Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[ClH:43].C(OCC)(=O)C>C(OCC)(=O)C.CO>[ClH:43].[ClH:43].[ClH:43].[ClH:43].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Fc1ccc(C(CN2CCN(CCCCc3cccc4ccccc34)CC2)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.62 g of 1-[2-(4-Fluorophenyl)-2-(4-t-butoxycarbonylpiperazino)ethyl]-4-(4-naphthalen-1-yl-butyl)piperazine was dissolved in a mixture of 3 ml of ethyl acetate and 3 ml of methanol, and 4 ml of 4M hydrogen chloride/ethyl acetate solution was added, followed by stirring at room temperature for 6 hours. The precipitated crystals were collected by filtration, and the crystals were washed with ethyl acetate to give 0.42 g of 1-[2-(4-fluorophenyl)-2-piperazinoethyl]-4-(4-naphthalen-1-yl-butyl)piperazine tetrahydrochloride as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]#[N:19]>C(#N)C>[C:18]([CH2:17][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1)#[N:19]
Reactant: OCCN1CCNCC1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 1-(2-hydroxyethyl)piperazine (2.60 g, 20 mmol) in acetonitrile (35 ml) was added potassium carbonate (3.04 g, 22 mmol) and chloroacetonitrile (1.51 g, 20 mmol) was dropped thereinto with ice cooling. The mixture was stirred at room temperature for 30 minutes and then stirred at 45° C. for 30 minutes. This reaction mixture was filtered off, the filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (100 g of silica gel; developing solvent, chloroform:ammonia-saturated methanol=20:1→10:1) to provide 3.20 g (yield 95%) of 4-(cyanomethyl)piperazine-1-ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[F:15][C:16]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[F:15][C:16]1[C:22]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cccc(C(F)(F)F)c1F

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-fluoro-3-trifluoromethylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[C:15]([NH:18][CH:19]=[O:20])[S:16][CH:17]=1)[C:10]([OH:12])=O.C[Si](CC(N)=O)(C)C.[NH2:29][CH:30]1[C:51](=[O:52])[N:32]2[C:33]([C:48]([OH:50])=[O:49])=[C:34]([CH2:37][S:38][C:39]3[N:43]([CH2:44][C:45]([OH:47])=[O:46])[N:42]=[N:41][N:40]=3)[CH2:35][S:36][C@H:31]12>C(OCC)(=O)C.O.CN(C)C=O>[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[C:15]([NH:18][CH:19]=[O:20])[S:16][CH:17]=1)[C:10]([NH:29][CH:30]1[C:51](=[O:52])[N:32]2[C:33]([C:48]([OH:50])=[O:49])=[C:34]([CH2:37][S:38][C:39]3[N:43]([CH2:44][C:45]([OH:47])=[O:46])[N:42]=[N:41][N:40]=3)[CH2:35][S:36][C@H:31]12)=[O:12]
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1csc(NC=O)n1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
Phosphorus oxychloride (1.01 g.) was added under ice-cooling to dry dimethylformamide (0.48 g.) and the mixture was stirred for 30 minutes at 40° C. Dry ethyl acetate (20 ml.) was added thereto and to the suspension was added at 0° to 5° C. 2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid (syn isomer) (1.26 g.), after which the resulting mixture was vigorously stirred for 30 minutes at the same temperature to give clear yellow solution. On the other hand, trimethylsilylacetamide (6.6 g.) was added to a suspension of 7-amino-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.74 g.) in dry ethyl acetate (60 ml.) and the mixture was stirred at ambient temperature to give a clear solution. To this solution was at a time added the above-obtained ethyl acetate solution with stirring at -20° C., and the resulting mixture was stirred for 2 hours at the same temperature. Water (70 ml.) and ethyl acetate (140 ml.) were added thereto and the mixture was shaken. The organic layer was separated and extracted with a sodium bicarbonate aqueous solution (80 ml.). To the aqueous extract was added ethyl acetate (100 ml.) and the mixture was adjusted to pH 1.5 with conc. hydrochloric acid and thereafter shaken. The ethyl acetate layer was separated, washed with a sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off and the residue was washed with ether, collected by filtration and dried to give 7-[2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.12 g.).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:22]2[CH:23]=[N:24][CH:25]=[CH:17][C:18]=2[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1ccc(Oc2ccccc2)cc1
Product: O=C(O)c1ccncc1NCc1ccc(Oc2ccccc2)cc1
Yield: 36 %

