Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([O:21][CH3:22])[CH:11]=2)=[O:8])=[CH:5][C:4]=1[N+:25]([O-])=O.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl.ClCCl>CO.[Pd].N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([O:21][CH3:22])[CH:11]=2)=[O:8])=[CH:5][C:4]=1[NH:25][S:29]([CH3:28])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(NC(=O)c2ccc(OC)c([N+](=O)[O-])c2)ccc1NS(C)(=O)=O
Agent: [Pd]
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(=O)Nc2ccc(NS(C)(=O)=O)c(OC)c2)cc1NS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
A suspension of 4-methoxy-3-nitro-N-(4-methanesulfonylamino-3-methoxyphenyl)benzamide (100 mg) in methanol (20 ml) was stirred under hydrogen with palladium on carbon (10%, 50 mg) for 18 hours. The solvents were removed in vacuo to give a brown gum. The residue was dissolved in pyridine (0.5 ml) and cooled to 0° C. when methanesulfonyl chloride (0.1 ml) was added, the mixture was kept at 0° C. for a further 30 minutes then brought to R.T. for 1 h. Dilute hydrochloric acid (10 ml, 1M) and dichloromethane were added, the organic layer separated, dried and evaporated in vacuo to give the product as a brown gum. Purification by column chromatography over silica gel eluting with dichloromethane containing ethyl acetate (0-100%) gave 3-methanesulfonylamino-4-methoxy-N-(3-methanesulfonylamino-4-methoxyphenyl)benzamide (65 mg, 56%) as a white solid.
Reaction SMILES: O[CH2:2][CH2:3][C@@:4]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[N:25]=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][C:21]=3[CH2:20]2)=[O:18])[CH2:8][C@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:66]([OH:69])(=[S:68])[CH3:67].C([O-])(O)=O.[Na+]>C1COCC1.O>[C:66](=[O:69])([S:68][CH2:2][CH2:3][C@@:4]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[N:25]=[CH:24][C:23]([C:29]([F:32])([F:30])[F:31])=[CH:22][C:21]=3[CH2:20]2)=[O:18])[CH2:8][C@H:7]([NH:9][C:10]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:16])[CH:6]=[CH:5]1)[CH3:67]
Reactant: CC(O)=S
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CCO)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)SCC[C@]1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 2 h

Procedure:
To a solution of the product of Example 1, Step D (1950 mg, 3.98 mmol, 1 eq) in THF (40 mL) at rt under Ar was added triphenylphosphine (2.09 g, 7.96 mmol, 2 eq), diisopropylazodicarboxylate (1.55 mL, 7.96 mmol, 2 eq) and thioacetic acid (0.59 mL, 7.96 mmol, 2 eq). After 2 hr, water and saturated NaHCO3 were added, the aqueous was extracted with ether, the organics combined, dried over MgSO4 and concentrated. Purification by chromatography (80 g column) eluting with 30 to 60% EtOAc/heptane afforded the product of Step A. 1H NMR (CHLOROFORM-d) δ: 8.71 (s, 1H), 7.71 (s, 1H), 6.21 (dd, J=5.6, 1.7 Hz, 1H), 5.80 (dd, J=5.6, 2.0 Hz, 1H), 4.75-4.94 (m, 3H), 4.64-4.75 (m, 1H), 3.96-4.07 (m, 1H), 3.86-3.96 (m, 1H), 3.14 (t, J=5.7 Hz, 2H), 2.69-2.79 (m, 2H), 2.65 (dd, J=13.4, 8.1 Hz, 1H), 2.27 (s, 3H), 1.95-2.13 (m, 2H), 1.81-1.94 (m, 1H), 1.44 (s, 9H). Calculated for C24H30F3N3O4S: 536.2 (M+23). found: 536.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:8]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([C:6]1[S:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[C:8]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(-c2ccncc2)c(-c2ccc(F)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(-c2ccncc2)c(-c2ccc(F)cc2)s1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
5-Ethoxycarbonyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)thiophene (15.17 g (46.3 mmol), prepared as described in 1)) was dissolved in ethanol (150 ml). To the solution was added an aqueous solution of 1 N sodium hydroxide (93 ml, 93 mmol), and the resulting mixture was stirred at 100° C. for 30 minutes. At the end of this time, ethanol was removed by distillation under reduced pressure. To the reaction residue was added water, and then an aqueous solution of 1 N hydrochloric acid (93 ml). The precipitated crystals were collected by filtration, to give the title compound (12.64 g) as a pale brown powder (yield 91%).
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[C:12](Br)(Br)([Br:14])[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:13][C:12]([Br:14])=[CH:6][C:5]1[S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[CH:4]=1
Reactant: O=Cc1cc2ccccc2s1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1cc2ccccc2s1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A solution of benzo[b]thiophene-2-carbaldehyde (1.0 g, 6.17 mmol) and carbon tetrabromide (3.1 g, 9.25 mmol) in methylene chloride (50 mL) was cooled to 0° C. A solution of triphenylphosphine (4.86 g, 18.3 mmol) in methylene chloride (20 mL) was added dropwise. After ½ hour the solution was placed on a plug of silica gel and eluted with 20% ethyl acetate:hexane. Concentration of the eluent resulted in the isolation of 1.3 g (67%) of 2-(2,2-Dibromo-vinyl)-benzo[b]thiophene as a yellow oil, which was used as such in the next step.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[C:10]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:9]=1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]([NH:14][C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl-N-[5-(oxane-4-carbonylamino)-6-(2-phenylethynyl)pyridin-2-yl]-carbamate C5b (29 mg, 0.07 mmol) and DCM:TFA (9:1, 3 ml) is stirred at RT for 2 h. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.Cl.[CH3:17][N:18]([CH2:20][CH:21]1[CH2:26][CH:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23][C:22]1=[O:35])[CH3:19]>CCOCC.CCCCCC>[CH2:9]([O:8][C:4]1[CH:3]=[C:2]([C:22]2([OH:35])[CH2:23][CH2:24][CH:25]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[CH2:26][CH:21]2[CH2:20][N:18]([CH3:17])[CH3:19])[CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: Cc1ccc(CC2CCC(=O)C(CN(C)C)C2)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1ccc(CC2CCC(O)(c3cccc(OCc4ccccc4)c3)C(CN(C)C)C2)cc1
Yield: 65 %

