Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]([C:7]1[C:12]([NH2:13])=[CH:11][C:10]([O:14][CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1)=[O:6].[CH:18](OCC)=O.Cl>O.O1CCCC1>[CH3:17][O:16][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[O:14][CH3:15])[N:13]=[CH:18][CH2:4][C:5]2=[O:6]
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Reactant: CCOC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(=O)CC=N2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
Tetrahydrofuran (THF) (5.3 L) and sodium methoxide (313 g) were added to 2-amino-4,5-dimethoxyacetophenone (337 g), and the mixture was stirred at 20° C. for 30 min. Ethyl formate (858 g) was added to the reaction solution at 0° C., and the mixture was stirred at 20° C. for one hr. Water (480 mL) was added thereto at 0° C., and the mixture was neutralized with 1 N hydrochloric acid. The resultant precipitate was collected by filtration, and the filtered product was slurried in water (2 L) for washing. The slurry was filtered, and the filtered product was then dried under the reduced pressure to give 6,7-dimethoxy-4-quinolone (352 g, yield 81.50%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]2[CH:13]=[CH:14][N:15]=[C:9]2[CH:8]=1.C1C(=O)N([I:23])C(=O)C1>C(O)C.C(OCC)(=O)C>[I:23][C:13]1[N:10]2[CH:11]=[CH:12][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][C:9]2=[N:15][CH:14]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(-c2ccn3ccnc3c2)nc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Ic1cnc2cc(-c3ccccn3)ccn12
Yield: 83 %

Procedure:
Dissolve 7-pyridin-2-yl-imidazo[1,2-a]pyridine (0.3 g, 1.5 mmol) in absolute ethanol (10 mL) and add NIS (0.35 g, 1 equiv.). Heat the reaction to 50° C. for 30 minutes under N2 then dilute with ethyl acetate. Wash the organic layer with 1 N NaOH followed by sat NaCl. Dry the organic layer over magnesium sulfate, filter and concentrate to give a light tan solid (0.4 g, 82%). MS (ES), m/z 322 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=O)=[CH:7]2)([O-:3])=[O:2].CN(C)CCCN=C=NCC.Cl.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C1C=CN=CC=1.ClCCl.CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:15])=[CH:7]2)([O-:3])=[O:2]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.44 g (26.39 mmol) of 5-nitro-1H-indole-2-carboxylic acid from Example XLVII, 7.59 g (39.58 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×HCl and 1.61 g (13.19 mmol) of 4-dimethylaminopyridine are initially charged in 400 ml of a 10:1 dichloromethane:DMF mixture. 2.95 g (2.89 ml, 31.67 mmol) of aniline are added, and the mixture is stirred at RT overnight. For work-up, the mixture is diluted and extracted with aqueous hydrochloric acid and dichloromethane. The organic phase is washed with sat. sodium chloride solution, dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][OH:17]>F[B-](F)(F)F.C[N+](C)(C)C>[C:1]([N:9]1[CH:14]([O:17][CH3:16])[CH2:13][CH2:12][CH2:11][CH:10]1[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCCCN1C(=O)c1ccccc1
Reactant: CO
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Product: COC1CCCC(C)N1C(=O)c1ccccc1
Yield: 77.6 %

