Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:8]([CH2:9][CH2:10][O:11][CH2:12][CH3:13])[N:7]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:5]=1[N+:18]([O-])=O)(=[O:3])[NH2:2].C([O-])=O.[NH4+]>CO.[OH-].[Pd+2].[OH-]>[NH2:18][C:5]1[C:6]([C:14]([O:16][CH3:17])=[O:15])=[N:7][N:8]([CH2:9][CH2:10][O:11][CH2:12][CH3:13])[C:4]=1[C:1](=[O:3])[NH2:2]
Reactant: CCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(N)=O
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOCCn1nc(C(=O)OC)c(N)c1C(N)=O

Procedure:
Palladium(II) hydroxide (100 mg) was added to a solution of the nitro compound of Step 3 (970 mg, 3.39 mmol) in methanol (20 mL) and the mixture warmed to reflux. Ammonium formate (1.07 g, 16.97 mmol) was added and the reaction mixture stirred at reflux for 2 hours. The catalyst was removed by filtration through Arbocel® and the reaction mixture concentrated in vacuo to yield the title product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[C@@H:9]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[F:36][C:37]([F:52])([F:51])[C:38]1[CH:39]=[C:40]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[C:41](Cl)=[O:42]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][C:41](=[O:42])[C:40]2[CH:44]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:46]=[C:38]([C:37]([F:36])([F:51])[F:52])[CH:39]=2)[C@@H:9]1[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 77 %

Procedure:
A solution of 2.67 g (10.0 mmol) of 4 -benzyl-3-(S)-(4-fluorophenyl)-2-morpholinone (Description 2) in 40 ml of dry THF was cooled to -78° C. The cold solution was treated with 12.5 ml of 1.0 M L-Selectride® solution in THF, maintaining the internal reaction temperature below -70° C. The resulting solution was stirred cold for 45 minutes and the reaction was charged with 3.60 ml (20.0 mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride. The resulting yellow mixture was stirred cold for 30 minutes and the reaction was quenched with 50 ml of saturated aqueous sodium bicarbonate solution. The quenched mixture was partitioned between 300 ml of ether and 50 ml of water and the layers were separated. The organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 300 ml of ether; the extract was dried and combined with the original organic layer. The combined organics were concentrated in vacuo. Flash chromatography on 150 g of silica gel using 37:3 v/v hexanes/ether as the eluant afforded 4.06 g (80%) of the title compound as a solid. 1H NMR (200 MHz, CDCl3) δ 2.50 (1H, dt, J=3.4, 12.0 Hz), 2.97 (1H, app d, J=12.0 Hz), 2.99 (1H, d, J=13.6 Hz), 3.72-3.79 (1H, m), 3.82 (1H, d, J=2.6 Hz), 4.00 (1H, d, J=13.6 Hz), 4.20 (dt, J=2.4, 11.6 Hz), 6.22 (1H, d, J=2.6 Hz), 7.22-7.37 (7H, m), 7.57 (2H, app d, J=6.8 Hz), 8.07 (1H, s), 8.47 (2H, s).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:22]#[N:23])[C:15](=[O:21])C(OCC)=O)=[CH:10][CH:9]=1.C=O>O.C(Cl)Cl>[OH:21][CH2:15][CH:14]([C:11]1[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=1)[C:22]#[N:23]
Reactant: CCOC(=O)C(=O)C(C#N)c1ccc(Cl)cc1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CC(CO)c1ccc(Cl)cc1
Reaction time: 0.03 h

Procedure:
