Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+].O>CN(C=O)C>[C:13]([O:12][C:10](=[O:11])[NH:9][CH2:8][CH2:7][CH2:6][N:17]=[N+:18]=[N-:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCN=[N+]=[N-]
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To a solution of compound 5 (12.56 g: 60 mmol) in dry DMF (150 mL) was added in small portions NaN3 (11.7 g: 180 mmol) with stirring over 30 min. The resulting solution was heated to 50° C. for 1 h and then stirred overnight at room temperature. Water (50 mL) was added with stirring, the solvent was removed, and the residue was extracted with ethyl acetate (2×175 mL). The combined organic layers were washed sequentially with water (2×50 mL) and brine (2×50 mL). The organic extract was dried over anhydrous sodium sulfate and evaporated to give compound 6 as a light yellow oil (10.54 g; 87% yield). 1H NMR (CDCl3-d6) δ 4.9 (s, 1H), 3.3 (m, 2H), 3.2 (m, 2H), 1.7 (m, 2H), 1.4 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]2[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:3].C1COCC1.[H-].[Na+].Cl[CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>O>[CH3:3][CH:2]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]2[C:11]3=[N:16][S:29](=[O:31])(=[O:30])[CH2:28][CH2:27][N:12]3[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(C)c1ccc(OCc2cccnc2N)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc(OCC2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 1 h
Yield: 36.8 %

Procedure:
A mixture of 3-{[4-(1-methylethyl)phenoxy]methyl}pyridin-2-amine (600 mg) and dehydrated THF (10 mL) was added to a mixture of sodium hydride (60%, 495 mg), 2-chloroethanesulfonyl chloride (1211 mg) and dehydrated THF (10 ml) at room temperature. The reaction mixture was stirred for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate) to give the title compound (303 mg) as a white solid. The obtained solid was crystallized from THF-diisopropyl ether to give a white solid.
Reaction SMILES: [ClH:1].[Cl-].O[CH2:4][CH2:5][CH2:6][N:7]([CH2:9][CH2:10][CH2:11][N+:12]([CH3:15])([CH3:14])[CH3:13])[CH3:8].S(Cl)([Cl:18])=O>>[ClH:18].[Cl-:1].[Cl:18][CH2:4][CH2:5][CH2:6][N:7]([CH2:9][CH2:10][CH2:11][N+:12]([CH3:15])([CH3:14])[CH3:13])[CH3:8]
Reactant: CN(CCCO)CCC[N+](C)(C)C
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: [Cl-]
Product: CN(CCCCl)CCC[N+](C)(C)C

