Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH2:7][N:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:10][C:5]=2[S:4][N:3]=1.[N+](=[CH2:17])=[N-]>CCOCC.C(O)C>[CH3:17][O:1][C:2]1[C:6]2[CH2:7][N:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:10][C:5]=2[S:4][N:3]=1
Reactant: COC(=O)N1CCc2snc(O)c2C1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)N1CCc2snc(OC)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.60 g (7.5 mmol) of methyl 3-hydroxy-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine-5-carboxylate (1)1 in ether (50 ml) and ethanol (2 ml) was added an excess of diazomethane. The mixture was stirred at room temperature for 1 hour, and the excess of diazomethane was destroyed by addition of glacial acetic acid. The mixture was evaporated in vacuo and the residue submitted to column chromatography on silica gel (eluent: toluene-ethyl acetate) yielding 890 mg of the title compound as a colourless oil.
Reaction SMILES: C1C(=O)N([O:8][C:9]([CH2:11][CH2:12][S:13][S:14][C:15]2[N:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)C(=O)C1.[NH3:21]>CO>[N:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:14][S:13][CH2:12][CH2:11][C:9]([NH2:21])=[O:8]
Reactant: O=C(CCSSc1ccccn1)ON1C(=O)CCC1=O
Reactant: N
Solvent: CO
Product: NC(=O)CCSSc1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-succinimidyl 3-(2-pyridyldithio)propionate (180 mg) was dissolved in methanol (4.5 ml), to which was added 1 ml of a methanol solution of ammonia (5% v/v). The mixture was stirred at 0° C. for 30 minutes, followed by concentration to 1 ml under reduced pressure. As a result, 3-(2-pyridyldithio)propanamide [disclosed in Japanese laid open Patent Application 57595/86 and CA105(19)173000q] was formed in the reaction solution. To this solution were added triethylamine (80 ml) and cysteamine hydrochloride (65 mg). The solution was stirred at room temperature for 10 minutes. Then, mitomycin A (50 mg) was added to the reaction solution, followed by stirring at room temperature for 2 hours. After addition of water (10 ml), the solution was extracted with chloroform (50 ml). The chloroform solution was dried with sodium sulfate, and the solvent was removed under reduced pressure. The material was chromatographed by the use of silica gel (10 ml; Wako-C200) and a solvent system of chloroform/methanol (9:1 v/v). The resultant blue fractions were collected combined, and concentrated. The concentrated fraction was dissolved in acetone and was dropwise added to cyclohexane to give precipitates. The precipitates were dryed under reduced pressure to obtain yellowish green powders of Compound 21 (15 mg) with a yield of 21%. The molar ratio of mitomycin-type substance contained in the produce was >99%.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[OH-].[K+]>O1CCCC1.CO>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)/[CH:16]=[C:2]1/[C:1](=[O:11])[C:10]2[C:5]([CH2:4][CH2:3]/1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=C1CCCc2ccccc21
Reactant: O=Cc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1/C(=C/c2cccc(Br)c2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 92.4 %

Procedure:
A 250 mL flask was charged with tetralone (5.2 g, 35.6 mmol) and 3-bromobenzaldehyde (8.51 g, 56 mmol). This was dissolved in warm tetrahydrofuran (20 mL), and to this yellow solution was slowly added a 4 wt % solution of KOH in methanol (160 mL). The reaction was stirred for 4 days at room temperature. The mixture was concentrated and reduced to approx 10% vol. The residue was filtered and washed with MTBE (3*50 mL), dried, to afford a light yellow powder (10.3 g, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#N.[OH2:11]>[Ni].C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:11]
Reactant: O
Reactant: N#Cc1ccc(F)c(Br)c1
Agent: [Ni]
Solvent: O=CO
Product: O=Cc1ccc(F)c(Br)c1
Yield: 85 %

Procedure:
17.0 g of a 50% strength alkaline suspension of Raney nickel were filtered under a nitrogen atmosphere and the material on the filter was washed until neutral. The Raney nickel obtained by this method was suspended in 150 ml of formic acid. 20.0 g (0.1 mole) of 3-bromo-4-fluoro-benzonitrile were added to this suspension. The mixture was heated at 80° to 90° C. for 3 to 5 hours and the reaction mixture was then cooled and poured into 300 ml of water. After filtering, the filtrate was twice extracted with, in each case, 200 ml of toluene. The toluene phase was dried over sodium sulphate and then concentrated. 17.2 g (85% of theory) of 3-bromo-4-fluoro-benzaldehyde with a boiling point of 63°-65° C./0.3 mm Hg were obtained.
