Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[CH3:26][S:27]([OH:30])(=[O:29])=[O:28]>CCO>[S:27]([OH:30])(=[O:29])(=[O:28])[CH3:26].[NH:12]([C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ncnc2cccnc12
Reactant: Nc1ccccc1
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1ccc(Nc2ncnc3cccnc23)cc1
Reaction time: 2 h
Yield: 57.2 %

Procedure:
A solution of 4-chloropyrido[3,2-d]pyrimidine (84 mg, 0.5 mmol), aniline (56 mg, 0.6 mmol) and triethylamine (62 mg, 0.6 mmol) in EtOH (2 mL) are refluxed under N with stirring for 2 h. The crude reaction mixture is purified on a preparative tic plate (silica), eluting once with 3% MeOH in CHCl3. The major band is extracted, and evaporated to dryness under reduced pressure, and the residual solid is dissolved in acetone, (5 mL), filtered, and methanesulfonic acid (32 μL, 0.5 mmol) is added slowly with swirling. The precipitate is collected by suction filtration, rinsed with acetone and dried in a vacuum oven to give 4-anilinopyrido[3,2-d]pyrimidine mesylate (91 mg, 57%) as dull yellow needles. 1H NMR (DMSO) δ 11.75 (1H, slbrs), 9.11 (1H, dd, J=1.5, 4.3 Hz), 8.97 (1H, s), 8.32 (1H, dd, J=1.5, 8.4 Hz), 8.12 (1H, dd, J=4.3, 8.5 Hz), 7.88 (2H, d, J=8.2 Hz), 7.49 (2H, t, J=8.0 Hz), 7.32 (1H, t, J=7.0 Hz), 2.34 (3H, s)
Reaction SMILES: [C:1]1([OH:13])[CH:12]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:3]([OH:4])[CH:2]=1.C(N)(C)(C)C.[CH3:19][C:20](=[CH:22][CH2:23][CH2:24][C:25](=[CH:27][CH:28]=O)[CH3:26])[CH3:21]>C1(C)C=CC=CC=1>[CH3:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1[CH:5]=[C:3]([OH:4])[C:2]2[CH:28]=[CH:27][C:25]([CH2:24][CH2:23][CH:22]=[C:20]([CH3:21])[CH3:19])([CH3:26])[O:13][C:1]=2[CH:12]=1
Reactant: CCCCCc1cc(O)cc(O)c1
Reactant: CC(C)=CCCC(C)=CC=O
Solvent: CC(C)(C)N
Solvent: Cc1ccccc1
Product: CCCCCc1cc(O)c2c(c1)OC(C)(CCC=C(C)C)C=C2
Temperature: 25 °C

Procedure:
To a three-necked round bottomed flask (100 ml capacity), fitted with a dropping funnel and a condenser was added 5 g. olivetol (27.8 mmole) and 2.03 g. (2.96 ml., 27.8 mmole) t-butyl amine in 55 ml toluene and the mixture was heated to 50°-60° C., 4.23 g. (4.76 ml., 27.8 mmole) of citral was then added dropwise. The mixture was refluxed for 9 hours, after which time it was cooled to room temperature and the solvent evaporated to give 9.3 g. of crude reaction mixture. Gas chromatographic analysis of the reaction mixture showed 59.46% CBC (molar conversion), 5.04% cannabicitran and trace amount of iso-CBC.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:6]12[O:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]2>O>[N:1]1([C@@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCC2OC2C1
Reactant: C1CCNC1
Solvent: O
Product: O[C@@H]1CCCC[C@H]1N1CCCC1
Temperature: 90 °C
Yield: 98 %