Sodium carbonate (204 mg, 1.9 mmol) dissolved in water (1.2 mL) was added dropwise over 10 min to a vigorously stirred mixture of the above ethyl 3-(4-chlorophenyl)-3-cyano-2-oxopropanoate (400 mg 1.59 mmol), 37% HCHO (131 μL 1.75 mmol) and methylene chloride (2 mL). After an additional 2 min, the mixture was diluted with ˜one mL each of water and methylene chloride and phase separated. Acidification of the aqueous phase and filtration of the precipitated solid recovered 68 mg (17%) of the starting material. The organic phase was washed twice with water, dried and stripped to give a colorless oil. Flash chromatography on 10 g of silica gel eluting with 5-50% ethyl acetate in hexane recovered 43 mg of a higher Rf product assumed to be 4-chloroatroponitrile, and 210 mg (75%) of the desired alcohol, Rf 0.09 (silica gel, ethyl acetate:hexane=1:4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16](=O)[C:11]2[C:12]([CH3:15])=[CH:13][O:14][C:10]=2[CH2:9]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17]/[C:16](=[N:23]\[NH:22][C:19]([NH2:21])=[NH:20])/[C:11]2[C:12]([CH3:15])=[CH:13][O:14][C:10]=2[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1coc2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1coc2c1/C(=N/NC(=N)N)CC(c1ccccc1Cl)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 160.3 %

Procedure:
To a mixture of 6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.35 g) and aminoguanidine hydrochloride (148 mg) were added ethanol (27 ml) and 6N hydrochloric acid (0.12 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 42) (0.38 g).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.1 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (200 mg, 0.76 mmol) and triphenylphosphine (198 mg, 0.76 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (150 mg, 0.84 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The orange reaction mixture was then treated with 2-aminopyridine (151 mg, 1.60 mmol), and the resulting reaction mixture was stirred at 25° C. for 15 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining residue was partitioned between water and ethyl acetate. The organic layer was washed with a 1N aqueous hydrochloric acid solution, washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-pyridin-2-yl-propionamide (83 mg, 32%) as a white solid: mp 127–128° C.; EI-HRMS m/e calcd for C20H24N2OS (M+) 340.1609, found 340.1611.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25](=[O:32])[CH2:26][C:27](=[O:31])[CH:28](Br)[CH3:29].O>CC(C)=O>[CH3:23][O:24][C:25]([CH2:26][C:27](=[O:31])[CH:28]([O:8][C:7]([C:4]1[CH:3]=[CH:2][C:1]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)=[O:9])[CH3:29])=[O:32]
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)CC(=O)C(C)Br
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CC(=O)C(C)OC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 22.5 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A mixture of biphenyl-4-carboxylic acid (800 g, 4.03 mol) in acetone (4.6 L) was treated with triethylamine (0.6 L, 4.3 mol, 1.07 eq) dropwise over 13 min while maintaining the temperature at 15-30° C. 4-Bromo-3-oxo-pentanoic acid methyl ester (880 g, 4.21 mol, 1.04 eq) was added dropwise over 21 min at 15-30° C. The mixture was stirred overnight at room temperature. Water (9.6 L) was added dropwise over 85 minutes at 15-30° C. The mixture was stirred for 2 h. The precipitated product was collected by filtration and washed twice with water (1 L). The product was dried under vacuum at 50° C. to afford 1291 g (98% yield, 96% HPLC purity) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.Br[C:8]1[C:13]([F:14])=[CH:12][C:11]([C@@H:15]([NH:17][S@@](C(C)(C)C)=O)[CH3:16])=[C:10]([F:24])[CH:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O1CCOCC1.CCOC(C)=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[F:24][C:10]1[CH:9]=[C:8]([N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]2)[C:13]([F:14])=[CH:12][C:11]=1[C@@H:15]([NH2:17])[CH3:16]
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1cc(F)c(Br)cc1F
Reactant: Cc1c[nH]cn1
Agent: [Pd]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cn(-c2cc(F)c([C@H](C)N)cc2F)cn1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 143.4 %