Procedure:
The title compound was prepared in 36% yield from 4-phenoxybenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.42 (br s, 1H), 8.18 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.57 (d, 1H, J=5.0 Hz), 7.35-7.40 (m, 4H), 7.13 (t, 1H, J=7.2), 6.97-7.02 (m, 4H), 4.55 (s, 2H). [M+H] calc'd for C19H16N2O3, 321. Found 321.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][NH2:14])[C:5]=2[O:4][CH2:3][CH2:2]1.Br[CH2:16][CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1.C(N(CC)CC)C.O>CS(C)=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][NH:14][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: NCCOc1cccc2c1OCCO2
Reactant: BrCCc1c[nH]c2ccccc12
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: c1cc(OCCNCCc2c[nH]c3ccccc23)c2c(c1)OCCO2
Temperature: 90 °C
Reaction time: 14 h

Procedure:
A solution of 2-(2,3-dihydrobenzo[1,4]dioxin-5-yloxy) ethylamine (0.38 g, 1.9 mmol), 3-(2-bromoethyl)-indole (0.24 g, 1.1 mmol) and triethylamine (0.22 g, 2.2 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir for 14 hours at 90° C. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene choride plus ammonium hydroxide) afforded 0.19 g (52%) as a yellow oil.
Reaction SMILES: [C:1]([O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[Br:23][C:24]1[C:25]([N:39]2[CH2:44][CH2:43][CH2:42][C@@H:41]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:40]2)=[C:26]2[C:32]([NH:33][C:34]([CH:36]3[CH2:38][CH2:37]3)=[O:35])=[CH:31][NH:30][C:27]2=[N:28][CH:29]=1.O>CN(C1C=CN=CC=1)C.ClCCl>[C:9]([O:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10].[Br:23][C:24]1[C:25]([N:39]2[CH2:44][CH2:43][CH2:42][C@@H:41]([NH:45][C:46]([O:47][C:48]([CH3:49])([CH3:51])[CH3:50])=[O:52])[CH2:40]2)=[C:26]2[C:32]([NH:33][C:34]([CH:36]3[CH2:38][CH2:37]3)=[O:35])=[CH:31][N:30]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:27]2=[N:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3c2c(NC(=O)C2CC2)cn3C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
di-tert-Butyl dicarbonate (150 mg, 0.687 mmol), DMAP (21 mg, 0.172 mmol) and triethylamine (174 mg, 0.239 mL, 1.72 mmol) were added to a solution of (R)-tert-butyl 1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (274 mg, 0.573 mmol; Example 29, Step B) in anhydrous dichloromethane (6 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was concentrated. The residue was taken up in EtOAc, washed with water (3×10 mL) and brine (3×10 mL), dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20-95% CH di-tert-butyl dicarbonate (150 mg, 0.687 mmol), DMAP (21 mg, 0.172 mmol) and triethylamine (174 mg, 0.239 mL, 1.72 mmol)CN/water, 25CV) to give (R)-tert-butyl 5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (237 mg, 71% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ 10.03 (br s, 1H), 8.48 (s, 1H), 8.19 (s, 1H), 3.93-3.73 (m, 1H), 3.67-3.45 (m, 1H), 3.41-3.30 (m, 1H), 3.06-2.99 (m, 1H), 2.27-2.17 (m, 1H), 2.06-1.95 (m, 1H), 1.90-1.77 (m, 1H), 1.63 (s, 9H), 1.60 (s, 1H), 1.42 (s, 9H), 1.22-1.05 (m, 2H), 1.03-0.85 (m, 2H). LCMS (APCI+) m/z 580 (M+2H)+, Retention time=4.53 minutes.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:13]=[C:14]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:38][C:35]4[CH:34]=[CH:33][C:32]([N:29]5[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]5)=[CH:37][CH:36]=4)[N:24]=3)[CH:9]=[CH:8][CH:7]=2)[CH:13]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN(c1cccc(CNc2cccn3nc(Cl)nc23)c1)S(C)(=O)=O
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(NCc5cccc(N(C)S(C)(=O)=O)c5)cccn4n3)cc2)CC1