Procedure:
1-bromo-3-benzyloxy-benzene and the base of compound (42) were reacted corresponding to the conditions described in Example 1. The product obtained was dissolved in ether/hexane and the base was extracted with 10% acetic acid. After adjusting to an alkaline pH, compound (43) was extracted with ether and dried over sodium sulphate. After removing the solvent by distillation the product was purified with 1:1 ether/diisopropyl ether via an alumina column (3.6% water). Compound (43) was obtained in a yield of 65% theoretical.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:18][CH2:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[CH:15][CH2:14]3)[C:9]2=[O:27])=[CH:5][CH:4]=1.CO>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)[C:9]2=[O:27])=[CH:28][CH:29]=1
Reactant: COc1ccc(CN2CCC(N3CC=C(c4ccc(OC)cc4)CC3)C2=O)cc1
Solvent: CO
Solvent: CCO
Product: COc1ccc(CN2CCC(N3CCC(c4ccc(OC)cc4)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-methoxybenzyl)-3-(4-(4-methoxyphenyl)-5,6-dihydropyridin-1(2H)-yl)pyrrolidin-2-one (G) (400 mg, 1.02 mmol), MeOH (4 ml) and ethanol (8 ml) was flushed with nitrogen, followed by the addition of 10% Pd/C (108 mg). Then the mixture was stirred overnight at rt and 25 psi hydrogen pressure. The catalyst was removed by filtration through Celite and the filtrate was concentrated under vacuum. Yield: 400 mg. LCMS (method F) RT 2.36 min, m/z 395.2 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]([CH3:12])[CH2:3]1.[CH:13]1([S:16](Cl)(=[O:18])=[O:17])[CH2:15][CH2:14]1>CN(C=O)C>[CH:13]1([S:16]([NH:1][CH:2]2[CH2:6][CH:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]([CH3:12])[CH2:3]2)(=[O:18])=[O:17])[CH2:15][CH2:14]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CCOC(=O)C1CC(N)CC1C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC(NS(=O)(=O)C2CC2)CC1C
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
A solution of ethyl 4-amino-2-methylcyclopentanecarboxylate (15.0 g, 88.0 mmol) in DMF (210 mL) was cooled to about 0° C. in an ice bath. TEA (30.5 mL, 219 mmol) was added and stirring was continued at about 0° C. for about 15 min and then cyclopropanesulfonyl chloride (12.3 g, 88.0 mmol, Matrix) was added drop-wise. The resulting solution was stirred at about 0° C. for about 2 h. The ice bath was removed and the reaction mixture continued stirring at ambient temperature for about 3 h. The reaction was concentrated under reduced pressure and EtOAc (200 mL) and water (100 mL) were added. The layers were separated and the organic layer was washed with saturated aqueous NaHCO3 (60 mL) and brine (60 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give a reddish brown oil. The crude material was purified by silica gel chromatography eluting with a gradient of 10-30% EtOAc in heptane to give ethyl 4-(cyclopropanesulfonamido)-2-methylcyclopentanecarboxylate (21.3 g, 88%) as a yellow oil: 1H NMR (CDCl3) δ 5.25 (d, J=9.9 Hz, 1H), 4.23-4.06 (m, 2H), 4.03-3.90 (m, 1H), 2.80 (td, J=3.1, 7.5 Hz, 1H), 2.46-2.30 (m, 2H), 2.29-2.14 (m, 2H), 1.97 (ddd, J=3.2, 4.2, 14.2 Hz, 1H), 1.42 (ddd, J=7.5, 11.5, 13.1 Hz, 1H), 1.29 (t, J=7.1 Hz, 3H), 1.20-1.14 (m, 2H), 1.02 (d, J=6.9 Hz, 3H), 1.00-0.96 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1.[CH2:16]([O:23][C:24](=[O:30])[NH:25][CH2:26][CH2:27][C:28]#[CH:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([O:23][C:24](=[O:30])[NH:25][CH2:26][CH2:27][C:28]#[C:29][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#CCCNC(=O)OCc1ccccc1
Reactant: Ic1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCC#Cc1ccc(I)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.5 %

