Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=2[CH3:16])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:20].C([O-])([O-])=O.C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH3:16])=[CH:10][CH:11]=[C:12]([C:14]#[N:15])[N+:13]=2[O-:20])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C#N)nc1-c1cccc(F)c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: OO
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)[n+]([O-])c1-c1cccc(F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
To a solution (50 mL) of 6-(3-fluorophenyl)-5-methylpyridine-2-carbonitrile (4.42 g, 20.8 mmol) in acetonitrile were added trifluoroacetic acid anhydride (17.6 g, 62.4 mmol) and sodium percarbonate (6.5 g, 41.6 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hr and at room temperature overnight. The reaction solution was divided into two layers with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution and subjected to extraction (3 times) with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The disappearance of sodium percarbonate was confirmed, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (1.4 g, 29%) as a white solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[S:24][CH:23]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][C:28]([Cl:35])=[N:29][C:30]=3Cl)[CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:36]>>[Si:1]([O:18][CH2:19][C@H:20]1[S:24][CH:23]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][C:28]([Cl:35])=[N:29][C:30]=3[NH2:36])[CH2:22][CH2:21]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1CCC(n2cnc3c(Cl)nc(Cl)nc32)S1)(c1ccccc1)c1ccccc1
Reactant: N
Product: CC(C)(C)[Si](OC[C@@H]1CCC(n2cnc3c(N)nc(Cl)nc32)S1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 86 %

Procedure:
A mixture of 12 (150 mg) and saturated ethanolic ammonia (50 mL) was heated at 50° C. in a glass-lined stainless steel pressure vessel for 48 hours. The reaction mixture was evaporated to dryness to afford a syrup which was purified on two silica gel thick plates (Analtech, GF, 1000 μm) that were developed in 99:1 CHCl3 -MeOH. The product was eluted with CHCl3 and evaporated. The residue was crystallized from EtOAc-cyclohexane to give pure 15 (125 mg, 86%); mp. 123°-125° C.; FAB MS 524 (M+H)+ ; 1H NMR (CDCl3) δ 8.14 (s, 1, H-8), 7.72 (m, 4, ArH), 7.42 (m, 6, ArH), 6.02 (brs, 2, NH2), 6.16 (m, 1'-H), 3.93 (m, 1, 5'-H), 3.84 (m, 1, 5'-H), 3.73 (m, 1, 4'-H), 2.36 (m, 2, 2'-H), 2.18 (m, 1, 3'-H), 1.90 (m, 1, 3'-H), 1.1 (s, 9, t-butyl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[C:14]([OH:16])=O.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[C:14]([N:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1)=[O:16]
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2F)s1
Product: Cc1nc(C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c(-c2ccccc2F)s1

Procedure:
prepared by reaction of 5-(2-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[O:12][CH:13]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:25])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOCC>[Br:25][C:13]1[O:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(-c2coc3ccccc23)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CSc1ccc(-c2c(Br)oc3ccccc23)cc1
Yield: 90.3 %

Procedure:
A solution of the product of Step 2 (100 mg), NBS (90 mg) and benzoyl peroxide in CCl4 (5 mL) was heated to reflux under a spotlight for 30 min. The mixture was cooled, diluted with Et2O (3 ml) and filtered. The filtrate was concentrated and the residue was purified by flash chromatography, eluted with 15:1 hexane/EtOAc to give the title compound (120 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=[O:17])[NH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[O:17]=[C:5]1[NH:4][CH2:3][CH2:2][N:6]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(NC(=O)NCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCNC2=O)cc1

Procedure:
Methyl 4-(3-(2-chloroethyl)ureido)benzoate (8.5 g, 33.1 mmol) was then stirred in N,N-dimethylformamide (80 ml) with K2CO3 (2.3 g, 16.7 mmol) at room temperature for 12 hours. The solid was filtered off and the solvent was removed in vacuum. The crude product was dissolved in dichloromethane and purified on ISCO system (30% EtOAc in dichloromethane) to give a pure product as a white crystalline (5.48 g, 75%): 1H NMR (400 MHz, CDCl3) δ 8.00 (d, 2H), 7.62 (d, 2H), 4.90 (br s, 1H), 3.97 (dd, 2H), 3.90 (s, 3H), 3.60 (dd, 2H). MS (ESI) m/z: Calculated: 220.08; Observed: 221.10 (M++1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7](C)=[CH:6][C:5]=1[OH:11])([CH3:3])[CH3:2].C([O-])=O.[NH4+:15]>C(O)C.[Pd]>[NH2:15][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([OH:11])[CH:6]=1
Reactant: [NH4+]
Reactant: Cc1ccc(C(C)C)c(O)c1
Agent: [Pd]
Agent: O=C[O-]
Solvent: CCO
Product: CC(C)c1ccc(N)cc1O

