Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:14](NC(C)C)([CH3:16])[CH3:15].[Li].C(Br)C=C>>[CH2:16]([CH:6]1[CH2:5][CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:2]1=[O:1])[CH:14]=[CH2:15]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: CC(C)NC(C)C
Agent: [Li]
Solvent: C=CCBr
Product: C=CCC1CCN(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 35.9 %

Procedure:
To a stirred solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.26 g, 6.80 mmol) at −78° C., was added lithiumdiisopropyl amine (4.76 mL, 9.52 mmol) (2 M in heptane/THF/benzene) dropwise over 15 minutes. After 15 min, allyl bromide (1.18 mL, 13.6 mmol) was added and the reaction stirred at −78° C. for 1 h then quenched with acetic acid (0.5 mL). The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on ISCO (0-100% ethyl acetate/hexanes) to afford Compound 1a (550 mg, 36%) as a clear oil. LCMS=1.95 min using analytical Method (B), 473.4 (2M+Na). 1H NMR (400 MHz, CDCl3-d) δ 5.89-5.69 (m, 1H), 5.18-5.00 (m, 2H), 3.76 (ddd, J=11.2, 8.5, 2.9 Hz, 1H), 3.58 (ddd, J=10.8, 9.0, 7.5 Hz, 1H), 2.70-2.50 (m, 2H), 2.29-2.07 (m, 2H), 1.79-1.64 (m, 1H), 1.53 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:35](=[O:44])[C:36]2[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=2[NH2:43])=[N:32][CH:33]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2].[B-][N+](C)(C)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:43][C:37]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:36]=2[C:35]([NH:34][C:31]2[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][N:32]=2)=[O:44])=[C:7]([O:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C=O)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Agent: [B-][N+](C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2CNc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
A solution of the 4-(tert-butyl)-2-(1-Boc-piperidine-4-yloxy)benzaldehyde (0.15 g, 0.42 mmol), N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide (0.12 g, 0.42 mmol) and catalytic pyridinium p-toluenesulfonate in toluene (8 mL) was treated with excess magnesium sulfate (0.5 g). The reaction mixture was then heated at 75° C. overnight. The reaction was cooled down to room temperature, filtered, and concentrated in vacuo to an oily residue which was redissolved in acetic acid (1.4 mL). The resulting solution was treated with borane-trimethylamine complex (0.2 g, 2.74 mmol) and stirred at room temperature for 3 h. The reaction mixture was then partition between 5 N aqueous sodium hydroxide and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated in vacuo to a residue which was purified on a silica gel chromatotron plate. Elution with ethyl acetate-hexanes (95:5) then (9:1) provided the title compound (0.23 g, 87%) as a yellow oil which foamed up under vacuum. Recrystallization of the oil from ethyl acetate-hexanes provided analytically pure product (0.17 mg) as a pale-yellow crystalline solid.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[F:6][C:7]([F:25])([F:24])[C:8]1[CH:9]=[C:10]([N:14]2[C:19](=[O:20])[NH:18][CH:17](SC)[NH:16][C:15]2=[O:23])[CH:11]=[CH:12][CH:13]=1>C(O)(=O)C>[F:6][C:7]([F:25])([F:24])[C:8]1[CH:9]=[C:10]([N:14]2[C:19](=[O:20])[NH:18][CH:17]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[NH:16][C:15]2=[O:23])[CH:11]=[CH:12][CH:13]=1
Reactant: CSC1NC(=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1
Reactant: CCCCN
Solvent: CC(=O)O
Product: CCCCNC1NC(=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1
Temperature: 145 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
