was added 4-carboxybenzene boronic acid (1.20 g, 7.23 mmol), sodium carbonate (7 ml of a 2 M solution) and tetrakis(triphenylphosphine)palladium(0) (1.12 g, 0.97 mmol). The reaction mixture was heated to reflux with stirring for 18 hours and allowed to cool. The reaction mixture was filetered and washed with ether (5×, 100 ml) to afford the title compound as a yellow solid (0.594 g, 35%); MS (ES+) m/e 351 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([OH:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1.[OH2:13].OO.N=O>C(O)(C)(C)C>[OH:1][CH:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:3][C:4]([OH:13])([CH3:12])[CH3:11])[C:4]([CH3:12])([CH3:11])[CH2:3]1
Reactant: O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: N=O
Agent: OO
Solvent: CC(C)(C)O
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 45 °C
Yield: 90 %

Procedure:
2,2'-Dipyridyl (0.16 g, 1.0 mmol) and 2.54 g (0.80 mmol) of 5% ferric chloride on silica gel are stirred together in 30 mL of tert-butyl alcohol which is heated to 45° C. To the mixture are added 3.44 g (20.0 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine and 10 mL of water. A solution of 9.4 g (138 mmol) of 50% aqueous hydrogen peroxide mixed with 20 mL of tert-butyl alcohol is added over four hours at 45-50° C. to the reaction mixture. The temperature is maintained at 45-50° C. for 30 minutes. Analysis by gas chromatography shows that the starting nitroxyl compound is completely reacted to form greater than 90% of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([OH:32])[C:24]=3[CH2:33][CH2:34][CH3:35])=[CH:17][CH:16]=2)=[O:13])[CH:6]=1)C.O1CCCC1.[OH-].[Na+].Cl>O.CO>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:12](=[O:13])[NH:11][C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:4]([OH:36])=[O:3])=[CH:16][CH:17]=2)=[C:24]([CH2:33][CH2:34][CH3:35])[C:25]=1[OH:32])(=[O:31])[CH3:30]
Reactant: CCCc1c(OCc2ccc(NC(=O)Nc3cccc(C(=O)OCC)c3)cc2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCc1c(OCc2ccc(NC(=O)Nc3cccc(C(=O)O)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 13 %

Procedure:
To 3-{3-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-ureido}-benzoic acid ethyl ester (200 mg, 0.40 mmol) in 1:1 tetrahydrofuran:methanol (10 mL) is added 2 N NaOH (5 mL). The reaction mixture is stirred vigorously at room temperature for 3 h. The reaction mixture is diluted with water (30 mL), acidified with 5N hydrochloric acid to pH=4, and extracted with ethyl acetate (3×70 mL). The combined organic extracts are washed with brine, dried over sodium sulfate, and concentrated to dryness. The resulting residue is purified by reverse phase HPLC using a gradient of 90:10 to 20:80 (H2O/0.1% TFA):CH3CN as eluent to give the title compound (24 mg, 12%). LC-MS (m/e): 461 (M−1); 1H NMR (DMSO-d6) δ 12.93 (1H, s), 12.85 (1 H, s), 8.93 (1 H, s), 8.77 (1 H, s), 8.15 (1H, s), 7.82 (1H, s), 7.30-7.60 (7 H, m), 6.75 (1H, d), 5.20 (2 H, s), 2.60 (5 H, m), 1.50 (2 H, m), 0.90 (3 H, t).
Reaction SMILES: [CH:1]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH:3]=[CH:2]1.ClC(OCC(C)C)=O.CN1CCOCC1.[Br:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH2:42])[CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH:28]=[CH:29][CH:30]=1>O1CCCC1.N1C=CC=CC=1>[Br:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH:42][C:6]([CH:1]4[CH2:5][CH2:4][CH:3]=[CH:2]4)=[O:8])[CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: O=C(O)C1C=CCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1)C1C=CCC1
Reaction time: 8 h
Yield: 23.1 %

Procedure:
A solution of 0.43 g of 2-cyclopentenoic acid in 5 ml of tetrahydrofuran was cooled in an ice bath. A 0.49 ml portion of isobutyl chloroformate followed by a 0.41 ml portion of N-methyl morpholine were added. After about 1 minute a solution of 1.0 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 10 ml of pyridine was added. The reaction was allowed to come to room temperature and stir overnight. Another 0.5 equivalents of mixed anhydride was added. The mixture was stirred for 5 hours. The solvents were removed at reduced pressure and the solid was purified by chromatography on silica gel to give 0.30 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-cyclopenteneamide: mass spectrum (m/e): 409 (M+H, EI).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+].OS([O-])(=O)=O.[K+]>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][OH:11])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
To a stirred solution of (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (35.2 g, 0.135 mol) in THF (500 mL) at −10° C. was added N-methylmorpholine (15 mL, 0.135 mol) followed by ethyl chloroformate (14.72 g, 0.135 mol). After 10 min, NaBH4 (15.37 g, 0.405 mol) was added in one portion. MeOH (1200 mL) was then added dropwise to the mixture over a period of 20 min at 0° C. The solution was stirred for an additional 20 min and then neutralized with 1M KHSO4. The organic solvent was removed and the aqueous layer was extracted with EtOAc (3×500 ml). The combined organic phases were washed consecutively with 1M KHSO4 (300 mL), H2O (300 mL), 5% aqueous NaHCO3 (300 mL), and dried (Na2SO4). The solvent was evaporated to give a residue, which was purified by column chromatography to give the desired (S)-methyl 4-(tert-butoxycarbonylamino)-5-hydroxypentanoate (24 g, 72%)
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[C:21]([F:24])([F:23])[F:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:2]([C:3]1[CH:11]=[CH:10][C:8]([O:9][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[C:21]([F:22])([F:24])[F:23])=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Temperature: 80 °C

