Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:44]([O:46][CH3:47])=[O:45]>C1COCC1>[F:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:10]([C:11]2[N:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:44]([O:46][CH3:47])=[O:45])[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[O:23])[CH:7]=1
Reactant: COC(=O)Cl
Reactant: O=C(NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1)c1ccc(N2CCNCC2)cn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(F)c3)nc2)CC1
Reaction time: 2 h

Procedure:
To a solution of N-((3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methyl)-5-(piperazin-1-yl)picolinamide 49-6 (64 mg, 0.14 mmol) and DIEA (0.07 mL, 0.42 mmol) in THF (1 mL) was added methyl chloroformate (13 uL, 0.17 mmol) dropwise at room temperature. The mixture was stirred for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give methyl 4-(6-((3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate 93 as a white powder. MS m/z 519.20 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.28 (t, 1H, J=6.4 Hz), 8.92 (d, 1H, J=5.2 Hz), 8.62 (m, 1H), 8.32 (m, 2H), 8.20 (d, 1H, J=5.2 Hz), 7.88-7.82 (m, 2H), 7.43 (dd, 1H, J1=7.0 Hz, J2=3.2 Hz), 4.59 (d, 2H, J=6.4 Hz), 3.73 (s, 3H), 3.54-3.51 (m, 4H), 3.37-3.35 (m, 4H).
Reaction SMILES: [C:1]([SH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH2:12]>C(Cl)(Cl)(Cl)Cl>[C:1]([S:9][C:11]([CH3:12])([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C(S)c1ccccc1
Reactant: C=C(C)CC(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)CC(C)(C)SC(=S)c1ccccc1
Temperature: 70 °C
Yield: 31.7 %

Procedure:
A mixture of dithiobenzoic acid (5 g), 2,4,4-trimethylpentene (7.3 g) and carbon tetrachloride (25 mL) was heated at 70° C. for two days. The resultant mixture was reduced to a crude oil. Purification of the residue, by column chromatography (Kieselgel-60, 70-230 mesh, petroleum spirit 40-60° C. eluent) gave 2,4,4-trimethylpent-2-yl dithiobenzoate (17) (2.74 g, 31.7% yield) as a dark red oil. 1H-nmr (CDCl3) d (ppm): 1.08 (s, 9H, 3×CH3), 1.77 (s, 6H, 2×CH3), 2.20 (s, 2H, CH2), 7.35 (dd, 2H, meta-ArH), 7.49 (dd, 1H, para-ArH) and 7.85 (d, 2H, ortho-ArH). 13C-nmr (CDCl3) d (ppm): 28.3, 31.5, 32.8, 50.5, 57.7, 126.6, 128.1, 131.5 and 147.9. The signal due to C═S (d>220.0 ppm) was beyond the frequency range of the spectrum.
Reaction SMILES: CO[C:3]1O[C:5](OC)=[CH:6][CH:7]=1.[NH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:29]([F:32])([F:31])[F:30])=[C:18]2[C:22]=1[N:21]([CH3:23])[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19]2.C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:23][N:21]1[C:22]2[C:18](=[C:17]([C:29]([F:32])([F:30])[F:31])[CH:16]=[CH:15][C:14]=2[O:13][CH2:12][CH2:11][N:10]2[CH:3]=[CH:7][CH:6]=[CH:5]2)[CH:19]=[C:20]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: COc1ccc(OC)o1
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCCN)c2n1C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCCn3cccc3)c2n1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 58.5 %

Procedure:
After 1.28 g (9.69 mmol) of 2,5-dimethoxyfuran was added to a solution of 2.91 g (8.81 mmol) of ethyl 7-(2-aminoethoxy)-1-methyl-4-trifluoromethyl-2-indolecarboxylate in 30 ml of acetic acid, the mixture was stirred at 50° C. for 4 hours and at 70° C. for further an hour. Toluene was added to the reaction mixture followed by concentration under reduced pressure. Ice water was poured onto the resulting residue. The mixture was then extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 1.96 g of ethyl 1-methyl-7-[2-(1H-pyrrol-1-yl)ethoxy]-4-trifluoromethyl-2-indolecarboxylate.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[NH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:29][CH:30](Cl)[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:15][CH2:37][C:34]2[CH:35]=[CH:36][C:31]([CH2:30][Cl:29])=[CH:32][CH:33]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(Cl)Cl)cc1
Reactant: N=C(Nc1ccccc1-c1ccccc1)Nc1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: ClCc1ccc(CN=C(Nc2ccccc2-c2ccccc2)Nc2ccccc2-c2ccccc2)cc1
Yield: 20.6 %

