Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:19][CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[C:15]([F:14])([F:24])[F:25])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: NCc1ccccc1C(F)(F)F
Product: Nc1cc2ncnc(NCc3ccccc3C(F)(F)F)c2cn1
Temperature: 150 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (225 mg, 1.17 mmol) and 2-(trifluoromethyl)benzylamine (0.90 mL, 6.42 mmol) is stirred under N2 at 150° C. for 1 h. The resulting product is chromatographed on silica gel (5% EtOH/EtOAc) to give 7-amino-4-(2-trifluoromethylbenzyl) aminopyrido[4,3-d]pyrimidine (0.22 g, 59%) as a white solid. 1H NMR (DMSO) δ 9.16 (1H, s), 8.88 (1H, t, J=5.7 Hz), 8.23 (1H, s), 7.75 (1H, d, J=7.7 Hz), 7.62 (1H, t, J=7.5 Hz), 7.50 (1H, d, J=7.4 Hz), 7.47 (1H, t, J=7.6 Hz), 6.51 (2H, brs), 6.39 (1H, s), 4.92 (2H, d, J=5.5 Hz).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Br)C.C(OCC)C.[F:17][C:18]1[CH:29]=[CH:28][C:21]([C:22](N(OC)C)=[O:23])=[CH:20][CH:19]=1.[NH4+].[Cl-].Cl>C1COCC1.O>[F:17][C:18]1[CH:29]=[CH:28][C:21]([C:22]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Reactant: Cn1cncc1Br
Agent: CC[Mg]Br
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Cn1cncc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.28 h

Procedure:
A clear colorless solution of 5-bromo-N-methyl-imidazole (47.7 g, 296 mmol) in THF (500 mL) was placed in an ice bath and ethylmagnesium bromide in diethyl ether (3.0 M, 98.7 mL, 296 mmol) was added via syringe fairly rapidly, over 17 min. The thick suspension was stirred at room temperature for 20 min. The mixture was again cooled in an ice water bath before addition of neat 4-fluoro-N-methoxy-N-methylbenzamide (45.2 g, 247 mmol, Intermediate 49, step a). The resulting suspension was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous NH4Cl (100 mL) followed by water (200 mL). The pH was adjusted to 7 by addition of 1 N aqueous HCl, the mixture was partially concentrated to remove THF, and was extracted with EtOAc (3×). The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was triturated with EtOAc:heptane(1:1, 150 mL) to afford the title compound as a white crystalline solid.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Br:9][C:10]1[C:11]([CH3:18])=[CH:12][C:13]([CH:16]=[O:17])=[N:14][CH:15]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(OCC)(=O)C>[Br:9][C:10]1[C:11]([CH3:18])=[CH:12][C:13]([CH:16]([OH:17])[C:2]([F:4])([F:3])[F:1])=[N:14][CH:15]=1
Reactant: Cc1cc(C=O)ncc1Br
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: Cc1cc(C(O)C(F)(F)F)ncc1Br
Temperature: 0 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
(Trifluoromethyl)trimethylsilane (2.0M solution in tetrahydrofuran, 0.75 mL) was added to a solution of 5-bromo-4-methylpicolinaldehyde (150 mg, 0.75 mmol). The mixture was cooled at 0° C. and tetra-N-butylammonium fluoride (1.0M solution in tetrahydrofuran, 2.2 mL) was added dropwise over 2 minutes. The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow solid (170 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.29 (s, 1H), 5.04 (d, J=7.2 Hz, 1H), 4.95 (p, J=6.7 Hz, 1H), 2.46 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]3[S:11][C:10]([C:12]#[N:13])=[C:9]([O:14][CH2:15][C:16]([O:18]C)=[O:17])[C:7]=3[S:8][C:4]=2[CH:3]=1.[OH-].[K+].O>C1COCC1.CO>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]3[S:11][C:10]([C:12]#[N:13])=[C:9]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:7]=3[S:8][C:4]=2[CH:3]=1
Reactant: COC(=O)COc1c(C#N)sc2c1sc1cc(Cl)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1sc2c(sc3cc(Cl)ccc32)c1OCC(=O)O
Yield: 74.1 %

