Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.[C:13]1([N:19]([CH2:23][CH2:24]O)[CH2:20][CH2:21][OH:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH2:24][CH2:23][N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21][OH:22])[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Reactant: OCCN(CCO)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C)n2nc(SCCN(CCO)c3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
Under a nitrogen atmosphere, 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol (500 mg, 2.78 mmol), N-phenyldiethanolamine (458 mg, 2.53 mmol), tetrahydrofuran (5 mL) and a magnetic stirring bar were added to a 50 mL RBF. Triphenylphosphine (861 mg, 3.28 mmol) was added followed by the slow addition of diisopropylazodicarboxylate (664 mg, 3.28 mmol) via syringe over 15 minutes. The mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by HPLC. The reaction was concentrated then ethyl acetate (40 mL) was added which caused a precipitate to form. The precipitate was removed by filtration and rinsed with ethyl acetate (4 mL). The organic layer was concentrated. The title compound was purified by silica gel column chromatography with a gradient elution of 65-100% ethyl acetate in hexanes. Fractions were combined and concentrated under reduced pressure. The resulting solid was triturated with ethyl acetate (3 mL) and dried to afford the title compound as a white solid (274 mg, 32% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.16 (m, 3H), 6.90 (d, 2H), 6.59 (t, 1H), 4.71 (t, 1H), 3.73 (m, 2H), 3.56 (q, 2H), 3.46 (t, 2H), 3.35 (m, 2H), 2.74 (s, 3H), 2.56 (s, 3H). EM (calc.): 343.1; MS (ESI) m/e: 344.2 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([I:32])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].Cl[CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39].C(N(CC)CC)C>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([I:32])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 15A (2.0 g) and (2-(chloromethoxy)ethyl)trimethylsilane (1.2 g) in dichloromethane (20 mL) was added triethylamine (1.55 g). The mixture was stirred at room temperature overnight and concentrated. The residue was purified by flash chromatography, eluting with 20% ethyl acetate in hexane, to give the title compound.
Reaction SMILES: C(OC([N:8]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([F:41])[CH:35]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][C:18]2=[O:29])[CH:11]([C:30]([OH:32])=[O:31])[CH2:10]1)=O)(C)(C)C.[ClH:42].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:42].[F:41][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][C:37]=1[CH3:40])[CH2:33][NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][C:18]2=[O:29])[CH:11]([C:30]([OH:32])=[O:31])[CH2:10]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N(Cc4ccc(C)c(F)c4)C(=O)OC(C)(C)C)CC3C(=O)O)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc(C)c(F)c4)CC3C(=O)O)c2c1
Reaction time: 0.67 h

Procedure:
To 5 mL of a methanol solution containing 80 mg of methyl 4-((tert-butoxycarbonyl) (3-fluoro-4-methybenzyl)amino)-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylate, 0.2 mL of 2 mol/L aqueous sodium hydroxide solution was added at room temperature, and stirred for 2.5 hours. Further, 0.2 mL of 2 mol/L aqueous sodium hydroxide solution and 0.5 mL of water were added, stirred at the sane temperature for 4 hour and 40 min, and allowed to stand overnight. The solvent was removed under reduced pressure, and the reaction mixture was adjusted to pH 7.0 with 2 mol/L hydrochloric acid. To the mixture, water and ethyl acetate were added, the organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 31 mg of 4-((tert-butoxycarbonyl) (3-fluoro-4-methybenzyl)amino)-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylic acid as a yellow solid. (2) To 5 mL of an ethyl acetate solution containing 31 mg of 4-((tert-butoxycarbonyl)(3-fluoro-4-methybenzyl)amino)-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylic acid, 0.1 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature, and stirred for 6 hours and 40 min, further, 0.1 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and stirred for 3.5 hours. The resulting solid was filtered to give 30 mg of 4-((3-fluoro-4-methybenzyl)amino)-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylic acid hydrochloride as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[Cl:20]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:18]([F:19])=[CH:17][C:16]([Cl:20])=[C:4]([CH:3]=1)[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(N)c2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1(Cc2cc(N)c(F)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
2.0 g (7.54 mmol) of tert-butyl 1-(3-amino-4-fluorobenzyl)cyclopropanecarboxylate were dissolved in 20.0 ml of acetonitrile, and 1.06 g (7.92 mmol) of N-chlorosuccinimide were added in several portions at RT. The reaction mixture was stirred at RT for 80 min and then at 45° C. for 8 h. After cooling, the acetonitrile was removed under reduced pressure. The residue was taken up in dichloromethane and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. By chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 30:1) 1.41 g (62.3% of theory) of the title compound were isolated from the crude product obtained in this manner.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]=[CH2:12].[CH:13]1([NH2:16])[CH2:15][CH2:14]1.O.Cl.C1(N)CC1>C1COCC1>[CH:13]1([NH:16][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]=[CH2:12])[CH2:15][CH2:14]1
Reactant: NC1CC1
Reactant: C=Cn1cnc2c(Cl)ncnc21
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C=Cn1cnc2c(NC3CC3)ncnc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6-Chloro-9-vinylpurine (0.54 g, 3 mmol) was mixed with cyclopropylamine (1.71 g, 30 mmol) in THF (10 mL) and the mixture was stirred for 5 h at rt. Water was added to dissolve the white precipitate (cyclopropylamine hydrochloride). The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then recrystallized from EtOAc/hexanes yielding the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]=[C:20]=[O:21])[CH:14]=1>N1C=CC=CC=1.CCOC(C)=O>[CH:14]1[C:13]2[C:18](=[CH:10][CH:2]=[CH:3][CH:4]=2)[CH:17]=[CH:16][C:15]=1[NH:19][C:20]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([OH:11])=[N:7]1)=[O:21]
Reactant: O=C=Nc1cccc(Br)c1
Reactant: Oc1n[nH]c2cc(Cl)ccc12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc2ccccc2c1)n1nc(O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 157 %

