Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C@@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:16][CH:17]=[CH2:18])[CH:10]=1.N1C=CC=CC=1.Cl[C:34]([O:36][CH3:37])=[O:35]>ClCCl>[CH3:37][O:36][C:34](=[O:35])[NH:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C@@H:15]([NH:19][C:20]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:26])[CH2:16][CH:17]=[CH2:18])[CH:10]=2)=[C:2]([NH2:1])[CH:7]=1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccc(N)cc2N)ccn1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccc(NC(=O)OC)cc2N)ccn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a cooled (−78° C.) clear, brown solution of 1E (2.63 g, 7.42 mmol) and pyridine (0.600 ml, 7.42 mmol) in dichloromethane (74.2 ml) was added dropwise over 30 min methyl chloroformate (0.516 ml, 6.68 mmol). The reaction was stirred at −78° C. After 1.5 h, the reaction was quenched with sat. NH4Cl and the reaction was allowed to warm to rt. The reaction was diluted with DCM and water and the layers were separated. The aqueous layer was extracted with DCM (1×). The combined organic layers were washed with sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue dissolved in DCM (˜10 mL) and then hexane (˜300 mL) was added to give a brown suspension with brown gummy sticky substance at the bottom. The mixture was sonicated to give a mostly clear solution with the brown substance at the bottom. The solution decanted and the bottom substance rinsed with hexane, dried to give 1F (2.7 g, 88%) as a slightly brown foam. MS (ESI) m/z: 413.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][N:13]2[C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)=[O:31])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: Fc1cc(C2NCCc3ccccc32)ccc1C(F)(F)F
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)c(F)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(3-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-isoquinoline (0.0845 g, 0.286 mmol, Example 71 Step 3) in 3 mL of DCM, 4-fluorophenyl isocyanate (0.0358 mL, 0.315 mmol) was added. The solution was stirred for 1 h. Solvent was evaporated and the residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to yield the title compound as a white solid. MS (ESI pos. ion) m/z: 433.1 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.51 (t, J=7.75 Hz, 1H) 7.22-7.39 (m, 6H) 7.06-7.19 (m, 2H) 6.96-7.05 (m, 2H) 6.63 (s, 1H) 6.45 (s, 1H) 3.59-3.81 (m, 2H) 2.76-3.08 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[N:14][C:15]([C:16]([O-:18])=O)=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][C:32]([O:34][CH3:35])=O)[CH:26]=2)C=CC=CC=1.[CH2:36]1CCN2C(=NCCC2)C[CH2:37]1.C(NC1C=CC(S(N=[N+]=[N-])(=O)=O)=CC=1)(=O)C>CC#N>[CH3:35][O:34][C:32]1[CH:31]=[C:27]2[C:26]([C:25]([O:18][CH2:16][C:15]3[N:14]=[N:13][N:10]4[CH:11]=[CH:12][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][C:9]=34)=[CH:30][CH:29]=[N:28]2)=[CH:37][CH:36]=1
Reactant: COC(=O)Cc1cc(-c2ccccc2)ccn1
Reactant: O=C([O-])c1nnn2ccc(-c3ccccc3)cc12
Reactant: C1CCC2=NCCCN2CC1
Agent: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Product: COc1ccc2c(OCc3nnn4ccc(-c5ccccc5)cc34)ccnc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-Phenyl-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate. To a solution of methyl 2-(4-phenylpyridin-2-yl)acetate (see Lohse, O.; Thevenin, P.; Waldvogel, E. Synlett 1999, 1, 45-48) (0.504 g, 2.22 mmol) in 12 mL CH3CN was added DBU (0.501 ml, 3.33 mmol) and the mixture cooled in an ice bath. To the solution, 4-acetamidobenzenesulfonyl azide (0.533 g, 2.22 mmol) was added and the mixture allowed to warm to rt. The mixture was stirred at rt for 5 h then evaporated. The residue was diluted with CH2Cl2, washed with water, brine, dried over Na2SO4, and filtered. The title compound was obtained after purification via flash chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][NH2:11].CC[O:14][C:15]([CH:17]1[C:22](=O)[CH2:21][CH2:20][CH2:19][CH2:18]1)=O.O>C1(C)C=CC=CC=1.C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:15](=[O:14])[C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[NH:11]1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: COc1ccc(NN)c(F)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-n2[nH]c3c(c2=O)CCCC3)c(F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 6.28 g (0.040 mole) of 2-fluoro-4-methoxyphenylhydrazine in 200 mL of toluene was added with stirring 6.82 g (0.040 mole) of ethyl 2-cyclohexanonecarboxylate. This mixture was heated at reflux under a nitrogen atmosphere while water was removed with a Dean-Stark trap. When all water had been removed, the reaction mixture was cooled, and the solvent was evaporated under reduced pressure, leaving a residue, which was then dissolved in acetic acid. This solution was heated at reflux for approximately sixteen hours, after which the solvent was evaporated under reduced pressure, leaving a residue. This residue was dissolved in toluene, which was also evaporated under reduced pressure. The residue was dissolved in ethyl acetate and placed on a silica gel column and eluted with ethyl acetate. An attempt to crystallize the product by dissolving it in diethyl ether after the ethyl acetate had been evaporated was unsuccessful. After the solvent had been evaporated from this product, it was again heated at reflux in acetic acid for 24 hours and allowed to cool to room temperature, where the solution stirred for an additional 48 hours. The solvent was evaporated under reduced pressure, leaving a residue weighing 4.32 g. Two additional fractions weighing 0.80 g and 2.75 g had been recovered by extracting the reaction mixture before the solvent was evaporated. The NMR spectrum of the residue showed it to be a mixture of 2-(2-fluoro-4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-indazol-3-one and the 2-fluoro-4-methoxyphenylhydrazone of 2-cyclohexanonecarboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[NH:15][C:16](=O)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=1.[N+:28]([C:31]1[S:35][C:34]([CH:36]=O)=[CH:33][CH:32]=1)([O-:30])=[O:29].N1C=CC=CC=1>ClC(Cl)C.C(O)(=O)C>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:16]2[N:1]([CH2:36][C:34]3[S:35][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=3)[C:2]3=[N:7][CH:6]=[C:5]([C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[O:9])[CH:4]=[C:3]3[N:15]=2)=[CH:19][CH:20]=1)[CH3:26]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: CCOc1ccc(CC(=O)Nc2cc(C(=O)N(CC)CC)cnc2N)cc1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOc1ccc(Cc2nc3cc(C(=O)N(CC)CC)cnc3n2Cc2ccc([N+](=O)[O-])s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 6-amino-5-[[(4-ethoxyphenyl)acetyl]amino]-N,N-diethyl-3-pyridinecarboxamide (30 mg, 0.08 mmol) in dichloroethane (0.5 mL) and acetic acid (0.5 mL) at room temperature was added 5-nitro-2-thiophenecarboxaldehyde (19 mg, 0.12 mmol). The mixture was stirred for 4.5 hours. BH3. pyridine (8.2 μL, 0.08 mmol) was added and the reaction brought to 84° C. After stirring overnight, the mixture was cooled to room temperature and 5-nitro-2-thiophenecarboxaldehyde (19 mg, 0.12 mmol) was added. The mixture was stirred for 5 hours. BH3.pyridine (8.2 μL, 0.08 mmol) was added and the reaction brought to 84° C. After stirring overnight, the reaction was quenched with 1 M NaOH aqueous solution (20 mL) and extracted with EtOAc (20 mL). The aqueous phase was back-extracted with additional dichloromethane (2×20 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using silica gel flash chromatography ([3% MEOH+0.5% NH4OH aq] in CH2Cl2) to provide the title compound 2-[(4-ethoxyphenyl)methyl]-N,N-diethyl-3-[(5-nitro-2-thienyl)methyl]-3H-imidazo[4,5-b]pyridine-6-carboxamide (purity: >84% at 215 nm, >81% at 254 nm, >68% at 280 nm). 1H-NMR (400 MHz, CDCl3): δ 1.23 (m, 6H), 1.40 (t, J=6.8 Hz, 3H), 3.36 (br s, 2H), 3.60 (br s, 2H), 3.98 (q, J=6.8 Hz, 2H), 4.29 (s, 2H), 4.84 (s, 2H), 6.80 (d, J=8.6 Hz, 2H), 7.07 (d, J=8.6 Hz, 2H), 7.66 (d, J=4.1 Hz, 1H), 7.77 (d, J=4.1 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H). MS (ESI) (M+H)+: 494.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][NH2:27])[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[C:28]([O:32][C:33]([N:35]1[CH2:39][CH2:38][C@H:37]([C:40](O)=[O:41])[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C.Cl.C(N(CC)CCCN=C=NCC)C.ON1C2C=CC=CC=2N=N1>ClCCl>[C:28]([O:32][C:33]([N:35]1[CH2:39][CH2:38][C@H:37]([C:40](=[O:41])[NH:27][CH2:26][CH2:25][CH2:24][NH:23][C:18]2[N:17]=[C:16]([C:13]3[S:12][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:2][CH2:3]5)[C:15]=4[CH:14]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: NCCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)NCCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)C1
