Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([CH2:18][OH:19])[O:9][N:8]=2)=[CH:4][CH:3]=1.CCN([CH2:25][CH3:26])CC.C([O-])(O)=[O:28].[Na+]>CC(OC(C)=O)=O>[C:25]([O:19][CH2:18][C:10]1[O:9][N:8]=[C:7]([C:5]2[O:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:28])[CH3:26]
Reactant: CCN(CC)CC
Reactant: O=C([O-])O
Reactant: OCc1onc(-c2ccc(Cl)o2)c1-c1ccccc1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1onc(-c2ccc(Cl)o2)c1-c1ccccc1
Reaction time: 1.5 h
Yield: 60 %

Procedure:
To a solution of 3-(5-chlorofuran-2-yl)-4-phenyl-5-hydroxymethylisoxazole (350 mg, 1.273 mmoli) in Ac2O (5.2 ml), kept stirring at 0° C., is added Et3N (0.213 ml, 1.531 mmole). The mixture is brought to ambient temperature and kept stirring for 1.5 h. The reaction is blocked by adding ice and 10 ml of saturated solution of NaHCO3. The two phases are separated and the aqueous phase is extracted three times with methylene chloride. The combined organic extracts are dried over Na2SO4 and the solvent distilled in a vacuum. The residue subjected to column chromatography (silica gel, petroleum ether/ethyl acetate=9:1, and 8:2 after the elution of the first substance) gives 237 mg of oily product with a yield of 60%. FT-IR (neat): 3132, 3053, 2921, 1751, 1636, 1517, 1432, 1412, 1372, 1359, 1226, 1127, 1048, 1018, 985, 939, 903, 790, 777, 704 cm−1. 1H NMR (400 MHz, CDCl3, δ): 7.44-7.42 (m, 3H, aromatic protons); 7.30-7.28 (m, 2H, aromatic protons); 6.24 (d, J=3.6 Hz, 1H, furyl proton); 6.11 (d, J=3.6 Hz, 1H, furyl proton); 5.07 (s, 2H, CH2); 2.02 (s, 3H, CH3).13C NMR (75 MHz, CDCl3, δ): 170.3, 163.5, 152.7, 143.1, 139.0, 130.2, 129.2, 129.2, 128.2, 118.2, 114.4, 108.2, 55.4, 20.7. GC-MS (70 eV) m/z (rel.int.): 319 [M(37Cl)+, 33], 317 [M(35Cl)+, 90], 277 (18), 276 (10), 275 (49), 240 (18), 238 (10), 217 (23), 216 (11), 213 (17), 212 (100), 211 (32), 190 (11), 188 (27), 182 (11), 154 (20), 153 (26), 152 (21), 129 (15), 127 (19), 91 (12), 89 (26), 73 (11), 43 (30). Anal. Calc. for C16H12ClNO3: C, 64.48; H, 3.81; N, 4.41. Found: C, 64.46; H, 3.82; N, 4.46.
Reaction SMILES: C[Si](Cl)(C)C.[I-].[Na+].[CH2:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([F:16])[C:11]=1[NH:17]C(=O)OC(C)(C)C)[CH3:9].CCOCC>C(#N)C>[NH2:17][C:11]1[C:12]([F:16])=[N:13][CH:14]=[CH:15][C:10]=1[CH2:8][CH3:9]
Reactant: CCc1ccnc(F)c1NC(=O)OC(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CCc1ccnc(F)c1N
Temperature: 25 °C

Procedure:
Trimethylsilyl chloride (2.2 g, (0.18 mmol) and sodium iodide (2.7 g, 0.18 mmol) were added to a solution of 3.6 g (0.15 mmol) of t-butyl N-(4-ethyl-2-fluoro-3-pyridyl)carbamate in 50 mL of dry acetonitrile with stirring at ambient temperature. After 2 hours the mixture was poured into ether and the resulting solution was washed with dilute aqueous sodium bisulfite, dried over magnesium sulfate, and filtered. The liltrate was concentrated by evaporation under reduced pressure to obtain an oil. This oil was purified by column chromatography to obtain 1.6 g (76 percent of theory) of the title compound as a gold oil.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:24]5[CH:25]=[N:26][CH:27]=[C:28]([CH:30]=[O:31])[CH:29]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:32][Li]>O1CCCC1>[CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:18][CH2:19][C:20]([C:24]5[CH:25]=[N:26][CH:27]=[C:28]([CH:30]([OH:31])[CH3:32])[CH:29]=5)([OH:23])[CH2:21][CH2:22]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)c1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(O)c1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 77 %

