Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:14])([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[S:4]1)[OH:2].[CH3:15][N:16]=[C:17]=[O:18]>>[CH3:15][NH:16][C:17]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:14])([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[S:4]1)=[O:18]
Reactant: CN=C=O
Reactant: CCCCCC1(C)SC(=NO)N=C1C
Product: CCCCCC1(C)SC(=NOC(=O)NC)N=C1C

Procedure:
2-oxo-4,5-dimethyl-5-pentyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4,5-dimethyl-5-pentyl-3-thiazoline-O-(methylcarbamoyl)-oxime as a viscous oil; nD44.5 =1.5256. The 2-oxo-4,5-dimethyl-5-pentyl-3-thiazoline-oxime starting material melts at 104°-106° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1ccc(F)cc1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(F)cc1
Yield: 70.9 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 4-fluorophenylboronic acid (available from Frontier Scientific, Inc.; 56 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-fluoro-biphenyl-2-carboxylic acid (63 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 13.18 (br s, 1H), 8.46 (s, 1H), 8.35 (d, J=8.5 Hz, 2H), 8.22 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.73-7.81 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.40-7.48 (m, 2H), 7.24-7.34 (m, 2H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:8]=[C:9]([CH2:13][OH:14])[CH:10]=[CH:11][CH:12]=1.O[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20].OC1C=C(C=CC=1)C(C1C=CC=CC=1)=O>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH2:13][O:14][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20]
Reactant: OCc1cccc(CC2OCCO2)c1
Reactant: O=Cc1cccc(O)c1
Agent: O=C(c1ccccc1)c1cccc(O)c1
Product: O=Cc1cccc(OCc2cccc(CC3OCCO3)c2)c1

Procedure:
The title compound was prepared as described in Example 22 with (3-((1,3-dioxolan-2-yl)methyl)phenyl)methanol and 3-hydroxybenzaldehyde replacing (4-((1,3-dioxolan-2-yl)methyl)phenyl)methanol and 3-hydroxybenzophenone, respectively, in Step 2.
Reaction SMILES: [CH3:1]CCCN1C(C(NC2C(C)=CC=CC=2C)=O)CCCC1.[CH3:22][NH:23][CH2:24][C@H:25]([OH:34])[C:26]1[CH:27]=[CH:28][C:29](O)=[C:30](O)[CH:31]=1>>[CH3:1][C@H:24]([NH:23][CH3:22])[C@H:25]([OH:34])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CNC[C@H](O)c1ccc(O)c(O)c1
Reactant: CCCCN1CCCCC1C(=O)Nc1c(C)cccc1C
Product: CN[C@@H](C)[C@H](O)c1ccccc1

