Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][C:24]([OH:26])=O)(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:52]([O:59][NH2:60])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>O1CCCC1>[C:53]1([CH2:52][O:59][NH:60][C:24](=[O:26])[CH2:23][NH:22][S:19]([C:16]2[CH:15]=[CH:14][C:13]([N:10]3[CH2:9][CH2:8][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:12][CH2:11]3)=[CH:18][CH:17]=2)(=[O:20])=[O:21])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: O=C(O)CNS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Reactant: NOCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(CNS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1)NOCc1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
In a separate flask containing a cool (5° C.), stirred solution of [4-(4-phenyl-piperidin-1-yl)-benzenesulfonylamino]-acetic acid (0.2307 g, 0.0006161 mol) and 1-hydroxy-benzo-1,2,3-triazole (0.0842 g, 0.000623 mol) in anhydrous tetrahydrofuran (10 mL) was added in one portion 1,3-dicyclohexylcarbodiimide (0.1449 g, 0.000702 mol). The mixture was stirred for 30 minutes at 5° C. then allowed to warm to room temperature. After 3 hours at room temperature, the mixture was added in one portion to the filtrate containing O-benzylhydroxylamine. The mixture was stirred at room temperature for 16 hours, then refluxed (74° C.) for 1 hour. The volatiles were rotary evaporated off, and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organics were combined, washed with 0.1 M NaOH, water, 0.1 M HCl, water, and saturated sodium chloride. The organic layer was dried (MgSO4) and rotary evaporated. The residue was dissolved in chloroform, and chromatographed on silica gel (34 g, 230-400 mesh) eluting with dichloromethane-acetone (9:1, 10×30 mL). Fractions containing product were rotary evaporated to give a white solid. The solid was dried in vacuo; yield 0.1448 g (49%), mp=163-165° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[CH:8]2)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[CH:8]2
Reactant: O=[N+]([O-])c1cnn2cnc3ccccc3c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cnn2cnc3ccccc3c12
Yield: 79.8 %

Procedure:
21.4 g (0.1 mole) of 1-nitropyrazolo[1,5-c]quinazoline are treated with hydrogen in ethanol and in the presence of palladium/carbon at room temperature and atmospheric pressure. When the hydrogen consumption ceases, the solution is filtered and evaporated. 14.7 g (80%) of 1-aminopyrazolo[1,5-c]quinazoline are obtained. M.p.: 168°-170° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[F:15][C:16]([F:43])([F:42])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>COCCOC>[F:15][C:16]([F:42])([F:43])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:38])=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A solution of 26.6 g. of diethyl malonate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then dded. The reaction mixture is refluxed for 4.5 hours, cooled, poured on ice, acidified, and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Addition of a small amount of ethanol to the residue gives a solid which is filtered and discarded. The ethanol filtrate is concentrated and the residue is recrystallized from ether to yield the product.
Reaction SMILES: [F:1][CH:2]([F:41])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:23]2[CH:24]=[N:25][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33](OC(F)(F)F)=[CH:32][CH:31]=3)=[CH:27][CH:28]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N+:19]([O-:22])=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].C1C=C(C([O-])=O)C([C:51]([O:53][O-])=[O:52])=CC=1.[Mg+2].[CH2:56](Cl)Cl>CO>[F:41][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:23]2[CH:24]=[N:25][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([C:51]([O:53][CH3:56])=[O:52])=[CH:34][CH:35]=3)=[CH:27][CH:28]=2)[CH2:15][C:16]2[CH:17]=[CH:18][N+:19]([O-:22])=[CH:20][CH:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:12])[F:13]
Reactant: ClCCl
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: [O-][n+]1ccc(CC(c2ccc(Oc3ccc(OC(F)(F)F)cc3)nc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Agent: [Mg+2]
Solvent: CO
Product: COC(=O)c1ccc(Oc2ccc(C(Cc3cc[n+]([O-])cc3)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
To a solution of 4-{2-[3,4-bis(difluoromethoxy)phenyl]-2-{6-[4-(methoxycarbonyl)phenoxy]-3-pyridyl}ethyl}pyridine from Example 1 (249 mg, 0.46 mmol) in a mixture of 5 mL of CH2Cl2 and 0.5 mL of MeOH, was added MMPP (171 mg, 0.28 mmol) in one portion. The mixture was stirred 24 h at room temperature, quenched with a saturated aqueous NaHCO3 solution and diluted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Gradient 20% to 40% EtOHiethyl acetate) to afford the title compound as a viscous oil (260 mg, 71%).
Reaction SMILES: F.F.F.C(N(CC)CC)C.C(N(CC)CC)C.[Si]([O:35][CH2:36][C@H:37]1[O:41][C@@H:40]([N:42]2[CH:49]=[C:48]([CH3:50])[C:46](=[O:47])[NH:45][C:43]2=[O:44])[C@H:39]([O:51][CH2:52][CH2:53][O:54][N:55]([CH3:57])[CH3:56])[C@@H:38]1[OH:58])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.C(Cl)Cl>[CH3:56][N:55]([CH3:57])[O:54][CH2:53][CH2:52][O:51][C@@H:39]1[C@H:38]([OH:58])[C@@H:37]([CH2:36][OH:35])[O:41][C@H:40]1[N:42]1[CH:49]=[C:48]([CH3:50])[C:46](=[O:47])[NH:45][C:43]1=[O:44]
Reactant: Cc1cn([C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Agent: F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
Triethylamine trihydrofluoride (3.91 mL, 24.0 mmol) was dissolved in dry THF and triethylamine (1.67 mL, 12 mmol, dry, kept over KOH). This mixture of triethylamine-2HF was then added to 5′-O-tert-butyldiphenylsilyl-2′-O-[N,N-dimethylaminooxyethyl]-5-methyluridine (1.40 g, 2.4 mmol) and stirred at room temperature for 24 hrs. Reaction was monitored by TLC (5% MEOH in CH2Cl2). Solvent was removed under vacuum and the residue placed on a flash column and eluted with 10% MeOH in CH2O2 to get 2′-O-(dimethylaminooxyethyl)-5-methyluridine (766 mg, 92.5%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6]([O:8][C:9]([C:11](=[CH:16][C:17]1[S:18][CH:19]=[C:20]([CH3:22])[CH:21]=1)[CH2:12][C:13](O)=O)=[O:10])[CH3:7]>C(OC(=O)C)(=O)C.ClCCl>[C:1]([O:4][C:13]1[C:21]2[C:20]([CH3:22])=[CH:19][S:18][C:17]=2[CH:16]=[C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C(=Cc1cc(C)cs1)CC(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC(C)=O)c2c(C)csc2c1
Yield: 58.3 %

