Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)C1C=CC=C([S:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[N:23]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])[N:24]=[N:25][C:26]=3[CH:27]([CH3:29])[CH3:28])=[CH:16][C:15]=2[CH3:38])([CH3:13])[CH3:12])C=1.[OH-:40].[Li+].[O:42]1[CH2:47][CH2:46]OCC1>>[Cl:37][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([Cl:36])[C:30]=1[N:23]1[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:11]([S:10][C:14]3[CH:15]=[CH:16][C:46]([C:47]([OH:42])=[O:40])=[CH:12][CH:11]=3)([CH3:13])[CH3:12])=[C:15]([CH3:38])[CH:16]=2)=[C:26]([CH:27]([CH3:28])[CH3:29])[N:25]=[N:24]1
Reactant: [OH-]
Reactant: C1COCCO1
Reactant: COC(=O)c1cccc(SC(C)(C)c2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)c1
Agent: [Li+]
Product: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1C(C)(C)Sc1ccc(C(=O)O)cc1
Temperature: 50 °C
Yield: 99 %

Procedure:
To an ambient temperature solution of 3-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-methyl-ethylsulfanyl)-benzoic acid methyl ester (110 mg, 0.188 mmol) in dioxane (2 mL) is added a solution of lithium hydroxide (282 μL, 0.564 mmol, 2.0N in water). The reaction is heated to 50° C. for 2 h. The reaction is concentrated and the residue is diluted with Et2O and water. The aqueous layer is adjusted to pH ˜4 and extracted with a second portion of Et2O. The combined organic layers are washed with water, dried (MgSO4), filtered, and concentrated to yield the title compound (106 mg, 99%). LC/MS (ES+): 570.0, 100.0%.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=O)(C)(C)C.[F:15][C:16]1([F:32])[CH2:20][CH2:19][C@@H:18]([C@@:21]([OH:31])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](O)=[O:23])[CH2:17]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(Cl)(Cl)[Cl:55]>C(OCC)(=O)C>[ClH:55].[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:22](=[O:23])[C@:21]([C@@H:18]2[CH2:19][CH2:20][C:16]([F:15])([F:32])[CH2:17]2)([OH:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:14]1
Reactant: ClC(Cl)Cl
Reactant: O=C(O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Product: Cl
Product: NC1CCN(C(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Reaction time: 3 h

Procedure:
To a solution of 220 mg of 4-t-butoxycarbonylaminopiperidine and 256 mg of (2R)-2-((1R)-3, 3-difluorocyclopentyl)-2-hydroxy-2-phenylacetic acid in 8 ml of chloroform, 203 mg of 1-hydroxybenzotriazole and 201 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide were added sequentially at room temperature, followed by stirring for 3 hours at the same temperature. The reaction mixture was diluted with ethyl acetate and, after sequential washing with an aqueous solution of 1N sodium hydroxide and brine, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 314 mg of the title compound was obtained by purifying the resultant residue by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=2/1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](C=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[NH:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1.[C:18](C1NC=CN=1)(C1NC=CN=1)=[O:19].C([NH+](CC)CC)C.CC(C)(C)C(Cl)=O>>[O:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:18]([N:13]3[CH2:17][CH:16]=[CH:15][CH2:14]3)=[O:19])[C:6]=2[O:1][CH2:2][CH2:3]1
Reactant: C1=CCNC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC(C)(C)C(=O)Cl
Agent: CC[NH+](CC)CC
Product: O=C(c1cccc2c1OCCO2)N1CC=CC1

