Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][S:5][C:6]1[S:7][C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:10]=1.C(O)(=O)C.S(=O)(=O)(O)O.O>C(OCC)(=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:6]([S:5][CH2:4][CH:3]=[O:2])[S:7][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2nc(SCC(OC)OC)sc2-c2ccc(OC)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2nc(SCC=O)sc2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7.0 g of 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]-acetaldehyde-dimethylacetal are mixed with 50 ml of acetic acid, 25 ml of sulphuric acid and 25 ml of water, stirred vigorously for 30 minutes, and then stirred into 1000 ml of ice-water. The oil which separates is taken up in 200 ml of ethyl acetate. Shaking is carried out with a further 200 ml of ethyl acetate and the combined organic phases are washed with water and then twice with cold sodium bicarbonate solution, dried over magnesium sulphate and concentrated to dryness by evaporation. The crude product is crystallised with diethyl ether. 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]-acetaldehyde having a melting point of 75°-76° is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][C:20]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:21]=1[C:22](O)=[O:23]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:22](=[O:23])[C:21]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:20]=3[CH3:19])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: Cc1ccc(C)c(C(=O)O)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(C)ccc3C)CC2)ccc1Cl
Yield: 10 %

Procedure:
The title compound (4 mg, 10%) was prepared analogously to example 8 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 2,5-dimethylbenzoic acid. MS: 401.4 (MH+).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C@H:14]([OH:17])[CH2:15][OH:16])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:20](OC)([CH3:22])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:21][C:20]1([CH3:22])[O:17][C@@H:14]([CH2:13][CH2:12][C:10]2[NH:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[CH2:15][O:16]1
Reactant: COC(C)(C)OC
Reactant: OC[C@@H](O)CCc1cc(-c2ccccc2)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)OC[C@H](CCc2cc(-c3ccccc3)n[nH]2)O1
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To a solution of (S)-4-(3-phenyl-1H-pyrazol-5-yl)butane-1,2-diol (2.5 g, 10.76 mmol) in acetone (50 mL) were added 2,2-dimethoxypropane (11.21 g, 108 mmol) and p-toluenesulfonic acid (0.185 g, 1.076 mmol) at room temperature. After stirring for 3 h, the reaction was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic extract was dried over MgSO4 and concentrated under reduced pressure to give the title compound (2.70 g) without further purification. LCMS m/z=273.0 [M+H]+.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].Cl>O1CCCC1.C1C=CC=CC=1>[CH:1]1([CH:6]2[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[CH:7]2[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1c2c(cc(O)c(Cl)c2Cl)CC1C1CCCC1
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: Oc1cc2c(c(Cl)c1Cl)C(O)C(C1CCCC1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-cyclopentyl-5-hydroxy-6,7-dichloro-1-indanone (8.55 g., 0.03 mole) in tetrahydrofuran (100 ml.) under nitrogen is added dropwise 70% sodium bis-(2-methoxyethoxy)-aluminum hydride in benzene (10 ml.) in tetrahydrofuran (30 ml.) over a ten minute period at 10°-15° C. The reaction mixture is stirred at 25° C. for 3 hours, cooled to 10° C., very slowly treated with 10% hydrochloric acid until frothing ceases, then with 20% hydrochloric acid until acidic. The tetrahydrofuran is decanted from a pasty residue, evaporated to dryness and the residue triturated with benzene to give 7.2 g. of 2-cyclopentyl-6,7-dichloroindan-1,5-diol which melts at 158°-160° C. after crystallization from benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.[C:26]1([CH3:35])[C:27]([N:32]=[C:33]=[O:34])=[CH:28][CH:29]=[CH:30][CH:31]=1>O1CCCC1>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:33]([NH:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[CH3:35])=[O:34])=[CH:18][CH:17]=3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1
Reactant: Cc1ccccc1N=C=O
