Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21]Cl>>[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1c(O)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)CCOc1cccc(F)c1[N+](=O)[O-]

Procedure:
1.82g of 3-fluoro-2-nitrophenyl (2-dimethylaminoethyl) ether were prepared in analogous manner to that described in a) above from 2g of 3-fluoro-2-nitrophenol using potassium carbonate and 2-dimethylaminoethyl chloride generated from the more stable hydrochloride salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45](O)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45]([NH:5][C:4]2[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:3]=2[O:2][CH3:1])=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]
Reactant: COc1ccc(OC)c(N)c1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cc(OC)ccc3OC)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.9 %

Procedure:
2,5-Dimethoxyaniline (0.172 g, 1.125 mmol), triethylamine (0.114 g, 1.125 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.190 g, 1.125 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.281 g, 0.750 mmol) and the resulting solution was stirred at room temperature for 4 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=95:5) to obtain the titled compound (0.149 g, 0.292 mmol, 39%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1>C(O)(=O)C>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])=[C:15]([F:20])[CH:14]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Br)cc1F
Reaction time: 0.5 h

Procedure:
A solution of 10 parts of 3,4,5,6-tetrahydrophthalic anhydride in 100 parts of glacial acetic acid was treated in one portion with 11 parts of 4-bromo-2-fluoroaniline and was stirred for 30 minutes. The reaction mixture was refluxed for 16 hours and then poured over 200 parts ice. The resulting purple crystals were filtered and recrystallized from 100 parts methanol at -40°C to yield 13 parts of pink plates of 2-(4-bromo-2-fluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione melting at 102.0°-102.5°C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)[CH:9]=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([N:8]3[C:6]4=[N:7][C:2]([C:24]5[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=5)=[CH:3][N:4]=[C:5]4[N:10]=[CH:9]3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: Brc1cnc2ncn(-c3ccc4[nH]ccc4c3)c2n1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cc(-c2cnc3ncn(-c4ccc5[nH]ccc5c4)c3n2)cc(OC)c1OC
Temperature: 150 °C

Procedure:
Following a method described in Pteridines, 2002, Vol. 13, 65-72, Intermediate BB was heated in anhydrous DMF at 175° C. for 15 min in a Personal Chemistry Optimizer. To the resulting 6-bromo-1-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazine 1 in CH3CN (1 mL) in a microwave reaction vial was added 3,4,5-trimethoxyphenylboronic acid (30 mg, 0.14 mmol), bis(triphenylphosphine)-palladium(II) dichloride (7.0 mg, 0.010 mmol), and 1 M Na2CO3 (1 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for 10 min in a Personal Chemistry Optimizer. The resulting mixture was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to give a residue that was purified via preparatory HPLC to give 4.7 mg of the title compound. HPLC retention time: 2.43 minutes; MS ESI (m/z): 402.8 (M+1)+, calc. 401.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6](=[O:31])[C:7]([C:29]#[N:30])=[N:8][NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([S:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[NH:20][N:19]=2)=[C:12]([Cl:28])[CH:11]=1)C.C([O-])(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[Cl:28][C:12]1[CH:11]=[C:10]([N:9]2[C:4](=[O:3])[NH:5][C:6](=[O:31])[C:7]([C:29]#[N:30])=[N:8]2)[CH:15]=[C:14]([Cl:16])[C:13]=1[S:17][C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[NH:20][N:19]=1
Reactant: CCOC(=O)NC(=O)C(C#N)=NNc1cc(Cl)c(Sc2cc(C(C)C)c(=O)[nH]n2)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)c1cc(Sc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Temperature: 120 °C
Yield: 103.2 %

Procedure:
A solution of (2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester (86) (2.98 g, 5.99 mmol) in glacial acetic acid (60 mL) was treated with sodium acetate (2.46 g, 29.95 mmol). The resulting mixture was heated to 120° C. for 3 h. At this time, LCMS indicated complete consumption of the starting material and conversion to product. The reaction was cooled to 25° C., poured onto water (200 mL) and was extracted with ethyl acetate (2×150 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×150 mL), dried with magnesium sulfate, filtered and concentrated under vacuum to give an orange solid. This solid was dissolved in a 1:1 methylene chloride:hexanes mixture and concentrated in vacuo three times. It was then dissolved in a 1:1 methylene chloride: methanol mixture and concentrated under vacuum to afford 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (87) (2.79 g) as an orange solid. The material was used without further purification; ES(+)-HRMS m/e calcd for C17H12Cl2N6O3S (M+H)+ 451.0142, found 451.0143. Exact Mass=450.0069; Molecular weight=451.29
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Br:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.O>CN(C=O)C>[Br:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: Oc1cccc(Br)c1
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
2-Bromomethylnaphthalene (5.00 g, 22.6 mmol) was dissolved in N,N'-dimethylformamide (100 ml) and potassium carbonate (9.4 g, 68 mmol) and 3-bromophenol (3.91 g, 22.6 mmol) were added. The mixture was stirred vigorously for 16 h at room temperature and then poured into water (700 ml). The precipitate was filtered off, washed with water and dried in vacuo at 50° C. for 16 h to give 6.17 g (87%) of 2-(3-bromophenoxymethyl)naphthalene as a solid.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CCCCCC>[CH:8](=[C:1]1[C:2](=[O:3])[CH2:4][O:5][C:6]1=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1COC(=O)C1
Agent: Cl
Solvent: CCCCCC
Product: O=C1COC(=O)C1=Cc1ccccc1

