Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][S:14][C:15]1[C:20]([NH:21][C:22](=[O:25])[CH2:23]O)=[C:19]([S:26][CH3:27])[CH:18]=[C:17]([CH3:28])[N:16]=1.[N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[NH:31][C:30]=1[S:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.O>[N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[NH:31][C:30]=1[S:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][N:44]([CH2:23][C:22]([NH:21][C:20]2[C:15]([S:14][CH3:13])=[N:16][C:17]([CH3:28])=[CH:18][C:19]=2[S:26][CH3:27])=[O:25])[CH2:43][CH2:42]1
Reactant: c1ccc2[nH]c(SCCN3CCNCC3)nc2c1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Yield: 51.4 %

Procedure:
Diethyl azodicarboxylate (1.88 mL, 4.33 mmol) was added dropwise to a solution of N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-hydroxyacetamide (373 mg, 1.44 mmol), 1-[2-(benzimidazol-2-ylthio)ethyl]piperazine (1.40 g, 5.34 mmol), and triphenylphosphine (1.34 g, 5.09 mmol) in dimethylformamide (DMF) (20 mL) under stirring with water cooling over 5 minutes. The resultant mixture was stirred at room temperature for 60 minutes, and water (2 mL) was added thereto so as to deactivate the reagent. The reaction mixture was partitioned between 1N hydrochloric acid (30 mL) and ethyl acetate (30 mL). The formed organic layer was extracted with 1N hydrochloric acid (15 mL×2). The formed aqueous layers were combined, and the thus-combined aqueous layer was washed with ethyl acetate (20 mL×2). The pH of the resultant mixture was adjusted to 8 to 9 with 1N sodium hydroxide. The formed aqueous layer was extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated brine, and dried over sodium sulfate anhydrate, followed by solvent removal under reduced pressure. The residue was purified through silica gel column chromatography (developer: chloroform:methanol=100:3). The obtained oily substances were crystallyzed from ethanol and ether, to thereby yield 2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide as colorless crystals (372 mg, yield: 51%).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH:4][CH3:5].[H][H]>>[CH3:1][C:3]1[CH2:4][CH2:5][CH:2]=[CH:3][CH2:4][CH2:1][C:2]=1[CH3:5]
Reactant: C=CC=CC
Reactant: [H][H]
Product: CC1=C(C)CCC=CCC1

Procedure:
20 Ml (100 mmoles) of 50 percent piperylene in other C5 hydrocarbons, 10 ml of toluene, 0.19 g (0.5 mmole) of tris(2,4-pentanedionato-O,O')-iron (also known as iron tri(acetylacetonate), CA registry number [14024-18-1]) and 0.3 g (1.0 mmole) of N,N'-(1,2-dimethyl-1,2-ethanediylidene)bis[4-methoxy-benzenamine] (CA registry [19215-52-2]) are combined under nitrogen in a 50-ml three-necked flask equipped with reflux condenser and nitrogen inlet. The mixture is stirred magnetically and heated to 55° C. 1.5 ml of triisobutyl aluminum (1.0M in toluene--1.5 mmoles) is added. A sample is taken after 1.6 hours and analyzed by gas chromatography. Piperylene is 90 percent converted. The dimethyl cyclooctadiene yield is 71 percent based on converted piperylene. In this embodiment R is methyl, R' is hydrogen and y is 2.
Reaction SMILES: [F:1][C:2]1([F:34])[CH2:7][S:6][C:5]([NH:8]C(=O)C2C=CC=CC=2)=[N:4][C:3]21[C:25]1[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)[CH:24]=1)[O:19][CH2:18][C:17]12[CH2:33][CH2:32]1.Cl.ONC.N1C=CC=CC=1.O>C(O)C.[Cl-].[Na+].O>[F:34][C:2]1([F:1])[CH2:7][S:6][C:5]([NH2:8])=[N:4][C:3]21[C:25]1[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)[CH:24]=1)[O:19][CH2:18][C:17]12[CH2:32][CH2:33]1
Reactant: O=C(NC1=NC2(c3cc(-c4cncnc4)ccc3OCC23CC3)C(F)(F)CS1)c1ccccc1
Agent: CNO
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: NC1=NC2(c3cc(-c4cncnc4)ccc3OCC23CC3)C(F)(F)CS1
Temperature: 70 °C
Reaction time: 27 h
Yield: 60.1 %

