Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[Zn]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:30][CH:31]=2)=[O:16])=[CH:17][CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [Zn]c1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)c2c[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
To a 0° C. solution of 4-(N-tert-butoxycarbonylaminomethyl)benzoic acid (5.07 g, 20.2 mmol) in CHCl3 was added DMF (200 μL) and oxalyl chloride (1.94 mL, 22.2 mmol). The cold bath was removed and the reaction mixture was stirred for 2 hours at ambient temperature, after which it was concentrated in vacuo. The residue was taken up in CH2Cl2 and added to a solution of indolylzinc (50.5 mmol, prepared as described in Example 1, step 4, except substituting indole for 6-(4-fluorophenyl)indole). The reaction mixture was stirred for 16 hours at ambient temperature, then quenched with saturated aqueous NH4Cl and partitioned between CH2Cl2 and saturated aqueous NH4Cl. The solids were filtered off and rinsed with CH2Cl2. The layers were separated and the organic phase was dried over MgSO4, filtered, and concentrated in vacuo. Pure 3-[4-(N-tert-butoxycarbonylaminomethyl)benzoyl]indole (3.10 g) was obtained by chromatography on silica gel (60% ether/hexanes, then 60% ethyl acetate/hexanes).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.[NH2:28][CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>C1COCC1.C(Cl)Cl>[NH2:34][C:33]1[CH:35]=[CH:36][C:30]([CH2:29][NH:28][C:2]2[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=3)[N:3]=2)=[CH:31][CH:32]=1
Reactant: NCc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(N)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
To a solution of the tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (2 g, 4.94 mmol) in THF (10 mL) was added 4-(aminomethyl)aniline (0.616 mL, 5.44 mmol) and Hunig's Base (3.45 mL, 19.76 mmol). The resulting mixture was stirred for 16 h. The reaction was then warmed to 65° C. for 2 h at which point the reaction became a homogeneous solution. The reaction was cooled and diluted with DCM and washed with water and brine. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum to give an oily residue. The residue was purified by silica gel chromatography using 40% EtOAc/Hexanes to give tert-butyl 4-(4-(4-aminobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1.5 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([CH3:18])[S:16][CH2:15][CH2:14][NH:13][C:12](=[S:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[K+].O.[CH3:22]I>O1CCCC1>[Si:1]([O:8][CH2:9][C@:10]1([CH3:18])[S:16][CH2:15][CH2:14][N:13]=[C:12]([S:17][CH3:22])[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)CC(=S)NCCS1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSC1=NCCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h
Yield: 100 %

Procedure:
The compound (2.00 g, 6.54 mmol) obtained in Example 4-0) was dissolved in tetrahydrofuran (11 mL). Potassium hydroxide (2.16 g, 39.72 mmol), water (7 mL), and methyl iodide (2.44 mL, 39.27 mmol) were added to the solution at room temperature, and the mixture was stirred for 1 h under a nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate (50 mL), and the organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.09 g, quant.) in a yellow oily form.
Reaction SMILES: OS(O)(=O)=O.C[C:7]1[C:12](C)=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:14].C([O-])([O-])=O.[Na+].[Na+].[N+:21]([O-])([OH:23])=[O:22]>>[N+:21]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:14])([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc[n+]([O-])c1C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 400 mL of concentrated H2SO4 was added slowly 130 g of impure 2,3-dimethylpyridine N-oxide. Fuming HNO3 (330 mL) was slowly added at a rate to keep the temperature between 120° C. and 170° C. After addition was complete, the temperature was held at 103° C. for 3 hours and then the reaction was cooled. The crude reaction was added to 1 kg ice in a large pan, then, with stirring, 1.1 kg Na2CO3 was added. After cooling to room temperature, the solids were removed by suction filtration from the solution. The filtrate was extracted with chloroform. The solids were washed with hot chloroform (3 times). The combined reduced organic extracts yielded 110 g of the crude desired nitropyridine N-oxide as an orange solid. ##STR8## 4-acetylamino-2,3-dimethylpyridine
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[CH:20][C:19]=1O.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[CH:20][C:19]=1[O:15][C:14](=[O:16])[CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reaction time: 48 h