Procedure:
In the same manner as in Example 5, there are electrolyzed 43.8 g of 1-benzoyl-2-methylpiperidine and 60.2 g of methanol in the presence of 0.3 g of tetramethylammonium tetrafluoroborate as conducting salt. After throughput of 2.5 Faraday per mol of 1-benzoyl-2-methylpiperidine the current is switched off. After work-up of the electrolysis solution, 39.0 g of 1-benzoyl-2-methyl-6-methoxypiperidine (boiling point 78°-81° C./0.1 mm Hg; nD25 =1.5340) are obtained which corresponds to a product yield of 77.5% and a current efficiency of 62.0%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:28])=[N:4][C:5]([CH3:27])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[CH:12][CH:11]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([NH:1][C:2]1[C:3]([CH3:28])=[N:4][C:5]([CH3:27])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[CH:14][CH:15]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(N)c(C)n1
Solvent: c1ccncc1
Product: CC(=O)Nc1c(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)cc(C)nc1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of 100 mg of the compound obtained in Example 69 placed in 2 ml of pyridine was added 1 ml of acetic anhydride, followed by stirring at 60° C. for three hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (8 g, chloroform:methanol=2:1), whereby 95 mg of a colorless powder of the title compound was obtained (yield: 86%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([NH:51][C:52]([NH:56][CH3:57])=[N:53][C:54]#[N:55])[CH:48]=[C:49]([Cl:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3].Cl>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[CH:46]=[C:47]([NH:51][C:52]([NH:56][CH3:57])=[N:53][C:54]#[N:55])[CH:48]=[C:49]([Cl:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(Cl)cc(NC(=NC#N)NC)cc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Product: CCCc1nc2c(Cl)cc(NC(=NC#N)NC)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 4d from 4'-[(2-n-propyl-4-chloro-6-(2-cyano-3-methyl-guanidino)-1H-benzimidazol-1-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl and methanolic hydrochloric acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:28])[C@@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O)(CC)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:9][O:8][C:5]1[C:4]([NH:10][C:11](=[O:28])[C@@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:3][C:2]([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)=[CH:7][N:6]=1
Reactant: COc1ncc(Br)cc1NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: COc1ncc(-c2cn[nH]c2)cc1NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-tert-butyl 1-(5-bromo-2-methoxypyridin-3-ylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 15.1.B (1.00 g, 2.22 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole (0.52 g, 2.66 mmol, available from Aldrich) in t-amyl alcohol (20 mL) was added K3PO4 (1.41 g, 6.66 mmol), Pd2(dba)3 (102 mg, 0.111 mmol) and XPhos (212 mg, 0.444 mmol). The mixture was stirred for 4 hours at 100° C. and then was filtered over celite. The organic phase was concentrated and purified by flash chromatography on silica gel to afford tert-butyl (S)-1-(2-methoxy-5-(1H-pyrazol-4-yl)pyridin-3-ylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 15.1.C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[C:12]1([CH:22]=O)[C:21]2[C:15]([CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:14][CH:13]=1.N1CCCC1>C(O)C>[C:12]1(/[CH:22]=[C:7]2\[C:8](=[O:11])[NH:9][C:10]3[C:6]\2=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[C:21]2[C:15]([CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:14][CH:13]=1
Reactant: O=C1Cc2cccc(Cl)c2N1
Reactant: O=Cc1ccc2cccccc1-2
Solvent: CCO
Solvent: C1CCNC1
Product: O=C1Nc2c(Cl)cccc2/C1=C/c1ccc2cccccc1-2
Yield: 57.5 %