Procedure:
The process, according to claim 1, which comprises reacting N,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide with oxetane in aqueous solution at a temperature of about 100° C., thereby forming 3[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminium bromide, reacting the latter compound with aqueous hydrochloric acid to form 3-[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminium chloride hydrochloride, and reacting the said 3-[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminium chloride hydrochloride with thionyl chloride to form 3-[N'-(3-chloropropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminium chloride hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([N:8]2[C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([NH2:25])[CH:19]=3)([OH:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:26])[CH:5]=[CH:6][CH:7]=1.[CH3:28][O:29][C:30](=[O:44])[C:31]([NH:33]/[C:34](=N/C(=O)C(OC)=O)/SC)=[O:32].C(#N)C.O>C(O)CCC>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([N:8]2[C:9](=[O:26])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2([C:18]2[CH:23]=[CH:22][C:21]3[N:24]=[C:34]([NH:33][C:31](=[O:32])[C:30]([O:29][CH3:28])=[O:44])[NH:25][C:20]=3[CH:19]=2)[OH:17])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C2(O)c3ccccc3C(=O)N2c2cccc(Cl)c2F)cc1N
Reactant: COC(=O)C(=O)/N=C(/NC(=O)C(=O)OC)SC
Solvent: O
Solvent: CC#N
Solvent: CCCCO
Product: COC(=O)C(=O)Nc1nc2ccc(C3(O)c4ccccc4C(=O)N3c3cccc(Cl)c3F)cc2[nH]1
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of 2-(3-chloro-2-fluorophenyl)-3-(3,4-diaminophenyl)-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (0.10 g, 0.26 mmol) and methyl {[(1Z)-{[(methyloxy)(oxo)acetyl]amino}(methylthio)methylidene]amino}(oxo)acetate (67 mg, 0.26 mmol) in n-butanol (2.0 mL) was heated to 80° C. for 5 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated. The resulting crude product was purified by reverse phase preparative HPLC (CH3CN/25 mM aqueous ammonium acetate). The fractions were collected, and the solvent was concentrated. The aqueous residue was partitioned with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration resulted in an oily residue, which was lyophillized from a mixture of acetonitrile-water (5.0 mL) to give methyl ({6-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}amino)(oxo)acetate (48 mg, 38% yield. 1H NMR (400 MHz, DMSO-d6): 11.86 (d, 1H), 7.87 (d, 1H), 7.65 (m, 2H), 7.53 (t, 1H), 7.33 (t, 1H), 7.30 (d, 1H), 7.25 (s, 1H), 7.20 (t, 1H), 6.99 (d, 1H), 6.91 (d, 1H), 3.57 (s, 3H); 13C NMR (400 MHz, DMSO-d6): 67.0, 92.5, 110.0, 113.8, 114.1, 115.7, 120.8, 121.4, 123.9, 125.3, 125.6, 126.0, 126.2, 129.5, 129.8, 130.5, 130.7, 134.3, 134.8, 150.3, 155.7, 155.8, 163.5, 166.2; MS (EI) for C24H16ClFN4O4: 436 (M-CO2CH3).
Reaction SMILES: [CH:1]([O-:3])=[O:2].[NH4+].Cl[C:6]1[N:11]=[C:10]([C:12]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:13])[CH:9]=[C:8]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:7]=1>O.[Pd]>[CH:1]([O-:3])=[O:2].[NH4+:7].[CH:22]1([O:21][C:8]2[N:7]=[CH:6][N:11]=[C:10]([C:12]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:13])[CH:9]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: O=C(OC1CCCCC1)c1cc(OC2CCCCC2)nc(Cl)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: O=C(OC1CCCCC1)c1cc(OC2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of ammonium formate was prepared by dissolving ammonium formate (13.40 g; 212 mmol) in water (30 ml). A suspension of palladium on calcium carbonate (754 mg; 0.71 mmol) in IPrOH (144 ml) and was treated with 7.5 mL of ammonium formate solution and with cyclohexyl 2-chloro-6-(cyclohexyloxy)pyrimidine-4-carboxylate (4.80 g; 14.2 mmol). After 10 min, a second aliquot of 7.5 mL of ammonium formate solution was added and the mixture was stirred at room temperature for 24 h. The mixture was filtered through a pad of celite and rinsed with MeOH. Solvents were concentrated under vacuum. The crude was dissolved in DCM and washed with water and brine. Organic phase was dried over MgSO4, filtered off and concentrated under vacuum to afford the title compound as an orange solid without further purification.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@:13]([CH2:23][OH:24])([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:10]1[OH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@:13]([CH2:23][O:24][S:41]([C:38]2[CH:39]=[CH:40][C:35]([CH3:45])=[CH:36][CH:37]=2)(=[O:43])=[O:42])([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:10]1[O:34][S:41]([C:38]1[CH:39]=[CH:40][C:35]([CH3:45])=[CH:36][CH:37]=1)(=[O:43])=[O:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cn([C@@H]2O[C@](CO)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@]2(COCc3ccccc3)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]2OCc2ccccc2)cc1
Yield: 79.4 %

