Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[CH:42]=[CH:41][C:33]5[C:34]([C:37]([O:39]C)=[O:38])=[N:35][S:36][C:32]=5[CH:31]=4)[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CO.O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:17])([F:19])[F:18])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[CH:42]=[CH:41][C:33]5[C:34]([C:37]([OH:39])=[O:38])=[N:35][S:36][C:32]=5[CH:31]=4)[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1nsc2cc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1nsc2cc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)ccc12

Procedure:
Methyl 6-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]isothiazole-3-carboxylate (37 mg, 0.062 mg) in a 3:2:1 THF-MeOH—H2O solution (1 mL) was treated with a 6N LiOH solution (85 μL, 0.49 mmol) at rt for 12 hours. After this time the organic was removed in vacuo and the residue was diluted with water (1 mL.) and cooled in ice. 3N NaOH was added dropwise until pH 7. The solid that separated was collected by filtration, washed with additional water and dried in vacuo to afford the 6-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]isothiazole-3-carboxylic acid as off white solid. 1H NMR (400 MHz, DMSO) δ 8.31 (d, J=8.0 Hz, 1H), 7.68-7.62 (m, 2H), 7.57-7.52 (m, 2H), 7.18 (bs, 1H), 6.90 (d, J=9.2 Hz, 1H), 4.31 (s, 2H), 4.18 (bs, 2H), 3.42 (m, 1H), 1.88-1.84 (m, 2H), 1.80 (1.78 (m, 4H), 1.53-1.49 (m, 2H), 1.15-1.03 (m, 5H). MS m/z 586.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=O)[N:3]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[C:16]1[NH:20][C:21]([C:23]1[C:31]2[NH:30][C:29]([NH2:32])=[N:28][C:27]=2[CH:26]=[CH:25][CH:24]=1)=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:17]1[CH:18]=[CH:19][N:15]=[C:16]1[NH:20][C:21]([C:23]1[C:31]2[N:30]=[C:29]([NH:32][C:12]([C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[C:6]([CH:5]=3)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[O:14])[NH:28][C:27]=2[CH:26]=[CH:25][CH:24]=1)=[O:22]
Reactant: Cc1nc(C(=O)O)cc2ccccc12
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)Nc2nc3c(C(=O)Nc4ncc[nH]4)cccc3[nH]2)cc2ccccc12
Yield: 14.8 %

Procedure:
17.6 mg (15%) of 1-methyl-isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was synthesized according to General Procedure A using 55 mg (0.29 mmol) of 1-methyl-isoquinoline-3-carboxylic acid, 70 mg (0.29 mmol) of intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide), 144 mg (0.38 mmol) of HBTU, 0.264 mL (1.5 mmol) of DIEA in 0.8 mL of DMF stirring at 85° C. for 2 h. 1H-NMR (400 MHz, DMSO): 8.66 (s, 1H), 8.38 (d, 1H), 8.28 (d, 1H), 7.89 (m 4H), 7.34 (m, 1H), 6.85 (b, 2H), 3.07 (s, 3H) ppm. LCMS: 412 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:1][CH2:2][CH2:3][N:4]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]2=3)=[CH:28][CH:27]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3ccccc23)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccc(Cl)cc3)c3ccccc23)CC1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
tert-Butyl 6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.533 g, 1.61 mmol), p-chlorophenol (0.224 g, 1.74 mmol, 1.08 equiv.) and triphenylphosphine (0.445 g, 1.70 mmol, 1.05 equiv.) was dissolved in THF (10 mL) and stirred at rt under N2. Diethyl azodicarboxylate (0.30 mL, 0.337 g, 1.93 mmol, 1.2 equiv.) was added, and the reaction mixture was stirred for 2.5 h. The reaction mixture was concentrated to give crude product (1.85 g), which was chromatographed (SiO2 175 g, eluted with 4:1 hexane:EtOAc) to give tert-butyl 6-[2-(4-chlorophenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.622 g) in 88% yield. 1H NMR (300 MHz, CD3OD) δ 1.48, 2.96-3.03, 3.05-3.14, 3.63-3.78, 4.15, 4.48, 6.70, 7.11, 7.15-7.20, 7.17, 7.27-7.31, 7.46-7.51; MS (ESI+) for C25H29ClN2O3 m/z 440.9 (M+H)+.
