Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2([CH3:28])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30]>C(#N)C>[O:30]=[C:29]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3([CH3:28])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]3)[CH2:11][CH2:10]2)[C@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]2[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N[C@H]3CCCC[C@@H]3N)CC2)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.1 %

Procedure:
A solution of tert-butyl 4-[4-[[(1S,2S)-2-aminocyclohexyl]amino]-1-piperidyl]-4-methyl-piperidine-1-carboxylate (10.0 mmol) in acetonitrile (30 mL) was added with 1,1′-carbonyldiimidazole (1.95 g, 12.0 mmol) and stirred at room temperature for 12 h. Concentrated in vacuo and was added with water (20 mL) and dichloromethane (100 mL), phases were separated and the aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with preparative LC/MS (high pH) to provide the title compound as white solid (1.18 g, 28% over two steps). 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.95 (s, 3H), 1.31-1.40 (m, 4H), 1.42 (s, 9H), 1.44-1.48 (m, 2H), 1.52-1.63 (m, 1H), 1.64-1.89 (m, 8H), 1.93-1.99 (m, 1H), 2.08-2.21 (m, 2H), 2.25-2.32 (m, 1H), 2.89-3.10 (m, 4H), 3.28-3.36 (m, 1H), 3.42-3.53 (m, 2H), 3.54-3.65 (m, 1H). MS (M+1): 421.3.
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[C:6]([CH3:16])=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:17][CH2:18][CH2:19]Br>C(O)C>[Br:17][CH2:18][CH2:19][O:4][C:5]1[C:6]([CH3:16])=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: BrCCBr
Reactant: CCOC(=O)c1cccc(O)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cccc(OCCBr)c1C

Procedure:
13.6 g (0.2 mol) of sodium methoxide are dissolved in 200 ml of ethanol. 36 g (0.2 mol) of ethyl 3-hydroxy-2-methylbenzoate are then added and the mixture is refluxed for 2 hours. 61.4 g (0.32 mol) of 1,2-dibromoethane are then added dropwise and the mixture is heated to reflux for 20 hours. The cooled reaction mixture is concentrated on a rotary evaporator. The residue is taken up with ethyl acetate and washed 3 times with dilute sodium hydroxide solution. The organic phase is dried and the solvent is distilled off. The useful product is purified by column chromatography. Yield: 14.6 g of oil
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][C:17](O)=O)[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:26]1CCCC1>>[CH2:1]([C:3]1([CH:16]([OH:26])[CH3:17])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH3:2]
Reactant: C1CCOC1
Reactant: CCC1(CC(=O)O)OCCc2c1[nH]c1ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC1(C(C)O)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
To solution of (1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (0.52 g, 2.0 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.114 g, 3.0 mmol) in several small portions. The mixture was stirred at room temperature for 6 hours. It was quenched with ethyl acetate carefully and washed with water. The organic layer was dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0.389 g (79%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3) δ 7.82 (br, 1H), 7.52 (d, 1H), 7.34 (d, 1H), 7.18 (td, 1H), 7.13 (td, 1H), 4.07 (m, 1H), 4.01 (m, 1H), 3.70 (m, 1H), 3.64 (m, 1H), 2.89 (m, 1H), 2.77 (dt, 1H), 2.71 (br, 1H), 2.20 (m, 1H), 2.05 (m, 1H), 2.00 (m, 1H), 1.90 (m, 1H), 0.94 (t, 3H); ESI (+) MS m/e=246 (MH+), ESI (−) MS m/e=244 (MH−).
