Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C[N:14](C=O)C>O>[Cl:1][C:2]1[C:11]([NH2:14])=[N:10][C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CN(C)C=O
Reactant: Clc1nc2ccccc2nc1Cl
Solvent: O
Product: Nc1nc2ccccc2nc1Cl
Temperature: 60 °C
Reaction time: 72 h
Yield: 53 %

Procedure:
2,3-dichloroquinoxaline (4 g, 20 mmol, commercially available from Aldrich) is dissolved in dry DMF (20 ml) and treated with solid (NH4)2CO3 (9.7 g, 101 mmol). The resulting mixture is stirred at 60° C. for 3 days (reaction showed 60% completion). The reaction mixture is diluted with water and the product is extracted with EtOAc. The organic layer is dried and the solvent was removed under reduced pressure. The crude residue obtained is purified via column chromatography by eluting with petroleum ether: EtOAc to afford 1.9 g (53%) of the title compound as a pale yellow solid. LC/MS: (ES+): 180.1.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH3:30])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[CH3:42][O:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48]Cl)=[CH:46][CH:45]=1>O.C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([N:22]([C:23]4[CH:27]=[CH:26][O:25][N:24]=4)[CH2:48][C:47]4[CH:50]=[CH:51][C:44]([O:43][CH3:42])=[CH:45][CH:46]=4)(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH3:30])[CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(Br)cc3OC)c2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 74.9 %

Procedure:
A 40-mL vial containing 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (750 mg, 1.517 mmol) and cesium carbonate (1483 mg, 4.55 mmol) was flushed with N2 and subsequently charged with DMF (2.5 mL) and 4-methoxybenzyl chloride (309 μl, 2.276 mmol). The brown slurry was stirred at rt for 5 d. The reaction was then diluted with H2O and extracted thrice with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to an oily orange residue. Column chromatography (25 g Snap Ultra column, 0% to 100% EtOAc/hept with 10% DCM) afforded 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (697.8 mg, 1.136 mmol, 74.8% yield) as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.71 (d, J=1.76 Hz, 6 H) 4.92 (s, 2 H) 6.74 (s, 1 H) 6.77-6.92 (m, 4 H) 7.22-7.29 (m, 2H) 7.59-7.72 (m, 2H) 7.76 (d, J=9.02 Hz, 1 H) 8.14-8.20 (m, 1 H) 8.38 (d, J=3.45 Hz, 1 H) 8.38 (s, 1 H) 8.82 (d, J=3.25 Hz, 1 H) 8.81 (s, 1 H). m/z (ESI) 614.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[NH:5][C:6]=1C(O)=O.[ClH:18]>>[ClH:18].[Br:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[NH:5][CH:6]=1
Reactant: COc1ccc(-c2nc(Br)c(C(=O)O)[nH]2)cc1
Agent: Cl
Product: COc1ccc(-c2nc(Br)c[nH]2)cc1
Yield: 70 %

Procedure:
A suspension of 9 (2.6 g, 0.0088 mol) in 8N HCl (100 ml) was heated at reflux for 20 hours. The solution was then cooled and filtered to yield 1.75 g (70%) of 10.
Reaction SMILES: C(O)=O.[C:4]([NH:8][S:9]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:25][C:26]3[CH:31]=[N:30][C:29]([CH3:32])=[C:28]4[O:33]C(C)(C)[O:35][CH2:36][C:27]=34)=[CH:20][CH:19]=2)=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5]>O>[C:4]([NH:8][S:9]([C:12]1[C:13]([C:18]2[CH:19]=[CH:20][C:21]([NH:24][CH2:25][C:26]3[CH:31]=[N:30][C:29]([CH3:32])=[C:28]([OH:33])[C:27]=3[CH2:36][OH:35])=[CH:22][CH:23]=2)=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1ncc(CNc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c2c1OC(C)(C)OC2
Solvent: O
Solvent: O=CO
Product: Cc1ncc(CNc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c(CO)c1O
Temperature: 100 °C
Yield: 67.4 %