Procedure:
169 e) N-Methyl-N-[3-({2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-phenyl]-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (82.0 mg, 0.224 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (48.0 mg, 0.251 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.024 g, 21%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.82 (d, J=6.6 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.42-7.28 (m, 4H), 6.96 (d, J=8.8 Hz, 2H), 6.65 (t, J=7.2 Hz, 1H), 6.54 (s, 1H), 6.29 (d, J=7.6 Hz, 1H), 5.19 (t, J=5.6 Hz, 1H), 4.49 (d, J=5.6 Hz, 2H), 3.30 (s, 3H), 3.17-3.13 (m, 4H), 2.81 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=521 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:17]#[N:18].[O:19]1[C:23]([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)=[CH:22][CH:21]=[N:20]1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:28][C:27]1[CH:26]=[CH:25][C:24]([C:23]2[O:19][N:20]=[CH:21][CH:22]=2)=[CH:30][CH:29]=1)#[N:18]
Reactant: CC(C)C[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Reactant: Nc1ccc(-c2ccno2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)C[C@@H](Nc1cnc(C#N)c(Nc2ccc(-c3ccno3)cc2)n1)C(N)=O
Reaction time: 20 h
Yield: 5 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-4-methylpentanamide (68 mg, 0.254 mmol), 4-(isoxazol-5-yl)aniline (60 mg, 0.375 mmol), K2CO3 (80 mg, 0.579 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(4-(isoxazol-5-yl)phenylamino)pyrazin-2-ylamino)-4-methylpentanamide (5 mg).
Reaction SMILES: [CH:1]1([CH:5]([C:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:17]=2[CH3:27])[O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:28][NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:5]([C:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:17]=2[CH3:27])[O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:29]([CH3:28])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:12])=[CH:14][CH:15]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1oc(-c2ccccc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCC1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1oc(-c2ccccc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
A solution of 4-[cyclobutyl(2-methyl-5-phenylfuran-3-yl)methoxy]benzoic acid (127 mg), ethyl 3-(methylamino)propanoate (55 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), hydroxybenzotriazole monohydrate (64 mg) and triethylamine (59 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (3 mL), tetrahydrofuran (3 mL) and 1N lithium hydroxide (2.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (115 mg, 73%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][NH:6][N:5]=1)[CH3:3].[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([N:6]2[CH:7]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:4]([CH:2]([CH3:1])[CH3:3])=[N:5]2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c[nH]nc1C(C)C
Reactant: COc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: COC(=O)c1cn(-c2cccc(OC)c2)nc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Methyl 3-(1-methylethyl)-1H-pyrazole-4-carboxylate (2.8 g) synthesized in Example 7(1) was dissolved in N,N-dimethylacetamide (50 mL), 3-methoxyphenylboronic acid (5.0 g), copper acetate (6.0 g) and pyridine (5.3 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (3.4 g, 75%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]([CH3:10])=[N:3]1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[CH2:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1>C1COCC1>[O:25]=[C:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([CH2:15][C:14]3[CH:13]=[C:12]([NH:11][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=4)=[O:8])[CH:28]=[CH:27][CH:26]=3)=[CH:17][CH:18]=2)[NH:22]1
Reactant: Nc1cccc(Cc2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(Cc3ccc4c(c3)NC(=O)C4)c2)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
A dry 25 mL flask was charged with 2,5-Dimethyl-2H-pyrazole-3-carbonyl chloride (0.146 g, 0.924 mmol) and THF (2 mL). 6-(3-Amino-benzyl)-1,3-dihydro-indol-2-one (as prepared in Example 91, 0.200 g, 0.840 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (2 mL). The ethanolic solution was treated with 1M NaOH(aq) (1 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The precipitate that formed was filtered and washed with THF (˜2 mL) affording the 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indol-6-ylmethyl)-phenyl]-amide (0.115 g, 0.319 mmol, 38%).
Reaction SMILES: [NH3:1].[Cl:2][CH2:3][CH:4]1[C:12]2[C:11]3[CH:13]=[CH:14][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:16][C:10]=3[C:9]([N+:21]([O-:23])=[O:22])=[CH:8][C:7]=2[N:6]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:5]1.O.Cl>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[Cl:2][CH2:3][CH:4]1[C:12]2[C:11]3[CH:13]=[CH:14][C:15]([S:17]([NH2:1])(=[O:19])=[O:18])=[CH:16][C:10]=3[C:9]([N+:21]([O-:23])=[O:22])=[CH:8][C:7]=2[N:6]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:5]1
Reactant: O=C(N1CC(CCl)c2c1cc([N+](=O)[O-])c1cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Reactant: N
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: NS(=O)(=O)c1ccc2c3c(cc([N+](=O)[O-])c2c1)N(C(=O)C(F)(F)F)CC3CCl
Temperature: 25 °C
Yield: 76.8 %

