Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].NC(N)=O.[NH2:8][C:9]([NH:11][N:12]([CH2:21][C:22]([O:24]C)=O)[C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=1)=[O:10].P([O-])([O-])([O-])=O>C(COC)OC.CCCCCC.CCOCC>[CH3:20][C:15]1[CH:14]=[C:13]([N:12]2[CH2:21][C:22](=[O:24])[NH:8][C:9](=[O:10])[NH:11]2)[CH:18]=[C:17]([CH3:19])[CH:16]=1
Reactant: COC(=O)CN(NC(N)=O)c1cc(C)cc(C)c1
Agent: C[O-]
Agent: NC(N)=O
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: COCCOC
Product: Cc1cc(C)cc(N2CC(=O)NC(=O)N2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Sodium methoxide (0.32 g, 5.96 mmol) was added to a stirred solution of the urea (Intermediate 37; 0.75 g, 2.98 mmol) in dimethoxyethane (30 ml) over 4A sieves under a nitrogen atmosphere. After stirring at room temperature for ca. 30 min the resultant slurry was added to pH 6.5 aqueous phosphate buffer (50 ml) and extracted with ethyl acetate (3×75 ml). The combined extracts were washed with saturated brine (50 ml), dried and evaporated to afford an orange solid. Trituration of this material with hexane/ether (1:1) (2×15 ml) gave the title compound as a light pink solid (0.52 g, 64%), m.p. ca 255° (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[C:24]([C:25]4[CH:26]=[C:27]([C:33]5[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][C:34]=5[CH3:46])[CH:28]=[N:29][C:30]=4[O:31][CH3:32])=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)[C@H:13]2[CH3:51])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[F:53][CH:54]1[CH2:57][NH:56][CH2:55]1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[F:53][CH:54]1[CH2:57][N:56]([C:21]2[N:20]=[C:19]([CH2:18][N:14]3[C@@H:13]([CH3:51])[C@@H:12]([C:4]4[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=[C:2]([F:1])[CH:3]=4)[O:16][C:15]3=[O:17])[C:24]([C:25]3[CH:26]=[C:27]([C:33]4[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[CH:35][C:34]=4[CH3:46])[CH:28]=[N:29][C:30]=3[O:31][CH3:32])=[CH:23][N:22]=2)[CH2:55]1
Reactant: FC1CNC1
Reactant: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-{5-[4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (INTERMEDIATE 48, 96 mg, 0.131 mmol) in THF (1.5 mL) was added 3-fluoroazetidine hydrochloride (44 mg, 0.394 mmol) and triethylamine (0.082 mL, 0.591 mmol). The resulting mixture was subjected to microwave irradiation at 120° C. for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried (sodium sulfate), filtered and concentrated to give crude tert-butyl 4-{5-[2-(3-fluoroazetidin-1-yl)-4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (95 mg, 0.131 mmol). LCMS (M+H)+: 726.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:13][CH3:12])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: CN
Solvent: CCO
Product: CNc1ccc(Br)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 7a from 2,5-dibromo-nitrobenzene and methylamine solution in ethanol.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7]2[CH:19]=[C:18]([CH:20]=[CH2:21])[CH:17]=[CH:16][C:8]=2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.I[C:25]1[CH:26]=[C:27]([O:31][CH3:32])[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=3)[CH:17]=[CH:16][C:8]=2[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(Nc2ccc(F)cc2)c1
Reactant: COc1cccc(I)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-(4-fluoroanilino)-4-vinylbenzoate 0.12 g were added 3-iodoanisole 0.18 g, cesium carbonate 0.25 g, tetrabutylammonium bromide 37 mg and polymer-carried bis(acetato)triphenylphosphine palladium(II) 58 mg at room temperature, and it was stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(3-methoxyphenyl)vinyl)benzoate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)[C:7]#[N:8])([O-:3])=[O:2].Cl>CO.[Fe]>[NH2:12][C:10]1[CH:9]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=1)[C:7]#[N:8]
Reactant: N#Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: N#Cc1cc(N)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a suspension of 3,5-dinitrobenzonitrile (4.5 g, 23.30 mmol) in MeOH (100 mL) was added concentrated HCl (15 mL), followed by iron powder (3.90 g, 69.9 mmol). The mixture was stirred at room temperature for 30 min. and then concentrated. The residue was treated with water and the resulting solid product was collected by filtration to give Intermediate 71A (2.3 g, 61%). HPLC: Rt=1.245 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.68 (1H, s), 7.64 (1H, s), 7.24 (1H, s), 6.33 (2H, s).
