Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([O:35]CC)=O)[C:15]1=[O:38].[NH2:39][CH2:40][CH2:41][N:42]1[CH2:46][CH2:45][NH:44][C:43]1=[O:47].OS([O-])(=O)=O.[Na+]>CCO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:39][CH2:40][CH2:41][N:42]2[CH2:46][CH2:45][NH:44][C:43]2=[O:47])=[O:35])[C:15]1=[O:38]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Reactant: NCCN1CCNC1=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(NCCN1CCNC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 1-(2-aminoethyl)-2-imidazolidinone (0.0078 g, 0.03 mmol, 50% W/W in IPA) for 30 min.@150° C. The reaction was further microwaved for 30 min.@150° C. after the addition of an additional 0.6 equivalents (0.015 mL) of the amine, cooled to ambient temperature, and treated with 1N NaHSO4. The resulting suspension was filtered and the filtrate was concentrated in vacuo. The filtrate residue was purified by reversed phase HPLC. Pure fractions were combined and concentrated to afford the title compound as a pale yellow glass: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.82 (s, 1 H), 3.38-3.51 (m, 4 H), 3.52-3.65 (m, 4 H), 4.00 (t, J=6.67 Hz, 2 H), 4.04-4.10 (m, 2 H), 4.26 (s, 1 H), 4.46 (t, J=6.74 Hz, 2 H), 6.91-7.04 (m, 2 H), 7.10-7.21 (m, 2 H), 7.70-7.78 (m, 3 H), 7.79-7.85 (m, 2 H), 8.51 (d, J=1.26 Hz, 1 H), 10.24 (t, J=6.04 Hz, 1 H); ES+ MS: 599 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH3:16])=[C:9]([C:12](=[O:15])[CH2:13]Br)[CH:10]=2)[C:5]([CH3:18])([CH3:17])[CH:4]([CH3:19])[CH2:3]1.[C:21]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CCO>[C:21]([NH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6]([C:5]([CH3:18])([CH3:17])[CH:4]([CH3:19])[CH2:3][C:2]3([CH3:20])[CH3:1])=[CH:7][C:8]=2[CH3:16])=[O:15])[CH2:32][CH2:31]1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: Cc1cc2c(cc1C(=O)CBr)C(C)(C)CC(C)C2(C)C
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C(=O)CN1CCC(NC(=O)c3ccccc3)CC1)C(C)(C)CC(C)C2(C)C
Yield: 24.1 %

Procedure:
A mixture of 1,1,3,4,4,6-hexamethyl-7-bromacetyl-1,2,3,4-tetrahydronaphthalene (7 g.), 4-benzamidopiperidine (4.27 g.) and triethylamine (3.5 g.) was refluxed in100 ml. EtOH for 2 hours. The resulting yellow solution was cooled, whereupon the product crystallised. This was recrystallised twice from EtOH/water to give the title compound (2.3 g.) as a pale yellow solid, m.p. 153°(dec.). Analysis Calculated for C30H40N2O2 ; C, 78.22%; H, 8.75%; N, 6.08%. Found: C, 78.29%; H, 8.92%; N, 6.14%.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:9]([O:23][CH3:24])[CH:8]=1)=[O:6].CO>O1CCCC1>[C:19]([O:18][C:16]([N:13]1[C:14]2[C:10](=[C:9]([O:23][CH3:24])[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:15]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)c1cc(OC)c2c(c1)N(C(=O)OC(C)(C)C)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc2c1CCN2C(=O)OC(C)(C)C
Yield: 88 %

