Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:29])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:29])=[CH:16][CH:17]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(OCc3ccccc3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(OCc2ccccc2)cc1)C1CCNCC1
Reaction time: 3 h
Yield: 100.3 %

Procedure:
The a solution of 4-(4-benzyloxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (313 mg, 0.79 mmol) in dichloromethane (10 mL) was added TFA (0.61 mL, 7.9 mmol). The reaction was stirred for 3 hours and then the solvent removed under vacuum and placed under high vacuum to afford the title compound (234 mg). LRMS m/z: ES+=295.9 (M+H), retention time 1.18.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]([O:21][S:22]([CH3:25])(=[O:23])=[O:24])=[CH:19][N:20]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(OS(C)(=O)=O)cn2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: CS(=O)(=O)Oc1cnc(NC2CCNCC2)nc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of 4-(5-methanesulfonyloxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.85 g, 2.3 mmol, 1.0 equiv) in ethanol (15 mL) was added 4 M HCl in dioxane (2.85 mL, 11.4 mmol, 5.0 equiv) and the mixture was warmed up to 50° C. After 16 h, the reaction mixture was cooled down to rt, then poured into ice water and the pH was adjusted to 9-10 by addition of a sat. solution of potassium carbonate. Then, this solution was extracted three times with dichloromethane/isopropanol (4:1). The combined organic layers were concentrated by evaporation under reduced pressure to yield 0.62 g (99%) of the title compound as a colorless solid. MS (ISP): 273.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH2:9]([N:16]=[C:17]=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[NH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][C:17]([NH:16][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:18]
Reactant: Nc1ccncc1N
Reactant: CCCCCCCN=C=O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCNC(=O)Nc1cnccc1N
Yield: 43.6 %

Procedure:
A mixture of 3,4-diaminopyridine (1.09 g), heptyl isocyanate (1.41 g) and 4-dimethylaminopyridine (0.37 g) was stirred in toluene (10 ml) at 50°-60° C. for 5 hrs. The solvent was distilled off and the residue was purified by a silica gel column chromatography (chloroform:methanol=4:1) to give 1-(4-amino-3-pyridyl)-3-heptylurea (1.09 g, 37%) and crystals.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:18]([O:29][CH3:30])[C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[C:5]([C:14]([O:16]C)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].O1CCCC1.[OH-].[Na+].O>CO>[C:1]([C:3]1[C:4]([CH:18]([O:29][CH3:30])[C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1C(OC)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(c1ccc2ccccc2c1)c1c(C(=O)O)sc(N2CCOCC2)c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To methyl 4-cyano-3-[methoxy(2-naphthyl)methyl]-5-(morpholin-4-yl)thiophene-2-carboxylate (10.56 g, 25 mmol) in a round bottom flask equipped with a stirbar was added tetrahydrofuran (278 mL) and 1.000 M of sodium hydroxide in water (208 mL, 208 mmol). Methanol (139 mL) was added to the mixture, and the resulting yellow mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of 1N HCl aqueous solution to adjust the pH to 2 and EtOAc was added. The mixture was transferred to a separatory funnel, separated layers, extracted aqueous 2× w/EtOAc, combined organics, washed w/brine, dried over Na2SO4, filtered, added celite, rotavapped, dried on high vacuum for 45 min. The crude material was purified using a dry load on 330 g silica gel ISCO column (gradient elution: 0-20% MeOH/DCM) to obtain the product as an impure beige solid (9.8 g). Took 2 g, redissolved in DCM, added Celite, rotovapped, dried on high vac 45 min. Repurified this portion of product on 120 g ISCO silica gel column (gradient elution: 0-12% MeOH/DCM) to obtain 2.0 g beige foam product (racemate). LC/MS (FA) ES− 407; NMR (400 MHz, DMSO) δ 13.57 (s, 1H), 7.96 (s, 1H), 7.89-7.86 (m, 3H), 7.53-7.46 (m, 3H), 6.68 (s, 1H), 3.73-3.67 (m, 4H), 3.50-3.45 (m, 4H), 3.43 (s, 3H). Enantiomeric separation of the enantiomers was performed by chiral HPLC on CHIRALPAK IC 4.6×250 mm with 85/5/10/0.1% HEX/IPA/ETOH/DEA 10 uL Injection at 1.0 mL/min for 50 min.
Reaction SMILES: OC1C=CSC=1C=O.[C:9]([O:12][CH:13]1[CH:18]([O:19][C:20](=[O:22])[CH3:21])[CH:17]([O:23][C:24](=[O:26])[CH3:25])[CH:16]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:15][CH:14]1[O:32][C:33]1[CH:37]=[C:36](C(C)C)[S:35][C:34]=1[C:41](=[O:50])C1C=CC(OC)=CC=1)(=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.ClCCl.O>[C:9]([O:12][CH:13]1[CH:18]([O:19][C:20](=[O:22])[CH3:21])[CH:17]([O:23][C:24](=[O:26])[CH3:25])[CH:16]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:15][CH:14]1[O:32][C:33]1[CH:37]=[CH:36][S:35][C:34]=1[CH:41]=[O:50])(=[O:11])[CH3:10]
Reactant: COc1ccc(C(=O)c2sc(C(C)C)cc2OC2OC(COC(C)=O)C(OC(C)=O)C(OC(C)=O)C2OC(C)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=Cc1sccc1O
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCC1OC(Oc2ccsc2C=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Reaction time: 60 h

