Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([C:26]3([C:29]([F:32])([F:31])[F:30])[CH2:28][CH2:27]3)=[N:24][N:25]=[C:20]2[C@H:19]([NH2:33])[CH2:18][CH2:17]1.[C:34]([N:41]1[CH:45]=[CH:44]N=[CH:42]1)(N1C=CN=C1)=[O:35].N1CC[CH:49]([C:52]2[C:53](=[O:58])[NH:54][N:55]=[CH:56][CH:57]=2)[CH2:48]C1>O1CCCC1.ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([C:26]3([C:29]([F:32])([F:30])[F:31])[CH2:27][CH2:28]3)=[N:24][N:25]=[C:20]2[C@H:19]([NH:33][C:34]([N:41]2[CH2:42][CH2:48][CH:49]([C:52]3[C:53](=[O:58])[NH:54][N:55]=[CH:56][CH:57]=3)[CH2:44][CH2:45]2)=[O:35])[CH2:18][CH2:17]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c1nnc2C1(C(F)(F)F)CC1
Reactant: O=c1[nH]nccc1C1CCNCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c1nnc2C1(C(F)(F)F)CC1)N1CCC(c2ccn[nH]c2=O)CC1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
Triethylamine (16 μL, 0.112 mmol) was added to a solution of the bis hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl)cyclopropyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-amine (20 mg, 0.045 mmol) and 1,1′-carbonyldiimidazole (13 mg, 0.079 mmol) in tetrahydrofuran (1.0 mL) at 0° C. After 20 min, additional 1,1′-carbonyldiimidazole (7.3 mg, 0.045 mmol) was added. After 30 min, 4-piperidin-4-ylpyridazin-3(2H)-one (10 mg, 0.056 mmol) and dichloromethane (1.0 mL) were added and the mixture was heated to 60° C. After 16 h, the reaction was allowed to cool to ambient temperature and concentrated. Purification by reverse phase HPLC (C-18, 10% acetonitrile/water→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (20 mg). MS 578.2315 (M+1).
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:8][C:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1)[CH2:4][CH2:5][CH:6]=[CH2:7]>CC(C)=O>[I-:2].[CH2:3]([O:8][C:9]1[C:13]([C:14]2[CH:15]=[N+:16]([CH3:1])[CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1)[CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: CI
Reactant: C=CCCCOc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: C=CCCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 7.5 mmol) and 3-(3-(4-pentenyloxy)-1,2,5-thiadiazol-4-yl)pyridine (2.5 mmol) in acetone (10 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.67 g (69%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[CH2:27](P(CCCC)CCCC)[CH2:28][CH2:29]C.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.CC(O)C>O1CCCC1>[CH3:27][CH:28]([O:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)[CH3:29]
Reactant: CCCCP(CCCC)CCCC
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)C)c2[nH]1
Temperature: 70 °C
Reaction time: 5.5 h
Yield: 84 %

Procedure:
A mixture of ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.0 g), tributylphosphine (2.6 mL), 1,1′-(azodicarbonyl)dipiperidine (2.69 g), 2-propanol (0.81 mL) and tetrahydrofuran (50 mL) was stirred at 70° C. for 5.5 h. Furthermore, tributylphosphine (0.7 mL) and 1,1′-(azodicarbonyl)dipiperidine (0.7 g) were added to the mixture. After stirring at 70° C. for 2 h, the mixture was cooled to 0° C. and a precipitate was removed by filtration. The filtrate was concentrated and the residue was purified by basic silica gel column chromatography (ethyl acetate/hexane 1/99 to 40/60), followed by silica gel column chromatography (ethyl acetate/hexane=1/99 to 35/65, volume ratio) to give the title compound (1.87 g, 84%) as a white amorphous solid. MS 418 (MH+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:24](=[O:27])([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:24](=[O:27])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added 4-trifluorobenzoyl chloride (96 mg, 0.64 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the title compound (129 mg, 62%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C:5](=O)[CH:6]([CH3:8])[CH3:7])[CH3:2].[C:11](=[O:15])([O:13][CH3:14])[NH2:12].CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:14][O:13][C:11]([NH:12][C:5](=[C:6]([CH3:8])[CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:10])=[O:15]
Reactant: CCOC(=O)C(=O)C(C)C
Reactant: COC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)C(NC(=O)OC)=C(C)C