Procedure:
To a refluxing solution of 2-isopropyl-5-methyl-phenol (1.3 g, 8.65 mmol) and ammonium formate (1.3 g, 20.62 mmol) in ethanol (50 mL) was added 10% Pd/C (887 mg, 8.33 mmol). The mixture was refluxed for an additional 5 minutes, cooled and filtered through a pad of celite. The solvent was removed by evaporation to give 5-amino-2-isopropylphenol which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 6.71 (d, J=8.1 Hz, 1H), 6.04 (d, J=2.2 Hz, 1H), 5.97 (dd, J=8.1, 2.2 Hz, 1H), 4.65 (s, 2H), 3.08-2.94 (m, 1H), 1.07 (d, J=6.9 Hz, 6H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1([S:12]([C:15]2[CH:16]=[CH:17][C:18](=O)[NH:19][N:20]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[Cl:3][C:18]1[N:19]=[N:20][C:15]([S:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: O=c1ccc(S(=O)(=O)c2ccccc2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: O=S(=O)(c1ccccc1)c1ccc(Cl)nn1
Temperature: 0 °C

Procedure:
To stirring phosphorous oxychloride (87 ml) at 80° C. was added four 2.0 g portions of 6-phenylsulfonyl-3-oxo-2,3-dihydropyridazine every 30 minutes. After additional two 1.0 g portions were added with stirring, the reaction mixture was slowly poured into ice-water over 1 hour to form the precipitate, which was collected, washed well with water, and dried to give 6-chloro-3-phenylsulfonylpyridazine (8.4 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[C:18](C3C=CC(C(N4CCNCC4)=O)=CC=3)[CH:19]=2)[CH:3]=1.N1(C(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=O)CCNCC1.[NH2:57][CH2:58][C:59]1[CH:60]=[C:61](B(O)O)[CH:62]=[C:63]([CH3:65])[CH:64]=1>>[NH2:57][CH2:58][C:59]1[CH:60]=[C:61]([C:18]2[CH:19]=[C:14]([C:4]3[CH:3]=[C:2]([NH2:1])[N:7]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:5]=3)[CH:15]=[N:16][CH:17]=2)[CH:62]=[C:63]([CH3:65])[CH:64]=1
Reactant: Cc1cc(CN)cc(B(O)O)c1
Reactant: Nc1cc(-c2cncc(-c3ccc(C(=O)N4CCNCC4)cc3)c2)cc(-c2ccccn2)n1
Agent: CC1(C)OB(c2ccc(C(=O)N3CCNCC3)cc2)OC1(C)C
Product: Cc1cc(CN)cc(-c2cncc(-c3cc(N)nc(-c4ccccn4)c3)c2)c1

Procedure:
This compound is prepared analogously to [4-(6′-Amino-[2,2′;4′,3″]terpyridin-5″-yl)-phenyl]-piperazin-1-yl-methanone (Example 2.50) by replacing piperazin-1-yl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone with 5″-(3-Aminomethyl-5-methyl-phenyl boronic acid (Intermediate B27).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:19])[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([NH2:18])[CH:12]=1)[CH3:10].[F:21][C:22]([F:28])([F:27])[CH2:23][C:24](O)=[O:25].Cl.C(N(CC)CCCN=C=NCC)C>CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([CH3:20])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:19])[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([NH:18][C:24](=[O:25])[CH2:23][C:22]([F:28])([F:27])[F:21])[CH:12]=1)[CH3:10]
Reactant: O=C(O)CC(F)(F)F
Reactant: Cc1nsc(NC(=O)C(C)c2ccc(O)c(N)c2)c1Cl
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1nsc(NC(=O)C(C)c2ccc(O)c(NC(=O)CC(F)(F)F)c2)c1Cl
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A mixture of N-(4-chloro-3-methylisothiazol-5-yl)-2-(3-amino-4-hydroxyphenyl)propionamide (0.65 g, 0.002 mol), 3,3,3-trifluoropropionic acid (0.267 g, 0.002 mol) and 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.40 g, 0.002 mol) was stirred in N,N-dimethylacetamide (8 ml) at room temperature for 7 hours and was then allowed to stand at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate:hexane 1:1, to give N-(4-chloro-3-methylisothiazol-5-yl)-2-[4-hydroxy-3-(3,3,3-trifluoropropionamido)phenyl]propionamide (0.62 g) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH2:18][CH2:17]2)[N:6]1[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1[O:40][CH3:41].[OH-].[Na+]>O1CCOCC1>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[C:7]([N:16]1[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH2:20][CH2:21]1)[N:6]([C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1[O:40][CH3:41])[CH:5]2[CH2:4][C:3]([OH:42])=[O:2]
Reactant: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cccc(N2CCN(C3=Nc4c(F)cccc4C(CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
Yield: 102.4 %

