Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14](=O)[CH:15]=[CH:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([Br:23])[CH:22]=1)C>CCOCC>[Br:23][C:21]1[CH:22]=[C:17]([CH:16]=[CH:15][CH2:14][OH:13])[CH:18]=[N:19][CH:20]=1
Reactant: CCOC(=O)C=Cc1cncc(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: OCC=Cc1cncc(Br)c1
Yield: 84.1 %

Procedure:
A solution of diisobutylaluminum hydride (DIBAL-H, 8.02 mls, 1.54 M in toluene) in ether (50 mls) is cooled to -78° C. under N2. A solution of 3-(5-bromo-3-pyridinyl)-2-propenoic acid ethyl ester [see Nishikawa, Y., et al.(1989) J. Chem. 32, 583-593] (1.54 gms, 6.00 mmol) in ether (50 mls) is added. After one hour the dry ice/acetone bath is removed and the mixture is diluted with methylene chloride, dried over Na2SO4, evaporated, and chromatographed (1:1 ethyl acetate:hexane followed by 2:1 ethyl acetate:hexane) to yield 1.08 gms of an oil (84%). 1H NMR (DMSO, 300 MHz) δ 8.60 (s,1H), 8.50 (s,1H), 8.15 (s,1H), 6.60 (m,2H), 5.00 (s,1), and 4.10 (d, J=3.8 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[C:22]([CH2:28][O:29][CH2:30][CH3:31])([OH:27])[C:23]([F:26])([F:25])[F:24])=[C:17]([O:33][CH3:34])[C:16]=1[F:35].C(O)(=O)C.[F-].[NH4+]>C1(C)C=CC=CC=1.O1CCOCC1.CCCCO.CCCCO.CCCCO.CCCCO.[Ti].C(OCC)(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[N:1][C:2]2[CH:11]=[C:10]([F:12])[CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:13])[NH:7]3)[C:22]([CH2:28][O:29][CH2:30][CH3:31])([OH:27])[C:23]([F:26])([F:25])[F:24])=[C:17]([O:33][CH3:34])[C:16]=1[F:35]
Reactant: CCOCC(O)(C(=O)c1ccc(Cl)c(F)c1OC)C(F)(F)F
Reactant: Nc1cc(F)cc2[nH]c(=O)ccc12
Agent: [Ti]
Agent: [F-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOCC(O)(C(=Nc1cc(F)cc2[nH]c(=O)ccc12)c1ccc(Cl)c(F)c1OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
285 mg (0.95 mmol) (4-Chloro-3-fluoro-2-methoxyphenyl)[2-(trifluoromethyl)-oxiranyl]methanone obtained in example 12 are stirred with 622 mg (1.9 mmol) Caesium carbonate in 8 ml ethanol. The reaction is quenched by addition of water after 1 day. The aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine, dried over sodium sulphate and then evaporated to yield 173 mg 1-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-ethoxymethyl-2-hydroxy propan-1-one. 1H-NMR (CDCl3); δ=1.20 (t, 3H), 3.60 (dq, 1H), 3.62 (dq, 1H), 3.79 (d, 1H), 3.97 (d, 3H), 4.09 (d, 1H), 4.72 (s, 1H), 7.11 (dd, 1H), 7.18 (dd, 1H). To 26 mg (0.15 mmol) 5-Amino-7-fluoro-1H-quinolin-2-one and 50 mg (0.15 mmol) 1-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-ethoxymethyl-2-hydroxypropan-1-one in 0.44 ml toluene and 0.13 ml 1,4-dioxane are added 30 μl acetic acid and 0.11 ml tetrabutyl orthotitanate. The mixture is heated over 20 hours to 110° C., cooled to room temperature and poured into aqueous ammonium fluoride solution. Ethyl acetate is added and the mixture is stirred vigorously for 30 minutes. Phases are separated and two times extracted with ethylacetate. The combined organic phases are concentrated to yield quantitatively 5-{[1-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-ethoxymethyl-2-hydroxypropylidene]amino}-7-fluoro-1H-quinolin-2-one. The raw imine in 4.7 ml methanol is cooled to 5° C. and 180 mg sodium boron hydride are added in multiple portions over the period of 72 hours. The reaction is quenched by addition of saturated ammonium chloride solution and diluted with water and ethyl acetate. The phases are separated, the aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent preparative thin layer chromatography on silica gel (acetone in methylene chloride 30%) yields 3.2 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:24][CH2:25][C@@H:26]1[CH2:30][C@@H:29]([O:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])[CH2:28][N:27]1[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:38]>CN(C)C(=O)C>[CH3:34][N:33]([CH3:35])[C:32]([O:31][C@H:29]1[CH2:28][N:27]([C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:38])[C@H:26]([CH2:25][CH2:24][O:8][C:7]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:30]1)=[O:36]
Reactant: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCCl
Reactant: Oc1c(F)cccc1CCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCOc1c(F)cccc1CCc1ccccc1
Yield: 81.2 %

