Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]#[N:15])[CH:11]=2)[NH:6][CH2:5]1.[C:16](O)(=[O:25])[C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[C:14]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH2:5][C@@H:4]([NH:3][C:16](=[O:25])[C@@H:17]([OH:18])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13]2)#[N:15]
Reactant: N#Cc1ccc2c(c1)CC(N)CN2
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: N#Cc1ccc2c(c1)C[C@H](NC(=O)[C@@H](O)c1ccccc1)CN2
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of 1D (10.03 g, 40.7 mmol) in DMF (100 mL) was added (S)-(+)-mandelic acid (7.45 g, 48.9 mmol), followed by EDAC (9.37 g, 48.9 mmol), HOBt (7.49 g, 48.9 mmol) and NMM (16.1 mL, 146.1 mmol). The reaction mixture was stirred at RT overnight, then diluted with EtOAc (200 mL), washed with water (50 mL×3), 1N aqueous HCl (50 mL), water (50 mL) and brine, dried (Na2SO4) and concentrated. The residue was chromatographed (silica gel) eluting with EtOAc/hexane (2:1), and the purified compound crystallized from acetone (3×) to give the title compound as the (S,S) diastereoisomer (2.54 g, 20% yield).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([NH:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)=[N:10][C:9]([C:19]1[NH:23][C:22](=[O:24])[NH:21][N:20]=1)=[CH:8]2.CC1C=CC=C(C)N=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:33]([N:16]1[CH2:17][CH2:18][C@H:14]([NH:13][C:11]2[C:12]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[F:2])[CH:8]=[C:9]([C:19]3[NH:23][C:22](=[O:24])[NH:21][N:20]=3)[N:10]=2)[CH2:15]1)(=[O:36])[CH:34]=[CH2:35]
Reactant: C=CC(=O)Cl
Reactant: O=c1[nH]nc(-c2cc3cccc(F)c3c(N[C@H]3CCNC3)n2)[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(F)c23)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 15.5 %

Procedure:
To a mixture of (S)-3-(8-fluoro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride (250 mg, 0.71 mmol) in DCM (15 mL) was added a solution of 2,6-dimethylpyridine (192 mg, 1.8 mmol) in DCM (1 mL). Acryloyl chloride (135 mg, 1.5 mmol) in DCM (1.35 mL) was added dropwise via syringe at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. Additional 2,6-dimethylpyridine (32 mg, 0.3 mmol) in DCM (0.32 mL) was added followed by acryloyl chloride (45 mg, 0.50 mmol) in DCM (0.45 mL). The reaction mixture was stirred at −10° C. for 20 minutes. The reaction was quenched with MeOH (1 mL) and the mixture was concentrated under vacuum. The crude product was purified by preparative HPLC to give the title compound as a white solid (40.58 mg, 15.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (s, 1H), 11.78 (s, 1H), 7.69-7.63 (m, 3H), 7.60-7.58 (m, 1H), 6.61-6.55 (m, 2H), 6.18-6.13 (m, 1H), 5.67-5.64 (m, 1H), 5.30-5.10 (m, 1H), 4.17-4.15 (m, 1H), 3.66-3.63 (m, 2H), 3.28-3.25 (m, 1H), 2.25-2.03 (m, 2H); ESI-MS m/z [M+H]+ 369.1.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20]C(=O)C(C)(C)C)[C:10]([C:27]#[N:28])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+]>C(O)C>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]2[C:10]([C:27]([NH2:28])=[N:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=32)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccccc2NC(=O)C(C)(C)C)c(C#N)nn1Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c2c(nn1Cc1ccccc1)c(N)nc1ccccc12
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A solution of N-[2-(1-benzyl-3-cyano-5-methyl-1H-pyrazol4-yl)phenyl]-2,2-dimethylpropanamide (2.40 g, 6.44 mmol) and sodium tert-butoxide (0.743 g, 7.73 mmol) in ethanol (28 mL) was heated at reflux for 1 day, then was allowed to cool to ambient temperature. A precipitate formed that was isolated by filtration and washed with water followed by water/ethanol (8:1) to provide 1.33 g of 2-benzyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a white powder, mp>250° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31].C(N(CC)CC)C.Cl>CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2)=[O:31]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccccc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccccc4Cl)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.40 