Procedure:
Pyrrolidine (4.26 g, 60 mmol) was added to a solution of cyclohexene oxide (1.96 g, 20 mmol) in H2O (6 mL), and the resulting mixture was heated at 90° C. for 16 hours. After cooling, the solvent was removed under reduced pressure and the resulting residue was extracted with DCM (10 mL×3). The organic phasew were combined and dried with anhydrous Na2SO4. After removing the Na2SO4 by filtration, the solvent was evaporated and the material dried under vacuum to afford the desired compound (+/−)-1 (3.3 g, 19.5 mmol, yield 98%). 1H NMR (CDCl3) δ 4.06 (s, 1H), 3.45-3.30 (m, 1H), 2.75-2.63 (m, 2H), 2.62-2.50 (m, 2H), 2.51-2.42 (m, 1H), 1.90-1.58 (m, 8H), 1.45-1.15 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C@H:11]([C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl.O1CCOCC1>[CH2:1]([O:8][C@@H:9]1[CH2:13][NH:12][C@H:11]([C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](OCc2ccccc2)CN1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of the title compound of example 1 (250 mg, 0.664 mmol) in 6N HCl/dioxane was stirred at room temperature for 20 min and then concentrated to dryness under reduced pressure. The residue was diluted with EtOAc (10 mL) and 2 N aqueous NaOH (3 mL). The mixture was stirred at room temperature for 15 min. The organic layer was separated, washed with a minimum amount of H2O and brine, dried (MgSO4) and concentrated to dryness under reduced pressure. The residue was dried under high vacuum to give 4(S)-benzyloxy-N-tert-butylpyrrolidine-2(S)-carboxamide, the carboxamide of formula 3 wherein R1 is C(CH3)3 and Y is OCH2Ph {C(O)NHR1 /Y=cis}.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[N:17]([O-])=O.[Na+].[Sn](Cl)Cl>Cl>[Br:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:17][NH:1]2)=[CH:4][CH:5]=1
Reactant: Nc1cc(Br)ccc1C(=O)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: Brc1ccc2c(-c3ccccc3)n[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
To a stirred mixture of (2-amino-4-bromophenyl)(phenyl)methanone (1.0 g, 3.6 mmol) in hydrochloric acid (6N aqueous solution, 5 mL) was added sodium nitrite (0.5 g, 7.2 mmol) over 3 min at 0° C. The mixture was stirred at 0° C. for 30 min before a solution of tin(II) chloride (2.7 g, 14.4 mmol in 5 mL concentrated hydrochloric acid) was added at 0° C. over 5 min. After stirring at 0° C. for 10 min and rt for 1 hr, the reaction mixture was filtered. The solid was washed with water (10 mL), 4N aqueous sodium hydroxide solution, and water (10 mL). The solid was dissolved in dichloromethane (20 mL), washed with brine (10 mL), dried (Na2SO4), and concentrated. Silica gel flash chromatography gave 6-bromo-3-phenyl-1H-indazole (0.42 g, 1.5 mmol, 42% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=2)[CH:5]=[C:4]([Cl:16])[N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([NH2:26])[CH3:25])=[CH:20][CH:19]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:16][C:4]1[N:3]=[C:2]([NH:26][C@H:24]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[CH3:25])[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=2)[CH:5]=1
Reactant: CC(C)n1cc(-c2cc(Cl)nc(Cl)c2)cn1
Reactant: C[C@H](N)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)n1cc(-c2cc(Cl)nc(N[C@@H](C)c3ccc(F)cc3)c2)cn1
Temperature: 85 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
145 mg of 2,6-dichloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyridine obtained by Step 2, 87 mg of (S)-(−)-1-(4-fluorophenyl)ethylamine, 34 mg of 2-(di-t-butylphosphino)biphenyl, 109 mg of sodium t-butoxide and 13 mg of palladium acetate were added in turn to 6 ml of degassed toluene, and then the mixture was stirred at 85° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 59 mg of the objective compound as pale yellow powder.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=4[F:22])[C:13](O)=[CH:12][C:11]3=[O:24])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=4[F:22])[C:13]([NH:31][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:12][C:11]3=[O:24])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1C=C(O)C(c2cccc(F)c2F)N1c1ccc2[nH]cnc2c1
