Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([NH:19][CH3:20])=[O:18].CCN(C(C)C)C(C)C>C1COCC1>[Cl:10][C:6]1[N:5]=[C:4]([S:11][CH3:12])[N:3]=[C:2]([NH:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([NH:19][CH3:20])=[O:18])[C:7]=1[C:8]#[N:9]
Reactant: CNC(=O)c1ccc(C)c(N)c1
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C)c(Nc2nc(SC)nc(Cl)c2C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (2.19 g, 10 mmol), 3-amino-4,N-dimethyl-benzamide (1.64 g, 10 mmol), and DIEA (1.40 g, 18.8 mmol) were mixed in THF (20 mL). The resulting mixture was stirred at room temperature for overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was concentrated and the crude product was purified by flash chromatography to obtain 3-(6-chloro-5-cyano-2-methylsulfanyl-pyrimidin-4-ylamino)-4,N-dimethyl-benzamide (2.78 g, 80%). MS (m/z): 348 (M+H).
Reaction SMILES: S(=O)(=O)(O)O.N([O-])=O.[Na+].[F:10][C:11]1[C:17]([F:18])=[C:16]([CH3:19])[C:15]([F:20])=[CH:14][C:12]=1N.[ClH:21]>C(O)(=O)C.[Cu]Cl>[F:18][C:17]1[C:11]([F:10])=[C:12]([Cl:21])[CH:14]=[C:15]([F:20])[C:16]=1[CH3:19]
Reactant: Cc1c(F)cc(N)c(F)c1F
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1c(F)cc(Cl)c(F)c1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To conc. sulfuric acid (3 ml) is added sodium nitrite (0.3 g). The mixture is stirred at.70° C. for 10 minutes and then cooled to below 40° C. and thereto a solution of 2,3,5-trifluoro-4-methylaniline (0.48 g) in acetic acid (5 ml) is added dropwise below 40° C. After stirring for 30 minutes, the reaction mixture is added dropwise to a solution of copper (I) chloride (1.04 g) in conc. hydrochloric acid (10.4 ml) and the mixture is stirred at 80° C. for 30 minutes and then cooled. The resultant is poured into ice-water, extracted with dichloromethane, and the extract is .washed with water and dried. The solvent is distilled off under reduced pressure and purified by silica-gel column-chromatography (eluent; dichloromethane: n-hexane =1 : 4) to give 2,3,6-trifluoro-4-chlorotoluene (0.22 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])=[O:34].ClC(OC(C)C(F)(F)F)=O>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:23][CH2:22][N:21]([C:33]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[Cl:42])=[O:34])[CH2:20]3)=[CH:13][C:12]2=[O:31])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Reactant: O=C(Cl)Oc1ccccc1Cl
Agent: CC(OC(=O)Cl)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-n2ccc(OCC3CCN(C(=O)Oc4ccccc4Cl)C3)cc2=O)cc1

Procedure:
Example 19 was prepared according to procedures described in Example 2, Step A and Step C, substituting tert-butyl 3-((1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)methyl)pyrrolidine-1-carboxylate for tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate in Step A and 2-chlorophenyl chloroformate for 1,1,1-trifluoropropan-2-yl chloroformate in Step C. 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J=8.80 Hz, 2H), 7.61 (d, J=8.80 Hz, 2H), 7.43 (d, J=8.25 Hz, 1H), 7.23-7.31 (m, 3H), 7.14-7.19 (m, 1H), 6.10-6.21 (m, 2H), 3.38-4.14 (m, 6H), 3.10 (s, 3H), 2.77-2.93 (m, 1 H), 2.15-2.32 (m, 1H), 1.83-2.00 (m, 1H). MS (ESI) 503 (M+H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[C:8]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(CC2CCCC2)C(=O)O)cc1OC
Reactant: Nc1nccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-propionic acid (0.50 g, 1.79 mmol) in methylene chloride (17.9 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (1.0 mL, 1.97 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 10 min and at 25° C. for 30 min. The reaction mixture was then treated with a solution of 2-aminothiazole (0.39 g, 3.95 mmol) and N,N-diisopropylethylamine (0.76 mL, 4.3 mmol) in tetrahydrofuran (8.98 mL). The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-N-thiazol-2-yl-propionamide (665 mg, 100%) as a pale yellow solid: mp 50-52° C.; EI-HRMS m/e calcd for C19H24N2O3S (M+) 360.1507, found 360.1516.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH:8]=1)[OH:7].O1CCOCC1.[CH:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>P(Cl)(Cl)(Cl)=O.O>[CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([C:18]2[C:17]([CH:16]=[O:23])=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([CH:8]=1)[OH:7]
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(O)c(-c2ccccc2C=O)c(O)c1

