Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([S:7][C:8]([F:11])([F:10])[F:9])[NH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.ClC1C=C(C=CC=1)C(OO)=[O:24].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[CH:6]=[C:5]([S:7]([C:8]([F:11])([F:10])[F:9])=[O:24])[NH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)Sc1cc(Br)c(-c2ccc(Cl)cc2)[nH]1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=S(c1cc(Br)c(-c2ccc(Cl)cc2)[nH]1)C(F)(F)F
Reaction time: 2 h
Yield: 50.1 %

Procedure:
A solution of 3-bromo-2-(p-chlorophenyl)-5-[(trifluoromethyl)thio]pyrrole (0.65 g, 0.00182 mol) in chloroform is cooled with an ice-water bath, treated with a solution of 3-chloroperoxybenzoic acid (0.52 g, 60% pure, 0.00182 mol) in chloroform, stirred for two hours, treated with saturated sodium metabisulfite solution, diluted with methylene chloride, washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a white solid. Flash chromatography of the solid using silica gel and a 1:10 ethyl acetate/hexanes solution gives the title product as a white solid (0.34 g, mp 177°-179° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[CH:5]=[CH:4][N:3]=1.[Br:10]Br>>[NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([Br:10])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Nc1nccc(F)c1O
Product: Nc1ncc(Br)c(F)c1O

Procedure:
When 2-amino-4-fluoro-3-pyridinol and bromine in a 1:1 molar ratio are passed through a glass tube heated at 350°, and the exit gases condensed and distilled, there is obtained 2-amino-5-bromo-4-fluoro-3-pyridinol.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:23][CH2:22][CH2:21][O:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:16][C:12]1[C:11]2[C:7]([C:34]3[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=3)=[N:8][N:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCOC1
Yield: 70 %

Procedure:
A solution of 4-methoxy-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (254 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (207 mg), tetrakis(triphenylphosphine)palladium(0) (77.0 mg) and 2M aqueous sodium carbonate solution (1.0 mL) in DME (15 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (181 mg).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O.[NH2:22][CH:23]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:24]([OH:28])[C:25]([NH2:27])=[O:26].O[NH-].O=[N-]>>[NH2:27][C:25](=[O:26])[C:24](=[O:28])[CH:23]([NH:22][C:14]([C@H:9]1[CH2:10][CH2:11][C:12](=[O:13])[N:8]1[CH2:7][C:6]1[CH:17]=[CH:18][CH:19]=[C:4]([O:3][C:2]([F:1])([F:21])[F:20])[CH:5]=1)=[O:16])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1cccc(OC(F)(F)F)c1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1cccc(OC(F)(F)F)c1

Procedure:
Coupling of (R)-1-(3-trifluoromethoxy-benzyl)-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4].[H-].[Na+].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.Cl>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2[nH]1
Reactant: Fc1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2n1Cc1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
To a mixture of the compound obtained in Example 22 (2) (1.2 g) and N,N-dimethylformamide (23 ml), 60% sodium hydride (204 mg) was added at 0° C. and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture was added 4-fluorobenzyl bromide (0.65 ml) at 0° C. and the mixture was stirred at 15 to 30° C. for 2 hours. 2N hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane) to obtain 1 g of the desired product in a white amorphous form.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CN1CCOCC1.[CH3:13][O:14][C:15]([C:17]1[N:18]=[C:19]([CH3:29])[S:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)=[O:16].O>C(Cl)Cl>[CH3:13][O:14][C:15]([C:17]1[N:18]=[C:19]([CH3:29])[S:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH:23]=1)=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1nc(C)sc1-c1cccc(N)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)c1nc(C)sc1-c1cccc(NS(C)(=O)=O)c1