mmol) and 2-chlorophenylisocyanate (0.16 mL, 1.40 mmol) in N,N-dimethylformamide (10 mL), was added triethylamine (0.38 mL, 2.7 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (40 mL) was added and the solids were isolated by filtration and washed with water (20 mL). The crude product was triturated in EtOAc (50 mL) for 0.5 h. The product was isolated by filtration and dried in vacuo to give 1-(2-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.56 g, 97% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 6.35 min (98.37%); mp: 235-237° C.; 1H NMR (DMSO-d6) δ 1.77-2.14 (m, 1H, CHH), 2.23-2.47 (m, 1H, CHH), 2.60 (d, J=17.2 Hz, 1H, CHH), 2.77-3.04 (m, 1H, CHH), 4.32 (d, J=17.4 Hz, 1H, CHH), 4.39-4.61 (m, 3H, CHH, CH2), 5.11 (dd, J=4.9, 13.2 Hz, 1H, CH), 6.88-7.04 (m, 1H, Ar), 7.15-7.32 (m, 1H, Ar), 7.34-7.50 (m, 2H, Ar), 7.54 (s, 1H, NH), 7.58 (t, J=5.8 Hz, 1H, NH), 7.71 (d, J=7.7 Hz, 1H, Ar), 8.17 (d, J=6.0 Hz, 2H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.50, 31.21, 42.83, 47.14, 51.59, 120.86, 121.28, 122.01, 122.61, 123.03, 127.00, 127.45, 129.08, 130.44, 136.57, 142.48, 144.30, 154.83, 167.92, 171.00, 172.85; LCMS: MH=427/429; Anal Calcd for C21H19N4O4Cl: C, 59.09; H, 4.49; N, 13.13; Cl, 8.31. Found: C, 58.86; H, 4.26; N, 12.88; Cl, 8.32.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][O:28][CH2:29][CH3:30])[N:21]([CH2:22][CH2:23][CH2:24][C:25]#[CH:26])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1.[OH:31][N:32]=[C:33](Cl)[CH3:34].C(=NO)C.ClN1C(=O)CCC1=O>C1COCC1>[Cl:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][O:28][CH2:29][CH3:30])[N:21]([CH2:22][CH2:23][CH2:24][C:25]3[O:31][N:32]=[C:33]([CH3:34])[CH:26]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CC(Cl)=NO
Reactant: C#CCCCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Agent: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CC=NO
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCCc1cc(C)no1

Procedure:
In the presence of triethylamine (5.2 mL, 10.7 mmol) in a solution of THF (50 mL), 4-chloro-2-(ethoxymethyl)-1-pent-4-ynyl-1H-imidazo[4,5-c]quinoline (prepared as described in Part F of Example 6, 3.50 g, 10.7 mmol) was reacted with N-hydroxyethanimidoyl chloride that was generated from acetaldehyde oxime (1.90 g, 32.1 mmol) and N-chlorosuccinimide (4.30 g, 32.1 mmol) using the method described in Part B of Example 5. The crude product was purified by flash chromatography (silica gel, gradient elution with 4:1 to 2:3 hexanes/ethyl acetate). The appropriate fractions were combined and concentrated to provide a solid that was triturated with diethylether. The solid was isolated by filtration and dried to yield 4-chloro-2-(ethoxymethyl)-1-[3-(3-methylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinoline (1.87 g) as a white solid.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[CH2:23][N:24]=[C:25]=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.Cl.CNC>ClCCl.O>[CH3:23][N:24]([CH3:25])[C:19](=[O:21])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[CH:13][CH:14]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(CC(=O)O)cc1
Agent: CNC
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution is prepared of 1.2 g (4.06 mmol) of 4-[2-(Boc-amino)ethoxy]benzeneacetic acid in 4 ml of dichloromethane and then 932 mg (4.87 mmol) of EDCI and 55 mg (0.406 mmol) of HOAT are added. After 10 minutes under agitation at ambient temperature, 400 mg (4.87 mmol) of dimethylamine hydrochloride are added. The reaction medium is then agitated at ambient temperature for 24 hours. The medium is then treated by the addition of 20 ml of water and then extracted 3 times with 50 ml of dichloromethane. The organic phases are then regrouped and washed 3 times with 50 ml of water, then dried on magnesium sulfate, and concentrated under reduced pressure. The raw product obtained is then purified by silica gel chromatography eluting with the help of a dichloromethane/ethanol mixture (95/5; v/v). In this way the expected product is obtained in the form of a colorless oil (yield=46%).