Procedure:
Tetronic acid (300 mg, 3 mmol) was added to benzaldehyde (1.0 mL, 9 mmol), and the resulting solution was stirred. HCl (37.7%, 0.1 mL) was added drop wise. The reaction mixture was vigorously stirred until it solidified. The solid product was crushed, soaked in hexane and washed with hexane. The crude product was purified by recrystallization (ethyl acetate/hexanes=8/2) to give compound TC-I-49 (0.27 g, 48%) as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:30]Cl.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=C(OC)C(OC)=C(OC)C=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:30][C:29]3[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: COc1cc(Cn2nc3c(c2-c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC3)cc(OC)c1OC
Product: COc1cc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc(OC)c1OC
Yield: 7 %

Procedure:
The title compound (0.006 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 3,4,5-trimethoxybenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(3,4,5-trimethoxy-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C23H26ClN3O3, 427.17; found, m/z 428.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.51-7.49 (m, 2H), 7.46-7.44 (m, 2H), 6.44 (s, 2H), 5.32 (s, 2H), 3.78 (s, 6H), 3.74 (s, 3H), 2.95-2.89 (m, 6H), 2.81-2.79 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.[CH3:18][C:19]1([CH3:25])[CH2:24][O:23][CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C>C(#N)C>[CH3:18][C:19]1([CH3:25])[CH2:24][O:23][CH2:22][CH2:21][N:20]1[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1
Reactant: CC1(C)COCCN1
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)COCCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (80 mg, 0.305 mmol, commercially available from Otava, Kiev, Ukraine) in acetonitrile (2 mL) was added 3,3-dimethylmorpholine (46.2 mg, 0.305 mmol, commercially available, for example from Otava, Kiev, Ukraine or Tyger Scientific, Ewing, USA) and triethylamine (0.127 mL, 0.914 mmol). The reaction mixture was then heated to 120° C. for 50 min in a microwave reactor. The reaction mixture was concentrated in vacuo and the crude product was purified by MDAP. The relevant fractions were combined and concentrated in vacuo. The product was dissolved in DCM and 1N HCl in ether (110 uL) was added. The mixture was concentrated in vacuo, triturated with ether, then dried in vacuo to yield the title compound (white crystals, 40 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21]C2C=CC=CC=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:36]([NH:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[Br:28])=[O:37])(=[O:13])=[O:12])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2Nc2ccccc2)cc1
Reactant: O=C=Nc1ccccc1Br
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2NC(=O)Nc2ccccc2Br)cc1
Yield: 23.8 %