Procedure:
Methanesulfonyl chloride (5.27 mmol) and 4-methylmorpholine (4.86 mmol) are added successively to a solution of 5-(3-amino-phenyl)-2-methyl-thiazole-4-carboxylic acid methyl ester (4.05 mmol) in DCM (50 mL). After stirring for 2 h water is added, the layers are separated and the aqueous layer is extracted once with DCM. The combined organic layers are washed with citric acid (10% solution in water), dried over MgSO4 and concentrated in vacuo to give a crude product which is used without further purification. LC-MS: tR=0.84 min; [M+H]+=327.2.
Reaction SMILES: C1C2C(COC(=O)[NH:17][S:18]([NH:21][CH2:22][CH2:23][NH:24][C:25]3[C:29]([C:30]4[N:34]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[C:37]([Br:42])[CH:36]=5)C(=O)[O:32][N:31]=4)=[N:28][O:27][N:26]=3)(=[O:20])=[O:19])C3C(=CC=CC=3)C=2C=CC=1.C1COCC1.NCCN(CCN)CCN.Cl>COC(C)(C)C.C(Cl)Cl>[NH2:17][S:18]([NH:21][CH2:22][CH2:23][NH:24][C:25]1[C:29]([C:30](=[N:31][OH:32])[NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([Br:42])[CH:36]=2)=[N:28][O:27][N:26]=1)(=[O:19])=[O:20]
Reactant: O=C(NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: NCCN(CCN)CCN
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: NS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.3 %

Procedure:
Into a 1 L 4-neck round bottom flask was charged 9H-fluoren-9-ylmethyl({[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]amino}sulfonyl)carbamate (25.0 g, 36.4 mmol) and anhydrous THF (250 mL) at ambient temperature to produce a homogeneous solution. The solution was then cooled to 0-5° C. in an ice bath before N,N-bis(2-aminoethyl)ethane-1,2-diamine (114 mL, 728 mmol) was added dropwise over 35 minutes via an addition funnel. The addition funnel was rinsed with anhydrous THF (50 mL) and the rinse was added to the reaction mixture. The cold bath was removed and the reaction was gradually warmed to ambient temperature and stirred at ambient temperature for 2.5 h. EtOAc (400 mL) was added and the resulting mixture was transferred to a 2 L 4-neck round bottom flask and cooled to about 0-5° C. in an ice bath. A solution of 2.0 M aqueous HCl (400 mL, 800.0 mmol) was added dropwise via an addition funnel, while maintaining the internal temperature at below 10° C. The two phases were separated and the aqueous phase was extracted with EtOAc (200 mL). The organic fractions were combined and cooled to about 6-7° C. A solution of 2.0 M aqueous HCl (200.0 mL, 400.0 mmol) was added dropwise to the cold organic fraction, maintaining the internal temperature at below 10° C. The two phases were separated and the organic phase was washed with water (2×400 mL), dried over MgSO4, and concentrated under reduced pressure to a light yellow syrup. The syrup was dissolved in EtOAc (60.0 mL) to yield a homogeneous solution. To the solution was added a solution of DCM (250.0 mL) and tert-butyl methyl ether (TBME, 100.0 mL) dropwise. The resulting slurry was stirred overnight at room temperature, then cooled in an ice bath for 1 h. The solids were collected by filtration, washed with an ice cold 250 mL solution of DCM (150 mL) and TBME (100 mL), and dried under vacuum to give 14.4 g of the crude desired product as white solids.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH:12][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccn(-c2ccccc2)n1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccn(-c2ccccc2)n1)C(=O)OCC

