Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=O)[O:28][C:26](=[O:27])[C:25]2=[CH:31][CH:32]=1>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:29](=[O:28])[C:24]5=[CH:23][C:22]([O:21][CH3:20])=[CH:32][CH:31]=[C:25]5[C:26]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: COc1ccc2c(c1)C(=O)OC2=O
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)N(CCN1CCC(c3noc4cc(F)ccc34)CC1)C2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.63 g. 0.01 mole) and 4-methoxyphthalic anhydride (1.78 g. 0.01 mole) in dichloromethane (100 ml) is stirred at room temperature for 3 hours. The solvent is then removed under reduced pressure and the residual material is purified by flash chromatography. The product is purified further by recrystallization to give N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-methoxyphthalimide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccccc3F)c2)CC1
Yield: 98.5 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 2-fluorobenzoyl chloride (82 μl, 0.687 mmol), 76.8 mg (99%) of the title compound were recovered.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I.O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:23])[C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)C(F)(F)F)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
N-(1-benzyl-4-piperidinyl)-2,2,2-trifluoroacetamide (1.0 g, 3.49 mmol) was added to a suspension of 60%-sodium hydride (147 mg, 3.67 mmol) in tetrahydrofuran (20 ml) at room temperature and stirred for 30 minutes. Then, methyl iodide (0.239 ml, 3.84 mmol) was added thereto and stirred for 5 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=100/1) to obtain N-(1-benzyl-4-piperidinyl)-2,2,2-trifluoro-N-methylacetamide (731 mg, 70%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[C:12]([F:27])=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]4)=[CH:9][N:8]([CH3:28])[C:4]=2[N:5]=[CH:6][N:7]=1.[ClH:29]>>[ClH:29].[ClH:29].[F:27][C:12]1[C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH3:28])[CH:9]=2)=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][NH:16]2
Reactant: Cn1cc(-c2ccc3c(c2F)CCN3C(=O)OC(C)(C)C)c2c(N)ncnc21
Agent: Cl
Product: Cn1cc(-c2ccc3c(c2F)CCN3)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
A suspension of 1,1-dimethylethyl 5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate (430 mg, 1.121 mmol) and HCl (4 M, dioxane) (10 mL, 329 mmol) was stirred at room temperature overnight. LCMS indicated the reaction was complete, so the reaction mixture was filtered and the residue washed with dioxane (10 mL) and dried at the pump for an hour to afford 5-(4-fluoro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (314 mg, 79% yield) as an off-white solid. LC-MS (ES) m/z=284 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ ppm 3.14 (t, J=7.93 Hz, 2H), 3.68 (t, J=7.90 Hz, 2H), 3.84 (s, 3H), 6.83 (br. s., 1H), 7.16 (t, J=6.99 Hz, 1H), 7.59 (s, 1H), 8.49 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[CH3:28]I>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([C:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH:23]=3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: CI
Reactant: COc1ccc(-c2nc(-c3ccncc3)sc2-c2ccc(OC)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(-c2nc(C3=CCN(C)CC3)sc2-c2ccc(OC)cc2)cc1
Reaction time: 48 h