Procedure:
To a solution of di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine (80 mg, 0.166 mmol) in toluene/dioxane (8 mL/2 mL) was added Pd2dba3 (60 mg, 0.066 mmol). The reaction mixture was sealed and heated to 120° C. and stirred for 5 minutes. The reaction was cooled to room temperature and 4-methyl-1H-imidazole (157 mg, 1.910 mmol), (R)—N—((S)-1-(4-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (500 mg, 1.470 mmol) and K3PO4 (624 mg, 2.94 mmol) was added to the reaction mixture. The reaction was sealed and heated to 120° C. for 2 hours. LCMS show complete conversion. The reaction mixture was then cooled to room temperature and diluted with EtOAc (20 mL) and water (10 mL). The aqueous layer was then extracted with EtOAc (2×20 mL). The combined organic was then concentrated. The residue was purified by silica gel chromatography (50% heptane in EtOAc to 10% MeOH in EtOAc) to give (S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethanamine (500 mg). LCMS (B) m/z 342.6 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:28])=[CH:4][C:5]2[N:11]([C:12](=[O:21])[CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:27]=1.[C:29](OCC)(=[O:32])[NH:30][NH2:31]>>[Cl:1][C:2]1[C:3]([Cl:28])=[CH:4][C:5]2[N:11]([C:12](=[O:21])[CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[C:8]3[N:7]([C:29](=[O:32])[NH:30][N:31]=3)[C:6]=2[CH:27]=1
Reactant: CCOC(=O)NN
Reactant: CCCN(CCC)CC(=O)N1c2cc(Cl)c(Cl)cc2NC(=S)c2cccnc21
Product: CCCN(CCC)CC(=O)N1c2cc(Cl)c(Cl)cc2-n2c(n[nH]c2=O)-c2cccnc21

Procedure:
In the manner given in Example 13, 8,9-dichloro-6,11-dihydro-11-[(dipropylamino)acetyl]-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-thione is heated to about 200° C. with ethyl carbazate to give 6,7-dichloro-2,9-dihydro-9-[(dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo-[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: [CH2:1]([C:3]([C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[C:30]([CH3:43])[CH:29]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]([O:23][CH2:24][O:25][CH3:26])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])=[C:8]([CH3:27])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH2:44]([O:46][C:47](=[O:56])[CH2:48][C:49]1[CH:50]=[N:51][C:52](Br)=[CH:53][CH:54]=1)[CH3:45].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.CN(C)C=O>[CH2:44]([O:46][C:47](=[O:56])[CH2:48][C:49]1[CH:50]=[N:51][C:52]([C:31]2[CH:32]=[CH:33][C:28]([C:3]([CH2:4][CH3:5])([C:6]3[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]([O:23][CH2:24][O:25][CH3:26])([C:19]([F:21])([F:22])[F:20])[C:15]([F:17])([F:16])[F:18])=[C:8]([CH3:27])[CH:7]=3)[CH2:1][CH3:2])=[CH:29][C:30]=2[CH3:43])=[CH:53][CH:54]=1)[CH3:45]
Reactant: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CCOC(=O)Cc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c3)cc2C)nc1
Temperature: 140 °C
Yield: 58.2 %

Procedure:
N,N-Dimethylformamide (0.7 mL) was added to 2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 25-(4); 50 mg, 0.082 mmol), (6-bromo-pyridin-3-yl)acetic acid ethyl ester (Example 74-(1); 40 mg, 0.165 mmol), tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol) and potassium phosphate (63.9 mg, 0.30 mmol). The mixture was stirred with microwave heating at 140° C. for seven minutes in a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=10/1, then dichloromethane/methanol=20/1) to give the title compound (31 mg, 58%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:34][C:35]1[C:43]([O:44][CH3:45])=[CH:42][CH:41]=[CH:40][C:36]=1[C:37]([NH2:39])=[O:38]>CC(N(C)C)=O.O.C([O-])(O)=O.[Na+]>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]3[NH:39][C:37](=[O:38])[C:36]4[C:35](=[C:43]([O:44][CH3:45])[CH:42]=[CH:41][CH:40]=4)[N:34]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1cccc(C(N)=O)c1N
