Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CC(C)(C)C(Cl)=O.Cl.[CH3:36][NH:37][O:38][CH3:39]>C(Cl)Cl>[CH3:36][N:37]([O:38][CH3:39])[C:16](=[O:18])[CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Reactant: CNOC
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A solution of 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propionic acid (2.6 grams, 10 mmol, from Step A) and DIEA (4.4 mL, 25 mmol) in 50 mL CH2Cl2 was cooled to 0° C. Trimethylacetyl chloride (1.4 mL, 11 mmol) was added and the mixture was stirred for 1 h. Solid N,O-dimethylhydroxylamine hydrochloride (1.4 grams, 15 mmol) was added and the mixture was warmed to rt and stirred for 16 h. The solvent was removed and the product was purified by flash chromatography (125 grams silica, 2/1 hexane/EtOAc eluant) to give 1.5 grams (50%) of the title compound. 1H NMR (300 MHz, CDCl3). δ1.05-1.18 (m, 2H), 1.45 (s, 9H), 1.53-1.75 (m, 4H), 2.4-2.5 (t, 2H), 2.6-2.77 (m, 2H), 3.18 (s, 3H), 3.63 (s, 3H), 4.0-4.15 (m, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=2)[CH2:4][CH2:3]1.[O-:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+]>C1(C)C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: [O-]c1ccccc1
Reactant: C[C@H]1CC[C@H](NC(=O)c2cccc(Br)n2)CC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H]1CC[C@H](NC(=O)c2cccc(Oc3ccccc3)n2)CC1

Procedure:
A nitrogen purged mixture of N-(trans-4-methylcyclohexyl)-6-bromo picolinamide (446 mg, 1.5 mmol), sodium phenoxide (209 mg, 1.8 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalldium(II) (1:1 complex with dichloromethane; 83 mg, 0.1 mmol) in toluene-tetrahydrofuran (9:1, 5 mL) was treated with bis(dibenzylideneacetone)palladium(II) (86 mg, 0.15 mmol) and the mixture heated at reflux overnight. After this time the reaction mixture was diluted with ethyl acetate (25 mL) and filtered. The organic solution was washed with water (2×20 mL), brine, dried over anhydrous MgSO4, filtered and concentrated. Chromatography of the crude product on silica (2 mm, chromatotron) with ethyl acetate-hexane (1:3, containing 1% diethylamine) afforded 97 mg (21%) of 410:
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:4]1=2)[CH3:2].O.NN>CCO.[Pd]>[NH2:15][C:13]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:10])[N:3]([CH2:1][CH3:2])[C:4]=2[CH:14]=1
Reactant: CCN1C(=O)CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCN1C(=O)CCCc2ccc(N)cc21
Yield: 101 %

Procedure:
To a solution of 1-ethyl-8-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (920 mg, 3.9 mmol, WO2002100327A2) in EtOH (13 mL) was sequentially added 10% Pd/C (155 mg) and hydrazine-monohydrate (3 mL). The solution was warmed to reflux for 2.5 h, cooled, filtered through celite, and repeatedly evaporated from toluene to remove residual hydrazine to afford 8-amino-1-ethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (805 mg, 100%) that had the following properties: LC/MS (ESI+): 205 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 6.97 (d, J=7.8, 1H), 6.55 (s, 1H), 6.52 (d, J=7.8, 1H), 3.95 (br s, 2H), 3.67 (br s, 2H), 2.60 (br s, 2H), 2.29 (m, 2H), 2.11 (m, 2H), 1.15 (t, J=6.2, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([C:25]([O:29][N:30]1N=NC2C=CC=C[C:31]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.CNOC>CN(C)C=O>[CH3:25][O:29][N:30]([CH3:31])[C:17]([C:16]1[CH:20]=[CH:21][C:13]([C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:12][CH2:11][CH2:10]2)=[CH:14][CH:15]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)O)cc2)CCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
To a solution of 4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)benzoic acid (2.5 g, 1 eq.) in dimethylformamide (10 mL) was added HBTU (3.41 g, 1.05 eq.) followed by triethylamine (6 mL, 5 eq.). The reaction mixture was stirred at room temperature for 10 minutes then the N,O-dimethylhydroxylamine hydrochloride was added (4.3 g, 5 eq.) and the mixture was stirred for 3 days. The reaction mixture was poured onto water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water (100 mL), brine (100 mL) then dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (20-50% ethyl acetate in dichloromethane), giving tert-butyl (1-(4-(methoxy(methyl)carbamoyl)phenyl)cyclobutyl)carbamate (1.5 g, 52%). LCMS: 335 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1>>[C:28]1([CH3:32])[CH:29]=[CH:30][CH:31]=[C:26]([NH:25][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:15][C@@H:10]4[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:12][C@@H:11]4[CH2:13]3)[CH:17]=[N:18][CH:19]=2)=[O:22])[CH:27]=1
Reactant: Cc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: Cc1cccc(NC(=O)c2cncc(N3C[C@H]4CN(C(=O)OC(C)(C)C)C[C@H]4C3)c2)c1