Reactant: NC1CCCCC1
Product: O=C1C=C(NC2CCCCC2)C(c2cccc(F)c2F)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-5-(2,3-difluorophenyl)-4-hydroxy-1H-pyrrol-2(5H)-one (0.12 g, 0.33 mmol) and cyclohexylamine (0.53 ml 4.62 mmol) according to method 7 described above.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:12]CCNC)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(C(C)C)C(C)C.[NH:37]1[CH:41]=[CH:40][N:39]=[C:38]1[NH:42][C:43]([N:45]1[CH:49]=[CH:48]N=[CH:46]1)=[O:44]>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:12][CH2:48][CH2:49][N:45]([CH3:46])[C:43]([NH:42][C:38]2[NH:37][CH:41]=[CH:40][N:39]=2)=[O:44])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CNCCCCN(Cc1ncc(C)cc1C)Cc1nccc2ccccc12
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(CN(CCCCN(C)C(=O)Nc2ncc[nH]2)Cc2nccc3ccccc23)c(C)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To a warm (70° C.), stirred, solution of N-(3,5-Dimethyl-pyridin-2-ylmethyl)-N-isoquinolin-1-ylmethyl-N′-methyl-butane-1,4-diamine (0.204 g, 0.56 mmol) and DIPEA (0.59 mL, 3.39 mmol) in DMF (5 mL) was added freshly prepared imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (2 equivs). After 1.5 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (50 mL) and washed with water (5×10 mL). The organic phase was dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 234 mg (86%) of COMPOUND 156 as a white solid. 1H NMR (CDCl3) δ 1.26-1.34 (m, 2H), 1.42-1.48 (m, 2H), 2.09 (s, 3H), 2.28 (s, 3H), 2.58 (t, 2H, J=7.5 Hz), 2.74 (s, 3H), 3.10 (t, 2H, J=7.5 Hz), 3.80 (s, 2H), 4.17 (s, 2H), 6.68 (s, 2H), 7.24-7.26 (m, 1H), 7.35-7.40 (m, 1H), 7.52-7.60 (m, 2H), 7.73 (d, 1H, J=8.1 Hz), 7.97 (d, 1H, J=8.7 Hz), 8.22 (s, 1H), 8.41 (d, 1H, J=5.7 Hz); 13C NMR (CDCl3) δ 18.33, 18.40, 23.93, 25.82, 34.90, 48.89, 54.57, 59.86, 59.96, 120.82, 126.71, 126.92, 127.20, 128.12, 130.13, 132.27, 133.15, 136.62, 139.08, 141.76, 145.16, 146.87, 154.33, 156.14, 159.39; ES-MS m/z 472 (M+1). Anal. Calcd. For C27H33N7O.0.5H2O: C, 67.48; H, 7.13; N, 20.40. Found: C, 67.57; H, 7.08; N, 20.52.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].Cl[CH:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13].C[O-].[Na+].[Na]>CO>[CH3:9][O:8][C:1]1[CH:7]=[CH:6][CH:5]=[CH:4][C:2]=1[O:3][CH:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COc1ccccc1O
Reactant: COC(=O)C(Cl)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Temperature: 45 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
25 g of guaiacol and 37 g of dimethyl chloromalonate were added dropwise in succession to a sodium methylate solution from 150 ml of methanol and 4.6 g of sodium. The suspension was stirred at 45° C. for 1 hour with the exclusion of moisture, thereafter the methanol was distilled off. The residue was taken up in 200 ml of toluene and washed with water, 1% sodium hydroxide solution and water until the organic phase was colorless. After drying and evaporating the solvent, the residue was distilled. There were obtained 39.5 g of dimethyl (o-methoxyphenoxy)malonate. B.p. 128° C./7 Pa.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[N+:13]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)(=O)C.[Fe]>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[NH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnccc1C1=CCCCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cnccc1C1=CCCCC1
Yield: 99 %

