Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][Si:10]([CH3:26])([C:22]([CH3:25])([CH3:24])[CH3:23])[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.CI>O1CCCC1>[CH3:26][Si:10]([CH3:9])([C:22]([CH3:23])([CH3:25])[CH3:24])[O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH3:1])[C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)O)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C(=O)O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Into dry tetrahydrofuran (20 ml) at 0° C. under anhydrous conditions was added slowly with stirring lithium diisopropylamide (2 67 g, 25 mmol) and then a solution of 4-(dimethy1-tert-butylsilyloxy)phenylacetic acid (2.66 g, 1.0 mmoles) in tetrahydrofuran (10 ml) was added dropwise. The resultant brown solution was stirred at 20°-25° C. for one hour and at 50° C. for 30 minutes. The solution was then cooled to 0° C. and methyl iodide (3.54 g, 25 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for about 16 hours and then quenched with saturated aqueous ammonium chloride (20 ml) and acidified with 3N hydrochloric acid. The reaction mixture was extracted with diethyl ether (3×100 ml) and the combined extracts washed with saturated aqueous sodium chloride (2×50 ml), dried over magnesium sulfate and the solvent removed in vacuo to afford a tan oil. The oil was chromatographed on a 5× 15 cm column of silica gel eluted with 10 percent isopropanol/hexane to yield the desired product as a solid. m.p. 52°-4° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[NH:12][C:11](=S)[NH:10][C:9](=[O:14])[CH:8]=2)[CH2:3][CH2:2]1.BrCC(O)=[O:18].[OH-].[Na+]>CCO.O>[CH:1]1([CH2:4][O:5][CH2:6][C:7]2[NH:12][C:11](=[O:18])[NH:10][C:9](=[O:14])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)CBr
Reactant: O=c1cc(COCC2CC2)[nH]c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=c1cc(COCC2CC2)[nH]c(=O)[nH]1
Temperature: 0 °C
Yield: 36.8 %

Procedure:
6-[(Cyclopropylmethoxy)methyl]-2-sulfanylidene-1,2,3,4-tetrahydropyrimidin-4-one (10.3 g, 48.5 mmol) was added to bromoacetic acid (21.5 g, 155 mmol, 3.2 eq) in EtOH (108 mL) and H2O (441 mL). The reaction mixture was refluxed for 16 h then cooled down to rt and basified to pH˜10 with sodium hydroxide (3 M, aq). The mixture was concentrated in vacuo and hydrochloric acid (aq, 10%) was added. The mixture was cooled to 0° C. The precipitate was isolated by filtration and dried to give the title compound as a solid (3.5 g, 37%).
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]([CH2:8][C:9]([OH:11])=O)([C:5](O)=O)O.[OH2:14]>>[CH3:5][C:3]1[C:2]2[CH:1]=[CH:2][C:3]([OH:14])=[CH:5][C:1]=2[O:13][C:9](=[O:11])[CH:8]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O
Product: Cc1cc(=O)oc2cc(O)ccc12

Procedure:
50 μl of the 4-UMO buffer solution and 25 μl of distilled water (or sample solution) were placed in a 96-well microplate and mixed at 25° C., followed by adding 25 μl of the lipase buffer solution to start enzyme reaction. After 30 minutes of reaction, 100 μl of 0.1M citric acid buffer (pH 4.2) was added to terminate the reaction, and the fluorescence of 4-methylumbelliferone (excitation wavelength: 355 nm, fluorescence wavelength: 460 nm) produced by the reaction was measured with a fluorescence plate reader (Labsystems, Fluoroskan Asent CF).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([F:11])[CH:3]=1.[Br-].[CH2:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH:13]1([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([F:11])[CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCCC1
Reactant: CC(=O)c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)c1ccc(OC2CCCC2)cc1F
Temperature: 70 °C

Procedure:
A suspension of 2.5 g 4′-hydroxy-2′-fluoroacetophenone, 2.0 mL cyclopentane bromide and 7.9 g cesium carbonate in acetonitrile (35 mL) was heated for 1 hour under reflux and then heated at 70° C. for 15 hours. Further, 1.0 mL cyclopentane bromide was added thereto, and the mixture was heated for 3 hours under reflux. The reaction mixture was diluted with ethyl acetate, washed with water and brine and dried over anhydrous sodium sulfate, and the solvent was removed, whereby 3.65 g of the title compound in a crude state (yellow oil) was obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:20])(=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O:21]=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:24][CH2:23]1>C1COCC1>[CH2:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][C:22]([CH:14]([C:13]([OH:20])=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])([OH:21])[CH2:23][CH2:24]1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCCCCC(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCC(C(=O)O)C1(O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Yield: 99.1 %

