Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13]O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].NC(N)=[S:17].[OH-].[Na+].Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][SH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCCO)cc1OC
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CCCS)cc1OC
Reaction time: 8 h
Yield: 12.4 %

Procedure:
A mixture of 5.00 g (25.5 mmoles) of 3-(3,4-dimethoxyphenyl)propanol, 1.94 g (25.5 mmoles) of thiourea, and 8.5 ml of 48% hydrobomic acid is heated on steam bath for 1 hour, allowed to stand overnight at room temperature, and then heated again on a steam bath for 2 hours. After cooling, the reaction mixture is treated with 76.5 ml of 1 M sodium hydroxide and heated on the steam bath for 11/2 hours. After cooling, the reaction mixture is made acidic with 1 N hydrochloric acid and extracted with methylene chloride (followed by a brine wash). Silica gel chromatography using 10% ethyl acetate/Skellysolve B as eluent gives 0.67 g of 3-(3,4-dimethoxyphenyl)-1-propanethiol.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH2:29]([CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C1COCC1>[CH2:29]([CH:36]1[CH2:41][CH2:40][N:39]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCC(Cc5ccccc5)CC4)cc2)CC3)cc1
Temperature: 25 °C

Procedure:
In THF (15 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (300 mg), and to the mixture was added 4-benzylpiperidine (408 μl). The mixture was refluxed for 19 hours. The reaction mixture was cooled to room temperature, and to the mixture was added water (100 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give N-[4—(4-benzyl-piperidinomethyl)phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 35) (259 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([F:26])=[CH:10][C:11]3[C:21](=[O:22])[C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:13]4[C@@H:14]([CH3:18])[CH2:15][S:16][C:17]=2[C:12]=34)[CH:5]=[C:4]([CH3:27])[N:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:29].[K+].[K+].S([O-])(O)(=O)=O.[K+].S([O-])([O-])(=O)=O.[K+].[K+]>C(O)(=O)CC>[CH3:27][C:4]1[CH:5]=[C:6]([C:8]2[C:9]([F:26])=[CH:10][C:11]3[C:21](=[O:22])[C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:13]4[CH:14]([CH3:18])[CH2:15][S@:16](=[O:29])[C:17]=2[C:12]=34)[CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1cc(-c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2SC[C@@H]4C)cc(C)n1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CCC(=O)O
Product: Cc1cc(-c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2[S@@](=O)CC4C)cc(C)n1
Yield: 30 %

