Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1B(O)O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:28]4[CH:29]=[C:24]([Cl:23])[CH:25]=[CH:26][C:27]=4[Cl:30])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(Cl)ccc4Cl)c3O2)cc1
Yield: 88.9 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.43 g, 3.73 mmol) with (2,5-dichlorophenyl)boronic acid (1.07 g, 5.59 mmol) generally according to the procedure described for Intermediate 184 provided 1.49 g (88%) of (±)[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:4.
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:8][CH2:7][O:6][C:4]1=[O:5].[N:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[C:10]=[O:11].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:9][C:10]([NH:2][CH:3]2[CH2:8][CH2:7][O:6][C:4]2=[O:5])=[O:11])=[CH:14][CH:15]=1
Reactant: NC1CCOC1=O
Reactant: Cc1ccc(CN=C=O)cc1
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CNC(=O)NC2CCOC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 142.6 %

Procedure:
A 0° C. slurry of α-amino-γ-butyrolactone hydrobromide (25 g, 0.137 mol) in THF (200 mL) was combined with 1-isocyanatomethyl-4-methyl-benzene (20.6 g, 0.139 mol) and then treated dropwise with N,N-diisopropylethylamine (19.5 g, 0.151 mol). The reaction mixture was stirred for at room temperature for 2 h. The solvent was removed in vacuo to give 48.5 g crude 1-(4-methyl-benzyl)-3-(2-oxo-tetrahydro-furan-3-yl)-urea that was utilized directly in the next reaction without purification. MS (ES30 ) Calc'd for C13H17N2O3 (M+1) 249. Found m/z 249 (100%). 1H NMR.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][N:3]=1.S(C1C=CC(C)=CC=1)(O[CH3:14])(=O)=O>>[CH3:14][N:3]1[CH2:4][CH2:5][CH2:6][C:7]([CH3:9])([CH3:8])[C:2]1=[CH2:1]
Reactant: CC1=NCCCC1(C)C
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: C=C1N(C)CCCC1(C)C

Procedure:
A mixture of 5 g of 2,3,3-trimethyl-3,4,5,6tetrahydropyridine and 12 g of methyl tosylate was reacted at 100° C. for 4 hours. The reaction mixture was cooled and extracted with water/chloroform. Then, 2 g of sodium hydroxide was added to the water layer and the mixture was stirred. The liquid was extracted with chloroform. The chloroform layer was concentrated to obtain a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]#[CH:13])[C:6]=2[CH:14]=1.[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]1=2.C(O)(=O)C>O>[CH2:11]([N:7]1[C:6]2[CH:14]=[C:2]([N:1]3[C:18](=[O:19])[C:17]4[CH2:21][CH2:22][CH2:23][CH2:24][C:16]=4[C:15]3=[O:20])[CH:3]=[CH:4][C:5]=2[O:9][C:8]1=[O:10])[C:12]#[CH:13]
Reactant: C#CCn1c(=O)oc2ccc(N)cc21
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Product: C#CCn1c(=O)oc2ccc(N3C(=O)C4=C(CCCC4)C3=O)cc21
Yield: 35 %

Procedure:
A mixture of 5-amino-3-(2-propynyl)-3H-benzoxazol-2-one (0.50 g), 3,4,5,6-tetrahydrophthalic anhydride (0.53 g) and acetic acid (5 ml) was heated at 100° to 110° C. under reflux for 3 hours. After being allowed to cool, water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, neuralized with sodium bicarbonate solution, dried and concentrated to give 2-[3-(2-propynyl)-3H-benzoxazol-2-on-5-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.30 g). m.p., 285.5° C.
Reaction SMILES: [CH:1]([N:3]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12]Br)[CH:5]=[CH:4]1)=[O:2].[N-:14]=[N+:15]=[N-:16].[Li+]>CO>[CH:1]([N:3]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][N:14]=[N+:15]=[N-:16])[CH:5]=[CH:4]1)=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: O=CN1C=CC=C(OCCBr)C=C1
Agent: [Li+]
Solvent: CO
Product: [N-]=[N+]=NCCOC1=CC=CN(C=O)C=C1