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3cc(Cl)ccc32)cc1

Procedure:
As described for Example 122, a mixture of 0.348 g of 2-chloro-5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine and 0.175 g of o-tolylisocyanate in 15 ml of tetrahydrofuran is refluxed overnight and worked-up to give the product as a solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:21]3[C@H:30]4[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]4)[CH2:24][CH2:23][CH2:22]3)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:21]1([C:19]([C:17]2[CH:18]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[S:15][CH:16]=2)=[O:20])[C@H:30]2[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@H]43)cs2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@H]21
Yield: 69.5 %

Procedure:
trans-4-[4-(Octahydro-quinoline-1-carbonyl)-thiophen-2-yl]-piperidine-1-carboxylic acid t-butyl ester (0.09 g, 0.32 mmol) was dissolved in DCM (2 mL) and TFA (1 mL) and the reaction stirred at room temperature for 6 hours. The solvent was evaporated and the residue product was purified by flash chromatography on an SCX-2 cartridge, washing with acetonitrile and then eluting with 2 M ammonia in methanol. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.074 g). LCMS m/z 333.20 [M+H]+ RT=6.23 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.2 (s, 1H), 6.9 (s, 1H), 3.7 (m, 1H), 3.5 (m, 1H), 3.4 (m, 1H), 3.2 (m, 2H), 2.9 (m, 1H), 2.7 (m, 2H), 2.2 (m, 1H), 2.0-1.9 (m, 4H) 1.8-1.0 (m, 13H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([CH3:22])[CH:3]=1.[CH3:23][C:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[C:26]([CH3:33])[N:25]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[C:4]([CH3:22])[CH:3]=2)[CH:27]=[C:26]([CH3:33])[N:25]=1
Reactant: Cc1cc(B(O)O)cc(C)n1
Reactant: Cc1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)cc(C)n1
Temperature: 75 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A 25 mL round-bottom flask maintained with an inert atmosphere of nitrogen was charged with tert-butyl 4[(4-bromo-2-methylphenyl)methyl]piperazine-1-carboxylate (368 mg, 1.00 mmol, 1.00 equiv), (2,6-dimethylpyridin-4-yl)boronic acid (300 mg, 1.99 mmol, 1.99 equiv), Pd(PPh3)4 (116 mg, 0.100 mmol, 0.10 equiv), potassium carbonate (414 mg, 3.00 mmol, 3.01 equiv), dioxane (6 mL) and water (1 mL). The resulting solution was stirred overnight at 75° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (3×10 mL) and the organic layers were combined, washed with brine (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1) to yield 350 mg (89% yield) of tert-butyl 4-[[4-(2,6-dimethylpyridin-4-yl)-2-methylphenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 396 [M+H]+.
Reaction SMILES: [CH:1]([O:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:3])[CH3:2].NN.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C>O1CCCC1.ClCCl>[CH:1]([O:4][NH:5][S:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)(=[O:28])=[O:27])([CH3:3])[CH3:2]
Reactant: CC(C)ON1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NOC(C)C)cc1
Reaction time: 1.5 h
Yield: 68.9 %

Procedure:
A vigorously stirred solution of 2-isopropoxy-1H-isoindole-1,3(2H)-dione [2.50 g, 12.2 mmol, Synth. Comm., 22(10), 1427-1432 (1992)] in 35 mL of tetrahydrofuran under an Argon atmosphere at ambient temperature was treated with anhydrous hydrazine (0.421 mL, 13.41 mmol). After 1.5 hours, 4-methoxybenzenesulphonyl chloride (3.024 g, 14.63 mmol), dichloromethane (20 mL) and N,N-diisopropylethylamine (6.38 mL, 36.6 mmol) was added with continued stirring. After an additional 2 hours at ambient temperature, the reaction mixture was evaporated in vacuo to a residue and partitioned between ethyl acetate and 1N hydrochloric acid. The layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with 5% w/v potassium carbonate and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue. The crude material was purified on Flash grade silica gel eluting with 30% ethyl acetate in hexane. Fractions containing the product were combined, evaporated in vacuo, and dried under high vacuum to provide N1-(isopropoxy)-4-methoxy-1-benzenesulfonamide (2.061 g, 69%) as a white solid. H1-NMR (chloroform-D3): 1.22 (d, 6H), 3.92 (s, 3H), 4.27 (m, 1H), 6.70 (s, 1H), 7.05 (d, 2H), 7.90 (d, 2H). MS(ESI): 268 (M+Na).