Procedure:
3.81 g of 3-hydroxy-thiophene-2-carbaldehyde, 30.5 g of (4,5-diacetoxy-6-acetoxymethyl-2-[5-isopropyl-2-(4-methoxy-benzoyl)-thiophen-3-yloxy]-tetrahydro-pyran-3-yl) actate, 37.0 g of potassium carbonate and 9.2 g of benzyltributylammonium chloride were dissolved in 850 ml of dichloromethane. 7.5 ml of water were added, and the reaction mixture was stirred for 60 h. The solution was extraced with water and saturated sodium chloride solution, and the organic phase was dried over sodium sulfate and evaporated. 60 ml of ethanol:water (9:1) were added to the resulting brownish foam, and the resulting fine precipitate was filtered off with suction. The product with the molecular weight: 458.44 (C19H22O11S), MS (ESI): 476 (M+NH4+) was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:8][CH:7]=[N:6][C:5]=1[CH3:9].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C(Cl)(Cl)Cl>[C:17]([O:1][CH2:2][CH2:3][C:4]1[S:8][CH:7]=[N:6][C:5]=1[CH3:9])(=[O:20])[CH:18]=[CH2:19]
Reactant: C=CC(=O)Cl
Reactant: Cc1ncsc1CCO
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCc1scnc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A one liter, three necked flask was equipped with overhead stirrer, nitrogen atmosphere and an addition funnel. The flask was charged with 100 g of 5-(2-hydroxyethyl)-4-methylthiazole (0.70 mol.), 71 g of triethylamine (0.70 mol.), 500 g of chloroform and 3 g of phenothiazine. Next, 63 g of acryloyl chloride (0.70 mol.) was slowly added to the reaction over 1.5 hour via the addition funnel. The reaction was stirred for 2 hours at room temperature. The reaction mixture was extracted with NaCl(aq.), NH4OH(10%), NaCl(aq.) and dried over MgSO4. The chloroform was evaporated with a rotoevaporator to yield 113 g (82%) of a dark brown liquid. The product was confirmed by IR and 13C NMR.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:27]=[CH:26][C:14]3[N:15]=[C:16]([NH:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]4=O)[S:17][C:13]=3[CH:12]=2)[CH:2]=1.N1C=CC=CC=1.[NH2:34][OH:35].Cl>CCO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:27]=[CH:26][C:14]3[N:15]=[C:16]([NH:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]4=[N:34][OH:35])[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: NO
Reactant: O=C1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 88 °C
Yield: 71.1 %

