Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:24][CH3:25])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[CH2:22][NH2:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[C:26]([C:30]1[CH:34]=[C:33]([NH:35][C:36](=O)[O:37]CC(Cl)(Cl)Cl)[N:32]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:31]=1)([CH3:29])([CH3:28])[CH3:27].C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[C:26]([C:30]1[CH:34]=[C:33]([NH:35][C:36]([NH:23][CH2:22][C:16]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:24][CH3:25])[N:6]=[CH:7]3)=[O:37])[N:32]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:31]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21)OC
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(Cn1ncc2cc(Oc3ccc(F)cc3CNC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)ccc21)OC
Temperature: 80 °C

Procedure:
(2-(1-(2,2-dimethoxyethyl)-1H-indazol-5-yloxy)-5-fluorophenyl)methanamine (2.00 g, 5.791 mmol), 2,2,2-trichloroethyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (3.516 g, 8.686 mmol) and N,N-diisopropylethylamine (3.026 mL, 17.37 mmol) were suspended in N,N-dimethylacetamide (50 mL) and heated at 80° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue diluted with EtOAc and saturated aqueous NH4Cl. The organics were washed with water (3×), brine, dried (MgSO4) and then concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant 35-45% EtOAc/Hexanes). After evaporation of the solvent, the desired product was obtained as a pale yellow foam (2.57 g, 74%). MS (APCI+) m/z 602 (M+1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.43 (d, 1H, J=9 Hz), 6.72-7.30 (m, 9H), 6.18 (s, 1H), 6.01 (br, 1H), 5.47 (t, 1H, J=6.1 Hz), 4.76 (t, 1H, J=5.3 Hz), 4.44 (t, 4H, J=5.6 Hz), 3.38 (s, 6H), 2.37 (s, 3H), 1.30 (s, 9H).
Reaction SMILES: [Na].Cl[C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[C:6]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])[N:7]2[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[CH:27]([OH:30])([CH3:29])[CH3:28]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:7]2[C:6]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[N:5][C:4]3[C:8]2=[N:9][CH:10]=[N:11][C:3]=3[O:30][CH:27]([CH3:29])[CH3:28])=[CH:13][CH:14]=1
Reactant: CC(C)O
Reactant: Clc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc3c(Cl)ncnc32)cc1
Agent: [Na]
Product: CC(C)Oc1ncnc2c1nc(-c1ccc(Cl)cc1Cl)n2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium (7 mg, 0.3 mmol) was dissolved in isopropanol (1 ml) and to it was added 6-chloro-9-(4-chlorophenyl)-8-(2,4-dichlorophenyl)-9H-purine I-(1A-1)d (30 mg, 0.07 mmol). After stirring at room temperature overnight, the reaction mixture was evaporated to dryness and extracted into ethyl acetate from saturated aqueous NaHCO3 solution. The organic layers were combined, dried (Na2SO4), filtered, and concentrated to dryness. The crude residue was purified on a TLC preparative plate using 4% methanol/methylene chloride as the solvent to yield title compound 1A-1. A solution of the material in methylene chloride was treated with excess 1 N HCl in diethyl ether, stirred, evaporated to dryness, and then triturated in diethyl ether to afford the hydrochloride salt of compound 1A-1 (8 mg, 26%): +ESI MS (M+1) 433.4; 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.49–7.45 (3H), 7.34 (d, J=9.1 Hz, 2H), 5.73 (septuplet, J=6.2 Hz, 1H), 1.48 (d, J=6.2 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20].[OH-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:20])([F:21])[F:22])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)c(C(F)(F)F)c1
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
To a solution containing 64.2 g (0.5 mole) of 4-chlorophenol and 112.7 g (0.5 mole) of 2-chloro-5-nitrobenzotrifluoride in 400 ml of DMSO was added dropwise with stirring at 30°-35° C. a solution containing 20 g (0.5 mole) of sodium hydroxide in 20 ml of water. After 1.5 hours, the reaction mixture was poured into cold water and extracted with 800 ml of ether. The ether solution was dried and concentrated under reduced pressure to give 158 g (99%) of product that crystallized on standing; melting point, 46°-48° C. (from hexane).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH3:7][C:8]1([CH3:30])[C:28]2[C:11](=[CH:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[O:25][CH3:26])=[N:15][C:14]=3[CH:27]=2)[NH:10][C:9]1=[O:29].C(N(CC)CC)C>CN(C)C=O>[CH3:7][C:8]1([CH3:30])[C:28]2[C:11](=[CH:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][C:21]([NH:24][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:20][C:19]=4[O:25][CH3:26])=[N:15][C:14]=3[CH:27]=2)[NH:10][C:9]1=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(N)ccc1-c1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.26 g. (11 mmol) methanesulphonyl chloride were slowly added dropwise to a solution of 3.6 g. (10 mmol) 7,7-dimethyl-2-(2-methoxy-4-aminophenyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one hydrochloride and 2.2 g. (22 mmol) triethylamine in 50 ml. dimethylformamide. After stirring for 2 hours at 25° C., the dimethylformamide was distilled off under a high vacuum. The residue was worked up with water and filtered off with suction. Subsequently, it was recrystallised from ethanol to give 2.9 g. (72.5% of theory) of the title compound; m.p. >300° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:17][CH:18]1[CH2:20][CH2:19]1)[C:9]([CH3:16])=[N:10]2)=[O:4].[C:21]([O:25][C:26]([NH:28][C@@H:29]([C@H:38]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH3:39])[C:30](=[O:37])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:27])([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:21]([O:25][C:26]([NH:28][C@@H:29]([C@H:38]([O:40][Si:41]([C:44]([CH3:46])([CH3:45])[CH3:47])([CH3:42])[CH3:43])[CH3:39])[C:30](=[O:37])[CH:31]([CH2:2][C:3]([C:5]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:17][CH:18]1[CH2:20][CH2:19]1)[C:9]([CH3:16])=[N:10]2)=[O:4])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1nc2ccc(F)c(C(=O)CBr)c2nc1NC1CC1
Reactant: CCOC(=O)CC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)c1c(F)ccc2nc(C)c(NC3CC3)nc12)C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.3 %

