Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:47])[CH2:9][NH:10][C:11]2[CH2:15][N:14](S(C(F)(F)F)(=O)=O)[C:13](=[O:23])[C:12]=2[C:24]2[N:28](C(OC(C)(C)C)=O)[C:27]3[CH:36]=[C:37]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[CH:38]=[C:39]([CH3:40])[C:26]=3[N:25]=2)[CH:5]=[CH:6][CH:7]=1.O.ClCCl.Cl>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:47])[CH2:9][NH:10][C:11]2[CH2:15][NH:14][C:13](=[O:23])[C:12]=2[C:24]2[NH:28][C:27]3[CH:36]=[C:37]([N:41]4[CH2:42][CH2:43][O:44][CH2:45][CH2:46]4)[CH:38]=[C:39]([CH3:40])[C:26]=3[N:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N2CCOCC2)cc2c1nc(C1=C(NC[C@@H](O)c3cccc(Cl)c3)CN(S(=O)(=O)C(F)(F)F)C1=O)n2C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2CCOCC2)cc2[nH]c(C3=C(NC[C@@H](O)c4cccc(Cl)c4)CNC3=O)nc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 138.9 %

Procedure:
To a stirred solution of (S)-4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-3-(1-tert-butyloxycarbonyl-4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-1-trifluoromethanesulfonyl-1,5-dihydro-pyrrol-2-one (0.014 g, 0.020 mmol) in N,N-dimethylformamide (2 mL) was added saturated sodium bicarbonate (10 drops) and this was heated at 80° C. for 6 hours. The reaction was cooled down to RT and water and dichloromethane were added. The pH of the aqueous phase was adjusted to 7 with 0.5 N hydrochloric acid. The aqueous phase was extracted with dichloromethane (5×). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue (0.012 g) was dissolved in dichloromethane (1.5 mL) and treated with SCX resin (0.750 g). This mixture was stirred at RT for 2 hours, then the resin was washed with dichloromethane, followed by ammonia (2N in methanol, diluted with dichloromethane (3 parts)). The ammonia solution was evaporated to give a residue (0.013 g) which was purified by Prep HPLC (acetonitrile/ammonium acetate/water) and afforded the acetic acid salt of the title material (0.0054 g, 51%) as a beige solid. HPLC: 95% (220 nm), LCMS (+ESI, M+H+) m/z 468, HRMS calcd for C24H26N5O3Cl=467.1724, found: 467.1715; IR ν (cm−1): 3382, 2922, 1636, 1597. 1H NMR (400 MHz, methanol-d4) δ (ppm): 1.89 (3H, s), 2.50 (3H, s), 3.11 (4H, br dd), 3.49 (1H, dd, J=13.7 and 7.9 Hz), 3.60 (1H, dd, J=13.7 and 4.1 Hz), 3.86 (4H, br dd), 4.15 (2H, d, JAB=18.1 Hz), 4.92 (1H, dd, J=7.0 and 4.3 Hz), 6.76 (1H, br s), 6.94 (1H, br s), 7.27–7.39 (3H, m), 7.50 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])[C:5]([N+:28]([O-])=O)=[C:6]([CH:27]=1)[O:7][C:8]1[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=1)[CH2:11][NH:12][S:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:15])=[O:14].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.O>[NH2:28][C:5]1[C:4]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])=[CH:3][C:2]([F:1])=[CH:27][C:6]=1[O:7][C:8]1[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=1)[CH2:11][NH:12][S:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:15])=[O:14]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2N)c1
Reaction time: 5 h
Yield: 30.1 %

