Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.Cl.[CH3:18][O:19][NH:20][CH3:21].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH:14]([NH:13][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=[C:2]([N:20]([O:19][CH3:18])[CH3:21])[CH:12]=1)([CH3:16])[CH3:15]
Reactant: CNOC
Reactant: CCOC(=O)c1cnc(Cl)cc1NC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N(C)OC)cc1NC(C)C
Temperature: 180 °C
Yield: 96.5 %

Procedure:
A mixture of ethyl 6-chloro-4-(isopropylamino)nicotinate (3.0 g, 12.4 mmol), O,N-dimethylhydroxylamine hydrochloride (35.0 g, 0.35 mol) in dioxane (10 mL) was heated at 180° C. for 6 h. After cooling to RT, the reaction mixture was neutralized with saturated Na2CO3 solution to pH 7-8. The aqueous mixture was concentrated under reduced pressure and was extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated to give ethyl 4-(isopropylamino)-6-(methoxy(methyl)amino)nicotinate (3.2 g, 97% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.48 (s, 1 H), 7.82 (d, J=7.2 Hz, 1 H), 6.10 (s, 1 H), 4.22 (q, J=7.2 Hz, 2 H), 3.77 (m, 4H), 3.18 (s, 3 H), 1.27 (t, J=7.2 Hz, 3 H), 1.20 (d, J=6.4 Hz, 6 H).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([O:16][CH3:17])=[C:10]([CH3:18])[C:9]=1[CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:20][CH2:21][CH2:22]O.C(N(CC)CC)C.[I-:37].[Na+]>ClCCl.O>[I:37][CH2:22][CH2:21][CH2:20][CH:19]([C:9]1[C:10]([CH3:18])=[C:11]([O:16][CH3:17])[C:12]([CH3:15])=[C:13]([CH3:14])[C:8]=1[O:7][CH3:6])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1c(C)c(C)c(OC)c(C(CCCO)c2ccccc2)c1C
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1c(C)c(C)c(OC)c(C(CCCI)c2ccccc2)c1C
Reaction time: 0.33 h
Yield: 309.5 %

Procedure:
A solution of 1.37 g (10×1.2 mmole) of methanesulfonyl chloride in dichloromethane (10 ml) was added dropwise to 3.28 g (10.0 mmole) of 4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-4-phenylbutan -1-ol and 2.10 ml (10×1.5 mmole) of triethylamine dissolved in dichloromethane (30 ml) at -5° C. over the period of 30 minutes, and the reaction was continued for 20 minutes under stirring, with ice cooling. The reaction was stopped by adding cold water to the reaction solution, and the dichloromethane layer was separated out, washed with cold dilute hydrochloric acid and aqueous sodium chloride solution successively, dried (magnesium sulfate) and evaporated. The residue was dissolved in acetone (50 ml), and 4.5 g (10×3 mmole) of sodium iodide was added to the solution, followed by stirring at 50° C. for 2 hours. The acetone was distilled off, and isopropyl ether and water were added to the residue to extract the product. The isopropyl ether layer was separated out, washed with aqueous sodium chloride solution, and evaporated, and the residual solution was chromatographed on a silica gel column to perform purification (elution with hexane/isopropyl ether) to thereby give 4.07 g (93%) of 1-iodo-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-4-phenylbutane. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 14.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.C([OH:22])(C)(C)C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)C.[Zn]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:22])[NH:13]2
Reactant: CC(C)(C)O
Reactant: Fc1cccc(-c2cccc3[nH]ccc23)c1F
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Yield: 97 %

Procedure:
4-(2,3-difluoro-phenyl)-1H-indole 6c (744 mg, 3.25 mmol) was dissolved in 12 ml of ethanol under stirring, and added successively with tert-butanol (21 ml), glacial acetic acid (6.4 ml) and pyridinium tribromide (3.12 g, 9.7 mmol) at room temperature. Upon completion of the addition, the reaction mixture was stirred for 3 hours, added with glacial acetic acid (16 ml) and zinc dust (1.1 g, 16.25 mmol), and stirred for another 1 hour. The reaction mixture was filtered and concentrated under reduced pressure. The residue was added with ethyl acetate (30 ml), washed successively with water (10 ml), saturated sodium bicarbonate solution (10 ml) and saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 6d (780 mg, yield 97%) as a white solid.
Reaction SMILES: [C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]\[C:31]([OH:33])=[O:32]>>[C:31](/[CH:30]=[CH:29]\[C:28]([O-:35])=[O:34])([OH:33])=[O:32].[C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][NH+:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)/C=C\C(=O)O
Reactant: CN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: C[NH+]1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: O=C([O-])/C=C\C(=O)O
Yield: 77.2 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and maleic acid (0.31 g, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium (Z)-3-carboxyacrylate as a crystalline white solid (1.01 g, 77% yield).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]([C@H:17]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][N:18]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=O.[CH3:34][O:35][C:36]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:37]=1[CH2:38][NH2:39]>CO.C(Cl)Cl>[CH3:34][O:35][C:36]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:37]=1[CH2:38][NH:39][CH2:15][C@H:17]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][N:18]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CNC[C@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)c(OC)c1
Temperature: 25 °C
Yield: 63 %