Procedure:
10.9 g (0.03 mole) of N,N'-bis-(2-phenylphenyl) guanidine, 5.7 g (0.033 mole) of α,α-dichloro-p-xylene and 2.1 g (0.015 mole) of anhydrous potassium carbonate were added to 50 ml of toluene. The thus-formed mixture was then refluxed under heating for 10 hours. After the mixture had been allowed to cool, the insoluble substance was removed by filtration. The thus-obtained filtrate was washed with water and then concentrated for the purpose of recovering the solvent and unreacted raw materials to obtain a slightly brown powder. The power was then recrystallized from acetone to obtain 3.1 g of white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]=C)[CH:12]=[CH:11][C:10]=1[N:17]1[S:21](=[O:23])(=[O:22])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:19](=[O:30])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:34]CC1.CC(O)(C)C.O.C([O-])(O)=O.[Na+]>CC(O)(C)C.O.O=[Os](=O)(=O)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=1[N:17]1[CH2:18][C:19](=[O:30])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[S:21]1(=[O:23])=[O:22])[CH:15]=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: C=Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C=O)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-(2-benzyloxy-4-vinylphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (1.9 g, 4.3 mmol) in 1:1:1 THF/t-BuOH/H2O (60 mL) is added 1-methylmorpholine-N-oxide (551 mg, 4.74 mmol) and OsO4 (2 mL of a 2.5 wt % solution in t-BuOH, 0.17 mmol). The reaction is stirred for 4 h at ambient temperature, then diluted with water (15 mL) and treated with NaIO4 (4.5 g, 21.5 mmol) and NaHCO3 (3.6 g, 43 mmol). The mixture is stirred vigorously for 1 h, then filtered through Celite. The solution is extracted with EtOAc. The organic phase is washed with saturated NaCl. The solution is dried over MgSO4 and the solvent removed under reduced pressure, then purified via silica gel chromatography using a gradient of 0-40% EtOAc/hexanes to afford 3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzaldehyde as a white solid: MS (M+NH4)+=464.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH2:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([C:14]1[CH:20]=[CH:19][C:17](C)=[CH:16][CH:15]=1)(=O)=O>>[CH2:4]1[CH2:5][CH2:6][CH:1]([N:7]=[C:8]=[N:10][CH:14]2[CH2:20][CH2:19][CH2:17][CH2:16][CH2:15]2)[CH2:2][CH2:3]1
Reactant: NC(=O)NC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: C(=NC1CCCCC1)=NC1CCCCC1
Reaction time: 9 h

