Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CC(C)([O-])C.[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>O1CCCC1.COC(C)(C)C>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]2=[O:18])=[CH:3][CH:4]=1
Reactant: O=C1CCCCC1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=C1CCCCC1c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
1-Bromo-4-trifluoromethylbenzene (5 mL), cyclohexanone (7.4 mL) and potassium tert-butoxide (8 g) were suspended in tetrahydrofuran (100 mL). Tris(dibenzylieneacetone)dipalladium (1.3 g) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (843 mg) were added and the mixture was heated with stirring at 70° C. in a nitrogen atmosphere for 1.5 hours. After leaving to cool, tert-butyl methyl ether was added, followed by filtration through celite. The resulting organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography three times. The resulting solid was washed with heptane to obtain the title compound (2.1 g). The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.N([O-])=O.[Na+].CC([O-])=O.[Na+].[N-:25]=[N+:26]=[N-].[Na+]>O>[N:1]([C:2]1[C:10]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[N+:25]=[N-:26]
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: [N-]=[N+]=Nc1c(C(=O)O)cccc1C(F)(F)F
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.67 g (10 mmol) of 2-amino-3-(trifluoromethyl)-benzoic acid (compound of formula (VIII)) with 40 ml of 6N HCl was cooled down to 5° C. and a solution of 760 mg of NaNO2 (11 mmol) in 17 ml of water were added dropwise in such a way that the temperature of the reaction mixture did not exceed 7° C. The resulting solution was stirred at this temperature for 30 minutes and then added slowly to a solution of 20.5 g of NaOAc and 715 mg (11 mmol) of NaN3 in 40 ml of water. The reaction mixture was stirred overnight at room temperature. The product was extracted with CH2Cl2 three times. The solvent was removed in vacuo and the residue dried in a desiccator over P2O5 affording the required compound in quantitative yleld.
Reaction SMILES: ClCl.[F-].[Cl:4][C:5]1[C:6]([F:12])=[C:7](F)[CH:8]=[CH:9][CH:10]=1.[F:13]C1C=C(F)C=CC=1[N+]([O-])=O>>[F:12][C:6]1[CH:7]=[C:8]([F:13])[CH:9]=[CH:10][C:5]=1[Cl:4]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Fc1cccc(Cl)c1F
Agent: ClCl
Agent: [F-]
Product: Fc1ccc(Cl)c(F)c1
Reaction time: 1.5 h
Yield: 91 %

Procedure:
The chlorine gas which is used is employed in anhydrous form. The reaction of the m-difluoronitro-aromatic compounds with the chlorine must be carried out in the absence of Lewis acids or other chlorinating catalysts. The required temperatures are within the range from 80° to 250° C. preferably 100° to 200° C. The reaction can be carried out in the presence or absence of a fluoride-capturing agent. The necessary chlorodifluorobenzene compound (starting compound) can, for example, be prepared as follows: 1800 g (11.3 mol) of 2,4-difluoronitrobenzene (anhydrous and free of Lewis acids) are initially introduced into a 2 l four-neck flask having a stirrer, gas-entry tube and distillation bridge. The reaction solution is brought to 160° C. A stream of chlorine of 4-6 l/h is then passed through the solution at this temperature. After 1-2 h, brown gases are formed which are absorbed in dilute sodium hydroxide solution. After 28 h, the entry of gas is stopped and the reaction solution is distilled (head temperature 127° C). 675.8 g of 2,4-difluorochlorobenzene are obtained, corresponding to a yield of 91%, based on reacted 2,4-difluoronitrobenzene.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>>[NH2:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22](=[CH:7][C:6]3[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=3)[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: Nc1ccc2c(c1)NC(=O)C2