Procedure:
Microspheres containing bupivacaine loaded to about 75 percent by weight with bupivacaine are prepared, in a percent loading of about 0.05 percent, by weight, using the methods described in EXAMPLES 1-3 or EXAMPLES 4-9, above. In addition, microspheres containing added epinephrine, in a percent loadings of 0.001 percent, 0.05 percent and 1 percent, without bupivacaine, are also prepared according to EXAMPLES 1-3 or EXAMPLES 4-9, above.
Reaction SMILES: [C:1]1([C@H](N)C)C=CC=CC=1.[OH:10][C:11]1[CH:23]=[CH:22][C:14]2[C@H:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:16][O:17][C:13]=2[CH:12]=1.S(=O)(=O)(O)O.CCCCCCC>CO.C1(C)C=CC=CC=1>[OH:10][C:11]1[CH:23]=[CH:22][C:14]2[C@H:15]([CH2:18][C:19]([O:21][CH3:1])=[O:20])[CH2:16][O:17][C:13]=2[CH:12]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C(O)C[C@@H]1COc2cc(O)ccc21
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: COC(=O)C[C@@H]1COc2cc(O)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a solution of [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetic acid (1R)-1-phenylethylamine salt (1.0 g) in methanol (3 mL)-toluene (8 mL) was added concentrated sulfuric acid (0.412 mg), and the mixture was stirred at 60° C. for 2 hr. The mixture was concentrated, toluene (5 mL) was added, and the mixture was concentrated again. To the residue were added toluene (5 mL), tetrahydrofuran (8 mL) and 1N hydrochloric acid (5 mL) to perform an extraction operation. The organic layer was washed with water, 5% aqueous sodium bicarbonate and water, and concentrated, and the residue was dissolved in toluene (8 mL). The activated carbon (100 mg) was added, and the mixture was stirred at room temperature for 30 min. After filtration, the filtrate was concentrated. The obtained crude product was dissolved in toluene (2 mL), seed crystal was added, and the mixture was stirred at room temperature for 16 hr. n-Heptane (6 mL) was added, and the mixture was stirred at room temperature for 5 hr and at 0° C. for 1 hr. The precipitated crystals were collected by filtration, and dried at 50° C. to give the title compound (554 mg) as white crystals. 99.7% ee.
Reaction SMILES: [Cl-].[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:10]=1)(=[O:4])[CH3:3].CC(C)([O-])C.[K+].[CH:37]([C:39]1[S:43][C:42]([C:44]([OH:46])=[O:45])=[CH:41][CH:40]=1)=O.O>CN(C)C=O>[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH:11]=[CH:37][C:39]2[S:43][C:42]([C:44]([OH:46])=[O:45])=[CH:41][CH:40]=2)[N:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)Nc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Reactant: O=Cc1ccc(C(=O)O)s1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C=Cc2ccc(C(=O)O)s2)cs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
To a solution of {[2-(acetylamino)-1,3-thiazol-4-yl]methyl}(triphenyl)phosphonium chloride (3.771 g, 8.325 mmol) in anhydrous N,N-dimethylformamide (35 ml) was added potassium tert-butoxide (2.515 g, 22.41 mmol) at 0° C., and the mixture was stirred for 15 min. 5-Formylthiophene-2-carboxylic acid (1.000 g, 6.404 mmol) was added by small portions, and the mixture was stirred at 0° C. for 30 min. The mixture was warmed to room temperature, stirred for 2 hr, and poured into iced water (300 ml). After stirring for 30 min, the mixture was washed twice with ethyl acetate. The aqueous layer was cooled to 0° C., and adjusted to pH 3 by dropwise addition of 6M hydrochloric acid. After stirring at 0-5° C. for 2 hr, the precipitated crystals were collected by filtration, washed 3 times with water, and twice with diisopropyl ether and dried under reduced pressure to give 5-{2-[2-(acetylamino)-1,3-thiazol-4-yl]vinyl}thiophene-2-carboxylic acid (1.104 g, 3.751 mmol, yield 58.6%) as a yellow ocher solid.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[OH:27][N:28]=[CH:29][C:30]1[N:31]2[CH:37]=[N:36][CH:35]=[C:32]2[S:33][CH:34]=1>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:36]3[CH:35]=[C:32]4[S:33][CH:34]=[C:30]([CH:29]=[N:28][OH:27])[N+:31]4=[CH:37]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: ON=Cc1csc2cncn12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(C=NO)[n+]4c3)[C@H](C)[C@H]12
Yield: 2.1 %

Procedure:
The same procedure as in Example 1 was repeated except that 102 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 70 mg of 3-(hydroxyimino)methylimidazo[5,1-b]thiazole were used, thereby obtaining 2.3 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:18]3[NH:22][C:21](=[O:23])[NH:20][N:19]=3)[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:4][CH:3]=1.CC1C=CC=C(C)N=1.[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>C(Cl)Cl>[C:32]([N:15]1[CH2:16][CH2:17][C@H:13]([O:12][C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[C:7]([C:18]3[NH:22][C:21](=[O:23])[NH:20][N:19]=3)[N:8]=2)[CH2:14]1)(=[O:35])[CH:33]=[CH2:34]
Reactant: C=CC(=O)Cl
Reactant: O=c1[nH]nc(-c2cc3ccc(F)cc3c(O[C@H]3CCNC3)n2)[nH]1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(F)cc23)C1
Temperature: -40 °C
Yield: 22.2 %

Procedure:
To (S)-3-(7-fluoro-1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5 (4H)-one (60 mg, 1.61 mmol) in DCM (10 mL) was added 2,6-dimethylpyridine (51 mg, 0.475 mmol). The mixture was cooled to −40° C. Acryloyl chloride (17 mg, 0.20 mmol) was added and the mixture was warmed to 0° C. over a 30 minute period. The reaction was subsequently quenched with MeOH (5 mL) and the mixture concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (16.4 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.06 (s, 1H), 11.82 (s, 1H), 8.17-8.13 (t, J=8 Hz, 1H), 8.05 (s, 1H), 7.88-7.85 (d, J=12 Hz, 1H), 7.78-7.76 (t, J=8 Hz, 1H), 6.50-6.70 (m, 1H), 6.19-6.13 (m, 2H), 5.73-5.67 (dd, J1=12 Hz, J2=4 Hz, 1H), 4.11-4.08 (m, 0.5H), 3.87-3.82 (m, 2H), 3.69-3.65 (m, 1.5H), 2.38-2.25 (m, 2H); ESI-MS m/z [M+H]+ 370.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[CH:7]=[C:6]([C:18]([O:20]CC)=[O:19])[C:5]2=[O:23]>Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:23]
Reactant: CCOC(=O)c1cn(CC(F)(F)F)c2c(C)cc(F)cc2c1=O
Agent: Cl
Product: Cc1cc(F)cc2c(=O)c(C(=O)O)cn(CC(F)(F)F)c12
Yield: 104.7 %

