Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[F:17])[NH:6][C:5]1=O)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:5]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[F:17])[N:6]=1
Reactant: CC(C)n1c(=O)[nH]n(-c2ccc(Cl)cc2F)c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)n1c(Cl)nn(-c2ccc(Cl)cc2F)c1=O
Reaction time: 30 h

Procedure:
4-Isopropyl-1-(4-chloro-2-fluorophenyl)-1,2,4-triazolidine-3,5-dione (6.32 g; 0.023 mol) and phosphorus oxychloride (50 ml) were boiled with stirring for 30 hours. After completion of the reaction, excessive phosphorus oxychloride was removed by distillation under reduced pressure. The separated oily substance was poured into icewater and extracted with chloroform (50 ml) three times. The chloroform layer was washed with a saturated sodium chloride solution until the washings became neutral, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting oily substance was chromatographed on silica gel to give 2.5 g of 3-chloro-4-isopropyl-1-(4-chloro-2-fluorophenyl)-1,2,4-triazolin-5-one.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]=[C:6]2[NH:16][N:17]=[C:18]([CH:19]3[CH2:21][CH2:20]3)[C:5]=12.Cl[CH2:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]=[C:6]2[N:16]([CH2:23][C:24]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[N:17]=[C:18]([CH:19]3[CH2:21][CH2:20]3)[C:5]=12
Reactant: O=C(CCl)N1CCCC1
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(C3CC3)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cn1nc(C2CC2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCCC1
Yield: 46 %

Procedure:
Sodium hydride (60% in mineral oil, 18 mg, 0.44 mmol) was added to a solution of 4-chloro-3-cyclopropyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (100 mg, 0.37 mmol) and 2-chloro-1-(pyrrolidin-1-yl)ethanone (82 mg, 0.55 mmol) in dry DMF (3 mL) at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, CH2Cl2/diethyl ether 8:2) to provide Compound Iee as a solid (65 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7](Cl)[CH:8]([OH:11])[CH2:9][CH3:10])=[C:4]([CH3:15])[CH:3]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(O)C>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH:8]([OH:11])[CH2:9][CH2:10][N:25]2[CH2:26][CH2:27][N:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)=[C:4]([CH3:15])[CH:3]=1
Reactant: CCC(O)C(Cl)Oc1ccc(Cl)cc1C
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CC(C)O
Product: Cc1cc(Cl)ccc1OCC(O)CCN1CCN(c2ccccc2)CC1
Product: Cl
Yield: 157.2 %

Procedure:
A mixture of 18.72 g (0.075 mole) of 1-(4-chloro-2-methylphenoxy)-2-hydroxybutyl chloride, 16.2 g (0.1 mole) of N-phenylpiperazine and 350 ml of 2-propanol was heated at reflux for 16 hr. The white crystalline precipitate which formed on standing at room temperature was filtered. The resulting white crystalline solid was identified as the hydrochloride salt of the N-phenylpiperazine. The filtrate was mixed with 60 ml of ethereal hydrogen chloride and precipitated in ether. The white crystalline solid was filtered off and recrystallized with acetone to give 17.6 g of title compound, m.p. 186°-188° C.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13]1[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C:17]=1[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:7]2.[H-].[Na+].Br[CH2:31][C:32]#[N:33].Cl>CN(C=O)C.O>[Br:1][C:2]1[C:3]2[C:8](=[CH:7][C:6]([C:13]3[O:14][C:15]4[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=4[C:17]=3[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5][CH:4]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:31][C:32]#[N:33]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Reactant: N#CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.9 %

Procedure:
To an ice-cooled solution of 1-[2-(5-bromo-6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (1.2 g, 2.8 mmol) in dry DMF (12 mL) was added sodium hydride (0.315 g, 7.88 mmol of a 60% dispersion on mineral oil) in three portions. Bromoacetonitrile (0.49 mL, 7.0 mmol) was added and the mixture was stirred at room temperature for 1.5 hours, then poured into excess water and acidified with 2N hydrochloric acid. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (Biotage apparatus) using 15% tert-butyl methyl ether in hexane as an eluant to afford 2-{[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetonitrile as a yellow solid (0.776 g, 60%), mp 98-100° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].Br[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCCCBr
Reactant: Sc1cccs1
Product: O=C(O)CCCCSc1cccs1