Yield: 90.2 %

Procedure:
A stirred suspension of 2-[2-(3-aminopropylamino)-5-chloropyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (500 mg, 1.24 mmol) in dichloromethane (30 mL) is treated at room temperature with (S)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (333 mg, 1.55 mmol), N,N-diisopropylethylamine (0.220 mL, 1.26 mmol), 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (240 mg, 1.25 mmol) and 1-hydroxybenzotriazole (171 mg, 1.21 mmol) for 24 hours. The mixture is then diluted with dichloromethane (30 mL), filtered, washed with water (30 mL) and diethyl ether (30 mL), and dried to provide (S)-3-{3-[5-chloro-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propylcarbamoyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (670 mg, 90%). A stirred mixture of this intermediate (665 mg, 1.11 mmol) in dichloromethane (25 mL) is treated at room temperature with TFA (2.5 mL) for 72 hours. The mixture is then concentrated under reduced pressure and subjected to chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane: 16-40%, to provide the title compound (474 mg, 82% yield). ES+(m/z) 499 (35Cl) and 501 (37Cl) [M+H].
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[S:15])[NH2:14].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[OH:29])=O>CCOC(C)=O>[CH3:6][O:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[S:15][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[OH:29])[N:14]=1
Reactant: COC(=O)CCCCC(N)=S
Reactant: COc1ccc(C(=O)CBr)c(O)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCc1nc(-c2ccc(OC)cc2O)cs1
Temperature: 25 °C
Yield: 165.9 %

Procedure:
Add THF (50 mL, anhydrous) to a roundbottom flask containing 5-thiocarbamoyl-pentanoic acid methyl ester (2.63 g, 15.0 mmol) and 2-bromo-1-(2-hydroxy-4-methoxy-phenyl)-ethanone (4.90 g, 15.0 mmol, 75% pure). Heat to reflux under N2 overnight. Cool to room temperature, add EtOAc, wash with saturated NaHCO3 solution, brine, and backextract from each aqueous layer with EtOAc. Dry combined organic layers over MgSO4 and concentrate to get 8 grams of a yellow solid. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes followed by flash chromatography on silica gel eluting with CHCl3 to afford the title compound (2.69 g, 56%). MS (IS) 322 (M+1)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N[C:17](=O)[NH:18][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.CC[O:28]C(C)=O.[CH3:32][N:33]([CH3:36])[CH:34]=[O:35]>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:34](=[O:35])[N:33]([CH3:36])[C:32](=[O:28])[N:18]([CH3:17])[CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CN(C)C=O
Reactant: O=c1[nH]cc(N2CCN(Cc3ccccc3)CC2)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cn1cc(N2CCN(Cc3ccccc3)CC2)c(=O)n(C)c1=O
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
9.6 g (33.53 mmol) of 5-(4-benzyl-piperazin-1-yl)-1H-pyrimidine-2,4-dione are placed at 0° C. in 10 mL of dimethylformamide. 2.95 g (73.56 mmol) of sodium hydride (at 60% in paraffin) are added portion wise. The mixture is stirred for 40 min at 0° C. 5 mL (80.5 mmol) of methyl iodide are added, the medium is stirred at room temperature for 7 h. After concentration of the reaction medium, the obtained residue is taken up with AcOEt and washed with water. After drying on MgSO4, the organic phase is concentrated. The obtained residue is triturated with ether, and then a precipitate is isolated by filtration. 4 g of intermediate 13a are obtained as a beige powder (yield: 38%).
