Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH:19]([C:23](OCC)=[O:24])[CH2:18]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].ClCCl.CO.[CH3:33][NH2:34]>[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH:19]([C:23]([NH:34][CH3:33])=[O:24])[CH2:18]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CN
Reactant: CCOC(=O)C1CCCN(Cc2ccc3c(c2)c2ccccc2n3CC)C1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Solvent: ClCCl
Product: CCn1c2ccccc2c2cc(CN3CCCC(C(=O)NC)C3)ccc21
Temperature: 140 °C
Reaction time: 24 h
Yield: 6 %

Procedure:
A 50-mL seal tube charge with a solution of ethyl 1-((9-ethyl-9H-carbazol-3-yl)methyl)piperidine-3-carboxylate (500 mg, 1.37 mmol, 1.00 equiv) in CH3NH2 (25 mL). To the mixture was added CuSO4 (100 mg, 0.51 mmol, 0.37 equiv). The resulting solution was stirred at 140° C. for 24 hours in an oil bath. The progress was monitored by TLC (dichloromethane/methanol=5:1). Upon completion, the solids were filtered out. The resulting solution was extracted with dichloromethane (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography eluted with dichloromethane/methanol (30:1) affording 1-((9-ethyl-9H-carbazol-3-yl)methyl)-N-methylpiperidine-3-carboxamide as white solid (28 mg, 6%). LCMS: [M+H]+: 350. 1H NMR (CDCl3, 300 MHz) δ 8.10 (d, 1H), 8.01 (s, 1H), 7.53-7.39 (m, 4H), 7.29-7.24 (m, 1H), 4.44-4.37 (q, 2H), 3.85-3.81 (d, 1H), 3.69-3.65 (d, 1H), 2.89 (m, 2H), 2.80-2.78 (d, 3H), 2.59 (br, 1H), 2.45 (br, 2H), 1.91 (m, 1H), 1.73-1.73 (m, 3H), 1.47 (t, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[BH4-].[Na+].O>C(O)C>[N:12]1[CH:13]=[CH:14][C:9]([NH:8][CH:5]([CH2:6][CH3:7])[CH2:4][OH:3])=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(CC)N(C(=O)OC(C)(C)C)c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(CO)Nc1ccncc1
Reaction time: 18 h
Yield: 94.4 %

Procedure:
A stirred solution of 2-(tert-butoxycarbonyl-pyridin-4-yl-amino)butyric acid ethyl ester (0.33 g) in ethanol (5 ml) was treated with sodium borohydride (0.12 g) and the stirring was continued for 18 h. Water (1 ml) was added and the mixture was concentrated under reduced pressure. The residue was absorbed on to silica and the resulting powder was loaded on to a flash chromatography column which was eluted with methanol:chloroform:aqueous ammonia (10:89:1). The title compound (0.168 g) was obtained as an oil after evaporation of the product containing fractions.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:26])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](O)=[O:24])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]1CCOCC1.ClC(OCC(C)C)=O>C1COCC1>[CH2:1]([NH:8][C:9](=[O:26])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:24])[NH:28][CH3:27])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)c1cccc(Oc2ncccc2C(=O)NCc2ccccc2)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccccc2)c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
N-Benzyl 2-(3-carboxyphenoxy)nicotinamide (1.00 gram, 2.87 mmol) is placed into a 100 ml 3-neck round bottom flask equipped with magnetic stir bar, thermometer, nitrogen inlet and a rubber septum. The flash is charged with 15 ml of THF and N-methylmorpholine (0.29 grams, 2.87 mmol) is added via syringe. The reaction is chilled to -10° C. and isobutyl chloroformate 0.39 grams, 2.87 mmol) added to the reaction via syringe while maintaining the temperature at less than 0° C. The reaction is stirred at -10° C. for 30 minutes. Monomethylamine gas is bubbled into the reaction via syringe while maintaining the temperature below 0° C. The reaction is allowed to slowly warm to room temperature. After stirring for 21/2hours, water (20 ml) is added to the reaction which is then extracted with ethyl acetate (2×100 ml). The organics are combined and washed with 2N sodium hydroxide (4×75 ml) and (1×100 ml) water. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield a paste. The crude product is purified by trituration with diethyl ether to yield 0.63 grams (60.6%) of the title product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:14]4[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]>>[C:25]([CH2:24][CH2:23][N:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:21])[N:7]2[C:14]2[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]1=2)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=3)([O:27][CH3:28])=[O:26]
Reactant: Cc1ccc2c(=O)n3c(nc2c1)[nH]c1cc(Cl)c(Cl)cc13
Reactant: COC(=O)CCCl
Product: COC(=O)CCn1c2cc(Cl)c(Cl)cc2n2c(=O)c3ccc(C)cc3nc12