Procedure:
(S)-10-(2,6-Dimethyl-4-pyridinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzothiazine-6-carboxylic acid (U.S. Pat. No. 4,839,355, Example 7f) (192 mg) and 153.7 mg of a mixture of potassium monopersulfate, potassium hydrogen sulfate and potassium sulfate (mole ratio 2:1:1) (Oxone®) (0.5 mM of potassium monopersulfate) in 20 ml of aqueous propionic acid (20% water) were combined at 0° C. with stirring. The mixture was allowed to come to room temperature, stirred for 4 hours and concentrated to dryness. Saturated sodium chloride solution was added to the mixture which was then extracted with chloroform. The chloroform extract was dried over sodium sulfate and concentrated to dryness. The resulting residue was treated with ethyl alcohol to give 60 mg (30% yield) of the title compound as a solid which was collected by filtration; m.p. 294.0°-295.0° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:42][N:43]=[C:44]=[O:45].C(NC(C)C)(C)C>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:44]([NH:43][CH3:42])=[O:45])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN=C=O
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CNC(=O)Oc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate (80 mg), methyl isocyanate (0.5 mL), dichloromethane (3 mL) and diisopropylamine (0.05 mL) was stirred at ambient temperature for 1 h. Solvent was evaporated and the residue was purified by chromatography (silica gel, hexanes/ethyl acetate, 3:1) to provide the title compound as a solid foam (57 mg). 1H NMR (DMSO-d6) δ 0.78 (3H, d), 0.82 (3H, d), 1.17 (1H, dd), 1.30-1.45 (1H, m), 1.9-2.0 (1H, m), 2.42 (1H, t), 2.6 (3H, d), 2.62-2.80 (3H, m), 2.99 (2H, dd), 3.15-3.20 (1H, m), 3.50-3.63 (4H, m), 3.7 (13H, t), 3.8 (1H, dd), 4.8 (1H, dd), 5.04 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.95 (2H, d), 7.05 (1H, d), 7.15 (2H, d), 7.2 (1H, s), 7.25 (1H, d), 7.5 (1H, quartet), 8.08 (1H, d); MS: 650 (MH+).
Reaction SMILES: C([Li])(C)(C)C.F[B-](F)(F)F.[CH:11]([S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])[CH3:12]>CCCCC.O1CCCC1>[C:21]1([S:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:11]([CH3:13])[CH3:12])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)[S+](c1ccccc1)c1ccccc1
Agent: F[B-](F)(F)F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)=S(c1ccccc1)c1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
2 ml of a solution of 1.6M of tert.-butyllithium in pentane was added dropwise at -70° C. under an inert atmosphere to a stirred mixture of 950 mg of the tetrafluoroborate of isopropyldiphenylsulfonium in 15 ml of tetrahydrofuran and the mixture was stirred at -70° C. for 30 minutes to obtain a solution of diphenylisopropylidene sulfurane. The said solution at -70° C. was added slowly with stirring under an inert atmosphere to a mixture of 350 mg of 5(RS) methoxy-2,5-dihydrofuran-2-one [prepared by method of Schroeter et al, Liebigs Ann. Chem., Vol. 697 (1966), p. 42] and 15 ml of tetrahydrofuran cooled to -90° C. and the mixture was allowed to stand at -78° C. for one hour and then at -50° C. for another hour. The mixture was poured into an aqueous monosodium phosphate solution and the mixture was extracted with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 1-1 ether-petrolum ether mixture yielded 480 mg of diphenyl sulfide, 260 mg of (1RS, 5SR) 6,6-dimethyl-4(RS)-methoxy-3-oxabicyclo [3,1,0]-hexan-2-one and 100 mg of unreacted lactone.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.C(O[CH:21]=[N:22][C:23]1[S:30][C:29]2[CH2:28][N:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26][C:25]=2[C:24]=1[C:36](OCC)=[O:37])C>C(O)C>[C:31]([N:27]1[CH2:28][C:29]2[S:30][C:23]3[N:22]=[CH:21][N:1]([CH2:2][CH2:3][N:4]4[CH2:5][CH2:6][N:7]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=5[O:16][CH3:17])[CH2:8][CH2:9]4)[C:36](=[O:37])[C:24]=3[C:25]=2[CH2:26]1)([O:33][CH2:34][CH3:35])=[O:32]
Reactant: COc1ccccc1N1CCN(CCN)CC1
Reactant: CCOC=Nc1sc2c(c1C(=O)OCC)CN(C(=O)OCC)C2
Solvent: CCO
Product: CCOC(=O)N1Cc2sc3ncn(CCN4CCN(c5ccccc5OC)CC4)c(=O)c3c2C1
Yield: 48.7 %

Procedure:
1.1 g (4.8 mM) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)-piperazine were added to 1.6 g (4.8 mM) of 2-ethoxymethyleneamino-3,5-dicarbethoxy-4,6-dihydrothieno[3,2-c]pyrrole in 25 ml of ethanol and refluxed for 2 h. The mixture was then concentrated in a rotary evaporator, and the crude product was purified by column chromatography (silica gel, mobile phase methylene chloride/methanol 96/4). After recrystallization from ethyl acetate, 1.1 g (47%) of product were isolated with melting point 153-155° C.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])[CH:9]=[CH:10][CH:11]=1)(=[O:5])[CH3:4]>O1CCOCC1.CCOCC>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])[CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)Nc1cccc(C(C)=O)c1
Reactant: BrBr
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)Nc1cccc(C(=O)CBr)c1
Reaction time: 2 h
Yield: 97.8 %

Procedure:
24.1 gm of bromine were added slowly over a period of 30 minutes to a stirred suspension of 28.5 gm of ethyl N-(3-acetyl-phenyl)-carbamate in 13.3 gm of dry dioxane and 245 ml of dry ether. After stirring the reaction solution for 2 hours more, it was cooled, and the product which crystallized out was collected and washed with ether, yielding 38.5 gm of the title compound, m.p. 108°-110° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:6]1[CH:5]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:9]=[CH:8][C:7]=1[OH:10])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(OC(F)(F)F)cc1
Product: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
53.4 g (0.3 mol) of 4-trifluoromethoxyphenol were allowed to drop at 25° C. in the course of 30 minutes into 75 ml of 30% strength nitric acid. The mixture was subsequently stirred for 2 hours at 25° C. and then poured into 500 ml of ice water, and the organic phase was separated off. Distillation of the latter yielded 56 g of product having a boiling point of 102° to 103° C. at 26 mbar, which corresponds to a yield of 83% of theory.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:19]([N:24]3[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]3)=[N:20][CH:21]=[CH:22][N:23]=2)[CH2:13][CH2:12]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18]2[C:19]([N:24]3[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]3)=[N:20][CH:21]=[CH:22][N:23]=2)[CH2:15][CH2:16]1
Reactant: OC1CCN(c2nccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CCN(c2nccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Temperature: 25 °C
Yield: 80 %