n-Butylamine (3.92 ml.) was added during 15 minutes to stirred acetic acid (2.4 ml.). After 30 minutes at room temperature, 3-(3-trifluoromethylphenyl)-6-methylthio-tetrahydro-1,3,5-triazine-2,4-dione (6.1 g.) was added to the acetic acid solution. The mixture obtained was then heated at 145° C., for 4 hours. (The liberated methylmercaptan was absorbed into a trap containing an excess of aqueous sodium hydroxide and sodium hypochlorite.) The reaction mixture was cooled to room temperature and then water (75 ml.) was added. The mixture was then stirred for 15 minutes and the white solid which formed was separated by filtration, washed with water (3×150 ml.), and dried (over phosphorus pentoxide) to give 3-(3-trifluoromethylphenyl)-6-n-butylamino-tetrahydro-1,3,5-triazine-2,4-dione (6.0 g., 95%), m.p. 245°-247° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=[C:4]([CH3:18])[N:3]=1.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C[C:49]([N:51](C)C)=O>FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O.[Zn].[C-]#N.[Zn+2].[C-]#N>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:6]2[N:5]=[C:4]([CH3:18])[N:3]=[C:2]([C:49]#[N:51])[CH:7]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(COc2cc(Cl)nc(C)n2)cc1
Reactant: CC(=O)N(C)C
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Agent: O=C([O-])C(F)(F)F
Product: COc1ccc(COc2cc(C#N)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The starting 4-chloro-6-[(4-methoxybenzyl)oxy]-2-methylpyrimidine from step 1 of this example (3.7 g 14 mmol), palladium trifluoroacetate (0.2 g, 0.6 mmol), racemic-2-(di-t-butylphosphino)-1,1-binaphthyl ligand (0.49 g, 1.23 mmol), zinc dust (0.17 g, 2.65 mmol) and zinc cyanide (0.92 g, 7.8 mmol) were added to a flask (100 mL), and dimethylacetamide (73 mL) was added. The flask was evacuated and back filled with N2 (3 times), and reaction solution was stirred at room temperature for 30 min. The reaction was then heated to 95° C. for 30 min and monitored until starting material was consumed. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with brine (50 mL, ×2), dried over MgSO4, filtered and concentrated i. vac. The crude pale yellow oil was purified by chromatography on silica gel (eluting 7.7% ethyl acetate/hexane) to yield the titled compound as a white solid. LC-MS (M+23): 278.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=[N:11]1.[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(OCC)C>CN(C)C=O.O>[Cl:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([N:10]2[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([C:18]([F:20])([F:21])[F:19])[CH:12]=[N:11]2)=[CH:4][C:5]=1[O:9][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)COc1cc(-n2ncc(C(F)(F)F)c(C)c2=O)c(F)cc1Cl
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
Then, 3.2 g (9.9 mmol) of 2-[2-fluoro-4-chloro-5-hydroxyphenyl]-4-methyl-5-trifluoromethylpyridazin-3-one was dissolved in about 50 ml of N,N-dimethylformamide, to which 0.44 g (11 mmol) of sodium hydride (60 wt % oil dispersion) was added at room temperature. The mixture was left stand at room temperature for 30 minutes and then cooled with ice, to which 1.8 g (11 mmol) of ethyl bromoacetate was added. The mixture was stirred at room temperature for 1 hour, to which diethyl ether and water were added in this order to make an extraction. The organic layer was washed with 10% aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution in this order, and then dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure, and the residue was subjected to silica gel column chromatography, which afforded 2.4 g (5.5 mmol) of ethyl 2-chloro-4-fluoro-5-(4-methyl-5-trifluoromethyl-3-pyridazinon-2-yl)phenoxyacetate (compound [1] wherein R is ethyl; hereinafter referred to as compound A), m.p., 102.0° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:12](=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:8][NH:7]1)=[O:5])[CH3:2].[C:33]([C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:45]=1[O:46][CH3:47])[C:40](O)=[O:41])([CH3:36])([CH3:35])[CH3:34].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:12](=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:8][N:7]1[C:40](=[O:41])[C:39]1[CH:43]=[C:44]([C:48]([CH3:49])([CH3:50])[CH3:51])[C:45]([O:46][CH3:47])=[C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:38]=1)=[O:5])[CH3:2]
Reactant: COc1c(C(C)(C)C)cc(C(=O)O)cc1C(C)(C)C
