Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1C=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1C#N.[OH-].[Na+].[C:16]([O:19]CC)(=[O:18])[CH3:17].CCCCCC>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:17]=1[C:16]([OH:19])=[O:18]
Reactant: CCOC(C)=O
Reactant: N#Cc1cc(C(F)(F)F)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCCC
Product: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Temperature: 0 °C
Yield: 9 %

Procedure:
A solution of 570 g (2.77 moles) of 2-chloro-5-trifluoromethylbenzonitrile (1) and 1140 g (28.5 moles) NaOH in 2.3 L water was heated at reflux in a 12 L flask overnight. TLC (silica gel, 20% ethyl acetate-hexane with 1 drop acetic acid/10 ml solution) showed reaction was complete. The solution was cooled, diluted with 3.5 L ice water and extracted with 1 liter ether. The aqueous extract was cooled in an ice bath, acidified to pH 2 with cold 50% H2SO4 and extracted with four 1.3 liter portions of ether. The ether extracts were dried over Na2SO4 and evaporated and the residue was triturated with 1.2 liters hot hexane, cooled, and filtered to afford 615 g (9%) of 2-chloro-5-trifluoromethylbenzoic acid as white needles, m.p. 93°-94° C.
Reaction SMILES: [CH2:1]=[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[O:3]1.C(N(CC)CC)C.[C-]#N.[K+].[CH3:21][C:22]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C(#N)C>[O:10]=[C:4]1[CH:5]2[CH2:9][CH:8]([CH2:7][CH2:6]2)[C:2]([O:3][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:32])[F:33])=[N:30][C:22]=2[CH3:21])=[CH:1]1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Reactant: C=C1OC(=O)C2CCC1C2
Agent: [C-]#N
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(C(F)(F)F)ccc1C(=O)OC1=CC(=O)C2CCC1C2
Temperature: 20 °C

Procedure:
2.07 g (0.015 mol) of distilled 4-methylene-3-oxabicyclo[3.2.1]octan-2-one and 3.34 g (0.033 mol) of triethylamine are stirred for 2.5 hours at a temperature of 60° C. in 50 ml of acetonitrile in the presence of 98 mg (1.5 mmol) of potassium cyanide. Cooling to a temperature of 20° C. is then carried out and 2.35 g (0.11 mol) of 2-methyl-6-trifluoromethylnicotinoyl chloride, freshly prepared according to WO 00/15615, dissolved in a small amount of acetonitrile are added. The 2-methyl-6-trifluoromethylnicotinic acid 4-oxobicyclo[3.2.1]oct-2-en-2-yl ester (known from WO 00/15615) obtained in situ as intermediate is fully converted within a period of 3.5 hours (monitoring by thin-layer chromatography). The reaction mixture is then acidified with dilute hydrochloric acid and extracted with ethyl acetate against water at a pH value of 2, dried over Na2SO4 and concentrated by evaporation. The product is purified by means of column chromatography (eluant: ethyl acetate/hexane 4:1) to yield 3.16 g of 90% 4-hydroxy-3-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)-bicyclo[3.2.1]oct-3-en-2-one (58.3% based on the 4-methylene-3-oxabicyclo[3.2.1]octan-2-one used or 83.3% based on the 2-methyl-6-trifluoromethylnicotinoyl chloride used).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.CN(C1C=CC=CN=1)C.[CH3:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1>C1C=CC=CC=1>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[O:1][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([CH3:24])[CH2:26][CH2:27]1)=[O:32]
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: Oc1ccc2oc3ccccc3c2c1
Agent: CN(C)c1ccccn1
Solvent: c1ccccc1
Product: CC1CCN(C(=O)Oc2ccc3oc4ccccc4c3c2)CC1
Yield: 104.2 %

