Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21])[C:12]#[N:13])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][CH2:10][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:21])([F:22])[F:23])[C:12]#[N:13]
Reactant: CC(C)(C)[Si](C)(C)OCCC(C#N)c1ccccc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#CC(CCO)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 92.9 %

Procedure:
4-(tert-Butyldimethylsilyloxy)-2-(2-trifluoromethylphenyl)butyronitrile (5 g) was dissolved in tetrahydrofuran (70 mL). Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran) (18 mL) was added and the mixture was stirred at room temperature for 4.5 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (3.1 g). The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH:10]1[C:14]([C:15]2[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=2)[NH2:18])=[N:13][N:12]=[N:11]1>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([C:14]3[NH:13][N:12]=[N:11][N:10]=3)[CH:16]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: O
Product: Fc1cnc(Cl)nc1Nc1cccc(-c2nnn[nH]2)c1

Procedure:
A reaction mixture containing 2,4-dichloro-5-fluoro-pyrimindine (1.2 equivalents) and 3-(tetrazol-5-yl)aniline (1 equivalents) in methanol:water (1:1; v/v) was heated at 60° C. for 24 h. Upon dilution with water and acidification, the solid formed was fitered, washed with water, dried and analyzed to give 2-chloro-5-fluoro-N4-[3–1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine (R926853). Alternatively this reaction can be achieved by treating 2,4-dichloro-5-fluoropyrimidine (1 equivalent) with 3-(tetrazol-5-yl)aniline (3 equivalents) in water (1:1; v/v) at 60° C. for 2–3 hours or at room temperature for 24 h to give 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine. 1H NMR (DMSO-d6): δ 10.25 (s, 1H), 8.43 (s, 1H), 8.37 (d, 1H, J=3.6 Hz), 7.90 (dd, 1H, J=0.9 and 9 Hz), 7.75 (d, 1H, J=7.5 Hz), 7.61 (t, 1H, J=7.8 Hz); LCMS: purity: 90%; MS (m/e): 292 (MH+).
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH:3]=O.[Br-].[CH2:8]([O:15][C:16]([CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1C(CC)C1>[OH:5][CH:2]([CH2:1][OH:6])[CH:3]=[CH:18][C:16]([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17]
Reactant: O=CC(O)CO
Reactant: O=C(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Agent: CCC1CO1
Agent: [Br-]
Product: O=C(C=CC(O)CO)OCc1ccccc1

Procedure:
A mixture of DL-glycerinaldehyde (4.5 g, 50 mmole) and (benzyloxycarbonylmethyl)-triphenyl-phosphoniumbromide (24.57 g, 50 mmole) in 100 ml 1,2-epoxybutane was refluxed overnight. The mixture was evaporated under vacuum and the product was isolated by silica gel column chromatography. Yield: 8 g=71%
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]([B-](F)(F)F)=[CH2:13].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH2:13])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: C=Cc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
Bromo-4-chloro-2-nitrobenzene (3 g, 12.69 mmol), potassium vinyltrifluoroborate (2.039 g, 15.23 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.857 g, 2.54 mmol), cesium carbonate (8.27 g, 25.4 mmol) and THF (50 mL) were heated in an 80° C. oil bath overnight. Volatiles were removed under reduced pressure. The pot residue was worked up with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated to afford a dark mixture. The resulting crude mixture was purified by flash chromatography (SiO2, Biotage 65i cartridge). The column was eluted by an EtOAc/hexane mixture (0% to 10%). Related fractions were pooled and evaporated to afford a yellow solid as the titled compound. 1H-NMR (CDCl3, 600 MHz) δ 7.94 (d, J=2.4 Hz, 1H), 7.60-7.54 (m, 2H), 7.12 (dd, J=17.4, 10.8 Hz, 1H), 5.75 (d, J=16.8 Hz, 1H), 5.52 (d, J=10.8 Hz).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:5]([O:7][CH3:8])=[O:6]>C(N(CC)CC)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:15]([C:14]1[C:10]2[C:11](=[CH:2][CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=2)[NH:12][CH:13]=1)([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccc(NCC=C(C)C)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc2[nH]cc(C(C)C)c2c1
Temperature: 110 °C
Yield: 79.4 %