Procedure:
A solution of 2-bromo-1-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone (613) (566 mg, 1.674 mmol) and (4S,5R)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-3-oxohexanoate (614) (995 mg, 2.465 mmol) in DMF (9 mL) was cooled in an ice-water bath and treated with K2CO3 (509 mg, 3.68 mmol) The mixture was stirred for 16 h at RT then heated at 60° C. in an oil bath for 4 h. The mixture was extracted into CHCl3 (3×100 mL) from saturated aq. NaHCO3 (100 mL), dried (Na2SO4), concentrated, and purified by flash chromatography on silica gel (40 g) eluting with a gradient of 0-10% EtOAc in DCM to give (4S,5R)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-2-(2-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxohexanoate (352a) (247 mg, 0.374 mmol, 22% yield) as a yellow foam. LC-MS m/z 661.1, [M+H]. A solution of (4S,5R)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-2-(2-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxohexanoate (352a) (247 mg, 0.374 mmol) in EtOH (3.0 mL) and AcOH (1.5 mL) was treated with NH4OAc (Aldrich) (432 mg, 5.61 mmol). The resulting yellow solution was heated at 60° C. for 64 h. The mixture was concentrated and extracted into EtOAc (3×100 mL) from saturated aq. NaHCO3 (150 mL). The organic extracts were dried (Na2SO4), concentrated, and purified by flash chromatography on silica gel (gradient: 0-15% EtOAc in DCM) to give the title compound (352b) as a yellow foam (184.5 mg). LC-MS m/z 642.2, [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15]C(=O)[O-])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])NCC1CCN(c2ccnc(Cl)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1CCN(c2ccnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
To a solution of (1-(2-chloropyrimidin-4-yl)piperidin-4-yl)methylcarbamate (Example 11, step i, 2.32 g, 6.73 mmol) in CH2Cl2 (30 ml) was added trifluoroacetic acid (6.0 ml, 81 mmol). After stirring for 3 h at room temperature the solvents were removed under reduced pressure to give (1-(2-chloropyrimidin-4-yl)piperidin-4-yl)methanamine 2,2,2-trifluoroacetate as a white solid (1.71 g). The crude product was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1.[H-].[Na+].Br[CH:15]([CH3:17])[CH3:16].Cl>CN(C=O)C>[CH:15]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1)([CH3:17])[CH3:16]
Reactant: OB1OCc2ccc(O)cc21
Reactant: CC(C)Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1)B(O)OC2
Temperature: 0 °C
Reaction time: 48 h
Yield: 61.5 %