Procedure:
To a solution of (E) (2.7 g) in methanol (15 ml), lithium azide (1.65 g) was added. The solution was refluxed for 6 hours and left over night at room temperature. The solvent was removed in vacuo, and the residue was extracted with three 15 ml portions of chloroform to give crude (F) which was purified by chromatography on silica gel with ethyl acetate as eluent. Pure (F) was obtained as a colourless oil. The IR spectrum (chloroform) showed strong bands at 2100 and 1650 cm-1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[CH3:16])=[CH:13]/[CH2:14][OH:15])=[CH:8][CH:7]=1.[CH2:17]([O:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:18]>>[CH2:17]([O:19][C@@H:20]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:15][CH2:14]/[CH:13]=[C:12](/[C:9]2[CH:10]=[CH:11][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][CH:8]=2)\[CH3:16])=[CH:31][CH:32]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:18]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2ccco2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccco3)cc2)cc1)OCC
Yield: 78 %

Procedure:
The title compound (678 mg, 77%) was prepared from (E)-3-(4-furan-2-yl-phenyl)-but-2-en-1-ol (430 mg, 2.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (526 mg, 2.21 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: FC(F)(F)S([O:6][C:7]1[CH:20]=[CH:19][C:10]2[C@H:11]([CH2:14][C:15]([O:17]C)=[O:16])[CH2:12][O:13][C:9]=2[CH:8]=1)(=O)=O.[CH3:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:27]=[C:26]([CH3:38])[C:25]=1[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45]O)[CH:40]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C>[CH3:38][C:26]1[CH:27]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:35])=[O:36])[CH:29]=[C:24]([CH3:23])[C:25]=1[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][O:6][C:7]2[CH:20]=[CH:19][C:10]3[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][O:13][C:9]=3[CH:8]=2)[CH:40]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(CC(=O)O)coc3c2)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
To a solution of methyl(S)-2-(6-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate (4.88 g) and (2′,6′-dimethyl-4′-(3-(methylsulfonyl)propoxy)-[1,1′-biphenyl]-3-yl)methanol (5.00 g) in acetonitrile (15 mL) was added tripotassium phosphate (4.57 g), and the mixture was stirred at 70° C. for 3 hr. The mixture was allowed to cool to room temperature and concentrated, toluene (60 mL) and water (60 mL) were added, and an extraction operation was performed. The organic layer was washed with water (60 mL) and 10% brine (60 mL), and concentrated. The obtained oil was dissolved in dimethyl sulfoxide (30 mL), and 2N sodium hydroxide (8 mL) was added at room temperature. The mixture was stirred at 70° C. for 1 hr, and allowed to cool to room temperature. Ethyl acetate (60 mL) and water (60 mL) were added, and the mixture was partitioned. The aqueous layer was acidified with 6N hydrochloric acid to pH 1, ethyl acetate (60 mL) was added, and an extraction operation was performed. The organic layer was washed with water (60 mL), and concentrated. The crude product was recrystallized from acetone (30 mL)-water (60 mL), and the obtained solid was dried at 60° C. under reduced pressure to give the title compound (4.82 g) as white crystals. Yield 64%.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:21][F:22])([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:4]#[C:5][C:6]([O:8][CH3:9])=[O:7]>ClC1C=CC=CC=1Cl>[F:22][CH2:21][C:3]1([CH2:2][F:1])[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:12]2[CH:13]=[C:14]([C:17]([F:18])([F:19])[F:20])[CH:15]=[CH:16][C:11]=2[O:10]1
Reactant: COC(=O)C#CC(CF)(CF)Oc1ccc(C(F)(F)F)cc1
Solvent: Clc1ccccc1Cl
Product: COC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Yield: 89.3 %