Procedure:
To a mixture of anhydrous THF and triethylamine (24 mL, 2/1, v/v) were sequentially added 1,4-diiodobenzene (2.03 g, 6.15 mmol) and copper (I) iodide (0.094 g, 0.246 mmol). The mixture was stirred at room temperature for 15 min. The flask was then evacuated and re-filled with Argon. The procedure was repeated three more times to ensure no oxygen remained. The catalyst, dichlorobis(triphenylphosphine)palladium(II) (0.173 g, 0.246 mmol) was added into the mixture under Argon protection. The other starting material, but-3-ynylcarbamic acid benzyl ester (0.50 g, 2.46 mmol), dissolved in THF (8 mL) was added dropwise over 6 hours. The newly formed reaction mixture was further stirred at room temperature overnight. The solid in the reaction mixture was vacuum filtered. The filtrate was concentrated. The residue was re-dissolved in dichloromethane and purified by column chromatography, eluting with a mixture of ethyl acetate (0-12%) and hexanes (100-88%) to afford the product 22 (0.852 g, 86%) as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 2.61 (t, J=6.4 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 5.07 (br s, 1H), 5.12 (s, 2H), 7.10 (d, J=8.3 Hz, 2H), 7.35 (m, 5H), 7.63 (d, J=8.3 Hz, 2H). m/z (APCI) 405 [C18H16NO2+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH3:14])([CH3:13])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:12])[CH2:9]C=O)[CH3:2].C([O:17]C(C)(C)CCCC(C)CC=CC(=O)C)C>>[CH2:1]([O:3][C:4]([CH3:14])([CH3:13])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:12])[CH:9]=[O:17])[CH3:2]
Reactant: CCOC(C)(C)CCCC(C)CC=CC(C)=O
Reactant: CCOC(C)(C)CCCC(C)CC=O
Product: CCOC(C)(C)CCCC(C)C=O

Procedure:
Using 7-ethoxy-3,7-dimethyloctan-1-al as the starting material in the process of either Example 9, 10 or 11, there is prepared 10-ethoxy-6,10-dimethylundec-3-en-2-one.
Reaction SMILES: [CH2:1]([N:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O.II.[I:22](O)(=O)(=O)=O>C(O)(=O)C.O>[I:22][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][CH2:1][N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])=[CH:4][CH:5]=1
Reactant: O=C1CCCN1CCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCN1CCc1ccc(I)cc1
Temperature: 60 °C

