Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=O)[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[NH3:12].C1C=CC([C@@H](O)C(O)=O)=CC=1>>[C:1](#[N:12])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: N
Reactant: O=C(O)C(O)c1ccccc1
Agent: O=C(O)[C@H](O)c1ccccc1
Product: N#CC(O)c1ccccc1

Procedure:
Microbial cells harvested from the plate culture were washed with a 50 mM phosphoric acid buffer solution (pH=7.5) and suspended in 10 ml of the same buffer solution to prepare a resting cell suspension at a cell concentration having an optical density at 630 nm (OD630 ) of from 1 to 50. To the cell suspension was added mandelonitrile to a concentration of 0.2 w/v %, and the system was allowed to react at 30° C. for 16 to 24 hours. Analysis of the reaction mixture by liquid chromatography (Shiseido ODS column); revealed the production of mandelic acid and ammonia. Further, analysis by means of a chiral cell for optical resolution("CHIRALPAK WH" column) revealed that the produced R(-)-mandelic acid had a high optical purity.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[CH2:11][CH2:12][CH2:13][OH:14]>>[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: Oc1cccc(Cl)c1
Reactant: OCCCCl
Agent: [Na]
Product: OCCCOc1cccc(Cl)c1
Yield: 84 %

Procedure:
To a solution of 37.3 g. (0.2 mol) 3-(3-chlorophenoxy)-1-propanol (obtained by the reaction of 3-chlorophenol sodium salt with 3-chloro-1-propanol in boiling ethanol; b.p.0.4 =112°-116°; yield 84%) and 42 ml. (0.3 mol) triethylamine in 150 ml. chloroform, one adds dropwise, with stirring, exclusion of moisture and cooling to -15°, a solution of 20 ml. (0.26 mol) methanesulphonic acid chloride in 50 ml. chloroform within 2 hrs., stirs for a further 2 hrs. at -10°, leaves to come to room temperature overnight and pours the reaction mixture, with stirring, into a mixture of 300 ml. ice water and 5 ml. 36% hydrochloric acid. After separating off the chloroform phase, one washes it twice with 100 ml. amounts of water and subsequently with aqueous sodium hydrogen carbonate solution to remove acid, dries over anhydrous sodium sulphate and evaporates under reduced pressure. One obtains, in practically quantitative yield (58.7 g.) 3-(3-chlorophenoxy)-propyl 1-methanesulphonate, still containing about 10% chloroform, as a slowly crystallising oil. The crystallisate has, after washing with petroleum ether and drying in a vacuum desiccator, the m.p. 36°-37°.
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1)=[CH2:2].[CH3:20][CH:21]1[CH2:25][CH2:24][CH2:23][NH:22]1>C(O)C>[CH3:20][CH:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:2][CH2:1][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: C=Cc1nc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: CC1CCCN1
Solvent: CCO
Product: CC1CCCN1CCc1nc2cc(-c3ccc(C#N)cc3)ccc2o1
Yield: 99.6 %