Procedure:
A 3 N aqueous KOH solution (6.5 mL, 19.5 mmol, 3 equiv.) was added to a solution of 4-methoxy-2,3-dihydro-indole-1,6-dicarboxylic acid 1-tert-butyl ester 6-methyl ester (2 g, 6.5 mmol, 1 equiv.) in a 1:4 MeOH:tetrahydrofuran solution (20 mL) and the mixture was shaken for 16 hours. The methanol was removed under vacuum and the pH was adjusted to 3 with 3 N aqueous HCl solution. The resulting slurry was diluted with ethyl acetate (20 mL), the organic layer was separated and the aqueous phase was extracted with EtOAc (2×20 mL). The organic layers were combined, dried over Na2SO4 and the solvent was removed under vacuum to afford 4-methoxy-2,3-dihydro-indole-1,6-dicarboxylic acid 1-tert-butyl ester, 1.68 g (88% yield). LC @215 nm; Rt 1.44: 83%, m/z (ES+): 238 (M-Boc+MeCN+H+.); δH (400 MHz; d6-DMSO) 12.58 (1H, br.s) 7.97 (1H, br.s), 6.94 (1H, d), 3.70 (2H, t), 3.61 (3H, s), 2.75 (2H, t), 1.28 (9H, s).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[CH3:30][S-:31].[Na+].O>CS(C)=O>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[N:7]=[C:2]([S:31][CH3:30])[CH:3]=[C:4]([NH:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[C:5]4=[N:10][CH:9]=3)=[CH:12][C:13]=2[CH3:23])[CH2:20][CH2:19]1
Reactant: Cc1cc(-c2cnc3c(NCC(C)(C)O)cc(Cl)nn23)ccc1C(=O)NC1CC1
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1cc(NCC(C)(C)O)c2ncc(-c3ccc(C(=O)NC4CC4)c(C)c3)n2n1
Temperature: 70 °C
Yield: 54.6 %

Procedure:
To a solution of 83 mg (201 μmol) 4-{6-chloro-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide which was prepared according to intermediate example 7a in 1.0 mL dimethyl sulfoxide were added 70 mg sodium methanethiolate and the mixture was heated under microwave irradiation at 70° C. for 1 hour. The mixture was poured into water and extracted with dichloromethane and methanol. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by recrystallisation to give 46.7 mg (55%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.Br[CH2:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O>[O:26]1[CH2:27][CH2:28][CH:23]([CH2:22][O:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:9]=[C:10]4[C:15](=[N:16][CH:17]=3)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]4)[CH:5]=[N:6][CH:7]=2)[CH2:24][CH2:25]1
Reactant: BrCC1CCOCC1
Reactant: NC(=O)N1CCCc2cc(-c3cncc(O)c3)cnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: NC(=O)N1CCCc2cc(-c3cncc(OCC4CCOCC4)c3)cnc21
Yield: 50.2 %

Procedure:
To a solution of 6-(5-hydroxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (25 mg, 0.092 mmol) in DMA (1 mL) is added 4-(bromomethyl)tetrahydropyran (20 mg, 0.11 mmol) and cesium carbonate (36 mg, 0.11 mmol). The resultant mixture is stirred at 70° C. for 16 h. Water is added and the mixture is extracted with EtOAc. The organic layers are combined, washed with brine and dried (Na2SO4). The solvent is evaporated and the crude product is purified by silica gel column eluting (0-10% MeOH in DCM) to afford the title compound (17 mg).
Reaction SMILES: Br[C:2]1[C:3]([CH3:33])=[CH:4][C:5]([O:29][CH:30]([CH3:32])[CH3:31])=[C:6]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[C:12]([CH3:28])=[CH:11][N:10]=2)[CH:7]=1.[C:34]([Si:36]([CH3:39])([CH3:38])[CH3:37])#[CH:35].C(N(CC)C(C)C)(C)C>O1CCOCC1.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I>[CH:30]([O:29][C:5]1[CH:4]=[C:3]([CH3:33])[C:2]([C:35]#[C:34][Si:36]([CH3:39])([CH3:38])[CH3:37])=[CH:7][C:6]=1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[C:12]([CH3:28])=[CH:11][N:10]=1)([CH3:32])[CH3:31]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(OC(C)C)c(Nc2ncc(C)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)cc1Br
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: N#Cc1ccccc1
Product: Cc1cc(OC(C)C)c(Nc2ncc(C)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)cc1C#C[Si](C)(C)C
Temperature: 22 °C
Reaction time: 20 h

