Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)C([N:8]1[C@H:11]([S:12]([CH3:15])(=[O:14])=[O:13])[C@@H:10]([C:16]([CH3:24])([CH3:23])[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]1=[O:25])=C(C)C.O=[O+][O-].O=O.CSC>C(Cl)Cl>[C:19]([SiH2:18][O:17][C:16]([CH3:24])([CH3:23])[C@@H:10]1[C@@H:11]([S:12]([CH3:15])(=[O:14])=[O:13])[NH:8][C:9]1=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)[C@H]1S(C)(=O)=O
Agent: O=O
Agent: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: CC(C)(C)[SiH2]OC(C)(C)[C@H]1C(=O)N[C@@H]1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 25 g (61.7 mmol) of 2-[(3S,4R)-3-(tert.-butyl-dimethyl-silyloxymethyl)-4-methylsulphonyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoic acid methyl ester in 400 ml of methylene chloride is treated at -10° with an ozone/oxygen mixture. The disappearance of the starting material is monitored by thin layer chromatography. When the reaction is complete, 30 ml of dimethyl sulphide are added and the whole is stirred for a further 3 hours at room temperature. The solution is concentrated and the residue is taken up in a mixture of 160 ml of methanol, 24 ml of ethyl acetate and 3 ml of water and heated for 40 minutes at 70°. The solvent is then removed and the residue is evaporated twice in the presence of toluene. The crystallising oil is taken up in methylene chloride and the crystals, consisting of (3S,4R)-3-hydroxymethyl-4-methylsulphonylazetidin-2-one, are isolated by filtration. The filtrate is concentrated and (3S,4R)-3-(tert.-butyl-dimethyl-silyloxymethyl)-4-methylsulphonylazetidin-2-one is obtained in pure form by chromatography over silica gel with toluene/ethyl acetate (3:1).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]2[NH:9][CH:10]=[C:11]([C:12]#[N:13])[C:6]2=[CH:5][CH:4]=1)=[CH2:2].[C:14]([C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[C:24](=[O:29])[N:23]([C:30]1[C:38]3[CH2:37][O:36]B(O)[C:34]=3[CH:33]=[CH:32][CH:31]=1)[N:22]=[CH:21]2)([CH3:17])([CH3:16])[CH3:15].N1C=CC=CC=1.[NH4+].[Cl-]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCCl>[C:14]([C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[C:24](=[O:29])[N:23]([C:30]1[C:38]([CH2:37][OH:36])=[C:34]([N:9]3[C:7]4=[N:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=[C:6]4[C:11]([C:12]#[N:13])=[CH:10]3)[CH:33]=[CH:32][CH:31]=1)[N:22]=[CH:21]2)([CH3:17])([CH3:15])[CH3:16]
Reactant: C=Cc1ccc2c(C#N)c[nH]c2n1
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc4c3COB4O)ncc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: C=Cc1ccc2c(C#N)cn(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)c2n1
Temperature: 45 °C
Reaction time: 48 h
Yield: 12.7 %

Procedure:
In a 25 mL round-bottomed flask, 6-vinyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (138 mg, 816 μmol, Eq: 1.00), 6-tert-butyl-8-fluoro-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)phthalazin-1(2H)-one (287 mg, 816 μmol, Eq: 1.00) and copper acetate (200 mg) were combined with 1,2-Dichloroethane (3.58 ml) to give a blue suspension. Pyridine (129 mg, 132 μl, 1.63 mmol, Eq: 2) was added. The reaction mixture was heated to 45° C. and stirred for 2 d. The reaction mixture was poured into 20 mL sat NH4Cl and extracted with sat EtOAc (3×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 10% MeOH in DCM), then by HPLC to give 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-vinyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (51 mg, 13%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:10](N(CC)CC)[CH3:11].C(OC(=O)C)(=O)C>ClCCl>[CH2:10]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:11]
Reactant: NCCN1CCCCC1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCNCCN1CCCCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 79 %