Procedure:
A solution of 24.6 mg (0.1 mmol) of 4-(2-vinyl-benzooxazol-5-yl)-benzonitrile and 24 mg of racemic 2-methyl-pyrrolidine (Aldrich, CAS #765-38-8) in 0.25 mL of ethanol was stirred at room temperature for 1 hour, then concentrated in vacuo to a glass to give pure product racemic 4-{2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-benzooxazol-5-yl}-benzonitrile 33 mg (100%): 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=1.8 Hz, 1 H), 7.77 (d, J=8.4 Hz, 2 H), 7.70 (d, J=8.4 Hz, 2 H), 7.58 (d, J=7.5 Hz, 1 H), 7.50 (dd, J=7.5, 1.8 Hz), 3.2-3.32 (m, 4 H), 1.44-2.65 (m, 7 H), 1.15 (m, 3 H); Mass spectrum: [M+H]+ 332.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[CH3:20][O:21][C:22]([C:24]1([CH2:30][CH:31]=O)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH3:20][O:21][C:22]([C:24]1([CH2:30][CH2:31][NH:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([N:9]3[CH2:13][CH2:12][C@@H:11]([N:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[CH3:19])[CH2:10]3)=[CH:5][CH:6]=2)[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)=[O:23]
Reactant: COC(=O)C1(CC=O)CCOCC1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C1(CCNc2ccc(N3CC[C@@H](N4CCC[C@@H]4C)C3)nc2C)CCOCC1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
2-Methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine (58 mg, 0.22 mmol) was dissolved in DCE (1 mL). To this solution was transferred a solution of 4-(2-oxo-ethyl)tetrahydro-pyran-4-carboxylic acid methyl ester (40 mg, 0.22 mmol) in DCE (1 mL). To this clear solution was then added acetic acid (38 μL, 0.66 mmol), followed by addition of powdered NaBH(OAc)3 (140 mg, 0.66 mmol) in one portion under N2 at rt. The yellowish milky solution was stirred at rt. overnight. The reaction was diluted with DCM (40 mL) and quenched with 30 mL of concentrated NH4OH in 70 mL of water. The two layers were separated, and the aqueous layer was extracted with DCM (10 mL×2). The combined DCM extracts were washed with sodium bicarbonate (10 mL), and brine (15 mL), dried (anhydrous potassium carbonate), filtered, and concentrated obtain 92 mg of a crude solid, which was used in the next step of the reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCCN.[C:15]([N:23]1[C:27]2[N:28]=[CH:29][C:30]3[C:31](OC4C=CC=CC=4)=[N:32][C:33]4[N:34]([N:36]=[CH:37][N:38]=4)[C:35]=3[C:26]=2[CH:25]=[N:24]1)(=O)[C:16]1C=CC=CC=1>>[C:2]1([NH:1][C:31]2[C:30]3[CH:29]=[N:28][C:27]4[N:23]([CH2:15][CH3:16])[N:24]=[CH:25][C:26]=4[C:35]=3[N:34]3[N:36]=[CH:37][N:38]=[C:33]3[N:32]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(c1ccccc1)n1ncc2c1ncc1c(Oc3ccccc3)nc3ncnn3c12
Agent: CN(C)CCCN
Product: CCn1ncc2c1ncc1c(Nc3ccccc3)nc3ncnn3c12

Procedure:
By substituting aniline for the 3-dimethylaminopropyl amine in the procedure of Example 1 (c), N-phenyl-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]-pyrimidin-5-amine is obtained.
Reaction SMILES: Br[C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[C:21](OCC)(=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[C:11]([O:10][C:9]([NH:8][C:7]1[C:2]([C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1Br
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1ncccc1NC(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
A solution of tert-butyl 2-bromopyridin-3-ylcarbamate (3.85 g, 14 mmol) (prepared from the procedure used by Kowol etc, J. Med. Chem., 2009, 52, 5032-5043) in dry THF (20 mL) was cooled to −78° C. and was treated drop-wise with n-butyllithium (11.2 mL of 2.5M solution in hexane, 2.0 eq) such that the temperature never exceeded −65° C., and the resulting mixture was stirred at −78° C. for an additional hour. After drop-wise addition of diethyl oxalate (4 mL, 29 mmol, 2.1 eq), the reaction mixture was allowed to warm to 0° C., maintained there for 1 h, and then quenched by the addition of NH4Cl (40 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (3×20 mL) and brine (20 mL). After drying, filtration, and evaporation, the residue was purified by column chromatography on silica gel with dichloromethane as eluant to afford ethyl 2-(3-(tert-butoxycarbonylamino)pyridin-2-yl)-2-oxoacetate as a white solid. Mass Spectrum (ESI) m/e=295 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:22])[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21].[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][N:25]=1.C(#N)C>CN(C)C=O.O>[CH3:3][C:4]1([CH3:22])[N:8]([CH2:30][C:28]2[CH:27]=[CH:26][N:25]=[C:24]([Cl:23])[CH:29]=2)[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21]
Reactant: CC1(C)NC(=O)N(c2ccc(OC(F)(F)F)cc2)C1=O
Reactant: Clc1cc(CBr)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1ccnc(Cl)c1
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
0.028 g of sodium hydride is added to a solution of 0.1 g of 5,5-dimethyl-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione in 2 ml of anhydrous dimethylformamide, under an inert atmosphere of argon at a temperature in the region of 20° C. Stirring is continued at this temperature for 30 minutes. A solution of 0.1 g of 2-chloro-4-(bromomethyl)pyridine in 2 ml of dimethylformamide is added, followed by addition of ice-cold water after reaction for 10 minutes. The reaction medium is placed on a cartridge 20 mm in diameter packed with 17 g of octadecyl-grafted 50 μm silica conditioned successively with acetonitrile and then with water. The elution is performed by gradient using the mixture (water/acetonitrile) of from 0 to 100% acetonitrile. The fractions containing the expected product are concentrated under reduced pressure. 0.130 g of crude product is thus obtained, which product is purified by a double chromatography using a cartridge packed with 10 g of 20-40 μm of conditioned silica, and then eluted with a mixture (cyclohexane/ethyl acetate), (8/2) (v/v) at a flow rate of 5 ml/minute. The fractions between 30 and 75 ml are concentrated under reduced pressure. 0.1 g of 5,5-dimethyl-1-(2-chloropyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione is thus obtained in the form of a white powder, the characteristics of which product are as follows:
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23]2.[N:34]1[CH:39]=[CH:38][C:37]([CH2:40]O)=[CH:36][CH:35]=1>C1(C)C=CC=CC=1>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:40][C:37]1[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=1)[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Reactant: OCc1ccncc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(F)ccc2n1Cc1ccncc1
Temperature: 20 °C
Reaction time: 48 h
Yield: 74.1 %