Reaction SMILES: [O:1]=[S:2]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].F[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>CN(C)C=O.O>[O:1]=[S:2]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: O=S1(=O)CCCCN1
Reactant: N#Cc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1N1CCCCS1(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.3 %

Procedure:
Added to a solution of 1,1-dioxo[1,2]thiazinane (3.37 g, 25 mmol) in dimethylformamide (35 mL) was sodium hydride (0.675 g, 25 mmol, 95%) and the mixture stirred at room temperature for 15 min. 2-Fluorobenzonitrile (3.37 mL, 31.3 mmol) was added and the mixture stirred at 80° C. for 18 h. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, then dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (SiO2) eluting with 10%-100% ethyl acetate/hexane. The isolated solid was recrystallized from hot ethyl acetate/hexane (2:1) to give the title compound as white crystals (4.15 g, 70% yield). 1H-NMR (300 MHz, CDCl3) δ ppm: 7.70 (1H, dd, J=7.7, 1.1 Hz), 7.64-7.53 (2H, m), 7.41 (1H, td, J=7.3, 1.6 Hz), 3.72 (2H, t, J=5.5 Hz), 3.32 (2H, t, J=6.0 Hz), 2.40-2.32 (2H, m), 2.05-1.97 (2H, m). LCMS [M+H]+ calcd for C11H12N2O2S: 237.06; found: 237.10.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH2:12]([O:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(Br)c1OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 5.22 g (23.9 mmol) of 2-bromo-6-nitrophenol, 3.0 ml (25.1 mmol) of benzyl bromide and 3.64 g (26.3 mmol) of potassium carbonate in 50 ml of acetonitrile was heated under reflux for 2 h. After cooling to RT, the solid was filtered off and the filtrate was freed from the solvent on a rotary evaporator. The residue obtained was dissolved in ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the mixture was filtered and the filtrate was concentrated on a rotary evaporator. The residue that remained was dried under high vacuum. This gave 7.53 g (99% of theory) of the title compound.
Reaction SMILES: C(=O)=O.C(O)C.Cl[C:8]([F:12])=[C:9]([F:11])[F:10].Cl[Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16].C([Li])CCC>C1COCC1>[CH2:15]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:8]([F:12])=[C:9]([F:11])[F:10])[CH3:16]
Reactant: CC[Si](Cl)(CC)CC
Reactant: FC(F)=C(F)Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCO
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)C(F)=C(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A reactor flushed with argon gas was cooled with a dry ice-ethanol cooling medium, and 2.03 g (0.0174 mol) of chlorotrifluoroethylene was introduced into the reactor. To this reactor, 17 ml of THF was introduced to bring the chlorotrifluoroethylene concentration to 1 mmol/ml, and then 2.35 g (0.016 mol) of chlorotriethylsilane was added. The reactor was cooled to -78° C., and 12 ml (0.018 mol) of butyllithium (1.47M hexane solution) was added in 1 hour. The mixture was stirred at 78° C. for 4 hours and at room temperature for about 1 hour. Workup was conducted in the same manner as in Example 1, whereby 2.64 g (86.2%) of triethyltrifluorovinylsilane was obtained.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[C:10]([NH2:18])[C:11]([OH:17])=[CH:12][C:13]=32)[CH2:6]1)=O.[C:21]([Cl:25])(=O)[CH2:22][CH3:23]>>[ClH:25].[CH2:22]([C:23]1[O:17][C:11]2[C:10]([N:18]=1)=[CH:9][C:8]1[CH:7]3[CH2:16][CH:14]([CH2:15][NH:5][CH2:6]3)[C:13]=1[CH:12]=2)[CH3:21]
Reactant: Nc1cc2c(cc1O)C1CC2CN(C(=O)C(F)(F)F)C1
Reactant: CCC(=O)Cl
Product: CCc1nc2cc3c(cc2o1)C1CNCC3C1
Product: Cl

Procedure:
2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-ethanone and propionyl chloride were converted to the title compound following the procedures described in Example 40 and Goldstein, S. W.; Dambek, P. J. J. Het. Chem. 1990, 27, 335. 1H NMR (400 MHz, CD3OD) δ 7.64 (s, 1H), 7.62 (s, 1H), 3.48 (d, J=2.5 Hz, 2H), 3.41 (d, J=12.0 Hz, 2H), 3.20 (2H), 3.01 (q, J=7.5 Hz, 2H), 2.45 (m, 1H), 2.17 (d, J=11.5 Hz, 1H), 1.42 (t, J=7.5 Hz, 3H). APCI MS m/e 229.2 [(M+1)+].