Procedure:
520 mg of 6-fluoro-2-(2-phenylethyl)phenol (prepared as described in Preparation 10) were dissolved in 10 ml of N,N-dimethylacetamide, allowed to react with 300 mg of potassium t-butoxide and 820 mg of (2S,4R)-2-(2-chloroethyl)-4-dimethylcarbamoyloxy-1-octyloxycarbonylpyrrolidine and extracted in the same manner as described in step (a) of Example 2. The resulting oily substance was purified by silica gel column chromatography, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 984 mg (yield 81 %) of the title compound as an oily substance.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([F:23])([CH:10]([O:15][Si](CC)(CC)CC)[C:11]([F:14])([F:13])[F:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[C:1]([N:4]1[CH2:5][CH2:6][C:7]([F:23])([CH:10]([OH:15])[C:11]([F:13])([F:12])[F:14])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C(F)(F)F)C1(F)CCN(C(C)=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(F)(C(O)C(F)(F)F)CC1

Procedure:
By use of 1-acetyl-4-fluoro-4-[2,2,2-trifluoro-1-(triethylsiloxy)-ethyl]piperidine (294 mg, 0.822 mmol) dissolved in tetrahydrofuran (5 mL) and a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (1.23 mL, 1.23 mmol), the mixture was stirred and reacted at room temperature for 30 minutes. The reaction was stopped by addition of water to the reaction mixture, and extraction with ethyl acetate was performed, followed by drying over anhydrous sodium sulfate.
Reaction SMILES: [Na].[N:2]([C:4]1[C:5]([NH2:12])=[N:6][C:7]([NH2:11])=[N:8][C:9]=1[NH2:10])=O.[OH:13][CH:14]([CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[CH2:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][C:22]#[N:23])=[CH:19][CH:18]=1>C(OCCO)C>[OH:13][CH:14]([CH2:26][N:27]1[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]1)[CH2:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]2[N:2]=[C:4]3[C:5](=[N:12][C:22]=2[NH2:23])[N:6]=[C:7]([NH2:11])[N:8]=[C:9]3[NH2:10])=[CH:19][CH:18]=1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)COc2ccc(CC#N)cc2)CC1
Agent: [Na]
Solvent: CCOCCO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)COc2ccc(-c3nc4c(N)nc(N)nc4nc3N)cc2)CC1
Temperature: 25 °C