Procedure:
A solution of 5.5 g (21.72 mmol) of 1,1′-azodicarbonyl-dipiperidine, in solution in 15 ml of dry toluene, is added, under argon at 20° C., dropwise, to a solution of 3 g (14.48 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate, 2.37 g (21.72 mmol) of 4-pyridylcarbinol and 5.45 ml (21.72 mmol) of n-tributylphosphine in 200 ml of toluene. The mixture is stirred at 20° C. for 48 h. The reaction mixture is subsequently concentrated under reduced pressure. The residue is purified by silica column chromatography (eluent:heptane/ethyl acetate). 3.2 g of the expected product are thus isolated, which product is used as it is in the subsequent synthesis.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:11][NH:12][C:13]1[CH:14]=[C:15]([C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1.O1CCCC1.C(N(CC)CC)C>O>[CH2:1]([NH:8][C:9](=[O:10])[N:12]([C:13]1[CH:14]=[C:15]([C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC(=O)CCc1ccc(-c2cccc(NC)c2)nc1
Reactant: CCCCCCCN=C=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OCC)cn2)c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 65.2 %

Procedure:
572 μL (3.5 mmol, 2 eq) of heptyl isocyanate are added to a solution of 500 mg (1.76 mmol, 1 eq) of ethyl 3-[6-(3-methylaminophenyl)pyrid-3-yl]propanoate in 10 mL of a 4/1 tetrahydrofuran/triethylamine mixture. The reaction mixture is stirred for 24 hours at 40° C. The reaction is stopped by adding 30 ml of water and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 488 mg of ethyl 3-{6-[3-(3-heptyl-1-methylureido)phenyl]pyrid-3-yl}propanoate are obtained. Yield=65%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:2]1.CCN(CC)CC.C(OCl)(C)(C)C.[CH3:36][C:37]([CH3:49])=[CH:38][CH2:39]B1C2CCCC1CCC2>C1COCC1>[CH3:36][C:37]([C:2]1[NH:1][C:9]2[C:4]([C:3]=1[CH2:10][CH2:11][N:12]1[C:13](=[O:22])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]1=[O:21])=[CH:5][CH:6]=[CH:7][CH:8]=2)([CH3:49])[CH:38]=[CH2:39]
Reactant: CC(C)=CCB1C2CCCC1CCC2
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccccc12
Agent: CC(C)(C)OCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(C)(C)c1[nH]c2ccccc2c1CCN1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[2-(1H-indol-3-yl)ethyl]-1H-isoindole-1,3(2H)-dione (3.77 g, 13.0 mmol) in dry THF (0.13 L) under argon was added NEt3 (1.84 mL, 13.0 mmol). This mixture was cooled to -78° C., and neat t-BuOCl (1.54 mL, 13.0 mmol) was added. The reaction mixture was stirred for 30 min at −78° C. A solution of 9-(3-methyl-2-butenyl)-9-bora-bicyclo[3.3.1]nonane (40 mmol) in hexanes was added. The reaction mixture was stirred for 6 h at −78° C. It was quenched with 1 M aq HCl, and permitted to warm to rt overnight. The reaction mixture was extracted with CH2Cl2. The CH2Cl2 extracts were dried, filtered, and concentrated to give an oil. The oil was purified by silica chromatography to give the title compound: TLC Rf=0.36 (CH2Cl2); MS (ESI+) m/z 381.2, 359.2; 1H NMR (300 MHz, CDCl3) δ 7.91 (1H), 7.88-7.69 (5H), 7.29 (1H), 7.10 (2H), 6.18 (1H), 5.25 (2H), 3.95 (2H), 3.16 (2H), 1.61 (6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[BH4-].[Na+]>CO>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10]([OH:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C(C)O)cc(Cl)c(C)c1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (23 g, 83 mmol) in methanol (200 mL) was added sodium tetrahydroborate (5.0 g, 130 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour and quenched with water (10 mL). The resulting mixture was concentrated under reduced pressure to about 30 mL. The residue was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and evaporated to yield the desired product. LCMS calculated for C10H11BrClO (M−OH)+: m/z=261.0, 263.0. found: 261.0, 263.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([OH:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][C:11](=[O:22])[CH:10]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.ClCCCCCCOC1C(OC)=CC=C2C=1NC(=O)C=C2NC1C(Cl)=CN=CC=1Cl>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([O:21][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][C:11](=[O:22])[CH:10]=1
Reactant: BrCCCCCCCBr
Reactant: CN1CCNCC1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Agent: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCN1CCN(C)CC1

