Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[CH:27][C:28]([C:32]([O:34]C)=[O:33])=[CH:29]4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1.CO.[OH-].[Na+]>O1CCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[CH:27][C:28]([C:32]([OH:34])=[O:33])=[CH:29]4)=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1
Reactant: COC(=O)c1ccc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3ccc(C(=O)O)cc3c2)cc1
Temperature: 100 °C
Yield: 77 %

Procedure:
A solution of methyl 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-naphthalenecarboxylate (0.126 g, 0.2 mmol) in tetrahydrofuran (2.0 mL) was placed in a microwave reaction tube. Methanol (1.0 mL) was added followed by 1 N sodium hydroxide (0.3 mL, 0.3 mmol). The tube was sealed and heated in a microwave reactor to 100° C. for 600 seconds. The solution was neutralized and concentrated. Water was added and the mixture was filtered. The resulting solid was dried in a vacuum oven at 45° C. with P2O5 to yield the title compound (0.082 g, 73.9% as 0.30 tetrahydrofuran) 1H NMR (DMSO-d6): δ 13.3-12.6 (broad s, approximately 1H), 8.61 (s, 1H), 8.29 (s, 1H), 8.02-7.87 (m, 4H), 7.68 (d, J=9 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.54 (dd, J=7, 9 Hz, 1H), 6.91 (d, J=9 Hz, 2H), 4.86 (s, 2H), 3.44 (septet, J=7 Hz, overlapping H2O, 1H), 1.33 (d, J=7 Hz, 6H). HRMS C30H23NO4Cl2 m/z 532.1082, (M+H)+cal; 532.1087 (M+H)+Obs.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:13][C:14]([NH:16][CH3:17])=O)[CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:13][CH2:14][NH:16][CH3:17])[CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2
Reactant: CNC(=O)CC(c1cc(OC)c2cc[nH]c2c1)c1ccccn1
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1cc(OC)c2cc[nH]c2c1)c1ccccn1

Procedure:
[3-(4-Methoxy-1H-indol-6-yl)-3-pyridin-2-yl-propyl]-methyl-amine CLXXVII was prepared from 3-(4-methoxy-1H-indol-6-yl)-N-methyl-3-pyridin-2-yl-propionamide using the procedure described for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=297.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:14][C:15]1[N:19]([CH2:20][CH3:21])[N:18]=[CH:17][CH:16]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Cu+2].O.C(O)(=O)C>[CH2:20]([N:19]1[C:15]([NH:14][C:2]2[C:3](=[CH:7][CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:16][CH:17]=[N:18]1)[CH3:21]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: CCn1nccc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nccc1Nc1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A mixture of 2-chloro-4-nitrobenzoic acid (4.03 g, 0.02 mol), 5-amino-1-ethylpyrazole (2.22 g, 0.02 mol), DMF (25 ml), K2CO3 (2.76 g, 0.02 mol) and Cu(OAc)2.H2O (0.5 g) was refluxed for 24 hours. The reaction mixture was cooled to room temperature, poured into ice-water and then acidified with acetic acid to a pH of 5. A solid formed which was collected by filtration and dried to afford 3.5 g (63%) of N-(1-ethylpyrazol-5-yl)-4-nitroanthranilic acid.
Reaction SMILES: O[C@H:2]1[C:23]2[C:14](=[CH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:13](O)[C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]3)=[CH:4][C:3]1=2.[CH2:25]([C:33]1C=CC=C[C:34]=1[SH:39])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>[I-].[Zn+2].[I-].C(Cl)Cl>[CH2:25]([CH2:33][CH2:34][S:39][C@H:2]1[C:23]2[C:14](=[CH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:13]([S:39][CH2:34][CH2:33][CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]3)=[CH:4][C:3]1=2)[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Sc1ccccc1CCc1ccccc1
Reactant: O[C@H]1c2cc3ccccc3cc2[C@H](O)c2cc3ccccc3cc21
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: c1ccc(CCCCS[C@H]2c3cc4ccccc4cc3[C@H](SCCCCc3ccccc3)c3cc4ccccc4cc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a mixture of trans-6,13-dihydroxy-6,13-dihydropentacene (1.0 g, 3.20 mmol) and zinc iodide (1.02 g, 3.20 mmol) were added successively dry CH2Cl2 (100 mL) and phenethylthiophenol (0.77 g, 7.03 mmol) at RT under an argon atmosphere. The resulting mixture was stirred at RT for 2 h, and then quenched with H2O. The mixture was extracted with CH2Cl2, and the organic layer was washed with brine and dried over anhyd. Na2SO4. After evaporation of solvents, the residue was purified by column chromatography on silica gel eluted with n-hexanes-CH2Cl2 (2:1) to give product as white solids in 71% yield (1.13 g). 1H NMR (500 MHz, CDCl3): δ 7.80 (m, 4H), 7.70 (s, 4H), 7.46 (m, 4H), 7.29 (t, 4H, J=7.56 Hz), 7.20 (m, 6H), 5.24 (s, 2H), 2.90 (s, 8H). LDI-MS m/z: 552 [M+], 416 [M+-SCH2CH2C6H5], 280 [M+-2(SCH2CH2C6H5)].
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=3[C:11]2=[O:26])[CH:5]=1.[CH:28](OCCl)=[O:29]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:25][S:24][C:21]1[N:22]=[CH:23][C:12]2[C:11](=[O:26])[N:10]([C:6]3[CH:5]=[C:4]([C:3]4[NH:27][C:28](=[O:29])[O:1][N:2]=4)[CH:9]=[CH:8][CH:7]=3)[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]=2[N:20]=1
Reactant: O=COCCl
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(N)=NO)c1)C2=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(=O)[nH]3)c1)C2=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 110.6 %