Procedure:
Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)-phenyl]-3,4-dihydroquinazolin-4-yl}acetate (64 g) is dissolved in 1,4-dioxane (450 ml) and 1N sodium hydroxide solution (325 ml) and stirred at room temperature for 2 h, then some of the solvent is distilled off at 30° C. in vacuo (400 ml). Subsequently, toluene (300 ml) is added and the phases are separated. The aqueous phase is washed with toluene (twice 150 ml), then the combined organic phases are extracted again with 1N sodium hydroxide solution (50 ml). The pH of the combined aqueous phases is adjusted to 7.5 with 2N hydrochloric acid (ca. 150 ml), then MIBK (150 ml) is added. The phases are separated, the aqueous phases are extracted again with MIBK (150 ml), then the combined MIBK phases are dried over sodium sulphate and concentrated at 45° C. A total of 64 g of (±)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid are obtained in quantitative yield as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1COCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:32])=[CH:26][CH:25]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4ccc(Cl)cc4)c3)c2cc1OC
Temperature: 80 °C

Procedure:
In a sealed reaction vessel, 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (100 mg, 0.34 mmol) was dissolved in 10 mL of dry THF. To this solution was added 4-chlorophenyl isocyanate (61 mg, 0.4 mmol). The reaction was heated to 80° C. for 2 hours. The solution was then concentrated to dryness and purified by silica gel chromatography eluting with an ethyl acetate/dichloromethane gradient 5-30% over 16 column volumes. The major peak was concentrated and recrystallized with ethyl acetate/hexanes, and the solid collected by vacuum filtration to give 26.53 mg. 1H (DMSO-d6) 8.9 (m, 2H), 8.5 (s, 1H), 7.8-7.2 (m, 9H), 6.9 (m, 1H), 4.1 (s, 6H) LCMS (ESI) m/z 515 (M+H)
Reaction SMILES: C(O[C:9](=O)[NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:39])[CH2:20][C:21](=[O:38])[NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[CH:24]=1)[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])C1C=CC=CC=1.[CH3:41][C:42]1[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][C:43]=1C=O.C([BH3-])#N.[Na+]>CO.[Pd]>[CH3:41][C:42]1[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][C:43]=1[CH2:9][NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:39])[CH2:20][C:21]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[C:25]([C:33](=[O:37])[N:34]([CH3:35])[CH3:36])[CH:24]=1)=[O:38])[C@@H:13]([OH:17])[CH2:14][CH2:15][CH3:16]
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CC(=O)Nc1cc(C(=O)N(C)C)cc(C(F)(F)F)c1
Reactant: Cc1ccc(C=O)c(C)c1
Agent: [Pd]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)NC(=O)CC(=O)Nc1cc(C(=O)N(C)C)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of {(2S,3S)-2-[2-(3-dimethylcarbamoyl-5-trifluoromethyl-phenylcarbamoyl)-acetylamino]-3-hydroxy-hex-4-ynyl}-carbamic acid benzyl ester (186 mg, 0.33 mmol) in MeOH (6 mL) was charged with 5% Pd/C, Degussa style (37 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (6 mL). The resultant solution was charged sequentially with 2,4-dimethylbenzaldehyde (46 mg, 0.33 mmol) and sodium cyanoborohydride (25 mg, 0.4 mmol), stirred for 12 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=551.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:38][CH3:39])[C:17]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([C:24](=[O:37])[N:25]([CH3:36])[N:26]4C(OC(C)(C)C)=O)=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:38][CH3:39])[C:17]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([C:24](=[O:37])[N:25]([CH3:36])[NH:26]4)=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)Nc1ccc2c(=O)n(C)n(C(=O)OC(C)(C)C)c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CCC(C(=O)Nc1ccc2c(=O)n(C)[nH]c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
112 mg (0.19 mmol) of tert-butyl 6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (racemate) were hydrolysed with TFA according to General Method 2. Yield: 34 mg (35% of theory)
Reaction SMILES: [Cl: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](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:23])=O>O1CCCC1>[Cl: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]([Cl:23])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-3-(trifluoromethyl)benzoic acid (5.26 g, 23.4 mmol) in tetrahydrofuran (50 mL) were added N,N-dimethylformamide (40 μL) and oxalyl chloride (2.8 mL, 31.9 mmol), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give 2-chloro-3-(trifluoromethyl)benzoyl chloride. To a solution of 5-amino-2-methylphenol (2.62 g, 21.2 mmol) in tetrahydrofuran (20 mL) was added water (30 mL) in which sodium hydrogen carbonate (2.68 g, 31.9 mmol) has been suspended, and the mixture was vigorously stirred at room temperature. To the mixture was added dropwise a solution of 2-chloro-3-(trifluoromethyl)benzoyl chloride produced above in tetrahydrofuran (30 mL) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The aqueous layer of the reaction mixture was separated, and the organic layer was diluted with ethyl acetate, and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, and filtered through a pad filled with silica gel. The solvent was concentrated under reduced pressure, and the obtained solid was washed with a mixed solvent of ethyl acetate and hexane to give the title compound (6.37 g, 91%) as a pale-brown powder. The obtained compound was used for the next reaction without further purification operation.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[C:10]([S:11](Cl)(=[O:13])=[O:12])[C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl.[NH2:16][CH2:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])[OH:19]>>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[CH:18]([OH:19])[CH2:17][NH:16][S:11]([C:10]1[C:6]2[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:7]=2[S:8][CH:9]=1)(=[O:13])=[O:12]
Reactant: NCC(O)c1ccc(F)cc1F
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Agent: Cl
Product: O=C1CCCc2c(S(=O)(=O)NCC(O)c3ccc(F)cc3F)csc21