Procedure:
To a solution of 15 mL (124 mmol) diisopropyl amine in 90 mL anhydrous THF at −40° C. was added dropwise 45 mL (113 mmol) of n-butyl lithium (2.5 M in hexanes) The reaction mixture was warmed to 0° C. A solution of 6.7 mL (62.1 mmol) hexanoic acid acid in 60 mL anhydrous THF was added dropwise. The reaction mixture stirred at −20° C. for an additional 20 m. The reaction mixture was cooled to −78° C. A solution of 15 g (64.3 mmol) benzyl 4-oxo-1-piperidine-carboxylate in 60 mL anhydrous THF was added dropwise. The reaction mixture slowly warmed to room temperature over 18 h. The reaction was quenched by addition of 25 mL of water. The mixture was acidified to pH 2 with 6N HCl. The aqueous layer was thrice extracted with EtOAc. The combined organic phase was dried over magnesium sulfate and evaporated under reduced pressure. Toluene was added to the light, yellow oil and evaporated under reduced pressure to provide 21.5 g (99%) of 4-(1-carboxy-pentyl)-4-hydroxy-piperidine-1-carboxylic acid benzyl ester: ms [M]+=350.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:14][CH3:15])=[C:4]([Cl:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:22][CH2:23][CH2:24][CH2:25]I>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH2:14][CH3:15])=[C:4]([Cl:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:25][CH2:24][CH2:23][Cl:22])[C:6]=2[CH:12]=1
Reactant: CCc1c(Cl)cc2c(c1Cl)OCC(=O)N2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCc1c(Cl)cc2c(c1Cl)OCC(=O)N2CCCCl
Yield: 67.1 %

Procedure:
6,8-Dichloro-7-ethyl-4H-benzo[1,4]oxazin-3-one (95MF46) (0.342 g, 1.39 mmol), Cs2CO3 (0.678 g, 2.08 mmol) and 3-chloro-1-iodopropane (0.313 g, 1.52 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (95MF52(2226)) (0.301 g, 67%). 1H NMR (CDCl3) δ 7.01 (s, 1H), 4.68 (s, 2H), 4.06 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.0 Hz, 2H), 2.91 (q, J=7.6 Hz, 2H), 2.10-2.18 (m, 2H), 1.16 (t, J=7.6 Hz, 3H); 13C NMR (CDCl3) δ 163.8, 140.6, 135.8, 127.9, 127.7, 123.6, 113.8, 67.9, 42.2, 39.3, 30.0, 24.7, 12.7.
Reaction SMILES: C([BH3-])#N.[Na+].C1(N2[C:15]([CH:16]3CCC[O:17]3)=[C:14]([C:21]3ON=[C:23]([C:26]4C=CC(C=O)=CC=4)[N:22]=3)C=N2)CCCCC1.C(O)(=[O:36])C>CO>[NH:22]1[CH2:21][CH2:14][CH:15]([C:16]([OH:17])=[O:36])[CH2:26][CH2:23]1
Reactant: CC(=O)O
Reactant: O=Cc1ccc(-c2noc(-c3cnn(C4CCCCC4)c3C3CCCO3)n2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(O)C1CCNCC1
Yield: 200 %