Procedure:
(S)—N′-hydroxy-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamidine (200 mg, 0.52 mmol) obtained in Step 1 of Example 75 was dissolved in pyridine (3.0 mL), and the mixture was stirred at 90° C. for 4 hours after adding chloromethyl formate (0.12 mL, 1.56 mmol) under ice-cooled conditions. The mixture was diluted with chloroform, washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-3-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazol-5(4H)-one (236 mg, quantitative).
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([F:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:15]([Mg]I)C>C1COCC1>[F:1][C:2]1[C:11]([CH:12]([OH:13])[CH3:15])=[C:10]([F:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=Cc1c(F)cc2ncccc2c1F
Reactant: CC[Mg]I
Solvent: C1CCOC1
Product: CC(O)c1c(F)cc2ncccc2c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of 5,7-difluoroquinoline-6-carbaldehyde (5.0 g, 25.9 mmol) in THF (80 mL) was added ethylmagnesium iodide (3 M, 9.5 mL, 28.5 mmol) at −78° C. After stirring at −78° C. for 1 hour, the reaction was quenched with saturated NH4Cl and concentrated under reduced pressure. The residue was diluted with water, extracted with DCM three times. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography (hexane/EtOAc) to give the title compound as a white solid (3.3 g, 58%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.97 (dd, 1H), 8.47 (d, 1H), 7.66-7.58 (m, 2H), 5.54 (d, 1H), 5.29 (m, 1H), 1.56 (d, 3H). LCMS (method A): [MH]+=210, tR=4.71 min.
Reaction SMILES: [OH:1][CH:2]([CH3:9])[C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5].Br[C:11]1[CH:12]=[C:13]([CH2:17][C:18]#[N:19])[CH:14]=[CH:15][CH:16]=1.C([O-])(O)=O.[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[C:18]([CH2:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:8][CH:3]([C:2](=[O:1])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])#[N:19]
Reactant: N#CCc1cccc(Br)c1
Reactant: C=C(C(=O)OC)C(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cccc(CC#N)c1)C(C)=O

