Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[CH:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[Mn]([O-])(=O)(=O)=O.[K+].OO>ClCCl.C(O)(=O)C>[CH3:10][O:9][C:7]([CH2:6][C:5]1[O:1][N:2]=[C:3]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8]
Reactant: COC(=O)CC=C(C(=NO)c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)Cc1onc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Reaction time: 4 h
Yield: 60 %

Procedure:
A 1.75 g (5 mmols) quantity of methyl 5-hydroxyimino-4,5-bis(4-methoxyphenyl)-3-pentenoate was dissolved in 8.5 ml of dichloromethane and 4 ml of acetic acid, then 0.79 g of potassium permanganate was slowly added to the solution at room temperature, and the mixture was stirred for 4 hours. After the completion of reaction, a hydrogen peroxide solution was added to the reaction mixture until the mixture became transparent. The mixture was diluted with 10 ml of dichloromethane, subsequently washed with water, with sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride successively, and dried over anhydrous magnesium sulfate. The dried product was subjected to silica gel column chromatography (eluants: ethyl acetate-n-hexane) for separation and purification, affording 10.2 g (yield 60%) of the above-identified compound as a white solid product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([O:25]CC2C=CC(OC)=CC=2)=[O:24])=[CH:21][CH:20]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:35][CH:36]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COC(=O)c2ccc(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)cc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(C(=O)O)cc1

Procedure:
4-Methoxybenzyl 4-(N-benzyloxycarbonyl-L-valyloxy)benzoate was de-esterified by the method described in Example A-I-1, step c. The title compound (1.86 g) was obtained after silica gel column chromatography (2, 10, 20% ethanol in dichloromethane). Rf (2%MeOH/CHCl3) 0.20. The compound can be activated and esterifed directly to a drug or further modified as described below.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].F[C:7]1[CH:17]=[C:16]([NH:18][CH3:19])[C:15]([N+:20]([O-:22])=[O:21])=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[H-].[Na+].C(O)(C(F)(F)F)=O>C1COCC1.CN(C=O)C>[F:1][CH:2]([F:5])[CH2:3][O:4][C:7]1[CH:17]=[C:16]([NH:18][CH3:19])[C:15]([N+:20]([O-:22])=[O:21])=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: OCC(F)F
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(NC)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(NC)cc1OCC(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,2-difluoroethanol (1.7 g; 20.6 mmol) in THF (50 mL) is added to a solution of ethyl 2-fluoro-4-(methylamino)-5-nitrobenzoate (5.0 g; 20.6 mmol) in DMF (100 mL). Sodium hydride (0.824 g; 60%; 20.6 mmol) is added in portions and the mixture is stirred overnight at rt. A solution of TFA (30 mL; 0.45 M aq) is added and the mixture is concentrated. The resulting precipitate is filtered off, washed with water, dried and recrystallized from EtOH/water to give the sub-title compound. Yield: 4.8 g (76%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5].[C:15]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:16][C:17]([CH3:19])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[N:1]=[C:17]([CH3:19])[C:16]=1[C:15]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CC(C)COc1cccc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)C)c2c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 2-amino-6-isobutoxybenzonitrile (Example 41b, 16.4 g, 86.32 mmol) and ethyl acetoacetate (10.9 mL, 86.32 mmol) in anhydrous toluene (200 mL) was added SnCl4 (19.9 mL, 172.63 mmol) over a period of 15 minutes at room temperature under nitrogen. The stirred reaction mixture was then refluxed for 3.5 h under nitrogen. After it was cooled down to room temperature, the reaction solution was concentrated to remove most of the solvent under reduced pressure. The residue was re-dissolved in EtOAc (3 L) and carefully neutralized to pH 8 with aqueous NaOH solution (6.0 N, ˜110 mL) at 0° C. The resultant mixture was stirred at room temperature overnight. The precipitate was filtered off, and the organic layer was separated and washed with brine (400 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 50% EtOAc in hexanes to give the title compound as a white solid (18.0 g, 69%). MS 303 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1.[CH2:16]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32](O)=[O:33])=[C:24]1[CH3:35])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]([N:1]2[CH2:6][CH2:5][C:4]3([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[O:7]3)[CH2:3][CH2:2]2)=[O:33])=[C:24]1[CH3:35])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1c(C(=O)O)c2ccccc2n1Cc1ccccc1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Product: Cc1c(C(=O)N2CCC3(CC2)OC(=O)c2ccccc23)c2ccccc2n1Cc1ccccc1