Procedure:
The urea was synthesized from 2-[(4-acetamidophenyl)sulfonylamino]phenyl aniline(1 mmol) and 2-bromophenylisocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.12 g, 24%). EI-MS mn/z 501(M−H)−.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21](C(OCC)C)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCCC1.Cl.[OH-].[Na+]>COC(C)(C)C>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(C)n1cc(-c2ncnc3c2ccn3COC(=O)C(C)(C)C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Method A. To a 1 L round bottom flask equipped with a stir bar and nitrogen inlet was charged {4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7yl]methyl pivalate (18, theoretical amount 41.6 g, 0.112 mol) made as described above and tetrahydrofuran (THF, 610 mL, 7.5 mol) at room temperature, and the resulting mixture was treated with an 2.0 N aqueous solution of hydrochloric acid (140 mL, 0.28 mol, 2.5 equiv) at room temperature. The resulting reaction mixture was subsequently stirred at room temperature for overnight. When the reaction was deemed complete, the reaction mixture was cooled to 0-5° C. before pH was adjusted to 9-10 with a 3 M aqueous sodium hydroxide (NaOH) solution (95 mL). The mixture was then extracted with ethyl acetate (2×300 mL) and the combined organic extracts were washed with 20% aqueous brine solution (250 mL), dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure to afford the crude product as off-white to light yellow solids. The crude product was treated with methyl t-butylether (MTBE, 200 mL) and the slurry was warm to reflux for 30 minutes before being cooled to room temperature. The solids were collected by filtration and washed with MTBE (2×40 mL), dried under reduced pressure to afford [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (19, 30.5 g, 33.52 g theoretical, 91% for two steps) as white to off-white solids. For 19: 1H NMR (DMSO-d6, 300 MHz) δ ppm 13.40 (br s, 1H), 8.75 (s, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 7.68 (d, 1H, J=3.8 Hz), 7.11 (d, 1H, J=3.8 Hz), 6.21 (s, 2H), 1.06 (s, 9H); C15H17N5O2 (MW, 299.33), LCMS (EI) m/e 300 (M++H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:28]=[CH:27][N:16]3[C:17](=[O:26])[C:18]([C:21]4[N:22]=[N:23][NH:24][N:25]=4)=[CH:19][N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)(C)(C)[CH3:2].CO[C:31]1C=CC(CN2N=NC(C3C(=O)N4C=CC(C(O)=O)=CC4=NC=3)=N2)=C[CH:32]=1.NC1SC2C=CC=CC=2N=1>>[S:8]1[C:9]2[CH:31]=[CH:32][CH:2]=[CH:1][C:5]=2[N:6]=[C:7]1[NH:10][C:11]([C:13]1[CH:28]=[CH:27][N:16]2[C:17](=[O:26])[C:18]([C:21]3[N:25]=[N:24][NH:23][N:22]=3)=[CH:19][N:20]=[C:15]2[CH:14]=1)=[O:12]
Reactant: COc1ccc(Cn2nnc(-c3cnc4cc(C(=O)O)ccn4c3=O)n2)cc1
Reactant: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)c(-c4nn[nH]n4)cnc3c2)n1
Agent: Nc1nc2ccccc2s1
Product: O=C(Nc1nc2ccccc2s1)c1ccn2c(=O)c(-c3nn[nH]n3)cnc2c1

Procedure:
Reactions were performed in the same manner as in Example 10, (F) by using 3-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carboxylic acid (60 mg, 0.16 mmol) and 2-aminobenzothiazole (30 mg, 0.17 mmol) to obtain 2 mg (3% for the two steps) of an orange compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([OH:23])=O)=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:24][C:25]([CH3:29])([CH3:28])[C:26]#[N:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:26]([C:25]([NH:24][C:21]([C:18]1[C:16]2=[N:17][C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)=[CH:13][N:14]=[C:15]2[NH:20][CH:19]=1)=[O:23])([CH3:29])[CH3:28])#[N:27]
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CC(C)(N)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C#N)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.6 %

Procedure:
A mixture of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (60 mg, 0.193 mmol), 2-amino-2-methylpropanenitrile (25 mg, 0.29 mmol), HATU (217 mg, 0.57 mmol) and DIEA (74 mg, 0.57 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. Then the mixture was filtered and the cake was washed with DMSO and MeOH to give N-(2-cyanopropan-2-yl)-2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (15 mg, 20.5%) as light yellow solid. MS: (M+H)+=400; 1H NMR (300 MHz, DMSO): δ 13.03 (s, 1H), 9.13 (s, 1H), 8.58 (s, 1H), 8.54-8.50 (m, 1H), 8.35 (s, 1H), 7.32-7.69 (m, 1H), 7.23-7.22 (m, 1H), 4.17 (s, 3H), 1.88 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]2OS(C(F)(F)F)(=O)=O.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[C:28]1([C:8]2[C:7]3[C:12](=[C:3]([C:2]([F:27])([F:26])[F:1])[CH:4]=[CH:5][CH:6]=3)[N:11]=[CH:10][C:9]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Yield: 95.3 %

Procedure:
Ethyl 8-(trifluoromethyl)-4-{[(trifluoromethyl)sulfonyl]oxy}quinoline-3-carboxylate (45.6 g, 109.3 mmol) was taken into dioxane (500 mL). Then phenylboronic acid (26.7 g, 218.6 mmol), K3PO4 (69.6 g, 327.9 mmol) and Pd(PPh3)4 (6.3 g, 5.5 mmol) was added and the reaction was brought to reflux for 1 hour. The reaction was filtered through Celite was still warm and concentrated. The resulting material was passed through a short silica gel plug and concentrated to yield the desired product as a brown viscous liquid (35.96 g). MS (ESI) m/z 346 ([M+H]+).
Reaction SMILES: Cl.[CH3:2][C:3]1[N+:12]([O-])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:14])[NH:8]2.[C:15]([O:18]C(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:18][CH2:2][C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:14])[NH:8]2)(=[O:17])[CH3:16]
Reactant: Cc1c2ccc(=O)[nH]c2cc[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)OCc1nccc2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture containing 38.2 g of 5-methyl-1,6-naphthyridin-2(1H)-one-6-oxide hydrochloride and 300 ml of acetic anhydride was refluxed with stirring on a steam bath for 48 hours and then the reaction mixture was cooled to room temperature. The separated product was collected, recrystallized from dimethylformamide and dried in vacuo at 80° C. to produce 10.5 g of 5-[(acetyloxy)methyl]-1,6-naphthyridin-2(1H)-one as its hydrochloride, m.p. 162°-165° C. with decomposition.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH2:16][CH:10]([CH2:11][S:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[OH:18]>O>[CH2:1]([N:8]1[CH2:15][CH:14]2[CH2:16][CH:10]([CH2:11][S:12](=[O:18])[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CC3CSCC(C3)C2)cc1
Reactant: CO
Solvent: O
Product: O=S1CC2CC(CN(Cc3ccccc3)C2)C1
Reaction time: 1 h

