Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6]1)=[O:4]>[Pd].CCO.CCO.C1COCC1>[CH3:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CNC(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)N1CCNCC1
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Palladium on carbon (300 mg, 10% by wt.) was placed under an inert atmosphere and suspended in EtOH (10 mL). A solution of 4-benzyl-piperazine-1-carboxylic acid methylamide (1.50 g, 6.43 mmol) dissolved in 2:1 v/v EtOH/THF (96 mL) was added. The reaction mixture was placed under H2 atmosphere (1 atmosphere pressure) and stirred overnight. The resulting mixture was filtered through a pad of Celite® and the solvent was concentrated in vacuo to give 916 mg (99%) of the title compound as clear oil. 1H-NMR (300 MHz, DMSO-d6) 6.30 (broad d, 1H), 3.15 to 3.12 (m, 5H), 2.59 to 2.55 (m, 4H), 2.53 (d, 3H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=O.O.[NH2:13][NH2:14]>C(C(CCCC)CO)C>[NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[N:13][NH2:14]
Reactant: NN
Reactant: O=C1Nc2ccccc2C1=O
Solvent: CCCCC(CC)CO
Solvent: O
Product: NN=C1Nc2ccccc2C1=O
Reaction time: 1 h

Procedure:
40.39 g of isatin (0.27 mol, purity 98.2%) were initially charged into a 500 ml four-neck flask and 200 ml of 2-ethylhexanol were added. With stirring (KPG, 250 rpm), 13.1 ml of hydrazine hydrate (13.5 g, 0.27 mol, purity 100.6%) were added within 15 minutes, which caused the temperature to increase from 23° C. to 45° C. and an intensely orange suspension to form. The reaction mixture was heated further and held at 50° C. for 60 minutes to form isatin hydrazone (yellow suspension). Afterwards, 6.12 g of DABCO (55 mmol, 98%) were added and the reaction mixture heated for a further about 0.5 hour until the DABCO had dissolved. The suspension was then charged in portions into 35 ml of 2-ethylhexanol in a receiver vessel which had been preheated to 145-150° C. Since addition of the cold suspension to the preheated 2-ethylhexanol resulted in an immediate temperature decrease which slowed the nitrogen elimination, the isatin hydrazone suspension was added in portions of each about 5 ml at intervals of 2-3 min to avoid this, so that the temperature in the receiver could be maintained in the target range of 140-145° C. Occasionally, an extension of the interval of up to 5 min was necessary. During the metering in (1.5-2 h), the reaction suspension foamed vigorously, particularly at the end of the reaction. During the nitrogen elimination, about 6.5 g of a biphasic mixture of water and some 2-ethylhexanol were distilled off. In this distillate 1, no hydrazine was found. The reaction mixture was held until complete conversion (about another 1.5 hours) at 140-145° C. (IPC control, GC: complete consumption of the hydrazone at 0.1-0.2 area %). 185 ml of 2-ethylhexanol were then distilled off at 90-95° C. (20-30 mbar, contained 0.02% by weight of hydrazine). The reaction solution was cooled to 55° C. and 80 g of MTBE were added. The reaction solution was cooled to 5° C. (in 0.5-1 h, then left to stand overnight at RT) to crystallize the 2-oxindole. The crystals were filtered off, washed with 3×5 ml of cold MTBE (0° C.) and sucked to dryness. 30.0 g of damp product were obtained which were dried for about 48 hours in a vacuum drying cupboard (80-90° C. and 50-65 mbar) to constant weight. Altogether, 23.9 g of dry 2-oxindole product (light brown) were obtained which corresponded to an overall yield of 66.5%.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C:5]([NH:12][C@H:13]([C:22]([OH:24])=O)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]>>[C:8]([O:7][C:5](=[O:6])[NH:12][C@H:13]([C:22](=[O:24])[N:3]([CH3:4])[CH3:2])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N)cc1)C(=O)O
Reactant: CNC
Agent: Cl
Product: CN(C)C(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C