Procedure:
3.08 g of tert-butyl [(3-{5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]-2-nitrophenoxy}benzyl)sulfamoyl]carbamate (4.55 mmol, 1 eq.) were dissolved in 88 mL THF and heated to 50° C. upon which a solution of 13.5 g sodium dithionite (77.4 mmol, 17 eq.) in 70 mL water was added and stirring was continued at that temperature for 5 h. The layers were separated and the THF layer was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with sodium bicarbonate solution and sodium chloride solution, dried, filtered and concentrated in vacuo. The residue was further purified by flash column chromatography (hexan to hexan/ethyl acetate 1:1 gradient) to yield 886 mg (30% yield) of the target compound (as a 2-3:1 regioisomeric mixture).
Reaction SMILES: [NH3:1].[O:2]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(Cl)(Cl)Cl>[O:2]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH2:1])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1cccc(Oc2ccccc2)c1
Reactant: N
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cccc(Oc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
Saturated with anhydrous ammonia a solution containing 23 g (0.1 mole) of 3-phenoxybenzoyl chloride and 250 ml of AR chloroform. Continued stirring for 30 min., chilled to 0° and filtered. The product was pulverised, triturated in cold water and oven-dried to give 21.3 g, m.p. 127°-128°.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH:9]([CH3:14])[CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH:9]([CH3:14])[CH2:10][NH:11]2)=[CH:6][CH:5]=1
Reactant: CC1CNc2cc([N+](=O)[O-])ccc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1CNc2cc(N)ccc2C1
Yield: 91 %

Procedure:
A solution of 7-nitro-1,2,3,4-tetrahydro-3-methylquinoline (8.2 mg, 0.042 mmol) in ethyl acetate (1 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (4 mg) at rt for 2 h. Filtration over Celite™ afforded 6.2 mg (89%) of 7-amino-1,2,3,4-tetrahydro-3-methylquinoline (structure 61A of Scheme XLVIII, where R1-2 =R4 =H, R3 =methyl) that was used without further purification for the next step. Compound 436 was prepared by General Method 13 (EXAMPLE 147) from 7-amino-1,2,3,4-tetrahydro-3-methylquinoline (6.2 mg, 0.0038 mmol), ZnCl2 (8.0 mg, 0.057 mmol) and ethyl 4,4,4- trifluoroacetoacetate (5.5 mL, 0.038 mol) to afford 5.8 mg (54%) of Compound 436 as a yellow solid. Data for Compound 436: 1H NMR (400 MHz, DMSO-d6) 11.80 (bs, 1H), 7.11 (s, 1H), 6.95 (s, 1H), 6.37 (s, 2H), 3.26 (m, 1H), 2.83 (m, 2H), 2.51 (dd, J=15.7, 10.3, 1H), 1.88 (s, 1H), 0.97 (d, J=6.6, 3H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:9]=2[CH:10]=1)CCC.[CH2:24]([O:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:55])[CH:32]([NH:37][C:38]1[CH:43]=[C:42]([CH2:44][CH2:45][CH2:46]C)[N:41]=[C:40]([C:48]2[CH:49]=[N:50][CH:51]=[C:52](Br)[CH:53]=2)[N:39]=1)[CH2:33][CH:34]([CH3:36])[CH3:35])[CH3:25]>CN(C)C=O.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>[CH2:24]([O:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:55])[CH:32]([NH:37][C:38]1[CH:43]=[C:42]([CH2:44][CH2:45][CH3:46])[N:41]=[C:40]([C:48]2[CH:49]=[N:50][CH:51]=[C:52]([C:6]3[O:7][C:8]4[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:9]=4[CH:10]=3)[CH:53]=2)[N:39]=1)[CH2:33][CH:34]([CH3:35])[CH3:36])[CH3:25]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2cc(F)ccc2o1
Reactant: CCCCc1cc(NC(CC(C)C)C(=O)NCCCOCC)nc(-c2cncc(Br)c2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCCc1cc(NC(CC(C)C)C(=O)NCCCOCC)nc(-c2cncc(-c3cc4cc(F)ccc4o3)c2)n1
Yield: 21.3 %