Procedure:
To a stirring solution of HJC-1-53 (500 mg, 2.6 mmol), water (1 mL), 95% sulfuric acid (285 mg, 2.9 mmol) and acetic acid (8 mL) was added iodine (335 mg, 1.3 mmol) and periodic acid (H5IO6, 150 mg, 0.7 mmol) at rt. The reaction mixture was warmed to 60° C. for 3 h. After cooling down to rt, the solution was extracted with EtOAc (80 mL) and H2O (20 mL), and washed with 10% NaHSO3 (20 mL), followed by 10% NaHCO3 (40 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give an oil residue. This residue was purified with silica gel column (Hexane/EtOAc=1/2) to obtain HJC-1-60 (130 mg, 16%) as a pale yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.60 (d, 1H, J=7.8 Hz), 7.26-7.30 (m, 1H), 7.19-7.21 (m, 1H), 6.96 (d, 1H, J=9.0 Hz), 3.48-3.53 (m, 2H), 3.23-3.26 (m, 2H), 2.83 (t, 1H, J=7.8 Hz), 2.78 (t, 1H, J=7.8 Hz), 2.32-2.36 (m, 2H), 1.91-1.97 (m, 2H).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:29][C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([F:25])[CH:27]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1cccc(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cccc(C=C(Br)Br)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred cooled (ice/salt, 0°) solution of carbon tetrabromide (48.82 g) in anhydrous CH2Cl2 (200 ml) was added portionwise over 3 minutes, triphenylphosphine (77.1 g), maintaining the temperature below 10°. The resulting orange suspension was stirred at 0° for 1 hour before adding to it , 3-fluorobenzaldehyde (7.8 ml). After the addition was complete, the suspension was stirred at 0° for 1 hour then quenched by the addition of water (75 ml). The organic phase was separated and washed with brine (75 ml), dried (Na2SO4) and evaporated to dryness. The residual gum was poured into cyclohexane (1L) and stirred for 30 minutes. The organic phase was decanted and the residue taken up into CH2Cl2and poured into cyclohexane (1L). This procedure was repeated twice more and the combined organic phases concentrated to ˜100 ml and passed through silica gel. The filtrate was concentrated to give the title compound as a mobile yellow oil (24 g, 100%).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@H:12]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]([NH:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:14])C1C=CC=CC=1>[Pd].C(O)(=O)C.C(O)C.O>[NH2:10][CH2:11][C@@H:12]([C:13]([NH:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:14])[NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNC(=O)[C@H](CN)NC(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
50 mg of palladium on activated carbon (10%) are added to a mixture of 0.41 g (0.847 mmol) of the compound from Example 260A in 80 ml of acetic acid/ethanol/water (4:1:1), and the mixture is then hydrogenated under atmospheric pressure for 12 h. The reaction mixture is filtered through kieselguhr, and the filtrate is concentrated in vacuo and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5](=[O:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[CH3:3].[Cl-].[Cl-].[Cl-].[Al+3].Cl.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:2]([O:4][C:5](=[O:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=1)=[O:15])[CH3:3]
Reactant: CCOC(=O)CCCCCCCC(=O)O
Reactant: Clc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)CCCCCCCC(=O)c1ccc(Cl)cc1

Procedure:
Using the method described by Papa et al. [J. Amer.Chem.Soc. 69 (1947), 3018], 12.3 g of azelaic acid ethyl ester chloride in 20 ml of chlorobenzene are mixed cold with 9.5 g of aluminium trichloride and the mixture is then heated at 150° overnight. After adding dilute hydrochloric acid to the complex, the organic phase is washed and concentrated; the residue is extracted with diethyl ether. After column chromatography, and concentration of the solution, 8.3 g of 9-(4-chlorophenyl)-9-oxo-nonanoic acid ethyl ester are obtained as a viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]1([C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13]1)[CH2:7]2)([O-])=O>CCOC(C)=O.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]1([C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13]1)[CH2:7]2
Reactant: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CC1(C2)NC(=O)NC1=O
Reaction time: 1 h

Procedure:
To a suspension of (±)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione (1.77 g, 7.16 mmol) in EtOAc (100 mL) and MeOH (100 mL) was added 10% Pd/C (400 mg) and the reaction stirred vigorously under hydrogen (ca. 1 atm). After 1 h, the catalyst was filtered off and the filtrate was concentrated to yield the title compound. MS: m/z=218 (M+1).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[C:13]([CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C@@H:21]([C@H:23]([C@@H:25]([C@@H:27]([CH2:29][OH:30])[OH:28])[OH:26])[OH:24])[OH:22])([OH:15])=[O:14]>>[C:13]([CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C@@H:21]1[O:22][C@:27]([OH:28])([CH2:29][OH:30])[C@@H:25]([OH:26])[C@@H:23]1[OH:24])([OH:15])=[O:14]
Reactant: O=C(O)CCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C(O)CCCNC[C@@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O