Procedure:
Dimethylamine hydrochloride (2.04 mmol) and Boc-p-amino-L-phenylalanine (1.7 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 4:1 dichloro-methaneldimethylformamide reaction solvent, washed with base only). The product was purified by chromatography on silica gel eluted with 50, 60, 70 and 100% ethyl acetate in hexanes. Yield 226 mg, 42%; HPLC (70/30) 2.45 minutes (100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH2:3]1.O>CCO.CC(O)=O.[Fe]>[CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2ncccc2[N+](=O)[O-])CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC1(C)CC=C(c2ncccc2N)CC1
Temperature: 70 °C
Yield: 102.2 %

Procedure:
A solution of 90.0 mg (0.387 mmol) of 2-(4,4-dimethyl-cyclohex-1-enyl)-3-nitro-pyridine (as prepared in the previous step) in EtOH (10 mL) and water (5 mL) was treated with AcOH (3 drops) and 121 mg (2.17 mmol) of Fe powder then heated to 70° C. for 1.5 h. The mixture was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with CH2Cl2 (3×40 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to afford 80.0 mg (100%) of the title product as a tan glass: Mass spectrum (ESI, m/z): Calcd. for C13H18N2, 203.2 (M+H), found 203.2.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[C:15]([F:24])[C:14]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:35][S-:36].[Na+].[I-].[K+].CN(C)C=O>O1CCCC1.O>[F:24][C:15]1[C:14]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:13][N:12]([S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][S:36][CH3:35])[CH:4]=2)(=[O:11])=[O:10])[C:16]=1[C:17]1[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[S-]
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(CCl)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CSCc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)c1
Reaction time: 21 h
Yield: 73.7 %

Procedure:
To a solution of tert-butyl {[1-{[3-(chloromethyl)phenyl]sulfonyl}-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (386 mg) in tetrahydrofuran (3 mL) were added sodium thiomethoxide (58 mg) and potassium iodide (125 mg) and the mixture was stirred for 21 hr. Dimethylformamide (3 mL) was added and the mixture was stirred at 100° C. for 76 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as a yellow oil (yield 291 mg, 74%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OC2C=CC=CC=2)=[CH:5][CH:4]=1.B(Br)(Br)[Br:22]>C(Cl)Cl>[Br:22][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc(CCCCCOc2ccccc2)cc1
Solvent: ClCCl
Product: Oc1ccc(CCCCCBr)cc1

Procedure:
5-Bromo-1-(4-hydroxy-phenyl)-pentane (9.4) was synthesized as in 9.1 using 8.4 (3.43 g, 12.7 mmol) in anhydrous CH2Cl2 (120 mL), and BBr3 (1M solution in CH2Cl2, 32 mL, 32 mmol). The title compound (9.4) was isolated as a viscous liquid after purification by flash column chromatography (2.84 g, 92% yield).
Reaction SMILES: C(N[C:15]1[CH:46]=[CH:45][C:18]([C:19]([C:21](S)(C2N(C3C=CC(O)=CC=3)N=NN=2)[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2Cl)=[O:23])=[O:20])=[CH:17][CH:16]=1)(=O)CCCCCCCCCCC.OC1C=CC(N2C(S)=NN=N2)=CC=1.S(Cl)([Cl:63])(=O)=O>C(O)C>[Cl:63][C:45]1[CH:46]=[CH:15][CH:16]=[CH:17][C:18]=1[C:19]([CH2:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23])=[O:20]
Reactant: CCCCCCCCCCCC(=O)Nc1ccc(C(=O)C(S)(C(=O)Nc2ccccc2Cl)c2nnnn2-c2ccc(O)cc2)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: Oc1ccc(-n2nnnc2S)cc1
Solvent: CCO
Product: O=C(CC(=O)c1ccccc1Cl)Nc1ccccc1

