Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][OH:13])=[C:5]2[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH:12]=[O:13])=[C:5]2[NH:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(CO)cnc3ccc(Cl)nc23)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2c(C=O)cnc3ccc(Cl)nc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
tert-butyl 4-((6-chloro-3-(hydroxymethyl)-1,5-naphthyridin-4-yl)amino)piperidine-1-carboxylate (0.39 g, 1 mmol) was dissolved in dichloromethane (10 mL), and to the solution added manganese dioxide (2.14 g, 32 mmol). The reaction mixture was stirred at room temperature for 3 h, filtered and the solid was washed with 30 mL of dichloromethane. The resulting wash liquid and the filtrate were combined and concentrated, and the resulting solid was recrystallized from methanol to give 0.311 g of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]4[CH2:29][O:28]C(C)(C)[O:26]4)=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]([OH:26])[CH2:29][OH:28])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(OCC4COC(C)(C)O4)cc3)n2)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(OCC(O)CO)cc3)n2)cc1Cl
Temperature: 70 °C
Yield: 88 %

Procedure:
3-(3-chloro-4-isopropoxyphenyl)-5-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1,2,4-oxadiazole (0.1 g, 0.225 mmol) and p-toluenesulfonic acid monohydrate (8.55 mg, 0.045 mmol) were added in methanol (2.4 mL). The reaction mixture was heated at 70° C. for 16 hr. The solution was cooled, methanol (1.5 mL) was added to the mixture and recrystallized, the resulted suspension was filtered, the solid was washed by abundant water to afford 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)propane-1,2-diol (0.08 g, 0.198 mmol, 88% yield) as white solid. LC/MS (Purity QC) Rt=2.97 min.; MS m/z: 405.18 (M+H)+. 1H NMR (400 MHz, Solvent d-DMSO) ppm 8.16-8.09 (m, 2H), 8.05 (d, J=2.13 Hz, 1H), 7.99 (dd, J=8.64, 2.15 Hz, 1H), 7.38 (d, J=9.05 Hz, 1H), 7.25-7.16 (m, 2H), 5.03 (d, J=5.19 Hz, 1H), 4.87-4.78 (m, 1H), 4.72 (t, J=5.68 Hz, 1H), 4.15 (dd, J=3.97, 10.01 Hz, 1H), 4.01 (dd, J=6.20, 10.03 Hz, 1H), 3.84 (dt, J=4.04, 5.69, 5.91 Hz, 1H), 3.47 (t, J=5.84 Hz, 2H), 1.35 (d, J=6.03 Hz, 6H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14](=[O:16])[CH3:15])=[CH:11][C:12]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: CC(=O)Cc1ccc(Cl)cc1
Reactant: O=S(=O)(O)Cl
Product: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Cl)c1
Temperature: 25 °C

Procedure:
To chlorosulfonic acid (25 ml, excess) cooled at −10° C. is added dropwise 4-chlorophenyl acetone (1.0 g, 5.93 mmol). The temperature is kept below 0° C. throughout the addition. The reaction mixture is then left to warm up to room temperature overnight. The reaction mixture is poured carefully onto ice (1500 ml). Once the ice is melted, the aqueous layer is extracted with dichloromethane (3×250 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford the titled compound as an off-white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][CH2:33][N:34]3[CH:39]=[C:38]([CH3:40])[C:37](SC#N)=[N:36][C:35]3=[O:44])[CH2:26][CH2:25]2)[CH:21]=[C:20]([C:45]([F:48])([F:47])[F:46])[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>C(#N)C>[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][CH2:33][N:34]3[CH:39]=[C:38]([CH3:40])[C:37]([O:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[N:36][C:35]3=[O:44])[CH2:26][CH2:25]2)[CH:21]=[C:20]([C:45]([F:46])([F:48])[F:47])[N:19]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: Oc1ccccc1
Reactant: Cc1cn(CCCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)nc1SC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cn(CCCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)nc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.2 %