Procedure:
(R)-2-((6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanone from Example 54 (70 mg, 0.19 mmol) was stirred in EtOH. Pyridine (100 μL, excess) and NH2OH.HCl (100 mg, excess) were added and the resulting mixture was heated at 88° C. for 1 h. LCMS showed that the reaction was complete. The mixture was then cooled to rt and purified by HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanone oxime (53 mg, 73%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.60 (s, 1H), 8.38 (d, J=4.0 Hz, 1H), 8.13-8.27 (m, 1H), 8.09 (dd, J=0.8, 7.9 Hz, 1H), 7.58-7.76 (m, 1H), 7.10-7.39 (m, 3H), 5.49 (s, 2H), 4.33-4.77 (m, 1H), 2.69-2.95 (m, 1H), 1.92-2.38 (m, 2H), 1.26-1.86 (m, 5H). LCMS (ESI) m/z 393 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[N:19]=[N:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[C:1]1([CH:7]2[CH2:9][CH:8]2[C:10]([N:13]([C:14]2[N:19]=[N:18][C:17]([N:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:27])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[CH2:24][CH2:25]3)=[CH:16][CH:15]=2)[C:10]([CH:8]2[CH2:9][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:11])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C1CC1c1ccccc1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(N(C(=O)C3CC3c3ccccc3)C(=O)C3CC3c3ccccc3)nn2)CC1

Procedure:
Following the procedure of Example 6, making variations only as required to use 2-phenylcyclopropanecarbonyl chloride in place of phenoxyacetyl chloride to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, both compounds were obtained from the reaction. 2-Phenylcyclopropanecarboxylic acid (2-phenylcyclopropanecarbonyl){6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazin-3-yl}amide was isolated by column chromatography eluting with EtOAc:hexane=40:60 and obtained as a white powder (20% yield). 1H NMR (300 MHz, CDCl3) δ 7.73, 7.62, 7.54, 7.34, 7.22, 7.16, 7.04, 6.84, 3.99, 3.82, 3.63, 3.28, 2.62, 2.31, 1.76, 1.38. MS (ES+) m/z 640.3 (M+1). 2-Phenylcyclopropanecarboxylic acid {6-[4-(2-trifluoromethyl-benzoyl)piperazin-1-yl]pyridazin-3-yl}amide was isolated by column chromatography eluting with EtOAc:hexane=50:50 and obtained as a white powder (16% yield). 1H NMR (300 MHz, CDCl3) δ 10.36, 8.39, 7.76, 7.64, 7.57, 7.34, 7.18, 7.12, 3.92, 3.52, 3.37, 3.18, 2.64, 2.30, 1.34. MS (ES+) m/z 496.3 (M+1).
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][OH:6].[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](Cl)[CH:10]=1.Cl.[Cl-].[Na+]>O1CCCC1>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][O:6][C:11]1[CH:10]=[C:9]([NH2:8])[CH:14]=[CH:13][N:12]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: CN(C)CCO
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOc1cc(N)ccn1
Temperature: 25 °C

Procedure:
A mixture of 5.55 g of sodium and 26.9 mL of 2-dimethylaminoethanol in tetrahydrofuran (180 mL) is heated to reflux for 20 hours. The reaction mixture is cooled to room temperature, treated with 4 g of 4-amino-2-chloropyridine and heated to 140° C. for 20 min (microwave irradiation). The reaction mixture is treated with concentrated HCl to pH 8 at 0° C., saturated with sodium chloride and extracted with diethyl ether. The organics are dried (magnesium sulfate) and concentrated to 11.9 g of crude product which is purified by silica gel chromatography (90:10:1 ethyl acetate/methanol/ammonium hydroxide) to give 2-(2-dimethylamino-ethoxy)-pyridin-4-ylamine as tan crystals. MS (m/z): 182 (M+1); Rf 0.1 (90:10:1 ethyl acetate/methanol/ammonium hydroxide).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](I)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]([Si:21]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[S-:22])([CH3:20])[CH3:19].[K+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:22][Si:21]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:18]([CH3:19])[CH3:20])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(I)ccc21
Reactant: CC(C)[Si]([S-])(C(C)C)C(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)[Si](Sc1ccc2c(ccn2C(=O)OC(C)(C)C)c1)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 88.8 %

