Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2.C(N(CC)CC)C>ClCCl>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:25]2
Reactant: Brc1ccc2c(c1)CNC2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Brc1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Yield: 85.5 %

Procedure:
Trityl chloride (2.30 g, 8.23 mmol) was added to a solution of 5-bromo-2,3-dihydro-1H-isoindole (1.64 g, 8.23 mmol) and triethylamine (1.4 mL, 9.9 mmol) in dichloromethane (20 mL). After 18 hours the solvent was removed in vacuo, the residue taken up in ethyl acetate and washed with water (×2) and brine, dried (MgSO4) and concentrated. The crude material was purified by flash chromatography on silica eluting with 1% triethylamine/10% ethyl acetate/petrol to give 5-bromo-2-trityl-2,3-dihydro-1H-isoindole as a reddish-brown solid (3.10 g, 85%). 1H NMR (CDCl3) 7.91-7.84 (1H, m), 7.57 (6H, d), 7.45-7.41 (1H, m), 7.33-7.14 (9H, m), 6.95 (1H, d), 3.90 (2H, s), 3.86 (2H, s). MS: Ph3C+ 243.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][C:13]3[N:17]=[CH:18][C:19]([C:21](Cl)=[O:22])=[CH:20][C:12]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[NH:25][C:26](=[NH:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].CCN(C(C)C)C(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][C:13]3[N:17]=[CH:18][C:19]([C:21]4[O:22][N:32]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=4)=[CH:20][C:12]2=3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cnc2c(c1)N(S(=O)(=O)c1ccc(F)cc1)CCO2
Reactant: CCOC(=O)C(=N)NO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1noc(-c2cnc3c(c2)N(S(=O)(=O)c2ccc(F)cc2)CCO3)n1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 49.2 %

