Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:13]=1[NH:22][C:23](=[O:48])[CH2:24][CH:25]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])=[CH:33][C:32]=1[O:46][CH3:47])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH3:11])([CH3:10])[CH3:9].C1(OC)C=CC=CC=1>C(Cl)Cl>[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:13]=1[NH:22][C:23](=[O:48])[CH2:24][CH:25]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:33][C:32]=1[O:46][CH3:47])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH3:9])([CH3:10])[CH3:11]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(OCC(=O)OC(C)(C)C)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(OCC(=O)O)cc1OC
Temperature: 30 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
1.0 ml (15.0 mmol) of trifluoroacetic acid was added to a solution of 575 mg (1.01 mmnol) of N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(4-t-butoxycarbonylmethoxy-2-methoxyphenyl)octanamide [prepared as described in step (i) above] and 241 μl (2.22 mmol) of anisole in 15 ml of methylene chloride, and the resulting mixture was stirred overnight at 30° C. At the end of this time, the reaction mixture was freed from the solvent and excess reagents by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 50 g of silica gel using ethyl acetate as the eluent, to give 506 mg (yield 98%) of the title carboxylic acid derivative as a foam-like substance.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:6][CH:5]([OH:7])[CH2:4]1.F[C:9]1[CH:10]=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([CH3:15])[CH:14]=1>C1COCC1.O>[CH3:15][C:13]1[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=1[N+:16]([O-:18])=[O:17])[O:7][CH:5]1[CH2:6][O:3][CH2:4]1
Reactant: OC1COC1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OC2COC2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
Sodium hydride (0.084 g, 2.11 mmol) was added to a solution of oxetan-3-ol (0.12 g, 1.62 mmol) in THF (10 mL) at 0° C. The mixture was stirred at 0° C. for 20 minutes, after which time a solution of 5-fluoro-2-nitrotoluene (0.26 g, 1.62 mmol) in THF (10 mL) was added. The mixture was allowed to warm to room temperature, and stirring was continued for 16 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with brine. The organic layer was concentrated under vacuum and the resulting crude material was purified by column chromatography (silica gel: 100-200 mesh, 8-30% EtOAc/hexane) to give the title compound (0.18 g, 54%) as a yellow gum. LCMS (ES+) no mass ion observed, RT 1.71 minutes (method 2).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.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.[NH2:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][O:91][CH2:92][CH2:93][C:94]([O:96][C:97]([CH3:100])([CH3:99])[CH3:98])=[O:95]>C(Cl)Cl>[C:97]([O:96][C:94](=[O:95])[CH2:93][CH2:92][O:91][CH2:90][CH2:89][O:88][CH2:87][CH2:86][O:85][CH2:84][CH2:83][NH:82][C:13](=[O:14])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:100])([CH3:99])[CH3:98]
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OC(=O)NCCCCCCCCCC
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)propanoic acid (15, 1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (2.4 eq), followed by tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate (1.2 eq). The reaction was stirred at room temperature for 4 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-100% EtOAc/Hex to afford the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10]([CH:22]=[CH2:23])=[N:11][C:12]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:13][C:14]=1[CH3:15])=[O:8].[OH-:26].[Na+].OO>C1COCC1>[CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10]([CH:22]([OH:26])[CH3:23])=[N:11][C:12]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[CH:13][C:14]=1[CH3:15])=[O:8]