Procedure:
To a solution of 621 g. of 5-methylresorcinol in 1 l. of dioxane were added 530 g. of benzaldehyde and 30 g. of phosphorus oxychloride as a catalyst. The resulting mixture was reacted at room temperature for 24 hours and then poured into 5 l. of a cold water. There was obtained a pale brown powdery resin.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CO.C(N(CC)CC)C.[Cl:15][CH:16]([O:20][N:21]=[CH:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:15][CH:16]([O:20][N:21]=[CH:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([N:3]([O:4][CH3:5])[CH3:2])=[O:18]
Reactant: CNOC
Reactant: O=C(Cl)C(Cl)ON=Cc1ccccc1Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C(Cl)ON=Cc1ccccc1Cl
Reaction time: 1 h

Procedure:
A mixture of 3.0 gm. (0.031 mole) of N,O-dimethylhydroxylamine hydrochloride and 60 ml. of methanol was cooled in ice bath; then 6.3 gm. (0.062 mole) of triethylamine was stirred in. A solution of 4.1 gm. (0.015 mole) of 2,6-dichlorobenzylideneaminooxyacetyl chloride in toluene was added dropwise and with cooling and stirring. After one hour more at ice-bath temperature the reaction mixture was allowed to stand overnight at room temperature; then evaporate to dryness under reduced pressure. The residue was ground under water, separated, extracted with methylene chloride and the extract was treated with decolorizing carbon, then filtered. The filtrate, evaporated to dryness under reduced pressure, gave 3.1 gm. (69.1%) of a solid melting at 62°-72° C. The melt was turbid, however, and the crude product was extracted with hot n-heptane. The hot extract was passed through a Florisil* column; evaporation of the solvent left product melting at 76°-78° C. (clear).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][C:10]1=[O:15].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]2=[O:15])=[CH:3][CH:4]=1
Reactant: O=C1COCCN1
Reactant: Brc1ccc(Br)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1COCCN1c1ccc(Br)cc1
Temperature: 105 °C
Yield: 67.6 %

Procedure:
A solution of 1,4-dibromobenzene (283 mg, 1.200 mmol), morpholin-3-one (101.104 mg, 1.000 mmol), dibasic potassium phosphate (348 mg, 2.000 mmol), copper (I) iodide (38.1 mg, 0.200 mmol) and N,N′-dimethylethylenediamine (0.043 ml, 0.400 mmol) in dioxane (3 ml) was purged with nitrogen for 2 min, sealed in a reaction vial and heated in a heating block at 105° C. for 15 h. The crude product mixture was filtered, and charged to a 12 g silica gel cartridge which was eluted with 0-50% EtOAc in hexanes to give the title compound (173 mg, 0.676 mmol, 67.6% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.56 (1H, none), 7.55 (2 H, d, J=8.80 Hz), 7.24 (2 H, d, J=8.58 Hz), 4.04 (2 H, dd, J=5.83, 4.29 Hz), 3.73-3.79 (2 H, m). HPLC (condition F): ret. Time 2.213 min; LC/MS [m/z, (M+H)] 258.0.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[S:6][C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH:17]C(=O)C(Cl)(Cl)Cl)[C:8]=2[N:24]=1)[CH3:2].C[O-].[Na+]>CO>[CH2:1]([O:3][CH2:4][C:5]1[S:6][C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:24]=1)[CH3:2]
Reactant: CCOCc1nc2c(NC(=O)C(Cl)(Cl)Cl)nc3ccccc3c2s1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trichloroacetyl isocyanate (0.7 mL) was added to a solution of 2-(ethoxymethyl)thiazolo[4,5-c]quinoline-5N-oxide (1.0 g) in dichloromethane (50 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated under vacuum to provide N-(2-(ethoxymethyl)thiazolo[4,5-c]quinolin-4-yl)trichloroacetamide. The amide was taken up in methanol and then combined with 1 equivalent of sodium methoxide. The reaction mixture was stirred at ambient temperature for 30 minutes and then concentrated under vacuum. The reaction was run a second time using 2 g of the N-oxide. The products were combined and recrystallized from isopropanol to provide 2.25 g of 2-(ethoxymethyl)thiazolo[4,5-c]quinoline-4-amine as light yellow needles, m.p. 149-151° C. Analysis: Calculated for C13H13N3OS: % C, 60.21; % H, 5.05; % N, 16.20; Found: % C, 59.86; % H, 4.97; % N, 16.16.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([NH:13][NH:14][C:15](=O)[CH2:16][CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:19][C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)=O)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:48])=CC=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[S:48][C:15]([CH2:16][CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:19][C:20]3[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)NNC(=O)c1ccc([N+](=O)[O-])c(F)c1)Cc1ccc(C(F)(F)F)nc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCc1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1)Cc1ccc(C(F)(F)F)nc1
Temperature: 100 °C
Yield: 89.1 %