Procedure:
0.3519 g 7-chlorooxindole (0.0021 mole) and 0.323 g azulene aldehyde (0.0021 mole) were dissolved in 30 mL dried ethanol. 1.5 mL pyrrolidine (1M) was then added and uniformly stirred at reflux temperature for two hours. After removal of dried ethanol, the results were extracted by dichloromethane and citric acid aqueous solution. The organic layer was collected, dried with anhydrous magnesium sulfate, filtered, concentrated under vacuum, and separated by silica gel column chromatography to give Z-form Compound 042 (0.3693 g). The total weight of 7-chlorooxindole-azulene was 0.3693 g (57.56%).
Reaction SMILES: [H-].[Na+].[Br-].[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:6])=[O:5].[CH3:30][C:31]1([CH3:59])[CH2:36][O:35][C:34]2([CH2:40][CH2:39][CH:38](/[CH:41]=[CH:42]/[CH:43]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[CH:37]2[CH2:56][CH:57]=O)[O:33][CH2:32]1.S([O-])(O)(=O)=O.[Na+].[Cl-].[Na+]>CS(C)=O.C(OCC)C>[CH3:59][C:31]1([CH3:30])[CH2:36][O:35][C:34]2([CH2:40][CH2:39][CH:38](/[CH:41]=[CH:42]/[CH:43]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[CH:37]2[CH2:56]/[CH:57]=[CH:10]\[CH2:9][CH2:8][CH2:7][C:4]([OH:6])=[O:5])[O:33][CH2:32]1
Reactant: CCCCCC(/C=C/C1CCC2(OCC(C)(C)CO2)C1CC=O)OC1CCCCO1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [Br-]
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCCCCC(/C=C/C1CCC2(OCC(C)(C)CO2)C1C/C=C\CCCC(=O)O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
640 mg of 80 % sodium hydride and 6 ml of dimethyl sulfoxide were heated for 1 hour to 65° C and, after cooling to room temperature, 4.7 g of 4-carboxybutyl-triphenylphosphonium-bromide in 8 ml of dimethylsulfoxide under argon were added and stirred for 20 minutes. To the red solution, 1.7 g of [3,3-dimethyl-8-[3-pentyl-3-tetra-hydropyranyloxy-trans-1-propenyl]-1,5-dioxaspiro-[5,4]-dec-7-yl]-acetaldehyde in 4 ml of dimethylsulfoxide were added dropwise and stirred for 15 hours at room temperature. 5% sodium hydrogen sulfate solution was added to that solution until pH 1 was reached, 50 ml of saturated sodium chloride solution were added and the mixture was esterified 3 times with 200 ml of diethyl ether, the combined organic phases were washed with water, dried and condensed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:15][C:14]=2[CH:28]=1>>[Cl:9][C:10]1[C:11]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:21])([F:20])[F:22])[C:16]([C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Sc3ccc(Cl)cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-chlorobenzenethiol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 251.7–253.3° C. 1H NMR (acetone-d6/300 MHz) 7.86 (s, 1H), 7.62 (m, SH), 6.39 (s, 1H), 5.78 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=6.5 Hz). ESLRMS m/z 419 (M−H). ESHRMS m/z 418.9559 (M−H, Calc'd 418.9523). Anal. Calc'd for C17H9Cl2F3O3S: C, 48.47; H, 2.15; Cl, 16.83; S, 7.61. Found: C, 48.38; H, 2.12; Cl, 17.09; S, 7.75.
Reaction SMILES: [N+:1]1([O-])[C:2]([C:10]([OH:12])=[O:11])=[CH:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:9][C:7]([C:6]1[N:1]=[C:2]([C:10]([OH:12])=[O:11])[CH:3]=[CH:4][CH:5]=1)=[O:8]
Reactant: CO
Reactant: O=C(O)c1cccc(C(=O)O)[n+]1[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C(=O)O)n1

Procedure:
40 g of the pyridine-2,6-dicarboxylic acid N-oxide was dissolved in 100 ml of methanol. 5 ml of sulfuric acid was added to the solution. The admixture was then heated under reflux for 2 hours and allowed, to cool so that crystals were deposited. The crystals thus deposited were filtered to obtain 28 g of 6-methoxycarbonylpyridine-2-carboxylic acid.
Reaction SMILES: [O:1]1[C:7]2([CH3:8])[CH:2]1[C:3]([O:5][C:6]2([CH3:10])[CH3:9])=[O:4].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13]>>[C:11]([O:1][C:7]1([CH3:8])[C:6]([CH3:9])([CH3:10])[O:5][C:3](=[O:4])[CH2:2]1)(=[O:14])[CH:12]=[CH2:13]
Reactant: CC1(C)OC(=O)C2OC21C
Reactant: C=CC(=O)Cl
Product: C=CC(=O)OC1(C)CC(=O)OC1(C)C
Yield: 85 %

Procedure:
The above-prepared 3-hydroxy-3,4,4-trimethyl-γ-butyrolactone was allowed to react with acryloyl chloride in a similar manner to that in Production Example 22 to thereby yield the title compound in a yield of 85%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]3[N:11]=[CH:12][CH:13]=[N:14][C:8]=3[N:7]([CH2:15][O:16][CH3:17])[C:6]=2[CH:18]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(OCC)(=O)C>[CH3:17][O:16][CH2:15][N:7]1[C:6]2[CH:18]=[C:2]([NH:1][C:19](=[O:21])[CH3:20])[CH:3]=[CH:4][C:5]=2[S:10][C:9]2[N:11]=[CH:12][CH:13]=[N:14][C:8]1=2
Reactant: CC(=O)OC(C)=O
Reactant: COCN1c2cc(N)ccc2Sc2nccnc21
Solvent: CCOC(C)=O
Product: COCN1c2cc(NC(C)=O)ccc2Sc2nccnc21