Procedure:
Method in which thiophene-2-thiol is reacted with 5-bromo valeric acid to obtain 5-(2-thienylsulfanyl) valeric acid represented by Chemical Formula [4].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][NH2:13])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH:16]=[CH:15]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([C:14](=[O:20])/[CH:15]=[CH:16]\[C:17]([OH:19])=[O:18])[NH2:13])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: O=C1C=CC(=O)O1
Reactant: NNc1ccc(C(F)(F)F)c(Cl)c1
Solvent: Cc1ccccc1
Product: NN(C(=O)/C=C\C(=O)O)c1ccc(C(F)(F)F)c(Cl)c1
Temperature: 50 °C
Yield: 64.8 %

Procedure:
10.5 g (0.05 mol) of 3-chloro-4-trifluoromethylphenylhydrazine were dissolved in 50 ml of toluene. 4.9 g of maleic anhydride (0.05 mol) in the solid form were introduced into this solution at room temperature. This caused the temperature to rise by a few degrees, while the reaction product precipitated in the crystalline form. The mixture was then heated to about 50° C. for some time, after which it was allowed to cool and the product was filtered off. 10 g (65% of theory) of maleic acid mono-(3-chloro-4-trifluoromethyl-phenyl)-hydrazide of melting point 180°-182° C. were obtained.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:22][CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[OH:25]>C(Cl)Cl>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([CH:24]2[O:25][C:11](=[O:13])[NH:22][CH2:23]2)=[CH:27][CH:28]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(C(O)CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C2CNC(=O)O2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Diisopropylethylamine (181 mg, 244 μL, 1.40 mmol) and triphosgene (138 mg, 0.466 mmol) were added successively to a stirred solution of 2-amino-1-(4-methylphenyl)ethanol (35.2 mg, 0.233 mmol) in dry CH2Cl2 (22 mL) at 0° C. under N2. The reaction was stirred at 0° C. for 1 h then concentrated in vacuo to a volume of about 5 mL. The mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-80% EtOAc in hexanes gradient) to afford 5-(4-methylphenyl)-1,3-oxazolidin-2-one. Rf=0.41 (50% EtOAc/hexanes). LCMS calc.=178.08; found=178.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.25 (d, J=7.4 Hz, 2H), 7.19 (d, J=7.4 Hz, 2H), 6.69 (br s, 1H), 5.55 (t, J=7.8 Hz, 1H), 3.93 (t, J=8.6 Hz, 1H), 3.52 (t, J=8.1 Hz, 1H), 2.35 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C1Cc2cc(-c3cccc(Cl)c3)ccc2N1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A solution of the 5-bromoxindole (0.5 g, 2.4 mmol) and tetrakis(triphenylphosphine)palladium (0.14 g, 0.12 mmol) in dimethoxyethane (10 cm3) was stirred under N2 for 20 min. To this mixture was then added 3-chlorophenylboronic acid (0.44 g, 2.83 mmol) and sodium carbonate (0.75 g, 7.1 mmol) in water (4 cm3). The solution was brought to reflux for 6 h then cooled to RT, poured into water and extracted with EtOAc (×3). The combined organic extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, ethyl acetate:hexane 1:3) to afford the title compound (0.49 g, 2.0 mmol, 86%) as a tan solid: m.p. 169-171° C., 1H NMR (THF-d8) δ 3.45 (s, 2H), 6.85 (d, 1H J=8.1 Hz), 7.25 (d, J=8.0 Hz, 1H), 7.35 (dd, J=7.8, 7.8 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.50 (s, 1H), 7.59 (dd, J=1.78, 1.78 Hz, 1H), 9.5 (br s, 1H); 13C NMR (THF-d8) δ 36.39 (t), 109.80, 123.97, 125.55, 127.19 (d), 127.68 (s), 130.89 (d), 133.73, 135.29, 144.23, 145.09, 176.45 (s); MS (EI) m/z 243, 245 (M)+; Anal. (C14H10ClNO) C, H, N.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].[N+:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[S:22](Cl)(=[O:24])=[O:23])([O-:12])=[O:11]>N1C=CC=CC=1>[N+:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[S:22]([O:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9])(=[O:24])=[O:23])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: Cc1occc(=O)c1O
Solvent: c1ccncc1
Product: Cc1occc(=O)c1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 28 %