Procedure:
2-Amino-4-chloro-benzoic acid (17.16 g, 100 mmol) was suspended in 90 ml of water and 20 ml of concentrated HCl. NaNO2 (6.9 g, 100 mmol) was dissolved in 15 ml water and added slowly at 0° C. The mixture was stirred at 0° C. for 30 minutes and Na2SO3 (34.0 g, 270 mmol) were added, dissolved in 150 ml water. The mixture was then stirred for 2 hours at room temperature. 30 ml of concentrated HCl were added and the mixture stirred overnight at room temperature and then at 80° C. for 2 hours. The solution is treated with aqueous NaOH until the pH is 5.5 and the precipitated was filtered and triturated with ethanol to yield 13.8 g (82%) of 6-chloro-1H-indazol-3-ol. 6-Chloro-1H-indazol-3-ol (700 mg, 4.15 mmol) was dissolved in 25 ml pyridine together with 1-bromo-3-isocyanato-benzene (990 mg, 5 mmol) and stirred at RT for 4 hours. The mixture was then diluted with EtOAc (100 ml) and washed 2× with 1 M HCl. The organic phase was dried with Na2SO4 and reduced under vacuum. The residue was now dissolved in 1 M NaOH and washed with EtOAc and then precipitated with HCl and the precipitate extracted into EtOAc, dried and reduced under vacuum. The product was then recrystallised from EtOAc and heptane to yield 1.1 g (79%) of crystalline solid (m.p. 223-225° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:28][Si](C)(C)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([NH2:28])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A cooled (0° C.) solution of rac-(3,4-dichloro-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Example 4; 441 mg, 1.45 mmol) in dichloromethane (10 mL) and N,N-dimethylformamide (one drop) was treated with oxalyl chloride (2.0 M solution in dichloromethane, 1.01 mL, 2.02 mmol). The reaction was stirred at 0° C. for 1 h, then 1,1,1,3,3,3-hexamethyldisilazane (1.10 mL, 5.06 mmol) was added and the resulting cloudy mixture was stirred at 25° C. for 16 h. The reaction was quenched with methanol (10 mL), washed with an aqueous solution of 5% sulfuric acid (2×15 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine (1×10 mL), then were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) to provide rac-2-(3,4-dichloro-phenyl)-2-(tetrahydro-pyran-4-yloxy)-acetamide (278 mg, 63% yield) as a white solid, mp 81.9-83.6° C.; FAB-HRMS m/e calcd for C13H15NCl2O3 (M+H)+ 303.0428, found 303.0426.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Br:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Br:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]#N>ICC.CO>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Br:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Br:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][CH3:22]
Reactant: N#CSc1c(C#N)nn(-c2c(Br)cc(C(F)(F)F)cc2Br)c1N
Solvent: CO
Solvent: CCI
Product: CSc1c(C#N)nn(-c2c(Br)cc(C(F)(F)F)cc2Br)c1N

