Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]1[CH3:26])[CH:2]([CH3:4])[CH3:3].[OH:34][C@@H:35]([CH3:40])[CH2:36][C:37](O)=[O:38].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CCCCCC.C(Cl)(Cl)Cl.C(Cl)Cl>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([C:37](=[O:38])[CH2:36][C@@H:35]([OH:34])[CH3:40])[CH2:16][CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])[N:9]=2)=[CH:28][N:29]=1
Reactant: C[C@H](O)CC(=O)O
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOC[C@@H]3C)nc(-c3cnc(N)nc3)nc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Cn1c(N2CCN(C(=O)C[C@H](C)O)CC2)nc2c(N3CCOC[C@@H]3C)nc(-c3cnc(N)nc3)nc21
Yield: 80.4 %

Procedure:
A methylene chloride (3 ml) solution of 5-{9-isobutyl-6-[(3S)-3-methylmorpholin-4-yl]-8-piperazin-1-yl-9H-purin-2-yl}pyrimidin-2-amine (94 mg, 0.21 mmol), (3S)-3-hydroxybutanoic acid (24 mg, 0.23 mmol), 1-hydroxybenzotriazole (28 mg, 0.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg, 0.31 mmol), and triethylamine (44 μl, 0.31 mmol) was stirred at room temperature for 21 hour. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (methylene chloride:methanol=95:5) to give an amorphous substance. Ethyl acetate-hexane was added to the resulting amorphous substance, the resulting mixture was solidified, and the solid was collected by filtration and dried to give the title compound (91 mg, 81%) as a powder.
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:9]([C:10](=[O:25])[CH2:11][NH:12][C:13]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([Cl:24])=[CH:19][CH:18]=3)=[O:14])[CH2:8][CH2:7][S:6]1)=[O:4].[OH-].[Na+]>CO>[Cl:24][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:13]([NH:12][CH2:11][C:10]([N:9]1[CH2:8][CH2:7][S:6][CH:5]1[C:3]([OH:4])=[O:2])=[O:25])=[O:14])=[CH:23]2
Reactant: COC(=O)C1SCCN1C(=O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCC(=O)N1CCSC1C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-{[(5-chloro-1H-indole-2-carbonyl)-amino]-acetyl}-thiazolidine2-carboxylic acid methyl ester (196 mg, 0.5 mmol) in methanol (10 mL) was treated with aqueous 1 N NaOH (0.5 mL) at 25° C. After 3 hours, more 1 N NaOH (0.25 mL) was added. The mixture was stirred at 25° C. overnight, concentrated, the residue stirred with ethyl acetate (30 mL) and 1 N NaOH (5 mL), and the resulting mixture acidified to pH 1.8 with aqueous 6 N HCl. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, dried, and concentrated giving a solid which was triturated with 1:1 ether-hexane and dried. Yield 186 mg, 99%; HPLC (60/40) 3.13 minutes (98%); TSPMS 368/370 (MH+, 70%), 339 (100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][C:6](=[N:8][CH2:9][C:10]([CH3:12])=[CH2:11])[CH2:5][C:4]([CH3:14])([CH3:13])[NH:3]1.CC([O-])(C)C.[K+].CS(C)=O>C1(C)C=CC=CC=1>[CH3:13][C:4]1([CH3:14])[CH2:5][C:6](=[N:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:7][C:2]([CH3:15])([CH3:1])[NH:3]1
Reactant: C=C(C)CN=C1CC(C)(C)NC(C)(C)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CC(C)=CN=C1CC(C)(C)NC(C)(C)C1
Temperature: 50 °C
Yield: 84.2 %

