Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH:9]=[CH:10][CH:11]=[C:12]([CH3:24])[CH:13]=[CH:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]=1[CH3:23])=[CH:3][CH:4]=[CH:5][C:6]([OH:8])=[O:7].[C:25]([NH:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)(=[O:27])[CH3:26].FC(F)(F)C([O-])=O>O1CCCC1>[CH3:1][C:2]([CH:9]=[CH:10][CH:11]=[C:12]([CH3:24])[CH:13]=[CH:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]=1[CH3:23])=[CH:3][CH:4]=[CH:5][C:6]([O:8][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:25](=[O:27])[CH3:26])=[CH:30][CH:31]=1)=[O:7]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: CC(C=CC=C(C)C=CC1=C(C)CCCC1(C)C)=CC=CC(=O)O
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OC(=O)C=CC=C(C)C=CC=C(C)C=CC2=C(C)CCCC2(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 5,9-dimethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenoic acid (0.5 g. 1.5 mmol) and 4-acetamidophenol (1.2 g, 8 mmol) in 40 ml of tetrahydrofuran (THF) was stirred in an ice bath under nitrogen and a solution of trifluroacetate (1.4 ml) in 5 ml of THF was added dropwise. The mixture was stirred at room temperature for 24 hours and concentrated in vacuo. The residue was diluted with methylene chloride and washed with aqueous NaHCO3 solution and brine. After drying with Na2SO4, the organic solution was concentrated in vacuo to give orange powders. Crystallization from ethyl acetate afforded 0.55 g. of the title compound as orange colored crystals. mp 219°-222° C., MS (EI): 459 (m+), 309, 291, 109; UV(MeOH) λmax. 394 nm, 245 nm.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:22])(=[O:21])[NH:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=2[F:20])=[CH:6][CH:5]=1.[OH-].[Na+]>O1CCOCC1>[F:20][C:13]1[CH:14]=[C:15]([F:19])[CH:16]=[C:17]([F:18])[C:12]=1[NH:11][S:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:23])=[O:2])=[CH:9][CH:8]=1)(=[O:21])=[O:22]
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2c(F)cc(F)cc2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2c(F)cc(F)cc2F)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
6.22 g (18 mmol) of 4-[N-(2,4,6-trifluorophenyl)sulfamoyl]-benzoic acid methyl ester is dissolved in 50 ml of dioxane, 18 ml (32 mmol) of 2N NaOH is added and stirred for 3 hours at 50° C. The solution is then concentrated by evaporation to about 10 ml under reduced pressure, acidified with 2N hydrochloric acid and the resulting solid precipitate is suctioned off. The filter residue is dissolved in ethyl acetate, the solution is shaken out with water, dried on sodium sulfate, filtered and evaporated to dryness. 5.58 g (16.85 mmol)=76.9% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][C:12](=[CH:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=2)[C:11]1=[O:31].Cl>CO>[OH:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][C:12](=[CH:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=2)[C:11]1=[O:31]
Reactant: CC(C)(C)c1cc(C=C2CCN(CCOC3CCCCO3)C2=O)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(C=C2CCN(CCO)C2=O)cc(C(C)(C)C)c1O
Yield: 62.2 %

Procedure:
300 mg of N-2-(2-tetrahydropyranyloxy)ethyl-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-pyrrolidone was hydrolyzed with hydrochloric acid in methanol according to the procedure of Example 5 to give 150 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[N:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[N:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH:10]=3
Reactant: O=c1c(Cc2cncnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Reactant: ClCCN1CCCCC1
Product: O=c1c(Cc2cncnc2)cn2c3c(cc(OCCN4CCCCC4)cc13)Sc1ccc(Br)cc1-2
Yield: 51.5 %

