Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13](B1OC(C)(C)C(C)(C)O1)[CH:12]=2)=[O:6].Br[C:28]1[C:29]([CH2:35][OH:36])=[N:30][CH:31]=[CH:32][C:33]=1[CH3:34].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.O>C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:28]1[C:29]([CH2:35][OH:36])=[N:30][CH:31]=[CH:32][C:33]=1[CH3:34])[CH:12]=2)=[O:6]
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)[C@@H]4C[C@@H]4F)ncc3c2)OC1(C)C
Reactant: Cc1ccnc(CO)c1Br
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccnc(CO)c1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Yield: 7 %

Procedure:
A mixture of (1S,2S)-2-fluoro-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)cyclopropanecarboxamide (56.5 mg; 0.159 mmol), (3-bromo-4-methylpyridin-2-yl)methanol (75 mg; 0.37120 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (9.1 mg; 0.013 mmol), potassium carbonate (65.2 mg; 0.472 mmol), dioxane (2.0 mL; 23 mmol), and water (0.2 mL; 10 mmol) was subjected to microwave irradiation at 100° C. for 60 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude reaction mixture was purified via reverse-phase preparatory HPLC and lyophilized to yield 3.9 mg (7%) of the title compound. LCMS (ESI): RT (min)=2.16, M+H=352.2, method=H; 1H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 9.15 (s, 1H), 8.53 (s, 1H), 8.48 (d, J=5.0 Hz, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.94 (s, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.34 (d, J=5.0 Hz, 1H), 4.95 (m, 2H), 4.25 (s, 2H), 2.28 (m, 1H), 2.07 (s, 3H), 1.77-1.61 (m, 1H), 1.28-1.12 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:18][CH:19]([F:27])[C:20]1[O:24][C:23]([CH2:25]O)=[CH:22][CH:21]=1.N(C(N(C)C)=O)=NC(N(C)C)=O>O1CCCC1>[F:18][CH:19]([F:27])[C:20]1[O:24][C:23]([CH2:25][N:14]2[CH2:15][CH2:16][N:12]([C:4]3[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=3)[C:13]2=[O:17])=[CH:22][CH:21]=1
Reactant: OCc1ccc(C(F)F)o1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)F)o3)C2=O)nc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
To the solution of ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate (0.35 g, 1.37 mmol) and (5-(difluoromethyl)furan-2-yl)methanol (0.20 g, 1.37 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise tributhylphosphine (0.51 mL, 2.06 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes and followed by the addition of 1,1′-azobis(N,N-dimethylformamide) (0.35 g, 2.06 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (4×20 mL). The organic solutions were combined, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (¼) to afford the title compound as a white solid in 53% yield (0.25 g): 1H NMR (300 MHz, CDCl3) δ 6.60-6.50 (m, 1H), 6.52 (t, JH-F=54.2 Hz, 1H), 6.37-6.29 (m, 1H), 4.45 (s, 2H), 4.21 (q, J=7.1 Hz, 2H), 4.09-3.98 (m, 2H), 3.60-3.49 (m, 2H), 2.54 (s, 3H), 1.27 (t, J=7.1 Hz, 3H); MS (ES+) m/z 386.3 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[Cu][C:12]#[N:13].O.[OH-].[NH4+]>CN1CCCC1=O>[NH2:7][C:6]1[C:5]([CH3:9])=[CH:4][C:3]([F:10])=[C:2]([CH:8]=1)[C:12]#[N:13]
Reactant: N#C[Cu]
Reactant: Cc1cc(F)c(Br)cc1N
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(F)c(C#N)cc1N
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
