Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][B:3](OC)OC.[F:8][C:9]1[CH:14]=[CH:13][C:12]([Mg]Br)=[CH:11][CH:10]=1>O1CCCC1>[F:8][C:9]1[CH:14]=[CH:13][C:12]([B:3]([C:12]2[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=2)[O:2][CH3:1])=[CH:11][CH:10]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: COB(OC)OC
Solvent: C1CCOC1
Product: COB(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
Trimethylborate (1.0 ml, 8.75×10−3 mol) is added dropwise to a freshly prepared solution of p-fluorophenyl magnesium bromide (18.4 ml, 1 M, 1.84×10−2 mol) in tetrahydrofuran (30 ml) under argon at −78° C. The mixture is warmed to room temperature and stirred overnight. The solution is cooled to −78° C. and excess grignard reagent is destroyed by the dropwise addition of methanol until no more effervescence is observed. The solvents are removed in vacuo and the residue dissolved in diethyl ether and washed with water. The organic layer is dried (MgSO4), filtered and the solvents removed in vacuo to give methyl di(p-fluorophenyl)borinate (1.93 g, 89%) as a solid which was used without further purification.
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.[CH2:8]1[CH2:18][CH2:17][N:16]2[C:11](=N[CH2:13][CH2:14][CH2:15]2)[CH2:10][CH2:9]1.[C:19]1([CH3:25])[CH:24]=CC=[CH:21][CH:20]=1>ClCCl>[CH3:25][C:19]1[CH:20]=[CH:21][C:17]2[N:16]3[C:15](=[C:14]([CH3:13])[C:7](=[O:6])[CH2:10][CH2:11]3)[CH2:9][CH2:8][C:18]=2[CH:24]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1ccccc1
Reactant: COS(=O)(=O)OC
Solvent: ClCCl
Product: CC1=C2CCc3cc(C)ccc3N2CCC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
To a solution of 6-methyl-1-(3-oxo-1-pentyl)-(1H)-3,4-dihydroquinolin-2-thione [compound 4 wherein (QW)n=Me, R1=R3=R4=R5=H, R2=Me] (350 mg, 1.40 mmol) in anhydrous toluene (4 ml) is added Me2SO4 (227 ml, 2.40 mmol) under stirring and nitrogen atmosphere. The solution is heated at reflux and after 5 min a red oil begins to separate. After further 15 min, DBU (365 ml, 2.40 mmol) is added dropwise to the refluxing two-phase reaction mixture, causing after a few minutes, a darkening of the mixture. The reflux is maintained for 20 min, then the solution is cooled at room temperature, diluted with dichloromethane (50 ml), washed with water (50 ml) and dried over Na2SO4. After filtration and evaporation of the solvent, the dark residual oil is chromatographed (ethyl acetate:light petroleum ether, 1:1, Rf=0.29) affording pure 8-methyl-2,3,5,6-tetrahydro-4-methyl-(1H)-benzo[c]quinolizin-3-one [compound I wherein (QW)n=Me, R1=R3=R4=R5=H and R2=Me] (152 mg, 50%) as an oil which became a solid on standing (mp 143-145° C.)
