Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:37][CH:38]([CH3:43])[CH2:39][CH2:40][CH2:41]O>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:41][CH2:40][CH2:39][CH:38]([CH3:43])[CH3:37])=[C:12]([C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)CCCO
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Product: CC(C)CCCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-methyl-1-pentanol in place of 2-ethyl-1-hexanol (yield: 120 mg, 52%). mp 98-99° C. 1H NMR (300 MHz, DMSO-d6) δ 0.73 (d, J=7 Hz, 6H), 1.02 (m, 2H), 1.29 (m, 1H), 1.54 (m, 2H), 3.30 (s, 3H), 4.40 (t, J=7 Hz, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 463 (M+H)+; (APCI−) m/z 497 (M+Cl)−. Anal. calc. for C23H24F2N2O4S: C, 59.72; H, 5.23; N, 6.05. Found: C, 59.57; H, 5.28; N, 6.01.
Reaction SMILES: N1C=CC=CC=1.Cl.[NH2:8][OH:9].[F:10][C:11]1[CH:12]=[C:13]([CH2:18][O:19][C:20]2[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][C:21]=2[C:22]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:23])[CH:14]=[CH:15][C:16]=1[F:17]>CO>[F:10][C:11]1[CH:12]=[C:13]([CH2:18][O:19][C:20]2[CH:34]=[CH:33][C:32](/[CH:35]=[N:8]\[OH:9])=[CH:31][C:21]=2[C:22]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:23])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: NO
Reactant: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)Nc2cccnc2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1cccnc1)c1cc(/C=N\O)ccc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyridine (0.44 ml, 5.43 mmol) and hydroxylamine hydrochloride (75 mg, 1.09 mmol) were added to a solution of 2-([(3,4-difluorophenyl)methyl]oxy)-5-formyl-N-3-pyridinylbenzamide (may be prepared by Example 80; 200 mg, 0.54 mmol) in methanol (10 ml), and the mixture was stirred at room temperature for 30 min. The mixture was evaporated under reduced pressure to half volume. The mixture was diluted with water (20 ml) and filtered. The solid was washed with water (20 ml)/methanol (5 ml) and air dried under vacuum to yield the title compound as a white solid. 167 mg.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([C:13]#[C:14][Si](C)(C)C)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([C:13]#[CH:14])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nnc2ccc(C#C[Si](C)(C)C)cn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2nnc(C(C)C)n2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a 250 mL round bottom flask was added 2.5 g (9.71 mmol) of 3-Isopropyl-6-trimethylsilanylethynyl-[1,2,4]triazolo(4,3-a)pyridine, 50 mL of methanol, and 4.03 g (29.1 mmol) of potassium carbonate. This suspension was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was suspended in 100 mL of water, which was extracted with (2×100 mL) ethyl acetate. The organic extracts were combined, washed with 100 mL of a 1:1 solution of brine and water, dried over magnesium sulfate, filtered, and concentrated to dryness to yield 1.47 grams (82%) of a light brown solid. HPLC tR=3.22 min (93%), LC-MS=186 (M+1).