Procedure:
A solution of the product of Example 89A (200 mg, 0.583 mmol) in anhydrous tetrahydrofuran (4 mL) under a nitrogen atmosphere was treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium methylene chloride complex (5 mg) and the solution was sparged with nitrogen for several minutes. Potassium triisopropylsilanethiolate (146.5 mg, 0.6411 mmol), prepared according to Tetrahedron Letters 35 (20) 3221 1994, was added and the reaction was heated at reflux for 15 minutes. The reaction was cooled to room temperature and the solvent removed by rotary evaporation under vacuum to provide the title compound as a colorless oil (210 mg, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH3:19]>CC(=O)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][CH3:19])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
4-Bromo-2-nitrophenol (5.0 g, 23 mmol) and potassium carbonate (9.52 g, 69 mmol) were suspended in 2-butanone (100 ml). Ethyl iodide (2.2 ml, 28 mmol) was added dropwise at room temperature and stirred for 30 minutes. The suspension was heated at reflux for 18 hours, cooled and filtered, and the residue washed with acetone. The filtrate was concentrated in vacuo to a crude solid that was used without further purification (D14). 1H-NMR (CDCl3) δ 7.42 (1H, d, J 2.5 Hz), 7.60 (1H, dd, J 9.0, 2.5 Hz), 6.96 (1H, d, J 9.0 Hz), 4.17 (2H, q, J 7.0 Hz), 1.47 (3H, t, J 7.0 Hz).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.[PH2](O)=[O:12].N([O-])=O.[Na+].[OH-].[Na+]>O>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2](=[O:12])[NH:3][C:4]=1[CH3:10]
Reactant: O=[PH2]O
Reactant: Cc1cc(N)nc(C)c1Br
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(=O)[nH]c(C)c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a solution of 2-amino-5-bromo-4,6-dimethylpyridine (0.7 g, 3.48 mmol) in water (6.4 mL) was added an aqueous solution of hypophosphorous acid (50%, 2.9 mL, 27.84 mmol). The mixture was cooled to about 0° C. and a solution of sodium nitrite (0.281 g, 4.07 mmol) in water (1.4 mL) was added with vigorous stirring, maintaining the temperature below 5° C. The mixture was stirred for 30 minutes at 0° C. and was then allowed to warm up to r.t. overnight. The solution was neutralized to pH 6-7 with an aqueous solution of sodium hydroxide (2.0M) and cooled to 5° C. for 5 h. The resulting precipitate was filtered off and washed with cold water. The solid obtained was dried in vacuo to give the title compound (0.681 g, 97%) as a white solid. δH (CDCl3) 6.35 (1H, s), 2.47 (3H, s), 2.29 (3H, s). LCMS (ES+) 201/203 (M+H)+, RT 2.16 minutes (Method 1).
Reaction SMILES: [N-]=[N+]=[N-].[Na+].[C:5]1([C:11]([NH:24][CH:25]2[C:47](=[O:48])[N:27]3[CH:28]([C:33]4[N:37]([CH2:38][C:39]5[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=5)[N:36]=[N:35][N:34]=4)[C:29]([CH3:32])([CH3:31])[S:30][C@H:26]23)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:5]1([C:11]([NH:24][CH:25]2[C:47](=[O:48])[N:27]3[CH:28]([C:33]4[N:37]([CH2:38][C:39]5[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=5)[N:36]=[N:35][N:34]=4)[C:29]([C:31]4[CH:19]=[CH:18][CH:11]=[CH:12][CH:13]=4)([C:32]4[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=4)[S:30][C@H:26]23)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(Cn2nnnc2C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(C)C)cc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COc1ccc(Cn2nnnc2C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the solution of 6-(triphenylmethylamino)-2,2-dimethyl-3-(p-tolylsulfonyloxy-[N-(p-methoxybenzylimino]methyl)penam prepared above is added 1.63 g. (1.25 equivalents) of sodium azide and the mixture allowed to stir at room temperature for 24 hours. The mixture is quenched in 3 l. of ice water and the biphasic system allowed to stir for 15 min. The resulting oily solid is filtered, trituated with water and subsequently recrystallized from chloroformisopropanol, 3.38 g., m.p. 177°-180° C. Further recrystallization raises the melting point to 186°-188° C., and provides a product which is essentially one spot in a benzene(200):ethyl acetate(10) silica gel chromatography system and indistinguishable from the final product of Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[CH:19][CH:18]=1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: Fc1ccc(CBr)cc1
Product: Cc1cc(C#Cc2cn(Cc3ccc(F)cc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=306.2 (M+H30), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-fluoro-benzylbromide.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C@@H:11]2[CH2:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)=[CH:19][CH:18]=3)[CH2:12]2)[N:7]=1)=O)C.[NH3:32]>>[F:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([N:13]2[C:14](=[O:16])[CH2:15][C@@H:11]([C:8]3[N:7]=[C:6]([C:4]([NH2:32])=[O:3])[O:10][N:9]=3)[CH2:12]2)=[CH:22][CH:21]=1
Reactant: N
Reactant: CCOC(=O)c1nc([C@@H]2CC(=O)N(c3ccc(OCc4cccc(F)c4)cc3)C2)no1
Product: NC(=O)c1nc([C@@H]2CC(=O)N(c3ccc(OCc4cccc(F)c4)cc3)C2)no1
Temperature: 50 °C
Yield: 44 %

