Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].ClCCl.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH3:19][S:20]([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(OS(C)(=O)=O)cc(C(=O)OC)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a 0° C. solution of dimethyl 5-hydroxyisophthalate (2.0 g, 9.5 mmol) in 3:1 dichloromethane:pyridine (100 mL) was added methanesulfonyl chloride (3.6 g, 31.4 mmol). The reaction warmed to room temperature over 18 h. The reaction mixture was concentrated in vacuo. The crude material was diluted with DCM and washed with 1N HCl, H2O (2×), brine, dried with MgSO4, filtered, concentrated and purified by flash chromatography (40 g silica, 25-40% EtOAc/hexanes) to give 1.37 g (50%) of dimethyl 5-[(methylsulfonyl)oxy]isophthalate. 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.12 (s, 2H), 3.97 (s, 6H), 3.23 (s, 3H).
Reaction SMILES: [C:1](OF)(=[O:4])[CH:2]=C.[C:7]([O-:12])(=[O:11])[C:8]([CH3:10])=[CH2:9].CC(N=NC(C#N)(C)C)(C#N)C>C1COCC1>[C:7]([OH:12])(=[O:11])[C:8]([CH3:10])=[CH2:9].[C:7]([O:12][CH2:2][CH2:1][OH:4])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C=C(C)C(=O)[O-]
Reactant: C=CC(=O)OF
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCOC1
Product: C=C(C)C(=O)O
Product: C=C(C)C(=O)OCCO

Procedure:
This example illustrates conjoint use of the fluoro acrylate and methacrylate. 75.81 g (40.8 wt. %) of the perfluoroalkyl methacrylate (DuPont's Zonyl-TM), 72.3 g (38.9 wt. %) of the perfluoroalkyl acrylate (Hoechst-Celanese NUVA HF), 17.61 g (9.5 wt. %) of methacrylic acid, and 19.98 g (10.8 wt. %) of 2-hydroxyethyl methacrylate were polymerized in 300 ml THF, using 0.55 g AIBN as initiator, employing above-described procedure. Yield: 79.1%.
Reaction SMILES: ClCCl.[CH:4]([C:6]1[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:8]([CH3:19])[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=1)=O.[N+:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([O-:27])=[O:26].CN1CCOCC1.[Cl-].[NH4+]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:32]([O:31][C:29](=[O:30])[C:28]([N+:25]([O-:27])=[O:26])=[CH:4][C:6]1[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:8]([CH3:19])[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=1)[CH3:33]
Reactant: CCOC(=O)c1c(C=O)cn(COCC[Si](C)(C)C)c1C
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1cn(COCC[Si](C)(C)C)c(C)c1C(=O)OCC)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A flask equipped with stirbar was charged with 4 mL tetrahydrofuran and cooled in an ice bath. Titanium(IV) chloride, 1M solution in dichloromethane (2.1 mL, 2.100 mmol) was added by syringe, providing a suspension. After 15 minutes, a solution of Example 93c (0.322 g, 1.034 mmol) and ethyl 2-nitroacetate (0.115 mL, 1.034 mmol) in tetrahydrofuran (0.5 mL) was added. After an additional 15 minutes, a solution of 4-methylmorpholine (0.45 mL, 4.09 mmol) in tetrahydrofuran (0.3 mL) was added dropwise. The solution was allowed to warm to ambient temperature and stirred for 18 hours. The heterogeneous reaction mixture was poured into aqueous ammonium chloride and extracted twice with ether. The combined organics were washed with saturated aqueous sodium chloride then dried over anhydrous magnesium sulfate. Filtration, solvent removal, and chromatography on a 12 g silica gel cartridge eluting with 0-60% ethyl acetate/heptane provided the title compounds as a 2.5:1 mixture of olefin isomers.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28](=O)[CH:27]=[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:29])[CH2:27][C:26]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc([N+](=O)[O-])c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) and 2,2-dimethyl-6-(3-nitro-phenyl)-[1,3]dioxin-4-one (Example J12) according to the general procedure K. Obtained as a light yellow solid (1.01 g).
Reaction SMILES: N1(O[C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:19][CH3:20])[CH:13]=2)C2C=CC=CC=2N=N1.CS([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)(=O)=O.[CH2:33](N(CC)CC)[CH3:34]>O1CCCC1>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:32][CH:29]2[CH2:30][CH2:31][N:26]([CH2:33][CH3:34])[CH2:27][CH2:28]2)=[O:21])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: COc1cc(C(=O)On2nnc3ccccc32)ccc1N
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN1CCC(NC(=O)c2ccc(N)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 90 h
Yield: 117 %

