Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[CH:10]=1)([O-:5])=[O:4].CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.C1(C)C=CC=CC=1>[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([OH:17])[CH3:16])[CH:10]=1)([O-:5])=[O:4]
Reactant: CC(=O)CCCCn1cc([N+](=O)[O-])cn1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(O)CCCCn1cc([N+](=O)[O-])cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a 0.1M solution of 6-(4-nitro-pyrazol-1-yl)-hexan-2-one (250 mg, 1.18 mmol) in THF was treated dropwise, at −78° C. with DiBAL (1.5 mL of a 1M solution in toluene, 1.5 mmol). The reaction mixture was stirred at −78° C. for 1 h. Sat. aq. Rochelle's salt (10 mL) was added and the reaction mixture was stirred for 2 h at rt. The aq. layer was extracted with EA (2×25 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound. TLC: rf (40:60 hept-EA)=0.2. LC-MS-conditions 02: tR=0.78 min; [M+H]+=214.23.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH3:14].[C:15]12([CH2:25][C:26](Cl)=[O:27])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>>[C:15]12([CH2:25][C:26]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=4)[N:4]=[C:3]3[CH3:14])=[O:27])[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]3)[CH2:16]1)[CH2:24]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Cc1nc2cc(Cl)ccc2c(=O)n1N
Product: Cc1nc2cc(Cl)ccc2c(=O)n1NC(=O)CC12CC3CC(CC(C3)C1)C2

Procedure:
3-Amino-7-chloro-2-methylquinazolin-4(3H)-one and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.59-1.74 (m, 12H), 1.93-1.98 (m, 3H), 2.08-2.18 (m, 2H), 2.40 (s, 3H), 7.57 (dd, J=8.5, 2.0 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 10.90 (s, 1H); MS (DCI/NH3) m/z 386 (M+H)+; Elemental Analysis: Calculated for C21H24ClN3O2.H2O: C, 62.45; H, 6.49; N, 10.40. Found: C, 62.63; H, 6.27; N, 10.36.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=[O:20].O>CC(C)=O>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([C:19](=[O:20])[CH2:18][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[O:9][CH3:10])=[CH:22][CH:23]=1
Reactant: COc1cc(F)ccc1O
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(F)ccc1OCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-fluoro-2-methoxy-phenol (3.0 g, 21.1 mmol) in acetone (250 mL) is treated with cesium carbonate (8.3 g, 25.3 mmol) followed by 2-bromo-1-(4-bromo-phenyl)-ethanone (5.9 g, 21.1 mmol). The resulting mixture is stirred at room temperature for 2 h. Water (600 mL) is added slowly to the vigorously stirring solution. After stirring for 30 minutes, the precipitate is filtered off and washed with copious water to give 1-(4-bromo-phenyl)-2-(4-fluoro-2-methoxy-phenoxy)-ethanone (G-1).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1>>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:31])([F:42])[F:43])[CH:34]=4)=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THE is mixed with 29.8 μl (0.21 mmol) of triethylamine and 40.0 mg (0.21 mmol) of 3-trifluoromethylphenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 51 mg (89% of theory) of the title compound are obtained.
Reaction SMILES: O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C([O:14][C:15]([C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[C:24]([C:33]#[N:34])[CH:23]=2)=[N:19][C:18]=1[CH3:35])=[O:16])C.Cl>O1CCCC1.C(OCC)(=O)C.O.ClCCl.CO>[CH3:35][C:18]1[N:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[C:24]([C:33]#[N:34])[CH:23]=2)[S:21][C:17]=1[C:15]([OH:16])=[O:14]
Reactant: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(-c2ccc(OCC(C)C)c(C#N)c2)sc1C(=O)O
Temperature: 60 °C