Procedure:
162.5 g of the N-(2,2,6,6-tetramethyl-4-piperidylidene)-2-methylallylamine are dissolved in 162 ml of toluene in a 500 ml three-necked flask with reflux condenser, and 4.86 g of potassium tert-butylate are added. To the reaction mixture are then added, with stirring, 50 ml of dimethyl sulfoxide, and stirring is maintained at 50° C. for 8 hours. The organic phase is afterwards extracted with 100 ml of distilled water, and the organic part, after separation of the solvent, is distilled to yield 136.9 g of N-(2,2,6,6-tetramethyl-4-piperidylidene)-2-methyl-1-amino-1-propene as a colourless liquid, b.p. 56° C. at 40 Pa (82% of theory).
Reaction SMILES: CN.[CH3:3][C:4]1[N:5]=[C:6]([NH:15][C:16]([N:18]2C=CN=[CH:19]2)=[O:17])[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1>O.CN(C=O)C>[CH3:19][NH:18][C:16]([NH:15][C:6]1[S:7][C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([CH3:3])[N:5]=1)=[O:17]
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccncc1
Agent: CN
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)Nc1nc(C)c(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylamine (0.030 ml of a 40% w/w/solution in water, 0.351 mmol) is added to a stirred suspension of imidazole-1-carboxylic acid (4-methyl-5-pyridin-4-yl-thiazol-2-yl)-amide (18a) (0.1 g, 0.351 mmol) in DMF (3 ml). The reaction mixture is stirred at room temperature for 1 hour and then the solvent is removed in vacuo. The crude product is dissolved in THF/DMF (10:1, 3 ml) and passed through a polymer supported isocyanate resin (0.9 g, 1.1 mmol/g loading) and washed through with THF. The solution is concentrated in vacuo and the residue washed with ethyl acetate and methanol to afford the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:18])[CH:5]=[C:6]([C:14]([O:16]C)=[O:15])[NH:7]2.[OH-].[Na+]>>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:18])[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[NH:7]2
Reactant: COC(=O)c1cc(=O)c2c(Cl)c(Cl)c(Cl)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(=O)c2c(Cl)c(Cl)c(Cl)cc2[nH]1
Yield: 75.1 %

Procedure:
Treatment of methyl 5,6,7-trichloro-4-oxo-1,4-dihydroquinoline-2-carboxylate (3 g) with sodium hydroxide (1.57 g) as described in Example 1c, gave 5,6,7-trichloro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (2.15 g). m.p. 290° C. (dec), δ (360 MHz, NAOD) 6.69 (1H, s, 3-H) and 7.66 (1H, s, 8-H) (Found: C, 40.90; H, 1.15; N, 4.78%, C10H4NO3Cl3 requires C, 41.06; H, 1.38; N, 4.79%).
Reaction SMILES: F[C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH:24]1([NH2:27])[CH2:26][CH2:25]1.CO.C(Cl)Cl>CS(C)=O>[CH:24]1([NH:27][C:2]2[C:3]([CH3:23])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:26][CH2:25]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1F
Reactant: NC1CC1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1NC1CC1
Temperature: 100 °C
Yield: 84.1 %

