Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:33]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH3:33])[CH:17]=[CH:16]4)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC(Br)c1ccccc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(C(C)c3ccccc3)ccc2c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of the product of Example 11 (200 mg), potassium carbonate (260 mg) and (1-bromoethyl)benzene (0.100 mL) in DMF (2 mL) was stirred at 80° C. for 17 hours. Further (1-bromoethyl)benzene (0.100 mL) and potassium carbonate (260 mg) was added and stirred at 80° C. for a further 24 hours. Additional (1-bromoethyl)benzene (0.5 mL) and potassium carbonate (500 mg) were added and the reaction stirred at 80° C. for a further 48 hours. The reaction mixture was filtered and purified by HPLC to yield the title compound (14 mg) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: Cc1ccc(F)c(B(O)O)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(C)ccc3F)cccc2c1N
Yield: 77.4 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2-fluoro-5-methyl-phenylboronic acid (154 mg, 1.000 mmol) were reacted to afford the title compound (127 mg, 77% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (br, 1H), 7.91 (m, 1H), 7.81-7.68 (m, 2H), 7.28 (m, 1H), 7.24-7.17 (m, 1H), 7.13-7.05 (m, 1H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 2.39 (s, 3H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 1.00 (t, J=7.0 Hz, 3H). MS APCI, m/z=339 (M+H). HPLC 1.86 min.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1([C:15]2[NH:19][C:18](=[O:20])[O:17][N:16]=2)[CH2:11][CH:10]1[CH:12]([CH3:14])[CH3:13])(C)(C)C.[ClH:22]>O1CCOCC1.CCOCC>[ClH:22].[NH2:7][CH2:8][C:9]1([C:15]2[NH:19][C:18](=[O:20])[O:17][N:16]=2)[CH2:11][CH:10]1[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C1CC1(CNC(=O)OC(C)(C)C)c1noc(=O)[nH]1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)C1CC1(CN)c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of {2-isopropyl-1-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-cyclopropylmethyl}-carbamic acid tert-butyl ester (3.30 g, 11.1 mmol) in dry 1,4-dioxane (20 ml) was added 4N HCl (40 mL, in 1,4-dioxane). The reaction mixture was stirred at room temperature overnight and diluted with ether (100 mL). The precipitate was collected and dried to give 1.6 g (62%) of 3-(1-aminomethyl-2-isopropyl-cyclopropyl)-4H-[1,2,4]oxadiazol-5-one hydrochloride as a white solid: mp: 178-179° C.; 1H NMR (300 MHz, D2O) δ 1.01 (d, J=5.8 Hz, 3H), 1.10 (d, J=5.8 Hz, 3H), 1.22 (t, J=6.1 Hz, 1H), 1.38-1.46 (m, 2H), 1.56 (m, 1H), 3.12 (d, J=14.2 Hz, 1H), 3.93 (d, J=14.2 Hz, 1H); 13C NMR (75 MHz, D2O) δ 18.1, 20.3, 21.7, 21.9, 29.0, 36.3, 39.3, 162.3, 162.5; MS (APCI) m/z 198 [M+H]+. Anal. Calcd. For C9H15N3O2—HCl: C, 46.26; H, 6.90; N, 17.98; Cl, 15.17. Found: C, 46.39; H. 6.84; N, 17.85; Cl, 14.79.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.[OH:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29]2.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:31]5[CH:30]=[CH:29][C:28]6[C:33](=[CH:34][CH:35]=[C:26]([OH:25])[CH:27]=6)[CH:32]=5)=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Reactant: OB(O)c1ccc2cc(O)ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cc(O)ccc4c3)cc2)C1
Temperature: 25 °C
Yield: 23 %