Procedure:
To a solution of N-[5″,5″-difluoro-6′-(pyrimidin-5-yl)-5″,6″-dihydrodispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]thiazin]-2″-yl]benzamide (76 mg, 0.16 mmol) in ethanol (4 mL) were added N-hydroxymethanamine hydrochloride (133 mg, 1.59 mmol) and pyridine (126 mg, 1.59 mmol), and the mixture was stirred for 27 hours at 70° C. After cooling, H2O and brine were added and the mixture was extracted with chloroform. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexane=50:50-100:0 and then EtOH/CHCl3=5:95) and a resultant solid was washed with iPr2O to give 5″,5″-difluoro-6′-(pyrimidin-5-yl)-5″,6″-dihydrodispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]thiazin]-2″-amine (36 mg).
Reaction SMILES: CS[C:3]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5]>CO.[Ni]>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])[CH:18]=[CH:17]2
Reactant: COC(=O)C(C)(SC)c1ccc2cc(OC)ccc2c1
Agent: [Ni]
Solvent: CO
Product: COC(=O)C(C)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.7 %

Procedure:
Methyl α-methylthio-α-(6-methoxy-2-naphthyl)propionate (372 mg) was dissolved in 2 ml of methanol, and 10 ml of a methanol suspension of 5.0 cc of Raney nickel (W-II) was added, and the mixture was stirred at room temperature for 15 hours. The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. Methylene chloride was added to the residue. The insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column using benzene as an eluent to afford 212 mg of methyl α-(6-methoxy-2-naphthyl)propionate as colorless crystals in a yield of 68%. The product had a melting point (from petroleum ether) of 67° to 69° C. The IR and NMR spectra of this product coincided with those of the authentic sample.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[OH-:10].[Ba+2].[OH-]>O>[CH3:1][NH:2][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:9])=[O:10]
Reactant: CN1CCCCCC1=O
Reactant: [OH-]
Agent: [Ba+2]
Solvent: O
Product: CNCCCCCC(=O)O
Temperature: 110 °C
Yield: 102.3 %

Procedure:
N-methyl-caprolactam (15 g, 118 mmol) was combined with barium hydroxide (10.1 g, 72 mmol) and water (150 ml). The suspension was warmed to 110° C. for 18 hours then cooled over an ice bath. Gaseous carbon dioxide was bubbled through the solution for 20 minutes. The suspension was filtered through a celite pad and the filtrate was concentrated to dryness. The residue was triturated with acetonitrile, collected, rinsed with ether and dried in vacuo to yield 6-(methylamino)hexanoic acid as a white solid (10.7 g). 6-(Methylamino)hexanoic acid (5 g, 34.5 mmol), and potassium carbonate (18 g, 130 mmol) were suspended in water (50 ml) and dioxane (25 ml) then cooled to 0° C. Methyl chloroformate (13 ml, 168 mmol) was added over 1 minute, then the mixture was stirred and allowed to warm slowly to room temperature for 16 hours. Conc. HCl (20 ml) was added then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give 6-[(methoxycarbonyl)(methyl)amino]hexanoic acid as a thick clear oil (5.7 g).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:38][C:39](Cl)=[O:40]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[O:12][CH2:38][C:39]1=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(CNCc1ccccc1)C(O)c1ccc(F)c(Cl)c1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC1CN(Cc2ccccc2)C(=O)COC1c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of (1RS,2SR)-3-(benzylamino)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-(3-chloro-4-fluorophenyl)propan-1-ol (14.1 g) and triethylamine (4.95 mL) in THF (100 mL) was added chloroacetyl chloride (2.59 ml) under ice-cooling, and the mixture was stirred at 0° C. for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained mixture was diluted with THF (300 ml), 1 N aqueous sodium hydroxide solution (63 mL) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (6.72 g).
Reaction SMILES: [NH2:1][C@H:2]([CH3:22])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.FC(F)(F)C([O-])=O.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C@@H:36]2[CH2:38][O:37]2)[CH:31]=1.CCN(C(C)C)C(C)C>C(#N)C>[OH:37][C@H:36]([C:32]1[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=1)[CH2:38][NH:1][C@H:2]([CH3:22])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: C[C@@H](N)Cc1c[nH]c2c(OCC(=O)NS(C)(=O)=O)cccc12
Reactant: c1cncc([C@@H]2CO2)c1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](Cc1c[nH]c2c(OCC(=O)NS(C)(=O)=O)cccc12)NC[C@H](O)c1cccnc1