Procedure:
Sodium cyanoborohydride (17.3 mg; 0.275 mmol) was added to a solution of 4-(5-(1-cyclohexyl-5-(tetrahydrofuran-2-yl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (99 mg; 0.25 mmol), obtained from step 2, and isonipecotic acid (64.6 mg; 0.50 mmol) in methanol (3 mL) and acetic acid (45 μL; 0.75 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the crude material purified by reverse phase preparative HPLC to give Example 125 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.20 (1 H, s), 8.04 (2 H, d, J=8.0 Hz), 7.54 (2 H, d, J=8.0 Hz), 5.72 (1 H, dd, J=9.5, 6.9 Hz), 4.47 (1 H, d, J=8.2 Hz), 4.16 (1 H, q, J=7.5 Hz), 3.97 (1 H, q, J=7.5 Hz), 3.57 (2 H, s), 2.79 (2 H, d, J=10.9 Hz), 2.55-2.50 (1 H, m), 2.26-2.13 (3 H, m), 2.11-1.78 (11 H, m), 1.72 (1 H, d, J=12.5 Hz), 1.65-1.52 (2 H, m), 1.50-1.35 (2 H, m), 1.35 (1 H, m). LC/MS: 506 (M+H)+. HPLC (Method B) Rt 2.77 min (Purity: 99.2%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:22])[CH2:20]Cl)=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH:23][C:24](=[O:35])[C:25]([O:31]C(=O)C)([CH3:30])[C:26]([F:29])([F:28])[F:27]>O.CC(C)=O>[Cl:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:22])[CH2:20][N:2]([CH3:3])[CH3:1])=[CH:16][CH:17]=2)[CH:8]=[CH:7][C:6]=1[NH:23][C:24](=[O:35])[C@:25]([OH:31])([CH3:30])[C:26]([F:28])([F:29])[F:27]
Reactant: CNC
Reactant: CC(=O)OC(C)(C(=O)Nc1ccc(Sc2ccc(NC(=O)CCl)cc2)cc1Cl)C(F)(F)F
Solvent: O
Solvent: CC(C)=O
Product: CN(C)CC(=O)Nc1ccc(Sc2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1

Procedure:
Dimethylamine (0.17 ml of a 40% solution in water) was added to a solution of (R)-N-{2-chloro-4-[4-(2-chloroacetylamino)phenylsulphanyl}phenyl -2-acetoxy-2-methyl-3,3,3-trifluoropropanamide (Method 19) (0.25 g) in acetone (1.5 ml). After 24 hours volatile material was removed by evaporation and the residue was dissolved in ethyl acetate, washed with water, and the organic layer was poured onto a Varian Chem Elut column. Elution with ethyl acetate gave the title compound (0.25 g) as a foam. NMR: 1.6 (s, 3H), 3.1 (s, 2H), 3.3 (s, 6H), 7.2 (d, 1H), 7.3 (s, 1H), 7.4 (d, 2H), 7.7 (m, 3H), 7.9 (d, 1H), 9.7 (s, 1H), 9.9 (s, 1H); MS (ESP−): 474.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:28][N:29](C)[C:30](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:44]>C(OCC)(=O)C.CC(O)C>[ClH:44].[F:1][C:2]1[C:3]([CH2:28][NH:29][CH3:30])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:18]=2)(=[O:15])=[O:16])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(CS(C)(=O)=O)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cccc(CS(C)(=O)=O)c2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-({3-[(methylsulfonyl)methyl]phenyl}sulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (266 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol and water to give the title compound as a white solid (yield 187 mg, 79%).
Reaction SMILES: C([O:4][CH:5]([O:12][C:13](=[O:15])C)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.[CH3:16]C1C=C(O)C(=CC=1)C(O)=O>S(=O)(=O)(O)O.C(O)(=O)C>[CH3:16][C:9]1[CH:10]=[CH:11][C:6]2[C:5](=[O:4])[O:12][CH2:13][O:15][C:7]=2[CH:8]=1
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: CC(=O)OC(OC(C)=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)OCOC2=O

Procedure:
61 g of benzal diacetate, 44.6 g of 4-methylsalicylic acid and 45 ml of acetic acid are combined and 5 drops of concentrated sulfuric acid are added and the mixture is heated under reduced pressure, allowing acetic acid to distill off. When the theoretical amount of acetic acid is collected (about 2.5 hours) the mixture is allowed to cool, diluted with ether and the ether solution washed with potassium carbonate solution, sodium bisulfite solution and dried over sodium sulfate. The ether is removed in vacuo and the resulting solid crystallized from ethyl acetate/hexane to give 7-methyl-1,3-benzodioxane-4-one.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13]([N:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1)=[O:14])[CH3:2]
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: C1CC(N2CCOCC2)CCN1
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCOCC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 170 mg (1.00 mmol) 4-piperidin-4-yl-morpholine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:5]=1[Br:11].Cl.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([N:15]([CH3:16])[CH3:14])[CH:7]=[CH:6][C:5]=1[Br:11]
Reactant: COC(=O)c1cc(F)ccc1Br
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(N(C)C)ccc1Br
Temperature: 70 °C
Reaction time: 11 h
Yield: 70 %

