Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]2[C:7]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][NH2:23])=[O:21])=[CH:15][CH:14]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1.[C:25](OCC)(OCC)(OCC)[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.C(OCC)(=O)C.O>[CH3:25][C:26]1[N:19]([C:16]2[CH:17]=[N:18][C:13]([O:12][C:7]3[C:6]4[C:2]([CH3:24])([CH3:1])[CH2:3][O:4][C:5]=4[C:10]([CH3:11])=[CH:9][CH:8]=3)=[CH:14][CH:15]=2)[C:20](=[O:21])[NH:22][N:23]=1
Reactant: Cc1ccc(Oc2ccc(NC(=O)NN)cn2)c2c1OCC2(C)C
Reactant: CCOC(C)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(Oc2ccc(-n3c(C)n[nH]c3=O)cn2)c2c1OCC2(C)C
Temperature: 25 °C

Procedure:
The crude N-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]pyridin-3-yl}hydrazinecarboxamide (330 mg, 1.0 mmol) was suspended in EtOH (4.5 mL) and triethyl orthoacetate (3 equiv) was added, followed by p-toluenesulfonic acid hydrate (0.1 equiv). The resulting solution was heated to reflux for 24 hrs and then evaporated to dryness. Since the reaction was not complete, the residue was re-dissolved in EtOH (4.5 mL), more triethyl orthoacetate (3 equiv) and p-toluenesulfonic acid hydrate (0.1 equiv) were added and the solution stirred at reflux for additional 18 hours. The mixture was cooled to room temperature and diluted with ethyl acetate and water. Saturated Na2CO3 solution was added the layers were separated and the organic washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified via silica chromatography, eluting with cyclohexane/ethyl acetate from 5/5 to 3/7. The fractions containing the product were combined and evaporated to dryness. The residue was further purified by triturating with methyl tert-butyl ether/n-heptanes. The solid was collected and washed with n-heptanes to afford 5-methyl-4-{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]pyridin-3-yl}-2,4-dihydro-3H-1,2,4-triazol-3-one as a white solid (177 mg).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[F:12][C:13]1[C:20]([O:21][CH3:22])=[C:19]([CH:23]=[CH2:24])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>C(Cl)Cl>[F:12][C:13]1[C:20]([O:21][CH3:22])=[C:19]([CH:23]2[CH2:24][O:9]2)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc(C#N)c(F)c1OC
Solvent: ClCCl
Product: COc1c(C2CO2)ccc(C#N)c1F
Temperature: 25 °C
Reaction time: 60 h