Procedure:
A suspension of 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(5-formyl-3-pyridyl)piperidin-4-ol (0.350 g, 0.852 mmol) in tetrahydrofuran (20 mL) under nitrogen was cooled to 0° C. Methyl lithium (1.0M in diethyl ether, 1.72 mL, 2 eq) was added dropwise with dissolution of the suspension as addition proceeded. The solution became a golden brown color. The reaction was warmed to 10° C. and stirred at this temperature for 2.5 h. At the end of this time period, the reaction was quenched with water (25 mL) and the aqueous phase extracted with ethyl acetate (3×20 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The reaction product was purified by flash chromatography over silica gel (30 mL, eluent: 10% methanol in diethyl ether) to yield 0.280 g (77%) of the title compound as a white solid. TLC analysis (Rf 0.17, 10% methanol in diethyl ether). 1H NMR (CDCl3, 300 MHz) 8.65 (d, J=2.2 Hz, 1H), 8.48 (d, J=2.0 Hz, 1H), 7.83 (t, J=2.1 Hz, 1H), 7.24 (m, 2H), 7.18 (m, 2H), 6.95 (m, 4H), 4.95 (q, J=6.5 Hz, 1H), 4.28 (br s, 1H), 3.49 (br s, 2H), 2.94 (m, 2H), 2.74 (m, 2H), 2.63 (br s, 2H), 2.13 (m, 2H), 1.76 (m, 2H), 1.59 (m, 3H) MS (CI, CH4) m/z 427 (M+1,100), 455 (M+29,17), 409 (62), 235 (11), 221 (22), 206 (17), 169 (28). The free base was dissolved in methylene chloride containing small amounts of methanol and acidified with ethereal HCl. The hydrochloride salt was precipitated by ether dilution, filtered, rinsed with fresh ether, and dried in vacuo (60° C., 10 pascal, 18 h) to yield a white solid, mp 177°-183° C. The analysis for dihydrochloride was not in agreement with calculated; 1H NMR and MS of salt were completely consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:13]2=[O:26])[CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1.[N:38]1C=CC=C[CH:39]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:13]2=[O:26])[CH2:9][CH2:10][NH:38][CH3:39])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N([C@@H](CCO)c2cccc(F)c2)c2ccccc2C12CCCCC2
Reactant: c1ccncc1
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CNCC[C@@H](c1cccc(F)c1)N1C(=O)C2(CCCCC2)c2ccccc21
Reaction time: 3 h

Procedure:
1′-[(1S)-1-(3-fluorophenyl)-3-hydroxypropyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one (0.27 g, 0.76 mmol) was dissolved in pyridine (4 mL) and toluenesufonyl chloride (0.29 g, 2.0 mmol) was added. Stirred for 3 hours then the reaction mixture was diluted with ethyl acetate and washed with water, 2N hydrochloric acid, saturated copper sulfate, 2N hydrochloric acid, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was immediately dissolved in methylamine (8M in ethanol, 30 mL) and stirred for 16 hours. The mixture was concentrated in vacuo and purified via chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 1′-[(1S)-1-(3-fluorophenyl)-3-(methylamino)propyl]spiro[cyclohexane-1.3′-indol]-2′(1′H)-one as a colorless oil (0.20 g). The freebase was dissolved in ether (5 mL) and treated with 1N hydrochloric acid in ether (0.55 mL, 1.0 equivalent). The white precipitate was collected and dried under vacuum to give 193 mg (63% over three steps) 1′-[(1S)-1-(3-fluorophenyl)-3-(methylamino)propyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one hydrochloride.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:18][C:19]1[CH:24]=[N:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][N:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1cnc(C)cn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc(C)cn2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.2 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.5 mmol) in N-methyl 2-pyrolidone (0.75 mL) was added powdered potassium hydroxide (0.281 g, 5.0 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrazine (0.151 g, 1.2 mmol) was added and stirred for further 2 h. at 60 deg C. After completion (TLC), reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (6% MeOH:DCM in silica 100-200 mesh, Diameter of column−2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as yellow oil (0.05 g, 31% yield). 2,8-Dimethyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.05 g, 0.156 mmol) was dissolved in THF (2.0 mL). A solution of oxalic acid dihydrate (0.015 g, 0.000119 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. Precipitate obtained was filtered and dried to give oxalate salt as white solid (0.03 g, 47% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@@H:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH:33]1([O:39][C:40]2[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][C:45]=2[C:46]([O:48][CH3:49])=[O:47])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([O:12][C:11]([N:10]([CH2:18][C@@H:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:42]2[CH:43]=[CH:44][C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:40]([O:39][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:41]=2)=[CH:3][CH:4]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc(B(O)O)cc1OC1CCCCC1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](OC1CCCCO1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](OC3CCCCO3)c3ccccc3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Temperature: 75 °C
Reaction time: 5 h
Yield: 83.1 %

