Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22]CC2C=CC=CC=2)[CH:17]=1)(=[O:3])[CH3:2]>[Pd].C(OCC)(=O)C.C(O)C>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C(=O)c2cccc(OCc3ccccc3)c2)[nH]c2cc(Cl)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Nc1c(C(=O)c2cccc(O)c2)[nH]c2cc(Cl)ccc12
Yield: 39.5 %

Procedure:
3-Acetylamino-2-(3-benzyloxybenzoyl)-6-chloroindole (Example 44, 0.42 g, 1.0 mmol) was hydrogenolyzed in the presence of palladium on activated carbon (10%, 0.10 g) in a mixture of ethyl acetate (10 ml) and ethanol (1.0 ml) at atmospheric pressure overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residual solid was recrystallization from ethyl acetate/hexane to afford 0.13 g (40%) of the title compound as a pale yellow solid. m.p.: 130-145° C. 1H-NMR (CDCl3) δ: 11.73 (1H, brs), 9.80-9.65 (2H, m), 7.62 (1H, d, J=8.4 Hz), 7.50-6.98 (5H, m), 1.76 (3H, s) The signal due to H of OH was not observed.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:34][CH:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[CH2:29][CH2:30]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NC1CCN(c2ccccn2)CC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(c3ccccn3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Yield: 68.5 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.175 g, 0.58 mmol), 1-pyridin-2-ylpiperidin-4-amine dihydrochloride (0.173 g, 0.69 mmol) and TEA (0.23 g, 2.31 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was purified by preparative HPLC to yield the title compound (0.175 g, 69%). 1H NMR (500 MHz, CDCl3): δ 8.08-8.03 (m, 1H), 7.50-7.44 (m, 2H), 7.41-7.32 (m, 4H), 6.55-6.47 (m, 2H), 5.28-5.20 (m, 1H), 4.02-3.93 (m, 2H), 3.11-3.00 (m, 1H), 2.41-2.30 (m, 2H), 1.73-1.60 (m, 2H), 1.67 (s, 9H), 1.36-1.24 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.8, 159.1, 148.0, 137.7, 134.2, 131.9, 130.1, 128.9, 125.4, 113.5, 107.5, 107.0, 61.7, 50.7, 44.1, 41.2, 32.0, 27.8; Mass Spectrum: M−H+ 441.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:16][CH:17]=2)=[N:9][CH:10]=1.[CH2:24]([O:26][C:27]1[C:31]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][NH:29][N:28]=1)[CH3:25].O>CN(C)C=O>[CH2:24]([O:26][C:27]1[C:31]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][N:29]([CH2:4][C:5]2[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]3[N:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:16][CH:17]=3)=[CH:7][CH:6]=2)[N:28]=1)[CH3:25]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: ClCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)nc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of 5-chloromethyl-2-(2-phenyl-4-thiazolylmethoxy)pyridine (475 mg), ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionate (657 mg, yield: 89%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[S:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]=1[Cl:24]>C(O)C>[Cl:24][C:23]1[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[S:20][C:19]=1[CH2:18][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Clc1c(CBr)sc2ccccc12
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2sc3ccccc3c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (148 mg, 1.0 mmol) was dissolved in absolute ethanol (8 mL), then triethylamine (180 μL, 1.3 mmol) and 2-(bromomethyl)-3-chloro-1-benzothiophene (300 mg, 1.2 mmol) were added. The mixture was stirred overnight at room temperature. The precipitate was filtered, washed with ethanol and water and then diethyl ether, and dried in vacuo to afford to 2-{[(3-chloro-1-benzothiophen-2-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (195 mg, 58% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.27 (s, 3H), 4.72 (s, 2H), 5.69 (s, 1H), 6.07 (bs, 1H), 7.43-7.53 (m, 2H), 7.73-7.76 (m, 1H), 7.97-8.00 (m, 114), 12.29 (bs, 1H); LRMS (ES+) m/z 323 (100%, M+1), 325 (35%, M+3).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7]Cl.Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15].C(=O)([O-])O.[Na+]>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][NH:19][CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:20]
Reactant: CCOC(=O)CN