Procedure:
6-(Carbomethoxyethyl)-3-methyl-8,9-dichlorobenzimidazo-[2,1-b]quinazolin-12(6H)one is prepared with 3-methyl-8,9-dichlorobenzimidazo[2,1-b]quinazolin-12(6H)one and methyl 3-chloropropionate.
Reaction SMILES: C[Al](C)C.CO[C:7]([CH:9]1[CH2:14][S:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[NH:10]1)=[O:8].[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[O:33][CH3:34]>>[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:7]([CH:9]2[CH2:14][S:13][CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[NH:10]2)=[O:8])=[CH:28][C:27]=1[O:33][CH3:34]
Reactant: COc1cc(N)ccc1Cl
Reactant: COC(=O)C1CSCC(c2ccc(OC)c(OC)c2)N1
Agent: C[Al](C)C
Product: COc1cc(NC(=O)C2CSCC(c3ccc(OC)c(OC)c3)N2)ccc1Cl
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A 2.0M solution of trimethylaluminum (0.39 ml, 0.78 mmol, 3.5 equivalents) was added to a solution of 5-(3,4-dimethoxy-phenyl)-thiomorpholine-3-carboxylic acid methyl ester (67 mg, 0.22 mmol, 1.0 equivalents) and 4-chloro-3-methoxyaniline (106 mg, 0.68 mmol, 3.0 equivalents). The solution was stirred at 50° C. for 18 hours. The reaction was quenched with 1N NaOH and extracted with dichloromethane. The dichloromethane extracts were dried with MgSO4, filtered and concentrated. The residue was purified on a 1000 micron preparative TLC. 5-(3,4-Dimethoxy-phenyl)-thiomorpholine-3-carboxylic acid (4-chloro-3-methoxy-phenyl)-amide was obtained as a peach solid (71 mg, 76% yield). Analysis H1 NMR (400 MHz, CDCl3): 8.61 (1H, s), 7.58 (1H, m), 7.26 (1H, m), 6.90 (2H, m), 6.78 (1H, d), 4.04 (1H, m), 3.91 (10H, m), 2.98 (1H, m), 2.78 (2H, m), 2.59 (1H, m). MS (LC-MS): Calculated for C20H23ClN2O4S 423.11, found 423.22.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[CH2:22][OH:23])[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[CH3:24][C:4]1[CH:3]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][OH:23])[CH2:13][CH2:12]1)=[O:10]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (intermediate 4) was reacted with 4-trifluoromethyl-phenyl boronic acid to give the title compound as off-white solid. MS: 461.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:23]3[C:14](=[CH:15][C:16]4[O:21][CH2:20][CH2:19][O:18][C:17]=4[CH:22]=3)[O:13][CH2:12]1)[C:5](=[O:11])[NH:6]2.Cl.Cl[CH2:26][C:27]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:23]3[C:14](=[CH:15][C:16]4[O:21][CH2:20][CH2:19][O:18][C:17]=4[CH:22]=3)[O:13][CH2:12]1)[C:5](=[O:11])[N:6]2[CH2:26][C:27]1[C:32]([C:33]([F:35])([F:34])[F:36])=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: O=C1Nc2cccc(F)c2C12COc1cc3c(cc12)OCCO3
Reactant: FC(F)(F)c1cccnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1N(Cc2ncccc2C(F)(F)F)c2cccc(F)c2C12COc1cc3c(cc12)OCCO3
Temperature: 60 °C
Yield: 82.6 %