Procedure:
A solution of 4,5-bis(4-methoxyphenyl)-2-(4-pyridyl)thiazole (1.78 g) and methyl iodide (2.96 ml) in a mixture of chloroform and methanol (5:2) (28 ml) was allowed to stand at ambient temperature for 2 days. The reaction mixture was evaporated in vacuo and the residue containing 4-[4,5-bis(4-methoxyphenyl)thiazol-2-yl]-1-methylpyridinium iodide was dissolved in a mixture of methanol (20 ml). To the resulting solution was added portionwise sodium borohydride (0.54 g) with stirring at 5° to 10° C. The reaction mixture was stirred for one hour at the same temperature. Water was added to the reaction mixture and the precipitate was collected by filtration. The precipitate was dissolved in chloroform and washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was recrystallized from a aqueous methanol to give 4,5-bis(4-methoxyphenyl)-2-(1-methyl-1,2,5,6-tetrahydro-4-pyridyl)thiazole (0.16 g).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:6][CH:7]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])([OH:17])[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8]1)[CH3:5].[CH3:25][S:26]([OH:29])(=[O:28])=[O:27]>O1CCCC1.O>[CH3:25][S:26]([OH:29])(=[O:28])=[O:27].[CH3:5][N:4]([CH2:6][CH:7]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])([OH:17])[CH2:15][CH2:14][C:9](=[O:10])[CH2:8]1)[CH3:3]
Reactant: Cc1ccccc1C1(O)CCC2(CC1CN(C)C)OCCO2
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1C1(O)CCC(=O)CC1CN(C)C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
178 ml of hydrochloric acid (32%, excess) were added rapidly at 0° C. to a solution of 7-dimethylaminomethyl-8-(2-methyl-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol hydrochloride (73.5 g, 215 mmol) in tetrahydrofuran/water mixture, and stirring was then carried out for 16 hours at RT. The mixture was adjusted to pH 12 with 32% sodium hydroxide solution, and extraction was carried out with ether. After evaporation of the solvent in vacuo, the residue was taken up in diisopropyl ether and EE, and the corresponding salt was precipitated by addition of methanesulfonic acid (13 ml, 200 mmol). 64.3 g (84%) of the product were obtained in the form of a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([F:10])([F:9])[F:8])=[N:3]1.C([Li])CCC.[B:16](OC)([O:19]C)[O:17]C>O1CCCC1>[CH3:1][N:2]1[C:6]([B:16]([OH:19])[OH:17])=[CH:5][C:4]([C:7]([F:10])([F:9])[F:8])=[N:3]1
Reactant: Cn1ccc(C(F)(F)F)n1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)F)cc1B(O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a stirred solution of 1-methyl-3-(trifluoromethyl)-1H-pyrazole (1.89 g, 12.6 mmol) in anhydrous tetrahydrofuran (20 mL) under nitrogen cooled to −78° C. was added n-butyllithium (8.3 mL, 1.6 M solution in hexanes, 13.2 mmol) slowly over 5 minutes. The resulting yellow solution was stirred at −78° C. for 1 hour and trimethyl borate (1.56 mL, 13.9 mmol) was then added slowly. The reaction flask was covered in foil and allowed to warm to room temperature for 16 hours. The white solution was quenched with aqueous 1 M hydrogen chloride solution (10 mL) and stirred at room temperature for 1.5 hours. The mixture was extracted with ethyl acetate (2×30 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo to give an off-white foam (2.11 g). The foam was triturated with dichloromethane, filtered and dried in vacuo to afford the title compound as a white solid (1.57 g, 64%).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:13][CH:12]2[CH:14]([O:21][CH3:22])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[CH:11]2[CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[ClH:1].[CH3:22][O:21][CH:14]1[CH:12]2[CH:11]([CH2:10][NH:9][CH2:13]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=2
Reactant: COC1c2ccccc2C2CN(Cc3ccccc3)CC21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC1c2ccccc2C2CNCC21
Yield: 90.5 %

Procedure:
The product from Example 5 (4.90 g) was hydrogenated with 2.45 g 20% Pd/C in 200 ml methanol at 3 atm, affording 3.17 g of the desired product, mp: 208°-209° C. NMR (d6DMSO/D2O) δ2.83 (m, 2H), 3.14-3.29 (m, 3H), 3.46 (dd, 1H), 3.55 (dd, 1H), 3.80 (s, 3H), 3.95 (m, 1H), 6.85 (d, 2H), 7.25 (t, 1H).
Reaction SMILES: Cl.[OH:2][C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)C(C)C)(C)C.[F:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F>C(#N)C>[F:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[N:5]1[CH2:6][CH2:7][C@@H:3]([OH:2])[CH2:4]1
Reactant: O[C@@H]1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CC[C@@H](O)C2)c(F)c1
Yield: 95.6 %

Procedure:
(3R)-3-Hydroxypyrrolidine hydrochloride (20 g, 0.163 M) was suspended by stirring in acetonitrile (200 ml) under nitrogen at 50°, and treated with N,N-diisopropylethylarnine (52.5 g, 0.41 M) and 3,4-difluoronitrobenzene (25.9 g, 0.153 M). The mixture was heated at 90° for 17 hours, then the solvent evaporated. The residue was dissolved in dichloromethane (500 ml) and washed with 5% aqueous sodium dihydrogen phosphate (300 ml), which caused partial precipitation. The precipitate was filtered, washed, and the combined aqueous layers re-extracted with dichloromethane (200 ml). The organic layers were evaporated, and the residue combined with the previously filtered material, and dried by azeotroping with toluene to give the desired product (35 g), of sufficient quality for use without purification.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1.CC(C)=O>[N:20]1([C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=4)[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2cc3c(N4CCCc5ccccc54)ncnc3[nH]2)cc1