Procedure:
The process of claim 1 in which D-glucose is aminated to N-3-carboxypropyl glucamine which in turn is oxidized to produce 6-(3-carboxypropyl)amino-6-deoxy-α-L-sorbofuranose which is reduced to produce N-(3-carboxypropyl)-1-deoxynojirimycin.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][NH:19][CH2:18]1>>[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][N:19]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH2:18]1
Reactant: CC1CNCC(C)C1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CC(C)CC(C)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3,5-dimethylpiperidine (6.8 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (0.7 mg). Calcd for C18H22N2O2: 298.1681, found 298.1692.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:32])[C:16]([N:18]2[CH2:23][CH:22]3[C@@:20]([CH2:24][OH:25])([CH2:21]3)[C@@H:19]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.FC(F)(F)C1C=C(C(NC)C)C=C(C(F)(F)F)C=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C1([C@@H]2NCC3[C@@]2(CO)C3)C=CC=CC=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(#N)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([CH:13]([N:15]([CH3:32])[C:16]([N:18]2[CH2:23][CH:22]3[C:20]([CH2:24][OH:25])([CH2:21]3)[CH:19]2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:8]=1
Reactant: C[C@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(C)C(=O)N1CC2C[C@@]2(CO)[C@@H]1c1ccccc1
Agent: CNC(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: OC[C@@]12CC1CN[C@H]2c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: CC(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(C)C(=O)N1CC2CC2(CO)C1c1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
Mixture of 4 isomers, one being (1S,2S)-1-hydroxymethyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid [(R)-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide. To a round bottom flask was added methylene chloride (8 mL), triethylamine (0.63 mL, 5.0 mmol), and [1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine (0.36 g, 1.2 mmol). The mixture was cooled to 0° C. and triphosgene (0.13 g, 0.49 mmol) in methylene chloride (3 mL) was added dropwise. The slurry was stirred for 16 hours at room temperature. To the reaction mixture was added racemic Intermediate 17 ((1S,2S)-2-phenyl-3-aza-bicyclo[3.1.0]hex-1-yl)-methanol (0.20 g, 1.1 mmol) and diisopropyl ethyl amine (0.19 mL, 1.2 mmol) in acetonitrile (8 mL). The reaction was heated to remove the methylene chloride and then refluxed for 2 hours. The solvent was removed at reduced pressure and the residue partitioned between 1N HCl and methylene chloride, the organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated to an oil. The crude product was purified on a Biotage Flash 40 system eluted with 20% ETOAc/Hexanes to give the title compound as an oil which is a 1:1 mix of racemic diastereomers (0.29 g, 57% yield).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[CH:23][CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][N:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[CH2:43][NH2:44].CS(C)=O.C(N(CC)CC)C>C(#N)C.CCCCCC.C(OCC)(=O)C>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:23]=[CH:22][C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:44][CH2:43][C:39]4[N:38]([CH3:37])[CH:42]=[CH:41][CH:40]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])=[CH:26][CH:25]=1
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Reactant: Cn1cccc1CN
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccn4C)n3Cc3ccccc32)cc1
Temperature: 80 °C
Yield: 40.3 %

Procedure:
To a suspension of 2,2,2-trichloro-1-{10-[(2′-methoxy-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 1 (1.175 g, 2.17 mmole) in acetonitrile (15 mL) was added (1-methyl-1H-pyrrol-2-yl)methylamine (0.263 g, 2.38 mmole) followed by dimethylsulfoxide (0.710 g, 9.06 mmole) and triethylamine (0.400 g, 4 mmole). The mixture was heated under nitrogen at 80° C. for 4 hours. The solvent was removed in vacuo, and the residue was flash chromatographed on silica Merck-60 using a gradient of 0-25% of ethyl acetate in dichloromethane, to provide a yellow foam that yields a solid (0.464 g) upon treatment with ethyl acetate and hexane, mp 148-150° C.