Procedure:
Aqueous barium hydroxide octahydrate solution (prepared by dissolving 55 g, 0.174 mol of barium hydroxide octahydrate in 350 mL water) was added to a solution of ethyl-2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole carboxylate (100 g, 0.29 mol) in tetrahydrofuran (1000 mL) and denatured spirit (300 mL). The reaction mixture was stirred at a temperature of about 60° C. for about 90 minutes to about 120 minutes. After completion of reaction, the mixture was cooled to a temperature of about 45° C. and diluted with ethyl acetate and water. The pH of the reaction mixture was adjusted to 0.5-0.8 with 6N HCl at about 35° C. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was treated with activated carbon (10 g) and filtered through hyflobed. The hyflobed was washed with ethyl acetate. The combined filtrate was concentrated at a temperature of about 45° C. under reduced pressure. The residue thus obtained was dissolved in a mixture of dichloromethane (400 mL) and methanol (1000 mL) and the solution was cooled to about 0° C., stirred for about 1 hour. The solid thus obtained was filtered, washed with a precooled mixture of methanol and methylene chloride, dried under reduced pressure to give febuxostat. (Yield: 81 g, 88%)
Reaction SMILES: Cl.[NH2:2][CH:3]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[Cl:36])[CH2:4][NH:5][C:6](=[O:28])[CH2:7][N:8]1[C:12](=[O:13])[N:11]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[N:9]1.[O-:37][C:38]#[N:39].[K+]>>[C:38]([NH:2][CH:3]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[Cl:36])[CH2:4][NH:5][C:6](=[O:28])[CH2:7][N:8]1[C:12](=[O:13])[N:11]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:17])[F:19])[C:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[N:9]1)(=[O:37])[NH2:39]
Reactant: NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(Cl)c1Cl
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Product: NC(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(Cl)c1Cl

Procedure:
Analogously to Example 23, 30 mg (51 μmol) of the compound of Example 55A and potassium cyanate gave 19 mg (63% of theory) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.Cl.[CH3:14][NH:15][O:16][CH3:17].CN(C)CCCN=C=NCC.N1C=CC=CC=1>O1CCCC1>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:12]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 107.3 %

Procedure:
In a round-bottomed flask, 5.0 g of indole-6-carboxylic acid, 3.3 g of N,O-dimethylhydroxylamine hydrochloride, 11.9 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 10 ml of pyridine are placed in 150 ml of tetrahydrofuran. The mixture is stirred at ambient temperature for 40 h. The mixture is concentrated, and the residue is taken up in 150 ml of ethyl acetate and 50 ml of water. The organic phase is washed with 50 ml of a 1N solution of sodium hydroxide and 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. 6.8 g of compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:22][CH:23]=[C:24](C)[CH3:25])[CH:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=2)=[CH:4][C:3]=1[O:27][CH3:28].F[C:30](F)(F)C(O)=O>O=[V].Cl.Cl.Cl.C(Cl)Cl>[OH:1][C:2]1[C:11]2=[C:10]3[CH:9]([CH2:12][C:13]4[CH:14]=[C:15]([OH:21])[C:16]([O:19][CH3:20])=[CH:17][C:18]=42)[N:8]([CH2:22][C:23]([CH3:30])=[CH:24][CH3:25])[CH2:7][CH2:6][C:5]3=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CC2c3cc(O)c(OC)cc3CCN2CC=C(C)C)cc1O
Agent: O=[V]
Agent: Cl
Solvent: ClCCl
Product: CC=C(C)CN1CCc2cc(OC)c(O)c3c2C1Cc1cc(O)c(OC)cc1-3

