Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C@@H:21]4[CH2:26][CH2:25][C@H:24]([CH2:27][S:28][C:29]#[N:30])[CH2:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CO.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[CH:17]=[N:18][N:19]([C@@H:21]3[CH2:22][CH2:23][C@H:24]([CH2:27][S:28][C:29]#[N:30])[CH2:25][CH2:26]3)[CH:20]=2)=[N:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](CSC#N)CC4)c3)ncnc21
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CSC[C@H]1CC[C@@H](n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl thiocyanate was dissolved in methanol (2.0 mL, 0.049 mol) and DCM (2.0 mL, 0.031 mol), and TFA (0.5 mL, 0.006 mol) was added. The resulting mixture was stirred at 25° C. for 16 hours. TLC analysis showed no starting material present and LCMS analysis showed product. The reaction was concentrated using a rotary evaporator and the concentrate was chromatographed on silica gel using 2% MeOH/EtOAc to give the product. LC/MS (M+H)+: 339, 1H NMR (CD3OD) δ 8.65 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 7.50 (d, 1H), 6.96 (d, 1H), 4.43 (m, 1H), 3.20 (d, 2H, J=7.6 Hz), 2.24 (m, 2H), 1.80-2.17 (m, 7H).
Reaction SMILES: B(F)(F)F.CSC.[C:8]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:31]4[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([O:38]C)[CH:32]=4)=[N:25][N:26]([CH2:28][C:29]#[N:30])[CH:27]=3)=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:10])[CH3:9]>ClCCl>[C:8]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:31]4[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([OH:38])[CH:32]=4)=[N:25][N:26]([CH2:28][C:29]#[N:30])[CH:27]=3)=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:10])[CH3:9]
Reactant: COc1cc(C)cc(-c2nn(CC#N)cc2-c2ccc(-c3cccc(C(C)=O)c3)nc2)c1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: CC(=O)c1cccc(-c2ccc(-c3cn(CC#N)nc3-c3cc(C)cc(O)c3)cn2)c1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (50.7 mg, 0.12 mmol) prepared in Example 68 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL), and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (39 mg, 69%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][O:10]C(=O)C2C=CC=CC=2)[CH:5]=[C:4]([F:19])[N:3]=1.C[O-].[Na+].[Cl-].[NH4+]>CO>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[CH:5]=[C:4]([F:19])[N:3]=1
Reactant: O=C(OCc1cc(F)nc(F)c1F)c1ccccc1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OCc1cc(F)nc(F)c1F
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
To a stirred solution of benzoic acid 2,3,6-trifluoro-pyridin-4-ylmethyl ester (3.43 g, 12.8 mmol) in anhydrous methanol (50 ml) at room temperature, was added sodium methoxide (693 mg, 12.8 mmol). After stirring for 20 min., excess ammonium chloride was added to the reaction mixture and stirring was continued for 30 min. The mixture was then evaporated in vacuo and the residue was dissolved in methanol-dichloromethane (1:9), filtered, and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexane (1:4) to EA) to afford 2.0 g (95%) of (2,3,6-trifluoro-pyridin-4-yl)-methanol as a white solid. m.p. 48-49° C.; 1H NMR (200 MHz, CDCl3) δ 2.18 (1H, t, J=5.6 Hz), 4.88 (2H, d, J=5.6 Hz), 7.02 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5].[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=2[C:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)=[O:5])=[O:27])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]
Reactant: COc1ccc(NC(=O)c2ccccc2N)cc1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1ccc(NC(=O)c2ccccc2NC(=O)c2ccc(C(C)=O)cc2)cc1
Yield: 37 %

Procedure:
Using the procedure described in Example 55, Part B, 2-amino-N-(4-methoxyphenyl)benzamide (1.06 g, 4.36 mmol) was reacted with 4-acetylbenzoic acid to yield 292 mg (37%) of the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C=O.[CH:17](O)=O>CO>[CH3:1][C@@H:2]1[N:7]([CH3:17])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: O=CO
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: C=O
Solvent: CO
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C
Temperature: 70 °C
Yield: 100.8 %