Reactant: C=Cc1nc(N2CCOCC2)cc(C)c1C(=O)NCCCC(C)(C)C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)nc(C(C)O)c1C(=O)NCCCC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 750 mg, (2.17 mmol) N-(4,4-dimethylpentyl)-4-methyl-6-morpholino-2-vinyl-pyridine-3-carboxylic acid amide (synthesized according to the methods described for example 9) in THF (10 ml) was added dropwise 730 μl (7.6 mmol) at 0° C. and the resulting mixture was stirred at RT for 16 h. The reaction mixture was cooled to 0° C. and a 1N aq. NaOH sol (4 ml) was added dropwise over a period of 0.5 h, followed by the addition of H2O2 (30% in water, 4 ml). Then the reaction mixture was stirred at RT for 4 h and was then extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. After CC (hexane/EtOAc 3:7) a mixture of N-(4,4-dimethylpentyl)-2-(2-hydroxyethyl)-4-methyl-6-morpholino-pyridine-3-carboxylic acid amide and N-(4,4-dimethylpentyl)-2-(1-hydroxyethyl)-4-methyl-6-morpholino-pyridine-3-carboxylic acid amide was obtained. This mixture was dissolved in THF (6 ml) and benzene (6 ml) and 24 mg, 0.0716 mmol) TBAHS was added at RT followed by the addition of a 25% aq. NaOH sol (6 ml) and 0.450 μl (7.16 mmol) iodomethane. Then the reaction mixture was slowly heated to 70° C. and stirred at the same temperature for 3 h. The additional 0.450 μl (7.16 mmol) iodomethane was added and stirring was continued at 70° C. for another 3 h. Then the organic layer was separated and the aq. layer was extracted with EtOAc. The combined organic layer was washed with water, and brine, dried over Na2SO4 and concentrated in vacuo. Purification of this residue by CC (hexane/EtOAc 3:2) provided 60 mg (0.16 mmol, 6%) N-(4,4-Dimethyl-pentyl)-2-(2-methoxy-ethyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 358). [M+H]+ 377.3
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[H-].[Na+].[H][H].Cl[C:14]1[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1>CN(C)C=O>[Cl:20][C:19]1[C:14]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[N:15][CH:16]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:18]=1
Reactant: [H][H]
Reactant: Oc1ccc(O)cc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Temperature: 0 °C
Yield: 43 %

Procedure:
To a solution prepared by dissolving 2.8 g of hydroquinone in 20 ml of N,N-dimethylformamide, 1.39 g of sodium hydride (60% oil-based) was added, slowly, with stirring under ice cooling. After completion of the generation of hydrogen gas from the reaction solution, a solution prepared by dissolving 5 g of 2,3-dichloro-5-trifluoromethylpyridine in 10 ml of N,N-dimethylformamide was added dropwise. After stirring at room temperature for 3 hours, the reaction solution was poured into ice-water, and extracted twice with 200 ml of diethyl ether. Then, the ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 2.88 g of 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenol (yield, 43%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](#[N:14])[CH:12]=[CH2:13]>C(O)C>[C:11]([CH2:12][CH2:13][NH:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)#[N:14]
Reactant: NCCCc1ccccc1
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCNCCCc1ccccc1

Procedure:
A mixture of 3-phenylpropylamine (0.95 g, 7 mmol) and acrylonitrile (0.55 ml, 8.4 mmol) in ethanol (30 ml) was refluxed for 2 hours to give N-(2-cyanoethyl)-3-phenyl-propylamine.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]2[O:15][CH2:16][O:17][C:12]2=[CH:11][C:10]=1[CH2:18][C:19]([O:21]C)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)C>[CH2:16]1[O:15][C:13]2=[CH:14][C:9]3[C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:25][NH:24][C:19](=[O:21])[CH2:18][C:10]=3[CH:11]=[C:12]2[O:17]1
Reactant: NN
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccccc1)OCO2
Solvent: CCO
Solvent: O
Product: O=C1Cc2cc3c(cc2C(c2ccccc2)=NN1)OCO3
Yield: 29.7 %

Procedure:
A solution of methyl 2-benzoyl-4,5-methylenedioxyphenylacetate (110 mg, 0.37 mmol) and hydrazine hydrate (30 μL, 0.53 mmol) in ethanol (15 mL) was refluxed for 5 days. The solvent was removed in vacuo and the resulting residue was separated by chromatography to yield the title compound (30 mg, 0.11 mmol, 29%), mp, 182°-184° C. 1H NMR (CDCl3) 8.59 (s, 1H), 7.60-7.41 (m, 5H), 6.83 (s, 1H), 6.63 (s, 1H), 6.03 (s, 2H), 3.46 (s, 2H). Anal. Calcd. for C16H12N2O3.0.25H2O: C, 67.48; H, 4.42; N, 9.84. Found C, 67.25; H, 4.21; N, 9.88.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:13]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Reactant: CBr
Product: CC(C(=O)O)c1ccc(Cl)cc1
Product: COC(=O)C(C)c1ccc(Cl)cc1

Procedure:
The same reaction and the same treatment as in Example 1 were followed using methyl p-chlorophenylacetate and methyl bromide, producing methyl p-chloro(α-methyl)phenylacetate in a yield of 83% and p-chloro(α-methyl)phenylacetic acid in a yield of 5%. The spectral data of the ester were as follows.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[C:17]2[C:22]([F:23])=[CH:21][N:20]=[C:19]([O:24][CH3:25])[CH:18]=2)[C:10](OC)=[O:11])=[CH:5][CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1([CH3:26])[C:6]([C:7]2[CH:8]=[C:9]([CH2:10][OH:11])[CH:14]=[CH:15][C:16]=2[C:17]2[C:22]([F:23])=[CH:21][N:20]=[C:19]([O:24][CH3:25])[CH:18]=2)=[CH:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(-c2cc(OC)ncc2F)c(C2=CCCC2(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(CO)cc2C2=CCCC2(C)C)c(F)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To methyl 3-(5,5-dimethylcyclopent-1-enyl)-4-(5-fluoro-2-methoxypyridin-4-yl)benzoate T8.2 (295 mg, 830 μmol) was added THF. The mixture was cooled to 0° C., and LAH (1660 μL, 1660 μmol) was added dropwise. The reaction was stirred at room temperature for 1 hour, and was quenched with water and a small amount of Rochelle's salt solution. Purification with silica gel chromatography afforded (3-(5,5-dimethylcyclopent-1-enyl)-4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)methanol T8.3 (201 mg) as an oil (74%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@H:10]([CH3:11])[O:9][C@@H:8]([CH3:12])[CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].I[CH2:24][C:25]#[C:26][C:27]([CH3:30])([OH:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)C>[CH3:1][O:2][C:3]([C@H:5]1[C@H:10]([CH3:11])[O:9][C@@H:8]([CH3:12])[CH2:7][N:6]1[S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:24][C:25]#[C:26][C:27]([OH:29])([CH3:30])[CH3:28])=[CH:20][CH:21]=1)(=[O:15])=[O:14])=[O:4]
Reactant: CC(C)(O)C#CCI
Reactant: COC(=O)[C@H]1[C@H](C)O[C@@H](C)CN1S(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)[C@H]1[C@H](C)O[C@@H](C)CN1S(=O)(=O)c1ccc(OCC#CC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2S,3R,6S)-4-(4-Hydroxy-benzenesulfonyl)-2,6-dimethyl-morpholine-3-carboxylic acid methyl ester, (200 mg, 0.607 mmol) (prepared according to the methods described in U.S. patent application Ser. No. 60/096256, filed Aug. 12, 1998) was dissolved in dimethyl formamide (6 mL). 5-Iodo-2-methyl-pent-3-yn-2-ol (272 mg, 1.214 mmol) and cesium carbonate (593 mg, 1.821 mmol) were added and the reaction stirred at room temperature for 4 hours. The reaction was diluted with diethyl ether (100 mL) and washed with water (5 times 10 mL) and brine (30 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the title compound. The crude material was used directly in the preparation of Example 1 without further purification. 1HNMR (400 MHz, CDCl3): δ=7.70 (d, J=8.9 Hz, 2H), 7.0 (d, J=8.9 Hz, 2H), 4.74 (bs, 2H), 4.50 (q, J=6.6 Hz, 1H), 4.26 (s, 1H), 3.92 (m, 1H), 3.54 (s, 3H), 3.50 (m, 1H), 2.93 (dd, J=12.3 and 11.0 Hz, 1H), 1.48(s, 6H), 1.44 (d, J=5.4 Hz, 3H), 1.01(d, J=6.0, 3H). MS: Calculated for C20H27NO7S (M−OH): 408.15. Found: 408.