Procedure:
200 mg of 8-amino-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was suspended in 10 ml of ethyl acetate. After adding 1 ml of acetic anhydride, the reaction mixture was subjected to ultrasonication. The crystals thus precipitated were filtered and washed with diethyl ether to thereby give 206 mg of the title compound as yellow crystals.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][C:19]3[CH:24]=[C:23]([O:25]CC4C=CC=CC=4)[C:22]([CH3:33])=[CH:21][C:20]=3[F:34])=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:35][CH3:36])(=[O:3])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][C:19]3[CH:24]=[C:23]([OH:25])[C:22]([CH3:33])=[CH:21][C:20]=3[F:34])=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:35][CH3:36])(=[O:3])[CH3:2]
Reactant: COc1cc2c(Nc3cc(OCc4ccccc4)c(C)cc3F)ncnc2cc1OCCOC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCCOC(C)=O
Yield: 14.8 %

Procedure:
A mixture of 7-(2-acetoxyethoxy)-4-(5-benzyloxy-2-fluoro-4-methylanilino)-6-methoxyquinazoline (133 mg, 0.27 mmol) and 10% palladium-on-charcoal catalyst (50 mg) in ethyl acetate (8 ml) was stirred under 1 atmosphere of hydrogen at ambient temperature for 18 hours. The catalyst was removed by filtration through diatomaceous earth and most of the solvent removed by evaporation and hexane added to the residue. The resulting precipitated product was collected by filtration and dried to give 7-(2-acetoxyethoxy)-4-(2-fluoro-5-hydroxy4-methylanilino)-6-methoxyquinazoline (16 mg, 15%).
Reaction SMILES: FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1.C1C(O)=CC=CC=1C.C([N:31]([CH2:39][C:40]1[S:44][C:43]([C:45]([NH:47][C@H:48]([C:63]([OH:65])=[O:64])[CH2:49][CH2:50][CH2:51][NH:52]C(OCC2C=CC=CC=2)=O)=[O:46])=[CH:42][CH:41]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)(OC(C)(C)C)=O>>[N:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][NH:31][CH2:39][C:40]1[S:44][C:43]([C:45]([NH:47][C@H:48]([C:63]([OH:65])=[O:64])[CH2:49][CH2:50][CH2:51][NH2:52])=[O:46])=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)O)s1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1cccc(O)c1
Product: NCCC[C@H](NC(=O)c1ccc(CNCc2ccccn2)s1)C(=O)O
Reaction time: 1.5 h
Yield: 53.3 %

Procedure:
A mixed solution of trifluoroacetic acid (1.4 ml), thioanisole (0.36 ml), and m-cresol (0.32 ml) was added to the compound obtained in Example 14-3 (56.2 mg). After 1.5 hours, the reaction solution was concentrated. Methanol was added to the residue and the mixture was washed with hexane. The methanol layer was concentrated and the residue was crude-purified by silica gel column chromatography (3 g, chloroform/methanol/water=7/3/0.5) to obtain the title compound (18.2 mg) as colorless syrup.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:24]=[C:25]([F:27])[CH:26]=1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:20][C:21]4[CH:22]=[C:23]([C:28]([F:29])([F:30])[F:31])[CH:24]=[C:25]([F:27])[CH:26]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc(C(F)(F)F)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-amino-5-fluorobenzotrifluoride were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-fluoro-5-trifluoromethylphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.75 (s, 1H), 9.32 (d, 1H, J=1.2 Hz), 8.13 (d, 1H, J=3.6 Hz), 7.99 (d, 1H, J=12.3 Hz), 7.77 (s, 1H), 7.21 (d, 1H, J=2.4 Hz), 7.13 (dd, 1H, J=2.1 and 8.7 Hz), 7.03 (d, 1H, J=9.0 Hz), 6.80 (d, 1H, J=8.7 Hz), 4.21 (s, 4H); LCMS: purity: 97%; MS (m/e): 425(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=3)[N:12]=[C:11]([C:23]([NH2:25])=O)[CH:10]=2)=[CH:5][CH:4]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=3)[N:12]=[C:11]([C:23]#[N:25])[CH:10]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(COc2cc(C(N)=O)nc3ccc(C(F)(F)F)cc23)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc(COc2cc(C#N)nc3ccc(C(F)(F)F)cc23)cc1
Reaction time: 2 h