Procedure:
The product from Example 33B and m-toluidine were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 423 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[C:14](=[O:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>CCOCC>[F:1][C:2]1[C:11]([F:12])=[C:10]([NH:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]2[C:14](=[O:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)CCN2C
Reactant: NCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(NCc4ccccc4)c3c1=O)CCN2C
Temperature: 80 °C
Yield: 75.1 %

Procedure:
62 mg of the compound (198) obtained in Example 69 and 50 mg of benzylamine were added to 2 ml of toluene, and the solution was heated at 80° C. for 24 hours. The reaction solution was added to chloroform and was washed with aqueous 5% citric acid solution. After drying over magnesium sulfate, the solvent was removed by distillation. Obtained solids were dispersed in ether and filtered off to obtain 59 mg of the subject compound (200) in a 74% yield.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=O)(C)(C)C.[Br:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1.C(#N)C>C(Cl)(Cl)Cl>[NH2:8][C:9]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:39][C:38]2[CH:41]=[CH:42][C:35]([Br:34])=[CH:36][CH:37]=2)[CH2:21][CH2:20]1)=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: BrCc1ccc(Br)cc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Br)cc2)CC1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethoxybenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 4-bromobenzyl bromide (0.060 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (0.8 mL) and chloroform (0.5 mL) was stirred at 60° C. for 12 h. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with 50% CHCl3/CH3OH (10 mL) and CH3OH (10 mL). Product was eluted using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material was added 4 N HCl in 1,4-dioxane (2 mL), and the solution was stirred overnight at room temperature. Concentration and preparative TLC afforded 4-[{N-(2-amino-5-trifluoromethoxybenzoyl) glycyl}aminomethyl]-1-(4-bromobenzyl)piperidine (Compound No. 1910) (6.5 mg, 24%): The purity was determined by RPLC/MS (96%); ESI/MS m/e 545 (M++H, C23H26BrF3N4O3).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>ClCCl>[C:19]([O:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([Cl:8])[O:10][C:11]=2[CH:17]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc2nc(Cl)oc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2nc(Cl)oc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (1.48 ml) was added to a suspension of 2-chloro-1,3-benzoxazol-6-ol (1.63 g) [see Preparation 34] in dichloromethane (20 ml), and after 5 minutes acetic anhydride (1.01 ml) was added. The reaction mixture was stirred at room temperature for 18 hours, after which time the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0, changing 40:10, changing to 0:100, by volume, hexane:ethyl acetate to afford 2-chloro-1,3-benzoxazol-6-yl acetate (1.63 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=2)[N:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1ccc(CNc2nc(Cl)nc3nc[nH]c23)cc1
Temperature: 80 °C