Procedure:
To a solution of (S)-tert-butyl 3-methylpiperazine-1-carboxylate (50 g, 0.250 mol) in 500 mL of methanol was added formaldehyde (41.6 mL, 0.5 mol, 37% aqueous solution) and formic acid (33 mL, 0.874 mol) and the mixture was heated to 70° C. for 16 hours, then concentrated under reduced pressure. The resulting residue was taken up in EtOAc (500 mL), washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure to give 54 g (100%) of the title compound.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH:16]=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:18]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1>[CH2:4]([O:3][C:1]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:23][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1CCCN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=C[C@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-carbobenzyloxypyrrolidine-2-carboxaldehyde (1.17 g, 5.00 mmol) in anhydrous tetrahydrofuran at −78° C. was added (carboethoxymethylene)triphenylphosphorane (2.09 g, 6.00 mmol, 1.2 eq) as a solid portionwise. The resulting reaction mixture was stirred at room temperature under nitrogen for 2 hours, and then heated at reflux under nitrogen for 1 hours. The reaction mixture was evaporated under reduced pressure and the residue was column chromatographed using silica gel (approximately 100 g) and elution with 20% diethyl ether in hexane to afford the title compound as a clear, colorless oil (1.11 g, 3.65 mmol, 73%): 1H NMR (CDCl3-d6) δ 7.34-7.25 (m, 5H), 6.89-6.76 (m, 1H), 5.88-5.74 (m, 1H), 5.18-5.05 (m, 2H), 4.60-4.43 (m, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.55-3.40 (m, 2H), 2.11-2.00 (m, 1H), 1.90-1.75 (m, 3H), 1.28 (t, J=7.1 Hz, 3H); 13C NMR (CDCl3) [Note: due to slow nitrogen inversion two conformers of the products are seen by NMR spectroscopy] δ 166.3, 154.7, 147.9, 147.4, 136.6, 128.4, 127.9, 120.9, 66.9, 65.8, 60.4, 58.1, 57.7, 46.8, 46.4, 31.6, 30.9, 23.6, 22.8, 22.6, 15.3, 14.2.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:26]=[CH:25][C:8]2[CH:9]=[C:10]([C:20]([O:22]CC)=[O:21])[CH:11]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[O:12][C:7]=2[CH:6]=1)([CH3:4])[CH3:3].[OH-].[Na+]>C1COCC1.C(O)C>[CH3:4][C:2]([C:5]1[CH:26]=[CH:25][C:8]2[CH:9]=[C:10]([C:20]([OH:22])=[O:21])[CH:11]([C:13]([F:18])([F:19])[C:14]([F:17])([F:16])[F:15])[O:12][C:7]=2[CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)C1=Cc2ccc(C(C)(C)C)cc2OC1C(F)(F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1ccc2c(c1)OC(C(F)(F)C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 23.3 h
Yield: 51.7 %

Procedure:
The ester from Step 3 (1.58 g 4.20 mmol) was dissolved in THF (3 mL) and ethanol (3 mL), treated with 2.5 N sodium hydroxide (2 mL, 5 mmol), and stirred at room temperature for 23.3 hours. The reaction mixture was concentrated in vacuo, acidified with 3 N HCl yielding a suspension. The solid was collected by filtration and was recrystallized from ethanol-water to yield a yellow solid (0.76 g, 52%): mp 171.0–173.5° C. 1H NMR (acetone-d6/300 MHz) 7.93 (s, 1H), 7.39 (d, 1H, J=8.1 Hz), 7.18 (dd, 1H, J=8.1 Hz 1.8 Hz), 7.02 (s, 1H), 6.01 (dd, 1H, J=23.1 Hz 3.2 Hz), 1.32 (s, 9 H). FABLRMS m/z 351 (M+H). EIHRMS m/z 350.0945 (M+, Calc'd 350.0941). Anal. Calc'd for C16H15F5O3: C, 54.86; H, 4.32. Found: C, 54.88; H, 4.32.
Reaction SMILES: [CH2:1]=[C:2]1[C:9]2[S:8][CH:7]=[CH:6][C:5]=2[CH:4]2[CH2:10][N:11]([CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:14])[CH2:12][CH:3]12>CO.[Pd]>[CH3:1][CH:2]1[C:9]2[S:8][CH:7]=[CH:6][C:5]=2[CH:4]2[CH2:10][N:11]([CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:14])[CH2:12][CH:3]12
Reactant: C=C1c2sccc2C2CN(C(C)c3ccccc3)CC12
Agent: [Pd]
Solvent: CO
Product: CC1c2sccc2C2CN(C(C)c3ccccc3)CC12
Temperature: 35 °C
Reaction time: 12 h
Yield: 72.5 %