Reaction SMILES: [C:1](=O)([O-])[OH:2].[Na+].[N:6]1[C:13]([Cl:14])=[N:12][C:10]([Cl:11])=[N:9][C:7]=1Cl>CO>[CH3:1][O:2][C:7]1[N:9]=[C:10]([Cl:11])[N:12]=[C:13]([Cl:14])[N:6]=1
Reactant: O=C([O-])O
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)nc(Cl)n1
Temperature: 0 °C

Procedure:
7 parts of sodium hydrogencarbonate was added to 50 parts of methanol. This mixture was cooled to 0° C. from outside. Then, 15 parts of cyanuric chloride was added to conduct a reaction for 60 minutes (First condensation). To the reaction mixture was added 100 parts of ice water, and the crystal precipitated was collected by filtration to obtain 2-methoxy-4,6-dichloro-1,3,5-triazine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.C=O.[C:24]([BH3-])#N.[Na+].C(O)(=O)C>CCO>[ClH:1].[ClH:1].[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:24])=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1
Reactant: Clc1ccc(-c2cc(OC[C@@H]3CCCN3)cnc2Cl)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCC[C@H]1COc1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of 6-Chloro-5-(4-chlorophenyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine from step 150b above (270 mg, 0.75 mmol) in EtOH (5.0 mL) was added formalin (37%, 5 mL), sodium cyanoborohydride (240 mg, 3.75 mmol) and acetic acid (0.15 mL), and the mixture was stirred at 25° C. for 16 h. The solvent was concentrated, and solid NaHCO3 was added to the residue. At pH 8 the mixture was extracted with EtOAc, which was dried (MgSO4) and concentrated. (320 mg). The residue was converted to the salt by treatment with hydrogen chloride in Et2O/THF to afford the title compound (270 mg, 96%): mp 183-185° C.; 1H NMR (CD3OD) δ 2.00-2.32 (m, 3H), 2.41 (m, 1H), 3.08 (s, 3H), 3.15 (m, 1H), 3.75 (m, 1H), 3.92 (m, 1H), 4.37 (dd, 1H, J=7.0, 11.0 Hz), 4.53 (dd, 1H, J=3, 11.0 Hz), 7.43-7.53 (m, 4H), 7.56 (d, 1H, J=4.5 Hz), 8.20 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 337 (M+H)+. Anal. Calcd for C17H18Cl2N2O.1.3 HCl.0.1 H2O: C, 52.84; H, 5.09; N, 7.25. Found: C, 52.84; H, 4.84; N, 7.58. [α]25D −6.6 (c 0.42, MeOH).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:14])=[C:7]([C:10]([F:13])=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[OH:15][CH2:16][CH2:17][CH:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1.CCN(C(C)C)C(C)C>C1COCC1.[Cl-].[Na+].O>[C:8]([C:7]1[C:6]([CH3:14])=[C:5]([C:3](=[O:4])[CH2:2][N:23]2[CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:19][CH:18]2[CH2:17][CH2:16][OH:15])[CH:12]=[CH:11][C:10]=1[F:13])#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCNC(CCO)C1
Reactant: Cc1c(C(=O)CBr)ccc(F)c1C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)CN2CCN(C(=O)OC(C)(C)C)CC2CCO)ccc(F)c1C#N
Reaction time: 8 h

Procedure:
3-(2-Bromoacetyl)-6-fluoro-2-methylbenzonitrile (prepared as described above, 5.11 g, 20.0 mmol) was dissolved in THF (100 mL), then known, commercially available compound tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (4.60 g, 20.0 mmol) was added, followed by Hunig's base (6.96 mL, 39.9 mmol) and the mixture was stirred overnight. The reaction mixed was poured into brine and extracted with ethyl acetate (twice), dried over Na2SO4, filtered and concentrated. The product was purified by MPLC chromatography using a 330 g ISCO Redi Sep column and 5% MeOH/DCM solvent system-to yield tert-butyl 4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-oxoethyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate: LC-MS (IE, m/z): 406 [M+1]+;