Procedure:
To a suspension of 15 g (0.0794 mol) of 2,6-dichloropurine in 250 mL of absolute ethanol was added 12.7 mL (0.0873 mol) of triethylamine and 10.62 mL (0.0873 mol) of 4-chlorobenzylamine. The mixture was refluxed at 80° C. for 16 h (the formation of creamy white precipitate was observed). The reaction mixture was cooled and the precipitated product was removed by filtration. The precipitate was washed with ethanol (350 mL) and dried in high vacuum for 24 h. Product was characterized by 1H-NMR.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH:10]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:25])[CH:10]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:11][C:12]1[N:13]=[CH:14][N:15]([C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]cn1)C(=O)OCc1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A solution of 2-tert-butoxycarbonylamino-3-(1H-imidazol-4-yl)-propionic acid benzyl ester (6.062 g, 17.57 mmol) and triethylamine (3.57 g, 4.90 mL, 35.14 mmol) in CHCl3 (50 mL) was cooled to 0° C. under argon. Trityl chloride (4.9 g, 17.57 mmol) in CHCl3 was added and after 20 minutes the solution became opaque. The solution was stirred at 0° C. overnight, warmed to room temperature, washed with water and brine, dried over MgSO4 and filtered. The solvent was removed and the crude material was chromatographed (silica gel, 25% EA/PE, Rf 0.78 75% EA/PE) to afford the title compound as a viscous gum (7.58 g, 74%). ESMS 588 (M+H+) 1H NMR (500 MHz, CDCl3) δ 1.42 (9H, s), 2.98 (1H, dd, J=4.65, 14.53 Hz), 3.05 (1H, dd, J=5.05, 14.53 Hz), 4.58 (1H, m), 5.02 (2H, d, J=2.55 Hz), 6.06 (1H, d, J=8.25 Hz), 6.47 (1H, s), 7.09 (6H, m), 7.26 (4H, m), 7.29 (10H, m), 7.36 (1H, s). 13C NMR (CDCl3) δ 28.11, 29.87, 53.61, 66.37, 74.95, 79.12, 119.30, 127.78, 128.16, 129.48, 135.29, 136.23, 138.48, 142.01, 155.34, 171.44.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[C:13]([F:32])=[CH:14][C:15]([C:26]4[CH2:27][CH2:28][O:29][CH2:30][CH:31]=4)=[CH:16][C:17]=3[C:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[CH:9][CH:8]=1)(=O)=O.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>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.CN(C=O)C>[O:29]1[CH2:30][CH:31]=[C:26]([C:15]2[CH:14]=[C:13]([F:32])[C:12]3[O:11][C:10]4[C:19](=[CH:20][C:7]([C:37]5[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=5)=[CH:8][CH:9]=4)[C@:18]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:17]=3[CH:16]=2)[CH2:27][CH2:28]1
Reactant: NC1=NC2(CO1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Reactant: OB(O)c1cccnc1
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: CN(C)C=O
Product: NC1=N[C@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Temperature: 75 °C