Procedure:
A mixture of (R)—N-{2-[3-(2-aminopropyl)-1H-indol-7-yloxy]-acetyl}methanesulfonamide.trifluoroacetate (40 mg, 0.091 mmol), (R)-(pyridin-3-yl)oxirane (48 mg, 0.36 mmol) and iPr2NEt (24 μL, 0.137 mmol) in acetonitrile (1 mL) is refluxed for 3 hours. After cooling, the mixture is concentrated and purified by preparative reversed phase HPLC (trifluoroacetic acid/water/acetonitrile) to give the desired N-(2-{3-[(2R)-2-((2R)-2-hydroxy-2-pyridin-3-ylethylamino)propyl]-1H-indol-7-yloxy}acetyl)methanesulfonamide.2 trifluoroacetate (3 mg, yield: 3%).
Reaction SMILES: [ClH:1].C(OC([N:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]2[N:20]([C:35]3[C:36]4[C@H:43]([CH3:44])[CH2:42][C@H:41]([F:45])[C:37]=4[N:38]=[CH:39][N:40]=3)[CH2:21][C:22]3([CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[C:15]=12)[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C>O1CCOCC1.C(Cl)Cl.CCOCC>[ClH:1].[ClH:1].[ClH:1].[F:45][C@@H:41]1[C:37]2[N:38]=[CH:39][N:40]=[C:35]([N:20]3[C:16]4[C:15](=[C:14]([CH2:13][NH:9][CH:10]([CH3:12])[CH3:11])[CH:19]=[CH:18][CH:17]=4)[C:22]4([CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)[CH2:21]3)[C:36]=2[C@H:43]([CH3:44])[CH2:42]1
Reactant: CC(C)N(Cc1cccc2c1C1(CCN(C(=O)OC(C)(C)C)CC1)CN2c1ncnc2c1[C@H](C)C[C@@H]2F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)NCc1cccc2c1C1(CCNCC1)CN2c1ncnc2c1[C@H](C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
4N HCl in dioxane (0.1 mL) was added to a solution of tert-butyl 4-((tert-butoxycarbonyl(isopropyl)amino)methyl)-1-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (12 mg, 0.020 mmol) in DCM (0.3 mL). The reaction mixture was stirred at room temperature overnight. The solvents were evaporated. The crude residue was taken up in MeOH and basified with 7N ammonia in MeOH. After evaporation of the solvent, the residue was purified by column chromatography (4% 7 N ammonia in MeOH/DCM) to yield the free base, which was taken up in DCM and acidified with 2N HCl in Et2O. Removal of the solvents afforded N-((1-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine trihydrochloride (9 mg, 88%) as a solid. LCMS (APCI+) m/z 410 [M+H]+; Rt=1.55 min.
Reaction SMILES: [C:1]1([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19]C(=O)OCC3C=CC=CC=3)[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.CO.C(Cl)(Cl)Cl>C(O)C.C(Cl)(Cl)Cl.[C].[Pd]>[C:1]1([C@H:13]2[CH2:14][CH2:15][C@H:16]([NH2:19])[CH2:17][CH2:18]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2
Reactant: O=C(N[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5% Palladium-carbon (5.00 mg) was added to benzyl [trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]carbamate (7.00 mg, 0.0180 mmol) in a mixture of ethanol (1 mL) and chloroform (1 mL) under an argon atmosphere, and after the reaction system was flushed with hydrogen, the reaction mixture was stirred at room temperature for one day and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (NH-PLC05 plate manufactured by Fuji Silysia Chemical Ltd.: methanol/chloroform=1/19 (v/v)) to give the title compound as a colorless solid (0.35 mg, yield 8.0%).
Reaction SMILES: [N+:1]([C:4](=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)C(=O)CCC)([O-:3])=[O:2].[H-].[Na+].[C:18](Cl)(=[O:20])[CH3:19]>C(COC)OC.C(Cl)(Cl)Cl>[C:18]([N:15]1[CH2:14][CH2:13][CH2:12][S:11][C:10]1=[CH:4][N+:1]([O-:3])=[O:2])(=[O:20])[CH3:19]
Reactant: CCCC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCSC1=C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 23 g of 1-nitro-1-(tetrahydro-2H-1,3-thiazin-2-yl-idene)-2-pentanone in 200 ml of monoglyme was added dropwise at 0° C. to a suspension of 4.65 g of a 57% sodium hydride/mineral oil dispersion in 100 ml of monoglyme. The stirred mixture was allowed to warm to room temperature and stirred overnight. A solution of 8.2 g of acetyl chloride in 50 ml of monoglyme was added dropwise to the reaction at 0° C. The resulting mixture was stirred for one hour at 0° C., then allowed to warm to room temperature and stirred for 30 minutes. The mixture was diluted with chloroform and extracted with 10% sodium hydroxide solution. The organic phase was separated, washed with water, then with saturated sodium chloride solution, and dried Na2SO4), and the solvent was evaporated under reduced pressure. The resulting liquid was chromatographed, using a wet column with silica gel. As eluent, there was first used 2 litres of a 98/2 chloroform/acetone mixture, then a 95/5 chloroform/acetone mixture was used. Three fractions were obtained. The last fraction was triturated with ether, then cooled, to give a solid yellow product, 3-acetyl-2-nitromethylene-tetrahydro-2-H-1,3-thiazine, m.p. 91°-92.5° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.O>C1COCC1>[C:1]([C:3]1([CH3:16])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (0.500 g, 2.38 mmol) in 15 mL of THF at −78° C. was added lithium bis(trimethylsilyl)amide (1 M solution in diethyl ether, 5.23 mL, 5.23 mmol). After 20 min, iodomethane (0.338 g, 2.38 mmol) was added dropwise, and the reaction was slowly warmed to rt. After 15 h, the mixture was cooled to 0° C., treated with water, and extracted 3× with ethyl acetate. The solution was extracted 3× with ethyl acetate, and the combined organic solution was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide tert-butyl 4-cyano-4-methylpiperidine-1-carboxylate that gave a proton NMR spectra consistent with theory.
Reaction SMILES: OO.[CH3:3][O:4][CH:5]1[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[N:14]=[N+:15]([O-:26])[C:16]3[CH:25]=[C:24]4[C:20]([CH2:21][CH2:22][CH2:23]4)=[CH:19][C:17]=3[N:18]=2)[CH2:6]1.C(O)(C(F)(F)F)=[O:28]>C(Cl)Cl.N>[CH3:3][O:4][CH:5]1[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[N:14]=[N+:15]([O-:26])[C:16]3[CH:25]=[C:24]4[C:20]([CH2:21][CH2:22][CH2:23]4)=[CH:19][C:17]=3[N+:18]=2[O-:28])[CH2:6]1
Reactant: O=C(O)C(F)(F)F
Reactant: COC1CN(CCCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Agent: N
Agent: OO
Solvent: ClCCl
Product: COC1CN(CCCNc2n[n+]([O-])c3cc4c(cc3[n+]2[O-])CCC4)C1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
H2O2 (70%, 2.0 mL, ca. 40 mmol) was added dropwise to a stirred solution of TFM (5.6 mL, 40 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 54 (1.3 g, 4.0 mmol) and TFA (1.5 mL, 20 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 20° C. for 26 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4×125 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1,4-dioxide 55 (400 mg, 30%) as a red solid: mp 150-152° C.; 1H NMR δ 8.12 (s, 1H, H-9), 8.10 (s, 1H, H-5), 8.06 (br s, 1H, NH), 4.18 (p, J=5.9 Hz, 1H, CHO), 3.91 (br s, 2H, CH2N), 3.64 (t, J=6.4 Hz, 2H, CH2N), 3.28 (s, 3H, OCH3), 2.98-3.13 (m, 6H, H-6, H-8, CH2N), 2.80 (t, J=6.3 Hz, 2H, CH2N), 2.20 (p, J=7.5 Hz, 2H, H-7), 1.82 (p, J=6.4 Hz, 2H, CH2); 13C NMR δ 155.7, 149.4, 145.7, 138.0, 129.7, 115.8, 111.6, 69.3, 61.4 (2), 57.3, 56.2, 40.4, 33.4, 32.4, 26.0, 25.6; MS (APCI) m/z 346 (MH+, 100%); HRMS (FAB+) calcd for C17H24N5O3 (MH+) m/z 346.1879, found 346.1878.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C@@H:10]([NH2:21])[CH2:11][O:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14].[OH-].[Na+].CCOCC>O1CCCC1>[NH2:21][C@@H:10]([CH2:11][O:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[CH2:9][OH:8]
Reactant: COC(=O)[C@@H](N)COC(C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(OC[C@H](N)CO)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of lithium aluminum hydride (212 mg) in tetrahydrofuran (5 ml) was added a solution of (S)-2-amino-3-(1-phenyl-ethoxy)-propionic acid methyl ester (280 mg) in tetrahydrofuran (5 ml) and the mixture was stirred for 2 hours at room temperature. Sodium hydroxide solution (4N) was added until gas evolution ceased, ether was added and the suspension was filtered through Celite. The solvent was evaporated and the residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: dichloromethane/MeOH=90:10) to yield a light yellow liquid, (130 mg, 24%); MS (ISP): 196.1 ((M+H)+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.Cl.[CH2:15]([O:22][CH2:23][C:24]([C:27]1[S:31][C:30]([NH:32][C:33](=[O:39])[CH:34]([NH2:38])[CH2:35][CH2:36][CH3:37])=[N:29][N:28]=1)([CH3:26])[CH3:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C.C(N(CC)CC)C>[CH2:15]([O:22][CH2:23][C:24]([C:27]1[S:31][C:30]([NH:32][C:33](=[O:39])[CH:34]([NH:38][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:35][CH2:36][CH3:37])=[N:29][N:28]=1)([CH3:25])[CH3:26])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Reactant: CCCC(N)C(=O)Nc1nnc(C(C)(C)COCc2ccccc2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1nnc(C(C)(C)COCc2ccccc2)s1
Reaction time: 0.25 h
Yield: 38.2 %