Procedure:
A mixture of 2-hydroxydibenzofuran (10.0 g, 54.3 mmol), dimethylaminopyridine (DMAP) (7.3 g, 59.8 mmol) and 4-methyl-1-piperidinecarbonyl chloride (8.8 ml, 59.7 mmol) in 200 mL of benzene was refluxed under nitrogen for 7 hours. The reaction was extracted with 1N HCl and then the organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give 17.51 g of a light brown solid. Recrystallization of the solid from diisopropyl ether gave 10.82 g (64%) of the title compound as a light brown crystalline solid, mp 123°-125° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:11]1[CH:18]3[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:20][CH:12]1[CH2:13]4)[CH2:17]3)[CH2:8]2.[Cl:21]Cl>ClC(Cl)(Cl)Cl>[Cl:21][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[C:2]1=[C:11]1[CH:12]3[CH2:20][CH:16]4[CH2:15][CH:14]([CH2:19][CH:18]1[CH2:17]4)[CH2:13]3)[CH2:10]2
Reactant: C1C2CC3CC1CC(C2)C3=C1C2CC3CC(C2)CC1C3
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Product: ClC12CC3CC(CC(C3)C1=C1C3CC4CC(C3)CC1C4)C2

Procedure:
In Tetrahedron Letters 1970, 4579-82, J. H. Wieringa, J. Strating and H. Wynberg describe a process in which adamantylidene adamantane is reacted with chlorine is tetrachloromethane at a temperature of -20° to +10° C. to form 4-eq.-chloroadamantylidene adamantane in addition to polychlorinated products. The chloro-substituted adamantane compound is the starting point for further reaction in the presence of AgNO3 and THF/H2O to form a mixture of the corresponding 4-hydroxy-adamantylidene adamantane compounds, which with the appropriate oxidant (Jones reagent: CrO3, H2SO4, acetone) are finally converted into the corresponding ketone compound, in which the carbonyl group is in the 4-position.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][C:6]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][CH2:14][CH2:15]Br>C(Cl)Cl.CO>[C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:15][CH2:14][O:13][CH3:12])[C:6]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(N)sc1C(C)(C)C
Reactant: COCCBr
Solvent: ClCCl
Solvent: CO
Product: COCCn1c(C)c(C(C)(C)C)sc1=N
Temperature: 85 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
A mixture of 5-tert-butyl-4-methylthiazole-2-ylamine (1.5 g, 8.8 mmol) and 2-bromoethyl methyl ether (0.91 mL, 9.7 mmol) was warmed to 85° C. and allowed to stir for 24 hours. The crude material was dissolved in ˜5 mL of a 1:1 mixture of CH2Cl2 and CH3OH and a small amount of silica gel was added. This mixture was concentrated to dryness and the residue was purified via flash column chromatography (SiO2, 9:1:01: CH2Cl2:CH3OH:NH4OH) to afford the title compound (1.0 g, 4.4 mmol, 50% yield). 1H NMR (300 MHz, CD3OD) δ ppm 1.41 (s, 9H) 2.38 (s, 3H) 3.35 (s, 3H) 3.66 (t, J=4.70 Hz, 2H) 4.16 (t, J=4.70 Hz, 2H); MS (DCI/NH3) m/z 229 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:24]([CH2:28][CH2:29]C)[CH2:25][CH2:26]O)=[O:23])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:31]C(C)([O-])C.[K+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:29][CH2:28][N:24]([CH:25]([CH3:26])[CH3:31])[C:22]4=[O:23])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)[O-]
Reactant: CCCN(CCO)C(=O)Nc1ccc(N2CCN(c3ccc(OC)cc3)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3ccc(N4CCN(C(C)C)C4=O)cc3)CC2)cc1
Yield: 76.8 %