Procedure:
A vial was charged with 2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (150 mg, 0.300 mmol), pyridin-3-ylboronic acid (111 mg, 0.899 mmol), and Pd(PPh3)4 (34.6 mg, 0.030 mmol). The vial was purged with Ar (g), then DMF (2 mL) and potassium carbonate (0.749 mL, 1.499 mmol) (as a 2.0 M aq. solution) were added in sequence. The vial was capped and heated in a Biotage Initiator microwave reactor for 1.5 h at 75° C. The product was purified via Gilson HPLC (gradient elution 20-90% MeCN/H2O, 0.1% TFA) to afford (R)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off white solid. Found MS: MH+=430.
Reaction SMILES: [OH:1][C:2]([C:23]1[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=1)([CH3:22])[C:3]([N:5]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][CH:7]=1)=[O:4].B(Br)(Br)Br>C(Cl)Cl>[OH:1][C:2]([C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)([CH3:22])[C:3]([N:5]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:4]
Reactant: COc1ccc(N(C(=O)C(C)(O)c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(O)(C(=O)N(c1ccc(O)cc1)c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
2-hydroxy-N,N,2-tris(4-methoxyphenyl)propanamide (0.60 g, 1.47 mmol) was to dissolved in 30 mL of anhydrous methylene chloride in a dry 250 mL round-bottomed flask fitted with a stiffing bar, anitrogen inlet and rubber stopper. BBr3 solution (6.00 mL of 1M CH2Cl2 solution, 6.00 mmol) was added dropwise with stiffing at 0° C. The reaction solution was stirred at room temperature overnight. The reaction was quenched by adding 20 mL of water and extracted with EtOAc (3×30 mL). The EtOAc layers were separated and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH2Cl2/MeOH=9/1 v/v) to give a white solid product, 2-hydroxy-N,N,2-tri(4-hydroxyphenyl)propanamide (11k), 0.42 g, 77.8% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9]([CH3:24])[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:36][N:37]([CH3:43])[C:38]([CH3:42])([CH3:41])[CH:39]=O.C(O)(=O)C.N1CCCCC1>CCO>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)=[C:9]([CH3:24])[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:39][C:38]([N:37]([CH3:43])[CH3:36])([CH3:42])[CH3:41])[C:33]#[N:34])=[O:35])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN(C)C(C)(C)C=O
Reactant: Cc1c(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc2n1C[C@@H]1CCCN1C(=O)CC#N
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc2n1C[C@@H]1CCCN1C(=O)C(C#N)=CC(C)(C)N(C)C
Temperature: 70 °C
Reaction time: 12 h
Yield: 4.2 %

Procedure:
To a solution of (S)-3-(2-((4-amino-6-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (0.1 g, 0.21 mmol, 1.0 eq) in EtOH (2 mL) was added 2-(dimethylamino)-2-methylpropanal (0.06 g, 0.53 mmol, 2.5 eq) and piperidine acetate (5 mg). The resulted solution was stirred at 70° C. for 12 h, concentrated and purified by pre-HPLC to afford the title compound as a white solid (5 mg, 4% in yield). LCMS m/z 564.1 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][C:4](=[N:8]O)[C:5](=O)[CH3:6].[CH3:11][CH:12]([CH3:18])[CH2:13][CH2:14][C:15](=O)[CH3:16].[N:19](Cl)=O.N=C=O>[Zn].C(O)(=O)C>[CH3:6][C:5]1[C:4]([CH2:3][CH:2]([CH3:10])[CH3:1])=[N:8][C:15]([CH3:16])=[C:14]([CH2:13][CH:12]([CH3:18])[CH3:11])[N:19]=1
Reactant: CC(=O)CCC(C)C
Reactant: CC(=O)C(CC(C)C)=NO
Reactant: O=NCl
Agent: N=C=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1nc(CC(C)C)c(C)nc1CC(C)C

Procedure:
f. 2,5-Dimethyl-3,6-diisobutyl-pyrazine was prepared by first forming 5-methyl-3-oximino-2-hexanone by reacting 5-methyl-2-hexanone with nitrosyl chloride according to the method of BOUVEAULT (loc.cit.). The autocondensation of two moles of the imino-ketone in the presence of zinc and acetic acid [according to the method described in Chimia 11, 310 (1957)] yielded 2,5-dimethyl-3,6-diisobutyl-pyrazine which had a b.p. of 69°-70°C./0.01 mm. Hg.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[O:1]=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:19][CH3:20])=[O:4]
Reactant: CCO
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)CCc1ccccc1

Procedure:
2-Oxo-4-phenylbutyric acid (130 g) is added to a mixture of 650 ml of ethanol and 13 ml of concentrated sulfuric acid, and the whole mixture is refluxed for 5 hours. The reaction mixture is concentrated to approximately half the original volume, and then diluted with 500 ml of water. The resulting oil is collected and, the aqueous layer is extracted with ethyl acetate. The extract and the oil are combined and dried, and the solvent is distilled off under reduced pressure. The residue is distilled under reduced pressure to give 113 g of ethyl 2-oxo-4-phenylbutyrate as a colorless oil boiling at 135°-141° C./3 mmHg.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C[O:11][C:12]1[CH:17]=CC=C[C:13]=1C=CC(=O)C>>[C:2]1([CH3:1])[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:12](=[O:11])[CH3:17])=[CH:4][CH:3]=1
Reactant: COc1ccccc1C=CC(C)=O
Reactant: Cc1ccc(C=O)cc1
Product: CC(=O)C=Cc1ccc(C)cc1