Procedure:
H181 (150 mg, 1.0 mmol) was dissolved in DMF (8.0 mL) and cooled to 0° C. with ice bath. To this solution under nitrogen were added in sequence NaH (60% in mineral oil, 160 mg, 4.0 mmol) and 2-bromopropane (0.40 mL, 4.0 mmol). The reaction mixture was stirred for 2 d then treated with 1.0 M HCl (10.0 mL). After extraction with ethyl acetate, the organic phase was washed with water and brine, and dried over anhydrous Na2SO4. The residue after rotary evaporation was purified by column chromatography over silica gel to give the title compound (118 mg, 61.5% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.10 (s, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 7.01 (dd, J=8.1 & 2.4 Hz, 1H), 4.90 (s, 2H), 4.63-4.53 (m, 1H) and 1.27 (d, J=6 Hz, 6H) ppm; Mp: 62-65° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20](=[O:21])[NH:19][N:18]=[C:17]4[CH2:22][C@@H:23]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]4)=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.O1CCOCC1.[ClH:41]>>[ClH:41].[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:17]([CH2:22][C@@H:23]5[CH2:27][CH2:26][NH:25][CH2:24]5)=[N:18][NH:19][C:20]4=[O:21])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(-c2ccc3occc3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
In a round bottom flask under nitrogen, a yellow mixture of tert-butyl (3S)-3-({4-[4-(1-benzofuran-5-yl)phenyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl}methyl)pyrrolidine-1-carboxylate (2.58 g, 5.60 mmol) in 4M HCl in dioxane (1.40 mL, 5.60 mmol) was stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo. Ethanol (300 mL) was added to the flask and the solvent was removed by concentration in vacuo to give the title compound as a cream coloured solid (2.14 g, 96%). MS(ES)+ m/e 361.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][N:14]=1>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][N:14]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)c1ccc(Br)nc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)c1ccc(-c2cc(F)ccc2F)nc1
Temperature: 90 °C
Yield: 39.6 %

Procedure:
To round-bottom flask was added 2,5-difluoro phenylboronic acid (306 mg, 1.94 mmol), palladium tetrakis(triphenylphosphine) (22.4 mg, 0.0194 mmol)) and tert-butyl 6-bromonicotinate (500 mg, 1.94 mmol) and the mixture was evacuated 3× with N2. The solids were dissolved in 25 mL of DMF, followed by addition of 2.9 mL of 2 M cesium carbonate. The resulting mixture was heated to ˜90° C. The mixture was cooled to rt and then poured into a sep. funnel, followed by addition of EtOAc and water (1×200 mL). The layers were separated and the organic extract washed with brine (1×200 mL), dried MgSO4, filtered and concentrated to afford an orange oil. The crude mixture was purified by chromatography (silica, 10% EtOAc:Heptane) to afford the desired product (224 mg, 40%). 1H NMR (400 MHz, DMSO-d6) □ ppm 9.07-9.19 (1H, m), 8.36 (1H, dd, J=8.2, 2.2 Hz), 7.99 (1H, dd, J=8.3, 1.8 Hz), 7.75-7.86 (1H, m), 7.36-7.52 (1H, m), 7.36-7.52 (2H, m), 1.59 (9H, s). LC/MS (M+H)=292.1 observed, 292.11 expected.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([C:19]([OH:21])=O)=[C:17]2[C:12]([C:13](=[O:33])[C:14]([CH3:32])=[C:15]([CH:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29][CH3:30])[CH2:24][CH2:23]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.[NH2:45][CH2:46][CH2:47][OH:48]>ClCCl.O.CN(C)C=O>[CH2:1]([O:8][C:9]1[C:18]([C:19]([NH:45][CH2:46][CH2:47][OH:48])=[O:21])=[C:17]2[C:12]([C:13](=[O:33])[C:14]([CH3:32])=[C:15]([CH:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29][CH3:30])[CH2:24][CH2:23]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: CCC(=O)N1CCC(c2oc3c(C(=O)O)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCC(=O)N1CCC(c2oc3c(C(=O)NCCO)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Reaction time: 15 h
Yield: 66.4 %

