Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25]C(=O)OC(C)(C)C)[CH3:24])[N:18]=[CH:17][C:16]=4[N:33]=3)=[C:8]([F:34])[CH:7]=2)[CH2:3][CH2:2]1.Cl.[C:36](OCC)(=[O:38])[CH3:37]>>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:36](=[O:38])[CH3:37])[CH3:24])[N:18]=[CH:17][C:16]=4[N:33]=3)=[C:8]([F:34])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1cc2oc(-c3cc(F)c(OCC4CC4)cc3F)nc2cn1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3cc(F)c(OCC4CC4)cc3F)nc2cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-2,5-difluorophenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate (1.64 g) was added 4M hydrogen chloride/ethyl acetate (5 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (5 mL) and acetic anhydride (5 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (411 mg).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH3:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18]>[OH-].[Na+]>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([CH:7]=[CH:18][C:17](=[O:19])[CH2:16][CH2:15][CH:14]=[C:13]([CH3:20])[CH3:12])=[CH:5][C:4]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)CCC=C(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC(C)=CCCC(=O)C=Cc1ccc2c(c1)OCO2

Procedure:
15 g of piperonal (0.1 mole) and 12.6 g of 6-methyl-5-heptene-2-one (0.1 mole) in an aqueous-alcoholic solution of sodium hydroxide (200 cm3 of 10% NaOH+20 cm3 of ethanol) are stirred for 15 days at ambient temperature. The product obtained is filtered off, washed with water, and recrystallised from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14](=[O:19])[CH2:15][CH:16]3[CH2:18][CH2:17]3)=[CH:10][C:9]=2[CH3:20])=[CH:4][CH:3]=1.[Br:21]N1C(=O)CCC1=O>C1COCC1>[Br:21][C:10]1[C:9]([CH3:20])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]([CH3:13])[C:11]=1[C:14](=[O:19])[CH2:15][CH:16]1[CH2:17][CH2:18]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C(=O)CC2CC2)n(C)c1-c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: Cc1c(Br)c(C(=O)CC2CC2)n(C)c1-c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 89.2 %

Procedure:
To a stirred solution of 1-(5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)-2-cyclopropylethanone (Step 1)(0.30 g, 1.04 mmol) in THF (10 ml) at −78° C. was added a solution of N-bromosuccinimide (0.18 g, 1.04 mmol) in THF (10.0 ml) in a drop wise manner. The resulting mixture was stirred at −78° C. for 10 min. The progress of the reaction was monitored by TLC. The reaction mixture was quenched by the addition of a saturated sodium bicarbonate solution (5 ml). The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (30 ml). The organic layer was washed with a saturated sodium bicarbonate solution (1×10 ml) followed by water (1×10 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain a crude product which was purified by column chromatography using 10% ethyl acetate in hexanes to obtain the title compound 4(0.34 g, 89.0%). MS: m/z 367 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11](O)=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[O:17][CH3:18].Cl.[CH3:20][NH:21][CH3:22]>>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([N:21]([CH3:22])[CH3:20])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[O:17][CH3:18]
Reactant: COc1c([N+](=O)[O-])cc2oc(C(=O)O)cc2c1Cl
Reactant: CNC
Agent: Cl
Product: COc1c([N+](=O)[O-])cc2oc(C(=O)N(C)C)cc2c1Cl
Yield: 66 %

Procedure:
4-Chloro-5-methoxy-N,N-dimethyl-6-nitrobenzofuran-2-carboxamide was prepared by the procedure described in Example 1, step 2 starting from 4-chloro-5-methoxy-6-nitrobenzofuran-2-carboxylic acid (1.17 g, 4.31 mmol) an dimethylamine hydrochloride (386 mg, 4.74 mmol). Purification via silica gel column chromatography (20-100% ethyl acetate/isohexane) gave 4-chloro-5-methoxy-N,N-dimethyl-6-nitrobenzofuran-2-carboxamide as a orange solid (850 mg, 66%).
Reaction SMILES: [BrH:1].[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9](N)[S:10][CH:11]=1)=[O:6])[CH3:3].[Na+].[Br-].N([O-])=O.[Na+]>O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9]([Br:1])[S:10][CH:11]=1)=[O:6])[CH3:3]
Reactant: Br
Reactant: CCOC(=O)c1csc(N)n1
Agent: [Cu+2]
Agent: O=N[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CCOC(=O)c1csc(Br)n1
Temperature: 0 °C