Procedure:
According to Example 34, the compound (110 mg) produced in Example 76 was reacted with 1-(2-chloroethyl)piperidine (69 mg) to obtain the title compound (71 mg; 51%).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([O:16][C@H:17]2[CH2:25][CH2:24][C@H:23]3[C@@H:19]([CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22]3)[C@@H:18]2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[CH2:14][OH:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>Cl.O1CCOCC1>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([O:16][C@H:17]2[CH2:25][CH2:24][C@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[C@@H:18]2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[CH2:14][OH:15])[CH:4]=[C:3]([C:2]([F:41])([F:40])[F:1])[CH:8]=1
Reactant: Cc1ccccc1[C@H]1[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CC[C@@H]1O[C@H](CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccccc1[C@H]1[C@@H]2CNC[C@H]2CC[C@@H]1O[C@H](CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The more polar isomer (1S) isomer of EXAMPLE 1 (tert-butyl (3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxylate, 2.0 g, 3.4 mmol) was stirred in 4 N HCl in dioxane for 1 hr. The volatiles were removed, and the residue was taken into ethyl acetate. The organic layer was separated, and the aqueous was extracted with ethyl acetate. The combined organic layers were washed consecutively with 2 N NaOH, brine, dried over MgSO4 and the solvent was removed to give 1.65 g of the amine title compound. M++1: 488.22
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([N:9]=[N+:10]=[N-:11])[CH2:7][OH:8])(=[O:3])[CH3:2].[C:12]([N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[N+:20]([O-:22])=[O:21])#[C:13][CH3:14]>>[C:1]([O:4][CH2:5][CH:6]([N:9]1[CH:14]=[C:13]([CH2:12][N:15]2[CH:19]=[CH:18][N:17]=[C:16]2[N+:20]([O-:22])=[O:21])[N:11]=[N:10]1)[CH2:7][OH:8])(=[O:3])[CH3:2]
Reactant: CC#Cn1ccnc1[N+](=O)[O-]
Reactant: CC(=O)OCC(CO)N=[N+]=[N-]
Product: CC(=O)OCC(CO)n1cc(Cn2ccnc2[N+](=O)[O-])nn1
Temperature: 60 °C
Yield: 51.7 %

Procedure:
A vial containing Compound 24 (500 mg, 3.14 mmol) and 1-propynyl-2-nitroimidazole (475 mg, 3.14 mmol) was heated at 60° C. overnight. The resultant solid was purified on a silica gel cartridge using EtOAc:Hex as the eluent to afford 504 mg (52% yield) of a white solid.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([C@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:25]([CH2:33][CH3:34])C(=O)OC(C)(C)C)[S:14]2)[C@H:10]1[F:35])C1C=CC=CC=1.B(Cl)(Cl)Cl>>[CH2:33]([NH:25][C:13]1[S:14][C@H:15]2[O:16][C@H:17]([C@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])[C@@H:9]([OH:8])[C@H:10]([F:35])[C@H:11]2[N:12]=1)[CH3:34]
Reactant: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](F)[C@H](OCc3ccccc3)[C@@H]([C@@](C)(O)C(F)(F)F)O[C@@H]2S1
Agent: ClB(Cl)Cl
Product: CCNC1=N[C@@H]2[C@@H](F)[C@H](O)[C@@H]([C@@](C)(O)C(F)(F)F)O[C@@H]2S1

Procedure:
The above material, tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate (0.100 g, 0.191 mmol), was deprotected with BCl3 using the procedure described for Example 20. After purification on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 1:17), (3aR,5S,6R,7R,7aR)-2-(ethylamino)-7-fluoro-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol was obtained as a white solid (0.053 g, 84%). 1H NMR (400 MHz, CD3OD) δ 6.26 (d, J=6.8 Hz, 1H), 5.04-4.92 (m, 1H), 4.54-4.50 (m, 1H), 4.15-4.07 (m, 1H), 3.73 (d, J=8.6 Hz, 1H), 3.34-3.21 (m, 2H), 1.33 (s, 3H), 1.17 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 163.47 (d, J=2.2 Hz), 127.40 (q, J=284.2 Hz), 93.11 (d, J=175.6 Hz), 89.36, 75.75 (q, J=27.3 Hz), 73.50 (d, J=27.2 Hz), 72.90, 68.94 (d, J=25.7 Hz), 39.95, 16.72 (q, J=1.5 Hz), 14.98; MS, (ES, m/z) [M+H]+ 333.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]1(O)[C:17]([F:20])([F:19])[F:18])=[O:5])[CH3:2].P(Cl)(Cl)(Cl)=O>>[CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[C:17]([F:19])([F:20])[F:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1OC(c2ccccc2)=NC1(O)C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1oc(-c2ccccc2)nc1C(F)(F)F
Yield: 75 %

