Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.C([O:13][C:14](=[O:22])[CH:15](Br)C(OCC)=O)C.C(=O)([O-])[O-].[K+].[K+].S(=O)(=O)(O)O.[OH-].[K+]>C(C(C)=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:15]([C:14]([OH:22])=[O:13])=[CH:7][C:6]=2[CH:9]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(O)c1cc2cc(F)ccc2o1
Yield: 19.4 %

Procedure:
5-Fluorosalicylaldehyde (4.4 g), diethylbromomalonate (11.3 g) and methyl ethyl ketone (35 ml) were stirred together. Anhydrous potassium carbonate (8.7 g) was added and the mixture was heated at reflux for 4 hours. Excess dilute sulphuric acid was added and the mixture was extracted with diethyl ether. The combined extracts were washed with water, dried and evaporated to leave an oil which was treated with 10% w/v ethanolic KOH (60 ml) and heated at reflux for 45 minutes. The solvent was evaporated and the residue treated with excess dilute sulphuric acid and heated briefly on a steam bath. After cooling the crude acid was filtered off. Recrystallisation from ethylacetate/ethanol gave a fawn coloured product (1.1 g), m.p. 261°-266° (decomp), I.R. νmax 1685 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:27])([CH3:26])[O:19][C:20]=3[C:21]([C:23](O)=[O:24])=[CH:22][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[F:32][C:33]([F:42])([F:41])[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:26])([CH3:27])[O:19][C:20]=3[C:21]([C:23]([NH:38][C:37]3[CH:39]=[CH:40][C:34]([C:33]([F:32])([F:41])[F:42])=[CH:35][CH:36]=3)=[O:24])=[CH:22][C:12]=2[N:11]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)O)c3c(c21)CC(C)(C)O3
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)Nc3ccc(C(F)(F)F)cc3)c3c(c21)CC(C)(C)O3
Yield: 7.3 %

Procedure:
The title compound was prepared by following the procedure as described for Example-108 using 2-((2-chloro-6-fluorophenyl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylic acid (Intermediate-49, 0.100 g, 0.2564 mmol), thionyl chloride (2.0 mL), 4-trifluoromethyl aniline (0.124 g, 0.769 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.010 g of the desired product. 1HNMR (DMSO-d6): δ 1.61 (s, 6H), 3.47 (s, 3H), 3.56 (s, 2H), 7.17-7.01 (m, 1H), 7.21 (bs, 2H), 7.29 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.4 Hz, 2H), 7.90 (d, J=7.8 Hz, 2H), 9.92 (bs, 1H), 10.52 (bs, 1H): MS [M+H]+: 533.25.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8](CC1C=CC(OC)=CC=1)[CH:7]=[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]2=O.S(Cl)([Cl:29])=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:5]2[Cl:29]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2)c2ccc(Br)cc2c1=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1Cl
Temperature: 75 °C
Reaction time: 16 h

Procedure:
On a larger scale, ethyl 6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate (5765 g, 13.85 mol) was charged to the vessel with thionyl chloride (28.8 L). An exotherm from 20-26° C. was observed. DMF (4.4 mL) was added with no observed exotherm and the batch heated to 75° C. and stirred for 17 h. HPLC showed 1.3% starting material remained with 98.0% product. The reaction was concentrated in vacuo and the residue azeotroped with toluene (25 L). The resulting solid was then slurried in heptane (18.5 L) for 2.5 h, filtered and washed with heptane (3×4 L). The solid was dried under vacuum at 35° C. to give 4077 g of the desired material (93% crude yield) which contained ˜5% of ethyl 6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate in addition to ˜4% hydrolysis product by HPLC (90% pure). The crude material (4077 g) was returned to the vessel and reprocessed with thionyl chloride (14.5 L) and DMF (2.2 mL). The mixture was heated to 75° C. for 40 h. The thionyl chloride was removed in vacuo and the residue azeotroped with toluene (10 L). The residue was slurried in heptane (18 L) for ˜16 h at 20° C. The solid was collected by filtration, one portion being filtered under nitrogen and washed with heptane (3 L) to yield 2196 g of desired material (90% NMR assay, 99% by HPLC). The remainder of the batch was filtered under air and washed with heptane (3 L) to yield 1905 g of the desired material (88% NMR assay, 99% by HPLC). The yellow solids were combined for further processing (4101 g, 3653 g active, 83% yield, 99% by HPLC).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[O:5]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[N:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccccc1
Reactant: CCCCOc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOc1ccc(C=Nc2ccccc2)cc1
Yield: 77 %