Procedure:
From 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (280 mg) and 2-amino-1-(2,4-difluorophenyl)-ethanol hydrochloride (the compound of Preparation Example 20) (281 mg), the title compound (290 mg) was obtained as a colorless solid, in the same way as Preparation Example 41.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:24][CH2:25][CH3:26])=[C:4]([CH:12]=[CH:13][C:14]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11].[C:27](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(=O)CC>[OH:1][C:2]1[C:3]([CH2:24][CH2:25][CH3:26])=[C:4]([CH:12]=[CH:13][C:14]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:27])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11]
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(OCCCCC#N)ccc(C(=O)c2ccccc2O)c1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCC#N)ccc(C(=O)c2ccccc2OC)c1O
Temperature: 25 °C
Yield: 84.3 %

Procedure:
Five grams of 5-[3-hydroxy-4-(2-hydroxybenzoyl)-2-propylphenoxy]pentanenitrile, 11.7 g of potassium carbonate, and 1.42 ml of dimethyl sulfate in 50 ml of 2-butanone were stirred at reflux for approximately 18 hours. After cooling to 25° C., the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with one volume of water and one volume of a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated to dryness leaving a yellow oil which crystallized on standing. Recrystallization from ethyl acetate/hexane provided 4.38 g of the desired title product, m.p. 85°-86.5° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:43])[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH:41]=O)=[CH:33][CH:32]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:41][C:34]3[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:31]([N:30]([CH3:29])[CH3:43])=[CH:32][CH:33]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Product: CN(C)c1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c2ccccc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-dimethylamino-naphthalene-1-carbaldehyde according to the procedure of Example 66. MS (ESI) m/z 562.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:21]([O:24][CH2:25][C:26]1[C:27]([N:41]2[CH2:52][CH2:51][N:50]3[C:43](=[CH:44][C:45]4[CH2:46][C:47]([CH3:54])([CH3:53])[CH2:48][C:49]=43)[C:42]2=[O:55])=[N:28][CH:29]=[CH:30][C:31]=1B1OC(C)(C)C(C)(C)O1)(=[O:23])[CH3:22].CC(O[Na])=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:21]([O:24][CH2:25][C:26]1[C:27]([N:41]2[CH2:52][CH2:51][N:50]3[C:43](=[CH:44][C:45]4[CH2:46][C:47]([CH3:54])([CH3:53])[CH2:48][C:49]=43)[C:42]2=[O:55])=[N:28][CH:29]=[CH:30][C:31]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:23])[CH3:22]
Reactant: Cn1cc(Br)cc(Nc2ccc(C(F)(F)F)nn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[Na]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(F)(F)F)nn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 23.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 301b (300 mg, 0.86 mmol), (2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetate 199e (824 mg, 1.72 mmol), CH3COONa (140 mg, 1.72 mmol), PdCl2(dppf) (70 mg, 0.086 mmol), K3PO4 (360 mg, 1.72 mmol), acetonitrile (20 mL), and water (0.5 mL). After bubbling nitrogen through the resulting mixture for 20 minutes, it was heated at 100° C. under nitrogen atmosphere for 2 h. The mixture was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 301c as white solid (125 mg, 23%). MS-ESI: [M+H]+ 622.3