Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(O[C:9]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[O:10])=CC=1)([O-])=O.[F:24][C:25]1[CH:26]=[C:27]([CH:31]2[CH:36]([CH2:37][N:38]([C@@H:46]([C:48]3[C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[CH:51]=[CH:50][CH:49]=3)[CH3:47])[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:35][CH2:34][NH:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1.C1COCC1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[C:41]([O:40][C:39]([N:38]([CH2:37][CH:36]1[CH2:35][CH2:34][N:33]([C:9]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)=[O:10])[CH2:32][CH:31]1[C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=1)[C@@H:46]([C:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50][CH:49]=1)[CH3:47])=[O:45])([CH3:42])([CH3:43])[CH3:44]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3cccc(F)c3)C2)c1
Reaction time: 8 h
Yield: 101.8 %

Procedure:
To a suspension of 5.000 g of methyl 3-hydroxybenzoate, 6.955 g of 4-nitrophenyl chloroformate, and 100 mL of toluene was added 4.81 mL of triethylamine at room temperature, followed by stirring overnight. The insolubles were removed by filtration, and as solvent was removed by distillation under reduced pressure to obtain 5.948 g of methyl 3-{[(4-nitrophenoxy)carbonyl]oxy}benzoate as a pale yellow solid. To a mixture of 100 mg of methyl 3-{[(4-nitrophenoxy)carbonyl]oxy}benzoate, 139 mg of tert-butyl {[3-(3-fluorophenyl)piperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate, and 4 ml of THF was added 0.084 mL of triethylamine at room temperature, followed by stirring overnight. A saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 196 mg of 3-(methoxycarbonyl)phenyl 4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidine-1-carboxylate as a pale yellow oily compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:41])[C:3]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[CH:30]=1)([C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)[OH:4].Cl.N1C=CC=CC=1>>[NH:8]1[CH:9]=[C:5]([C:3]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]3[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=3)[CH:30]=2)([OH:4])[CH:2]([CH3:41])[CH3:1])[N:6]=[CH:7]1
Reactant: CC(C)C(O)(c1cccc(-c2ccncc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(O)(c1cccc(-c2ccncc2)c1)c1c[nH]cn1
Yield: 80.6 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 2-methyl-1-[3-(4-pyridyl)phenyl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.08 g) and pyridine hydrochloride (419 mg), the colorless amorphous title compound (477 mg) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([C:11]2[CH:15]=[C:14](Br)[N:13]([CH3:17])[N:12]=2)=[O:10])=[CH:3][CH:2]=1.C(OC([N:25]1[C:33]2[C:28](=[CH:29][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:32]=2)[CH:27]=[C:26]1[C:43]1[O:47][N:46]=[C:45]([CH3:48])[N:44]=1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([C:11]2[CH:15]=[C:14]([C:30]3[CH:29]=[C:28]4[C:33](=[CH:32][CH:31]=3)[NH:25][C:26]([C:43]3[O:47][N:46]=[C:45]([CH3:48])[N:44]=3)=[CH:27]4)[N:13]([CH3:17])[N:12]=2)=[O:10])=[CH:3][CH:2]=1
Reactant: Cn1nc(C(=O)NCc2ccncc2)cc1Br
Reactant: Cc1noc(-c2cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3n2C(=O)OC(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc(-c2cc3cc(-c4cc(C(=O)NCc5ccncc5)nn4C)ccc3[nH]2)n1
Temperature: 100 °C
Yield: 16.1 %

Procedure:
To a solution of 5-Bromo-l-methyl-1H-pyrazole-3-carboxylic acid(pyridin-4-ylmethyl)-amide (90 mg, 0.3 mmol), and 2-(3-Methyl-1,2,4-oxadiazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-indole-1-carboxylic acid tert-butyl ester (142 mg, 0.33 mmol) in N,N dimethylformamide (1.5 ml) is added aqueous Na2CO3 (0.4 ml, 0.77 mmol). The mixture is purged with argon for 10 minutes. (Bis(di-t-butyl(4-dimethylaminutesophenyl)phosphine)dichloropalladium(II) (40 mg, 0.06 mmol), is then added and the reaction mixture is sealed in a seal tube and heated to 100° C. in a microwave reactor for 30 minutes. The reaction mixture is diluted with ethyl acetate (70 ml), washed with water (20 ml), brine (2×25 ml), dried over Na2SO4, filtered, and concentrated in vacuo. Purified by reverse phase LC/MS to provide the title compound 20 mg, (16%), LC/MS ESI m/z (M+H)+=414.9.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:11][C@H:12]([CH3:17])[C:13](OC)=[O:14])[CH2:8][CH2:9][CH3:10].O>C1COCC1>[CH2:7]([O:11][C@H:12]([CH3:17])[CH2:13][OH:14])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCO[C@H](C)C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCO[C@H](C)CO
Yield: 65.8 %