Procedure:
To a solution of 1-(4-fluorophenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonyl chloride (200 mg, 0.561 mmol) in DCM (5 mL) and water (1 mL) was added ethyl 2-(hydroxyamino)-2-iminoacetate (143.5 mg, 1.086 mmol) and DIPEA (230 μL, 1.317 mmol) to give a pink suspension. The reaction was stirred at 40° C. for 1.5 hours. LCMS analysis of the reaction mixture indicated complete consumption of starting material. The reaction mixture was extracted with DCM (2×10 mL) dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was dissolved in THF (6 mL) and treated with TBAF (0.561 mL, 0.561 mmol). The resulting yellow solution was stirred overnight. LCMS analysis of the reaction indicated consumption of the intermediate. The solvent was removed under reduced pressure. The resulting paste was purified by flash column chromatography using a gradient elution of hexanes with 30-100% EtOAc. Ethyl 5-(1-(4-fluorophenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-1,2,4-oxadiazole-3-carboxylate (120 mg, 0.276 mmol, 49.2%) was isolated as an off-white solid. LCMS (+ESI) m/z=435.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][NH2:23])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:26]([O:30][C:31]([NH:33][C@@H:34]([CH:38]([CH3:40])[CH3:39])[C:35](O)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1>[C:26]([O:30][C:31](=[O:32])[NH:33][C@@H:34]([CH:38]([CH3:39])[CH3:40])[C:35]([NH:23][NH:22][C:20](=[O:21])/[CH:19]=[CH:18]\[N:15]1[CH:16]=[N:17][C:13]([C:5]2[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=2)=[N:14]1)=[O:36])([CH3:29])([CH3:28])[CH3:27]
Reactant: NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: -60 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
In a 10 mL round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.25 g, 1.0 eq.) was dissolved in THF (5 mL) and cooled to −60° C. where (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.19 g, 1.3 eq.) was introduced dropwise. T3P (50% in EtOAc) (0.81 mL, 2 eq.) was added dropwise followed by DIPEA (0.48 mL, 4 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (S,Z)-tert-butyl(1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate (0.07 g, yield: 18%). In a 10 mL round-bottom flask, (S,Z)-tert-butyl(1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate was then dissolved in dichloromethane (2 mL). TFA (0.05 mL) was added and the reaction mixture was stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product (0.01 g), which was triturated with petroleum ether and dried under reduced pressure to yield (S,Z)-2-amino-N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-methylbutanehydrazide 2,2,2-trifluoroacetate (0.006 g, yield: 2%).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[CH3:26][O:27][C:28](=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35](Cl)=[O:36]>C(Cl)Cl>[CH3:26][O:27][C:28](=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:1][CH:2]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[C:3](=[O:4])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:36]
Reactant: COC(=O)CCCCCCC(=O)Cl
Reactant: COc1ccc(C(O)C(=O)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCC(=O)OC(C(=O)c1ccccc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a solution of 2-hydroxy-2-(4-methoxyphenyl)-1-phenyl-ethanone (8.2 g, 0.034 mol) prepared in Step 3 and triethylamine (5.21 g, 0.051 mol) in methylene chloride (100 mL) was slowly added a solution of 7-chlorocarbonylheptanoic acid methyl ester (5.64 g, 0.034 mol) in methylene chloride (20 mL). A final reaction solution was stirred at room temperature for 12 hours and then diluted with 200 mL of methylene chloride. The obtained organic layer was washed twice with 100 mL of a saturated sodium bicarbonate solution and then successively washed twice with 100 mL of a brine solution. The obtained organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure, to give 12.90 g (yield: 92%) of octanedioic acid 1-(4-methoxyphenyl)-2-oxo-2-phenylethyl ester methyl ester.
Reaction SMILES: [CH2:1]([N:7]([CH3:27])[C:8]([CH:10]1[CH2:14][CH:13]([OH:15])[CH2:12][CH:11]1[C:16]([NH:18][C:19]1([C:24](O)=[O:25])[CH2:21][CH:20]1[CH:22]=[CH2:23])=[O:17])=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].CCN=C=NCCCN(C)C.[CH:39]1([S:42]([NH2:45])(=[O:44])=[O:43])[CH2:41][CH2:40]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:39]1([S:42]([NH:45][C:24]([C:19]2([NH:18][C:16]([CH:11]3[CH2:12][CH:13]([OH:15])[CH2:14][CH:10]3[C:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])[CH3:27])=[O:9])=[O:17])[CH2:21][CH:20]2[CH:22]=[CH2:23])=[O:25])(=[O:44])=[O:43])[CH2:41][CH2:40]1
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)O)CC1C=C
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C=C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
The crude acid 10d (410 mg, 1.09 mmol) was dissolved in DMF (1.5 ml) and DCM (4.5 ml) followed by addition of EDAC (417 mg, 2.18 mmol) at room temperature. The mixture was allowed to incubate with stirring at room temperature. After 10 min, DMAP (133 mg, 1.09 mmol) was added followed by another 20 min incubation at room temperature. Subsequently, a pre-mixed solution of cyclopropanesulfonic acid amide (527 mg, 4.36 mmol) and DBU (663 mg, 4.36 mmol) in DMF (2 ml) and DCM (2 ml) was added followed by heating in the microwave to 100° C. for 30 min. The resulting red solution was concentrated in vacuo and re-dissolved in EtOAc (20 ml). The organic phase was washed with 1 M HCl (aq) (3×10 ml) and brine (10 ml), dried (MgSO4) and filtered. The solvent was evaporated in vacuo to yield the crude sulfonamide which was further purified by chromatography (Silica, EtOAc:MeOH, 97.5:2.5) which gave the title compound (403 mg, 77%); LC/MS >95%, m/z (ESI+)=482 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:40])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39](=[O:40])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:35][CH:34]=2)=[CH:11][C:10]=1[CH2:16][O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1COC(=O)NC1CCCCC1
Reactant: O=C(c1ccccc1)c1ccc(OCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1COC(=O)NC1CCCCC1
Temperature: 80 °C
Yield: 62.5 %