Procedure:
To a solution of 10% formic acid in water (50 mL) was added 3-[(2,2,8-trimethyl-4H-[1,3] dioxino [4,5-c]pyridin-5-ylmethyl)-amino]-benzonitrile (1) (336 mg, 0.7 mmol) and the reaction mixture was heated at 100° C. under nitrogen atmosphere. The reaction mixture was then concentrated to dryness. The resulting pale yellow solid was dissolved in small amount of dichloromethane and diethyl ether was added to induce precipitation of a yellow solid. The 4′-[(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amino]-biphenyl-2-sulfonic acid tert-butylamide (2) (215 mg, 70% yield) was collected by filtration as a pale yellow solid.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[N:8][N:7]([CH2:17][CH3:18])[C:6](=[O:19])[C:5]=1[N+:20]([O-])=O)(=[O:3])[CH3:2].N[C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][N:28]=[CH:29]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[N:8][N:7]([CH2:17][CH3:18])[C:6](=[O:19])[C:5]=1[NH:20][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][N:28]=[CH:29]2)(=[O:3])[CH3:2]
Reactant: Nc1cccc2cnccc12
Reactant: CCn1nc(-c2cccc(Cl)c2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2cccc(Cl)c2)c(C(C)=O)c(Nc2cccc3cnccc23)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
To a stirred solution of 100 mg (0.311 mmol) of 5-acetyl-2-ethyl-4-nitro-6-(3-chlorophenyl)pyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 5-amino-isoquinoline (67 mg, 0.467 mmol) was added. The resulting mixture was stirred at room temperature for two hours. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyl acetate 1:2) to yield the title compound (28 mg, 21.5% yield).
Reaction SMILES: [CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)[CH2:13][C:12]3([CH3:27])[CH3:26])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]([CH3:34])([CH3:33])[C:30]([OH:32])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:20]=[C:21]([NH:28][C:29]([CH3:34])([CH3:33])[C:30]([OH:32])=[O:31])[CH:22]=[CH:23][CH:24]=2)[CH2:13][C:12]3([CH3:27])[CH3:26])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1cccc(C2CC(C)(C)c3cc(S(=O)(=O)NC4CCC4)ccc3N2)c1)C(=O)O
Temperature: 25 °C
Yield: 69.9 %

Procedure:
A mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (150 mg, 0.34 mmol), copper(I) iodide (20 mg, 0.1 mmol), 2-amino-2-methyl-propionic acid (138 mg, 1.3 mmol) and potassium carbonate (140 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-cyclobutylsulfamoyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (112.1 mg, 70.0%) as a white solid: MS (ESI) M+1=472.1.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]([C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH2:7]1)=O)C.C(OC(N1CCC(N)CC1)=O)(C)(C)C.N(C(C)C)=C=O.[BH4-].[Li+]>C1COCC1>[C:36]([N:8]1[CH2:9][CH2:10][C@H:11]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C@H:6]([CH2:4][OH:3])[CH2:7]1)(=[O:40])[CH2:37][CH2:38][CH3:39]
Reactant: CCCC(=O)N1CC[C@H](NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3ccccc23)[C@H](C(=O)OCC)C1
Agent: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(C)N=C=O
Agent: [BH4-]
Solvent: C1CCOC1
Product: CCCC(=O)N1CC[C@H](NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3ccccc23)[C@H](CO)C1