Reaction SMILES: C(OCC)(=O)C.[CH3:7][NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20].C(N(CC)CC)C>O>[CH3:7][N:8]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][Cl:15]
Reactant: CNC1CCCCC1
Reactant: O=C(Cl)CCCCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C(=O)CCCCl)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl acetate (400 ml) is added N-methylcyclohexylamine (26 ml), and to the mixture are added dropwise with stirring 4-chlorobutyryl chloride (25 ml) and triethylamine (33.5 ml) over a period of 20 minutes with keeping the inner temperature at 10° to 20° C. by ice-cooling. The mixture is further stirred at room temperature for one hour. After the reaction, water is added to the reaction mixture. The organic layer is separated and washed with water an aqueious saturated potassium carbonate solution, 10% aqueous hydrochloric acid and water in order, and then dried over anhydrous sodium sulfate. After filtering off sodium sulfate, the mother liquor is concentrated and distilled under reduced pressure to give N-methyl-N-cyclohexyl-4-chlorobutyramide (41.5 g), b.p. 133°-136° C./2 mmHg.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][S:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH:11]1([CH2:14][CH:15]([C:17]2[CH:18]=C(O)[CH:20]=[C:21]([CH:23]=2)[OH:22])[CH3:16])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH:15]([C:17]2[CH:23]=[C:21]([OH:22])[C:20]3[C:2]4[CH2:6][CH2:5][S:4][C:3]=4[C:7](=[O:8])[O:9][C:10]=3[CH:18]=2)[CH3:16])[CH2:12][CH2:13]1
Reactant: COC(=O)C1SCCC1=O
Reactant: CC(CC1CC1)c1cc(O)cc(O)c1
Product: CC(CC1CC1)c1cc(O)c2c3c(c(=O)oc2c1)SCC3

Procedure:
Following a procedure similar to that described in Example 1B hereinabove, methyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylate is reacted with 5-(3-cyclopropyl-2-propyl)resorcinol to give 7-(3-cyclopropyl-2-propyl)-1,2-dihydro-9-hydroxy-4-oxo-4H-thieno[2,3-c] [1]benzopyran.
Reaction SMILES: N1CCC1=O.[C:6]([O:10][C:11]([C:13]([N:18]1[CH:21]([S:22]C=O)[CH:20]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:19]1=[O:36])=[C:14]([OH:17])[CH2:15]Br)=[O:12])([CH3:9])([CH3:8])[CH3:7]>ClCCl>[O:28]([CH2:27][C:26]([NH:25][CH:20]1[C:19](=[O:36])[N:18]2[C:13]([C:11]([O:10][C:6]([CH3:8])([CH3:7])[CH3:9])=[O:12])=[C:14]([OH:17])[CH2:15][S:22][C@H:21]12)=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)C(=C(O)CBr)N1C(=O)C(NC(=O)COc2ccccc2)C1SC=O
Agent: O=C1CCN1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1=C(O)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12

Procedure:
The azetidin-2-ones provided by this invention are useful as intermediates in the preparation of 3-hyroxy cephalosporin antibiotics. In particular, a 1-(1-protectedcarboxy-2-hydroxy-3-bromo-1-propenyl)-3-amido(or imido)-4-formylthio-azetidin-2-one of this invention can readily be cyclized to provide the corresponding 7-amido (or imido)-4-protected-carboxy-3-hydroxy-3-cephem. Such cyclization of the azetidinone is effected by reaction with a cyclizing agent, such as for example 1,5-diazobicyclo[5.4.0]undec-5-ene (DBU) or mercuric acetate. As an example, 1-(1-tert.-butyloxycarbonyl-2-hydroxy-3-bromo-1-propenyl)-3-phenoxyacetamido-4-formylthio-azetidin-2-one can be treated with DBU in a suitable solvent, for instance dichloromethane, thereby effecting a cyclization of the azetidinone to provide tert.-butyl 7-phenoxyacetamido- 3-hydroxy-3-cephem-4-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12](=[O:36])[NH:13][C:14]1[CH:15]=[C:16]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33]CC)=[O:32])=[CH:27][CH:26]=2)[C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12](=[O:36])[NH:13][C:14]1[CH:15]=[C:16]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=2)[C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(-c2cc(NC(=O)[C@@H]3CCN3C(=O)OC(C)(C)C)ccc2OC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
A mixture of (S)-2-(4′-Ethoxycarbonyl-6-trifluoromethoxy-biphenyl-3-ylcarbamoyl)-azetidine-1-carboxylic acid tert-butyl ester (188 mg) in ethanol (15 ml) and sodium hydroxide (2M, 5 ml) was stirred at room temp for 18 h. The mixture was acidified and the ethanol evaporated. The residue was extracted with DCM and the dried extracts evaporated giving the crude acid as a pale orange gum (154 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]#[N:13])[C:5]([O:7][CH3:8])=[O:6].OO.C(=O)([O-])[O-:17].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([NH2:13])=[O:17])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C#N)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C(N)=O)c(Br)c1