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][CH2:13][C@@H:14]1[O:32][CH2:31][C@:17]2([C:33]3[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:34]=3[F:40])[N:18]=[C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:20][CH2:21][C@@H:16]2[CH2:15]1)C1C=CC=CC=1>ClCCl>[Br:39][C:37]1[CH:36]=[CH:35][C:34]([F:40])=[C:33]([C@:17]23[CH2:31][O:32][C@@H:14]([CH2:13][OH:12])[CH2:15][C@H:16]2[CH2:21][S:20][C:19]([NH:22][C:23](=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:18]3)[CH:38]=1
Reactant: O=C(NC1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1)c1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: O=C(NC1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](CO)C[C@H]2CS1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Boron trichloride (45.8 mL, 45.8 mmol) was added to a solution of N-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C32) (8.70 g, 15.3 mmol) in dichloromethane (76 mL) at 0° C., while maintaining the internal temperature below 5° C. The heterogeneous mixture was allowed to stir for 10 minutes at 0° C. and then at room temperature for 16 hours. The reaction mixture was then quenched by drop-wise addition of methanol (100 mL). The methanol solution was refluxed for 15 minutes and then concentrated under reduced pressure. The residue was re-dissolved in dichloromethane (100 mL) and washed sequentially with 1 N sodium hydroxide (2×100 mL) and with brine (100 mL), dried over sodium sulfate and filtered. Purification via silica gel chromatography (Gradient: 30% to 100% ethyl acetate in heptane) afforded the product as an off-white solid. Yield: 4.98 g, 68%. LCMS m/z 410 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.13 (d, J=6.8 Hz, 1H), 7.59-7.45 (m, 4H), 7.16 (dd, J=12.1, 8.6 Hz, 1H), 4.15-4.11 (m, 1H), 3.91 (d, J=11.9 Hz, 1H), 3.79-3.73 (m, 1H), 3.59 (d, J=5.1 Hz, 1H), 3.21 (br s, 1H), 2.96 (dd, J=13.0, 4.0 Hz, 1H), 2.76 (dd, J=13.2, 2.8 Hz, 1H), 1.81-1.90 (m, 1H), 1.72-1.68 (m, 1H).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[NH:6][C:7]([CH3:29])=[C:8]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:10]=1[C:11]([O-:13])=[O:12].C(O)(=O)C.O>CO>[CH3:4][C:5]1[NH:6][C:7]([CH3:29])=[C:8]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CC1=C(C(=O)[O-])C(c2cccc([N+](=O)[O-])c2)C(c2ccncc2)=C(C)N1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(c2ccncc2)=C(C)N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.35 g (25 mmol) of sodium methoxide was dissolved in 20 ml of anhydrous methanol. To this solution was added, with ice-cooled, 2.02 g (5 mmols) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(4-pyridyl)pyridine-3-carboxylate. The reaction mixture was stirred at room temperature for 5 hours and neutralized with acetic acid. To this reaction mixture was added 400 ml of water. Crystals were separated from the reaction mixture, which were collected, washed with water and dried under reduced pressure, whereby the captioned compound was obtained. The yield was 1.71 g (98%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([NH:31][CH3:32])=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:4][CH:3]=1
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CNC(=O)CCl
Product: CNC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3OC)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-Chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N-methyl-acetamide gave the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:8]=[N:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>CCO>[N:10]1[N:9]=[N:8][N:4]2[CH:5]=[CH:6][N:7]=[C:2]([N:14]3[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]3)[C:3]=12