Procedure:
A solution of 1-(3,5-di-O-benzyl-4-C-(hydroxymethyl)-β-D-ribofuranosyl)thymine 35 (1.48 g, 3.16 mmol), DMAP (1.344 g, 0.011 mol) and p-toluenesulphonyl chloride (1.45 g, 7.6 mmol) in dichloromethane (20 ml) was stirred for 3 h at room temperature. The reaction mixture was diluted with dichloromethane (30 ml) and washed with saturated aqueous solutions of sodium hydrogen carbonate (3×20 ml) and sodium chloride (2×25 ml). The organic phase was dried (Na2SO4), filtered and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography using methanol:dichloromethane (1:99, v/v) as eluent to give nucleoside 72 (1.95 g, 80%) as a white solid material. FAB-MS m/e 776. δC (CDCl3) 162.9, 149.8 (C-2, C-4), 145.8, 145.2 (2×Ts), 136.9, 136.8 (2×Bn), 134.3 (C-6), 132.1, 132.0, 130.0, 129.9, 129.0 128.9, 128.4, 128.3, 128.2, 128.0, 127.7 (2×Ts, 2×Bn), 111.2 (C-5), 85.3, 84.0 (C-1′, C-4′), 78.9, 78.3, 75.2, 74.3, 72.7, 69.1 (C-2′, C-3′, C-5′, C-1″, 2×Bn), 21.7 (2×CH3), 11.9 (CH3). Anal. Calcd. for C39H40N2S2O11: C, 60.30; H, 5.19; N, 3.61. Found: C, 59.95; H, 5.11, N 3.81.
Reaction SMILES: C1CCCCC1.C([N-]C(C)C)(C)C.[Li+].[C:15]([O:26][CH:27]([CH3:29])[CH3:28])(=[O:25])[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20].[CH:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>O1CCCC1>[OH:37][CH:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:18]([C:19]([O:21][CH:22]([CH3:23])[CH3:24])=[O:20])[CH2:17][CH2:16][C:15]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25]
Reactant: CC(C)OC(=O)CCCC(=O)OC(C)C
Reactant: O=Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)OC(=O)CCC(C(=O)OC(C)C)C(O)c1ccccc1
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
38 ml of a 1.5M lithium diisopropylamide cyclohexane solution was dissolved in 400 ml of tetrahydrofuran, and 20 ml of a tetrahydrofuran solution containing 10.3 g of diisopropyl glutarate was dropwise added at -78° C. in a nitrogen atmosphere. After stirring at the same temperature for 30 minutes, 10 ml of a tetrahydrofuran solution containing 3.9 g of benzaldehyde was dropwise added thereto, followed by stirring at -78° C. for 1.5 hours. 2N hydrochloric acid was added to the reaction solution, and the temperature was brought to room temperature. Then, the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1→3/1) to obtain 6.14 g of the above-identified compound as a colorless oily substance.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=[O:31].O>C(#N)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:30](=[O:31])[CH2:29][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:33][CH:34]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2CC(=O)c2ccc(Cl)cc2)CC1
Yield: 13.1 %

Procedure:
K2CO3 (0.129 mol) was suspended in a solution of ethyl 4-(1H-benzimidazol-2-yl-amino)-1-piperidinecarboxylate (0.0347 mol) and 2-bromo-1-(4-chlorophenyl)ethanone (0.0647 mol) in acetonitrile (150 ml). The mixture was stirred and refluxed for 8 hours, then cooled, poured out into H2O and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97.5/2.5/0.1). The pure fractions were collected and the solvent was evaporated. Part of this fraction (3 g) was taken up in 2-propanone and diethyl ether. The precipitate was filtered off and dried, yielding 2 g of ethyl 4-[[1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (interm. 1).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]#N)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:13][C:14]1[NH:15][CH:16]=[CH:17][N:18]=1.[OH-:19].[Na+].[OH2:21]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]([OH:21])=[O:19])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:13][C:14]1[NH:15][CH:16]=[CH:17][N:18]=1
Reactant: N#Cc1ccc2oc(Cc3ncc[nH]3)c(Cl)c2c1
Reactant: O
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1ccc2oc(Cc3ncc[nH]3)c(Cl)c2c1