Procedure:
1-phenyl-3-amino-pyrazole, m.p. 90°-91° C. (18 g) was reacted with diethyl ethoxymethylenemalonate (29.3 g) in anhydrous ethanol (180 ml) at the reflux temperature for 15 hours. After cooling the solution was evaporated in vacuo to dryness: the residue was dissolved in isopropyl ether (200 ml) and decolorized by charcoal. Crystallization obtained by dilution with hexane gave diethyl N-(1-phenyl-pyrazol-3-yl)-aminomethylenemalonate, m.p. 81°-82° C. (31 g), which was reacted with polyphosphoric acid (13 g; 6.1 g of P2O5 and 6.9 g of H3PO4) and POCl3 (57 g) under stirring at the reflux temperature for 30 minutes. After cooling the reaction mixture was diluted with ice water and then the solution was decolorized, with charcoal: neutralization with 35% NaOH gave a precipitate which was filtered and washed with water. Washing with hexane gave 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid, ethyl ester, m.p. 187°-190° C. (24.2 g), which was hydrolized by heating with a mixture 1:1 of 37% HCl:acetic acid (1.2 l) at the reflux temperature for 4 hours. After cooling the reaction mixture was neutralized to pH=6 with 35% NaOH and the precipitate was filtered and washed with water: crystallization from isopropyl alcohol gave 9.7 g of 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid m.p. 185°-190° C. dec., N.M.R. (DMSO-d6) δ p.p.m.: 6.94 (d) (1H, C-3 proton), 7.59 (s) (5H, phenyl protons), 8.74 (d) (1H, C-2 proton), 8.81 (s) (C-5 proton).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Br:20])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Br:20])[CH:14]=1)[C:49]([CH3:51])([CH3:50])[CH:48]2[OH:52])=[O:21])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2cc(Cl)cc(Br)c2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(Cl)cc(Br)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a mixture of 4-{[1-(3-bromo-5-chloro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (6.4 g, 17.5 mmol) and ytterbium(III) triflate hydrate (1.08 g, 1.75 mmol) in dry tetrahydrofuran (50 mL) at 25° C. was added isobutyraldehyde (1.59 mL, 17.5 mmol) and water (0.32 mL, 17.5 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-5-chloro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (7.67 g, 100%) as a light yellow oil: LC/MS m/e calcd for C20H21BrClNO3 M+: 438.8, observed: 438.8, 440.8.
Reaction SMILES: N[C:2]1[C:7]([OH:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10]([NH2:16])[C:11]1[O:15][CH:14]=[CH:13][CH:12]=1>>[Br:9][C:5]1[CH:6]=[C:7]([OH:8])[CH:2]=[N:3][CH:4]=1.[CH2:10]([NH2:16])[C:11]1[O:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ncc(Br)cc1O
Agent: NCc1ccco1
Product: Oc1cncc(Br)c1

Procedure:
In another example, 6-bromooxazolo[4,5-b]pyridine, when submitted sequentially to palladium catalyzed coupling to N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine and deprotection with trifluoroacetic acid, gives (4E)-N-methyl-5-(6-oxazolo[4,5-b]pyridinyl)-4-penten-2-amine. The requisite 6-bromooxazolo[4,5-b]pyridine can be produced from 2-amino-5-bromo-3-pyridinol by condensation with formic acid or a trialkyl orthoformate, using methodology similar to that of M—C. Viaud et al., Heterocycles 41: 2799-2809 (1995). The use of other carboxylic acids produces 2-substituted-6-bromooxazolo[4,5-b]pyridines, which are also substrates for the Heck reaction. The synthesis of 2-amino-5-bromo-3-pyridinol proceeds from furfurylamine (Aldrich Chemical Company). Thus, 5-bromo-3-pyridinol (produced from furfurylamine according to U.S. Pat. No. 4,192,946) can be chlorinated, using methods described by V. Koch et al., Synthesis, 499 (1990), to give 2-chloro-5-bromo-3-pyridinol, which in turn can be converted to 2-amino-5-bromo-3-pyridinol by treatment with ammonia.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:13][C:14](=[O:16])[CH3:15])[CH:9]=2)[N:4]=1.S(Cl)([Cl:19])=O>>[ClH:19].[Cl:19][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:13][C:14](=[O:16])[CH3:15])[CH:9]=2)[N:4]=1
Reactant: CC(=O)Nc1ccc2nc(CO)ccc2c1
Reactant: O=S(Cl)Cl
Product: CC(=O)Nc1ccc2nc(CCl)ccc2c1
Product: Cl
Reaction time: 2 h