Procedure:
81.3 mg (0.9 mmol) of phenol and 325.5 mg (2.4 mmol) of K2CO3 were added to 400.0 mg (0.78 mmol) of 1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-2-oxo-1,2-dihydropyrimidin-4-yl thiocyanate from Example 7.1 in 40 ml of acetonitrile and 500.0 mg of molecular sieves (3 Å). The reaction mixture was then stirred at room temperature for 12 hours. Insolubles were filtered off, methylene chloride was added to the filtrate, followed by extraction with aqueous brine. The residue after drying of the organic phase, removal of the desiccant by filtration and evaporation of the solvent in vacuo was taken up in 100 ml of diisopropyl ether and heated. The precipitate was filtered off with suction and the mother liquor was concentrated somewhat. The mother liquor was then mixed with pentane and cooled in an ice bath. The precipitated solid was filtered off with suction, washed and dried in vacuo at 40° C., resulting in 120 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])(=[O:11])=[O:10])=[CH:4][CH:3]=1.C[Li].[CH3:26][C:27]([CH3:29])=[O:28].FC(F)(F)C(O)=O>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:23][O:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][S:9]([CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:27]([OH:28])([CH3:29])[CH3:26])(=[O:10])=[O:11]
Reactant: CC(C)=O
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(Br)cc2)c(OC)c1
Agent: [Li]C
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1ccc(CNS(=O)(=O)C(c2ccc(Br)cc2)C(C)(C)O)c(OC)c1
Temperature: -78 °C

Procedure:
Under inert gas, 28 g of C-(4-bromophenyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide were initially charged in 250 ml of THF, and then, at a temperature of −78° C., 93 ml of a 1.6 N methyllithium solution in hexane were added dropwise and the mixture was left to stir while cooling with ice for 5 minutes. Subsequently, the reaction solution was cooled again to −78° C. and 20 ml of acetone were added. The mixture was allowed to come to room temperature and stirred for 30 minutes. The reaction solution was admixed with 13 ml of trifluoroacetic acid and 500 ml of ethyl acetate, and washed with 300 ml of a saturated aqueous sodium hydrogencarbonate solution and 300 ml of a saturated aqueous sodium chloride solution, and the organic phase was dried over Na2SO4 and concentrated by rotary evaporation. The residue was used in the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:13][CH2:14][CH2:15]Br.C[O:18][C:19](=[O:32])[CH:20]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([OH:31])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1)[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:13][CH2:14][CH2:15][O:31][C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][CH:28]=1)[N:22]([C@@H:20]([CH3:21])[C:19]([OH:32])=[O:18])[CH:23]=[CH:24]2
Reactant: COC(=O)C(C)n1ccc2cc(O)ccc21
Reactant: BrCCOc1ccc2cc(Br)ccc2c1Br
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)O)n1ccc2cc(OCCOc3ccc4cc(Br)ccc4c3Br)ccc21
Temperature: 50 °C

Procedure:
To a solution of 1,6-dibromo-2-(2-bromo-ethoxy)naphthalene (0.4 g, 0.98 mmol) (Example 15) in dry DMF (6 mL) was added 2-(5-hydroxy-indol-1-yl)-propionic acid methyl ester (0.215 g, 0.98 mmol) (Example 7) followed by cesium carbonate (1.59 g, 4.9 mmol). The reaction mixture was heated to 140° C. for 10 minutes and subsequently at 50° C. for 16 h. A saturated aqueous NaHCO3 solution was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified on reverse phase HPLC with gradient of 40% to 100% of acetonitrile and water mixture. The racemic mixture of the title compounds (122 mg, 46.3%) was collected as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.23-7.22(1H, m), 8.00-7.97 (2H, m), 7.71 (1H, dd), 7.63 (1H, d), 7.38 (1H, d), 7.29 (1H, d), 7.12 (1H, d), 6.79 (1H, dd), 6.36 (1H, d), 5.24 (1H, q), 4.58-4.55 (2H, m), 4.37-4.34 (2H, m), 1.68 (3H, d). LC/MS m/z 530 (M+H)−, RT 3.60 min
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH3:7].[C:9]([CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])#[N:10].C(O)(=O)C.N1CCCCC1>>[CH2:15]([O:14][C:12](=[O:13])[C:11]([C:9]#[N:10])=[C:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCC(=O)CCC
Reactant: N#CCC(=O)OCc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCCC(CCC)=C(C#N)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 26.5 %