Procedure:
Under an atmosphere of argon, a solution of tributyl(5-fluorobenzofuran-2-yl)stannane (17 mg), 2-[2-(5-bromopyridin-3-yl)-6-butylpyrimidin-4-ylamino]-4-methylpentanoic acid (3-ethoxypropyl)amide (20 mg) and (PPh3)2PdCl2 (2 mg) in N,N-dimethylformamide (1 mL) was heated at 80° C. for 12 h and then quenched with water (10 mL). The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic extracts were dried over sodium sulfate and concentrated. The crude product was purified by semi-preparative HPLC to give 4.6 mg of 2-{2-[5-(5-fluorobenzofuran-2-yl)pyridin-3-yl]-6-propylpyrimidin-4-ylamino}-4-methylpentanoic acid (3-ethoxypropyl) amide as a TFA salt. ESI-MS (m/z) 562 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[N:3][CH:4]=1
Reactant: CN1CCNCC1
Reactant: CNC(=O)c1ccc(Cl)nc1
Product: CNC(=O)c1ccc(N2CCN(C)CC2)nc1
Temperature: 100 °C
Yield: 1011.7 %

Procedure:
A mixture of 52.0 g (30.5 mmol) 6-chloro-N-methyl-nicotinamide and 176 ml (1.58 mol) 1-methylpiperazine was heated at 100° C. for 1.5 h in an autoclave. After cooling to room temperature excess 1-methylpiperazine was removed by distillation. The residue was partitioned in 1000 ml dichloromethane/1 N aqueous sodium hydroxide solution. The layers were separated and the aqueous layer was extracted with three 500 ml portions of dichloromethane. Concentration and short column chromatography yielded 72.3 g (97%) of the title compound as a light brown solid.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:7]1[C:8]([NH2:11])=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[N:6]=1
Reactant: COc1ccc(N)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(N)c(Br)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.6 %

Procedure:
Bromine (4.72 g, 29.5 mmol) is added to a mixture of 2-methoxy-5-aminopyridine (3.66 g, 29.5 mmol) and sodium acetate (4.84 g, 7.32 mmol) in acetic acid (50 mL) and stirred at rt for 20 minutes. Acetic acid is evaporated off in vacuo. The residue is dissolved in EtOAc (40 mL), and washed with water (40 mL), saturated sodium carbonate aqueous solution (20 mL), water (20 mL) and brine (20 mL). The organic layer is dried (Na2SO4), filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-40% EtOAc in heptane to afford 2-bromo-3-amino-6-methoxypyridine (4.35 g) as an oil. MS: 202 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.89 (s, 3H), 6.60(d, H), 7.07(d, H).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([CH2:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24](=[O:36])[NH:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)[CH:13]=[CH:12][N:11]=1)=[O:8])C.[OH-].[Na+].O.Cl>CO>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([CH2:27][O:26][NH:25][C:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][CH2:16][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:7](=[O:8])[NH:6][CH2:5][C:4]([OH:37])=[O:3])[CH:15]=2)=[O:36])=[CH:29][CH:30]=1)#[N:35]
Reactant: CCOC(=O)CNC(=O)Nc1cc(CNc2ccccc2C(=O)NOCc2ccc(C#N)cc2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(CONC(=O)c2ccccc2NCc2ccnc(NC(=O)NCC(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of [3-(4-{[2-(4-cyano-benzyloxycarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-ureido]-acetic acid ethyl ester (Example 529, 188 mg) in methanol (4 ml) was added 2 M aqueous sodium hydroxide (2 ml). The reaction mixture was stirred at room temperature for 15 minutes. Water (6 ml) was added and the pH of the mixture was adjusted to 5 by addition of 4 M hydrochloric acid. The resulting precipitated material was isolated by filtration and dried under high vacuum, affording the title compound. 13C-NMR (DMSO-d6) δ 171.7, 167.5, 154.7, 153.5, 151.3, 148.4, 146.7, 141.9, 132.6, 132.1, 129.1, 128.0, 118.7, 115.3, 114.8, 112.8, 111.5, 110.7, 109.2, 75.9, 45.3, 41.4
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])[CH2:19][CH3:20]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:28]([C:25]1[CH:26]=[CH:27][C:22]([C:18]([CH3:17])([CH3:21])[CH2:19][CH3:20])=[CH:23][CH:24]=1)(=[O:30])=[O:29])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: CCC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 1.16 mg of (2-Amino-5-chloro-phenyl)-phenyl-methanone and 123 mg of 4-(1,1-dimethyl-propyl)-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 0.56 (t, 3H, J=7.2 Hz), 1.18 (s, 6H), 1.54 (q, 2H, J=7.2 Hz), 7.25 (d, 2H, J=8.4 Hz), 7.34 (d, 1H, J=2.8 Hz), 7.40 (m, 4H), 7.45 (dd, 1H, J=8.8 Hz, 2.0 Hz), 7.56-7.62 (m, 3H, 7.78 (d, 1H, J=8.8 Hz), 9.95 (s, 1H). MS: m/z 442.0 (M++1).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:11][N:12]1[CH:16]=[CH:15][C:14]([NH2:17])=[N:13]1.C1(C2C3C(=CC=CC=3)C(C3C4C(=CC=CC=4)C=CC=3)=C(P)C=2C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C1(C)C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:17][C:14]2[CH:15]=[CH:16][N:12]([CH3:11])[N:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Cn1ccc(N)n1
Agent: O=C([O-])[O-]
Agent: Pc1c(-c2ccccc2)c(-c2ccccc2)c2ccccc2c1-c1cccc2ccccc12
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1ccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 130 °C
Yield: 54.4 %