Procedure:
To a solution of 1-(2-aminoethyl)piperidine(5.01 g) in dichloromethane (100 ml) were added triethylamine(11 ml) and acetic anhydride(4.4 ml) and then the mixture was stirred at room temperature for 40 minutes. The reaction solution was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated under a vacuum. The residue was dropped into a suspension of lithium aluminium hydride (3.46 g) in tetrahydrofuran(100 ml). After being refluxed with heating for 1 hour, the reaction mixture was filtrated. The filtrate was concentrated, thereby yielding 4.43 g(79%) of 1-[2-(ethylamino)ethyl]piperidine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:21]3[C:20](=[O:28])[N:19]([CH2:29][C:30]([OH:32])=[O:31])[C:18](=[O:33])[N:17]([CH3:34])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH3:34][N:17]1[C:16]2[N:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:21]=2[C:20](=[O:28])[N:19]([CH2:29][C:30]([OH:32])=[O:31])[C:18]1=[O:33]
Reactant: CC(C)=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CC(=O)O)c(=O)n2C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)=CCn1c(N2CCNCC2)nc2c1c(=O)n(CC(=O)O)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[3-Methyl-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (70 mg) and potassium carbonate (28 mg) were dissolved in N,N-dimethylformamide (1.5 ml), and ethyl bromoacetate (22 μl) was added thereto. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was concentrated by distillation, and ethanol (1.5 ml) and 2 N sodium hydroxide aqueous solution (0.5 ml) were added to the resulting residue. The reaction mixture was stirred at room temperature for 3 hours, diluted with water, and neutralized with 2 N hydrochloric acid. After the mixture was extracted with ethyl acetate, the organic layer was concentrated by distillation to give 75 mg of 4-[1-carboxymethyl-3-methyl-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. Then, the resulting 4-[1-carboxymethyl-3-methyl-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (10 mg) was dissolved in trifluoroacetic acid (0.5 ml), and the reaction mixture was stirred at room temperature for 30 minutes. After the solvent was removed by distillation, a half of the residue was purified by HPLC with a reversed phase column using water-acetonitrile-trifluoroacetic acid system as eluent to give 5.9 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([I:12])=[C:8]2[C:4]=1[CH:5](O)[N:6](C(C)(C1C=CC=CC=1)C)[C:7]2=[O:13].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([I:12])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:13]
Reactant: COc1ccc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: COc1ccc(I)c2c1CNC2=O
Yield: 77.3 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-methoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (2.50 g, 5.91 mmol) was dissolved in nitromethane (100 mL), and the solution was treated with trifluoroacetic acid (4.50 mL, 59.1 mmol) and triethylsilane (1.90 mL, 11.8 mmol). The obtained solid was collected by filtration and washed with ethyl acetate. The obtained solid was dried under reduced pressure to obtain 4-methoxy-7-iodoisoindolinone (1.32 g, yield 78%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.[OH:13][C:14]1[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1.N1C2C(=CC=CC=2)C=CC=1>>[F:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:26][CH:27]=1)[CH:11]=[CH:10]2
Reactant: Fc1ccc2nc(Cl)ccc2c1
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)C(C)Oc1ccc(Oc2ccc3cc(F)ccc3n2)cc1

Procedure:
was prepared from 2-chloro-6-fluoroquinoline and ethyl 2-(4-hydroxyphenoxy)propionate following essentially the same procedure as that described in Example 1. The compound was isolated as a pale yellow oil. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 8.1-6.8 (9H, m, quinoline and phenyl protons); 4.8 (1H, q, CH-CH3); 4.3 (2H, q, OCH2 -CH3); 1.6 (3H, d, CH-CH3); 1.2 (3H, t, OCH2 -CH3).
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>COCCOC>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=2[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:35][CH:34]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1-c1ccc(Cl)cc1
Yield: 27.9 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 4-chlorophenylboronic acid (29 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with 30% ethyl acetate/hexanes to afford the product as a beige solid (15 mg, 0.034 mmol, 27%). LC-MS m/e 441.25 (M+H+)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:23][C:13]4([C:21]5[C:16](=[N:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][C:7]=3[CH:8]=2)[N:3]=1.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:22]=[C:14]1[NH:15][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[C:13]21[CH2:12][C:7]1[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=1[CH2:23]2)[N:3]=[C:2]([C:32]1[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=1)[C:26]([O:25][CH3:24])=[O:27])[CH:11]=[CH:10]3
Reactant: O=C1Nc2ncccc2C12Cc1cc3ccc(Cl)nc3cc1C2
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cccc(-c2ccc3cc4c(cc3n2)CC2(C4)C(=O)Nc3ncccc32)c1