Reactant: Cc1ccc([N+](=O)[O-])c(CCl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNCc1cc(C)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 6 h

Procedure:
5.0 g (27 mmol) of 5-methyl-2-nitrobenzyl chloride was dissolved in 100 ml of ethanol. 7.5 g (54 mmol) of glycine ethyl ester hydrochloride and 6.8 g (81 mmol) of sodium hydrogencarbonate were added to the obtained solution, and they were stirred at 70° C. for 6 hours. The solvent was evaporated. After the extraction with ethyl acetate, the extract was washed with 1 N hydrochloric acid. The obtained aqueous layer was made basic with 1 N sodium hydroxide. After the extraction with ethyl acetate, the obtained organic layer was washed with saturated aqueous sodium chloride solution and then dried. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:13]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C:8](=O)[CH3:9].Cl.[NH2:25][OH:26].CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[N:13]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C:8](=[N:25][OH:26])[CH3:9]
Reactant: NO
Reactant: CC(=O)c1nc2ccn(S(=O)(=O)c3ccc(C)cc3)c2cc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NO)c1nc2ccn(S(=O)(=O)c3ccc(C)cc3)c2cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
A mixture of 1-(6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone (480 mg, 1.38 mmol), hydroxylamine hydrochloride (478 mg, 6.88 mmol), NaOAc (1.13 g, 13.76 mmol) in EtOH (10 mL) was stirred at RT overnight. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (4:1) to afford 514 mg (94%) of 1-(6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone oxime as white solid. MS (ESI): m/z=364.0 [M+1]+.
Reaction SMILES: [I:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[I:1][C:2]1[N:6]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C1=COCCC1
Reactant: CCOC(=O)c1c(C)n[nH]c1I
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C)nn(C2CCCCO2)c1I
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A solution of ethyl 5-iodo-3-methyl-1H-pyrazole-4-carboxylate (2.1 g, 7.50 mmol, 1.00 equiv), 3,4-dihydro-2H-pyran (3.15 g, 37.45 mmol, 4.99 equiv) and toluenesulfonic acid (258 mg, 1.50 mmol, 0.20 equiv) in tetrahydrofuran (100 mL) was stirred at 80° C. for 8 h. The reaction mixture was cooled to room temperature and then diluted with H2O. The pH value of the solution was adjusted to 7 with saturated sodium bicarbonate solution. The resulting solution was extracted with 3×80 mL of ethyl acetate. The combined organic layers were washed with 1×80 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-25% of ethyl acetate in petroleum ether to give 1.5 g (55%) of (R/S) ethyl 5-iodo-3-methyl-1-(oxan-2-yl)-1H-pyrazole-4-carboxylate as a yellow oil. 1H-NMR (300 MHz, DMSO-d6): δ 5.45 (dd, J=9.9 Hz, 1H), 4.24 (q, J=7.2 Hz, 2H), 3.88-3.84 (m, 1H), 3.69-3.60 (m, 1H), 2.49 (s, 3H), 1.95-1.75 (m, 2H), 1.65-1.45 (m, 4H), 1.29 (t, J=7.2 Hz, 3H) ppm. LCMS (method D, ESI): RT=1.55 min, m/z=365.0 [M+H]+.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[N+:16]([O-])=O)=O)C>CO.C(O)(=O)C.[Fe]>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]2[NH:8][CH2:7][CH2:6][C:4](=[O:3])[NH:16][C:10]=2[CH:11]=1
Reactant: CCOC(=O)CCNc1ccc(C)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc2c(c1)NC(=O)CCN2
Temperature: 25 °C
Yield: 16 %

Procedure:
A mixture of N-(2-ethoxycarbonylethyl)-4-methyl-2-nitroaniline (11.25 g) and iron powder (12.45 g) in a mixture of methanol (70 ml) and acetic acid (7 ml) was refluxed for 1 hour and the solution was cooled to ambient temperature. The mixture was filtered through celite and the filtrate was evaporated in vacuo. The residue was dissolved with chloroform (50 ml) and the solution was basified with saturated sodium bicarbonate aqueous solution. The solution was filtered through celite and the organic layer was washed with brine. The solution was dried over magnesium sulfate and the solvent was removed. A mixture of the residue (8.00 g) in a mixture of concentrated hydrochloric acid (16 ml) and water (12 ml) was refluxed for 1 hour and the solution was cooled to ambient temperature. The mixture was basified with concentrated ammonium hydroxide and then the resulting solution was extracted with chloroform. Drying over magnesium sulfate, filtering and the removal of solvents afforded a crude product. The crude product was triturated with diethyl ether - isopropyl ether (1:1) to give 8-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (1.26 g) as a brown powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:5]=1[NH2:6].Cl[C:28]1[N:29]=[C:30]([NH:47][C:48]2[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:49]=2[C:50](N)=[O:51])[C:31]2[CH:36]=[CH:35][N:34]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C:32]=2[N:33]=1.