Procedure:
1,4-Benzodioxan-6-carboxaldehyde is oxidized to the corresponding acid by the procedure of Shriner and Kleiderer in Organic Syntheses, Coll. Vol. 2:538 (1943). Coupling of the acid with 3-pyrroline is conducted by employing the same method as employed for the preparation of Invention Compound V, which uses carbonyl diimidazole in order to activate the carboxylic acid, or any other method known in the art, such as, for example, activation by the reaction of the triethylammonium salt with trimethylacetyl chloride. The product is crystallized from CCl4/Et2O/hexanes. EMIS m/z=231 (parent), 163 (base), 135, and 107. 1H NMR δ 4.25-4.30 (m, 6), 4.43 (br, 2), 5.75 (m, 1), 5.85 (m, 1), 6.88 (d, 1, J=8.42 Hz), 7.06 (dd, 1, J=8.38, 2.03 Hz), and 7.09 (d, 1, J=2.05 Hz).
Reaction SMILES: [Li]CCCC.[CH2:6]([N:8]([CH2:19][CH3:20])[C:9]([O:11][C:12]1[C:13]([F:18])=[N:14][CH:15]=[CH:16][CH:17]=1)=[S:10])[CH3:7].[CH2:21]([N:23]([CH2:27][CH3:28])[C:24](Cl)=[O:25])[CH3:22].Cl>C1COCC1.O>[CH2:21]([N:23]([CH2:27][CH3:28])[C:24](=[O:25])[C:12]1([O:11][C:9](=[S:10])[N:8]([CH2:6][CH3:7])[CH2:19][CH3:20])[CH:17]=[CH:16][CH:15]=[N:14][CH:13]1[F:18])[CH3:22]
Reactant: CCN(CC)C(=S)Oc1cccnc1F
Reactant: CCN(CC)C(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)C1(OC(=S)N(CC)CC)C=CC=NC1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
250 ml (400 mmol) of n-BuLi (1.6M in hexane) are added to a solution of 57.9 g (410 mmol) of TMP in 750 ml of THF at -10° C. After the mixture has been stirred for 1 hour at -10° C., a solution of 64 g (280 mmol) of 3-diethylthiocarbamoyloxy-2-fluoropyridine in 200 ml of THF is added dropwise at -78° C. in the course of 30 minutes. After the mixture has been stirred for 1 hour at -78° C., 81.4 g (600 mmol) of diethylcarbamoyl chloride are added in the course of 1 minute, the mixture is stirred at -78° C. for 2 hours and heated to -20° C., 130 ml of 3N HCl are added, and the mixture is diluted with 1 l of water and brought to pH 7. The organic phase is washed 3 times with water. The combined aqueous phases are extracted twice using Et2O, and the combined organic phases are washed twice with water, dried over Na2SO4 and concentrated in vacuo at 60° C.: 116 g of a brown oil. Chromatography (ethyl acetate/hexane 1:1) gives 60 g (65% ) of beige crystals of m.p. 87°-92° C.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:8]=2)=[C:4]([F:27])[CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[C:43]1([CH2:49][C:50]([N:52]=[C:53]=[S:54])=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(OCC)C>C(O)C.CCCCCC>[F:27][C:4]1[CH:3]=[C:2]([NH:1][C:53]([NH:52][C:50](=[O:51])[CH2:49][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[S:54])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:8]=1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCO
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ncn2)CC1
Reaction time: 0.08 h
Yield: 16.8 %