Procedure:
To the N-[2-(hydroxymethyl)-6-quinolinyl]acetamide (1.00 g, 4.62 mmol) obtained in Reference Example 5 was added thionyl chloride (23 ml) under ice-cooling, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was washed with ethyl acetate to obtain the titled compound (900 mg) as a powder.
Reaction SMILES: [F:1][C:2]([F:48])([P:44]([OH:47])([OH:46])=[O:45])[C:3]1[CH:43]=[CH:42][C:6]([CH2:7][C:8]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([O:40]C)=[O:39])=[CH:34][CH:33]=2)([C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:24])[CH2:9][C:10]2[CH:15]=[CH:14][C:13](OP(C(F)F)(=O)O)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH-:49].[Na+]>C1COCC1.CO>[F:1][C:2]([F:48])([P:44]([OH:46])([OH:45])=[O:49])[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:8]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([OH:40])=[O:39])=[CH:36][CH:37]=2)([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:48])[P:44]([OH:47])([OH:46])=[O:45])=[CH:43][CH:42]=2)[C:23]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[O:24])=[CH:11][CH:12]=1
Reactant: [OH-]
Reactant: COC(=O)c1ccc(C(Cc2ccc(OP(=O)(O)C(F)F)cc2)(Cc2ccc(C(F)(F)P(=O)(O)O)cc2)C(=O)c2ccc(F)cc2)cc1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(Cc2ccc(C(F)(F)P(=O)(O)O)cc2)(Cc2ccc(C(F)(F)P(=O)(O)O)cc2)C(=O)c2ccc(F)cc2)cc1
Reaction time: 18 h

Procedure:
The compound of Example 10 (0.080 g, 0.112 mmol) was treated with NaOH in THF/MeOH at 60° C. After a period of 18 h, Dowex H+ was added. After a few minutes, the resin was filtered and the solvent evaporated to provide the title compound.
Reaction SMILES: CS(OCC[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:37][O:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48]N)[CH2:43][CH2:42]1>C(N(CC)CC)C>[ClH:31].[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[CH:20]1[C:19]2[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=2[C:17]2[N:16]=[C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([CH2:48][CH2:47][N:44]4[CH2:45][CH2:46][N:41]([CH2:40][CH2:39][O:38][CH3:37])[CH2:42][CH2:43]4)=[CH:9][CH:10]=3)[N:24]=[CH:23][C:22]=2[CH2:21]1
Reactant: COCCN1CCN(CCN)CC1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(Cl)cc2Cl)C3)cc1
Solvent: CCN(CC)CC
Product: COCCN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3C(c3ccc(Cl)cc3Cl)C4)cc2)CC1
Product: Cl

Procedure:
This was synthesized by using 4-(6-(2,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, 2-(4-(2-methoxyethyl)piperazin-1-yl)ethanamine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=208-212° C. 1H NMR (DMSO) 400 MHz δ 9.70 (s, 1H), 8.39-8.31 (m, 2H), 7.85-7.80 (m, 2H), 7.71-7.69 (m, 1H), 7.58-7.46 (m, 2H), 7.31-7.25 (m, 3H), 7.05 (d, J=7.6 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 4.80-4.75 (m, 1H), 3.88-3.00 (m, 21H). LCMS 588 [M+H]. Calc. for C33H35Cl2N5O.3.1 Hydrochloric Acid.0.3 Water 0.2 Ethyl Acetate: C, 56.03; H, 5.61; N, 9.67. Found C, 56.04; H, 5.60; N, 9.66.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=1.I[CH3:21].O>CN(C)C=O>[CH3:21][O:3][C:4]1[CH:5]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=1
Reactant: CI
Reactant: CCOC(=O)c1cc(O)cc(C(=O)OCC)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OC)cc(C(=O)OCC)n1
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
To a suspension of 60% sodium hydride (0.351 g, 8.77 mmol) in dimethylformamide(7.5 mL), a solution of diethyl 4-hydroxy-2,6-pyridinedicarboxylate (1.4 g, 5.85 mmol) in dimethylformamide (9 mL) was added dropwise under argon at room temperature and the reaction mixture was stirred for 5 minutes. Iodomethane (1.245 g, 8.77 mmol) was added and the reaction was stirred at room temperature for 20 hours. The mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was dried, concentrated to give 1.45 g (97.8%) diethyl 4-methoxy-2,6-pyridinedicarboxylate.
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C1C=CC=CC=1>CCOCC>[N:24]1[CH:25]=[CH:26][C:21]([CH2:20][NH:19][CH:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[O:12][C:13]3[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:22][CH:23]=1
Reactant: NCc1ccncc1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: CCOCC
Solvent: c1ccccc1
Product: c1ccc2c(c1)Oc1ccccc1C2NCc1ccncc1