Procedure:
(±)-(cis)-1-Butyryl-4-[4-(2-methyl-benzoylamino)-naphthalene-1-sulfonylamino]-piperidine-3-carboxylic acid ethyl ester was made following general procedure in Scheme 5, substituting (±)4-amino-1-benzyl-piperidine-3-carboxylic acid ethyl ester (5) for 4-amino-piperidine-1-carboxylic acid tert-butyl ester and substituting butyl chloride for 2-isocyanato-propane. To the solution of (±)-(cis)-1-butyryl-4-[4-(2-methyl-benzoylamino)-naphthalene-1-sulfonylamino]-piperidine-3-carboxylic acid ethyl ester (48 mg, 0.085 mmol) in THF (5 mL), was added lithium borohydride in THF solution (0.5 mL, 0.25 mmol) and the resultant solution was stired at 0° C. for 2 h. The solvent was removed in vacuo and the crude material was purified by HPLC to give the title compound. 1H NMR (300 MHz, MeOD) δ 8.81 (d, 1H), 8.34 (d, 1H), 8.25 (d, 1H), 7.95 (d, 1H), 7.72 (m, 3H), 7.40 (m, 3H), 3.46 (m, 7H), 2.56 (s, 3H), 2.32 (m, 2H), 2.55 (s, 3H), 1.52 (m, 5H), 0.92 (m, 3H); LC/MS m/z 525 (M+H)+
Reaction SMILES: C([N:4](CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:34][C:35]1[CH:36]=[CH:37][C:38]([O:78][CH3:79])=[C:39]([C:41]([CH3:77])([CH3:76])[CH2:42][C:43]([OH:75])([C:71]([F:74])([F:73])[F:72])[CH2:44][NH:45][C:46]2[CH:54]=[C:53]([CH3:55])[CH:52]=[C:51]3[C:47]=2[CH:48]=[N:49][N:50]3[C:56]2[CH:57]=[C:58]([C:62]([N:64]([CH3:70])[C@H:65]([C:67](O)=[O:68])[CH3:66])=[O:63])[CH:59]=[CH:60][CH:61]=2)[CH:40]=1.N.O1CCOCC1>CN(C=O)C.CO>[NH2:4][C:67](=[O:68])[C@@H:65]([N:64]([CH3:70])[C:62](=[O:63])[C:58]1[CH:59]=[CH:60][CH:61]=[C:56]([N:50]2[C:51]3[C:47](=[C:46]([NH:45][CH2:44][C:43]([OH:75])([C:71]([F:74])([F:73])[F:72])[CH2:42][C:41]([C:39]4[CH:40]=[C:35]([F:34])[CH:36]=[CH:37][C:38]=4[O:78][CH3:79])([CH3:77])[CH3:76])[CH:54]=[C:53]([CH3:55])[CH:52]=3)[CH:48]=[N:49]2)[CH:57]=1)[CH3:66]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N(C)[C@@H](C)C(=O)O)c1)C(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N(C)[C@@H](C)C(N)=O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
N,N-Diisopropylethylamine (0.044 mL, 0.25 mmol) and HATU (20.1 mg, 0.053 mmol) were added to a solution of N-{[3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)phenyl]carbonyl}-N-methyl-L-alanine (32.4 mg, 0.05 mmol) in DMF (1 mL) and the solution stirred at room temperature under nitrogen for 10 min. Ammonia in dioxan (5M, 1.01 mL, 5.05 mmol) was added and the mixture stirred at room temperature overnight. The mixture was diluted with methanol and purified by mass directed autopreparation (System B) and product containing fractions were partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phase was separated, combined with a second dichloromethane extract, washed twice with water, dried through a hydrophobic frit and evaporated to give the title compound (11 mg).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH:5]([OH:38])[CH2:6][CH:7]([OH:37])[CH2:8][CH2:9][C:10]1[N:11]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:12]=[C:13]([C:18](=[O:29])[N:19]([CH3:28])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C:14]=1[CH:15]([CH3:17])[CH3:16].[OH-].[Na+:41]>CO>[Na+:41].[F:36][C:33]1[CH:32]=[CH:31][C:30]([N:11]2[C:10]([CH2:9][CH2:8][C@@H:7]([OH:37])[CH2:6][C@@H:5]([OH:38])[CH2:4][C:3]([O-:39])=[O:2])=[C:14]([CH:15]([CH3:17])[CH3:16])[C:13]([C:18](=[O:29])[N:19]([CH3:28])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])=[N:12]2)=[CH:35][CH:34]=1
Reactant: COC(=O)CC(O)CC(O)CCc1c(C(C)C)c(C(=O)N(C)Cc2ccccc2C)nn1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1CN(C)C(=O)c1nn(-c2ccc(F)cc2)c(CC[C@@H](O)C[C@@H](O)CC(=O)[O-])c1C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.1 %

Procedure:
To a solution of 7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid methyl ester (0.7920 g, 1.47 mmol) in MeOH (5 ml), NaOH solution (1.028N, 1.50 ml, 1.54 mmol) was added. The reaction mixture was stirred at 25° C. for 12 hrs. After solvent was evaporated, the crude product was dried azeotopically with toluene (×3). It was dissolved in MeOH/CH2Cl2 mixture (1:9, 10 ml) and diluted with CH2CI2 (15 ml). It was filtered through cotton and the filtrate was concentrated, trituated with Et2O for 12 hrs. The product was isolated by filtration and dried under vacuum at 60° C. for 12 hrs to afford (3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid sodium salt (798 mg, 99%): MS(APCI+) 526.3 m/z (M+H); H-NMR (DMSO-d6) [Mixture of rotamers at 25° C.] δ 7.79-7.65, 7.58-7.46, 7.41-7.24, 7.22-7.07, 4.85-4.60, 3.62-3.58, 3.46-3.44, 2.89-2.85, 2.84, 2.74-2.66, 2.54-2.45, 2.29, 1.93-1.88,1.73-1.67, 1.53-1.10.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16][C:15]2=[O:25])=[CH:9][C:8]=1[O:26][CH3:27].C(Cl)(Cl)Cl.[C:42](Cl)(=[O:44])[CH3:43]>CCOC(C)=O>[C:42]([N:22]1[CH2:21][CH2:20][N:19]([C:17]2[S:18][C:14](=[CH:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]4[CH:28]=[CH:29][C:30]([C:32]([F:35])([F:33])[F:34])=[CH:31][C:3]=4[C:2]([F:36])([F:1])[F:37])=[C:8]([O:26][CH3:27])[CH:9]=3)[C:15](=[O:25])[N:16]=2)[CH2:24][CH2:23]1)(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: COc1cc(C=C2SC(N3CCNCC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cc(C=C2SC(N3CCN(C(C)=O)CC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 40 %