Procedure:
The polymer bound cyclohexylurea (PS-DCU; 1 g of 1.25 mmol/g) recovered after N-acylation is suspended in dimethylformamide (DMF; 10 ml) in a two-necked round-bottom flask (50 ml) equipped with a silicone rubber septum and a reverse filter funnel under exclusion of moisture and air. Tosyl chloride (TsCl; 0.47 g, 2.5 mmol) is added slowly over a period of 20 minutes to the above suspension of PS-DCU. The mixture is shaken gently for 8-10 hours and supernatant is removed by reverse filtration and replaced by 10% aqueous NaOH (5 ml) and tetrahydrofuran (20 ml). The suspension is shaken for 1 hour and supernatant is removed. The polymer is washed with tetrahydrofuran (2×25 ml) to remove excess of water, DMF and base and dried under vacuum to furnish PS-DCC.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:33]([O:35]C)=[O:34])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[C:1]1([C:7]2[C:16]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=4)[CH2:21][CH2:22]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:33]([OH:35])=[O:34])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(C(F)(F)F)cn4)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(C(F)(F)F)cn4)CC3)nc2c1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-phenyl-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate (210.8 mg, 0.43 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (85.5 mg, 2.14 mmol, 5.00 equiv) in water (1.5 mL), which was added dropwise with stirring. The suiting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrochloric acid. The mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 78 mg (38%) of 2-phenyl-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: C[C:2]1(C)[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.N1C=CC=CC=1.BrBr>C(Cl)(Cl)(Cl)Cl>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3][CH2:2][CH:7]=1
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C1=C(c2ccccn2)c2ccccc2OC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.5 g of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran was dissolved in 10 ml of carbon tetrachloride at room temperature and 0.25 ml of pyridine and 0.12 ml of bromine were added. The mixture was stirred at room temperature for 1 hour, then at 35° C. for 1 hour and finally at 65° C. for 1 hour. After cooling the mixture was washed with sodium bicarbonate solution, the aqueous washings were extracted with dichloromethane and the combined organic phases were washed with water, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 2% (v/v) methanol/dichloromethane for the elution. The product was recrystallized from t-butyl methyl ether to give 230 mg of 6-bromo-3,4-dihydro-2,2-dimethyl)-4-(2-pyridyl)-2H-1-benzopyran of melting point 134°-136° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[[2-(dimethylamino)ethyl](methyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 81) (630 mg, 1.40 mmol) in dichloromethane (5 ml) was treated with trifluoroacetic acid (5 ml) and stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue azeotroped from dichloromethane. The residue was purified by column chromatography on silica gel eluting with a gradient system of 100:0 (dichloromethane:methanol) gradually changing to 90:10 (dichloromethane:methanol) to afford the title compound as a colourless gum (453 mg).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([N+]([O-])=O)=[C:18]([CH:21]=1)[C:19]#[N:20]>CN(C=O)C.CCOCC>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])=[C:18]([CH:21]=1)[C:19]#[N:20]
Reactant: COc1ccc([N+](=O)[O-])c(C#N)c1
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(ON=C(C)C)c(C#N)c1
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
In 400 ml of DMF was dissolved acetone oxime (34.5 g) followed by potassium t-butoxide (51 g). After this mixture had stirred for 30 minutes, 5-methoxy-2-nitro-benzonitrile (70 g) was added. After stirring overnight, the reaction was diluted with ether (~4 L) and filtered. The filtrate was washed with ethyl acetate and combined organics were washed with water (3×1.5 L), dried (MgSO4) and concentrated in vacuo. Preparative liquid chromatography (silica gel) eluting with 4:1 heptane/EtOAc yielded the expected product (10 g).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[OH:30].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][O:30][C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[CH:7]=1)[C:3]([OH:2])=[O:19]
Reactant: Oc1ccc2ccccc2c1
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2ccc3ccccc3c2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and 2-naphthol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][C:9]2[CH:14]=[N:13][C:12]([CH:15]3[CH2:17][CH2:16]3)=[CH:11][N:10]=2)[CH2:5][N:4]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>CO>[CH:15]1([C:12]2[N:13]=[CH:14][C:9]([O:8][C@H:6]3[CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:3]([CH2:2][NH:1][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:7]3)=[N:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2cnc(C3CC3)cn2)C[C@H]1CN
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CNC[C@@H]1C[C@@H](Oc2cnc(C3CC3)cn2)CN1C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
A solution of the product from Example 174D (2 g, 5.98 mmol) in methanol (3 mL) was treated with triethylamine (1.834 mL, 13.16 mmol) and methyl 2-bromoacetate (0.608 mL, 6.58 mmol), and the mixture was stirred at 65° C. for 3 hours. The resulting material was partitioned between water and ethyl acetate. The organic extract was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on a 24 g silica gel column eluting with 5% ethyl acetate/hexanes for 3 minutes then a gradient to 100% ethyl acetate over 20 minutes to afford the title compound as a colorless oil (1.10 g, 45.2%).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[C:15]([CH3:16])=[C:14]([OH:17])[C:13]([CH3:18])=[CH:12][C:10]=1[OH:11].C(O[CH:23]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(=O)C>CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C(O)C>[CH3:18][C:13]1[C:14](=[O:17])[C:15]([CH3:16])=[C:9]([CH3:8])[C:10](=[O:11])[C:12]=1[CH:23]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CCOC(=O)CCCCC(OC(C)=O)c1cccs1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1cccs1
Temperature: 60 °C
Yield: 74.8 %

Procedure:
D-Camphor-10-sulfonic acid (0.1 g) was added to a toluene solution (50 ml) of 2,3,5-trimethylhydroquinone (3.1 g, 0.02 mole) and ethyl 6-acetoxy-6-(2-thienyl)hexanoate (5.6 g, 0.02 mole), and the mixture was heated at 60° C. for 6.5 hours, with stirring. After cooling, ethanol (100 ml) and a 10% aqueous solution (20 ml) of ferric chloride were added to the reaction solution, followed by stirring for 10 minutes. The reaction product was extracted with isopropyl ether, and the organic layer was washed with water, dried (over magnesium sulfate) and concentrated under reduced pressure. The residue was chromatographed on a silica gel column, and elution was performed with isopropyl etherhexane (1:1) to give ethyl 6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-6-(2-thienyl)hexanoate (5.6 g, 76%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 2 to 8 were prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:30])([F:29])[F:28])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH:65]1[CH2:69][C:68](=[O:70])[NH:67][CH2:66]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:30])([F:28])[F:29])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:65]4[CH2:69][C:68](=[O:70])[NH:67][CH2:66]4)=[O:23])=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: O=C1CNCN1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CNC(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoic acid (900 mg, 1.99 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL), HATU (1.1 g, 2.89 mmol, 1.45 equiv), DIEA (770 mg, 5.96 mmol, 2.99 equiv), imidazolidin-4-one hydrochloride (489 mg, 3.99 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at rt. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine. The resulting organic phase was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/30-1/10). This resulted in 600 mg (58%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]imidazolidin-4-one as a light yellow solid.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]([O:19]C)=[O:18])[CH:11]=[CH:10][C:9]=3[C:8]2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([O:33][CH3:34])[CH:26]=1)[NH2:24].O1CCCC1>CO>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:23]2[CH:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([C:17]([OH:19])=[O:18])=[CH:13][C:14]=4[CH2:15][CH2:16]3)=[N:24]2)=[CH:26][C:27]=1[O:33][CH3:34])#[N:30]
Reactant: COC(=O)c1ccc2c(c1)CCC(=CC1CCCC1)C2=O
Reactant: COc1cc(NN)ccc1C#N
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)ccc1C#N
Yield: 49 %