Reaction SMILES: [F:1][C:2]([F:23])([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:38][C:39]1[NH:43][N:42]=[C:41]([NH2:44])[CH:40]=1>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:23])([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=1)[C:3]1[N:12]=[C:11]([NH:44][C:41]2[CH:40]=[C:39]([CH3:38])[NH:43][N:42]=2)[C:10]2[C:5](=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: COc1cccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc12
Agent: O=P(Br)(Br)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cccc2c(Nc3cc(C)[nH]n3)nc(C(F)(F)c3ccc(F)cn3)nc12
Temperature: 105 °C
Reaction time: 72 h
Yield: 30.3 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methoxyquinazolin-4-ol (450 mg, 1.4 mmol) were added phosphoryl tribromide (3.14 g) and toluene (4 mL) followed by DIEA (0.488 mL, 2.8 mmol). The mixture was heated at 105° C. for 1 h. The mixture was allowed to cool and was partitioned between EtOAc and saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (300 mg, 3.1 mmol) in DMF (4 mL) and the mixture was stirred at rt for 3 days. The crude mixture was purified by preparative HPLC (Varian C-18 reverse phase column, eluting with a gradient of solvent B=0.05% formic acid/ACN and solvent A=0.05% formic acid/H2O/5% ACN) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methoxy-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (170 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.16 (s, 3H) 3.95 (s, 3H) 5.91 (s, 1H) 7.38 (d, J=7.91 Hz, 1H) 7.56 (t, J=8.10 Hz, 1H) 7.93-8.06 (m, 2H) 8.19 (d, J=8.10 Hz, 1H) 8.66 (s, 1H) 10.53 (br s, 1H) 12.15 (br s, 1H); LC-MS (ESI) m/z 401 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@@:7]([C:16]([F:19])([F:18])[F:17])([OH:15])[C:6]=2[CH:5]=[C:4]([O:20][CH2:21][CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[CH:3]=1.[CH3:28][C:29]([N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1)([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[OH:15][C@@:7]1([C:16]([F:19])([F:17])[F:18])[C:6]2[CH:5]=[C:4]([O:20][CH2:21][CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[CH:3]=[C:2]([C:39]3[CH:38]=[N:37][N:36]([C:29]([CH3:28])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:40]=3)[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: CCOC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(O)CCCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)n1cc(-c2cc(OCCCC(C)(C)O)cc3c2-c2ccccc2[C@]3(O)C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 94.6 %

Procedure:
Under an argon atmosphere, (9R)-4-chloro-2-(4-hydroxy-4-methylpentyloxy)-9-(trifluoromethyl)-9H-fluoren-9-ol (169 mg) was dissolved in 1,4-dioxane (1.5 ml), ethyl 2-methyl-2-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazol-1-yl]propionate (194 mg), water (0.5 ml), tripotassium phosphate (178 mg), palladium acetate (9 mg), and SPhos (33 mg) were added, and the mixture was stirred at 100° C. for 4.5 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (twice). The obtained organic layer was washed successively with water (twice) and saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the solvent in the filtrate was evaporated. The obtained residue was purified by silica gel column chromatography (a mixture of hexane and ethyl acetate at a mixing ratio 1:1 (hexane:ethyl acetate) was used as an elution solvent) to give the title compound (218 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][OH:7].C([Li])CCC.C([O:20][B:21]([O:25]CC)[O:22]CC)C.[Cl-].[NH4+]>O1CCCC1>[OH:7][CH2:6][C:5]1[CH:8]=[C:9]([O:11][CH3:12])[C:10]([O:20][B:21]([OH:25])[OH:22])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(CO)cc(OC)c1
Reactant: CCOB(OCC)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(CO)cc(OC)c1OB(O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-dimethoxybenzyl alcohol (2.71 g) in tetrahydrofuran (50 mL) was added n-butyllithium (1.56M hexane solution; 36.2 mL)while cooling with ice with ice bath, and the internal temperature was raised to room temperature and stirred for 1 hour. The internal temperature was then cooled to −78° C., to the mixture was added triethoxyborane (9.6 mL), and the temperature was raised to room temperature while stirring. After completion of the reaction, saturated aqueous ammonium chloride was added to the reaction mixture while cooling with ice and the reaction mixture was extracted with ethyl acetate, and then after washing the organic extract with brine, it was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (50 g) and the title compound (1.72 g) was obtained as a white amorphous solid from the ethyl acetate fraction.