Procedure:
A stirred mixture of methyl 3-hydroxy-2-methylenebutanoate (11.37 ml), 2-(3-bromophenyl)acetonitrile (22 g) PdOAc2 (3.15 g), tetrabutylammonium bromide (30.1 g) and NaHCO3 (19.64 g) in THF (40 ml) was heated at reflux for 24 h. The mixture was partitioned between ether and water, the organics separated, washed with water, dried and evaporated under reduced pressure to give the subtitle compound, 22 g.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]=O)[CH:2]=[CH2:3].C([N:14]1C=CC=C1C=O)(C)C.C1CCCCC1>ClCCl>[CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]#[N:14])[CH:2]=[CH2:3]
Reactant: CC(C)n1cccc1C=O
Reactant: C=CCn1cccc1C=O
Solvent: C1CCCCC1
Solvent: ClCCl
Product: C=CCn1cccc1C#N
Yield: 50 %

Procedure:
In the same manner as described in Reference Example 2 (1) except that 1-allylpyrrole-2-carbaldehyde (prepared in the same manner as described in Can. J. Chem., 55, 4112, 1977, b.p. 80°-83° C./7 mmHg) (8.1 g, 60 mmole) is used instead of 1-isopropylpyrrole-2-carbaldehyde and further the product is isolated by silica gel column chromatography (solvent, cyclohexane:dichloromethane=3:1) instead of distillation under reduced pressure, there is obtained 1-allylpyrrole-2-carbonitrile (4.0 g, yield: 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[O:24][CH3:25].[C:26](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:26])[C:10]2=[O:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[O:24][CH3:25]
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1[N+](=O)[O-]
Yield: 83.5 %

Procedure:
3-(4Chloro-6-fluoro-3-methoxy-2-nitrophenyl)-6trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (9 g, 23.5 mmol) was dissolved in dimethylformamide (90 ml) and to this were added potassium carbonate (3.9 g, 28.2 mmol) and dimethylsulfate (10.2 g, 47 mmol) with stirring. The solution was stirred at ambient temperature for 12 hr and water was added. Product was extracted in ethyl acetate and the organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent afforded a crude product which was purified by column chromatography on silica gel. Elution of the column with methylene chloride afforded the title compound (7.8 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([F:28])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:6][N:7]=1.Cl.[OH-].[Na+].C([O-])(O)=O.[Na+]>C(#N)C.O>[NH2:1][C:2]1[C:3]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([F:28])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CCC4(CC3)OCCO4)cnc2N)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(-c2nc(C3CCC(=O)CC3)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of methyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazin-2-yl)-2-fluorobenzoate (6.2 g, 16.00 mmol) in Acetonitrile (100 mL), Water (40 mL), was added 3M aqueous solution HCl (13.34 mL, 80 mmol). The reaction was stirred at room temperature for 30 min. The reaction mixture was basified with 6M NaOH (10 mL), then use sat. NaHCO3 to adjust to pH 8. After acetonitrile was removed in vacuo, the solid suspension residue was filtered and washed with water and heptane, air-dried to give methyl 4-(3-amino-6-(4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate as light yellow solid in 67% yield. LCMS (m/z): 344.0 (MH+), 0.70 min.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([I:8])=[CH:6][CH:7]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>CC(O)(C)C>[I:8][C:5]1[N:4]=[N:3][C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1
Reactant: Clc1ccc(I)nn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(I)nn2)CC1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
3-chloro-6-iodopyridazine (510 mg, 2.1 mmol) and tert-butyl piperazine-1-carboxylate (415 mg, 2.23 mmol) were taken up in tBuOH (8 mL). iPr2NEt (480 μL, 2.8 mmol) was added and the stirred reaction mixture was heated to 100° C. After 48 h, the reaction mixture was cooled and was partitioned between EtOAc and water. The phases were separated, and the organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-25% Et2O in DCM) to afford tert-butyl 4-(6-iodopyridazin-3-yl)piperazine-1-carboxylate 7.12. LCMS-ESI+ (m/z): [M+H—CO2tBu]+ calcd for C8H121 N4: 291.0; found: 291.0.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[CH2:13](Br)[CH2:14][CH3:15].[OH-].[Na+].C(OC(=O)C)C>CCCCCC>[CH2:13]([S:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:4]=2[N:3]=1)[CH2:14][CH3:15]
Reactant: Cc1cc2nc(S)[nH]c2cc1C
Reactant: CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCSc1nc2cc(C)c(C)cc2[nH]1