Procedure:
2-Phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid was prepared according to the procedure described in Bioorg. Med. Chem. Lett. 2003, 13, 1517. A solution of 2-chloro-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (436 mg, 2 mmol) and benzamide (484 mg, 4 mmol) in ethanol (6 mL) in a sealed tube was heated at 120 degrees for 30 h. After cooling to room temperature, the reaction mixture was concentrated and purified by flash chromatography (silica gel 60, 230-400 mesh, 0-80% ethyl acetate in hexane for 25 min) to give 4-hydroxy-2-phenyl-4-trifluoromethyl-4,5-dihydro-oxazole-5-carboxylic acid ethyl ester as an off-white solid (229 mg, 38% yield). LCMS calcd for C13H12F3NO4 (m/e) 303, obsd 304 (M+H). The ester was dehydrated by heating with 2 mL of phosphorus oxychloride at 80 degree overnight. The reaction mixture was cooled and concentrated. The resulting residue was mixed with THF and concentrated again to remove remaining POCl3. The oily residue was quenched with water and extracted with DCM (2×). The organic layer was concentrated. The crude product was purified by flash chromatography (silica gel 60, 230-400 mesh, 0-50% ethyl acetate in hexane for 25 min) to yield 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid ethyl ester as an off-white solid (160 mg, 75% yield). The ester was hydrolyzed by stirring with lithium hydroxide monohydrate in a mixed solvent of 3:1:1 of THF:MeOH:water (3 mL) at RT for 4 h. The reaction was concentrated and water was added. The pH of the solution was adjusted to ˜1-2 with 1 N HCl. The white precipitate was collected by centrifugation and washed with water. After drying under vacuum, 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid was obtained as a white solid (141 mg, 98% yield. LCMS calcd for C11H6F3NO3 (m/e) 257, obsd 258 (M+H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:40][CH3:41])[CH2:4][NH:5][C:6]([CH:8]([CH2:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])[CH2:9][CH:10]([OH:33])[CH:11]([NH:20][C:21]([C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:7].CN(C1C=CC=CN=1)C.[C:51](OC(=O)C)(=[O:53])[CH3:52]>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][CH:3]([O:40][CH3:41])[CH2:4][NH:5][C:6]([CH:8]([CH2:34][CH2:35][C:36]([OH:39])([CH3:37])[CH3:38])[CH2:9][CH:10]([O:33][C:51](=[O:53])[CH3:52])[CH:11]([NH:20][C:21]([C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: COC(CNC(=O)C(CCC(C)(C)O)CC(O)C(Cc1cccc(F)c1)NC(=O)c1cnc2ccccc2n1)OC
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(CNC(=O)C(CCC(C)(C)O)CC(OC(C)=O)C(Cc1cccc(F)c1)NC(=O)c1cnc2ccccc2n1)OC
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid [4-(2,2-dimethoxy-ethylcarbamoyl)-1-(3-fluoro-benzyl)-2,7-dihydroxy-7-methyl-octyl]-amide (192 mg, 0.336 mmol) in pyridine (0.6 mL) was added dimethylaminopyridine (DMAP) (10 mg, 0.082 mmol) and acetic anhydride (0.093 mL, 0.984 mmol). The resulting solution was stirred for 3 hours then diluted with methylene chloride and washed with 1 M hydrochloric acid. The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound as a white foam (198 mg, 96%).
Reaction SMILES: [H-].[K+].[Cl:3][C:4]1[C:5]([Cl:25])=[CH:6][C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1.Br[CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:3][C:4]1[C:5]([Cl:25])=[CH:6][C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13][C:9]=3[N:10]([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:11]=2[CH:12]=1
Reactant: BrCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Cl)c(Cl)cc3c2CC1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCCc3ccccc3)c3cc(Cl)c(Cl)cc23)CC1
Reaction time: 0.25 h
Yield: 79.2 %

