Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH:12]([F:14])[F:13].C(N(CC)C(C)C)(C)C.Cl.Cl.[O:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]2)[CH2:28][CH2:27]1>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH:12]([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:38][CH:35]2[CH2:34][CH2:33][N:32]([CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)[CH2:37][CH2:36]2)[CH:7]=1
Reactant: NC1CCN(C2CCOCC2)CC1
Reactant: O=[N+]([O-])c1cc(C(F)F)c(Cl)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(C(F)F)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 70 °C
Yield: 95.1 %

Procedure:
A stirred solution of 1-chloro-2-(difluoromethyl)-5-fluoro-4-nitrobenzene (D96, 200 mg, 0.89 mmol) in dimethylformamide (4 ml) at room temperature under argon was treated with N,N-diisopropylethylamine (0.47 ml, 2.7 mmol), followed by 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine dihydrochloride (D40, 240 mg, 0.94 mmol) and then heated at 70° C. for 1.5 hrs. The reaction mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried and concentrated under vacuum to leave an orange solid. This was purified by chromatography on silica gel eluting with 0-20% methanol/ethyl acetate to afford the title compound as a yellow solid (330 mg, 96%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li:16])CCC.[S:17](=[O:19])=[O:18]>C(OCC)C.CCCCCC>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([S:17]([O-:19])=[O:18])=[CH:3][CH:4]=1.[Li+:16]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: [Li]CCCC
Reactant: O=S=O
Solvent: CCCCCC
Solvent: CCOCC
Product: O=S([O-])c1ccc(C(F)(F)F)cc1
Product: [Li+]
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-bromobenzotrifluoride (34.2 g.) in diethyl ether at -20° to -25°C. was added over 25 minutes 71 ml. of a 1.95 M solution of n-butyllithium in hexane. After stirring an additional 20 minutes at -20°C., a solution of 20 g. of sulfur dioxide in 50 ml. of diethyl ether was added over 10 minutes at -20° to -30°C. The suspension was allowed to come to room temperature over 45 minutes and the lithium p-trifluoromethylphenyl sulfinate was isolated by centrifugation. The solid was slurried with 200 ml. of diethyl ether and recentrifuged, collected and dried under vacuum. The product had m.p. 259.5°-264.5°C. and analyzed for 84% sulfinic acid salt.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([I:1])[C:3]=1[O:12][CH3:13])[CH:7]=[O:8]
Reactant: COc1cc(C=O)cc(I)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)cc(I)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
lodomethane (2.5 mL, 40 mmoles) was added to a mixture of 5-iodovanillin (10 g, 36 mmoles), potassium carbonate (25 g, 180 mmoles) in DMF (100 ml) and the resulting mixture was stirred at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with water (200 mL), dried over MgSO4 and evaporated in vacuo to afford 9.78 g (93%) of 3,4-dimethoxy-5-iodobenzaldehyde, m.p. 58-63° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=O)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:32][CH:33]([CH3:36])[CH2:34][OH:35].CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl.CN(C=O)C>[OH:35][CH2:34][CH:33]([NH:32][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([C:18]2[CH:19]=[C:14]([NH:13][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])[N:12]=3)[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=2)[CH:21]=1)[CH3:36]
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Reactant: CC(N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(CO)NC(=O)c1cccc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 15.2 %

Procedure:
A mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (50 mg, 0.121 mmol), 2-aminopropan-1-ol (10 mg, 0.133 mmol), 1-methyl-1H-imidazole (40 mg, 0.484 mmol) and EDCI (92 mg, 0.484 mmol) in dichloromethane (10 mL) and DMF (0.2 mL) was stirred at room temperature for 20 h then extracted with ethyl acetate (50 mL) and washed with water (2×2 mL), then brine (2×2 mL). After drying and concentration, the residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, methanol:dichloromethane=1:50) and further purified by Prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 45% acetonitrile/55% water (0.1% TFA, v/v) in a linear fashion over 9 min) to afford N-(1-hydroxypropan-2-yl)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (8.7 mg, 14%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.91 (s, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.17-8.00 (m, 4 h), 7.65 (t, 1H, J=7.8 Hz), 7.58-7.55 (m, 1H), 6.40 (d, 1H, J=7.5 Hz), 6.28 (d, 1H, J=8.4 Hz), 4.25-4.21 (m, 2H), 3.71-3.58 (m, 3H), 3.54-3.48 (m, 1H), 2.19-2.07 (m, 3H), 1.81 (brs, 1H), 1.29 (d, 3H, J=6.3 Hz), 1.19 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 472, tR=1.654 min, HPLC: 99.36% at 214 nm, 98.85% at 254 nm, tR=5.697 min.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:26]([CH3:38])[CH:25]=3)([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][CH:8]=1.Cl>CO.O1CCCC1>[CH3:36][C:33]([CH3:34])([CH3:35])[C:32](=[O:37])[CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([OH:40])=[O:4])=[CH:12][CH:11]=3)=[C:14]([CH3:39])[CH:15]=2)([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:25][C:26]=1[CH3:38]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.296 mL, 0.296 mmol) was added to a solution of (4′-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 50-(1); 50.7 mg, 0.099 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at 60° C. for two hours. The reaction mixture was then poured into 0.5 N hydrochloric acid aqueous solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (43.3 mg, 87%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.F[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1>>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 1, react imidazole with 1-fluoro-4-nitrobenzene to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[CH3:9])=[CH:4][N:3]=1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.CC1(C)CCCC(C)(C)N1.C([Li])CCC>C1COCC1.O>[F:1][C:2]1[C:7]([B:18]([OH:23])[OH:19])=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=2)[CH3:9])=[CH:4][N:3]=1
Reactant: CSc1ccc(C(C)c2ccc(F)nc2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(C(C)c2cnc(F)c(B(O)O)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
2-Fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridine (1.078 g, 4.359 mmol) and triisopropyl borate (2.50 mL, 10.9 mmol) were dissolved in THF (11.5 mL). In a separate flask, 2,2,6,6-tetramethylpiperidine (1.11 mL, 6.54 mmol) was dissolved in THF (12 mL) and the flask was cooled in an ice water bath. Then, n-butyllithium solution (1.6 M in hexanes, 3.8 mL, 6.1 mmol) was added via syringe, and the yellow solution was stirred under nitrogen for 15 min. Then, the contents were transferred via syringe to the other flask, which was pre-cooled in a dry ice/acetone bath. After completing the transfer, the reaction was stirred under nitrogen at −78° C. for 1 h. Then, the reaction was allowed to slowly warm up to room temperature while being stirred overnight. The reaction was treated with water (30 mL) and stirred for about 30 min. The layers were separated, and the organic phase was extracted with 1 N aqueous NaOH (15 mL). The organic phase was discarded, and the aqueous phase was treated with aqueous 5N HCl to lower the pH to around 5-6. The aqueous phase was extracted with 10:1 DCM/MeOH. The extracts were combined, concentrated, and dried under high vacuum to afford 2-fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridin-3-ylboronic acid (1.2342 g). 