Procedure:
A solution of 3-chloro-2-(1-imidazolylmethyl)benzofuran-5-carbonitrile (0.35 g) in concentrated sulphuric acid (5 ml) and water (5 ml) was heated under reflux for 1 hour and then cooled. The solution was diluted with 5 ml of water and made just alkaline by the addition of 5N sodium hydroxide solution. The solution was filtered and made acidic by the addition of acetic acid. The solid which crystallised out on standing was filtered off, washed with water and dried to give 3-chloro-2-(1-imidazolylmethyl)benzofuran-5-carboxylic acid (0.20 g), m.p. 248°-250°.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]3[C:11]([SH:14])=[N:12][N:13]=[C:6]3[C:5]=2[CH:4]=[N:3]1.[K].[CH3:16]I>CN(C)C=O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]3[C:11]([S:14][CH3:16])=[N:12][N:13]=[C:6]3[C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c1ncn1c(S)nnc21
Reactant: CI
Agent: [K]
Solvent: CN(C)C=O
Product: CSc1nnc2c3cnn(C)c3ncn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3 g. of 7-methyl-3mercapto-7H-pyrazolo[4,3-e][1,2,4]-triazolo[4,3-c]pyrimidine, potassium salt, in 25 ml. of dimethylformamide, 2.1 g. of methyl iodide are added and the mixture is stirred for 1 hour at room temperature. The reaction mixture is then poured into 200 ml. of water and the product, 7-methyl-3-methylthio-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]-pyrimidine, is filtered under suction, crystallized from dimethylformamide and obtained as yellowish crystals, m.p. 204°-206°.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[K+].Cl[CH2:15][CH:16]([OH:20])[CH2:17][CH2:18][Cl:19]>O.C(O)(C)C>[Cl:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: OC(CCl)CCCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: OC(CCCl)COc1cccc(C(F)(F)F)c1
Temperature: 65 °C

Procedure:
To a mixture of 0.5 mole (75 g) of m-trifluoromethylphenol, 1 mole (56 g) of potassium hydroxide, 100 ml of water and 400 ml of isopropanol was added 0.6 mole (84 g) of 1,4-dichloro-2-butanol with stirring at temperature below 55° C. The resulting reaction mixture was heated at 65° C. for 20 hr, mixed with 2 liters of water, and extracted with 400 ml of isopropyl ether. The ether extract was washed with 0.5 N sodium hydroxide and then with water, dried over sodium sulfate and distilled under reduced pressure. The distillate which was collected at 120°-124° C./0.01 mm solidified at room temperature and melted at 50°-52° C.
Reaction SMILES: F[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][NH2:10]>>[I:8][C:7]1[C:2]([NH:10][CH3:9])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ncccc1I
Reactant: CN
Product: CNc1ncccc1I
Temperature: 25 °C
Yield: 95 %

Procedure:
A 1 L round bottom flask was charged with 2-fluoro-3-iodopyridine (27.0 g, 121 mmol) and 500 mL of 40% aqueous solution of methylamine. This was stirred at reflux for 4 h before being cooled to ambient temperature. The product was extracted with dichloromethane. Evaporation of the dichloromethane gave 3-iodo-N-methylpyridin-2-amine (26.8 g, 95% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:14]([CH3:38])[N:13]=2)=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:44]1[S:45][CH:46]=[CH:47][CH:48]=1)CCC>O1CCOCC1.C(OCC)(=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.Cl[Pd]Cl>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([S:25]([NH:24][C:15]2[N:14]([CH3:38])[N:13]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:4]=[CH:3][C:2]([C:44]4[S:45][CH:46]=[CH:47][CH:48]=4)=[CH:7][N:6]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:27])=[O:26])=[CH:29][CH:30]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(OCCOc3ncc(-c4cccs4)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 16 h
Yield: 67.2 %

Procedure:
To N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 3) (111 mg) in 1,4-dioxane (5 ml) at room temperature was added 2-(tributylstannyl)thiophene (103 mg) and bis(triphenylphosphine)palladium (II) chloride (6.5 mg) the mixture was stirred and heated to reflux for 3 hrs followed by 16 hrs. at room temperature. To the mixture was added bis(triphenylphosphine) palladium (II) chloride (6.5 mg) and the mixture was heated to reflux for a further 4 hrs. The reaction was diluted with ethyl acetate (100 ml), washed with a 10% solution of potassium fluoride in water (100 ml) and brine (100 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with ethyl acetate:hexane (1:1) to yield the title compound as a white solid (75 mg).
Reaction SMILES: C([NH:4][CH2:5][C:6]1O[CH:8]=[CH:9][CH:10]=1)(=O)C.[CH3:11][O:12][C:13]1([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[CH:17]=[CH:16][CH:15]([O:18][CH3:19])[O:14]1>C(O)(=O)C>[CH3:11][O:12][C:13]1([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[O:14]1.[NH2:4][C:5]1[CH:6]=[CH:10][CH:9]=[CH:8][CH:11]=1
Reactant: CC(=O)NCc1ccco1
Reactant: COC1C=CC(CNC(C)=O)(OC)O1
Solvent: CC(=O)O
Product: COC1CCC(CNC(C)=O)(OC)O1
Product: Nc1ccccc1

