Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[NH:7][CH:6]=1)=[O:4].[CH3:13][O:14][CH2:15][CH2:16]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][CH2:16][CH2:15][O:14][CH3:13])=[N:7][CH:6]=1
Reactant: COC(=O)c1c[nH]c(=O)c(Br)c1
Reactant: COCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1ncc(C(=O)OC)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
5-Bromo-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid methyl ester (15 g, 65 mmol, CA 381247-99-0) was suspended in THF (500 mL). To this suspension was added with stirring 2-methoxyethanol (7.1 mL, 97 mmol), diisopropylazodicarboxylate (21.5 mL, 97 mmol) and triphenylphosphine (25.4 g, 97 mmol). This mixture was stirred for 1 h at room temperature and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica (heptane/ethylacetate, 2:1) to give the title compound (8.65 g) as a yellow solid; MS (ISP) 290.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:32]
Reactant: NCc1ccccc1
Reactant: COCCCCCCCCCCCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCCCCCCCCCCC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 70 %

Procedure:
To a solution of benzylamine (486 mg, 4.5 mmol) in 20 mL of methylene chloride at 0° C. was added dropwise diisopropylethylamine (0.45 ml, 5 mmol) followed by the title product of example 11 (1.0 g, 4 mmol). After stirring at room temperature for 6 days, the reaction mixture was washed successively with 1N HCl, water, saturated NaHCO3, water and brine, dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in anhydrous methanol and passed through a basic ionexchange resin and eluted with anhydrous methanol. Concentration afforded the title compound (895 mg) as a white solid, m.p. 77.7°-79.4° C. (DSC). The structure was supported by NMR, infrared spectroscopy, elemental analysis, and mass spectroscopy.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([CH:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.Cl.[CH3:20]O>CO>[C:14]1([CH3:17])[CH:13]=[CH:12][C:11]([CH:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:18])=[CH:2][CH:3]=2)[C:8]([O:10][CH3:20])=[O:9])=[CH:16][CH:15]=1
Reactant: CO
Reactant: Cc1ccc(C(C(=O)O)c2ccc(C)cc2)cc1
Agent: Cl
Product: COC(=O)C(c1ccc(C)cc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of di-p-tolylacetic acid (4.90 g, 20.4 mmol) in methanol was treated with sat'd HCl/MeOH solution at room temperature. The mixture was stirred at room temperature (3 h). The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (21). The crude product was used directly.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([CH3:30])=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH3:20])[CH:13]=3)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])(O)=O.[Na+].Cl[C:37]([O:39][C:40]([CH3:42])=[CH2:41])=[O:38]>CCOC(C)=O>[CH2:41]=[C:40]([O:39][C:37](=[O:38])[NH:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([CH3:30])=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([N:19]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH3:20])[CH:13]=3)[CH:5]=[CH:6][C:7]=1[F:8])[CH3:42]
Reactant: COc1ccc(CN(C)c2cc3nc(C)c(-c4ccc(F)c(N)c4)cc3cn2)cc1
Reactant: C=C(C)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(N(C)Cc4ccc(OC)cc4)cc3nc2C)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Treat a solution of 3-(3-amino-4-fluorophenyl)-N-(4-methoxybenzyl)-N,2-dimethyl-1,6-naphthyridin-7-amine (0.334 g, 0.830 mmol) in EtOAc (10 mL) with satd. NaHCO3 (10 mL), add isopropenyl chloroformate (0.100 mL, 0.913 mmol) and stir at RT for 2 h. Separate the layers, extract the aqueous layer with EtOAc (2×), dry the combined organics over MgSO4 and concentrate to dryness to afford the title compound (398 mg, 99%). MS (ESI) m/z: 487.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[N:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15]C)[CH:10]=3.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:26]=[N:25][CH:24]=[N:23][CH:22]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:15])[CH:10]=3
Reactant: COc1cc2c(=O)c(Cc3cncnc3)cn3c4cc(Br)ccc4c(c1)c23
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c(Cc2cncnc2)cn2c3cc(Br)ccc3c3cc(O)cc1c32
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
9-bromo-2-methoxy-5-(5-pyrimidylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (260 mg) produced in Example 125 was suspended in anhydrous methylene chloride (16 ml), and boron tribromide (3.7 ml) was added dropwise at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was poured into ice water and saturated aqueous solution of sodium hydrogencarbonate was added thereto until the termination of foaming. The crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with ethanol and ether in succession to obtain the title compound (250 mg, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([NH:15][C:25](=[O:26])[C@@H:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])[CH3:28])[CH:3]=1
Reactant: Nc1cc(F)ccc1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cc(F)ccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-fluoro-N1-phenylbenzene-1,2-diamine (866 mg, 4.3 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (890 mg, 4.7 mmol), HOAt (640 mg, 4.7 mmol), 4-methylmorpholine (1.0 mL, 9.5 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (900 mg, 4.7 mmol) in DCM (20 mL) was stirred at RT for 2 h. The reaction mixture was then partitioned between DCM (50 mL) and a saturated solution of NaHCO3. The organic layer was washed with brine, then dried (MgSO4) and concentrated in vacuo affording (S)-tert-butyl 1-(5-fluoro-2-(phenylamino)phenylamino)-1-oxopropan-2-ylcarbamate as a yellow-orange solid (quantitative), used in the following step without further purification. LCMS: RT 3.83 min [M+H]+ 374.1
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[N:12][CH:11]=[CH:10]3)=[CH:5][N:6]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:24][S:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=1>CC(O)C>[CH:13]1[C:14]2[C:9](=[CH:8][C:7]([C:4]3[O:3][C:2]([NH:17][C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH2:28][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)=[N:6][CH:5]=3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: Clc1ncc(-c2ccc3cnccc3c2)o1
Reactant: Nc1cccc(NS(=O)(=O)Cc2ccccc2)c1
Solvent: CC(C)O
Product: O=S(=O)(Cc1ccccc1)Nc1cccc(Nc2ncc(-c3ccc4cnccc4c3)o2)c1
Temperature: 80 °C
Yield: 72.3 %

