Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([Br:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:6]1=[O:25])C=C.C1([SiH3])C=CC=CC=1>C(Cl)Cl.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>[Br:19][C:17]1[CH:18]=[C:11]2[C:10]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:9][CH:8]=[C:7]3[C:12]2=[C:13]([CH:16]=1)[C:14](=[O:15])[N:5]([OH:4])[C:6]3=[O:25]
Reactant: C=CCON1C(=O)c2ccc(N3CCCC3)c3cc(Br)cc(c23)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: O=C1c2ccc(N3CCCC3)c3cc(Br)cc(c23)C(=O)N1O
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
To a 0° C. solution of 2-allyloxy-5-bromo-7-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.81 g, 2.0 mmol, from Example G2) in CH2Cl2 (40 mL) was added phenysilane (0.32 g, 3.0 mmol) and Pd(PPh3)4 (0.050 g, 0.043 mmol). The reaction was stirred for 15 minutes, and the resulting precipitate removed by filtration, washed with CH2Cl2, and dried to give 0.60 g of the title compound, mp 234-235° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-].P(Cl)(Cl)([Cl:12])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: Cc1cc[n+]([O-])c(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nc(Cl)c1
Yield: 43 %

Procedure:
A mixture of 2-chloro-4-methyl-pyridine 1-oxide (1.0 g, 7.0 mmol) and phosphorus oxychloride (10 mL) was heated at reflux for 4 h. The volatiles were evaporated and the residue dissolved in ethyl acetate. The solution was washed with ice-water followed by sodium bicarbonate solution. The organic phase was again washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated to obtain a residue which was purified by column chromatography over silica gel (60-120 mesh) using petroleum ether as eluent to afford 2,6-dichloro-4-methyl-pyridine (491 mg, 43%) as a white solid.
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.Br[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N+:23]([C:20]1[N:21]=[CH:22][C:17]([N:3]2[CH2:4][CH:5]3[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc([N+](=O)[O-])nc1)C2
Temperature: 140 °C

Procedure:
tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.4 g; 1.9 mmol), prepared as described in (J. Med. Chem., (1998) 41, 674), 5-bromo-2-nitropyridine (0.43 g; 2.27 mmol), prepared as described in (J. Am. Chem. Soc., (1945) 67, 668), and triethylamine (0.23 g; 2.27 mmol) in toluene (10 mL) were heated at reflux for 14 hours. After evaporation of the solvent, additional triethylamine (0.23 g) was added and the mixture further heated at 140° C. for 2 hours. The residue was purified on SiO2 (CH2Cl2:EtOAc 9:1) to provide the title compound.
Reaction SMILES: [C:1]([CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5][CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[N+:28]([O-:30])=[O:29])=[CH:22][CH:21]=1>C(OCC)C>[CH2:11]([O:10][C:8]([CH2:7][C@@H:6]1[CH2:5][C@@:4]([C:1](=[O:3])[CH3:2])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@@H:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=2)[C@@H:27]1[N+:28]([O-:30])=[O:29])=[O:9])[CH3:12]
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1
Reactant: CCOC(=O)C=CCC(C(C)=O)C(=O)OCC
Solvent: CCOCC
Product: CCOC(=O)C[C@@H]1C[C@@](C(C)=O)(C(=O)OCC)[C@@H](c2ccc(OC)cc2)[C@@H]1[N+](=O)[O-]
Reaction time: 24 h
Yield: 83 %

Procedure:
To a solution of diethyl 5-acetylhex-2-enedioate (4a, 0.3 mmol, 1.0 eq) and 1-methoxy-4-((E)-2-nitrovinyl)benzene (0.6 mmol, 2.0 eq) in diethyl ether (0.4 mL) was added catalyst VI (Q-NH2) (0.06 mmol, 0.2 eq) at room temperature (22° C.). The resulting mixture was stirred vigorously for 24 hours, then the reaction was continued for about 6 hours after removal of the solvent. After the reaction was completed (monitored by TLC and crude NMR), the title product was afforded by flash chromatography over silica gel (Et2O:Hexane=1:10 to 1:3) in 83% yield.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:21])[C:7](=[O:20])[C:8]([CH3:19])([CH3:18])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1OC.O.Cl>C(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([CH3:19])([CH3:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[C:11]2=[N:12][C:2]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)=[N:3][CH:4]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 96.2 %