Procedure:
A solution of methyl 3-iodo-4-(3-methyl-but-2-enylamino)-benzoate (2.0 g, Reference Example 53) in triethylamine (1.6 ml) and acetonitrile (35 ml) was treated with palladium acetate (0.05 g). The mixture was sealed in a bomb and heated at 110° C. for 18 hours. After cooling the reaction mixture was filtered and the filtrate was evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petroleum ether (1:4, v/v) to give the title compound (1.0 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])=[CH:20][C:19]=1[OH:38].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:33])([F:35])[F:34])[N:27]([CH3:36])[C:26]2=[O:37])=[CH:20][C:19]=1[O:38][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)COc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1nc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
A mixture of 1.0 g of 6-chloro-2-(methoxycarbonyl)methoxy-3-nitropyridine, 1.37 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol, 0.67 g of potassium carbonate and 5 ml of N,N-dimethylformamide was stirred for 1 hour at room temperature, then at 50° C. for 30 minutes. The resulted residue was added to ice water, extracted with ethyl acetate, and organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.25 g of 6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxy-3-nitropyridine.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40](Cl)(=[O:42])=[O:41]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([S:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[F:33])(=[O:42])=[O:41])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: Cc1c(N2CCN(S(=O)(=O)c3ccccc3F)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure M using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and 2-fluorobenzene-1-sulfonyl chloride to give 5,7-difluoro-2-(4-(2-fluorophenylsulfonyl)-piperazin-1-yl)-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (DMSO-d6) δ ppm 2.00 (br s, 3H), 3.04 (t, J=4.4 Hz, 4H), 3.26 (br s, 4H), 3.33-3.37 (m, 4H), 3.68 (t, J=4.0 Hz, 4H), 6.48 (s, 1H), 7.14-7.19 (m, 1H), 7.26-7.29 (m, 1H), 7.45-7.54 (m, 3H), 7.77 (d, J=2.4 Hz, 2H), 7.81-7.85 (m, 1H), 8.35 (s, 1H). Mass Spectrum (ESI) m/e=599.4 (M+1).
Reaction SMILES: [CH2:1]1[C:11]2[C:4](=[CH:5][C:6]([C:8]([CH:10]=2)=[O:9])=[O:7])[NH:3][CH:2]1C(O)=O.OC1C=C2C(=CC=1O)NC(C(O)=O)=C2>>[OH:9][C:8]1[CH:10]=[C:11]2[C:4](=[CH:5][C:6]=1[OH:7])[NH:3][CH:2]=[CH:1]2
Reactant: O=C1C=C2CC(C(=O)O)NC2=CC1=O
Agent: O=C(O)c1cc2cc(O)c(O)cc2[nH]1
Product: Oc1cc2cc[nH]c2cc1O

Procedure:
TRP-2 catalyzes the tautomerization of DOPAchrome to 5,6-dihydroxyindole-2-carboxylic acid (DHICA). In the absence of TRP-2, DOPAchrome undergoes a spontaneous decarboxylation to form 5,6-dihydroxyindole (DHI).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)=[O:6].[CH:12](I)([CH3:14])[CH3:13]>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[N:8]=[CH:9][N:10]([CH:12]([CH3:14])[CH3:13])[CH:11]=1)=[O:6]
Reactant: COC(=O)c1c[nH]cn1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C(C)C)cn1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 17.6 %