Procedure:
mCPBA (85%, 9.9 g, 48.9 mmol) was added to the solution of 2-fluoro-3-methoxy-4-vinylbenzonitrile (3.4 g, 19.2 mmol) in 160 mL of DCM at 0° C. The mixture was stirred at room temperature for 60 hours before being diluted with 300 mL of DCM and cooled to 0° C. The mixture was washed subsequently with saturated NaHCO3 (50 mL), aqueous Na2SO3 (2×50 mL), 5% NaOH (50 mL) and brine. The organic layer was concentrated, and the residue was purified by column chromatography (PE:EtOAc=5:1) to afford 2-fluoro-3-methoxy-4-(oxiran-2-yl)benzonitrile: 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J=7.6 Hz, 1H), 6.98 (d, J=7.6 Hz, 1H), 4.14-4.18 (m, 1H), 4.03 (s, 3H), 3.17-3.19 (m, 1H), 2.63-2.66 (m, 1H); MS m/z 194 (M+1)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH2:10][C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[C:18]([O:20][CH:21]([Cl:23])[CH3:22])=[O:19].CN1CCOCC1>ClCCl.C(OCC)C>[Cl:23][CH:21]([O:20][C:18]([NH:2][CH2:3][C:4]1([CH2:10][C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:19])[CH3:22]
Reactant: CC(Cl)OC(=O)Cl
Reactant: C=CCOC(=O)CC1(CN)CCCCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCOC(=O)CC1(CNC(=O)OC(C)Cl)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a solution of compound (13) (30 g, 0.121 mol) in dichloromethane (100 mL) was slowly added 1-chloroethyl chloroformate (13 mL, 16.9 g, 0.119 mol). The reaction mixture was cooled to 0° C. and N-methylmorpholine (26.39 mL, 24.28 g, 0.24 mol) was slowly added over a period of 1 h while maintaining a temperature of less than 10° C. The resulting turbid solution was stirred for 30 min, and the reaction mixture was then diluted with diethyl ether (250 mL), washed with water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give the desired product (14) as light yellow viscous liquid (38 g, 99% yield). 1H NMR (CDCl3, 400 MHz): δ 1.35-1.58 (m, 10H), 1.78 (d, 3H), 2.32 (s, 2H), 3.22 (d, 2H), 4.57 (d, 2H), 5.25 (dd, 1H), 5.32 (dd, 1H), 5.52 (br. s, 1H), 5.90-5.94 (m, 1H), 6.54 (q, 1H).
Reaction SMILES: C(N1CCN([C:14]2[CH:23]=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)CC1)C1C=CC=CC=1.ClC(O[CH:28]=[CH2:29])=O>C(Cl)Cl>[N:15]1([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:21]=2[N:22]=[CH:23][CH:14]=[N:15]3)[CH2:29][CH2:28][NH:22][CH2:23][CH2:14]1
Reactant: c1ccc(CN2CCN(c3cnc4ccccc4n3)CC2)cc1
Reactant: C=COC(=O)Cl
Solvent: ClCCl
Product: c1cc(N2CCNCC2)c2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 127.3 %

Procedure:
To a room temperature solution of 1-benzyl-4-(quinoxalin-yl)-piperazine (1.0 g, 3.3 mmol) in anhydrous CH2Cl2 under nitrogen was added vinyl chloroformate (0.34 mL, 3.9 mmol) drop wise. The reaction mixture was heated at reflux 2 hours. The reaction was cooled, concentrated to dryness and concentrated HCl (25 mL) and 1,4-dioxane (25 mL) were added. The resulting solution was stirred at ambient temperature overnight. The solution was basified with 2.5 N NaOH (300 mL) and extracted into EtOAc (3×200 mL). The organic layers were combined, dried over Na2SO4, concentrated and chromatographed (10% MeOH/CH2Cl2/NH4OH) to give 450 mg (64%) of an orange solid: mp 106-108° C.: MS (+) ESI m/e 215 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]1[CH2:29][CH2:28][N:27]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH2:26][CH2:25]1
Reactant: CC(C)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
According to Scheme 4 Step 1: Isobutyryl chloride (1.24 mmol, 0.13 mL) and Et3N (2.48 mmol, 0.35 mL) were added to a solution of 1-(2-chloro-4-nitrophenyl)piperazine (0.83 mmol, 200 mg) in DCM (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The organic phase was washed with a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The organic phase was washed with brine, was dried over Na2SO4, was filtered and was concentrated under reduced pressure to afford 1-(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)-2-methylpropan-1-one (0.83 mmol, 261 mg, 100%). The product was used without further purification.
Reaction SMILES: N[C@H](C(O)=O)CC1C=CC=CC=1.[N+:13]([C:16]1[CH:27]=[CH:26][C:19]([CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:22])=[CH:18][CH:17]=1)([O-])=O.[H][H]>[Na].[Pd]>[NH2:13][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:22])=[CH:26][CH:27]=1
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na]
Product: Nc1ccc(C[C@H](N)C(=O)O)cc1
Temperature: 5 °C