Procedure:
To a solution of 10-chloro-2-cyclopentyl-4,4,6-trimethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 126; 308 mg, 1 mmol) and 4-amino-3-methoxybenzoic acid (Aldrich; 155 mg, 1.13 mmol) in ethanol (5 mL) was added water (15 mL) and concentrated hydrochloric acid (0.17 mL, 2 mmol). The mixture was heated under reflux for 36 hours. The reaction was cooled and a precipitate formed. This was filtered, dried and triturated under cold acetonitrile refiltered and dried in vacuo. To give the title compound as a brown solid (394 mg, 96%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH:11]=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)C.[Cl-].[NH4+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[OH:12])[NH:8][C:5]2=[CH:6][N:7]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cc2cc(Cl)ncc2[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cc2cc(Cl)ncc2[nH]1
Temperature: -15 °C
Reaction time: 5 h
Yield: 49 %

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (156 mg, 0.86 mmol) in tetrahydrofuran (5 mL) was added 3.0 M phenylmagnesium bromide in diethyl ether (0.58 mL, 1.74 mmol) at −78° C. under a nitrogen atmosphere. The reaction mixture was slowly warmed to −15° C. After stirring for ca. 5 h, additional 3.0 M phenylmagnesium bromide in diethyl ether (0.15 mL, 0.45 mmol) was added. The reaction mixture was stirred for another 1 h, warming to 0° C. The reaction mixture was poured into a 2:1 solution of saturated ammonium chloride and water, and extracted with ethyl acetate (3×). The combined organic extracts were washed with water and brine, and dried over sodium sulfate. After filtration and concentration, the crude product was purified by Biotage chromatography (1 to 100% ethyl acetate in hexanes) to give (5-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)(phenyl)methanol (109 mg, 49%) as a yellow foam: 1H NMR (300 MHz, CDCl3) 8.69 (1H, s), 6.23 (1H, s), 7.33-7.61 (6H, m), 8.49 (1H, s), 8.69 (1H, br s); ESI MS m/z 259 [C14H11ClN2O+H]+.
Reaction SMILES: Cl.[CH:2]1([NH:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].O.[CH3:16][C:17]1[O:18][C:19]([CH3:26])=[C:20]([CH3:25])[C:21]=1[C:22](Cl)=[O:23]>ClCCl>[CH:2]1([N:8]([C:22]([C:21]2[C:20]([CH3:25])=[C:19]([CH3:26])[O:18][C:17]=2[CH3:16])=[O:23])[OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: ONC1CCCCC1
Reactant: Cc1oc(C)c(C(=O)Cl)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1oc(C)c(C(=O)N(O)C2CCCCC2)c1C