Procedure:
Following the general procedure I as described above, the acylation of 3H-spiro[2-benzofuran-1,4′-piperidin]-3-one prepared as described in example 16 above with 1-benzyl-2-methyl-1H-indole-3-carboxylic acid (preparation described in example 1), gave the title compound. ES-MS m/e (%): 451.6(M+H+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([NH:26][C:27]1[C:32]([CH2:33][O:34][CH3:35])=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[N:28][C:27]([NH:26][CH2:24][CH3:25])=[C:32]([CH2:33][O:34][CH3:35])[CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CCNc1ncc(B2OC(C)(C)C(C)(C)O2)cc1COC
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1COC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (stage 205.1.1, 0.067 mmol) and ethyl-[3-methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine (Stage 206.1.1) to give the title compound as a yellow solid. (HPLC: tR 2.20 min (Method A); M+H=458 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.22-8.18 (m, 1H), 8.13 (s, 1H), 8.05-8.00 (m, 1H), 7.88-7.84 (m, 1H), 7.45-7.40 (m, 2H), 6.09 (t, 1H), 4.38-4.30 (m, 2H), 3.92 (s, 3H), 3.56 (s, 3H), 3.45-3.37 (m, 2H), 3.33 (s, 3H), 1.95 (s, 3H), 1.14 (t, 3H))
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:13]3[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:12])=[N:8][C:7]=2[CH:32]=1)#[N:2].[CH3:33][Mg]Cl>C1COCC1>[C:28]([O:27][C:25]([N:17]1[C:18]2[C:14](=[C:13]([C:11]([C:9]3[O:10][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:32][C:7]=4[N:8]=3)([OH:12])[CH3:33])[C:21]([O:22][CH3:23])=[CH:20][C:19]=2[CH3:24])[CH:15]=[CH:16]1)=[O:26])([CH3:29])([CH3:31])[CH3:30]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(=O)c1nc2cc(C#N)ccc2o1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(O)c1nc2cc(C#N)ccc2o1
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 4-(5-cyanobenzo[d]oxazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (600 mg, 1.39 mmol) in THF (14 mL) at 0° C. methylmagnesium chloride, 3M in THF (1.39 mL, 4.17 mmol) was added. The reaction mixture was stirred for 15 min and then quenched with a saturated aq. solution of NH4Cl at 0° C. The layers were separated and the aqueous layer was extracted with EtOAc. The organic phase was dried over MgSO4 filtered and concentrated. The resulting residue was absorbed onto silica and purified by flash chromatography (0-50% EtOAc:heptanes) to give the title compound. MS (ESI+) m/z 448.22 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([N:6](CC2C=CC(OC)=CC=2)[S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[C:25]([OH:26])=[CH:24][C:23]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=4)=[C:22]([F:35])[CH:21]=2)[C:15](=[O:36])[CH:14]=[CH:13]3)(=[O:9])=[O:8])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:53]([CH3:56])[C:54]#[N:55].O>CN(C=O)C>[C:54]([CH:53]([O:26][C:25]1[C:20]([N:16]2[C:17]3[C:12](=[CH:11][C:10]([S:7]([NH:6][C:3]4[CH:4]=[CH:5][O:1][N:2]=4)(=[O:8])=[O:9])=[CH:19][CH:18]=3)[CH:13]=[CH:14][C:15]2=[O:36])=[CH:21][C:22]([F:35])=[C:23]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)[CH:24]=1)[CH3:56])#[N:55]
Reactant: CC(Br)C#N
Reactant: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(-c4cc(F)cc(F)c4)cc3O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C#N)Oc1cc(-c2cc(F)cc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 16 h

Procedure:
To a solution of N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1-(2,3′,5′-trifluoro-5-hydroxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide (0.066 g, 0.104 mmol) in DMF (0.208 ml) at room temperature was added potassium carbonate (0.016 g, 0.115 mmol) followed by 2-bromopropanenitrile (0.014 ml, 0.156 mmol). The reaction mixture was stirred 16 hr. The resulting mixture was transferred to a sep.funnel containing water and the aqueous layer was washed 3× with DCM. The organic layers were combined, dried with MgSO4, filtered and concentrated to an oil. The crude material was taken onward to the next step without further purification, assuming quantitative yield. m/z (ESI) 687.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=2[OH:15])[CH:5]=[C:4]([Cl:16])[N:3]=1.[CH2:17](O)[CH2:18][CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:17][CH2:18][CH3:19])=[C:8]([C:6]2[CH:5]=[C:4]([Cl:16])[N:3]=[C:2]([NH2:1])[N:7]=2)[CH:13]=1
Reactant: Nc1nc(Cl)cc(-c2cc(Br)ccc2O)n1
Reactant: CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Reaction time: 16 h
Yield: 52.5 %