Procedure:
A mixture of tert-butyl ((1R)-4-(2-((3-fluoro-4-nitrophenyl)carbonyl)hydrazino)-4-oxo-1-((6-(trifluoromethyl)-3-pyridinyl)methyl)butyl)carbamate (214 mg, 394 μmol) and Lawesson's reagent (207 mg, 512 μmol) in THF (3 mL) was heated in a Biotage® microwave reactor at 100° C. for 15 minutes. The mixture was concentrated under reduced pressure, and the resulting yellow solid was taken up in MeOH/DCM, absorbed onto silica gel, and purified by flash chromatography (silica gel, 2% to 6% MeOH/DCM) to provide tert-butyl (R)-4-(5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ylcarbamate (190 mg, 89.1% yield) as a light yellow solid. LCMS (API-ES) m/z: 564.0 (M+Na+)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20](O)=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3][CH2:2]1)=[O:21]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: O=C(O)c1ccnc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CCN(C(=O)c2ccnc(F)c2)CC1
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl piperidin-4-ylmethylcarbamate 93-1 (1.07 g, 5.0 mmol), 2-fluoroisonicotinic acid 93-2 (706 mg, 5.0 mmol) and HATU (1.90 g, 5.0 mmol) in DMF (20 mL) was added DIEA (2.5 mL, 15.0 mmol) at room temperature. The mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate (100 mL), washed with H2O and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, and eluted with 5% methanol in dichloromethane to give tert-butyl (1-(2-fluoroisonicotinoyl)piperidin-4-yl)methylcarbamate 93-3 as a pale yellow solid. MS m/z 338.1 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]([OH:9])[CH2:6][O:7][CH3:8].C(Cl)Cl.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>CO>[CH3:1][O:2][C:3](=[O:14])[C:4]([NH:10][C:11](=[O:13])[CH3:12])=[C:5]([O:9][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:6][O:7][CH3:8]
Reactant: COCC(O)C(NC(C)=O)C(=O)OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COCC(OS(C)(=O)=O)=C(NC(C)=O)C(=O)OC