Procedure:
An amount (0.28 g) of methyl 5-fluoro-4-fluoromethyl-4-(4-trifluoromethylphenoxy)-2-pentynoate was added dropwise to o-dichlorobenzene (1.0 ml) during refluxing under a nitrogen atmosphere. After the end of the dropwise addition, the reaction mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluent; 10% tetrahydrofuran/hexane) to give the titled compound (0.25 g).
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][NH:5][C:6](=[O:42])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31](C(OC(C)(C)C)=O)[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([C:11]4[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=4)[O:8][CH2:7][C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:43])=[O:42])[N:24]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: CN(C)CCNC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCNC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-(2-(2-(dimethylamino)ethylamino)-2-oxoethoxy)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.18 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-(dimethylamino)ethyl)acetamide. (19 mg, 0.039 mmol, 22%).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][O:10][CH2:11][CH2:12][N:13]2[C:21]3[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=[C:17](OC4C=CC=CC=4)[C:16]=3[N:15]=[C:14]2[CH3:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+:36].Cl>>[CH3:31][C:14]1[N:13]([CH2:12][CH2:11][O:10][CH2:9][C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:21]2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=[C:17]([NH2:36])[C:16]=2[N:15]=1
Reactant: [NH4+]
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOCC#Cc3ccccc3)c2c1C
Agent: CC(=O)[O-]
Agent: Cl
Product: Cc1nc(N)c2nc(C)n(CCOCC#Cc3ccccc3)c2c1C
Temperature: 150 °C
Yield: 41.2 %

Procedure:
1-[2,6,7-Trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]eth-2-yl (3-phenylprop-2-ynyl) ether (5.4 g, 13.122 mmol) from Part H and ammonium acetate (54 g) were combined in a glass pressure vessel. The vessel was sealed with a teflon screw cap, and the reaction mixture was heated to 150° C. for 45 hours. The reaction was essentially complete, and the resulting reaction solution was cooled with an ice bath, acidified to a pH of 1 with 10% hydrochloric acid, and washed with dichloromethane (3×500 mL). The combined organic portions were washed with 10% hydrochloric acid (4×). The acidic aqueous portions were combined, basified with potassium hydroxide pellets to a pH of 14. The resulting brown solids were filtered off and recrystallized from methanol. A first crop of 0.6 g was collected for use in Example 5, and a second crop was collected and found to contain about 2% of the 4-hydroxy compound by NMR analysis. The second crop was returned to the mother liquor, and dichloromethane was added until all solids were dissolved. 1M Hydrochloric acid in diethyl ether (20 mL) was added to the resulting solution, and the solids that formed were filtered off, and dissolved in water, which was basified to a pH of 14 with potassium hydroxide pellets. The resulting solution was washed with dichloromethane (3×). The organic portions were combined, washed with water (2×) and brine (2×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting white solid (1.8 g) was dissolved in dichloromethane (150 mL), and 1M hydrochloric acid in diethyl ether (5.3 mL) was added to the resulting solution. The acidified solution was concentrated under reduced pressure. The resulting solids were dissolved in water, and this aqueous solution was filtered to remove an oily sludge. The filtrate was basified with a few drops of 20% potassium hydroxide and then 1N potassium hydroxide to a pH of 13. The fine white precipitate that formed was filtered off, rinsed with diethyl ether, and dried under vacuum for 18 hours to provide 1.8064 g of 2,6,7-trimethyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 186.8–187.5° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]1[C:28]2([CH2:33][CH2:32][CH:31](O)[CH2:30][CH2:29]2)[O:27][CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:24]1[C:28]2([CH2:33][CH2:32][CH:31]([N:16]3[C:17]4=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]4[C:14]([C:11]4[CH:12]=[CH:13][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:9][CH:10]=4)=[N:15]3)[CH2:30][CH2:29]2)[O:27][CH2:26][CH2:25]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 15) (3.36 g, 11.1 mmol, 1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M) (5.26 g, 33.3 mmol), Triphenylphosphine (5.81 g, 22.2 mmol) were suspended in 130 ml of tetrahydrofuran. The reaction mixture was cooled in an ice-water bath and diethyl azodicarboxylate (3.9 ml, 22.2 mmol) was added dropwise. 10 minutes later, the reaction mixture was allowed to warm up to room temperature. After stirring for 2 hours, solvent was removed and the residue was taking into ethyl acetate. The organic layer was washed, dried and evaporated. The crude product was purified via Biotage flash column chromatography using dichloromethane/ethyl acetate (from 50:50 to 10:90) as the mobile phase to yield 3.829 g of 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (CDCl3) 1.83 (m, 2H), 1.945 (m, 2H), 2.05 (m, 2H), 2.45 (m, 2H), 3.99 (s, 4H), 4.86 (m, 1H), 5.74 (bs, 2H), 7.09 (m, 2H), 7.15 (m, 3H), 7.39 (m, 2H), 7.66 (d, J=8.70 Hz, 2H), 8.37 (s, 1H); LC/MS (MH+32 444).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1.[C-:14]#[N:15].[Na+]>CN(C)C=O>[C:14]([CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)#[N:15]
Reactant: ClCCCc1n[nH]c2ccccc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCCc1n[nH]c2ccccc12
Temperature: 90 °C
Yield: 449.8 %