Procedure:
3-Hydroxy-2-methyl-4H-pyran-4-one (0.5 g, 4.0 mmol) was reacted with 2,4-dinitrobenzenesulfonyl chloride (1.58 g, 5.9 mmol) in 40 mL of pyridine to afford PZBG-2d in 28% yield (0.39 g, 1.1 mmol). 1H NMR (500 MHz, CDCl3) δ=8.72 (d, J=2.3 Hz, 1H), 8.56 (dd, J1=9.2 Hz, J2=2.3 Hz, 1H), 8.44 (d, J=8.6 Hz, 1H), 7.71 (d, J=5.8 Hz, 1H), 6.31 (d, J=5.8 Hz, 1H), 2.53 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ=171.6, 163.3, 154.9, 139.3, 136.4, 133.8, 126.8, 120.5, 117.5, 16.1. ESI-MS(+): m/z 357.03 [M+H]+, 378.99 [M+Na]+.
Reaction SMILES: [NH2:1][C:2](N)=[S:3].[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH2:15][O:16][CH2:17][CH2:18][O:19]C(=O)C2C=CC=CC=2)=C(Cl)N=1>C(O)(C)C>[OH:19][CH2:18][CH2:17][O:16][CH2:15][N:12]1[CH:11]=[N:10][C:9]2[C:2](=[S:3])[NH:1][C:6]([NH2:5])=[N:14][C:13]1=2
Reactant: Nc1nc(Cl)c2ncn(COCCOC(=O)c3ccccc3)c2n1
Reactant: NC(N)=S
Solvent: CC(C)O
Product: Nc1nc2c(ncn2COCCO)c(=S)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
Thiourea (0.28 g) was added to a refluxing solution of 2-amino-6-chloro-9-(2-benzoyloxyethoxymethyl)purine (1.27 g) in isopropanol (40 ml). The reaction mixture was heated at reflux for 11/2 hours and then chilled. 9-(2-benzoyloxyethoxymethyl)thioquanine (0.58 g, m.p. 199°-202° C.) was removed by filtration. This was added to 40 ml of aqueous ammonia (about 7 N) and the mixture heated on a steam bath for 10 minutes and then stirred overnight at room temperature. The water and ammonia were removed in vacuo and the residue triturated with acetone and then with ether to remove benzamide. The remaining solid was recrystallized twice from water to give yellow flakes of 9-(2-hydroxyethoxymethyl)thioguanine (0.26 g, m.p. 251°-254° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](=[N:9][OH:10])[NH2:8])([O-:3])=[O:2].[C:14](OC)(=O)[CH2:15][C:16]([CH3:18])=[O:17]>C1(C)C=CC=CC=1>[O:17]=[C:16]([CH3:18])[CH2:15][C:14]1[O:10][N:9]=[C:7]([C:6]2[CH:11]=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:8]=1
Reactant: NC(=NO)c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Cc1nc(-c2cccc([N+](=O)[O-])c2)no1
Yield: 83.5 %

