Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:9]=1.[CH3:34][O:35][C:36]1[N:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:10]2[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:39]3[CH:40]=[N:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=3)[N:13]=[C:12]([CH3:14])[N:11]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccccc3N)n2)cc1
Reactant: COc1ccc(B(O)O)cn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccccc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(2-aminophenyl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.54 g, 1.22 mmol), copper acetate (0.33 g, 1.83 mmol, Aldrich, St. Louis, Mo.), 6-methoxypyridin-3-ylboronic acid (0.56 g mg, 3.67 mmol, Boron Molecular, Research Triangle Park, N.C.) and diisopropylethylamine (0.85 mL, 4.89 mmol) in DCM (15 mL) was stirred at room temperature for 16 h, filtered through a pad of Celite® (diatomaceous earth), and the solvent was removed in vacuo. The crude material was adsorbed onto silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 0% to 2% 2 M NH3-MeOH in CH2Cl2, to give the title compound as a dark yellow oil. m/z (ESI, +ve ion) 548.8 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([NH2:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH:4]=1)#[N:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.O>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]#[N:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH:4]=1)#[N:2]
Reactant: CCS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C(N)=O
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C#N
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
The reaction was carried out under argon. (rac)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1000 mg, 2.03 mmol) was initially charged in dry THF (50 ml), methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 726 mg, 3.046 mmol) was added and the mixture was stirred at RT. After 75 min, HPLC control showed complete conversion. Water (20 ml) was then added, the reaction mixture was concentrated and the residue was taken up in ethyl acetate (200 ml).
Reaction SMILES: [F:1][CH:2]([F:22])[C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][C:17]2=[O:21])[C@H:13]2[C@H:4]1[C@@H:5]1[C:10]([CH2:11][CH2:12]2)=[CH:9][CH2:8][CH2:7][CH2:6]1.C(OCC)C.[Cl-].[NH4+].[C:30]([Mg]Br)#[C:31][CH3:32]>C1COCC1>[F:1][CH:2]([F:22])[C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][C@@:17]2([OH:21])[C:30]#[C:31][CH3:32])[C@H:13]2[C@H:4]1[C@@H:5]1[C:10]([CH2:11][CH2:12]2)=[CH:9][CH2:8][CH2:7][CH2:6]1
Reactant: CC#C[Mg]Br
Reactant: C[C@]12C[C@H](C(F)F)[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1CCC2=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CCCC[C@@H]4[C@H]3[C@@H](C(F)F)C[C@@]21C
Reaction time: 16 h

Procedure:
A mixture of 11β-difluoromethylestr-4-en-17-one (XII, Example 14, 0.9 g) in propynyl magnesium bromide (0.5M, 10 ml) and THF is kept at 20°-25° for 16 hours. Diethyl ether and aqueous ammonium chloride are added and the diethyl ether phase is separated and washed with water and concentrated to a solid. The solid is purified by chromatography through silica gel using ethyl acetate/hexane (20/80) as the irrigant. The appropriate fractions are pooled and concentrated to give the title compound, IR (mull) 3400, 2237 and 1666 cm-1 ; MS (m/e) 348, 330, 315, 266 and 251; NMR (CDCl3) 0.87, 1.86 and 6.0 δ.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26]C)=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([OH:26])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC[C@H]3C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of (R)-methyl 2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (95 mg, 0.26 mmol) in methanol (50 mL) was added sodium hydroxide (95 mg, 2.38 mmol) and water (2 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted to pH 6 with HCl (3N), and filtered to give (R)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (29.2 mg, 32%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:15][C:16](OCC)=O.[OH2:21]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:16][CH2:15][O:11][CH2:10][C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: CCOC(=O)CBr
Reactant: OCCNCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1COCCN1Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of N-benzyl ethanolamine (60.4 g, 0.40 mol) in toluene (400 ml) was added over a period of 1 hour to a mechanically stirred suspension of sodium hydride (60% dispersion in mineral oil, 17.6 g, 0.44 mol) in toluene (800 ml). The reaction was heated under reflux for 2 hours before being cooled to room temperature and a solution of ethyl bromoacetate (44.4 ml, 0.40 mol) in toluene (600 ml) added over a period of 30 minutes. The reaction was then heated under reflux for 15 hours before being cooled to room temperature and water (1000 ml) added. The aqueous phase was extracted with ethyl acetate (3×200 ml) and the combined organic phases washed with brine (500 ml), dried with sodium sulphate and evaporated in vacuo. The resulting oil was purified by flash column chromatography upon silica gel using ethyl acetate: hexanes: triethylamine (70:28:2) as eluant affording the desired product as a yellow oil, 32 g, M+ found: 191.
Reaction SMILES: [CH3:1][C:2]1([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[O:6][N:5]=[C:4]([C:7]([O:9]CC)=[O:8])[CH2:3]1.N.[H][H]>C(O)C>[NH2:5][CH:4]([CH2:3][C:2]([OH:6])([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH3:1])[C:7]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: CCOC(=O)C1=NOC(C)(Cc2c[nH]c3ccccc23)C1
Agent: N
Solvent: CCO
Product: CC(O)(Cc1c[nH]c2ccccc12)CC(N)C(=O)O