Procedure:
49 Parts of N-cyclohexylhydroxylamine hydrochloride is dissolved in 400 parts of dichloromethane; at room temperature a solution of 50.4 parts of sodium hydrogen carbonate in 500 parts of water and subsequently 51.6 parts of 2,4,5-trimethylfuran- 3-carboxylic chloride are added to the mixture. After the mixture has been stirred for 2 hours the dichloromethane phase is separated, dried over anhydrous sodium sulfate and evaporated. There is obtained 75 parts of N-cyclohexyl-2,4,5-trimethylfuran-3-hydroxamic acid in the form of an oil. This oil is dissolved in 300 parts of dichloromethane. To this solution there is added 36 parts of sodium hydroxide in 200 parts of water and 75.6 parts of dimethyl sulfate and the whole is stirred for 2 hours. The dichloromethane phase is then separated, washed with water until neutral, dried over anhydrous sodium sulfate and evaporated. Upon distillation of the residue there is obtained 52 parts of O-methyl-N-cyclohexyl-2,4,5-trimethylfuran-3-hydroxamic acid having a boiling point at 0.3 mm Hg of 128° to 130° C and the refractive index nD25 : 1.5021. ##SPC11##
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.ClC(OCC)=O.[CH2:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH2:32])[CH3:25]>C(N(CC)CC)C>[CH2:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH:32][C:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[O:1][CH2:2][CH2:3][CH2:4]2)=[O:13])[CH3:25]
Reactant: O=C(O)c1cccc2c1OCCC2
Reactant: CCN1CCCC1CN
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CCCC1CNC(=O)c1cccc2c1OCCC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
46 g of chroman-8-carboxylic acid, 188 ml of chloroform and 26 g of triethylamine were introduced into a 1-liter round-bottomed flask. The contents were cooled to 0° C. and 28 g of ethyl chloroformate were then added in small amounts, between 0° and 5° C. The contents were stirred for 30 minutes at 5° C. and 36 g of 1-ethyl-2-aminomethylpyrrolidine were then poured in dropwise, between 5° and 10° C. The contents were then stirred for 1 hour at 10° C. and the temperature was then allowed to rise. The chloroform was distilled off under slight vacuum, the residue was taken up with water and acetic acid was added until a pH of 4 was obtained. The solution obtained was filtered with charcoal and then made alkaline with 20% ammonia until a color change of phenolphthalein was observed.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]1[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH2:31])=[O:30]>N1C=CC=CC=1.CN(C)C=O>[NH2:26][C:27]1[C:28]([C:29](=[O:30])[NH2:31])=[CH:32][CH:33]=[CH:34][C:35]=1[NH:36][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][N:9]=1)=[O:13]
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: NC(=O)c1cccc(N)c1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2cccc(C(N)=O)c2N)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(methoxycarbonyl)picolinic acid (3.33 g, 18.4 mmol) in a mixture of pyridine (20 mL) and N,N-dimethylformamide (35 mL) was treated with 1,1′-carbonyldiimidazole (3.28 g, 20.2 mmol) at 45° C. for 2 hours. After cooling, 2,3-diaminobenzamide (HCl salt) (4.12 g, 18.4 mmol) was added and the mixture stirred at room temperature overnight. The mixture was concentrated and the residue used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Cl:11]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:11][C:7]1[C:2]([OH:1])=[N:3][CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])c1ccc(O)nc1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
2-Hydroxy-5-nitropyridine (50 g, 357 mmol) and N-chlorosuccinimide (55 g, 410 mmol) were suspended in anhydrous DMF (150 mL). The suspension was stirred at room temperature for 18 hours. The resulting homogeneous reaction mixture was diluted by the slow addition of water (750 mL), which resulted in a pale yellow precipitate. The solids were isolated via filtration and dried under high vacuum to provide 3-chloro-5-nitro-2-hydroxypyridine (59 g, 95% yield).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:49])[CH2:10][C:11]1[CH:48]=[CH:47][CH:46]=[CH:45][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[N:30][CH:31]=2)[N:16]=1>C(Cl)Cl>[NH:35]1[CH2:36][CH2:37][CH:32]([C:29]2[N:30]=[CH:31][C:26]([NH:25][C:17]3[N:16]=[C:15]([CH2:14][CH2:13][C:12]4[CH:45]=[CH:46][CH:47]=[CH:48][C:11]=4[CH2:10][C:9]([NH2:8])=[O:49])[C:20]([C:21]([F:23])([F:22])[F:24])=[CH:19][N:18]=3)=[CH:27][CH:28]=2)[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)nc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.5 %