Procedure:
2-(p-lauroylaminobenzoyl)-2-(1-p-hydroxy-phenyltetrazole-5-yl)-mercapto-(o-chloro)-acetanilide (Compound 2) Analogously to Synthesis Example 1, 4.32 g. (0.02 mol) Na-salt of 1-(p-hydroxyphenyl)-5-mercaptotetrazole are reacted with 10.12 g (0.02 mol) 2-chloro-2-(p-lauroylamino)-benzoyl-(o-chloro)-acetanilide. An an intermediate product the respective 2-chlorobenzoylacetanilide was prepared according to the method "chlorination with sulfurylchloride in methylene" analogously to Synthesis Example 2. yield=7.2 g. (1×ethanol)=76% of theoretical; melting point 142° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[OH:4].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:10]([O:9][C:7]1[CH:6]=[CH:5][C:3]([OH:4])=[C:2]([CH3:1])[CH:8]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(O)ccc1O
Reactant: O=C(Cl)c1ccccc1
Product: Cc1cc(OC(=O)c2ccccc2)ccc1O
Yield: 68.2 %

Procedure:
Using 2.5 g of methylhydroquinone and 2.8 g of benzoyl chloride, the procedure in Reference Example was followed. Recrystallization from ethanol-isopropyl ether gave 3.1 g of 4-benzoyloxy-2-methylphenol as white crystals, m.p. 120-122° C. Then, using 2.3 g of the crystals, 1.4 g of anhydrous potassium carbonate, 4.6 g of chloromethyloxirane and 1.9 g of 1-(2-methoxyphenyl)piperazine, the procedures of Examples 3 and 4 were followed to give 3.2 g of white crystals, m.p. 192-194° C. (decomp.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1([O-:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+].N>>[CH:14]1[CH:15]=[CH:16][C:11]([O:17][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: [O-]c1ccccc1
Agent: N
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 9 h

Procedure:
157.6 g of p-chloronitrobenzene and 116.1 g of sodium phenolate were initially introduced into a steel autoclave. At room temperature, 100 g of liquid ammonia were pumped into the pressure vessel, the mixture was heated to 70° C. and allowed to completely react with stirring over a period of 9 hours. The pressure of 28 bar initially observed dropped during the reaction to 22 bar. Removal of the ammonia by distillation and workup of the distillation residue gave-4-nitrodiphenyl ether with a yield of 213.8 g=99.4% of the theoretical yield. The product is 99.2% pure.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.C(=O)([O-])O.[Na+].C1COCC1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:18]1([C:17]([N:2]2[CH2:5][CH:4]([OH:6])[CH2:3]2)=[O:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccccc1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.1 %

Procedure:
To a mixture of azetidin-3-ol hydrochloride (200 mg), saturated aqueous sodium hydrogen carbonate solution (2 mL) and THF (2 mL) was added benzoylchloride (132 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 3 days, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (130 mg).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].P(Br)(Br)[Br:12].CO.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:12][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10]
Reactant: COc1ccccc1CO
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccccc1CBr
Reaction time: 1.5 h
Yield: 137.2 %

Procedure:
To a solution of 1-hydroxymethyl-2-methoxy-benzene (28.7 g, 0.207 mol) in CH2Cl2 (574 mL) at 0° C. under nitrogen was added slowly PBr3 (13.66 mL, 0.145 mol). After stirring for an additional 1.5 hours, MeOH (13.66 mL) was added and stirred for 5 minutes. To this mixture was added dropwise 10% Na2CO3 (2 mL) solution and stirred for 5 minutes. The mixture was then washed with 10% Na2CO3 (50 mL, 2×) and brine (100 mL). It was dried over MgSO4, and filtered. The filtrate was removed under vacuum to give an oil (40 g) of 1-bromomethyl-2-methoxy-benzene. This material was used without purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][NH2:13].[C-:14]#[N:15].[Na+]>CCOCC.O>[CH2:1]([O:8][CH2:9][CH:10]([NH:15][CH3:14])[C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: O=CCOCc1ccccc1
Reactant: CN
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CNC(C#N)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of known benzyloxy-acetaldehyde (10 g) in 25 mL ether, was added to an aqueous solution of methylamine (5.16 g of a 40% solution in water) at 0° C. followed by addition of NaCN (6.4 g dissolved in 10 mL water). The reaction mixture was stirred overnight at room temperature. The reaction was monitored by TLC and after completion, the ether layer was separated. The aqueous layer was extracted with 2×30 mL ethyl acetate and the combined organic layers were then dried over sodium sulfate, filtered and the volatiles where then concentrated to afford the crude product which was purified by column chromatography using basic alumina to give 3-benzyloxy-2-methylamino-propionitrile (5.0 g) as a dark brown oil.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][OH:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: OCc1cccc(C#CCCCOc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: OCc1cccc(CCCCCOc2ccccc2)c1
Yield: 100.3 %