Reactant: Clc1nccn2nnnc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nccn3nnnc23)CC1
Yield: 89.7 %

Procedure:
A 3 L round bottom flask was charged with 8-chlorotetrazolo[1,5-a]pyrazine (350 g, 2.3 mol), tert-butyl piperazine-1-carboxylate (420 g, 2.3 mol), triethylamine (460 g, 4.5 mol), and EtOH (2 L). The mixture was heated at reflux for 1 h. Work-up: the reaction mixture was concentrated in vacuo. The residue was mixed with saturated aqueous NaHCO3 (1 L) and then extracted with CH2Cl2 (1 L×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 8% EtOAc in CH2Cl2 (containing 2% Et3N), to afford 630 g (91%) of the product as a white solid. MS m/z: 306 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:22]3[C:23]4=[C:24]5[C:19](=[CH:20][CH:21]=3)[CH:18]=[CH:17][CH:16]=[C:15]5[CH:14]=[CH:13][C:12]4=[CH:11][CH:10]=2)[CH:5]=[C:6](Br)[CH:7]=1.C1(B(O)O)C2C3=C4C(=CC=2)C=CC=C4C=CC3=CC=1.CCCCCC.C([Li])CCC.[I:55]CCI.S(=O)(O)[O-].[Na+]>C(Cl)Cl.O.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:22]3[C:23]4=[C:24]5[C:19](=[CH:20][CH:21]=3)[CH:18]=[CH:17][CH:16]=[C:15]5[CH:14]=[CH:13][C:12]4=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[I:55]
Reactant: Brc1cc(Br)cc(-c2ccc3ccc4cccc5ccc2c3c45)c1
Reactant: ICCI
Agent: O=S([O-])O
Agent: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Brc1cc(-c2ccc3ccc4cccc5ccc2c3c45)ccc1I
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
Under the atmosphere of argon gas, 9 g of 1-(3,5-dibromophenyl)pyrene synthesized from 3,5-diboromoiodobenzene and 1-pyrenyl boronic acid was dissolved into 100 ml of anhydrous tetrahydrofuran (THF) and cooled down to −70° C. 14 ml of 1.6M n-butyllithium hexane solution was dropped therein and the resultant was stirred for 30 minutes. 5.9 g of 1,2-diiodoethane was added therein and the resultant was stirred for 5 hours. After the resultant was left overnight, water and methylene chloride were added therein, and then sodium bisulfite was added therein until the burned umber of the reaction solution was changed to yellow. The organic layer was extracted therefrom, and then it was washed by water and saturated salt water. Subsequently the organic layer was dried by using anhydrous sodium sulfate, and then the solvent was removed by distillation. The residue was refined through a silica gel chromatography (developing solvent: toluene/hexane=1/3) and then 8.4 g of 1-(3-bromo-4-iodophenyl)pyrene of cream color solid was obtained (Yield: 84%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.Cl[C:18]1[N:23]=[C:22]([C:24]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])([CH3:26])[CH3:25])[CH:21]=[C:20]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][C@@H:38]2[CH3:43])[N:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.COCCOC.O.C(O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:36][C:33]1[CH:34]=[CH:35][C:30]([S:27]([C:24]([C:22]2[CH:21]=[C:20]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][C@@H:38]3[CH3:43])[N:19]=[C:18]([C:9]3[CH:10]=[CH:11][C:12]([NH2:13])=[CH:14][CH:15]=3)[N:23]=2)([CH3:26])[CH3:25])(=[O:28])=[O:29])=[CH:31][CH:32]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccc(F)cc2)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: CCO
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccc(F)cc2)nc(-c2ccc(N)cc2)n1