Procedure:
5-amino-1-[2,6-dibromo4-(trifluoromethyl)phenyl]-4-thiocyanato-1H-pyrazole-3-carbonitrile, which was used directly in step 2 with iodoethane and methanol as solvent to give the 5-amino-1-[2,6-dibromo-4-(trifluoromethyl)phenyl]-4-methylthio-1H-pyrazole-3-carbonitrile, m.p.211-214° C.
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:31]([C:34]1[CH:35]=[C:36](O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])[CH3:32]>>[C:31]([C:34]1[CH:39]=[C:38]([CH:37]=[CH:36][CH:35]=1)[O:1][CH:2]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)(=[O:33])[CH3:32]
Reactant: COc1ccc(C(O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1
Reactant: CC(=O)c1cccc(O)c1
Product: COc1ccc(C(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)Oc2cccc(C(C)=O)c2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-acetylphenol: ESMS m/e: 529.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([OH:19])=[N:9][CH:8]=1>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[C:10]([OH:19])=[N:9][CH:8]=[C:7]2[N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc2c(O)ncc(Br)c2c1
Reactant: c1cn[nH]c1
Product: COc1ccc2c(O)ncc(-n3cccn3)c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
1H-pyrazole (0.201 g, 2.95 mmol) was taken in sealed tube vessel and heated to 80° C. To the melted compound 4-bromo-6-methoxyisoquinolin-1-ol (0.25 g, 0.984 mmol) was added and heating was raised to 150° C. and stirred for overnight. The reaction mixture was cooled to RT. The resulting solid (6-methoxy-4-(1H-pyrazol-1-yl) isoquinolin-1-ol (0.25 g, 0.114 mmol) 11.59% yield) was taken to the next step without further purification. MS: MS m/z 242.10 (M++1).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:45])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:45])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCCCCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 62.9 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, undecanoyl chloride (0.45 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: EtOAc 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}undecanamide (0.53 g, 63%) as a white solid: mp 138-139° C.; 1H NMR (DMSO-d6) δ 11.12 (s, 1H), 8.42 (t, J=5.9 Hz, 1H), 7.85-7.78 (m, 2H), 7.71-7.65 (m, 1H), 5.18-5.11 (dd, J=5.4 and 12.5 Hz, 1H), 4.72 (d, J=5.9 Hz, 2H), 2.96-2.83 (m, 1H), 2.64-2.47 (m, 2H), 2.18 (t, J=7.3 Hz, 2H), 2.08-2.04 (m, 1H), 1.55-1.50 (m, 2H), 1.24 (s, 14H), 0.85 (t, J=6.1 Hz, 3H); 13C NMR (DMSO-d6) δ 172.74, 172.63, 169.80, 167.47, 166.93, 139.55, 134.65, 133.10, 131.50, 127.04, 121.79, 48.83, 37.55, 35.21, 31,28, 30.92, 28.94, 28.74, 28.67, 25.20, 22.08, 21.97, 13.94; Anal. Calcd. For C25H33N3O5: C, 65.91; H, 7.30; N, 9.23. Found: C, 66.08; H, 7.13; N, 9.23.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[OH-].[Na+]>CCO>[Br:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([OH:7])=[O:5])[N:9]=1
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nc(Br)c2ccccc2c1O
Reaction time: 2 h

Procedure:
A mixture of 1-bromo-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (8.18 g, 25 mmol; Example D-28 a) aqueous 2N NaOH (80 ml, 160 mmol) and EtOH (80 ml) was refluxed with stirring for 2 h. Then the solution was concentrated in vacuo to ½ of its volume, diluted with water (200 ml), and was acidified by addition of concentrated aqueous HCl. After stirring at ambient temperature for 1 h the resulting suspension was submitted to vacuum filtration. The filter cake was washed thoroughly with water and dried in vacuo at 75° C. to give the title compound as a white solid (6.10 g); 1H NMR (DMSO-d6): δ=8.30 to 8.37 (m, 1H), 8.16 to 8.22 (m, 1H), 7.93 to 8.03 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([CH3:29])[C@H:26]([C:30]([N:32]3[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=4)=[O:40])[CH2:34][CH2:33]3)=[O:31])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([CH3:29])[C@H:26]([C:30]([N:32]2[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][CH:48]=3)=[O:40])[CH2:34][CH2:33]2)=[O:31])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CCCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 0.83 h