Procedure:
THF (200 ml) was added to LiAlH4 (16.8 g), followed by agitating the mixture under ice cooling, dropwise adding thereto a solution of (R)-methyl 2-butoxypropionate (54 g) in THF (150 ml), agitating the mixture at room temperature for 3 hours, again cooling it with ice, adding water, extracting with heptane (300 ml) water-washing, concentrating and distilling the resulting concentrate under reduced pressure to obtain (R)-2-butoxy-1-propanol (29.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[NH:5][C:6]=1[CH3:7].[F:11][C:12]1[C:17](O)=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:13]=1[F:22].C(Cl)CCl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][C:17]2[C:16]([F:19])=[C:15]([F:20])[C:14]([F:21])=[C:13]([F:22])[C:12]=2[F:11])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: Cc1[nH]c(C(=O)O)cc1Br
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1[nH]c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Bromo-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 18, 2.16 g, 10.59 mmol) was dissolved an THF (10 ml). Pentafluorophenol and EDC (2.03 g, 10.59 mmol) were added and the mixture was stirred at room temperature for 6 h. The solvent was removed under vacuum and EtOAc (50 ml) was added. The organic phase was washed with water, 10% Na2CO3 (2×25 ml), water (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated in vacuo to give the title compound as an off white solid (2.23 g).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=O)=[CH:12][CH:11]=1.CSC1C=CC(C=O)=CC=1.FC1C=CC(CCl)=CC=1>C1(C)C=CC=CC=1.CC(O)=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:6]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[NH:7][C:17]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:14][CH:15]=1
Reactant: NNc1ccccc1
Reactant: CS(=O)(=O)c1ccc(C(=O)Cc2ccc(F)cc2)cc1
Agent: CSc1ccc(C=O)cc1
Agent: Fc1ccc(CCl)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2[nH]c3ccccc3c2-c2ccc(F)cc2)cc1
Reaction time: 1 h

Procedure:
To phenylhydrazine (50 uL) in toluene-HOAc (2:1, 2 mL) was added 2-(4-fluorophenyl)-1-(4-(methylsulfonyl)phenyl)ethanone (105 mg) (prepared from 4-(methylthio)benzaldehyde and 4-fluorobenzyl chloride by the same method as described in Step 1 of Example 4). After 1 hr at 85° C., the reaction mixture was extracted with EtOAc and HCl. After drying over NaSO4 and evaporation in vacuo the title compound was purified by flash chromatography (67 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].B(OCC)(OCC)OCC.[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>CN(C)C=O.C(OCC)(=O)C>[CH3:29][C:28]1[CH:30]=[CH:31][C:25]([S:22]([O:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([OH:9])[CH:4]=2)(=[O:24])=[O:23])=[CH:26][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1ccc(O)c(O)c1
Agent: CCOB(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Oc2ccc(O)c(O)c2)cc1
Reaction time: 1 h
Yield: 50.2 %

Procedure:
1.37 g of 1,2,4-trihydroxy benzene and 40 ml of anhydrous dimethylformamide were mixed together under an inert gas atmosphere and then 0.984 g of sodium hydride in suspension at 53% in oil were added slowly at 15°-20° C. The mixture was stirred for one hour and then 1.906 ml of triethyl borate were added, followed by stirring for one hour. Then, a solution of 2.072 g of tosyl chloride in 15 ml of dimethylformamide were added over 2 hours and the mixture was stirred for 4 hours at ambient temperature. The mixture was poured into a water-ice-hydrochloric acid mixture and extraction took place with ethyl acetate followed by evaporating to dryness. The crude residue was washed with petroleum ether and after chromatography on silica and eluting with a cyclohexane-ethyl acetate (1-1) mixture, 1.53 g of the expected product were obtained which was crystallized from a flugene-isopropyl ether mixture.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[C:7]2=[N:6][C:5]=1[CH3:16].N1C=CN=C1.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[Si:26]([O:15][CH:14]1[C:7]2=[N:6][C:5]([CH3:16])=[C:4]([CH2:3][CH2:2][Cl:1])[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28]
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1nc2n(c(=O)c1CCCl)CCCC2O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (1.0 g, 4.12 mmol) in DMF (5 mL) was treated with 1H-imidazole (701.24 mg, 64.66 mmol), followed by a solution of t-butyldimethylchlorosilane (683.12 mg, 4.53 mmol) in DMF (1 mL). After stirring for 18 h at room temperature, the solvents were removed under vacuum and the residue was taken up in dichloromethane/water (10 mL/10 mL) with addition of a spatula of potassium carbonate. The aqueous layer was extracted with dichloromethane (three times 10 mL). The combined organic fractions were dried over Na2SO4, filtered, and the solvent was removed under vacuum. The crude mixture was used without further purification in the next step. (ESI-MS (M+1) 357)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[C:17](=O)(O)[O-].[Na+]>CO>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cc(O)ccc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(O)ccc1O