Procedure:
To a stirred mixture of 2-amino-thiazole-4-carboxylic acid ethyl ester hydrobromide (10 g, 58 mmol), CuSO4 (26.9 g, 168 mmol) and NaBr (22.7 g, 221 mmol) in 9M H4SO4 (aq) (120 mL) at −5° C.−0° C., a pre-cooled solution of NaNO2 (4.4 g, 64 mmol) in H2O (40 mL) was added at such a rate to maintain the temperature at or below 0° C. After complete addition the mixture was maintained at 0° C. for another 30 min then warmed to RT over 2.5 h. The reaction mixture was diluted with H2O (120 mL) and extracted with Et2O (3×100 mL). The aqueous layer was separated, basified to pH 12 with 5N NaOH (aq), then extracted with Et2O (2×100 mL). The organic layers were combined, dried over Na2SO4, filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel (1:9, EtOAc:hexane) to yield the title compound as a white amorphous solid. MS m/z: 235.8, 237.8 (M+H). Calc'd. for C6H6BrNO2S-234.93.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:9]
Reactant: O=C(O)c1cc(Cl)cnc1N1CCC(Oc2cccc(F)c2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(Oc4cccc(F)c4)C3)CC2)cc1
Yield: 53.8 %

Procedure:
The title compound (D197) (180 mg) was prepared according to the experimental procedure described in Description 146 starting from 5-chloro-2-(3-(3-fluorophenoxy)pyrrolidin-1-yl)nicotinic acid (D140) (225 mg, 0.656 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (149.36 mg, 0.656 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23](O)=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:44][O:45][C:46](=[O:50])[C@H:47]([CH3:49])[NH2:48].CCN(CC)CC>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:48][CH:47]([CH3:49])[C:46]([O:45][CH3:44])=[O:50])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:26]
Reactant: COC(=O)[C@H](C)N
Reactant: Cc1cc(-c2cc(C(=O)O)on2)ccc1NC(=O)Nc1c(F)cccc1F
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)NC(=O)c1cc(-c2ccc(NC(=O)Nc3c(F)cccc3F)c(C)c2)no1
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 92 %

Procedure:
To a solution of 3-(4-(3-(2,6-difluorophenyl)ureido)-3-methylphenyl)isoxazole-5-carboxylic acid (1.0 equiv.) in 50 ml of THF was added N-methylmorpholine (1.0 equiv.) at RT. The reaction mixture was then cooled to −20° C. and isobutylchloroformate (1.0 equiv.) was added and stirred at −20° C. for 5 min. L-alanine methyl ester hydrochloride (1.1 equiv.) was neutralized with Et3N (1.1 equiv.) in 25 ml of THF and added to the above mixture. The mixture was stirred at −20° C. for 5 min and then gradually warmed to RT over a period of 1 hr. THF was evaporated under vacuum and the residue was triturated with EtOAc with minimum quantity of MeOH and collected by filtration. This yielded the title compound as a white solid (92%) after drying in vacuo. 1H NMR (300 MHz, DMSO-d6) δ: 1.38-1.41 (d, J=7.2 Hz, 3H), 2.32 (s, 3H), 3.64 (s, 3H), 4.47-4.51 (t, J=7.2 Hz, 1H), 7.12-7.17 (m, 2H), 7.25-7.32 (m, 1H), 7.61 (S, 1H), 7.67-7.70 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 8.05-8.08 (d, J=8.7 Hz, 1H), 8.34 (s, 1H), 8.67 (s, 1H), 9.35-9.37 (d, J=6.9 Hz, 1H); ms (ESI) m/z 459.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5](Cl)[N:6]=[C:7]2[O:12][CH3:13].[CH3:15][O-:16].[Na+].O>CS(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([O:16][CH3:15])[N:6]=[C:7]2[O:12][CH3:13]
Reactant: COc1nc(Cl)cc2c(Br)cccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(Br)cccc2c(OC)n1
Temperature: 90 °C