Procedure:
A mixture of 4′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.31 g, 1.00 mmol), 2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride (0.29 g, 1.50 mmol) and cesium carbonate (0.98 g, 3.00 mmol) in N,N′ dimethylformamide (10 mL) was heated at 60° C. for 2 h and was filtered while hot. The filtrate was allowed to cool to ambient temperature and water was added, causing a precipitate to be deposited. The solid was collected by filtration, washed with water (50 mL) and dried under vacuum. The residue was recrystallized from N,N′ dimethylformamide/water to afford 4′-fluoro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.39 g, 82%) as a beige solid: mp 245-247° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.68 (d, J=4.5 Hz, 1H), 8.27 (d, J=7.65 Hz, 1H), 7.59 (dd, J=7.8, 4.9 Hz, 1H), 7.30 (ddd, J=8.2, 8.2, 5.8 Hz, 1H), 6.86 (d, J=9.0 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.54 (s, 1H), 6.49 (s, 1H), 5.25 (ABq, J=17.4 Hz, 2H), 4.79 (q, J=9.4 Hz, 2H), 4.22-4.10 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.5, 157.9 (d, 1JC-F=247 Hz), 154.6, 152.3, 152.1 (d, 5JC-F=1.2 Hz), 144.9 (d, 4JC-F=8.9 Hz), 144.3, 137.6, 135.1 (q, 4JC-F=4.9 Hz), 130.8 (d, 4JC-F=8.6 Hz), 125.6 (q, 1JC-F=274 Hz), 123.0, 122.9 (d, 2JC-F=32.3 Hz), 119.4, 117.1 (d, 3JC-F=19.3 Hz), 111.5, 109.9 (d, 3JC-F=19.9 Hz), 105.7 (d, 5JC-F=2.9 Hz), 98.4, 77.4, 64.1, 63.5, 56.0 (d, 5JC-F=1.7 Hz), 42.3 (q, 5JC-F=3.3 Hz); MS (ES+) m/z 460.9 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[CH2:7][C:8]([CH2:11][CH2:12][C:13](O)=[O:14])([CH3:10])[O:9][C:4]=2[C:3]=1[CH2:19][CH2:20][CH3:21].P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:28]>O1CCCC1>[OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[CH2:7][C:8]([CH2:11][CH2:12][C:13]([NH2:28])=[O:14])([CH3:10])[O:9][C:4]=2[C:3]=1[CH2:19][CH2:20][CH3:21]
Reactant: N
Reactant: CCCc1c(O)ccc2c1OC(C)(CCC(=O)O)CC2=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCc1c(O)ccc2c1OC(C)(CCC(N)=O)CC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the title product of Example 3, (1.0 g, 3.4 mmole) in 50 ml of dry tetrahydrofuran cooled to 0° was added 2.1 g (10.2 mmole) of phosphorus pentachloride. After the mixture was stirred for 30 minutes, approximately 2 ml of liquid ammonia was added, and the solution was warmed to room temperature and stirred for an additional 30 minutes. The solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed successively with saturated sodium bicarbonate solution, water, and brine, dried over MgSO4, filtered, and concentrated to dryness. The crude product, mp. 108°-115°, was not purified further. Structure assignment was supported by nmr and infrared spectra.
Reaction SMILES: C[C:2](=[CH2:25])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH2:8]2.[O:26]=[O+][O-]>>[O:26]=[C:2]([CH3:25])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:9][CH2:8]2
Reactant: C=C(C)COc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O
Reactant: O=[O+][O-]
Product: CC(=O)COc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O

Procedure:
Treatment of 6-(2-methyl-2-propenyloxy)-2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline with ozone under conditions of ozonolysis described in example 1 yields 6-(2-oxopropyloxy)-2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH2:1]([O:3][C:4]([C:6]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1(c2cccs2)CCC=CCC1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)C1(c2cccs2)CCCCCC1
Yield: 86.7 %