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:57][C:53]1[CH:54]=[CH:55][CH:56]=[C:48]2[C:49]=1[C:50](=[O:51])[N:29]1[C:28]([NH:6][C:5]3[CH:7]=[CH:8][C:9]([N:11]4[CH2:16][CH2:15][CH:14]([N:17]5[CH2:18][CH2:19][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:21][CH2:22]5)[CH2:13][CH2:12]4)=[CH:10][C:4]=3[O:3][CH3:2])=[N:33][C:32]3[N:34]([S:37]([C:40]4[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=4)(=[O:38])=[O:39])[CH:35]=[CH:36][C:31]=3[C:30]1=[N:47]2
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c2nc3cccc(F)c3c(=O)n12
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A solution of 2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline hydrochloride (3 g, 7.41 mmol) and 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (3 g, 6.52 mmol) in trifluroroethanol (200 mL) and HCl in dioxane (14.16 ml, 56.6 mmol) and KI (300 mg, 1.807 mmol) was stirred at 90° C. in a 300 mL pressure vessel behind a blast shield for 15 hours. After cooling to rt, the solution was neutralized with aqueous NaHCO3 (400 mL), the black suspension was added to CH2Cl2 (500 mL), and the layers separated. Addition of brine (200 mL) helped to separate the organic and aqueous layers. The organic layers were concentrated under reduced pressure and then suspended in CH2Cl2 (20 mL) and Et2O (150 mL). The solid was filtered to obtain 8-fluoro-5-[(2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one as brown powder (4.5 g, 5.81 mmol, 89% yield). This material was used without further purification. ESIMS (M+H)+=775.32 (100%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[S:16][CH:17]=[CH:18][N:19]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[CH:5][CH:4]=1
Reactant: Brc1nccs1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2nccs2)cc1

Procedure:
Using (4-(trifluoromethyl)phenyl)boronic acid (0.5 g, 3.06 mmol) and 2-bromo thiazole (1.1 g, 61.3 mmol) and following the procedure described in Example 7, Step 1, the title compound was obtained after purification by flash chromatography (60-120 mesh, 2% ethyl acetate in hexane) as white solid (0.5 g, 83% Yield). 1H NMR (400 MHz, DMSO-d6): δ 8.15 (d, 2H), 8.00 (d, 1H), 7.90 (d, 1H), 7.85 (d, 2H); LC-MS m/z calculated for [M+H]+ 230.02, found 230.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=O)=[CH:4][CH:3]=1.[CH3:13]CCCCC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=[CH2:13])=[CH:4][CH:3]=1
Reactant: O=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: CCCCCC
Product: C=C[C@H]1C[C@@H]1c1ccc(Br)cc1

Procedure:
The product from Example 30A was subjected to the conditions outlined in in Example 26E, followed by chromatography (100% hexane) to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:26]=[C:25]([C:27](OCC)=[O:28])[CH:24]=[CH:23][N:22]=1)[CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>CCO>[CH3:18][N:17]([CH2:16][CH:13]1[CH2:12][CH2:11][CH:10]([CH2:9][N:8]([CH2:20][C:21]2[CH:26]=[C:25]([CH2:27][OH:28])[CH:24]=[CH:23][N:22]=2)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:15][CH2:14]1)[CH3:19]
Reactant: CCOC(=O)c1ccnc(CN(CC2CCC(CN(C)C)CC2)C(=O)OC(C)(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CN(C)CC1CCC(CN(Cc2cc(CO)ccn2)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