Procedure:
6.49 g. (16.9 mmol) (-)-7-Hydroxy-1-(3-hydroxy-4-methoxybenzyl)-6-methoxy-2-(3-methylbut-2-enyl)-1,2,3,4-tetrahydroisoquinoline are then reacted in 55 ml. trifluoroacetic acid and 55 ml. anhydrous methylene chloride with 2.3 ml. (4.23 g., 24.4 mmol) vanadium oxytrichloride at -10° C. in a manner analogous to that described in Example 1. The (+)-5,6,6a,7-tetrahydro-1,9-dihydroxy-2,10-dimethoxy-6-(2-methylbut-2-enyl)-4H-dibenzo(de,g)quinoline obtained upon working up can, without further purification, be used in the subsequent methylation.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10](OC(=O)C2C=CC=CC=2)[CH2:9][N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:7]1)=[O:5])[CH3:2].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC1OC(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1=CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of the crude 4-benzoyloxy-pyrrolidine-1,3-dicarboxylic acid 1-tert.-butylester 3-ethylester from the benzoylation described above in 75 ml dry toluene was added 4.11 g (27 mmol) DBU. The dark, heterogeneous mixture was stirred at room temperature for 16 h. After this time no starting material was detectable by TLC and GC analysis. The mixture was filtered through a short column of silica (elution with petrolether/ethyl acetate 1:1) and evaporated. Bulb-to-bulb distillation of the residual slightly yellow oil gave 4.16 g (86%) 2,5-dihydro-pyrrole-1,3-dicarboxylic acid 1-tert.-butylester 3-ethyl ester as a colorless oil b.p. 110° C./0.2 mbar, which slowly solidified to a waxy mass on standing in the freezer.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:8]2[CH2:27][C:28]([OH:30])=[O:29])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([CH3:19])([CH3:17])[CH3:18])=[CH:13][CH:14]=3)[C:9]([S:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:41])=[C:8]2[CH2:27][C:28]([OH:30])=[O:29])=[CH:31][CH:32]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1ccc2c(c1)c(Sc1ccccc1)c(CC(=O)O)n2Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)c1ccc2c(c1)c(S(=O)c1ccccc1)c(CC(=O)O)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (-10°) solution of 1-(p-chlorobenzyl)-5-(t-butyl)-3-phenylthioindole-2-acetic acid (67 mg) from Example 12 in 1.45 mL dry methylene chloride, under nitrogen, was added 34 mg of m-chloroperbenzoic acid. The reaction mixture was stirred at -10° for 1 h and room temperature for 30 min. The reaction mixture was then diluted with ether and washed with water (2×) and brine and dried over MgSO4. Filtration and concentration gave a solid which was passed through a short column of silica gel. Elution with ethyl acetate gave the title compound, mp 160°-161° (dec.).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:7]=[CH:6][N:5]=[CH:4]1.[OH-].[Na+].[IH:15].CS[C:18]1[C:26]2[CH:27]=[CH:28][CH:29]=[C:24]3[C:25]=2[C:20](=[CH:21][CH:22]=[CH:23]3)[N:19]=1>C(O)C>[IH:15].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:18]2[C:26]3[CH:27]=[CH:28][CH:29]=[C:24]4[C:25]=3[C:20](=[CH:21][CH:22]=[CH:23]4)[N:19]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CSC1=Nc2cccc3cccc1c23
Reactant: NCCCCn1ccnc1
Agent: Cl
Agent: I
Agent: [Na+]
Solvent: CCO
Product: c1cc2c3c(cccc3c1)C(NCCCCn1ccnc1)=N2
Temperature: -10 °C

Procedure:
A 2.2 g portion 4(1H-imidazol-1-yl)butanamine dihydrochloride and 2 ml of 10N sodium hydroxide in 200 ml of ethanol was stirred for 10 minutes and then treated with 3.2 g of 2-(methylthio)benz[cd]indole hydroiodide. This mixture was heated at reflux for 16 hours and then cooled to -10° C. The mixture was reheated to boiling, clarified while hot and the filtrate cooled to -10° C. The solid was collected, washed with ethanol, then ether and dried at 60° C. in vacuo, giving 2.0 g of the desired product, mp 144°-147° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:32])=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1>[O:32]=[C:9]1[C:10]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:31])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:18]=3)[NH:14][C:11]=2[CH2:12][CH2:13][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(-c3ccnc(NC(=O)c4ccccc4)n3)cc2C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(Nc1nccc(-c2cc3c([nH]2)CCNC3=O)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2-Benzoylamino-pyrimidin-4-yl)-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester in THF was added HCl 4N in dioxane and the reaction was left under stirring at room temperature for 2h. Solvent evaporation gave the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[CH:4][N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][N:3]=1
Reactant: Cc1ccc(C#C[Si](C)(C)C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C)nc1
Reaction time: 2 h
Yield: 74.5 %