The starting 5-bromo-4-fluoro-2-methylaniline (1) (20 g, 98 mmol) was dissolved in anhydrous 1-methylpyrrolidinone (100 mL), and copper (I) cyanide (17.6 g, 196 mmol) was added. The reaction was heated to 180° C. for 3 hours, cooled to room temperature, and water (300 mL) and concentrated ammonium hydroxide (300 mL) added. The mixture was stirred for 30 minutes and extracted with EA (3×200 mL). The combined extracts were dried over magnesium sulfate, and the solvent was removed under reduced pressure. The oily residue was washed with hexanes (2×100 mL), and the solid dissolved in dichloromethane and loaded onto a silica gel column. Eluting with 0 to 25% EA in hexanes gradient provided 5-amino-2-fluoro-4-methylbenzonitrile (10.06 g, 67.1 mmol). LC/MS (m/z: 151 M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH3:18])=[CH:9][CH:8]=1)#[N:6].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH3:18])=[C:9]([N+:1]([O-:4])=[O:2])[CH:8]=1)#[N:6]
Reactant: COc1ccc(C#N)c2ccccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COc1c([N+](=O)[O-])cc(C#N)c2ccccc12
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
A solution of 100% nitric acid (0.91 ml, 22 mmol) in 8 ml of acetic anhydride was added dropwise to a solution of 1-cyano-4-methoxynaphthalene (3.66 g, 20 mmol) in 50 ml of acetic anhydride containing two drops of conc. sulfuric acid while maintaining the temperature at -30° to -40° C. The mixture was stirred for an additional 10 min. and filtered. The solid was washed with water and dried to give 3.5 g (77%) of 4-cyano-1-methoxy-2-nitronaphthalene. The crude product was dissolved in a mixture of 25 ml of tetrahydrofuran and 10 ml of N,N-dimethylformamide. Then 5 ml of cyclohexylamine was added, and the mixture was stirred at room temperature for 2 h. The mixture was evaporated to dryness, and the residue was triturated with light petroleum to give 4,5 g (90%) of 4-cyano-1-cyclohexylamino-2-nitronaphthalene. The crude product, suspended in 200 ml of 96% ethanol was hydrogenated at room temperature and atmospheric pressure in the presence of 5% palladium-on-carbon. When the theoretical amount of hydrogen was taken up, the catalyst was filtered off, and the filtrate was evaporated to dryness. The resulting diaminonaphthalene was immediately suspended in a mixture of 20 ml of dry tetrahydrofuran and dry triethylamine (1.95 ml, 14 mmol). Then a solution of ethyl oxalylchloride (1.56 ml, 14 mmol) in 10 ml of dry tetrahydrofuran was added dropwise with stirring at 0° C. The mixture was stirred at room temperature over night, and then heated at reflux for 1 h. The cooled mixture was filtered, and the solid was washed with tetrahydrofuran and water. Recrystallization from 2-methoxyethanol afforded 1.84 g (41%) of the title compound. M.p. >300° C.; IR (KBr): 2220, 1700 cm-1 ; 1 -NMR (DMSO-d6): 0.93-4.77 (m, 11H, cyclohexyl), 7.97-8.63 (m, 5H, ArH), 11.8 (broad s, 1H, NH); MS (m/z): 319 (M+, 16%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:17]=2[N:16]([CH2:18][CH2:19][CH3:20])[N:15]=[C:14]3[C:21]2[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C1CCCCC=1>>[OH:27][C:24]1[CH:23]=[CH:22][C:21]([C:14]2[C:13]3[C:17](=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=4)[CH:10]=[CH:11][CH:12]=3)[N:16]([CH2:18][CH2:19][CH3:20])[N:15]=2)=[CH:26][CH:25]=1
Reactant: CCCn1nc(-c2ccc(OC)cc2)c2cccc(-c3ccc(OC)cc3)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCn1nc(-c2ccc(O)cc2)c2cccc(-c3ccc(O)cc3)c21
Yield: 76.5 %