By General Procedure U from ethyl 2-({[(tert-butoxy)carbonyl]({4-[(dimethylamino)methyl]cyclohexyl}methyl)amino}methyl)pyridine-4-carboxylate) (1.0 equiv.) in EtOH. Stirred at reflux for 2 hours. Cooled to room temperature and sat. NH4Cl solution was added. Evaporated to dryness. Purification by column chromatography (DCM, MeOH (10%) and HN4OH (1%)) gave the title product as light yellow oil. 1H NMR (300 MHz, chloroform-d): δ ppm 8.41 (d, 1H), 7.17 (m, 2H), 4.65 (s, 2H), 4.50 (d, 2H), 3.10 (m, 2H), 2.17 (s, 6H), 2.07 (d, 2H), 1.74 (m, 4H), 1.41 (m, 11H), 0.87 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:30][CH2:31][CH2:32][CH2:33][S:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([C:7]([NH:30][CH2:31][CH2:32][CH2:33][S:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: NCCCSc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCCSc2ccncc2)s1
Yield: 64.5 %

Procedure:
To a solution of 1.27 g (8.91 mmol) of 5-methyl-2-thiophenecarboxylic acid and 1.33 g (11.6 mmol) of N-hydroxysuccinimide in 90 ml of methylene chloride, 2.05 g (10.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1 hour. Further, 1.50 g (8.91 mmol) of 4-(3-aminopropylthio)pyridine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder thus obtained was washed with ether and dried to obtain 1.68 g of the desired compound (yield: 64.5%, colorless powder).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[O:18][CH2:17][CH2:16][O:15]2)=[CH:10][C:9]=1[CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)[OH:27].[Br:35][CH2:36][C:37](Br)=[O:38]>C(Cl)Cl>[Br:35][CH2:36][C:37]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:18][CH2:17][CH2:16][O:15]2)=[CH:10][C:9]=1[CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)[OH:27])=[O:38]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(O)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(CBr)Nc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
K2CO3 10% (250 ml) was added to a mixture of intermediate (9) (0.072 mol) in DCM (250 ml). Then bromo-acetyl bromide (0.072 mol) was added dropwise at room temperature. The mixture was stirred at room temperature overnight. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The product was used without further purification, yielding (quant.) of 2-bromo-N-[4-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-2-[(3-chlorophenyl)hydroxymethyl]phenyl]-acetamide (intermediate 10).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[CH2:22]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH2:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:21])[CH2:6][CH2:7]2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: CCc1ccc(C=O)cc1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCc1ccc(CNC2CCN(CCn3c(=O)cnc4ccc(F)cc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5 mL of a chloroform solution containing 301 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 143 mg of 4-ethylbenzaldehyde, 60 μL of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 352 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=1:1], to give 1-(2-(4-(4-ethylbenzylamino)piperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one as pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[O:49][N:48]=[C:47]([CH3:50])[N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[O:49][N:48]=[C:47]([CH3:50])[N:46]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1noc(CCl)n1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1noc(Cn2nc3nc(C(C)(C)C)nc(N4CCC(F)(F)C4)c3n2)n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole and isolated as light yellow gum. MS (m/e): 379.3 (MH+).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[C:16]([CH3:21])=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10](=[O:29])[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=[O:4].[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>>[CH2:22]([N:11]1[C:12]2[C:7](=[C:6]([OH:36])[C:5]([C:3]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:4])=[N:14][C:13]=2[C:15]2[C:16]([CH3:21])=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:10]1=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1nc(-c2cccnc2C)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: Cc1ncccc1-c1nc(C(=O)NCCC(=O)O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 63.4 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-8-(2-methyl-pyridin-3-yl)-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (28 mg, 0.059 mmol), β-alanine (628 mg, 7.0 mmol) and NaOMe solution (10.5 mL, 5.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 20 mg of the title compound. MS: (+) m/z 535.51 (M+1).