Reactant: CC(C)N1CCN(c2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S([O-])O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cccc2c(=O)[nH]c(-c3ccc(N4CCN(C(C)C)CC4)cc3)nc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
A mixture of 4-(4-isopropylpiperazin-1-yl)benzaldehyde (0.562 g, 2.40 mmol), NaHSO3 (0.310 g, 2.90 mmol), and p-TsOH (0.046 g, 0.24 mmol) was added to a solution of 2-amino-3-methoxybenzamide (0.400 g, 2.40 mmol) in DMA (15 mL). The reaction was stirred at 120° C. overnight. The mixture was diluted with H2O and saturated NaHCO3 and extracted with CH2Cl2. The organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 0% to 10% MeOH/CH2Cl2 afforded the title compound (0.140 g, 15%). 1H NMR (300 MHz, DMSO-d6): δ 12.27 (s, 1H), 8.10 (d, J=8.9 Hz, 2H), 7.64-7.70 (m, 1H), 7.31-7.39 (m, 2H), 7.03 (d, J=9.1 Hz, 2H), 3.93 (s, 3H), 3.27-3.32 (m, 4H), 2.64-2.75 (m, 1H), 2.56-2.59 (m, 4H), 1.00 (d, J=6.6 Hz, 6H). ESI MS m/z 379 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:15]([O:16]S(C2C3C=CC(=[N+]=[N-])C(=O)C=3C=CC=2)(=O)=O)=[C:14]([O:33][S:34]([C:37]2[C:46]3[CH:45]=[CH:44][C:43](=[N+:47]=[N-:48])[C:42](=[O:49])[C:41]=3[CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[N+](=C1C=CC2C(S(OC3C(OS(C4C5C=CC(=[N+]=[N-])C(=O)C=5C=CC=4)(=O)=O)=C(OS(C4C5C=CC(=[N+]=[N-])C(=O)C=5C=CC=4)(=O)=O)C=CC=3C(C3C=CC=CC=3)=O)(=O)=O)=CC=CC=2C1=O)=[N-].[N+](=C1C=CC2C(S(OC3C=CC(C(C4C=CC(OS(C5C6C=CC(=[N+]=[N-])C(=O)C=6C=CC=5)(=O)=O)=CC=4)=O)=CC=3)(=O)=O)=CC=CC=2C1=O)=[N-].OC1C=C(OS(C2C3C=CC(=[N+]=[N-])C(=O)C=3C=CC=2)(=O)=O)C=CC=1C(C1C=CC=CC=1)=O.[N+](=C1C=CC2C(S(OC3C=C(OS(C4C5C=CC(=[N+]=[N-])C(=O)C=5C=CC=4)(=O)=O)C=CC=3C(C3C=CC=CC=3)=O)(=O)=O)=CC=CC=2C1=O)=[N-].BrC(CBr)COS(C1C2C=CC(=[N+]=[N-])C(=O)C=2C=CC=1)(=O)=O>>[OH:1][C:2]1[C:15]([OH:16])=[C:14]([O:33][S:34]([C:37]2[C:46]3[CH:45]=[CH:44][C:43](=[N+:47]=[N-:48])[C:42](=[O:49])[C:41]=3[CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: [N-]=[N+]=C1C=Cc2c(cccc2S(=O)(=O)Oc2ccc(C(=O)c3ccccc3)c(O)c2OS(=O)(=O)c2cccc3c2C=CC(=[N+]=[N-])C3=O)C1=O
Agent: [N-]=[N+]=C1C=Cc2c(cccc2S(=O)(=O)OCC(Br)CBr)C1=O
Agent: [N-]=[N+]=C1C=Cc2c(cccc2S(=O)(=O)Oc2ccc(C(=O)c3ccc(OS(=O)(=O)c4cccc5c4C=CC(=[N+]=[N-])C5=O)cc3)cc2)C1=O
Agent: [N-]=[N+]=C1C=Cc2c(cccc2S(=O)(=O)Oc2ccc(C(=O)c3ccccc3)c(O)c2)C1=O
Product: [N-]=[N+]=C1C=Cc2c(cccc2S(=O)(=O)Oc2ccc(C(=O)c3ccccc3)c(O)c2O)C1=O

Procedure:
2-hydroxy-3,4-bis(6-diazo-5,6-dihydro-5-oxo-1-naphthalenesulfonyloxy)benzophenone (1); 2,3,4-tris(6-diazo-5,6-dihydro-5-oxo-1-naphthalenesulfonyloxy)benzophenone (11); 4,4'-bis(6-diazo-5,6-dihydro-5-oxo-1-naphthalenesulfonyloxy)benzophenone (12); 2-hydroxy-4-(6-diazo-5,6-dihydro-5-oxo-1-naphthalenesulfonyloxy)benzophenone (2); 2,4-bis(6-diazo-5,6-dihydro-5-oxo-1-naphthalenesulfonyloxy)benzophenone (15); or 2,3-dibromo-1-(6-diazo-5,6-dihydro-5-oxo-1-naphthalenesulfonyloxy)propane (17).
Reaction SMILES: [CH2:1]([N:3]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[CH3:32][O:33][C:34](=[O:44])[CH2:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38](Br)[CH:37]=1>>[CH3:32][O:33][C:34](=[O:44])[CH2:35][C:36]1[CH:37]=[C:38]([C:14]2[CH:15]=[CH:16][C:17]([C:19]([F:21])([F:22])[F:20])=[CH:18][C:13]=2[CH2:12][N:3]([C:4](=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:1][CH3:2])[CH:39]=[C:40]([Cl:42])[CH:41]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)c1ccccc1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: N-ethyl-N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-benzamide and (3-bromo-5-chloro-phenyl)-acetic acid methyl ester.