Procedure:
1-Thiophen-2-yl-cyclohept-4-enecarboxylic acid ethyl ester (Example 5b) (2.86 g) was dissolved in ethanol (30 mL) and tris(triphenylphosphine)rhodium(I) chloride (0.100 g) was added. The reaction mixture was stirred rapidly under 5 atmospheres of hydrogen overnight. Further tris(triphenylphosphine)rhodium(I) chloride (0.050 g) was added and the reaction mixture was stirred under 5 atmospheres of hydrogen for 3 days. A third addition of tris(triphenylphosphine)rhodium(I) chloride (0.050 g) was made and the reaction mixture was stirred under 3 atmospheres of hydrogen overnight. The contents were evaporated to dryness and purified on silica eluting with ethyl acetate/isohexane (5/ 95) to afford the sub-titled compound (2.500 g) as a clear almost colourless oil
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3([CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[O:15][C:14]3[C:23]([CH3:30])=[C:24]([CH3:29])[C:25]([OH:28])=[C:26]([CH3:27])[C:13]2=3)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].Cl.Cl[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.O>CN(C)C=O>[CH:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[C:16]3([CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[O:15][C:14]3[C:23]([CH3:30])=[C:24]([CH3:29])[C:25]([O:28][CH2:33][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[C:26]([CH3:27])[C:13]2=3)=[CH:10][CH:11]=1)([CH3:5])[CH3:4]
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1OCc1ccncc1)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 187.3 mg, 4.98 mmol) was added to a solution of 3-(4-isopropylphenyl)-1′,4,6,7-tetramethylspiro[benzofuran-2(3H),4′-piperidine]-5-ol (817.7 mg, 2.15 mmol) in N,N-dimethylformamide (30 mL) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 4-chloromethylpyridine hydrochloride (364.5 mg, 2.22 mmol) and the mixture was stirred for further 30 minutes at room temperature. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Chromatorex NH DM1020, Fuji Silysia Chemical LTD) (hexane/ethyl acetate=4/1) to obtain the title compound (575 mg, yield 57%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[CH3:9][NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:9][N:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([C:3]1[CH:4]=[CH:5][NH:1][CH:2]=1)=[O:8]
Reactant: CCOC(=O)CCNC
Reactant: O=C(O)c1cc[nH]c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(C)C(=O)c1cc[nH]c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
Into a suspension of 3.30 g (30 mmol) of 3-pyrrolecarboxylic acid in 10 me of dichloromethane, a solution of 5.90 g (45 mmol) of ethyl N-methyl-3-aminopropionate in 50 ml of dichloromethane, a solution of 4.55 g (45 mmol) of triethylamine in 50 ml of dichloromethane, and 8.63 g (45 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were successively added, followed by stirring at room temperature for 3 hours. Dichloromethane was added to the reaction mixture, and the resulting organic layer was washed successively with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure, whereby 5.31 g of the title compound were obtained (yield: 79%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].O>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)C#Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1ccc([N+](=O)[O-])cc1

Procedure:
4-Nitrophenyltrimethylsilylacetylene is reacted at ambient temperature for 3 hours with 3 g of potassium carbonate in 300 ml of methanol. The resulting reaction product mixture is poured into 1500 ml of distilled water to precipitate crude 4-nitrophenylacetylene product. The crude product is separated by filtration, washed with water, and dried in a vacuum oven at 50° C. and 1 Torr.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:30])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[CH:25]1([S:22]([N:19]2[CH2:20][CH2:21][CH:16]([C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([F:30])[CH:11]=4)[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[C:14]=3[CH3:15])[CH2:17][CH2:18]2)(=[O:23])=[O:24])[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)C3CCCC3)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)C2CCCC2)CC1
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To a solution of [4-(1-cyclopentanesulfonyl-piperidin-4-yl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (64.8 mg, 0.145 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (69.5 mg, 1.7 mmol) in water (2.0 mL) at room temperature. The resulting solution was stirred for three hours under a nitrogen atmosphere. The solvent was evaporated. Water (20 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (3 mL). The resulting white precipitate was collected by filtration, washed with water and hexanes, and dried under high vacuum. This crude product was further purified using preparative reverse-phase HPLC to give [4-(1-cyclopentane-sulfonyl-piperidin-4-yl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid (19 mg, 30%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (br. s., 1H), 7.97-8.17 (m, 1H), 7.90 (dd, J=9.03, 6.53 Hz, 1H), 7.69 (s, 1H), 7.35 (t, J=7.53 Hz, 1H), 3.78 (br. s., 6H), 3.11 (br. s., 2H), 2.42 (br. s., 4H), 1.96-2.08 (m, 2H), 1.80-1.93 (m, 2H), 1.53-1.78 (m, 6H). MS cald. for C23H29FNO4S [(M+H)+]: 434, obsd. 434.2.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([S:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:31])=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCNC(=O)Nc1nc2cccc(Sc3ccccc3)c2s1
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cccc(S(=O)c3ccccc3)c2s1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 38.6 %