Procedure:
3,5-Dibromo-1-methyl-1H-pyridin-2-one (469 mg, 1.76 mmol), 1-Methyl-1H-pyrazol-3-ylamine (205 mg, 2.11 mmol), tris(dibenzylidineacetone)dipalladium(0) (80 mg, 0.087 mmol), 2,2′-bis(diphenyl phosphino-1,1′-binaphthalene (82 mg, 0.13 mmol), and cesium carbonate (801 mg, 2.46 mmol) were deposited in a sealed vial with 10 mL toluene. This was heated at 130° C. for 18 hours. The resulting mixture was poured into 50 mL water. This was extracted with ethylacetate. The ethylacetate layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (eluted with ethylacete/hexanes) to yield 5-Bromo-1-methyl-3-(1-methyl-1H-pyrazol-3-ylamino)-1H-pyridin-2-one (271 mg, 0.957 mmol). MS (EST) 284.9 (M+H)+.
Reaction SMILES: [IH:1].CS[C:4]1[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]=1.C(O)C.O.[NH2:15][NH2:16]>CCOCC>[IH:1].[NH:15]([C:4]1[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]=1)[NH2:16]
Reactant: CSC1=NCCCCN1
Reactant: NN
Agent: I
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: NNC1=NCCCCN1
Temperature: -10 °C

Procedure:
A 40.8 gm. (0.15 mole) portion of 2-methylthio-4,5,6,7-tetrahydro-1H-1,3-diazepine hydroiodide in 150 ml. of ethanol is treated with 10 ml. (0.2 mole) of hydrazine hydrate. The solution is stirred at reflux for 3 hours, clarified while hot and then cooled at -10°C. overnight. A 200 ml. portion of ether is added and the mixture is cooled at -10°C. The precipitate is collected, washed with ether and dried at 60°C. under reduced pressure. Yield 20.5 gm., melting point 133°-135°C. Analysis calculated for: C5H12N4 . HI: C, 23.45; H, 5.12; N, 21.88; I, 49.56. Found: C, 22.85; H, 4.96; N, 21.90; I, 50.35.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[CH:11].[CH2:13]([O:15][C:16](=[O:20])/[CH:17]=[CH:18]\I)[CH3:14]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][CH:18]=[CH:17][C:16]([O:15][CH2:13][CH3:14])=[O:20]
Reactant: CCOC(=O)/C=C\I
Reactant: C#Cc1ccccc1C(=O)OC
Product: CCOC(=O)C=CC#Cc1ccccc1C(=O)OC