Procedure:
To a mixture of 0.8813 g (3.1 mmole) of 4-amino-3-methoxy-benzoic acid benzotriazol-1-yl ester and 8 mL of dry tetrahydrofuran at 0 degrees was added 0.6995 g (3.1 mmole) of 1-methanesulfonyl-piperidin-4-ylamine followed by 0.7842 g (7.75 mmole) of triethylamine. The cooling bath was removed and the mixture stirred at room temperature for 90 hours. Volatiles were removed under reduced pressure and the residue taken up in ethyl acetate, and the organic layer washed twice with 50 mL of 0.5 M sodium carbonate, 50 mL water, and then 50 mL brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.0056 g 4-amino-N-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9].[Br:12][C:13]1[C:14](Cl)=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:12][C:13]1[C:14]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CNC(=O)CCNCCOC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)CCN(CCOC)c1nc(Cl)ncc1Br
Temperature: 25 °C

Procedure:
3-(2-methoxyethylamino)-N-methyl-propanamide (Intermediate 111; 608 mg, 3.79 mmol) 5-Bromo-2,4-dichloropyrimidine (Aldrich; 950 mg, 4.17 mmol), Triethylamine (555 μL, 3.98 mmol), and DCM (5 mL) were combined and stirred over the weekend at room temperature.
Reaction SMILES: C([C:5]([Br:17])(CCCC)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)CCC.C1C=C(Cl)C=C(C(OO)=O)C=1.[S:29]([O-])([O-:31])=[O:30].[Na+].[Na+].C(OCC)(=O)C>C(Cl)Cl>[S:29](=[C:5]([Br:17])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)(=[O:31])=[O:30]
Reactant: O=S([O-])[O-]
Reactant: CCCCC(Br)(CCCC)c1ccc(F)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(=O)=C(Br)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a solution of 8.5 g (25 mmol) of sulfide obtained from Step 3 in 200 mL of CH2Cl2 at 0° C. was added 15.9 g (60 mmol) of mCPBA (64% peracid). The resulting solution was stirred cold for 10 min, then was allowed to stirred ambient temperature for 5 hours. To the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was washed several times with saturated Na2CO3, dried (MgSO4), and concentrated in vacuo to give 10.2 g (98%) of the desired product as a colorless oil: 1H NMR (CDCl3) d 0.91 (t, J=7.05 Hz, 6H), 1.03-1.4 (m, 8H), 1.65-1.82 (m, 2H), 1.90-2.05 (m, 2H), 3.54 (s, 2H), 5.01 (s, 2H), 7.04-7.23 (m, 1H), 7.30 (dd, J=8.87, 2.42 Hz, 1H), 8.03 (dd, J=8.86, 5.64, 1H), 9.49 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([O:22]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=O)=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1.[N:37]1[CH:42]=[CH:41][CH:40]=[N:39][C:38]=1[NH2:43].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:43][C:38]4[N:39]=[CH:40][CH:41]=[CH:42][N:37]=4)(=[O:21])=[O:22])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: Nc1ncccn1
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ncccn3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a solution of perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (15.0 g, 25.24 mmol) and pyrimidin-2-amine (4.8 g, 50.48 mmol, Alfa Aesar) in THF (300 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 50.5 mL, 50.5 mmol, Aldrich) at 78° C. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with 1.5 N HCl (300 mL) and extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with 1.5N HCl (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to get the crude product which was purified by column chromatography (Silica gel; 60-120 mesh, eluent: 3-5% Methanol in DCM) to obtain 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-N-2-pyrimidinyl-1,2-dihydro-6-quinolinesulfonamide (9.6 g, 75.3%) as off white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.56-8.42 (m, 3H), 8.26 (d, J=9.6 Hz, 1H), 7.95 (dd, J=8.9, 2.1 Hz, 1H), 7.66 (d, J=6.2 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.05 (s, 1H), 6.79 (dd, J=16.1, 9.3 Hz, 2H), 3.68 (s, 3H); LCMS (ESI) m/z 505.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[CH2:36][C:37]([N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)=[O:38]>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[C:13]([N:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:36][C:37]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:38])[CH2:23][CH2:22]2)[C@H:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]1)=[O:14]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Reactant: O=C(CCl)N1CCOCC1
Product: O=C(CN1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1)N1CCOCC1