Procedure:
To the stirred solution of 2-(2-amino-6-chloro-pyrimidin-4-yl)-4-bromo-phenol (0.060 g, 0.20 mmol), 1-propanol (0.036 g, 0.60 mmol), and triphenylphosphine (0.157 g, 0.60 mmol) in tetrahydrofuran (5.0 ml) was added diethyl azodicarboxylate (0.104 g, 0.60 mmol). After stirring for 16 hours, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:6) to provide 4-(5-bromo-2-propoxy-phenyl)-6-chloro-pyrimidin-2-ylamine (0.036 g, 52% yield) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:3]=1.[H-].[Na+].Cl.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19]Cl.C(O)C>CN(C)C=O.O>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][N:9]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)[C:10](=[O:12])[CH3:11]
Reactant: CN(C)CCCl
Reactant: CC(=O)Nc1cc(C)cc(C)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(=O)N(CCN(C)C)c1cc(C)cc(C)n1
Reaction time: 0.25 h

Procedure:
One hundred and seventy seven grams (1.08 moles) of N-(4,6-dimethyl-2-pyridyl)acetamide is dissolved in 1.8 l of dry dimethylformamide in a 3 liter 3-neck flask equipped with a mechanical stirrer, thermometer, drying tube and slow nitrogen sweep. Sodium hydride in mineral oil (57%, 45.5 g) is added over a 30 minute period. After stirring for an additional 15 minutes, one hundred thirteen grams of 2-dimethylaminoethyl chloride hydrochloride is added in three portions over a 30 minute period. This is followed by 25.7 g of sodium hydride added in portions over a 60 minute period. Then 58.7 g of 2-dimethylaminoethyl chloride hydrochloride is added over a few minute period followed by 25.7 g of sodium hydride. A total of 96.9 g (2.3 mole) of 57% sodium hydride in mineral oil and 171.7 g (1.2 mole) of 2-dimethylaminoethyl chloride hydrochloride are used. The reaction mixture is stirred at 50° for 30 minutes then heated at 95° for 21/2 hours. After adding 75 ml of ethanol and 75 ml of water, the dimethylformamide is removed by distillation in vacuum.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:34])[C:20]([C:27]4[C:28]([CH3:33])=[N:29][O:30][C:31]=4[CH3:32])=[CH:21][C:22]=3[Cl:26])[C:17]2=[O:35])=[C:13]([CH3:36])[CH:12]=[C:11]([CH3:37])[N:10]=1)C1C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:26][C:22]1[CH:21]=[C:20]([C:27]2[C:28]([CH3:33])=[N:29][O:30][C:31]=2[CH3:32])[C:19]([Cl:34])=[C:18]2[C:23]=1[CH2:24][CH2:25][N:16]([CH2:15][C:14]1[C:9](=[O:8])[NH:10][C:11]([CH3:37])=[CH:12][C:13]=1[CH3:36])[C:17]2=[O:35]
Reactant: Cc1cc(C)c(CN2CCc3c(Cl)cc(-c4c(C)noc4C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CN2CCc3c(Cl)cc(-c4c(C)noc4C)c(Cl)c3C2=O)c(=O)[nH]1
Yield: 74.7 %