Procedure:
2-Propylthio-5,6-dimethylbenzimidazole (II) was prepared by the same procedure for I from 0,89 g (0,005 mol) 2-mercapto-5,6-dimethyl-benzimidazole, 0,8 g (0,006 mol) propylbromide in the presence 0,24 g (0,006 mol) sodium hydroxide in a yield of 0,72 g (60%), m.p. 122-123° C. (from mixture ethylacetate with hexane).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br-].[F:13][C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[CH2:16][Zn+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=1[CH2:16][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: Fc1ccc(F)c(C[Zn+])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2cc(F)ccc2F)c1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 79.1 %

Procedure:
To a solution of methyl 2-chloroisonicotinate (5.6 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) in anhydrous THF (100 mL) was added (2,5-difluorobenzyl)zinc(II) bromide (0.5 M in THF) (100 mL, 50.00 mmol) dropwise under nitrogen. The reaction mixture was heated at 60° C. for 15 h. The reaction mixture was quenched by addition of methanol (50 mL) and then filtered. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with satd NH4Cl solution and brine, then dried. The solvent was evaporated under reduced pressure. The residue was suspended in ethanol, filtered and the solid washed with ethanol. The filtrate was concentrated. The residue was dissolved in MTBE (150 mL), then HCl (4 M in dioxane, (8.15 mL) and MeOH (7.5 mL) were added. The resulting suspension was stirred for 20 min, the solid collected, washed with MTBE (×2) and air dried. The solid was dissolved in DCM (200 mL) and washed with satd NaHCO3. The organic phase was dried using a phase separator and evaporated to yield methyl 2-(2,5-difluorobenzyl)isonicotinate (6.8 g, 79%). MS m/z 264 (M+H)+
Reaction SMILES: [CH:1]1([C:7](=[NH:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:19][C:20]([SH:23])(Cl)Cl>C(Cl)Cl>[Cl:19][C:20]1[S:23][N:8]=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Clc1nc(C2CCCCC2)ns1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
Cyclohexanecarboximidamide (100 mg, 792 μmol) and DIPEA (512 mg, 3.96 mmol) in 10 mL DCM at 0-5° C. were treated with perchloromethyl mercaptan (147 mg, 792 μmol) in 5 mL DCM and stirred for 1 hr at 0-5° C. The mixture was concentrated in vacuo to give a brown solid which was used with out further purification in the subsequent step.
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:5])[OH:4])[CH3:2].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:4])[O:5][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:2]
Reactant: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COP(=O)(CC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
In the same manner, P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid (500 mg., 1.22 mmol) and ethyl bromoacetate (408 mg, 2.44 mmol) are reacted together with potassium carbonate (253 mg, 1.83 mmol) in 2-butanone (10 ml) to yield ethoxycarbonylmethyl P-ethyl-2-nitro-5-(2-chloro-4-tri-fluoromethylphenoxy)phenylphosphinate.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([Cl:10])=[CH:5][C:4]=1[NH2:11].[C:12](O)(=[O:16])[C:13](O)=[O:14].Cl>>[Cl:10][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][C:7]=1[CH3:9])[NH:2][C:13](=[O:14])[C:12](=[O:16])[NH:11]2
Reactant: O=C(O)C(=O)O
Reactant: Cc1cc(N)c(N)cc1Cl
Agent: Cl
Product: Cc1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Yield: 81.1 %

Procedure:
A mixture of 1,2-diamino-4-chloro-5-methylbenzene hydrochloride (1.90 g, 9.84 mmol), oxalic acid (1.24 g, 13.8 mmol) and 4M aqueous hydrochloric acid solution (49 mL) was heated under reflux for 4.5 hours. After being cooled, the solid precipitate was collected by filtration, washed well with water and dried under reduced pressure at 80° C. to afford 6-chloro-7-methyl-2,3(1H, 4H)-quinoxalinedione (1.68 g, 81%) as a dark grey solid, mp >330° C.
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=2)[C:13]1=[O:26])(=[O:4])[CH3:3].C1C(C(N)=O)=CN(CC2C=CC=CC=2)C=C1>>[C:2]([C:5]1[CH:10]([CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]2=[O:26])[CH:9]=[CH:8][N:7]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=1)(=[O:4])[CH3:3]
Reactant: COc1cc2c(cc1OC)C(=O)C(Cc1cc[n+](Cc3ccccc3)cc1C(C)=O)CC2
Agent: NC(=O)C1=CN(Cc2ccccc2)C=CC1
Agent: [Br-]
Product: COc1cc2c(cc1OC)C(=O)C(CC1C=CN(Cc3ccccc3)C=C1C(C)=O)CC2