Procedure:
The title compound was prepared from 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one (Intermediate 3), 1,7-dibromoheptane, and 1-methylpiperazine following the procedures outlined for Intermediate 4 (modifications: NMP (N-methylpyrrolidone) used as solvent and 5.0 equiv of dibromide used) and Example 18, Step 2. 1H NMR (400 MHz, DMSO-d6, bis HCl salt): δ 11.87 (br, 2H), 10.46 (s, 1H), 9.22 (s, 1H), 8.81 (s, 2H), 8.01 (d, 1H), 7.16 (d, 1H), 4.95 (s, 1H), 4.01 (t, 2H), 3.94 (s, 3H), 3.84-3.20 (br m, 8H), 3.11 (m, 2H), 2.82 (s, 3H), 1.84-1.68 (m, 4H), 1.48-1.30 (m, 6H); MS (ESI): 548.3.
Reaction SMILES: Cl.[CH2:2]([C@@H:9]1NC(C)(C)N(C)C1=O)[C:3]1[CH:8]=CC=C[CH:4]=1.[CH:18]([CH:20]=[CH2:21])=[O:19].C=CC(=C)C>C[N+]([O-])=O.O>[CH3:8][C:3]1[CH2:2][CH2:9][C@@H:20]([CH:18]=[O:19])[CH2:21][CH:4]=1
Reactant: C=CC=O
Reactant: CN1C(=O)[C@H](Cc2ccccc2)NC1(C)C
Agent: Cl
Solvent: C=CC(=C)C
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CC1=CC[C@H](C=O)CC1
Temperature: 0 °C
Reaction time: 7 h
Yield: 84 %

Procedure:
To a 0° C. solution of 7(32 mg, 0.12 mmol) in CH3NO2/H2O (95/5 v/v, 1.0 M) was added acrolein (1.0 mL, 15 mmol), and isoprene (0.50 mL, 5 mmol). The solution was stirred at 0° C. for 7 hr, then directly placed onto a silica gel column and eluted with 3% Et2O/pentane, affording the title compound as a colorless oil in 84% yield (745 mg, 89% ee). Product ratios were determined by GLC (Bodman Γ-TA column, 35° C., 0.25° C./min gradient, 23 psi) tr=84.1 min, 85.3 min. 1H NMR, 13C NMR, and IR data were consistent with previously reported values (see Ishihara et al. (1998), supra). The absolute configuration was determined by oxidation to 4-methyl-3-cyclohexene-1-carboxylic acid and correlation of the optical rotation to the reported value; see Poll et al. (1985) Tetrahedron Lett. 26:3095-3098. To the aldehyde (255 mg, 2 mmol) was added a solution of isobutylene in THF (2.0 M, 30 mL) followed by tBuOH-H2O(5/1, 20 mL), KH2PO4(840 mg, 6 mmol), and NaClO2(540 mg, 6 mmol). The heterogenous mixture was stirred for 4 hr, then partitioned between EtOAc and H2O. The organic extract was washed with brine, dried (MgSO4), and concentrated. The white solid was purified by silica gel chromatography (20% EtOAc/hex): [α]D20=+89(c=4.0, 95% EtOH). Literature [α]D20=−107 (c=4, 95% EtOH) for (S)-4-methyl-3-cyclohexene-1-carboxylic acid.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=3)[N:10]=2)[CH:6]=[CH:5][C:4]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>>[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]([NH:22][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:21])=[CH:18][CH:19]=3)[N:10]=2)[CH:6]=[CH:5][C:4]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30].[ClH:1].[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]([NH:22][CH2:34][C:35]([OH:37])=[O:36])[CH3:21])=[CH:18][CH:19]=3)[N:10]=2)[CH:6]=[CH:5][C:4]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(-c2nc(-c3ccc(C(C)N)cc3)no2)ccc1-c1ccccc1C(F)(F)F
Agent: Cl
Product: Cc1cc(-c2nc(-c3ccc(C(C)NCC(=O)O)cc3)no2)ccc1-c1ccccc1C(F)(F)F
Product: Cc1cc(-c2nc(-c3ccc(C(C)NCC(=O)OC(C)(C)C)cc3)no2)ccc1-c1ccccc1C(F)(F)F