Procedure:
Add sodium hydride (2.87 g, 71.7 mmol, 60% in mineral oil) portion-wise over 10 minutes to a cooled (0° C.) solution of 1H-imidazole-4-carboxylic acid methyl ester (6.03 g, 47.8 mmol) in dimethylformamide (150 ml). Remove the cooling bath and stir at room temperature for 4.5 hrs. Cool the mixture to 0° C. and add isopropyl iodide (8.94 g, 52.6 mmol) dropwise over 10 min. Remove the cooling bath and stir at room temperature for 20 hrs. Quench the mixture with saturated aqueous ammonium chloride and extract with ethyl acetate (3×). Wash the combined extracts with brine, dry over sodium sulfate, filter and concentrate under reduced pressure to give an oil. Purify the oil by flash chromatography (silica gel) eluting with 25% acetone/hexanes to provide the product as an oil (1.41 g, 8.4 mmol, 17% yield). M/S (m/z): 169 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20](=[N:26]O)[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[O:12][N:26]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1
Reactant: O=C(O)Cc1cccc(F)c1F
Reactant: CCOC(=O)C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1noc(Cc2cccc(F)c2F)n1
Yield: 7.8 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(2,3-difluorophenyl)acetic acid (0.651 g; 3.78 mmol) and oxalyl chloride (0.352 mL; 4.16 mmol) in dichloromethane (12 mL) and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (6 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.079 g (8%) of ethyl 5-(2,3-difluorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:39][CH2:40][CH2:41][N:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]2([CH2:52][CH2:51]2)[C:43]1=[O:53]>CC(=O)CC>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:39][CH2:40][CH2:41][N:42]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:44]4([CH2:52][CH2:51]4)[C:43]3=[O:53])[CH2:10][CH2:11]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)Nc1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reactant: O=C1N(CCCCl)c2ccccc2C12CC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CS(=O)(=O)Nc1cccc(CN2CN(c3ccccc3)C3(CCN(CCCN4C(=O)C5(CC5)c5ccccc54)CC3)C2=O)c1
Temperature: 78 °C
Reaction time: 18 h
Yield: 30.5 %

Procedure:
To a solution of N-(3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenyl)methanesulfonamide (0.2 g, 0.48 mmol), sodium iodide (0.029 g, 0.19 mmol) and potassium carbonate (0.133 g, 0.96 mmol) in 2-butanone (5 mL), was added 1′-(3-chloropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one (0.114 g, 0.48 mmol). After stirring at 78° C. for 18 hours, the reaction mixture was filtered and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.09 g, 31%); 1H NMR (DMSO-d6): δ 1.51 (t, 2H, J=3.6 Hz), 1.58 (t, 2H, J=3.6 Hz), 1.64 (d, 2H, J=13.2 Hz), 1.80 (br, 2H), 2.37 (br, 2H), 2.51-2.57 (m, 2H), 2.68-2.73 (m, 4H), 2.96 (s, 3H), 3.82 (t, 2H, J=6.8 Hz), 4.52 (s, 2H), 4.58 (s, 2H), 6.76 (t, 1H, J=7.6 Hz), 6.84 (d, 2H, J=8.4 Hz), 6.96-7.02 (m, 3H), 7.09 (s, 1H), 7.12 (d, 1H, J=8 Hz), 7.17-7.24 (m, 4H), 7.32 (t, 1H, J=8 Hz), 9.81 (s, 1H); MS for C34H39N5O4S m/z 614.4 (M+H)+.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.O[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]#[N:19])[CH2:13][CH2:12]1>C(Cl)Cl>[F:7][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]#[N:19])[CH2:13][CH2:12]1
Reactant: CCN(CC)S(F)(F)F
Reactant: N#CCN1CCC(O)CC1
Solvent: ClCCl
Product: N#CCN1CCC(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
DAST (4.36 mL, 33 mmol) was added to a solution of (4-hydroxy-piperidin-1-yl)-acetonitrile (4.25 g, 30 mmol) in DCM (80 mL) at −30° C., the mixture was then stirred at rt for overnight. The reaction was cooled to −30° C. and quenched with methanol (10 mL) for 30 mins. The organic layer was then washed with NaHCO3 and dried. The residue was purified on a silica gel column to give 3 g (71%) of (4-fluoro-piperidin-1-yl)-acetonitrile.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([S:29]([N:32]=CN(C)C)(=[O:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:7]2[C:13](=[O:14])[CH:12]([F:15])[CH2:11][S:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].Cl>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:24]([S:29]([NH2:32])(=[O:30])=[O:31])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)[C:7]2[C:13](=[O:14])[CH:12]([F:15])[CH2:11][S:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3S(=O)(=O)N=CN(C)C)cc1)C(=O)C(F)CS2
Agent: Cl
Solvent: CCO
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3S(N)(=O)=O)cc1)C(=O)C(F)CS2
Yield: 96.4 %