Procedure:
The product of step f) (226 mg, 0.80 mmol) was added to a suspension of 10% Pd/C (339 mg) in 8 mL of methanol. The reaction chamber was evacuated from air and was filled with H2 (1 atm). The reaction mixture was stirred under H2 for 12 hours at 35° C. The reaction mixture was filtered through Celite and evaporated in vacuo to give the subtitle compound as an oil (165 mg, 72.5%). MS calculated for C18H21NS +H: 284, observed: 284.
Reaction SMILES: Br[C:2]1[C:3]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][C:20]([OH:24])=[CH:19]2.C(=O)([O-])[O-].[Cs+].[Cs+].C(CC(=O)C(C)(C)C)(=O)C(C)(C)C>CN1CCCC1=O.[Cu]Cl>[F:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][C:20]([O:24][C:2]1[C:3]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1)=[CH:19]2
Reactant: CC(C)(C=O)c1ncccc1Br
Reactant: Oc1cnc2c(F)cccc2c1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: CC(C)(C=O)c1ncccc1Oc1cnc2c(F)cccc2c1
Temperature: 130 °C
Reaction time: 16 h
Yield: 34.1 %

Procedure:
0.41 g of 2-(3-bromo-pyridin-2-yl)-2-methyl-propioaldehyde were dissolved in 4 ml of N-methylpyrrolidone. 0.59 g of 8-fluoro-3-hydroxyquinoline, 1.2 g of cesium carbonate, 0.07 g of dipivaloylmethane and 0.18 g of copper (I) chloride were added thereto followed by stirring for 16 hours at 130° C. Subsequently, the reaction solution was cooled to room temperature and purified by silica gel column chromatography to obtain 0.19 g of 2-[3-(8-fluoro-quinolin-3-yloxy)-pyridin-2-yl]-2-methyl-propioaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][CH2:15][C:16]2[C:24]3[C:23]([C:25]([O:27]C)=[O:26])=[CH:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][CH2:15][C:16]2[C:24]3[C:23]([C:25]([OH:27])=[O:26])=[CH:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccnc2[nH]cc(CNC3CCCN(C(=O)OC(C)(C)C)C3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC(NCc2c[nH]c3nccc(C(=O)O)c23)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3-((1-(tert-butoxycarbonyl)piperidin-3-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (315 mg, 0.811 mmol) in dioxane (5 mL) at 0° C. was added 1N LiOH (2.03 mL, 2.03 mmol) and stirred for 4 h at rt. The reaction mixture was partitioned between ether and water. The separated aqueous layer was neutralized with 1N HCl, and concentrated in vacuo to afford 3-((1-(tert-butoxycarbonyl)piperidin-3-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid as an off-white solid. [M+H] found 375.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:13][CH:14]=2)O1.[F-].[K+].Cl[C:27]1[CH:36]=[CH:35][N:34]=[C:33]2[C:28]=1[CH:29]=[CH:30][C:31]([CH3:37])=[N:32]2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:37][C:31]1[N:32]=[C:33]2[C:28]([C:27]([C:9]3[CH:10]=[C:11]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:12]=[CH:13][CH:14]=3)=[CH:36][CH:35]=[N:34]2)=[CH:29][CH:30]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Product: Cc1ccc2c(-c3cccc(-c4ccccc4C#N)c3)ccnc2n1
Reaction time: 18 h
Yield: 8.1 %