Procedure:
A solution consisting of 20.5 g (0.1 mol) of alcohol 8, 1 l of methylene chloride, and 20.5 ml of triethylamine was cooled to 0° under an argon atmosphere. Methanesulfonyl chloride (8.5 ml) was added dropwise with stirring. The resultant solution was maintained at 0° for 1/2 hr. Methanol (0.4 ml) was added, and the solvent was removed in vacuo (35°). The white solid residue was triturated with ethyl acetate and the extract filtered through a column containing silica gel (200 g). The fractions containing product (as determined by thin layer chromatography) were concentrated in vacuo yielding 2-acetamido-3-mesyloxy-4-methoxy-butenoic acid methyl ester (9) as a partially crystalline residue. Crystallization from ethyl acetate/petroleum ether (bp 35°-60°) gave one of the diastereomers as a white crystalline solid: mp 101.5°-104.5°; NMR (CDCl3) δ 6.4 (broad d, 1H, NH), 5.2 (m, 1H, CH2CH), 5.0 (m, 1H, CHNH), 3.8 (s, 3H, CH3O2C--), 3.6 (m, 2H, CH3OCH2 --), 3.3 (s, 3H, CH3OCH2 --), 3.0 (s, 3H, CH3SO 3 --), 2.0 (s, 3H, CH3CONH--). (Calcd. for C9H17NO7S: C, 38.16; H, 6.05; N, 4.94; S, 11.31. Found: C, 38.34; H, 6.21; N, 4.92; S, 11.27).
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.[CH2:15]([O:17][C:18](=[O:35])[CH2:19][CH2:20][CH2:21][CH:22]([NH:33][CH3:34])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)[CH3:16].[F:36][C:37]([F:52])([F:51])[C:38]1[CH:39]=[C:40]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[C:41](Cl)=[O:42]>O1CCCC1>[CH2:15]([O:17][C:18](=[O:35])[CH2:19][CH2:20][CH2:21][CH:22]([N:33]([C:41](=[O:42])[C:40]1[CH:44]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:46]=[C:38]([C:37]([F:36])([F:51])[F:52])[CH:39]=1)[CH3:34])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)[CH3:16]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CCCC(Cc1c[nH]c2ccccc12)NC
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)CCCC(Cc1c[nH]c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.16 ml (8.32 mmol) of triethylamine and then a solution of 947 mg (2.38 mmol) of 6-(1H-indol-3-yl)-5-methylamino-hexanoic acid ethyl ester trifluoracetic acid salt in 10 ml of tetrahydrofuran are added dropwise at 0° C. in the course of 30 minutes to a solution of 0.49 ml (2.61 mmol) of 97% 3,5-bistrifluoromethyl-benzoyl chloride in 10 ml of tetrahydrofuran. The mixture is stirred at room temperature for 18 hours, then filtered and washed with 10 ml of tetrahydrofuran. The filtrate is concentrated by evaporation and diethyl ether is added. The mixture is then filtered over silica gel and the filtrate is concentrated by evaporation. The title compound is obtained in the form of a brown oil. MS (EI): 528 (M+.), 483, 398, 257, 241, 130. TLC: ethyl acetate, Rf =0.66.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:8])[CH3:7].Cl[O-:10].[Na+].ClCl>O1CCCC1.O>[CH3:7][C:6]1[O:8][CH:5]=[CH:4][C:3](=[O:10])[C:2]=1[OH:1]
Reactant: [O-]Cl
Reactant: CC(O)c1ccco1
Agent: ClCl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1occc(=O)c1O

Procedure:
To a solution of 1(2-furyl)-1-ethanol (0.05 mole) in 15 ml of tetrahydrofuran and 15 ml of water at 5° C. is added 21.7 ml of 2.8 M sodium hypochlorite solution. Chlorine (0.05 mole) is added to the reaction flask via a gas inlet tube maintaining the reaction temperature below 5° C. The reaction mixture is then heated to reflux and the tetrahydrofuran removed by distillation. Heating is continued for an additional hour. The reaction mixture is cooled and maltol is isolated by the procedure described in Example 1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[N:1]1([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCc2ccccc21
Temperature: 80 °C
Yield: 73.2 %