Procedure:
A stirred mixture of (±)-2-chloro-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (204 mg, 0.634 mmol, described in Intermediate 20), 3-methoxycarbonylphenylboronic acid (229 mg, 1.27 mmol), PdCl2(PPh3)2 (44 mg, 0.063 mmol), and potassium carbonate (290 mg, 2.10 mmol), in 1,2-dimethoxyethane (3 mL) and H2O (1 mL) was heated at 80° C. for 18 h. The cooled mixture was partitioned between H2O (40 mL) and EtOAc (40 mL). The organic layer was removed and the aqueous phase was extracted further with EtOAc (40 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The product-containing fractions were combined and concentrated to give the title compound. MS: m/z=422 (M+1). HRMS: m/z=422.1504; calculated m/z=422.1499 for C26H20N3O3.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([Sn](C)(C)C)[N:7]=[C:6]([C:14]#[N:15])[N:5]=1)[CH2:2][CH3:3].[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[C:20](Br)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[C:20]([C:8]2[CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]=[C:6]([C:14]#[N:15])[N:7]=2)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1
Reactant: CCCc1cc([Sn](C)(C)C)nc(C#N)n1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCCc1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(C#N)n1
Yield: 35.1 %

Procedure:
Bis(triphenylphosphine)palladium dichloride (34 mg, 0.05 mmol) was added under a nitrogen atmosphere to a mixture of 4-propyl-6-trimethylstannanyl-pyrimidine-2-carbonitrile (155 mg, 0.50 mmol) and 3,5-bis-trifluoromethyl-bromobenzene (0.10 mL, 0.58 mmol) in dimethylformamide (3 mL). The mixture was refluxed for 4 hours then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: DCM) to afford a solid which was triturated in pentane. After filtration, 4-(3,5-bis-trifluoromethyl-phenyl)-6-propyl-pyrimidine-2-carbonitrile (63 mg, 35%) was obtained as an off white solid (mp=112° C.).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Br)=[CH:7]2.BrC1C=C2C(=CC=1)C(F)=C(N)C=C2.F[B-](F)(F)F.[H+].FC1C=C2C(=CC=1)C=C(Br)C=C2.[CH2:45]([CH:50]1[CH2:55][CH2:54][CH:53]=[CH:52][CH2:51]1)[CH2:46][CH2:47][CH2:48][CH3:49]>>[F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C@H:53]1[CH2:52][CH2:51][C@H:50]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:55][CH2:54]1)=[CH:7]2
Reactant: CCCCCC1CC=CCC1
Reactant: Fc1ccc2cc(Br)ccc2c1F
Agent: F[B-](F)(F)F
Agent: Fc1ccc2cc(Br)ccc2c1
Agent: Nc1ccc2cc(Br)ccc2c1F
Product: CCCCC[C@H]1CC[C@H](c2ccc3c(F)c(F)ccc3c2)CC1

Procedure:
The procedure of Example 14 was followed except that 5,6-difluoro-2-bromonaphthalene (synthesized by converting 6-bromo-1-fluoro-2-naphthylamine to a diazonium salt of tetrafluoroboric acid, and then subjecting the diazonium salt to thermal decomposition) was used instead of 6-fluoro-2-bromonaphthalene and 4-pentylcyclohexanene was used instead of 4-propylcyclohexanene to obtain 5,6-difluoro-2-(trans-4-pentylcyclohexyl)naphthalene.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:13][CH:14]([C:16]1[N:21]=[N:20][C:19]([NH:22][C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=2)=[N:18][CH:17]=1)[CH3:15])=O)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O>ClCCCl.ClCCl.CO.C([O-])([O-])=O.[Na+].[Na+]>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:21]2[C:16]([CH:17]=[N:18][C:19]([NH:22][C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)=[N:20]2)=[C:14]([CH3:15])[N:13]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3OC(C)=O)nn2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4OC(C)=O)n3n2)cc(OC)c1OC
Temperature: 25 °C
Yield: 44.5 %