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]([S@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>ClCCl.[O-]S([O-])(=O)=O.[Cu+2]>[CH:1]1(/[CH:7]=[N:15]/[S@@:13]([C:10]([CH3:12])([CH3:11])[CH3:9])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCCC1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/C1CCCCC1
Temperature: 37 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Cyclohexanecarbaldehyde, 26-a, (13.58 g, 0.121 mol) in dichloromethane (250 mL) were added (R)-2-methylpropane-2-sulfinamide (17.6 g, 0.145 mol), PPTS (3.03 g, 0.0121 mmol) and anhydrous CuSO4 (58 g, 0.363 mol). The resulting mixture was stirred at 37° C. overnight. The mixture was then filtrated and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to provide the product, 26-b, (23 g, 88%).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:26])([CH3:25])[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[CH:22]=4)[N:17]3[CH3:29])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=O.[Cl-].[C:31]([CH2:33][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:32]>>[C:31]([CH:33]=[CH:1][C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:25])([CH3:26])[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[CH:22]=4)[N:17]3[CH3:29])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:32]
Reactant: COc1ccc2c(c1)C(C)(C)C1(C=Nc3c(c(C=O)cc4ccccc34)O1)N2C
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: COc1ccc2c(c1)C(C)(C)C1(C=Nc3c(c(C=CC#N)cc4ccccc34)O1)N2C

Procedure:
This compound is prepared according to the method employed for Example 4, from 0.39 g (1 mmol) of the compound of Example 2 and 0.34 g (1 mmol) of cyanomethyltriphenylphosphonium chloride.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:15])[N:4]2[C:8](=[C:9]([C:11](=[O:14])[CH2:12][CH3:13])[CH:10]=1)[CH2:7][CH2:6][CH2:5]2.CCN(CC)CC.C1(N[S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])C=CC=CC=1>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[S:30]([O:1][C:2]1[C:3](=[O:15])[N:4]2[C:8](=[C:9]([C:11](=[O:14])[CH2:12][CH3:13])[CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:32])=[O:31]
Reactant: CCC(=O)c1cc(O)c(=O)n2c1CCC2
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c(=O)n2c1CCC2
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a stirred, cooled (0° C.) solution of 6-hydroxy-8-propionyl-2,3-dihydroindolizin-5-(1H)-one (1.10 g, 4.53 mmol) in CH2Cl2 (10 mL) was added Et3N. After stirring for 20 min., N-phenyltrifluoromethane sulfonamide was added in one portion. The mixture was stirred at RT for 6 h and quenched with H2O. the mixture was extracted with CH2Cl2 (3×) and the combined organic layers were dried over MgSO4, concentrated and purified by ISCO (40% EtOAc/Hexanes) to give the title compound as a white solid (1.50 g, 99%).