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
Methyl 3-bromo-4-cyanobenzoate (prepared as described in Wang, G. T. et al. Bioorg. Med. Chem. Lett. 2005, 15(1), 153(1) (130 mg, 0.54 mmol) was dissolved in DMSO (1.5 mL) and was cooled in a cold water bath. 30% aqueous hydrogen peroxide (0.1 mL) and potassium carbonate (23.9.0 mg, 0.17 mmol) were added and the mixture was stirred at room temperature for 18.5 h. The reaction mixture was partitioned between ethyl acetate and 10% aqueous lithium chloride. The aqueous portion was extracted with ethyl acetate. The combined organic portions were dried over sodium sulfate, filtered and concentrated to afford methyl 3-bromo-4-(aminocarbonyl)benzoate (quantitative yield) as a yellow oil. GCMS for C9H8BrNO3: 257, 259 (M+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25]#[N:26].C([O-])(=O)C.[Na+].Cl.[NH2:33][OH:34]>COCCO>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25](=[N:33][OH:34])[NH2:26]
Reactant: NO
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C#N)OCO3
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=NO)OCO3
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A mixture of 2.80 g (8.0 mmol) of compound XXIII, 30 ml of 2-methoxyethanol, 0.84 g (10 mmol) of sodium acetate and 0.60 g (8.8 mmol) of hydroxylamine hydrochloride was stirred for 0.5 h, then concentrated in vacuum. The residue was treated with water, the precipitated crystals were filtered off and washed with water to yield 3.05 g (100%) of the title compound, Mp.: 138-145° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[C:12]1([Mg]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCCCCCCCCCCCC.Cl>C1COCC1.C1(C)C=CC=CC=1>[C:12]1([C:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: O=C1CCc2ccccc2C1
Agent: CCCCCCCCCCCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C1=C(c2ccccc2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
1.32 mL (10.0 mmol) 2-tetralone in 5 mL of THF was added to a solution of 5.77 mL (12.0 mmol) 2.08 M phenylmagnesium chloride in THF at 0° C. The mixture was allowed to warm to room temperature, and was then stirred for an additional 1 hour. Tridecane (1.22 mL; 5.00 mmol; internal GC standard) was added, the mixture was cooled to 0°, 10 mL of 6N HCl was added. The mixture was heated to 65° and vigorously stirred for 4 hours. The mixture was then cooled to room temperature and diluted with toluene. GC analysis of the organic phase showed the presence of 2.9 mmol 2-phenyl-3,4-dihydronaphthalene (29% yield on 2-tetralone) and 4.6 mmol 2-tetralone (46% recovery). No benzylic alcohol intermediate from addition of the arylmagnesium reagent to the ketone was detected, indicating that its dehydration to the vinylaromatic had been completed by the warm acid treatment.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19]2)=[N:2]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(O)(=O)C.[BH4-].[Na+]>ClC(Cl)C>[N:25]1([CH2:23][C:20]2[CH:21]=[CH:22][N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)[CH:19]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: C1COCCN1
Reactant: O=Cc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: C(=C/c1n[nH]c2ccccc12)\c1ccccc1-n1ccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
Compound 167 (0.08 g, 0.26 mmol) was dissolved in dichloroethane (2.0 mL) and the solution was added with morpholine (67 μL, 0.77 mmol), acetic acid (84 μL, 0.77 mmol) and sodium borohydride (0.16 g, 0.77 mmol) followed by stirring at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, the organic layer was concentrated and the residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to obtain Compound 182 (0.04 g, 41%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:21])[CH2:5][CH2:6][N:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]1=[O:20].