Procedure:
To a solution of 2-{[(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)amino]carbonyl}phenyl acetate (Intermediate 26) (60 mg, 0.13 mmol) in 1,2-dichloroethane (6 mL) was added phosphorous oxychloride (0.10 mL, 1.1 mmol). The mixture was heated to reflux for 5 hours. After cooling to room temperature the reaction was diluted with dichloromethane (125 mL), methanol (20 mL) and aqueous saturated Na2CO3 (40 mL). The aqueous layer was extracted with dichloromethane, then the combined organic layers were dried over MgSO4, concentrated and chromatographed on silica gel, eluting with 2.5% MeOH/DCM to give 2-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl acetate (26 mg) as a yellow oil. MS m/z 449 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([NH2:12])[CH:6]=1)C.[NH2:14][NH2:15]>CCO>[NH2:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[CH3:11])[C:4]([NH:14][NH2:15])=[O:3]
Reactant: CCOC(=O)c1ccc(C)c(N)c1
Reactant: NN
Solvent: CCO
Product: Cc1ccc(C(=O)NN)cc1N
Temperature: 25 °C

Procedure:
To a solution of 3-amino-4-methyl-benzoic acid ethyl ester (10 g) in EtOH (25 mL) was added anhydrous hydrazine (20 mL) dropwise over 45 min at rt. The reaction was stirred at rt. overnight, then concentrated to afford 3-amino-4-methyl-benzoic acid hydrazide (10 g) as a yellow solid. The hydrazide (500 mg) was dissolved in THF (5 mL) and TMS-isocycanate (0.41 mL) was added. After 2-3 h, HPLC analysis indicated 50-60% conversion of the hydrazide. No further conversion was found after 3 days at rt. Evaporation of the THF was followed by addition of 1 N NaOH (2 mL) and the solution was heated to 100° C. overnight. LCMS analysis indicated the desired oxo-triazole to be present along with the carboxylic acid corresponding to hydrolysis of the hydrazide. The solution was neutralized with 1N HCl and the crude product collected by filtration. The crude 5-(3-amino-4-methyl-phenyl)-2,4-dihydro-[1,2,4]triazol-3-one (100 mg) was dissolved in DMF (1 mL) along with 4-chloro-5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester (119 mg), and the solution was heated to 55° C. overnight. The product was purified by reverse phase preparative HPLC to afford Example 51 as a white solid (151 mg, TFA, hydrate), HPLC ret. t. (min): 2.33, MW: 379.4, LCMS[M+H2O+H]+=398.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[S:21][C:20]([N:22]3[CH2:28][CH2:27][CH2:26][NH:25][C:24](=[O:29])[CH2:23]3)=[N:19][CH:18]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.ClC1C=CC=C(C(OO)=[O:38])C=1>ClCCl.[O-]S([O-])(=S)=O.[Na+].[Na+]>[CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[S:21][C:20]([N:22]3[CH2:28][CH2:27][CH2:26][NH:25][C:24](=[O:29])[CH2:23]3)=[N:19][CH:18]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([S:15]([CH3:16])=[O:38])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccnc(Nc2cc(C)cc(-c3cnc(N4CCCNC(=O)C4)s3)c2)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(S(C)=O)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Reaction time: 3 h
Yield: 6.4 %