Procedure:
To a solution of 5-bromo-3-chloro-1-methoxyisoquinoline (420 mg, 1.54 mmol) in DMSO (4.0 mL) was added NaOMe (0.5 M in MeOH, 4.0 mL, 2.0 mmol). The solution was heated at 90° C. for 1.5 hours in a microwave reactor. The mixture was poured into water then extracted with EtOAc. The organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 15% EtOAc/hexanes to afford the title compound: 1H NMR (500 MHz, CDCl3): δ 8.15 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H); 7.18 (t, J=8.0 Hz, 1H), 6.85 (s, 11-1), 4.18 (s, 3H), 4.05 (s, 3H). LC6: 3.67 min, (M+H): 268.
Reaction SMILES: C[Si](C)(C)[O-].[K+].[CH:7]1([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:38][C@@H:37]([C:39]4[CH:50]=[CH:49][C:42]5[O:43][C:44]([CH3:48])([CH3:47])[O:45][CH2:46][C:41]=5[CH:40]=4)[O:36]C3=O)[CH:18]=2)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.P([O-])([O-])([O-])=O>C1COCC1>[CH:7]1([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][CH2:38][C@@H:37]([C:39]3[CH:50]=[CH:49][C:42]4[O:43][C:44]([CH3:47])([CH3:48])[O:45][CH2:46][C:41]=4[CH:40]=3)[OH:36])[CH:18]=2)=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)NC5CCCCC5)c4)C(=O)O3)ccc2O1
Agent: C[Si](C)(C)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3cccc(NC(=O)NC4CCCCC4)c3)ccc2O1
Temperature: 65 °C
Yield: 69.6 %

Procedure:
Potassium trimethylsilanolate (0.177 g) was added to a solution of N-cyclohexyl-N′-(3-{[2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy]methyl}phenyl)urea (0.207 g) in deoxygenated anhydrous THF (6 ml) whilst stirring under nitrogen. The reaction mixture was heated to 65° C. for 4.5 h, at which point the reaction mixture was cooled to room temperature. Phosphate buffer (25 ml, pH6.5) was added and the mixture left to stir for 10 min before extracting with EtOAc (3×25 ml). The combined organic layers were separated and dried over Na2SO4 before filtering. Solvent evaporation in vacuo gave a residue which was purified by Biotage. Elution with 150:8:1 dichloromethane:EtOH:ammonia followed by solvent evaporation in vacuo gave the title compound (0.138 g). LCMS RT=2.87 min, ES+ve 598 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[C:40]([O:41][CH3:42])=[CH:39][C:27]2[CH2:28][CH2:29][N:30]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:31][CH2:32][C:26]=2[CH:25]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[N:7][C:2]([NH:23][C:24]2[C:40]([O:41][CH3:42])=[CH:39][C:27]3[CH2:28][CH2:29][N:30]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:31][CH2:32][C:26]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Product: COc1ccc(Nc2nc(Nc3cc4c(cc3OC)CCN(CC(=O)N(C)C)CC4)ncc2Cl)c(-n2cccn2)c1

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine, of Example 611c, was reacted with 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide, in a similar manner as Example 601b, to yield desired product {7-[5-Chloro-4-(4-methoxy-2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-N,N-dimethyl-acetamide as a lyophylate (38%); 1H NMR (400 MHz, DMSO-d6) δ 9.80 (bm, 2H), 8.20 (s, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.86 (d, J=9.07 Hz, 1H), 7.79 (s, 1H), 7.60 (s, 1H), 7.23 (d, J=2.06 Hz, 1H), 6.98 (d, J=8.92 Hz, 1H), 6.90 (s, 1H), 6.52 (s, 1H), 4.32 (s, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.63 (bs, water+H), 3.4-2.95 (m, 6H), 2.95 (s, 6H); MS (m/e) 577.42 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(Nc2ccccc2N)cc1
Reaction time: 4 h