1H NMR (400 MHz, CDCl3) δ 8.17-8.05 (m, 2H), 7.25-7.19 (m, 2H), 7.15-7.10 (m, 2H), 4.16 (q, J=7.37 Hz, 1H), 2.47 (s, 3H), 1.66 (d, J=7.24 Hz, 3H). m/z (ESI, +ve ion) 292 (M+H)+.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:59]1[C:42](=[CH:43][C:44]3[O:48][N:47]=[C:46]([CH2:49][C:50]4[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=4)[C:45]=3[CH:58]=1)[CH2:41][O:40]2)C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1.B(Cl)(Cl)Cl.CO>ClCCl>[CH2:56]([C:53]1[CH:54]=[CH:55][C:50]([CH2:49][C:46]2[C:45]3[CH:58]=[C:59]4[C@:10]5([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]5)[O:40][CH2:41][C:42]4=[CH:43][C:44]=3[O:48][N:47]=2)=[CH:51][CH:52]=1)[CH3:57]
Reactant: CCc1ccc(Cc2noc3cc4c(cc23)[C@]2(OC4)O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: Cc1cc(C)c(C)c(C)c1C
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc(Cc2noc3cc4c(cc23)[C@]2(OC4)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
(3′R,4′S,5S,5′S,6′R)-3′,4′,5′-tris-benzyloxy-6′-benzyloxymethyl-3-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydro-spiro[furo[3,4,f]benzoisoxazole-5(7H),2′-[2H]pyran] (86.9 mg, 0.110 mmol) was dissolved in dichloromethane (3.7 mL). Pentamethylbenzene (0.245 g, 1.65 mmol) was added thereto, and then this solution was cooled to −78° C. A solution of boron trichloride in dichloromethane (1.0 M, 0.55 mL) was added dropwise thereto. The resulting mixture was stirred for 2 hours, and then methanol (2.5 mL) was added thereto. The temperature of the mixture was raised to room temperature. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (developing solution=methanol:dichloromethane (1:12)), to thereby obtain the titled compound (23.0 mg, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][OH:39]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:37][CH2:38][OH:39])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol (compound 443) (50 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (54 mg) and 2-bromoethanol (0.03 ml) were added to the solution, and the mixture was stirred at 70° C. overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (29 mg, yield 51%).
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][NH:4][S:5]([C:8]1[CH:19]=[C:12]2[C:13]([O:15]C(=O)[NH:17][C:11]2=[CH:10][CH:9]=1)=[O:14])(=[O:7])=[O:6].[Cl:21]C1C=CC(S(Cl)(=O)=O)=CC=1C(O)=O>>[Cl:21][C:11]1[CH:10]=[CH:9][C:8]([S:5](=[O:7])(=[O:6])[NH:4][CH2:3][CH:2]([CH3:20])[CH3:1])=[CH:19][C:12]=1[C:13]([OH:15])=[O:14].[CH3:1][CH:2]([CH3:20])[CH2:3][NH:4][S:5]([C:8]1[CH:19]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([NH2:17])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CC(C)CNS(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Product: CC(C)CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CC(C)CNS(=O)(=O)c1ccc(N)c(C(=O)O)c1

Procedure:
5-[N-(2-Methylpropyl)-sulfamoyl]-isatoic anhydride, which is to be used as the starting material, can be obtained, for example, in a manner analogous to that described in Example 1, using 2-chloro-5-chlorosulfonylbenzoic acid as the starting material, the product being obtained via 2-chloro-5-[N-(2-methylpropyl)-sulfamoyl]-benzoic acid with a melting point of 163°-166° and 5-[N-(2-methylpropyl)-sulfamoyl]-anthranilic acid with a melting point of 203°-205°; the product melts at 270°-273°.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1.[H-].[Na+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O>CN(C)C=O>[CH2:12]([N:4]1[C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=[C:3]1[CH3:2])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cc1nc(C)c(C)[nH]1