Procedure:
L-Phenylalanine was converted to 4-nitro-L-phenylalanine by a conventional nitration process known in the art. Thereafter, about 100 g of 4-nitro-L-phenylalanine was dissolved in about 600 mL of about 3.5% methanolic sodium hydroxyide solution and hydrogenated by hydrogen gas at a pressure of about 45 psi in the presence of a 5% palladium/carbon catalyst with the pH of the solution being about 11. The temperature of the reaction mixture was maintained from about 20° C. to about 40° C. The reaction mixture was periodically monitored for the completion of reaction by use of HPLC analysis. The reaction mixture was then filtered to remove the palladium/carbon catalyst and neutralized to about pH 7 with acetic acid. The neutralized filtrate was cooled to about 5° C., until 4-amino-L-phenylalanine precipitated out. The precipitate was isolated by filtration, washed with methanol and dried. (Weight 76 g, HPLC Purity 98%.)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:43]1[CH:44]=[CH:45][C:46]([C:49]#[N:50])=[N:47][CH:48]=1)CCC>CN1CCCC1=O.C(OCC)(=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:43]3[CH:44]=[CH:45][C:46]([C:49]#[N:50])=[N:47][CH:48]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C#N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4ccc(C#N)nc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 56.6 %

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-methylbenzene (597 mg) obtained in Example 159-(1) was dissolved in N-methyl-2-pyrrolidone (10 ml) and added thereto were tri-n-butyl(2-cyano-5-pyridyl)tin (590 mg), dichlorobis(triphenylphosphine)palladium(II) (70 mg) and copper(I) iodide (19 mg). The mixture was heated under stirring at 100° C. for 4 hours. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was washed with water and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2cyano-5-pyridyl)-2-thienylmethyl)-4-methylbenzene (351 mg) as colorless powder. APCI-Mass m/Z 621 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].O>CN(C=O)C>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27])[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCOC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8.8 %

Procedure:
Solid NaH (60% w/w in mineral oil, 352 mg, 4.6 mmol) was added to a stirring solution of 1-Benzyl-4-hydroxypiperidine (841 mg, 4.4 mmol) in DMF (50 mL) at 0° C. The resulting suspension was stirred for 5 min then Intermediate 19 (2.6 g, 8.8 mmol) was added. The reaction mixture was warmed to rt then heated to 70° C. over night. The resulting solution was cooled then pour into H2O (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (100 mL), brine (100 mL), dried over Na2SO4, and concentrated to give crude either 2.96 g as yellow oil. Chromatography (1:3, hexanes/EtOAc) afforded the title compound (157 mg, 8%) as clear oil. ES/MS calcd for C24H44NO2Si+ 406.3. Found m/z=406.3 (M+H)+.
Reaction SMILES: C(O[C:5]1[CH:10]=CC=[CH:7][C:6]=1O)(C)C.[CH3:12][NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17].P(Cl)(Cl)(Cl)=O.[C:24]1(C)[CH:29]=CC=C[CH:25]=1>>[CH3:12][NH:13][C:14](=[O:18])[O:15][C:16]1[CH:7]=[CH:6][CH:5]=[CH:10][C:17]=1[CH:24]([CH3:29])[CH3:25]
Reactant: CCOC(=O)NC
Reactant: Cc1ccccc1
Reactant: CC(C)Oc1ccccc1O
Solvent: O=P(Cl)(Cl)Cl
Product: CNC(=O)Oc1ccccc1C(C)C

Procedure:
To a solution of 2-isopropoxyphenol (1.38 g, 0.01 mole) and ethyl N-methylcarbamate (1.03 g, 0.01 mole) in toluene (10 ml), was added phosphoryl chloride (1.54 g, 0.01 mole) and refluxed for six hours. The reaction mixture was worked up as described earlier to give 2-isopropylphenyl N-methylcarbamate of the formula (VII) as a solid, crystallised from pet. ether, m.p. 88° C. to 93° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4](SC)[CH:5]=[CH:6][C:7]=1[Br:8].Cl[C:18]1C=CC=C(C(OO)=O)C=1.[S:28](=[O:31])(O)[O-:29].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([S:28]([CH3:18])(=[O:31])=[O:29])[CH:5]=[CH:6][C:7]=1[Br:8]
Reactant: O=S([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(Br)c(Cl)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Br)c(Cl)c1-c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 2.5 g (8.0 mmol) of 3-chloro-4-bromo-2-phenyl(methylthio)benzene in 75 mL of dichloromethane was cooled with an ice bath and 5.7 g of meta-chloroperbenzoic acid was added in small portions with cooling and stirring. The mixture was allowed to warm to ambient temperature and stir overnight and was then heated to reflux for a short time. An aqueous solution of sodium bisulfite was added and the mixture was made basic with sodium carbonate. The organic phase was separated, washed with dilute aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The 3.0 g of residue was the title compound as a low melting white solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:30][CH:26]1[CH2:29][CH2:28][CH2:27]1)=[O:13])[CH2:8]2
Reactant: NC1CCC1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1NC1CCC1