Procedure:
This product is prepared in a manner analogous to that described in Example 6 from 4-chloro-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and 1,2,3,4-tetrahydroquinoline (2.1 equivalents). FAB-MS: (M+H)+ =372 (corresponds to C21H17N5O2); Rf value (toluene-acetone--4:6)=0.36.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([N:12]([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH3:13])[CH2:9][C@H:8]1[CH2:20][O:21][Si](C(C)(C)C)(C)C)=[O:6])[CH:2]=[CH2:3].Cl.C(=O)([O-])O.[Na+].O>C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([N:12]([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH3:13])[CH2:9][C@H:8]1[CH2:20][OH:21])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N(C)[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCC=C)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N(C)[C@H]1C[C@@H](CO)N(C(=O)OCC=C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a solution of (2S,4S)-1-allyloxycarbonyl-4-(N-allyloxycarbonyl-N-methylamino)-2-t-butyldimethylsilyloxymethylpyrrolidine (3.73 g) in ethyl acetate (100 ml) was added 12N hydrochloric acid (0.82 ml) at ambient temperature. After stirring at ambient temperature for 30 minutes, to the mixture were added sodium hydrogen carbonate (1.90 g) and cold water (100 ml). The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (100 ml) eluting with a mixture of n-hexane and ethyl acetate (7:3-2:8 V/V) to give (2S,4S)-1-allyloxycarbonyl-4-(N-allyloxycarbonyl-N-methylamino)-2-hydroxymethylpyrrolidine (2.04 g).
Reaction SMILES: [CH3:1][N:2]([OH:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])=[O:4].C(=O)([O-])[O-].[K+].[K+].CS(C)=O.Cl[CH:26](Cl)[CH3:27]>O>[CH3:1][N:2]1[C:3](=[O:4])[N:5]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=2[Cl:13])[CH2:27][CH2:26][O:14]1
Reactant: CC(Cl)Cl
Reactant: CN(O)C(=O)Nc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN1OCCN(c2ccc(Cl)cc2Cl)C1=O
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 65.5 %

Procedure:
A mixture of 11 g of N-methyl-N-hydroxy-N'-(2,4-dichlorophenyl)-urea, 55 g of potassium carbonate and 66 ml of dimethylsulfoxide was stirred for 20 minutes at 20° C and then 11 g of dichloroethane were added. The mixture was stirred for 16 hours at 20°-25° C and was then poured into water. The mixture was vacuum filtered and the recovered precipitate was taken up in ethyl acetate. The solution was dried and evaporated to dryness under reduced pressure. The residue was crystallized from isopropyl ether to obtain 8 g of 2-methyl-4-(2',4'-dichlorophenyl)-3-oxo-5,6-dihydro-1,2,4-oxadiazine melting at 94°-95° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([NH:20][C:21]([C:23]1[S:27][C:26]([NH2:28])=[N:25][C:24]=1[CH3:29])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:21]([C:23]1[S:27][C:26]([NH:28][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:25][C:24]=1[CH3:29])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(O)CCCc1ccccc1
Product: Cc1nc(NC(=O)CCCc2ccccc2)sc1C(=O)NCc1ccccc1
Yield: 47 %

Procedure:
Following the procedure as described in Example 11, making variations only as required to use 4-phenylbutanoic acid in place of 5-phenylpentanoic acid to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 47% yield; m.p. 45-46° C.; 1H NMR (CDCl3, 300 MHz) δ 11.13 (s, br, 1H), 7.35-7.09 (m, 10H), 6.24 (t, J=5.0 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 2.63 (t, J=7.5 Hz, 2H), 2.52 (s, 3H), 2.41 (t, J=7.5 Hz, 2H), 2.00 (q, J=7.5 Hz, 2H); MS (ES+) m/z 397.5 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[C:4]([C:6]1[S:10][C:9]2[C:11]([N+:23]([O-:25])=[O:24])=[C:12]([O:19]C(=O)C)[C:13]([O:15]C(=O)C)=[CH:14][C:8]=2[C:7]=1[Cl:26])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:27]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[S:10][C:9]2[C:11]([N+:23]([O-:25])=[O:24])=[C:12]([OH:19])[C:13]([OH:15])=[CH:14][C:8]=2[C:7]=1[Cl:26])=[O:5])[CH3:28]
Reactant: CCN(CC)C(=O)c1sc2c([N+](=O)[O-])c(OC(C)=O)c(OC(C)=O)cc2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCN(CC)C(=O)c1sc2c([N+](=O)[O-])c(O)c(O)cc2c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5,6-Diacetoxy-3-chloro-7-nitro-benzo[b]thiophene-2-carboxylic acid diethylamide (0.32 g) was dissolved in methanol (16 ml) and a solution of potassium carbonate (0.61 g) in water (3 ml) was added to the reaction solution. It was stirred at room temperature for one hour. Methanol was evaporated and the residue was kept in cool and filtered. The solid was washed with water and recrystallized from methanol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:33](=[O:37])[CH2:32]2)=[CH:38][CH:39]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=C1CN(CCc2ccc(F)cc2)CCN1
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccc(F)cc5)CC4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 76.1 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (514 mg, 1.356 mmol) and 4-(4-fluorophenethyl)piperazin-2-one (301 mg, 1.356 mmol) were reacted following the procedure for Example 53 (step b) to provide the title compound (537 mg, 76%) as a white solid: ESI MS m/z 521 [M+H]+.
Reaction SMILES: [H][H].[CH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH:3]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: c1ccccc1
Product: c1ccc(C2CCCCC2)cc1