Reactant: CCCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCn1c(C)nc(C)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dissolve 16.0 g (0.019 mole) of 2,4,5-trimethyl-1H-imidazole hydrochloride in 125 ml dry N,N-dimethylformamide and cool to 0° C. Add 8.75 g (0.218 mole) of sodium hydride (60%), stir at 0° C. for 30 minutes and then heat reaction mixture to 100° C. for one hour. Cool to 0° C. and then add 18.0 ml (0.114 mole) of n-heptyl bromide to reaction mixture. Upon completion of addition, heat to 100° C. for four hours, following the progress of the reaction by thin-layer chromatography on silica gel (methanol:1M sodium chloride, 95:5). At the completion of the reaction, cool to room temperature and add 2 ml water. Filter precipitated salts and evaporate solvent.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.CON(C)[C:17]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:26][CH:25]=[CH:24][C:23]=2[C:35]([F:38])([F:37])[F:36])=[O:18].Cl>C1COCC1.CO>[CH3:8][C:4]1[CH:3]=[C:2]([C:17]([C:19]2[CH:20]=[N:21][C:22]3[C:27]([C:28]=2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:26][CH:25]=[CH:24][C:23]=3[C:35]([F:38])([F:37])[F:36])=[O:18])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(C(=O)c2cnc3c(C(F)(F)F)cccc3c2-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
3-Bromotoluene (0.078 mL, 0.64 mmol) was taken into THF (3 mL) and cooled to −78° C. Next, BuLi (0.32 mL of a 2.0 M Solution, 0.64 mmol) was added dropwise and then stirred for 30 minutes. Next, N-methoxy-N-methyl-4-phenyl-8-(trifluoromethyl)quinoline-3-carboxamide (0.231 g, 0.64 mmol) in THF (2 mL) was added quickly via syringe and allowed to stir overnight. MeOH and 2 N HCl were added and stirred for 5 minutes. Then the mixture was extracted with ethyl acetate and dried over magnesium sulfate and concentrated. The resulting material was purified via column chromatography using 10% ethyl acetate in hexane as the eluent to afford 0.060 g of desired product as an off white solid. MS (ESI) m/z 392 ([M+H]+); Anal. Calcd. for C24H16F3NO: C, 73.65; H, 4.12; N, 3.58. Found: C, 73.34; H, 4.08; N, 3.31.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][C:17]([CH3:35])([C:19]2[N:23]([CH3:24])[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[N:21][N:20]=2)[CH3:18])=[C:6]([C:8]2[O:9][CH:10]=[C:11]([C:13](O)=O)[N:12]=2)[CH:7]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C1CCN2C(=[N:55]CCC2)CC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(N(CC)CC)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][C:17]([CH3:18])([C:19]2[N:23]([CH3:24])[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:32])[F:33])=[N:21][N:20]=2)[CH3:35])=[C:6]([C:8]2[O:9][CH:10]=[C:11]([C:13]#[N:55])[N:12]=2)[CH:7]=1
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1-c1nc(C(=O)O)co1
Reactant: C1CCC2=NCCCN2CC1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1-c1nc(C#N)co1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,3-oxazole-4-carboxylic acid (375 mg) was mixed with dichloromethane (10 ml), and triethylamine (0.52 ml) was added, followed by ice-cooling and addition of trifluoromethanesulfonic anhydride (0.316 ml). After stirring at room temperature overnight, it was further stirred at 40° C. for 3 hours. DBU (0.222 ml) was added to the reaction solution, followed by stirring for one hour. Trifluoroacetic anhydride was added to the reaction solution, followed by stirring at 40° C. for 3 hours, and trifluoroacetic anhydride (0.158 ml) and triethylamine (0.52 ml) were added thereto, followed by stirring at 40° C. for one hour. The reaction solution was cooled to room temperature and saturated aqueous sodium bicarbonate was added thereto, followed by extraction with chloroform. The organic layer was washed with water and then saturated brine in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=200:1), and the resulting residue was washed with diisopropylether to obtain, as a beige solid, 2-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,3-oxazole-4-carbonitrile (190 mg).