Procedure:
A solution of methyl [(6-chloro-2-cyanothieno[3,2-b][1]benzothien-3-yl)oxy]acetate (100 mg, 0.3 mmol) and potassium hydroxide (39 mg, 2 eq) in THF (2 mL), MeOH, (1 mL), and water (1 mL) was stirred at room temperature for 4h. The solvents were removed by evaporation, and the resulting oil was acidified with aq. hydrochloric acid, filtered, washed with water and dried in a vacuum oven overnight to provide [(6-chloro-2-cyanothieno[3,2-b][1]benzothien-3-yl)oxy]acetic acid (72 mg). This sample was further purified by reverse phase HPLC to provide 23 mg of the product.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:20]=[CH:19][C:15]4[NH:16][CH:17]=[N:18][C:14]=4[CH:13]=3)[CH:10]=2)[NH:5][CH:4]=1)=O.C([O-])(=O)C.[NH4+].[N+:26]([CH3:29])([O-:28])=[O:27].CN(C)C=O>CS(C)=O>[N+:26]([CH:29]=[CH:1][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:20]=[CH:19][C:15]4[NH:16][CH:17]=[N:18][C:14]=4[CH:13]=3)[CH:10]=2)[NH:5][CH:4]=1)([O-:28])=[O:27]
Reactant: O=Cc1c[nH]c2ccc(-c3ccc4[nH]cnc4c3)cc12
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])C=Cc1c[nH]c2ccc(-c3ccc4[nH]cnc4c3)cc12
Temperature: 25 °C
Yield: 86 %

Procedure:
A mixture of 5-(3-formylindol-5-yl)-1H-benzimidazole (0.40 g, 1.53 mmol) and ammonium acetate (50 mg) in a solution of nitromethane (10 mL), N,N-dimethylformamide (5 mL), and dimethyl sulfoxide (1 mL) was heated at reflux under nitrogen for 4 hours. The resulting reaction mixture was cooled to room temperature and filtered to afford the title compound (0.40 g, 86%) as a yellow solid: mp >280° C.; 13C NMR (DMSO-d6) δ 146.9, 145.3, 144.3, 137.4, 136.6, 135.5, 134.2, 132.1, 129.8, 127.8, 125.0, 119.9, 118.7, 115.9, 113.4, 108.7. Anal. calcd for C16H11N5O2.0.125 H2O: C, 62.49; H, 3.69; N, 22.77. Found: C, 62.34; H, 3.51; N, 22.45.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH2:15]([OH:17])[CH3:16].[OH-].[Na+].C(O)(=O)C>C(O)(=O)CO.O>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:16]([CH2:15][OH:17])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCO
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Agent: O=C(O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCn1c(=O)c2[nH]c(CO)nc2n(CC)c1=O
Temperature: 4 °C

Procedure:
2.1 grams of 5,6-diamino-1,3-diethyluracil were stirred in 3.4 grams glycolic acid for 1 hour at 100° C. A 1:1 solution of ethanol and water (20 ml) was thereafter added to the cooled and stirred mixture, followed by the addition of 8 grams of sodium hydroxide in 30 ml water, which raised the pH to above 12. The solution was then refluxed for 2.5 hours, cooled, 30 ml acetic acid were added, and the mixture was then cooled overnight at 4° C. The resulting precipitate was collected and dried, to give 1,3-diethyl-8-hydroxymethylxanthine (1.5 gram).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[C:15]([C:21]#[N:22])=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[I:23]I.C(=O)=O.CC(C)=O>C1COCC1>[F:13][C:14]1[C:15]([C:21]#[N:22])=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[I:23]
Reactant: N#Cc1ncc(F)cc1F
Reactant: II
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CC(C)=O
Product: N#Cc1ncc(F)c(I)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.1 %

Procedure:
THF (42 mL) and diisopropylamine (5.6 ml, 39.27 mmol) were combined and cooled at 0° C. then n-butyllithium (17.3 ml, 2.5 M in hexane) was added dropwise at 0° C., and stirred for another 30 minutes. The mixture was then cooled in a dry ice/acetone bath to about −78° C. and a solution of 3,5-difluoropicolinonitrile (5 g, 35.7 mmol) in THF (25 mL) was slowly added. After 30 minutes a solution of I2 (9 g, 35.7 mmol) in THF (35 mL) was added. The reaction was stirred for another 40 minutes at −78° C. in the dry ice/acetone bath, then warmed slightly and quenched with 50 mL sodium thiosulfate solution (10% aq) followed by dilution with water and EtOAc (300 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to a residue which was purified by silica column chromatography eluting with petroleum ether-ethyl acetate (5:1) to give 3,5-difluoro-4-iodopicolinonitrile as a solid (2 g, 21% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.58 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])=[CH:5][N:6]=1.Cl[C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]2)[CH:15]=1>>[OH:29][CH2:28][CH2:27][N:24]1[CH2:23][CH2:22][N:21]([C:16]2[N:17]=[C:18]([CH3:20])[N:19]=[C:14]([NH:1][C:2]3[S:3][C:4]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])=[CH:5][N:6]=3)[CH:15]=2)[CH2:26][CH2:25]1
Reactant: Cc1nc(Cl)cc(N2CCN(CCO)CC2)n1
Reactant: CC(C)OC(=O)c1cnc(N)s1
Product: Cc1nc(Nc2ncc(C(=O)OC(C)C)s2)cc(N2CCN(CCO)CC2)n1
Yield: 65.2 %