Procedure:
Dissolve 2.5 g. of t-butoxycarbonyl-glycyl-glycine in dimethylformamide (20 ml.) containing 2,4,5-trichlorophenol (2.13 g.) and N-hydroxysuccinimide (1.4 g.) . Cool the solution in an ice bath and stir while adding dicyclohexylcarbodiimide (2.44 g.) in dimethylformamide (5 ml.). Allow the reaction mixture to stand at room temperature for 48 hours, filter the reaction mixture and evaporate the filtrate to dryness under reduced pressure. Chromatograh the residue on silica gel (150 g.). The desired product is eluted with 20% ethyl acetate/chloroform and crystallized from ether-hexane (m.p. 90°-91° C.).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][NH:19][C:18]2=[O:22])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[H-].[Na+].[CH2:25](I)[CH3:26].Cl>O1CCCC1.C(OCC)C.O>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([CH2:25][CH3:26])[C:18]2=[O:22])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)c1cc(C=C2SCNC2=O)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN1CSC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reaction time: 48 h

Procedure:
To a solution of 9.58 g of 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-4-thiazolidinone in 150 ml of tetrahydrofuran were added 1.20 g of a 60% dispersion of sodium hydride in mineral oil. After gas evolution ceased, 2.4 ml of ethyl iodide were added and the reaction mixture was stirred for two days under an argon atmosphere. The mixture was heated at reflux for six hours, cooled, diluted with diethyl ether and water, and adjusted to pH 3 with 1N hydrochloric acid. The layers were separated, and the organic layer was washed with a saturated sodium bicarbonate solution followed by a saturated sodium chloride solution. Concentration of the dried organic solution and chromatography of the resulting residue over silica gel eluting with a 10-30% ethyl acetate in hexane gradient provided 3.65 g of the desired title product, m.p. 169°-172.5° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([NH2:9])=[O:8])=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)(=O)=O>C(#N)C>[Br:1][C:2]1[C:3]([C:7](=[O:8])[NH2:9])=[N:4][N:5]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH:6]=1
Reactant: NC(=O)c1n[nH]cc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c(C(N)=O)n2)CC1
Yield: 37 %

Procedure:
4-bromo-1H-pyrazole-3-carboxamide (673 mg), potassium carbonate (636 mg) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (1187 mg) in acetonitrile (20 ml) were stirred at 90° C. overnight. The mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 55 to 100% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-(4-bromo-3-carbamoyl-pyrazol-1-yl)piperidine-1-carboxylate (489 mg) as a solid. NMR Spectrum: (DMSOd6): 1.41 (s, 9H), 1.78 (dd, 1H), 1.83 (dd, 1H), 1.96-2.04 (m, 2H), 2.90 (bs, 2H), 4.03 (m, 2H), 4.33-4.41 (m, 1H), 7.30 (s, 1H), 7.44 (s, 1H), 8.14 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[Cl:35][C:36]1[C:37]([O:46][CH2:47][CH:48]2[CH2:52][CH2:51][CH2:50][NH:49]2)=[N:38][CH:39]=[C:40]([C:42]([O:44][CH3:45])=[O:43])[CH:41]=1>CN(C=O)C.CCOC(C)=O>[Cl:35][C:36]1[C:37]([O:46][CH2:47][CH:48]2[CH2:52][CH2:51][CH2:50][N:49]2[C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:38][CH:39]=[C:40]([C:42]([O:44][CH3:45])=[O:43])[CH:41]=1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1cnc(OCC2CCCN2)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (317.0 mg, 0.660 mmol), methyl 3chloro-2-[(2-pyrrolidinyl)methoxy]pyridine-5-carboxylate (172.0 mg, 0.635 mmol), Et3 N (105 ul, 0.756 mmol) in DMF (2.0 mL) was stirred for 1 hr at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure to afford methyl 3chloro-2-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate as a brownish oil. To a stirred solution of this compound in THF (6.0 mL) and H2O (2.0. mL) was added LiOH (45.3 mg, 1.89 mmol), and the reaction mixture was stirred for 5 hr at room temp. The mixture was diluted with n-hexane and extracted with 1N-NaOH. The aqueous layer was acidified by the addition of 1 N HCl and extracted with CHCl3. The extract was washed with brine, dried over Na2SO4. The solvent was removed under a reduced pressure and the obtained crude solid was recrystallized from n-hexane-EtOAc-EtOH to afford 242.2 mg (70%/0) 47 as an orange crystalline powder. mp 122–125; IR (KBr) 3354, 1709, 1593, 1535, 1454, 1257 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 1.67–2.03 (m, 4H), 2.50 (s, 3H), 3.33–3.42 (m, 1H), 3.52 (m, 2H), 3.58 (d, J=4.4 Hz, 1H), 3.83 (s, 3H), 4.27–4.31 (m, 2H), 4.42–4.47 (m, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.87–6.95 (m, 3H), 7.11–7.17 (m, 2H), 7.79 (d, J=8.3 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 8.14 (dd, J=2.0, 8.8 Hz, 1H), 8.46 (s, 1H), 8.56 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 13.06 (br s, 1H); MS (FAB) m/z 553 (M++1); Anal. Calcd for C28H29ClN4O6: C, 60.81; H, 5.29; N, 10.31. Found: C, 60.98; H, 5.50; N, 9.46.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[S:21][N:20]=[C:19]([CH2:22][CH3:23])[N:18]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[S:21][N:20]=[C:19]([CH2:22][CH3:23])[N:18]=2)=[O:12])[C:3]1=[O:15]
Reactant: CCc1nsc(N)n1
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Solvent: Brc1ccccc1
Product: CCc1nsc(NC(=O)c2c(O)cc(C)n(C)c2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.5 %