Procedure:
The title compound, MS: m/e=613.1 (M+H+), was prepared in accordance with the general method of example 35 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and 4-(2-chloroacetyl)morpholine.
Reaction SMILES: [OH:1][C@@H:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].[NH:11]1[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]1=[O:13].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[OH:1][C@@H:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].[C:19]([NH:16][C:15]1[CH:17]=[CH:18][NH:11][C:12](=[O:13])[N:14]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc[nH]c(=O)n1
Agent: O=C([O-])O
Agent: OC[C@H]1O[C@@H](O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(Nc1cc[nH]c(=O)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A suspension of 1.22 g (5.02 mmol) of cytosine-β-D-arabinofuranoside in 50 mL of dry pyridine was cooled to 0° C. 10 mL of benzoyl chloride was added and the mixture was stirred at room temperature for 16 hours. The mixture was poured into 75 mL of 5% aq sodium bicarbonate solution and extracted with CH2CL2 (2×150 mL). The organic phases were washed with water (50 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The mixture was dissolved in 50 mL of pyridine/methanol/water (5:3:2 v/v) and cooled in an ice bath. To this solution was added cold 50 mL of 2M sodium hydroxide in pyridine/methanol/water (5:3:2 v/v). The reaction mixture was stirred at 0° C. for 15 minutes and then the pH was adjusted to 7 with the addition of ammonium chloride. The mixture was concentrated in vacuo and 20 mL of methanol was added. The mixture was filtered and the solid washed with more methanol (3×20 mL). All washings and filtrate were collected, combined and concentrated in vacuo. Redissolved in 50 mL of methanol/CH2Cl2 (2:8 v/v) and the mixture was purified by flash chromatography using methanol/CH2Cl2 (1:9-2:8 v/v). A second flash chromatography as described above was needed to remove all impurities to give 1.5 g (86%) of N4-Benzoylcytosine-β-D-arabinofuranoside 16.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:25]([OH:27])=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:28](=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[CH3:28][O:26][C:25](=[O:27])[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 10.45 g of Nα -Boc-Nε -Cbz-L-lysine in 125 ml methanol and 17 ml water. Neutralize the solution with 27.5 ml of 0.5M cesium carbonate solution and concentrate the resulting solution to a syrup at aspirator pressure and 35° C. Dissolve the syrup in 100 ml. dimethylformamide and concentrate; repeat once more. Dissolve the residue in 75 ml. dimethylformamide and 2.7 ml. methyi iodide. Stir the reaction mixture overnight at room temperature then remove the dimethylformamide under vacuum (oil pump). Add 250 ml. water to the residue and extract into 150 ml. ethyl acetate. Wash the ethyl acetate extract twice with 100 ml. portions of water then dry the organic phase over MgSO4. Filter and concentrate the dried solution in vacuo to obtain Nα -Boc-Nε -Cbz-L-lysine methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:13][CH2:12]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH:27]1([C:25]([N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:15][CH2:16]2)=[O:26])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2NS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 39 %