Reaction SMILES: C([Si](CC)(CC)[O:4][C@H:5]1[CH2:10][C@H:9]([O:11][Si](CC)(CC)CC)[CH2:8]/[C:7](=[CH:19]/[CH:20]=[C:21]2\[CH2:22][CH2:23][CH2:24][C@@:25]3([CH3:41])[C@H:29]\2[CH2:28][CH2:27][C@@H:26]3[C@@:30]2([CH3:40])[O:34][CH2:33][C@H:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[CH2:31]2)/[C:6]1=[CH2:42])C>CC#N.CCN(CC)CC>[OH:38][C:36]([CH3:39])([CH3:37])[CH2:35][C@@H:32]1[CH2:33][O:34][C@@:30]([C@@H:26]2[C@:25]3([CH3:41])[C@H:29](/[C:21](=[CH:20]/[CH:19]=[C:7]4\[C:6](=[CH2:42])[C@@H:5]([OH:4])[CH2:10][C@H:9]([OH:11])[CH2:8]\4)/[CH2:22][CH2:23][CH2:24]3)[CH2:28][CH2:27]2)([CH3:40])[CH2:31]1
Reactant: C=C1/C(=C\C=C2/CCC[C@@]3(C)[C@H]2CC[C@@H]3[C@]2(C)C[C@@H](CC(C)(C)O)CO2)C[C@@H](O[Si](CC)(CC)CC)C[C@@H]1O[Si](CC)(CC)CC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C1/C(=C\C=C2/CCC[C@@]3(C)[C@H]2CC[C@@H]3[C@]2(C)C[C@H](CC(C)(C)O)CO2)C[C@@H](O)C[C@@H]1O
Reaction time: 0.17 h
Yield: 90 %

Procedure:
HF-Py (0.4 mL) was added to a solution of compound 16 (134 mg, 0.2 mmol) in CH3CN (2.5 mL) and Et3N (1.5 mL). After 10 min, the reaction was quenched by the addition of saturated NaHCO3 (5 mL). The mixture was extracted with Et2O (2×20 mL). The combined organic phase was washed with saturated NaCl (25 mL) and H2O (25 mL), dried, filtered and concentrated in vacuum. The residue was purified by flash chromatography (SiO2, 1.5×9.5 cm, 50% EtOAc-hexanes) to give compound A (80 mg, 88%, white solid, mp: 128° C.).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:30][N:31]2[CH:35]=[C:34]([CH2:36][OH:37])[N:33]=[N:32]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C[O-].[Na+].[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:30][N:31]2[CH:35]=[C:34]([CH2:36][OH:37])[N:33]=[N:32]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H](Cn4cc(CO)nn4)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@@H](Cn1cc(CO)nn1)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-(1-(2-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3,3-dimethylbutyl)-1H-1,2,3-triazol-4-yl)methanol, 218a, (0.11 g, 0.19 mmol) in THF (5 mL) was added NaOMe (0.17 mL of 25% solution in MeOH, 0.75 mmol). After stirring the reaction mixture at room temperature for 30 minutes, the mixture was diluted into aqueous saturated NH4Cl solution (5 mL) and EtOAc (10 mL). The organic layer was separated, dried (MgSO4), filtered concentrated in vacuo. The crude product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to afford 41 mg of the desired product as an off-white solid: 1H NMR (400 MHz, CD3OD) δ 8.51 (d, J=8.0 Hz, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.93 (d, J=3.5 Hz, 1H), 7.38 (s, 1H), 5.08 (m, 1H), 5.00-4.90 (m, 1H), 4.74 (s, 2H), 4.60 (m, 1H), 1.2 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=1.90 minutes (M+H) 429.26.