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[S-:8][C:9]#[N:10].CN([S+](N(C)C)N(C)C)C>C(#N)C>[CH2:2]([S:8][C:9]#[N:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: N#C[S-]
Reactant: CCCCCCBr
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: CC#N
Product: CCCCCCSC#N
Reaction time: 3 h
Yield: 85 %

Procedure:
A 7.4-g (0.45 mole) sample of 1-bromohexane was added at ambient temperature to a stirred solution of 11.1 g (0.05 mole) of tris(dimethylamino)sulfonium thiocyanate in 25 ml acetonitrile, and the rate of the reaction was followed by gas-liquid partition chromatography (glc). The reaction was one-half completed after 3 hr, and was essentially completed after 20 hr. The reaction mixture was poured into water and extracted with ether. The ether extract was dried (MgSO4) and distilled to give 5.47 g (85%) of n-hexyl thiocyanate as a colorless liquid, bp 93°-94° (10 mm).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:31])[C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C@H:12]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([OH:40])[CH:34]=2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:41][O:42][CH2:43][CH2:44][O:45][CH2:46]Cl.O>CN(C)C=O>[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:31])[C:17]2[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C@H:12]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([O:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH3:46])[CH:34]=2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COCCOCCl
Reactant: Cc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCOc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% in mineral oil, 18 mg) was added by small portions to an ice-cooled solution of (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)piperazine (0.20 g) in N,N-dimethylformamide (2 ml) below 5° C. under nitrogen atmosphere. After the mixture was stirred for 5 minutes, (2-methoxyethoxy)methyl chloride (0.064 ml) was added to the mixture. The whole was stirred at room temperature for 2.5 hours, and thereto water was added. The whole was extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using mixed solvents of hexane and ethyl acetate (7:3). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]piperazine (0.21 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(F)cc2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.7 g), 1-(bromomethyl)-4-fluorobenzene (0.27 mL), potassium carbonate (0.51 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.56 g, 62%).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH:4]([O:26][CH:27]([CH3:29])[CH3:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>O1CCCC1.O>[CH:27]([O:26][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:19][CH:20]=2)=[CH:8][CH:7]=1)[C:3]([OH:30])=[O:2])([CH3:28])[CH3:29]
Reactant: COC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
2-Isopropoxy-3-[4-(2-{4-methylsulfonyloxyphenyl}ethoxy)phenyl]propanoic acid methyl ester (0.1 g; 0.229 mmole) was dissolved in tetrahydrofuran(2 ml). Lithium hydroxide (0.006 g; 0.25 mmole) in water (2 ml) was added. The reaction mixture was stirred at room temperature for 8 hours. Tetrahydrofuran was evaporated. The remaining water solution was extracted with diethyl ether. The water solution was then acidified with hydorchloric acid (1%) to pH˜2 and extracted twice with ethyl acetate. The organic phases were combined and dried with magnesium sulfate. The solvent was evaporated and 0.085 g (88% yield) of 2-isopropoxy-3-[4-(2-{4-methylsulfonyloxyphenyl}ethoxy)phenyl]propanoic acid was obtained.