[CH:22](OCC)=[O:23]>C(COC)OC>[CH:22]([CH:14]([CH2:13][C:10]1[CH:11]=[CH:12][N:7]([CH2:6][CH2:5][N:4]([CH3:3])[CH3:21])[C:8](=[O:20])[CH:9]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:23]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1ccn(CCN(C)C)c(=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccn(CCN(C)C)c(=O)c1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a stirred, cooled suspension of 50% sodium hydride in oil (5.73 g) in dimethoxyethane (50 ml) was added dropwise over 50 minutes a mixture of ethyl β-[N-(2-dimethylaminoethyl)- 2-oxo-4-pyridyl]propionate (25.43 g) and ethyl formate (10.60 g). The reaction temperature was maintained below 3° C., and then was allowed to warm to room temperature overnight. The reaction mixture was poured on to ice and the resultant brown solution was extracted with petroleum ether (40°-60°) (80 ml) and diethyl ether (3×60 ml). The combined organic extracts were washed with water (20 ml). The combined aqueous solution and aqueous washings were taken to pH 5 with glacial acetic acid, the solvent volume was halved by evaporation under reduced pressure and taken to pH 8 with sodium bicarbonate solution. The solvents were removed by thorough evaporation under reduced pressure and the residue taken up in hot isopropanol-acetone, filtered over diatomaceous earth and evaporated under reduced pressure to yield an oil which was washed with petroleum ether (40°-60°) to afford as a brown oil, ethyl α-formyl-β-(N-(2-dimethylaminoethyl)-2-oxo-4-pyridyl]propionate (25.05 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]2[NH:15][CH:16]=[C:17]([CH3:19])[N:18]=2)[CH2:3]1.[I:20]N1C(=O)CCC1=O.O>C(Cl)Cl>[I:20][C:16]1[NH:15][C:14]([C@@H:4]2[CH2:3][C@H:2]([CH3:1])[CH2:6][N:5]2[C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])=[N:18][C:17]=1[CH3:19]
Reactant: Cc1c[nH]c([C@@H]2CC(C)CN2C(=O)OC(C)(C)C)n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: O
Product: Cc1nc([C@@H]2C[C@H](C)CN2C(=O)OC(C)(C)C)[nH]c1I
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a stirred solution of tert-butyl (2S)-4-methyl-2-(4-methyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (307 mg, 1.013 mmol) in CH2Cl2 (15 mL) is added N-iodosuccinimide (240 mg, 1.013 mmol) at 5° C. The reaction mixture is stirred for one hour and water (2 mL) is added. The organic layer is separated, dried over Na2SO4, and evaporated to dryness. The residue is purified by flash column chromatography on silica gel (12 to 100% EtOAc in Hexanes) to give tert-butyl (2S,4S)-2-(5-iodo-4-methyl-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (246 mg, 62%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:19])[C:17]#[N:18])=[C:12]([O:20][CH3:21])[CH:11]=1.O1C2C=CC=CC=2N=[C:23]1C1C=CC(C#N)=C(OC)C=1.ICC>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH2:19][CH3:23])[C:17]#[N:18])=[C:12]([O:20][CH3:21])[CH:11]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1C(C)C#N
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1C#N
Solvent: CCI
Product: CCC(C#N)c1ccc(-c2nc3ccccc3o2)cc1OC

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]propanenitrile, 4-(1,3-benzoxazol-2-yl)-2-methoxybenzonitrile (300 mg, 1.1 mmol) was reacted with iodoethane (90 μL, 1.1 mmol) to afford the desired 2-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]butanenitrile as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 7.87–7.84 (d, 1H), 7.79–7.74 (m, 2H), 7.59–7.53 (m, 2H), 7.37–7.34 (m, 2H), 4.22–4.17 (t, 1H), 3.97 (s, 3H), 1.95–1.89 (m, 2H), 1.13–1.08 (t, 3H). MS (ESI) 293 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].CI.[C:17]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC.O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([O:10][CH3:17])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cc(Br)cc(C=O)c1O
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C=O)cc(Br)cc1C(C)(C)C
Temperature: 50 °C
Yield: 98.8 %

Procedure:
A mixture of 27 (3.83 g), MeI (2.32 mL) and K2CO3 (6.18 g) in DMF (50 mL) was heated at 50° C. for 1 h then cooled to RT and diluted with ether and water. The organic layer was thrice washed with water then brine, dried (MgSO4) and concentrated to afford 3.99 g of 5-bromo-3-tert-butyl-2-methoxybenzaldehyde (28) as a yellow solid.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.Cl[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1.CN(C)C=O>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[CH2:13][O:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH2:4][OH:3]