Procedure:
To a slurry of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-N′-2-methylethyl-N′-[2-hydroxyethyl]urea (Formula Va, 35.0 mmol, 14.4 g) in tetrahydrofuran (600 mL) was added potassium tert-butoxide (123.0 mmol, 11.2 g). The reaction vessel was cooled in an ice bath and a tetrahydrofuran (200 mL) solution of p-toluenesulfonyl chloride (57.0 mmol, 10.9 g) was added over a period of 0.5 hours. The resulting beige mixture was allowed to stir at ambient temperature for 14 hours before addition of water (200 mL). The mixture was filtered and the product was washed with water (200 mL) and dried. A white powder of 1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3-(1-methylethyl)-2-oxoimidazolidine (10.6 g) was obtained in 77% overall yield from 4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=9.2 Hz, 2 H, Ar), 6.96 (d, J=9.2 Hz, 2 H, Ar), 6.95 (d, J=9.2 Hz, 2 H, Ar), 6.86 (d, J=9.2 Hz, 2 H, Ar), 4.30-4.20 (m, 1 H, CH), 3.76 (s, 3 H, OCH3), 3.82-3.72 (m, 2 H, CH2), 3.45-3.38 (m, 2 H, CH2), 3.32-3.20 (m, 8 H, CH2). The product was shown by HPLC retention time and NMR spectroscopy to be identical to an authentic standard prepared by the literature procedure. More importantly, the product of the present invention was demonstrated by HPLC to be purer (99.97 area %) relative to that of material prepared by the literature procedure (99.39 area %). Furthermore the product of the present invention did not contain the impurity which may negatively impact the quality of Pramiconazole, and which was present in material prepared by the literature procedure.
Reaction SMILES: [CH2:1]([C:6]1[C:11]([CH:12]=[CH:13][C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=[C:8]([C:18]([F:21])([F:20])[F:19])[N:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Li+].[OH-]>C1COCC1.O>[CH2:1]([C:6]1[C:11]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=[C:8]([C:18]([F:21])([F:19])[F:20])[N:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1nc(C(F)(F)F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCc1nc(C(F)(F)F)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a suspension of compound 3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid, methyl ester (366 mg, 1.22 mmol) in THF (3 ml) was added a solution of 1 N-LiOH (3.0 ml), and the mixture was stirred for 3 hours at room temperature. The resulting residue was dissolved in H2O and then washed with EtOAc, acidified with 1N HCl to pH 1˜2. The solution was extracted three times with methylene chloride and then dried over anhyd. MgSO4 and concentrated in vacuo to give 3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (340 mg, 97%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]2[O:31][CH2:30][CH2:29][O:28]2)[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.Cl.O1CCOCC1>CO>[CH3:29][O:28][CH:27]([O:31][CH3:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:17]1[CH:16]=[C:15]([CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:7])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCCCCCC2OCCO2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(CCCCCOc1cccc(C(N)c2ccccc2)c1)OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 85.2 %

Procedure:
To a solution of tert-butyl((3-((5-(1,3-dioxolan-2-yl)pentyl)oxy)phenyl)(phenyl)-methyl)carbamate (0.483 g, 1.10 mmol) in methanol (4 mL), was added hydrogen chloride in dioxan (4 M, 4 mL, 16 mmol). The reaction was stirred at ambient temperature for 7 hours. The solvent was evaporated at reduced pressure, and the residue loaded onto an SCX-2 cartridge. The cartridge was eluted with methanol (eight column volumes) followed by ammonia/methanol. Fractions containing the product were combined and evaporated at reduced pressure to afford the title compound as a colourless oil (0.322 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:27]([O:29][CH3:30])=[O:28])[C:5]2[C:6](=[O:26])[CH:7]([C:20]3[N:24]([CH3:25])[N:23]=[CH:22][N:21]=3)[CH:8]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:9](O)[C:10]=2[CH:11]=1.Cl>CO.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([C:27]([O:29][CH3:30])=[O:28])[C:5]2[C:6](=[O:26])[CH:7]([C:20]3[N:24]([CH3:25])[N:23]=[CH:22][N:21]=3)[CH:8]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[NH:9][C:10]=2[CH:11]=1
Reactant: COC(=O)c1cc(F)cc2c1C(=O)C(c1ncnn1C)C(c1ccc(F)cc1)N2O
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(F)cc2c1C(=O)C(c1ncnn1C)C(c1ccc(F)cc1)N2
Yield: 30.1 %