Reactant: CCOC(=O)[C@@H]1C[C@H](NC(=O)CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CN1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)[C@@H]1C[C@H](NC(=O)CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CN1C(=O)c1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To the solution of (2S,4S)-4-[6,6-Bis-(4-fluoro-phenyl)-hexanoylamino]-pyrrolidine-2-carboxylic acid ethyl ester (32) (0.39 g, 0.88 mmol) in dry CH2Cl2 (20 ml) was added 3,5-di-tert-butyl-4-methoxy benzoic acid (0.23 g, 0.88 mmol). To the reaction was added EDC (0.34 g, 1.76 mmol) and DMAP (cat), and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (10 ml), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using pet ether: EtOAc (1:1) to give 0.46 g of desired product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:12]Br.[OH-].[Na+]>CC(O)=O>[Br:12][C:9]1[C:8]([NH2:11])=[CH:7][CH:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[N:10]=1
Reactant: CS(=O)(=O)c1ccc(N)cn1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(N)c(Br)n1
Reaction time: 1 h
Yield: 39.6 %

Procedure:
A solution of 510 mg (2.96 mmol) of 6-methanesulfonylpyridin-3-ylamine in 1.25 mL of AcOH was added a solution of 0.15 mL (2.96 mmol) of bromine in 0.5 mL of AcOH at room temperature dropwise. The resulting slurry was stirred for 1 hour. The reaction was carefully basified to pH=10 with 6 M NaOH. The solution was then extracted with two 150 mL portions of dichloromethane, dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture showed a 3:1 mixture of product:dibromo product by NMR. These two products were separated by silica chromatography (hexanes/EtOAc) to afford 294 mg (40%) of 2-bromo-6-methanesulfonylpyridin-3-ylamine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:16][CH2:17][N:18]([C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:19][CH:20]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[OH-:30].[Na+].BrBr>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@:15]23[O:30][C@@H:16]2[CH2:17][N:18]([C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])[CH2:19][CH2:20]3)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: C[C@H](c1ccccc1)N1CC=C(c2ccc(OCc3ccccc3)cc2)CC1
Agent: Br
Agent: BrBr
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](c1ccccc1)N1CC[C@]2(c3ccc(OCc4ccccc4)cc3)O[C@@H]2C1
Temperature: 2.5 °C
Reaction time: 1.5 h

Procedure:
44.3 g of (R)-4-(4-Benzyloxy-phenyl)-1-(1-phenyl-ethyl)-1,2,3,6 tetrahydropyridine (120 mmol) was suspended in 440 mL of dioxane at room temperature. Under stirring 40.4 g of 48% aqueous hydrogen bromide (240 mmol) was added at 15-20° C. within 5 minutes, followed by 24 mL of water. At the same temperature, the pH of the mixture was adjusted to pH 2 using 65 mL of 2 N NaOH. The slightly turbid solution was cooled to 2-3° C, and 21.2 g of bromine (133 mmol) was continuously added over 1.5 hours from a syringe pump via a teflon cannula. After the bromine addition, stirring at 2-3° C. was continued for another 1.5 hours. At this point, all starting material had reacted. At 0° C., 160 mL of 4 N NaOH (640 mmol) was added over 30 minutes and stirring was continued. After 2 hours the intermediate had completely reacted to the final product. The reaction mixture was extracted using a mixture of 500 mL of ethyl acetate and 200 mL of 20% aq. sodium chloride. The aqueous phase was separated and extracted with 1 portion of 300 mL of ethyl acetate. The organic phases were washed with 300 ml of 20% aq. sodium chloride, combined, dried (MgSO4) and evaporated under reduced pressure to give 51.3 g crude product as a brown oil. The crude product was taken up in 50 mL of ethyl acetate. Immediately after dissolution crystals started to separate. 50 mL of diethyl ether was added and the suspension was cooled to 0° C. A second portion of 25 mL of diethyl ether was added and the suspension was stirred for another 1 hour at 0° C. The crystals were collected on a filter funnel and washed with a portion of cold diethyl ether. The product was then dried for 2 hours at 26 mbar/45° C. There was obtained 23.5 g of (1R, 6R)-6-(4-benzyloxy-phenyl)-3-[(R)-1-phenyl-ethyl]-7-oxa-3-aza-bicyclo [4.1.0] heptane.
