Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][CH3:12])[CH:5]=1.C([O-])(=O)C.[Na+].[Br:18]Br.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[CH3:12][O:11][CH2:10][C:6]1[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=[CH:8][C:7]=1[Br:18]
Reactant: BrBr
Reactant: COCc1cccc(COC)c1
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COCc1ccc(Br)c(COC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.9 %

Procedure:
To a solution of m-xylylene dichloride (25.0 g) in methanol (125 ml) was added a 28% methanol solution (82.6 g) containing sodium methoxide at room temperature, and the mixture was stirred with heating at 60° C. for 3 hr. The solvent was evaporated and water (150 ml) was added to the residue. The mixture was extracted twice with heptane (80 ml) and heptane was evaporated under reduced pressure to give m-xylylene glycol dimethyl ether (25.3 g). m-Xylylene glycol dimethyl ether (25.3 g) was dissolved in acetic acid (125 ml) and sodium acetate (68 g) was added, which was followed by dropwise addition of bromine (68 g) at room temperature. The mixture was stirred at room temperature for 3 hr and poured into 10% aqueous sodium sulfite solution (750 ml), which mixture was extracted twice with heptane (350 ml). The heptane layer was extracted twice with 10% aqueous sodium hydroxide solution (150 ml) and once with water (150 ml). The solvent was evaporated and the residue was purified by silica gel column chromatography using heptane-ethyl acetate (15:1) as an eluent to give the title compound (10.4 g, yield:29.7%) as a colorless transparent oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14].CO.CCOC(C)=O>C1COCC1>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccnc1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a stirred suspension of NaH (60% dispersion in oil, 0.65 g, 16.2 mmol) at 0° C. was added imidazole (1 g, 14.7 mmol) in THF (14 mL). The mixture was warmed to room temperature over 30 min, then re-cooled to 0° C. followed by an addition of (2-(chloromethoxy)ethyl)trimethylsilane (2.73 ml, 15.4 mmol). The combined mixture was warmed to room temperature over 1 h, quenched with saturated aqueous ammonium chloride, concentrated to dryness and partitioned between water and EtOAc. Organic phase was collected, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (eluents EtOAc, then MeOH/EtOAc 20:80), to afford the title compound (2.04 g, 70% yield) as a white solid. MS (m/z) 199.3 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]([O:32]C2CCCCO2)[C:12]2[CH:31]=[CH:30][C:15]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:27])[CH2:25][CH3:26])=[C:20]([OH:28])[C:19]=3[CH3:29])=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1)=O.[S-:39][C:40]#[N:41].[K+].C1(C)C=CC(S(O)(=O)=[O:50])=CC=1>C(O)C>[OH:32][CH:11]([C:12]1[CH:13]=[CH:14][C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:27])[CH2:25][CH3:26])=[C:20]([OH:28])[C:19]=2[CH3:29])=[CH:30][CH:31]=1)[C:7]1[CH:6]=[C:5]([C:3]2[NH:41][C:40](=[O:50])[S:39][CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CCC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C(=O)CCl)c3)cc2)c(C)c1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Product: CCC(=O)c1ccc(OCc2ccc(C(O)c3cccc(-c4csc(=O)[nH]4)c3)cc2)c(C)c1O
Yield: 308.2 %

Procedure:
Heat a solution of 1-(4-{4-[[3-(2-chloro-acetyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzyloxy}-2-hydroxy-3-methyl-phenyl)-propan-1-one (0.250 mg, 0.466 mmol) and potassium thiocyanate (90.5 mg, 0.931 mmol) in ethanol (0.20 M) overnight at 70° C. Add p-toluenesulfonic acid (10 mg) and stir overnight. Evaporate solvents and chromatograph residue. Major fraction isolated was the title compound (0.086 g, 0.179 mmol, 39%): 1H NMR (400 MHz, DMSO-d6) δ 1.09 (t, J=7.2 Hz, 3H), 2.02 (s, 3H), 3.03 (q, J=9.6 Hz, 2H), 5.10 (s, 2H), 5.20 (s, 2H), 5.82 (d, J=3.9 Hz, 1H), 6.11 (d, J=3.9 Hz, 1H), 6.70 (d, J=9.0 Hz, 1H), 7.42 (q, J=11.2 Hz, 4H), 7.51 (t, J=7.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 8.04 (s, 1H), 12.88 (s, 1H). MS (m/z): 474 (M−H).
Reaction SMILES: F[C:2]1[CH:10]=[C:9](F)C=CC=1C([Cl:6])=O.FC1C=CC(F)=CC=1OC.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:30]([C:32]1[CH:37]=[C:36]([F:38])[C:35]([O:39][CH3:40])=[CH:34][C:33]=1[F:41])=[O:31].Br.BrC/C=C/CBr.[CH2:49]([NH:52][CH3:53])[CH:50]=[CH2:51]>>[CH2:49]([N:52]([CH3:53])[CH2:2]/[CH:10]=[CH:9]/[CH2:40][O:39][C:35]1[C:36]([F:38])=[CH:37][C:32]([C:30]([C:24]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=2[F:22])=[O:31])=[C:33]([F:41])[CH:34]=1)[CH:50]=[CH2:51].[ClH:6]
Reactant: C=CCNC
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: COc1cc(F)c(C(=O)c2ccc(F)cc2F)cc1F
Agent: Br
Agent: BrC/C=C/CBr
Agent: COc1cc(F)ccc1F
Product: C=CCN(C)C/C=C/COc1cc(F)c(C(=O)c2ccc(F)cc2F)cc1F
Product: Cl

