Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7](Cl)[C:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)=[C:5]2[Cl:25].[CH3:26][O-:27].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([O:27][CH3:26])[C:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)=[C:5]2[Cl:25]
Reactant: Cc1cc(Br)cc2c(Cl)c(-c3ccc(OC(F)(F)F)cc3)c(Cl)nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc2c(C)cc(Br)cc2c(Cl)c1-c1ccc(OC(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-bromo-2,4-dichloro-8-methyl-3-(4-(trifluoromethoxy)phenyl)quinoline (1.97 g, 4.367 mmol, Intermediate 58, step c) and sodium methoxide (1.18 g, 21.837 mmol) in toluene (20 mL) was heated in a sealed tube at 110° C. for 24 hours, cooled to RT, diluted with DCM, stirred at room temperature for 30 min, and filtered through Celite® rinsing several times with DCM. The solvents were removed under reduced pressure and the off-white solid product precipitated from MeOH, filtered and dried to provide the title compound.
Reaction SMILES: [H-].[Na+].CC1C=CC(S(/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)(=O)=O)=CC=1.[N+:24]([CH2:26][C:27]([O:29][CH3:30])=[O:28])#[C-:25]>O1CCCC1.O.C(OCC)(=O)C>[N+:21]([C:18]1[CH:17]=[CH:16][C:15]([C:14]2[CH:13]=[CH:25][NH:24][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:20][CH:19]=1)([O-:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)/C=C/c2ccc([N+](=O)[O-])cc2)cc1
Reactant: [C-]#[N+]CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1[nH]ccc1-c1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 111.2 %

Procedure:
To a suspension of 1.62 g (40.63 mmol) of 60% sodium hydride in mineral oil in 100 cm3 of tetrahydrofuran is added dropwise over 25 minutes, at a temperature in the region of 20° C. under an argon atmosphere, a mixture of 5.87 g (19.35 mmol) of 1-[(E)-2-(4-methylphenyl)sulfonylvinyl]-4-nitrobenzene and 3.7 cm3 (38.7 mmol) of methyl isocyanoacetate dissolved in 150 cm3 of tetrahydrofuran. After stirring for 5 hours at a temperature in the region of 20° C., the reaction mixture is taken up in a mixture of 100 cm3 of water and 200 cm3 of ethyl acetate. The organic phase is washed with twice 100 cm3 of water and 150 cm3 of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 5.3 g of a brown oil, which is purified by flash chromatography [eluent: dichloromethane]. After concentrating the fractions under reduced pressure, 2.12 g of methyl 3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate are obtained in the form of a yellow solid; M.W.=246, IE: m/z=246 M+, m/z=214 [M-CH3OH]+.
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)C.[Na+].[Cl:17][C:18]1[CH:19]=[C:20]([S:24][CH2:25][CH:26]([CH3:29])[CH:27]=[O:28])[CH:21]=[CH:22][CH:23]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[C:20]([S:24][CH2:25][CH:26]([CH3:29])[CH:27]([OH:28])[CH2:2][C:3](=[O:4])[CH3:5])[CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C=O)CSc1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CC(O)C(C)CSc1cccc(Cl)c1
Reaction time: 3 h
Yield: 46.5 %

Procedure:
9.86 Grams of methyl acetoacetate were dissolved in 15 ml of water, and 12.67 g of a 30% aqueous sodium hydroxide solution were added thereto by drops while cooling the mixture to 25° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.0 with a concentrated aqueous hydrochloric acid solution. Thereafter, 0.49 g of sodium acetate and 2.42 g of tetrabutylammonium bromide were added thereto and then an additional concentrated aqueous hydrochloric acid solution was added to the mixture so that the mixture was adjusted to pH 6.8 to 6.9. Further, 27.93 g of a toluene solution containing 38.4% of 3-(3-chlorophenylthio)-2-methylpropanal were added thereto and was stirred at 45°-50° C. for 8 hours The organic layer separated from the mixture was washed with a 5% aqueous acetic acid solution and then with a saturated aqueous sodium chloride solution. Then the layer was dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave a crude 6-(3-chlorophenylthio)-4-hydroxy-5-methyl-2-hexanone. A purified product was obtained by column chromatography in a yield of 46.5%. The purified product had an nD21 of 1.5647.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>O.CS(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][CH:5]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CC(=O)COc1ccc(Br)cc1
Reaction time: 0.42 h
Yield: 68 %