Procedure:
Potassium hydride (45 mg, 1.1 mmol) was added to a solution of tert-butyl 8,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.20 g, 0.56 mmol) in DMF (1.0 mL). After 15 min, 1-bromo-3-phenylpropane (0.13 mL, 0.86 mmol) was added. After 5 h, the reaction was quenched with saturated aqueous NH4Cl (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40S) with heptane/EtOAc (3:1) to give 0.21 g (78%) of a yellow solid: mp 119-124° C.; IR (diffuse reflectance) 2980, 2973, 2941, 2932, 1686, 1478, 1462, 1417, 1365, 1247, 1178, 1160, 1112, 855, 699 cm−1; MS (EI) m/z 472 (M+), 416, 227, 226, 224, 211, 188, 153, 115, 90, 56; Anal. Calcd for C26H30Cl2N2O2: C, 65.96; H, 6.39; N, 5.92; found: C, 66.01; H, 6.47; N, 5.82.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:23]([O-])([O-:25])=[O:24].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>>[N+:23]([C:5]1[CH:4]=[CH:3][C:2]([CH2:1][C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:12][CH:13]=2)=[CH:7][CH:6]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1ccc(Cc2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
6.0 Grams of methyl 5-benzylpicolinate were dissolved in 20 ml. of concentrated sulfuric acid at room temperature. A solution of 2.7 g of sodium nitrate in 20 ml. of concentrated sulfuric acid was added dropwise thereto under cooling to keep internal temperature at 5° C. After three hours, the reaction solution was poured into ice-water and neutralized with sodium carbonate. After extraction with ethyl acetate, washing with water and drying, the solvent was distilled out. The residue was recrystallized from methanol to obtain 3.5 g of 172°-178° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7](COCC[Si](C)(C)C)[N:8]=[C:9]2[C:14]=1[CH:13]=[C:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[F:23])[C:11]([CH3:24])=[CH:10]2)=[O:5])[CH3:2].Cl>CCO>[F:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[CH3:24])[NH:8][N:7]=[C:6]2[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1c2cc(-c3ccc(OC)cc3F)c(C)cc2nn1COCC[Si](C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1n[nH]c2cc(C)c(-c3ccc(OC)cc3F)cc12
Temperature: 90 °C
Yield: 92.6 %

Procedure:
To a solution of 5-(2-fluoro-4-methoxyphenyl)-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-3-carboxylic acid ethyl ester (440 mg, 0.96 mmol) in EtOH (6 mL) was added 3 N HCl solution (1.5 mL, 4.5 mmol). The reaction mixture was heated to 90° C. for 1 hour, cooled to room temperature and concentrated in vacuo. The residue was partitioned between water and EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo to give the title compound (292 mg, 93% yield) as an amber color solid. MS (ES+) 329.3 (M+H)+. 1H NMR (500 MHz, CDCl3) δ 8.06 (s, 1H), 7.48 (s, 1H), 7.22 (t, J=8.54 Hz, 1H), 6.81 (dd, J=8.54, 1.95 Hz, 1H), 6.75 (d, J=11.47 Hz, 1H), 4.52 (q, J=7.16 Hz, 2H), 3.89 (s, 3H), 2.34 (s, 3H), 1.47 (t, J=7.07 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][C:5]1[C:14]([C:15]([O:17]CC)=[O:16])=[C:13]([C:20]([O:22]CC)=[O:21])[C:12]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2.[OH-].[Na+].[NH4+].[Cl-].Cl>CO.C1COCC1>[F:32][C:2]([F:1])([F:31])[CH2:3][O:4][C:5]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([C:20]([OH:22])=[O:21])[C:12]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: CCOC(=O)c1c(C(=O)OCC)c(OCC(F)(F)F)c2ncccc2c1OCC(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(C(=O)O)c(OCC(F)(F)F)c2ncccc2c1OCC(F)(F)F
Yield: 100 %