Procedure:
3-[6-(4-Amino-2-fluorophenoxy)pyrimidin-4-yl}-1-methyl-1-(1-methylpiperidin-4-yl)urea (50 mg) was dissolved in ethanol (1 ml), and then D-10-camphorsulfonic acid (62.3 mg) was added thereto, followed by stirring for 5 min. Phenylacetyl isothiocyanate (toluene solution, 0.355 M, 0.565 ml) was added thereto, followed by stirring further for 1 hr. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (0.5 ml)-hexane (2.0 ml) was then added to suspend a solid. The solid was filtered off and dried under aeration to provide the titled compound (12.4 mg, 16.8%) as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[Cl:21])[C:6]([CH:12]=[O:13])=[N:7]2.[CH2:22]1COCC1.C[Mg]Br.C(OCC)C>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[Cl:21])[C:6]([CH:12]([OH:13])[CH3:22])=[N:7]2
Reactant: C1CCOC1
Reactant: O=Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a stirring heterogeneous mixture of 5-chloro-3-(2-chloro-5-fluorophenyl)-quinoxaline-2-carbaldehyde (0.1650 g, 0.514 mmol) in THF (5.00 mL, 0.514 mmol) was added methylmagnesium bromide 3 M in diethyl ether (0.257 mL, 0.771 mmol) dropwise at 0° C., and the mixture was then allowed to warm to room temperature and stirred at room temperature. After 5.5 h, the reaction was quenched with NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min and then 50% isocratic of EtOAc for 10 min as eluent to give 1-(5-chloro-3-(2-chloro-5-fluorophenyl)quinoxalin-2-yl)ethanol as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.17 (1H, dd, J=8.4, 1.4 Hz), 8.09 (1H, dd, J=7.8, 1.2 Hz), 7.88-7.96 (1 H, m), 7.72 (1H, dd, J=9.0, 5.1 Hz), 7.61 (1H, br. s.), 7.44-7.53 (1H, m), 5.36 (1H, d, J=6.3 Hz), 4.83 (1H, br. s.), 1.49 (3H, br. s.); LC-MS (ESI) m/z 337.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[O:12][N:11]=[C:10]([CH2:13][S:14]([C:16]2[CH:31]=[CH:30][C:19]([CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)=[O:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl.CO>[CH2:1]([C:8]1[O:12][N:11]=[C:10]([CH2:13][S:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:20][CH2:21][NH2:22])=[CH:30][CH:31]=2)=[O:15])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(S(=O)Cc2noc(Cc3ccccc3)n2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(S(=O)Cc2noc(Cc3ccccc3)n2)cc1
Reaction time: 4 h
Yield: 101.9 %

Procedure:
To a solution of the sulfoxide of Example 21 (0.92 g, 2.04 mmol) in dichloromethane (14 mL) and methanol (2 drops) was added trifluoroacetic acid (3.5 mL). This mixture was stirred for 4 h, and TLC indicated the absence of starting material. The volatile components were removed in vacuo and the residue was taken up into dichloromethane (50 mL) and washed with dilute aqueous sodium bicarbonate (2×). The organic phase was dried (Na2SO4), filtered and completely evaporated to leave 0.71 g of pure title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[NH2:18].Cl.NO.N1C=CC=CC=1>C(O)C>[F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([NH2:15])[C:3]=1[NH2:18]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: Cl
Agent: NO
Solvent: c1ccncc1
Solvent: CCO
Product: CN1CCN(c2ccc(N)c(N)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 50 mL round bottom flask was charged with 1 (680 mg, 2.5 mmol), hydroxylamine HCl (191 mg, 2.75 mmol), pyridine (0.25 mL, 3.0 mmol) and ethanol (10 mL). The resulting reaction mixture was stirred at rt overnight. The crude product was concentrated, absorbed onto silica gel, and purified by flash chromatography (97:3 CH2Cl2/MeOH to give 2 as an orange solid. LCMS m/z 289.2 (MH+), tR=2.06 min.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>C1(C)C=CC=CC=1>[C:1]1([O:7][C:9](=[O:15])/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C1C=CC(=O)O1
Agent: [Na]
Solvent: Cc1ccccc1
Product: O=C(O)/C=C/C(=O)Oc1ccccc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
A mixture of phenol (22.41 g), sodium (5.47 g) and toluene (500 ml) was heated for 4 hours while refluxing. The reaction mixture was cooled to 85° C., and maleic anhydride (23.35 g) was added. After stirring at 85° C. for 1 hour, the reaction mixture was poured over ice-water, and the aqueous layer was collected. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then treated with activated charcoal, after which the solvent was distilled off, to yield fumaric acid monophenyl ester (10.59 g, 23%), which was then recrystallized from ethyl acetate-hexane to yield colorless needles having a melting point of 127° to 128° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=[O:24])=[CH:4][CH:3]=1.CI.C(=O)([O-])[O-].[K+].[K+].[NH2:33]OS(C1C(C)=CC(C)=CC=1C)(=O)=O>O1CCCC1.O>[NH2:33][N:15]1[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][C:18](=[O:19])[N:13]([C:5]2[C:6]3[O:10][C:9]([CH3:11])([CH3:12])[CH2:8][C:7]=3[C:2]([Cl:1])=[CH:3][CH:4]=2)[C:14]1=[O:24]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: CC1(C)Cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CC1(C)Cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(N)c3=O)c2O1
Yield: 88.7 %