Procedure:
To a stirred solution of methyl 7-fluoro-2-(4-fluorophenyl)-1-hydroxy-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (10) (41.4 mg, 0.1 mmol) in methanol (5 mL) was added concentrated HCl solution (w/w 37%, 1 mL) and reductive powdered Fe (56 mg, 1 mmol). The reaction mixture was refluxed for 3 hours. After the disappearance of compound (10) as monitored by LC-MS, the reaction system was partitioned between ethyl acetate (20 mL) and water (20 mL) and then the aqueous phase was extracted with ethyl acetate (10 mL×3). The combined organic phase was dried with Na2SO4, concentrated in vacuo and purified by column chromatography (ethyl acetate:petroleum ether=1:1) to give the title compound (5) as a pale yellow solid (12 mg, yield 30%). LC-MS (ESI) m/z: 399 (M+1)+. 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.58 (s, 3H), 3.87 (s, 3H), 4.17 (d, 1H), 4.87 (s, 1H), 5.38 (d, 1H), 6.50 (dd, 2H), 6.99 (dd, 2H), 7.38 (dd, 2H), 7.80 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:16](Br)=[C:15](Br)[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:28])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccc(OC)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(OC)cc2)c1O

Procedure:
Prepared in analogy to that of Example 6(a) from 2,3-dibromo-7-cyano-4-hydroxy-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, ammonium formate and Pd/C. The title compound, ESI MS (m/z): 352 (M+H)+.
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[F:7][C:8]([F:17])([F:16])[C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)N.C(O)(=O)C>O>[F:7][C:8]([F:17])([F:16])[C:9]1[CH:15]=[C:14]([NH:6][C:2]([CH3:1])=[CH:3][C:4]#[N:5])[CH:13]=[CH:11][CH:10]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: C/C(N)=C\C#N
Solvent: CC(=O)O
Solvent: O
Product: CC(=CC#N)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Aminocrotonitrile (1.0 g, 12.2 mmol), 3-trifluoromethylaniline (2.0 g, 12.4 mmol), and acetic acid (1.23 g, 20.5 mmol) are dissolved in water (8 ml). The reaction mixture is stirred at room temperature for 30 minutes. The mixture is extracted with toluene three times and the organic phase is dried over sodium sulfate. The solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH2:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.Br[C:16]1[CH:24]=CC=C2[C:17]=1C(CCN)=CN2.[O-]S([O-])(=O)=O.[Na+].[Na+]>CC(C)=O.C(O)CCC>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]3[CH2:12][CH2:13][NH:14][C:16]([CH3:24])([CH3:17])[C:8]=3[NH:9]2)=[CH:5][CH:4]=1
Reactant: NCCc1c[nH]c2cc(Br)ccc12
Reactant: NCCc1c[nH]c2cccc(Br)c12
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CC(C)=O
Product: CC1(C)NCCc2c1[nH]c1cc(Br)ccc21
Temperature: 60 °C
Reaction time: 96 h
Yield: 15 %