Procedure:
A mixture of 7.2 g (0.040 mol) of 4-butoxybenzaldehyde, 4.0 g (0.044 mol) of aniline, 0.10 g of p-toluenesulfonic acid, and 75 mL of toluene was heated at reflux for 16 hr, with continuous azeotropic separation of the water evolved. Upon cooling, the contents of the flask were chromatographed on silica gel using dichloromethane as the eluent to give 7.8 g (77%) of N-(4-butoxylbenzylidene)aniline as a viscous oil. Crystallization from heptane afforded an analytical sample of a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:14][C:13](=[O:15])[C:12]2[C:7](=[C:8](Cl)[C:9]([CH3:17])=[C:10](Cl)[CH:11]=2)[N:6]=1)=[O:4].O[Li].O>CO.O.[Pd]>[C:3]([C:5]1[CH2:14][C:13](=[O:15])[C:12]2[C:7](=[CH:8][C:9]([CH3:17])=[CH:10][CH:11]=2)[N:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)C1=Nc2c(cc(Cl)c(C)c2Cl)C(=O)C1
Agent: [Pd]
Agent: [Li]O
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1)N=C(C(=O)O)CC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
2-(Methoxycarbonyl)-4-oxo-6,8-dichloro-7-methylquinoline (28.5 g, 99.6 mmol) was suspended in methanol (1 L) and a solution of LiOH.H2O (20.5 g, 0.5 mol) in water (200 mL) was added to the solution. The resulting reaction mixture was stirred at ambient temperature for 0.5 hours. Pd/C (5.8 g) was added to the reaction mixture and the resulting reaction mixture was shaken under 50 Psi hydrogen overnight. The reaction mixture was filtered, concentrated under reduced pressure to remove methanol, diluted with water (300 mL) and the pH was adjusted to between pH 3 and pH 4 by 2N HCl. The precipitate was collected by filtration, washed with water and dried to afford a white solid, 2-carboxy-4-oxo-7-methylquinoline (20 g, 90%); NMR (DMSO-d6) 2.40 (s, 3), 6.60 (s, 1), 7.20 (d, 1), 7.68 (s, 1), 7.96 (d, 1) ppm.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Cl[CH2:14][CH:15]([O:18][CH2:19][O:20][CH3:21])[CH2:16]Cl>CS(C)=O.C(OCC)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:16][CH:15]([O:18][CH2:19][O:20][CH3:21])[CH2:14]2)=[CH:6][CH:5]=1
Reactant: COCOC(CCl)CCl
Reactant: N#CCc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOCC
Product: COCOC1CC(C#N)(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
Potassium hydroxide (2.57 g) was dissolved in dimethyl sulfoxide (8.0 mL). (4-Chlorophenyl)acetonitrile (1.58 g, 10.4 mmol) and 1,3-dichloro-2-(methoxymethoxy)propane (1.993 g) were dissolved in ethyl ether (3 mL), and this mixture was added dropwise to the vigorously stirred potassium hydroxide solution at room temperature. After stirring at room temperature for one hour, the reaction was quenched by adding ice-cold water (5.5 mL). The mixture was filtered through a pad of celite which was washed with ether (30 mL). The filtrate was added to a separatory funnel, and the aqueous layer was extracted with ether (3×15 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. The product was purified by silica gel chromatography to provide 1-(4-chlorophenyl)-3-(methoxymethoxy)cyclobutanecarbonitrile (1.28 g) as a mixture of isomers (ca. 2:1).
Reaction SMILES: [H-].[Na+].CCCCCC.[CH3:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl[C:22]1[CH:27]=[N:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][N:23]=1>CN(C)C=O.O>[CH3:9][C:10]([C:22]1[CH:27]=[N:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][N:23]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Clc1cnc(-c2ccccc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)C(C)(C(=O)OCC)c1cnc(-c2ccccc2)cn1
Temperature: 50 °C