Procedure:
A solution of 50% (w/w) NaOH in water (188 mL) in DMSO (800 mL) was stirred at room temperature until a precipitate formed, treated dropwise with a solution of 4-bromophenol (101.2 g) in DMSO (200 mL) over 25 minutes, stirred for 25 minutes, treated with ethyl 4-chloro-3-oxobutanoate (102.2 g) over 40 minutes, adjusted to pH 3 with 6M HCl, treated with water (200 mL) over 12 minutes, stirred for 5 hours, treated with water (150 mL) over 20 minutes, and filtered. The solid was washed with sequentially with water and 40% ethanol/water and dried under vacuum (100 mm Hg) at 50° C. with a nitrogen bleed to provide 119.8 g of the desired product. 1H NMR (300 MHz, CDCl3) δ7.40 (m, 2H), 6.79 (m, 2H), 4.65 (s, 2H), 4.20 (q, 2H, J=7 Hz), 3.62 (s, 2H), 1.26 (t, 3H, J=7Hz).
Reaction SMILES: [Li].[C:2]1([C-:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][SiH:18]([N:20](Cl)[C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:19]>C1COCC1>[CH3:17][SiH:18]([N:20]([CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9]1)[C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:19]
Reactant: c1ccc(-[c-]2ccc3ccccc32)cc1
Reactant: C[SiH](C)N(Cl)C(C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: C[SiH](C)N(C1C=C(c2ccccc2)c2ccccc21)C(C)(C)C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
Lithium-1-Phenylindenide (5.53 g, 0.0279 moles) in THF (50 mL) was added dropwise to a solution of dimethylsilyl(t-butylamino)chloride (4.62 g, 0.0279 moles) in THF (100 mL). This mixture was allowed to stir 16 hours. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. Removal of the hexane resulted in the isolation of the desired product as an oil (8.63 g, 96.2 percent).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:13][C:12]([O:26]C)=[CH:11][CH:10]=3)[CH:2]=1.C(=O)(O)[O-].[Na+]>Br>[OH:26][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)CCCCCc1c(-c2cccnc2)[nH]c2ccc(OC)cc12
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCCCCc1c(-c2cccnc2)[nH]c2ccc(O)cc12

Procedure:
A solution of 1.5 g of 2-(3-pyridyl)-3-[5-(ethoxycarbonyl)-pentyl]-5-methoxyindole in 15 ml of 48% hydrobromic acid is treated at reflux temperature for 2.5 hours. The reaction solution is cooled and neutralized with sodium bicarbonate solution to pH 6-7, and then extracted with ethyl acetate. The organic extract is dried (MgSO4), filtered, and concentrated to give a solid which is recrystallized from acetonitrile to give 5-hydroxy-2-(3-pyridyl)-3-(5-carboxypentyl)-indole, m.p. 185°-187°.
Reaction SMILES: C[Mg]I.Br[C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2.O.[CH3:16]C(OCC)=O>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2
Reactant: CCOC(C)=O
Reactant: Brc1cccc2cnccc12
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: C[Mg]I
Solvent: CCOCC
Solvent: O
Product: Cc1cccc2cnccc12

Procedure:
A 3M solution of methyl magnesium iodide in ether (50 ml, 0.15 mol) was added dropwise to a stirred, ice-cooled solution of 5-bromoisoquinoline (21 g, 0.10 mol), obtained by the method described in J. Org. Chem., 1964, 29, 329, and [1,3-bis(diphenylphosphino)-propane]nickel(II) chloride (400 mg, 0.7 mmol) in anhydrous ether and the reaction mixture heated under reflux for 5 days, allowed to cool, then poured into water (500 ml). The organic phase was separated, combined with ether extracts of the aqueous phase, washed with saturated brine, dried (MgSO4) and evaporated under reduced pressure to yield an oil, chromatography of which on silica gel, using a 5-50% ether in hexane elution gradient, provided the required. product (8.4 g). Rf 0.40 (SS 8), m/e 144 (M+H)+. Found: C,79.57; H,6.26; N,8.61. C10H9N; 0.27 CH3CO2CH2CH3 requires C,79.70; H,6.74; N,8.39%.
Reaction SMILES: [C:1]1([P:7]([CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][C:27]=2[CH2:36][P:37]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=O)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CCCC)CCCC)CCC.C1([SiH](Cl)Cl)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:45]1([P:37]([CH2:36][C:27]2[CH:28]=[CH:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]=2[C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][C:16]=2[CH2:15][P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=P(Cc1ccc2ccccc2c1-c1c(CP(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12)(c1ccccc1)c1ccccc1
Agent: Cl[SiH](Cl)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Product: c1ccc(P(Cc2ccc3ccccc3c2-c2c(CP(c3ccccc3)c3ccccc3)ccc3ccccc23)c2ccccc2)cc1