Procedure:
Sodium metall (0.22 g, 9.6 mg-atom) was dissolved in 2-ethoxyethanol (60 ml) at 40°-50° C., the solution was cooled to room temperature and 5-nitroso-2,4,6-triamino-pirimidine (1.46 g, 9.5 mmol) was added, followed by 4-[2-hydroxy-3-[4-(tert-butoxy-carbonyl)-1-piperazinyl]propoxy]benzylcyanide (3.92 g, 10.4 mmol) prepared as described in Example 45. The mixture was stirred under reflux in an atmosphere of nitrogen for one hour and the obtained dark brown solution was cooled to room temperature. After dilution with 200 ml of ethyl acetate the precipitate was collected, washed with ethyl acetate and dried to yield a yellow powder, mp. 244°-246° C. (dec.). The filtrate was concentrated and the residue was dissolved in 30 ml of methanol. After treatment with decolorizing carbon the solution was concentrated to a volume of 10 ml and the separated crystals were collected. Total yield of the two generations: 84.8%.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][NH2:13].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:11][C:4]1[N:3]=[C:2]([NH:13][CH3:12])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1nc(Cl)ccc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
To a stirred solution of 10 g (52 mmol) of 2,6-dichloro-3-nitropyridine in 300 mL of N,N-dimethylformamide was added 26 mL (52 mmol) of methylamine (2M in tetrahydrofuran) and 9.3 g (88 mmol) of sodium carbonate and the resulting mixture was stirred for 24 h. The solution was diluted with 500 mL water and extracted with three 700 mL portions of ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and evaporated in vacuo to yield a viscous oil. The crude material was purified by flash chromatography on a Biotage Horizon® system (silica gel, 0 to 10% ethyl acetate/hexanes gradient) to give 6-chloro-N-methyl-3-nitropyridin-2-amine as a yellow solid. LC/MS 188.1 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[S:13][C:12](=[O:14])[NH:11][N:10]=1.Cl[CH2:16][C:17](=[O:19])[CH3:18]>O1CCOCC1>[CH3:7][O:8][C:9]1[S:13][C:12](=[O:14])[N:11]([CH2:16][C:17](=[O:19])[CH3:18])[N:10]=1
Reactant: COc1n[nH]c(=O)s1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1nn(CC(C)=O)c(=O)s1
Reaction time: 20 h

Procedure:
69 g of potassium carbonate are added to a solution of 33 g of 5-methoxy-3H-[1,3,4]thiadiazol-2-one in 400 ml of dioxane and the reaction mixture is heated to 60°. Then 21 g of chloroacetone are added dropwise within a short period of time and the reaction mixture is stirred at 70° for 20 hours and then, at 20°, is filtered over Celite. The filtrate is concentrated by evaporation. The residue is stirred with diisopropyl ether and filtered with suction. 45 g of crystals of the title compound having a melting point of 66°-67° are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([F:37])[CH:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([F:37])[CH:30]=1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: N#Cc1ccc(CBr)cc1F
Product: N#Cc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1F

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and 4-bromomethyl-2-fluoro-benzonitrile (CAS Reg. No. 222978-03-2). Off-white powder (89%). MS (Turbo Spray): m/z=510.3 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15](Br)[CH:16]([Br:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[N:25]1[S:29](=[O:31])(=[O:30])[NH:28][C:27](=[O:32])[CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][O-:34].[Na+]>CO.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]([O:34][CH3:33])[CH:16]([Br:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[N:25]1[S:29](=[O:31])(=[O:30])[NH:28][C:27](=[O:32])[CH2:26]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: O=C1CN(c2ccc(C(Br)C(Br)c3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-[2-benzyloxy-4-(1,2-dibromo-2-phenylethyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (25 mg, 0.043 mmol) in MeOH/methylene chloride (1:1, 4 mL) is added NaOMe (0.17 mL, 0.086 mmol, 0.5M in THF). The solution is stirred at RT for 2 h and the solvent is removed under reduced pressure to give the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:9]=2[C:8]=1[C:27]1[C:28]([CH3:37])=[C:29]2[C:34](=[CH:35][CH:36]=1)[O:33][CH2:32][CH2:31][CH2:30]2)[C:3]([O:5][CH3:6])=[O:4].C(O[C:42]([CH3:45])([CH3:44])[CH3:43])(=O)C.Cl(O)(=O)(=O)=O>>[C:42]([O:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[N:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:9]=2[C:8]=1[C:27]1[C:28]([CH3:37])=[C:29]2[C:34](=[CH:35][CH:36]=1)[O:33][CH2:32][CH2:31][CH2:30]2)[C:3]([O:5][CH3:6])=[O:4])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)C(O)c1c(-c2ccc3c(c2C)CCCO3)c2ccn(Cc3ccc(OC)cc3)c2c(=O)n1C
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2ccn(Cc3ccc(OC)cc3)c2c(=O)n1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.7 %