Procedure:
A mixture of 3-(2-cyclohexylcarbamoyloxymethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (50 mg, 0.13 mmol; Example 652 Step D), [4-(3-bromo-propoxy)-phenyl]-phenyl-methanone (64 mg, 0.2 mmol, Bull Chem. Soc. Jpn. 1990, 63, 1342) and potassium carbonate (53 mg, 0.39 mmol) in acetonitrile (6 mL) was heated at 80° C. overnight. Ethyl acetate (20 mL) and H2O (20 mL) were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude mixture was purified by silica gel column chromatography (hexane/ethyl acetate 4/1) to give the title compound (50 mg, 62%). 1H-NMR (300 MHz, CDCl3): δ 7.74 (d, 2H, J=8.5), 7.68 (d, 2H, J=7.7), 7.48 (d, 1H, J=8.4), 7.40 (m, 2H), 7.05 (d, 1H, J=8.5), 6.90 (d, 2H, J=8.6), 6.85 (s, 1H), 6.74 (dd, 1H, J=8.5, 2.2), 5.04 (s, 2H), 4.68 (d, 1H, J=7.3), 4.17 (t, 2H, J=5.9), 4.09 (t, 2H, J=5.9), 3.43 (m, 1H), 2.82 (t, 2H, J=7.8), 2.40 (t, 2H, J=7.8), 2.21 (qn, 2H, J=5.9), 1.85 (m, 2H), 1.67-1.02 (m, 8H), 1.36 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][CH3:7])=[S:5])[NH2:3].N1C=CC=CC=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](Cl)=[O:20]>CCOCC>[CH3:1][N:2]([C:4]([NH:6][CH3:7])=[S:5])[NH:3][C:19]([C:15]1[S:14][CH:18]=[CH:17][CH:16]=1)=[O:20]
Reactant: O=C(Cl)c1cccs1
Reactant: CNC(=S)N(C)N
Solvent: CCOCC
Solvent: c1ccncc1
Product: CNC(=S)N(C)NC(=O)c1cccs1

Procedure:
To a stirred, room temperature, solution of 2,4-dimethylthiosemicarbazide (3.75 g, 3.15×10-2 mole) and pyridine (30 ml) was added dropwise 2-thiophenecarbonyl chloride (3.20 ml, 2.99×10-2 mole). After stirring overnight the pyridine was evaporated at reduced pressure and the concentrate was treated with H2O. The resulting semi-solid was extracted into ethyl acetate. The ethyl acetate extract was washed with saturated NaCl and subsequently dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure, leaving a slightly yellowish solid. This was treated with Et2O and the solid was collected by filtration affording a colorless powder: 4.7 g (68%), mp 176°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13](SCC)[N:12]2[CH:18]=[C:19]([CH2:21][N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[N:20]=[C:11]2[CH:10]=1.[OH-:29].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([OH:29])[N:12]2[CH:18]=[C:19]([CH2:21][N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[N:20]=[C:11]2[CH:10]=1
Reactant: CCSc1nc(-c2ccc(Cl)cc2Cl)cc2nc(CN3CCN(C)CC3)cn12
Reactant: [OH-]
Agent: [K+]
Product: CN1CCN(Cc2cn3c(O)nc(-c4ccc(Cl)cc4Cl)cc3n2)CC1

Procedure:
In analogy to Example 10A, 500 mg (97% of theory) of the product are obtained from 675 mg (1.31 mmol) of 7-(2,4-dichlorophenyl)-5-(ethylsulphanyl)-2-[(4-methylpiperazin-1-yl)methyl]-imidazo[1,2-c]pyrimidine (Example 93A) by heating in methanolic potassium hydroxide solution.
Reaction SMILES: [CH2:1]=[O:2].[CH:3](=[O:7])[CH:4]([CH3:6])[CH3:5].[C-]#N.[Na+].S(=O)(=O)(O)O.[CH3:16][OH:17]>>[CH3:5][C:4]1([CH3:6])[CH:3]([OH:7])[C:16](=[O:17])[O:2][CH2:1]1
Reactant: C=O
Reactant: CC(C)C=O
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [C-]#N
Agent: [Na+]
Product: CC1(C)COC(=O)C1O
Reaction time: 0.33 h
Yield: 76 %