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]=[O:10].C1(=[O:18])CCCCC1>C(O)(=O)C.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:11])[C:2]=1[C:9]([OH:18])=[O:10]
Reactant: Cc1cc(C)c(C=O)c(C)c1
Reactant: O=C1CCCCC1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1cc(C)c(C(=O)O)c(C)c1

Procedure:
To a flask equipped with a stirrer, condenser and an oxygen inlet were added mesitaldehyde (14.8 g, 0.10 mol), 30 mL (0.29 mol) of cyclohexanone and 10 mg of cobalt (II) acetate dissolved in 1 mL of acetic acid. Oxygen was bubbled in while the solution was stirred rapidly. Within an hour the temperature had risen to 70°, then declined rapidly. After 3 hr the solution was mixed with 75 ml of methylene chloride and 100 ml of water. Aqueous potassium hydroxide (40%) was added dropwise until the pH reached 7.5. The aqueous layer was separated and rinsed first with 50 mL of methylene chloride, then with 50 mL of petroleum ether. After acidification with concentrated hydrochloric acid, the white crystalline product was collected by filtration, washed with water and air dried: 12.54 g (77%) of mesitoic acid, mp 154°-156°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:33])[C:10]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[C:28][Si](C)(C)C)=[CH:23][CH:22]=2)[CH:17]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=1>CO.O1CCOCC1.O>[CH3:7][O:8][C:9](=[O:33])[C:10]1[CH:19]=[C:18]([O:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]#[CH:28])=[CH:25][CH:26]=2)[CH:17]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=1
Reactant: COC(=O)c1cc(Oc2ccc(C#C[Si](C)(C)C)cc2)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: C#Cc1ccc(Oc2cc(C(=O)OC)cc(C(=O)OC)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
Powdered potassium carbonate (3.0 g) was added to a solution of dimethyl-5-(4-trimethylsilylethynylphenoxy)-isophthalate (5.0 g) in a mixture of methanol (80 ml) and dioxane (20 ml). A crystalline precipitate gradually formed upon stirring at ambient temperature for two hours. The reaction mixture was diluted with water (100 ml) and filtered to yield dimethyl-5-(4-ethynylphenoxy)isophthalate as a tan crystalline solid (3.0 g), m.p. 124°-125° C. Calculated for C18H14O5 : C, 69.67%; H, 4.55%. Found: C, 69.76%; H, 4.84%.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[F:19][C:20]1[CH:21]=[C:22]([NH2:27])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([NH:27][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Nc1cc(F)cc(F)c1
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1cc(F)cc(F)c1
Temperature: 130 °C

Procedure:
Prepared according to procedure A using diethyl 2-methylmalonate (34.5 mL, 205 mmol), pyridine (15.6 mL, 190 mmol), and 3,5-difluorobenzenamine (12.4 g, 96 mmol). The reaction was heated to 130° C. for 2 days. Purification afforded ethyl 3-(3,5-difluorophenylamino)-2-methyl-3-oxopropanoate. Mass Spectrum (ESI) m/e=258 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[Cl:13][C:14]1[CH:15]=[N+:16]([O-:43])[CH:17]=[C:18]([Cl:42])[C:19]=1[CH2:20][C@H:21]([O:32][C:33]([C:35]1[S:36][C:37]([CH:40]=O)=[CH:38][CH:39]=1)=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[Cl:42][C:18]1[CH:17]=[N+:16]([O-:43])[CH:15]=[C:14]([Cl:13])[C:19]=1[CH2:20][C@H:21]([O:32][C:33]([C:35]1[S:36][C:37]([CH2:40][NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:4]([O:3][Si:2]([CH3:12])([CH3:11])[CH3:1])[CH:5]=2)=[CH:38][CH:39]=1)=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: C[Si](C)(C)Oc1cccc(N)c1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(C=O)s2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CNc3cccc(O[Si](C)(C)C)c3)s2)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-((trimethylsilyl)oxy)aniline (0.14 g, 0.77 mmol) and [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-formylthiophene-2-carboxylate (0.186 g, 0.39 mmol) in DCM (5 mL) was stirred at room temperature for 18 h. NaBH(OAc)3 (0.206 g, 0.97 mmol) and acetic acid (0.043 mL, 0.75 mmol) was added and the reaction mixture was stirred at room temperature for a further 3 h. The reaction mixture was diluted with DCM (10 mL) and washed with saturated aqueous NaHCO3 solution (25 mL). The aqueous phase was further extracted with DCM (10 mL), and the combined organic phases were washed with brine (20 mL), filtered through a phase separator cartridge and the solvent was removed in vacuo, co-evaporated with MeCN to give [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[(3-trimethylsilyloxyanilino)methyl]thiophene-2-carboxylate as a light brown gum. A mixture of this material (0.185 g, 0.29 mmol) and (R)-quinuclidin-3-yl carbonochloridate (0.162 g, 0.72 mmol) in MeCN (5 mL) was heated in a microwave at 80° C. for 6 min. Additional (R)-quinuclidin-3-yl carbonochloridate (0.08 g, 0.35 mmol) was added and heated in the microwave at 80° C. for a further 6 min. The solvent was removed in vacuo and the residue was partitioned between EtOAc (20 mL) and water (20 mL). The separated aqueous phase was basified by the addition of saturated aqueous NaHCO3 solution and extracted with EtOAc (2×20 mL). The organic extracts were combined and filtered through a phase separator and the solvent was removed in vacuo. Purification by preparative HPLC gave the title compound as a white solid (0.02 g, 9.6%).