Procedure:
3-{(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester (0.110 g, 0.25 mmol) was dissolved in 3.5 ml of ammonia (2 M solution in methanol). The resulting mixture was stirred at 50° C. for half an hour. The mixture was cooled at 0° C. and a solid precipitated. The reaction mixture was filtrated and the solid washed with hexane and dried under vacuum. The residue was suspended in ethyl acetate and heated to reflux. Diethyl ether was added and the suspension cooled to 0° C. and filtrated to yield the title compound as a light brown solid (0.045 g, 44% of theory). MS (m/e)=397.4 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32].O1CCOCC1>C(OCC)(=O)C>[ClH:32].[NH:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][N:23]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Yield: 84 %

Procedure:
To a mixture of 4-[3-(5-trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester (312 g, 0.718 mol) in ethyl acetate (2.8 L) at 0° C. to −5° C. was added streamwise over a 20 min period, 4.0 M hydrogen chloride in dioxane (800 mL, 3.2 mol). No significant temperature change was noted. The resulting suspension was stirred at temperatures reaching 22° C. over the next 17 h. The suspension was filtered. The solid was washed with EtOAc (500 mL) and pressed as dry as possible under suction. The damp solid was dried in vacuo at 33° C. for 7 h to afford 225 g (84%) of product.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=O)[CH:5]=[CH:4][C:3]1=2.[OH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][NH2:28]>ClCCl>[OH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][NH:28][C:17](=[O:19])[CH2:16][CH2:15][C:14]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:1])([CH3:21])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)=[O:20]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CCC(=O)O)ccc21
Reactant: NCCOCCO
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C(=O)CCC(=O)NCCOCCO)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
A suspension of 2.88 g (10 mmoles) of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-oxo butyric acid, described in Example III, and 1.95 g (12 mmoles) of N,N'-carbonyl diimidazole in 50 cm3 of anhydrous dichloromethane is stirred for 2 hours at ambient temperature. The resulting solution is cooled to a temperature between +5° and +10° C. and 1.26 g (12 mmoles) of N-2-hydroxyethoxyethylamine are added. Stirring is continued for 3 hours while permitting the reaction mixture to return to ambient temperature. The reaction mixture is transferred to a separatory funnel and diluted to 100 cm3. After washing with 0.1N HCl and then with water, the dichloromethane phase is dried on sodium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica 60 gel in a 40/25/25/10 dichloromethane/toluene/ethyl acetate/isopropanol eluant mixture. After evaporation and drying, there are obtained 2.5 g of N-(2-hydroxyethoxyethyl) 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-oxo butyramide in the form of a thick colorless oil kept out of contact with light.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2=[O:23]>>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2([OH:23])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1ccc2ccccc2c1
Yield: 91.6 %

Procedure:
With 11.1 g of 2-bromonaphthalene and 5.00 g of 5-chloroisatin as starting materials, 7.81 g of the title compound was obtained by a similar method to Step 21-1.