Procedure:
20.48 g (0.03 mol) of 2,2'-bis(diphenylphosphinylmethyl)-1,1'-binaphthyl are suspended in 80 ml of xylene and 30.6 g (0.165 mol) of tri-n-butylamine in the absence of air and moisture, and 26.57 g (0.15 mol) of phenyldichlorosilane are added dropwise with stirring. The mixture is then refluxed for 13 hours to give a clear solution. Xylene is distilled off at atmospheric pressure, and the mixture is allowed to cool with stirring. This results in the formation of 2,2'-bis(diphenylphosphinomethyl)-1,1'-binaphthyl as a colorless solid, which is filtered off under an inert gas and washed with 20 ml of degassed acetone. 18.5 g (95%) of colorless crystals of melting point 160° to 161° C. are obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2)CC1
Yield: 92.8 %

Procedure:
Using general procedure A, 1-Boc-4-piperidone (2.42 g, 12.1 mmol) and aniline (1.0 mL, 11.0 mmol) gave 4-phenylamino-piperidine-1-carboxylic acid tert-butyl ester as a white solid (2.82 g, 93%).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH2:5][S:4][CH2:3]1.[N:14]1[CH:18]=[C:17]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[NH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N:21]1([C:19]([C:17]2[N:16]([CH:2]3[C:11]4[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=4)[CH2:5][S:4][CH2:3]3)[CH:15]=[N:14][CH:18]=2)=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: N#Cc1ccc2c(c1)CSCC2O
Reactant: O=C(c1cnc[nH]1)N1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)CSCC2n1cncc1C(=O)N1CCCC1
Temperature: 0 °C