Procedure:
A mixture of 38.0 g of 6-fluoro-1,4-dihydro-8-methyl-4-oxo-1-(2,2,2-trifluoroethyl)-3-quinolinecarboxylic acid, ethyl ester and 800 ml of 6N hydrochloric acid was heated at reflux for 1.5 hours; the reaction mass was cooled, filtered, washed with water, and dried to give 36.4 g of 6-fluoro-1,4-dihydro-8-methyl-4-oxo-1-(2,2,2-trifluoroethyl)-3-quinolinecarboxylic acid, m.p. 221°-223°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[O:5][CH2:4]1.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH:22]=[N:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:34])[NH:29]2.C(OCC)C>C1COCC1.CCCCCC>[F:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH:22]([NH:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:34])[NH:29]2)[C:3]1([C:2]([F:7])([F:6])[F:1])[CH2:4][O:5]1
Reactant: COc1ccc(C=Nc2cccc3[nH]c(=O)ccc23)c(F)c1
Reactant: FC(F)(F)C1CO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C(Nc2cccc3[nH]c(=O)ccc23)C2(C(F)(F)F)CO2)c(F)c1
Temperature: -10 °C
Yield: 8.7 %

Procedure:
To 600 mg (3.9 mmol) 5-Amino-7-fluoro-1H-quinolin-2-one and 624 mg (3.9 mmol) 2-fluoro-4-methoxybenzaldehyde in 12 ml toluene are added 18 μl acetic acid and 2 g molecular sieve. The mixture is heated over 25 hours under reflux and filtrated through a path of cellites after cooling. The solvent is evaporated and the residue is two times azeotrophed with small portions of toluene to obtain 5-{[1-(2-fluoro-4-methoxyphenyl)-methylidene]amino}-1H-quinolin-2-one are quantitatively. 0.81 ml (11.6 mmol) 1,1,1-trifluoroepoxypropane in 12 ml THF and 3.5 ml hexane are cooled to −100° C. and 3.75 ml of a 2.5 M n-butyl lithium solution (9.4 mmol) in hexane are added over 10 minutes while the temperature does not exceed −95° C. 10 Minutes after complete addition 1.11 g (12 mmol) 5-{[1-(2-fluoro-4-methoxyphenyl)-methylidene]amino}-1H-quinolin-2-one in 10 ml THF are added over 15 minutes while the temperature does not exceed −95° C. After tree hours at −100° C. 3.75 ml diethyl ether are added and the reaction mixture is warmed to −10° C. over one hour. The reaction is quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer is extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (acetone in hexane 0 to 80%) yields 410 mg of 5-{[(2-Fluoro-4-methoxyphenyl)(2-trifluoromethyl-oxiranyl)methyl]amino}-1H-quinolin-2-one.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:13]2[C:9]([S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=32)=[N:8][CH:7]=1)=O)C.NC1SC2C=CC=CC=2N=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:8]1[CH:7]=[C:6]([CH2:4][OH:3])[N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[S:10][C:9]=12
Reactant: CCOC(=O)c1cnc2sc3ccccc3n12
Agent: Nc1nc2ccccc2s1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnc2sc3ccccc3n12
Yield: 74 %

Procedure:
A solution of imidazo[2,1-b]benzothiazole-3-carboxylic acid ethyl ester (Formula J-1), (synthesized from 2-aminobenzothiazole by a modification of the procedures described by Fajeli et al., Heterocycles, 1986, 24, 379) (4.5 g) in THF (75 mL) was treated with LiAlH4 (0.91 g) and reacted for 5.25 hours. The suspension was quenched by serial additions of water and 15% sodium hydroxide. The suspension was diluted with THF and filtered. The filtrate was evaporated, the residue was triturated with hexane to yield imidazo[2,1-b]benzothiazole-3-methanol (Formula J-2) (2.77 g, 74%). Crude imidazo[2,1-b]benzothiazole-3-methanol (Formula J-2) was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([CH3:10])[N:3]=1.[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[C:15]([O:14][C:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([CH3:10])[N:3]=1)=[O:11])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1nc(N)ccc1C#N
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)OC(C)(C)C)ccc1C#N
Reaction time: 3 h