Procedure:
To a stirred solution of 5.24 g (22.5 mmol) 2-Bromo-5-fluoro-benzoic acid methyl ester (Rarechemicals) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 11 h at 70° C. in an autoclave and was concentrated with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 16a was obtained in 70% yield (4.08 g, 15.8 mmol).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[CH3:17][N:18]([CH3:31])[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[CH:21][CH:20]=1.N1CCCCC1>CCO>[CH3:17][N:18]([CH3:31])[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][NH:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:3]=2[C:14]([NH2:16])=[O:15])=[CH:21][CH:20]=1
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)c1ccc(CNc2[nH]nc(Nc3cccnc3)c2C(N)=O)c2ccccc12

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide 8 (100 mg) was suspended in EtOH (3 mL) and 4-Dimethylamino-1-naphthaldehyde (1 eq.) and piperidine (I drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-(((4-(dimethylamino)naphthalen-1-yl)methyl)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([OH:26])=O)[CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.S(Cl)([Cl:29])=O>CN(C=O)C>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([Cl:29])=[O:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CN1CCN(c2ccc(-c3nc4ccc(C(=O)O)cc4s3)cn2)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(-c3nc4ccc(C(=O)Cl)cc4s3)cn2)CC1
Temperature: 70 °C

Procedure:
2-[6-(4-Methylpiperazin-1-yl)pyridin-3-yl]-1,3-benzothiazole-6-carboxylic acid hydrochloride acid (46 mg, 0.12 mmol) was added to thionyl chloride (3 mL), followed by 3 drops DMF, before heating at 70° C. o.n. The solvent was thereafter evaporated in vacuo and once with toluene to give crude 2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,3-benzothiazole-6-carbonyl chloride. Ammonium hydroxide (conc., 3 mL) was added dropwise to this crude product and the mixture was thereafter stirred for 1 h at r.t. The r.m. was extracted twice with DCM, dried (Na2SO4), and evaporated in vacuo. The obtained residue was purified by prep. HPLC to give the title compound (7 mg) as a light yellow solid. 1H NMR δ 8.81 (d, 1H) 8.58 (s, 1H) 8.16 (dd, 1H) 8.07 (br. s., 1H) 7.99 (s, 2H) 7.45 (br. s., 1H) 7.00 (d, 1H) 3.61-3.71 (m, 4H) 2.37-2.46 (m, 4H) 2.23 (s, 3H) 1.89 (s, 3H); MS m/z (M+H) 354.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][O:14][CH2:15][C:16]2[CH:29]=[CH:28][C:19]([CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[NH:40]1[CH:44]=[CH:43][N:42]=[C:41]1[CH:45]=O>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:28][CH:29]=2)=[CH:11][CH:10]=1)[CH2:45][C:41]1[NH:40][CH:44]=[CH:43][N:42]=1
Reactant: CCCN(CCC)Cc1ccc(COCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: O=Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(COCc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The compound (136 mg) obtained in Example 80-4 was dissolved in anhydrous methanol (3.0 ml) and then added with sodium cyanoborohydride (40.6 mg), acetic acid (1.00 ml), and 2-imidazole carboxaldehyde (46.6 mg), followed by stirring under a nitrogen atmosphere at 60° C. overnight. After completion of the reaction, the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (109 mg) of the subject compound as a white solid.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[OH-].[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH2:15][C:14](=O)[CH2:13][CH2:12]2>O>[CH3:20][O:19][C:18]1[CH:17]=[C:16]2[C:11](=[CH:10][C:9]=1[O:8][CH3:7])[CH2:12][C:13](=[N:4][O:2][CH3:3])[CH2:14][CH2:15]2
Reactant: CON
Reactant: COc1cc2c(cc1OC)CC(=O)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON=C1CCc2cc(OC)c(OC)cc2C1
Yield: 89.1 %