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cc(N)ccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-amino-2-oxindole to give 0.3 g of 6-amino-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]=[C:10]=[O:11])[CH:5]=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[C:20]([NH:27]C(=O)C)[N:21]=[CH:22]2.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[NH2:27][C:20]1[N:21]=[CH:22][C:23]2[C:18]([CH:19]=1)=[C:17]([NH:16][C:10]([NH:9][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:12]([F:13])([F:14])[F:15])=[C:2]([F:1])[CH:7]=1)=[O:11])[CH:26]=[CH:25][CH:24]=2
Reactant: O=C=NCc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(=O)Nc1cc2c(N)cccc2cn1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)c(F)c3)cccc2cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-Fluoro-4-(isocyanatomethyl)-1-(trifluoromethyl)benzene (2.59 mmol) in toluene (10 mL) was treated with N-(5-amino-3-isoquinolinyl)acetamide (400 mg, 1.99 mmol) and DIEA (1.8 mL). The mixture was heated at 80° C. for 5 hours, cooled to room temperature, and filtered. The solid was triturated with 97:3 CH2Cl2:CH3OH and stirred as a suspension in 48% aqueous HBr (8 mL) at 60° C. for 2 hours. After cooling to room temperature, the mixture was poured into concentrated NH4OH (20 mL). The solid was washed with water and air-dried to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.68 (s, 1H), 7.94 (s, 1H), 7.76 (t, 1H, J=7.9 Hz), 7.35-7.49 (m, 3H), 7.26 (s, 1H), 7.09 (s, 1H), 6.92 (s, 1H), 6.84 (t, 1H, J=6.0 Hz), 6.62 (s, 1H), 4.41 (d, 2H, J=6.1 Hz).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:22]2[C:23]([C:34](OCC)=[O:35])=[N:24][N:25]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[C:26]=2[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>O1CCCC1>[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:22]2[C:23]([CH2:34][OH:35])=[N:24][N:25]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[C:26]=2[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1
Reactant: CCOC(=O)c1nn(C2CCCCO2)c(C)c1-c1cc(OCCOC)cc(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOc1cc(-c2c(CO)nn(C3CCCCO3)c2C)cc(C(F)(F)F)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a mixture of LiAlH4 (60 mg, 1.58 mmol, 4.01 equiv) in anhydrous tetrahydrofuran (15 mL) maintained under nitrogen at −40° C. was added dropwise a solution of (R/S) ethyl 4-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (180 mg, 0.39 mmol, 1.00 equiv) in tetrahydrofuran (5 mL). The reaction was stirred at −40° C. for 30 min then at 25° C. for 1 h. The reaction was quenched with 0.1 mL of saturated NH4Cl solution. The solid material was removed by filtration. The filtrate was extracted with 3×10 mL of ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 30-100% of ethyl acetate in petroleum ether to afford 70 mg (43%) of (R/S) (4-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methanol as a colorless oil. LCMS (method A, ESI): RT=1.49 min, m/z=415.0 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH:5]=[CH2:6])[C:3]#[N:4].[CH2:7]([O:14][C:15]1[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=1[N:22]1[S:26](=[O:28])(=[O:27])[NH:25][C:24](=[O:29])[CH2:23]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:7]([O:14][C:15]1[CH:20]=[C:19](/[CH:6]=[CH:5]/[CH:2]([CH3:1])[C:3]#[N:4])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:23][C:24](=[O:29])[NH:25][S:26]1(=[O:28])=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC(C)C#N