Procedure:
To a mixture of 4-heptanone (2.0 mL, 14.3 mmol) and benzyl cyanoacetate (2.51 g, 14.3 mmol) at 0° C. was added acetic acid (0.08 mL, 1.43 mmol), then piperidine (0.14 mL, 1.43 mmol) dropwise. The ice bath was removed, and stirring continued for 10 min. Additional acetic acid (0.08 mL) and piperidine (0.14 mL) were added, followed by the additional of oven-dried 4A molecular sieves such that stirring was not impeded. The mixture was stirred for 1 h, then partitioned between EtOAc and sat. sodium bicarbonate (NaHCO3) (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated to provide 1.03 g (27%) of 2-cyano-3-propyl-hex-2-enoic acid benzyl ester as a colorless oil. 1H NMR (CDCl3) δ 7.35 (m, 5H), 5.24 (s, 2H), 2.71 (m, 2H), 2.52 (m, 2H), 1.60 (m, 2H), 1.49 (m, 2H), 1.00 (t, J=7.3 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H). 13C NMR δ 182.46, 161.72, 135.37, 128.83, 128.58, 128.21, 115.87, 104.77, 67.26, 40.77, 35.80, 22.36, 21.86, 14.54, 14.32. LRMS: m/z 272.1 (M+1). IR (neat) 2223, 1729 cm−1. Anal. Calcd for C17H21NO2: C, 75.25; H, 7.80; N, 5.16. Found: C, 75.44; H, 7.80; N, 5.22.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[CH:22][N:23]3[CH:26]([CH3:28])[CH3:27])=[C:19]([C:29](=[O:43])[NH:30][CH2:31][C:32]3[C:33](=[O:42])[NH:34][C:35]([CH3:41])=[CH:36][C:37]=3[CH2:38][CH2:39][CH3:40])[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:41][C:35]1[NH:34][C:33](=[O:42])[C:32]([CH2:31][NH:30][C:29]([C:19]2[C:20]3[CH:21]=[CH:22][N:23]([CH:26]([CH3:27])[CH3:28])[C:24]=3[CH:25]=[C:17]([O:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]=2)=[O:43])=[C:37]([CH2:38][CH2:39][CH3:40])[CH:36]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(OCCN2CCN(C(=O)OC(C)(C)C)CC2)cc2c1ccn2C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(OCCN2CCNCC2)cc2c1ccn2C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
To a stirred solution of 4-(2-{1-isopropyl-4-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-pyridin-3-ylmethyl)-carbamoyl]-1H-indol-6-yloxy}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (280 mg, 0.472 mmol; prepared following the procedure of Example xx) in dichloromethane (15 mL) was added TFA (1.5 mL) at room temperature and then stirred for 3 h at room temperature. Reaction mixture was concentrated under reduced pressure, diluted with water (20 mL) and washed the resulting aqueous layer with diethyl ether (2×15 mL). The aqueous layer was basified with (pH ˜8) with saturated aqueous NaHCO3 solution and extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine solution (2×25 mL) and concentrated. Purification by preparative HPLC afforded 1-isopropyl-6-(2-piperazin-1-yl-ethoxy)-1H-indole-4-carboxylic acid (6-methyl-2-oxo-4-propyl-1,2-dihydro-pyridin-3-ylmethyl)-amide (48 mg, 20%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 0.93 (t, 3H), 1.42 (d, 6H, J=6.8 Hz), 1.57 (m, 2H), 2.14 (s, 3H), 2.45-2.2 (m, 4H), 2.68 (t, 2H), 2.75 (t, 4H), 4.15-4.19 (m, 2H), 4.35 (d, 2H), 4.78-4.72 (m, 1H), 5.91 (s, 1H), 6.73 (d, 1H), 7.03 (s, 1H), 7.24 (s, 1H), 7.42 (d, 1H), 8.12 (t, 1H), 11.58 (bs, 1H). LCMS (ES+): m/z=494.57 [M+H].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9]O)=[N:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33]>ClCCl>[Br:33][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=1
Reactant: OCc1ccc(C(F)(F)F)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CBr)nc1
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To (5-trifluoromethyl-pyridin-2-yl)-methanol (1.65 g) in dichloromethane (20 ml) at 0° C. (ice-bath) under nitrogen was added triphenylphosphine (3.66 g, 13.98 mmol) in portions, followed by addition of carbon tetrabromide (3.23 g) in portions. The ice-bath was removed and the flask was sealed with a glass stopper. The reaction mixture was gently stirred for 1 hour. The crude reaction mixture was loaded onto a silica gel column (120 g), and eluted with methyl acetate/hexane to give 2-bromomethyl-5-trifluoromethyl-pyridine as a light orange oil (1.65 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[C:3]=1[C:4]([N:6]([CH3:28])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[O:14])[N:8]=1)=[O:5]>FC(F)(F)C(O)=O.C(Cl)Cl>[F:34][C:29]1[CH:30]=[C:31]([F:33])[CH:32]=[C:2]([F:1])[C:3]=1[C:4]([N:6]([CH3:28])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])[N:8]=1)=[O:5]
Reactant: CN(C(=O)c1c(F)cc(F)cc1F)c1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)c1c(F)cc(F)cc1F)c1cccc(C(=O)C2CCNCC2)n1
Reaction time: 0.75 h
Yield: 85 %