Procedure:
A mixture of ethyl 4-[(2-nitrophenyl)amino]benzoate from Step A (755 mg, 2.64 mmol) and 10% Pd/C (505 mg) in EtOH (25 mL) was stirred under an atmosphere of hydrogen (ca.1 atm) for 4 h. The mixture was filtered through a pad of Celite, washing with EtOH, and the filtrate was concentrated to give the title compound. MS: m/z=257 (M+1).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:9]=1[CH2:10][N:11]1[C:16](=[O:17])[C:15]([CH3:18])=[N:14][N:13]=[C:12]1[N:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1.[CH3:38][N:39]1C(=O)CCC1>CC(O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[K+].[Fe+2]>[C:38]([C:8]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:9]=1[CH2:10][N:11]1[C:16](=[O:17])[C:15]([CH3:18])=[N:14][N:13]=[C:12]1[N:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1)#[N:39]
Reactant: Cc1nnc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2Br)c1=O
Reactant: CN1CCCC1=O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(C)O
Solvent: O
Product: Cc1nnc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2C#N)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a mixture of Na2CO3 (53 mg, 0.50 mmol) and Pd(OAc)2 (3 mg, 0.013 mmol) in NMP (0.5 mL) was added i-PrOH (3 drops) and water (2 drops). The mixture was stirred at RT for 5 min. A solution of (R)-tert-butyl 1-(4-(2-bromo-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate (18, 246 mg, 0.496 mmol) in NMP (1.0 mL) was added. The mixture was heated to 140° C. and then K4[Fe(CN)6].3H2O (209 mg, 0.496 mmol) was added. The mixture was heated at 140° C. for 12 h. After cooling to RT, the mixture was diluted with water (10 mL), and extracted with EtOAc (20 mL×2). The combined extracts were washed with brine, dried over MgSO4, and concentrated to give crude product. This was purified by column chromatography on silica gel, and eluted with 20-35% EtOAc in petroleum ether to provide (R)-tert-butyl 1-(4-(2-cyano-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate (20). MS: m/z, 418 (20%), 443 (100%, M+1), 465 (95%, M+23).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.N.[CH3:22][N:23](C=O)[CH3:24]>>[CH3:22][N:23]([CH3:24])[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Reactant: CN(C)C=O
Agent: N
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(N(C)C)c2)c1
Temperature: 180 °C
Reaction time: 72 h
Yield: 78 %

Procedure:
A mixture of 2-chloro-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 45; 0.91 g, 0.0032 mol) and 50 mL of liquid ammonia in 20 mL of DMF was stirred in a sealed tube under 1800 psi, at 180° C. for 72 hours. After the solution was cooled, the solvent was removed under vacuum and the residue was purified by chromatography on silica gel (ethyl acetate/hexane, 2:8) to give 0.73 g (78% yield) of product as a yellow crystal: mp: 84-85° C.; Anal. Calc'd. for C18H20N4: C, 73.94; H, 6.89; N. 19.16. Found: C, 73.68; H, 6.74; N, 19.13.
Reaction SMILES: [CH3:1][C:2]([CH3:18])=[CH:3][CH2:4][C:5]1[C:15](=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:7](=[O:8])[C:6]=1[OH:17].S(=O)(=O)(O)O>>[CH3:1][C:2]1([CH3:18])[O:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:7]([C:6](=[O:17])[C:5]=2[CH2:4][CH2:3]1)=[O:8]
Reactant: CC(C)=CCC1=C(O)C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Product: CC1(C)CCC2=C(O1)c1ccccc1C(=O)C2=O