Procedure:
A mixture of 6,8-difluoro-3,4-dihydro-1H-naphthalen-2-one (521 mg, 2.86 mmol), 2-amino-pentanoic acid [5-(2-benzyloxy-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide HCl (1140 mg, 2.86 mmol) in methylene chloride (25 mL) was treated with triethyl amine (0.4 mL), then acetic acid (0.7 mL) and sodium sulfate. After stirring for 15 min, 95% pure sodium triacetoxy borohydride (767 mg, 3.4 mmol) was added and the resulting mixture was stirred at rt overnight. The mixture was quenched with dilute water, acidified to pH 3, extracted twice with methylene chloride. The orgainic layer was washed with dilute sodium hydroxide to pH 7, separated, dried and concentrated to give a dark brown oil. The oil was purified by silica gel column chromatography using 1% methanol in methylene chloride as eluent to give 2-(6,8-difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid [5-(2-benzyloxy-1,1-dimethyl-ethyl)-[1,3,4]thiadiazol-2-yl]-amide (578 mg) as a brown oil, LC-MS, RT=2.6 min, M+1=529.1. The corresponding HCl salt was prepared as a light pink solid after triturating with hexane.
Reaction SMILES: [Cl:1][CH:2]([CH2:8][Cl:9])[C:3]([N:5]=[C:6]=[O:7])=[O:4].[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[Cl:18])[NH2:14]>C1C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:6]([NH:5][C:3](=[O:4])[CH:2]([Cl:1])[CH2:8][Cl:9])=[O:7])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C=NC(=O)C(Cl)CCl
Solvent: c1ccccc1
Product: O=C(NC(=O)C(Cl)CCl)Nc1ccc(Cl)c(Cl)c1
Temperature: 20 °C
Yield: 75.8 %