Reaction SMILES: C(=O)([O-])O.[Na+].Br[CH2:7][C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:15]([NH2:25])(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1.C(OCC)(=O)C>[CH2:12]([O:11][C:9]([C:8]1[N:25]=[C:15](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:24][CH:7]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=O)C=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1coc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
Synthesis was conducted in accordance with the report (J. Org. Chem., 1996, Vol. 61, p. 6496) by Panek et al. Sodium hydrogencarbonate (22.8 g) and ethyl bromopyruvate (10.5 ml) were added to a solution of cinnamamide (10.0 g) in tetrahydrofuran (250 ml) at room temperature, and the mixture was heated under reflux for 48 hours. The reaction mixture was allowed to cool to room temperature, filtered through Celite and then concentrated under reduced pressure to obtain residue. Trifluoroacetic anhydride (30 ml) was added to a solution of this residue in tetrahydrofuran (30 ml) at 0° C., and the mixture was gradually warmed to room temperature. After the mixture was stirred for 63 hours, a saturated aqueous solution (500 ml) of sodium hydrogencarbonate and ethyl acetate (150 ml) were added to the reaction mixture, and an organic layer was separated. The water layer was extracted with ethyl acetate (150 ml). The organic layers were combined, washed with saturated saline (150 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1→3:1) to obtain the title compound (10.9 g) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[CH:8]=[O:9].[Na+].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([S:17]([C:2]2[CH:6]=[C:5]([Cl:7])[S:4][C:3]=2[CH:8]=[O:9])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S([O-])c1ccccc1
Reactant: O=Cc1sc(Cl)cc1Cl
Agent: [Na+]
Product: O=Cc1sc(Cl)cc1S(=O)(=O)c1ccccc1

Procedure:
The title compound was prepared by the method of Preparation 42a using 3,5-dichlorothiophene-2-carbaldehyde and benzenesulfinic acid sodium salt.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][C:12]([OH:15])([CH3:14])[CH3:13]>C(OCC)C.CN(C)C1C=CN=CC=1>[C:12]([O:15][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Br:1])([CH3:14])([CH3:13])[CH3:11]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.1 %

Procedure:
To a solution of 2-bromobenzoyl chloride 2.0 g, 9.11 mmol) in dry diethyl ether (40 mL) was added 2-methyl-2-propanol (0.96 mL, 10.02 mmol) followed by 4-(dimethylamino)pyridine (111 mg, 0.911 mmol) and the reaction mixture stirred at room temperature under nitrogen for 48 hours. The resulting white suspension was then partitioned between ethyl acetate (100 mL) and 1 M hydrochloric acid (100 mL). The organic phase was separated, washed with 1 M hydrochloric acid (100 mL), 2 M sodium hydroxide (2×100 mL), water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a yellow oil. Purification by flash chromatography using ethyl acetate/hexane as eluant gave the title compound (1.22 g, 52%) as a colorless oil.
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[C:14](=[O:18])[CH2:15][CH2:16][CH:17]=1)(=[O:6])[CH3:5]>CO.C(O)(=O)C>[C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[C:14](=[O:18])[CH2:15][CH2:16][CH:17]1[C:1]#[N:2])(=[O:6])[CH3:5]
Reactant: CC(=O)OCCCCCC1=CCCC1=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)OCCCCCC1C(=O)CCC1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
98 g [1.5 mols] of potassium cyanide were suspended in 600 ml of methanol, and 105 g [0.5 mol] of 2-(5-acetoxypentyl)- cyclopent-2-ene-1-one, dissolved in 45 ml of acetic acid, were added dropwise within 2.5 hours. After 20 hours, agitation at room temperature, the suspension was dropped into ice-water with agitation, extracted thrice with diethyl ether, the ether phases were united, washed with water, dried over sodium sulfate and concentrated. The oily residue was stirred for 5 hours at room temperature in 200 ml of pyridine and 30 ml of acetic anhydride, the solvent was then distilled off under reduced pressure and the residue was distilled in a bulb tube. 102 g having a boiling point of 180° C. at 0.4 mm Hg were obtained; IR spectrum: 2220 cm-1.