Procedure:
A solution of vanillin (1.65 g, 10.86 mmol) and 4-fluoro-3-trifluoromethyl-benzonitrile (10.26 mmol) in DMF (15 mL) was treated with K2CO3 (2.83 g, 21.72 mmol), and the mixture was heated in an oil bath at 80° C. for 12 h. The reaction was cooled to RT and partitioned between EtOAc and H2O. The organic phase was washed with water (3×), dried over Na2SO4 and concentrated in vacuo. Silica gel chromtagraphy (EtOAc/hexanes) afforded the title compound. 1H NMR (400 Hz, CDCl3) δ 10.00 (s, 1H), 8.00 (m, 1H), 7.68 (dd, 1H), 7.58-7.53 (m, 2H), 7.29 (d, 1H), 6.75 (d, 1H), 3.83 (s, 3H); LC/MS (m/z) [M+1]+ 322.1 (calculated for C16H11F3NO3, 322.06).
Reaction SMILES: [CH2:1]([C:4]1(C(CC=C)NC)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:13])[CH:2]=[CH2:3].N1C2C(=CC=CC=2)CC1=O.[O-]CC.[Na+].[H-].[Na+].C(Br)C=C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCC(NC)C1(CC=C)C(=O)Nc2ccccc21
Agent: CC[O-]
Agent: O=C1Cc2ccccc2N1
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C=CCBr
Product: C=CCC1C(=O)Nc2ccccc21
Reaction time: 8 h

Procedure:
3-Allyl-3-[allyl(methyl)aminomethyl]-indolin-2-one. Oxindole was acylated with ethyl acetate in the presence of sodium ethoxide as described (Chem. Abstr. 1953, 47, p7488). The crude product (9.16 g; 52.3 mmol) was treated with sodium hydride (56 mmol) in DMF at ice bath temperature for 30 min. Allyl bromide (51 mmol) was added and the reaction mixture left at room temperature overnight. The crude product after workup was purified by SGC (EtOAc/isohexanes 1:2). The acetyl group was removed by treatment with triethylamine/water 1:1 at 65° C. for 12 h and the the 3-allyloxindole thus obtained was treated with an excess of allylmethylamine and one equivalent of paraformaldehyde in acetic acid at 70 for 4 h. The crude material after evaporation of solvents was partioned between DCM and basic water. SGC using EtOAc/isohexanes 1:1 gave a reddish oil of the title product(83%).
Reaction SMILES: Cl.[NH:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:3]([C:14]([OH:16])=O)[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:13])[NH:9][N+:10]([O-:12])=[O:11].CN1CCOCC1.OC1C2N=NNC=2C=CC=1.[NH:41](C(OC(C)(C)C)=O)[C@H:42]([C:47]([NH:49][C@H:50]([C:62]([NH:64][C@H:65]([C:76]([NH:78][C@H:79]([C:84]([NH:86][CH2:87][C:88]([O:90][CH3:91])=[O:89])=[O:85])[C@H:80]([CH2:82][CH3:83])[CH3:81])=[O:77])[CH2:66][CH2:67][CH2:68][NH:69][C:70](=[NH:75])[NH:71][N+:72]([O-:74])=[O:73])=[O:63])[CH2:51][C:52](=[O:61])[O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:48])[C@H:43]([CH2:45][CH3:46])[CH3:44]>CN(C=O)C.C(Cl)CCl>[NH:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:3]([C:14]([NH:41][C@H:42]([C:47]([NH:49][C@H:50]([C:62]([NH:64][C@H:65]([C:76]([NH:78][C@H:79]([C:84]([NH:86][CH2:87][C:88]([O:90][CH3:91])=[O:89])=[O:85])[C@H:80]([CH2:82][CH3:83])[CH3:81])=[O:77])[CH2:66][CH2:67][CH2:68][NH:69][C:70](=[NH:75])[NH:71][N+:72]([O-:74])=[O:73])=[O:63])[CH2:51][C:52](=[O:61])[O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:48])[C@H:43]([CH2:45][CH3:46])[CH3:44])=[O:16])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:13])[NH:9][N+:10]([O-:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)N[C@H](C(=O)NCC(=O)OC)[C@@H](C)CC
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)OC(C)(C)C)[C@@H](C)CC)C(=O)NCC(=O)OC

Procedure:
A sample HCl salt 13 and about 1.2 molar equivalents of Boc-Arg(NO2)-OH are mixed in DMF with N-methylmorpholine and hydroxybenztriazole; the solution is then treated with EDC and, after 3 h, the reaction is worked up exactly as described for pentapeptide (12) to give the compound (14) as a white solid.