Procedure:
A solution of 4.0 g. of 9-acetoxyxanthene and 2.0 g. of 4-aminomethylpyridine in 100 ml. of benzene is refluxed for 24 hours. The reaction mixture is stripped of solvent and the residue dissolved in ether. The ether solution is washed with cold 5% sodium carbonate and water and dried over potassium carbonate and chromatographed with alumina and eluting with ether/hexane. The eluate is extracted with ether/acetone and concentrated in vacuo to give 4-pyridylmethyl-9-xanthylamine having a m.p. of 83°-85° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:44])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]([CH3:35])[N:27]=4)[N:24]=3)[N:19](COCC[Si](C)(C)C)[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:4][CH2:5][N:6]([C:9](=[O:44])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]([CH3:35])[N:27]=4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:7][CH2:8]1)#[N:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)cn3COCC[Si](C)(C)C)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCC(C#N)CC4)C4CC4)c3n2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
In a round-bottomed flask, 2-(1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (0.158 g, 0.193 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (0.6 ml, 7.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was redissolved in dichloromethane (1 ml) and ethylenediamine (0.8 ml, 11.7 mmol) was added. The solution was stirred at room temperature for 1 h then quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel with MeOH/CH2Cl2 (0.5% NH4OH) (gradient 0-4% MeOH) followed by trituration with ethyl acetate to afford 31 mg (32%) of 2-(1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a light yellow powder. MS: (M+H)+=483; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.89 (br. s., 1H), 9.17 (s, 1H), 8.79 (d, J=7.9 Hz, 1H), 8.65 (d, J=8.3 Hz, 1H), 8.45 (d, J=9.4 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.13-7.33 (m, 1H), 4.88 (t, J=7.9 Hz, 1H), 4.19 (s, 3H), 3.68-4.05 (m, 2H), 3.34-3.66 (m, 2H), 3.14 (br. s., 1H), 1.47-2.07 (m, 4H), 1.34 (br. s., 1H), 0.37-0.65 (m, 4H).
Reaction SMILES: C([N:5]1[C:9]([Cl:10])=[C:8]([CH2:11][S:12][C:13]2[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][N:14]=2)[C:7]([C:20]([F:23])([F:22])[F:21])=[N:6]1)(C)(C)C.Br.C(O)(=O)C>O>[Cl:10][C:9]1[NH:5][N:6]=[C:7]([C:20]([F:21])([F:23])[F:22])[C:8]=1[CH2:11][S:12][C:13]1[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][N:14]=1
Reactant: CC1(C)CC(SCc2c(C(F)(F)F)nn(C(C)(C)C)c2Cl)=NO1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CC(SCc2c(C(F)(F)F)n[nH]c2Cl)=NO1
Temperature: 45 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
19.8 g (53.4 mmoles) of 3-(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline was added to 170 ml of a 25% hydrogen bromide-acetic acid solution. The mixture was stirred at 40 to 50° C. for 2 hours to give rise to a reaction. After the completion of the reaction was confirmed, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 12.0 g (yield: 60.6%) of 3-(5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as light yellow crystals (melting point: 120.0 to 122.0° C.)