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C#N)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 110 °C

Procedure:
A mixture of 2-methyl-but-3-enenitrile (18 mg, 0.225 mmol), 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (50 mg, 0.113 mmol), Pd(OAc)2 (5 mg, 0.023 mmol) and triethylamine (11 mg, 0.107 mmol) in THF (3 mL) is placed in a microwave vial and heated at 110° C. for 10 min. The mixture is filtered and the filtrate concentrated. The residue is purified by reverse phase HPLC to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([Br:14])=[CH:20][N:19]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(Br)cn1
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,6-Dichlorobenzoyl isocyanate (2.16 grams; 0.01 mole) and 5-bromo-2-aminopyridine (1.73 grams; 0.01 mole) were mixed in 50 ml. of ethyl acetate, at room temperature. The reaction mixture was stirred at room temperature for 4 hours, during which the product precipitated. It was separated by filtration and recrystallized from ethanol, m.p. 228°-230° C., yield 2.0 grams. Elemental analysis showed:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]2[O:16][CH2:15][CH2:14][O:13][C:12]=12)[C:6]([O:8]C)=[O:7].[OH-].[Li+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]2[O:16][CH2:15][CH2:14][O:13][C:12]=12)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(OC)c2c(c1)OCCO2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc2c1OCCO2
Reaction time: 15 h

Procedure:
Combine methyl 3-methoxy-4,5-ethylenedioxybenzoate (0.46 g, 2.0 mmol) and tetrahydrofuran (15 mL). Add a 1 M aqueous solution of lithium hydroxide (2.5 mL, 2.5 mmol). Heat to reflux. After 15 hours, cool the reaction, concentrate in vacuo to remove most of the tetrahydrofuran. Cool in a ice bath and acidify with a 1 M aqueous hydrochloric acid solution to give a solid. Collect the solid by filtration and dry to give the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:15]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]2[CH:13]=[C:12]3[C:7]([NH:8][C:9](=O)[CH2:10][O:11]3)=[CH:6][C:5]=2[O:4][C:3]1([CH3:27])[CH3:26].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)([O-])O.[Na+].[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]\[C:42]([OH:44])=[O:43]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]\[C:42]([OH:44])=[O:43].[CH3:26][C:3]1([CH3:27])[C@H:2]([OH:1])[C@@H:15]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]2[CH:13]=[C:12]3[C:7]([NH:8][CH2:9][CH2:10][O:11]3)=[CH:6][C:5]=2[O:4]1
Reactant: CC1(C)Oc2cc3c(cc2[C@H](NCCc2ccccc2)[C@H]1O)OCC(=O)N3
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)Oc2cc3c(cc2[C@H](NCCc2ccccc2)[C@H]1O)OCCN3
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
To a solution of (7R*,8S*)-7-hydroxy-6,6-dimethyl-8-[(2-phenylethyl)amino]-4,6,7,8-tetrahydro-1,5-dioxa-4-aza-anthracene-3-one (42 mg, 0.11 mmol) in tetrahydrofuran (1.2 mL), lithium aluminum hydride (1M solution in tetrahydrofuran, 570 μL, 0.57 mmol) was added at room temperature, and the resulting mixture was stirred at 90° C. for 1.5 hour. Upon the completion of the reaction, saturated aqueous sodium hydrogencarbonate solution was added thereto, the resulting solution was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Maleic acid (13 mg, 0.11 mmol) and hexane (1 mL) were added to the solution of the resulting mixture in ethyl acetate (600 μL) at room temperature, and the resulting mixture was stirred at room temperature for 15 minutes. The resulting crystal was filtered off and the aimed product was obtained (yield: 60%).