Procedure:
An ice cold solution of methyl 2-hydroxy-2-(1-(4-methoxybenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (325 mg, 0.647 mmol) in tert-butyl acetate (8735 μl, 64.7 mmol) was treated with perchloric acid (55.6 μl, 0.647 mmol), and stirred for 20 min. The reaction was then kept in the refrigerator without stirring for 2 days. The reaction was quenched with sat. NaHCO3 at 0° C., extracted with EtOAc 2×, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/Hexane) gave methyl 2-(tert-butoxy)-2-(1-(4-methoxybenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (219.3 mg, 0.393 mmol, 60.7% yield, racemate) as white solid. The racemate was resolved using a Chiralpak IC column (30×250 mm) with isocratic conditions of 10% EtOH in hexane. The flow rate was 40 mL/min and the baseline was monitored at 280 nm using an Agilent 1100 series prep LC. The third isomer eluting from the column was isolated to afford (S)(M)-methyl 2-(tert-butoxy)-2-(1-(4-methoxybenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (52.9 mg, 0.095 mmol, 14.6% yield) as clear oil: 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.29 (d, J=8.5 Hz, 2H), 6.99-6.91 (m, 2H), 6.85 (d, J=8.5 Hz, 2H), 6.69 (d, J=8.4 Hz, 1H), 5.86 (d, J=14.6 Hz, 1H), 5.71-5.61 (m, 2H), 5.09 (s, 1H), 4.20 (t, J=5.2 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.65 (s, 3H), 2.76-2.62 (m, 2H), 2.13-2.04 (m, 2H), 1.91 (s, 3H), 1.11 (s, 9H); LCMS (m/z) ES+=559 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([CH3:33])([CH3:32])[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[CH:17]=1)[C:10]([CH3:35])([CH3:34])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:33][C:23]([NH:22][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:34])([CH3:35])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)([CH3:32])[C:24]([N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)=[O:25]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1)C(=O)N1CCOCC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 4.3 %

