Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:37]([O:39][CH2:40][CH3:41])=[O:38])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][C@H:16]([N:18]([CH2:27][C@@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[OH:29])[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:5])[CH3:2].CC1C=CC=C(C)N=1.[Si:50](OS(C(F)(F)F)(=O)=O)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51]>C(Cl)Cl>[CH2:40]([O:39][C:37]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][C@H:16]([N:18]([CH2:27][C@H:28]([O:29][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[C:19]([O:21][CH2:22][C:23]([Cl:25])([Cl:24])[Cl:26])=[O:20])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:38])[CH3:41]
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N(C[C@H](O)c3cccc(Cl)c3)C(=O)OCC(Cl)(Cl)Cl)cc2O1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)C(=O)OCC(Cl)(Cl)Cl)cc2O1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To a -78° C. solution of 3.75 g (5.47 mmol) (R,R)-5-{2-[[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester and 60 mL of CH2Cl2 was added 1.27 mL (1.17 g, 10.94 mmol) of 2,6-lutidene followed by 1.38 mL (1.59 g, 6.03 mmol) of TBSOTf. After stirring at -78° C. for 1.5 h, the reaction mixture was quenched with 50 mL sat. aq. NaHCO3 and warmed to room temperature. After extraction with 3×150 mL Et2O, the combined organics were washed with 1×200 mL sat. CuSO4, 1×200 mL brine, dried over MgSO4, filtered and evaporated to a cloudy white oil. Flash chromatography on silica gel, eluting with hexanes/EtOAc (8/1 to 4/1) gave 3.42 g (4.46 mmol, an 82% yield) of the title compound (Rf =0.31; 4/1 hexanes/EtOAc) as a gummy colorless solid; 1H NMR (300 MHz, CDCl3): δ-0.13-(-0.08) (m, 3H), 0.00-0.06 (m, 3H), 0.85-0.91 (m, 9H), 1.05 (d, J=6.7 Hz, 3H), 1.33 (t, J=7.1 Hz, 6H), 2.60-2.75 (m, 1H), 2.77-2.96 (m, 1H), 3.00-3.31 (m, 2H), 3.77-4.00 (m, 1H), 4.35 (q, J=7.1 Hz, 4H), 4.65-4.88 (m, 2H), 5.02-5.20 (m, 1H), 6.60-6.85 (m, 4H), 7.15-7.37 (m, 3H); MS (ES) m/z (relative intensity): 790 (M+ +Na, 100), 768 (M+ +H, 20).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27](=[O:34])[N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27](=[O:34])[N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[N:17]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCC(=O)N3CCCCC3)ncc2[N+](=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](CNc2nc(NCC(=O)N3CCCCC3)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
(4-{[5-Nitro-2-(2-oxo-2-piperidin-1-yl-ethylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester (36 mg, 0.07 mmol) was dissolved in CH2Cl2 (10 mL) and TFA (1 mL) was added to the solution. The reaction mixture was stirred at room temperature for 16 h. The solution was treated with 3M Na2CO3 to pH 9 and the organic phase was separated. The aqueous phase was extracted with CH2Cl2 and the combined organic phase was dried over Na2SO4 and then concentrated. The resulting residue was purified by silica gel prep TLC using 10:1:0.3 CH2Cl2:MeOH:Et3N as an eluent to afford 27 mg of the title compound as a yellow solid (93%), m/z 392.6 [M+1]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH:31]([NH2:34])([CH3:33])[CH3:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH:31]([CH3:33])[CH3:32])[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Reactant: CC(C)N
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CNC(C)C)C2

Procedure:
The title compound was prepared (0.064 g, 52%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and isopropylamine (0.40 g, 6.76 mmol). mp 213-215° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]3[S:42][C:43]([C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)=[CH:44][CH:45]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:53]=[O:54])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:55]=[O:56].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]3[S:42][C:43]([C:46]4[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=4)=[CH:44][CH:45]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:55][OH:56])[CH:53]=[O:54])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 9h (1.53 g, 2.1 mmol) was dissolved in 15 mL 1,4-dioxane, followed by addition of 3.4 mL 37% formaldehyde solution and 6.3 mL 1 M sodium hydroxide. The reaction mixture was stirred for 16 hour at 70° C., and was partitioned after 50 mL saturated sodium chloride solution were added. The aqueous phase was extracted with ethyl acetate (50 mL×3) and the organic extracts were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 91 (2.0 g, pale yellow grease), which was used directly in the next step without purification.
Reaction SMILES: C[N:2]1[C:6]([NH:7][C:8]([O:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4([C:34]([OH:36])=[O:35])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:4]=[N:3]1.Br[C:38]1C=CC(C2N(C)N=NC=2C(O)=O)=CC=1>>[CH3:38][N:4]1[C:5]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4([C:34]([OH:36])=[O:35])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)=[C:6]([NH:7][C:8]([O:10][C@@H:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])=[O:9])[N:2]=[N:3]1
Reactant: C[C@@H](OC(=O)Nc1c(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)nnn1C)c1ccccc1
Reactant: Cn1nnc(C(=O)O)c1-c1ccc(Br)cc1
Product: C[C@@H](OC(=O)Nc1nnn(C)c1-c1ccc(-c2ccc(C3(C(=O)O)CC3)cc2)cc1)c1ccccc1