Procedure:
A solution of 4-((4-methoxybenzyl)oxy)-6-(trifluoromethyl)quinoline-2-carboxamide (9 g, 24 mmol) from above step B, and TEA (10 mL, 72 mmol) was treated with trifluoroacetic anhydride (4.35 mL, 31.3 mmol) at room temperature and stirred for 2 h (completion of reaction monitored by LCMS). Solvent was removed under vacuum and the residue was purified by recrystallization from EtOAc/Hex to give the title compound.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([N:5]([CH2:15][CH:16]1[O:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:2]([F:1])([F:30])[C:3]([N:5]([CH2:15][CH:16]1[O:21][CH2:20][CH2:19][NH:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCOC(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N(CC1CNCCO1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
To a solution of tert-butyl 2-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido) methyl)morpholine-4-carboxylate (820 mg, 1.914 mmol) in dichloromethane (DCM) (8 mL) was added TFA (2 mL, 26.0 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was concentrated and the residue was treated with saturated NaHCO3 solution and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dried under vacuum to give 533 mg of product as colorless oil. MS: (M+H)+=329.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.28-1.83 (m, 2H), 2.40-2.98 (m, 5H), 3.45-3.95 (m, 5H),7.06-7.39 (m, 5H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>O1CCCC1>[C:3]([CH:2]([CH2:13][C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a solution of ethyl acetoacetate (10 g, 76.8 mmol) in tetrahydrofuran (50 ml) at 0° C. was added sodium hydride (4 g, 60% in mineral oil, 100 mmol) portionly. The reaction mixture was stirred for minutes, and 2-bromoacetophenone (16.8 g, 84.5 mmol) in tetrahydrofuran (20 ml) was added dropwisely. After warming the mixture to room temperature, it was stirred for 4 hours. The resulting solution was quenched with water and normal work-up accomplished with diethyl ether. The organic layer was dried with MgSO4, and purified by silica gel column chromatography (EtOAc:Hx=1:5) to produce desired compound (19 g, 98%) as light yellow color oil.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@H:11]([N:24]1[CH:28]=[C:27]([C:29]([O:31]C)=O)[N:26]=[CH:25]1)[CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:34]>CN(C=O)C>[CH2:1]([O:8][C@H:9]([C@H:11]([N:24]1[CH:28]=[C:27]([C:29]([NH2:34])=[O:31])[N:26]=[CH:25]1)[CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cn([C@H](CCc2cccc3ccccc23)[C@H](C)OCc2ccccc2)cn1
Agent: [OH-]
Solvent: CN(C)C=O
Product: C[C@H](OCc1ccccc1)[C@@H](CCc1cccc2ccccc12)n1cnc(C(N)=O)c1
Temperature: 100 °C
Yield: 93.3 %

Procedure:
A mixture of methyl 1-[(2S,3R)-2-benzyloxy-5-(1-naphthyl)-3-pentyl]imidazole-4-carboxylate (obtained in Example 3(20)) (160 mg) in ammonium hydroxide (10 ml) and DMF (5 ml) was heated at 100° C. for 8 h in a sealed tube and then concentrated in vacuo. Flash chromatography (dichloromethane:methanol=20:1) gave 1-[(2S,3R)-2-benzyloxy-5-(1-naphthyl)-3-pentyl]imidazole-4-carboxamide (144 mg, 93.3%) as an oil.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH:4](Cl)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.C(=O)([O-])[O-:16].[Ca+2].[OH-].[Na+].Cl>O.O1CCOCC1>[OH:16][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[C:3]([OH:2])=[O:14]
Reactant: COC(=O)C(Cl)Cc1ccc(C)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Ca+2]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(CC(O)C(=O)O)cc1
Temperature: 25 °C

Procedure:
A mechanically stirred suspension of 2-chloro-3-p-tolyl-propionic acid methyl ester (23 g, 0.1 mol), calcium carbonate (11 g, 0.1 mol), sodium hydroxide (5.5 g, 0.11 mol), 200 ml of dioxane and 300 ml of water is heated at reflux for 16 hours. After cooling to room temperature, 1.3 l of 2 N hydrochloric acid are added and the mixture is extracted with ethyl acetate. The combined organic layer is washed with brine, dried over magnesium sulfate and evaporated to yield 2-hydroxy-3-p-tolyl-propionic acid, which is sufficiently pure to be used in the next step.