Procedure:
Prepared similar to that described in Example 131 using rac-2-(3-fluoro-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 156; 62.4 mg, 0.201 mmol) and cyclopropanamine (Alfa Aesar, Ward Hill, Mass.; 0.042 mL, 0.603 mmol) in DMSO (1.0 mL), heating at 100° C. for 1.5 h. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished rac-2-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (58.8 mg, 0.169 mmol, 84% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (1H, br. s.), 7.99 (1H, d, J=7.4 Hz), 7.53-7.64 (2H, m), 7.36 (1H, t, J=7.7 Hz), 7.18 (1H, d, J=1.8 Hz), 6.98 (1H, br. s.), 3.46-3.58 (1H, m), 3.05-3.20 (2H, m), 2.88-2.98 (1H, m), 2.51 (3H, br. s.), 1.24 (3H, d, J=6.5 Hz), 0.88-1.00 (2H, m), 0.68-0.78 (2H, m). m/z (ESI, +ve) 348.2 (M+H)+. Separation of this material by supercritical-fluid chromatography (Chiralpak AS-H (250×21 mm, 5 μn), 60% liquid CO2/40% MeOH (+20 mM NH3), 70 mL/min) separately afforded: 2-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one, first-eluting enantiomer (160; 19.6 mg, 0.056 mmol) as a yellow solid; and 2-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one, second-eluting enantiomer (161; 19.2 mg, 0.055 mmol) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[CH2:5][CH:4]1[CH2:6]O.S(Cl)(Cl)=O>ClC(Cl)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]23[CH2:5][CH:4]2[CH2:6][NH:1][CH2:2]3)=[CH:9][CH:10]=1
Reactant: NCC1(c2ccc(Br)cc2)CC1CO
Solvent: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Brc1ccc(C23CNCC2C3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [2-aminomethyl-2-(4-bromo-phenyl)-cyclopropyl]-methanol (9.49 g, 37.02 mmol) in dichloroethane (120 mL), was added thionylchloride (3.2 mL, 44.4 mmol) at 0° C. and stirred for 2 h at r.t. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with water (30 mL) at 0° C. Dichloroethane layer was separated from the acidic layer and discarded. The acidic layer was neutralized with sodium bicarbonate at 0° C. till pH=8 and extracted with 5% methanol in DCM (3×300 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated to yield the title compound in crude form (5.20 g, 59%) as white gel, which was used as such in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[C:14]([O:18][C:19](=[O:30])[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=1)([CH3:17])([CH3:16])[CH3:15]>CCO>[C:14]([O:18][C:19](=[O:30])[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][C:2]2[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=2)[CH:23]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1cccc(CNc2ncc([N+](=O)[O-])c(SC#N)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To a solution of 2-chloro-5-nitro-4-thiocyanato-pyrimidine (1.31 g, 6.05 mmol) in EtOH (10 mL) at 0° C. was added a solution of (3-aminomethyl-benzyl)-carbamic acid tert-butyl ester (1.43 g, 6.05 mmol) dropwise over 45 min. The reaction was allowed to stir at room temperature overnight and the resulting precipitate filtered and washed with EtOH. The crude material was purified by column chromatography (silica gel, 10:90 to 12:88 EtOAc/hexane) to afford {3-[(5-nitro-4-thiocyanato-pyrimidin-2-ylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester (1.43 g, 56%) as a yellow solid.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(N(C(C)C)CC)(C)C.O[CH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](=[O:35])[C:27]1([CH3:37])[CH3:36].[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1>ClCCl.C([O-])(O)=O.[Na+].C(OCC)(=O)C>[N:38]1([CH:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:35])[C:27]2([CH3:37])[CH3:36])[CH:42]=[CH:41][N:40]=[CH:39]1
Reactant: c1c[nH]cn1
Reactant: CC1(C)C(=O)c2ccccc2C1O
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)c2ccccc2C1n1ccnc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of trifluoromethansulfonic anhydride (1.13 mL, 6.75 mmol) in dichloromethane (10 mL) at −78° C. is added, via cannula, a solution of diisopropylethylamine (1.8 mL, 10.1 mmol) and 3-hydroxy-2,2-dimethyl-indan-1-one, prepared as described in Example 20, (400 mg, 2.25 mmol) in dichloromethane (5 mL). The reaction is stirred at −78° C. for 10 minutes and then is placed at −10° C. for 10 minutes. The reaction is then re-cooled to −78° C. and a solution of imidazole (920 mg, 13.5 mmol) in dichloromethane (12 mL) is added via cannula. The reaction is then placed at room temperature for 1 hour, at which time it is diluted with saturated aqueous NaHCO3 and ethyl acetate. The layers are separated and the aqueous layer is extracted two times with ethyl acetate. The combined organic layers are dried with MgSO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 1:3 to 1:0), to afford 3-imidazol-1-yl-2,2-dimethyl-indan-1-one; MS: (ESI) m/z 227 (M+H)+; 1H NMR: (400 MHz, CDCl3) δ ppm 0.80 (s, 3 H), 1.41 (s, 3 H), 5.52 (s, 1 H), 6.73 (s, 1 H), 7.12 (s, 1 H), 7.51 (d, J=7.6 Hz, 1 H), 7.56 (s, 1 H), 7.62 (t, J=7.5 Hz, 1 H), 7.70-7.80 (m, 1 H), 7.91 (d, J=7.6 Hz, 1 H).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][S:15][CH3:16])[NH:9][C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20]>CC(C)=O>[CH2:18]([NH:21][C:22]([N:9]1[CH:10]([CH2:13][CH2:14][S:15][CH3:16])[C:11](=[O:12])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:17])=[O:23])[CH2:19][CH3:20]
Reactant: CSCCC1NC(=O)N(c2ccccc2)C1=O
Reactant: CCCN=C=O
Solvent: CC(C)=O
Product: CCCNC(=O)N1C(=O)N(c2ccccc2)C(=O)C1CCSC