Procedure:
A mixture of 2-amino-5-cyano-6-methylpyridine (10.0 g, 75.1 mmol), (BOC)2O (16.39 g, 75.1 mmol), triethylamine (11.5 ml, 82.6 mmol) and DMAP (0.92 g, 7.5 mmol) in methylene chloride (200 ml) was stirred for 3 h. More triethylamine (4.22 ml) and (BOC2)O (1.64 g) were added and after 16 h the reaction was diluted with ethyl acetate and was washed with 1 M AcOH (3 times), dried (Na2SO4) and evaporated in vacuo to give dark brown solid. The crude product was purified by flash column chromatography (10% ethylacetate/hexanes) to give the title compound as a white solid:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[CH:24][C:25]=3[F:27])[N:20]=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:18]=2[CH3:35])[C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]([CH3:15])([CH3:14])[CH2:9]2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+].[NH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1>C1(C)C=CC=CC=1.O.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]>[CH3:14][C:10]1([CH3:15])[O:11][CH2:12][CH2:13][N:8]([C:5]2[C:4]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([F:28])=[CH:24][C:25]=4[F:27])[N:20]=[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:18]=3[CH3:35])=[CH:3][C:2]([N:76]3[CH2:81][CH2:80][O:79][CH2:78][CH2:77]3)=[CH:7][N:6]=2)[CH2:9]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Br)cnc1N1CCOC(C)(C)C1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOC(C)(C)C1
Temperature: 100 °C
Reaction time: 21 h

Procedure:
A stirred mixture of N-(5-bromo-2-(2,2-dimethylmorpholino)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.061 g, 0.11 mmol), 2-dicyclohexylphosphino-2′,4′,6′,-tri-i-propyl-1,1′-biphenyl (0.011 g, 0.023 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.011 g, 0.012 mmol), and sodium tert-butoxide (0.034 g, 0.35 mmol) in dry toluene (1.0 mL) was purged three times with argon and placed under vacuum three times. Before heating, morpholine (0.05 mL, 0.57 mmol) was added via syringe, then the mixture was heated to 100° C. After 21 h, the reaction was cooled to rt, then diluted with water and extracted three times with EtOAc. The organic extractions were combined and washed twice with brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. After dissolving in MeOH then syringe filtration, the mixture was purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were concentrated then diluted with EtOAc. After washing twice with satd aq. sodium carbonate solution and once with brine, the solvent was removed under reduced pressure to yield N-(2-(2,2-dimethyl-4-morpholinyl)-5-(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, MeOH) δ ppm 8.71 (1H, d, J=5.1 Hz), 8.06 (1H, td, J=7.7, 1.8 Hz), 7.84 (1H, d, J=7.8 Hz), 7.64 (3H, m), 7.29 (1H, ddd, J=13.7, 9.0, 2.3 Hz), 6.53 (1H, d, J=2.7 Hz), 4.03 (7H, m), 3.16 (7H, m), 2.10 (3H, s), 1.41 (6H, m). Mass Spectrum ESI (pos.) m/e: 547.3 (M+H)+.
Reaction SMILES: Cl.C[O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH2:15]([C:19]1[N:20]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])[C:21]([CH2:30][C:31](O)=[O:32])=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:23]=1)[CH2:16][CH2:17][CH3:18].ClC1C=CC=CC=1CN1C(C(O)=O)=CN=C1SCCC>>[CH2:15]([C:19]1[N:20]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])[C:21]([CH2:30][C:31]([NH:6][C@H:5]([C:4]([OH:3])=[O:14])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:32])=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:23]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCc1nc(-c2ccccc2)c(CC(=O)O)n1Cc1ccccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CCCSc1ncc(C(=O)O)n1Cc1ccccc1Cl
Agent: Cl
Product: CCCCc1nc(-c2ccccc2)c(CC(=O)N[C@@H](Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl

Procedure:
The title compound is prepared following the procedure of Example 1-(iii-iv) using phenylalanine methyl ester hydrochloride in place of glycine methyl ester hydrochloride and using 2-[n-butyl-1-(2-chlorophenyl)methyl-4-phenyl-1H-imidazol-5-yl]acetic acid (prepared as in U.S. Pat. No. 4,340,598) in place of 1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazole-5 carboxylic acid.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[NH2:8][C:9]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].N1C=CC=CC=1.O>ClCCl>[Br:19][C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([NH:8][C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])[CH:18]=1
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)cc1NC(=O)OC(C)C
Reaction time: 5.5 h
Yield: 96.4 %