Procedure:
A solution of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.256 mmol) in dioxane (1.5 mL) was treated with (6-hydroxy-2-naphthalenyl)boronic acid (0.281 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (10 mg), and 2M aq potassium carbonate (0.767 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in a microwave (Biotage Initiator) at 150° C. for 15 min. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The aqueous phase was then diluted with brine (50 mL) and extracted with tetrahydrofuran, which was subsequently combined with the dichloromethane organic phase. The resulting organic phase was treated with Si-Thiol (Silicycle, 20 mg), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (20-50% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions from the HPLC were combined, adjusted to pH˜5 with the addition of saturated aq sodium bicarbonate, further diluted with brine, and extracted with tetrahydrofuran. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting product was purified by reverse phase HPLC (10-40% acetonitrile/water+0.1% NH4OH) to afford the title compound as an amorphous white solid (23%). MS(ES)+ m/e 455.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:17]2=[CH:18][CH:19]=[N:20][CH:21]=[C:16]2[C:5]2[C:6]([OH:15])=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:9][C:4]=2[O:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:15][C:6]1[C:5]2[C:16]3[C:17]([C:2]([CH3:1])([CH3:22])[O:3][C:4]=2[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=1)=[CH:18][CH:19]=[N:20][CH:21]=3)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Solvent: c1ccncc1
Product: CCCCCc1cc(OC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
10-Acetoxy-5,5-dimethyl-8-n-pentyl-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-n-pentyl-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.
Reaction SMILES: [Cl:1][CH:2]1[CH:12]=[CH:11][CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:4]2[CH2:3]1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>ClC1C(Cl)=C(Cl)C=CC=1>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:13]1[C:9](=[O:10])[C:4]2=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=[C:5]2[C:6]1=[O:8]
Reactant: O=C1OC(=O)C2CC(Cl)C=CC12
Reactant: Nc1ccccn1
Agent: Clc1cccc(Cl)c1Cl
Product: O=C1c2ccc(Cl)cc2C(=O)N1c1ccccn1
Reaction time: 9 h
Yield: 84 %

Procedure:
5.2 grams of 4-chlorotetrahydrophthalic anhydride, 2.6 grams of 2-aminopyridine, 50 milliliters of trichlorobenzene and 6.0 grams of Calgon Carbon S-Sorb was combined in a 3 neck flask. The flask was fitted with a reflux condenser and an inlet tube adjusted to deliver air as bubbles below the surface. The third neck was fitted with a drying tube to remove water. After about 9 hours, N-(2-pyridyl)-4-chlorophthalimide was formed in about 84% yield as determined by GC-MS.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([C:23](=[O:29])[NH:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:11][N:10]=1)(C)(C)C.Cl>CCOC(C)=O>[CH3:28][O:27][CH2:26][CH2:25][NH:24][C:23]([C:12]1[C:13]2[C:18](=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)[C:9]([CH2:8][NH2:7])=[N:10][CH:11]=1)=[O:29]
Reactant: COCCNC(=O)c1cnc(CNC(=O)OC(C)(C)C)c2c(OC)cc(OC)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCNC(=O)c1cnc(CN)c2c(OC)cc(OC)cc12
Yield: 31.4 %

Procedure:
As described in example 1, 92 mg of [6,8-dimethoxy-4-(2-methoxy-ethylcarbamoyl)-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester was treated with HCl in EtOAc to give 22 mg (32%) of 1-aminomethyl-6,8-dimethoxy-isoquinoline-4-carboxylic acid (2-methoxy-ethyl)-amide. H1-NMR (Free base) (CDCl3): δ, 8.47 (s, 1H), 7.33 (s, 1H), 6.63 (s, 1H), 6.57 (s, 1H), 4.45 (s, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.73 (q, J=4.8 Hz, 2H), 3.63 (d, J=5.1 Hz, 2H), 3.61 (s, 3H), 3.40 (s, 3H); MS: APCI (M+H) calc'd for C16H21N3O4+H 320.4; found 320.2.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[C:10]([CH3:14])([CH3:13])[CH:11]=[O:12].Cl.N1C=CC=CC=1.Cl>CCOCC>[Br:9][C:6]1[CH:7]=[CH:8][C:3]2[O:2][CH:11]([OH:12])[C:10]([CH3:14])([CH3:13])[C:4]=2[CH:5]=1
Reactant: COc1ccc(Br)cc1C(C)(C)C=O
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC1(C)c2cc(Br)ccc2OC1O
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
2-(2-Methoxy-5-bromophenyl)-2-methyl-1-propanal (30 g, 0.115 mole) was added to molten pyridine hydrochloride (60 g) and the mixture heated with stirring at 190°-200° C. for 50 minutes. Addition to ice-water containing a little hydrochloric acid and isolated through ether gave, after recrystallisation from petroleum ether (b.p. 80°-100° C.) 11.7 g (42%) title product m.p. 114°-5° C.
Reaction SMILES: Cl.Cl[C:3]1[S:7][C:6]([C:8](=[O:14])[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[SH:26].C(=O)([O-])[O-].[K+].[K+].Cl>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[S:26][C:3]1[S:7][C:6]([C:8](=[O:14])[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: CN(C)CCC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)CCC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 17 %