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[CH2:16][CH2:15][CH2:14]2.C(O)(=O)C>O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[CH:16]([C:3]([O:6][CH3:7])=[O:8])[CH2:15][CH2:14]2
Reactant: COC(=O)OC
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1CCc2cc(OC)ccc2C1=O
Temperature: 0 °C
Yield: 95.2 %

Procedure:
A suspension of 24.0 g (0.60 mole) of sodium hydride (60% dispersion in mineral oil) and 49.5 ml (52.9 g; 0.59 mole) of dimethyl carbonate (freshly distilled from sodium hydride) in 240 ml of tetrahydrofuran under a nitrogen atmosphere was stirred and heated to reflux. Reflux was maintained while a solution of 29.7 g (0.17 mole) of 6-methoxy-1-tetralone in 105 ml of tetrahydrofuran was added dropwise over two hours. After addition was complete, the mixture was stirred at reflux for an additional 90 minutes, cooled in ice, and treated dropwise with 36 ml of glacial acetic acid, followed by 450 ml of ice water. The two-phase reaction mixture was extracted with ethyl acetate (4×250 ml), and the combined organic layers were washed with water (1×600 ml), 5% aqueous sodium bicarbonate solution (3×600 ml), and water again. The ethyl acetate extract was dried (anhydrous sodium sulfate and evaporated (vacuum). The residue was pulverized and stirred in 500 ml of hexane. Filtration yielded 37.9 g (96% yield) of the ester product, mp 79°-81°, suitable for further synthesis. A sample purified by bulb-to-bulb distillation followed by recrystallization from hexane/ethyl acetate was analytically pure, mp 82°-84° (a mp of 88°-89° is given by J. Jacques and A. Horeau, Bull. Soc. Chem. France, 512 (1950)).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[CH:13]([CH3:15])[OH:14].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[O:14][CH:13]([CH3:15])[C:12]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(=O)C(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
2,4-Difluoronitrobenzene (15.9 g; 0.10 mole), ethyl lactate (11.8 g; 0.10 mole), and anhydrous potassium carbonate (13.8 g, 0.10 mole) are combined in dioxane (200 ml) and the temperature is brought to 95° C. over a 1.5 hour period and maintained at 95° C. for 3 hours. The reaction mixture is cooled to room temperature, the inorganic solids removed by filtration and the solvent removed under vacuum to afford a dark colored oil, from which low boiling fractions are removed by distillation (bp., 79° C./0.5 mm). The pot residue is then cooled to afford 15.9 g of crude product, which is recrystallized from ligroin/acetone to afford ethyl 2-(5-fluoro-2-nitrophenoxy)propionate as yellow needles, m.p. 64°-65° C. Elemental anal. Calcd for C11H12FNO5 : C, 51.4; H, 4.70; F, 7.38; N, 5.45. Found: C, 51.35; H, 4.74; F, 7.60; N, 5.44.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>CCO>[CH2:18]([O:17][C:15](=[O:16])[C:14](=[CH:13][NH:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cn1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)OCC
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A solution of 5-amino-2-methoxypyridine (Aldrich, 100 g, 0.806 mole) and diethyl ethoxymethylenemalonate (Aldrich, 163 mL, 0.806 mole) in EtOH (1 L) was heated at reflux for 4 hours, then was cooled to RT. Concentration to dryness gave the title compound (238 g, quantitative).
Reaction SMILES: C([CH:3]([CH2:19][C:20]([OH:22])=[O:21])[N:4]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:5][C:6]1C=CC=CC=1)C.[ClH:23].[H][H]>[Pd].C(O)C>[ClH:23].[CH2:5]([N:4]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3][CH2:19][C:20]([OH:22])=[O:21])[CH3:6]
Reactant: [H][H]
Reactant: CCOC(=O)CCN(Cc1ccccc1)C(CC)CC(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCN(CC)CCC(=O)O

Procedure:
A mixture of 192.8 parts of ethyl N-[2(ethoxycarbonyl)-ethyl]-N-(phenylmethyl)-β-alanine and 280 parts of absolute ethanol is stirred in an hydrogenation vessel. Then there are added 45 parts of hydrochloric acid solution. After cooling, 10 parts of palladium-on-charcoal catalyst 5% are added and the whole is shaken at room temperature while one equivalent of hydrogen is taken up. The catalyst is filtered off and the filtrate is evaporated, yielding ethyl N-[2-(ethoxycarbonyl)ethyl]-β-alanine hydrochloride as an oily residue.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[NH:25][C:24]4=[O:30])=[C:19]([F:31])[CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:32]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH3:28])[C:26](=[O:29])[N:25]([CH3:32])[C:24]4=[O:30])=[C:19]([F:31])[CH:18]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)c(F)c3)CC2)c(C)c1
