Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:14]C)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])[CH3:2].C(OCC)=[O:18].[Na].C(O)C>O>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:5]([CH:14]=[O:18])[C:4]([O:3][CH2:1][CH3:2])=[O:16]
Reactant: CCOC=O
Reactant: CCOC(=O)C(CC)c1ccccc1OC
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 2-methoxy-phenylacetic acid ethyl ester (11 g), ethyl formate (8.2 ml) and sodium (1.5 g) was added drop by drop with ethanol (5 ml) at 0° C., and the resulting mixture was stirred for 2 days at room temperature. Water was added, the organic layer was separated, the aqueous phase was washed with diethyl ether and extracted three times with ethyl acetate. The combined extracts were washed with water, dried and evaporated, to give 2 g of ethyl 2-(2-methoxy-phenyl)-3-oxo-propionate. The compound described above (2 g) was dissolved in water (50 ml), added with sodium carbonate (0.95 g), and the resulting mixture was added drop by drop with a solution of benzydamine (1.1 g) in water. The mixture was then heated under stirring for 10 hours at 60° C., acidified and extracted 3 times with methylene chloride. The combined extracts were washed with an 8% sodium bicarbonate aqueous solution, with water, dried and evaporated. The solid residue was crystallized from diethyl ether, to give the title product as a white solid (0.4 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:12](=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(#N)C>[O:21]1[CH2:22][CH2:23][N:18]([CH2:2][C:3]2[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:12])=[O:8])=[CH:5][CH:4]=2)[CH2:19][CH2:20]1
Reactant: O=C([O-])[O-]
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Commercially available 4-bromomethylbenzoic acid (300 mg) was dissolved in acetonitrile (10 ml). Potassium carbonate (30 mg) and morpholine (130 μl) were added to the solution, and the mixture was stirred at room temperature for one hr. The reaction layer was subjected to separation with chloroform and a saturated aqueous sodium hydrogencarbonate solution. The organic layer was then concentrated to give methyl 4-(morpholinomethyl)benzoate. Methanol (1 ml), water (150 μl), and potassium hydroxide (15 mg) were added to the residue, and the mixture was heated at 60° C. for one hr. After the completion of the reaction, the solvent was removed by distillation to give 4-(morpholinomethyl)benzoic acid. Toluene (20 ml) and thionyl chloride (1 ml) were added to the residule, and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 4-(morpholinomethyl)-1-benzenecarbonyl isothiocyanate was prepared using the resultant 4-(morpholinomethyl)-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-(morpholinomethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (74 mg, yield 78%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[C:21](=[O:22])[N:20](CC=C)[C:19]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:18]2)(=[O:16])=[O:15])=[C:10]([O:33][CH3:34])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)=O.C(N(CC)CC)C>O1CCOCC1.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:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[C:21](=[O:22])[NH:20][C:19]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)=[N:18]2)(=[O:16])=[O:15])=[C:10]([O:33][CH3:34])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCn1c(-c2ccc(Cl)cc2)nn(S(=O)(=O)c2ccc(C(=O)NC(C)(C)C)cc2OC)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: C1COCCO1
Product: COc1cc(C(=O)NC(C)(C)C)ccc1S(=O)(=O)n1nc(-c2ccc(Cl)cc2)[nH]c1=O

Procedure:
An amount of 194 mg (0.384 mmol) of N-tert-butyl-4-{[3-(4-chlorophenyl)-5-oxo-4-prop-2-en-1-yl-4,5-dihydro-1H-1,2,4-triazol-1-yl]sulphonyl}-3-methoxybenzenecarboxamide from Example 1 was dissolved under argon in 2 ml of degassed dioxane and admixed with 18 mg (0.015 mmol) of tetrakis(triphenylphosphine)palladium(0), 29 μl (0.77 mmol) of formic acid and 134 μl (0.96 mmol) of triethylamine. The mixture was stirred under reflux for 2 h. The dioxane was concentrated on a rotary evaporator and the residue in the flask was taken up in methanol. It was filtered over kieselguhr, the solid product was washed with methanol and the solvent was removed on a rotary evaporator. Ethyl acetate was added to the residue in the flask. Washing with water was carried out twice. The organic phase was dried over sodium sulphate and freed from the solvent on a rotary evaporator. Purification of the residue by flash chromatography on silica gel (solvent gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate 100%) gave 152 mg (85% of theory) of the target compound.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:16][CH2:15][N:14]([C:17]([C:19]4[S:27][C:26]5[CH2:25][CH2:24][NH:23][CH2:22][C:21]=5[CH:20]=4)=[O:18])[CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([CH3:45])[C:42]([S:46](Cl)(=[O:48])=[O:47])=[C:41]([CH3:50])[CH:40]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH3:50])[C:42]([S:46]([N:23]2[CH2:24][CH2:25][C:26]3[S:27][C:19]([C:17]([N:14]4[CH2:15][CH2:16][C:11]5([CH2:28][CH2:29][N:8]([C:5]6[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=6)[CH2:9][CH2:10]5)[CH2:12][CH2:13]4)=[O:18])=[CH:20][C:21]=3[CH2:22]2)(=[O:47])=[O:48])=[C:43]([CH3:45])[CH:44]=1
Reactant: O=C(c1cc2c(s1)CCNC2)N1CCC2(CC1)CCN(c1ccncc1)CC2
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N2CCc3sc(C(=O)N4CCC5(CC4)CCN(c4ccncc4)CC5)cc3C2)c(C)c1
Reaction time: 15 h

Procedure:
(9-(Pyridin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)(4,5,6,7-tetrahydrothieno[3,2-c]-pyridin-2-yl)methanone hydrochloride (89 mg, 0.208 mmol) was dissolved in dichloromethane (5 ml) and cooled, and triethylamine (0.07 ml, 0.52 mmol) was added thereto. At 0° C., a solution of 4-methoxy-2,6-dimethylbenzenesulfonyl chloride (50 mg, 0.208 mmol) in dichloromethane (5 ml) was added dropwise, and then stirring was carried out for 15 h at room temperature. Saturated sodium hydrogen carbonate solution (10 ml) was added, the mixture was stirred for 15 min. and the phases were separated. The aqueous phase was extracted with dichloromethane (30 ml), and then the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol/-ammonia (25% aq.), 400:20:1). Yield: 70 mg (56%). MS, R=3.4 min; m/z=595.3 [MH]+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH3:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=2)[C:13]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[C:12]([C:27]#[N:28])[C:11]1=[O:29]>N1C=CC=CC=1>[CH3:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=2)[C:13]([N:21]2[CH2:26][CH2:25][N:24]([C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:23][CH2:22]2)=[C:12]([C:27]#[N:28])[C:11]1=[O:29]
Reactant: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2C
Reactant: O=C(Cl)c1cccs1
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3cccs3)CC1)c(C#N)c(=O)n2C
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
2-Thiophene carbonyl chloride (160 μL, 1.5 mmol) was added to a stirred solution of Compound 28 (282 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 277 mg (70%) of white solids. M.P. 214° C. 1H NMR (DMSO-d6): δ 2.41 (s, 3H), 3.55 (s, 3H), 3.63 (m,4H), 3.92 (m, 4H), 7.16 (t, J=4.1 Hz, 1H), 7.47 (m, 2H), 7.56 (d, J=8.7 Hz, 1H), 7.68 (s, 1H), 7.80 (d, J=4.9 Hz, 1H). EIMS m/z 393 (M+1), 415 (M+23). Anal. (C21H20N4O2S) C, H, N.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)CC(O)c1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(CC(C)C)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