Procedure:
Concentrated HCl (10 mL) was added to a suspension of a 2:1 mixture of 2-(6-bromo-1H-indol-3-yl)ethanamine and 2-(4-bromo-1H-indol-3-yl)ethanamine (9.90 g, 41.4 mmol) and Na2SO4 (30 g) in 1:1 acetone/n-butanol (100 mL). The resulting suspension was heated at 60° C. with stirring for 4 d. The suspension was cooled and concentrated under reduced pressure. The residue was diluted with EtOAc, and the suspension was filtered. The filtrate was washed with saturate NaHCO3 solution, dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH) 100:0 to 0:100) yielded the title compound (1.68 g, 15%) as a red foam: 1H NMR (500 MHz, CDCl3) δ 7.66 (br s, 1H), 7.45 (d, J=1.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 1.5 Hz, 1H), 3.20 (t, J=5.5 Hz, 2H), 2.68 (t, J=5.5 Hz, 2H), 1.47 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:17])[CH:4]=[C:5]([CH3:16])[C:6](=[O:15])[C:7]=1[C:8]([CH3:14])([CH3:13])[CH2:9][C:10]([OH:12])=[O:11].[Cl:18][CH2:19][CH2:20][N:21]([CH2:29][CH2:30][Cl:31])[C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1>>[CH3:1][C:2]1[C:3](=[O:17])[CH:4]=[C:5]([CH3:16])[C:6](=[O:15])[C:7]=1[C:8]([CH3:13])([CH3:14])[CH2:9][C:10]([O:12][C:25]1[CH:24]=[CH:23][C:22]([N:21]([CH2:20][CH2:19][Cl:18])[CH2:29][CH2:30][Cl:31])=[CH:27][CH:26]=1)=[O:11]
Reactant: Oc1ccc(N(CCCl)CCCl)cc1
Reactant: CC1=CC(=O)C(C)=C(C(C)(C)CC(=O)O)C1=O
Product: CC1=CC(=O)C(C)=C(C(C)(C)CC(=O)Oc2ccc(N(CCCl)CCCl)cc2)C1=O
Yield: 9 %

Procedure:
Using an analogous procedure to that described in Example 5, 3-(2,5-dimethyl-1,4-benzoquinonyl)-3-methylbutyric acid was reacted with 4-[bis(2-chloroethyl)amino]phenol to give 4-[bis(2-chloroethyl)amino]phenyl 3-(2,5-dimethyl-1,4-benzoquinonyl)-3-methylbutyrate as a solid in 9% yield; NMR Spectrun: (CDCl3) 1.52 (s, 6H), 1.98 (m, 3H), 2.16 (s, 3H), 3.2 (s, 2H), 3.55-3.73 (m, 8H), 6.42 (m, 1 H), 6.6-6.9 (m, 4H); Mass Spectrum: (M+H+) 452.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.[CH2:15]([N:19](CCCC)CCCC)[CH2:16][CH2:17][CH3:18].C(N)CCC>C(Cl)Cl>[CH2:15]([NH:19][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN(CCCC)CCCC
Reactant: O=C(O)CCCCCCCCCCBr
Solvent: ClCCl
Solvent: CCCCN
Product: CCCCNC(=O)CCCCCCCCCCBr
Temperature: -10 °C
Reaction time: 3 h

Procedure:
11-Bromoundecanoic acid (45 mmol) was dissolved in dry CH2Cl2 (200 ml) and tributylamine (54 mmol). After the mixture had cooled at −10° C., isobutylchlorofomate (60 mmol) was added and allowed to react for 2 hrs. At this moment, excess N-butylamine (225 mmol) was added and later the cooling bath was removed. After 3 hrs, CH2Cl2 was added and the organic phase was washed with 1 N HCl, saturated NaHCO3, and water. After drying by MgSO4, the solvent was removed and the crude product was purified by column chromatography. The pure amide product was eluted with solvent, hexane (80)—EtOAc (20).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2(O)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Br)n2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(Br)n2)CC1
Temperature: 0 °C