Procedure:
In a 250 ml flask, place 10 g (0.055 m) of 3-nitrobenzamidoxime (9a), 9.6 g (0.083 m) of methyl acetoacetate (10b; R1=methyl), and 100 ml of toluene. Heat and stir the reaction mixture under reflux with a Dean-Stark trap for 16 hrs. Distill off toluene under a reduced pressure at 50-60° C. to thick oil. Add 60 ml of heptane to the oil with stirring, cool and stir at 0-5° C. for 30 min. Collect solid, wash with heptane, and dry in air to give 11.4 g (84%) of 5-(2-oxopropyl)-3-(3-nitrophenyl)-1,2,4-oxadiazole [Formula II: R1=methyl and R2=3-nitrophenyl].
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:13]Cl>CN(C=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:13][N:4]1[CH:5]=[N:6][C:2]([NH2:1])=[N:3]1
Reactant: ClCc1cc(Cl)cc(Cl)c1
Reactant: Nc1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncn(Cc2cc(Cl)cc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Amino-1,2,4-triazole (420 mg, 5.0 mmol) was dissolved in DMF (3 mL) under argon atmosphere, sodium hydride (55%, 218 mg, 5.0 mmol) was added at room temperature in small portions and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C., 3,5-dichlorobenzyl chloride (977 mg, 5.0 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured onto water and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered, the solvents were evaporated and the residue purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a white solid (357 mg, 29%).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:9][O:10][C:11](=[O:17])[CH2:12][C:13]([CH2:15]Cl)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:26][O-:27].[Na+]>C1COCC1.CO>[C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:9][O:10][C:11](=[O:17])[CH2:12][C:13](=[O:14])[CH2:15][O:27][CH3:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCl)CC(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COCC(=O)CC(=O)OCCC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
2.5 ml of a solution of 0.879 mg (2.66 mmol) of (3,3-diphenylpropane-1-yl)4-chloroacetoacetate in 2.5 ml of THF was added dropwise to a suspension of 160 mg of sodium hydride (60% oily) in 5 ml of THF at 0° C. and they were stirred for 30 minutes. 820 μl of 28% solution of sodium methoxide in methanol was added to the obtained mixture. After stirring overnight, methanol was added to the reaction mixture, and the obtained mixture was concentrated and fractionated with ethyl acetate and water. After the drying over sodium sulfate followed by the purification by the silica gel chromatography (hexane/ethyl acetate=3/1), the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[OH:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:26]([CH:27]3[CH2:32][CH2:31][CH:30]([CH2:33][OH:34])[CH2:29][CH2:28]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: O=C(O)C1CCC(CO)CC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCC(CO)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(4-hydroxymethyl-cyclohexanecarbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 4-hydroxymethyl-1-cyclohexanecarboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white solid. MS m/e: 489.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.[C-:12]#[N:13].[Na+].[Cl-].[NH4+:16]>CO.[OH-].[NH4+]>[NH2:16][CH:7]([C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:10][CH3:11])[C:12]#[N:13]
Reactant: [NH4+]
Reactant: [C-]#N
Reactant: COc1ccc(Cl)cc1C=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cl)cc1C(N)C#N
Temperature: 25 °C
Yield: 94 %

Procedure:
A solution of 5-chloro-2-methoxy-benzaldehyde (prepared according to U.S. Pat. No. 4,602,035) (2.04 g, 12.0 mmol) in methanol (80 mL) was added to a stirred solution of sodium cyanide (0.90 g) and ammonium chloride (1.50 g) in aqueous ammonium hydroxide (33% solution, 30 mL) at 0° C. then warmed to room temperature for 18 hours. The mixture was evaporated to dryness, the residues partitioned between DCM and water, the organics separated, washed with brine and evaporated under vacuum to afford 2.21 g (94%) of 2-amino-2-(5-chloro-2-methoxyphenyl)acetonitrile as an orange oil. LCMS (ESI) m+H=197.2.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[C:4]([O:16][CH3:17])[CH:3]=1.C([Li])CCC.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[CH:28]=[O:29].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>>[C:10]([Si:7]([CH3:9])([CH3:8])[O:6][C:5]1[CH:14]=[CH:15][C:2]([CH:28]([C:27]2[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:25]([O:24][CH3:23])[CH:26]=2)[OH:29])=[CH:3][C:4]=1[O:16][CH3:17])([CH3:13])([CH3:12])[CH3:11]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: COc1cc(Br)ccc1O[Si](C)(C)C(C)(C)C
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(O)c2ccc(O[Si](C)(C)C(C)(C)C)c(OC)c2)c1

