Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][CH:7]=1.C([Li])CCC.[S:16](Cl)([Cl:19])(=[O:18])=[O:17].C(OCC)(=O)C>O1CCCC1.CCCCCC>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:16]([Cl:19])(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)Cl
Reactant: c1cc(C2OCCO2)cs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(Cl)c1sccc1C1OCCO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 23.4 g of 3-(1,3-dioxolan-2-yl)thiophene (S. Gronowitz, et al., Arkiv. Kemi., 20, 407 (1963)) in 100 ml of anhydrous tetrahydrofuran was added 100 ml of 1.6 molar n-butyllithium in hexane, with ice bath cooling. After stirring at room temperature for 20 minutes the mixture was cooled to -78° and sulfuryl chloride (16.2 g) was then added dropwise. This addition caused the suspended solids to form a tarry mass which broke up when the mixture was allowed to warm to room temperasture. After stirring one and one half hours at room temperature the mixture was cooled to -10° and 10 ml of ethyl acetate was added dropwise. The reaction mixture was then poured into ice water and extracted with ethyl ether. The ether portions were combined, dried over magnesium sulfate, filtered and the ether removed in vacuo-to yield 19.6 g of an oil. Infrared absorption spectra of this product showed peaks at 1330 and 1180 cm-1, consistent for the desired sulfonyl chloride. Mass spectrum analysis: calc. 254, found 253 (Mass-1H) and the presence of a chlorine atom.
Reaction SMILES: [Se](=O)=[O:2].[O:4]1[CH2:9][CH2:8][O:7]CC1.CC([C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)=O>O>[OH2:2].[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]([CH:8]=[O:7])=[O:4])=[CH:14][CH:15]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=[Se]=O
Reactant: C1COCCO1
Solvent: O
Product: O=CC(=O)c1ccc(O)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Selenium dioxide (11.1 g, 0.1 mol) was added to a mixed solution of p-dioxane (60 cc) and water (2 cc) and dissolved therein on heating at 60° C., followed by adding 4-hydroxyacetophenone (13.6 g, 0.1 mol) all at once, reacting the mixture on heating under reflux for 4 hours, filtering off an inorganic material deposited after completion of the reaction, distilling off p-dioxane from the filtrate, adding water (80 cc) to the resulting red-brown oily material, heating the mixture with stirring at 80° C. for 2 hours, allowing the reaction liquid to cool down to room temperature after completion of the reaction, and filtering off and drying deposited crystals to obtain the objective product (10.7 g). M.p.: 109°~111° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25])=[C:19]([Cl:30])[CH:18]=3)=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].[CH3:39][NH:40][CH2:41][CH2:42][OH:43].O>CN(C)C=O>[Cl:30][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:40]([CH2:41][CH2:42][OH:43])[CH3:39])=[C:7]([O:31][CH3:32])[CH:8]=3)[N:13]=[CH:12][CH:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25]
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCCBr)c(OC)cc23)cc1Cl
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCCN(C)CCO)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A starting compound (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-propylurea, 52 mg), potassium carbonate (138 mg), and 2-(methylamino)ethanol (0.040 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 51 mg (yield 98%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O.[CH3:16][NH2:17]>C1COCC1.[Pd]>[CH3:16][NH:17][CH2:11][C:10]1[CH:9]=[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:15]=[CH:14][CH:13]=1
Reactant: CN
Reactant: COCCOCOc1cccc(C=O)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CNCc1cccc(OCOCCOC)c1
Reaction time: 24 h

Procedure:
To a solution of 3-(2-methoxyethoxy-methoxy)-benzaldehyde (2.10 g, 10 mmol, example 8a) in THF (60 mL) is added methylamine (20 mL, 2M in THF) followed by palladium on carbon (210 mg, 10% Pd). The resulting mixture is stirred for 24 h under an atmosphere of hydrogen gas, then purged with nitrogen, filtered through celite and the filtrate concentrated. The residue is purified by flash chromatography (silica, 10% methanol in dichloromethane) to give the title compound as an oil.
Reaction SMILES: O[NH:2][C:3]([C:5]1[CH:29]=[CH:28][C:8]([O:9][CH:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[NH:4].C(OC(=O)C)(=O)C.[H][H]>C(O)(=O)C.[Pd]>[C:11]([OH:13])(=[O:12])[CH3:10].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:23])[CH3:24])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:28][CH:29]=1)(=[NH:2])[NH2:4]
Reactant: CCOc1cc(C(Oc2ccc(C(=N)NO)cc2)C(=O)OC)ccc1OC(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOc1cc(C(Oc2ccc(C(=N)N)cc2)C(=O)OC)ccc1OC(C)C
Yield: 181.7 %