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH2:22]([Li])[CH2:23][CH2:24][CH3:25].O>O1CCCC1.CCCCCC>[NH2:1][C:2]1[CH:13]=[CH:12][C:11]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17])=[CH:10][C:3]=1[C:4](=[O:5])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: [Li]CCCC
Reactant: CON(C)C(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1N
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methylbenzamide (4.97 g, 16.0 mmol) in tetrahydrofuran (50 ml) was added dropwise slowly 1.6 M solution (20 ml) of n-butyllithium in n-hexane at −78° C., and after the completion of the dropwise addition, the mixture was stirred at −78° C. for 30 min. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 1-(2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}phenyl)pentan-1-one (3.45 g, yield 70%) as a pale-yellow oil.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([CH:51]4[CH2:56][CH2:55][CH2:54][CH:53]([C:57]([O:59][CH3:60])=[O:58])[CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:61][C:62]([F:73])([F:72])[C:63]1[CH:71]=[CH:70][C:66]([C:67](Cl)=[O:68])=[CH:65][CH:64]=1>>[O:50]=[C:47]1[C:48]2[C:44](=[CH:43][CH:42]=[C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:67](=[O:68])[C:66]4[CH:70]=[CH:71][C:63]([C:62]([F:61])([F:72])[F:73])=[CH:64][CH:65]=4)=[CH:40][CH:39]=3)[CH:49]=2)[CH2:45][N:46]1[CH:51]1[CH2:56][CH2:55][CH2:54][CH:53]([C:57]([O:59][CH3:60])=[O:58])[CH2:52]1
Reactant: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)C1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(C(F)(F)F)cc5)cc4)cc3C2=O)C1
Yield: 82 %

Procedure:
The compound of example 550 was prepared analogous to compound of example 97 by reaction of compound of example 543 with 4-trifluoromethyl benzoyl chloride.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[CH2:24]([NH2:27])[CH2:25][CH3:26].C(O)(=O)C.O>CCO>[CH2:24]([NH:27][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4])[CH2:25][CH3:26]
Reactant: CCCN
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 80 °C
Yield: 51.2 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (35 mg, 0.11 mmol) and n-propylamine (0.1 mL, 1.1 mmol) in 2 mL of EtOH was heated in a sealed tube at 80° C. for 4 h. After cooling to r.t., acetic acid (0.1 mL) and water (3 mL) were added. The mixture was extracted several times with EtOAc. The combined organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (5-35% EtOAc/hexanes) to give 19 mg of the title compound. MS: (+) m/z 338.02 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([O:23][C:24]([N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C@H:27]1[C:32]([O:34][CH3:35])=[O:33])=[O:25])([CH3:22])([CH3:21])[CH3:20].[CH:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1.[Cl-].[NH4+]>[C:19]([O:23][C:24]([N:26]1[C:30](=[O:31])[CH:29]([CH:36]([OH:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:28][C@H:27]1[C:32]([O:34][CH3:35])=[O:33])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COC(=O)[C@@H]1CC(C(O)c2ccccc2)C(=O)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To 40 ml of tetrahydrofuran were added 1.54 ml (11 m mol) of diisopropylamine and 6.9 ml of 1.6M butyllithium-hexane solution, followed by stirring for 10 minutes under a stream of nitrogen. A solution of 2.43 g of methyl (S)-N-tert-butoxycarbonylpyroglutamate in 15 ml of tetrahydrofuran, was added and stirred for 10 minutes at -78° C. and further for 20 minutes at -40° C. To the reaction mixture which was again cooled to -78° C. was added dropwise a solution of 1.12 ml (11 m mol) of benzaldehyde in 4 ml of tetrahydrofuran. After stirring for 10 minutes, the reaction mixture was diluted with a saturated ammonium chloride solution, stirred until the temperature of the mixture reached room temperature and extracted with