Procedure:
To a solution of 7-(benzyloxy)-3-methyl-4-oxo-2-(1-propanoylpiperidin-4-yl)-4H-chromene-8-carboxylic acid (200 mg, 0.44 mmol) obtained in Example 35-1 in dichloromethane (4 mL), thionyl chloride (97 μL, 1.33 mmol) was added dropwise under cooling with ice. Then, a catalytic amount of dimethylformamide was added dropwise thereto, and the mixture was brought back to room temperature and stirred for 15 hours. The reaction solution was concentrated under reduced pressure, and then the residue was subjected to azeotropy with toluene (2 mL). Dichloromethane (4 mL) was added to the obtained residue. Triethylamine (93 μL, 0.67 mmol) and 2-aminoethanol (53 μL, 0.89 mmol) were added dropwise thereto under cooling with ice, and then the mixture was brought back to room temperature and stirred for 8 hours. Water was added to the reaction solution, followed by extraction with dichloromethane. Then, the organic layer was dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0→95/5) to obtain 144 mg of the title compound (yield: 66%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[CH2:13]([N:20]1[C:24]([CH2:25][CH2:26][CH2:27]I)=[N:23][N:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([N:20]1[C:24]([CH2:25][CH2:26][CH2:27][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)=[N:23][N:22]=[N:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ICCCc1nnnn1Cc1ccccc1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Solvent: CCO
Product: O=c1ccc2cc(OCCCc3nnnn3Cc3ccccc3)ccc2[nH]1
Reaction time: 5 h

Procedure:
Into 100 ml of ethanol, 3.22 g of 6-hydroxycarbostyril and 3.51 ml of 1,5-diazabicyclo[5,4,0]-undecene-5 (DBU) are added and refluxed under stirring. Then 100 ml of ethanol containing 7 g of 1-benzyl-5-γ-iodopropyltetrazole is added dropwise for 90 minutes. After completion of the addition, the reaction mixture is further refluxedfor 5 hours and then concentrated. The residue is extracted with 300 ml of chloroform and the chloroform layer is washed with a diluted NaOH aqueous solution, a diluted hydrochloric acid and water and dried with Na2SO4. After the removal of the solvent, the residue is recrystallized from water-containing ethanol to obtain 4 g of 6-[3-(1-benzyltetrazol-5-yl)propoxy]carbostyril in the form of colorless needle-like crystals. Melting point: 152°-154° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH2:6])[CH3:5].Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1>>[CH3:1][O:2][CH2:3][CH:4]([N:6]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][CH:8]1[NH2:9])[CH3:5]
Reactant: COCC(C)N
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: COCC(C)N1C=C([N+](=O)[O-])C=CC1N