Procedure:
A benzene solution (90 mL) of ethyl-3-methyl-2-oxobutanoate (4.03 g, 28.0 mmol), methyl carbamate (2.098 g, 28.0 mmol) and pyridine 4-methylbenzenesulfonate (0.70 g, 2.80 mmol) was heated to reflux in a round bottom flask equipped with a Dean-Stark trap and reflux condenser. After 44 hours of heating the mixture was cooled and then partitioned between ethyl acetate (50 mL) and brine (50 mL). The organic phase was washed with brine (2×50 mL) then dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (ethyl acetate-hexanes) to provide the title compound as an off white crystalline solid (1.487 g, 26%).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]2[C@@H:8](I)[C@H:4]([C@@H:5]([C:18]([O:20][CH3:21])=[O:19])[N:6]2[C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:3]1.O.[F-:23].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.C(OCC)(=O)C>[F:23][C@@H:8]1[C@H:4]2[CH2:3][C@@H:2]([OH:1])[C@@H:7]1[N:6]([C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C@@H:5]2[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)[C@@H]1[C@@H]2C[C@@H](O)[C@@H]([C@H]2I)N1[C@H](C)c1ccccc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1[C@@H]2C[C@@H](O)[C@@H]([C@@H]2F)N1[C@H](C)c1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of methyl (1S,3S,4S,6R,7S)-6-hydroxy-7-iodo-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (100 mg) in acetonitrile (8 mL), was added tetrabutylammonium fluoride hydrate (102 mg). The mixture was stirred at 80° C. for 30 minutes. The resulting mixture was diluted with ethyl acetate, and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (1:1) to give the target compound (59.5 mg)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C@H:11]([CH3:27])[CH2:10]1.[Si]([C:32]([F:35])([F:34])[F:33])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])([CH3:25])[C:32]([F:35])([F:34])[F:33])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C@H:11]([CH3:27])[CH2:10]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(=O)c1ccc(S(=O)(=O)N2CCN(c3ccc(F)cc3F)C[C@H]2C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C[C@@H]1CN(c2ccc(F)cc2F)CCN1S(=O)(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Yield: 81 %

Procedure:
To a solution of (R)-1-(4-(4-(2,4-difluorophenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)ethanone (360 mg, 0.87 mmol, prepared according to procedures similar to those described in Example 29A) was added TMSCF3 (5.2 mL, 0.5 M in THF, 2.6 mmol) and TBAF (0.87 mL, 1 M in THF, 1.0 mmol) at 0° C. The resultant mixture was stirred for 6 h then rt overnight. It washed with aq. NH4Cl and aq. layer was extracted with DCM. The organic layer was dried over Na2SO4. The crude product was purified on SiO2 column eluted with hexanes/EtOAc to give the desired product as a white solid (329 mg, 81%). HRMS: calcd for C20H21F5N2O3S+H+, 465.12658. found (ESI-FTMS, [M+H]1+), 465.12565.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:8]([CH2:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])[CH:9]=[CH:10][N:11]=1>>[ClH:3].[Cl:3][CH2:6][C:7]1[N:8]([CH2:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])[CH:9]=[CH:10][N:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1nccn1CC(F)(F)C(F)F
Product: Cl
Product: FC(F)C(F)(F)Cn1ccnc1CCl

Procedure:
To thionyl chloride (7.0 ml) was gradually added 2-hydroxymethyl-1-(2,2,3,3-tetrafluoropropyl)imidazole (0.70 g) at 0° C., and the mixture was refluxed for 45 minutes. The reaction mixture was concentrated under reduced pressure, to which was added diethyl ether, then precipitating crystals were collected by filtration. The crystals were dissolved in ethanol, followed by recrystallization from diethyl ether to give 2-chloromethyl-1-(2,2,3,3-tetrafluoropropyl)imidazole hydrochloride (0.90 g) as colorless needles, m.p. 104°-107° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:24]=[CH:23][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH:34]=O)=[CH:31][CH:32]=4)[NH:27][N:26]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:34][C:30]1[CH:29]=[C:28]2[C:33]([C:25]([C:22]3[CH:23]=[N:24][C:19]([N:16]4[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]4)=[CH:20][CH:21]=3)=[N:26][NH:27]2)=[CH:32][CH:31]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CN1CCN(c2ccc(-c3n[nH]c4cc(C=O)ccc34)cn2)CC1
Product: CN1CCN(c2ccc(-c3n[nH]c4cc(C=C5C(=O)Nc6ccc(Br)cc65)ccc34)cn2)CC1
Yield: 88.2 %