Reactant: CI
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C)c(F)c3)CC2)c(C)c1

Procedure:
Using 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-2-fluorophenyl}-5-methylimidazolidine-2,4-dione (90 mg) described in Example 528 and methyl iodide (17 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (22 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[C:4]([C:22]([F:25])=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:18]2[CH:17]=[N:16][C:15]([C:19]([OH:21])=O)=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[CH2:27]([O:34][NH2:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][NH:35][C:19]([C:15]1[N:16]=[CH:17][C:18]2[N:6]([CH2:5][C:4]3[C:22]([F:25])=[CH:23][CH:24]=[C:2]([Cl:1])[C:3]=3[F:26])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:21])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1cc2c3ccccc3n(Cc3c(F)ccc(Cl)c3F)c2cn1
Reactant: NOCc1ccccc1
Product: O=C(NOCc1ccccc1)c1cc2c3ccccc3n(Cc3c(F)ccc(Cl)c3F)c2cn1

Procedure:
The title compound is prepared by coupling of 9-(3-chloro-2,6-difluorobenzyl)-9H-β-carboline-3-carboxylic acid and O-benzyl hydroxyamine under conditions similar to those provided in step (b) of example 7.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[C:17]([CH:44]=[O:45])=[C:18]([N:22]3[CH:26]=[C:25]([C:27]#[N:28])[C:24]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)=[O:37])=[CH:32][CH:31]=4)=[N:23]3)[CH:19]=[CH:20][CH:21]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C[OH:49]>ClCCl.O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[C:17]([CH2:44][OH:45])=[C:18]([N:22]3[CH:26]=[C:25]([C:27]([NH2:28])=[O:49])[C:24]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([N:38]5[CH2:39][CH2:40][O:41][CH2:42][CH2:43]5)=[O:37])=[CH:32][CH:31]=4)=[N:23]3)[CH:19]=[CH:20][CH:21]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3C=O)ncc2c1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3CO)ncc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(3-(6-tert-Butyl-1-oxophthalazin-2(1H)-yl)-2-formylphenyl)-3-[4-(morpholine-4-carbonyl)phenylamino]pyrazole-4-carbonitrile (53 mg, 0.0875 mmol) was dissolved in 6 mL of dichloromethane and 2 mL of methanol. Sodium borohydride solution (8.28 mg, 0.219 mmol) in water (0.5 mL) and methanol (1.0 mL) was added in drops. The mixture was stirred at room temperature for 1 hr. LC/MS showed a clean desired product. The mixture was evaporated to dryness and extracted with dichloromethane and water. The organic layer was dried over sodium sulfate and evaporated to give a pure desired 1-[3-(6-tert-butyl-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl]-3-[4-(morpholine-4-carbonyl)phenylamino]-1H-pyrazole-4-carbonitrile (52.8 mg, 100% yield). LC/MS clacd for C34H33N7O4 (m/e) 603.26, obsd 604.1 (M+H, ES+); 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 9H), 3.61-3.77 (m, 8H), 4.35 (br. s., 2H), 6.59 (br. s., 1H), 7.43 (d, J=8.6 Hz, 2H), 7.50 (d, J=8.1 Hz, 1H), 7.58 (d, J=8.6 Hz, 2H), 7.67 (t, J=8.1 Hz, 1H), 7.80 (d, J=1.7 Hz, 1H), 7.83 (dd, J=8.1, 1.3 Hz, 1H), 7.97 (dd, J=8.6, 1.7 Hz, 1H), 8.39 (d, J=0.5 Hz, 1H), 8.48 (d, J=8.6 Hz, 1H), 8.79 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:19])[CH3:18])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(F)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(F)c(F)c1
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 3,4-difluoroaniline (50 ml; 0.5 mole) and triethylamine (70 ml; 0.5 mol) in dichloromethane (1.51) is cooled down using an ice bath. Acetic anhydride (71.5 ml; 0.75 mol) is added dropwise and the reaction mixture is then agitated for 1 hour at ambient temperatue. The mixture obtained is then washed successively with water, a 10% solution of sodium bicarbonate and saturated salt water. The organic fraction is dried over sodium sulphate and concentrated under reduced pressure. The residue is suspended in pentane, filtered and dried under reduced pressure in order to produce the product in the title (78 g; 91% yield) in the form of a whitish solid (M.p. 126–127.5° C.).