Procedure:
The same apparatus and process was used as in Example 1 except as follows: The starting product comprised 5.45 l/hr. of formalin (30%), 5.35 l/hr. of isobutyraldehyde, 2.35 l/hr. of methanol, 9.25 l/hr. of NaCN solution and 12 l/hr. of sulfuric acid (46%). The latter was used in the hydrolysis step. The residence time in the circulation reactor was 20 min. The temperature in the same reactor was 5° C. The time for the aftertreatment reaction was 40 min. The temperature in the tubular reactor was 150° C. and the residence time therein was 6 min. There were obtained 7 kg pantolactone of 90% purity. The yield was 76%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:11]2[N:12]=[N:13][N:14]([CH3:16])[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH:17][CH2:18][C:19]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=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]1.[H-].[Na+]>CN(C)C=O>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[N:12]=[N:13][N:14]([CH3:16])[N:15]=2)=[CH:4][C:3]=1[CH2:2][O:17][CH2:18][C:19]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH2:20]1
Reactant: COc1ccc(-c2nnn(C)n2)cc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnn(C)n2)cc1COCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-(3-(Bromomethyl)-4-methoxyphenyl)-2-methyl-2H-tetrazole (35.0 mg, 0.12 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (40.0 mg, 0.14 mmol) were combined in dimethylformamide (1 mL) and cooled to 0° C. The reaction was treated with sodium hydride (3.2 mg, 0.14 mmol), stirred at 0° C. for 1 h, and at room temperature overnight. The solvents were removed in vacuo and the crude product purified by column chromatography on silica gel (30% ethyl acetate/hexanes) to afford 30 mg (50%). LC/MS (HPLC method 3): tR=3.29 min, 494.25 (MH)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:27]I>C1C=CC=CC=1>[CH:19](=[N:1][C:2]([CH3:27])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CI
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CCCCCCC(N)C(=O)OCC
Solvent: c1ccccc1
Product: CCOC(=O)CCCCCCC(C)(N=Cc1ccccc1)C(=O)OCC
Reaction time: 8 h
Yield: 91.8 %

Procedure:
Diethyl 2-aminononanedioate (5.0 g) was heated with benzaldehyde (2.15 g) in benzene (10 ml) under reflux for 12/3 hours, removing the water formed by means of a Dean and Stark apparatus. The benzene was evaporated in vacuo and the residual oil was taken up in dry tetrahydrofuran (20 ml), stirred under dry nitrogen, treated with sodium hydride (0.61 g of a 80% dispersion in mineral oil), and heated until evolution of hydrogen began. Thereafter, reaction was allowed to proceed at room temperature. When effervescence had ceased, the pale yellow-brown solution was cooled in icewater and, with continued stirring, treated with methyl iodide (6.83 g); the cooling bath was removed after 15 minutes and the mixture was set aside at room temperature overnight. The resulting suspension of solid ws diluted with ether (100 ml) and skaken with ice-cold water (100 ml), and the ethereal phase was washed with H2O, dried over sodium sulphate, and evaporated, to leave crude diethyl 2-(benzylideneamino)-2-methylnonanedioate (6.4 g) as a yellow oil.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]I.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1>>[I-:1].[I-:1].[CH2:2]([N+:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N+:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1
Reactant: c1ccc2cnccc2c1
Reactant: ICCCCCCCCI
Product: [I-]
Product: c1ccc2c[n+](CCCCCCCC[n+]3ccc4ccccc4c3)ccc2c1
Temperature: 65 °C
Yield: 92 %

Procedure:
1,8-Diiodooctane (mmol) was added to a solution (30 mL) of isoquinoline, and the solution heated for 24 hours at 65° C. The resulting precipitate was filtered, and the product washed five times with dry diethyl ether. The resulting yellow solid was isolated in an 92% yield. 1H NMR (300 MHz, DMSO-D6) δ 10.05 (1H, d, C1-H), 8.77 (1H, d, C3-H), 8.58 (1H, d, C8-H), 8.48 (1H, d, C4-H), 8.35 (1H, d, C7-H), 8.26 (1H, t, C5-H), 8.07 (1H, t, C6-H), 4.68 (2H, t, C′1-CH2), 2.00 (2H, m, C′2-CH2), 1.30 (4H, m, C′3&4-CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[N:27]=[C:26](/[CH:35]=[CH:36]/[C:37]([O:39]C)=[O:38])[CH:25]=3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[N:27]=[C:26](/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38])[CH:25]=3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/c1cc(-c2ccc(OCc3cc(OC)ccc3-c3ccc(Cl)cc3)cc2)n(C2CCCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(Cl)cc2)c(COc2ccc(-c3cc(/C=C/C(=O)O)nn3C3CCCCC3)cc2)c1