Procedure:
To a solution of 4-hydroxy-isothiochroman-7-carbonitrile, which can be prepared as described in Example 12, (300 mg, 1.6 mmol) in THF (20 mL) is added (3H-imidazol-4-yl)-pyrrolidin-1-yl-methanone (200 mg, 1.2 mmol), and triphenylphosphine (420 mg, 1.6 mmol). The reaction is cooled to 0° C. and diisopropyl azodicarboxylate (310 μL, 1.6 mmol) is added. The reaction is permitted to warm to room temperature and stirred until LC-MS analysis indicates complete consumption of 4-hydroxy-isothiochroman-7-carbonitrile. The reaction mixture is diluted with saturated aqueous NaHCO3 and ethyl acetate. The layers are separated and the organic layer is dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:1) to afford 4-[5-(Pyrrolidine-1-carbonyl)-imidazol-1-yl]-isothiochroman-7-carbonitrile; MS: (ESI) m/z 339.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.88-2.08 (m, 4 H), 3.17-3.37 (m, 2 H), 3.53-3.68 (m, 2 H), 3.69-3.77 (m, 2 H), 3.79-3.98 (m, 2 H), 6.55 (t, J=4.6 Hz, 1 H), 7.19 (d, J=8.1 Hz, 1 H), 7.39 (s, 1 H), 7.43-7.48 (m, 2 H), 7.50 (s, 1 H). The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 4-[5-(Pyrrolidine-1-carbonyl)-imidazol-1-yl]-isothiochroman-7-carbonitrile.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:23])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4](C([O-])=O)[CH2:3]1.[ClH:27]>O1CCOCC1>[ClH:27].[F:18][C:15]([F:16])([F:17])[C:14]([C:11]1[CH:10]=[CH:9][C:8]([N:7]2[CH2:6][CH2:5][NH:4][CH2:3][C@@H:2]2[CH3:1])=[CH:13][CH:12]=1)([OH:23])[C:19]([F:22])([F:21])[F:20]
Reactant: C[C@H]1CN(C(=O)[O-])CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CNCCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
A 100 mL round-bottomed flask was charged with (3S)-3-methyl-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.250 g, 0.565 mmol) and 10 mL of 4N HCl in dioxane. After 2 h at room temperature, the mixture was concentrated to give (S)-1,1,1,3,3,3-hexafluoro-2-(4-(2-methylpiperazin-1-yl)phenyl)-2-propanol hydrochloride as a yellow foam (0.214 g) which was used without purification.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:33][CH3:34])=[C:25]([O:28][CH2:29][CH2:30][CH2:31]Cl)[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[C:13]([F:35])[CH:12]=1.C(Cl)Cl>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:33][CH3:34])=[C:25]([O:28][CH2:29][CH2:30][CH2:31][N:7]4[CH2:8][CH2:9][N:4]5[CH:3]=[N:2][N:1]=[C:5]5[CH2:6]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[C:13]([F:35])[CH:12]=1
Reactant: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OCCCCl
Reactant: c1nnc2n1CCNC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OCCCN1CCn2cnnc2C1
Temperature: 80 °C
Reaction time: 36 h
Yield: 18.6 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.15 g) in DMF (8 mL) was added Ag2CO3 (1.00 g) and a solution of N-(4-bromo-2-fluorophenyl)-6-(3-chloropropoxy)-7-methoxy quinazolin-4-amine (0.40 g) in DMF (2 mL) at room temperature under stirring. The mixture was stirred at 80° C. for 36 h under N2 and cooled to room temperature. To this, CH2Cl2 (100 mL) was added. The mixture was washed with brine (100 mL×3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the product (89 mg, 18.50%), HPLC: 91.13%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 528.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.03-2.10 (m, 2H), 2.68 (t, J=13.20 Hz, 2H), 3.03 (t, J=10.80 Hz, 2H), 3.75 (s, 2H), 3.89 (s, 3H), 4.03 (t, J=10.80 Hz, 2H), 4.08 (t, J=12.40 Hz, 2H), 7.03 (m, 1H), 7.24 (s, 1H), 7.32 (m, 1H), 7.38 (s, 1H), 7.81-7.84 (m, 2H), 8.46 (s, 1H), 8.70 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCN(c3ccc(Cl)c(Cl)c3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
To a solution of 1-(3,4-dichloro-phenyl)-piperazine (0.14 g, 0.601 mmol) in isopropanol (6.0 mL) was added 2,6-lutidine (95 uL, 0.802 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.37 g, 1.0 mmol), added in three portions over 2 h. The reaction was then stirred at 80° C. for 18 hours. The reaction was concentrated in vacuum, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/10% methanol) to yield the title compound as a white solid (0.15 g, 69%). 1H-NMR (MeOD) δ: 1.55 (6H, s), 2.35–2.65 (8H, m), 3.15–3.25 (4H, m), 5.30 (2H, br s), 6.20 (1H, t), 6.82 (1H, dd), 7.23–7.55 (5H, m), 7.59 (1H, d), 8.50 (1H, dd). ESI-MS m/z: 524 (M+1), UV retention time: 1.66 min.
Reaction SMILES: C[Al](C)C.[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH2:10].C([O:16][C:17]([C:19]1[C:20]([O:34][CH2:35][CH3:36])=[N:21][C:22]2[C:27]([C:28]=1[OH:29])=[CH:26][CH:25]=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=2)=O)C.CCOC(C)=O.CCCCCC>C1(C)C=CC=CC=1.O>[CH2:35]([O:34][C:20]1[C:19]([C:17]([NH:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([F:5])[CH:7]=2)=[O:16])=[C:28]([OH:29])[C:27]2[C:22](=[CH:23][C:24]([C:30]([F:33])([F:31])[F:32])=[CH:25][CH:26]=2)[N:21]=1)[CH3:36]
Reactant: CCOC(=O)c1c(OCC)nc2cc(C(F)(F)F)ccc2c1O
Reactant: NCc1cccc(F)c1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1nc2cc(C(F)(F)F)ccc2c(O)c1C(=O)NCc1cccc(F)c1
Temperature: 80 °C
Yield: 40 %