Methyl 4-hydroxybenzoate (609 mg, 4.00 mmol), 1-(4-bromophenyl)-3-methylbutan-1-ol (1.95 g, 8.00 mmol) and triphenylphosphine (2.10 g, 8.00 mmol) were dissolved in tetrahydrofuran (10 mL). Diisopropyl azodicarboxylate (1.58 mL, 8.00 mmol) was added. The resulting solution was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (50 mL) and washed with 0.1M HCl (3×100 mL) and brine. The organics were dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography (0-30% ethyl acetate in heptane) gave (+/−)-methyl 4-(1-(4-bromophenyl)-3-methylbutoxy)benzoate (1.4 g, 93%) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 7.89-7.83 (m, 2H), 7.46-7.40 (m, 2H), 7.21-7.16 (m, 2H), 6.83-6.78 (m, 2H), 5.16 (dd, J=9, 4.7 Hz, 1H), 3.83 (s, 3H), 1.99-1.91 (m, 1H), 1.88-1.75 (m, 1H), 1.58-1.51 (m, 1H), 0.97 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24]CC3C=CC=CC=3)[CH:17]=2)=[O:14])=[CH:11][C:10]=1[O:34]C)C1C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CN(C)C=O.CO.[Pd]>[OH:34][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:9]=1[O:8][CH3:1])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=1)=[O:14]
Reactant: COc1cc(C(=O)Nc2ccc(OC)c(OCc3ccccc3)c2)ccc1OCc1ccccc1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(NC(=O)c2ccc(OC)c(O)c2)cc1O
Yield: 40.2 %

Procedure:
A solution of the 4-Benzyloxy-3-methoxy-N-(3-benzyloxy-4-methoxyphenyl)benzamide (1.05 g) in a mixture of N,N-dimethylformamide/methanol (1:5, 120 ml) was hydrogenated in presence of 10% palladium on carbon at 40 Psi at room temperature for 12 hrs. Removal of the catalyst by filtration and purification by flash chromatography over silica gel eluting with 65% ethyl acetate/hexane provided 0.26 g of 3-hydroxy-N-(3-hydroxy-4-methoxyphenyl)-4-methoxybenzamide. Yield=41.6%
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][C:21]([OH:23])=O)=[CH:17][CH:16]=1.CCOCC>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]([N:2]([CH3:1])[C@@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]2[N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:23])=[CH:24][CH:25]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C(=O)COc1ccc(Cl)cc1)[C@@H]1CCCC[C@H]1N1CCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Trans-N-Methyl-2-(1-pyrrolidinyl]cyclohexanamine (0.182 g) was dissolved in methylene chloride (10 ml) and stirred at room temperature. The acid chloride of 4-chlorophenoxyacetic acid (0.205 g) dissolved in methylene chloride (10 ml) was added and let stand for 12 hours. Ether was added to rapidly stirred solution until no more precipitate appeared. After further rapid stirring for one hour, the precipitate was filtered and dried in a vacuum oven at 90° C. for one hour, and stored in a predried bottle. The product was in the form of white needles (360 mg) mp 184°-186° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([CH3:25])=[CH2:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1>C(OC)(C)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]3([CH3:25])[CH2:24][O:38]3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC2(C)CO2)(c2ccccc2)OC1=O
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
To a 1.0 L 2-neck RBF was charged (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (135.8 g, 59 wt %, 3.1:1 dr, 193 mmol, 1.00 equiv), dichloromethane (700 mL), and then 3-chloroperbenzoic acid (m-CPBA, 70%, 95.3 g, 386 mmol, 2.0 equiv). The resulting solution was agitated at rt (Tint=20-25° C.) for 1 h, which HPLC analysis indicates >99 A % (220 nm) conversion. The resulting solution was diluted with 700 mL of methyl tert-butyl ether (MTBE) and washed with 1×500 mL of 30 wt % solution of sodium thiosulfate and 1×500 mL of saturated aqueous solution of sodium bicarbonate. The wash sequence was repeated until the peak on an HPLC trace of the organic solution that corresponds to a HPLC sample peak of m-CPBA is <2.5 A % (220 nm), which in this example the wash sequence was repeated 3 times. The resulting organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated to an oil via reduced pressure. The resulting material was diluted with 200 mL of anhydrous tetrahydrofuran and then concentrated to a thick oil via reduced pressure to provide (6S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one which was used directly in Step 5.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O-])=O.[H][H]>C(O)C.[Pd]>[N:11]1([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[NH2:1])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1N1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccncc1N1CCCCC1