Procedure:
Prepared from isopropyl 2-aminothiazole-5-formate and Compound 4: isopropyl 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-formate was obtained (yield: 65.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([OH:21])[N:5]([C:12]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[C:6]2=[O:11].CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.CN([CH:44]=[O:45])C>C1COCC1.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH:44]=[O:45])=[C:7]2[C:3]=1[CH:4]([OH:21])[N:5]([C:12]([CH3:13])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:20])[C:6]2=[O:11]
Reactant: CC(C)(c1ccccc1)N1C(=O)c2cccc(Cl)c2C1O
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(c1ccccc1)N1C(=O)c2c(C=O)ccc(Cl)c2C1O
Reaction time: 2 h
Yield: 91 %

Procedure:
4-Chloro-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (1.00 g, 3.31 mmol) was dissolved in THF (40 mL), and the solution was added with TMEDA (1.10 mL, 7.28 mmol), and added with sec-butyllithium-hexane solution (0.99 mol/L, 7.36 mL, 7.28 mmol) by drops at −78° C. for 5 minutes under argon atmosphere, and the mixture was stirred for 2 hours at the same temperature. Then, the mixture was added with DMF (0.384 mL, 4.97 mmol) and warmed from −78° C. to room temperature for 3.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (hexane/ethyl acetate=95/5, 60/40) and preparative thin-layer chromatography (hexane/ethyl acetate=1/1) to obtain 4-chloro-3-hydroxy-7-formyl-2-(1-methyl-1-phenylethyl)isoindolinone (993 mg, yield 91%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].Cl[CH2:13][C:14]([OH:16])=[O:15].[OH-].[K+].Cl>O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:13][C:14]([OH:16])=[O:15])=[C:3]([O:10][CH3:11])[CH:4]=1)=[O:7]
Reactant: O=C(O)CCl
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C=O)ccc1OCC(=O)O
Yield: 57 %

Procedure:
A solution of 30.4 g of 4-hydroxy-3-methoxybenzaldehyde, 31.2 g of chloroacetic acid and 34 g of potassium hydroxide in 300 ml of water was refluxed for 7 hours. After cooling, hydrochloric acid was added and the precipitate was filtered off and dried. Yield 57%.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:8][CH:7]=1)C.[OH-].[Na+].O>CO>[CH2:13]([O:12][C:9]1[CH:8]=[CH:7][C:6]([C:5](=[O:31])[C:4]([OH:32])=[O:3])=[CH:11][CH:10]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)C(=O)O)cc1
Yield: 88.5 %

Procedure:
To 2.9 g (6.45 mmol) of 4-(octadecyloxy)-alpha-oxobenzeneacetic acid ethyl ester in 200 ml of hot methanol was added 7.1 ml (7.1 mmol) of 1.0 N NaOH. The reaction mixture was stirred at reflux for 5 minutes, 50 ml of water was added and the solvents were removed at reduced pressure. Water (300 ml) was added and the product was extracted with methylene chloride-THF (4:1). The dried extract was concentrated at reduced pressure and the residual solid was recrystallized from acetone-hexane to give 2.39 g (88% yield, mp 78°-80°) of 4-(octadecyloxy)-alpha-oxobenzeneacetic acid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:16](Br)[CH3:17]>CCO>[CH2:16]([S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1)[CH3:17]
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Reactant: CCBr
Solvent: CCO
Product: CCSc1nnc(-c2ccc3[nH]cnc3c2)o1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and ethylbromide (0.112 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:12][CH2:11][CH2:10][C:9]2[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23]C(=O)OC(C)(C)C)[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[C:6]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:5][C:4]1=2>C(O)(C(F)(F)F)=O>[NH2:23][C:19]1([C:16]2[CH:15]=[CH:14][C:13]([C:7]3[C:6]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:5][C:4]4[C:3](=[N:2][OH:1])[CH2:12][CH2:11][CH2:10][C:9]=4[N:8]=3)=[CH:18][CH:17]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=NO)CCC4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=NO)CCC4)cc2)CCC1
Reaction time: 0.01 h
Yield: 46 %