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]([F:13])([F:12])[CH:10]=[CH2:11].[SH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].COC(OC)(C1C=CC=CC=1)C(C1C=CC=CC=1)=O>[OH-].[Na+]>[F:8][C:9]([F:13])([F:12])[CH2:10][CH2:11][S:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: C=CC(F)(F)F
Reactant: O=C(O)CCS
Agent: COC(OC)(C(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(O)CCSCCC(F)(F)F
Reaction time: 4 h

Procedure:
A 250 mL three-neck round bottomed flask was charged with toluene (81 mL) and cooled to <−50° C. with a dry ice/acetone bath. 3,3,3-Trifluoropropene (10.28 g, 107.0 mmol) was bubbled into the solvent and the ice bath was removed. 3-Mercaptopropionic acid (9.200 g, 86.70 mmol) and 2,2-dimethoxy-2-phenylacetophenone (1.070 g, 4.170 mmol) were added and the long wave light (366 nm, 4 watt UVP lamp) was turned on (Starting temperature: −24° C.). The reaction reached a temperature of 27.5° C. due to heat from the lamp. The reaction was stirred under the black light on for 4 hours. After 4 hours the black light was turned off and the reaction concentrated by rotary evaporation (41° C., 6 mm Hg) giving a pale yellow oil (18.09 g, 51:1 linear:branched isomer, 90 wt % linear isomer by GC internal standard assay, 16.26 g active, 93%). The crude material was dissolved in 10% sodium hydroxide w/w (37.35 g) and was washed with toluene (30 mL) to remove non-polar impurities. The aqueous layer was acidified to pH˜2-3 with hydrochloric acid (2 N, 47.81 g) and was extracted with toluene (50 mL). The organic layer was washed with water (40 mL) and dried over magnesium sulfate, filtered, and concentrated by rotary evaporation giving a pale yellow oil (14.15 g, 34:1 linear:branched isomer, 94 wt % linear isomer by GC internal standard assay, 13.26 g active, 76%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24]C3C=CC=C(C#N)C=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.BrC[C:36]1[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=1>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]#[N:43])[C:10](=[O:33])[CH:9]=2)[CH2:3]1
Reactant: N#Cc1ccccc1CBr
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)cc(=O)n(Cc2ccccc2C#N)c1=O

Procedure:
Title compound 18 was prepared by the methods used in the preparation of compound 17, except that α-bromo-o-tolunitrile was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.64 (d, J=6.8 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.8 Hz, 2H), 7.44 (t, J=7.6 Hz, 1H), 7.38 (t, J=7.5 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 5.45 (s, 1H), 5.15-5.32 (m, 4H), 3.36-3.47 (m, 2H), 2.98 (m, 2H), 2.10 (m, 1H), 1.91 (m, 1H), 1.68 (m, 2H). MS (ES) [m+H] calc'd for C25H25N6O2, 441.2; found 441.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[I:9]Cl>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:9]
Reactant: Nc1cc(Cl)ncn1
Reactant: ClI
Solvent: CN(C)C=O
Product: Nc1ncnc(Cl)c1I
Temperature: 45 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of 3.03 g (23.39 mmol) of 6-chloropyrimidin-4-amine in 60 mL of dimethylformamide was added dropwise a solution of iodine monochloride (2.34 mL, 46.70 mmol) in 40 mL of dimethylformamide. Then the mixture was stirred at 45° C. overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane and a 4% aqueous solution of sodium bicarbonate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed in vacuum. The product was purified by flash chromatography (0% to 20%, methanol-dichloromethane) to obtain 4.28 g (72% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([NH:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1.[CH3:25][C:26](=O)[CH3:27].[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([NH:18][CH:19]3[CH2:20][CH2:21][N:22]([CH:26]([CH3:27])[CH3:25])[CH2:23][CH2:24]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: [H][H]
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3cncnc32)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)N1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Yield: 27.2 %

Procedure:
A mixture of 4.9 parts of 9-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-9H-purin-8-amine, 1 part of a solution of thiopene in methanol 4%. 120 parts of methanol and 8 parts of 2-propanone was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1.5 parts (27.2%) of 9-[(4-fluorophenyl)methyl]-N-[1-(1-methylethyl)-4-piperidinyl]-9H-purin-8-amine; mp. 185.6° C. (compound 138).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH:9]=[C:8]2[C:24]1[N:33](S(C2C=CC(C)=CC=2)(=O)=O)[C:27]2=[N:28][CH:29]=[C:30]([F:32])[CH:31]=[C:26]2[CH:25]=1>O.CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH:9]=[C:8]2[C:24]1[NH:33][C:27]2=[N:28][CH:29]=[C:30]([F:32])[CH:31]=[C:26]2[CH:25]=1
Reactant: COc1cc2c(-c3cc4cc(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCN3CCOCC3)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(-c3cc4cc(F)cnc4[nH]3)cn(CCN3CCOCC3)c2cc1OC
Yield: 60.8 %

Procedure:
A solution of 2.08 g of potassium hydroxide in 7 ml of water is added to a solution of 0.83 g of 2-[5,6-dimethoxy-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl]-5-fluoro-1-(toluene-4-sulfonyl)—1H-pyrrolo[2,3-b]pyridine in 100 ml of methanol brought to reflux. The mixture is agitated at reflux for 3 hours 30 minutes. After returning to around 20° C., the mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 50 ml of water and extracted with three times 80 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: ethyl acetate/methanol (90/10 by volume)]. 0.37 g of 2-[5,6-dimethoxy-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl]-5-fluoro-1H-pyrrolo[2,3-b] pyridine is obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27].C(N(CC)CC)C>ClCCl>[CH3:1][N:2]([CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[S:28]([CH2:26][CH3:27])(=[O:30])=[O:29]
Reactant: CCS(=O)(=O)Cl
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N(C)C1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of compound 7B (15 mg, 0.044 mmol), ethanesulfonyl chloride (5 μL, 1.5 eq), triethylamine (15 μL, 3.0 eq) and dichloromethane (1 mL) was stirred at room temperature overnight. The clear solution was directly loaded on silica gel column and eluted with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (12.5 mg, 82% yield)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[N:28]1[CH:33]=[CH:32][C:31]([CH2:34]Cl)=[CH:30][CH:29]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:34][C:31]2[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2OCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
A mixture of 4-(2-Hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (18 mmol, 5 g), DMF (40 ml) and cesium carbonate (40 mmol, 13 g) was stirred at room temperature for 15 minutes, followed by addition of 4-picolyl chloride hydrochloride (18 mmol, 2.953 g). The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured onto ice/water and extracted with ethyl acetate (3×). The combined organic layer was washed with Sat. NaCl. The crude product was purified on silica column using 75% EtOAc/hexanes to give 4-[2-(Pyridin-4-ylmethoxy)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (4.5 g).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1COCC1.[CH2:15]([CH:18]1[CH2:23][CH2:22][CH:21]([CH:24]2[CH2:29][CH2:28][CH:27]([CH:30]=[O:31])[CH2:26][CH2:25]2)[CH2:20][CH2:19]1)[CH2:16][CH3:17].Cl>[Zn].C(OCC)(=O)C>[F:8][C:2]([F:9])([CH:30]([OH:31])[CH:27]1[CH2:26][CH2:25][CH:24]([CH:21]2[CH2:22][CH2:23][CH:18]([CH2:15][CH2:16][CH3:17])[CH2:19][CH2:20]2)[CH2:29][CH2:28]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCC1CCC(C2CCC(C=O)CC2)CC1
Reactant: CCOC(=O)C(F)(F)Br
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC1CCC(C2CCC(C(O)C(F)(F)C(=O)OCC)CC2)CC1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 10.7 g of well-dried zinc, 25.0 g of ethyl bromodifluoroacetate (e-14) and 25 ml of THF were added, and the resultant mixture was cooled to 0° C. and stirred for 1 hour. The solution was slowly added dropwise in a temperature range of 20° C. to 25° C. to another reaction vessel under a nitrogen atmosphere in which 19.4 g of 4′-propyl-[1,1′-bi(cyclohexane)]-4-carboaldehyde (e-1) and 100 ml of THF were put, and the resultant mixture was further subjected to heating reflux for 4 hours. After cooling the resultant reaction mixture to 25° C., 300 ml of 1 N HCl aqueous solution and 300 ml of ethyl acetate were added to separate the mixture into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was isolated, and washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then the resultant solution was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the resultant residue was purified by a preparative isolation operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 in a volume ratio) as an eluent and silica gel as a filler, the resultant product was dried, and thus 16.2 g of ethyl 2,2-difluoro-3-hydroxy-3-(4′-propyl-[1,1′-bi(cyclohexane)]-4-yl)propanoate (e-15) was obtained. A yield based on compound (e-1) was 54.8%.