Procedure:
The title compound (E/Z=3:4, 65 mg, 88%) was synthesized as an orange solid according to the method described for (E/Z)-3-((3-iodo-1H-indazol-6-yl)methylene)-5-methoxyindolin-2-one-(oil temp 75° C., reflux 3 h) using 5-bromoindolin-2-one (32 mg, 0.15 mmol) and 3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indazole-6-carbaldehyde (46 mg, 0.143 mmol). 1H NMR (400 MHz, DMSO-d6) E isomer: δ 13.41 (s, 1H), 10.80 (s, 1H), 8.76 (s, 1H), 8.20-8.03 (m, 2H), 7.91 (s, 1H), 7.87 (s, 1H), 7.67 (d, 1H), 7.48-7.40 (m, 2H), 7.99 (d, J=8.8 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 3.57 (t, 4H), 2.41 (t, 4H), 2.23 (s, 3H); Z isomer: δ 13.48 (s, 1H), 10.84 (s, 1H), 9.02 (s, 1H), 8.76 (s, 1H), 8.20-8.03 (m, 5H), 7.38 (d, J=8.0 Hz, 1H), 6.98 (d, J=9.6 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 3.57 (t, 4H), 2.41 (t, 4H), 2.23 (s, 3H); MS ESI 515.4 [M+H]+, calcd for [C26H23BrN6O+H]+ 515.1.
Reaction SMILES: [CH:1]1([C@H:7]2[N:12]3[CH:13]=[C:14]([C:19](C(F)(F)F)=[O:20])[C:15]4[CH:16]=[CH:17][CH:18]=[C:10]([C:11]=43)[O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:25].[Na+].Cl>O1CCOCC1>[CH:1]1([C@H:7]2[N:12]3[CH:13]=[C:14]([C:19]([OH:25])=[O:20])[C:15]4[CH:16]=[CH:17][CH:18]=[C:10]([C:11]=43)[O:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [OH-]
Reactant: O=C(c1cn2c3c(cccc13)OC[C@H]2C1CCCCC1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1cn2c3c(cccc13)OC[C@H]2C1CCCCC1

Procedure:
To a solution of (R)-3-cyclohexyl-6-trifluoromethylcarbonyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine (628 mg, 1.86 mmol) in 1,4-dioxane (20 ml) was added 4 N NaOH (5.0 ml). The mixture was refluxed for 42 h, then acidified to pH 1 using 5 N hydrochloric acid and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane, and combined organic layers were washed with brine, dried over Na2SO4 and concentrated to afford (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (572 mg). The title compound was prepared following the method of Example 7, using (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid amide (prepared from (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid) instead of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid amide. EsIMS: m/z 411.0 [M+H]+; [α]D22−30.7° (c=1.50 mg/ml in chloroform)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[F:38]>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)=[CH:19][C:18]=1[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[F:38]
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccncc3F)c2)OC1(C)C
Product: Fc1cnccc1-c1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 38.7 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 4-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-3-fluoropyridine (89 mg, 0.28 mmol) as described in Example 7 part g), affording 5-[4-fluoro-3-(3-fluoropyridin-4-yl)phenyl]-2-trifluoromethyl[1,8]naphthyridine (33 mg, 40%). δH (360 MHz, CDCl3) 7.43-7.49 (2H, m), 7.58-7.61 (3H, m), 7.86 (1H, d, J 8.8), 8.55 (2H, dd, J 6.0 and 2.1), 8.63 (1H, d, J 1.8), 9.30 (1H, d, J 4.2). m/z (ES+) 388 [MH]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]3[CH:35]=[CH:34][NH:33][C:30]3=[N:31][CH:32]=2)O1>>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:27]3[CH:28]=[C:29]4[CH:35]=[CH:34][NH:33][C:30]4=[N:31][CH:32]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]=2[C:6]([CH3:14])=[N:7]1)([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: COC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Product: COC(=O)c1cc(-c2cnc3[nH]ccc3c2)cc2c1c(C)nn2C(C)C