Procedure:
To a solution of 1-(5-chloro-4-nitro-2-thienyl)-3-dimethylamino-propan-1-one hydrochloride salt from the above (0.180 g, 0.687 mmol) and 2,4-dichlorobenzenethiol (0.123 g, 0.687 mmol) in N,N-dimethylformide (3 mL), was added potassium carbonate (0.237 g, 1.71 mmol). The resulting reaction mixture was stirred at ambient temperature for 5 hours. After this time, the reaction mixture was quenched with ice water and stirred at room temperature for 20 min and the precipitate which formed was collected by filtration and washed with water, and dried under vacuum. The crude solid was purified by silica gel chromatography to afford a yellow solid. The resulting solid was treated with hydrochloric acid (2 M). The solution was concentrated and dried under vacuum to afford the corresponding hydrochloride salt of the title product (90 mg, 17% yield). 1H NMR (400 MHz, MeOD) δ: 8.61 (1H, s), 8.05 (1H, m), 7.98 (1H, dd), 7.72 (1H, dd), 3.48 (2H, m), 3.33 (2H, m), 2.78 (3H, s). MS m/z: 404.9 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[S:12](=[O:15])(=[O:14])[N:11]=[C:10]([C:16]3[C:17](=[O:34])[N:18]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:19]4[C:24]([C:25]=3[OH:26])=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:9][C:8]=2[S:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1C=CC=CC=1.[OH-].[NH4+]>[NH2:1][CH2:4][C:5]1[C:13]2[S:12](=[O:15])(=[O:14])[N:11]=[C:10]([C:16]3[C:17](=[O:34])[N:18]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:19]4[C:24]([C:25]=3[OH:26])=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:9][C:8]=2[S:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2
Agent: [NH4+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To the solution of the product of Example 344 (136.2 mg, 0.28 mmol) in pyridine (1.68 mL) and concentrated ammonium hydroxide (1.12 mL) was added triphenylphosphine (145 mg, 0.55 mmol) at room temperature. The solution was stirred at room temperature overnight and concentrated in vacuo. The residue was diluted with toluene and the solid was filtered to give the title compound as a light brown solid (100.78 mg, 78%). MS (ESI+) m/z 467 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 4.10 (s, 2 H) 5.41 (br s, 2 H) 7.07-7.32 (m, 8 H) 7.43 (m, 1 H) 8.10 (dd, J=7.91, 1.65 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]3[C:11]4[C:36](=[O:37])[NH:35][C:34](=[O:38])[C:12]=4[C:13]4[C:14]5[C:19]([N:20]([C@@H:22]6[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25](O)[C@H:23]6[OH:24])[C:21]=4[C:9]=3[NH:8][C:6]=2[CH:7]=1)=[CH:18][C:17]([F:33])=[CH:16][CH:15]=5.CS(Cl)(=O)=O>N1C=CC=CC=1>[C@@H:22]1([N:20]2[C:21]3[C:9]4[NH:8][C:6]5[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=5[C:10]=4[C:11]4[C:36](=[O:37])[NH:35][C:34](=[O:38])[C:12]=4[C:13]=3[C:14]3[C:19]2=[CH:18][C:17]([F:33])=[CH:16][CH:15]=3)[O:30][C@@H:29]2[CH2:31][O:32][C@@H:25]([C@@H:27]2[OH:28])[C@H:23]1[OH:24]
Reactant: O=C1NC(=O)c2c1c1c3ccc(F)cc3[nH]c1c1c2c2ccc(F)cc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: O=C1NC(=O)c2c1c1c3ccc(F)cc3[nH]c1c1c2c2ccc(F)cc2n1[C@@H]1O[C@@H]2CO[C@H]([C@H]1O)[C@@H]2O
Reaction time: 6 h