Temperature: 90 °C
Reaction time: 4 h
Yield: 79.2 %

Procedure:
Dichlorobis(triphenylphosphine)palladium(II) (170 mg, 0.24 mmol) was added to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.376 g, 6.28 mmol) and 2-chloro-4-[2-(4-fluorophenyl)sulfonylpropan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (2 g, 4.83 mmol), and sodium carbonate (5 mL, 10.00 mmol) in 18% DMF in DME:water:ethanol (7:3:2) (20 mL). The resulting solution was stirred at 90° C. for 4 hours. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with water (2×20 mL1). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 60% ethyl acetate in isohexane, to give the desired material as a cream solid (1.80 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:29])[CH2:10][O:11][P:12]([OH:28])([N:14]2[C:17](=[O:18])[C@@H:16]([NH:19]C(=O)OC(C)(C)C)[C@@H:15]2[CH3:27])=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8].[K].C1(OC)C=CC=CC=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl.C1(C)C=CC=CC=1>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[NH2:19][C@@H:16]1[C:17](=[O:18])[N:14]([P:12](=[O:13])([OH:28])[O:11][CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=2)=[O:29])[C@H:15]1[CH3:27]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1P(=O)(O)OCC(=O)c1ccc(O)c(O)c1
Agent: [K]
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Solvent: ClCCl
Product: C[C@H]1[C@H](N)C(=O)N1P(=O)(O)OCC(=O)c1ccc(O)c(O)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of (2S-trans)-[1-[[2-(3,4-dihydroxyphenyl)-2-oxoethoxy]hydroxyphosphinyl]-2-methyl-4-oxo-3-azetidinyl]carbamic acid, 1,1-dimethylethyl ester, monopotassium salt (117 mg, 0.25 mmol) in 2.5 ml of dry dichloromethane was added 100 μl of anisole and the mixture was then cooled to 0° C. in an ice bath under argon. Trifluoroacetic acid (1 ml) was added and the mixture stirred for two hours. The reaction mixture was diluted with 5 ml of dry toluene and the solvents removed in vacuo at room temperature yielding a yellow oily residue. The residue was triturated with hexanes (2×10 ml) followed by trituration with ether (2×10 ml). The solid was dried in vacuo yielding the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[C:4]([C:6]1[CH:34]=[CH:33][C:9]2[N:10]([CH2:14][CH2:15][O:16][C:17]3[CH:32]=[CH:31][C:20]([CH:21]=[C:22]([C:27]([O:29][CH3:30])=[O:28])[C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=3)[C:11](=[O:13])[S:12][C:8]=2[CH:7]=1)=[O:5]>CO.C1COCC1.O1CCOCC1.[Pd]>[Cl:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[C:4]([C:6]1[CH:34]=[CH:33][C:9]2[N:10]([CH2:14][CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:21][CH:22]([C:23]([O:25][CH3:26])=[O:24])[C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=3)[C:11](=[O:13])[S:12][C:8]=2[CH:7]=1)=[O:5]
Reactant: COC(=O)C(=Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4Cl)ccc32)cc1)C(=O)OC
Agent: [Pd]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4Cl)ccc32)cc1)C(=O)OC
Temperature: 25 °C

Procedure:
The compound obtained in Example 37 is dissolved in a methanol/THF/dioxane solvent mixture and then a catalytic amount of palladium-on-carbon is added and the reaction is stirred at ambient temperature under a hydrogen atmosphere. The palladium-on-carbon is then filtered off and the solvents are removed by evaporation under reduced pressure. The resulting residue is taken up in isopropyl ether and stirred magnetically. The resulting precipitate is filtered off and recrystallised from methanol.