Procedure:
The aforementioned 5-(RS)-methyl-5-(3-indolylmethyl)-4,5-dihydroisoxazole-3-carboxylic acid in an amount of 540 mg was dissolved in 4 ml of ethanol, and 10 ml of 28% aqueous ammonia and 300 mg of 5% Rh—C were added thereto. Reduction performed at room temperature in an atmosphere of hydrogen at 10 atm for 12 hrs. The catalyst was removed by filtration, and after vacuum concentrating the filtrate, the product was again dissolved in water followed by freeze-drying resulting in 370 mg of 2-amino-4-hydroxy-4-(3-indolylmethyl)pentanoic acid (1.41 mmol) as light brown powder (Compound No. 5 in Table 1).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N+:7]([O-:10])=[CH:8][CH:9]=1)([O-])=O.C([Br:20])(=O)C>C(O)(=O)C>[Br:20][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N+:7]([O-:10])=[CH:8][CH:9]=1
Reactant: CC(=O)Br
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(-c2ccccn2)c1
Solvent: CC(=O)O
Product: [O-][n+]1ccc(Br)cc1-c1ccccn1
Yield: 95 %

Procedure:
To 4-nitro-2,2′-bipyridyl-N-oxide (Wenkert, D.; Woodward, R. B. J. Org. chem. 48,283 (1983)) (5 g) dissolved in 30 mL acetic acid in a 100 ml round bottom flask was added 16 mL acetyl bromide. The yellow mixture was refluxed for 1.5 h and then rotovaporated to dryness. The resulting light yellow solid was sufficiently pure enough for the next step without further purification. Yield: 95%
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[Br:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=3)[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: Brc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(C)c(C)cc2nc1OC
Product: COc1nc2cc(C)c(C)cc2nc1NC(=O)N1CCN(c2cccc(Br)c2)CC1
Yield: 69 %

Procedure:
Ethyl N-(2-methoxy-6,7-dimethylquinoxalin-3-yl)carbamate and 1-(3-bromo phenyl)piperazine were reacted by the same way with the example 183 to obtain the titled compound (yield, 69%). 1H NMR (300 MHz, CDCl3) δ 2.33 (s, 3H), 2.40 (s, 3H), 3.22-3.31 (m, 4H), 3.73-3.76 (m, 3H), 4.13 (s, 4H), 6.85 (m, 1H), 7.00-7.20 (m, 3H), 7.40 (br s, 1H), 7.53 (s, 1H), 7.59 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[F:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([F:46])=[C:24]([NH:23][C:8]([C:7]5[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=5)=[O:10])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: CCn1nc(C)cc1C(=O)O
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 53.1 %

Procedure:
In the same manner as in Example 259 and using 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (120 mg, 0.79 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (89 μL, 1.0 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.61 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (150 mg, 53%) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][C:7]2([CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[N:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH2:12][CH2:11]2)[C:6]1=[O:26].[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC.O.CCO>[CH3:31][N:32]1[CH:36]=[C:35]([C:2]2[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=2[CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][C:7]3([CH2:15][CH2:14][N:13]([C:16]4[CH:25]=[N:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=4)[CH2:12][CH2:11]3)[C:6]2=[O:26])[CH:34]=[N:33]1
Reactant: O=C1N(Cc2ccccc2Br)CCCC12CCN(c1cnc3ccccc3n1)CC2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: Cn1cc(-c2ccccc2CN2CCCC3(CCN(c4cnc5ccccc5n4)CC3)C2=O)cn1
Temperature: 120 °C
Yield: 194.8 %