Procedure:
125 g of compound no. 27 (0.5 mole), 42.5 g of propylisocyanate (0.5 mole) and 50 g of TEA (0.5 mole), all being dissolved in anhydrous acetone, are heated under reflux for several hours.
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:12][C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:21])[CH:5]=1)=[O:3].[C:22]1([CH2:28][C:29]([N:31]=[C:32]=[S:33])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH3:1][S:2]([C:4]1[S:12][C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:32]([NH:31][C:29](=[O:30])[CH2:28][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[S:33])=[CH:16][C:15]=2[F:21])[CH:5]=1)=[O:3]
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CS(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Solvent: C1CCOC1
Product: CS(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reaction time: 3 h
Yield: 52.8 %

Procedure:
To a suspension of 234 (280 mg, 0.868 mmol) in THF (8 mL) was added 2-phenyl acetyl isothiocyanate (185 mg, 1.04 mmol). The reaction mixture was stirred for 3 hours, concentrated; the solid residue washed with Et2O and dried, to afford title compound 235 (229 mg, 53% yield) as a white-rose solid. 1HNMR: (DMSO-d6) δ (ppm): 12.41(s, 1H), 11.75(s, 1H), 8.54(d, J=5.3 Hz, 1H), 7.98 (s, 1H), 7.96(d, J=13.5 Hz, 1H), 7.48(d, J=5.0 Hz, 2H), 7.30-7.26(m, 2H), 7.26-7.18(m, 3H), 6.69(d, J=5.5 Hz, 1H), 3.25(s, 2H), 2.98(s, 3H). MS (m/z): 500.1 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][C:4]1([CH:10]([C:18]([CH3:20])=[CH2:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][NH:6][C:5]1=[O:9].[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH3:1][CH:2]([CH3:21])[CH2:3][C:4]1([CH:10]([C:18]([CH3:20])=[CH2:19])[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:8][CH2:7][N:6]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:5]1=[O:9]
Reactant: C=C(C)C(C(=O)OC(C)(C)C)C1(CC(C)C)CCNC1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)C(C(=O)OC(C)(C)C)C1(CC(C)C)CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 117.3 %

Procedure:
A cold (0° C.) solution of tert-butyl 3-(2-methylpropyl)-2-oxo-α-(propen-2-yl)-3-pyrrolidineacetate (1.11 g, 3.76 mmol) in dry THF (25 mL) is treated with NaH (60% dispersion in mineral oil, 226 mg, 5.64 mmol) in one portion. After 30 minutes, benzyl bromide (537 μL, 4.51 mmol) is added. The solution is allowed to slowly warm to room temperature, stirring under N2 overnight. The mixture is quenched with H2O (25 mL) and extracted with EtOAc (3×25 mL). The organic extracts are combined, washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield 1.70 g of yellow oil. The oil is purified by silica gel chromatography (30 g SG, 10% EtOAc/hexane) to give 1.37 g (94%) of the title compound as a clear, colorless oil.
Reaction SMILES: [ClH:1].O[CH2:3][CH2:4][NH:5][C:6]1[N:10]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[N:7]=1.[CH:24](O)(C)C>>[ClH:1].[OH:13][CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:1])=[CH:16][CH:15]=1)[CH2:11][N:10]1[C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[N:7]2[CH2:24][CH2:3][CH2:4][N:5]=[C:6]12
Reactant: O=C(Cn1c(NCCO)nc2ccccc21)c1ccccc1
Reactant: CC(C)O
Agent: Cl
Product: OC(CN1C2=NCCCN2c2ccccc21)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
Slowly add isopropanolic hydrogen chloride to an isopropanol solution of the base obtained in Step A. Wait for 30 minutes. Suction-filter, and wash with acetone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[CH3:25][C:26]1([NH:30][C:21]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[N:10][C:11]=3[CH3:24])=[CH:20][N:19]=2)=[O:23])[CH2:29][O:28][CH2:27]1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)O)cn1
Reactant: CC1(N)COC1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)NC2(C)COC2)cn1
Yield: 63 %