Reaction SMILES: C([O:5][CH2:6][CH2:7][NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:17][C:18]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([CH2:32][N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][C:34]4=[O:40])=[C:27]([CH:30]=[O:31])[N:28]=3)[CH2:23][CH2:22][CH2:21]2)=[O:19])[CH:10]=1)(C)(C)C.C(C(O)=O)(F)(F)F>C(Cl)Cl>[C:15]([C:14]1[C:9]([NH:8][CH2:7][CH2:6][OH:5])=[CH:10][C:11]([NH:17][C:18]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([CH2:32][N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][C:34]4=[O:40])=[C:27]([CH:30]=[O:31])[N:28]=3)[CH2:23][CH2:22][CH2:21]2)=[O:19])=[N:12][CH:13]=1)#[N:16]
Reactant: CN1CCN(Cc2cc3c(nc2C=O)N(C(=O)Nc2cc(NCCOC(C)(C)C)c(C#N)cn2)CCC3)C(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(Cc2cc3c(nc2C=O)N(C(=O)Nc2cc(NCCO)c(C#N)cn2)CCC3)C(=O)C1
Reaction time: 48 h

Procedure:
A solution of N-(4-((2-(tert-butoxy)ethyl)amino)-5-cyanopyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (Example 196, 1.11 g, 2.02 mmol) in DCM (10 ml) was treated with CF3CO2H (1.56 ml, 20.23 mmol). The reaction mixture was stirred for 48 h. The reaction was quenched by addition of saturated Na2CO3 solution. The reaction mixture was stirred for 16 h. The aqueous was extracted with DCM (×2) and the combined organic extracts were concentrated under reduced pressure. The solid was dissolved in a minimum amount of DCM with a drop of MeOH, then Et2O was added to give a precipitate which was filtered. The solid was triturated with Et2O and filtered to afford the title compound.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH2:8](O)[C:9]([CH3:12])([CH3:11])[CH3:10].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[C:1]([O:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:6])[CH2:2][C:3]([O:5][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: CC(C)(C)CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)COC(=O)CC(=O)OCC(C)(C)C
Yield: 94.8 %

Procedure:
Malonic acid (40 g, 0.38 mol) and neopentyl alcohol (77.5 g, 0.88 mol) in 110 ml of toluene in the presence of 0.2 ml of concentrated sulfuric acid are refluxed for 3 hours in a reactor equipped with Dean-Stark apparatus. The water formed is removed azeotropically. The organic phase is washed 3 times with water and dried over sodium sulfate. After filtration and evaporation of the solvent under vacuum, 88 g (yield: 94%) of dineopentyl malonate are obtained in the form of a colorless oil and used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([F:24])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C1COCC1.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>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=2)=[C:17]([F:24])[CH:16]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: CC(=O)Nc1cc(Cl)c(C=O)cn1
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: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cc(-c2ccc(Cl)cc2F)c(C=O)cn1
Temperature: 85 °C
Yield: 59.6 %

Procedure:
To a stirred solution of N-(4-chloro-5-formylpyridin-2-yl)acetamide (3 g, 15.11 mmol), (4-chloro-2-fluorophenyl)boronic acid (2.63 g, 15.11 mmol), cesium carbonate (9.84 g, 30.2 mmol) in a mixture of water (8 mL) and THF (25 mL) was added Pd(PPh3)4 (19.19 mg, 0.017 mmol) and the reaction was heated to 85° C. for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, brine, dried over sodium sulphate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using hexane/ethyl acetate as eluant yielding N-(4-(4-chloro-2-fluorophenyl)-5-formylpyridin-2-yl)acetamide (2.8 g, 9.01 mmol, 60% yield) as an off-white solid. LCMS (ESI) m/e 291.0 [(M)−, calcd for C14H9ClFN2O2 291.0] LC/MS retention time (method A): tR=1.69 min; 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.84 (d, J=Hz, 1H), 8.88 (s, 1H), 8.13 (s, 1H), 7.61 (dd, J=2.00, 10.00 Hz, 1H), 7.46-7.48 (m, 2H), 2.11 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9]C(=O)OCC2C=CC=CC=2)=[N:7][CH:8]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1
Reactant: [H][H]
Reactant: CCc1ccc(NC(=O)OCc2ccccc2)nc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(N)nc1
Yield: 99.2 %

Procedure:
A suspension of benzyl (5-ethyl-2-pyridyl)carbamate (1.9 g., 7.43 mmoles) and 10% palladium-on-carbon (0.4 g.) in ethanol (100 ml.) was shaken with hydrogen at a pressure of 3.5 kg./cm2 hours. The catalyst was removed by filtration and the filtrate concentrated to yield 2-amino-5-ethylpyridine (0.9 g., 99.4%) as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:18])[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:7](=[O:17])[NH:6]1)=[O:4].[OH-].[Na+].Cl>CO>[F:16][C:13]1[CH:12]=[CH:11][C:10]([N:8]2[CH2:9][C:5]([CH3:18])([C:3]([OH:4])=[O:2])[NH:6][C:7]2=[O:17])=[CH:15][CH:14]=1
Reactant: COC(=O)C1(C)CN(c2ccc(F)cc2)C(=O)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C(=O)O)CN(c2ccc(F)cc2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-(4-fluoro-phenyl)-4-methyl-2-oxo-imidazolidine-4-carboxylic acid methyl ester (247 mg, 0.98 mmol) in methanol (15 mL) was treated with aqueous NaOH (1.50 mL, 6.38 mmol). After stirring 1 hour at room temperature, the mixture was treated with 1N HCl to pH 1 and the resulting white precipitate collected by filtration (135 mg, 58%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:7][C:2]([NH:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=2)=[N:3][CH:4]=1
Reactant: COc1cccc(CCNc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CCCO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(CCNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 90.3 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.50 g, 1.7 mmol) (prepared according to Example 8, Step A) and 3-(3-aminophenyl)propan-1-ol (0.34 g, 2.3 mmol) in 1,4-dioxane (14.3 mL) was added p-toluenesulfonic acid monohydrate (0.12 g, 0.61 mmol). The mixture was heated at 100° C. for 16 hours and the reaction was complete. To the mixture was added NaHCO3 aqueous solution (saturated). The organic solvent was removed under vacuum. Water and EtOAc were added to the residue. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as a light brown gel (0.634 g, 92%). LCMS for C22H26ClN4O2 (M+H)+: m/z=413.0.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([CH2:15][CH3:16])[C:9]2=[O:17])=[N:6][CH:7]=1.[I-:18].[Na+].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.[Cu]I>[I:18][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([CH2:15][CH3:16])[C:9]2=[O:17])=[N:6][CH:7]=1
Reactant: CCN1C(=O)N(c2ncc(Br)cn2)CC1(C)C
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN1C(=O)N(c2ncc(I)cn2)CC1(C)C
Temperature: 100 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
(350 mg, 1.17 mmol) 1-(5-Bromo-pyrimidin-2-yl)-3-ethyl-4,4-dimethyl-imidazolidin-2-one (Example 143, step 2) was dissolved in dioxane (20 ml) and sodium iodide (700 mg, 4.68 mmol, 4 equiv.), copper(I) iodide (21 mg, 0.234 mmol, 0.2 equiv.) and trans-N,N′-dimethylcyclohexane-1,2-diamine (33 mg, 37 μl, 0.234 mmol, 0.2 equiv.) were added. The mixture was stirred for 16 hours at 100° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times ethyl acetate. The organic layers were extracted with brine, dried over sodium sulfate and evaporated to dryness. The desired 1-(5-iodo-pyrimidin-2-yl)-3-ethyl-4,4-dimethyl-imidazolidin-2-one (350 mg, 86% yield) was obtained as a brown solid, MS: m/e=347.0 (M+H+) and was used without further purification in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[Cl-].[CH:21]([NH:24]C(C)C)([CH3:23])[CH3:22]>C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:5]=1[C:6]([NH:24][CH:21]([CH3:23])[CH3:22])=[O:8])([O-:3])=[O:2]
Reactant: CC(C)NC(C)C
Reactant: O=C(O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A solution of 34A (1.0 g, 3.86 mmol) in CH2Cl2 (15 mL) was treated with one drop of DMF. Oxaly chloride (2.2 mL, 2M in CH2Cl2, 4.4 mmol) was added dropwise at room temperature. The reaction mixture was stirred for 1 hour, and then concentrated to dryness. The crude acid chloride was dissolved in CH2Cl2 and cooled to 0° C. Diisopropylamine (600 mg, 10 mmol) in CH2Cl2 (2 mL) was added slowly and the resulting mixture was stirred for one hour at room temperature. The reaction was concentrated and partitioned between EtOAc (20 mL) and 1M HCl (20 mL). The organic layer was washed with 1 M HCl (20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to a brown solid. The crude amide was recrystallized from EtOAc/heptane to afford 34B (740 mg, 64%).