Procedure:
from 2,4-difluorobenzoyl chloride and 2,5-difluoroanisole via (2,4-difluoro-phenyl)-(2,5-difluoro-4-methoxy-phenyl)-methanone, which is deprotected with hydrogen bromide and reacted with (E)-1,4-dibromo-2-butene and N-allyl-methyl-amine, there is obtained (E)-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-2,5-difluoro-phenyl]-(2,4-difluoro-phenyl)-methanone•hydrochloride (1:1), m.p. 141° C.,
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[S:36](Cl)(=[O:38])=[O:37]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:36]([C:27]4[CH:28]=[CH:29][C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:26]=4)(=[O:38])=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc5ccccc5c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and naphthalene-2-sulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[CH:13]1([CH2:18][CH2:19][C:20](OC)=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(CCC(O)=O)CCCC1.S(=O)(=O)(O)O>C1COCC1.CO>[CH:13]1([CH2:18][CH2:19][C:20](=[O:21])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)CCC1CCCC1
Reactant: COP(C)(=O)OC
Agent: O=C(O)CCC1CCCC1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: COP(=O)(CC(=O)CCC1CCCC1)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
To a solution of dimethyl methylphosphonate (2.17 ml, 20 mmol) in anhydrous THF (20 mL), cooled at −78° C. was added n-BuLi (1.6 M in hexane, 13.7 mL, 22 mmol). The mixture was stirred for 30 minutes at this temperature under nitrogen. Methyl 3-cyclopentylpropanoate (1.56 g, 10 mmol), prepared from 3-cyclopentylpropionic acid (Aldrich) and methanol at the presence of the catalytic amount of the concentrated sulfuric acid (the procedure described in Intermediate 17.1), was added dropwise for 10 minutes. The mixture was stirred for 2 hours at −78° C., gradually was warm to room temperature. The mixture was quenched with addition of 1N HCl to pH 4-5. The organic layer was separated, washed with brine and dried over MgSO4. The residue was purified through flash chromatography on silica gel (EtOAc:Hexanes=1:1) to give the product (1.80 g) with colorless oil in 82% yield. 1HNMR (CD3OD, ppm) δ 1.03 (m, 2H), 1.51 (m, 1H), 1.61 (m, 6H), 1.73 (m, 2H), 2.63 (t, J=7.4 Hz, 2H), 3.09 (d, J=22.7 Hz, 2H), 3.76 (s, 3H), 3.87 (s, 3H)
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[C:9]([O:10][CH3:11])=[N:8][C:7](Cl)=[CH:6][N:5]=1.[CH3:15][Zn]C.O>O1CCCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][O:10][C:9]1[C:4]([CH:3]=[O:2])=[N:5][CH:6]=[C:7]([CH3:15])[N:8]=1
Reactant: C[Zn]C
Reactant: COc1nc(Cl)cnc1C(OC)OC
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(C)cnc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
After dissolving 3.34 g of 5-chloro-3-methoxypyrazine-2-carboxaldehyde dimethylacetal in 50 ml of tetrahydrofuran, 400 mg of [1,3-bis(diphenylphosphino)propane]dichloronickel (II) was added, 9.17 ml of dimethyl zinc (2.0 M, toluene solution) was added dropwise under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours and then at 50° C. for 1.5 hours. The reaction solution was cooled on ice, water was added and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 16 ml of acetone, 4 ml of 5N hydrochloric acid was added and the mixture was allowed to stand at room temperature for 15 minutes. A sodium bicarbonate solution was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (1.43 g, 61% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C@@H:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:32]2[CH:33]=[CH:34][C:35](F)=[C:36]([CH:40]=2)C(N)=O)=[CH:4][CH:3]=1.NC1N=C(C(NC(=[O:72])CC2C3C(=CC=C(F)C=3)NC=2)CC2C=C(F)C=C(F)C=2)C(Br)=CC=1.[F:74][C:75]([F:87])([F:86])[CH2:76]C1C=C(B(O)O)C=CC=1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=2)[C:5]([C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([O:72][CH2:76][C:75]([F:87])([F:86])[F:74])[CH:40]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1
Reactant: NC(=O)c1cc(-c2ccc(N)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)ccc1F
Reactant: OB(O)c1cccc(CC(F)(F)F)c1
Product: Nc1ccc(-c2cccc(OCC(F)(F)F)c2)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 1H of Example 1 utilizing 1G and (3-(2,2,2-trifluoroethyl)phenyl)boronic acid. 1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 7.61-7.55 (m, 3H), 7.30 (dd, J=8.7, 4.6 Hz, 2H), 7.26-7.11 (m, 2H), 7.11-6.95 (m, 4H), 6.87 (t, J=9.4 Hz, 1H), 6.47 (m, 2H), 5.02 (d, J=6.6 Hz, 1H), 4.79-4.61 (m, 2H), 2.91 (m, 2H). MS (m/z) 599.2 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:7][O:6][C@H:5]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=2[F:16])[C@@H:4]([NH:17]C(=O)OC(C)(C)C)[CH2:3]1.[F:25][C:26]([F:38])([F:37])[C:27]1[N:28]=[CH:29][C:30]2[CH2:36][CH2:35][NH:34][CH2:33][C:31]=2[N:32]=1.[B][B][B][B][B][B][B][B][B][B].[ClH:49]>CO>[ClH:49].[ClH:49].[F:38][C:26]([F:25])([F:37])[C:27]1[N:28]=[CH:29][C:30]2[CH2:36][CH2:35][N:34]([C@H:2]3[CH2:7][O:6][C@H:5]([C:8]4[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=4[F:16])[C@@H:4]([NH2:17])[CH2:3]3)[CH2:33][C:31]=2[N:32]=1
Reactant: FC(F)(F)c1ncc2c(n1)CNCC2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(=O)CO[C@@H]1c1cc(F)c(F)cc1F
Agent: Cl
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: N[C@H]1C[C@@H](N2CCc3cnc(C(F)(F)F)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 8 h