Procedure:
A solution containing diethyl 5,8-bis(2,2,2-trifluoroethoxy)quinoline-6,7-dicarboxylate 3 (84.7 g, 180 mmol), 5 N NaOH (180 ml), THF (360 ml) and MeOH (180 ml) was heated to 60 C for 1.5 h. This mixture was then added to half-saturated NH4Cl and acidified with 2 N HCl to pH 0-1. The product was extracted into i-PrOAc:THF 1:1, dried over Na2SO4 and concentrated. It was triturated with ether:hexane 1:4 to yield the diacid 4 as an off-white solid (approx 100% yield).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCCCCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCCCCc2ccccc2)cc1
Reaction time: 2 h
Yield: 12.7 %

Procedure:
Diethylazodicarboxylate (0.49 g, 2.8 mmol) in tetrahydrofuran (2 mL) was added to a solution of 4-hydroxybenzaldehyde (0.25 g, 2.05 mmol), 5-phenyl-1-pentanol (0.34 mL, 2.05 mmol) and triphenylphosphine (0.73 g, 2.80 mmol) in tetrahydrofuran (10 mL) at rt. The reaction was stirred for 2 h. The reaction mixture was concentrated in vacuo. Silica gel chromatography eluting with 20% ethyl acetate/hexane yielded 0.070 g of desired product: 1H NMR (500 MHz, CD3OD): δ 9.83 (s, 1H), 7.86 (d, J=8.7 Hz, 2H), 7.25 (t, 2H), 7.14-7.20 (m, 3H), 7.06 (d, J=8.7 Hz, 2H), 4.09 (t, J=6.4 Hz, 2H), 2.65 (t, J=7.7 Hz, 2H), 1.80-1.88 (m, 2H), 1.68-1.75 (m, 2H), 1.49-1.57 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][OH:10].Cl[C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[OH:10][CH2:9][CH:5]1[CH2:6][CH2:7][CH2:8][N:4]1[CH2:3][CH2:2][NH:1][C:19]1[C:18]2[C:17](=[O:27])[C:16]3[C:25](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:24](=[O:26])[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Reactant: NCCN1CCCC1CO
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)c2c(NCCN3CCCC3CO)cccc21
Temperature: 65 °C
Reaction time: 24 h

Procedure:
To [1-(2-aminoethyl)-pyrrolidin-2-yl-]methanol (1.63 g, 11.3 mmol) in pyridine (10 mL) was added 1-chloroanthraquinone (1.37 g, 5.646 mmol), and the mixture was stirred at 65° C. for 24 hours. Pyridine was removed in vacuo and the resulting mixture of oil and solid was dissolved in CH2Cl2 and washed with H2O (3×50 mL) to remove any unreacted amine. The separated organic layer was removed in vacuo and the crude product was chromatographed using CH2Cl2/CH3OH (97:3). The desired product was yielded as a red powder (0.21 g, 11%). M.p. 113-115° C.; δH(250 MHz; CDCl3); 1.75-2.0 (m, 4H), 2.25-2.35 (m, 1H), 2.6-2.8 (m, 2H), 3.15-3.3 (m, 2H), 3.35-3.55 (m, 4H), 3.75-3.85 (2×d, 1H), 7.0 (2×d, 1H), 7.45-7.6 (m, 2H), 7.65-7.8 (m, 2H), 8.2 (2×d, H), 8.45 (2×d), and 10.05 (s, 1H, C(1)NH); δC(62.9 MHz; CDCl3); 24.11, 27.15, 41.64, 52.99, 53.82, 62.61, 65.26, 113.15, 115.60, 126.57, 132.86, 133.81, 135.32, 151.49, 183.77, and 184.89; FAB MS, m/z(M+H)+ 351; Anal. calcd for C21H22N2O3: C, 71.98; H, 6.33; N, 8.00. Found: C, 71.79; H, 6.13; N, 8.07.
Reaction SMILES: ClCCl.[NH2:4][C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]2[C:19]3[C:14](=[C:15]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])[CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[CH2:13][CH2:12][C:11]2=[O:30])=[CH:7][CH:6]=1.N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>O>[CH3:39][S:40]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:19]3[C:14](=[C:15]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])[CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[CH2:13][CH2:12][C:11]2=[O:30])=[CH:31][CH:32]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccc(N)cc1)C(=O)CC2
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccc(NS(C)(=O)=O)cc1)C(=O)CC2
Yield: 92 %