Procedure:
Tert-butyl (1-(4-(5-(hydroxyimino)-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (7 mg, 0.017 mmol) was dissolved in TFA (1 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (3 mg, 35% yield). 1H NMR (500 MHz, CH3OD) 8.45 (s, 1H), 7.46 (m, 5H), 7.34 (d, 2H), 7.21 (d, 2H), 3.10 (t, 2H), 2.90 (t, 2H), 2.74-2.78 (m, 2H), 2.56-2.6 (m, 2H), 2.20-2.28 (m, 1H), 2.02-2.10 (m, 2H), 1.93-1.98 (m, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][C:20](=[O:22])[N:19]([N:23]([CH3:36])[CH:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[CH:18]([C:37](OC)=[O:38])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[NH3:41].CO>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][C:20](=[O:22])[N:19]([N:23]([CH3:36])[CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=4)[CH2:28][CH2:29]3)[CH:18]([C:37]([NH2:41])=[O:38])[CH2:17]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: COC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1N(C)C1CCN(c2ccncc2)CC1
Reactant: N
Agent: Cl
Solvent: CO
Product: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1C(N)=O

Procedure:
Methyl 4-[(6-chloro-2-naphthyl)sulfonyl)-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinecarboxylate hydrochloride (0.3 g) obtained in Example 54 and 13% ammonia/methanol solution (3.5 ml) were heated in a sealed tube at 90° C. for 2 days. The reaction system was cooled, and concentrated under reduced pressure. The residue was purified on a CHP-20 column (water→1% 1N hydrochloric acid-containing 30% aqueous solution of acetonitrile) to obtain the title compound (0.11 g) as a colorless powder.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].CS(O[CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)(=O)C.CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:26]=[C:27]([O:31][CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:42])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH:28]=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CCc1nn(Cc2cccc(OCCCNC(=O)OC(C)(C)C)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 82.5 °C
Yield: 25 %

Procedure:
To a solution of N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (50 mg, 0.121 mmol) (Prepared as in Example 17, Step A) and 3-(tert-butoxycarbonylamino)propyl methanesulfonate (107 mg, 0.422 mmol) in N,N-dimethylacetamide (2.0 mL) was added cesium carbonate (79.0 mg, 0.242 mmol). The mixture was heated at 80-85° C. for 90 minutes. The mixture was allowed to cool and diluted with ethyl acetate and methanol. The suspension was filtered and concentrated under a stream of nitrogen. The material was purified using preparative thin layer chromatography on silica, eluting with 5% methanol and 1% triethylamine in ethyl acetate to give the product (17.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.C[Si]([C:18]#[N:19])(C)C>[Zn+2].[I-].[I-].CC#N>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:18]#[N:19])=[CH:8][CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc2c(c1)OCCC2=O
Agent: [I-]
Agent: [Zn+2]
Solvent: CC#N
Product: COc1ccc2c(c1)OCC=C2C#N

Procedure:
7-Methoxy-4-chromanone (7 g) was added to trimethylsilyl cyanide (TMSCN) (7 ml), CH3CN (10 ml) and a catalytic amount of ZnI2 and refluxed for 2 hrs. The reaction was cooled, evaporated to dryness, then isopropyl alcohol saturated with HCl(g) (100 ml) was added and this solution refluxed 2 hrs. The reaction was cooled, evaporated to dryness, and saturated aqueous NaCl added. This was then extracted with CH2Cl2, the organic layer separated, dried (Na2SO4), filtered and evaporated affording 7.1 of product. IR(CHCl3): 2218 cm-1.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([C:15]1[N:20]=[N:19][C:18]([N:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[C:17]([CH3:28])[C:16]=1[CH3:29])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][NH:31]1>>[CH2:8]([C:15]1[N:20]=[N:19][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([N:31]3[CH2:32][CH2:33][C:34]4[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:30]3)[CH2:23][CH2:22]2)=[C:17]([CH3:28])[C:16]=1[CH3:29])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCC(=O)CC2)c1C
Reactant: c1ccc2c(c1)CCNC2
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(N3CCc4ccccc4C3)CC2)c1C