Procedure:
This compound was prepared using the same method as described for the preparation of 1-{4′-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid in Example 2, except that 5-(4-bromo-phenyl)-1-methyl-1H-[1,2,3]triazole-4-carboxylic acid (from step 4b in Example 1) was used. LC/MS calcd for C28H26N4O4 (m/e) 482.0, obsd 483.0 (M+H); 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.30 (m, 2.4H), 1.32-1.62 (m, 4.6H), 4.05 (s, 3H), 5.69 (br m, 1H), 7.20-7.40 (br m, 5H), 7.46 (d, J=8.1 Hz, 2H), 7.59 (d, J=−8.1 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H), 7.77 (d, J=7.6 Hz, 2H), 9.34 (br s, 1H), 12.39 (s, 1H).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:16]=[CH:15][C:10]2[CH2:11][CH2:12][CH2:13][O:14][C:9]=2[CH:8]=1.[C:17](=[O:19])=[O:18].C(OCC)C>O1CCCC1>[F:6][C:7]1[CH:16]=[CH:15][C:10]2[CH2:11][CH2:12][CH2:13][O:14][C:9]=2[C:8]=1[C:17]([OH:19])=[O:18]
Reactant: O=C=O
Reactant: Fc1ccc2c(c1)OCCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1c(F)ccc2c1OCCC2
Temperature: -78 °C

Procedure:
A stirred solution of 30.4 mL (0.076 mole) of n-butyllithium (2.5M in hexanes) in 200 mL of tetrahydrofuran was cooled to -78 °C., and 10.5 grams (0.069 mole) of 3,4-dihydro-7-fluoro-2H-1-benzopyran was added portionwise. Upon completion of the addition, the reaction mixture was maintained at -78° C. for 30 minutes. The reaction mixture was then exposed to a carbon dioxide atmosphere for 18 hours. The reaction mixture was then stirred with diethyl ether and extracted with an aqueous 5% sodium hydroxide solution. The basic layer was washed with diethyl ether, made acidic with concentrated hydrochloric acid, and then extracted with diethyl ether. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 10.2 grams of 3,4-dihydro-7-fluoro-2H-1-benzopyran-8-ylcarboxylic acid. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][C@@H:15]3[CH2:17][C@H:12]2[CH2:13][N:14]3[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:29]COCC>CO>[F:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][C@@H:15]3[CH2:17][C@H:12]2[CH2:13][N:14]3[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=2)[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:29])=[O:5]
Reactant: CCOCC
Reactant: O=C(O)c1ccc(N2C[C@@H]3C[C@H]2CN3c2cccc(C(F)(F)F)c2)cc1F
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(N2C[C@@H]3C[C@H]2CN3c2cccc(C(F)(F)F)c2)cc1F
Yield: 46.3 %

Procedure:
A stirring solution of title compound 225 (250 mg 0.657 mmol), 2N HCl in ether (1 mL, 2.00 mmol) and methanol (25 mL) was refluxed over the weekend. The mixture was concentrated and the residue was purified by chromatography: 20 g SiO2, dry loaded on a samplet, 0% to 50% ethyl acetate in hexanes over 20 minutes to afford title compound 226 (120 mg, 46%) as a white foam. LRMS (ESI): (calc.) 394.13. (found) 395.3 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[CH:7][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=1)[OH:6].[CH2:16](I)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:5]=1[O:6][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCI
Reactant: COC(=O)c1ccc(NC(C)=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1cc(NC(C)=O)ccc1C(=O)OC
Temperature: 70 °C
Reaction time: 30 h
Yield: 69.9 %

Procedure:
A mixture of p-acetylaminosalicylic acid methyl ester (5.0 g), hexyl iodide (7.6 g), potassium carbonate (9.9 g), and dimethylformamide (20 ml) is stirred at 70° C. for 30 hours. The reaction mixture is poured into ice-water and extracted with diethyl ether. The organic layer is washed successively with aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated. The residue is chromatographed on silica gel with chloroform-methanol (20:1) to give 4-acetylamino-2-hexyloxybenzoic acid methyl ester (4.9 g) as an oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:14]([CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:16]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[C:1]1([C:7]2[CH:8]=[C:9]3[N:14]([C:15]=2[C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([O:26][S:16]([C:19]4[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=4)(=[O:18])=[O:17])=[CH:35][CH:34]=2)[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc3ccccn3c2)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C(=O)Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Oc2ccc(C(=O)c3c(-c4ccccc4)cc4ccccn34)cc2)cc1
Reaction time: 12 h
Yield: 52.3 %