Procedure:
A mixture of tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.025 mmol), 3′-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (384 mg, 1.3 mmol), potassium fluoride (161 mg, 2.8 mmol) and 5-chloro-2-methyl-[1,8]naphthyridine (prepared as described by G. B. Barlin and W. L. Tan, Aust. J. Chem., 1984, 37, 1065-73; 150 mg, 0.84 mmol) was degassed by evacuating the reaction vessel and refilling it with nitrogen. Tri-tert-butylphosphine (0.50 ml of a 0.1 M solution in THF) and THF (15 ml) were added, and the mixture was degassed via three “freeze-thaw” cycles before stirring under nitrogen for 18 h. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel, eluting with 10% to 100% EtOAc in dichloromethane, yielding 3′-(7-methyl-[1,8]naphthyridin-4-yl)biphenyl-2-carbonitrile as a white solid (22 mg, 8%): δH (400 MHz, CDCl3) 2.83 (3H, s), 7.40 (1H, d, J 8.2), 7.45 (1H, d, J 4.3), 7.48-7.52 (1H, m), 7.57-7.60 (1H, m), 7.59 (1H, s), 7.67-7.71 (4H, m), 7.82 (1H, dd, J 0.8 and 7.8), 8.36 (1H, d, J 8.6), 9.11 (1H, d, J 4.3); m/z (ES+) 322 [MH]+.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>>[C:21]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)C(C)(C)C)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and pivaloyl chloride, there is obtained ethyl N-pivaloyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 350 (2), 321 (5), 293 (100), 265 (18), 194 (29), 167 (92);
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH2:3]1.[BH-](OC(C)=O)(OC(C)=O)O[C:20](C)=O.[Na+].C=O.[NH4+].[OH-]>C(Cl)Cl.O>[NH4+:4].[OH-:17].[CH3:8][C@H:6]1[N:7]([CH3:20])[C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH2:5]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)c1cccc(N2C[C@@H](C)N[C@@H](C)C2)c1
Agent: C=O
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cccc(N2C[C@@H](C)N(C)[C@@H](C)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 156.7 %

Procedure:
A mixture of 1-[3-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-phenyl]-ethanone (226 mg, 0.974 mmol), NaBH(OAc)3 (309 mg, 1.46 mmol) and CH2O (37% water solution, 0.087 ml, 1.17 mmol) in DCM (10 ml) was stirred at room temperature overnight. The resulting solution was diluted with water, brought to basic conditions with NH4OH and extracted with DCM. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by SCX cartridge (eluent: MeOH and then 3% NH4OH in MeOH) to give 188 mg of 1-[3-((3R,5S)-3,4,5-trimethyl-piperazin-1-yl)-phenyl]-ethanone.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([S:10][C:11]([F:14])([F:13])[F:12])=[CH:5][N:4]=1.[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21](O)=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([S:10][C:11]([F:13])([F:12])[F:14])[CH:7]=[C:8]2[N:9]=1
Reactant: CNc1ncc(SC(F)(F)F)cc1N
Reactant: O=C(O)c1sccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(-c2sccc2Cl)nc2cc(SC(F)(F)F)cnc21
Temperature: 90 °C
Reaction time: 10 h
Yield: 89.3 %