Procedure:
The method according to claim 14, wherein the lapachol is reacted with sulfuric acid to provide β-lapachone.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C(OCC)(=O)C>CN(C=O)C>[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:11]2[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6](=[O:7])[C:5]3[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:9][C:10]2=[O:19])=[CH:27][CH:26]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(Cc2ccc(Br)cc2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 mg (0.067 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of DMF. 3 mg (0.8 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 20 mg (0.08 mmol) of 4-bromobenzyl bromide was added to the obtained mixture and they were stirred at 60° C. overnight. The reaction mixture was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the crude product. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: Cl.NC1NC=C(CO)N=1.C1(C([O-])=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)[N+]([O-])=O.Cl.Cl.NCCS.[NH2:32][C:33]1[NH:34][CH:35]=[C:36]([CH2:38][S:39][CH2:40][CH2:41][NH2:42])[N:37]=1.[N+:43]([CH:46]=[C:47](SC)[S:48][CH3:49])([O-:45])=[O:44]>>[N+:43]([CH:46]=[C:47]([S:48][CH3:49])[NH:42][CH2:41][CH2:40][S:39][CH2:38][C:36]1[N:37]=[C:33]([NH2:32])[NH:34][CH:35]=1)([O-:45])=[O:44]
Reactant: NCCSCc1c[nH]c(N)n1
Reactant: CSC(=C[N+](=O)[O-])SC
Agent: Cl
Agent: NCCS
Agent: Nc1nc(CO)c[nH]1
Product: CSC(=C[N+](=O)[O-])NCCSCc1c[nH]c(N)n1

Procedure:
Reaction of 2-amino-4-hydroxymethylimidazole hydrochloride (which is obtained by treating the picrate salt with hydrochloric acid) with cysteamine hydrochloride and reaction of the resulting 2-amino-4-[(2-aminoethyl)thiomethyl]imidazole with 1-nitro-2,2-bis-methylthioethylene according to the procedure of Example 8(i) gives 1-nitro-2-methylthio-2-[2-((2-amino-4-imidazolyl)methylthio)ethylamino]ethylene. Finally, reaction with methylamine by the procedure of Example 8(ii) produces the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH:40]1([NH2:46])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>O1CCCC1>[CH:40]1([NH:46][C:18](=[O:20])[C@@H:17]2[CH2:21][CH2:22][CH2:23][N:16]2[C:14](=[O:15])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: NC1CCCCC1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCC1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 58.8 %

Procedure:
3.2 g (0.01 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline were dissolved in 50 ml of dry tetrahydrofuran and the solution was cooled to -10° C. 1.27 ml (0.01 mol) of N-ethylmorpholine were added followed by 1.31 ml (0.01 mol) of isobutyl chloroformate and the solution was stirred at -10° C. for 20 minutes. 1.21 ml (0.01 mol) of cyclohexylamine were then added and the mixture was stirred at 0° C. for 1 hour and then left to stand at room temperature for 16 hours. The mixture was evaporated and the residue was treated with 100 ml of ethyl acetate, washed with 80 ml of 1-N hydrochloric acid, 80 ml of water and 80 ml of 5% sodium bicarbonate solution, dried over sodium sulphate and evaporated to an oil. The product crystallised from ethyl acetate/ethyl to yield 2.36 g of N-benzyloxycarbonyl-L-alanyl-L-proline cyclohexylamide of melting point 130.5°-131.5° C. A second crop (0.95 g; melting point 130.5°-131.5° C.) was obtained on leaving the mother liquor to stand overnight. The total yield was 83%, [α]D20 =-96.3° (c=1.175% in methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:11]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH3:10])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CNC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(Cc1ccc(Cl)nc1)C1CCCCC1
Temperature: 80 °C
Yield: 95.2 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (500 mg, 3.08 mmole) in 8 mL of dry acetonitrile is 384 mg (3.39 mmol) of N-methylcyclohexylamine followed by 468 mg (3.39 mmol) of potassium carbonate. The reaction is heated at 80° C. for 20 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 700 mg (95% yield) of (6-Chloro-pyridin-3-ylmethyl)-cyclohexyl-methyl-amine. C13 NMR 26.1, 26.6, 28.9, 37.7, 54.5, 62.8, 124.1, 135.1, 139.5, 149.9; MS 239.3 (M+H).