Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7](C(OC(C)(C)C)=O)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)(=[S:3])[NH2:2].Cl[CH2:24][C:25](=O)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CCO>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:1]2[S:3][CH:24]=[C:25]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:2]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)n1ncc(C(N)=S)c1-c1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)Cc1csc(-c2cn[nH]c2-c2ccc(F)cc2)n1
Yield: 68.8 %

Procedure:
A solution of the mixture (415 mg, 1.29 mmol) obtained in step 6 and ethyl 4-chloroacetoacetate (0.192 mL, 1.42 mmol) in EtOH (3.6 mL) was heated under reflux for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (solvent gradient; 50→66% ethyl acetate/hexane) to give ethyl {2-[5-(4-fluorophenyl)-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}acetate (294 mg, 69%) was obtained as a colorless oil
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36](O)(=[O:38])[CH3:37].N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[C:36]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)(=[O:38])[CH3:37]
Reactant: CC(=O)O
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 22-L, 3 neck round bottom flask equipped with a mechanical stirrer, thermocouple, addition funnel and nitrogen bubbler was charged with 422 g (1.91 mol) of benzyl (3R)-3-hydroxypyrrolidine-1-carboxylate (Intermediate 1, Step A), 12 L of toluene, 751 g (2.86 mol) of triphenylphosphine, and 164 mL (2.86 mol) of glacial acetic acid. The resultant mixture was stirred at ambient temperature and then 500 g (2.87 mol) of diethyl azodicarboxylate was added via the addition funnel over a period of about 30 min, keeping the internal temperature <28° C. with a cold water bath. The reaction was stirred at ambient temperature overnight. The solvent was removed in vacuo and the residue was triturated with 6 L of diethyl ether. The solid was filtered off and washed well with diethyl ether. The filtrate and ether washings were combined and concentrated to a thick yellow oil with solids. Purification by flash chromatography (silica gel, eluting sequentially with 5% and a gradient of 10% to 30% ethyl acetate/hexane) gave the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH3:12])=[C:6]([N+:13]([O-])=O)[CH:5]=1>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH3:12])=[C:6]([NH2:13])[CH:5]=1
Reactant: CCNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCNc1ccc(C(=O)OC)cc1N
Yield: 92.3 %

Procedure:
3-Amino-4-ethylamino-benzoic acid methyl ester (3.2 g) was prepared by following General Procedure B starting from 4-ethylamino-3-nitro-benzoic acid methyl ester (4.0 g) and Pd/C (20% by weight, 800.0 mg) in MeOH:EtOAc (1:1, 30.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[NH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1.N1C=CC=CC=1>C(OCC)(=O)C>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1nccs1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1nccs1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 4-nitrophenyl chloroformate, 5.04 g (25 mMole), in 25 ml of dry ethyl acetate was added dropwise to an ice cooled, stirred solution of 2-aminothiazole, 5.01 g (50 mMole) in dry ethyl acetate, 25 ml, and dry pyridine, 50 ml. The ice bath was removed as the reaction mixture became viscous. Stirring was continued at 22° C. for three hours. Ethyl acetate was added. The insolubles were filtered, rinsed with ethyl acetate, with water, with acetone, dried and recrystallized from acetone furnishing 3.55 g of 2-(4-nitrophenoxycarbonyl)aminothiazole, m.p 211°-212° C. dec, which was characterized by nuclear magnetic resonance, mass spectra, infrared spectra and elemental analyses.
Reaction SMILES: Cl[Si:2]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[OH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:15]([CH2:26][OH:27])[CH2:14]1.C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.ClCCl>[OH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@H:15]([CH2:26][O:27][Si:2]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4])[CH2:14]1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(O)C[C@H]1CO
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](OC[C@@H]1CC(O)CCN1C(=O)OC(C)(C)C)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Chlorotriisopropylsilane (2.284 g, 11.85 mmol) was added dropwise to a 0° C. solution of Example 260A (2.65 g, 10.77 mmol), triethylamine (1.253 g, 12.39 mmol) and 4-(dimethylamino)pyridine (0.263 g, 2.154 mmol) in dichloromethane (25 mL). The mixture was stirred at 0° C. for 20 minutes and at room temperature for 16 hours. Water (50 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (twice), and the combined extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (gradient of 0-30% ethyl acetate/heptanes) to give the title compound as a mixture of diastereomers. MS (ESI+) m/z 388.0 (M+H)+.
Reaction SMILES: [Br:1][CH:2]=[CH:3][C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].P(Br)(Br)Br.FC(F)(C(F)(F)F)CCO>>[Br:1][CH2:2][CH2:3][C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)C(F)(F)C=CBr
Agent: BrP(Br)Br
Agent: OCCC(F)(F)C(F)(F)F
Product: FC(F)(F)C(F)(F)CCBr