Procedure:
To a solution of 0.22 g of the compound of example 27 and 0.08 mL of triethylamine (TEA) in 5 mL of CH2Cl2, stirred at r.t. under anhydrous nitrogen atmosphere, was added dropwise a solution of 0.04 mL of methanesulphonyl chloride in 0.5 mL of CH2Cl2. The solution was stirred for 6 h at room temperature, afterwards, it was evaporated to dryness in vacuo and the residue was purified by flash chromatography (CH2Cl2-MeCN 9:1) affording 0.10 g (39%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([N+:16]([O-])=O)=[CH:4][CH:3]=1.O.[H][H]>O1CCCC1.[Ni]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([NH2:16])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCC1CCOCC1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Cl)nc1NCC1CCOCC1

Procedure:
A solution of Example 7A (1.057 g, 3.89 mmol) in tetrahydrofuran (1 mL) was added to 50% Raney® nickel in water (335.5 mg, 5.72 mmol) in a pressure bottle. The mixture was stirred under 60 psi hydrogen at room temperature for 13 hours. The mixture was filtered through a polypropylene membrane and concentrated to give the crude title compound which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[N:23]=3)[C:13]=2[C:14]([OH:16])=[O:15])[N:4]=1.[CH:32]([NH2:35])([CH3:34])[CH3:33]>C1COCC1>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([O:30][CH3:31])[N:23]=[C:22]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:12]([O:11][C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=3)[C:13]=2[C:14]([O-:16])=[O:15])[N:27]=1.[CH:32]([NH3+:35])([CH3:34])[CH3:33]
Reactant: COc1cc(OC)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)O)n1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)[NH3+]
Product: COc1cc(OC)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)[O-])n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2,6-bis[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoic acid (2.0 g) and isopropylamine (1.0 9) were dissolved in 30 ml of THF, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, and crystals thereby precipitated, were washed with hexane to obtain the above identified compound as white crystals (1.9 g). (Melting point: 99°-102° C.)
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Si](OCC)(OCC)(OCC)OCC.[CH:31]([C:34]1[CH:40]=[CH:39][CH:38]=[C:37]([CH:41]([CH3:43])[CH3:42])[C:35]=1[NH2:36])([CH3:33])[CH3:32].OS(O)(=O)=O>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](/[C:9](=[N:36]/[C:35]2[C:37]([CH:41]([CH3:42])[CH3:43])=[CH:38][CH:39]=[CH:40][C:34]=2[CH:31]([CH3:33])[CH3:32])/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[OH:17]
Reactant: Cc1cc(Br)c(O)c(C(=O)c2ccccc2)c1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CCO[Si](OCC)(OCC)OCC
Agent: O=S(=O)(O)O
Product: Cc1cc(Br)c(O)c(/C(=N/c2c(C(C)C)cccc2C(C)C)c2ccccc2)c1
Temperature: 170 °C
Reaction time: 35 h
Yield: 69.1 %