Procedure:
Prepared according to Method D step C from 7-(4-methoxyphenyl)-3-(4-methoxy-phenyl)-1-propyl-1H-indazole (0.04 g, 0.11 mmol), boron tribromide (0.04 mL, 0.43 mmol) and 0.1 mL of cyclohexene to give the product (0.029 g) as an light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:12][C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[N:16]=[C:15]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:41])OC4C=CC=CC=4)=[CH:28][CH:27]=3)[N:14]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.FC1C=C(S([C:53]([C:56]2C=C(N3CCOC[C@@H]3C)N=C(C3C=CC(NC(=O)OC4C=CC=CC=4)=CC=3)[N:57]=2)(C)C)(=O)=O)C=C(F)C=1>>[F:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:12][C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[N:16]=[C:15]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:57][CH2:56][CH3:53])=[O:41])=[CH:28][CH:27]=3)[N:14]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2cc(F)cc(F)c2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2cc(F)cc(F)c2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Product: CCNC(=O)Nc1ccc(-c2nc(CS(=O)(=O)c3cc(F)cc(F)c3)cc(N3CCOC[C@@H]3C)n2)cc1

Procedure:
The following compounds were made in an analogous fashion from either phenyl N-[4-[4-[(3,5-difluorophenyl)sulfonylmethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate or phenyl N-[4-[4-[2-(3,5-difluorophenyl)sulfonylpropan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate and the appropriate amine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CC(C)=O.O.C(Cl)Cl>[CH2:17]([O:24][C:25]([NH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1cccc(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cccc(NC(=O)OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
A solution of methyl 6-aminopicolinate (10.65 g, 70 mmol, 1 eq) and sodium bicarbonate (13 g, 154 mmol, 2.2 eq) was dissolved in a mixture of acetone/water (2:1, 1M), and the solution cooled to 0° C. Benzyloxycarbonyl chloride (Cbz-Cl, 11.3 ml, 80.5 mmol, 1.15 eq) was added dropwise, and the reaction was warmed to room temperature and stirred for 18 hours. Water (200 mL) was added, and the resultant suspension was filtered to give a white solid. This solid was dissolved in methylene chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide methyl 6-(benzyloxycarbonylamino)picolinate (17.5 g).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:17]([CH:30]([OH:34])[CH:31]([CH3:33])[CH3:32])=[N:16][C:15]=2[N:14]([CH3:35])[C:13]1=[O:36])(C(C)(C)C)(C)C.Cl>C(O)C.O.C(OCC)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:18]2[C:19]3[C:20](=[O:21])[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[C:13](=[O:36])[N:14]([CH3:35])[C:15]=3[N:16]=[C:17]2[CH:30]([OH:34])[CH:31]([CH3:32])[CH3:33])=[CH:28][CH:27]=1
Reactant: CC(C)C(O)c1nc2c(c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C)n1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CC(C)C(O)c1nc2c(c(=O)n(CCCO)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
Step 2 1-(3-((tert-Butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(1-hydroxy-2-methylpropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.19 g, 0.355 mmol) was dissolved in ethanol (5 mL) and 6 N HCl (0.5 mL) was added. The clear solution was stirred at room temperature for 1 h. The reaction was diluted with water (75 mL) and extracted with DCM (3×50 ml). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to yield a white solid. Solid was slurried in diethyl ether (4 mL) and collected to give 7-(4-chlorobenzyl)-8-(1-hydroxy-2-methylpropyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.085 g, 56% yield) as a white solid. LCMS retention time=3.263 min and 94% purity, LCMS MH+ 421. 1H NMR (CDCl3) δ 7.23 (dd, 4H, J=8 Hz and 68 Hz), 5.59 (dd, 2H, J=16 Hz and 40 Hz), 4.43 (t, 1H, J=8 Hz). 4.17 (t, 2H, J=8 Hz), 3.59 (s, 3H), 3.48-3.54 (m, 2H), 3.35-3.40 (m, 1H), 2.48 (d, 1H, J=8 Hz), 2.08-2.16 (m, 1H), 1.85-1.92 (m, 2H), 1.03 (d, 3H, J=8 Hz), 0.82 (d, 3H, J=8 Hz).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:8]([CH:11]=1)[CH2:9][OH:10].[CH2:18](Cl)[CH:19]=[CH2:20].O>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:20]([O:10][CH2:9][C:8]1[CH:11]=[C:4]([NH2:3])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[CH:19]=[CH2:18]
Reactant: Nc1ccc(N2CCOCC2)c(CO)c1
Reactant: C=CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOCc1cc(N)ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.3 %

Procedure:
To a suspension of NaH in cold tetrahydrofuran (80 mg/20 mL), 5-amino-2-morpholinobenzyl alcohol (400 mg, 2 mmol) was added. The mixture was stirred for 15 minutes then allyl chloride (150 mg, 2 mmol) and tetrabutylammonium iodide (37 mg, 5 mol %) were added. The resulting mixture was stirred at room temperature for 2 hours then at 60° C. overnight. After cooling to room temperature, water was added (200 μL) and the mixture stirred for 10 minutes then diluted with ethyl acetate. The organic phase was washed sequentially with 10% aqueous ammonium chloride and brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid. The crude product was purified with 50% ethyl acetate in petroleum spirit to obtain 3-((allyloxy)methyl)-4-morpholinobenzenamine as a light orange oil (250 mg, 50% yield). 1H NMR (300 MHz, CDCl3) δ 6.95 (d, J=8.3 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 6.61 (dd, J=8.2, 2.7 Hz, 1H), 6.10-5.90 (m, 1H), 5.34-5.28 (m, 1H), 5.23 (dd, J=10.5, 1.9 Hz, 1H), 4.57 (s, 2H), 4.07-4.05 (m, 2H), 3.80 (t, J=4.8 Hz, 4H), 3.55 (br s, 2H), 2.83 (t, J=4.6 Hz, 4H). LC-ESI-MS (method B) rt 5.91 min.; m/z 249.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([CH3:11])[N:6](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:5]2.C1(O)C=CC=CC=1.C(O)(=O)CC.[H-].[Na+]>Br>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([CH3:11])[NH:6][CH2:5]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3cc(Br)ccc3C2C)cc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Product: CC1NCc2cc(Br)ccc21
Yield: 89.7 %