Reaction SMILES: [CH:1]1([N:4]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[C:45]=2[Cl:51])[C:5]([C:7]2[C@@H:8]([CH2:38][O:39][CH2:40][O:41][CH3:42])[N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[CH:15][CH:14]=2)=[O:6])[CH2:3][CH2:2]1>FC(F)(F)C(O)=O.ClCCl>[CH:1]1([N:4]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[C:45]=2[Cl:51])[C:5]([C:7]2[C@@H:8]([CH2:38][O:39][CH2:40][O:41][CH3:42])[NH:9][CH2:10][CH2:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[CH:15][CH:14]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCOC[C@@H]1C(C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)=C(c2ccc(OCCOc3c(Cl)cccc3Cl)cc2)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCOC[C@H]1NCCC(c2ccc(OCCOc3c(Cl)cccc3Cl)cc2)=C1C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
9A (50 mg, 64 μmol) was dissolved in 10% trifluoroacetic acid in dichloromethane. The mixture was stirred at room temperature for 2 hours. Solvent was removed under vacuum. The residue was purified by preparatory LCMS (water:acetonitrile, 40-65%) to give Compound 5 (15 mg, 33%). ESI-MS:m/z 679.3 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH2:6])=[O:5].OC1C=CC=CN=1.[C:16]([O:20][C:21](=[O:50])[NH:22][C@H:23]([C@@H:41]1[CH2:45][C@@H:44]([CH:46]([CH3:48])[CH3:47])[C:43](=[O:49])[O:42]1)[CH2:24][N:25]1[CH2:30][C:29](=[O:31])[N:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:38])[CH2:27][C:26]1([CH3:40])[CH3:39])([CH3:19])([CH3:18])[CH3:17]>C(N(CC)CC)C>[C:16]([O:20][C:21](=[O:50])[NH:22][C@@H:23]([CH2:24][N:25]1[CH2:30][C:29](=[O:31])[N:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:38])[CH2:27][C:26]1([CH3:39])[CH3:40])[C@@H:41]([OH:42])[CH2:45][C@H:44]([C:43](=[O:49])[NH:1][CH2:2][C:3]([C:4](=[O:5])[NH2:6])([CH3:8])[CH3:7])[CH:46]([CH3:48])[CH3:47])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(CN)C(N)=O
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Agent: Oc1ccccn1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2ccccc2Cl)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NCC(C)(C)C(N)=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 66.9 %

Procedure:
140 mg of 3-amino-2,2-di(methyl)propionamide obtained in Reference Example 2 (1.21 mmol) and 38 mg of 2-hydroxypyridine (0.40 mmol) were added to a solution of 205 mg of {(S)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (1m) (0.40 mmol) in triethylamine (4 ml), and the mixture was stirred at 80° C. for four hours. The reaction mixture was cooled and then concentrated under reduced pressure and further stirred at 80° C. for 14 hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride/methanol=40/3) to obtain 167 mg of the title compound (yield: 66%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([C:12](=[O:14])[CH3:13])[CH:5]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=[O:29].Cl.[BH4-].[Na+]>C1COCC1.CC(=O)OCC>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH:12]([OH:14])[CH2:13][CH:28]([OH:29])[C:27]2[CH:26]=[C:25]([CH3:24])[CH:32]=[CH:31][CH:30]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(OC)c(C(C)=O)c1
Reactant: Cc1cccc(C=O)c1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC)c(C(O)CC(O)c2cccc(C)c2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
3-Acetyl-4-methoxy-benzoic acid methyl ester (150 mg, 0.720 mmol) was dissolved in THF (3 ml), cooled to −78° C., and a freshly prepared solution of lithium diisopropylamide (obtained by addition of n-butyllithium in n-hexane (0.317 ml, 2.5 M solution) to diisopropylamine (80.1 mg, 0.792 mmol) in THF (3 ml) at 0° C. and stirring for 10 min) was slowly added with stirring. After 10 min, 3-methylbenzaldehyde (86.5 mg, 0.720 mmol) was added at −78° C. After 30 min at −78° C., 2 N hydrochloric acid and EA were added, the cooling bath was removed, the mixture was brought to room temperature. The phases were separated, the aqueous phase was extracted three times with EA, the combined organic extracts were dried over sodium chloride, decanted and evaporated to dryness. The residue was dissolved in methanol (5 ml), sodium borohydride (28.7 mg, 0.761 mmol) was added, and the mixture was stirred at room temperature for 30 min. The mixture was evaporated to dryness and the residue was purified by silica gel chromatography (HEP/EA gradient) to give 140 mg of the title compound as a mixture of diastereomers.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[N:40]([CH2:43][CH2:44]O)=[N+]=[N-].C(N(CC)CC)C.C(S)(S)CC>C1COCC1.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:44][CH2:43][NH2:40])=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: [N-]=[N+]=NCCO