Procedure:
2,10-Difluoro-12,13-dihydro-12-[β-D-glucopyranosyl]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (1.0 g, 1.91 mmol) was dissolved in dry pyridine under nitrogen at room temperature and treated with flame-dried, powdered 4A molecular sieves (0.60 g). The mixture. was cooled to −20° C. for 15 min before methanesulfonyl chloride (0.26 mL, 3.34 mmol, 1.75 eq.) was added neat. The flask was sealed and stored at 0° C. for 6 h prior to concentration in vacuo. Purification of the residue by flash chromatography on silica gel (elution with tetrahydrofuran/dichloromethane/methanol, 68:30:2) gave an enriched fraction (280 mg, 24%) containing the title compound as well as a small amount of other closely-spaced by-products which was carried on directly. Potassium phthalimide (0.45 g, 2.43 mmol) was added in one portion to a stirred solution of 2,10-difluoro-12,13-dihydro-12-[6—O-(methylsulfonyl)-β-D-glucopyranosyl]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (200 mg, 0.33 mmol) in anhydrous dimethylformamide (10 mL) before the mixture was heated to 130° C. for 3 h, cooled to ambient temperature, and concentrated down in vacuo overnight. The residue was then taken up in ethyl acetate (some tetrahydrofuran was added) and washed with 0.1N hydrochloric acid and brine. Following drying and solvent concentration, the residue was purified by flash chromatography on silica gel (elution with 7% methanol in chloroform) to yield 2,10-difluoro-12,13-dihydro-12-[6-deoxy-6-(phthalimido)-β-D-glucopyranosyl]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (46 mg, 21%) as a yellow solid as well as the title compound (22 mg, 13%, 2 steps) also as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH:10]2[NH:15][C:14](=O)[CH2:13][NH:12][C:11]2=O)[CH:6]=[CH:5][CH:4]=1.CSC.B.C1COCC1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH:10]2[CH2:11][NH:12][CH2:13][CH2:14][NH:15]2)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(CC2NC(=O)CNC2=O)n1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(CC2CNCCN2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a 50-mL round-bottomed flask was added 3-((6-methoxy-2-pyridinyl)methyl)-2,5-piperazinedione (423 mg, 1.80 mmol), borane methyl sulfide, complex (0.68 mL, 7.19 mmol, Aldrich, St. Louis, Mo.), and THF (6 mL). The reaction mixture was stirred at 70° C. for 2 h and allowed to cool to room temperature. The reaction mixture was diluted with MeOH (1 mL), followed by 1N NaOH (12 mL), and extracted with DCM (2×50 mL). The organic extracts were washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude 2-((6-methoxy-2-pyridinyl)methyl)piperazine as light-yellow viscous oil, which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[CH:13]([N:16](CC)C(C)C)(C)[CH3:14].BrCC#N.O>O1CCCC1>[C:13]([CH2:14][NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6])#[N:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(C)c(N)c1
Agent: N#CCBr
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(NCC#N)c1
Reaction time: 12 h

Procedure:
To a stirred solution of 3-amino-4-methyl-benzoic acid, methyl ester (10.0 g) in dry tetrahydrofuran was added N,N-diisopropylethylamine (12.6 mL) followed by the addition of bromoacetonitrile (5.1 mL). The reaction was heated at reflux under an atmosphere of nitrogen with stirring for 12 h. Water was added and the mixture extracted with ethyl acetate. The pooled organics were washed with brine, dried (MgSO4), filtered and the solvent removed under reduced pressure to afford the subtitle compound as a solid (12.4 g).
Reaction SMILES: [CH2:1]([N:5]([CH2:7][C:8]1[S:12][C:11]([C:13]([O:15]C)=[O:14])=[CH:10][CH:9]=1)[CH3:6])[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+]>O1CCOCC1.CO.O>[CH2:1]([N:5]([CH2:7][C:8]1[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=1)[CH3:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)Cc1ccc(C(=O)OC)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CCCCN(C)Cc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-{[butyl(methyl)amino]methyl}thiophene-2-carboxylate (280 mg, 1.16 mmol) in 2:1:1 dioxane/methanol/water (8.0 mL) is added lithium hydroxide monohydrate (146 mg, 3.38 mmol) and the reaction mixture stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure and the solid residue partitioned between ethyl acetate and water The aqueous phase is acidified to pH 1 with 1 N hydrochloric acid and extracted several times with 3:1 chloroform/2-propanol. The combined organic phase is washed with water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the title compound in pure form. 1H NMR (300 MHz, CD3OD) δ 7.75 (d, J=4 Hz, 1H), 7.41 (d, J=4 Hz, 1H), 4.63 (s, 2H), 3.20–3.14 (m, 2H), 2.85 (s, 3H), 1.82–1.72 (m, 2H), 1.42 (tq, J=8, 7 Hz, 2H), 0.99 (t, J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[N:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:24]=[O:25].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:24]([NH:23][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:25])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: COC(=O)CN=C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CNC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Reaction time: 18 h
Yield: 57.1 %