Procedure:
A mixture of 2-[3-(1,1-dimethyl-2-morpholin-4-yl-2-oxo-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.87 g, 1.8 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 50° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(1,1-dimethyl-2-morpholin-4-yl-2-oxo-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (35 mg, 4%) as a light yellow solid: LC/MS m/e calcd for C26H33N3O4 (M+H)+: 452.57, observed: 452.1.
Reaction SMILES: ClCCC([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)=O.[Cl-:18].[Al+3].[Cl-].[Cl-].[Cl-].[Na+].[Cl-].[K+]>>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[C:7](=[O:6])[CH2:16][CH2:15][Cl:18])[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: O=C1CCc2cc(OC(=O)CCCl)ccc2N1
Reactant: [Cl-]
Agent: [Al+3]
Agent: [K+]
Agent: [Na+]
Product: O=C1CCc2cc(O)c(C(=O)CCCl)cc2N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
20 Grams of 6-(β-chloropropionyloxy)-3,4-dihydrocarbostyril, 60 g of pulverized anhydrous aluminium chloride, 6 g of sodium chloride and 6 g of potassium chloride were mixed together and the mixture was melted by heating and stirred at 150°-170° C. for 1 hour. The reaction mixture was poured into ice-water and allowed stand overnight to obtain crystalline precipitates. The precipitates were collected by filtration, washed with water and dried, then recrystallized from methanol to obtain 12 g of 6-hydroxy-7-(3-chloropropionyl)-3,4-dihydrocarbostyril in white crystals. Melting point: 205°-208° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:26]1([C:29](O)=[O:30])[CH2:28][CH2:27]1.CCN=C=NCCCN(C)C>>[CH:26]1([C:29]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:30])[CH2:28][CH2:27]1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)C4CC4)c3)c2c1
Yield: 24.4 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (600 mg, 1.79 mmol) with cyclopropanecarboxylic acid (0.43 mL, 0.46 g, 5.4 mmol) and EDCI (1.06 g, 5.4 mmol) furnished 140 mg (26% yield) of the title compound. 1H NMR (DMSOd6) δ 13.4 (br s, 1H), 10.4 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 8.1 (br s, 1H), 7.9 (dd, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.5 (t, 1H), 7.35 (s, 1H), 1.9–1.68 (m, 1H), 0.8 (m, 4H); ES-MS (m/z) 321 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]23OCC[O:17]2)=[C:5]([CH3:21])[O:4][N:3]=1.Cl>C(O)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3=[O:17])=[C:5]([CH3:21])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C1(OCCO1)C(=O)N2
Agent: Cl
Solvent: CC(=O)O
Product: Cc1noc(C)c1-c1ccc2c(c1)C(=O)C(=O)N2
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A solution of compound 5′-(3,5-dimethylisoxazol-4-yl)spiro[[1,3]dioxolane-2,3′-indolin]-2′-one (150 g, 0.52 mol), acetic acid (10 mL), and concentrated HCl solution (300 mL) was heated to 90° C. After 1 h, the mixture was poured into ice-water, and the expected compound 5-(3,5-Dimethylisoxazol-4-yl)indoline-2,3-dione was collected by filtration and washed with water, EtOH, and EtOAc, and afforded target compound (115 g, 92%). 1H NMR (DMSO-d6) δH 11.14 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.51 (s, 1H), 7.00 (d, J=8.0 Hz, 1H), 2.37 (s, 3H), 2.20 (s, 3H). MS (ESI) m/e [M+1]+ 243.
Reaction SMILES: Br[C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[F:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:26]1[CH:31]=[C:30]([C:2]2[C:3]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)=[CH:13][CH:12]=3)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)[CH:29]=[CH:28][N:27]=1
Reactant: COc1cnc(Oc2ccc(Nc3ccc(C)cn3)cc2)c(Br)c1
Reactant: OB(O)c1ccnc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cnc(Oc2ccc(Nc3ccc(C)cn3)cc2)c(-c2ccnc(F)c2)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
N-(4-(3-bromo-5-methoxypyridin-2-yloxy)phenyl)-5-methylpyridin-2-amine (0.076 g, 0.20 mmol), 2-fluoropyridine-4-boronic acid (0.056 g, 0.39 mmol), and tetrakis(triphenylphosphine)palladium (0.023 g, 0.020 mmol) were mixed in dioxane (0.8 mL) under an argon atmosphere. Sodium carbonate (0.30 mL, 0.59 mmol, 2.0 M in water) was added via syringe, and the reaction mixture was stirred at 80° C. for 20 h before being warmed to 90° C. and stirred for 24 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography to give N-(4-(2′-fluoro-5-methoxy-3,4′-bipyridin-2-yloxy)phenyl)-5-methylpyridin-2-amine. MS (ESI, pos. ion) m/z: 403.2 (M+1). IC50 (uM) 0.004.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[C:5]2[N:6](C3C=CC(F)=CC=3)[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.Br[C:27]1[S:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>>[NH2:1][C:2]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[C:5]2[N:6]([C:27]3[S:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[N:31]=3)[C:7](=[O:12])[C:8]([CH3:10])([CH3:11])[O:9][C:4]=2[CH:3]=1
Reactant: Brc1nc2ccccc2s1
Reactant: CC1(C)Oc2cc(N)cc(C(F)(F)F)c2N(c2ccc(F)cc2)C1=O
Product: CC1(C)Oc2cc(N)cc(C(F)(F)F)c2N(c2nc3ccccc3s2)C1=O
Yield: 5.4 %

Procedure:
7-Amino-4-(4-fluorophenyl)-2,2-dimethyl-5-(trifluoromethyl)-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 3(1), 200 mg) and 2-bromobenzothiazole (445 mg) were treated in the same manner as described in Reference Example 61 to give 7-amino-4-(1,3-benzothiazol-2-yl)-2,2-dimethyl-5-(trifluoromethyl)-2H-1,4-benzoxazin-3(4H)-one (12 mg) as a pale yellow powder.