Reaction SMILES: [C:1]([N:4]1[CH:9]=[CH:8][C:7]([C:16](=[O:18])[CH3:17])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5]1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([N:4]1[CH2:5][CH2:6][C:7]([C:16](=[O:18])[CH3:17])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N1C=CC(C(C)=O)(c2ccccc2)C=C1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCC(C(C)=O)(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
1.2 grams of 1,4-Diacetyl 4-phenyl 1,4-dihydropyridine from Example 1 was dissolved in methanol (100 ml) and subjected to hydrogenation in an autoclave in presence of Palladium/carbon (10%) at 60° C. with hydrogen pressure of 5-6 kg for 10 hrs. Thin layer chromatography showed the completion of the reduction. The reaction mixture was cooled to room temperature and filtered to remove palladium/carbon. The filtrate was concentrated completely and the product was precipitated using chilled isopropyl alcohol. The product was filtered and the solid product 1,4 diacetyl 4-phenyl piperidine was dried under vacuum.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH:29]=[CH:28][S:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[CH:10][CH:9]=1)(=[O:7])=[O:6].CCN(S(F)(F)[F:36])CC>C(Cl)Cl.C1COCC1>[F:36][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH:29]=[CH:28][S:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCO)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCF)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
To a solution of N-(2-hydroxyethyl)-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzenesulfonamide (120 mg, 0.28 mmol) in methylene chloride (10 mL) and THF (6 mL) under nitrogen at −78° C. was added DAST (89 mg, 0.56 mmol) and the reaction mixture was stirred at −78° C. for 2 h and warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated and the residue was purified by column chromatography (silica gel, ethyl acetate/hexanes gradient). The resulting crude residue was triturated in methylene chloride and filtered to afford the desired product (90 mg, 75%) as a off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.10 (t, J=5.9 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.76 (d, J=5.4 Hz, 1H), 7.56 (d, J=9.1 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.43 (d, J=9.2 Hz, 1H), 5.75 (d, J=5.4 Hz, 1H), 4.51 (t, J=4.9 Hz, 1H), 4.42 (t, J=4.9 Hz, 1H), 3.71 (s, 3H), 3.24 (q, J=5.2 Hz, 1H), 3.19 (q, J=5.2 Hz, 1H); ESI MS m/z 433 [C20H17FN2O4S2+H]+; HPLC 93.4% (AUC), tR=15.64 min.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH+:12]([O-:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22]>ClCCl>[CH3:20][Si:21]([CH3:23])([CH3:22])[O:8][CH:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[NH+:12]([O-:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1
Reactant: CC1(C)CC(O)CC(C)(C)[NH+]1[O-]
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CC(O[Si](C)(C)C)CC(C)(C)[NH+]1[O-]
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution in which 48.6 g (480 mmol) of triethylamine and 68.9 g (400 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxide (TEMPOL) were dissolved in 100 mL of di-chloromethane, 47.8 g (440 mmol) of trimethylsilyl chloride was added at 0° C. The temperature was raised to 25° C. to carry out a reaction for 2 hours, and it was then concentrated by a rotary evaporator. To the residue 500 ml of water was added, and an extraction was carried out using 500 ml in total of ethyl acetate. The organic layer was concentrated by a rotary evaporator and the residue was dissolved in hexane and recrystallized to obtain 96.2 g of 4-trimethylsilyloxy-2,2,6,6-tetramethylpiperidine-N-oxide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]2C(=O)C3=CC=CC=C3C2=O)=[CH:6][CH:5]=[C:4]([Cl:20])[N:3]=1.NN.O>CCO.CN(C=O)C>[Cl:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=[C:4]([Cl:20])[N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: NCc1ccc(Cl)nc1Cl
Yield: 81.9 %

Procedure:
In a mixture of 50 ml EtOH and 20 ml DMF was dissolved 3.1 g (0.01 mole) of N-(2,6-dichloro-3-pyridylmethyl)phthalimide under heating, followed by addition of 0.75 g (0.015 mole) of H2NNH2.H2O under reflux. After 1 hour of refluxing, EtOH and DMF were distilled off. To the residue were added 10 ml of concentrated hydrochloric acid and 5 ml of water, and the mixture was refluxed for 30 minutes. The resulting crystals were filtered off and the filtrate was neutralized with NaHCO3 and extracted with CH2Cl2 (30 ml×3). The extract was dried over MgSO4 and the solvent was distilled off to give 1.45 g of the title compound as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[OH:12])=[O:4].C([O-])(=O)C.[Na+]>C(O)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]2[O:12][CH2:2][C:3](=[O:4])[C:5]=2[CH:10]=1
Reactant: O=C(CCl)c1cc(Cl)ccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1COc2ccc(Cl)cc21
Temperature: 0 °C
Yield: 75 %

Procedure:
(Ref: J. Org. Chem. 1955; 20; 813-818) A solution of 2-chloro-1-(5-chloro-2-hydroxy-phenyl)-ethanone (5 g; 24.4 mmol) in ethanol was heated to reflux for 10 minutes and sodium acetate (2 g; 24.4 mmol) was added to the hot mixture. Mixture continued to reflux an additional 10 minutes, and reaction was stoppered and chilled to 0° C. for 20 minutes. Mixture was quenched with water and mixture extracted with ethyl acetate (3×75 mL). Combined organics was washed with brine and dried over MgSO4. Crude material was purfied by chromatography using 0-1% methanol/DCM to afford 5-chlorobenzofuran-3-one as a oily solid. (3.0 g; 75% yield).
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH:5][C@@H:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C2C(CCCC2)CCC1>[CH3:13][C@H:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:4][NH:5]1
Reactant: C[C@H](NCCBr)c1ccccc1
Agent: Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCC2CCCCC2C1
Product: C[C@@H]1NCCc2ccccc21
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 73.5 %

Procedure:
5.0 g (16.18 mmole) of (S)-(−)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example (2) above was suspended in 50 ml of decalin and then heated to 140° C. 6.47 g (48.54 mmole) of anhydrous aluminum chloride (AlCl3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at constant temperature, and cooled to room temperature. The supernatant was removed and the lower layer was added to 70 g of ice-water with stirring. 20 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 100 ml of ethyl acetate, and the aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of ethyl acetate. The extracts were combined, washed with 40 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 1.75 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[NH:7][C:6]3[CH2:12][CH:13]4[NH:17][CH:16]([C:5]=3[C:4]=2[C:3]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14]4.[H-].[Na+].I[CH3:28]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[N:7]([CH3:28])[C:6]3[CH2:12][CH:13]4[NH:17][CH:16]([C:5]=3[C:4]=2[C:3]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14]4
Reactant: Cc1cc(Br)c(C(=O)OC(C)(C)C)c2c3c([nH]c12)CC1CCC3N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Br)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
To a solution of the product of step B (410 mg, 1.05 mmol) in DMF (3.5 ml) at 0° C., under nitrogen was added sodium hydride (60% dispersion in mineral oil, 51 mg, 2.09 mmol). The mixture was stirred for 45 min at 0-5° C. before iodomethane (0.13 mL, 2.09 mmol) was added. The mixture was stirred for a further 90 min then quenched with ice water. The mixture was diluted with ethyl acetate, washed with water, brine and dried over anhydrous sodium sulfate. Concentration in vacuo afforded a viscous oil which was dissolved in a minimal amount of ethyl acetate and precipitated by addition of hexanes. The separated solid was filtered and dried in vacuo to give tert-butyl 2-bromo-4,5-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (340 mg, 80%) as an off-white solid. 1H NMR (CDCl3, 300 MHz): δ 7.43 (d, J=1.2 Hz, 1H), 6.94 (d, J=1.2 Hz, 1H), 5.05-5.30 (m, 1H), 4.52-4.70 (m, 1H), 3.80 (s, 3H), 3.15-3.47 (m, 1H), 2.69 (s, 3H), 2.43 (dd, J=15.9, 0.9 Hz, 1H), 2.23-2.30 (m, 1H), 2.08-2.22 (m, 1H), 1.85-1.95 (m, 1H), 1.58-1.64 (m, 1H), 1.39 (br s, 9H).