Procedure:
TFA (0.5 mL) was added to a solution of tert-butyl 4-(5-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (A47) (58 mg, 0.099 mmol) in DCM (5 mL) and the resulting solution stirred for 18 hours at room temperature. The volatiles were evaporated under reduced pressure and the residue partitioned between 2 M aqueous NaOH (10 mL) and EtOAc (25 mL). The organic layer was separated and washed with water (25 mL), brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound 13 as a white solid (41 mg, 85%); 1H NMR (400 MHz, d4-MeOH) δ 8.78 (d, J=2.1 Hz, 1H), 8.61 (d, J=0.6 Hz, 1H), 8.19 (dd, J=8.6, 2.6 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.26 (d, J=6.3 Hz, 1H), 7.24-7.15 (m, 3H), 3.67 (s, 2H), 3.22-3.15 (m, 4H), 3.14-3.05 (m, 2H), 2.90-2.70 (m, 3H), 1.93 (d, J=13.9 Hz, 2H), 1.75 (m, 2H). LCMS-A: rt 4.552 min; m/z 485 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:15]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]3)=[N:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[N:29]1([CH2:35][CH2:36][OH:37])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CN1CCOCC1.OC1C2N=NNC=2C=CC=1.CN(C)CCCN=C=NCC.Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:15]([N:16]3[CH2:17][CH2:18][CH:19]([C:22]([N:32]4[CH2:33][CH2:34][N:29]([CH2:35][CH2:36][OH:37])[CH2:30][CH2:31]4)=[O:24])[CH2:20][CH2:21]3)=[N:14][CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: O=C(O)C1CCN(c2nccc3nc(NCc4ccccc4Cl)ncc23)CC1
Reactant: OCCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(C1CCN(c2nccc3nc(NCc4ccccc4Cl)ncc23)CC1)N1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.5 %