Procedure:
To 9B (575 mg, 1.43 mmol) in acetic acid (14 mL) was added acetic anhydride (0.155 mL, 1.64 mmol) and 10% Pd/C (90 mg). The mixture was hydrogenated with a hydrogen balloon at rt for 3.0 h. After removal of solvent, 9C (580 mg, 100% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.24 (d, J=6.16 Hz, 6H) 1.30 (t, J=7.03 Hz, 3H) 1.69 (s, 3H) 3.66 (s, 3H) 4.00 (q, J=7.03 Hz, 2H) 4.46-4.50 (m, 1H) 6.09 (s, 1H) 6.90 (d, J=8.35 Hz, 1H) 6.97-7.14 (m, 4H) 7.72 (d, J=9.23 Hz, 2H). LC-MS 387 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([O:6][C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ccc(OC2CCCC2)nc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OC2CCCC2)nc1
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a solution of 2-cyclopentyloxy-5-nitro-pyridine (0.3099 g, 1.49 mmol), in MeOH (2 mL) was added 10% Pd/C (90 mg). The solution was degassed and was kept stirring under hydrogen atmosphere for overnight. It was filtered through a pad of celite and the filtrate was evaporated to afford the desired product as a brown oil (248 mg, 94% yield). 1H-NMR (300 MHz, CDCl3): δ 7.69 (d, 1H), 7.04 (m, 1H), 6.56 (d, 1H), 5.25 (m, 1H), 1.93 (m, 2H), 1.78 (m, 4H), 1.60 (m, 2H). LC/MS (ESI) calcd for C10H14N2O 178.23, found [M+41+1]+ 220.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]Br>CO.CC(O)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:17])[CH:12]=[C:11]([CH3:15])[C:10]=1[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(OCc2ccccc2)c1N
Reactant: BrBr
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(OCc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-benzyloxy-6-methylphenylamine (3.4 g, 16 mmol) in MeOH (50 mL) and AcOH (20 mL) is added Br2 (0.82 mL, 16 mmol) in AcOH (10 mL) at 0° C. The mixture is then stirred at ambient temperature for 18 h. The solvent is then removed under reduced pressure. Then K2CO3 solution is added followed by EtOAc. The organic layer is washed with water and brine, dried and concentrated. The residue is then purified by flash chromatography to give the title compound as a red liquid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]([CH3:13])=[N:5][CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].C(Cl)Cl.C[OH:18]>>[Cl:1][CH2:2][C:3]1[C:4]([CH3:13])=[N+:5]([O-:18])[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:10])[F:11]
Reactant: Cc1nccc(C(F)(F)F)c1CCl
Reactant: CO
Solvent: ClCCl
Product: Cc1c(CCl)c(C(F)(F)F)cc[n+]1[O-]

Procedure:
3-Chloromethyl-2-methyl-4-trifluoromethyl -pyridine from step 2 above was oxidized using the procedure as given in step 3 of Example 3. 3-Chloromethyl-2-methyl-4-trifluoromethyl-pyridine-N-oxide was obtained as a white solid (TLC Rf = 0.21 (97:3 CH2Cl2 :MeOH)).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])[S:6][CH:7]=1>C(Cl)(Cl)Cl.CO.[O-2].[Mn+4].[O-2]>[CH:2]([C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])[S:6][CH:7]=1)=[O:1]
Reactant: CCOC(=O)Nc1nc(CO)cs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Nc1nc(C=O)cs1
Reaction time: 2 h
Yield: 106.4 %