Reaction SMILES: C(OC(=O)[N:6]([CH2:22][C@@H:23]([NH:32]C(OC(C)(C)C)=O)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[N:17][CH:16]=[CH:15]3)[CH:8]=1)C=C.C[Si](C)(C)NO[Si](C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:32][C@@H:23]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[CH2:22][NH:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[N:17][CH:16]=[CH:15]3)[CH:8]=1
Reactant: C=CCOC(=O)N(C[C@H](Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C)c1cc(-c2ccc3cnccc3c2)no1
Agent: [Pd]
Agent: C[Si](C)(C)NO[Si](C)(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CNc1cc(-c2ccc3cnccc3c2)no1)Cc1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
To a solution of 2-propen-1-yl((2S)-2-((tert-butoxycarbonyl)amino)-3-(4-chlorophenyl)propyl)(3-(6-isoquinolinyl)-5-isoxazolyl)carbamate (0.095 g, 0.17 mmol) in 2.5 mL of DCM was added N,O-bis(trimethylsilyl)hydroxylamine (0.11 mL, 0.51 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.0058 g, 0.0051 mmol). The mixture was stirred for 15 minutes. The reaction was quenched with 5 mL of aqueous NH4Cl and the biphasic mixture was stirred for 2 hours. The mixture was then partitioned and the aqueous portion was extracted twice with 5 mL of DCM. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure afforded a residue that was taken up in 3 mL of DCM and 0.5 mL of TFA was then added. After 30 minutes, the reaction was diluted with 20 mL of DCM and transferred to a separatory funnel. 10 mL of 5% aqueous NaOH was added, and the biphasic mixture was shaken vigorously and partitioned. The aqueous portion was extracted twice with 15 mL of DCM, and the combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (2.5 to 7.5% MeOH/CH2Cl2) afforded N-((S)-2-amino-3-(4-chlorophenyl)propyl)-3-(isoquinolin-6-yl)isoxazol-5-amine (0.025 g, 39% yield) as a yellow powder. LCMS (API-ES) m/z: 379 (M+1); 1H NMR (400 MHz, CD3O) δ ppm 9.29 (s, 1H), 8.51 (d, J=5.7 Hz, 1H), 8.29 (s, 1H), 8.20 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 7.92 (d, J=5.7 Hz, 1H), 7.37 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.60 (s, 1H), 3.45-3.20 (m, 3H), 2.92 (dd, J=5.7 Hz, 13.9 Hz, 1H), 2.72 (dd, J=7.1 Hz, 13.5 Hz, 1H).
Reaction SMILES: N[C@H:2](C(O)=O)CC1C=CC=CC=1.[ClH:13].[NH2:14][C@H:15]([C:21]([OH:23])=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20].Cl>CO>[ClH:13].[ClH:13].[CH3:2][O:22][C:21](=[O:23])[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[NH2:14]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H](N)CCCCN
Yield: 81.3 %

Procedure:
The same esterification procedure as in Example 1 was followed with the exception that the L-phenylalanine was replaced with 182.6 g of L-lysine hydrochloride and that 182.6 g of methanol and 87.3 g of hydrochloric acid were used. Following cooling in order to deposit the crystals, the latter were collected by filtration and then dried to obtain 196.2 g (81.3% yield) of L-lysine methyl ester dihydrochloride having a purity of 96.6% and containing 0.2% of water and 1.3% of L-lysine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=2)=[N:14]1.CN(C=O)C.C(Cl)Cl>O>[Br:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=3)=[N:14]2)=[O:9])[N:6]=1
Reactant: O=C(O)c1c[nH]c(Br)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1c[nH]c(Br)n1
Yield: 2.3 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 2-bromo-1H-imidazole-4-carboxylic acid (5.75 mmol, 1.099 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (3.84 mmol, 1 g) using DMF (10 ml) as the solvent. DCM and water were added, the phases were separated and the water phase was extracted with DCM. The combined organics were washed three times with water. The DCM phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 37.8 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.09 (d, 3H), 4.23-4.48 (m, 3H), 6.95 (d, 1H), 7.64 (s, 1H), 7.82 (d, 1H), 7.94-8.05 (m, 2H), 8.08 (s, 1H), 8.21 (d, 1H), 13.22 (bs, 1H).