Procedure:
To a solution of 45 mg (0.13 mmol) of tert-butyl [(2R,3S)-5-oxo-2-(2,4,5-trifluorophenyl) tetrahydro-2H-pyran-3-yl]carbamate and 27 mg (0.13 mmol) of 2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine in 2.0 mL of dry methanol was added 5.0 mg (0.039 mmol) of decaborane. The reaction mixture was stirred overnight and concentrated in vacuo, then purified by preparative thin layer chromatography using an Analtech® 1000 micron plate (5% methanol/methylene chloride, 1% concentrated ammonium hydroxide) to give the product which was stirred with hydrochloric acid in methanol (1.3M, 4 mL) for 1 h to give the title product. LC/MS 432.93 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[C:3]=1[OH:11].C(C1C=C(C=C(C)C=1O)[C:17]([NH:19][OH:20])=[NH:18])C>>[OH:11][C:3]1[C:4]([CH2:8][CH2:9][CH3:10])=[CH:5][C:6]([C:17]([NH:19][OH:20])=[NH:18])=[CH:7][C:2]=1[CH3:1]
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: CCCc1cccc(C)c1O
Product: CCCc1cc(C(=N)NO)cc(C)c1O

Procedure:
The title compound is prepared from commercially available 2-methyl-6-propyl-phenol in analogy to literature procedures (e.g B. Roth et al. J. Med. Chem. 31 (1988) 122-129; and literature cited for 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine); LC-MS: tR=0.54 min; [M+1]+=209.43; 1H NMR (D6-DMSO): δ0.90 (t, J=7.3 Hz, 3H), 1.48-1.59 (m, 3H), 2.19 (s, 3H), 2.56 (t, J=7.3 Hz, 2H), 7.37 (s, 1H), 7.40 (s, 1H), 9.34 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH3:20])[CH:10]=[CH:9][N:8]=1)(=[O:4])=[O:3].[SH:21][C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>C(O)C>[CH2:19]([O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:6][S:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=2)[C:12]=1[CH3:13])[CH3:20].[CH3:1][S:2]([O-:5])(=[O:4])=[O:3]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCOCCCOc1ccnc(COS(C)(=O)=O)c1C
Solvent: CCO
Product: CCOCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Product: CS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture comprising 4.2 g of {4-(3-ethoxypropoxy)-3-methylpyridine-2-yl}methyl methanesulfonate, 1.87 g of 2-mercaptobenzimidazole and 30 ml of ethanol was stirred at a room temperature for one hour and distilled to remove the ethanol. The obtained residue was purified by silica gel column chromatography to obtain 0.88 g of the title compound and 5.1 g of methanesulfonate of the title compound.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:9])[CH:6]([CH3:8])[CH3:7].[CH3:11][O:12][C:13]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].Cl>CCCCCC.C(OCC)(=O)C>[C:5]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:13]([O:12][CH3:11])=[O:14])=[CH:18][CH:19]=1)(=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)COc1ccc(C(=O)C(C)C)cc1
Temperature: 0 °C

Procedure:
To an oven-dried round bottom flask was added anhydrous AlCl3 (24.1 g, 0.18 mol), which was subsequently purged with Ar. Methylene chloride (10 mL) was added via syringe and the resulting slurry was cooled to 0° C. in an ice bath. The isobutryl chloride (6.9 mL, 6.6×10−2 mol) was added dropwise via syringe. The methyl phenoxy acetate (8.7 mL, 6.0×10−2 mol) was added dropwise via syringe. The reaction was stirred until deemed complete by thin layer chromatography (TLC) (25% ethyl acetate in hexane) (approximately 2 h). The reaction mixture was poured slowly into a mixture of ice (100 g) and concentrated HCl (40 mL). The organic layer was separated and the organic layer extracted with methylene chloride (3×100 mL). The combined organic layers were washed with water (3×100 mL) and dried over MgSO4. The solvent was removed in vacuo to reveal 14 g of a white, crystalline solid (quantitative yield). 1H NMR (300 NMR, CDCl3) δ7.97 (2H, d, J=8.9 Hz), 6.96 (2H, J=8.9 Hz), 4.71 (2H, s), 3.82 (3H, s), 3.51 (1H, septet, J=6.8 Hz), 1.22 (6H, d, J=6.8 Hz).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]>>[CH:14]([C:13]1[CH:12]=[C:11]([CH:18]=[CH:17][CH:16]=1)[O:10][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:15]
Reactant: N#Cc1ccc(F)cc1
Reactant: O=Cc1cccc(O)c1
Product: N#Cc1ccc(Oc2cccc(C=O)c2)cc1

Procedure:
4-Fluorobenzonitrile and 3-hydroxybenzaldehyde were processed as described in Example 48A to provide the title compound.
Reaction SMILES: CN1CCC(N[C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])F)[CH:12]=[C:11]([NH2:19])[CH:10]=2)CC1.N1C=CC=C[CH:21]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].Cl>C(Cl)Cl.O>[F:18][C:15]([C:13]1[CH:12]=[C:11]([NH:19][C:27](=[O:28])[O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:10]=[CH:9][CH:14]=1)([F:17])[CH3:21]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC(Nc2cc(N)cc(C(F)(F)F)c2)CC1
Reactant: c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(F)(F)c1cccc(NC(=O)Oc2ccccc2)c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
Dissolve the amine obtained in Step 2 (760 mg, 4.8 mmol) and pyridine (765 mg, 9.7 mmol) in DCM (15 mL) and cool to 0-5° C. on ice bath. Add dropwise phenyl chloroformate (831 mg, 5.3 mmol). After addition, stir the mixture at 0-5° C. for 2 hrs. Pour the mixture to water (50 mL), adjust pH to neutral with 1M HCl solution. Extract with EtOAc (15 mL×3), combine the organic layers and wash with brine (100 mL), dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product (1.15 g) which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:33])[CH:4]([CH:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:5]([CH2:12][CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])([O:7][Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:6]=1.CS(Cl)(=O)=O.N12CCCN=C1CCCCC2.S([O-])(O)(=O)=O.[K+]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3](=[O:33])/[C:4](=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])/[C:5]([CH2:12][CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])([O:7][Si:8]([CH3:10])([CH3:11])[CH3:9])[CH:6]=1.[Cl:1][C:2]1[C:3](=[O:33])/[C:4](=[CH:22]/[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])/[C:5]([CH2:12][CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])([O:7][Si:8]([CH3:10])([CH3:11])[CH3:9])[CH:6]=1
Reactant: COC(=O)CCCCCC(O)C1C(=O)C(Cl)=CC1(CCC(C)CCCC(C)C)O[Si](C)(C)C
Agent: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCCCC/C=C1/C(=O)C(Cl)=CC1(CCC(C)CCCC(C)C)O[Si](C)(C)C
Product: COC(=O)CCCCC/C=C1\C(=O)C(Cl)=CC1(CCC(C)CCCC(C)C)O[Si](C)(C)C
Reaction time: 1.5 h
Yield: 52 %
Yield: 30 %