Procedure:
A solution of (3-chloropropyl)indazole (Sasakura et al, Synth. Comm., 18, pg 259 (1988)) (750 mg, 3.75 mM) in dimethylformamide (25 ml) was stirred at room temperature and sodium cyanide (370 mg, 7.5 mM) added in one portion. The resulting mixture was heated at 90° C. for 4 hr. The dimethylformamide was removed in vacuo and the residue partitioned between water and ethyl acetate. The combined organics were dried over magnesium sulfate. Column chromatography (ethyl acetate/cyclohexane, 1:1) provided 3-(3-cyanopropyl)indazole as a clear oil (3.21 g, 83%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([NH2:11])=[N:3]1.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:1][N:2]1[C:6]([C:7]([F:8])([F:9])[F:10])=[CH:5][C:4]([NH:11][C:13](=[O:14])[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:3]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cn1nc(N)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Yield: 70.9 %

Procedure:
Using the procedure described in Example 161C, 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (0.38 g, 2.3 mmol) and phenyl chloroformate (0.438 g, 2.8 mmol) were reacted in the presence of K2CO3 (0.415 g, 3 mmol) in THF (10 mL), to afford phenyl 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate as solid (0.465 g, 71%). 1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.17-7.45 (m, 5H), 6.93 (s, 1H), 3.91 (s, 3H); LC-MS (ESI) m/z 286 (M+H)+.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Cl.[CH3:24][C:25]([NH:28][C:29]1[O:30][C:31]([C:38]([OH:40])=[O:39])=[C:32]([C:34]([F:37])([F:36])[F:35])[N:33]=1)([CH3:27])[CH3:26]>O>[CH3:27][C:25]([NH:28][C:29]1[O:30][C:31]([C:38]([O:40][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([C:13]([F:23])([F:22])[F:12])[CH:15]=2)=[O:39])=[C:32]([C:34]([F:35])([F:37])[F:36])[N:33]=1)([CH3:24])[CH3:26]
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)OCc2cccc(C(F)(F)F)c2)o1
Temperature: 25 °C
Yield: 161.3 %