Reaction SMILES: [CH3:1][C@H:2]([N:9]1[CH2:13][CH2:12][C:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([CH2:14][CH2:15]OS(C)(=O)=O)[C:10]1=[O:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:30]([O:32][CH2:33][CH2:34][N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[CH3:31]>>[CH3:1][C@H:2]([N:9]1[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][N:48]2[CH2:47][CH2:46][CH:45]([NH:44][C:36]3[N:35]([CH2:34][CH2:33][O:32][CH2:30][CH3:31])[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)[CH2:50][CH2:49]2)([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:10]1=[O:29])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](c1ccccc1)N1CCC(CCOS(C)(=O)=O)(Cc2ccc(F)cc2)C1=O
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CCC3(Cc4ccc(F)cc4)CCN([C@@H](C)c4ccccc4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-((S)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (Rf=0.71 silica gel, ethyl acetate) (0.45 g, 1.06 mmol) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl) (piperidin-4-yl)amine to give a diastereomer of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[C:8]2=[O:26])=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[C:8]2=[O:26])=[CH:27][CH:28]=1
Reactant: COc1ccc(C2CCN(C3CCN(Cc4ccc(F)cc4)C3=O)CC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1C(N2CCC(c3ccc(O)cc3)CC2)CCN1Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one (AJ) (3 g, 7.9 mmol) in dry dichloromethane (100 mL) under a N2 atmosphere at −78° C. was added 1 M boron tribromide in dichloromethane (39 mL, 39 mmol) and the resulting mixture was allowed to warm up to room temperature over 3 h, with stirring. The reaction was quenched with water (30 mL) and the organic layer was separated, washed with water and brine, and concentrated. The crude product was purified by flash chromatography on silica gel using 15% EtOAc in petroleum ether to yield racemic 1-(4-fluorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (2.1 g, 73%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49-1.74 (m, 4H) 1.90-2.11 (m, 2H) 2.24-2.42 (m, 2H) 2.65-2.80 (m, 2H) 2.99-3.23 (m, 3H) 3.40-3.54 (m, 1H) 4.27-4.46 (m, 2H) 6.61-6.70 (m, 2H) 6.95-7.04 (m, 2H) 7.17-7.31 (m, 4H) 9.10-9.16 (m, 1H). LCMS: R.T. 0.880 min. LCMS (ES-API), 369.2 m/z (M+H). A portion of the racemate (40 mg) was separated via SFC on a Chiralpak-IA 250 mm×4.6 mm, 5 microm column eluting with 35% solvent B, where solvent A=CO2 and solvent B=0.3% DEA in methanol at a total flow of 3 mL/min. Peak 1 showed a RT of 4.35 min and Peak 2 showed a RT of 6.29 min.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:7]([C:9]1[CH:10]=[C:11]([C:27]([NH:29][CH3:30])=[O:28])[C:12](=[O:26])[N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:14]=1[CH3:15])=O>C(#N)C>[NH2:1][C:2]1[S:3][C:6]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)=[C:7]([C:9]2[CH:10]=[C:11]([C:27]([NH:29][CH3:30])=[O:28])[C:12](=[O:26])[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=3)[C:14]=2[CH3:15])[N:4]=1
Reactant: NC(N)=S
Reactant: CNC(=O)c1cc(C(=O)C(Br)c2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: CC#N
Product: CNC(=O)c1cc(-c2nc(N)sc2-c2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 120 °C
Yield: 17.5 %

Procedure:
Thiourea (8.5 mg, 0.11 mmol) was added to 5-[bromo(4-chlorophenyl)acetyl]-N,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (SM4, mg, 55 mmol) in acetonitrile (1 ml) and the mixture was heated in a microwave oven to 120° C. for 10 min. The crude product was purified on an Xterra C8 column using a gradient of acetonitrile/water. Freeze drying of the mixture afforded the title compound (10 mg, 35%).