Procedure:
To a mixed solution of ethyl 4-(hydroxymethyl)-1,3-thiazol-2-ylcarbamate (446 mg) in chloroform (30 ml) and methanol (3 ml) was added portionwise manganese (IV) oxide chemicals treated (1.92 g) at room temperature. After the mixture was stirred at the same temperature for 2 hours, then treated manganese (IV) oxide chemicals (250 mg) was added again to the solution, and it was stirred at 50° C. for 3 hours. Manganese (IV) oxide was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10 g) using a mixed solvent of hexane and ethyl acetate (4:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give colorless powder (470 mg, 106.4%).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11]1(/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:15][C:14]([C:17](O)=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[C:11]1(/[CH:20]=[CH:21]/[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=[CH:13][C:14]([C:17]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:18])=[CH:15][CH:16]=1
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(O)c1ccc(/C=C/c2ccccc2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(/C=C/c2ccccc2)cc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.269 g (1.2 mmol) of (E)-4-stilbenecarboxylic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate/dichloromethane=4/1/1), after which it was recrystallized from hexane to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH:17]=O)=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[O:20]([NH2:22])[CH3:21].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:21][O:20][N:22]=[CH:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[CH:9]=[N:10][C:11]=2[CH:16]=1
Reactant: O=Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CON=Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of 28 from Example 7 (2.95 g, 9.8 mmol) in abs. ethanol (100 ml) is added methoxylamine hydrochloride (1.23 g, 14.7 mmol) and the mixture is heated to 70° C. Sodium bicarbonate (1.23 g, 14.7 mmol) is added in portions over 20 min. Following the addition the mixture is stirred at 70° C. for additionally 2 hours. After cooling the solvent is removed under reduced pressure. Water is added to the residue and the product is filtered off, washed with water and dried. Yield: 2.77 g (86%). Mp 119-120° C.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Cl[C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.CN(C=O)C>O>[CH2:1]([S:3][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:18]=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Nc1cc(C(F)(F)F)ccn1)c1ncccc1Cl
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cccnc1C(=O)Nc1cc(C(F)(F)F)ccn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
0.86 g of sodium ethanethiolate was added to a mixture of 1.23 g of 3-chloro-N-(4-trifluoromethylpyridin-2-yl)picolinamide and 3 mL of DMF, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture cooled to room temperature was poured to water, and the precipitated solid was taken by filtration. The resulting solid was dissolved in ethyl acetate, and the mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.23 g of 3-ethylsulfanyl-N-(4-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 8).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl>O>[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][N:2]([CH3:3])[CH3:1]
Reactant: CNC
Reactant: ClCc1ccccc1Cl
Solvent: O
Product: CN(C)Cc1ccccc1Cl

Procedure:
The dimethylamine and water streams were initially combined and preheated to 130° C. The stream of o-chlorobenzyl chloride was then introduced by way of a mixing chamber. The temperature in the reaction tube was set to approximately 140° C. After running through the reaction zone, the mixture was cooled and depressurized. The workup analogous to example 1 afforded the (2-chlorobenzyl)dimethylamine target product with a yield and purity as in example 3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([N:29]2[CH2:34][CH2:33][CH:32]([N:35](C)[C:36](=O)OC(C)(C)C)[CH2:31][CH2:30]2)[CH:23]=[CH:24][C:25]=1[N+:26]([O-])=O>>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:6]2[C:5]([CH3:17])=[CH:4][N:3]=[C:2]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([N:29]4[CH2:34][CH2:33][CH:32]([NH:35][CH3:36])[CH2:31][CH2:30]4)=[CH:21][C:20]=3[O:19][CH3:18])[N:7]=2)=[CH:9]1
Reactant: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Reactant: COc1cc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Product: CNC1CCN(c2ccc(Nc3ncc(C)c(-c4c[nH]c5ccccc45)n3)c(OC)c2)CC1

Procedure:
Starting materials: 3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (INTERMEDIATE 1) and tert-butyl 1-(3-methoxy-4-nitrophenyl)piperidin-4-yl(methyl)carbamate (INTERMEDIATE 10).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl>C(O)C.O1CCCC1.[OH-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][CH:37]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: COC(=O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.2 %

Procedure:
Methyl 4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoate (850 mg) was dissolved in a mixed solvent of ethanol (3.29 mL)/tetrahydrofuran (3.29 mL), 1N aqueous sodium hydroxide solution (3.29 mL) was added, and the mixture was stirred at room temperature for 20 hrs. 1N Hydrochloric acid (3.29 mL) was added to the reaction mixture and the mixture was diluted with water (20 mL). The precipitated crystals were collected by filtration, washed with water (10 mL), and dried under reduced pressure to give the title compound (738 mg).
Reaction SMILES: [CH2:1]([C:19]1[CH:24]=[C:23](C)[CH:22]=[C:21](CCCCCCCCC)[C:20]=1O)[C:2]1C=C(C)C=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CCCC)[C:3]=1O.[OH:36]C1C(CCCCCCCCC)=CC(C)=CC=1CC1C(O)=C(CC2C=C(C)C=C(CCCCCCCCC)C=2O)C=C(C)C=1>>[CH2:1]([C:19]1[CH:24]=[CH:23][C:22]([OH:36])=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCc1cc(C)cc(Cc2cc(C)cc(Cc3cc(C)cc(CCCCCCCCC)c3O)c2O)c1O
Reactant: CCCCCCCCCc1cc(C)cc(Cc2cc(C)cc(CCCCCCCCC)c2O)c1O
Product: CCCCCCCCCc1ccc(O)cc1