Procedure:
213 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 120 mg of 5-amino-3-ethyl-1,2,4-thiadiazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 4 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 231 mg of 1,6-dimethyl-N-(3-ethyl-1,2,4-thiadiazol-5-yl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 19) represented by the formula:
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][CH:24]=3)=[C:14]([CH:19]3[CH2:21][CH2:20]3)[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:38][CH3:39])C1C=CC=CC=1>C(O)(C(F)(F)F)=O.C1(SC)C=CC=CC=1>[C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:38][CH3:39])[CH:11]=3)[N:16]=[CH:15][C:14]=2[CH:19]2[CH2:21][CH2:20]2)=[CH:24][CH:25]=1)(=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)c(C3CC3)cnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)c(C3CC3)cnc2cc1O

Procedure:
A mixture of N-[4-(7-benzyloxy-3-cyclopropyl-6-methoxy-quinolin-4-yloxy)-phenyl]-benzamide (50 mg, 0.097 mmol) in TFA (750 μl) and thioanisole (90 μl) was refluxed for 1 hour, cooled and concentrated under high vacuum to use crude in the next stage.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27]>>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:27]
Reactant: O=C(Cl)c1ccco1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccco1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2-furoyl chloride, there is obtained ethyl N-(2-furoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6carboximidate, m.p. 87°-92° C.;
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:28]1([C:34]2[O:38][CH:37]=[N:36][C:35]=2[C:39]([OH:41])=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:39]([C:35]3[N:36]=[CH:37][O:38][C:34]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:41])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ncoc3-c3ccccc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 78 and 5-phenyl-1,3-oxazole-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: [C:1]1([CH:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:8][CH2:9][O:10][C:11](=[O:36])[C:12]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])=[C:16]([C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:27])[C:15]([CH3:34])=[N:14][C:13]=2[CH3:35])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:43](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[C:1]1([CH:7]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:8][CH2:9][O:10][C:11](=[O:36])[C:12]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])=[C:16]([C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH3:43])[CH2:30][CH2:29]3)=[O:27])[C:15]([CH3:34])=[N:14][C:13]=2[CH3:35])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2c(C(=O)OCCC(c3ccccc3)c3ccccc3)c(C)nc(C)c2C(=O)N2CCNCC2)c(C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cc1ccc(-c2c(C(=O)OCCC(c3ccccc3)c3ccccc3)c(C)nc(C)c2C(=O)N2CCN(C)CC2)c(C)c1
Reaction time: 0.5 h