Procedure:
22 mg (44 micromoles) of 2-chloro-4-(3,7-dimethyloctyl)-5-(1-hydroxy-6-methoxycarbonyl)-4-trimethylsilyloxy-2-cyclopentenone obtained in Example 4 was dissolved in 500 microliters of pyridine, and 50 microliters (646 micromoles) of methanesulfonyl chloride was added. The mixture was stirred for 1.5 hours. 200 microliters (1.34 mmoles) of 1,8-diazabicyclo[5.4.0]undec-7-ene was added, and the mixture was stirred for 30 minutes. A saturated aqueous solution of potassium hydrogen sulfate was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was chromatographed on a thin silica gel layer to give 6.3 mg (yield 30%) of 2-chloro-4-(3,7-dimethyloctyl)-5-[(Z)-6-methoxycarbonylhexylidene]-4-trimethylsilyloxy-2-cyclopentenone and 11.0 mg (yield 52%) of 2-chloro-4 -(3,7-dimethyloctyl)-5-[(E)-6-methoxycarbonylhexylidene]-4-trimethylsilyloxy-2-cyclopentenone.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C@H:12]1[C@H:18]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:17]2[CH:32]=[CH:33][CH:34]=[CH:35][C:16]=2[O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[O:11]=[C:12]1[CH:18]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:17]2[CH:32]=[CH:33][CH:34]=[CH:35][C:16]=2[O:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN([C@@H]2c3ccccc3OCC[C@H]2O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C2C(=O)CCOc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
At −78° C., 0.88 ml of oxalyl chloride (10 mmol) is poured into 25 ml of dichloromethane and then, at the same temperature, there are slowly added 1.02 ml of dimethyl sulphoxide (14.3 mmol). Stirring is carried out for 10 minutes at −78° C. 2.5 g (7.17 mmol) of the compound obtained in Step B of Example 8, dissolved in 15 ml of dichloromethane, are poured into the reaction mixture. Stirring is carried out for 15 minutes at −78° C. and there are then added, over 20 minutes, 5 ml (35.9 mmol) of triethylamine. The mixture is then allowed to return to 0° C. and the reaction mixture is then poured into 100 ml of ice-cold water. Extraction with dichloromethane, drying, filtration and evaporation to dryness are carried out to yield the expected product in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.Cl([O-])(=O)(=O)=O.[Li+].[N:25]1([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:28]1[CH2:29][CH2:30][N:25]([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)[CH2:26][CH2:27]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: c1csc(N2CCNCC2)n1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: C[C@@H](N1CCN(c2nccs2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 77.3 %

Procedure:
To a mixture of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane IV (502 mg, 2 mmol) and lithium perchlorate (320 mg, 3 mmol) in acetonitrile (10 ml), 2-(piperazin-1-yl)thiazole (X)(507 mg, 3 mmol) was added. The resulting mixture was heated under reflux for 48 h. The reaction mixture was cooled, concentrated under reduced pressure. The residue was disolved in chloroform, washed with water, brine, dried (Na2SO4) and concentrated. The resulting product was purified on a column of silica gel using ethyl acetate and hexane (4:1) as eluent to give the title compound as colorless solid (650 mg, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Product: COc1cc2nc(NC(=O)N3CCN(c4cccc(Cl)c4)CC3)c(OC)nc2cc1OC
Yield: 74 %

Procedure:
Ethyl N-(2,6,7-trimethoxyquinoxalin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 190 to obtain the titled compound (yield, 74%). 1H NMR (300 MHz, CDCl3) δ 3.29-3.31 (m, 4H), 3.79 (m, 4H), 3.97 (s, 3H), 4.00 (s, 3H), 4.12 (s, 3H), 6.82 (m, 1H), 6.86-6.88 (m, 1H), 6.89-6.91 (m, 1H), 7.14 (s, 1H), 7.19-7.22 (m, 3H).