Procedure:
A mixture of 0.50 g of N2-methyl-5-trifluoromethylthiopyridine-2,3-diamine, 0.44 g of 3-chloro-thiophene-2-carboxylic acid, 0.51 g of EDCI hydrochloride, 30 mg of HOBt and 5 ml of pyridine was stirred at 90° C. for 10 hours. Water was poured into the cooled reaction mixture, and the deposited precipitate was filtered. The filtrate was applied to a silica gel column chromatography to obtain 0.7 g of 2-(3-chlorothiophen-2-yl)-3-methyl-6-trifluoromethylthio-3H-imidazo[4,5,b]pyridine.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]#[N:38])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[CH:2]([C:3]1[N:29]([C@H:30]2[CH2:31][CH2:32][C@H:33]([CH2:36][C:37]#[N:38])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)([CH3:6])[CH3:1]
Reactant: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reactant: CC(C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-methylpropanamide (80 mg, 0.9 mmol) and triethyloxonium tetrafluoroborate (170 mg, 0.89 mmol) in tetrahydrofuran (0.4 mL) was stirred at room temperature for 1 h and then concentrated. A mixture of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (22 mg, 0.077 mmol) and the above made reagent in ethanol (0.70 mL) was heated at reflux for 2 h. The mixture was purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (2.9 mg, 11%). LCMS calculated for C19H23N4S (M+H)+: m/z=339.2. Found: 339.0.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6](I)[CH:7]=1.[C:11]([O:14][CH2:15][C:16]1[C:17]([N:31]2[N:40]=[CH:39][C:38]3[C:33](=[C:34]([F:45])[CH:35]=[C:36]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:37]=3)[C:32]2=[O:46])=[N:18][CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1)(=[O:13])[CH3:12].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:11]([O:14][CH2:15][C:16]1[C:17]([N:31]2[N:40]=[CH:39][C:38]3[C:33](=[C:34]([F:45])[CH:35]=[C:36]([C:41]([CH3:43])([CH3:42])[CH3:44])[CH:37]=3)[C:32]2=[O:46])=[N:18][CH:19]=[CH:20][C:21]=1[C:6]1[CH:7]=[C:2]([Br:1])[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cn1cc(I)cc(Br)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 30 °C
Yield: 32.9 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 142b, (1.37 g, 4.38 mmol, 1.0 eq.), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridine-4-ylboronic acid 116c (2.07 mg, 5.0 mmol), Pd(dppf)Cl2 (179 mg, 0.219 mmol, 0.050 eq.), sodium acetate (718 mg, 8.76 mmol, 2.0 eq.), K3PO4 (1.86 g, 8.76 mmol, 2.0 eq.), acetonitrile (20 mL), and water (1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 30° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/ethanol to afford 142c (800 mg, 32%) as a yellow solid. MS-ESI: [M+H]+ 555.2. 1H NMR (500 MHz, DMSO-d6) δ 8.66 (d, J=5.0 Hz, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.14 (d, J=2.5 Hz, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.91 (d, J=1.5 Hz, 1H), 7.82-7.79 (m, 1H), 7.62 (d, J=6.5 Hz, 1H), 5.02 (s, 2H), 3.59 (s, 3H), 1.78 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]2[C:26]3[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[NH:7]([C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17]2[C:26]3[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:30][CH:31]=1)=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC(=O)c1cccc2c(NCc3ccc(N)cc3)ncnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc2c(NCc3ccc(NC(=O)Nc4ccccc4)cc3)ncnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
Phenyl isocyanate (240 μL, 0.5 M in anhydrous DCM, 0.11 mmol, 1.1 equiv.) was added to a solution of 4-[(4-aminobenzyl)amino]quinazoline-8-carboxamide (32 mg, 0.1 mmol, 1.0 equiv.) and triethylamine (40 μL, 0.3 mmol, 3.0 equiv.) in anhydrous DCM (2 mL). The resulting mixture was stirred at rt overnight. The title compound was obtained by pre-HPLC in 27% yield. Mass: M+H+: 413.
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[C:12]([I:13])=[C:11]([CH3:14])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].O>C(O)C>[I:13][C:12]1[C:11]([CH3:14])=[CH:10][CH:9]=[C:6]2[C:5]=1[NH:3][N:2]=[C:7]2[NH2:8]
Reactant: NN
Reactant: Cc1ccc(C#N)c(F)c1I
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(N)n[nH]c2c1I
Temperature: 100 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A solution of hydrazine monohydrate (0.56 mL, 11.6 mmol) and 2-fluoro-3-iodo-4-methylbenzonitrile (WO2006094187, 1.00 g, 3.8 mmol) in ethanol (7 mL) was stirred and heated to 100° C. in a sealed tube. After stirring overnight, the mixture was cooled and water was added. The resultant precipitate was filtered, washed with water and hexanes, and then dried in vacuo to give the title compound (0.91 g, 87%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18]CC)=[O:17])=[C:8]3[S:14][CH2:13][CH:12]([CH3:15])[N:9]32)=[CH:4][C:3]=1[F:22].C(O)C.[OH-].[K+]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([OH:18])=[O:17])=[C:8]3[S:14][CH2:13][CH:12]([CH3:15])[N:9]32)=[CH:4][C:3]=1[F:22]
Reactant: CCOC(=O)c1c2n(c3cc(Br)c(F)cc3c1=O)C(C)CS2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1CSc2c(C(=O)O)c(=O)c3cc(F)c(Br)cc3n21
Yield: 93.7 %

Procedure:
Then 600 mg (1.55 mmol) of ethyl 8-bromo-7-fluoro-1-methyl-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a)quinoline-4-carboxylate separated by column chromatography was suspended in 50 ml of ethanol containing 1.2 grams (0.02 mol) of potassium hydroxide and the mixture was heated to reflux for 1.5 hours. The content was concentrated under reduced pressure and, after water was added to the residue, insoluble matters were filtered and removed. This was acidified with acetic acid and crystals separated therefrom were collected by filtration, washed with water and dried to give 520 mg (93.7 percent) of the title compound. Recrystallized from dimethyl formamide. Melting point 290° to 291° C. (decomposition). Elementary analysis calculated as C13H9BrFNO3S: C 43.59, H 2.53, N 3.91; Found: C 43.78, H 2.55, N 3.93.