Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:6][N:7]1[CH2:12][CH2:11][O:10][C@@H:9]([CH2:13][NH:14][C:15](=[O:18])[CH2:16]Cl)[CH2:8]1.[CH2:23]([O:25][C:26]([C:28]1[N:29]=[C:30]([SH:33])[S:31][CH:32]=1)=[O:27])[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:6][N:7]1[CH2:12][CH2:11][O:10][C@@H:9]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][S:33][C:30]2[S:31][CH:32]=[C:28]([C:26]([O:25][CH2:23][CH3:24])=[O:27])[N:29]=2)[CH2:8]1
Reactant: CCOC(=O)c1csc(S)n1
Reactant: O=C(CCl)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The resultant product (776 mg) of (1-2) and the resultant product (379 mg) of (1-3) were dissolved in dimethylformamide (6 mL), potassium carbonate (829 mg) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (850 mg) as a pale-yellow oil.
Reaction SMILES: [CH:1]1([NH2:13])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].C(O)C.[I-].C([N+]1(C)[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)C>O>[CH:1]1([N:13]2[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: NC1CC2CCCc3cccc1c32
Reactant: CC[N+]1(C)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCN(C2CC3CCCc4cccc2c43)CC1
Yield: 14 %

Procedure:
To a mixture of 1,2,2a,3,4,5-hexahydroacenaphthylen-1-ylamine, potassium carbonate (3.89 g) and ethanol (60 ml) was added 1-ethyl-1-methyl-4-oxopiperidinium iodide (8.36 g) dissolved in water (15 ml), and the mixture was heated under reflux for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 1-(1,2,2a,3,4,5-hexahydroacenaphthylen-1-yl)piperidin-4-one (1.01 g, 14%) as an oil.
Reaction SMILES: I[C:2]1C=C[C:5]([N:8]2C[C@H](CNC(=O)OC(C)(C)C)O[C:9]2=[O:22])=[CH:4][CH:3]=1.F[C:24]1[CH:25]=[C:26]([N:31]2[CH2:35][C@H:34]([CH2:36][NH:37][C:38](=[O:40])[CH3:39])[O:33][C:32]2=[O:41])[CH:27]=[CH:28][C:29]=1I>>[O:41]=[C:32]1[N:31]([C:26]2[CH:27]=[CH:28][C:29]([CH:3]3[CH2:4][CH2:5][NH:8][C:9](=[O:22])[CH2:2]3)=[CH:24][CH:25]=2)[CH2:35][C@H:34]([CH2:36][NH:37][C:38](=[O:40])[CH3:39])[O:33]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCNC(=O)C3)cc2)C(=O)O1

Procedure:
N-({(5S)-2-oxo-3-[4-(2-oxopiperidin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)acetamide is prepared as described in the route described in Example 16 substituting tert-butyl [(5S)-3-(4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methylcarbamate for N-{[(5S)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide. 1H-NMR (DMSO) δ: 8.25, 7.55, 7.47, 7.30, 4.70, 4.10, 3.73, 3.40, 3.17, 3.02, 2.31, 1.87, 1.83
Reaction SMILES: [OH:1][CH:2]([CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[CH3:8])[CH2:3][C:4](=[O:6])[CH3:5].N1C=CC=CC=1.[C:33](Cl)(=[O:35])[CH3:34]>C1C=CC=CC=1>[C:33]([O:1][CH:2]([CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)[CH3:8])[CH2:3][C:4](=[O:6])[CH3:5])(=[O:35])[CH3:34]
Reactant: CC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)CC(OC(C)=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-hydroxy-5-[4-(4-trifluoromethylphenoxy)phenoxy]-2-hexanone (3.5 mmol) and pyridine (3.5 mmol) in benzene (20 ml) is added acetyl chloride (4.0 mmol). The mixture is stirred at RT overnight. The reaction mixture is diluted with benzene, washed with water, dried and the solvent is removed in vacuo to give 4-acetoxy-5-[4-(4-trifluoromethylphenoxy)phenoxy]-2-hexanone (cpd. 10, Table B).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH:17]([F:19])[F:18])([CH3:4])([CH3:3])[CH3:2].[I:20]N1C(=O)CCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:8]=[C:7]([I:20])[C:6]=1[O:15][CH2:16][CH:17]([F:18])[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)c1ccc(OCC(F)F)c(C(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(I)c(OCC(F)F)c(C(C)(C)C)c1
Temperature: 38 °C
Yield: 100.1 %