Procedure:
A heterogeneous solution of 4-cyclohexenyl-3-nitropyridine (1.0 eq.) and iron (6.0 eq) in acetic acid, at a concentration of 0.4 M, was stirred vigorously for 2 hours. The mixture was then passed through a celite pad, eluting with MeOH. Upon removal of the volatiles in vacuo, the residue was dissolved in EtOAc, washed with Na2CO3(sat.), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding 4-cyclohexenylpyridin-3-amine (99%) as an oil. LCMS (m/z): 175.0 (MH+); LC Rt=1.86 min.
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH2:20][CH3:21])[C:6]1=[O:22])=[O:4].[NH2:23][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:28]>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH2:20][CH3:21])[C:6]3=[O:22])=[O:4])[CH:39]=[CH:38][CH:37]=2)=[O:28])=[CH:31][CH:32]=1
Reactant: Nc1cccc(C(=O)Nc2ccc(Cl)cc2)c1
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C3(C)OCCO3)ccc21
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)Nc3ccc(Cl)cc3)c2)c2cc(C(C)=O)ccc21

Procedure:
Prepared as in Example 1 from 1-ethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-(4-chloro-phenyl)-benzamide. Recrystallized from ethyl acetate-hexanes. mp 119-121° C.
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:5]=[C:6](Cl)[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1.II.[O:15]1[CH2:19][CH2:18][CH:17]([CH:20]=[O:21])[CH2:16]1>O1CCCC1>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:20]([CH:17]2[CH2:18][CH2:19][O:15][CH2:16]2)[OH:21])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COc1cc(Cl)cc(OC)c1
Reactant: O=CC1CCOC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(O)C2CCOC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Magnesium turnings (8.5 g, 0.35 mol) are activated by stirring at room temperature overnight under argon and suspended in anhydrous tetrahydrofuran (60 ml). 10 ml of a solution of 3,5-dimethoxychlorobenzene (60.4 g, 0.35 mol) in anhydrous tetrahydrofuran (75 mL) is added, followed by a crystal of iodine, and the mixture is placed in an ultrasonic bath for 10 minutes. A further 10 mL of the solution of 3,5-dimethoxychlorobenzene in tetrahydrofuran is added and reaction is heated at 80° C. for 1 h. The remainder of the starting material is added dropwise to the reaction mixture at 80° C. over 50 minutes, then heating is continued at 80° C. for a further 30 minutes. The reaction mixture is cooled to below room temperature in an ice/water bath and a solution of tetrahydrofuran-3-carbaldehyde (35 g, 0.35 mol) in anhydrous tetrahydrofuran (35 mL) is added dropwise over 30 minutes. Once the addition is complete, the reaction mixture is stirred at room temperature overnight. The reaction mixture is decanted and 2M aqueous hydrochloric acid is carefully added to the decanted solution, until the pH of the reaction mixture reaches pH 1. The reaction mixture is extracted with ethyl acetate (4×100 mL) and the organic extracts are combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue is purified by column chromatography on silica gel to give (3,5-dimethoxyphenyl)(tetrahydrofuran-3-yl)methanol as a yellow oil.
Reaction SMILES: C1([Se]Cl)C=CC=CC=1.N1C=CC=CC=1.[CH3:15][CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:18](=[O:27])[CH2:17]1>ClCCl>[CH3:15][CH:16]1[CH2:17][C:18](=[O:27])[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH2:21]1
Reactant: CCOC(=O)C1CCC(C)CC1=O
Agent: Cl[Se]c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=CCC(C)CC1=O
Temperature: 0 °C
Yield: 105.2 %

Procedure:
A suspension of phenylselenium chloride (27.29 g) in dichloromethane (250 mL) was stirred at 0° C. and treated dropwise with pyridine (11.81 g). The resulting mixture was stirred for 30 min, and then treated with a solution of racemic ethyl 4-methyl-2-oxocyclohexanecarboxylate (25 g) in dichloromethane (20 mL) in one portion. The color changed from brown to yellow, and the mixture was stirred at 0° C. for 15 min. After this time, the mixture was washed twice with 1 M aqueous HCl. The organic layer was cooled to 0° C. and then treated with 30% aqueous hydrogen peroxide (10.5 mL). After stirring for 10 min, an additional 30% aqueous hydrogen peroxide (10.5 mL) was added, followed by another an additional 30% aqueous hydrogen peroxide (10.5 mL) after 20 min. The resulting solution was stirred for 15 min and then treated with water (100 mL). The aqueous and organic layers were separated and the aqueous layer was extracted twice more with dichloromethane. The combined organic layers were washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated under vacuum to provide racemic ethyl 4-methyl-6-oxocyclohex-1-enecarboxylate (26 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([O:15][CH3:16])=[O:14])=[C:6]2[C:10]=1[O:9][C:8]([CH3:12])([CH3:11])[CH2:7]2.Cl[C:18]1[N:27]=[CH:26][C:25]2[N:24]([CH3:28])[C:23](=[O:29])[C@@H:22]([CH2:30][CH3:31])[N:21]([CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:20]=2[N:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CC(O)CC(C)C>[CH:32]1([N:21]2[C:20]3[N:19]=[C:18]([NH:1][C:2]4[CH:3]=[CH:4][C:5]([C:13]([O:15][CH3:16])=[O:14])=[C:6]5[C:10]=4[O:9][C:8]([CH3:12])([CH3:11])[CH2:7]5)[N:27]=[CH:26][C:25]=3[N:24]([CH3:28])[C:23](=[O:29])[C@H:22]2[CH2:30][CH3:31])[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: COC(=O)c1ccc(N)c2c1CC(C)(C)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)CC(C)O
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)OC)c4c3OC(C)(C)C4)nc2N1C1CCCC1
Yield: 106.7 %