Procedure:
2,5-Dihydroxybenzoic acid, 30 grams (0.195 moles), was heated to reflux with 10 ml conc'd. sulphuric acid in 500 ml methanol for 72 hours. Then it was neutralized with solid sodium bicarbonate and striped in vacuo. The product was extracted with ethyl acetate and the organic extract was dried and stripped in vacuo to give 29.8 grams of methyl 2,5-dihydroxybenzoate of >90% purity.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]([OH:30])=O)=[CH:15]3)=[N:9][CH:10]=1)(=[O:4])=[O:3].Cl.C[N:33](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.N>CN(C)C=O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]([NH2:33])=[O:30])=[CH:15]3)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)nc1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)nc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
A mixture of 5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxylic acid (2.5 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.2 g), 1-hydroxybenzotriazole (1.6 g), and N,N-dimethylformamide (25 mL) was stirred at 50° C. for 30 min. The reaction mixture was cooled to room temperature, 10% aqueous ammonia (4 mL) was added and the mixture was stirred at room temperature for 1.5 hr. The reaction solution was concentrated under reduced pressure, water was added to the residue, and ethyl acetate-tetrahydrofuran was added. The precipitated solid was collected by filtration to give the title compound (0.69 g) as a pale-yellow solid. The filtrate was concentrated under reduced pressure to evaporate the organic solvent. The precipitate was collected by filtration to give the title compound (0.72 g) as a pale-yellow solid (total yield 1.41 g, 64%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[S:15][C:14]([C:16]2[CH2:20][C:19]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)=[CH:13][C:12]=1[CH3:33].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:32][C:27]1[CH:26]=[C:25]([C:19]2([C:21]([F:22])([F:24])[F:23])[O:18][N:17]=[C:16]([C:14]3[S:15][C:11]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[C:12]([CH3:33])[CH:13]=3)[CH2:20]2)[CH:30]=[C:29]([Cl:31])[CH:28]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1-c1ccncc1
Reaction time: 22 h
Yield: 40.2 %

Procedure:
Pyridine-4-boronic acid (30 mg) is added to a solution of 3-(5-bromo-4-methyl-thiophen-2-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (100 mg), K2CO3 (90 mg) and Pd(PPh3)4 (20 mg) in a mixture of THF and water (0.4 ml, 9:1). After 22 hours at 70° C., the reaction is quenched with water and extracted three times with ethyl acetate. The organic phases are combined, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 4-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-pyridine (40 mg) as a colorless oil. MS (HPLC/MS): 457 (MH+). Retention time: 5.20 min.
Reaction SMILES: Cl.[CH2:2]([S:9][C:10]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]2[C:13]([CH2:14][CH2:15][NH:16][CH2:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:23]([N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[C:19]([N+:20]([O-:22])=[O:21])[C:10]([S:9][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:11][CH:12]=2)[CH2:17]1)(=[O:25])[CH3:24]
Reactant: O=[N+]([O-])c1c(SCc2ccccc2)ccc2c1CNCC2
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)N1CCc2ccc(SCc3ccccc3)c([N+](=O)[O-])c2C1

Procedure:
A mixture of 17.5 g. (0.052 mole) of 7-benzylthio-8-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride, 15 ml. of acetic anhydride and 4.5 g. (0.055 mole) of sodium acetate in 150 ml. of acetic acid was heated on a steam bath for one hour, then evaporated. Water and aqueous ammonia was added to the residue until the mixture was basic. The mixture was extracted with methylene chloride, the extracts combined and washed with water, 10% hydrochloric acid, 5% sodium bicarbonate, dried over sodium sulfate and concentrated. Chromatography of the residue on silica (ethyl acetate) gave 2-acetyl-7-benzylthio-8-nitro-1,2,3,4-tetrahydroisoquinoline, melting point 94°-95° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[C:31]([O:35][C:36]([N:38]1[CH2:42][C@@H:41]([CH2:43][NH2:44])[CH2:40][C@H:39]1[C:45]([N:47]1[CH2:51][CH2:50][S:49][CH2:48]1)=[O:46])=[O:37])([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>CN(C=O)C>[C:31]([O:35][C:36]([N:38]1[CH2:42][C@@H:41]([CH2:43][NH:44][C:6]([C:4]2[N:3]=[CH:2][S:1][CH:5]=2)=[O:8])[CH2:40][C@H:39]1[C:45]([N:47]1[CH2:51][CH2:50][S:49][CH2:48]1)=[O:46])=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Reactant: O=C(O)c1cscn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cscn2)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.3 %