Procedure:
The general procedure was used to convert 2-Ethynyl-benzoic acid methyl ester and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (20% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (410 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 7.96-7.95 (d, J=7.8, 1H), 7.70-7.68 (d, J=8.2, 1H), 7.50-7.46 (t, J=7.5, 1H), 7.37-7.41 (t, J=7.7, 1H), 6.46-6.43 (d, J=11.4, 1H), 6.18-6.15 (d, J=11.4, 1H), 4.27-4.21 (q, J=7.1, 2H), 3.92 (s, 3H), 1.31-1.27 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 166.31, 164.65, 134.69, 131.79, 131.74, 130.42, 128.73, 128.70, 123.23, 122.91, 99.64, 90.93, 60.40, 52.23, 14.27. Anal. Calcd. for C15H14O4: C, 69.76; H, 5.46; Found C, 69.93; H, 5.59.
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl-].[OH:7][NH3+:8].[F:9][C:10]1[CH:11]=[C:12]([C:16]2([CH:41]=O)[CH2:21][CH2:20][CH2:19][N:18]3[N:22]=[C:23](/[CH:25]=[CH:26]/[C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]5)=[C:29]([O:39][CH3:40])[CH:28]=4)[N:24]=[C:17]23)[CH:13]=[CH:14][CH:15]=1.O.C(=O)(O)[O-].[Na+]>C(O)C.C(OCC)(=O)C>[F:9][C:10]1[CH:11]=[C:12]([C:16]2([CH:41]=[N:8][OH:7])[CH2:21][CH2:20][CH2:19][N:18]3[N:22]=[C:23](/[CH:25]=[CH:26]/[C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]5)=[C:29]([O:39][CH3:40])[CH:28]=4)[N:24]=[C:17]23)[CH:13]=[CH:14][CH:15]=1
Reactant: [NH3+]O
Reactant: COc1cc(/C=C/c2nc3n(n2)CCCC3(C=O)c2cccc(F)c2)ccc1-n1cnc(C)c1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3(C=NO)c2cccc(F)c2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.8 %