Procedure:
Sodium triacetoxyborohydride (3.1 g, 15 mm) was added to a mixture of (3R)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.3 g, 5.0 mmol theory), 2,4-dimethoxybenzylamine (0.77 ml, 5.5 mmol), and dry 4 A sieves in 1,2-dichloroethane (25 ml) stirring at ambient temperature. After stirring at ambient temperature overnight the reaction solution was transferred to a separatory funnel with EtOAc and saturated NaHCO3. Extraction with EtOAc (2×), washing the combined organic layers with brine and drying over MgSO4 afforded 1.6 g of crude product. Flash chromatography (SiO2, 1 to 10% 2N N3 in MeOH/CH2Cl2) gave pure product (1.3 g, 63% yield over the previous 3 steps). MS (ESI) 413 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]([OH:18])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=2)[N:3]=1.[C:19]1([CH3:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[OH:18][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=1)[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2](/[CH:4]=[CH:8]/[CH:9]([OH:18])[CH2:10][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:19][CH3:25])[N:3]=1
Reactant: Cc1ccccc1
Reactant: OCc1cccc(C(O)Cc2cccc(Br)n2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCCCCCCCC(O)/C=C/c1cccc(CC(O)c2cccc(CO)c2)n1

Procedure:
Under the conditions of example 24D, 96 mg of 2-bromo-6-[(2RS)-2-hydroxy-2-(3-hydroxymethylphenyl)-ethyl]-pyridine and 160 mg of (1E)-1-(tri-n-butylstannyl)-1-undecen-(3RS)-3-ol in 1 ml of toluene is reacted in the presence of 1,1'-bis-(diphenylphosphino)-ferrocene-palladium(II) chloride as catalyst and worked up. The crude product is chromatographed on silica gel with hexane/0-25% ethyl acetate. 20 mg of the title compound is obtained as wine-red oil.
Reaction SMILES: [OH:1][CH:2]([CH3:45])[C:3]([CH3:44])([CH3:43])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]3[N:40]=[CH:41][N:42]=[C:12]23)=[CH:7][CH:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:44][C:3]([CH3:43])([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:23][CH:24]=3)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]3[N:40]=[CH:41][N:42]=[C:12]23)=[CH:7][CH:6]=1)[C:2](=[O:1])[CH3:45]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(OC(C)(C)C(C)O)cc2)c2ncnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(OC(C)(C)C(C)=O)cc2)c2ncnn12
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a solution of 4-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.24 g) in methylene chloride (4 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.25 g), and the mixture was stirred for 3 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.20 g, 85%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[C:13]([OH:32])[CH:12]=1.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[F:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]2[N:18]([CH:19]3[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:23][CH2:24]3)[C:34](=[O:36])[O:32][C:13]=2[CH:12]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(O)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2c(cc1F)oc(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 276.3 %