Procedure:
A mixture of N2-(5-Bromo-2-isopropoxy-4-methyl-phenyl)-5-methyl-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (Example 5, Step 4, 110 mg, 0.21 mmol), ethynyl-trimethyl-silane (0.14 mL), N,N-diisopropyl ethylamine (0.10 mL), PdCl2(PhCN)2 (12 mg), tBu3PHBF4 (17 mg), and CuI (4 mg) in 1 mL 1,4-dioxane is stirred at 22° C. for 20 hrs followed by heating at 60° C. for an additional 2 hrs. The reaction mixture is filtered through a small Celite plug and concentrated. The residue is purified over a 4 g SiO2 column (ISCO) using a gradient of 0 to 20% ethyl acetate in hexanes as eluent, affording N2-(2-Isopropoxy-4-methyl-5-trimethylsilanylethynyl-phenyl)-5-methyl-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine as a yellow viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[CH:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1.[C:13](Cl)(=[O:17])C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>>[CH2:23]([NH:27][C:13]([C:7]1[C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:9][C:8]=1[CH3:10])=[O:17])[CH:24]([CH3:26])[CH3:25]
Reactant: COc1ccc2cc(C)oc2c1
Reactant: CC(C)CN
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc2c(C(=O)NCC(C)C)c(C)oc2c1
Yield: 73 %

Procedure:
This material was prepared from 6-methoxy-2-methylbenzofuran 12a (500 mg, 3.1 mmole) by acylation with oxalyl chloride in the presence of AlCl3, followed by treatment with isobutylamine in a manner as previously described for example 1c to give 585 mg (73%) of an off-white solid. 1H NMR (DMSO-d6) δ 7.95 (1H, t, J=5.8 Hz), 7.56 (1H, d, J=8.6 Hz), 7.15(1H, d, J=2.3 Hz), 6.91 (1H, dd, J=8.6, 2.3 Hz), 3.76 (3H, s), 3.07 (2H, m), 2.57 (3H, s), 1.83 (1H, m), 0.88 (6H, d, J=6.8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[C:16](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(Br)cn1
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
Tert-butyl 5-bromopyridin-2-ylcarbamate (10 g) and cesium carbonate (20 g) were added to 50 mL of DMF. Methyl iodide (4 mL) was subsequently slowly added to the stirring reaction mixture. After 30 minutes tlc indicates that the reaction is complete. The majority of the DMF was removed under hi-vacuum and the reaction mixture was extracted with ethyl acetate and water. The organic layer was dried, filtered and concentrated. The crude product was purified by Isco 0-30% gradient (WE) over 25 mins. The tubes were pooled and concentrated to get 9.85 g of tert-butyl 5-bromopyridin-2-yl(methyl)carbamate as a clear oil.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6]=1[CH3:25])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([Li])[CH2:27][CH2:28]C.IC(C)C>O1CCCC1>[C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N:16]([CH:27]([CH3:28])[CH3:26])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6]=1[CH3:25])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(Nc2cc3c(c(C(C)(C)C)c2C)OCC3(C)C)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)I
Product: COc1ccc(N(c2cc3c(c(C(C)(C)C)c2C)OCC3(C)C)C(C)C)cc1
Yield: 8.9 %

Procedure:
Following general procedure L and using 7-t-butyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 53, 0.13 g, 0.38 mmol), 1.6M solution of n-butyllithium in hexanes (0.5 mL, 0.8 mmol) and 2-iodopropane (0.5 mL, 5 mmol) in 2 mL of anhydrous tetrahydrofuran, the title compound (0.013 g, 8.9%) was obtained as a brown oil after separation from recovered 7-t-butyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 53, 0.07 g) by preparative normal phase HPLC using 4% ethyl acetate in hexanes as the mobile phase. 1H NMR (300 MHz, C6D6): δ 6.82 (d, 2H, J=9.1 Hz), 6.75 (s, 1H), 6.56 (d, 2H, J=9.1 Hz), 4.09(heptet, 1H, J=6.5 Hz), 3.89 (s, 2H), 3.40(s, 3H), 2.40 (s, 3H), 1.68 (s, 9H), 1.10-1.25(m, 3H), 0.99-1.10(m, 3H), 0.99 (s, 6H).
Reaction SMILES: ClCC([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C@H:11]2[NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:7][CH:6]=1)=O.[Cl:21]C1C=C(C=CC=1)C(OO)=O.F[C:33](F)(F)[C:34]([OH:36])=[O:35].[OH-].[NH4+]>ClCCl.O>[Cl:21][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C@:11]2([O:36][C:34]([CH3:33])=[O:35])[NH:14][C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])=[CH:7][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(CCl)c1ccc2c(c1)[C@H](NC(=O)C(F)(F)F)CC2
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)O[C@]1(NC(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 96 h
Yield: 46.6 %