Procedure:
A solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5,8-dichloro-7-(3,5-dimethyl-1,2-oxazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (253h, 400 mg, 0.75 mmol) in trifluoroacetic acid (10 mL) was stirred at 45° C. for 3 hours, then concentrated under vacuum to remove volatiles. The residue was partitioned between dichloromethane (15 mL) and saturated aqueous sodium bicarbonate solution (4×20 mL). The organic layer was washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, concentrated, and purified by silica gel chromatography (eluting with 10:1 dichloromethane/methanol) to give 5,8-dichloro-7-(3,5-dimethyl-1,2-oxazol-4-yl)-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one (Example 253, 250 mg, 75% yield) as a white solid. 1H NMR (600 MHz, DMSO-17 mm) δ 11.57 (s, 1H), 7.67 (s, 1H), 5.89 (s, 1H), 4.57 (s, 2H), 3.51 (t, J=6.33 Hz, 2H), 2.95 (t, J=6.33 Hz, 2H), 2.24 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H), 2.06 (s, 3H). MS: 446 [M+1].
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][C:11]=1[C:25]1[CH:26]=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:14]2[CH:13]=[CH:12][C:11]([C:25]3[CH:30]=[N:29][C:28]([NH2:31])=[N:27][CH:26]=3)=[C:10]([F:9])[CH:15]=2)=[N:3][CH:4]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 838 using 5-bromopyrazin-2-amine in Step A and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine in Step B. MS (ESI): mass calcd. for C20H15FN6, 358.13; m/z found, 359.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.50-8.44 (d, J=1.4, 2H), 7.95-7.90 (d, J=1.5, 1H), 7.63-7.55 (m, 2H), 7.52-7.44 (m, 3H), 7.43-7.38 (m, 1H), 7.06-7.03 (m, 1H), 7.03-7.01 (dd, J=6.2, 1.6, 1H).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[C:24]([CH:29]=O)[CH:23]=[CH:22]4)=[N:16][CH:17]=2)=[CH:10][CH:9]=[N:8]1.[CH2:33]1[C@@H:37]2[CH2:38][NH:39][CH2:40][CH2:41][N:36]2[C:35](=[O:42])[O:34]1.N1NC(C2C=CC(OC3C=C4C(=CC=3)N=C(CN3CCC(N5CCOC5=O)CC3)C=C4)=NC=2)=CC=1>>[N:8]1[NH:7][C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[C:24]([CH2:29][N:39]3[CH2:40][CH2:41][N:36]5[C:35](=[O:42])[O:34][CH2:33][C@@H:37]5[CH2:38]3)[CH:23]=[CH:22]4)=[N:16][CH:17]=2)=[CH:10][CH:9]=1
Reactant: O=C1OC[C@@H]2CNCCN12
Reactant: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc3nc(C=O)ccc3c2)nc1
Agent: O=C1OCCN1C1CCN(Cc2ccc3cc(Oc4ccc(-c5ccn[nH]5)cn4)ccc3n2)CC1
Product: O=C1OC[C@@H]2CN(Cc3ccc4cc(Oc5ccc(-c6ccn[nH]6)cn5)ccc4n3)CCN12

Procedure:
The title compound 16 is synthesized from intermediate D (0.100 g, 0.220 mmol) and (S)-hexahydro-oxazolo[3,4-a]pyrazin-3-one (48.0 mg, 0.269 mmol) according to the procedure described for the synthesis of compound 11.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5])C.[N+](C1C(C(O)=O)=NNC=1)([O-])=O.S(Cl)(Cl)=O.CO>CCO>[CH3:1][O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5]
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: CO
Product: COC(=O)c1n[nH]cc1[N+](=O)[O-]

Procedure:
The compound was prepared in a manner analogous to 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester (Example 16A) using 4-nitro-1H-pyrazole-3-carboxylic acid (100 g, 636 mmol), thionyl chloride (55.5 ml, 764 ml) and MeOH (750 ml), instead of EtOH. 4-Nitro-1H-pyrazole-3-carboxylic acid methyl ester was obtained as an off-white solid (109 g, 100%). (LC/MS (acidic method): Rt 1.82 min, [M+H]+ 172).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:12][CH2:13][CH:14]=[CH2:15])=[CH:6][CH:5]=1)([O-])=O.Cl.[OH-].[Na+]>[Fe].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH:11]([CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:12][CH2:13][CH:14]=[CH2:15])=[CH:8][CH:9]=1
Reactant: C=CCCC(CCC=C)Oc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C=CCCC(CCC=C)Oc1ccc(N)cc1
Yield: 688.6 %