Procedure:
This compound was prepared with the same method described before by using 2-methoxy-1-methylethylamine and 2-chloro-5-nitro-pyridine to give N-(2-methoxy-1-methylethyl)-2-amino-5-nitro-pyridine. LCMS calcd for C9H13N3O3 m/e 211.22, obsd 210.2 (AP, M−H). The nitro compound was hydrogenated under the same condition described before to give N2-(2-methoxy-1-methylethyl)-2,5-diaminopyridine.
Reaction SMILES: O=[C:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][N:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]4)=[C:18]([O:28][CH3:29])[N:17]=3)[N:15]=[C:8]12)=[O:6].C(Cl)(=O)C(Cl)=O.P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:29][O:28][C:18]1[N:17]=[C:16]([C:14]2[N:15]=[C:8]3[CH:7]([C:5]4[O:6][C:2]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:3][N:4]=4)[CH2:12][CH2:11][CH2:10][N:9]3[N:13]=2)[CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: COc1nc(-c2nc3n(n2)CCCC3C(=O)NCC(=O)c2ccccc2)ccc1-n1cnc(C)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1nc(-c2nc3n(n2)CCCC3c2ncc(-c3ccccc3)o2)ccc1-n1cnc(C)c1
Yield: 12.8 %

Procedure:
2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid (2-oxo-2-phenylethyl)amide obtained in Example 172 (35.7 mg) was suspended in toluene (0.5 mL). Oxalyl chloride (20.4 mg) was added and the mixture was stirred with heating under reflux for two hours. Toluene (3 mL) and phosphoryl chloride (60 μL) were added, followed by further stirring for two hours and 30 minutes. The reaction solution was ice-cooled. Then, chloroform and a saturated sodium bicarbonate solution were added and the organic layer was separated. The resulting organic layer was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (4.4 mg). The compound was further purified by CHIRALPAK™ IA (2 cm×25 cm; mobile phase:hexane:ethanol=50:50) to obtain the title compound (1.2 mg, racemate). The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:4][CH:3]=1.Cl.[CH3:18][O:19][C:20](=[O:34])[C:21]1[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][C:22]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33].F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([OH:27])[C:21]=2[C:20]([O:19][CH3:18])=[O:34])=[O:16])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Reactant: Nc1ccc(CCC(=O)O)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)CCc1ccc(N)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.5 %

Procedure:
A mixture of 3-(4-amino-1-naphthyl)propanoic acid (160 mg, 0.74 mmol), 2-(4-amino-butoxy)-6-hydroxy-benzoic acid methyl ester hydrochloride (200 mg, 0.72 mmol), [(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium tetrafluoroborate (TBTU) (275 mg, 0.857 mmol) and N,N-diisopropylethylamine (0.4 mL, 2.3 mmol) in DMF (3 mL) was stirred at ambient temperature for 1.5 hour, poured into water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers were washed with water (2×5 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to an oil. The product was purified on silica gel, eluting with 75% ethyl acetate/hexanes to provide the titled compound (165 mg, 52%).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[NH:21]1[CH:25]=[CH:24][CH:23]=[N:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:21]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: c1cn[nH]c1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-n3cccn3)nc2c1
Temperature: 50 °C
Yield: 78.3 %

Procedure:
A mixture of 0.24 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.14 g of pyrazole, 0.69 g of potassium carbonate and 4 ml of DMF was stirred while heating at 50° C. for two hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.22 g of 2-[3-(pyrazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 58”).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[N:6]=[CH:5]2
Reactant: CC(C)CBr
Reactant: Brc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1ncc2cc(Br)ccc21
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
The crude 5-bromo-1H-indazole (compound 2f; 100 mmol) was dissolved in 250 mL of DMF. K2CO3 (20.7 g, 150 mmol) and 1-bromo-2-methylpropane (16.3 mL, 150 mmol) were added. The mixture was heated to 120° C. under nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Water (200 mL) and CH2Cl2 (200 mL) were added to the residue and stirred vigorously for 30 minutes. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4, filtered through Celite, and concentrated under reduced pressure to provide about 30 g of crude material. The crude material was purified by chromatography (1:9 to 1:4 ether/hexanes) to provide 12.870 g of compound 3f as a dark red oil, yielding 50.8% for steps A and B. MS ESI (+) m/z 253 and 255 (M+1) detected. 1H-NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.87 (m, 1H), 7.43 (m, 1H), 7.29 (m, 1H), 7.29 (m, 1H), 4.15 (m, 2H), 2.33 (m, 1H), 0.92 (m, 6H).