Procedure:
A mixture of 654 mg (3.45 mmol) of 2-methyl-5-trimethylsilanylethynyl-pyridine and 8 mL of 1 M TBAF in THF was stirred for 2 h. The mixture was concentrated and chromatographed (10–50% EtOAc in hexanes) to provide 301 mg of 2-methyl-5-ethynyl pyridine.
Reaction SMILES: [CH:1]1([N:5]([CH3:26])[C:6](=[O:25])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([Cl:20])=[CH:18][C:17]([CH:21]=O)=[CH:16][C:15]=3[Cl:23])[CH:10]=[CH:9][C:8]=2[OH:24])[CH2:4][CH2:3][CH2:2]1.[CH2:27]1[S:33][C:31](=[O:32])[NH:30][C:28]1=[O:29].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH:1]1([N:5]([CH3:26])[C:6](=[O:25])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([Cl:20])=[CH:18][C:17]([CH:21]=[C:27]4[S:33][C:31](=[O:32])[NH:30][C:28]4=[O:29])=[CH:16][C:15]=3[Cl:23])[CH:10]=[CH:9][C:8]=2[OH:24])[CH2:2][CH2:3][CH2:4]1
Reactant: CN(C(=O)c1cc(Oc2c(Cl)cc(C=O)cc2Cl)ccc1O)C1CCC1
Reactant: O=C1CSC(=O)N1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CN(C(=O)c1cc(Oc2c(Cl)cc(C=C3SC(=O)NC3=O)cc2Cl)ccc1O)C1CCC1
Yield: 75 %

Procedure:
To a solution of the title compound of Step H (40 mg, 0.10 mmol) and thiazolidinedione (13 mg, 0.11 mmol) in toluene (2 ml) was added acetic acid (1.5 μl, 0.025 mmol), piperidine (2.5 μl, 0.025 mmol) and powdered 3 A° molecular sieves. The reaction mixture was heated to reflux and stirred at reflux for about 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic layer was washed with 1N HCl (2×10 ml), brine (10 ml), dried, filtered, and concentrated. The crude product was purified by preparative TLC (7% MeOH in dichloromethane) to afford the title compound (37 mg). MS (APCl−) Calc: 492.0, found: 491.0 (M−1).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][NH2:34]>>[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][NH:34][C:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)=[O:27]
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Reactant: NCC1CCCO1
Product: CN(C(=O)Oc1ccc(C(=O)NCC2CCCO2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and C-(tetrahydro-furan-2-yl)methylamine. The crude product was used without further purification (86%, oil). HPLC-MS: m/z=(M+1); Rt: min.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][O:28][CH2:29][CH2:30][C:31](O)=[O:32]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][CH2:29][O:28][CH3:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: COCCC(=O)O
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, white solid (51 mg, 50%), MS (ISP) m/z=413.5 [(M+H)+], mp 136° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 3-methoxy-propionic acid.
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25](C1CCCCN1CCCN)C>>[CH3:25][CH:12]1[CH2:11][CH2:10][C:9]2[N:8]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:23][CH:24]=3)[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:15][C:14]=2[CH2:13]1
Reactant: O=C(O)c1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1
Reactant: CCC1CCCCN1CCCN
Product: CC1CCc2c(cc(-c3ccccc3)n2-c2ccc(C(=O)O)cc2)C1
Yield: 62 %

Procedure:
Following the general methods as outlined under Example 1, starting from 4-(2-phenyl-4,5,6,7-tetrahydro-1H-indol-1-yl)benzoic acid (Intermediate 7) and 3-(2-ethylpiperidin-1-yl)propan-1-amine, the title compound (8) was isolated as a beige solid in 62% yield (94% purity by HPLC). MS(ESI+): 470.8; MS(ESI−): 468.7.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10](=[O:18])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]#[CH:27].O>C(#N)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]([O:18][CH2:27][C:26]#[CH:25])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCBr
Reactant: CCOC(=O)c1cc(=O)[nH]n1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C#CCOc1cc(C(=O)OCC)n(-c2ncccc2Cl)n1
Yield: 95 %