Procedure:
Indoline (1.07 g, 8.98 mmol), ethyl bromoacetate (1.20 ml, 10.8 mmol), potassium carbonate (2.10 g, 15.2 mmol) were added to dimethylformamide (14 ml), and the mixture was heated at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature and diluted with ethyl acetate, and then washed with water and dried over sodium sulfate. Insoluble solids were removed by filtration and the filtrate was evaporated under reduced pressure. The resulting oil was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound as yellow oil (1.35 g, yield: 73%).
Reaction SMILES: [CH3:1][C:2]1(C)[CH2:7]CCC(C)(C)N1.C(=O)=O.[Li]CCCC.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=1.C(=O)CC>C1COCC1>[Cl:19][C:20]1[N:21]=[CH:22][C:23]2[C:24](=[O:26])[O:25][CH:1]([CH2:2][CH3:7])[C:27]=2[CH:28]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCC=O
Solvent: C1CCOC1
Product: CCC1OC(=O)c2cnc(Cl)cc21
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (5 ml, 30 mmol) in a 100 ml round bottomed flask equipped with a magnetic stirrer, is put under argon atmosphere and 20 ml of dry THF is added. The reaction mixture is cooled to −50° C. by adding a controlled amount of dry ice to an acetone bath. The cooled reaction mixture is treated dropwise with nBuLi solution (16 mL of a 2.5 M solution in hexanes, 40 mmol) and the reaction is let stir at that −50 C for 0.5 h. A solution of 6-chloro-nicotinic acid (1.58 g, 10 mmol) in THF (20 mL) is added dropwise to the reaction at −50° C. The reaction is stirred at −50° C. for 1.5 h and then cooled to −78° C. The reaction mixture is treated with propionaldehyde (4.2 ml, 58 mmol) dropwise at −50° C. The reaction is stirred at −78° C. for 2 h and warmed to room temperature overnight. The reaction mixture is concentrated to remove solvent and water and ether are added. The aqueous layer is extracted with ether (6×50 ml). The aqueous phase is treated with aqueous 1N HCl solution, until the pH of aqueous layer is ˜6 and is then extracted with ether (3×40 mL). The aqueous solution is treated with aqueous 1N HCl solution until the pH ˜2 and solution is heated at 100° C. overnight. An oily residue separates from solution. Dichloromethane is added to the aqueous phase which dissolves the oily residue. Without extracting, the solution is poured into a separatory funnel and the organic phase is collected. The organic phase is washed with saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered and concentrated to give the title compound (1.45 g, 73%) as a yellow oil.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Br:5][CH:6]([F:12])[C:7](OCC)=[O:8]>C(O)C.C(O)CO>[CH:1]([NH:4][C:7](=[O:8])[CH:6]([Br:5])[F:12])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(F)Br
Reactant: CC(C)N
Solvent: OCCO
Solvent: CCO
Product: CC(C)NC(=O)C(F)Br
Reaction time: 2 h

Procedure:
A solution of 14.8 grams (0.25 mole) isopropyl amine in 25 milliliters ethanol was added dropwise to a solution of ethyl bromofluoroacetate, 40 grams (0.22 mole), and 5 drops ethylene glycol in 100 milliliters ethyl alcohol at 10°-15° C. The solution was stirred at 10°-20° C. for 2 hours and was then stored at -15° C. for 3 days. At this time the solution was evaporated to leave a liquid, 41.8 grams, nD30 1.4629, identified by infrared spectroscopy as the title compound.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:14][CH3:15])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[O:22]=[C:23]1[N:27]([CH2:28][C:29]([OH:31])=O)[C:26]2[CH:32]=[C:33]([O:36][C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:35][C:25]=2[O:24]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.FC(F)(F)C(O)=O>CN(C)C=O.CC#N.O>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][C:4]([CH:7]([N:14]([CH3:15])[C:29](=[O:31])[CH2:28][N:27]2[C:26]3[CH:32]=[C:33]([O:36][C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:35][C:25]=3[O:24][C:23]2=[O:22])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1
Reactant: O=C(O)Cn1c(=O)oc2ccc(OC(F)(F)F)cc21
Reactant: CNC(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)Cn1c(=O)oc2ccc(OC(F)(F)F)cc21)C(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Reaction time: 0.25 h
Yield: 6.3 %

Procedure:
[1-(4-biphenylyl)-2-(1-pyrrolidinyl)ethyl]methylamine (0.09 g, 0.32 mmol) and [2-oxo-5-[(trifluoromethyl)oxy]-1,3-benzoxazol-3(2H)-yl]acetic acid (0.097 g, 0.35 mmol) were dissolved in 1 mL of dimethylformamide. Triethylamine (0.13 mL, 0.96 mmol) was delivered to the room temperature mixture, and the solution was allowed to stir for several minutes before a separate solution of 1H-1,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.155 g, 0.32 mmol) dissolved in 1 mL of dimethylformamide was added to the mixture at room temperature. The reaction was maintained at that temperature for 18 hours, before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=2.0 min and m/e 541 [M+1]+. The reaction mixture was filtered through a 0.45 μm PTFE Acrodisk and the crude residue was purified by prep HPLC (Waters, 30×75 mm, 84 mL/min, A: acetonitrile B: water (pH=10, NH4OH), A: 10 to 99% over 15 min, UV detection at 214 nm) to give the title compound (0.011 g. 0.02 mmol, 6%) as an off-white amorphous solid. MS (ES) m/e 541 [M+H]+.