Procedure:
Hünig's base (0.5 mL, 2.86 mmol) was added to a solution of 1,1-dimethylethyl 4-[(4-fluoro-2-hydroxy-5-methylphenyl)amino]-1-piperidinecarboxylate (D1, 593 mg, 1.34 mmol) in dichloromethane (10 mL) at rt under argon. The reaction was cooled to 0° C. and the triphosgene (167 mg, 0.564 mmol) was added. The reaction was then stirred for 1.5 h at 0° C. and quenched with saturated aqueous NaHCO3 (10 mL) before being partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×) and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give an orange oil. The residue was purified via chromatography (silica, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) to give 1,1-dimethylethyl 4-(6-fluoro-5-methyl-2-oxo-1,3-benzoxazol-3(2H)-yl)-1-piperidine carboxylate (D2, 546 mg, 73% purity, 85% yield) as an orange oil.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:29][CH2:28]2.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[CH:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:29][CH2:28]4)=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CCOC(=O)CC1CCc2cc(O)ccc21
Reactant: CCc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1CCc2cc(OCc3c(-c4ccc(CC)cc4)nsc3C(F)(F)F)ccc21
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed [3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methyl methanesulfonate (160 mg, 0.44 mmol, 1.00 equiv), ethyl 2-(5-hydroxy-2,3-dihydro-1H-inden-1-yl)acetate (97 mg, 0.44 mmol, 1.01 equiv), potassium carbonate (183 mg, 1.32 mmol, 3.02 equiv), N,N-dimethylformamide (3 mL). The resulting solution was stirred overnight at 30° C. The resulting solution was diluted with 20 mL of H2O. The resulting mixture was washed with 3×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (15:85). This resulted in 200 mg (93%) of ethyl 2-(5-[[3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-2,3-dihydro-1H-inden-1-yl)acetate as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1I.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(OCC)C.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10]
Reactant: Fc1ccc(Cl)c(I)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[Si](C)(C)C#Cc1cc(F)ccc1Cl
Temperature: 90 °C
Yield: 55.1 %

Procedure:
A mixture of 1-chloro-4-fluoro-2-iodobenzene (10 g, 40 mmol), (trimethylsilyl)acetylene (28 mL, 190 mmol), copper(I) iodide (740 mg, 3.9 mmol), (triphenylphosphine)palladium(0) (2.5 g, 2.2 mmol), and N,N-diisopropylethylamine (14 mL, 78 mmol) in 1,4-dioxane (100 mL) was heated at 90° C. for 2 hours. The cooled reaction mixture was then diluted with diethyl ether (200 mL) and washed with water (300 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 220 g, ISCO, heptane) to afford the title compound as a pale yellow oil (5 g, 60%), which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]3[O:29][C:28]([C:30](O)=[O:31])=[CH:27][C:26]=3[CH:33]=2)[CH2:18][CH2:17]1)#[N:2].CS([O-])(=O)=O.[Cl:39]C1C=CC=C[N+:41]=1C>>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:23]=[CH:24][C:25]3[O:29][C:28]([C:30](=[O:31])[NH2:41])=[CH:27][C:26]=3[CH:33]=2)[CH2:20][CH2:21]1)#[N:2].[ClH:39]
Reactant: C[n+]1ccccc1Cl
Reactant: N#Cc1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(C(=O)O)cc5c4)CC3)c2c1
Agent: CS(=O)(=O)[O-]
Product: Cl
Product: N#Cc1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(C(N)=O)cc5c4)CC3)c2c1

Procedure:
Analogously to Example 3, starting from 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carboxybenzofuran-5-yl)piperazine reaction with 2-chloro-l-methylpyridinium methanesulfonate gives 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)piperazine, m.p. 269-272° (hydrochloride).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:19][CH:20]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.[OH:31][C:32]1[C:36]([CH:37]=[O:38])=[CH:35][N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:33]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:37]([C:36]1[C:32]([O:31][CH2:2][C:3]2[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:19][CH:20]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=2)=[N:33][N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:35]=1)=[O:38]
Reactant: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)c1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A mixture of ethyl (3-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (7.20 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (3.01 g), potassium carbonate (2.21 g) and N,N-dimethylformamide (100 mL) was stirred at 80° C. for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate as colorless crystals (6.84 g, yield 73%) from a fraction eluted with ethyl acetate-hexane (3:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 145-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:24][O:23][CH2:22]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:31].[Na+].P([O-])(O)(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:31])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]2[CH2:24][O:23][CH2:22]2)=[CH:17][CH:18]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(OCC4COC4)cc3)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCC4COC4)cc3)cc12
Temperature: 0 °C
Reaction time: 12 h
Yield: 34.9 %