Procedure:
A sodium hydride-mineral oil suspension (54%; 3.1 g., 0.069 mole) is stirred with three 50 ml. portions of dry hexane, each portion being pipetted out to remove the mineral oil. Dimethylformamide (30 ml., previously distilled and dried over a molecular sieve) is added through a pressure equalized addition funnel while a slow stream of nitrogen is passed through the mixture. The reaction vessel is cooled in an ice-bath while diethyl methylmalonate (12 g., 0.069 mole) is added dropwise to the stirred mixture. After the addition is complete, the ice-bath is replaced by an oil bath and the temperature is raised to 50° C. To the mixture is added dropwise 2-chloro-5--phenylpyrazine (10 g., 0.053 mole) in warm dimethylformamide (55 ml.). After this addition is complete, the mixture is heated for 31/2 hours during which time the temperature is raised to 120° C. The reaction mixture is cooled to about 80° C. and water (4 ml.) is added. The mixture is concentrated to a small volume, and the residual liquid is diluted with 50 g. of ice and extracted with ether several times. The combined ether extracts are washed with 5% hydrochloric acid, then with water, and then dried and evaporated. The resulting oil is chromatographed on a column of 500 g. of Merck acid-washed alumina. Elution with benzene-hexane (4:1) through ethyl acetate-benzene (1:3) yielded diethyl α-methyl-5-phenylpyrazinylmalonate.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[CH:13]1([CH:16]([OH:25])[C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[C:20]#[N:21])[CH2:15][CH2:14]1>CCOC(C)=O>[CH:13]1([C:16]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[C:20]#[N:21])=[O:25])[CH2:15][CH2:14]1
Reactant: N#Cc1cccc(C(O)C2CC2)c1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(C(=O)C2CC2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 131.4 %

Procedure:
The key intermediate 3-(Cyclopropanecarbonyl)benzonitrile was prepared as follows; a) Cyclopropylmagnesium bromide (1M in THF, 6 ml, 6 mmol) was added to a solution of 3-formylbenzonitrile in THF (12 ml) at −78° C. and stirred at 0° C. for 5 hours. The reaction was quenched with saturated NH4Cl solution (30 ml), extracted with EtOAc, washed with water (×2) and brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica (EtOAc/Hexanes 20/80-50/50) to give 3-(cyclopropyl(hydroxy)methyl)benzonitrile (778 mg, 91%). b) 2-Iodoxybenzoic acid (IBX) was added to a solution of 3-(cyclopropyl(hydroxy)methyl)benzonitrile (171 mg, 1 mmol) in EtOAc (5 ml) at room temperature and stirred at 80° C. for 2 hours. After cooling to 0° C., the precipitated materials were filtered off and washed with EtOAc (3 ml×2), then the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica (EtOAc/Hexanes 5/95-30/70) to give 3-(cyclopropanecarbonyl)benzonitrile (225 mg, 100%).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31]C)=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:28][O:27][C:26]1[C:3](=[O:2])[C:4]([CH3:33])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:24](=[O:31])[C:25]=1[O:29][CH3:30]
Reactant: COc1ccc(-c2ccc(Cc3c(C)c(OC)c(OC)c(OC)c3OC)cc2C(=O)O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccc(OC)cc3)c(C(=O)O)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-methoxy-phenyl)benzoic acid (440 mg, 0.9734 mmol) was dissolved in a mixed solvent of acetonitrile (30 ml) and water (10 ml), then CAN (1.10 g, 2.0072 mmol) was added thereto at room temperature and the mixture was stirred for 3 hour. The reaction solution was poured into water and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (5% methanol-methylene chloride) to give the title compound (259 mg, 0.6137 mmol, 63%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:18])=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.S(=O)(=O)(O)[OH:20].[OH-].[Na+]>>[CH3:18][C:12]1[C:11]([O:10][C:4]2[C:5]([C:8]([NH2:9])=[O:20])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)=[CH:16][CH:15]=[C:14]([CH3:17])[N:13]=1
Reactant: Cc1ccc(Oc2cc(Br)cnc2C#N)c(C)n1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(Oc2cc(Br)cnc2C(N)=O)c(C)n1
Temperature: 25 °C
Yield: 92 %