Procedure:
A reaction vessel was charged with 50 ml of dimethylformamide, 2.6 g (18.8 mmol) of potassium carbonate, and 5.36 g (28 mmol) of m-trifluoromethyl benzyl chloride. With this mixture stirred at ambient temperature under a nitrogen atmosphere, there was added 4.03 g (17 mmol) of 2-[(1,1-dimethylethyl)amino]-4-trifluoromethyl-5-oxazolecarboxylic acid (prepared by Example 26). The reaction mixture was stirred at ambient temperature for 36 hours. Then, the mixture was added to water and extracted four times with ethyl ether. The ether extracts were washed with large amounts of water, then dried over magnesium sulfate, and concentrated under reduced pressure to yield 11.25 g of a yellow oily solid material. This solid material was dissolved in ethyl ether, washed with large amounts of water, dried over magnesium sulfate, and concentrated under reduced pressure to yield 10.8 g of a gold viscous oil. Then, 5.0 g of this oil was subjected to Kugelrohr distillation (83°-85° C. @ 0.5 mm Hg) to yield 1.38 g of a gold viscous oil which upon standing overnight formed an oily solid product identified in Table I.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH3:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[C:27](=[O:31])[N:26]([CH2:32][C:33]([OH:35])=O)[CH2:25]3)[N:18]=1.ON1C2C=CC=CC=2N=N1.[CH2:46]([O:48][C:49](=[O:57])[CH2:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:47]>CN(C=O)C>[CH2:46]([O:48][C:49](=[O:57])[CH2:50][N:51]1[CH2:56][CH2:55][N:54]([C:33](=[O:35])[CH2:32][N:26]2[CH2:25][C:24]3[C:28](=[CH:29][CH:30]=[C:22]([C:19]4[N:18]=[C:17]([CH3:16])[O:21][N:20]=4)[CH:23]=3)[C:27]2=[O:31])[CH2:53][CH2:52]1)[CH3:47]
Reactant: Cc1nc(-c2ccc3c(c2)CN(CC(=O)O)C3=O)no1
Reactant: CCOC(=O)CN1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(C(=O)CN2Cc3cc(-c4noc(C)n4)ccc3C2=O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
DCC (0.433 g; 2.1 mmol) was added with vigorous stirring to a solution of the compound of example 66d (0.53 g; 1.9 mmol) and 1-hydroxybenzotriazole (0.338 g; 2.47 mmol) in dry DMF (15 ml) at 0° C. After 10 min. piperazin-1-yl-acetic acid ethyl ester (0.43 g; 2.47 mmol) was added to the mixture It was stirred at 0° C. for 1 h and then kept in the freezer over night. The DCU was filtered off and the filtrate was washed with 1N aqueous NaHCO3, water, 1N aqueous HCl, brine, dried (Na2SO4), concentrated and purified using flash chromatography (silica gel, 5% MeOH in chloroform) to obtain the title compound. Yield, 0.64 g (77%); mp, 189-90° C.; MS (ESI+): 450 (M++Na), analysis: C21H25N5O5 requires C, 59.01; H, 5.90; N, 16.38; found: C, 58.80; H, 5.93; N, 15.80%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.Br[CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:20]([O:19][C:18]([NH:17][CH2:16][C:6]1[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:8][C:9]2[C:4]([C:5]=1[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1)=[CH:3][C:2]([O:1][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:11][CH:10]=2)=[O:24])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)CCCCBr
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(O)cc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
A mixture of tert-butyl {[6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.7 g, 6.3 mmol), ethyl 5-bromopentanoate (1.4 g, 7.0 mmol), potassium carbonate (0.97 g, 7.0 mmol) and N,N-dimethylformamide (30 ml) was stirred at 50° C. for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 5-{[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}pentanoate (2.2 g, yield 67%) as crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:29][O:30][CH2:31][CH2:32]Br>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:32][CH2:31][O:30][CH3:29])=[CH:20][CH:21]=1)[CH3:2]
Reactant: COCCBr
Reactant: CCn1c(-c2ccc(O)cc2)c(C#N)c2ccc(OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2ccc(OCCOC)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
1-Ethyl-2-(4-hydroxy-phenyl)-6-methoxy-1H-indole-3-carbonitrile (40 mg, 0.14 mmol), prepared as in example 1Ga step B, is combined with K2CO3 (77 mg, 0.56 mmol), bromoethyl methyl ether (26 μL, 0.28 mmol), and DMF (450 μL). This is stirred at room temperature for 1 hour, and then at 75° C. for 3 hours. The reaction mixture is then partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2, 0-5% EtOAc) yields 1-ethyl-6-methoxy-2-[4-(2-methoxyethoxy)-phenyl]-1H-indole-3-carbonitrile (44 mg, 90%) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][N: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)#[N:4].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[C:3]([C:5]([N: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)=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)#[N:4]
Reactant: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Reactant: O=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(C#N)=Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
To sodium hydride (0.1 g) taken in dry DMF (5 ml), under nitrogen, compound tert-butyl 4-(cyanomethyl)piperazine-1-carboxylate (0.5 g) was added and allowed to stir at room temperature for half an hour. Benzaldehyde (280 mg) was added to the above reaction mixture and allowed to stir for 3 hours at room temperature. The reaction mixture was quenched with ice water (50 ml) and extracted with ethyl acetate (3×10 ml). The combined organic layer was washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using MeOH: CH2Cl2 (0.5:9.5) as an eluent to afford tert-butyl 4-(1-cyano-2-phenylvinyl)piperazine-1-carboxylate as pure product.