Procedure:
A mixture of 2-chloro-5-(isoquinolin-6-yl)oxazole 14 (0.069 g, 0.30 mmol) and N-(3-aminophenyl)-1-phenylmethanesulfonamide 26 (0.157 g, 0.599 mmol) in 2-propanol (20 mL) was heated to 80° C. for 24 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide N-(3-((5-(isoquinolin-6-yl)oxazol-2-yl)amino)phenyl)-1-phenylmethanesulfonamide 27 (0.099 g, 72% yield) as pale yellow solid. MS (ES) m/z 457 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]1=2)=[O:6].C1C2C(=O)N[C:30]3C=CC=C[C:29]=3[NH:28][C:27]=2[CH:26]=CC=1.BrCCCC(Cl)=O>C1(C)C=CC=CC=1>[CH2:27]([N:28]([CH2:29][CH3:30])[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]1=2)=[O:6])[CH3:26]
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Reactant: O=C1Nc2ccccc2N(C(=O)CCCBr)c2ccccc21
Agent: O=C(Cl)CCCBr
Solvent: Cc1ccccc1
Product: CCN(CC)CCCC(=O)N1c2ccccc2NC(=O)c2ccccc21

Procedure:
The 5-(4-bromobutyryl)-5,10-dihydro-11H-dibenzo(b,e)(1,4)-diazepine-11-one, starting material, was synthesized similarly to the starting material described in Example 1, from 5,10-dihydro-11H-dibenzo(b,e)(1,4)-diazepine-11-one and 4-bromobutyryl chloride. The yield is 74.3% of the theoretical yield and the melting point is 159°-161° C. (toluene).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:7])[CH2:3][CH2:2]1.[F-].[Cs+].CS(O[CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)(=O)=O>CC(N(C)C)=O>[CH:1]1([CH2:4][NH:5][C:6](=[O:7])[NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[CH:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: O=C(NCC1CC1)Nc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)NCC3CC3)cc2)CC1
Temperature: 85 °C