Procedure:
A mixture of 0.56 g (6.7 mmol) of methoxylamine hydrochloride and 6.5 ml (6.5 mmol) of a 1 M aqueous solution of NaOH was added to 0.689 g (3.34 mmol) of 6,7-dimethoxy-2-tetralone (IV). While under a nitrogen atmosphere the mixture was warmed to ca. 100° for 15 minutes and then kept at 40° using an infrared lamp for 18 hours. Water was added to the mixture which was then extracted with ether. The combined extracts were dried (MgSO4) and the solvent was removed on a rotary evaporator, affording 0.700 g (89.2%) of brown oil: nmr (CDCl3) δ2.3-2.9 (m, 4H), 3.32 (S, 1H), 3.57 (S, 1H), 3.73 (S, 6H), 3.78 (S, 3H), 6.4-6.6 (m, 2H). The compound was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O[C@@H:12]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][C@H:12]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1)(=[O:10])[CH3:9]
Reactant: O=C(Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1)C1CC1
Reactant: CC(=O)c1cccc(O)c1
Product: CC(=O)c1cccc(O[C@@H](CCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure B and Scheme B1 using 1-(3-hydroxyphenyl)ethanone and N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)cyclopropanecarboxamide: ESMS m/e: 497.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl[C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1>CC(O)C>[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[N:8]=[CH:7]1
Reactant: NCCc1c[nH]cn1
Reactant: Clc1cnccn1
Solvent: CC(C)O
Product: c1cnc(NCCc2c[nH]cn2)cn1

Procedure:
1 g (8.9 mmol) of histamine and 1.03 g (8.9 mmol) of 2-chloropyrazine are brought to reflux in 20 ml of 2-propanol for 72 h, evaporated and the crude solid residue is chromatographed through silica gel, using chloroform/methanol mixtures (1%, 5%, 10% and 20% respectively). The product is converted to the dioxalate in absolute ethanol and addition of ether gives the title compound which is recrystallized from a 2-propanol/diethyl ether mixture in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.CC(C)([O-])C.[K+]>C1(C)C(C)=CC=CC=1.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:3]=1
Reactant: C1CNCCN1
Reactant: Brc1cccnc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: c1cncc(N2CCNCC2)c1
Temperature: 120 °C
Yield: 33.9 %

Procedure:
3-Bromopyridine (1.0 g, 6.32 mmol) and piperazine (3.2 g, 37.9 mmol) were dissolved in xylene (10 mL) and the solution was purged with argon for 10 min. Potassium tert-butoxide (0.99 g, 8.86 mmol) and catalytic Pd(PtBu3)2 (320 mg, 0.63 mmol) were added and the reaction mixture was heated to 120° C. for 10 h, cooled to room temperature, diluted with EtOAc and filtered through Celite. The filtrate was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 10% MeOH in CH2Cl2) to get 1-(pyridin-3-yl)piperazine (350 mg, yield 35%). 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J=3.0 Hz, 1H), 7.97-7.95 (dd, J=4.6 Hz, 1.1 Hz, 1H), 7.29-7.26 (m, 1H), 7.20-7.16 (m, 1H), 3.08-3.06 (m, 4H), 2.83-2.81 (m, 4H). MS (ESI) m/z: Calculated for C9H13N3: 163.11. found: 164.0 (M+H)+
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=[O:7])=O.C[O-].[Na+].Cl>CN(C)C=O.CO>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([C:14]2[O:13][C:4]3[C:5]([C:6]([OH:8])=[O:7])=[CH:10][CH:11]=[CH:12][C:3]=3[CH:1]=2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: COC(=O)c1cccc(C=O)c1OCc1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)c1cccc2cc(-c3ccc([N+](=O)[O-])cc3)oc12
Reaction time: 0.17 h
Yield: 59.8 %

Procedure:
16.1 g of methyl 3-formyl-2-(4-nitrobenzyloxy)benzoate are dissolved in 100 ml of dimethylformamide and a solution of 5.4 g of sodium methoxide in 20 ml of methanol is added dropwise to the solution at 120° C. The mixture is stirred at the same temperature for 10 minutes. The reaction mixture is acidified with 10% hydrochloric acid and then extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The resultant crystals are collected, washed and dried to give 8.65 g of 2-(4-nitrophenyl)benzofuran-7-carboxylic acid as pale orange powder.