Procedure:
This compound was prepared in a manner analogous to that used for the para isomer (Example 6). Thus 1.856 g of 3-(5-phenoxy-1-pentyn-1-yl)benzyl alcohol in 100 ml of CH3OH was treated with 333 mg 5% palladium on charcoal and 30 PSI hydrogen for 1.25 hours. The product mixture was filtered in the customary manner through celite and the filtrate was evaporated in vacuo to yield 1.89 g of the 3-(5-Phenoxypent-1-yl)benzyl alcohol in the form of a tan solid.
Reaction SMILES: [C:1]1(/[CH:18]=[CH:19]\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][O:17][C:11]=3[CH2:10]2)=[O:8])=[CH:3][CH:2]=1.[CH3:26][NH:27][CH3:28].[CH2:29]=O>C(O)(=O)C>[CH3:26][N:27]([CH2:29][C:16]1[O:17][C:11]2[CH2:10][N:9]([C:7]([C:4]3[CH:3]=[CH:2][C:1](/[CH:18]=[CH:19]\[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:6][CH:5]=3)=[O:8])[CH2:14][CH2:13][C:12]=2[CH:15]=1)[CH3:28]
Reactant: C=O
Reactant: O=C(c1ccc(/C=C\c2ccccc2)cc1)N1CCc2ccoc2C1
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)c1ccc(/C=C\c3ccccc3)cc1)CC2
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
To a solution of 0.250 g (0.759 mmol) of (Z)-6-(4-stilbenecarbonyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 20 ml of acetic acid, 0.10 ml (1.1 mmol) of 50% aqueous dimethylamine and 0.09 ml (1.1 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 45 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate, and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform/methanol=50/1) to yield the desired product.
Reaction SMILES: [I:1](O)(=O)(=O)=O.[I-:6].[K+].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Br:15]>S(=O)(=O)(O)O>[Br:8][C:9]1[CH:14]=[C:13]([I:6])[C:12]([I:1])=[CH:11][C:10]=1[Br:15]
Reactant: [I-]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: Brc1ccccc1Br
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Brc1cc(I)c(I)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a 1 L three-necked flask fitted with a mechanical stirrer were added 36.9 g (162 mmol) of periodic acid and 150 ml of sulfuric acid. After periodic acid was dissolved, 80.7 g (486 mmol) of potassium iodide was added portionwise. The temperature of the content was cooled to 0° C. and 75.0 g (318 mmol) of 1,2-dibromobenzene was added. The resulting mixture was stirred at 0° C. for 30 minutes. After the reaction mixture was poured into ice, the whole was filtrated and a solid was taken out. The solid was recrystallized from THF/methanol twice to obtain white crystals of 1,2-dibromo-4,5-diiodobenzene (76.2 g, yield 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:35]2[NH:39][C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[CH:37][CH:36]=2)[CH2:13][C@H:14]2[CH2:34][CH2:33][C:16]3(O[C@H](C4C=CC=CC=4)[C@@H](C4C=CC=CC=4)[O:17]3)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:35]2[NH:39][C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[CH:37][CH:36]=2)[CH2:13][C@H:14]2[CH2:34][CH2:33][C:16](=[O:17])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3ccccn3)[nH]2)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC(=O)C2)c2ccc(-c3ccccn3)[nH]2)cc1Cl
Temperature: 55 °C
Reaction time: 5 h
Yield: 89.6 %