Procedure:
Using the procedure of Example 2, 330 mg of the product of Example 12, 3.3 ml of ethanol and i ml of concentrated hydrochloric acid were reacted to obtain 285 mg of the crude product which was used as is in the following example and melted at 208° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[N:3]=1.O.[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(COC)OC.C(O)C>[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]3[CH3:14])[CH:5]=[C:4]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[N:3]=2)=[CH:25][CH:24]=1
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(Cl)n1
Reactant: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: CN(C)C=O
Product: CNc1ccc(-c2nc(CS(C)(=O)=O)cc(N3CCOC[C@@H]3C)n2)cc1
Temperature: 90 °C
Yield: 90.2 %

Procedure:
2-Chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (1.01 g, 3.30 mmol) was dissolved in 18% DMF in 7:3:2 dimethoxy ethane:water:ethanol (7 mL). N-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.00 g, 4.29 mmol), 2M sodium carbonate solution (4 mL) and dichlorobis(triphenylphosphine) palladium (116 mg, 0.16 mmol) were added to the solution. The reaction was refluxed at 90° C. for 3 hours under nitrogen atmosphere then the mixture allowed to cool and partitioned ethyl acetate (30 mL) and water (30 mL). The organic layer was dried over magnesium sulphate, filtered and evaporated to dryness. The brown oil was dissolved in DCM and filtered to remove insoluble material then the filtrate chromatographed on silica, eluting with 0-4% methanol in DCM, to give the desired product as a yellow foam (1.12 g, 90%)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[O:10][C:11](=[O:15])[N:12]([CH3:14])[CH3:13])#[N:2].[ClH:16].[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[ClH:16].[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[O:10][C:11](=[O:15])[N:12]([CH3:13])[CH3:14]
Reactant: [H][H]
Reactant: CN(C)C(=O)Oc1cc(F)ccc1C#N
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)C(=O)Oc1cc(F)ccc1CN
Yield: 38 %