ethyl acetate. The combined organic layers were washed with water and then a saturated saline solution, dried over sodium sulfate and distilled to remove the solvent. The residue was subjected to a silica gel column (2.5×40 cm) chromatography (developed by ethyl acetate-hexane=1:3→1:2→1:1) to obtain 2.26 g (65%) of methyl (S)-N-tert-butoxycarbonyl-4-(α-hydroxybenzyl)pyroglutamate as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:23])[N:16]([CH2:18][CH2:19][O:20][CH2:21][CH3:22])[CH:17]=2)=O)=[C:4]([CH3:34])[CH:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:23])[N:16]([CH2:18][CH2:19][O:20][CH2:21][CH3:22])[CH:17]=2)=[N:36]\[OH:37])=[C:4]([CH3:34])[CH:3]=1
Reactant: CCOCCn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2C)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOCCn1cc(/C(CC(c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2C)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)-1-(2-ethoxyethyl)pyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless foam, MS (ESI+): m/z=517.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:11]1[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])O[C:12]=1[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([C:11]1[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[N:21]([OH:22])[C:12]=1[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1c(C)oc(C)cc1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCc1c(C)n(O)c(C)cc1=O
Temperature: 25 °C

Procedure:
A mixture of 21 (200 mg, 0.75 mmol), hydroxylamine hydrochloride (1.05 g, 15.2 mmol), sodium acetate (1.24 g, 15.2 mmol), water (1 mL), and ethanol (2 mL) was heated at reflux for 3 days. After the reaction mixture was cooled to room temperature, the crude was concentrated under diminished pressure to afford a yellow oil. The residue was purified by chromatography on a silica gel column. Elution with 5:1 chloroform/methanol gave 3-decyl-1-hydroxy-2,6-dimethylpyridin-4(1H)-one (CPD-7) as a light yellow oil: yield 0.08 g (40%); silica gel TLC Rf 0.4 (3:1 ethyl acetate/methanol); 1H NMR (CDCl3, 400 MHz) δ 0.84-0.88 (m, 3H), 1.24-1.44 (m, 16H), 2.27 (s, 3H), 2.48 (s, 3H), 2.57-2.61 (m, 2H) and 6.65 (s, 1H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[CH:8]=1)=O>O=P(Cl)(Cl)Cl>[C:2]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[CH:8]=1)#[N:1]
Reactant: NC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc2cc([N+](=O)[O-])ccc2o1
Temperature: 0 °C

Procedure:
A heterogeneous solution of 2-aminocarbonyl-5-nitrobenzofuran (0.206 g, 1 mmol) in POCl3 (5 mL) was heated at 100° C. for 24 to give a clear solution. The resulting clear solution was carefully poured over ice-water to give a solid mass which was isolated by filtration followed by washing with water to give 2-cyano-5-nitrobenzofuran. 1H NMR (DMSO-d6): δ 8.80 (d, 1H, J=2.4 Hz), 8.42 (dd, 1H, J=2.7 and 9.0 Hz), 8.27 (s, 1H), 7.99 (d, 1H, J=8.7 Hz); LCMS: purity: 98%, MS (m/e): 189 (MH+).
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=[NH:5])#[N:2].Cl.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.O>C(OCC)(=O)C>[ClH:14].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:1]([NH:3][C:4]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)=[NH:5])=[NH:2])=[CH:20][CH:19]=1
Reactant: N#CNC(=N)NCc1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: N=C(NCc1ccc(Cl)c(Cl)c1)NC(=N)Nc1ccc(Cl)cc1
Yield: 130.2 %

Procedure:
To 20 g of N1 -cyano-N3 -(3,4-dichlorobenzyl)-guanidine and 13.5 g of 4-chloroaniline hydrochloride, 200 ml of water was added, which was heated and refluxed for 2 hours. When cooled gradually after reaction, crystals was precipiated. After filtering the crystals, by drying the crystals obtained by heat treatment in 200 ml of ethyl acetate, 21.8 g of the captioned compound was obtained.