Procedure:
To a suspension of N-ethyl-N′-[7-(phenylsulfanyl)-1,3-benzothiazol-2-yl]urea (107 mg, 0.32 mmol) in CH2Cl2 (5 mL) was added MCPBA (60 mg, 0.24 mmol, 70%). The reaction mixture was stirred at about 20° C. for about 1.5 hrs. The reaction mixture was then concentrated in vacuo. The crude reaction mixture was purified by flash chromatography on SiO2 (EtOAc/CH2Cl2 10/90). 32 mg (29%) of pure product was isolated. LC/MS 346 (MH+); RP-HPLC RT 12.96 min.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[CH:10]=[N:9][CH:8]=[N:7]1.[C:11]([NH:14][C:15]1(N)[NH:24][C:23](=O)[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=3)[N:21]=2)[NH:16]1)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([NH:14][C:15]1[N:24]=[C:23]([C:10]2[N:9]=[CH:8][NH:7][N:6]=2)[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=3)[N:21]=2)[N:16]=1)(=[O:13])[CH3:12]
Reactant: COc1ccc(-c2cnc3c(n2)C(=O)NC(N)(NC(C)=O)N3)cc1OC
Reactant: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cnc3nc(NC(C)=O)nc(-c4nc[nH]n4)c3n2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
To a solution of phosphorus oxychloride (1.68 ml, 18 mmoles) and 1,2,4-triazole (4.96 g, 72 mmoles) in dry pyridine (110 ml) was added the compound of example 102 (2.45 g, 7.18 mmoles). The suspension was stirred at room temperature for 4 hours. The precipitate was filtered off, washed with pyridine, toluene and diethyl ether. The resulting solid was dried over P2O5 under vacuum, providing the title compound as a yellow powder (2 g, yield: 80%) which afforded the following mass spectrum: 392 ([M+H]+, 100).
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]2[OH:12])#[N:9]
Reactant: N#Cc1ccccc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc2c(C#N)cccc2c1O
Temperature: 60 °C

Procedure:
Anthranilonitrile (8.23 g) and diethyl ethoxymethylenemalonate (14 mL) are heated at 130° C. for 1 hour. The reaction is cooled to 60° C., poured into 50 mL hexanes, and the resulting enamine intermediate filtered and dried. The enamine is added to 60 mL diphenyl ether and heated to 250° C. for 1 hour with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature and the orange-brown solid filtered, washed thoroughly with hexanes, and dried to give ethyl 8-cyano-4-hydroxyquinoline-3-carboxylate (5.69 g). A mixture of this ester (1.00 g) is added to 60 mL 1:1 THF:MeOH. Lithium hydroxide (1.0 M solution, 16 mL) is added dropwise and the reaction mixture heated at 40° C. overnight. The reaction is poured into 20 mL acetic acid. The volume is reduced by half on the rotary evaporator after which a solid precipitated. The solid is filtered, washed with water, and dried. An additional crop of the desired acid is obtained by further reducing the volume of the filtrate. The crops are combined to yield 0.72 g of 8-cyano-4-hydroxyquinoline-3-carboxylic acid. The acid (0.24 g) and carbonyldiimidazole (0.20 g) are added to 10 mL freshly distilled tetrahydrofuran and heated at reflux overnight. The reaction is cooled to room temperature and 4-chlorobenzylamine (0.13 mL) is added dropwise. The reaction is stirred at room temperature for 24 hours, then at reflux for 6 hours. The reaction is cooled and a white solid filtered and dried to give the desired product (0.17 g).