Procedure:
67.46 g of 5-bromo-1-methyl-2-(p-toluene sulfonyl)isoindoline (3-8) was suspended in 325 ml of 47% hydrobromic acid and 48 ml of phenol and 197 ml of propionic acid were added thereto and the resulting mixture was heated under reflux for 4 hours. After the reaction was completed, the reaction mixture was adjusted to be alkaline with 8N sodium hydride solution and extracted with chloroform and the resulting organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel chromatopraphy (eluent; chloroform:methanol=19:1) to obtain 35.03 g of 5-bromo-1-methylisoindoline.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C@H:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nncn1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc(Cn2cnnc2[C@H]2CCCN2)cc1
Yield: 118.3 %

Procedure:
De-Boc by HCl procedure: A solution of Boc-protected triazole from Example 3 (1.95 g, 5.374 mmol) in 100 mL of 4 N HCl in dioxane was stirred at room temperature for 4 h. The mixture was concentrated in vacuo and then treated with minimum amount of MeOH, diluted with ether, white crystal precipitated out. After filtration, the white crystal was collected and dried in vacuo to yield the HCl salt of desired product (1.67 g, 92.6%, yield calculated based on 2 eq. HCl attached).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C1C(=O)N([Br:26])C(=O)C1>C(#N)C>[Br:26][C:5]1[S:1][C:2]([CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccs2)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of tert-butyl 4-(thiazol-2-yl)piperidine-1-carboxylate (530 mg, 1.97 mmol) in acetonitrile (10 mL) was added NBS (1.40 g, 7.86 mmol). The mixture was stirred at RT for 14 hours and heated at 50° C. for 4 hours. The reaction mixture with some starting material recovered was poured into a solution of Na2SO3 (30 mL) and 6N NaOH (2 mL). The aqueous layer was extracted with EtOAc, dried over MgSO4, and the combined organics concentrated in vacuo. The residue was purified by silica gel chromatography to provide tert-butyl 4-(5-bromothiazol-2-yl)piperidine-1-carboxylate as a yellow oil [210 mg (0.61 mmol); 1H NMR (300 MHz, CDCl3) 7.59 (s, 1H), 4.20 (brd, J=12.9 Hz, 2H), 3.13 (tt, J=3.8, 11.5 Hz, 1H), 2.89 (t, J=11.6 Hz, 2H), 2.08 (d, J=11.7 Hz, 2H), 1.72 (dq, J=4.3, 11.9 Hz, 2H), 1.49 (s, 9H)].
Reaction SMILES: C([O:8][C:9]1[C:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[N:11][C:12]([N:16]([CH3:18])[CH3:17])=[N:13][C:14]=1[CH3:15])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:18][N:16]([CH3:17])[C:12]1[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:9]([OH:8])=[C:14]([CH3:15])[N:13]=1
Reactant: CCCCCCCCCCCCCCCCc1nc(N(C)C)nc(C)c1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCc1nc(N(C)C)nc(C)c1O
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution containing 100 mg (0.21 mmol) 5-(benzyloxy)-4-hexadecyl-N,N,6-trimethylpyrimidin-2-amine in 5 mL of methanol were added 5 mg of 20% palladium hydroxide on carbon (Degussa type E101 NE/E). The reaction mixture was stirred at 23° C. under hydrogen atmosphere for 15 min. The reaction mixture was filtered through celite and the filtrated was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (8×3 cm). Elution with 4:1 hexane-ethyl acetate afforded the expected product as white solid: yield 20 mg (25%); mp: 86-87° C.; silica gel TLC Rf 0.45 (4:1 hexanes-ethyl acetate); 1H NMR (methanol-d4) δ 0.89 (t, 3H, J=6.8 Hz), 1.28-1.34 (m, 26H), 1.67 (quint, 2H, J=7.2 Hz), 2.28 (s, 3H), 2.63 (dd, 2H, J=7.6, 7.6 Hz) and 3.07 (s, 6H); 13C NMR (methanol-d4) δ 12.96, 17.52, 22.27, 27.23, 29.00, 29.12, 29.12, 29.20, 29.20, 29.20, 29.30, 29.30, 29.30, 29.30, 29.30, 31.21, 31.61, 36.50, 36.50, 138.02, 155.61, 157.31 and 159.41; mass spectrum (APCI), m/z 378.3491 (M+H)+ (C23H44N3O requires 378.3484).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.Br.BrC[CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>>[CH3:16][C:6]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:2]([CH3:1])[N:3]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:23][CH2:24][N:25]([CH2:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[CH2:26][CH2:27]2)=[O:20])[N:5]=1
Reactant: BrCCc1cccnc1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Agent: Br
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3cccnc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and 3-(bromo ethyl)pyridine hydrobromide in the same manner as in Example 32.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][SH:35].CC(C)([O-])C.[Na+]>CS(C)=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:35][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(I)cc3F)c2C#N)CC1
Reactant: CN(C)CCS
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(SCCN(C)C)cc3F)c2C#N)CC1
Temperature: 120 °C