Procedure:
In a 50 mL Claisens flask under an argon atmosphere, a mixture of 13.5 g (46.3 mmol) of 33, 20.2 g (97.2 mmol) of Si(OEt)4, and 9.03 g (50.9 mmol) of 2,6-diisopropylaniline was heated to 170° C., and then 0.37 mL of 96% H2SO4 was added. This mixture was stirred at this temperature for 35 hr, and the formed ethanol was slowly distilled off Later, 300 mL of cold water was added, and the product was extracted with 2×100 mL of diethyl ether. The combined extract was dried over K2CO3 and then evaporated to dryness. The product was isolated by flash-chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-diethyl ether, 100:1, vol.). This procedure gave 14.4 g (69%) of 34.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:16]1[CH2:17][CH2:18][CH:13]([OH:12])[CH2:14][CH2:15]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCC(O)CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
To a solution of 1.55 g (10 mmol) of 2-fluoro-5-nitrotoluene in 35 mL of N,N-dimethylformamide were added 1.01 g (10 mmol) of 4-hydroxypiperidine and 1.8 g (13 mmol) of potassium carbonate, and the mixture was stirred for 2 hours at 120° C. The reaction mixture was poured into ice and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/1) to give 1.5 g (63%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:5]2[C:15](=[O:31])[N:16]([CH2:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[C:17](=O)[C:4]2=[CH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:5]2[C:15](=[O:31])[N:16]([CH2:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[C:17](=[S:41])[C:4]2=[CH:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Solvent: Cc1ccccc1
Product: Cn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=S
Temperature: 120 °C
Yield: 178.9 %

Procedure:
5-Methyl-7-morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-5H-pyrrolo[3,4-c]pyridine-1,3,6-trione (0.7 g, 1.67 mmol, see Example 1) was dissolved in toluene (20 ml), stirred and heated to 120° C. and Lawesson's reagent (0.338 g, 0.836 mmol) was added. The reaction was stirred at 120° C. for 16 h. The reaction mixture was cooled to r.t., filtered though a pad of silica gel and concentrated to afford the crude title compound (0.65 g, 77% yield), which was used in the next steps without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([Mg]Br)[CH:7]=[CH:6]2.[CH:15]([C:17]1[S:21][CH:20]=[N:19][CH:18]=1)=[O:16].[CH2:22]1[CH2:26]OC[CH2:23]1>[Cl-].[NH4+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:15]([C:17]1[S:21][CH:20]=[N:19][CH:18]=1)([OH:16])[CH:22]([CH3:26])[CH3:23])[CH:7]=[CH:6]2
Reactant: O=Cc1cncs1
Reactant: C1CCOC1
Reactant: COc1ccc2cc([Mg]Br)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc2cc(C(O)(c3cncs3)C(C)C)ccc2c1
Reaction time: 0.33 h

Procedure:
To a solution of 6-methoxynaphthalen-2-ylmagnesium bromide in THF (1.3 M; 10 ml) was added dropwise a solution of 5-formylthiazole (1.70 g) in THF (10 ml) under ice cooling, and the mixture was stirred for 20 min under ice cooling. The mixture was diluted with saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, washed with saturated sodium chloride solution and dried. The solvent was distilled off and the residue was purified by silica gel chromatography (eluent, hexane:ethyl acetate=2:1→1:1) to give the titled compound (3.47 g) as a colorless powder.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH:5]([CH3:7])[CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][NH2:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][CH:5]([CH3:7])[CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][NH:11][S:20]([C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[Cl:12])(=[O:22])=[O:21]
Reactant: CC1CC(C)N(CCCN)C1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Solvent: c1ccccc1
Product: CC1CC(C)N(CCCNS(=O)(=O)c2cc(Cl)ccc2Cl)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 67 %

Procedure:
2,4-Dimethyl-1-(3-aminopropyl)pyrrolidine in (4.7 g, 0.03 mol) benzene (30 ml) was added dropwise at room temperature to a solution of 2,5-dichlorobenzenesulphonylchloride (7.3 g, 0.03 ml) in benzene (100 ml). Thereafter, the mixture was stirred for 4 days at room temperature until the reaction was complete. Finally, the reaction product was obtained as a viscous, oily paste. The benzene mother liquor was decanted. The residue was dissolved in water, the solution was adjusted to pH 9.8 with 10% NaOH and extractes with petroleum ether (40°-60°) (4×100 ml). The combined extracts were dried over Na2SO4 and evaporated. The residue (5 g) was recrystallised twice from 100 ml petroleum ether to yield the product (3.7 g as white needles), m.p. 65°-67° C. Yield=67% of theoretical