Reaction time: 15 h
Yield: 73 %

Procedure:
To a solution of 4-nitro-3-(piperidin-1-yl)pyridine 1-oxide (1.0 equiv.) in ethanol, at a concentration of 0.1 M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 15 hours. At this time LC/MS analysis indicated that the nitro was reduced to the amine, but the N-oxide was remaining. More 10% palladium on carbon (0.2 eq.) was added and the mixture was resubmitted to a balloon atmosphere of hydrogen. After stirring for 24 hours, more 10% palladium on carbon (0.2 eq.) was added and the mixture was resubmitted to a balloon atmosphere of hydrogen. After stirring for an additional 3 days the mixture was filtered through a pad of celite eluting with methanol. The volatiles were removed in vacuo yielding 3-(piperidin-1-yl)pyridin-4-amine (73%). LCMS (m/z): 178.0 (MH+); LC Rt=1.66 min.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[N:9]=[C:8]([C:10]2[S:14][C:13]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[O:7][N:6]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:16]1([CH2:15][C:13]2[S:14][C:10]([C:8]3[O:7][N:6]=[C:5]([CH2:4][NH:3][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:9]=3)=[CH:11][CH:12]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NCc1noc(-c2ccc(CN3CCCCCC3)s2)n1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1noc(-c2ccc(CN3CCCCCC3)s2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 64.3 %

Procedure:
585 mg (2.0 mmol) of the free form compound obtained in Example 8 was dissolved in 20 ml of methylene chloride, 0.6 ml (4.0 mmol) of triethylamine, 0.28 ml (2.4 mmol) of benzoyl chloride and 4-DMAP (cat.) were added, and the mixture was stirred at room temperature for 19 hours. The reaction solution was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was subjected to a silica gel column chromatography, which was eluted with chloroform-methanol (80:1) to give 510 mg of the title compound in its free form. Using 140 mg (1.2 mmol) of fumaric acid, a 490 mg (1.24 mmol) portion of this compound was subjected to salt formation to give 348 mg of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](Cl)(=[O:32])[C:29](Cl)=[O:30].[CH2:34]([OH:36])[CH3:35].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:32])[C:29]([O:36][CH2:34][CH3:35])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: FC(F)(F)Oc1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indole (2.80 g, 7.62 mmol) in dry THF (40 mL) under nitrogen at 0° C. was added oxalyl chloride (2.0 mL, 23 mmol). The reaction mixture was stirred for one hour. It was cooled in an ice bath and ethanol (4.5 mL) was added. The reaction mixture was stirred for 25 minutes at room temperature then poured into excess aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated to dryness. The residue was purified by flash chromatography using 5–10% ethyl acetate in hexane as an eluant. Drying for 35 minutes at 60° C. yielded the title compound as a yellow gum (3.05 g, 86%): 1HNMR (300 MHz, DMSO-d6): δ8.75 (s, 1H), 8.45 (s, 1H), 7.8 (d, 2H, J=9.2 Hz), 7.75 (d, 1H, J=9.2 Hz), 7.6 (d, 1H, J=9.2 Hz), 7.45 (d, 2H, J=9.2 Hz), 7.3–7.4 (m, 5H), 5.85 (s, 2H), 4.35 (q, 2H, J=7.5 Hz), and 1.35 ppm (t, 3H, J=7.5 Hz).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Al](C)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([C:33]3[CH:43]=[CH:42][C:36]([C:37](OCC)=[O:38])=[CH:35][CH:34]=3)[NH:25][C:26]=2[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:18][CH:17]=1.CO.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:2]([O:9][NH:10][C:37](=[O:38])[C:36]1[CH:42]=[CH:43][C:33]([C:24]2[NH:25][C:26]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[C:22]([C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[N:23]=2)=[CH:34][CH:35]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Reactant: NOCc1ccccc1