Procedure:
To 5-bromo-3-(2,6-dimethylpyridin-3-yloxy)picolinonitrile (25 g, 82 mmol) was added concentrated sulfuric acid (25 ml) and the mixture stirred at ambient temperature over night. The mixture was poured onto ice (500 ml) and the aqueous mixture neutralized using 50% NaOH. A solid formed at pH 7. The solid was collected and dried in vacuo to afford 3-(2,6-dimethylpyridin-3-yloxy)-5-bromopicolinamide (24.2 g, 92%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13](=[NH:16])[NH:14][OH:15])(=[O:3])[CH3:2].[C:17](Cl)(=O)[CH2:18][CH2:19][CH3:20]>N1C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]1[N:16]=[C:17]([CH2:18][CH2:19][CH3:20])[O:15][N:14]=1)(=[O:3])[CH3:2]
Reactant: CCCC(=O)Cl
Reactant: CC(=O)N1c2ccccc2CC1C(=N)NO
Solvent: c1ccncc1
Product: CCCc1nc(C2Cc3ccccc3N2C(C)=O)no1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of intermediate (14) (0.00898 mole) and butanoyl chloride (0.0094 mole) in pyridine (140 ml) was stirred at room temperature for 40 hours and then heated to reflux. After 21 hours the reaction was cooled and concentrated in vacuo. The residue was extracted between DCM and saturated aqueous NaHCO3 and the organic fraction was dried over Na2SO4, filtered, and concentrated. The residue was subjected to silica gel flash column chromatography (eluent 100% CH2Cl2 to 95/5 CH2Cl2/ether), yielding 1-acetyl-2,3-dihydro-2-(5-propyl-1,2,4-oxadiazol-3-yl)-1H-indole (compound 89, mp. 93-94° C.).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:26]=[CH:25][C:21]3[S:22][CH:23]=[CH:24][C:20]=3[CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.[Li+].[OH-]>CC(O)C.C(Cl)Cl.O>[S:22]1[CH:23]=[CH:24][C:20]2[CH:19]=[C:18]([C:16]([NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:7][C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:14]3)=[O:17])[CH:26]=[CH:25][C:21]1=2
Reactant: CCOC(=O)C1(NC(=O)c2ccc3sccc3c2)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(C)O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1ccc2sccc2c1
Reaction time: 114 h
Yield: 99.6 %

Procedure:
A 50 mL flask containing the 2-[(benzo[b]thiophene-5-carbonyl)-amino]-indane-2-carboxylic acid ethyl ester (184, 0.45 g, 1.25 mmol) is charged with 1,4-dioxane (8 mL) and MeOH (8 mL). A stirring bar is added and stirring is initiated. After dissolution, water (4.0 mL) is added followed by the LiOH (131 mg, 3.11 mmol). After 114 h, tlc analysis (silica, 5% i-PrOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜12 mL). The contents of the flask are poured into a separatory funnel containing EtOAc (30 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic extracts are washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated. Pumping to constant weight gives 0.42 g of off-white solid.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[C:14]1[CH:34]=[CH:33][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1)[CH:2]([CH3:4])[CH3:3].CN(C)C=O.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=1.[H-].[Na+]>C(OCC)(=O)C.CO.CCCCCC>[CH2:1]([N:5]([C:40]([C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)=[O:47])[CH2:6][CH2:7][C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=2)=[CH:33][CH:34]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(Cl)c1cccnc1
Reactant: Cc1nc(-c2ccc(OCCCCCOc3ccc(C#N)cc3)cc2)c(CCNCC(C)C)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(OCCCCCOc3ccc(C#N)cc3)cc2)c(CCN(CC(C)C)C(=O)c2cccnc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
310 mg (0.65 mmol) of 4-(5-{4-[5-(2-isobutylaminoethyl)-2-methyl-thiazol-4-yl]phenoxy}pentyloxy)-benzonitrile compound (14b) obtained in Preparative Example 6-1 was added to 20 ml of dimethylformamide, and the mixture was cooled to 0°. To the mixture, 139 mg (0.78 mmol) of nicotinoyl chloride and 65 mg (1.62 mmol) of sodium hydride were added, and the mixture was stirred at room temperature 8 hrs. The reaction solution was diluted with ethyl acetate, and washed with purified water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed therefrom, and the residue was purified by column chromatography using ethyl acetate:n-hexane:methanol=7:5:1 as an eluent to obtain 200 mg (yield: 53%) of a title compound (29).
Reaction SMILES: C(C1C=CC(NC2C(F)=CN=C(NC3C=CC4OC(C(O)=O)CC=4C=3)N=2)=CC=1)(C)(C)C.C([O:34][C:35]([C:37]1[NH:38][C:39]2[C:44]([CH:45]=1)=[CH:43][C:42]([NH:46][C:47]1[N:52]=[C:51]([NH:53][C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([OH:60])[CH:55]=3)[C:50]([F:61])=[CH:49][N:48]=1)=[CH:41][CH:40]=2)=[O:36])C.[Li+].[OH-]>>[C:35]([C:37]1[NH:38][C:39]2[C:44]([CH:45]=1)=[CH:43][C:42]([NH:46][C:47]1[N:52]=[C:51]([NH:53][C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([OH:60])[CH:55]=3)[C:50]([F:61])=[CH:49][N:48]=1)=[CH:41][CH:40]=2)([OH:36])=[O:34]
Reactant: CCOC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2[nH]1
Agent: CC(C)(C)c1ccc(Nc2nc(Nc3ccc4c(c3)CC(C(=O)O)O4)ncc2F)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2[nH]1