Procedure:
2,4-Di-tert-butyl-1-(2,2-difluoro-ethoxy)-benzene (6.75 g, 25 mmol), N-iodosuccinimide (6.74 g, 30 mmol) and p-toluenesulfonic acid monohydrate (1.90 g, 10 mmol) were combined in dichloromethane (75 mL) and heated at 38° C. for 7 h. TLC (hexanes) indicated a small amount of starting material still present and the reaction was treated with additional N-iodosuccinimde (0.33 g). After 4 h the reaction was washed with 10% Na2SO2O3 solution (50 mL). The aqueous was backwashed with dichloromethane (100 mL) and then the combined organic portions washed with water (75 mL) and the combined organic portions washed with water (100 mL), dried (MgSO4), filtered and evaporated in vacuo to provide an orange oil (9.92 g). The material was purified by flash chromatography using hexane to give 8.88 g (90%) of a light pink oil which solidified over time. 1H NMR (250 MHz, CDCl3): δ 7.66 (d, 1H, J=2.4), 7.36 (d, 1H, =2.4), 6.29 (tt, 1H, J=55.3, J=4.3), 4.24 (td, 2H, J=13.2, J=4.3), 1.40 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].[Li]CCCC.[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH:16]1C(Cl)=O.Cl>C1COCC1.CCOCC>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH:21]1[CH2:22][CH2:23][C:24]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20]1)[CH3:2]
Reactant: O=C(Cl)C1CCc2ccccc2C1
Reactant: CCOC(=O)CC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C1CCc2ccccc2C1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 93.5 %

Procedure:
A solution of malonic acid monoethyl ester (3.8 g, 29 mmol) in THF (80 ml) was cooled to −78° C. n-BuLi (36 ml, 58 mmol, 1.6 M in hexane) was added dropwise so that the temperature of the reaction mixture at the end the addition was −5° C. After 5 min. stirring at −5° C., reaction mixture was cooled to −65° C. and treated with a solution of (RS)-1,2,3,4-tetrahydro-naphthalene-2-carbonyl chloride (3.2 g, 16.5 mmol) in THF. Mixture was stirred for 10 min. at −65° C. and then added to a stirring mixture containing Et2O (200 ml) and 1N HCl (100 ml). Aqueous phase was extracted with Et2O (2×150 ml). Combined organic phases were washed successively with a saturated solution of NaHCO3 (100 ml) and NaCl (100 ml), dried over Na2SO4 and concentrated to provide (RS)-3-oxo-3-(1,2,3,4-tetrahydro-naphthalen-2-yl)-propionic acid ethyl ester (3.8 g, 93%) as a light brown oil, MS: m/e=246 (M+).
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]3[CH2:30][O:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[N:14][C:13]=2[CH:38]=1>CO>[ClH:1].[CH3:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH:18]3[CH2:30][O:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[N:14][C:13]=2[CH:38]=1
Reactant: Cc1ccc2oc(N3CCN(C(=O)OC(C)(C)C)CC3COc3cccnc3)nc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc2oc(N3CCNCC3COc3cccnc3)nc2c1
Reaction time: 8 h
Yield: 34 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(5-methylbenzo[d]oxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (212.9 mg, 0.502 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were brought to pH 12 with 1 N NaOH and were extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (1 equiv. HCl, 0.057 mL) was added. The mixture was concentrated under reduced pressure to give 60.8 mg (34%) of the desired product as the hydrochloride salt. LC-MS: RT=4.45 min, [M+H]+=325.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:27]#[N:28])=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][CH2:6][C:7]([CH3:23])([CH3:22])[CH2:8][NH:9][C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:11].[S:29](Cl)(=[O:32])(=[O:31])[NH2:30]>>[S:29]([NH:1][C:2]1[C:3]([C:27]#[N:28])=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][CH2:6][C:7]([CH3:23])([CH3:22])[CH2:8][NH:9][C:10]([NH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)=[O:11])(=[O:32])(=[O:31])[NH2:30]
Reactant: NS(=O)(=O)Cl
Reactant: COc1ccc(CNC(=O)NCC(C)(C)COc2cccc(N)c2C#N)cc1
Product: COc1ccc(CNC(=O)NCC(C)(C)COc2cccc(NS(N)(=O)=O)c2C#N)cc1
Yield: 100 %