Procedure:
To a stirring solution of 1-(cyclopropylmethyl)-3-(4-hydroxyphenyl)urea (6.79 mmol, 1.4 g) in dimethylacetamide (50 mL) was added cesium fluoride (20.36 mmol, 3.09 g) followed by a solution of tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (8.15 mmol, 2.276 g) in dimethylacetamide (50 mL). The resulting suspension was heated to 85° C. overnight. The reaction mixture was filtered and the filtrate concentrated under vacuum. The residue was dissolved in dichloromethane and washed with water. The organic layer was separated, dried over magnesium sulfate and concentrated under vacuum. The residue was dissolved in dichloromethane and purified by column chromatography (eluent 2-8% methanol in dichloromethane) to afford the title compound. MS (ESI) m/z 390.0 [M+H]+
Reaction SMILES: [C:1]([O:20]C)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].I[CH2:23]I.Cl.[OH-].[K+]>CCOCC.[Cu].[Zn].O1CCCC1.CO.O>[CH2:11]([C@H:10]1[CH2:23][C@H:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: ICI
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: [Cu]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCC[C@H]1C[C@H]1CCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 2.2 g of zinc-copper couple in 30 mL of dry ether is added 5.7 mL (16.9 mmol) of methyl oleate and 5.4 mL (70.7 mmol) of diiodomethane. The reaction mixture is refluxed overnight, cooled to room temperature, poured into 1.0N HCl, and extracted three times with ether. The organic layers are combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give an oil. The oil is subjected to the conditions described in Example 51 above to give an oil free of starting material. The oil is taken up in a combination of tetrahydrofuran:methanol:water (2:1:1), followed by the addition of 4.0 g of 85% KOH. After 4 hours stirring at room temperature, the solvents are evaporated, the residue taken up in 0.1N KOH, and extracted three times with ether. The aqueous phase is acidified using concentrated HCl and extracted three times with ether. The ether layers are combined, washed with brine, dried over, MgSO4, filtered, and concentrated in vacuo to give cis-8-(2 -octylcyclopropyl) octanoic acid. Spectral data follows: 1H NMR (CDCl3, 400 MHz) δ 2.35 (t, 2H, J=7.0 Hz, CH2C=O), 0.6-1.7 (m, 33H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:12][CH3:13])[N:11]=1)[C:6]([OH:8])=[O:7].[CH2:15](NC)C>>[CH2:12]([C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([N:2]([CH2:14][CH3:15])[CH3:1])[N:11]=1)[C:6]([OH:8])=[O:7])[CH3:13]
Reactant: CCc1cc(C(=O)O)cc(N(C)C)n1
Reactant: CCNC
Product: CCc1cc(C(=O)O)cc(N(C)CC)n1

Procedure:
2-Ethyl-6-(ethyl-methyl-amino)-isonicotinic acid is prepared in analogy to 2-dimethylamino-6-ethyl-isonicotinic acid using ethyl-methyl-amine; LC-MS: tR=0.56 min; [M+1]+=209.20; 1H NMR (D6-DMSO: δ 1.16 (t, J=7.0 Hz, 3H), 1.24 (t, J=7.3 Hz, 3H), 2.95 (q, J=7.0 Hz, 2H), 3.57 (s, 3H), 3.76 (q, J=6.3 Hz), 6.98 (s, 1H), 7.23 (s, 1H).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH2:30][CH2:29][C:27](=[O:28])[NH:26][C:24]=4[CH:25]=3)[CH2:11][CH2:10]2)[C:4]([Cl:8])=[C:5]([Cl:7])[CH:6]=1.FC(F)(F)C(O)=O.O.[OH-].[Na+]>O1CCCC1>[CH2:11]1[N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]3[CH:30]=[CH:29][C:27]([NH:26][C:24]=3[CH:25]=2)=[O:28])[CH2:13][CH2:14][N:9]([C:3]2[CH:2]=[CH:1][CH:6]=[C:5]([Cl:7])[C:4]=2[Cl:8])[CH2:10]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Temperature: 25 °C
Yield: 102.3 %

Procedure:
Aripiprazole (Formula VIA; 15 g, 0.03 mol) was dissolved in anhydrous tetrahydrofuran (360 mL). Trifluoroacetic acid (12 mL, 0.16 mol) was added to the clear solution. 1,2-Dichloro-4,5-dicyano quinone (24.3 g, 0.11 mol) was added and the mixture was stirred at room temperature under nitrogen atmosphere. The reaction was stirred for 40 minutes and TLC showed no starting material remaining Water (1.5 L) was added then reaction mixture basified with 50% aq NaOH until pH 12. The reaction mixture was extracted with dichloromethane (3×1 L) and the combined organics were dried (MgSO4) to give the crude product. This was purified by column chromatography on silica eluting with dichloromethane to 10% methanol/dichloromethane. The product was further purified by recrystallisation from 2-propanol to give the desired product (13.7 g, 92%) as an off white solid. 1H-NMR (400 MHz, CDCl3) δ 12.33 (1H, br s), 7.72 (1H, d), 7.42 (1H, d), 7.16-7.11 (2H, m), 6.98-6.93 (1H, dd), 6.83-6.79 (2H, m), 6.53 (1H, d), 4.10 (2H, t), 3.09 (4H, br s), 2.67 (4H, br s), 2.52 (2H, t), 1.93-1.70 (4H, m). LCMS (acidic method) [M+H]+ 446.02, rt 14.246 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=[CH:12][C:11]=1[CH:25](O)[C:26]([OH:28])=[O:27].[NH:30]1C2C=CC=CC=2N=N1.S(Cl)(Cl)=O.[N-]=[N+]=[N-].[Na+]>C(Cl)Cl.O>[NH2:30][CH:25]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:10]=1[O:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:26]([OH:28])=[O:27]
Reactant: O=C(O)C(O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Reactant: c1ccc2[nH]nnc2c1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=S(Cl)Cl
Product: NC(C(=O)O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Reaction time: 1.5 h
Yield: 62 %