Procedure:
To 4-[5-(3-methyl-5-{[4-(methylsulfanyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (50 mg, 0.117 mmol) stirring in dichloromethane (586 μL) at room temperature was added 3-chloroperbenzoic acid (27.6 mg, 0.123 mmol). Stirred for 3 hr. at room temperature, diluted with 10% Na2S2O3 (aq.), and washed with sat. NaHCO3 (aq.) and brine. The organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purified by reverse phase preparative HPLC (0:100 to 95:5 acetonitrile:water: 0.1% v/v trifluoroacetic acid modifier) to afford 4-[5-(3-methyl-5-{[4-(methylsulfinyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (3.3 mg, 7.5 μmol, 6.36% yield) as a yellow solid. MS APCI: [M+H]+ m/z 443.1. 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J=4.9 Hz, 1H), 7.68 (s, 1H), 7.48 (s, 1H), 7.44 (d, J=4.9 Hz, 1H), 7.34-7.29 (m, 1H), 7.19 (s, 1H), 6.96 (s, 1H), 5.93-5.85 (m, 1H), 4.28 (s, 2H), 3.46 (s, 2H), 2.93 (s, 2H), 2.37 (s, 3H), 2.16-2.01 (m, 2H), 1.25 (s, 3H). rhSYK activity=+++.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:10]=[C:9]3[NH:26][N:27]([CH3:29])[CH2:28][C:8]=23)=[CH:4][CH:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>C(Cl)(Cl)Cl.O.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>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:11]2[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[C:7]([C:5]3[S:6][C:2]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:3][CH:4]=3)[C:8]3[C:9](=[N:26][N:27]([CH3:29])[CH:28]=3)[N:10]=2)=[CH:20][CH:21]=1
Reactant: OB(O)c1cccnc1
Reactant: CN1Cc2c(nc(-c3ccc(F)cc3)c(-c3ccncc3)c2-c2ccc(Br)s2)N1
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: [K+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cn1cc2c(-c3ccc(-c4cccnc4)s3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Temperature: 80 °C
Yield: 37.8 %

Procedure:
A suspension of 4-(5-bromothien-2-yl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.10 g, 0.2 mmol, obtained in example 188), 3-pyridylboronic acid (0.04 g, 0.3 mmol), K2CO3 (0.06 g, 0.4 mmol), Pd(PPh3)4 (0.017 g, 0.01 mmol), 1,2-dimethoxyethane (1.31 mL) and water (0.04 mL) was heated at 80° C. under argon atmosphere overnight. It was allowed to cool and diluted with CHCl3 and water. The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 35 mg of the desired compound (yield: 50%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1)[C:5]#[N:6].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:70][CH2:71][OH:72]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[CH:17]1[N:16]=[CH:15][N:14]2[CH:10]([C:9]3[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[O:72][CH2:71][CH3:70])[CH2:11][CH2:12][C:13]=12
Reactant: CCO
Reactant: N#Cc1ccc(C2CCc3cncn32)c(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCOc1cc(C#N)ccc1C1CCc2cncn21
Temperature: 135 °C

Procedure:
A solution of 3-bromo-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile (0.090 g, 0.312 mmol) given in Example 3 (table 2), Pd2(dba)3 (0.029 g, 0.031 mmol), BINAP (0.039 g, 0.062 mmol), Cs2CO3 (0.204 g, 0.625 mmol), EtOH (0.091 mL, 1.54 mmol), and DME (4 mL) is heated in a microwave reactor at 135° C. for 1.5 h. At that point LCMS showed consumption of the starting material. The mixture is filtered and then the filtrate is concentrated. The residue is then purified by flash chromatography (0-10% MeOH/DCM) give 4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-ethoxybenzonitrile. MS (ESI) m/z 254.1 (M+H); 1H NMR (400 MHz, MeOD) (TFA salt) δ ppm 1.32 (t, J=6.9 Hz, 3 H), 2.69-2.82 (m, 1 H), 3.07-3.22 (m, 3 H), 4.02-4.22 (m, 2 H), 5.92-6.03 (m, 1 H), 7.27 (d, J=7.8 Hz, 1 H), 7.31 (s, 1 H), 7.36 (dd, J=7.8, 1.5 Hz, 1 H), 7.43 (d, J=1.3 Hz, 1 H), 8.68 (s, 1 H).