Procedure:
Tert-butyl N-[1-(4-{5-[2-methyl-2′-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)ethyl]glycinate was prepared following the general procedure 11 starting from 1-(4-{5-[2-methyl-2′-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)ethanamine, hydrochloride salt and tert-butyl bromoacetate. It was hydrolyzed following general procedure 8, affording the title compound as a white powder. 1H NMR: (DMSO-d6, 300 MHz) δ 8.18 (m, 3H), 8.08 (m, 1H), 7.91 (d, J=7.90 Hz, 1H), 7.77 (m, 3H), 7.69 (m, 1H), 7.41 (m, 2H), 4.74 (m, 1H), 3.74 (m, 1H), 3.52 (m, 1H), 2.11 (s, 3H), 1.61 (d, J=6.8 Hz, 3H). LC/MS (Method B): 482.2 (M+H)+, 480.2 (M−H)−. HPLC (Method A) Rt 4.25 min (Purity: 99.9%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1.CC([O-])(C)C.[K+].CS(C)=O>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=2)=[C:6]([C:7]#[N:8])[CH:9]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: N#Cc1cc(Br)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(Nc2ccc(Br)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.9 %

Procedure:
A flask was charged with 5-bromo-2-fluorobenzonitrile (5 g, 25.00 mmol), ethyl 4-aminobenzoate (4.54 g, 27.5 mmol), and KOtBu (5.11 g, 45.5 mmol). To this was added DMSO (100 mL). After stirring at room temperature for 20 min, the reaction mixture was diluted with ethyl acetate and water. The aqueous was extracted with ethyl acetate, the combined organic was washed with water (3×), brine, dried over MgSO4 and filtered. The filtrate was concentrated. The residue was suspended in ethyl acetate, collected the solid by filtration. Repeated above procedure for several times (each collected solid was checked by LCMS) until the collected solid is pure. The mixture residue was further purified via silica gel chromatography (0-30% ethyl acetate in hexanes) to give total 7.15 g of ethyl 4-(4-bromo-2-cyanophenylamino)benzoate. MS (ESI) m/z 345.2 (M+H). 1H NMR (CDCl3) δ ppm 8.02 (2H, d, J=8.55 Hz), 7.65 (1H, d, J=2.44 Hz), 7.53 (1H, dd, J=9.00, 2.29 Hz), 7.25 (1H, d, J=9 Hz), 7.14 (2H, d, Hz), 6.47 (1H, s), 4.36 (2H, q, J=7.22 Hz), 1.38 (3H, t, J=7.17 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][O:10][NH:11][C:12]([C@@H:14]1[CH2:20][CH2:19][C@@H:18]2[CH2:21][N:15]1[C:16](=[O:27])[N:17]2[O:22]S(O)(=O)=O)=[O:13])([CH3:4])([CH3:3])[CH3:2].F[C:30](F)(F)[C:31](O)=O>C(Cl)Cl>[OH:22][N:17]1[C:16](=[O:27])[N:15]2[CH2:21][C@H:18]1[CH2:19][CH2:20][C@H:14]2[C:12]([NH:11][O:10][C@H:9]1[CH2:31][CH2:30][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:8]1)=[O:13]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate 44 (0.19 g, 0.45 mmol) in DCM (6.0 mL) was added trifluoroacetic acid (0.30 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, concentrated and washed with ether. The white solid was collected by centrifugation. The crude product was purified by preparative HPLC to provide Compound 9 (Table 1) (44 mg) as a white solid.