Procedure:
To a solution of ethyl 1-(3-chloro-2-pyridinyl)-2,3-dihydro-3-oxo-1H-pyrazole-5-carboxyate (i.e. the product of Example 1, Step B) (0.5 g, 1.9 mmol) in acetonitrile (20 mL) was added potassium carbonate (0.6 g, 3.8 mmol) and propargyl bromide (1.0 mL, 9.4 mmol). The reaction mixture was heated at reflux for 15 minutes. The mixture was then cooled and treated with water and extracted with a 1:1 mixture of diethyl ether and ethyl acetate. The organic extracts were then washed with a saturated solution of sodium chloride and dried over magnesium sulfate. The extract was concentrated to dryness on a rotary evaporator and chromatographed on silica gel using hexane/ethyl acetate (7:3) as eluent to isolate the title compound (0.45 g, 95% purity) as a red oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][CH:6]=1.C1C(=O)N([I:19])C(=O)C1>CN(C)C=O>[I:19][C:6]1[NH:5][N:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]=1[CH3:1]
Reactant: CCOC(=O)c1n[nH]cc1C
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CCOC(=O)c1n[nH]c(I)c1C
Temperature: 50 °C
Reaction time: 6 h
Yield: 73.4 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of ethyl 4-methyl-1H-pyrazole-3-carboxylate (600 mg, 3.89 mmol) in N,N-dimethylformamide (20 mL). NIS (2.2 g, 9.78 mmol) was added and the resulting mixture was stirred for 6 h at 50° C., then quenched with water (10 mL). The mixture was extracted with ethyl acetate (3×40 mL) and the combined organic extracts were washed with aqueous Na2S2O3 (sat., 2×30 mL) and brine (2×20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by a silica gel chromatography with ethyl acetate/petroleum ether (1:10) as eluent to obtain the title compound as a white solid (800 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CN2CCNCC2)c1
Yield: 61.2 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(piperazin-1-ylmethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol) and piperazine (0.043 g; 0.5 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 10 minutes. Flash chromatography on silica gel (eluent 20 to 50% methanol in dichloromethane) furnished 0.035 g (61%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:6](=[O:7])S[C:4](=[O:8])[C:3]=1[F:9].FC1(F)SC(=[O:16])C(F)=C1F.FC1(F)SC(F)(F)C(F)=C1F>>[F:1][C:2]1=[C:3]([F:9])[C:4]([O:7][C:6]1=[O:16])=[O:8]
Reactant: O=C1SC(F)(F)C(F)=C1F
Reactant: O=C1SC(=O)C(F)=C1F
Agent: FC1=C(F)C(F)(F)SC1(F)F
Product: O=C1OC(=O)C(F)=C1F

Procedure:
Both difluoro-2,5-dihydrothiophene-2,5-dione and tetrafluoro-2,5-dihydrothiophene-2-one are made by the reaction of SO3 with hexafluoro-2,5-dihyrothiophene (Example 3, infra). Thus reaction of the hexafluoro-2,5-dihydrothiophene with SO3 under reaction conditions less vigorous than those reported herein that produce difluoromaleic anhydride will produce difluoro-2,5-dihydrothiophene-2,5-dione and/or tetrafluoro-2,5-dihydrothiophene-2-one. Less vigorous conditions include one or more of lower reaction temperatures, shorter reaction times, lesser amounts of SO3 and the absence of catalysts. Since difluoro-2,5-dihydrothiophene-2,5-dione and tetrafluoro-2,5-dihydrothiophene-2-one are both intermediates in the reaction of hexafluoro-2,5-dihydrothiophene with SO3 to produce difluoromaleic anhydride, reaction of either difluoro-2,5-dihydrothiophene-2,5-dione or tetrafluoro-2,5-dihydrothiophene-2-one with SO3 under conditions described herein will yield difluoromaleic anhydride.