Procedure:
1-Bromo-3,3,4,4,4-pentafluoro-1-butene may be prepared by a three step sequence beginning with reaction of phosphorous tribromide with 3,3,4,4,4-pentafluoro-1-butanol to give 4-bromo-1,1,1,2,2-pentafluorobutane. Thermal bromination of 4-bromo-1,1,1,2,2-pentafluorobutane at 350-400° C. gives 4,4-dibromo-1,1,1,2,2-pentafluorobutane which may in turn be heated with powdered potassium hydroxide to give the desired bromobutene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[NH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O>C1(C)C=CC=CC=1>[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[N:30]1[C:13](=[O:15])[C@H:12]([C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=1)[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc([C@H](CC2CCCC2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1Cl
Temperature: 80 °C
Yield: 26.6 %

Procedure:
A mixture of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared in Example 92, 6.07 g, 18.35 mmol), (R)-(+)-4-benzyl-2-oxazolidinone (2.83 g, 15.96 mmol), and triethylamine (6.68 ml, 47.71 mmol) in toluene (50 mL) was heated at 80° C. under argon until a homogeneous solution was obtained. The reaction mixture was then treated with trimethylacetyl chloride (3.55 mL, 28.81 mmol) in toluene (10 mL), and the reaction became yellow in color and a precipitate formed. The reaction mixture was then heated at 80° C. for 36 h. The reaction was cooled to 25° C. and then the toluene was removed in vacuo. The residue was diluted with ethyl acetate (150 mL). The organic layer was washed with a IN aqueous hydrochloric solution (1×100 mL), a 10% aqueous sodium carbonate solution (1×100 mL), and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/5/5 methylene chloride/hexanes/ethyl acetate) afforded (1) 4(R)-benzyl-3-[2(S)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-oxazolidin-2-one (2.08 g, 23%) as a white foam: [α]23589 =+10.4° (c=0.144, chloroform); FAB-HRMS m/e calcd for C25H28ClNO5S (M+H)+490.1455, found 490.1457 and (2) 4(R)-benzyl-3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-oxazolidin-2-one (2.20 g, 25%) as a white foam: [α]23589 =−93.9° (c=0.165, chloroform); FAB-HRMS m/e calcd for C25H28CINO5S (M+H)+490.1455, found 490.1443.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[O:26][CH3:27].O>CN(C=O)C>[CH3:27][O:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23][N:12]1[CH:13]=[C:8]([C:4]2[O:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])[C:9](=[O:15])[NH:10][C:11]1=[O:14]
Reactant: COC(CCBr)OC
Reactant: Cc1nc(C)c(-c2c[nH]c(=O)[nH]c2=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2oc(C)nc2C)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
5-(2,4-Dimethyl-oxazol-5-yl)-1H-pyrimidine-2,4-dione (Prep62, 480 mg, 2.32 mmol) and K2CO3 (320 mg, 2.32 mmol) were suspended in dry DMF (6 ml) and stirred at room temperature for 1 h. A solution of 3-bromo-1,1dimethoxy-propane (467 mg, 2.55 mmol) in dry DMF (2 mL) was added dropwise and the mixture stirred at room temperature for 72 hours. Water (80 mL) was added and the product extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 377 mg of the final compound that was used without any other purification in the next step (53% yield).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.N1C=CC=CC=1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(Cl)Cl.O>[C:9]([O:8][C:7]([NH:6][C@H:3]1[CH2:4][CH2:5][N:1]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:2]1)=[O:13])([CH3:10])([CH3:12])[CH3:11]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (4.2 g, 22 mmol) in methylene chloride (49 mL) was cooled at 0° C. and treated with pyridine (2.2 mL, 29 mmol) and benzyl chloroformate (3.8 mL, 29 mmol). The mixture was stirred at 0° C. for 30 minutes and then warmed to ambient temperature and stirred for 4 hours. The reaction mixture was diluted with water (100 mL) and methylene chloride (100 mL), the organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 40 g, ISCO, 1-100% ethyl acetate in heptanes) to afford the title compound as a white solid, which was used in the next step without any further purification (5.2 g, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:10][C:9]1([CH3:29])[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]1([CH:37]=CC(O)=[CH:33][CH:32]=1)O.C=CC=C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:33][CH:32]=[CH:30][CH2:37]2)[O:10][C:9]1([CH3:28])[CH3:29])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C=CCC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Reactant: Oc1ccc(O)cc1
Agent: C=CC=C
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC=CCC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Temperature: -78 °C
Yield: 174.6 %