Procedure:
The title compound was prepared from Methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate; Preparation 18 (310 mg, 1.09 mmol) and 4-hydrazinyl-2-methoxybenzonitrile hydrochloride; Preparation 4 (282 mg, 1.42 mmol) according to Method B (methanol was used in place of ethanol as solvent) and Method C. The crude precipitate was purified by reverse phase chromatography with 40-95% acetonitrile/water to give the title compound (yellow solid, 220 mg, 0.53 mmol, 49% yield). The title compound was largely present as (±)-(3SR,3aRS)-2-(4-cyano-3-methoxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (m, 7H), 1.65-1.90 (m, 2H), 1.99-2.12 (m, 1H), 2.18-2.27 (m, 1H), 2.82-2.95 (m, 1H), 3.04-3.13 (m, 1H), 3.52-3.63 (m, 1H), 3.90 (s, 3H), 4.94 (dd, J=9.67, 5.37 Hz, 1H), 6.80 (dd, J=8.59, 1.88 Hz, 1H), 6.90 (d, J=1.61 Hz, 1H), 7.45 (d, J=8.59 Hz, 1H), 7.81 (dd, J=8.19, 1.48 Hz, 1H), 7.85 (s, 1H), 8.08 (d, J=8.06 Hz, 1H), 13.02 (s, 1H). ES-MS m/z 416 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].C(N(CC)C(C)C)(C)C.[F:16][C:17]([F:38])([F:37])[C:18]([N:20]([CH:28]1[CH2:30][CH:29]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:19]>C(#N)C>[C:5]([CH2:4][CH2:3][CH2:2][N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:20]([CH:28]2[CH2:30][CH:29]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18](=[O:19])[C:17]([F:16])([F:37])[F:38])[CH2:27][CH2:26]1)#[N:6]
Reactant: N#CCCCBr
Reactant: O=C(N(CC1CCNCC1)C1CC1c1ccccc1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#CCCCN1CCC(CN(C(=O)C(F)(F)F)C2CC2c2ccccc2)CC1

Procedure:
Added 4-bromobutanenitrile (100 mg, 0.674 mmol) to a solution of N,N-diisopropylethylamine (0.353 mL, 2.022 mmol), 2,2,2-trifluoro-N-(2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (220 mg, 0.674 mmol) in acetonitrile (25 mL) and heated to reflux for 16 hours. Concentrated on rotovap and the residue was purified via Biotage (0% to 100% EtOAc:Hex; then 0% to 20% MeOH:DCM to get off more product: 10 g-HP—silica gel column).
Reaction SMILES: Br.[C:2]1([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([N:18]1[CH2:17][CH2:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:21]([OH:23])=[O:22])[CH2:20][CH2:19]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C1(c2ccccc2Sc2ccccc2)CCNCC1
Agent: Br
Solvent: c1ccncc1
Product: CC(=O)N1CCC(C(=O)O)(c2ccccc2Sc2ccccc2)CC1

Procedure:
A mixture of 8 g of 4-(2-phenylthiophenyl)piperidine-4-carboxylic acid hydrobromide and 10 ml of acetic anhydride in 50 ml of pyridine is refluxed for 4 hours. Thereafter, any excess pyridine is removed by distillation under vacuum and the residue is triturated in 100 ml of 1 N hydrochloric acid before being extracted thrice with chloroform. The combined chloroform extracts are successively washed well with water, dried and concentrated under vacuum. The residue is recrystallized from boiling acetone to provide 1-acetyl-4-(2-phenylthiophenyl)piperidine-4-carboxylic acid.