Procedure:
Dissolve the 2,4,6-trifluoro-N-methyl-N-[6-(1-t-butoxycarbonyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide in 50% trifluoroacetic acid/CH2Cl2 (24 mL) and stir for 45 min. Remove volatiles under reduced pressure and extract with ethyl acetate and aqueous NaOH (2M). Combine the organic layers and dry with sodium sulfate. Concentrate and purify the residue by chromatography (silica gel/6% of (2M NH3 in methanol)/CH2Cl2) to afford 2,4,6-trifluoro-N-methyl-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide (77 mg, 85% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:10][C:8]=2[CH:9]=1)=[O:4].[OH-].[Li+].Cl>O1CCOCC1>[N:17]1([CH2:16][CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:7]3[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][C:8]=3[CH:10]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1cc2cc(OCCN3CCCC3)ccc2o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cc2cc(OCCN3CCCC3)ccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.1 %

Procedure:
To an ice-cooled solution of 5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carboxylic acid methyl ester (960 mg, 3.3 mmol) anhydrous ethylene glycol dimethyl ether (10 ml) was added dropwise degassed aqueous lithium hydroxide solution (2.0 ml, 2.0M). After stirring at room temperature for 4 h, the solution was cooled down and the pH was adjusted to 2 with 4.0 M HCl in dioxane. A gummy tan precipitate formed. The solvent was removed and the gummy residue was frozen and lyophilized. The tan colored solid was dissolved in boiling 2-propanol (90 ml), the solution was filtered hot and then cooled to give 5-(2-pyrrolidin-1-yl-ethoxy)-benzofuran-2-carboxylic acid as beige colored needles (528 mg). Additional 153 mg was obtained from the mother liquor.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C@H:14]2[C@H:19]3[CH2:20][CH2:21][C@H:16]([CH2:17][N:18]3[S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].CCCCCC>C(O)(C)C>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([CH:14]2[CH:19]3[CH2:20][CH2:21][CH:16]([CH2:17][N:18]3[S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:23])=[O:24])[CH2:15]2)=[O:13])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(NC(=O)[C@@H]2C[C@@H]3CC[C@H]2N(S(=O)(=O)c2cn(C)cn2)C3)cc1
Solvent: CCCCCC
Solvent: CC(C)O
Product: CC(C)Oc1ccc(NC(=O)C2CC3CCC2N(S(=O)(=O)c2cn(C)cn2)C3)cc1
Yield: 49.3 %

Procedure:
The compound (60 mg, 0.138 mmol) synthesized in Example 26 was optically resolved using normal-phase chiral HPLC(CHIRALPAK AD 2 cm ø×25 cmL (Daicel Chemical Industries, Ltd.); mobile phase: hexane:isopropyl alcohol=60:40; flow rate: 10 ml/min; isogradient), and (1R**,4S**,6R**)-N-(4-isopropoxyphenyl)-2-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-2-azabicyclo[2.2.2]octane-6-carboxamide (retention time: 14.2 min; 26.6 mg), and (1S**,4R**,6S**)-N-(4-isopropoxyphenyl)-2-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-2-azabicyclo[2.2.2]octane-6-carboxamide (retention time: 30.7 min; 29.4 mg) were obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[N:7][C:6]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:2][CH3:3].COC(C1C=NC(Cl)=C(Br)N=1)=O.[F:31][C:32]1[CH:37]=CC(CO)=[CH:34][CH:33]=1.N1CCCC1.[OH-].[K+]>>[F:31][C:32]1[CH:33]=[CH:34][C:2]([CH2:1][O:4][C:5]2[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[N:7][C:6]=2[N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:3][CH:37]=1
Reactant: CCCOc1nc(C(=O)O)cnc1N1CCCC1
Reactant: OCc1ccc(F)cc1
Agent: COC(=O)c1cnc(Cl)c(Br)n1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCNC1
Product: O=C(O)c1cnc(N2CCCC2)c(OCc2ccc(F)cc2)n1
Yield: 13 %