Reactant: ClCc1ccc2ccccc2n1
Reactant: OCc1cccc(O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride dispersion in oil (0.70 g, 17.5 mmol) was washed with hexane under nitrogen and suspended in dry tetrahydrofuran (30 ml). A solution of 3-hydroxymethylphenol (2.14 g, 17.2 mmol) in dry dimethylformamide was added dropwise to the stirred suspension at 5°-10° C. and the mixture was stirred for 30 minutes at room temperature. A solution of 2-chloromethylquinoline (3.07 g, 17.2 mmol) in tetrahydrofuran (10 ml) was added dropwise and the mixture was stirred for 22 hours at room temperature and 7 hours at 40° C. then poured onto saturated ammonium chloride solution (100 ml) and extracted with dichloromethane. The extract was washed with water, dried and evaporated to a viscous oil which crystallised from ethyl acetate-hexane, m.p. 70° C.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]CC2C=CC=CC=2)=[CH:21][CH:20]=1)[C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])C1C=CC=CC=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[NH2:10][C@@H:11]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[C@H:12]([OH:17])[C:13]([F:15])([F:16])[F:14]
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@H](O)C(F)(F)F)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N[C@@H](Cc1ccc(O)cc1)[C@H](O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[(1S,2S)-1-(4-Benzyloxyphenyl)methyl-3,3,3-trifluoro-2-hydroxypropyl]carbamic acid benzyl ester (2.19 g, 4.8 mmol) was dissolved in ethyl acetate (30 ml), and thereto was added 20% palladium hydroxide (1 g). The mixture was stirred at room temperature for 2 hours under hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the desired compound (1.11 g, yield: quantitatively) as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:17][CH2:18][CH2:19][OH:20])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[C:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)(=[O:25])[CH3:24]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:3][C:2]([CH3:22])([CH3:21])[CH3:1])[CH2:17][CH2:18][CH2:19][O:20][C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:23](=[O:25])[CH3:24])=[CH:28][CH:29]=2)=[CH:6][C:7]=1[C:13]([F:14])([F:15])[F:16])#[N:10]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: CC(C)(C)CN(CCCO)c1ccc(C#N)c(C(F)(F)F)c1
Product: CC(=O)Nc1ccc(OCCCN(CC(C)(C)C)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(2,2-dimethylpropyl)(3-hydroxypropyl)amino]-2-(trifluoromethyl)benzonitrile and 4-acetamidophenol: MS (ESI) m/z 448 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=2)[C:4](=[O:22])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]#[C:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)CCC>CN(C=O)C.C(Cl)Cl.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:29]#[C:28][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=3)[C:4](=[O:22])[CH:3]=2)=[CH:31][CH:32]=1
Reactant: CCCC[Sn](C#Cc1ccc(Cl)cc1)(CCCC)CCCC
Reactant: COc1cc(-n2ccc(Cl)cc2=O)ccc1OCC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-n2ccc(C#Cc3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A mixture of 4-chloro-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one Part D of Procedure 9 (100 mg, 0.31 mmol), tributyl((4-chlorophenyl)ethynyl)stannane Part A (237 mg, 0.56 mmol), copper (I) iodide (17.6 mg, 0.09 mmol), and PalladiumTetrakis (54 mg, 0.05 mmol) in DMF (1.5 mL) was stirred under nitrogen at 70° C. overnight. The reaction was diluted with DCM, filtered, washed with 1N HCl, sat. NaHCO3, dried (MgSO4), and concentrated. The residue was purified using ISCO flash chromatography (silica gel/hexanes/ethyl acetate 100:0 to 0:100 gradient). The product was repurified using HPLC (Phen Luna Axia C18 5μ 10:90:0.1 to 90:100.1 MeOH—H2O-TFA) to afford the desired product 4-((4-chlorophenyl)ethynyl)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyepyridin-2(1H)-one F-4 (90 mg, 0.21 mmol, 66.7% yield) as a light yellow solid. LC/MS 424 (M+H)+, tR 1.00 min (method 5). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.54 (2H, m), 7.37-7.44 (3H, m), 6.96-7.02 (2H, m), 6.93 (1H, d, J=2.26 Hz), 6.89 (1H, dd), 6.50 (1H, d, Hz), 3.88 (5H, s), 1.38 (6H, s)