Procedure:
The title compound was prepared from methyl 6-bromo-1-isopropyl-3-methyl-1H-indazole-4-carboxylate, (0.7 g, 2.25 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.65 g, 2.70 mmol) in the same manner as described for example 80 (step a). The product was collected as an off-white solid (600 mg, 82.5%). 1H NMR (DMSO-d6, 400 MHz): δ 1.489 (d, J=6.4 Hz, 6H), 2.603 (s, 3H), 3.949 (s, 3H), 5.140-5.172 (m, 1H), 6.547 (s, 1H), 7.545 (s, 1H), 7.935 (s, 1H), 8.253 (s, 1H), 8.377 (s, 1H), 8.667 (s, 1H), 11.774 (s, 1H). LCMS (ES+) m/z: 349.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[C:42]([O:46][C:47](=[O:50])[CH2:48][NH2:49])([CH3:45])([CH3:44])[CH3:43]>CN(C=O)C>[C:42]([O:46][C:47](=[O:50])[CH2:48][NH:49][C:8]([C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10])([CH3:45])([CH3:44])[CH3:43]
Reactant: O=C(O)c1ncccc1O
Reactant: CC(C)(C)OC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)c1ncccc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.5 %

Procedure:
To a solution of 3-hydroxypicolinic acid (0.20 g, 1.44 mmol) in DMF (5 mL) at 0° C. under N2 is added diisopropylethylamine (DIPEA) (0.75 ml, 4.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.412 g, 2.9 mmol) and 1-hydroxybenzotriazole (HOBt) (0.019 g, 0.14 mmol). The resulting mixture is stirred for 5 min before glycine tert-butyl ester HCl (0.36 g, 2.9 mmol) is introduced. The resulting solution is stirred at room temperature for 3 days then concentrated under reduced pressure. The reaction mixture is diluted with EtOAc then washed with 1M HCl, sat. NaCl, and the organic layer is dried (MgSO4), filtered and concentrated under reduced pressure to a crude oil that is purified over silica (EtOAc/heptane 1:4) to afford 0.078 g (22% yield) of the desired compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 11.80 (1H, s), 8.39 (1H, br s), 8.02 (1H, dd, J=4.4, 1.5 Hz), 7.27 (1H, dd, J=8.8, 4.4 Hz), 7.25 (1H, dd, J=8.4, 1.5 Hz), 4.06 (2H, d, J=5.5 Hz), 1.44 (9H, s). HPLC-MS: m/z 197 [M-tBu]+.
Reaction SMILES: [I:1][Si](C)(C)C.COC([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([N:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:26])[C:20]=3[C:19]3=[N:27][O:28][C:29]([CH3:30])=[C:18]3[C:17]2=[O:31])[CH2:11]1)=O.CO.C(OCC)C>ClCCl>[IH:1].[Cl:26][C:21]1[C:20]2[C:19]3[C:18](=[C:29]([CH3:30])[O:28][N:27]=3)[C:17](=[O:31])[N:16]([CH:12]3[CH2:13][CH2:14][CH2:15][NH:10][CH2:11]3)[C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)N1CCCC(n2c(=O)c3c(C)onc3c3c(Cl)cccc32)C1
Reactant: C[Si](C)(C)I
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: Cc1onc2c1c(=O)n(C1CCCNC1)c1cccc(Cl)c21
Product: I
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
Add iodotrimethylsilane (1.87 mL, 13.16 mmol) to a solution of 3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-piperidine-1-carboxylic acid methyl ester (2.06 g, 5.48 mmol) in dichloromethane (40 mL). Stir the solution at room temperature under nitrogen overnight. Add methanol (3.2 mL, 78.93 mmol) dropwise, and stir the reaction at room temperature for 30 minutes. Concentrate the reaction, add to diethyl ether, sonicate, and filtere. Dry the solids on a vacuum pump to give 2.36 g of the title compound as a tan solid, 97% yield. 1H NMR: consistent with structure. MS (ion spray) 318 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][O:31][CH2:32][CH2:33]SC)[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.CO.[C:38](OO)(C)(C)C.[S:44]([O-:48])([O-])(=[O:46])=S.[Na+].[Na+]>ClCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][S:44]([CH3:38])(=[O:48])=[O:46])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: CSCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reactant: CC(C)(C)OO
Reactant: O=S([O-])([O-])=S