Procedure:
Methyl 7-amino-2,2-dimethyl-3H-benzofuran-4-carboxylate 4d (770 mg, 3.48 mmol) was dissolved in 20 mL of 1,3-dimethyl-butanol followed by the addition of (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-5H-pteridin-6-one 1o (1.23 g, 4.18 mmol) and p-toluenesulfonic acid (1.06 g, 5.57 mmol) successively. The reaction solution was heated to reflux for 2 hours with stirring. The resulting solution was added with 50 mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with water (30 mL), saturated sodium chloride solution (20 mL) successively and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,2-dimethyl-3H-benzofuran-4-carboxylate 4e (1.78 g, yield: 100%) as a light yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:20][CH:21]2[CH2:25][CH2:24][CH:23]([O:26]C3CCCCO3)[CH2:22]2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:26][CH:23]1[CH2:24][CH2:25][CH:21]([CH2:20][CH:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])[CH2:22]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(OC3CCCCO3)C2)C(=O)Nc2nccs2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCC(O)C2)C(=O)Nc2nccs2)cc1
Temperature: 60 °C
Yield: 85.8 %

Procedure:
A solution of 2-(4-methanesulfonyl-phenyl)-3-[3-(tetrahydropyran-2-yloxy)-cyclopentyl]-N-thiazol-2-yl-propionamide (450 mg, 0.94 mmol) in ethanol (9.4 mL) was treated with pyridinium p-toluenesulfonate (24 mg, 0.094 mmol). The resulting reaction mixture was heated at 60° C. for 4 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The resulting yellow residue was diluted with ethyl acetate (100 mL) and then washed with a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 to 1/7 hexanes/ethyl acetate) afforded the 3-(3-hydroxy-cyclopentyl)-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (318 mg, 86%) as a white foam: mp 69-72° C.; FAB-HRMS m/e calcd for C18H22N2O4S2 (M+H)+ 395.1099. found 395.1091.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[N+:11]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH2:2][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7]#[N:8])([O-:13])=[O:12]
Reactant: C1CCNC1
Reactant: N#Cc1ccc(CBr)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2CCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.9 %

Procedure:
To a stirred solution of 4-(bromomethyl)-3-nitrobenzonitrile (5.12 g, 21.57 mmol) and pyrrolidine (1.84 g, 25.88 mmol) in CH2Cl2 (72 mL) was added triethylamine (6.54 g, 64.71 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 1.5 h and evaporated to dryness under reduced pressure. The residue was diluted with water (30 mL) and extracted with CH2Cl2 (3×100 mL). The CH2Cl2 solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 3-nitro-4-(pyrrolidin-1-ylmethyl)benzonitrile (2.24 g, 45%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.16 (d, 1 H, J=1.6 Hz), 7.94 (br d, 1H, J=8.0 Hz), 7.83 (dd, 1H, J=8.0, 1.6 Hz), 3.99 (s, 2H), 2.54 (br s, 4H), 1.79 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[N:10]=[CH:11][S:12][CH:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:27]1[C:36]2[C:31](=[C:32](F)[C:33](F)=[C:34]([S:38]([O-])(=[O:40])=[O:39])[C:35]=2F)[C:30]([Cl:44])=[N:29][C:28]=1C1C(F)=C(F)C(F)=C(F)C=1F>C1COCC1>[Cl:44][C:30]1[C:31]2[C:36](=[CH:35][C:34]([S:38]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[N:10]=[CH:11][S:12][CH:13]=3)(=[O:40])=[O:39])=[CH:33][CH:32]=2)[CH:27]=[CH:28][N:29]=1
Reactant: O=S(=O)([O-])c1c(F)c(F)c2c(Cl)nc(-c3c(F)c(F)c(F)c(F)c3F)c(F)c2c1F
Reactant: COc1ccc(CNc2cscn2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2cscn2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a flask containing ice cold suspension of N-(4-methoxybenzyl)thiazol-4-amine (Intermediate PPPPP; 0.085 g, 0.384 mmol) in THF (1.408 ml) was added lithium bis(trimethylsilyl)amide (0.403 ml, 0.403 mmol) drop wise over 10 min. The mixture was stirred for 15 minutes prior to the addition of a solution of perfluorophenyl-1-chloroisoquinoline-6-sulfonate (From Step 1 in Example 73; 0.15 g, 0.366 mmol) in THF (1.0 ml). After 45 minutes of stirring (ice melt) LCMS indicated that the reaction was nearly complete. The mixture was allowed to stir and slowly warm to room temperature overnight. LCMS indicated that the reaction was complete. The reaction was quenched by the addition of acetic acid (˜2 ml) and the resulting mixture was dried under reduced pressure and purified via silica gel chromatography (40 g silicycle HP column) ramping EtOAc in heptane (0-50%) providing product 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)isoquinoline-6-sulfonamide. m/z (ESI) 446.1 (M+H)+.