Reaction SMILES: Cl[C:2]1[CH:32]=[CH:31][C:5]([CH2:6][C:7]2[C:16]3[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[N:12]([CH3:23])[C:11]=3[N:10]=[CH:9][C:8]=2[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[CH:4][CH:3]=1>CO.CC(=O)OCC.O.[Pd]>[CH2:6]([C:7]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[N:12]([CH3:23])[C:11]=2[N:10]=[CH:9][C:8]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[C:5]1[CH:31]=[CH:32][CH:2]=[CH:3][CH:4]=1
Reactant: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(F)c3)cnc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccccc3)c(-c3cccc(F)c3)cnc21
Temperature: 25 °C
Yield: 39.7 %

Procedure:
To a solution of 5-(4-chlorobenzyl)-6-(3-fluorophenyl)-3-(3-hydroxypropyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (25 mg, 0.06 mmol) in MeOH (1 mL) was added 10% Pd/C (10 mg). The reaction was hydrogenated (15 psi) at 70° C. for 1 h, cooled to RT then diluted with EA (30 mL) and water (30 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-benzyl-6-(3-fluorophenyl)-3-(3-hydroxypropyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 mg, 43.5% yield) as a solid. 1H NMR (CDCl3) δ: 8.52 (s, 1H), 7.35 (d, J=8.0, 6.0 Hz, 1H), 7.23-7.06 (m, 4H), 6.98 (t, J=8.0 Hz, 1H), 6.93-6.87 (m, 1H), 6.84 (d, J=6.9 Hz, 2H), 4.68 (s, 2H), 4.17 (dd, J=20.0, 13.9 Hz, 2H), 3.77 (s, 3H), 3.42 (t, J=5.2 Hz, 2H), 2.89 (s, 1H), 1.91-1.80 (m, 2H). LCMS: MH+ 420 and TR=2.83 min.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[O:14]1CC[O:17][CH2:16][CH2:15]1.[C:20]1(=O)OCC1>CCCCCC>[CH2:1]([NH:13][C:16](=[O:17])[CH:15]([OH:14])[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCO1
Reactant: CCCCCCCCCCCCN
Reactant: C1COCCO1
Solvent: CCCCCC
Product: CCCCCCCCCCCCNC(=O)C(C)O
Temperature: 30 °C
Reaction time: 5 h
Yield: 82.2 %

Procedure:
25.34 g (0.1367 mol) of dodecylamine and 30 g of dioxane were fed into a 200-ml four-necked flask equipped with a stirrer, a dropping funnel and a thermometer to thereby prepare a transparent solution. Then, 9.85 g (0.1367 mol) of β-propiolactone was dropwise added to the transparent solution over a period of about 15 min. During this period, the temperature of the reaction system was maintained at 25° to 30° C. The obtained reaction mixture was further stirred at 30° C. for 5 hrs. The obtained crude product having a temperature of its melting point or above was dropwise added to 100 ml of hexane to crystallize. Thus, 28.93 g of N-dodecyl-2-hydroxypropionamide was obtained (yield: 82%). The infrared absorption spectrum data and 1H-NMR spectrum data of the obtained compound were as follows:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18].CN(C=O)C>C(OCC)(=O)C>[NH2:8][C:3]1[C:2]([Br:1])=[C:6]([CH3:7])[N:5]([CH2:16][C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[O:18])[N:4]=1
Reactant: Cc1[nH]nc(N)c1Br
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Br)c(N)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Bromo-5-methyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography ethyl acetate afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): 6.94-7.02 (m, 2H), 6.82-6.88 (t, 2H), 4.84 (s, 2H), 4.1 (s, 2H), 3.72-3.78 (m, 4H), 3.04-3.08 (m, 4H), 2.16 (s, 3H). MS (ES) M+H expected 317.37, found 318.1. MS (ES) M+H expected 396.27, found 396.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[Cl:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]2[CH3:30])[C:17]([CH3:31])=[C:16]([CH3:32])[N:15]=1>CN(C)C=O>[ClH:13].[CH3:31][C:17]1[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]2[CH3:30])=[N:19][C:14]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:15][C:16]=1[CH3:32]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Reactant: CCCCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCNc1nc(C)c(C)c(N2CCc3ccccc3C2C)n1
Product: Cl
Yield: 68.5 %

Procedure:
After butylamine(0.52 ml, 5.22 mmol) and triethylamine(0.36 ml, 2.59 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.74 mmol) in dimethylformamide, 430 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.