Reaction SMILES: [OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH:3]=O.[NH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2>>[F:16][C:15]([F:18])([F:17])[C:2]([CH:3]=[N:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2)([OH:1])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:14])[CH3:7]
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccccc1
Reactant: Nc1cccc2ncccc12
Product: CC(C)(CC(O)(C=Nc1cccc2ncccc12)C(F)(F)F)c1ccccc1

Procedure:
Analogously to Example 13, 120 mg of 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentanal and 61 mg of 5-aminoquinoline are converted into 95 mg of product.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[O:10][CH:11]([CH3:15])[C:12]([NH2:14])=O)([O-:3])=[O:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1.O1CCOCC1>[N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[O:10][CH:11]([CH3:15])[C:12]#[N:14])([O-:3])=[O:2]
Reactant: CC(Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1)C(N)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(C#N)Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Temperature: 0 °C
Yield: 100.5 %

Procedure:
In a mixture of 12 ml of pyridine and 35 ml of dioxane was suspended 4.55 g of 2-[3-(2-nitrophenoxy)phenoxy]propionamide and, then, 3.6 g of trifluoroacetic anhydride was added dropwise with ice-cooling and stirring. The mixture was then stirred at that temperature for 30 minutes and, following addition of ice-water, extracted with ether. The ether extract was washed with diluted hydrochloric acid and sodium hydrogen carbonate solution in that order, dried and concentrated to give 4.3 g of the title compound as a light yellow oil.
Reaction SMILES: [C:1]([Si:5]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:6][CH:7]1[CH2:11][CH2:10][CH:9]([OH:12])[CH:8]1[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.C(N(CC)C(C)C)(C)C>CS(C)=O.N1C=CC=CC=1>[C:1]([Si:5]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[O:6][CH:7]1[CH2:11][CH2:10][C:9](=[O:12])[CH:8]1[CH2:13][O:14][C:15]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](OC1CCC(O)C1COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)[Si](OC1CCC(=O)C1COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
The compound of formula (XIII) obtained in Example 2-1 (60 g, 97.9 mmol) was mixed with DMSO (36 ml) and methylene chloride (300 ml). The resulting solution was cooled to 0° C. and N,N-diisopropylethylamine (DIPEA) (59.7 ml, 0.343 mol) was added thereto, followed by adding a mixture solution of pyridine.SO3 complex (31.2 g), pyridine (15.9 ml) and DMSO (36 ml). The mixture thus obtained was stirred for 30 min. After completion of the reaction, the organic layer thus obtained was washed with saturated ammonium chloride (300 ml), 2M HCl solution (300 ml), sodium bicarbonate solution (300 ml) and brine (300 ml) respectively, dried over anhydrous sodium sulfate, filtered, and condensed under a reduced pressure to obtain the title compound (60 g, yield: 99%).
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38](O)=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:64][NH:65][CH2:66][CH2:67][CH2:68][CH2:69][OH:70].C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[F:49][C:2]([F:48])([F:1])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:46])([F:47])[F:45])[CH:43]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38]([N:65]([CH2:66][CH2:67][CH2:68][CH2:69][OH:70])[CH3:64])=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7]
Reactant: CNCCCCO
Reactant: O=C(O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(CCCCO)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
The compound (400 mg, 0.576 mmol) obtained in Example 1j was dissolved in dichloromethane (30 mL), triethylamine (0.12 mL, 1.04 mmol) and pivaloyl chloride (0.11 mL, 0.864 mmol) were added under ice cooling, and the mixture was stirred at the same temperature under a nitrogen atmosphere for 15 minutes. Subsequently, a solution of 4-(methylamino)butan-1-ol (178 mg, 1.73 mmol) in dichloromethane (2 mL) was added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate, 10:1, v/v) to give the title compound (347 mg; yield, 77%) as a colorless oily substance.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl[C:31]([O:33][CH3:34])=[O:32]>>[CH3:34][O:33][C:31]([N:12]1[CH2:13][CH2:14][C@H:9]([O:8][CH2:7][C:6]2[CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=[C:4]([C:3]([F:2])([F:28])[F:29])[CH:5]=2)[C@H:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11]1)=[O:32]
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: COC(=O)Cl
Agent: Cl
Product: COC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Yield: 67 %

Procedure:
The compound (0.15 g) obtained in Example 1 and methyl chloroformate (0.040 ml) were reacted and treated in the same manner as in the method described in Example 2 to obtain the title compound as colorless oil (0.11 g, 67%).