Procedure:
As described for example 80c, 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (83 mg, 0.25 mmol), was converted, using 3-methyl-3-oxetanamine instead of 4-aminotetrahydropyran, to the title compound (63 mg, 63%) which was obtained as an off white solid. MS: m/e=399.2 [M+H]+.
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)#[N:12].[NH2:22][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][N:38]=1)[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[CH2:29]([NH:28][C:26](=[O:27])[C:25]1[CH:36]=[CH:37][N:38]=[C:23]([NH:22][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([C:11]#[N:12])=[CH:14][CH:15]=2)[CH:24]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: O=C(Cl)c1ccccc1F
Product: N#Cc1ccc(C(=O)Nc2cc(C(=O)NCc3ccccc3)ccn2)cc1
Yield: 35 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 4-cyanobenzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(4-cyanobenzamido)isonicotinamide was obtained as a colorless solid in 35% yield: mp 180-181° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.97 (s, 1H), 8.63 (s, 1H), 8.41 (t, J=5.0 Hz, 1H), 8.03-8.00 (m, 2H), 7.82-7.79 (m, 2H), 7.60 (dd, J=5.1, 1.2 Hz, 1H), 7.36-7.29 (m, 5H), 6.69 (m, 1H), 4.65 (d, J=5.7 Hz, 2H); MS (ES+) m/z 357.5 (M+1).
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[NH:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:8])=[O:5])C.[Li+].[OH-].OS([O-])(=O)=O.[Na+]>CO.O>[C:4]([CH2:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[NH:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:8])([OH:5])=[O:3]
Reactant: CCOC(=O)CC(=O)c1ccc2ccccc2c1NCC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CNc1c(C(=O)CC(=O)O)ccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To-a solution of 2-[ethoxycarbonylmethylcarbonyl][(1,1-dimethylethoxycarbonyl)methyl]aminonaphthalene (730 mg, 1.95 mmol) in methanol (5.0 mL) was added a solution of LiOH (123 mg, 2.91 mmol) in water (3.0 mL). The resulting reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was acidified by 2N NaHSO4 to pH 3, then extracted by ethyl acetate (3×10 mL). The organic layer was evaporated in vacuo to afford 2-[carboxymethylcarbonyl][(1,1-dimethylethoxycarbonyl)methyl]aminonaphthalene (270 mg) as a white solid.
Reaction SMILES: [O:1]1[C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH:12]=[CH:13][CH:14]=1>>[OH:1][C:3]1([CH2:2][NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][N:18]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:28])[CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Nc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: C1CCC2(C1)CO2
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(NCC2(O)CCCC2)c1

Procedure:
Reaction between 1-oxaspiro[2.4]heptane and 2-(3-(3-aminophenyl)propyl)isoindoline-1,3-dione gives 2-(3-(3-(((1-hydroxycyclopentyl)methyl)amino)phenyl)propyl)isoindoline-1,3-dione.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19](Cl)=[O:20].Cl>C(#N)C.O>[OH:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]2[NH:1][C:19](=[O:20])[CH2:18][O:10][C:3]=2[CH:4]=1
Reactant: Cc1cc(O)cc(O)c1N
Reactant: O=C(Cl)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(O)cc2c1NC(=O)CO2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1.0 g (7.2 mmol) 4-amino-5-methylbenzene-1,3-diol and 2.2 g (15.8 mmol) potassium carbonate in 20.0 mL acetonitrile were cooled in the ice bath. 0.65 mL (7.9 mmol) bromoacetyl chloride were added dropwise and the reaction mixture was stirred for 30 min at RT and for 1 h at 70° C. The mixture was combined with water, acidified with aqueous hydrochloric acid and extracted with dichloromethane. The organic phase was separated off, dried and evaporated down i.vac.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].N1C=CC=CC=1.[S:23]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24]1>ClCCl>[O:16]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:12]([F:15])([F:13])[F:14])=[N:11][N:2]1[NH:1][C:29](=[O:30])[CH2:28][C:25]1[CH:26]=[CH:27][S:23][CH:24]=1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: O=C(Cl)Cc1ccsc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1ccsc1)Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A mixture of the product of Example 11B (30.2 mg, 0.13 mmol), pyridine (0.14 mL, 0.17 mmol), and 2-(thiophen-3-yl)acetyl chloride (24.0 mg, 0.15 mmol) in dichloromethane (0.4 mL) was stirred for 3 hours, concentrated, and chromatographed (20% acetone/hexanes) to give the title compound (33.8 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.82-11.94 (m, 1H), 8.44 (dd, J=7.9, 1.5 Hz, 1H), 8.11-8.17 (m, 1H), 8.00-8.09 (m, 2H), 7.36-7.58 (m, 2H), 7.14 (dd, J=4.9, 1.3 Hz, 1H), 3.74 (s, 2H); MS (ESI−) M/Z 352 (M−H)−.