Procedure:
A 200-mL flask was equipped with a magnetic stirrer, an ice bath, and a condenser with nitrogen inlet. To a stirred, chilled (5° C.) solution of the amine (27, 1.4 g, 6 mmol) in methanol (60 mL) was added dropwise a solution of NaIO4 (1.35 g, 6.3 mmol) in water (15 mL) over 30 min. After stirring for one hour, the suspension was filtered and washed with methanol (50 mL); the washings and filtrate were combined and concentrated to a residue which was partitioned between H2CCl2 and water (40 mL each). Additional extracts (HCCl3, 3×40 mL) of the aqueous layer were combined with the initial extract, and the solution was dried (Na2SO4) and concentrated to afford an oil which solidified upon standing. Recrystallization (HCCl3 /pentane) of the solid gave 1.15 g (76.9%) of crystalline (49); mp 140°-141° C. IR (KBr) cm-1 3085, 3065, 3030, 2955, 2920, 2895, 2815, 1495, 1020, 740, 705; 1H NMR (DCCl3) δ1.59 [bd, 1 H, H(9), J=13.3 Hz], 1.86 [bd, 1 H, H(9), J=13.2 Hz], 2.20 [d, 2 H, H(2,4)ax, J=11.7 Hz], 2.37 bs, 2 H, H(1,5)], 2.62 [d, 2 H, H(6,8)ax, J=12.0 Hz], 2.78 [d, 2 H, H(2,4)eq, J=11.8 Hz], 3.51 [d, 2 H, H(6,8)eq, J=11.7 Hz], 3.55 [s, 2 H, ArCH2 ], 7.26-7.39 (m, 5 H, Ar--H); 13C NMR (DCCl3) ppm 31.86 [t, C(9)], 32.59 [d, C(1,5)], 57.42 [t, C(2,4)], 58.59 [C(6,8)], 62.88 (ArCH2), 127.20, 128.39, 129.12, 137.67; 15N NMR (DCCl3) ppm 49.37 [N(7)]. Anal. Calcd. for C14H19NOS: C, 67.43; H, 7.68. Found: C, 67.61; H, 7.73.
Reaction SMILES: [CH2:1]([N:4]([CH2:36][CH2:37][CH3:38])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:32][C:33]([OH:35])=[O:34])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)[CH2:19][C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1)[CH2:2][CH3:3].C(Cl)(Cl)Cl.[OH2:43]>>[N:4]1([CH2:36][CH2:37][O:34][C:33](=[O:35])[CH2:32][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:36][CH2:37][CH3:38])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:26][C:27]3[NH:28][CH:29]=[CH:30][N:31]=3)[CH2:19][C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:6][O:43][CH2:2][CH2:1]1
Reactant: O
Reactant: CCCN(CCC)CCCCN(CC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)CCCCN(CC(=O)OCCN1CCOCC1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Reaction time: 8 h

Procedure:
The compound (185.8 mg) obtained in Example 65-1 was dissolved in a small amount of water. The solution was added with chloroform and a 1 mol/l sodium hydroxide aqueous solution, and the organic layer and an oily substance were collected, followed by drying with anhydrous magnesium sulfate. After filtration, the solvent was distilled off. An anhydrous DMF solution (2 ml) containing the resultant sodium salt (143.6 mg) and N-(2-hydroxyethyl)morpholine (38 mg) was added with HOBt (37 mg) and WSCI hydrochloride (63 mg) and the whole was stirred overnight. After the solvent was distilled off, the resultant was dissolved in chloroform and washed with a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with chloroform and dried with anhydrous magnesium sulfate. The reaction mixture obtained by distillating the solvent off was purified through silica gel column chromatography (chloroform). The resultant was dissolved in dioxane and a salt was allowed to precipitate with a 4 mol/l hydrogen chloride/dioxane solution. After the solvent was distilled off, the solid substance was pulverized and dried under reduced pressure, thereby obtaining a hydrochloride (143,4 mg) of the subject compound as a white solid.