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[O:26][CH:25]=[CH:24][C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([C:16]([C:21]([OH:23])=O)=[N:17][NH:18]4)=[CH:14][CH:13]=3)[N:10]=2)[CH2:3][CH2:2]1.[NH:27]1[C:35]2[C:30](=CC=C[CH:34]=2)C(C([O-])=O)=N1.C1(N)CC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH:35]1([NH:27][C:21]([C:16]2[C:15]3[C:19](=[CH:20][C:12]([NH:11][C:9]4[N:10]=[C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)[C:6]5[O:26][CH:25]=[CH:24][C:7]=5[N:8]=4)=[CH:13][CH:14]=3)[NH:18][N:17]=2)=[O:23])[CH2:34][CH2:30]1
Reactant: O=C([O-])c1n[nH]c2ccccc12
Reactant: O=C(O)c1n[nH]c2cc(Nc3nc(NC4CC4)c4occc4n3)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1n[nH]c2cc(Nc3nc(NC4CC4)c4occc4n3)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
6-(4-(Cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-1H-indazole-3-carboxylic acid (0.13 g, 0.37 mmol, [prepared using I from methyl 6-nitro-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxylate [WO 2010/027500 page 171 intermediate 83 step A], B with Preparation #A.1, J and AI), cyclopropylamine (0.013 mL, 0.18 mmol), and HATU (0.078 g, 0.20 mmol) were combined in DMF (1.9 mL). DIEA (0.081 mL, 0.46 mmol) was added and the mixture was stirred at rt for about 18 h. Additional cyclopropylamine (0.013 mL, 0.19 mmol) was added and the mixture was stirred for about 6 h. HATU (0.04 g, 0.10 mmol) and DIEA (0.1 mL) were added and the mixture was stirred for about 24 h. A solution of 1 M aqueous Na2CO3 (5 mL) was added. The aqueous layer was separated and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in a mixture of MeOH and DCM and adsorbed onto silica gel (˜3 mL). The residue was purified by column chromatography (25 g silica gel) eluting with 2-8% MeOH in DCM to give N-cyclopropyl-6-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-1H-indazole-3-carboxamide (0.052 g, 72%) as a white solid on drying under vacuum at about 40° C.: LCMS (Table 2, Method c) Rt=1.80 min.; MS m/z: 390 (M+H)+. Syk IC50=A
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([C:13]3[N:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1.[CH3:21][O-:22].[Na+].ClCCl>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([C:13]3[N:18]=[C:17]([C:19](=[NH:20])[O:22][CH3:21])[CH:16]=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: N#Cc1cccc(-c2cnc(-c3cncc(F)c3)s2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=N)c1cccc(-c2cnc(-c3cncc(F)c3)s2)n1

Procedure:
6-[2-(5-Fluoropyridin-3-yl)-1,3-thiazol-5-yl]pyridine-2-carbonitrile (0.33 g, 1.17 mmol) and sodium methoxide (0.13 g, 0.23 mmol) were stirred in methanol (10 ml) and dichloromethane (10 ml) at room temperature for 3 d. The precipitated solid was filtered off and the solvent of the filtrate was removed under reduced pressure. The residue was dissolved in dichloromethane and filtered through Celite. The solvent of the filtrate was removed under reduced pressure. This gave 0.32 g (83% of theory) of methyl 6-[2-(5-fluoropyridin-3-yl)-1,3-thiazol-5-yl]pyridine-2-carboximidoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[N:6][C:7]=1[C:8]#[N:9].[NH2:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29]([C:33]#[N:34])=[CH:28][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[C:8]([C:7]1[N:6]=[CH:5][C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:3][C:2]=1[NH:25][C:26]1[CH:27]=[CH:28][C:29]([C:33]#[N:34])=[C:30]([CH3:32])[N:31]=1)#[N:9]
Reactant: Cc1nc(N)ccc1C#N
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Br)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)ccc1C#N
Temperature: 100 °C

Procedure:
To a flask containing tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)amino]cyclohexyl}carbamate (PrepEx 1.1) (120 mg, 0.30 mmol), 6-amino-2-methylpyridine-3-carbonitrile (40 mg, 0.30 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (29 mg, 0.061 mmol), Pd2(dba)3 (28 mg, 0.031 mmol) and cesium carbonate (198 mg, 0.609 mmol) was added degassed dioxane (3 mL). The reaction mixture was heated to 100° C. overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, and the organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by chromatography on silica gel (0-40% ethyl acetate/hexanes, linear gradient) afforded tert-butyl [(1S,2R)-2-({6-cyano-5-[(5-cyano-6-methylpyridin-2-yl)amino]pyridin-3-yl}amino)cyclohexyl]carbamate. MS ESI calc'd for C24H30N7O2 [M+H]+ 448. found 448. 1H NMR (500 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.92-7.86 (m, 2H), 7.26 (s, 1H), 6.81 (d, J=8.8 Hz, 1H), 6.64 (d, J=8.5 Hz, 1H), 6.56 (d, J=7.7 Hz, 1), 3.75-3.64 (m, 2H), 2.47 (s, 3H), 1.75-1.42 (m, 8H), 1.26 (s, 9H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][C:21]([NH2:24])([CH3:23])[CH3:22]>>[CH3:20][C:21]([NH:24][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)([CH3:23])[CH3:22]
Reactant: CC(C)(C)N
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: CC(C)(C)Nc1nccc(-n2cnc3ccccc32)n1
Temperature: 40 °C

Procedure:
The title compound was prepared from 2-methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine according to the procedure described in EXAMPLE 1, Step C except using 1,1-dimethylethylamine as the solvent and heating at 40° C. Mass Spectrum (CI): m/e 268.3 (M+1). ). 1H NMR (500 MHz, CDCl3): δ 8.69 (s, 1H); 8.40 (d, J=5.5 Hz, 1H); 8.07 (d, J=7.3 Hz, 1H); 7.88 (m, 1H); 7.40 (m, 2H); 6.81 (d, J=5.2 Hz, 1H); 5.40 (br s, 1H); 1.54 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:30]2[O:31][C:32]3[CH:40]=[CH:39][C:38]([CH2:41][C:42](O)=[O:43])=[CH:37][C:33]=3[C:34]=2[S:35][CH3:36])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>ClCCl>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:30]2[O:31][C:32]3[CH:40]=[CH:39][C:38]([CH2:41][C:42]([N:17]4[CH2:18][CH2:19][N:14]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[CH2:15][CH2:16]4)=[O:43])=[CH:37][C:33]=3[C:34]=2[S:35][CH3:36])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(-c2oc3ccc(CC(=O)O)cc3c2SC)cc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2oc3ccc(CC(=O)N4CCN(c5ccccc5)CC4)cc3c2SC)cc1OC
Reaction time: 16 h
Yield: 554 %

Procedure:
Triethylamine and 12.992 mg of 1-phenyl-piperazine (0.080 mM) were added to the solution containing 35 mg of 3[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-acetic acid (35a; 0.068 mM) dissolved in 2 ml of dichloromethane. The reaction mixture was stirred for 16 hours and the remaining solvent was removed. The remaining residue was purified with Silica gel column chromatography with a mobile phase (dichloromethane:methanol=20:1) to obtain white solid type of 2-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl)-1-(4-phenyl-piperazin-1-yl)-ethanone (37a; 223 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[C:13]([C:15](=[C:20]1[CH2:29][C:24]2([CH2:28][CH2:27][CH2:26][CH2:25]2)[O:23][CH2:22][CH2:21]1)[C:16]([O:18][CH3:19])=[O:17])#[N:14]>C1COCC1.[Cu](I)I>[C:13]([CH:15]([C:20]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:29][C:24]2([CH2:25][CH2:26][CH2:27][CH2:28]2)[O:23][CH2:22][CH2:21]1)[C:16]([O:18][CH3:19])=[O:17])#[N:14]
Reactant: Brc1ccccn1
Reactant: COC(=O)C(C#N)=C1CCOC2(CCCC2)C1
Agent: I[Cu]I
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)C(C#N)C1(c2ccccn2)CCOC2(CCCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A solution of 2-bromopyridine (14.4 ml, 150 mmo) in THF (75 ml) was added dropwise to a solution of isopropylmagnesium chloride (75 ml, 2M in THF) at 0° C. under N2, the mixture was then stirred at rt for 3 h, copper Iodide (2.59 g, 13.6 mmol) was added and allowed to stir at rt for another 30 min before a solution of a mixture of E and Z isomers of methyl 2-cyano-2-[6-oxaspiro[4.5]decan-9-ylidene]acetate (16 g, 150 mmol) in THF (60 ml) was added in 30 min. The mixture was then stirred at rt for 18 h. The reaction mixture was poured into a 200 g ice/2 N HCl (100 ml) mixture. The product was extracted with Et2O (3×300 ml), washed with brine (200 ml), dried (Na2SO4) and concentrated. The residual was purified by flash chromatography (100 g silica gel column, eluted by EtOAc in hexane: 3% 2 CV; 3-25%, 12 CV; 25-40% 6 CV gave methyl 2-cyano-2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetate (15.44 g, 72% yield, m/z 315.0 [M+H]+ observed) as an amber oil.