Procedure:
6-Chloroacetyl-N-trifluoroacetyl-(R)-1-aminoindan (30.57 g, 0.1 mol) was dissolved in anhydrous dichloromethane (210 ml) and 3-chloroperoxybenzoic acid (70%, 44.87 g, 0.26 mol) was added all of once. The suspension was cooled to 0° C. and trifluoroacetic acid (11.4 g, 0.1 mol) was added dropwise for 5-10 minutes. The reaction flask was protected from light and the mixture was stirred for 3-5 days at room temperature. The reaction mixture was poured into water (300 ml.). The mixture was neutralized with ammonium hydroxide solution. The layers were separated. The aqueous layer was extracted with dichloromethane (200 ml). The combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure to give a solid, which was recrystallized from ethanol to give 15 g (48%) of a white solid mp: 169-170° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2=[O:22])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I.O>CN(C=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH3:25])[C:14]3[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2=[O:22])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c2c(c1C)OC(=O)C2c1ccc(C(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c2c(c1C)OC(=O)C2(C)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-2 (3H)-one synthesized in Reference Example 2 (2.10 g, 7.13 mmol) in DMF (30 mL) was added sodium hydride (a 60% fluidized paraffin dispersion, 314 mg, 7.84 mmol) at 0° C., and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added methyl iodide (1.11 g, 7.84 mmol) and the mixture was stirred for at room temperature 30 minutes. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 2.07 g (yield 94%) of the title compound as an oily matter.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH3:29][N:30]1[CH:35]2[CH2:36][CH2:37][CH:31]1[CH2:32][CH:33]([O:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=1)[CH2:34]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N>ClCCCl.O1CCCC1.C(O)(=O)C>[CH2:1]([N:3]([CH2:43][C:42]1[CH:41]=[CH:40][C:39]([O:38][CH:33]2[CH2:34][CH:35]3[N:30]([CH3:29])[CH:31]([CH2:37][CH2:36]3)[CH2:32]2)=[CH:46][CH:45]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN1C2CCC1CC(Oc1ccc(C=O)cc1)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(Cc1ccc(OC2CC3CCC(C2)N3C)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a solution of pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (65 mg) and 4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yloxy)benzaldehyde (65 mg) in 1,2-dichloroethane (2 ml) were sequentially added acetic acid (0.07 ml) and sodium triacetoxyborohydride (120 mg) under a nitrogen atmosphere, and the solution was stirred overnight at room temperature. Tetrahydrofuran and aqueous ammonia were sequentially added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (58 mg).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=O.Cl.[NH:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=1)[NH2:19]>C(O)C>[CH3:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([N:18]2[C:5]([C:7]3[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=3)=[CH:4][C:3]([C:2]([F:16])([F:15])[F:1])=[N:19]2)=[N:21][CH:22]=1)(=[O:27])=[O:28]
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)nc1
Yield: 53.7 %