Procedure:
To a mixture of 6-chloro-5-[4-(oxetan-3-ylmethoxy)phenyl]-1H-indole-3-carbaldehyde (70 mg, 0.2 mmol) in acetonitrile/t-butanol=1/1(5 mL) was added 2-methyl-2-butene (0.5 mL). The reaction was cooled to 0° C. and an aqueous solution of sodium chlorite (180 mg, 2.00 mmol) and sodium dihydrogen phosphate (270 mg, 6.00 mmol) in water (0.5 mL) were added dropwise via additional funnel. Then ice bath was removed, the reaction was stirred at room temperature for 12 h. The reaction was quenched with sodium sulfite. The mixture was partitioned between EtOAc (20 mL×3) and water. The combined organics was concentrated to give a residue, which was purified by reverse phase HPLC to give the title compound (25 mg, 35% yield) as an off-white solid. MS (AP+) 358.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.95 (s, 1H), 7.61 (s, 1H), 7.35 (d, 2H), 7.04 (d, 2H), 4.74 (t, 2H), 4.46 (t, 2H), 4.26 (t, 2H), 3.44-3.42 (m, 1H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[OH:12][CH:13]([N:26]1[C:32](=[O:33])[C@@H:31]2[C@H:27]1[S:28][C:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[N:30]2)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15]>O.ClCCl.CC(C)=O>[OH:12][CH:13]([N:26]1[C@H:27]([SH:28])[C@H:31]([NH:30][C:29](=[O:8])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32]1=[O:33])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@H]3N=C(Cc4ccccc4)S[C@H]32)cc1
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Toluene-4-sulphonic acid (3.42 g, 17.98 mmol) in water (8 ml) was added to a solution of 4-methoxybenzyl (2RS)-2-hydroxy-2-[(1R,5R)-3-benzyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-7-on-6-yl]acetate (4.12 g, 10.0 mmol) in dichloromethane (20 ml) and acetone (20 ml). After stirring for 2.5 h at room temperature, the reaction mixture was diluted with dichloromethane, washed with water (×2), dried and concentrated in vacuo to yield crude 4-methoxybenzyl (2RS)-2-hydroxy-2-[(3R,4R)-4-mercapto-3-phenylacetamidoazetidin-2-on-1-yl]acetate as a colourless foam. The crude thiol was dissolved in acetone (50 ml) and treated with a solution of 2-bromoacetyl-5-methyltetrahydrofuran (1.67 g, 8.1 mmol) in acetone (5 ml). After 10 min., potassium carbonate (687 mg, 5.0 mmol) was added, and the mixture stirred for a further 30 min. The reaction mixture was diluted with ethyl acetate, washed successively with water (×2) and brine, dried and concentrated. The residue was purified by chromatography on silica gel eluting with 50, 70 and 80% ethyl acetate in hexane to yield the title compound as a colourless foam (2.68 g, 60%); νmax (CH2Cl2) 3412, 1781, 1744, 1685 and 1515 cm-1. [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (579)].
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13](O)=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:20][CH:21]([CH:28]([CH3:30])[CH3:29])[CH:22]([OH:27])[C:23]([F:26])([F:25])[F:24].C(N(CC)CC)C.[OH:38]S([O-])(=O)=O.[K+]>C(Cl)Cl>[OH:27][CH:22]([C:23]([F:24])([F:25])[F:26])[CH:21]([N:20]1[CH2:13][CH2:12][CH2:16][C@H:17]1[C:18]([NH:11][C:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:10])=[O:38])[CH:28]([CH3:30])[CH3:29]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)C(N)C(O)C(F)(F)F
Reactant: O=S(=O)([O-])O
Agent: Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(C(O)C(F)(F)F)N1CCC[C@H]1C(=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of 1.1 g of N-phenylmethyloxycarbonyl proline TDO-ester (Cf Hollitzer, Seewald and Steglichm Ang.Int. Edit. 1976, Vol. 15, 444) and 0.42 g of 3-amino-1,1,1-trifluoro-4-methyl-2-pentanol hydrochloride in 50 ml of CH2Cl2 was added dropwise 0.40 g of triethylamine. After stirring for 14 hours at 25° C., aqueous KHSO4 was added, the layers separated and the organic layer washed with aqueous KHSO4, aqueous KHCO3, H2O and then brine (2×). After drying (MgSO4), solvents were flash evaporated to yield 0.54 g of a solid residue which was recrystallized in Et2O to give 0.24 g of the analytically pure expected amide; m.p. 99° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]#[N:22])=[CH:11][CH:10]=2)[C:6]2[CH:23]=[C:24]([N:27]([CH3:37])[S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:25]=[CH:26][C:5]=2[N:4]=1)[CH3:2].[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C)C=O>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:40][N:39]=[N:38][N:22]=3)=[CH:13][CH:14]=2)[C:6]2[CH:23]=[C:24]([N:27]([CH3:37])[S:28]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)(=[O:29])=[O:30])[CH:25]=[CH:26][C:5]=2[N:4]=1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1nc2ccc(N(C)S(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2ccc(N(C)S(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 41 from 4'-[[2-ethyl-6-(N-benzenesulphonyl-methylamino)-benzimidazol-1-yl]methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.