Procedure:
To a dichloromethane (20 ml) solution of 1.00 g (0.00243 mM) of 5-[1-(4-aminobenzyl)-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione were successively added pyridine (2.0 ml) and 0.21 ml (0.0027 mM) of methanesulfonyl chloride under ice cooling with stirring. The mixture was stirred at the same temperature for 30 minutes, and water was added to stop the reaction. The resultant was washed (twice with water and once with saturated sodium chloride solution), dried (magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate=1:10→1:1), giving 1.1 g (92% yield) of the target compound as a white amorphous solid.
Reaction SMILES: [CH2:1]([CH:3]1[NH:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]([NH2:15])[CH2:5][CH2:4]1)[CH3:2].C([C@@H]1N[C@@H](C2C=CC=CC=2)[C@@H](N)CC1)C.C([C@H]1N[C@H](C2C=CC=CC=2)[C@H](N)CC1)C.[CH3:46][O:47][C:48]1[CH:57]=[C:56]2[C:51]([N:52]([CH3:60])[C:53](=[O:59])[CH:54]3[CH2:58][CH:55]32)=[CH:50][C:49]=1[CH:61]=O>>[CH2:1]([CH:3]1[NH:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]([NH:15][CH2:61][C:49]2[CH:50]=[C:51]3[C:56](=[CH:57][C:48]=2[O:47][CH3:46])[CH:55]2[CH2:58][CH:54]2[C:53](=[O:59])[N:52]3[CH3:60])[CH2:5][CH2:4]1)[CH3:2]
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)C1CC21
Reactant: CCC1CCC(N)C(c2ccccc2)N1
Agent: CC[C@@H]1CC[C@@H](N)[C@@H](c2ccccc2)N1
Agent: CC[C@H]1CC[C@H](N)[C@H](c2ccccc2)N1
Product: CCC1CCC(NCc2cc3c(cc2OC)C2CC2C(=O)N3C)C(c2ccccc2)N1

Procedure:
By a procedure similar to the previous examples 9 and 9A: prepared through the reaction of 6-Ethyl-2-phenyl-piperidin-3-ylamine [or (2S,3S,6S)-6-Ethyl-2-phenyl-piperidin-3-ylamine or (2R,3R,6R)-6-Ethyl-2-phenyl-piperidin-3-ylamine] with 6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde [or (1S,1aR)-6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde or (1R,1aS)-6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde]. Melting Point: 231–234° C. (dec); 1H-NMR (dihydrochloride, 400 MHz, CD3OD): δ 0.48 (app. q, J=5.0 Hz, 1H), 1.02 (t, J=7.5 Hz, 3H), 1.64 (ddd, J=4.2, 9.1, 9.1 Hz, 1H), 1.70–1.85 (comp, 3H), 2.21 (ddd, J=5.0, 7.5, 9.5 Hz, 1H), 2.35–2.50 (comp, 3H), 2.61 (ddd, J=8.3, 8.3, 5.5 Hz, 1H), 3.28 (s, 3H), 3.61 (m, 1H), 3.71 (s, 3H), 4.00 (m, 1H), 4.14 (ab q, J=13.3, 6.2 Hz, 2H), 5.12 (d, J=4.97 Hz, 1H), 7.09 (d, J=12.9 Hz, 2H), 7.59–7.60 (m, 3H), 7.80–7.82 (m, 2H).