Procedure:
1.5 ml (3.0 mmol, 2M in toluene) trimethylaluminium and 350 μl (3.0 mmol) 3-fluorobenzylamine were added consecutively at RT to a solution of 500 mg (1.5 mmol) 2-ethoxy-4-hydroxy-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in toluene (10 ml). The RS was subsequently heated to 80° C. for 4 h. The mixture was subsequently diluted with water and extracted with EtOAc. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in a vacuum. After CC (EtOAc/hexane 1:9) of the residue, 250 mg (0.6 mmol, 41%) 2-ethoxy-N-(3-fluorobenzyl)-4-hydroxy-7-(trifluoromethyl)quinoline-3-carboxylic acid amide was obtained.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=2[O:2]1.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([Cl:24])=[CH:19][CH:20]=2)[N:15]=1>O.C(O)CC>[Cl:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([NH:13][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)=[N:15]2)=[CH:20][CH:19]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Solvent: CCCO
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc2c(c1)OCO2
Temperature: 4 °C
Yield: 39.3 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3,4-methylenedioxybenzoic acid (16.6 g), N,N'-carbonyldiimidazole (16.2 g) and 2-amino-7-chloro-1,8-naphthyridine (11.7 g). The product produced by precipitation in water (15.7 g; m.p. 256° C.) is dissolved in 1-propanol (1000 cc). After 16 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with 1-propanol (3×20 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-3,4-methylenedioxybenzamide (8.4 g) is produced, m.p. 256° C.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][C@@H:12]([N:15]2[CH:19]=[C:18]([C:20]3[C:21]([O:35][CH:36]4[CH2:39][CH2:38][CH2:37]4)=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]([O:32][CH3:33])=[O:31])[C@@H:25]([CH3:34])[CH2:24][CH2:23]4)[CH:17]=[N:16]2)[C@@H:11]([F:40])[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[CH:36]1([O:35][C:21]2[C:20]([C:18]3[CH:17]=[N:16][N:15]([C@@H:12]4[CH2:13][CH2:14][NH:9][CH2:10][C@@H:11]4[F:40])[CH:19]=3)=[CH:29][CH:28]=[C:27]3[C:22]=2[CH2:23][CH2:24][C@H:25]([CH3:34])[N:26]3[C:30]([O:32][CH3:33])=[O:31])[CH2:37][CH2:38][CH2:39]1
Reactant: COC(=O)N1c2ccc(-c3cnn([C@@H]4CCN(C(=O)OC(C)(C)C)C[C@@H]4F)c3)c(OC3CCC3)c2CC[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)N1c2ccc(-c3cnn([C@@H]4CCNC[C@@H]4F)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
Hydrogen chloride (4.0 N in 1,4-dioxane, 0.23 mL, 0.931 mmol) was added to a solution of (S)-methyl 6-(1-((3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (101 mg, 0.186 mmol) in 1,4-dioxane (1.0 mL), and the reaction mixture stirred at room temperature for 3 h. The reaction solution was concentrated under a stream of nitrogen, diluted with saturated aqueous sodium bicarbonate (1 mL) and extracted with ethyl acetate (3×1 mL). The combined organic layers were added directly to a plug of silica gel and eluted with 30% ethyl acetate in methanol to afford methyl (S)-5-cyclobutoxy-6-(1-((3S,4R)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (38 mg, 47%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.07 (d, J=6.45 Hz, 3H), 1.19-1.39 (m, 2H), 1.47-1.58 (m, 1H), 1.96-2.18 (m, 8H), 2.34-2.43 (m, 2H), 2.55-2.72 (m, 1H), 2.77-2.89 (m, 2H), 3.00-3.13 (m, 1H), 3.14 (br d, J=4.98 Hz, 1H), 3.65 (s, 3H), 4.02-4.12 (m, 1H), 4.37-4.49 (m, 1H), 4.78-4.94 (m, 1H), 7.21 (d, J=8.50 Hz, 1H), 7.32 (d, J=8.79 Hz, 1H), 7.83 (s, 1H), 8.02 (s, 1H). MS (ESI, pos. ion) m/z 443 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([CH:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:19]=2)[OH:17])=[C:11]([F:37])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([CH:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[OH:17])=[C:11]([F:37])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2cc(F)c(OCc3ccccc3)cc2F)c2cccnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1cc(F)c(OCc2ccccc2)cc1F)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
To (4-Benzyloxy-2,5-difluoro-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (601, 1.00 g. 1.91 mmol) in tetrahydrofuran (15.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.63 g, 2.04 mmol). The reaction was stirred at room temperature for 10 minutes. The reaction was roto-evaporated and purified with silica gel column chromatography eluting with 50% ethyl acetate in hexane to give the compound as a white solid (P-1902, 0.59 g, 84.0%). MS(ESI) [M+H+]+=367.4.