Reaction SMILES: O[CH:2]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])[CH2:8][CH2:7]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+].C(OCC)C>ClC(Cl)C>[CH3:19][C:13]1[C:14]([CH3:18])=[CH:15][CH:16]=[CH:17][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH:3]=[CH:2][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]3)[CH2:11][CH2:10]1
Reactant: Cc1cccc(N2CCN(CCCC(O)c3ccc4c(c3)CCC(=O)N4)CC2)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: Cc1cccc(N2CCN(CCC=Cc3ccc4c(c3)CCC(=O)N4)CC2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.8 Grams of 6-{1-hydroxy-4-[4-(2,3- dimethylphenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril and 0.5 g p-toluenesulfonic acid were disposed in 100 ml of dichloroethane then the mixture was refluxed for 20 minutes. The reaction mixture was concentrated under a reduced pressure to dryness then to the residue thus obtained were added 10N-NaOH and diethyl ether and stirred at a room temperature for 30 minutes. The crystals thus precipitated were collected by filtration and separated by a silica-gel chromatography. Recrystallized from ethanol-acetone- chloroform to obtain 6-{4-[4-(2,3-dimethylphenyl)- piperazinyl]-1-butenyl}-3,4-dihydrocarbostyril in coloress needle-like crystals. Yield: 1.9 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:26]([O:25][C:21](=[O:24])/[CH:22]=[CH:23]/[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)[CH3:27]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
tert-Butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (800 mg) was dissolved in DMF (4 ml), and ethyl acrylate (368 mg), palladium(II) acetate (27 mg), tris(2-methylphenyl)phosphine (290 mg), and DIPEA (1.26 g) were added thereto, followed by stirring at 100° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and then EtOAc was added thereto. The insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 4-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyridin-2-yl}piperazine-1-carboxylate (790 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CCN(C(C)C)C(C)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[C:4]([C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[NH:1][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:5])[NH2:6]
Reactant: NC(=O)c1ccc(Cl)cc1N
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=O)Nc1cc(Cl)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a solution of 2-amino-4-chlorobenzamide (393 mg, 2.30 mmol) and DIEA (0.60 mL, 3.45 mmol) in THF (15 mL) at 0° C. was added ethyl chlorooxoacetate (0.28 mL, 2.53 mmol). The solution was allowed to warm to rt and stir for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 10-50% EtOAc/hexanes to afford ethyl 2-(2-carbamoyl-5-chlorophenylamino)-2-oxoacetate as a solid (545 mg, 88%). 1H NMR (300 MHz, DMSO-d6) δ 1.32 (t, J=6.97 Hz, 3 H), 4.31 (q, J=6.97 Hz, 2 H), 7.34 (d, J=8.48 Hz, 1 H), 7.86-8.03 (m, 2 H), 8.44 (br s, 1 H), 8.62 (s, 1 H), 13.24 (s, 1 H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][N:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27].ClCCl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:26](=[O:27])[C:25]([CH3:30])([CH3:29])[CH3:24])[CH2:10][N:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC(OC(=O)C(C)(C)C)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
4-Hydroxypyrazolidine-1,2-dicarboxylic acid 1-benzyl ester 2-tert-butyl ester, 28, (1.42 mg, 4.40 mmol) is dissolved in pyridine (22 mL). 4-Dimethylamino-pyridine (10 mg) is added followed by trimethylacetyl chloride (1.63 mL, 13.2 mmol). The reaction is stirred at ambient temperature for 12 hours. The cloudy reaction mixture is then concentrated in vacuo to afford a white residue. Dichloro-methane (75 mL) is added to the residue and the mixture washed with a 1.0 N aqueous solution of hydrochloric acid (75 mL). The aqueous layer is extracted with dichloro-methane (75 mL), the combined organic layers washed with a saturated aqueous solution of NaHCO3 (75 mL), water (75 mL), brine (75 mL), then dried, filtered and concentrated in vacuo to afford the crude product. The crude product is purified over silica(4:1 to 1:1 hexane/ethyl acetate) to afford 1.76 g (98% yield) of the desired product as a clear, viscous oil.