Agent: C[Al](C)C
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NOCc1ccccc1)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.7 %

Procedure:
To a stirred suspension of O-benzyl-hydroxylamine hydrochloride (1.2 g, 7.8 mmol) in toluene (20 mL) at 0° C. was added trimethylaluminum (2.0 M in toluene, 3.9 mL, 7.8 mmol). The reaction mixture was warmed to rt and stirring was continued at this temperature for 1 h. Ethyl 4-[4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazol-2-yl]benzoate (1.0 g, 2.6 mmol) [See Ex. 14 above] was added and the reaction mixture was heated at reflux for 3 h. After cooling, the reaction was poured into 10% MeOH/CHCl3 containing silica gel. The solids were removed by filtration and washed with 10% MeOH/CHCl3. The combined washings were evaporated and the residue was purified by flash chromatography eluting with a solvent gradient of 1-10% MeOH/CHCl3. Trituration with ether afforded the title compound as a white solid (0.25 g, 21%): 1H NMR (CDCl3/MeOH-d4): d 8.16 (d, 2H); 7.77 (d, 2H); 7.53 (d, 2H); 7.23 (m, 5H); 7.10 (m, 4H); 6.88 (t, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]([C:28]1[S:29][CH:30]=[CH:31][N:32]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])=[N:15][CH:14]=[C:13]2[F:27])(=[O:9])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:46][C:47]#[N:48]>CN(C=O)C.C(OCC)(=O)C>[C:47]([CH2:46][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:16]1[C:17]2[C:12](=[CH:11][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:3]=3[O:2][CH3:1])[C:28]3[S:29][CH:30]=[CH:31][N:32]=3)(=[O:8])=[O:9])=[CH:19][CH:18]=2)[C:13]([F:27])=[CH:14][N:15]=1)#[N:48]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4O)ncc(F)c3c2)c(OC)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4OCC#N)ncc(F)c3c2)c(OC)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
N-(2,4-dimethoxybenzyl)-4-fluoro-1-(2-hydroxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.078 g, 0.141 mmol) was dissolved in DMF (0.7 mL) and cesium carbonate (0.148 g, 0.456 mmol) was added, followed by bromoacetonitrile (10.58 μl, 0.152 mmol). The reaction was heated to 60° C. and stirred overnight. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-100% EtOAc:Heptane) to afford 1-(2-(cyanomethoxy)phenyl)-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide. (ESI) 591.2 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C]=O.[CH:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:2]2[C:1]([O:6][C:4](=[O:5])[CH:3]=2)=[O:7])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:4]1(=[O:5])[O:6][C:1](=[O:7])[CH2:2][CH2:3]1
Reactant: O=C1C=CC(=O)O1
Reactant: c1ccccc1
Agent: [C]=O
Product: O=C1C=C(c2ccccc2)C(=O)O1
Product: O=C1CCC(=O)O1
Temperature: 220 °C

Procedure:
In the same autoclave as used in Example 1, 50 ml of benzene, 0.98 g of maleic anhydride and 0.019 g of Rh4 (CO)12 were charged, followed by supply of carbon monoxide under 30 kg/cm2. The charge in the autoclave was heated at 220° C. for 7 hours. The reaction mixture was cooled and benzene was removed by distillation under reduced pressure. The residue was separated by silica column chromatography to obtain 0.363 g of phenylmaleic anhydride and 0.136 g of succinic anhydride. Each product was identified based on the infrared absorption spectrum (hereinafter referred to as "IR") of the standard substance and the retention time in GC.