Procedure:
A 300 ml-capacity three neck flask containing a stirring bar and connected to a condenser was sufficiently dried. Then, a nitrogen atmosphere was established in the flask. 1-nitro-4-(1,8-nonadiene-5-yloxy)benzene (11) (4.01 g, 1.4 mmol), an iron powder (3.13 g, 5.6 mmol), and ethanol (50%, 10 ml) were introduced into the flask, and the mixture thus obtained was started to be stirred while heating the flask in an oil bath. Further, HCl (0.52 ml) and ethanol (50%, 2.5 ml) were slowly added to the mixture, which was then stirred for 2 hours. Thereafter, an aqueous sodium hydroxide solution was added to the mixture to stop the reaction, and an organic layer was extracted with ethyl acetate. This organic layer was dried over Na2SO4 and filtered, a solvent was distilled of under reduced pressure, and the organic layer was purified by flash chromatography on silica gel (hexane:ethyl acetate=10:1). Thus, 1-amino-4(1,8-nonadiene-5-yloxy)benzene (12) (2.39 g, 9.64×10−3 mol, yield: 69%) was obtained as an intended compound.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34]C(=O)OCC3C=CC=CC=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]=O)=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=O)(C)(C)C.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>>[NH2:34][C:33]1[C:24]([C:22]([NH:21][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10]2)=[O:23])=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([CH2:45][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)[CH:27]=2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc3cc(C=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Reactant: C1COCCN1
Product: Nc1cc2ccc(CN3CCOCC3)cc2nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1

Procedure:
The title compound was prepared according to the procedure of Example 19 using benzyl (2-{[(4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-formylquinolin-3-yl)carbamate and morpholine as the starting materials to give the title compound in 40% yield. LCMS calc. for C25H32N7O2 (M+H)+: m/z=462.3. Found: 462.2.
Reaction SMILES: NS(C1C=CC(CCN[C:14]([C:16]2[CH:21]=[N:20][C:19]([CH3:22])=[CH:18][N:17]=2)=[O:15])=CC=1)(=O)=O.CC1N=CC([C:30](O)=[O:31])=NC=1>CO>[CH3:30][O:31][C:14]([C:16]1[CH:21]=[N:20][C:19]([CH3:22])=[CH:18][N:17]=1)=[O:15]
Reactant: Cc1cnc(C(=O)NCCc2ccc(S(N)(=O)=O)cc2)cn1
Reactant: Cc1cnc(C(=O)O)cn1
Solvent: CO
Product: COC(=O)c1cnc(C)cn1

Procedure:
According to the invention there is provided a process for the preparation of N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of the formula I: ##STR15## consisting of: i) treating 5-methylpyrazine-2-carboxylic acid of the formula VIII: ##STR16## with methanol under reflux to obtain 5-methylpyrazine-2-carboxylic acid methyl ester of the formula VIII A ##STR17## ii) reacting 5-methylpyrazine-2-carboxylic acid methyl ester of the formula VIII A with 2-phenylethylamine of the formula II: ##STR18## at 100° to 200° C. to obtain 5-methylpyrazine 2-(2-phenylethyl) carboxamide of the formula IX: ##STR19## iii) chlorosulfonating the 5-methylpyrazine-2(2-phenylethyl)carboxamide of the formula IX with chlorosulfonic acid at 0°-45° C. to obtain [N-[2-[4-Chlorosulfonyl)phenyl]ethyl]-5-methylpyrazine carboxamide] of the formula X: ##STR20## iv) and treating the (N-[2-[4-(chlorosulfonyl)phenyl]ethyl]-5-methyl pyrazine-carboxamide] of the formula X with ammonia to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine carboxamide of the formula I.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([O:11][CH3:12])[C:3]=1[O:13][CH2:14][O:15][CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[C:36](=[O:40])[O:35][CH2:34]3)O1>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[C:36](=[O:40])[O:35][CH2:34]3)=[C:3]([O:13][CH2:14][O:15][CH3:16])[C:4]=1[O:11][CH3:12])[CH3:10]
Reactant: CCOc1ccc(Br)c(OCOC)c1OC
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(OCOC)c1OC
Temperature: 85 °C
Yield: 40.2 %

Procedure:
A stirring solution of 1-bromo-4-ethoxy-3-methoxy-2-(methoxymethoxy)benzene (200 mg, 0.722 mmol) in dimethylformamide (5 mL) was purged with argon for 1 h, to this cesium carbonate (700 mg, 2.166 mmol), Pd(PPh3)4 (41 mg, 0.036 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one (280 mg, 1.08 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded 5-(4-Ethoxy-3-methoxy-2-(methoxymethoxy)phenyl)isobenzofuran-1(3H)-one as a solid (100 mg, 40%).