Procedure:
To a solution of tert-butyl [2-(4-bromophenyl)ethyl]-[(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-carbamate (620 mg) in 1,2-dimethoxyethane (7 ml) were added [3-(cyclohexyloxy)-4-(methoxycarbonyl)phenyl]boronic acid (410 mg), tetrakis(triphenylphosphine)palladium (99 mg) and aqueous solution of sodium carbonate (2M, 1.35 ml), and the mixture was stirred at 75° C. for 5 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=9/1) to give methyl 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]-3-(cyclohexyloxy)-4-biphenylcarboxylate (672 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)CCl.C(OCC)(=O)C>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([NH:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)=[O:18]
Reactant: COc1cc(N)c2ncccc2c1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COc1cc(NC(=O)c2c(Cl)cccc2Cl)c2ncccc2c1
Yield: 68.2 %

Procedure:
A mixture of 8-amino-6-methoxyquinoline (121 mg), 2,6-dichlorobenzoyl chloride (175 mg) and triethylamine (91.4 mg) in ethylene chloride (3 ml) was refluxed for 3 hours. After cooling, the mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate:n-hexane, 1:2, v/v) to give 8-(2,6-dichlorobenzoylamino)-6-methoxyquinoline (164.5 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:8]=[C:9]2[CH:14]=[C:13]([C:15]3[NH:16][N:17]=[C:18]([CH3:20])[N:19]=3)[CH:12]=[CH:11][N:10]2[CH:21]=1)=[O:5])[CH3:2].F[C:23](F)(F)C(N)=O.CN(C(C=C)=O)C>C(O)C>[CH3:23][N:17]1[C:18]([CH3:20])=[N:19][C:15]([C:13]2[CH:12]=[CH:11][N:10]3[CH:21]=[C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[N:8]=[C:9]3[CH:14]=2)=[N:16]1
Reactant: NC(=O)C(F)(F)F
Reactant: CCNC(=O)Nc1cn2ccc(-c3nc(C)n[nH]3)cc2n1
Agent: C=CC(=O)N(C)C
Solvent: CCO
Product: CCNC(=O)Nc1cn2ccc(-c3nc(C)n(C)n3)cc2n1
Temperature: 125 °C

Procedure:
A mixture of nitrile 4 (0.500 g, 1.7 mmol), 0.50 g trifluoroacetamide and 0.25 g dimethylaminoacrolein in 5 mL ethanol was heated to 125° C. for 2 h by microwave irradiation (CEM, 300 watt). The reaction was then evaporated in vacuo and the residue was purified by silica gel chromatography (gradient elution: 0-20% ethyl acetate/dichloromethane) to give pyrimidine 5.
Reaction SMILES: CN(C)C=O.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:13](=[O:24])[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1.[H-].[Na+].F[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31]>O>[C:30]([C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[N:14]1[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=[C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=2)[C:13]1=[O:24])#[N:31]
Reactant: N#Cc1ccccc1F
Reactant: O=c1[nH]cc(-c2ccccc2)cc1-c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-n1cc(-c2ccccc2)cc(-c2ccccn2)c1=O
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
5 ml of a dimethylformamide solution containing 0.26 g of 3-(2-pyridyl)-5-phenyl-2(1H)-pyridone was incorporated with 0.04 g of sodium hydride. After 15 minutes, the solution was further incorporated with 0.15 g of 2-fluorobenzonitrile and 00.10 g of cuprous iodide, and vigorously stirred at 100° C. for 2 hours. The solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then saturated saline water, and dried by magnesium sulfate anhydride. The solvent was distilled off under a vacuum. The residue was refined by silica gel chromatography (ethyl acetate/hexane=1:2), to obtain 0.03 g of the light yellow, powdery subject compound.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:30]2[N:39]=[CH:38][C:37]3[C:32](=[C:33]([F:44])[CH:34]=[C:35]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:36]=3)[C:31]2=[O:45])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH:24]3[CH2:26][CH2:25]3)[N:21]([CH3:27])[N:20]=2)[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:40]([C:35]1[CH:36]=[C:37]2[C:32](=[C:33]([F:44])[CH:34]=1)[C:31](=[O:45])[N:30]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([CH:24]5[CH2:26][CH2:25]5)[N:21]([CH3:27])[N:20]=4)[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:39]=[CH:38]2)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C4CC4)n(C)n3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: Cn1nc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)cc1C1CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
A mixture of 126g (100 mg, 0.16 mmol) and lithium hydroxide (72 mg, 3.0 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 50° C. for 2 h. The mixture was evaporated under reduced pressure. The residue was purified by reverse-phase Combiflash to afford 126 (32 mg, 35%) as a white solid. MS-ESI: [M+H]+ 570.3. 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=5.0 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 7.94 (d, J=1.5 Hz, 1H), 7.56-7.55 (m, 2H), 7.53-7.51 (m, 2H), 7.33 (s, 1H), 5.53 (s, 1H) 4.49-4.48 (m, 2H), 4.04-4.02 (m, 1H), 3.79 (s, 3H), 3.69 (s, 3H), 1.69-1.65 (m, 1H), 1.43 (s, 9H), 0.97-0.94 (m, 2H), 0.68-0.65 (m, 2H).
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:13]=[CH:12][O:11][CH:10]=1.[CH:14]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)=[O:15].C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CN(C=O)C>[O:11]1[CH:12]=[CH:13][C:9]([C:20]2[CH:21]=[C:16]([CH:17]=[CH:18][CH:19]=2)[CH:14]=[O:15])=[CH:10]1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Brc1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cccc(-c2ccoc2)c1
Yield: 9.7 %