Procedure:
In a microwave reaction tube was placed 4-[5-cyano-6-(2-fluoro-4-iodo-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (10 mg, 0.19 mmol), 2-dimethylamino-ethanethiol (27 mg, 0.19 mmol), di-m-bromobis (tri-t-butylphosphino)dipalladium (I) (8 mg, 0.0095 mmol), sodium t-butoxide (55 mg, 0.57 mmol), and DMSO (0.5 mL). The reaction mixture was heated at 120° C. under microwave for 4 hours. The resulting mixture was filtered through a syringe filter and purified by preparative HPLC. 1H NMR (CDCl3, 400 MHz) δ 1.26 (d,6H), 1.86 (m, 2H), 2.00 (m, 2H), 2.86 (s, 6H), 3.20 (m, 2H), 3.30 (m, 2H), 3.43 (m, 2H), 3.78 (m, 2H), 4.94 (m, 1H), 5.44 (m, 1H), 7.22 (s, 1H), 7.24 (s, 1H), 7.35 (s, 1H), 8.11 (t, 1H), 8.45 (s, 1H). Exact mass calculated for C24H31 FN6O3S 502.22, found 503.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[C:5]([C:7]1[CH:34]=[CH:33][C:10]2[N:11]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:30][CH2:31][CH3:32])[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=3)[C:12](=[O:14])[S:13][C:9]=2[CH:8]=1)=O.[CH3:38][O:39][NH2:40]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[N:40][O:39][CH3:38])[C:7]2[CH:34]=[CH:33][C:10]3[N:11]([CH2:15][CH2:16][O:17][C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:30][CH2:31][CH3:32])[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=4)[C:12](=[O:14])[S:13][C:9]=3[CH:8]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4cccc(Cl)c4)ccc32)cc1)C(=O)OC
Reactant: CON
Product: CCOC(Cc1ccc(OCCn2c(=O)sc3cc(C(=NOC)c4cccc(Cl)c4)ccc32)cc1)C(=O)OC

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C(N(CC)CC)C.[NH2:19][C:20]1[CH:26]=[C:25]([N:27]2[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]2)[CH:24]=[CH:23][C:21]=1[NH2:22]>O=S(Cl)Cl.CN(C1C=CN=CC=1)C.C1COCC1>[NH2:19][C:20]1[CH:26]=[C:25]([N:27]2[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]2)[CH:24]=[CH:23][C:21]=1[NH:22][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: Cc1cn(-c2ccc(N)c(N)c2)cn1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(C)c(I)c3)c(N)c2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37 %

Procedure:
A solution of 3-iodo-4-methylbenzoic acid (0.26 g, 1 mmol) in SOCl2 (5 mL) was refluxed for 2 h, and then evaporated in vacuo to remove excess SOCl2. The residue was dissolved in 5 mL anhydrous THF and added to a solution of triethylamine (0.12 g, 1.2 mmol), 2-amino-4-(4-methyl-1H-imidazol-1-yl)aniline (0.18 g, 1 mmol) and DMAP (24 mg) in 5 mL anhydrous THF in dropwise. The result mixture was stirred at rt for 20 hrs, and evaporated in vacuo. The residue was purified by chromatography on silica gel (CH2Cl2/CH3OH 97:3) to give 0.16 g product as a pale yellow solid (37.0%). LC/MS: m/z [M+H]+ 433.0520.