Reaction SMILES: [ClH:1].C[N:3]1C(C)=C(C)C(=O)[C:5](OCC2C=CC=CC=2)=[C:4]1OC.[CH3:22][O:23][CH2:24][C:25]1O[C:27]([CH3:40])=[CH:28][C:29](=[O:39])[C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N)C>>[ClH:1].[CH2:4]([N:3]1[C:27]([CH3:40])=[CH:28][C:29](=[O:39])[C:30]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:25]1[CH2:24][O:23][CH3:22])[CH3:5]
Reactant: COc1c(OCc2ccccc2)c(=O)c(C)c(C)n1C
Reactant: COCc1oc(C)cc(=O)c1OCc1ccccc1
Agent: CCN
Agent: Cl
Product: CCn1c(C)cc(=O)c(OCc2ccccc2)c1COC

Procedure:
The title compound was prepared by the method outlined for 1,6-dimethyl-2-methoxy-methyl-3-benzyloxy-pyridin-4(1H)-one hydrochloride, using 6.5 g (25 mmol, 1 eq.) of 2-(1-methoxymethyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one and 4.82 g (75 mmol, 3 eq.) of 70% aqueous ethylamine to yield the pure product 3.7 g (45.7%) after recrystallisation from methanol/diethyl ether, as a white crystalline solid m.p. 114-116° C.
Reaction SMILES: [C:1](/[C:3](=[C:12](/OCC)\[CH3:13])/[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:19]=1[NH2:20]>C(O)C>[C:1](/[C:3](=[C:12](/[NH:20][C:19]1[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:18]=1[CH3:17])\[CH3:13])/[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: CCOC(=O)NC(=O)/C(C#N)=C(/C)OCC
Reactant: Cc1cccc(C)c1N
Solvent: CCO
Product: CCOC(=O)NC(=O)/C(C#N)=C(/C)Nc1c(C)cccc1C

Procedure:
α-Cyano-β-ethoxy-N-ethoxycarbonylcrotonamide (0.05 mol) is reacted with 2,6-dimethylaniline (0.05 mol) in hot ethanol using the procedure of Example 1 to yield α-cyano-β-(2,6-dimethylanilino)-N-ethoxycarbonylcrotonamide, which is cyclized by heating in tetralin to yield 5-cyano-1-(2,6-dimethylphenyl)-6-methyl-uracil, m.p. 302°-303°.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:67][C:68]1[O:69][C:70]2[C:76]([C:77]([F:80])([F:79])[F:78])=[CH:75][CH:74]=[CH:73][C:71]=2[N:72]=1>>[F:78][C:77]([F:80])([F:79])[C:76]1[C:70]2[O:69][C:68]([S:67][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]4[C:39]([N:51]5[CH2:56][CH2:55][O:54][CH2:53][CH2:52]5)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=4[N:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[O:36])[CH2:32][CH2:33]3)=[N:72][C:71]=2[CH:73]=[CH:74][CH:75]=1
Reactant: FC(F)(F)c1cccc2nc(S)oc12
Reactant: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCOCC2)n1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCSc3nc4cccc(C(F)(F)F)c4o3)CC2)c(N2CCOCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercapto-7-trifluoromethylbenzoxazole, to thereby yield the title compound as a colorless foamed substance.