Procedure:
In a flask, containing a solution of 6.5g (0.044 mol) of 2-phenylindolizine in 100 ml of dichlorethane, 12.4 g (0.04 mol) of 4-tosyloxy-benzoyl chloride were added at room-temperature. The mixture was stirred for 12 hours and then poured into a 10%-solution of sodium carbonate. The product which precipitated was washed to neutrality and recrystallized from carbon tetrachloride. In this manner, 2-phenyl-3-(4-tosyloxy-benzoyl)-indolizine was obtained in a yield of 52.3%. M.P. 177°-178° C.
Reaction SMILES: [C:1]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1C(=O)N([Br:19])C(=O)C1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:19][CH2:2][C:1]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1)=[O:3]
Reactant: CCOC(=O)C1(C(C)=O)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)C1(C(=O)CBr)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a 100 mL of round-bottomed flask was added ethyl 1-acetylcyclo-propanecarboxylate (15.6 g, 100 mmol) and NBS solid (21.36 g, 120 mmol), followed by p-toluene sulfonic acid (1.9 g, 10 mmol). After stirring at rt for 8 hrs, the reaction mixture was extracted with diethyl ether (200 mL) and washed with 80 mL of water. The organic phase was then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (1:30(v/v)EtOAc/n-hexane) to give the title compound as colorless oil (16.68 g, 71%).
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[C:8]=2[C:7]([CH:20]=[O:21])=[CH:6][CH:5]=1.S(=O)(=O)([OH:25])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[F:22][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[C:8]=2[C:7]([C:20]([OH:25])=[O:21])=[CH:6][CH:5]=1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a stirring solution of 4-(difluoromethoxy)-8-nitrodibenzo[b,d]furan-1-carbaldehyde (6.5 g, 0.021 mol) and sulphamic acid (3.7 g, 0.038 mol) in acetone (25 mL) was added sodium chlorite (3.0 g, 0.033 mol) in water (25 mL) dropwise at 5-10° C. After 15 minutes, the reaction slurry was allowed to stir at room temperature for 17 hours. The reaction slurry was poured into ice-cold water and filtered. The solid obtained was washed with hexane and dried. Yield—81.9%. 1H-NMR (DMSO-d6) δ: 7.44-7.64-7.80 (t, 2H), 8.09-8.16 (m, 2H), 8.53-8.55 (m, 1H), 9.80 (d, 1H), 13.75 (s, 1H); HPLC (purity): 87.6%; Mass calculated for C14H7F2NO6-323.2, observed—322.0; Rf—0.25 (Ethyl acetate:Hexane (1:1).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([C:21]([O:23]C)=[O:22])[CH:18]=[CH:17][N:16]4[C:25]=3[CH3:26])[CH:8]=[CH:7][C:5]=2[N:6]=1.O.Cl>CO.[OH-].[Na+]>[NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][N:16]4[C:25]=3[CH3:26])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COC(=O)c1ccn2c(C)c(CCc3ccc4nc(N)oc4c3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(C(=O)O)ccn12
Temperature: 25 °C
Reaction time: 20 h
Yield: 31.3 %

Procedure:
A mixture of 2-amino-6-[2-(7-methoxycarbonyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.8 g) in methanol (8 ml) and 1N sodium hydroxide (6.8 ml) was stirred for 20 hours at ambient temperature. To the reaction mixture was added a water and the mixture was adjusted to pH 5 with 4N-hydrochloric acid. The isolated precipitate was collected by filtration and dried to give 2-amino-6-[2-(7-carboxy-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.24 g).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=4)[N:23]=2)[N:20]=[CH:19][CH:18]=[CH:17]3)[CH2:10][CH2:9]1)=[O:7])C.Cl>C(O)C.O>[F:34][C:31]([F:32])([F:33])[O:30][C:26]1[CH:25]=[C:24]([C:22]2[N:23]=[C:14]([CH:11]3[CH2:10][CH2:9][CH:8]([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]3)[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(OC(F)(F)F)c3)n2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCC(c2cc3cccnc3c(-c3cccc(OC(F)(F)F)c3)n2)CC1
Temperature: 45 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Potassium hydroxide (2M (aq), 2.5 ml) is added to a solution of 4-[8-(3-trifluoromethoxyphenyl)-[1,7]naphthyridin-6-yl]-cyclohexanecarboxylic acid ethyl ester (250 mg, 0.56 mmol) in ethanol (10 ml) and stirred 45° C. for 1 h. The reaction mixture is diluted with water and acidified with c.HCl to pH3. The mixture is stirred for 2 h. then filtered, and the filter cake washed with water to yield the product as a white powder (218 mg). MS (AP+) 417.65
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br.[CH3:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CS(C)=O.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][N:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[CH3:16]
Reactant: BrCc1cccc(Br)c1
Reactant: Cc1nc2ccccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc2ccccc2n1Cc1cccc(Br)c1
Reaction time: 4 h