Procedure:
Add isopropyl chloroformate (104 mL, 104 mmol, 1.0 M in toluene) dropwise to a solution of methyl 2-amino-4-bromobenzoate (14.5 g, 63.0 mmol) and pyridine (10.3 mL, 126.0 mmol) in dichloromethane (210 mL) at room temperature under nitrogen and stir for 5.5 h. Pour the reaction into water (500 mL) and separate the layers. Extract the aqueous layer with dichloromethane (2×100 mL) and combine the organic extracts and wash with 2 N HCl, saturated sodium bicarbonate and brine (100 mL each), then dry over sodium sulfate, filter and remove the solvent under reduced pressure to afford the title compound as a pale orange solid (19.2 g, 96%)
Reaction SMILES: [CH:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:16]([OH:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH3:29].ClCCl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>CCCCCC>[CH:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:1]([O:30][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:15])[CH3:2]
Reactant: CCCCC=CCCCCCCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: CCCCC=CCCCCCCCC=O
Agent: c1cc[nH+]cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCC=CCCCCCCCCOC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
A 2/1 trans to cis ratio of 9-tetradecenal was evaluated in the same manner as was used in the preceding example. The 9-tetradecenal was prepared from 9-tetradecenyl alcohol prepared in the same manner as described in the preceding example. About 21 grams of the alcohol in a 50/50 weight ratio selection of dichloromethane was added dropwise to a flask charged with 43 g (0.2 mol) pyridinium chlorochromate, 20 g celite and 200 mL dichloromethane. The mixture was stirred at room temperature for about 2 hours after addition of the alcohol solution was complete. Then 200 mL of hexane was added and the mixture was filtered. The solvent was evaporated and the product vacuum distilled through a 2 ft.×3/4 in. packed column (Penn State stainless steel packing). A 36% yield of pure 9-tetradecenyl acetate was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[N:9]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C>CC(O)CC>[CH2:18]([O:17][C:15]([N:9]1[CH2:14][CH2:13][N:12]([C:2]2[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=2)[CH2:11][CH2:10]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1cc(Cl)nc[nH]1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)O
Product: O=C(OCc1ccccc1)N1CCN(c2cc(=O)[nH]cn2)CC1
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A mixture of 6-chloro-3H-pyrimidin-4-one (36984-063-A; 3.90 g, 29.9 mmol), benzyl 1-piperaz-inecarboxylate (Aldrich; 8.81 g, 40.0 mmol), and diisopropylethylamine (7.0 mL, 40.2 mmol) in 2-butanol (100 mL) was heated in a 250 mL round-bottomed flask equipped with a reflux condenser in an oil-bath at about 80° C. (oil-bath temperature) for 8 hours. The heating bath was removed and the reaction mixture was left standing at room temperature overnight. The white solid was filtered off, washed with 2-butanol, and air-dried to give 4-(6-oxo-1,6-dihydro-pyrimidin-4-yl)-piperazine-1-carboxylic acid benzyl ester (7.76 g, 83%) as a white powder, mp 247-249° C. 1H NMR (d6-DMSO) δ 1.39 (s, 9H), 3.45-3.50 (m, 8H), 5.08 (s, 2H), 5.26 (s, 1H), 7.28-7.38 (m, 5H), 7.90 (s, 1H), 11.66 (br s, 1H).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[C:9]1([CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCC>[OH-].[Na+].O.C1C=CC=CC=1>[C:9]1([CH2:15][CH2:16][CH2:17][C:18]([N:1]2[CH2:8][CH2:7][CH2:6][C@@H:2]2[C:3]([OH:5])=[O:4])=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)[C@H]1CCCN1
Reactant: O=C(Cl)CCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Solvent: CCCCCC
Product: O=C(O)[C@H]1CCCN1C(=O)CCCc1ccccc1
Yield: 67.4 %

Procedure:
3.45 g of D-proline was dissolved in 60 ml of 1N of sodium hydroxide and 30 ml of water. To the solution thus obtained, a solution prepared by dissolving 5.56 g of 4-phenylbutanoyl chloride in 30 ml of benzene was added dropwise with stirring. Subsequently, 30 ml of 1N sodium hydroxide was further added and the mixture was stirred at room temperature overnight. The benzene layer was removed and the water layer was washed twice with 50 ml of ether. To this water layer was added 7% hydrochloric acid to acidify it, followed by extraction with 70 ml of ethyl acetate three times. The extract was dried over anhydrous sodium sulfate. Ethyl acetate was evaporated to obtain an oily residue, which was treated with hexane to obtain 5.28 g of N-(4-phenylbutanoyl)-D-proline as colorless crystals.