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 100 g (0.7 mol) of 2-chloro-4-fluorotoluene in 250 ml of concentrated H2SO4 is added portion-wise 85 g (0.875 mol) of KNO3 at 0° C. (addition of the whole amount of KNO3 is finished in about 1 hour). The reddish mixture is slowly warmed-up at room temperature overnight and quenched over crushed ice and extracted with EtOAc. The organic layers are combined, dried over MgSO4 and concentrated. The crude oil is then purified over a large silica plug (eluent: 97/3 hexanes/EtOAc) to afford 2-chloro-4-fluoro-5-nitrotoluene as a pale yellow oil that solidifies upon standing. 1H NMR (CDCl3, 400 Mz): 7.97 (d, J=8.0 Hz, 1H), 7.32 (d, J=10.4 Hz, 1H), 2.43 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([N:18]1[C@@H:30]2[C@@H:21]([C@H:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=32)[CH2:20][CH2:19]1)=[O:17])=[O:8].O.[NH2:38][CH2:39][CH2:40][OH:41]>>[OH:41][CH2:40][CH2:39][NH:38][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([N:18]1[C@@H:30]2[C@@H:21]([C@H:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=32)[CH2:20][CH2:19]1)=[O:17])=[O:8]
Reactant: O=C(CCCCCBr)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Reactant: NCCO
Solvent: O
Product: O=C(CCCCCNCCO)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Yield: 73 %

Procedure:
6-Bromo-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexyl)hexanamide (150 mg, 0.27 mmol) was stirred in 2-aminoethanol (3 ml) at 60° C. for 6 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel column chromatography and eluted with ethyl acetate-methanol (5:1, v/v) to give the title compound (106 mg, 73%) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[S:18][C:17]([CH2:19][CH2:20][CH3:21])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1)(=O)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.BrC(C)[CH2:35][N:36]1[CH:40]=[CH:39][CH:38]=[CH:37]1>ClCCl>[CH2:19]([C:17]1[S:18][C:9]2[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH2:2][CH2:35][N:36]4[CH:40]=[CH:39][CH:38]=[CH:37]4)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:15])[C:10]=2[N:16]=1)[CH2:20][CH3:21]
Reactant: CCCc1nc2c(N)nc3cc(OC(C)=O)ccc3c2s1
Reactant: CC(Br)Cn1cccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3cc(OCCCn4cccc4)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 45.8 %

Procedure:
A mixture of 4-amino-2-propylthiazolo[4,5-c]quinolin-7-ol acetate (318 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. 1-(2-Bromopropyl)pyrrole (206 mg, 1.1 mmol) was added dropwise over a period of 10 minutes. After 3 hours an additional equivalent of cesium carbonate was added in a single portion followed by the dropwise addition of an equivalent of 1-(2-bromopropyl)pyrrole. After 1 additional hour the heat source was removed; the reaction mixture was diluted with water (250 mL), stirred for 1 hour, and then filtered. The isolated solid was rinsed with water and then dried to provide a brown powder. This material was dissolved in dichloromethane and then purified by HPFC eluting with a gradient of 0-20% CMA in chloroform over 1500 mL. The resulting solid was recrystallized from acetonitrile to provide 168 mg of 2-propyl-7-[3-(pyrrol-1-yl)propoxy]thiazolo[4,5-c]quinolin-4-amine as an off-white solid, mp 152.0-154.0° C. MS (ESI) m/z 367 (M+H)+; Anal. calcd for C20H22N4OS: C, 65.55; H, 6.05; N, 15.29. Found C, 65.52; H, 5.80; N, 15.37.