Procedure:
To a flask was added 5-[1-[4-(2,4-bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-methylidene]-2-piperazin-1-yl-thiazol-4-one (51, mg, 94 μL) from Example 23, chloroform (5 mL), acetyl chloride (1.5 equiv, 10 μL) and TEA (3 equiv, 40 μL). The reaction solution was stirred at 45° C. for 1.5 hours. The solution was then diluted with EtOAc (75 mL) and filtered through a Buchner funnel to remove excess K2CO3. The solution was washed with aq NH4Cl (50 ml×2), dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed (SiO2, DCM/MeOH 100:0 to 94:06) to provide the title compound (19 mg, 40% yield). 1H NMR (CDCl3) δ 7.95-7.97 (2H, m), 7.84 (2H, d, J=7.7 Hz), 7.77 (1H, s), 7.08-7.11 (2H, m), 6.87 (1H, d, J=8.2 Hz), 5.44 (2H, s), 4.09-4.11 (2H, m), 3.97 (3H, s), 3.79-3.81 (2H, m), 3.61-3.66 (4H, m), 2.17 (3H, s), 1.60 (3H, s); MS (ESI) 588 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[CH:12][C:11]2[C:14](=[C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:32])[O:15][CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[C:9]=1[Cl:33]>C(O)(C)C>[Cl:33][C:9]1[C:10]2[CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:15][C:14](=[C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:32])[C:11]=2[CH:12]=[N:13][C:8]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2ccccc2C1=C1OC(c2ccccc2)c2c1cnc(Cl)c2Cl
Reactant: C1COCCN1
Solvent: CC(C)O
Product: O=C1Nc2ccccc2C1=C1OC(c2ccccc2)c2c1cnc(N1CCOCC1)c2Cl
Temperature: 25 °C
Yield: 44.9 %

Procedure:
A solution of morpholine (155 mg, 1.78 mmol) in 4 mL of isopropanol is treated with 3-(6,7-Dichloro-1-phenyl-1H-furo[3,4-c]pyridin-3-ylidene)-1,3-dihydro-indol-2-one (100 mg, 0.25 mmol) in one portion and the reaction mixture is heated to reflux overnight. The reaction mixture is cooled to room temperature, absorbed to silica gel and purified by chromatography (silica gel, MeOH, chloroform). The product containing fractions are concentrated to give the title compound as a yellow solid (50 mg, 45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:18]=[C:17]([OH:19])[C:16]3[C:11](=[C:12]([C:23](O)=[O:24])[CH:13]=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(=O)([O-])[O-].[K+].[K+].[NH2:55][CH2:56][CH2:57][C:58]1[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=1>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:18]=[C:17]([OH:19])[C:16]3[C:11](=[C:12]([C:23]([NH:55][CH2:56][CH2:57][C:58]4[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=4)=[O:24])[CH:13]=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1
Reactant: NCCc1cccnc1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(F)cc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCc1cccnc1)c1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(F)cc3)nc12
Reaction time: 0.08 h
Yield: 65.4 %