Procedure:
EX-601A) To a toluene (10 mL) solution of 3-bromofuran (0.54 mL, 6.0 mmol) was added 3-formylphenylboronic acid (1.00 g, 6.7 mmol) and DMF (4 mL). To the resulting solution was added K2CO3 (1.85 g, 13.4 mmol) and Pd(PPh3)4 (0.40 g, 0.35 mmol). The slurry was heated to reflux under argon for 2 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 5% ethyl acetate in hexane gave 0.10 g (10%) of the desired 3-(3-furanyl)benzaldehyde product as a yellow oil. MS: m/Z=173.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])OC4C=CC=CC=4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[C:37](OCC)=[O:38].O1CCOCC1>CN(C)C1C=CN=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[C:37](=[O:38])[CH:32]5[CH2:33][CH2:34][CH2:35][CH2:36][N:31]5[C:22]4=[O:30])=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1CCCCN1
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3)CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(c3ccc(N4C(=O)C5CCCCN5C4=O)cc3)CC2)cc1
Reaction time: 5 h
Yield: 47.5 %

Procedure:
A mixture of 50 parts of phenyl [4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]carbamate, 22.7 parts of ethyl 2-piperidinecarboxylate, 4 parts of N,N-dimethyl-4-pyridinamine and 300 parts of 1,4-dioxane was stirred for 5 hours at reflux temperature. After saturation with water, the reaction mixture was heated for 30 minutes. After cooling, the precipitated product was filtered off, washed with 2-propanol and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1-butanol. The product was filtered off and dried, yielding 24.8 parts (47.5%) of 5,6,7,8-tetrahydro-2-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]imidazo[1,5-a]pyridine-1,3(2H,8aH)-dione; mp. 223.4° C. (int. 17).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:7]=[CH:6]1.CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32].[OH-].[Na+]>C(Cl)Cl.C(Cl)Cl.CO>[CH3:30][S:31]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:7]=[CH:6]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: NCCCn1cnc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCCn1cnc(-c2ccc(F)cc2)c1-c1ccncc1

Procedure:
To the compound of Example 4, described above (79 mg, 0.26 mmol) in CH2Cl2 (0.5 mL) was added Et3N (72 uL, 0.52 mmol), and then methanesulfonyl chloride (25 uL, 0.31 mmol). The reaction exothermed to CH2Cl2 reflux briefly. The reaction was over within 1 min based on tlc (19:1 CH2Cl2 /MeOH) and was poured into 10% NaOH (5 mL) and extracted with EtOAc (3×20 mL). The extracts were washed with H2O (10 mL) and satd aq Nacl (10 mL), dried (Na2 SO4), concentrated and flash chromatographed (1×10 cm silica) with 0-8% MeOH in CH2Cl2 to afford 63 mg (65%). mp=186°-187°.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:15])=[C:9]([C:33](=[O:51])[NH:34][C:35]3[N:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=4)=[CH:37][N:36]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:33](=[O:51])[NH:34][C:35]3[N:36]=[CH:37][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:48])[F:49])[CH:42]=4)=[CH:39][N:40]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ncc(-c3cccc(C(F)(F)F)c3)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ncc(-c3cccc(C(F)(F)F)c3)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.6 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(4-(piperidin-1-yl)-2-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-ylcarbamoyl)phenylcarbamoyl)benzylthio)propanoate (250 mg, 0.35 mmol, 1.00 equiv) in dichloromethane (3.5 mL), and 2,2,2-trifluoroacetic acid (1.7 mL). The resulting solution was stirred for 2 h at 25° C. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 12.9 mg (6%) of a light yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 11.38 (s, 1H), 11.19 (s, 1H), 9.10 (s, 2H), 8.04-8.20 (m, 3H), 7.62-7.79 (m, 5H), 7.37-7.49 (m, 3H), 3.76 (s, 4H), 3.29 (s, 6H), 2.40-2.44 (m, 2H), 1.68 (m, 4H), 1.53-1.54 (d, J=3.6 Hz, 2H). MS (ES, m/z): 664.00 [M+H]+.