Procedure:
169 mg (0.301 mmol) of 4-(2,4-dimethylphenyl)-2,6-dimethyl-5-(piperazine-1-carbonyl)nicotinic acid (3,3-diphenylpropyl) ester was dissolved in 10 ml of DMF. 62.4 mg (01.301 mmol) of potassium carbonate was added and stirred for 30 minutes. 51.3 mg (0.361 mmol) of methyl iodide was added under cooling with ice and stirred at the same temperature for 1 hour. The reaction mixture was further stirred for 10 minutes after adding water. After evaporating DMF under reduced pressure, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol =50/1 to 10/1) to obtain the title compound.
Reaction SMILES: FC(F)(F)C1C=CC(NC2N=C3C=CC=C([C:18]4[CH:19]=[CH:20][C:21]5[N:25]=[C:24]([C:26]([NH2:28])=[O:27])[NH:23][C:22]=5[CH:29]=4)N3N=2)=CC=1.OO.[OH-].[Na+].FC(F)(F)C(O)=O>CS(C)=O.O>[NH:23]1[C:22]2[CH:29]=[CH:18][CH:19]=[CH:20][C:21]=2[N:25]=[C:24]1[C:26]([NH2:28])=[O:27]
Reactant: NC(=O)c1nc2ccc(-c3cccc4nc(Nc5ccc(C(F)(F)F)cc5)nn34)cc2[nH]1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
6-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-benzo[d]imidazole-2-carboxamide. A mixture of 6-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-c]pyridin-5-yl)-1H-benzo[d]imidazole-2-carbonitrile (300 mg, 0.5 mmol), hydrogen peroxide (30%, 1.0 mL) and sodium hydroxide (40 mg, 1.0 mmol) in dimethylsulfoxide (5 mL) was stirred at room temperature for 3 h. The reaction mixture was poured into water (15 mL), and the mixture was extracted with ethyl acetate (15 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by reverse-phase preparatory HPLC (35-65% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give 64244-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-c]pyridin-5-yl)-1H-benzo[d]imidazole-2-carboxamide (65 mg, 29.7% yield) as a trifluoroacetic acid salt, which was converted to the hydrochloride salt with methanolic hydrochloride solution. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.19 (s, 1H), 8.37 (s, 1H), 7.95 (m, 5H), 7.73 (m, 4H), 7.29 (d, J=7.2 Hz, 1H); MS (ESI): m/z 438.1 [M+1]+.
Reaction SMILES: [BH4-].[Na+].Cl.[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[O:23])[CH2:15][CH2:14]2)=[N:5]1.Cl>C(O)C>[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH:22]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[OH:23])[CH2:15][CH2:14]2)=[N:5]1
Reactant: O=C(CCCN1CCN(c2nsc3ccccc23)CC1)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(CCCN1CCN(c2nsc3ccccc23)CC1)c1ccc(F)cc1
Reaction time: 20 h
Yield: 69 %

Procedure:
Sodium borohydride (1.0 g., 0.026 mole) is added portionwise to a stirred suspension of 4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanone hydrochloride (3.34 g., 0.008 mole) in 150 ml. of absolute ethanol. The mixture is stirred for a 20 hr. period, acidified with ethanolic hydrogen chloride, stirred for an additional 2 hr. period and concentrated in vacuo. Residual material is partitioned between chloroform and 1 N aqueous sodium hydroxide and the chloroform phase dried over magnesium sulfate and concentrated in vacuo to afford 2.31 g. (69% yield) of the title compound as the free base. The free base is converted to the hydrochloride in ethanol with ethanolic hydrogen chloride to afford α-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]propyl]-4-fluorobenzenemethanol hydrochloride, m.p. 200°-202° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:9]2)[S:5][C:6]=1[CH3:7].[Li]CCCC.[F:30][C:31]1[C:36]([C:37](N(OC)C)=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1>C1COCC1>[F:30][C:31]1[C:36]([C:37]([C:2]2[N:3]=[C:4]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:9]3)[S:5][C:6]=2[CH3:7])=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: Cc1sc(N2CCN(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C2)nc1Br
Reactant: CON(C)C(=O)c1cccnc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1sc(N2CCN(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C2)nc1C(=O)c1cccnc1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
tert-butyl (25)-4-(4-bromo-5-methyl-thiazol-2-yl)-2-isobutyl-piperazine-1-carboxylate (921 mg, 1.737 mmol) in THF (10 mL) was cooled to −78° C. before BuLi (729.6 μL, 2.5 M in hexanes, 1.824 mmol) was added dropwise over approx. 10 mins (temperature kept below −70° C. during addition). Once added, mixture stirred at −78° C. for 30 mins before a solution of 2-fluoro-N-methoxy-N-methyl-pyridine-3-carboxamide (319.9 mg, 1.737 mmol) in THF (3 mL) was added dropwise at −78° C. at such a rate that temperature did not exceed −70° C. (−5 mins). Mixture then stirred at −78° C. for 2 h allowed to warm to room temperature over the weekend (3.5 days). Reaction quenched with water, diluted with EtOAc and organic layer separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by flash chromatography (80 g SiO2, 0 to 15% EtOAc/petrol) to leave product as a yellow solid (208 mg, 26%); 1H NMR DMSO-d6 δ 0.85 (d, 6H), 1.40-1.35 (m, 12H), 2.63 (s, 3H), 2.97-2.94 (m, 2H), 3.10 (dd, 1H), 3.58 (d, 2H), 3.87-3.80 (m, 1H), 4.20-4.13 (m, 1H), 7.49-7.46 (m, 1H), 8.17-8.12 (m, 1H), 8.39 (dd, 1H); ES+ 463.22.