Procedure:
A suspension of 2-(4-fluorophenyl)amino-4-hydroxy-6-nitroquinazoline-8-carboxylic acid (41.1 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (23.3 mg), 1-hydroxybenzotriazole hydrate (15.6 mg), and potasium cabonate (16.3 mg) in DMF (2.00 mL) was stirred for 5 minutes and then briefly (15 seconds) heated with a heat gun. The solution was allowed to return to room temperature over 10 minutes of stirring and then 3-(2-aminoethyl)pyridine (17.0 mg) was added. After stirring for an additional 18 hours the resulting mixture was transfered into a centrifuge tube and water (20 mL) was added. A yellow precipitate formed and was the suspension was centrifuged. The aqueous layer was decanted away from the yellow pellet in the bottom of the tube. The yellow pellet was then resuspended in water (20 mL), centrifuged, and decanted two additional times. The resulting yellow pellet was dried in vacuo at 40° C. for 16 h to afford the title compound (35.0 mg). 1H NMR (300 MHz, DMSO-d6 (w/TFA (50 uL,)): 8.97 (d, J=3.0 Hz, 1H), 8.81 (m, 2H), 8.75 (s, 1H), 8.35 (d, J=8.3 Hz, 1H), 7.98 (dd, J=8.1, 5.9 Hz, 1H), 7.50 (dd, J=8.9, 5.0 Hz, 2H), 7.32 (t, J=8.7 Hz, 2H), 3.50 (m, 2H), 2.84 (m, 2H). HPLC (Method G): 1.59 min. MS (APCI+): m/z 449.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)=[O:8]>>[Cl:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]2[C:11]=1[C:6](=[O:2])[C:7](=[O:8])[NH:9]2
Reactant: O=S(=O)(O)O
Reactant: CC(=O)Nc1cccc(Cl)c1
Product: O=C1Nc2cccc(Cl)c2C1=O
Temperature: 90 °C

Procedure:
To 775 ml of concentrated sulfuric acid, preheated to 70° C., was added, with stirring, 136 g of isonitroso-3-chloroacetanilide at such a rate as to maintain the reaction medium at a temperature between 75° and 85° C. When all the solid had been added, the reaction mixture was heated at 90° C. for an additional 30 minutes. The reaction mixture was then cooled, and poured slowly onto ca 2 liters of ice, with stirring. Additional ice was added as necessary to maintain the temperature below room temperature. A red-orange precipitate formed which was recovered by filtration, washed with water and dried. The resultant solid was slurried in 2 liters of water, and then it was brought into solution by the addition of ca 700 ml of 3N sodium hydroxide. The solution was filtered, and then pH was adjusted to 8 with concentrated hydrochloric acid. At this point, 120 ml of a mixture of 80 parts water and 20 parts concentrated hydrochloric acid was added. The solid which precipitated was recovered by filtration, washed with water and dried to give 50 g of crude 4-chloroisatin. The filtrate from which the 4-chloroisatin had been recovered was further acidified to pH 0 using concentrated hydrochloric acid, wherenupon a further precipitate formed. It was recovered by filtration, washed with water and dried, to give 43 g of crude 6-chloroisatin.
Reaction SMILES: [NH2:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C@H:26]([NH2:32])[CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH3:16]>C(O)(=O)C>[NH2:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[NH2:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:9])[N:32]([C@@H:26]([C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH2:15][CH3:16])[CH:19]=1)[CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:5]2=[O:7]
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Agent: COc1ccc2c(c1N)C(=O)OC2=O
Solvent: CC(=O)O
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3ccc(OC)c(N)c3C2=O)ccc1OC

Procedure:
3-Amino-4-methoxy-phthalic anhydride is prepared according to a procedure based on Rudolf Grewe (Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1938), 71B 907-11). A stirred mixture of 3-amino-4-methoxy-phthalic anhydride (1 mmol) and (S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (1 mmol) in acetic acid is heated to reflux overnight. The solvent is removed in vacuo. The residue is extracted with water and ethyl acetate. The organic layer is dried over MgSO4. The solvent is removed in vacuo to give the crude (S)-4-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-5-methoxy-isoindole-1,3-dione. The product is purified by column chromatography or recrystallization. To a stirred solution of (S)-4-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-5-methoxy-isoindole-1,3-dione (0.5 mmol) in anhydrous CH2Cl2, is added iodotrimethylsilane (3 mmol). The mixture is stirred at room temperature for 24 hours. The reaction mixture is diluted with brine and is extracted with CH2Cl2. The solvent is removed in vacuo to afford crude (S)-4-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-5-hydroxy-isoindole-1,3-dione. The product is purified by column chromatography or recrystallization.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([O:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Reactant: Oc1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(Oc2ccccc2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, phenol and DBU in DME. ES-MS m/e (%): 333 (M+H+, 100).