Procedure:
To a solution of 2-(5-{1-[3-chloro-4-(methylsulfonyl)phenyl]-2-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]ethyl}-1H-pyrrol-2-yl)pyridine (580 mg) in tetrahydrofuran (4.5 mL) was added 1M hydrochloric acid (4.5 mL), and the mixture was stirred at 55° C. for 5 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (360 mg, yield 90%) was obtained as a white amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 443 (MH+).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:29])[CH2:7][N:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=2)[C:9]1=[O:28])C.Cl>C(O)C.O>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][CH:10]2[C:11]([CH3:14])([CH3:13])[CH2:12][N:8]([CH2:7][C:6]([OH:29])=[O:5])[C:9]2=[O:28])=[CH:17][C:18]=1[C:24]([F:27])([F:26])[F:25])#[N:23]
Reactant: CCOC(=O)CN1CC(C)(C)C(Oc2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CN(CC(=O)O)C(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydroxide (50% in water, 10 mL) was added to a stirring solution of [3-(4-cyano-3-trifluoromethyl-phenoxy)-4,4-dimethyl-2-oxo-pyrrolidin-1-yl]-acetic acid ethyl ester (3) (16.8 mmoles) in ethanol (50 mL) and water (40 mL). The reaction was stirred at ambient temperature overnight. The pH of reaction mixture was adjusted to 2.0 by adding hydrochloric acid (37% in water). The reaction mixture was concentrated in vacuo to remove the ethanol. The desired product (3′) that precipitated from the residue was filtered and dried in a vacuum oven overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[CH:4][C:3]=1[F:25].ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23]([CH3:24])=[O:37])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[CH:4][C:3]=1[F:25]
Reactant: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)c(F)c3)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(CCC#N)c3ccc(Cl)c(F)c3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
300 mg (0.81 mmol) of the compound from Example 152 were introduced into 55 ml of dichloromethane at 0° C., 198 mg (0.81 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvents were removed in a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 266 mg (85% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9][CH2:8][N:7]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:6]1)=[O:4].[OH-].[Li+]>C1COCC1.CO.O>[C:37]([O:36][C:34]([N:7]1[CH2:8][CH2:9][CH:10]([NH:11][S:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:19][CH:20]=2)(=[O:13])=[O:14])[CH:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3CCN(C(=O)OC(C)(C)C)CC3C(=O)O)cc2)c2ccccc2n1

Procedure:
A solution of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.3 g, 0.525 mmol) and lithium hydroxide (0.1 g, 4.2 mmol) in THF:methanol:water (2.5: 1.5:1.5 mL) was stirred at 25° C. for 19 h. The solution was concentrated in vacuo to provide 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester as a crude solid (0.170 g, 58%). MS: 557 (M+H)+
Reaction SMILES: [N:1]1([C:7]2([C:13](N)=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na]>C(O)CC.CCCCCC>[N:1]1([C:7]2([CH2:13][OH:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)C1(N2CCCCC2)CCNCC1
Agent: [Na]
Solvent: CCCCCC
Solvent: CCCO
Product: OCC1(N2CCCCC2)CCNCC1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
In a three neck round-bottom flask equipped with a stirring bar, reflux condenser, and rubber septa is placed [1,4′]bipiperidinyl-4′-carboxylic acid amide (5.01 g, 23.7 mmol) in 140 mL of anhydrous 1-propanol and the solution is heated to reflux. Sodium metal (˜9.276 g, 403.4 mmol) rinsed in hexane to remove mineral oil) is added in portions. Once the sodium metal completely dissolves, the mixture is allowed to stir over the weekend. The reaction mixture is cooled to room temperature and the solvent removed under reduced pressure. Distilled water is added and the solution extracted with chloroform. The organic layer is collected, dried over sodium sulfate, filtered, and the solvent removed under reduced pressure to afford 4.4 g of the desired product which is used without further purification. 1H NMR (CD3OD, 300 MHz) δ 1.48–1.60 (m, 8H), 1.72–1.80 (m, 2H), 2.61–2.71 (m, 6H), 2.92–3.01 (m, 2H), 3.37 (s, 1H), 3.56 (s, 2H). MS (ESI) m/z 199 (M+H+).