Procedure:
1-(3-((1-(quinolin-2-yl)piperidin-4-yl)oxy)pyrazin-2-yl)piperidin-4-ol (see Example 1.1; 0.10 g, 0.25 mmol) was dissolved in anhydrous CH2Cl2 (10 mL), treated with Dess-Martin periodinane (DMP) (200 mg, 0.50 mmol, 2.0 equiv) and stirred at RT until complete conversion. The organic layer was washed with an aqueous solution of NaHCO3/Na2S2O3 (3×10 mL)), dried over Na2SO4, filtered and evaporated. The resulting residue was purified by flash chromatography on silica gel (20% to 40% EtOAc in petroleum ether) to give 1-(3-((1-(quinolin-2-yl)piperidin-4-yl)oxy)pyrazin-2-yl)piperidin-4-one (0.084 g, 0.20 mmol, 83% yield) as a white solid. ESI-MS (M+1): 404 calc. for C23H25N5O2 403.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=3)[CH:19]=[CH:18]2)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3ccc(F)cc3)c2c1

Procedure:
The titled compound (36 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 4-fluorobenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-])=O)=[CH:15][CH:16]=2)[CH:11]=[C:10]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1.I.CS[C:36]([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)=[NH:37]>C(O)C.C(OCC)C.[Pd]>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:36]([C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)=[NH:37])=[CH:15][CH:16]=2)[CH:11]=[C:10]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1
Reactant: CN1CCCC1CCn1c(Cc2ccc(OC(F)(F)F)cc2)cc2cc([N+](=O)[O-])ccc21
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: CN1CCCC1CCn1c(Cc2ccc(OC(F)(F)F)cc2)cc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
Compound 12 (95 mg, 0.212 mmol) was dissolved in anhydrous ethanol (10 mL) in a dry argon purged flask. Palladium, 10 wt % on activated carbon (22.6 mg, 0.0212 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 3 hours, thin layer chromatography in a solvent system of 2M NH3 in MeOH:CH2Cl2, 5:95 shows complete conversion to 13, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol (5 mL) and the ethanolic solution of the amine 13 is charged to a small, argon purged flask fitted with a magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide (78.6 mg, 0.276 mmol) is added to the flask and the reaction was stirred under argon at ambient temperature for 44 hours. The solution was diluted with diethyl ether (100 ml) and cooled in an ice bath. No precipitate formed thus the solvent was evaporated. The residue was partitioned between H2O and ethyl acetate and 1M sodium hydroxide solution added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the crude freebase purified via chromatography on silica gel (2M NH3 in MeOH:CH2Cl2, 2.5:97.5 to 5:95) to yield compound 14 (60 mg, 53.7%) as a yellow solid. 1H NMR (DMSO-d6) δ 1.36-48 (m, 2H), 1.53-1.60 (m, 3H), 1.80-1.86 (m, 1H), 1.92-2.05 (m, 2H), 2.08 (s, 3H), 2.87-2.93 (m, 1H), 4.00 (t, 2H, J=8.0 Hz), 4.19 (s, 2H), 6.12 (s, 1H), 6.23 (brs, 2H), 6.63-6.67 (m, 1H), 6.93 (s, 1H), 7.07-7.10 (m, 1H), 7.26 (d, 1H, J=8.6 Hz), 7.31-7.41 (m, 4H), 7.5 8 (d, 1H, J=5.3 Hz), 7.71 (d, 1H, J=3.7 Hz); ESI-MS (m/z, %): 527 (MH+, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(Br)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(Br)cc3)CC2)cc1

Procedure:
1-(4-Bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4- carboxylic acid ethyl ester (16.5 g, 33.3 mmol) dissolved in THF:methanol 3:1 and 10N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 6.18 g (40%); tan solid; mp 215° C.; MS: 469.7 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: Cc1cccc(CC(=O)O)c1
Reactant: CC(C)COC(=O)[C@H](C)N
Product: Cc1cccc(CC(=O)N[C@@H](C)C(=O)OCC(C)C)c1

Procedure:
Following General Procedure BI above, and using 3-methylphenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[S:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:13].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(O)(C)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)[CH:5]=[CH:4][C:3]=1[S:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:13]
Reactant: O=[N+]([O-])c1c(Cl)ccc(S(=O)(=O)Oc2ccccc2)c1Cl
Reactant: CN1CCNCC1
Solvent: CC(C)O
Product: CN1CCN(c2ccc(S(=O)(=O)Oc3ccccc3)c(Cl)c2[N+](=O)[O-])CC1