Procedure:
Conc. aqueous NH3 (0, 32 mL, 4.7 mmol) was added to a solution of 116 (215 mg, 0.47 mmol) in THF (10 mL) at −78° C. After 10 min water (10 mL), aqueous HCl (2 N, 5 mL, 9.4 mmol), and EtOAc (20 mL) were added and the mixture was allowed to warm to room temperature. Brine was added and the mixture was extracted with EtOAc (×2). The combined extracts were washed with brine and dried, and the EtOAc solution was evaporated onto silica. Chromatography eluting with EtOAc/petroleum ether (1:10 then 1:3 then 2:1) gave 1-(chloromethyl)-5-nitro-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-7-sulfonamide (123) (158 mg, 77%) as a pale yellow solid: mp (EtOAc) 274-278° C. (dec.); 1H NMR [(CD3)2SO] δ 9.11 (s, 1H), 8.89 (d, J=1.6 Hz, 1H), 8.50 (d, J=8.9 Hz, 1H), 8.11 (dd, J=8.9, 1.7 Hz, 1H), 7.66 (s, 1H), 4.73-4.64 (m, 2H), 4.57-4.49 (m, 1H), 4.24-4.11 (m, 2H). Anal. (C15H11ClF3N3O5S) C, H, N.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH2:39]([NH:41][CH2:42][CH3:43])[CH3:40]>CN(C=O)C>[CH2:39]([N:41]([CH2:42][CH3:43])[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6])[CH3:40]
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccc(F)c4)cc23)CC1
Temperature: 100 °C
Reaction time: 0.02 h
Yield: 21.6 %

Procedure:
To a solution of 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-fluorophenyl)-1H-indazole-7-carboxamide (0.222 mmol) in DMF (4 mL) was added K2CO3 (61 mg, 0.444 mmol) and diethyl amine (115 uL, 1.11 mmol). The reaction mixture was heated to 100° C. overnight. The solution was filtered and the filtrate was purified by using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 10% B to 80% B in 10 min, hold for 1 min where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (24.7 mg, 22% for 2 steps).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]([O:21]C)=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:23]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([C:19]([NH2:23])=[O:21])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnn(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: N
Solvent: CO
Product: NC(=O)c1cnn(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 80 °C
Yield: 15 %

Procedure:
A solution of methyl 1-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazole-4-carboxylate (0.9 g, 0.003 mol) in 10 mL of methanol in a sealed tube treated with excess liquid ammonia at low temperature. Then the reaction mixture was heated at 80° C. for 48 hours. Solvent was removed and the residue was triturated with ethyl acetate to give 0.13 g of product as a yellow solid (15% yield), mp 215-216° C.; Anal. Calcd. For C15H11FN4O: C, 63.38; H, 3.93; N, 19.85. Found: C, 63.21; H, 3.98; N, 19.37.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].ClCCl.[NH2:11][C:12]1[CH:37]=[CH:36][C:15]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[N:31]([CH3:32])[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[CH:27]=3)[CH2:22][CH2:21]2)=[CH:14][CH:13]=1>C(Cl)(Cl)Cl.[OH-].[Na+]>[CH3:32][N:31]1[C:26]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][O:16][C:15]3[CH:36]=[CH:37][C:12]([NH:11][C:3](=[O:4])[C:2]([F:7])([F:6])[F:1])=[CH:13][CH:14]=3)[CH2:21][CH2:22]2)=[CH:27][C:28](=[O:35])[N:29]([CH3:34])[C:30]1=[O:33]
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1c(N2CCN(CCCOc3ccc(N)cc3)CC2)cc(=O)n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cn1c(N2CCN(CCCOc3ccc(NC(=O)C(F)(F)F)cc3)CC2)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
0.5 ml of anhydrous trifluoroacetic acid was added dropwise at 0° C. to 20 ml of a dichloromethane solution containing 1.1 g of 6-[4-(3-[4-aminophenoxy]propyl)piperazin-1-yl]-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione obtained in Example 6, and the solution was then stirred at the same temperature for 10 minutes and further at room temperature for 1 hour. Next, the reaction mixture was diluted with 100 ml of chloroform and 50 ml of a 0.5N aqueous sodium hydroxide solution so as to dissolve insolubles therein, and the resultant organic layer was then separated. The aqueous layer was neutralized and then extracted with 50 ml of chloroform, and the extract layer was mixed with the organic layer previously separated and the mixture was dried and then concentrated to obtain 0.52 g (yield: 38% ) of 1,3-dimethyl-6-[4-(3-[4-trifluoroacetylaminophenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.