Procedure:
(4-bromo-2-methoxyphenoxy)-tert-butyldimethylsilane (4.37 g, 13.77 mmol), n-butyl lithium (5.51 ml, 13.77 mmol), and 3,5-dimethoxybenzaldehyde (2.08 g, 12.52 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified via flash column chromatography (5% EtOAc in hexane gradient to 20% EtOAc in hexane in about 40 min.) to give [4-(tert-butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-(3,5-dimethoxy-phenyl)-methanol a clear oil (3.94 g, 78%): 1HNMR (CDCl3) 6.89 (s, wide, 1H, Ar), 6.78 (s, wide, 2H, Ar), 6.53 (d, J=2 Hz, 2H, Ar), 6.36 (t, J=2 Hz, 1H, Ar), 5.69 (d, J=3 Hz, 1H, CHOH), 3.77 (s, 3H, OCH3), 3.76 (s, 6H, 2OCH3), 2.19 (d, J=3 Hz, 1H, OH), 0.98 (s, 9H, 3CH3), 0.14 (s, 6H, 2CH3). The product was carried over to the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([CH:30]=1)[C:7]([N:9](C(=O)C1C=C(F)C=CC=1C)[C:10]1[N:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=1)=[O:8].[OH-].[Na+]>CO.O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([CH:30]=1)[C:7]([NH:9][C:10]1[N:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)=[O:8]
Reactant: COC(=O)c1ccc(N(C(=O)c2cc(F)ccc2C)C(=O)c2cc(F)ccc2C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
A mixture of 12.0 g of methyl 6-[[bis(5-fluoro-2-methylbenzoyl)]amino]pyridine-3-carboxylate, 60 ml of methanol-tetrahydrofuran (1:1) and 23 ml of 5N NaOH is stirred at room temperature for 16 hours. The mixture is concentrated under vacuum, diluted with 25 ml of water, cooled and acidified with 1N HCl. The mixture is filtered and the solid washed with water to give 6.3 g of the product as a white solid.
Reaction SMILES: [C:1]([N:10]([CH2:12][C:13]([NH2:15])=[S:14])[CH3:11])([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:2].N1C=CC=CC=1.[Cl:22][CH2:23][C:24](=O)[CH2:25]Cl>C(O)C>[Cl:22][CH2:23][C:24]1[N:15]=[C:13]([CH2:12][N:10]([C:1]([O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:2])[CH3:11])[S:14][CH:25]=1
Reactant: CN(CC(N)=S)C(=O)Oc1ccccc1
Reactant: O=C(CCl)CCl
Solvent: CCO
Solvent: c1ccncc1
Product: CN(Cc1nc(CCl)cs1)C(=O)Oc1ccccc1
Yield: 77.1 %

Procedure:
To a cooled solution of (N-carbophenoxy-N-methylamino)thioacetamide (1.0 g; 4.46 mmoles) and dry pyridine (0.36 ml, 4.46 mmoles) in 6 ml of absolute ethanol was added a solution of 1,3-dichloropropanone (0.57 g; 4.49 mmoles) in 3 ml of absolute ethanol. The mixture was heated at reflux temperature for 1.5 hours, then evaporated under reduced pressure and the oil residue partitioned between ether and water. The aqueous layer was extracted with ether and the combined ether phase was washed with water, saturated aqueous sodium chloride solution and dried. Filtration and evaporation yielded 1.02 g of the title compound as a viscous oil; TLC [silica/CH2Cl2 :CH3CN (85:15)] gave Rf=0.82. The NMR spectrum (60 MHz) in CDCl3 gave the following resonances δ: 7.16 (m, 6H); 4.77 (broad s, 2H); 4.60 (s, 2H); 3.07 (broad s, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:6]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[CH2:23][C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:24]([CH2:23][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:6]3[CH:14]=[CH:15][C:16]([O:20][CH3:21])=[C:17]([O:18][CH3:19])[C:5]=3[O:4][CH3:3])[CH2:9][CH2:10]2)=[O:25])=[CH:28][CH:29]=1
Reactant: COc1ccc(OC(=O)CCl)cc1
Reactant: COc1ccc(CN2CCNCC2)c(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OC(=O)CN2CCN(Cc3ccc(OC)c(OC)c3OC)CC2)cc1

Procedure:
A mixture of 1-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride (prepared by the method disclosed in Japanese Patent First Publication (Kokai) No. 32889/1973) (17.0 g), 4-methoxyphenyl chloroacetate (prepared by the method disclosed in U.S. Pat. No. 3,657,318) (10 g), potassium carbonate (27.6 g) and N,N-dimethylformamide (200 ml) is stirred at 50° C. for 4 hours. To the reaction mixture is added water (400 ml), and the mixture is extracted with chloroform (400 ml). The organic layer is washed with water twice and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to give crude 1-[(4-methoxyphenoxy)carbonylmethyl]-4-(2,3,4-trimethoxybenzyl)piperazine (free base) (20 g) as an oily substance. This crude free base (20 g) is dissolved in ethanol (100 ml) and thereto is added a solution of hydrochloric acid in ethanol (10% w/w) (50 ml) and the precipitated crystals are separated by filtration. The crystals are recrystallized from methanol to give 1-[(4-methoxyphenoxy)carbonylmethyl]-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride (11.5 g) as colorless crystals.