Procedure:
In a manner similar to the preparation of N4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine, N2-(2-ethoxycarbonylindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine upon LiOH treatment gave N2-(2-carboxyindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.83 (m, 1H), 7.73 (s, 1H), 7.50 (bd, 1H, J=8.7 Hz), 7.30–7.11 (m, 5H), 6.68 (bd, 1H); LCMS: ret. time: 16.50 min.; purity: 97%; MS (m/e): 380 (MH+).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])=[CH:4][CH:5]=1
Reactant: COc1ccc(Br)cc1
Reactant: CCCCCCCCCCCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
An about 3.70 g portion of magnesium was placed in a 100 ml, two-necked round bottom flask. The flask was flamed several times and about 28.5 g of p-bromoanisole and tetrahydrofuran were added. As soon as the reaction stopped it was refluxed for about 2 hours and then added to a boiling solution of about 21.07 g of tetradecyl bromide in tetrahydrofuran. Then about 9 ml of lithium cupric chloride was added and the mixture was refluxed for about 2 hours, then stirred at room temperature for about 16 hours, quenched with dilute hydrochloric acid, washed with ammonium chloride solution, sodium bicarbonate solution, brine and dried, giving about 23 g of the desired title compound, mp 38° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[CH2:8][CH2:7][CH2:6]1)=[O:4].[F-].[K+].[F:19][C:20]([F:36])([F:35])[C:21]1[CH:34]=[CH:33][C:24]([O:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]2)=[CH:23][CH:22]=1>C(#N)C.C1COCC1>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:5]1([C:3](=[O:4])[CH2:2][N:29]2[CH2:30][CH2:31][CH2:32][CH:27]([CH2:26][O:25][C:24]3[CH:33]=[CH:34][C:21]([C:20]([F:19])([F:35])[F:36])=[CH:22][CH:23]=3)[CH2:28]2)[CH2:8][CH2:7][CH2:6]1
Reactant: COc1ccccc1C1(C(=O)CCl)CCC1
Reactant: FC(F)(F)c1ccc(OCC2CCCNC2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccccc1C1(C(=O)CN2CCCC(COc3ccc(C(F)(F)F)cc3)C2)CCC1
Reaction time: 8 h
Yield: 30.1 %

Procedure:
2-Chloro-1-[1-(2-methoxy-phenyl)-cyclobutyl]-ethanone (55 mg) in 2 mL acetonitrile was treated with freshly flamed-dried KF on Celite (200 mg) and 3-(4-trifluoromethyl-phenoxymethyl)-piperidine (66 mg, 1.1 equiv). The mixture was stirred overnight, diluted with THF (5 mL), filtered, concentrated in vacuo and purified on silica gel to give the desired 1-[1-(2-methoxy-phenyl)-cyclobutyl]-2-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethanone (32 mg, 30%). Data for this amino ketone: MS 462 (M+1); 1H NMR (300 MHz, CDCl3) partial: δ 6.8-7.6 (m, 8H), 3.85-3.95 (m, 2H, methylene adjacent to aryl ether), 3.09 (s, 2H, methylene adjacent to keto and amine moieties).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[S:24]1(=[O:29])(=[O:28])[CH2:27][CH2:26][NH:25]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:25]3[CH2:26][CH2:27][S:24]3(=[O:29])=[O:28])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: O=S1(=O)CCN1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 7.5 %

Procedure:
Using [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (210 mg) described in Preparation Example 108 and [1,2]thiazetidine 1,1-dioxide (54 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (15 mg) was obtained.