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)CCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-{3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(methylthio)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (70.0 mg) was dissolved in dichloromethane (5.0 mL), titanium tetraisopropoxide (0.10 mL), methanol (0.50 mL) and 70% aqueous tert-butyl hydroperoxide solution (8.0 mL) were added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium thiosulfate solution was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1 hr and extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=90:10). Crystallization from diethyl ether/ethyl acetate/hexane gave the title compound (62.5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]([O:17]CC)=O)=[N:10]2)[CH:5]=[CH:4][N:3]=1.[NH2:20][NH2:21].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]([NH:20][NH2:21])=[O:17])=[N:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: NN
Reactant: CCOC(=O)c1nc(C)n(Cc2ccnc(Cl)c2)n1
Solvent: O
Solvent: CO
Product: Cc1nc(C(=O)NN)nn1Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazole-3-carboxylate (218 mg, 0.81 mmol) in MeOH (4.5 mL) was added NH2NH2.H2O (122 μL, 1.22 mmol) and TEA (511 μL, 3.6 mmol). The reaction was allowed to stir overnight at RT. The solvent was then removed under reduced pressure and the crude material was spun down from toluene (3×) to give 1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazole-3-carbohydrazide as a white solid, which was used directly for the next step without further purification. MS (ES+) C10H11ClN6O requires: 266 found: 267[M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.C(Br)C1C=CC=CC=1>[CH2:23]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]=2[C:6]2[C:14]1=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cccc2c3c([nH]c12)CCCC3=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: Cc1cccc2c3c(n(Cc4ccccc4)c12)CCCC3=O
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
8-Methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.1967 g, 0.99 mmol) is added to a slurry of pentane-washed NaH (0.0485 g, 0.0012 mol) in DMF (2 mL) and after stirring for 30 min, benzyl bromide (0.14 mL, 0.0012 mol) is added. After 3 h starting material still remained, so additional benzyl bromide (0.015 mL, 0.013 mmol) is added and the mixture is stirred overnight at room temperature. The mixture is then partitioned between aq. sodium bicarbonate and ethyl acetate and the organic layer is dried over sodium sulfate and concentrated to dryness. The resulting solids are recrystallized from ethyl acetate/hexane/dichloromethane to give 0.2076 g (73%) of the title compound; mp 165-166° C.; MS (ESI+) for C20H19NO m/z 290.2 (M+H)+; IR (drift) 2940, 1637, 1599, 1538, 1494, 1462, 1447, 1416, 1357, 1322, 1121, 787, 752, 727, 697 cm−1; 1H NMR (CDCl3) δ2.21, 2.51, 2.59, 2.82, 5.58, 6.89, 6.95, 7.16, 7.29, 8.23. Anal. Calcd for C20H19NO: C, 83.01; H, 6.62; N, 4.84. Found: C, 82.53; H, 6.62; N, 4.86.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[N:12]=[C:13](S(C)(=O)=O)[N:14]=[C:15]([CH3:16])[C:10]=2[CH:9]=[CH:8][C:7]1=[O:21].[CH2:22]([NH2:24])[CH3:23]>C1COCC1>[CH2:22]([NH:24][C:13]1[N:14]=[C:15]([CH3:16])[C:10]2[CH:9]=[CH:8][C:7](=[O:21])[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]=2[N:12]=1)[CH3:23]
Reactant: COCCCn1c(=O)ccc2c(C)nc(S(C)(=O)=O)nc21
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1nc(C)c2ccc(=O)n(CCCOC)c2n1
Yield: 50 %

Procedure:
8-(3-methoxypropyl)-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one, and a solution of 2M ethylamine in THF (20 mL) was stirred for 2 h. THF was removed under reduced pressure and the crude product was purified by flash column chromatography to give 2-(ethylamino)-8-(3-methoxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.18 g, 50% yield over 2 steps).