Procedure:
Sodium acetate (58.7 mg) and hydroxylammonium chloride (49.8 mg) were added to a solution of 8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbaldehyde (164 mg) in ethanol (10 mL), and the reaction solution was stirred at room temperature for five hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 169 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[N:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:14])[N:4]([CH3:15])[CH:5]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ncc(N2CCOCC2)cc1Br
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(N2CCOCC2)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of 3-bromo-5-morpholinopyridin-2-ol (1.0 equiv.) in DMF (0.1 M) was added potassium carbonate (2.0 equiv.) and iodomethane (1.0 equiv.). The solution was stirred at room temperature for 3 hours. Partitioned between water and ethyl acetate, the organic phase was washed with brine, dried with sodium sulfate, filtered and concentrated to dryness. Isolated 3-bromo-1-methyl-5-morpholinopyridin-2(1H)-one in 87% yield. LCMS (m/z) (M+H)=273.0/275.0, Rt=0.41 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:20](=[CH:21][CH:22]=1)[O:19][C:7]1([CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:23].[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[O:23]=[C:5]1[C:4]2[C:20](=[CH:21][CH:22]=[C:2]([C:30]3[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=3)[C:24]#[N:25])[CH:3]=2)[O:19][C:7]2([CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:6]1
Reactant: O=C1CC2(CCC(c3ccccc3)CC2)Oc2ccc(Br)cc21
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC2(CCC(c4ccccc4)CC2)O3)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
In a 50 mL round bottom flask was placed 6-bromo-4′-phenylspiro[chroman-2,1′-cyclohexan]-4-one (300 mg, 0.811 mmol), 3-cyanobenzeneboronic acid (155 mg, 1.06 mmol), PdCl2(PPh3)2 (57 mg, 0.08 mmol) and cesium carbonate (661 mg, 2.03 mmol). This solid mixture was dissolved in a Dioxane/water mixture (8 mL, 6:1 ratio, respectively). The solution was purged with a N2 stream for 30 seconds. A condenser was attached to the flask and the reaction was allowed to stir at 95° C. for 1 hour. At this time, the mixture was filtered through a Celite plug. The plug was rinsed with dichloromethane (20 mL) and water (20 mL). The phases in the filtrate were separated. The aqueous phase was back-extracted with dichloromethane twice (5 mL/each). The combined organic phases were dried over MgSO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 12 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 3-(4-oxo-4′-phenylspiro[chroman-2,1′-cyclohexane]-6-yl)benzonitrile (173 mg, 0.440 mmol, 58% yield) as a light yellow oil.
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].C([O:20][C:21]([C:23]1[N:24]=[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:35]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=4)=[N:34][N:33]4[CH2:43][CH2:44][CH2:45][C:32]=34)=[CH:27][N:26]2[CH:46]=1)=O)C>ClCCl>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][C:21]([C:23]1[N:24]=[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:35]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=4)=[N:34][N:33]4[CH2:43][CH2:44][CH2:45][C:32]=34)=[CH:27][N:26]2[CH:46]=1)=[O:20]
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1cn2cc(-c3c(-c4cccc(C)n4)nn4c3CCC4)ccc2n1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2nn3c(c2-c2ccc4nc(C(=O)NCCN(C)C)cn4c2)CCC3)n1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
Add 2M trimethylaluminum in toluene (0.38 mL, 0.38 mmol) to a solution of N,N-dimethylethylenediamine (0.034 g, 0.38 mmol) in dichloromethane (20 mL). Stir for 20 min and transfer via cannula to a solution of 6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (0.1 g, 0.26 mmol) in dichloromethane (20 mL). Heat at 45° C. and stir for 1.5 h. Add saturated aqueous sodium bicarbonate and extract into dichloromethane. Reversed phase chromatography gives the titled compound (0.067 g, 60%) as a white solid. MS ES+ m/e 430.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]([OH:10])=O)=[N:3]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[Cl:43][C:44]1[CH:45]=[C:46]([C:51]2[O:55][C:54]([CH2:56][CH2:57][NH2:58])=[CH:53][CH:52]=2)[CH:47]=[CH:48][C:49]=1[Cl:50]>CN(C=O)C.O>[Cl:43][C:44]1[CH:45]=[C:46]([C:51]2[O:55][C:54]([CH2:56][CH2:57][NH:58][C:8]([C:4]3[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[N:3]=3)=[O:10])=[CH:53][CH:52]=2)[CH:47]=[CH:48][C:49]=1[Cl:50]
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: Cc1cc(C(=O)O)nn1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)nn1C
Reaction time: 0.5 h

Procedure:
1,5-Dimethyl-1H-pyrazole-3-carboxylic acid (100 mg, 0.71 mmol) was dissolved in dry DMF (2 ml). EDCl (205 mg, 1.1 mmol), HOBt (145 mg, 1.1 mmol) and DIPEA (0.19 ml, 141 mg, 1.1 mmol) were added at RT. The solution was stirred for 30 min. Then, 2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylamine hydrochloride (313 mg, 1.1 mmol) dissolved in the mixture of dry DMF (4 ml) and DIPEA (0.19 ml, 141 mg, 1.1 mmol) was added to the solution at RT. After stirring overnight water was added. The product was extracted into ethyl acetate. The organic phase was washed with water, dried and evaporated. The crude product was purified by flash chromatography using CH2Cl2-MeOH as a gradient eluent (100:0-95:5). Another purification was done also by flash chromatography using CH2Cl2-MeOH as a gradient eluent (100:0-99.7:0.3). The product was triturated in heptane-CH2Cl2 at RT. 1H NMR (400 MHz, DMSO-d6): 2.26 (3H, s), 2.92 (2H, t), 3.52 (2H, m), 3.76 (3H, s), 6.31 (1H, d), 6.38 (1H, s), 7.01 (1H, d), 7.60 (1H, distorted dd), 7.64 (1H, distorted d), 7.83 (1H, d), 8.09 (1H, t).