Procedure:
5-Cyclobutylamino-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and cyclobutylamine. Mass spectrum (ES) MH+=391.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[C:24]([NH:31][C:32]([C:34]5[N:35]=[CH:36][S:37][CH:38]=5)=[O:33])[CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:47]>>[ClH:47].[N:11]1([CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[C:24]([NH:31][C:32]([C:34]5[N:35]=[CH:36][S:37][CH:38]=5)=[O:33])[CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccc4cccc(NC(=O)c5cscn5)c4n3)c2)CC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(Nc1cccc2ccc(-c3cccc(CN4CCNCC4)c3)nc12)c1cscn1
Yield: 32 %

Procedure:
Tert-butyl-4-(3-(8-(thiazole-4-carboxamido)quinolin-2-yl)benzyl)piperazine-1-carboxylate from above was treated with a mixture of 25% TFA in CH2Cl2 for 18 hours, concentrated to dryness. The residue was suspended in CH2Cl2, washed with aqueous NaHCO3 (sat.), dried (Na2SO4) and concentrated. The resulting residue was diluted in a minimal amount of dioxane, treated with a slight excess of HCl in methanol, followed by diethyl ether. The resulting HCl salt of N-(2-(3-(piperazin-1-ylmethyl)phenyl)quinolin-8-yl)thiazole-4-carboxamide was collected by filtration. (24 mg 32% yield over two steps). MS (ESI) calcd for C24H23N5OS (m/z): 429.16. found: 430 [M+1].
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1.C(OCC)(=O)C>CN(C)C=O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Nc1nccs1
Reactant: S=C=NCCC1=CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: S=C(NCCC1=CCCCC1)Nc1nccs1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (3.3 g, 20 mmol) and 2-aminothiazole (2.0 g, 20 mmol) in N,N-dimethylformamide (20 mL) was heated at 100° C. for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 2.66 g (50%) of the title product:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C@@:13]3([CH3:27])[CH2:17][O:16]C(C)(C)[N:14]3C(OC(C)(C)C)=O)=[N:10][N:9]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[C:32](#N)[CH3:33].O>>[NH2:14][C@@:13]([C:11]1[S:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH2:8][CH2:32][CH3:33])=[C:3]([C:28]([F:31])([F:30])[F:29])[CH:4]=2)=[N:9][N:10]=1)([CH3:27])[CH2:17][OH:16]
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)c1nnc(-c2ccc(O)c(C(F)(F)F)c2)s1
Solvent: O
Product: CCCCCCCCCOc1ccc(-c2nnc([C@@](C)(N)CO)s2)cc1C(F)(F)F