Procedure:
25 ml of trifluoroacetic acid and 0.83 ml of trifluoromethanesulfonic acid were added dropwise, whilst ice-cooling, to a solution of 2.5 g of (2S,4S)-4-(4-methoxybenzylthio)-1-methyl-2-[4-(4-nitrobenzyloxycarbonyl)-1-homopiperazinylcarbonyl]-pyrrolidine [prepared as described in step (iii) above] in 5.2 ml of anisole, and the resulting mixture was stirred at the same temperature for 50 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was decanted, in turn, with hexane and with diethyl ether, to give 2.7 g of the title compound as an amorphous solid.
Reaction SMILES: ClC1C=CC([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:32])([F:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[N:12][CH:13]=2)=C(F)C=1.BrC[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=1>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:15]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][N:19]=[N:18]1)[C:14]([F:31])([F:32])[C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)=[CH:13][N:12]=1
Reactant: Fc1cccc(CBr)c1
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2ccc(Cl)cc2F)cn1
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2cccc(F)c2)cn1

Procedure:
Compound 3 was prepared in a similar manner to compound 1 from 1-(bromomethyl)-3-fluorobenzene to afford a syrup (0.02 g, 0.04 mmol, 15.5%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.25 (d, J=2.5 Hz, 1H), 7.52 (t, J=3.5 Hz, 2H), 7.40-7.26 (m, 3H), 7.17 (d, J=9.5 Hz, 1H), 7.12-7.04 (m, 2H), 6.77-7.6.75 (m, 1H), 6.66 (t, J=9.0 Hz, 1H), 5.56 (d, J=14.0 Hz, 1H), 5.12 (s, 2H), 5.06 (d, J=14.5 Hz, 1H). MS (ESI): m/z 478.2 [M++1]. HPLC: 99.49%.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[C:18](=O)[CH3:19].[CH3:21][O:22][C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1)=[O:24]>>[CH3:17][C:4]1[C:3](=[C:18]([NH:32][NH:31][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:34][CH:33]=2)[CH3:19])[C:2](=[O:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:5]=1
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Reactant: CC(=O)c1c(C)nn(-c2cccc(C(F)(F)F)c2)c1O
Product: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3cccc(C(F)(F)F)c3)N=C2C)cc1

Procedure:
From 1-(5-hydroxy-3-methyl-1-(3-trifluoromethylphenyl)-1H-pyrazol-4-yl)-ethanone and 4-methoxycarbonylbenzhydrazide, 59.9 mg of the desired product was obtained in the same manner as in Synthetic Example 4 as a yellow solid (yield 65%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([OH:31])=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([O:31][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21]
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N5CCCC5)sc34)ccc12

Procedure:
This material was prepared from the reaction of (7-chloro-thieno[3,2-b]pyridin-2-yl)-pyrrolidin-1-yl-methanone 28a with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 16e and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) □8.47 (1H, d, J=5.3 Hz), 7.82 (1H, s), 7.74 (1H, d, J=8.4 Hz), 7.14 (1H, d, J=1.7 Hz), 7.02 (1H, dd, J=1.7, 8.4 Hz), 6.55 (1H, d, J=5.3 Hz), 5.91 (1H, bs), 3.84 (2H, m), 3.70 (2H, m), 3.65 (3H, s), 3.05 (3H, d, J=4.5 Hz), 2.72 (3H, s), 2.02 (4H, m). LCMS (ESI+) [M+H]/z Calc'd 449, found 449.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[CH:5][N:4]=1.[C:10]([C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([C:20](=[O:22])[CH3:21])[CH:19]=1)[NH2:16])(=[O:12])[CH3:11].Cl.[OH-].[K+]>O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:16][C:15]2[CH:14]=[C:13]([C:10](=[O:12])[CH3:11])[CH:19]=[C:18]([C:20](=[O:22])[CH3:21])[CH:17]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(Cl)n1
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CSc1nccc(Nc2cc(C(C)=O)cc(C(C)=O)c2)n1
Reaction time: 0.17 h
Yield: 94.2 %

Procedure:
Illustrative compound 62 was synthesized by mixing 803 mg (5 mmol) 2-methylmercapto-4-chloropyrimidine and 886 mg (5 mmol) 3,5-diacetylaniline in 20 ml of water. In addition, 0.42 ml concentrated HCl was added. This reaction mixture was heated at 90°-100° C. for 4 hours, and then cooled down in an ice bath. The cooled mixture had 5 ml of 1N KOH added to neutralize the acid pH from the HCl. The mixture was stirred for 10 minutes in an ice bath to form a precipitate. The precipitate was filtered out to give 1.44 g dry pale brown crude product. A thin layer chromatography (TLC) analysis in methanol:CH2 Cl2 (1:25) showed only one spot. The crude precipitate was recrystalized from methoxyethanol and dried under vacuum to give 1.42 grams of pure 2-methylmercapto-4-(3',5'-diacetylphenyl) aminopyrimidine (compound 62) with an overall yield of 94%. The NMR analysis found the formula C15H15N3O2S with a molecular weight of 301.38.