Procedure:
First 1.23 g (11 mmol) of potassium-tert-butoxide and after 45 minutes 2.62 g (10.5 mmol) of 3-bromo-benzylbromide are added to a solution of 1.32 g (10 mmol) of 2-methyl-benzimidazole in 10 ml of absolute dimethylsulphoxide and the reaction mixture is stirred for 4 hours. The mixture is then diluted with ethyl acetate, washed 3× with 14% NaCl solution, dried, concentrated and purified by flash chromatography (silica gel; petroleum ether/ethyl acetate=9:1 to ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34][NH2:35])([CH3:29])([CH3:28])[CH3:27].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([NH:35][CH2:34][CH2:33][NH:32][C:31](=[O:36])[O:30][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)c(CC(=O)NCCNC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Yield: 75 %

Procedure:
a Fluorescent Indo-Coumarinyl Analog: Compound 27cc, N-{2-(Coumarin-3-carboxylamido)ethyl}-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide, was synthesized by the method depicted in FIG. 6. Briefly, indomethacin was complexed with tert-Butyl-2-aminoethylcarbamate for 16 hours at room temperature in the presence of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCl), 1-hydroxybenzotriazole (HOBt), N,N-diisopropylethylamine (DIPEA), and N,N-dimethylformamide (DMF). A yellow solid of tert-Butyl 2-[2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamido]ethylcarbamate was produced as a yellow solid at 75% yield. This product was then dissolved in dichloromethane and treated with HCl (gas) for 2 hours at room temperature, producing N-(2-Aminoethyl)-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide hydrochloride as a brown solid with a yield of 98%, which was reacted with N,N-diisopropylethylamine (DIPEA) in dichloromethane for 5 minutes at room temperature prior to the addition of Coumarin-3-carboxylic acid, 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCl), 1-hydroxybenzotriazole (HOBt), and N,N-diisopropylethylamine (DIPEA) in dichloromethane. The reaction proceeded for 16 hours at room temperature and produced Compound 27cc as a yellow solid (35% yield).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11]([OH:13])=O)(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[NH2:22]>>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11]([NH:22][C:21]1[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=[C:19]([C:18]([F:17])([F:30])[F:31])[CH:20]=1)=[O:13])(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: COc1ccc(C(=O)C(C)C)cc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COc1ccc(C(=O)C(C)C)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 61.4 %

Procedure:
Using 5-isobutyryl-2-methoxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[C:19]3[CH:24]=[C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[N:22]=[C:21](S(C)(=O)=O)[N:20]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[CH:39]([NH2:42])([CH3:41])[CH3:40]>CN1C(=O)CCC1.O>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[C:19]3[CH:24]=[C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[N:22]=[C:21]([NH:42][CH:39]([CH3:41])[CH3:40])[N:20]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(COc2cc(-c3c[nH]c4ccc(-c5cncc(C6CC6)n5)cc34)nc(S(C)(=O)=O)n2)cc1
Reactant: CC(C)N
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(COc2cc(-c3c[nH]c4ccc(-c5cncc(C6CC6)n5)cc34)nc(NC(C)C)n2)cc1
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with 5-(6-cyclopropylpyrazin-2-yl)-3-(6-(4-methoxybenzyloxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1H-indole (26 mg, 0.049 mmol) and isopropylamine (0.4 ml, 4.66 mmol) in NMP (0.5 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 1 h. The mixture was diluted with water and extracted with CHCl3/iPrOH (4:1). The combined organic layer was washed with water, dried, filtered and concentrated to give the crude compound, which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 507.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH3:12].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:4]1[C:3]([O:2][CH3:1])=[C:8]([O:9][CH2:10][CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCOc1ccnc(C)c1OC
Solvent: ClC(Cl)(Cl)Cl
Product: CCCOc1ccnc(CBr)c1OC
Yield: 27.9 %

Procedure:
To a solution of 3-methoxy-2-methyl-4-propoxypyridine (1.0 g) in carbon tetrachloride (70 ml), was added N-bromosuccinimide (1.0 g) and the mixture was irradiated with and infrared lamp (Toshiba, 100 V, 375 WR) for 2 hours at reflux. An insoluble substance was filtered off, and the filtrate was concentrated and purified by column chromatography on silica gel, to give 2-bromomethyl-3-methoxy-4-propoxypyridine (0.4 g) as a reddish brown oil.