Reaction SMILES: [CH:1]1([C:4](Cl)=O)[CH2:3][CH2:2]1.[F:7][C:8]1[CH:29]=[CH:28][C:11]([CH2:12][N:13]2[CH2:27][CH2:26][N:16]3[C:17]4[N:25]=[CH:24][CH:23]=[CH:22][C:18]=4[NH:19][CH2:20][CH2:21][CH:15]3[CH2:14]2)=[CH:10][CH:9]=1.CN(CC)C.[OH-].[Na+]>C(Cl)Cl.O.CO>[CH:1]1([CH2:4][N:19]2[CH2:20][CH2:21][CH:15]3[CH2:14][N:13]([CH2:12][C:11]4[CH:10]=[CH:9][C:8]([F:7])=[CH:29][CH:28]=4)[CH2:27][CH2:26][N:16]3[C:17]3[N:25]=[CH:24][CH:23]=[CH:22][C:18]2=3)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Fc1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1
Agent: CCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(CN2CCN3c4ncccc4N(CC4CC4)CCC3C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cyclopropanecarbonyl chloride (0.043 ml, 0.478 mmol) was added to a solution of the product of Example 64C (97 mg, 0.31 mmol) in CH2Cl2 (2.0 mL). The mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The residue was taken up in 1 MNaOH (5 mL) and extracted with ethyl acetate (2×10 mL). The combined extract was washed with saturated brine (5 mL), dried (Na2SO4) and concentrated under vacuum. The residue was dissolved in tetrahydrofuran (5 mL) and stirred with alane-N,N-dimethylethylamine complex (Aldrich, 0.5 Min toluene, 2.9 mL, 1.45 mmol) at room temperature for 90 minutes. Methanol (1 mL) was added followed by water (5 mL) and 25% NaOH (1 mL). The mixture was stirred at room temperature for 10 minutes, and the aqueous phase was separated and extracted with ethyl acetate (2×7 mL). The combined organic was washed with saturated brine (5 mL), dried (Na2SO4) and concentrated under vacuum. The residue was purified by chromatography (SiO2 eluted with CH2Cl2—CH3OH 95:5) and then by HPLC (30×100 mm, C18, Waters XBridge™ column eluted with aqueous 0.1 M (NH4)2CO3—CH3OH, 80:20-0:100 over 15 minutes) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 0.15-0.23 (m, 2H), 0.51-0.61 (m, 2H), 0.94-1.06 (m, 1H), 1.66-1.80 (m, 1H), 1.80-1.95 (m, 1H), 2.19 (t, J=9.7 Hz, 1H), 2.42 (td, J=10.5, 3.1 Hz, 1H), 2.59 (d, J=10.9 Hz, 1H), 2.74-2.84 (m, 1H), 2.95 (d, J=6.4 Hz, 2H), 3.22 (ddd, J=11.5, 6.1, 4.1 Hz, 1H), 3.30-3.39 (m, 1H), 3.38-3.48 (m, 2H), 3.52 (d, J=6.4 Hz, 2H), 3.61 (dt, J=12.5, 3.4 Hz, 1H), 6.75 (dd, J=7.8, 4.7 Hz, 1H), 6.95 (dd, J=7.8, 1.7 Hz, 1H), 6.97-7.05 (m, 2H), 7.32 (dd, J=8.5, 5.8 Hz, 2H), 7.80 (dd, J=4.7, 1.7 Hz, 1H); MS (DCI) m/z 367 (M+H)+.
Reaction SMILES: [CH2:1]([NH:7][C:8]1[CH:40]=[CH:39][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[N:20]=[C:19]([CH2:21][O:22][C:23]4[CH:36]=[CH:35][C:26]([CH2:27][CH:28]5[S:32][C:31](=[O:33])[NH:30][C:29]5=[O:34])=[CH:25][CH:24]=4)[N:18]([CH3:37])[C:17]=3[CH:38]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]=[C:49]=[O:50])=[CH:44][CH:43]=1>O1CCCC1>[O:33]=[C:31]1[NH:30][C:29](=[O:34])[CH:28]([CH2:27][C:26]2[CH:35]=[CH:36][C:23]([O:22][CH2:21][C:19]3[N:18]([CH3:37])[C:17]4[CH:38]=[C:13]([O:12][C:11]5[CH:39]=[CH:40][C:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:49]([NH:48][C:45]6[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=6)=[O:50])=[CH:9][CH:10]=5)[CH:14]=[CH:15][C:16]=4[N:20]=3)=[CH:24][CH:25]=2)[S:32]1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCCCCCNc1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Solvent: C1CCOC1
Product: CCCCCCN(C(=O)Nc1ccc(F)cc1)c1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Reaction time: 48 h

Procedure:
A mixture of 5-[4-[6-(4-n-hexylaminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.39 g), 4-fluorophenyl isocyanate (0.11 g) and anhydrous tetrahydrofuran (20 ml) was allowed to stand at room temperature for 2 days. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:2 as the eluant and the product was reprecipitated from a mixture of ethyl acetate and diisopropyl ether to afford the title compound (0.32 g, Rf=0.45: thin layer chromatography on a silica gel plate using ethyl acetate:n-hexane=2:1 as the eluant).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([OH:9])=O)[N:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:32]([C:36]1[CH:45]=[CH:44][C:39]([C:40](=[NH:43])[NH:41]O)=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C.O.CCOC(C)=O>[C:32]([C:36]1[CH:45]=[CH:44][C:39]([C:40]2[N:41]=[C:7]([C:4]3[N:3]=[C:2]([CH3:1])[NH:6][N:5]=3)[O:9][N:43]=2)=[CH:38][CH:37]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: Cc1nc(C(=O)O)n[nH]1
Reactant: CC(C)(C)c1ccc(C(=N)NO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(-c2nc(-c3ccc(C(C)(C)C)cc3)no2)n[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
5-Methyl-1H-1,2,4-triazole-3-carboxylic acid (200 mg, 1.57 mmol), EDC.HCl (360 mg, 1.89 mmol), and HOBT (255 mg, 1.89 mmol) were dissolved in DMF (15 mL) and the solution was stirred at RT for 30 min. 4-(tert-Butyl)-N-hydroxybenzimidamide (363 mg, 1.89 mmol) was added and the reaction was stirred at RT for 1 h and then at 140° C. for an additional 2 h. The reaction mixture was cooled to RT, and diluted with H2O (100 mL) and EtOAc (100 mL). The organic layer was separated, washed with H2O (2×50 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product which was purified by silica gel chromatography (EtOAc/Hexane 12%-100% EtOAc) to afford 3-(4-(tert-butyl)phenyl)-5-(5-methyl-1H-1,2,4-triazol-3-yl)-1,2,4-oxadiazole as a yellow solid (210 mg, 47%). MS (ES+) C15H17N5O requires: 283. found 284 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.02 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 2.50 (s, 3H), 1.34 (s, 9H).
Reaction SMILES: C1(N2C3C(=CC=C(F)C=3OC)C(=O)C(C(OCC)=O)=C2S)CC1.[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33](F)=[C:34]([F:39])[C:35]=3[O:37][CH3:38])[C:30](=[O:41])[C:29]3[C:42]([OH:47])=[C:43]([C:45]#[N:46])[S:44][C:28]2=3)[CH2:26][CH2:25]1>>[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([F:39])[C:35]=3[O:37][CH3:38])[C:30](=[O:41])[C:29]3[C:42]([OH:47])=[C:43]([C:45]#[N:46])[S:44][C:28]2=3)[CH2:25][CH2:26]1
Reactant: COc1c(F)c(F)cc2c(=O)c3c(O)c(C#N)sc3n(C3CC3)c12
Agent: CCOC(=O)c1c(S)n(C2CC2)c2c(OC)c(F)ccc2c1=O
Product: COc1c(F)ccc2c(=O)c3c(O)c(C#N)sc3n(C3CC3)c12

Procedure:
The title compound is prepared from ethyl 1-cyclopropyl-7-fluoro-2-mercapto-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate using the method described above for the preparation of 9-cyclopropyl-6,7-difluoro-3-hydroxyl-8-methoxy-4-oxo-4,9-dihydrothieno[2,3-b]quinoline-2-carbonitrile. 1H NMR: δ1.03 (br, 2H), 1.27 (m, 2H), 3.90 (m, 1H), 3.94 (s, 3H), 7.45 (m, 1H), 8.02 (m, 1H). 19F NMR: δ−121.70 (s). LCMS: m/z calcd for C16H11FN2O3S ([M]+) 330. found ([M+H]+) 331.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1>C(Cl)Cl.CN(C=O)C>[Cl:37][C:38]1[CH:44]=[CH:43][C:41]([N:42]2[CH:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:11][CH2:12][CH:13]2[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:40][CH:39]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(C(O)CCC(O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C2CCC(c3ccc([N+](=O)[O-])cc3)N2c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
The product of Example 1B (0.50 g, 1.51 mmol) was suspended in CH2Cl2 (15 mL). Triethylamine (0.626 mL, 4.51 mmol) was added at 0° C., the resulting mixture was stirred for 30 min, and methanesulfonyl chloride (0.293 mL, 3.76 mmol) was added. The mixture was stirred at rt for 1 hr and then concentrated in vacuo to give a light yellow solid. The solid was dissolved in DMF (6 mL), 4-chloroaniline (1.92 g, 15.05 mmol) was added, and the resulting mixture was stirred at 50° C. overnight. The mixture was partitioned between EtOAc and 1N aq HCl, and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-12% EtOAc in hexane to give the title compound (0.226 g, 35%).