Procedure:
Clauson-Kaas and Tyle [Acta Chem. Scand. 6, 667 (1952)] described the methoxylation of 2(acetamidomethyl)-furan (Formula II) to 2,5-dimethoxy-2(acetamidomethyl)-2,5-dihydrofuran (Formula III). This compound was hydrogenated with catalyst to give 2,5-dimethoxy-2(acetamidomethyl)-tetrahydrofuran (Formula IV), which with aniline in acetic acid medium gave 1-phenyl-2-(acetamidomethyl)-pyrrole (Formula V), with a mean yield of 81% according to the following scheme: ##STR4##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].C1[CH:35]=[CH:36][C:37]2N(O)N=[N:40][C:38]=2C=1.CCN=C=NCCCN(C)C.[CH:55]1([N:58]2CCN[CH2:60][CH2:59]2)C[CH2:56]1>CN(C=O)C>[CH:37]1([CH2:38][N:40]2[CH2:60][CH2:59][N:58]([C:30]([C:26]3[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]4\[C:17](=[O:22])[NH:18][C:19]5[C:15]\4=[CH:14][C:13]([S:10]([CH2:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=5)[NH:28][C:27]=3[CH3:29])=[O:31])[CH2:55][CH2:56]2)[CH2:36][CH2:35]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: C1CN(C2CC2)CCN1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (200 mg, 0.4 mmol), HOBt (54 mg, 1 eq.) and EDAC (154 mg, 2 eq.) in DMF (1.5 mL) was stirred at rt for 30 mins. To the mixture was added 1-cyclopropyl-piperazine (112 mg, 2 eq.) in DMF (1.5 mL). After stirring at rt for overnight, the precipitate was collected by vacuum filtration, washed with water, sodium bicarbonate and water and dried to give 227 mg (90%) of the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][Br:10])[CH:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1cc(C)cc(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)cc(CBr)c1
Temperature: 25 °C
Yield: 249.8 %

Procedure:
To a solution of 1-bromo-3,5-dimethylbenzene (25.0 g, 135.0 mmol) in CCl4 (150 mL), 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (14.5 g, 54.0 mmol) and dibenzoyl peroxide (BPO) (0.2 g) were added and the mixture was refluxed for 7 h. After the reaction was cooled to room temperature, the precipitate was filtered though Celite, and then the solid was rinsed two times with pentane (50 mL). The combined filtrate was washed with water (50 mL), followed by saturated sodium bicarbonate (50 mL) and sodium thiosulfate (50 mL×2). The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded the compound 1-bromo-3-(bromomethyl)-5-methylbenzene (35.6 g, 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=1)([O-])=O.C1CCCCC=1>CCO.[Pd]>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=1
Reactant: O=C1NS(=O)(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Nc1ccc2c(c1)S(=O)(=O)NC2=O
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a solution of 6-nitro-1,1-dioxo-1,2-dihydro-1lambda*6*-benzo[d]isothiazol-3-one (11.4 g, 50.0 mmol) and cyclohexene (25.4 mL, 250 mmol) in EtOH (100 mL) was added 5% Pd—C (35 g) at about 0° C. The mixture was refluxed overnight with stirring and then cooled to rt, filtered through Celite® several times until the filtrate became clear. The filtrate was concentrated under reduced pressure. The material was dissolved in saturated aqueous NaHCO3 (200 mL), filtered and to the filtrate was added concentrated hydrochloric acid (pH=7). The precipitate was collected by filtration and washed with water (2×50 mL) to provide 6-amino-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (8.0 g, 68%): 1H NMR (DMSO-d6) δ: 7.61 (s, 1H), 7.59 (s, 1H), 6.95 (d, J=2.0 Hz, 2H), 6.91 (d, J=2.4 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H).