Procedure:
1-[2-(2-Chloro-benzylamino)-pyrido[4,3-d]pyrimidin-5-yl]-piperidine-4-carboxylic acid 14 (50 mg, 0.13 mmol), 2-piperazin-1-yl-ethanol (17.0 mg, 0.13 mmol) and 4-Methylmorpholine (70 μL, 0.64 mmol) were dissolved in DMF (3 mL). To this mixture hydroxybenzotriazole (17.0 mg, 0.13 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide×HCl (24.0 mg, 0.13 mmol) were added and the mixture was stirred for 48 h at room temperature. Water was added to the mixture and the precipitate formed was filtered off and dried in vacuo. The residue was purified by silica chromatography (ethyl acetate/cyclohexane) to yield in a colorless solid (27.8 mg, 0.05 mmol, 43%) characterized as 15.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=4[Cl:33])=[CH:22][C:21]3=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.Cl>O1CCCC1.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=3[Cl:33])=[CH:22][C:21]2=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (prepared as in Example 79, 145 mg, 0.27 mmol) in tetrahydrofuran (20 mL) was treated with 2N aqueous hydrochloric acid (10 mL). The reaction mixture was stirred for 4 h at 25° C. The reaction mixture was diluted with ethyl acetate, washed with water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated to afford (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide as a fluffy material. This material was dissolved in dichloromethane (20 mL) and treated with 1M hydrogen chloride in diethyl ether (2 mL). Solvents were evaporated and the residue was triturated with diethyl ether. The mixture was filtered to give (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide hydrochloride (85 mg, 59%) as a yellow solid: HR-ES-MS m/z calculated for C22H26Cl2N4O5 [M+H]+ 497.1353, observed 497.1355; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 1.35-1.66 (m, 2H), 1.67-1.86 (m, 1H), 3.19-3.38 (m, 2H), 3.70-3.93 (m, 2H), 4.09 (dd, J=13.4, 3.5 Hz, 1H), 4.16-4.32 (br. s., 2H), 4.23 (m, J=18.4 Hz, 1H), 4.62 (d, J=18.4 Hz, 1H), 4.82-4.91 (m, 1H), 4.92 (s, 1H), 6.41 (d, J=1.5 Hz, 1H), 7.42-7.59 (m, 3H), 7.64 (d, J=7.5 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH2:10][CH:9]([C:12]([CH3:14])=[O:13])[O:8][CH2:7][C:6]=2[C:5](=[O:15])[CH:4]=[CH:3]1.C(O[CH:20]=[CH:21][CH:22]=[CH2:23])(=O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>C1C=CC=CC=1>[O:1]=[C:2]1[C:11]2[CH2:10][CH:9]([C:12]([CH3:14])=[O:13])[O:8][CH2:7][C:6]=2[C:5](=[O:15])[C:4]2[C:3]1=[CH:20][CH:21]=[CH:22][CH:23]=2
Reactant: C=CC=COC(C)=O
Reactant: CC(=O)C1CC2=C(CO1)C(=O)C=CC2=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CC(=O)C1CC2=C(CO1)C(=O)c1ccccc1C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
A mixture of methyl (5,8-dioxo-3,4,5,8-tetrahydrobenzo [2,3-C] pyran-3-yl) ketone (100 mg, 0.485 mmol) and acetoxybutadiene (75 μl, 0.630 mmol) in dry benzene (5 mL) was heated for 12 hours at 60° C. under argon atmosphere. The solvent was then removed in vacuo and the resulting adduct dried under reduced pressure. The adduct was dissolved in 10 mL of ethanol and to this solution was added 1 mL of 1% K2CO3 aqueous solution. After stirring for 2 hours at R.T., the reaction mixture was neutralized (pH=6) and extracted with CH2Cl2 (2×50 mL). The organic layer was then washed with water (3×50 mL) and dried over MgSO4. Flash chromatography (toluene:ethyl acetate; 95%:5%) of the residue gave 69 mg (55% yield) of pure titled compound. (MP: 135°-136° C.).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].Cl(O)(=O)(=O)=O.C([O-])(O)=O.[Na+].C(O[C:24]([CH3:27])([CH3:26])[CH3:25])(=O)C>>[O:6]=[C:5]1[NH:1][C@H:2]([C:7]([O:9][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:8])[CH2:3][CH2:4]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
To a suspension of L-pyroglutamic acid (13.2 g, 102 mmol) in t-butyl acetate (200 mL), was added perchloric acid (70%, 9.7 mL, 113 mmol). The mixture was stirred at rt for 20 h, then poured into sat. NaHCO3. NaHCO3 (s) was added until neutral. The aqueous phase was extracted with EtOAc (6×). The combined organic extract was dried (Na2SO4) and concentrated to afford 13.68 g (72%) of the title compound, 1a. 1H NMR (300 MHz, CDCl3) δ6.17 (br s, 1H), 4.13 (dd, J=7.4, 5.2, 1H), 2.44-2.31 (m, 3H), 2.22-2.15 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16](=O)[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][O:25][NH2:26].Cl>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16](=[N:26][O:25][CH3:24])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CON
Reactant: O=C1CC2(CC(C#Cc3cccc(Cl)c3)=NO2)c2ccccc21
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CON=C1CC2(CC(C#Cc3cccc(Cl)c3)=NO2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
To a solution of the Compound of Example 83 (0.14 g, 0.44 mmol) in 1.5 mL of pyridine was added O-methylhydroxylamine (0.04 g, 0.48 mmol). After 4 hours stirring at r.t., the reaction was checked by TLC and considered to completion. It was diluted with water, acidified by 1N HCl and extracted with EtOAc. After drying on Na2SO4 and evaporation to dryness, the residue from evaporation was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 95:5 to 1:1) to give the title compound as a colorless oil. Yield: 75.4%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH2:16][CH2:17]Cl)[C:8]([S:19]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[N:7]1.[CH3:35][NH2:36].Cl.CCOCC>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH2:16][CH2:17][NH:36][CH3:35])[C:8]([S:19]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)(=[O:20])=[O:21])=[N:7]1
Reactant: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2c(OCCCl)cccc12
Reactant: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CNCCOc1cccc2c(S(=O)(=O)c3cccc4ccccc34)nn(Cc3cccc(Cl)c3)c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(3-chloro-benzyl)-7-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.065 g, 0.12 mmoles) and methylamine (0.48 mmoles) in DMF (1 mL) was stirred under nitrogen at 100° C. overnight. Mixture was cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. Compound was purified by flash chromatography using as eluent 5% CH3OH/EtOAc. The purified compound was dissolved in methanol, 1M HCl in ether (0.1 mL, 0.1 mmoles) was added, and compound was dried to afford the title compound as the HCl salt, MS: (ES+) 507 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([O-:19])=[O:18].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:9])[C:11]=1[OH:16])([O-:19])=[O:18]
Reactant: O=C(Nc1ccccc1)c1ccccc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 42.1 %

Procedure:
2-Phenylaminocarbonylphenol (5.00 g, 23 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (2.20 g, 25.5 mmol). The addition of sulfuric acid (30 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product(2.50 g, 42%). 1H NMR (CD3COCD3): d 8.15 (d,1H), 8.09 (d,1H), 7.51 (d, 1H), 7.30 (d, 1H), 7.10 (t, 1H), 7.01 (t, 1H).