Procedure:
A solution of 4-benzyl-5-(3-ethoxycarbonyl-allyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (6.55 g) in toluene (50 ml) was placed in a stainless steel bomb equipped with a PTFE liner. Hydroquinone (350 mg) was added, and the vessel cooled to −78° C. 1,3-butadiene (100 g) was condensed into the vessel, which was then sealed and heated to 150° C. for 16 hours. After cooling, the vessel was opened and the contents removed and evaporated to dryness. The residue was subjected to flash chromatography on silica gel eluting with hexane/ethyl acetate (95:5) to afford 4-benzyl-5-(6-ethoxycarbonyl-cyclohex-3-enylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.54 g, 34%) as a mixture of trans isomers (mass spectrum 458 [M+H]+) together with recovered starting material (2.17 g, 33%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[N+:10]([O-:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1>>[CH3:11][N:10]1[C@H:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C@@H:14]2[C:13](=[O:19])[CH2:18][CH2:17][CH2:16][C@@H:15]2[O:12]1
Reactant: O=C1C=CCCC1
Reactant: C[N+]([O-])=CCCc1ccccc1
Product: CN1O[C@H]2CCCC(=O)[C@H]2[C@H]1CCc1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
N-(3-Phenylpropylidene)methylamine N-oxide (1.50 g, 9.19 mmol) and 2-cyclohexenone (5 ml) were heated at 80°-90° C. for 24 hours in a sealed tube under nitrogen. The solution was cooled to room temperature and the excess 2-cyclohexenone was removed under reduced pressure using Kugelrohr distillation to yield the crude product as a dark yellow oil (2.36 g, 99%). The crude product was purified by flash chromatography using 60:40 v/v light petroleum (fraction of bp 40°-60° C.):ethyl acetate as the solvent system to give the title compound as a colourless oil (2.11 g, 89%), vmax (film) 2941, 2872, 1710, 1454, 1235 cm-1 ; δH (250 MHz, CDCl3 --Me4Si) 1.70-2.0 (6H, br m), 2.25-2.55 (2H, m), 2.60-2.80 (2H, m), 2.70 (3H, s), 2.75 (1H, t), 3.25 (1H, br m), 4.45 (1H, br m), 7.10-7.30 (5H, br m); M/z 259 (M+ 100%) (Found: M+ 259.1572; C16H21NO2 requires M+ 259.1603).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]([CH3:43])[C:39](=[O:44])[CH:38]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]([CH3:43])[C:39](=[O:44])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cn1ccc(Br)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 42.9 %

Procedure:
A mixture of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (200 mg, 0.42 mmol), 4-bromo-1-methylpyridin-2(1H)-one (118 mg, 0.63 mmol), Pd(Ph3P)2Cl2 (20 mg), and 2 M aq Cs2CO3 solution (5 mL, 10 mmol) in 1,4-dioxane (20 mL) was stirred and heated to reflux for 2 h. When the reaction was finished, the mixture was washed with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by preparative TLC to give (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (83 mg, 43%). LC-MS Method 2 tR=1.16 min, m/z=921.5; 1H NMR (CDCl3) 1.11 (s, 3H), 1.18 (s, 3H), 1.22 (t, 1H), 1.52 (m, 3H), 2.21 (s, 2H), 2.22-2.34 (m, 2H), 2.34-2.46 (m, 1H), 2.85 (m, 1H), 3.57 (s, 3H), 5.59 (m, 1H), 6.33 (d, 1H), 6.68 (s, 1H), 7.01 (d, 2H), 7.29-7.41 (m, 8H); 1H NMR (CD3OD) 0.98 (s, 3H), 1.29 (s, 3H), 1.58 (d, 3H), 2.17 (s, 2H), 2.22 (m, 1H), 2.50 (m, 2H), 3.08 (m, 1H), 3.59 (s, 3H), 5.59 (m, 1H), 6.61 (d, 1H), 6.66 (s, 1H), 7.08 (m, 2H), 7.30-7.40 (5H), 7.42 (d, 2H), 7.70 (d, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Br:10]Br.Cl>[OH-].[Na+]>[Br:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: c1ccc2[nH]ncc2c1
Reactant: BrBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Brc1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.4 %

Procedure:
The title compound was prepared as outlined in a procedure described by B. E. Boulton, B. A. Coller, Aust. J. Chem., 1974, 27, 2343. To a mechanically stirred solution of indazole (5.0 g, 42 mmol) in 20% aq. NaOH (75 mL) was added bromine (1.4 mL, 27 mmol) dropwise. After stirring at ambient temperature for 2 h, the reaction mixture was cooled and acidified by careful addition of concentrated HCl. The solids formed were filtered and dried to give 5.5 g of the title compound.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[C:24]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)#[CH:25]>>[C:24]([C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]2)[CH2:10][CH2:11]3)=[O:3])=[CH:28][CH:27]=1)#[CH:25]
Reactant: C#Cc1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: C#Cc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 15.3 %