Procedure:
To a stirred solution of Example 1 Part B compound (1.009 g, 2.19 mmol) in CH2Cl2 (20 mL) under argon at room temperature was added a solution prepared from benzotriazole (570 mg, 4.8 mmol) and thionyl chloride (570 mg, 4.8 mmol) in CH2Cl2 (5 mL) over 2 min. The reaction mixture was stirred for 90 min, then diluted with water and extracted twice with CH2Cl2. The extracts were combined, washed once with water, once with 0.5 M NaOH (25 mL) and once with brine, dried (MgSO4) and evaporated. The residuum was immediately dissolved in DMF (8 mL), treated with sodium azide (570 mg, 8.8 mmol) and stirred at room temperature under argon for 1 h. The reaction mixture was quenched with water and extracted twice with Et2O. The extracts were combined, washed twice with water, once with brine dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 657 mg (62% yield). LC/MS gave the correct molecular ion [(M+H)+=486] for the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[NH2:8]
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCCCC2)c(F)c1

Procedure:
The product from Example 10A (12.7 mmol) was hydrogenated (balloon) as a solution in ethyl acetate over 5% Pd/C overnight at room temperature. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 6.72-6.78 (m, 1H), 6.26-6.34 (m, 2H), 4.92 (br s, 2H), 2.76 (m, 4H), 1.56-1.63 (m, 4H), 1.42-1.49 (m, 2H); MS (APCI+) m/z 195.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(-c4cccc(C#N)c4)ccc3O2)CC1
Temperature: 90 °C

Procedure:
To a mixture of 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid isopropyl ester (37 mg) and 3-cyanophenylboronic acid (18 mg) in N,N-dimethyl-formamide (2 mL) a 2 M aqueous Na2CO3 solution (0.125 mL) is added. The mixture is sparged with argon and PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (8.2 mg) is added. The resulting mixture is stirred over night at 90° C. After cooling to room temperature, the mixture is filtered through basic alumina, washed with DMF/MeOH (9:1) and concentrated. The residue is purified by preparative HPLC (eluent water (+0.1% TFA)/MeOH) to yield the desired product. HPLC (method 8): tR=1.95 min; Mass spectrum (ESI+): m/z=391 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:32])=[N:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.C(OCC)C>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:32])=[N:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1
Reactant: Cc1ccc(-c2cnc(N)c(-c3nnc(C4CCN(C(=O)OC(C)(C)C)CC4)o3)c2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(-c2cnc(N)c(-c3nnc(C4CCNCC4)o3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[5-(2-amino-5-p-tolyl-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.574 mmol) in DCM (20 mL) was added 2M HCl in diethyl ether (20 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature, and was stirred for 2 h. After completion of the reaction, reaction mixture was filtered and washed with diethyl ether (2×30 mL), which afforded the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[CH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]=[CH:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=CCCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-4-(4-phenyl-but-1-enyl)-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].N[OH:17].C(N(CC)CC)C>CO>[C:1]([O:5][C:6]([C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[N:14][OH:17])=[CH:11][CH:12]=1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(C#N)cc1
Reactant: NO
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(C=NO)cc1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
In 100 ml of methanol were dissolved 20.5 g of 4-cyanobenzoic acid t-butyl ester and 13.9 g of hydroxylamine. To the solution was added, while stirring at room temperature, 128 g of triethylamine, and the mixture was stirred for one hour at 85° C. The reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, and the solution was washed with water. The organic layer was concentrated under reduced pressure to give a crude product, which was recrystallized from isopropyl ether to afford 11.45 g of the title compound as a colorless crystalline product.