Procedure:
The title compound 162 is prepared according to the procedure reported in Example 39.1 with compound 132 (51 mg, 0.1 mmol) and BNAH (21.4 mg, 1 equiv) as reactants. Yellow solid. (Yield 20.3 mg, 50%).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[O:3].[C:8](OC(=O)C)(=[O:10])[CH3:9]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>[C:8]([O:3][C:2](=[CH2:4])[C:1]([O:6][CH3:7])=[O:5])(=[O:10])[CH3:9]
Reactant: COC(=O)C(C)=O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Product: C=C(OC(C)=O)C(=O)OC
Yield: 34.7 %

Procedure:
102.1 Grams(1 mole) of methyl pyruvate is dissolved in 204.2 g(2 moles) of acetic anhydride and 5.0 g(20 millimoles) of pyridinium p-toluenesulfonate is added thereto, followed by conducting a reaction at 100 to 110° C. for 7 hours with stirring and refluxing with stirring for 11 hours. After cooling, the reaction solution is poured into 5000 ml of water and the precipitated oily substance is extracted with ethyl ether. The extract layer is washed with water, dried over anhydrous magnesium sulfate, concentrated and distilled under reduced pressure to give 50.0 g of methyl 2-acetyloxyacrylate as colorless oil having bp. 65 to 68° C./11 mmHg.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=O.N[N:15]1[CH:19]=[N:18][N:17]=[CH:16]1>C1(C)C(C)=CC=CC=1>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[C:19]2[N:15]([CH:16]=[N:17][N:18]=2)[N:2]=[CH:3][CH:4]=1
Reactant: CN(C)C=CC(=O)c1ccccn1
Reactant: Nn1cnnc1
Solvent: Cc1ccccc1C
Product: c1ccc(-c2ccnn3cnnc23)nc1

Procedure:
As for Example 16, a mixture of 3-dimethylamino-1-(2-pyridyl)-2-propen-1-one, 4-amino-1,2,4-triazole and xylene is refluxed for 16 hours to give the product of the Example.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Br[CH2:33][CH2:34][O:35][CH2:36][CH2:37]Br>CN(C)C=O.C(OCC)(=O)C>[O:35]1[CH2:36][CH2:37][N:1]([C@H:2]2[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=3[N+:20]([O-:22])=[O:21])[CH2:6][CH2:7]2)[CH2:33][CH2:34]1
Reactant: BrCCOCCBr
Reactant: NS(=O)(=O)c1ccc(NC[C@H]2CC[C@H](N)CC2)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(NC[C@H]2CC[C@H](N3CCOCC3)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 451B (0.85 g) and diisopropylethylamine (2.03 mL) in N,N-dimethylformamide (7 mL) was added bis(2-bromoethyl)ether (0.54 g) as a solution in N,N-dimethylformamide (1 mL). The reaction was stirred at room temperature for 1 hour and heated to 70° C. overnight. The reaction was cooled, diluted with ethyl acetate (100 mL), washed with water (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Revleris 120 g) eluting with a gradient of 0.75% to 7.5% over 30 minutes (flow=80 ml/min) gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:8]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[CH:9][CH:10]=1)=[O:4].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[CH:17]=2)[C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(C=CC(=O)O)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CCC(=O)O)c(-c2cccc(C(F)(F)F)c2)c1
Yield: 92.6 %

Procedure:
The compound of step 1 (400 mg, 1.14 mmol) and Palladium (10%) on charcoal (23 mg) were suspended in methanol (30 ml). The mixture was hydrogenated for 3 h at 4 bar hydrogen pressure, subsequently filtered over Celite and evaporated to dryness to yield the title compound (372 mg).