Procedure:
The title compound was prepared from 4-methyl-benzaldehyde (6.0 g, 50.0 mmol), following the procedure describing the synthesis of 4-(2-methoxy-phenyl)-but-3-en-2-one (example 1/a stage 1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([S:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=3)=[CH:13][N:14]=2)[CH:3]=1.[N:25]1([CH2:31][CH2:32][OH:33])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CCCCO>[OH:33][CH2:32][CH2:31][N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]3[S:11][C:12]([S:15][C:16]4[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=4)=[CH:13][N:14]=3)[CH:3]=2)[CH2:27][CH2:26]1
Reactant: OCCN1CCNCC1
Reactant: Cc1nc(Cl)cc(Nc2ncc(Sc3ccnc(C(=O)O)c3)s2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1nc(Nc2ncc(Sc3ccnc(C(=O)O)c3)s2)cc(N2CCN(CCO)CC2)n1
Temperature: 115 °C
Yield: 69 %

Procedure:
To a stirring solution of 4-(2-(6-chloro-2-methylpyrimidin-4-ylamino)thiazol-5-ylthio)picolinic acid (104 mg, 0.274 mmol) and 2-(piperazin-1-yl)ethanol (195 mg, 1.50 mmol) in n-BuOH (2 mL) was added i-Pr2NEt (0.20 mL, 1.15 mmol). The reaction was then heated to 115° C. in a sealed reaction vessel overnight. The reaction was cooled to room temperature and the solid collected by filtration, the filter cake was washed with n-BuOH then air dried to give the title material (89.5 mg, 69%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 11.59 (1H, s), 8.27 (1H, d, J=5.05 Hz), 7.71 (1H, s), 7.53 (1H, d, J=2.02 Hz), 7.07 (1H, dd, J=5.05, 2.02 Hz), 6.03 (1H, s), 4.45 (1H, t, J=4.67 Hz), 3.49 (6H, s), 2.41 (2H, t, J=6.32 Hz), 2.33 (3H, s). LC/MS (M+H)+: 474. HPLC ret. time (Condition I): 1.097 min.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Cl:19])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[CH3:27][NH2:28]>O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH:28][CH3:27])=[O:13])=[CH:14][C:15]([Cl:19])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 60 °C

Procedure:
To a solution of the benzoxazinone product of Example 10, Step E (0.20 g, 0.44 mmol) in tetrahydrofuran was added methylamine (2.0 M solution in THF, 0.514 mL, 1.02 mmol), and the reaction mixture was heated to 60° C. for 90 minutes and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was triturated with ether, filtered, and dried to afford the title compound, a compound of the present invention, as a solid (40 mg), m.p. 162-154° C.
Reaction SMILES: CNC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH3:14][Si:15](Cl)([CH3:17])[CH3:16].CCOCC.[OH2:24]>>[CH3:14][Si:15]([O:24][Si:15]([CH3:17])([CH3:16])[CH3:14])([CH3:17])[CH3:16]
Reactant: C[Si](C)(C)Cl
Reactant: O
Agent: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCOCC
Product: C[Si](C)(C)O[Si](C)(C)C

Procedure:
N-Methylglucamine (10 g, 0.05 mol) was suspended (partly dissolved) in dry freshly-distilled pyridine and cooled in an ice-bath. Trimethyl silylchloride (30 g, 0.28 mol) was added in portions so that the temperature did not rise above 20°- 25°. After 1 hour the reaction slurry was poured into ether (200 ml) and water (200 ml) and shaken; the ether layer was washed several times with water, dried and evaporated at 50°-60° to leave the oily per-trimethylsilyl ether containing a trace of pyridine. Yield: ca. 20 g (50%).