Procedure:
Prepared as in Example 215a from 1-(3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropyl)-3-(4-methoxybenzyl)urea (Example 252b) and sulfamoyl chloride in 100% yield. MS 462 (MH+).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH:7]([CH3:9])[CH3:8])[N:6]=1.[Li]CCCC.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>CCOCC>[CH:7]([C:5]1[N:6]=[C:2]([Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])[S:3][CH:4]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1csc(Br)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1nc(C(C)C)cs1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-bromo-4-isopropyl-thiazole (6.79 mmol) in anhydrous Et2O (30 mL) under nitrogen at −78° C. was added dropwise nBuLi (7.47 mmol). The reaction was stirred for 30 min and the temperature reached to −40° C. The reaction mixture was cooled down to −78° C. and tri-n-butyltinchloride (8.15 mmol) was added slowly. The reaction mixture was allowed to warm up to room temperature and stirred during 36 hrs. Et2O was added and the reaction was quenched with saturated NH4Cl. The organic layer was washed with saturated NH4Cl and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 219 as a pale yellow oil in quantitative yield.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]([NH:19][CH3:20])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[N+:16]([O-])=O.[ClH:21]>C(O)C.O.[Fe]>[ClH:15].[ClH:21].[NH2:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[CH2:8][CH:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])[NH:19][CH3:20]
Reactant: CNC(Cc1ccc(Cl)cc1[N+](=O)[O-])c1sccc1C
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNC(Cc1ccc(Cl)cc1N)c1sccc1C

Procedure:
A solution of 10 g of α-(3-methyl-2-thienyl)-N-methyl-4-chloro-2-nitrobenzeneethana mine in 150 ml of 95% ethanol and 40 ml water was treated with 22 g of reduced electrolytic iron and 1 ml of concentrated hydrochloric acid, and the mixture was refluxed for 0.5 hr, with stirring. The resulting mixture was filtered, and the filter cake was washed with 95% ethanol. The filtrate was basified with 10% sodium hydroxide solution, extracted with dichloromethane and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue was accomplished by preparative HPLC (Water's Associates Prep LC/System 500A, silica gel, eluted with methanol, flow rate of 200 ml/min, Gow-Mac Model 80-800 UV detector). The appropriate fractions were collected, combined and concentrated. The residue was dissolved in ether, the solution was filtered, and the filtrate was concentrated. The residue was dissolved in methanol, a few drops of ethereal hydrogen chloride was added followed by anhydrous ethyl ether dropwise until a precipitate appeared. The precipitate was collected, and the filter cake was recrystallized from methanol and anhydrous ether to afford 8.4 g of product.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CO.C(=O)=O>>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Agent: O=C=O
Solvent: CO
Product: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Yield: 42.4 %