Procedure:
To a solution of tert-butyl 4-(6-bromopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (100 mg) in pyridine (2.5 ml) is added, at 0° C. under argon, POCl3 (0.26 ml). The mixture is stirred at 0° C. and then slowly warmed to room temperature. The mixture is stirred at room temperature overnight. The reaction mixture is subsequently admixed with saturated sodium hydrogencarbonate solution and the aqueous phase is removed. After the aqueous phase has been extracted with tert-butyl methyl ether, the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography. This gives tert-butyl 6-bromo-3′,6′-dihydro-2,4′-bipyridine-1′(2′H)-carboxylate (60 mg).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[F:14][C:15]([F:34])([F:33])[O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][NH:27][CH2:26][CH:25]([C:29]([O:31][CH3:32])=[O:30])[CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[F:34][C:15]([F:14])([F:33])[O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][N:27]([C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[CH2:26][CH:25]([C:29]([O:31][CH3:32])=[O:30])[CH2:24]2)=[CH:19][CH:18]=1
Reactant: COC(=O)C1CNCC(c2ccc(OC(F)(F)F)cc2)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., 5.32 g (26.4 mmol) of 4-nitrophenyl chloroformate were added slowly to 8.0 g (26.4 mmol) of methyl 5-(4-(trifluoromethoxy)phenyl)piperidine-3-carboxylate and 5.34 g (26.3 mmol) of triethylamine in 666 ml of dichloromethane. The mixture was stirred at RT for 2 h. For workup, the reaction mixture was washed first with saturated aqueous sodium hydrogencarbonate solution, then with water. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by means of flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:2->1:1). Yield: 7.32 g (54% of theory)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([F:12])[CH:3]=1.C(OCC)C.C([Li])CCC.[F:23][C:24]1[CH:29]=[C:28]([CH:30]2[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:25]=1[C:39]([F:43])=[C:40](F)[F:41]>C1(C)C=CC=CC=1>[F:43]/[C:39](/[C:25]1[CH:26]=[CH:27][C:28]([CH:30]2[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:31]2)=[CH:29][C:24]=1[F:23])=[C:40](/[F:41])\[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([F:12])[CH:3]=1
Reactant: Fc1cc(Br)ccc1C(F)(F)F
Reactant: CCCC1CCC(c2ccc(C(F)=C(F)F)c(F)c2)CC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCC1CCC(c2ccc(/C(F)=C(\F)c3ccc(C(F)(F)F)c(F)c3)c(F)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (2.28 g) and diethyl ether (70 ml) were added, and cooling was carried out to −70° C. Thereto, a n-butyllithium (1.57 M) n-hexane solution (7.10 ml) was added dropwise in a temperature range of −70° C. to −65° C., and stirring was carried out for another 1 hour. Subsequently, a diethyl ether (10 ml) solution of compound (T-9) (2.68 g) was added dropwise in a temperature range of −70° C. to −65° C., and stirring was carried out for 4 hours while returning to room temperature. The resultant reaction mixture was poured into ice water (100 ml), and mixing was carried out. Toluene (100 ml) was added to separate layers into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was sequentially washed with a 1 N hydrochloric acid solution, a saturated aqueous solution of sodium hydrogencarbonate and water, and drying over anhydrous magnesium sulfate was carried out. The resultant solution was concentrated under reduced pressure, and a residue was purified by fractionation by means of column chromatography (silica gel; heptane), and further purified by recrystallization from a heptane/Solmix A-11 mixed solvent, and thus (E)-1-(1,2-difluoro-2-[3-fluoro-4-(trifluoromethyl)phenyl]vinyl)-2-fluoro-4-(4-propylcyclohexyl)benzene (1-1-25) (2.24 g) was obtained. The yield based on compound (T-9) was 57%.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1)=[O:3].C(O)C.[H-].[Na+].Cl.[C:17](=O)([O:21]CC)[O:18][CH2:19][CH3:20]>O>[Cl:10][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:17]([O:18][CH2:19][CH3:20])=[O:21])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloroacetophenone (23.9 g, 154 mmol) in diethyl carbonate (150 ml) was added ethanol (0.3 ml), and sodium hydride (60% in oil, 12.4 g, 309 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 2 hrs. To the reaction solution was added 6N hydrochloric acid to stop the reaction, and water (500 ml) was added. Then, the mixture was extracted with ethyl acetate (500 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1-5:1) to give the objective substance (24.8 g, 71%).