Procedure:
To a solution of thiazole-4-carboxylic acid (2.25 g, 17.6 mmol) and HOBt (2.60 g, 19.2 mmol) in anhydrous DMF (80 mL) at 0° C. was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.69 g, 19.2 mmol) followed by the dropwise addition of a solution of Example 17D (5.07 g, 16 mmol) in anhydrous DMF (50 mL) over 10 minutes, after which anhydrous triethylamine (4.45 mL, 32 mmol) was added to the mixture via syringe. The mixture was allowed to stir for 12 hours at room temperature, concentrated under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and H2O (30 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated to provide a yellow solid. The yellow solid was crystallized from ethyl acetate (30 mL). The white crystals were dried under vacuum at 40° C. for 12 hours to provide a white powder (4.8 g) as the titled compound. MS (ESI) m/e 427 (M+H)+, 425 (M−H)−; 1H NMR (500 MHz, CD3OD) δ ppm 1.41 (s, 5 H) 1.44 (s, 4 H), 1.66 (m, 1 H), 2.49 (m, 1 H), 2.59 (m, 1 H), 3.03 (m, 1 H), 3.13 (m, 1 H), 3.21 (m, 1 H), 3.48 (m, 2 H) 3.75 (m, 2 H) 3.85 (m, 1 H) 4.53 (m, 2 H) 4.66 (m, 1 H), 8.25 (s, 1 H), 8.99 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11]([C:12]([O:14]C)=[O:13])=[C:10]([C:16]([O:18]C)=[O:17])[C:9]3[CH2:20][O:21][CH2:22][CH2:23][C:8]2=3)=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([C:12]([OH:14])=[O:13])=[C:10]([C:16]([OH:18])=[O:17])[C:9]3[CH2:20][O:21][CH2:22][CH2:23][C:8]2=3)=[CH:24][CH:25]=1
Reactant: COC(=O)c1c2c(n(Cc3ccc(F)cc3)c1C(=O)OC)CCOC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c2c(n(Cc3ccc(F)cc3)c1C(=O)O)CCOC2
Temperature: 90 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
A suspension of dimethyl 1-(4-fluorobenzyl)-1,4,6,7-tetrahydropyrano[4,3-b]pyrrole-2,3-dicarboxylate (3.92 g, 11.29 mmol) and KOH (3.17 g, 56.4 mmol) in Ethanol (113 ml) was heated to 90° C. After 18 h, the reaction mixture was poured into 1M HCl and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford 1-(4-fluorobenzyl)-1,4,6,7-tetrahydropyrano[4,3-b]pyrrole-2,3-dicarboxylic acid (3.1 g, 9.71 mmol, 86% yield). LCMS (m/z) ES+=320 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:35])[C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([S:19][C:20]3[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:44])C=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:35])[C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([S:19]([C:20]3[CH:25]=[C:24]([C:26]([CH3:27])([CH3:28])[CH3:29])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=3)=[O:44])[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(S(=O)c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 5-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (Ex. 4a, 490 mg, 0.94 mmol) in 10 mL of dichloromethane at room temperature under N2 was added m-chloroperbenzoic acid (247 mg, 1.1 mmol) in 5 portions during a period of 30 min. The resulting suspension was stirred for 3 h at room temperature and then the reaction was quenched by pouring the suspension onto ice (20 g). The mixture was extracted with ethyl acetate (2×40 mL) and the combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. Chromatography (3-50% Ethyl acetate/hexanes) gave 5-[4-(3,5-di-tert-butyl-4-hydroxy-benzenesulfinyl)-piperidine-1-sulfonyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester a white solid (480 mg, 95%). ESI/Cl-MS m/z 537 ([M−H]−).
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:9]1[CH2:17][O:16][C@H:12]([C:13](O)=[O:14])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:26]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:9]1[CH2:17][O:16][C@H:12]([C:13]([NH2:26])=[O:14])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CC[C@@H](N(Cc2ccccc2)Cc2ccccc2)CO1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@@H]1CC[C@@H](N(Cc2ccccc2)Cc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.1 %

Procedure:
The compound (870 mg, 2.67 mmol) obtained in Step 1 above was dissolved in N,N-dimethylformamide (30 ml), 1-hydroxybenzotriazole (361 mg, 2.67 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (614 mg, 3.20 mmol) were added and the resulting mixture was stirred at room temperature for 15 minutes. Ammonium chloride (285 mg, 5.44 mmol) and N,N-diisopropylethylamine (1.86 ml, 10.7 mmol) were added and the resulting mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with saturated sodium bicarbonate solution and brine in this order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 495 mg (57%) of the title compound as a solid.