Procedure:
Enantiomers of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (2.120 g, 7.46 mmol, racemic mixture) were separated by using chiral SFC (Chiralcel AD-H (250×21 Mm), 45% methanol/CO2 (100 bar), 65 mL/min, 220 nm) to give 877 mg of the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 278 (M+H).
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:24])(=[O:3])[CH3:2].[OH:25]O.O>C(O)(=O)C>[C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=2)=[O:25])[CH2:6][C:5]1=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C1C(=O)CC(CCS(=O)c2ccc(C(F)(F)F)cc2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of 2.3 g of 2-acetyl-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione in 10 ml of acetic acid, 1.8 g of 30% H2O2 was dropped under cooling with ice-water bath. After stirring for 1 hour at room temperature, the reaction solution was poured into water and extracted with ethyl acetate. Removal of solvent afforded 1.83 g of 2-acetyl-5-[2-(4-trifluoromethylphenylsulfinyl)ethyl]cyclohexane-1,3-dione. m.p. 99°-100° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]23[CH2:17][CH:16]([OH:18])[CH2:15][CH:14]2[CH2:13][O:12][N:11]3[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[CH:7]=[CH:8][CH:9]=1.[CH3:30]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([C:10]23[CH2:17][CH:16]([O:18][CH3:30])[CH2:15][CH:14]2[CH2:13][O:12][N:11]3[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: COc1ccc(CN2OCC3CC(O)CC32c2cccc(Br)c2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2OCC3CC(OC)CC32c2cccc(Br)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.9 %

Procedure:
Sodium hydride (0.076 g, 1.89 mmol) is added to a 0° C. solution of racemic (3aRS,5RS,6aSR)-6a-(3-bromophenyl)-1-(2,4-dimethoxybenzyl)hexahydro-1H-cyclopenta[c]isoxazol-5-ol (0.684 g, 1.57 mmol) in DMF (7 mL). The reaction is warmed to room temperature for 10 minutes and then cooled to 0° C. Methyl iodide (0.246 g, 1.73 mmol) is added and the reaction is stirred at room temperature for 6 hours. Additional sodium hydride (0.032 g, 0.790 mmol) and methyl iodide (0.112 g, 0.790 mmol) is added and the reaction is stirred at room temperature for 18 hours. The reaction is quenched with water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the solvent is removed under reduced pressure. The resulting residue is purified by silica gel chromatography with 10% ethyl acetate in CH2Cl2 to give the title compound (0.443 g, 63%). ES/MS m/e (79Br/81Br) 448, 450 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-])=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CO.[Pd]>[CH2:1]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([NH:16][C:17]1[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:10]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1NC1CC2CCC(C1)N2Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccccc1NC1CC2CCC(C1)N2Cc1ccccc1
Reaction time: 3.5 h
Yield: 79.2 %

Procedure:
2.92 g (9.04 mmol) 8-benzyl-N-(2-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-amine was dissolved in 150 ml EtOAc and 25 ml Methanol. 1 g Pd/C was then added and the mixture was stirred at 1 atm H2 for 3.5 hrs. Yellow color disappeared and the reaction mixture was filtered through celite. The solvent was removed to afford 2.2 g of desired solid.
Reaction SMILES: [OH-].[Na+:2].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([OH:13])(=[O:12])=[O:11])=[CH:6][C:5]=1[I:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.S(=O)(=O)(O)O>C(O)(C)C>[CH2:15]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O-:13])(=[O:11])=[O:12])=[CH:6][C:5]=1[I:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+:2]
Reactant: BrCc1ccccc1
Reactant: O=S(=O)(O)c1ccc(O)c(I)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=S(=O)([O-])c1ccc(OCc2ccccc2)c(I)c1
Temperature: 84 °C
Reaction time: 0.21 h