Procedure:
contacting benzene and hydrogen under hydroalkylation conditions to produce cyclohexylbenzene;
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:33])[C:14]=2[NH:18][C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)[C:9]1=[O:34])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[Cl:33][C:13]1[C:14]([NH:18][C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:30])([F:31])[F:29])[CH:22]=2)=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:34])[N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[CH:17]=[CH:16]2
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(F)c(C(F)(F)F)c3)c(Cl)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@H](CO)n1ccc2c(NC(=O)Cc3ccc(F)c(C(F)(F)F)c3)c(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
A round bottom flask was charged with (R)-2-(6-chloro-5-(2-(4-fluoro-3-(trifluoromethyl)phenyl)acetamido)-1-oxoisoquinolin-2(1H)-yl)propyl acetate (250 mg, 0.00050 mol), potassium carbonate (100 mg, 0.00075 mol) and methanol (8 mL, 0.2 mol) and 2 drops of water. The reaction was stirred at room temperature for 30 minutes. The reaction mixture was filtered, washed with methanol. The solvent was removed and the residue purified by preparative HPLC (reverse phase) to obtain the product as an off white solid (about 150 mg). MS m/z=457.4 (M+1). 1H NMR (400 MHz; DMSO) δ 10.17 (s, 1H), 8.16 (d, J=8.85 Hz, 1H), 7.82 (d, J=7.76 Hz, 1H), 7.72-7.74 (m, 1H), 7.59 (d, J=8.84 Hz, 1H), 7.54-7.49 (m, 2H), 6.42 (d, J=7.50 Hz, 1H), 5.03-4.93 (m, 2H), 3.90 (s, 2H), 3.66-3.56 (m, 2H), 1.28 (d, J=7.63 Hz, 3H).
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[C:3](=O)[CH2:4][CH2:5]2.[C:8]1([CH2:14][CH2:15][CH2:16][SH:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)C.C(N(CC)CC)C>[C:8]1([CH2:14][CH2:15][CH2:16][S:17][C:2]2[C:6](=[O:1])[CH2:5][CH2:4][CH:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: SCCCc1ccccc1
Reactant: O=C1CCC2OC12
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C1CCC=C1SCCCc1ccccc1
Yield: 63.7 %

Procedure:
2,3-Epoxycyclopentanone (1.0 g) and 1.06 g of 3-phenylpropyl mercaptan were dissolved in 20 ml of diethyl ether, and 20 drops of triethylamine were added. They were reacted at room temperature for 2 hours. After the reaction, the solvent was distilled off from the reaction mixture under reduced pressure. The residue (1.50 g) was chromatographed on a dry column with cyclohexane/ethyl acetate (=8/2) to afford 1.03 g of 2-(3-phenylpropylthio)cyclopent-2-en-1-one in a yield of 64%. The product had the following characteristics.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([CH2:22]C=C)[C@@:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.[F:25][C:26]([F:52])([C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45])[CH2:27][CH2:28][CH:29]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH2:41])[C:30]([O:32]CC)=[O:31]>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([CH2:22][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH:29]([CH2:28][CH2:27][C:26]([F:52])([F:25])[C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:46])([F:47])[F:45])[C:30]([OH:32])=[O:31])[C@@:8]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CC[C@H]1c2ccc(OC)cc2SC[C@@]1(C)c1ccc(OC)cc1
Product: C[C@@]1(c2ccc(O)cc2)CSc2cc(O)ccc2[C@@H]1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the (3R,4R)-7-methoxy-3-(4-methoxyphenyl)-3-methyl-4-(2-propenyl)thiochroman resolved as Peak 2 in Example 17 and the ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate prepared in Example 3, a procedure analogous to that as shown in Example 8 was repeated to give 10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid.
Reaction SMILES: [OH:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].F[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>C1COCC1>[F:19][C:17]1[CH:16]=[CH:15][C:14]([N+:20]([O-:22])=[O:21])=[C:13]([CH:18]=1)[O:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(C)O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-Hydroxybutyrate (6.5 ml) was dissolved in THF (350.0 ml) at 0° C. and NaH (4.8 g) was added. The reaction was stirred at room temperature for 30 min. Then 5.5 g 2,4-difluoronitrobenzene was added and the mixture was heated at reflux overnight. The reaction was concentrated in vacuo and the residue was dissolved in water and dichloromethane. The organic layer was separated, dried and concentrated in vacuo. The residue was purified by chromatography (silica/dichloromethane) to yield the title compound.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[F:17][C:18]1[CH:19]=[C:20]([CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[CH:21]=[CH:22][CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH:24]([O:25][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Reactant: OC(c1ccccc1)c1cccc(F)c1
Product: O=C(OC(c1ccccc1)c1cccc(F)c1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with (3-fluoro-phenyl)-phenyl-methanol.