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[O:35][CH:36]=[C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[N:38]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:37]6[N:38]=[C:34]([CH3:33])[O:35][CH:36]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: Cc1nc(C2(N)CC2)co1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5coc(C)n5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.15 g, 0.34 mmol, 1 eq), 1-(2-methyloxazol-4-yl)cyclopropanamine (0.047 g, 0.34 mmol, 1 eq), EDCI.HCl (0.076 g, 0.4 mmol, 1.2 eq), HOBT (0.054 g, 0.4 mmol, 2 eq) and TEA (0.14 ml, 1.02 mmol, 3 eq) were dissolved in dichloromethane and the reaction was stirred at room temperature for 14 h. The reaction was diluted with water and the product was extracted with dichloromethane and purified by preparative HPLC yielding the desired product. Yield: 47 mg (25%)1H NMR (400 MHz, DMSO-d6): δ 1.12-1.15 (m, 2H), 1.21-1.24 (m, 2H), 2.29 (s, 3H), 2.34 (s, 3H), 2.81-2.82 (d, 3H, J=4.60 Hz), 3.95 (s, 3H), 7.12 (s, 1H), 7.31-7.32 (m, 1H), 7.34-7.40 (t, 2H, J=3.21 Hz), 7.56 (s, 1H), 7.61 (s, 1H), 7.71 (s, 1H), 7.73 (s, 1H), 7.97-8.01 (m, 2H), 8.46-8.48 (m, 1H), 8.67 (s, 1H). LCMS: (ES+) m/z=554.2 (M+H). Column: Ascentis Express C18 (5×2.1 mm-2.7 μm). Mphase A: 2% ACN-98% H2O-10 mM NH4COOH. Mphase B: 98% ACN-2% H2O-10 mM NH4COOH. Flow-1 mL/Min
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([NH:10][C:11]2[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=2)[CH:4]=1.CN(C)C=O.P(Cl)(Cl)([Cl:25])=O>ClCCl>[Cl:25][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([NH:10][C:11]2[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=2)[CH:4]=1
Reactant: Cc1cnc(Nc2ncc(C#N)s2)cc1CO
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cnc(Nc2ncc(C#N)s2)cc1CCl

Procedure:
2-(4-Hydroxymethyl-5-methyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (9-8, 0.400 g, 1.62 mmol) was stirred in 5 mL of anhydrous dichloromethane. N,N-Dimethylformamide (0.125 mL, 1.62 mmol) was added followed by the addition of phosphorous oxychloride (0.151 mL, 1.62 mmol). After 2 hours the reaction was concentrated in vacuo. Half-saturated NaHCO3 (aq) was added and the resulting precipitate was filtered and washed with water. Air drying provided the titled product, 9-9 contaminated with BINAP oxide. 1H NMR (DMSO-d6) δ 8.24 (s, 1H), 8.22 (s, 1H), 7.17 (s, 1H), 4.80 (s, 2H), 2.28 (s, 3H).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][S:12]C(=O)NCC)=[O:8])(=O)C.C[O-].[Na+]>CO.Cl>[SH:4][CH2:5][CH:6]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][SH:12])=[O:8]
Reactant: CCNC(=O)SC[C@H](NC(=O)C(CSC(C)=O)CC(=O)OC)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(CS)C(=O)N[C@@H](CS)C(=O)O

Procedure:
To a solution of N-[3-(acetylthio)-2-(methoxycarbonylmethyl)propanoyl]-S-(N-ethylcarbamoyl)-L-cysteine (1.9 g.) in methanol (10 ml.), sodium methoxide (0.84 g.) is added. After thirty minutes, the solution is diluted with 0.1 N hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness in vacuo to yield N-[3-mercapto-2-(methoxycarbonylmethyl)propanoyl]-L-cysteine.
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][S:5]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(=[O:7])=[O:6]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][S:5]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(=[O:7])=[O:6]
Reactant: C[Si](C)(C)CCS(=O)(=O)n1ccc2cc(CO)ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C[Si](C)(C)CCS(=O)(=O)n1ccc2cc(C=O)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
A solution of [1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indol-5-yl]-methanol (2.1 g, 6.74 mmol) in methylene chloride (30 mL) was added at 0° C. to a mixture of activated manganese dioxide (22 g, azeotropically dried with toluene (2×)) and methylene chloride (70 mL) in a 500 mL round bottom flask. The reaction mixture was stirred at 0° C. for 30 min and filtered through a pad of celite. Solvents were removed in vacuo to afford the title compound as a white solid (1.8 g, 80%). 1H-NMR (CDCl3, 500 MHz) δ 10.06 (s, 1H), 8.15 (s, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.87 (dd, J=8.6, 1.5 Hz, 1H), 7.54 (d, J=3.4 Hz, 1H), 6.80 (d, J=3.6 Hz, 1H), 3.24-3.20 (m, 2H), 0.86-0.82 (m, 2H), −0.06 (s, 9H). 13C-NMR (CDCl3, 125 MHz) δ 191.9, 138.5, 132.3, 130.7, 128.8, 125.3, 125.1, 1134.6, 108.4, 51.4, 10.2, −2.1. Mass spec. 310.12 (MH)+.