Procedure:
Sodium hydroxide (pellets, 110 g, 2.75 mol, 3.00 eq) was added portionwise to the vigorously stirring aqueous solution of the 4-hydroxy-3-iodo-benzenesulfonic acid. After addition was complete, 10-15 min., isopropyl alcohol (150 mL) was added to the resulting white suspension. The dropping-funnel was charged with benzyl bromide (Aldrich; 164.9 g, 0.964 mol, 1.05 eq.) and added to the reaction mixture over a period of approx. 5 mins. and the reaction mixture was heated to 80°≦Tint≦84° C. After approx. 25 min. it was determined that the reaction was not proceeding further and therefore additional sodium hydroxide (3.67 g, 91.8 mmol, 0.1 eq.) and then benzyl bromide (15.7 g, 91.8 mmol, 0.1 eq.) were added to the reaction mixture to give a homogenous solution. After 70 min. from the original benzyl bromide addition, the heating was stopped and the reaction was allowed to cool slowly in the oil-bath with stirring. At 7.5 h, the reaction mixture appeared as a suspension of fine-reflective precipitate in brown liquid. The reaction mixture was acidified with 3:1 water-sulfuric acid from about pH 13 to between pH 7.5 and 8 (approx. 70 mL is required). The reaction mixture was then cooled gradually to about 5° C. and stirred at that temperature for ˜1 h. The waxy white plaques were collected by filtration, washed with dichloromethane and dried under high vacuum (lyophilizer, 100-200 mTorr) for ˜24 h to give sodium 4-benzyloxy-3-iodo-benzenesulfonate as a brilliant white, crystalline solid, (267.7 g, 71%).
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][N:14]1[C@@H:19](/[CH:20]=[CH:21]/[C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][N:14]1[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][C@@H:19]1/[CH:20]=[CH:21]/[CH:22]([OH:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CCCC=CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCC=CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.8 %

Procedure:
Sodium borohydride (2.0 mg, 0.053 mmol), followed by MeOH (0.1 mL), was added to a solution of 7-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-enoic acid methyl ester (10 mg, 0.026 mmol) in CH2Cl2 (0.5 mL) at 0° C. The mixture was allowed to warm to rt. After 10 min at rt, the reaction was quenched with aqueous HCl (1.0 M, 1 mL) and extracted with EtOAc (3×5 mL). The combined organic phase was washed with brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 9.9 mg (98%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:12]([CH3:14])[CH3:13])[N:5]=[C:6]([O:10][CH3:11])[CH:7]([CH3:9])[N:8]=1.C([Li])(C)(C)C.Br[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29].[Cl-].[NH4+]>O1CCCC1>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][C@@:7]1([CH3:9])[C:6]([O:10][CH3:11])=[N:5][C@H:4]([CH:12]([CH3:14])[CH3:13])[C:3]([O:2][CH3:1])=[N:8]1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1C
Reactant: Clc1ccccc1CCBr
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC1=N[C@@](C)(CCc2ccccc2Cl)C(OC)=N[C@@H]1C(C)C
Reaction time: 1 h

Procedure:
A solution of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-methylpyrazine (1.0 g, 5.0 mmol) in tetrahydrofuran (23 ml) was cooled to −70° C., then tert.butyllithium (1.7 M in pentane, 3.26 ml, 5.55 mmol) was added and the mixture was stirred for 1 hour. A solution of 1-(2-bromo-ethyl)-2-chlorobenzene (1.44 g, 6.56 mmol) in tetrahydrofuran (10 ml) was added slowly and the mixture was stirred overnight at −70° C. At room temperature saturated ammonium chloride solution was added and the mixture was extracted three times with ether. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, heptane/EtOAc=1:1 to yield an orange solid, (1.22 g, 72%); MS (ISP): 337.1; 339.1 ((M+H)+.).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([CH3:13])([CH3:12])[CH:9]3[O:11][CH:10]3[C:5]=2[CH:4]=1)#[N:2].[OH-].[NH4+:17]>>[C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([CH3:13])([CH3:12])[C@@H:9]([OH:11])[C@H:10]([NH2:17])[C:5]=2[CH:4]=1)#[N:2]
Reactant: [NH4+]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: [OH-]
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O

Procedure:
The title compound was prepared by stirring 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran in ethanolic ammonium hydroxide solution at room temperature until thin layer chromatography showed consumption of the starting epoxide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1)=[O:17].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[O:26])[CH2:22][NH:21][CH2:20]1)=[O:17]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)cc2c1CCCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)cc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (100 mg) was dissolved in dichloromethane (0.5 ml), TFA (0.5 ml) was added, and the mixture was stirred at room temperature for 15 min. The solvent was evaporated under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (10 ml×2), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dried under reduced pressure to give the object product (45 mg).