Procedure:
The title compound was prepared from protected phenyl-thiadiazole 6a in 90% (579 mg) yield. HPLC retention time on a C8(2) column (30×50 mm, 3 μL) is 1.68 min with gradient 50-98% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=446.2; 1H NMR (400 MHz, DMSO-d6) δ 8.21 (dd, 1H, J=9.0 Hz, J=2.0 Hz), 8.15 (d, 1H, J=2.0 Hz), 7.45 (d, 1H, J=8.4), 4.21 (t, 2H, J=6.2 Hz), 3.74-3.85 (m, 3H), 1.68-1.77 (m, 5H), 1.25-1.45 (m, 12H), 0.849 (t, 3H, J=6.4).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][O:7][C:8]1[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([O:18][CH3:19])=[C:12]([CH3:20])[C:9]=1[CH2:10]Br>CN(C)C=O.C(N(CC)CC)C.O>[CH3:19][O:18][C:13]1[C:14]([CH3:17])=[C:15]([CH3:16])[C:8]([O:7][CH3:6])=[C:9]([CH3:10])[C:12]=1[CH2:20][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1c(C)c(C)c(OC)c(CBr)c1C
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(C)c(C)c(OC)c(Cn2ccnc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a solution of 499 mg (7.33 mmol) of imidazole and 2.0 g (7.33 mmol) of 2,5-dimethoxy-3,4,6-trimethylbenzyl bromide in 12 ml of dimethylformamide, 1.2 ml of triethylamine was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried, from which the solvent was evaporated off. The residue was purified with silica gel column chromatography (chloroform-methanol(1:1)) and recrystallized from isopropyl ether, to give 0.9 g (47.3%) of 1-(2,5-dimethoxy-3,4,6-trimethylbenzyl)imidazole. m.p. 82°-83° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH2:14][CH2:13][CH:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)[CH2:11][CH:10]=1.C(N(CC)CC)C.[O:29]1C[CH2:32][CH2:31][CH2:30]1.C(Cl)(=O)C=C>O>[C:30]([O:21][C@H:18]1[CH2:17][CH2:16][C@H:15]([CH:12]2[CH2:13][CH2:14][C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])=[CH:10][CH2:11]2)[CH2:20][CH2:19]1)(=[O:29])[CH:31]=[CH2:32]
Reactant: C1CCOC1
Reactant: O[C@H]1CC[C@H](C2CC=C(c3cccc(F)c3F)CC2)CC1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)O[C@H]1CC[C@H](C2CC=C(c3cccc(F)c3F)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
First, 4.6 g of trans-4-[4-(2,3-difluorophenyl)-3-cyclohexenyl]cyclohexanol, 1.76 g of triethylamine, and 60 ml of dry tetrahydrofuran were placed in a 100 ml flask. Then, 1.57 g of acryloyl chloride was added dropwise to the reaction mixture under ice water cooling. The resultant reaction mixture was allowed to warm to room temperature and stirred overnight. Water was added to the reaction mixture, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: benzene/hexane=2/3) and recrystallized from hexane to obtain 2.74 g of trans-4-[4-(2,3-difluorophenyl)-3-cyclohexenyl]cyclohexyl acrylate (Y: 50.4%). The compound thus obtained had a purity of 99.8% by HPLC and 1 spot by TLC. Furthermore, the phase transition temperature of the compound was as follows.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[C@@H:14]2[C@@H:9]([C:10]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:11]=3[CH2:12][CH2:13]2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[C@@H:14]2[C@@H:9]([C:10]3[CH:18]=[CH:17][C:16]([O:19][C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)=[CH:15][C:11]=3[CH2:12][CH2:13]2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCC[C@@H]2c3ccc(O)cc3CC[C@@H]21)C(F)(F)F
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Oc2ccc3c(c2)CC[C@H]2[C@@H]3CCCN2C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of cis-2,2,2-trifluoro-1-(8-hydroxy-2,3,4a,5,6,10b-hexahydro-1H-benzo[f]quinolin-4-yl)-ethanone (0.98 g), 4-methoxyphenylboronic acid (1.00 g), pyridine (1.30 mL), copper(II) acetate (0.60 g), molecular sieves 3 Å (3.60 g), and dichloromethane (15 mL) is stirred in air at room temperature overnight. The mixture is diluted with dichloromethane and filtered over Celite. The filtrate is concentrated and the residue is chromatographed on silica gel (dichloromethane/methanol containing 1% NH3 99:1→95:5) to give the title compound as a colorless resin-like solid. Yield: 1.05 g (79% of theory); LC (method 1): tR=5.00 min; Mass spectrum (ESI+): m/z=406 [M+H]+.