Procedure:
A lubricating oil composition comprising, as essential components, (A) 100 parts by weight of a base oil having a kinematic viscosity at 40° C. of 5 to 500 cSt, a pour point of -30° C. or lower, a cloud point of -20° C. or lower and a viscosity index of 70 or more, and (B) 0.01 to 5 parts by weight of at least one alkyl group-substituted phenol compound having a melting point of 20° C. or lower selected from the group consisting of 2,2'-methylenebis(4-methyl-6-nonylphenol); 2,6-bis(2-hydroxy-3-nonyl-5-methylbenzyl)p-cresol; and p-nonylphenol in which the nonyl group is formed by removing a hydrogen from propylene trimer.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.C([Li])CCC.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].II>O1CCCC1.C(OCC)(=O)C>[Cl:11][C:9]1[C:10]2[C:2]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: CCOC(=O)Cl
Agent: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (40.0 g, 173 mmol) in dry tetrahydrofuran (700 mL) at −78° C. was added n-butyl lithium (195 mL, 2.5 M solution in hexane, 487 mmol) over the period of 2 hours. The reaction mixture was stirred for another 30 minutes at −78° C., after which ethyl chloroformate (17.8 mL, 186 mmol) was added over 30 minutes. The reaction mixture was stirred for 2 hours at −60° C. and then the temperature was slowly increased to 30° C. The reaction mixture was allowed to stir for 12 hours at 30° C. The progress of the reaction was monitored by TLC using 25% ethyl acetate in petroleum ether using iodine and 254 nm UV light to visualize the spot. The reaction mixture was then quenched with saturated solution of ammonium chloride (200 mL) at 0° C. and the reaction mixture was extracted with ethyl acetate (×3). The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a crude reaction mixture. The residue was purified by chromatography on silica eluting with 5-100% ethyl acetate/petroleum ether to afford ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as pale yellow solid. LRMS (ESI) calc'd for C9H7ClN3O2 [M−H]+: 224. found 224. 1H NMR (400 MHz, DMSO-D6): δ 13.28 (s, 1H), 8.70 (s, 1H), 8.39 (s, 1H), 4.31 (q, J=7.2, 6.8 Hz, 2H), 1.34 (t, J=7.6, 6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH2:29]C#N)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([C:29]2[O:20][N:19]=[C:16]3[CH:15]=[CH:14][C:13]([C:12]4[N:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)[N:9]=[CH:10][CH:11]=4)=[CH:18][C:17]=23)[CH:26]=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2)cc1
Reactant: N#CCc1cccc(F)c1
Product: Fc1ccc(-n2nccc2-c2ccc3noc(-c4cccc(F)c4)c3c2)cc1

Procedure:
The title compound, light yellow solid (74 mg, 56%), MS (ISP) m/z=374.1 [(M+H)+], mp 176° C., was prepared in accordance with the general method of example 1 from 1-(4-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate C) (100 mg, 353 μmol) and commercially available 2-(3-fluoro-phenyl)-acetonitrile.
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1C.[F:24][C:25]1[CH:30]=[C:29]([O:31]C)[CH:28]=[CH:27][C:26]=1[N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:35][CH2:34]1>>[F:24][C:25]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:26]=1[N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:35][CH2:34]1
Reactant: COc1ccc(N2CCN(CCc3ccccc3)CC2)c(F)c1
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1C
Product: Oc1ccc(N2CCN(CCc3ccccc3)CC2)c(F)c1
Yield: 50.8 %

Procedure:
Production Example 10 was repeated except that 1-(4-methoxy-3-methylphenyl)-4-phenethylpiperazine was replaced with 1-(2-fluoro-4-methoxyphenyl)-4-phenethylpiperazine (367 mg), and the resulting crude product was purified on TLC (developer, chloroform: methanol=17:1) to provide 3-fluoro-4-(4-phenethyl-piperazin-1-yl)phenol (178 mg).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10]C)=[O:9])=[O:5].[OH-].[K+].C(O)C.Cl>O>[F:1][C:2]1[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)CCC(=O)OC)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)CCC(=O)O)c(F)c1
Temperature: 25 °C

Procedure:
A solution of 5.4 g. of methyl 3-[2-fluoro-4-(hexadecylamino)benzoyl]propionate is stirred with 5.4 g. of potassium hydroxide in 100 ml. of 95% ethanol for 3 hours at reflux. The reaction mixture is cooled, diluted with 50 ml. of ethanol and 100 ml. of water, and neutralized with hydrochloric acid. The solution is cooled to room temperature and filtered. The white solid is washed with 50% aqueous ethanol and dried. The product is recrystallized from ethanol to yield 3-[2-fluoro-4-(hexadecylamino)benzoyl]propionic acid as a white crystalline solid.