Procedure:
A solution of 1.0 gram (0.003 mole) of 3-(4-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-yl)-6-trifluoromethyluracil (prepared in a manner analogous to that of Example 1, Step G, except that methyl iodide and potassium carbonate were not used) in 30 mL of tetrahydrofuran was stirred, and 0.5 gram (0.003 mole) of potassium carbonate, then 0.7 gram (0.003 mole) of 1-aminooxysulfonyl-2,4,6-trimethylbenzene were added. Upon completion of the addition, the reaction mixture was stirred for one hour and then diluted with water and extracted with three portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with 1:4 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated, yielding 1.0 gram of 1-amino-3-(4-chloro-2,3-dihydro-2,2-dimethylbenzofuran- 7-yl)-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:5][C:6]([CH:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:9]1[C:13]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=2[N:11](C(OC(C)(C)C)=O)[C:10]1=[O:27])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:18]([C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:10](=[O:27])[N:9]([CH:8]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:6]([OH:7])=[O:5])[C:13]=2[CH:14]=1)#[N:19]
Reactant: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(C#N)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2[nH]c(=O)n(C(C(=O)O)c3ccccc3)c2c1
Temperature: 25 °C

Procedure:
tert-Butyl 3-(tert-butoxycarbonylphenylmethyl)-5-cyano-2-oxo-2,3-dihydro-benzimidazole-1-carboxylate 695 mg (1.55 mmol) of tert-butyl 3-(tert-butoxycarbonylphenylmethyl)-5-cyano-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (VIIc) were dissolved in dichloromethane (30 ml) and, while stirring at room temperature, trifluoroacetic acid (20 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 449 mg (99%) of white solid
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][NH:13][C:12](=[O:17])[C:11]=3[C:10]([C:18]3[CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[S:21][CH:22]=3)=[N:9]2)=[CH:5][CH:4]=1.CO.C1COCC1.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][NH:13][C:12](=[O:17])[C:11]=3[C:10]([C:18]3[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[S:21][CH:22]=3)=[N:9]2)=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc(-c2nn(Cc3ccc(OC)cc3)c3cc[nH]c(=O)c23)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(Cn2nc(-c3csc(C(=O)O)c3)c3c(=O)[nH]ccc32)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A mixture of methyl 4-(1-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylate (46.5 mg) obtained in Example 113 in a mixed solvent of methanol (2 mL)/THF (2 mL)/water (2 mL) was added 8 M aqueous sodium hydroxide solution (0.037 mL) at 0° C. The reaction mixture was stirred at 90° C. for 2 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.1 N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (40.8 mg).
Reaction SMILES: CN(C)C=O.[O:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([NH2:24])=[N:16]2)[CH2:8][CH2:7]1.Br.Br[CH2:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[O:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([NH:24][CH2:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[N:16]2)[CH2:8][CH2:7]1
Reactant: Nc1nn(CCCN2CCOCC2)c2ccccc12
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nn(CCCN2CCOCC2)c2ccccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 57.9 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 4.21 g of 1-(3-morpholinopropyl)-3-aminoindazole obtained by the same method as described in Example 149, 8.98 g of 3-bromopropyldiethylamine hydrobromide and 7.89 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 200 g) using chloroform as the developing solvent to give 3.50 g of 1-(3-morpholinopropyl)-3-(3-diethylaminopropylamino)indazole having the following analytical values in a yield of 58%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:19])[CH:12]=[CH:11][C:10]=1[C:20](=[O:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:19])[CH:12]=[CH:11][C:10]=1[C:20]([CH3:23])([OH:22])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc2cccc(C)c2c1OCc1ccccc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccc2ccc(C(C)(C)O)c(OCc3ccccc3)c12
Temperature: -78 °C
Reaction time: 72 h