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[N+:11]([O-])([OH:13])=[O:12]>CCOCC>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[OH:10]
Reactant: O=[N+]([O-])O
Reactant: COc1ccccc1O
Solvent: CCOCC
Solvent: O
Product: COc1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 50 ml of water, 150 ml of ether and 15.0 g of 2-methoxyphenol was added dropwise 12.7 ml of 61% nitric acid, and the mixture was stirred at room temperature for 15 minutes. The ether layer was separated from the aqueous layer and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica-gel column-chromatography using Wakogel® C-200 [eluent: chloroform-n-hexane (1:1)] to give 4.72 g of 2-methoxy-6-nitrophenol.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Reactant: C1CCNC1
Product: O=C(O)c1cnn(-c2nc(N3CCCC3)c3cc(Cc4ccccc4)c(F)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. for C23H20FN5O2, 417.2
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][CH:4]=1)#[N:2].CO.O>C(N(CC)CC)C>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1ccc(C#N)cc1
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 82 °C
Yield: 91.9 %

Procedure:
A mixture containing ethyl p-cyanobenzoate (87.5 g, 0.5 mol), methanol (192.5 g), and water (449.2 g) was placed in a 1 l-flask. The mixture was heated to 82° C., and triethylamine was added thereto so as to adjust the pH of the mixture at 9.0-9.3. Six hours after the reaction started, liquid chromatographic analysis revealed that the reaction mixture contained 67.6 g of p-cyanobenzoic acid (yield 92%). The reaction mixture was cooled to 30° C., and hydrochloric acid was added thereto to lower the pH to 3.1. The mixture was heated again to 82° C., and methanol was added thereto so that the mixture dissolves. The resultant mixture was cooled for crystallization, to thereby obtain 62.4 g of p-cyanobenzoic acid crystal (purity 97.8%, yield 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]2[C:7]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])=[C:8]([C:10]3[CH:11]=[N:12][NH:13][CH:14]=3)[O:9][C:5]=2[CH:4]=1.ClCCl.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.O=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]2[C:7]([C:15]([C:17]3[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=3)=[O:16])=[C:8]([C:10]3[CH:14]=[N:13][N:12]([C:39]4[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=4)[CH:11]=3)[O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(-c3cn[nH]c3)oc2c1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2cc(-c3oc4cc(OC)ccc4c3C(=O)c3cc(OC)c(OC)c(OC)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14.4 %

Procedure:
To an 8 mL screw cap glass vial was added [6-methoxy-2-(1H-pyrazol-4-yl)-benzofuran-3-yl]-(3,4,5-trimethoxyphenyl)-methanone (11 mg, 0.027 mmol), 3 Å molecular sieves, dichloromethane (0.5 mL), cupric acetate (10 mg, 0.054 mmol), 4-methoxy-phenyl boronic acid (9 mg, 0.059 mmol) and pyridine (15 μL, excess) and the capped vial was shaken at room temperature for two days with occasional removal of the cap to expose the mixture to atmospheric oxygen. After this time the reaction mixture was filtered through celite and the filtrate was concentrated and purified by silica-gel flash chromatography (eluent=hexane:ethyl acetate, 3:1) to afford the product as a yellow solid (2 mg, 15% yield). 1H-NMR (CDCl3) δ 8.56 (s, 1H), 8.17 (s, 1H), 7.60 (d, J=8.9 Hz, 2H), 7.15 (s, 2H), 7.14 (d, J=8.7 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 6.96 (d, J=8.9 Hz, 2H), 6.81 (dd, J=8.7, 2.0 Hz, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H), 3.78 (s, 6H).