Procedure:
A suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (3.2 g.), methyl 2-isocyanatoacetate (1.4 g.) and triethylamine (1.2 g.) in acetonitrile (50 cc.) is stirred for 18 hours at a temperature of about 20° C. A further amount of methyl 2-isocyanatoacetate (0.7 g.) is added and stirring is continued for a further 3 hours. The precipitate is filtered off and is dissolved in methylene chloride (35 cc.). Decolourising charcoal (0.5 g.) is added. After filtration, diisopropyl ether (105 cc.) is added to the filtrate. The crystalline precipitate which forms is filtered off, washed with diisopropyl ether (15 cc.) and then dried to give 2-(7-chloro-1,8-naphthyridin-2-yl)-3-methoxycarbonylmethylaminocarbonyloxy-isoindolin-1-one (2.5 g.) melting at 208°-210° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C@H:18]([C:31]([O:33]CC2C=CC=CC=2)=[O:32])[CH2:19][CH2:20][C:21]([O:23]CC2C=CC=CC=2)=[O:22])=[O:16])=[CH:10][CH:9]=1)[CH2:5][CH2:6][Cl:7]>CN(C=O)C.[Pd]>[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH:17][C@H:18]([C:31]([OH:33])=[O:32])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])=[CH:12][CH:13]=1)[CH2:5][CH2:6][Cl:7]
Reactant: O=C(Nc1ccc(N(CCCl)CCCl)cc1)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C(O)CC[C@H](NC(=O)Nc1ccc(N(CCCl)CCCl)cc1)C(=O)O

Procedure:
A solution of dibenzyl N-(4-[N,N-bis-(2-chloroethyl)amino]-phenylcarbamoyl)-L-glutamate (1.138 g) in DMF (15 ml) was hydrogenated over 10% Pd/C for 16 h. After filtration and evaporation in vacuo, the residue was dissolved in CHCl3 (20 ml). After 18 h the crystalline precipitate was filtered off and dried in vacuo to obtain N-(4-[N,N-bis-(2-chloroethyl)amino]phenylcarbamoyl)-L-glutamic acid. Yield, 730 mg (93%). After recrystallization from acetone/CHCl3 microscopic rods formed m.p. 116°-118°. NMR (CD3 COCD3): δ8.0(s)1H; 7.2(d)2H; 6.6(d)2H; 6.2(d)2H NH; 4.4(m)1H; 3.6(m)8H; 2.5-1.9(m)4H.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2.[S:23]1[CH:27]=[C:26]([CH2:28][C:29](O)=[O:30])[N:25]=[CH:24]1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:29](=[O:30])[CH2:28][C:26]4[N:25]=[CH:24][S:23][CH:27]=4)[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2
Reactant: Nc1ccc2nc(NC3CCc4cccc(F)c43)ccc2c1
Reactant: O=C(O)Cc1cscn1
Product: O=C(Cc1cscn1)Nc1ccc2nc(NC3CCc4cccc(F)c43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method described in example 6 from rac-N2-(7-fluoro-indan-1-yl)-quinoline-2,6-diamine and 4-thiazole acetic acid (CAS 7504-44-1); MS: m/e=419.1 (M+H+).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C@@H:10]([OH:16])[C@@H:11]([OH:15])[CH2:12][C:13]#[CH:14])=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:8][C@@H:9]([CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[C@@H:10]([OH:16])[C@@H:11]([OH:15])[CH2:12][C:13]#[CH:14]
Reactant: C#CC[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C#CC[C@H](O)[C@H](O)[C@@H](N)CC1CCCCC1
Yield: 104.3 %

Procedure:
A solution of compound of Step 6 (0.926 g, 2.85 mmol) and trifluoroacetic acid (5.49 mL, 71.3 mmol) in CH2Cl12 (5.49 mL) was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue was dissolved in 1.0N KOH (7 mL) and extracted with ethyl acetate (4×10 mL). The combined organic layers were dried over MgSO4 and then concentrated to give the title amine as an off-white solid (0.67 g, 100% yield). 1H and 13C NMR spectral data were consistent with the proposed structure.