Procedure:
4,4,4-Trifluoro-1-(4-bromophenyl)1,3-butanedione (600 mg) (prepared according to the method of Thomas D. Penning, et al.; J. Med. Chem., 1997, 40, 1347-1365.) and 2-hydrazino-5-(methylsulfonyl)pyridine hydrochloride (420 mg) were mixed in ethanol (40 mL), and the resulting solution was refluxed for 3 days. Upon cooling, white precipitates came out. The white precipitates were collected by filtration and purified by flash chromatography using 70:30 of methylene chloride and hexane to give the title compound (450 mg).
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[NH:8][CH2:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]([O:13]CC)=O)[CH3:3].[NH3:16]>CO>[CH3:3][CH:2]([CH:4]1[NH:8][CH2:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]([NH2:16])=[O:13])[CH3:1]
Reactant: CCOC(=O)CN1C(=O)CNC1C(C)C
Reactant: N
Solvent: CO
Product: CC(C)C1NCC(=O)N1CC(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An ice cold solution of 3.8 g (0.018 mol) of ethyl 2-(1-methylethyl)-5-oxo-1-imidazolidineacetate in 100 ml of methanol was saturated with gaseous ammonia. The solution was stirred at room temperature overnight and the solvent was evaporated under reduced pressure, to give 2-(1-methylethyl)-5-oxo-1-imidazolidineacetamide (3.4 g) as a viscous oil (Rf 0.33; ethyl acetate/methanol 6:4; silica gel plates). Monohydrate of sulphate salt m.p. 64° C. resolidifying with final decomposition at 114°-118° C.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11](=[O:41])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][C:24]2[CH:29]=[C:28]([C:30]#[C:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:27]=[C:26](Br)[CH:25]=2)=[CH:16][C:15]=1[CH3:40]>CN(C=O)C.C(N(CC)CC)C.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.[Cu]I>[CH3:9][O:10][C:11](=[O:41])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][C:24]2[CH:25]=[C:26]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:27]=[C:28]([C:30]#[C:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:29]=2)=[CH:16][C:15]=1[CH3:40]
Reactant: C#Cc1ccccc1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCOCC3)c2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccccc3)c2)cc1C
Temperature: 60 °C

Procedure:
A mixture of phenylacetylene (169 mg, 1.66 mmol), (4-{3-[3-bromo-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (100 mg, 0.195 mmol, example 6), Pd(PPh3)2Cl2 (22 mg, 0.02 mmol), CuI (10 mg, 0.055 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 1 hour at 60° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using methylene chloride/THF mixtures to give (2-methyl-4-{3-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-phenylethynylphenyl]-prop-2-ynyloxy}-phenoxy)-acetic acid methyl ester in 70 mg (67%) yield.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[O:36][CH:35]=[CH:34][C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([C:16]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[N:17][N:18]4COCC[Si](C)(C)C)=[CH:14][CH:13]=3)[N:10]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1.[NH4+].[OH-]>ClCCCl>[CH:1]1([NH:4][C:5]2[C:6]3[O:36][CH:35]=[CH:34][C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([C:16]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[N:17][NH:18]4)=[CH:14][CH:13]=3)[N:10]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C(=O)c1nn(COCC[Si](C)(C)C)c2cc(Nc3nc(NC4CC4)c4occc4n3)ccc12
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: C1COCCO1
Product: CN(C)C(=O)c1n[nH]c2cc(Nc3nc(NC4CC4)c4occc4n3)ccc12
Temperature: 70 °C
Yield: 40.4 %

Procedure:
In a vial, 6-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-N,N-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxamide (0.94 g, 0.19 mmol, prepared using E.2 from Preparation #AI.1 with dimethylamine) and an aqueous solution of HCl (6 N, 0.401 mL, 2.41 mmol) in DCE (4 mL) were added. The mixture was heated at about 70° C. for about 15 h. The mixture was concentrated under reduced pressure and 1,4-dioxane (4 mL) and NH4OH (0.956 mL, 7.36 mmol) were added. The mixture was heated at about 75° C. for about 3 h, concentrated under reduced pressure and the residue was suspended in MeOH (1 mL) and filtered. The filtrate was purified by column chromatography eluting with 35 to 85% of 10% MeOH in DCM/DCM (12 g silica gel) to give 6-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-N,N-dimethyl-1H-indazole-3-carboxamide (0.029 g, 42%): LC/MS (Table 2 Method c) Rt=1.52 min.; MS m/z: 378 (M+H)+. Syk IC50=A