Procedure:
The mixture of 2-(2-bromobenzyl)-9-(quinoxalin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one (58 mg, 0.11 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [761446-44-0] (34 mg, 0.16 mmol), (Ph3P)2PdCl2 and sodium carbonate (39 mg, 0.37 mmol) in the solvent mixture DME/H2O/EtOH (2 ml, 7:3:2) was placed in a microwave tube. The tube was sealed and the suspension was heated at 120° C. over 1 h under microwave conditions. The reaction mixture was concentrated under reduced pressure. Methanol was added and the mixture filtered through PL-thiol MP SPE cartridge (previously washed with MeOH) and evaporated to give 100 mg of a yellow oil which was purified by preparative HPLC (column Waters Sunfire C18, 5 um, 4.6×50 mm, flow 5 ml/min, solvent A: Water+0.1% TFA; Solvent B: Acetonitrile+0.1% TFA/gradient 5-100% B in 2.5 min). The product containing fractions were adjusted to pH 7 with aqueous sodium bicarbonate an extracted with ethyl acetate to yield the title compound (35 mg, 66%). [1H NMR (600 MHz, DMSO-d6) ppm 8.84 (s, 1H), 7.92 (s, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.54-7.64 (m, 3H), 7.32-7.42 (m, 2H), 7.22-7.31 (m, 2H), 7.02-7.11 (m, 1H), 4.59 (s, 2H), 4.22-4.34 (m, 2H), 3.44 (t, J=11.1 Hz, 2H), 3.13 (t, J=5.9 Hz, 2H), 2.02-2.13 (m, 2H), 1.86-1.95 (m, 2H), 1.75-1.85 (m, 2H), 1.61 (d, J=13.5 Hz, 2H); LCMS RtC=3.11 min, [M+H]+=467.2].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([CH:50]=[CH:51][CH:52]=2)[CH2:35][NH:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][C@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:32]3[CH:33]=[C:34]([CH:50]=[CH:51][CH:52]=3)[CH2:35][NH:36][CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:48])([CH3:49])[CH3:47])=[O:44])[CH2:39][CH2:38]3)[N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: C[C@H]1CCCN1c1cccc(Nc2nc(Cl)nc3scnc23)c1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1CCCN1c1cccc(Nc2nc(-c3cccc(CNC4CCN(C(=O)OC(C)(C)C)CC4)c3)nc3scnc23)c1

Procedure:
To a solution of (S)-5-chloro-N-(3-(2-methylpyrrolidin-1-yl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (200 mg, 0.58 mmol) and crude tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylamino)piperidine-1-carboxylate in 10 mL of 1,4-dioxane and 2 mL of water was added Na2CO3 (184 mg, 1.74 mmol) followed by Pd(PPh3)4 (184 mg, 0.03 mmol) under nitrogen with stirring. The mixture was refluxed for 15 hours under nitrogen. After cooled, the solvent was evaporated by rotary evaporation under reduced pressure. The residue was poured into water and extracted with EtOAc (3×15 mL). The organic layer was washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography (silica gel, eluting with EtOAc) to give (S)-tert-butyl 4-(3-(7-(3-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzylamino)piperidine-1-carboxylate (110 mg, 32% for the two steps). LC-MS: 250.6 [M/2+H]+, 600 [M+H]+, tR=1.57 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCCc1ccccc1
Reactant: COc1ccc(C=O)cc1O
Product: COc1ccc(C=O)cc1OC(=O)CCCc1ccccc1

Procedure:
Following the method of Example 64, the title compound was prepared from 3-hydroxy-4-methoxybenzaldehyde (ALDRICH) and 4-phenyl-1-butanol (Aldrich). M/z calculated for C18H20O3 : 284.1412. Found: 284.1435.
Reaction SMILES: [CH3:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[C:8]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:9]([C:15]4[CH:20]=[CH:19][C:18]([C:21]5([NH:25]C(=O)OC(C)(C)C)[CH2:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][N:3]=1.[ClH:39].CCOC(C)=O>CO.C(Cl)Cl>[ClH:39].[CH3:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[C:8]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:9]([C:15]4[CH:16]=[CH:17][C:18]([C:21]5([NH2:25])[CH2:22][CH2:23][CH2:24]5)=[CH:19][CH:20]=4)=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][N:3]=1
Reactant: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)nc3ccn12
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(N)CCC5)cc4)nc3ccn12
Temperature: 25 °C