Procedure:
This compound as a TFA salt is prepared from compound 24 and 1,2,3,4-tetrahydro-isoquinoline following a procedure used in example 56.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])([O:6][CH2:7]C)([O:3][CH2:4]C)[CH3:2].[OH:12][CH2:13]C(CO)(CO)CO.C(O)C>CC1C=CC(S(O)(=O)=O)=CC=1.COCCOCCOC>[CH2:13]([C:11]12[CH2:4][O:3][C:1]([CH3:2])([O:6][CH2:7]1)[O:9][CH2:10]2)[OH:12]
Reactant: CCOC(C)(OCC)OCC
Reactant: OCC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCOCCOC
Solvent: CCO
Product: CC12OCC(CO)(CO1)CO2
Temperature: 170 °C
Yield: 88.8 %

Procedure:
Into a flask equipped with a stirrer, a distilling column, a nitrogen inlet, a heating jacket, and a thermometer were charged 486 g of triethyl orthoacetate, 408 g of pentaerythritol, 300 g of diethylene glycol dimethyl ether, and 0.9 g of PTSA. The mixture was gradually heated to 170° C. over a period of 5 hours. During this time 490 g of distillate were obtained. The distillate contained mostly ethanol and small amounts of diethylene glycol dimethyl ether. The temperature was lowered to 100° C., and the remaining diethylene glycol dimethyl ether was distilled off under reduced pressure (30 mbar). The residue was subjected to vacuum distillation. The fraction having a boiling temperature of 126-130° C. at a pressure of 4 mbar yielded 426 g of oil. This oil solidified to a clear solid having a melting point of 99° C. and had the following structure
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][CH3:8])=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([NH:16][C@@H:17]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:39])[F:38])[CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)=[O:15])[S:12][CH:13]=2)[N:4]([CH3:41])[N:3]=1.NN>O1CCCC1.CO>[NH2:19][CH2:18][C@@H:17]([NH:16][C:14]([C:11]1[S:12][CH:13]=[C:9]([C:5]2[N:4]([CH3:41])[N:3]=[C:2]([Cl:1])[C:6]=2[CH2:7][CH3:8])[CH:10]=1)=[O:15])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38]
Reactant: CCc1c(Cl)nn(C)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: CCc1c(Cl)nn(C)c1-c1csc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)c1
Yield: 81.2 %

Procedure:
To a solution of 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (190 mg, 0.32 mmol) in tetrahydrofuran (1.58 ml) and methanol (1.58 ml) at 25° C. was added hydrazine (0.08 ml, 2.53 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH4OH)). The free base was transferred to the HCl salt by addition of excess 4M HCl in Ether (2 ml) to the residue in DCM (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (145 mg, 0.26 mmol, 83% yield) as a yellow solid: LCMS (ES) m/z=471, 473 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.80 (br. s., 1H) 7.87-7.99 (m, 6H) 7.69 (d, J=7.71 Hz, 1H)) 7.57 (d, J=7.83 Hz, 1H) 7.40-7.44 (m, 1H) 4.43-4.48 (m, 1H) 3.74 (s, 3H) 2.99-3.06 (m, 4H) 2.40 (d, J=7.58 Hz, 2H) 1.04 (t, J=7.58 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10]([Mg]Br)[CH2:11][CH:12]=[CH2:13]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:13][CH2:12][CH:11]=[CH2:10])[CH:7]=[CH:8][CH:9]=1
Reactant: C=CCC[Mg]Br
Reactant: O=Cc1cccc(I)c1
Solvent: C1CCOC1
Product: C=CCCC(O)c1cccc(I)c1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a stirred solution of 3-iodo-benzaldehyde (3.0 g, 12.93 mmol) in dry THF (45 mL) at −78° C. under nitrogen was added 0.5 M 3-butenyl magnesium bromide in THF (25.86 mL, 12.93 mmol) over 20 min. The reaction was stirred for 0.5 h and allowed to warm to −30° C. over 1 h and then quenched with sat ammonium chloride (20 mL). The reaction was diluted with water (10 mL) and then extracted with ethyl acetate (2×50 mL). The extracts were dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (5% to 10% ethyl acetate/petroleum ether) gave the title compound as a clear oil (3.5 g, 95%) and was used directly in the next step.