Procedure:
4.8 g of 1'-benzyloxy-8'-methyl-2'-acetonaphthone was dissolved in 200 ml of tetrahydrofuran and cooled down to -78° C. At the temperature, 28 ml of a tetrahydrofuran solution of 1M methylmagnesium bromide was added, followed by returning to room temperature. It was agitated at room temperature for 72 hours and was further reacted at 80° C. for 2 hours. The reaction solution was cooled down to 0° C., to which a saturated ammonium chloride aqueous solution was added portion by portion, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to obtained 1.8 g of the captioned compound as a brown oily substance.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:31]([F:34])([F:33])[F:32])[O:16][N:15]=[C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27]([O:29]C)=[O:28])=[CH:19][CH:18]=3)[CH2:13]2)[CH:8]=[C:9]([Cl:11])[CH:10]=1.CO>O.O1CCCC1>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:31]([F:33])([F:32])[F:34])[O:16][N:15]=[C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27]([OH:29])=[O:28])=[CH:19][CH:18]=3)[CH2:13]2)[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of lithium hydroxide monohydrate (350 mg, 8.34 mmol) in water (10 mL) was added to a stirred solution of methyl 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenecarboxylate (i.e. the product of Step B, 650 mg, 1.39 mmol) in tetrahydrofuran (10 mL), followed by the addition of methanol (10 mL). The resulting mixture was stirred overnight at room temperature and then partitioned between water and diethyl ether. The aqueous layer was acidified with 6 N aqueous hydrochloric acid to pH 2 and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to provide the title compound as a white solid (450 mg). 1H NMR (CDCl3): δ 9.08 (d, 1H), 8.80 (d, 1H), 8.31 (d, 1H), 7.71 (m, 2H), 7.57 (m, 3H), 7.46 (dd, 1H), 4.28 (d, 1H), 3.91 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:19]C)C(OC)=CC=C(CO)C2)=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].[CH3:24][O:25][C:26]1[CH:27]=[C:28](Br)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1.[Mg].COC1C=CC(C=O)=CC=1[N+]([O-])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:28]2[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=2)[OH:19])=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22]
Reactant: COc1cc(Br)cc(OC)c1
Reactant: COC1=CC=C(CO)CC1(OC)c1ccc(OC)c([N+](=O)[O-])c1
Agent: COc1ccc(C=O)cc1[N+](=O)[O-]
Agent: [Mg]
Product: COc1cc(OC)cc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)c1
Yield: 60 %

Procedure:
(4-Methoxy-3-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol was prepared analogously to 3-(4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol using 3,5-dimethoxy-bromobenzene (5.0 g, 23.0 mmol), magnesium turning (0.6 g, 23.0 mmol) and 4-methoxy-3-nitro-benzaldehyde (3.5 g, 19.2 mmol). The crude product was purified by flash chromatography (silica gel, Hexane:EtOAc 1:1) to afford (4-methoxy-3-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol (3.7 g, 60%) as an oil: 1H NMR (CDCl3) δ 7.88 (s, 1H), 7.54-7.50 (dd, J=2, 8 Hz, 1H), 7.04 (d, J=8 Hz, 1H), 6.38 (d, J=1 Hz, 1H), 5.72 (d, J=3 Hz, 1H), 3.93 (s, 3H), 3.76 (s, 6H), 2.45 (d, 2 Hz, 1H).