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (example 10, step c), the title compound was synthesized from 6-bromo-5-chloro-pyrazine-2-carboxylic acid methyl ester, (4-fluoro-phenyl)-methanol (commercially available), pyrrolidine (commercially available) and subsequent saponification with KOH in 13% yield. m/z (ES+): 318.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][CH2:16][C:17](Br)=[O:18].Cl>O.ClCCl>[Br:15][CH2:16][C:17]([NH:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: Cc1cncc(N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1cncc(NC(=O)CBr)n1

Procedure:
6-Methyl-pyrazin-2-ylamine (150 mg) and potassium carbonate (571 mg) were added to dichloromethane (25 mL). 2-Bromoacetyl bromide (0.120 mL) was added to the suspension with stirring. The reaction was stirred overnight then water (0.1 mL) was added with further stirring. Further quantities of potassium carbonate (571 mg), 2-bromoacetyl bromide (0.120 mL) and water (0.1 mL) were added over 2 hours until the reaction had proceeded to completion. The reaction was diluted with water (100 mL), carefully acidified with hydrochloric acid and extracted with dichloromethane (2×50 mL) which was dried and evaporated to afford the sub-titled compound which was used crude (365 mg).
Reaction SMILES: N#N.[CH3:3][N:4]1[C:8]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]4[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:7][N:6]=[CH:5]1>CO.[Pd]>[CH3:3][N:4]1[C:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]4[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:32])([F:34])[F:33])=[O:28])[CH:23]=[CH:24][CH:25]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:7][N:6]=[CH:5]1
Reactant: Cn1cncc1C#Cc1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: Cn1cncc1CCc1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Reaction time: 7.5 h
Yield: 9.2 %

Procedure:
To an evacuated flask back-filled with N2 containing 1-{3-[7-(3-methyl-3H-imidazol-4-ylethynyl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (65.7 mg, 0.15 mmol) in MeOH was added Pd (10 wt % on activated carbon) (25.5 mg). The flask was filled with H2 and the reaction stirred for a total of 7.5 hours. The reaction was filtered and the filtrate concentrated in vacuo. The crude product was purified by preparative HPLC to give pure product (6.1 mg). MS: [M+H]+443.
Reaction SMILES: [C:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].[CH:11]1[C:16]([CH:17]=O)=[CH:15][C:14]2[O:19][CH2:20][O:21][C:13]=2[CH:12]=1.N1CCOCC1.Cl>O.CS(C)=O>[CH2:20]1[O:21][C:13]2[CH:12]=[CH:11][C:16]([CH:17]=[CH:2][C:1]([CH:4]3[C:8](=[O:9])[CH2:7][CH2:6][C:5]3=[O:10])=[O:3])=[CH:15][C:14]=2[O:19]1
Reactant: CC(=O)C1C(=O)CCC1=O
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: C1COCCN1
Product: O=C(C=Cc1ccc2c(c1)OCO2)C1C(=O)CCC1=O
Yield: 49 %

Procedure:
2-Acetyl-1,3-cyclopentanedione (3.39 g.) was treated with piperonal (4.79 g.) in 60 ml. of dimethylsulfoxide in the presence of 5 ml. of morpholine at 85° C for 45 minutes. After cooling, the reaction mixture was poured into 150 ml. of water containing 7 ml. of conc. hydrochloric acid. Deposited crystals were separated by filtration and washed with water, and dried. 2-(3,4-Methylenedioxycinnamoyl)-1,3-cyclopentanedione (3.23 g.) was obtained in a yellow crystalline form, which showed mp. 181° - 182° C. after recrystallization from a mixed solvent of dioxane and ethanol.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]=[C:25]1[NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([C:35](O)=[O:36])[C:28]=2[O:27][CH2:26]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:34]2[C:28]3[O:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=3[CH:31]=[CH:32][CH:33]=2)=[O:36])=[O:10])[N:12]=1
Reactant: O=C1COc2c(cccc2C(=O)O)N1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCC(=O)N3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylic acid. LC-MS (basic): tR=0.77 min; [M+H]+=503.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.O.[OH-].[Na+]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[N:6][CH:7]=1
Reactant: Brc1ccc(C2CCC3(CC2)OCCO3)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1CCC(c2ccc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103 %

Procedure:
5-Bromo-2-(1,4-dioxaspiro[4,5]decane-8-yl)pyridine (9.0 g) described in Reference Example 102(2) was dissolved in trifluoroacetic acid (15 ml) and stirred at room temperature overnight. After completion of the reaction, water was added under ice cooling, neutralized by the addition of 4N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give 4-(5-bromopyridin-2-yl)cyclohexanone (7.9 g) as a pale yellow solid.