Procedure:
Methyl ester 3.2 (40 mg) and 1N LiOH (1 ml) in 3 ml MeOH/THF (1:2) was stirred at rt 18 h before being concentrated and partitioned between EtOAc and H2O. The aqueous layer was acidified with 1N HCl and extracted with EtOAc (3×). The organic extracts were washed with H2O, brine, and dried (Na2SO4). Concentration gave 3.3, 39 mg (100%). HRMS (ESI) calc'd for C32H32ClN2O4 542.1972; found 543.2050 (MH+); 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=15.8, 1H), 7.39–7.23 (m, 7H), 7.18 (d, J=2.6, 1H), 6.99–6.94 (m, 3H), 6.45 (s, 1H), 6.38 (d, J=6.1, 1H), 4.94 (s, 2H), 4.13–4.01 (m, 1H), 3.88 (s, 3H), 2.04–1.83 (m, 6H), 1.32–1.21 (m, 4H).
Reaction SMILES: P([O-])(O)(O)=O.[K+].N(S([O-])(=O)=O)(S([O-])(=O)=[O:10])[O].[K+].[K+].[OH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([O:30][CH:31]([CH3:35])[C:32]([OH:34])=[O:33])=[CH:22][CH:21]=1>O.C(O)C>[C:32]([CH:31]([O:30][C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:19])[C:21](=[O:10])[CH:22]=1)[CH3:35])([OH:34])=[O:33]
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Reactant: CC(Oc1ccc(O)c2ccccc12)C(=O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(OC1=CC(=O)C(=O)c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 38.0 g potassium dihydrogen phosphate in 7.5 liters of distilled water (pH 4.0) was added 89.4 g (0.33 mole) of potassium nitrosodisulfonate (Fremy's reagent). To this solution was added immediately a solution of 34.8 g (0.15 mole) of 2-(4-hydroxy-1-naphthoxy)propionic acid in 125 ml ethanol. The mixture was stirred for 2.5 hours under nitrogen at room temperature. The yellow-brown solid was collected, washed with a little water and dried (under nitrogen). The yield was 30.0 g (81 percent). The crude product melted at 182° to 184° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[C:25](=[O:31])[N:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1>>[CH3:30][N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)[C:25]1=[O:31]
Reactant: Cn1cccc(Br)c1=O
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: Cn1cccc(N2CCC3(CC2)CCN(c2ccc(OC(F)(F)F)cc2)C3=O)c1=O

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 3-bromo-1-methyl-1H-pyridin-2-one. Light yellow solid. MS (ESI): 422.1 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15].O.Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[O:16][CH2:17][CH3:18])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Br)cc1C(F)(F)F
Reaction time: 0.67 h

Procedure:
After to a solution of 4-bromo-2-trifluoromethylaniline (2.805 ml) in pyridine (15 ml) was added dropwise ethyl chloroformate (2.130 ml) during 15 minutes in an ice bath, the reaction mixture was stirred for 40 minutes. Then, to the solution was added dropwise ethyl chloroformate (1.000 ml) during 5 minutes in an ice bath again. The reaction mixture was stirred for 1 hour. After to the reaction solution was added water, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated brine, saturated aqueous sodium bicarbonate solution, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (6.4509 g, quantitative yield).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([OH:15])=O.[NH2:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([NH2:28])=[O:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20].O>O1CCOCC1>[NH:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([NH2:28])=[O:27])=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])=[O:15]
Reactant: CC(C)C[C@H](N)C(=O)NCC(N)=O
Reactant: O=C(O)c1ccc[nH]1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)c1ccc[nH]1)C(=O)NCC(N)=O
Reaction time: 2 h

Procedure:
7.0 ml of triethylamine and 10.4 g of the N-hydroxysuccinimide ester of pyrrole-2-carboxylic acid were added to 9.4 g of L-leucyl-glycinamide in 120 ml of dioxane at 10° C. and the reaction mixture was stirred for 2 hours at this temperature, after which 30 ml of water were added and the stirred mixture was allowed to react for 20 hours at room temperature.