Procedure:
Phenyl 2,4-dichloro-3-nitrobenzenesulfonate (17.4 g, 0.05 mol) and 25 ml of methylpiperazine in 100 ml of isopropanol were refluxed for 10 minutes and subsequently concentrated. The residue was stirred with 50 ml of 50% methanol, filtered off with suction, and washed with 50% methanol and finally with water. Melting point 94-95° C. (after recrystallization from cyclohexane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[C:7]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[C:8]1=O)[O-])[CH3:2].[K+].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][N:18]=1>>[CH2:1]([O:3][C:4]([C:5]1[C:7]2[CH2:12][C@H:11]3[CH2:10][C@H:9]3[C:8]=2[N:23]([C:20]2[CH:19]=[N:18][C:17]([Br:16])=[CH:22][CH:21]=2)[N:24]=1)=[O:14])[CH3:2]
Reactant: CCOC(=O)C([O-])=C1C[C@H]2C[C@H]2C1=O
Reactant: NNc1ccc(Br)nc1
Agent: [K+]
Product: CCOC(=O)c1nn(-c2ccc(Br)nc2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method C using potassium 2-ethoxy-2-oxo-1-((1R,5R)-2-oxobicyclo[3.1.0]hexan-3-ylidene)ethanolate and 2-bromo-5-hydrazinylpyridine. LCMS m/z=348.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.58 (td, J=4.8, 3.4 Hz, 1H), 1.30 (td, J=7.8, 5.1 Hz, 1H), 1.39 (t, J=7.2 Hz, 3H), 2.29-2.39 (m, 2H), 2.90 (d, J=16.6 Hz, 1H), 3.02 (dd, J=16.6, 6.2 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 7.59 (d, J=8.2 Hz, 1H), 8.09 (dd, J=8.5, 2.9 Hz, 1H), 8.87 (d, J=2.8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1.[OH-].[Na+]>O1CCOCC1>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccccc1
Temperature: 100 °C
Yield: 80.6 %

Procedure:
To a solution of methyl 2-(4-methyl-2,6-diphenylpyrimidin-5-yl)pentanoate (80 mg; 0.222 mmol) in dioxane (1.5 mL) was added a 10 N sodium hydroxide solution (222 μL; 2.219 mmol) and the mixture was heated at 100° C. for 48 h. After removing the solvent under reduced pressure, the residue was dissolved in water, and acidified with a 6N hydrochloric acid. The precipitate was filtered, washed with water and dried under reduced pressure over phosphorus pentoxide to give 62 mg (80%) of the title compound as a white solid. ESI/APCI(+): 347 (M+H). ESI/APCI(−): 713 (2M−H+Na); 301 (M−CO2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][C:3]=1[CH3:23].[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:25]([F:24])([F:33])[F:34])[N:30]=2)=[O:14])=[CH:4][C:3]=1[CH3:23]
Reactant: Cc1cc(-c2cc(C(=O)O)cnc2OCC(F)(F)F)ccc1Cl
Reactant: NCc1nc(C(F)(F)F)no1
Product: Cc1cc(-c2cc(C(=O)NCc3nc(C(F)(F)F)no3)cnc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-3-methylphenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BJ) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 100%, 493.0523 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C([O:14][C:15](=O)/[CH:16]=[C:17](/[O:20][C:21]1[C:26]2[N:27]=[C:28]([CH3:30])[O:29][C:25]=2[CH:24]=[CH:23][CH:22]=1)\[CH2:18]Br)C.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:18][C:17]([O:20][C:21]2[C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[CH:24]=[CH:23][CH:22]=2)=[CH:16][C:15]1=[O:14])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc2oc(C)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc3oc(C)nc23)=CC1=O
Temperature: 100 °C
Yield: 55.8 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.570 g, 3.14 mmol), (E)-4-bromo-3-(2-methyl-benzooxazol-4-yloxy)-but-2-enoic acid ethyl ester (0.970 g, 2.85 mmol) and N,N-diisopropylethylamine (0.809 g, 6.21 mmol) in acetonitrile (20 mL) in a sealed tube was heated at 100° C. for 5 h. The reaction mixture was then cooled to room temperature and ethyl acetate was added. The mixture was then filtered. The filtrate was washed successively with aqueous saturated ammonium chloride, water, and brine and then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 mL) and microwaved in an Emry Optimizer microwave reaction vessel at 160° C., for 3 h. The mixture was then cooled and concentrated in vacuo and the residue was purified by ISCO Combiflash chromatography (40 g Silicycle, 5% to 50% ethyl acetate/hexanes) to afford (S)-4-methyl-2-[4-(2-methyl-benzooxazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (0.570 g, 56%) as a brown oil.