Procedure:
In a similar manner to Example 63, ((2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-ethynylaniline (40.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-ethynylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (10.0 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11]C(=O)C3C=CC(Cl)=CC=3)[CH:9]=2)[C:4]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:3]1[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32].C[O-].[Na+]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[C:4]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:3]1[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)C(C)(C)Cc1c(Cc2ccc(Cl)cc2)c2ccc(OC(=O)c3ccc(Cl)cc3)cc2n1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(C)Cc1c(Cc2ccc(Cl)cc2)c2ccc(O)cc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 425 mg of p-chlorobenzoate from Step A in 3 mL of MeOH was added 1.9 mL of a solution of 1.3M NaOMe in MeOH. The mixture was stirred at R.T. for 1 h, poured into 20 mL of 25% aq. NH4OAc, and extracted with ethyl acetate. The organic extract was dried over Na2SO4 and evaporated to dryness to give an oil which was chromatographed on flash silica gel using ethyl acetate:hexane (30:70 as eluant to give the title compound as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([Br:10])[N:3]=1.[Br:11]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:11])[CH:5]=[C:4]([Br:10])[N:3]=1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1cc(Br)nc(Br)c1
Solvent: ClCCl
Product: BrCc1cc(Br)nc(Br)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
A solution of 0.5 g of 2,6-dibromo-4-(hydroxymethyl)pyridine in 7 ml of dichloromethane is added dropwise to a solution of 0.95 g of dibromotriphenylphosphorane in 5 ml of dichloromethane, under an inert atmosphere of argon at a temperature in the region of 0° C. The mixture is stirred to a temperature in the region of 20° C. over about 2 hours. The reaction medium is taken up in 100 ml of dichloromethane and then washed with 100 ml of water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue thus obtained is purified by flash chromatography using a cartridge 37 mm in diameter packed with 50 g of 20-40 μm conditioned silica, and then eluted with a mixture (cyclohexane/ethyl acetate) (9/1) (v/v), at a flow rate of 8 ml/minute. The fractions between 135 and 200 ml are concentrated under reduced pressure. 0.349 g of 2,6-dibromo-4-(bromomethyl)pyridine is thus obtained.
Reaction SMILES: C([O:4][C:5]([CH2:7][O:8][CH2:9][C@@H:10]1[CH2:14][C@H:13]([S:15][C:16]2[C@H:22]([CH3:23])[C@H:21]3[N:18]([C:19](=[O:27])[C@@H:20]3[C@H:24]([OH:26])[CH3:25])[C:17]=2[C:28]([O:30]CC=C)=[O:29])[CH2:12][N:11]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[O:6])C=C.C(C(CCCC)C([O-])=O)C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[H][H]>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].[OH-].[OH-].[Pd+2]>[C:5]([CH2:7][O:8][CH2:9][C@@H:10]1[CH2:14][C@H:13]([S:15][C:16]2[C@H:22]([CH3:23])[C@H:21]3[N:18]([C:19](=[O:27])[C@@H:20]3[C@H:24]([OH:26])[CH3:25])[C:17]=2[C:28]([OH:30])=[O:29])[CH2:12][NH:11]1)([OH:6])=[O:4]
Reactant: [H][H]
Reactant: C=CCOC(=O)COC[C@@H]1C[C@H](SC2=C(C(=O)OCC=C)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCC(=O)O)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2S,4S)-2-(allyloxycarbonylmethyloxymethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.33 g), sodium 2-ethylhexanoate (0.75 g) and triphenylphosphine (0.21 g) in tetrahydrofuran (60 ml) was added tetrakis(triphenylphosphine)palladium(O) (0.25 g), at ambient temperature. The mixture was stirred at the same temperature for 1 hour. To the mixture was added 0.3M acetate buffer (pH 5.8) (60 ml). The mixture was stirred at ambient temperature for 6 hours in the presence of 20% palladium hydroxide on carbon (0.5 g) under atmospheric pressure of hydrogen. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to remove the tetrahydrofuran. The resulting aqueous solution was washed with ethyl acetate (60 ml x 3)and evaporated to remove the organic solvent. The residual solution was subjected to a column chromatography on nonionic adsorption resin, "Diaion HP-20" [60 ml}and eluted with a mixture of acetone and water (2:98 V/V). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(carboxymethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.37 g).