Procedure:
A solution of 17.0 g (0.1 mole) of 2,3-dichloropropionyl isocyanate in 50 ml of wash benzine was added dropwise to a solution of 16.0 g (0.1 mole) of 3,4-dichloroaniline in 150 ml of dry benzene at 0° to 5° C, while cooling. In the course thereof, the reaction product crystallized out. The mixture was stirred for a further hour at 20° C and was filtered, and the product was washed with petroleum ether and dried. 25 g of N-(3,4-dichlorophenyl)-N'-(2,3-dichloropropionyl)-urea of melting point 145° to 148° C, with decomposition, were obtained. The yield was 76% of theory.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:9](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C(N(CC)CC)C.BrCC(=O)C(C)(C)C>C1COCC1>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[C@H:6]([CH2:7][CH3:8])[CH3:9]
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CC(C)(C)C(=O)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 127.1 %

Procedure:
Using the procedure described in Example 5, treatment of a solution of L-proline-L-isoleucine benzylamide (69 mg, 0.21 mmol), with triethylamine (151 uL, 1.08 mmol, 5.0 eq), and 1-bromopinacolone (58 uL, 0.43 mmol, 2 eq) in THF (5 mL), provided 35 mg (39%) of L-isoleucine, N-[1-(2-tert-butyl-2-oxoethyl)-L-proline] benzylamide as a colorless oil.