Procedure:
To a solution of tert-butyl {1-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (1-6f) (9.23 g, 18.26 mmol) in MeOH (20 mL) and DCM (100 mL) was added a 4N solution of HCl in EtOAc (91 mL, 365 mmol). The sealed reaction mixture was permitted to stir at room temperature. After 18 hours the reaction mixture was filtered to give 1-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutanamine hydrochloride (1-17) as an off-white solid. HRMS (M+H)+: observed=406.2047, calculated=406.2026.
Reaction SMILES: C(S[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]1[N:27]([CH3:28])[C:17]2=[N:18][CH:19]=[C:20]([S:22][C:23]([F:26])([F:25])[F:24])[CH:21]=[C:16]2[N:15]=1)C.Cl[C:30]1C=CC=C(C(OO)=O)[CH:31]=1.C(=O)([O-])O.[Na+].[S:45]([O-:49])([O-])(=[O:47])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:30]([S:45]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[C:14]1[N:27]([CH3:28])[C:17]2=[N:18][CH:19]=[C:20]([S:22][C:23]([F:26])([F:24])[F:25])[CH:21]=[C:16]2[N:15]=1)(=[O:49])=[O:47])[CH3:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cc(C(F)(F)F)ccc1-c1nc2cc(SC(F)(F)F)cnc2n1C
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cc(C(F)(F)F)ccc1-c1nc2cc(SC(F)(F)F)cnc2n1C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-(2-ethylsulfanyl-4-trifluoromethylphenyl)-3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine and chloroform (5 ml), 69% of 3-chloroperbenzoic acid (1.05 g) was added under ice-cooling, and then heated to room, temperature, and stirred for 1.5 hours. Then, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution was poured, and extracted with chloroform. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.20 g of 2-(2-ethylsulfonyl-4-trifluoromethylphenyl)-3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine (hereinafter, Present Compound 306).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.SC[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8][CH2:10][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(SCCc2ccccn2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-mercaptoethylpyridine and DBU in dioxane. ES-MS m/e (%): 379 (M{81Br}+H+, 100), 377 (M{79Br}+H+, 95).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:6]=1[NH:19][C:20]([C:22]1[C:31](=[O:32])[C:30]([CH2:36][CH2:37][CH3:38])([CH2:33][CH2:34][CH3:35])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]=1[OH:39])=O)(=[O:4])=[O:3].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:6]2[NH:19][C:20]([C:22]3[C:31](=[O:32])[C:30]([CH2:33][CH2:34][CH3:35])([CH2:36][CH2:37][CH3:38])[C:29]4[C:24]([C:23]=3[OH:39])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:1][S:2](=[O:4])(=[O:3])[C:5]=2[CH:10]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCC1(CCC)C(=O)C(C(=O)Nc2ccc(OCc3ccccc3)cc2S(N)(=O)=O)=C(O)c2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Temperature: 140 °C
Reaction time: 18 h
Yield: 37.9 %

Procedure:
A solution of the compound of Example 2E (300 mg, 0.547 mmol) in anhydrous pyridine (5.2 mL) was treated with 1,8diazabicyclo[5.4.0]undec-7-ene (82 μL, 0.55 mmol) and stirred at 140° C. for 18 hours, cooled to 25° C. and the pyridine removed by short path distillation under high vacuum (50° C./0.3 mm Hg). A solution of the residue in ethyl acetate was washed with water (2×) and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate in hexane to give the title compound (110 mg, 38%). 1H NMR (300 MHz, DMSO-d6): δ 8.11 (d, J=7.72 Hz, 1 H), 7.64 (m, 1 H), 7.41 (m, 8 H), 5.21 (s, 2 H), 2.14 (m, 2 H), 1.83 (m, 2 H), 0.87 (m, 2 H), 0.64 (m, 8 H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=3)([CH2:12][CH2:13]1)[CH2:10][O:9]2)(=O)=O.[C-:29]#[N:30].[Na+]>CS(C)=O.C(Cl)Cl>[O:22]([C:18]1[CH:17]=[C:16]([C:11]23[CH2:12][CH2:13][C:8]([CH2:7][CH2:6][C:29]#[N:30])([CH2:15][CH2:14]2)[O:9][CH2:10]3)[CH:21]=[CH:20][CH:19]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#CCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of 110A compound (100 mg, 0.25 mmol) and NaCN (61 mg, 1.2 mmol) in DMSO (3 mL) was stirred at 80° C. overnight. The mixture was cooled to rt, diluted with DCM, washed with 1N aq HCl, dried (MgSO4), and concentrated in vacuo. The crude was chromatographed (SiO2; continuous gradient of hexanes/EtOAc from 100:0 to 50:50) to afford the title compound (62 mg, 75% yield) as a colorless oil. LCMS [M+H]+=334.3. 1H NMR (400 MHz, CDCl3) δ 7.38-7.32 (m, 2H), 7.31-7.25 (m, J=7.9, 7.9 Hz, 1H), 7.14-7.09 (m, 1H), 7.00 (dd, J=8.6, 1.1 Hz, 3H), 6.96 (t, J=2.0 Hz, 1H), 6.84 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 3.96 (s, 2H), 2.47-2.41 (m, 2H), 2.12-2.03 (m, 2H), 2.00-1.89 (m, 4H), 1.84-1.78 (m, 2H), 1.74-1.64 (m, 2H).