Procedure:
To a solution of intermediate 132, dimethyl-carbamic acid 2-cyano-5-fluoro-phenyl ester, (340 mg, 1.63 mmol) in ethyl acetate (20 mL) and ethanol (20 mL), was added conc.HCl (0.4 mL) and 10% Pd—C (100 mg) and the mixture hydrogenated in a Parr Shaker at 55 psi of hydrogen for 20 hrs. The reaction mixture was filtered through Celite, and the filtrate concentrated in vacuo to give an oil which was partitioned between ethyl acetate (10 mL) and water (10 mL). After separation, the aqueous phase was washed with additional ethyl acetate (5 mL). The combined extracts were concentrated in vacuo to dryness. The residual oil was triturated with ether to provide 145 mg (Yield 38%) of the title compound, as a tan powder: 1H NMR (CD3OD, 500 MHz) δ ppm: 3.06 (3H, s, NMe), 3.21 (3H, s, NMe), 4.11 (2H, s, NCH2), 7.13 (2H, m, Ar-Hs), 7.60 (1H, m, Ar—H); 13C NMR (CD3OD, 125.77 Hz) δ ppm: 36.03, 36.25 37.58, 110.79, 110.99, 113.26, 113.43, 122.32, 132.18, 132.25, 151.55, 154.72, 162.69, 164.67. HRMS (ESI) calcd for C10H13N2O2F (M+H) 213.1039, found 213.1039.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:40][C:41]1([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:50]3[C:51]([CH3:56])=[N:52][O:53][C:54]=3[CH3:55])[CH:48]=2)[NH:43][C:42]1=[O:57]>C(Cl)Cl.O>[CH3:2][N:3]([CH3:8])[CH2:4][C:5]([NH:40][C:41]1([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:50]3[C:51]([CH3:56])=[N:52][O:53][C:54]=3[CH3:55])[CH:48]=2)[NH:43][C:42]1=[O:57])=[O:6]
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(N)(c1ccccc1)C(=O)N2
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1noc(C)c1-c1ccc2c(c1)C(NC(=O)CN(C)C)(c1ccccc1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
A mixture of 2-(dimethylamino)acetic acid hydrochloride (87 mg, 0.62 mmol), HATU (118 mg, 0.31 mmol), and Et3N (94 mg, 0.93 mmol) in CH2Cl2 (10 mL) was stirred at RT for 0.5 hours, and then 3-amino-5-(3,5-dimethylisoxazol-4-yl)-3-phenylindolin-2-one (100 mg, 0.31 mmol) was added and the mixture was stirred for another 12 h. And water (10 mL) was added, the mixture was extracted with CH2Cl2 (2×20 mL), combined organic phase, washed with brine (20 mL), dried with Na2SO4, concerned in vacuo, the mixture was purified with column chromatography to give product (50 mg, 40%) as a solid. 1H NMR (400 MHz, DMSO-d6): δH 10.70 (s, 1H), 9.74 (s, 1H), 7.26-7.40 (m, 7H), 6.99 (d, J=8.0 Hz, 1H), 4.07 (d, J=16.0 Hz, 1H), 3.93 (d, J=16.0 Hz, 1H), 2.78 (s, 3H), 2.71 (s, 3H), 2.38 (s, 3H), 2.20 (s, 3H). MS (ESI) m/e [M+1]+ 405.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([NH2:23])[C:8]([NH2:22])=[CH:9][C:10]=1[O:11][C:12]1[CH:13]=[N:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1.[N:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[C:34](O)=O>>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:10]([O:11][C:12]2[CH:13]=[N:14][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:16][CH:17]=2)=[CH:9][C:8]2[NH:22][C:34]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][N:28]=3)=[N:23][C:7]=2[CH:6]=1
Reactant: O=C(O)c1cnccn1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2F)cn1
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccccc2F)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 197 or in accordance with the method or by combining it with an ordinary method but using 4-(2-fluoro-phenoxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 200 and pyrazine-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:14]=3[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Li])CCC.[I:31]I>O1CCCC1.CCCCCC>[I:31][C:12]1[N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[C:15]2[N:16]=[CH:17][N:18]=[C:19]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:14]=2[CH:13]=1
Reactant: II
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccnc4)ncnc32)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cccnc4)ncnc32)cc1
Reaction time: 1.5 h
Yield: 19.1 %

Procedure:
To a solution of 7-[(4-methylphenyl)sulfonyl]4-pyridin-3-yl-7H-pyrrolo[2,3-d]pyrimidine [1 g, Reference Example 2] in tetrahydrofuran (20 mL) at −78° C. was added drop wise a solution of butyl lithium in hexane (2 mL, 1.6M) under inert atmosphere. The solution was stirred at that temperature for 1.5 hour and iodine (796 mg) was added. The reaction mixture was stirred at −78° C. for another 1 hour and allowed to reach room temperature. The reaction mixture was partitioned between ethyl acetate and aqueous sodium sulfite solution. The organic phase was separated, then dried over magnesium sulfate and then evaporated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with a gradient of ethyl acetate and cyclohexane (50:50, to 100, v/v) to give the title compound (260 mg) as an amorphous solid. MS: 477 [MH]+. LCMS (Method B) RT=3.26 minutes.