Agent: CCC(S)S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NCCOc1ccc(I)cc1
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a magnetically stirred solution of 4-iodophenol (15 grams, 0.068 mol) in 100 mL THF was sequentially added triphenylphosphine (19.67 grams, 0.075 mol), diethyl azodicarboxylate (13.06 grams, 0.073 mol), and 2azidoethanol (5.93 grams, 0.068 mol). The mixture was stirred overnight, concentrated in vacuo, diluted with 90 mL ethyl acetate and diluted with hexane (400 mL), and the resulting solids filtered away. The filtrate was concentrated in vacuo, diluted with diethyl ether, and extracted with 1N NaOH and water. Pentane was added to induce precipatation of a white solid that was again filtered away. The fitrate was concentrated in vacuo, and dissolved in methanol (60 mL). Triethylamine (27 grams, 0.267 mol) and propanedithiol (23 grams, 0.215 mol) were added and the mixture stirred at room temperature overnight. The solution was diluted with 100 mL water and partitioned between methylene chloride and 1N NaOH. The organic layer was extracted with 2×200 mL 1N HCl and the aqueous layer washed with 100 mL methylene chloride, made basic with 2N NaOH and extracted 3×75 mL methylene chloride. The combined organics were dried over sodium carbonate, filtered and concentrated in vacuo to yield 12.97 grams of 2-(4-iodophenoxy)ethyl amine (72%). 1H NMR (CDCl3, dTMS) 7.56 (2H, d, 3JHH =9 Hz, Ar--H), 6.63 (2H, d, 3JHH =9 Hz, Ar--H), 4.03 (2H, t, 3JHH =5 Hz, CH2N3), 3.57 (2H, t, 3JHH =5 Hz, OCH2). 13C NMR (CDCl3) 158.0, 138.2, 116.9, 83.4, 66.9, 49.9. IR (NaCl, cm-1) 2930, 2107 (s), 1589, 1483, 1284, 1237, 1058, 819.
Reaction SMILES: CO[C:3](=O)[CH:4]([N+:15]([O-:17])=[O:16])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:6].[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=C.Cl>C(O)(C)(C)C.C(OCC)C>[CH3:24][O:23][C:19](=[O:22])[CH2:6][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH:4]([N+:15]([O-:17])=[O:16])[CH2:3][CH2:20][C:19]([O:23][CH3:24])=[O:22]
Reactant: C=CC(=O)OC
Reactant: COC(=O)C(C(C)c1ccc(Cl)c(Cl)c1)[N+](=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C(CC(=O)OC)c1ccc(Cl)c(Cl)c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 350 g of nitro-3-(3,4-dichlorophenyl)butanoic acid methyl ester, 118 g of methyl acrylate and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-(3,4-dichlorophenyl)heptanedioic acid dimethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH:10]=O)[CH:8]=1)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[NH:19][CH2:18][CH2:17]2>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]([CH2:10][CH2:9][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]1)[CH2:18][CH2:17]2
Reactant: COc1cc2c(cc1OC)NCC2
Reactant: O=CCn1cc([N+](=O)[O-])cn1
Solvent: ClCCl
Product: COc1cc2c(cc1OC)N(CCn1cc([N+](=O)[O-])cn1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-nitro-1H-pyrazol-1-yl)acetaldehyde (942 mg, 6.08 mmol) in DCM (60.0 mL), 5,6-dimethoxyindoline (from step 1) (1.09 g, 6.08 mmol) and STAB (1.55 g, 7.29 mmol) was added. After stirring at rt for 1 h, the reaction mixture was quenched with water and extracted with DCM (2×). The combined org. layers were concentrated and purification was performed by FC (EtOAc/hex 1:4 to 1:1) to yield 5,6-dimethoxy-1-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)indoline as a brown solid. LC-MS conditions B: tR=0.65 min, [M+H]+=319.19.