Procedure:
Sodium acetate (90 g, 1.08 mol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(4-methylthien-2-yl)but-3-enoic acid (61 g, 0.24 mol) in 700 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 500 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 250 mL of dichloromethane. The combined solutions were washed by 350 mL of a saturated aqueous solution of NaHCO3 and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (250×150 mm) with hexane/ethyl acetate mixture (3:1) to give the desired product 38.5 g (140 mmol, 58%) as a solid.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:5]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1cccnc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A solution of N'-t-butyl-N-benzoylhydrazine (2.0 g) and nicotinoyl chloride hydrochloride in 20 ml of methylene chloride at 23° C. was treated dropwise with triethylamine (4 ml). The reaction mixture was stirred at 23° C. for 0.5 hours. Solids were removed by filtration. The filtrate was diluted with 10N HCl and ether. The layers were separated and the organic layer was washed with 10N HCl. The aqueous layer was neutralized with solid sodium bicarbonate and extracted with ether. The ether extracts were treated with charcoal and then dried with magnesium sulfate. Evaporation of solvents afforded a yellow oil which was chromatographed on silica gel using as eluant a mixture of 10% CH3OH, 40% CH2Cl2, 50% Et2O to afford N'-t-butyl-N-benzoyl-N'-nicotinoylhydrazine as a yellow foam: m.p. 60°-63° C.
Reaction SMILES: [C:1]1([N:7]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:29])C(=O)C1.O>C(Cl)Cl.C(#N)C>[Br:29][C:4]1[CH:3]=[CH:2][C:1]([N:7]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)=[CH:6][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1c2ccccc2c2ccccc2n1-c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: O=c1c2ccccc2c2ccccc2n1-c1ccc(Br)cc1
Reaction time: 4 h

Procedure:
6.0 g (22 2 mmol) of 5-phenyl-5H-phenanthridin-6-one are initially introduced in 150 ml of CH2Cl2. A solution of 4 g (22 5 mmol) of NBS in 100 ml of acetonitrile is subsequently added dropwise at −15° C. with exclusion of light, the mixture is allowed to come to room temperature and is stirred at this temperature for a further 4 h. 150 ml of water are subsequently added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot hexane and filtered off with suction. Yield: 7.4 g (21 mmol), 80% of theory, purity according to 1H-NMR about 96%.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]1[CH:11]=[C:12]([S:17](Cl)(=[O:19])=[O:18])[CH:13]=[CH:14][C:15]=1[Cl:16]>C(Cl)Cl.N1C=CC=CC=1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:17]([C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=1)(=[O:19])=[O:18]
Reactant: Nc1ccccc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1ccccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a solution of o-phenylenediamine (4 mmol) in DCM (20 mL) and pyridine (4 mL) at 0° C., 3,4-dichlorobenzenesulfonyl chloride (4.4 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with water (2×20 mL) and 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 760 mg of N-(2-amino-phenyl)-3,4-dichloro-benzenesulfonamide. LC: Tr 0.98 min, MS: 317.0 (M+1)+; 1H NMR (CDCl3, 400 MHz): δ 4.95 (bs, 2H), 6.45 (t, 1H), 6.11 (d, 1H), 6.72 (d, 1H), 6.92 (t, 1H), 7.59 (dd, 1H), 7.80 (d, 3H) ppm.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:23])OC1C=CC([N+]([O-])=O)=CC=1)[CH2:8]2.[NH:24]1[CH2:27][CH:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:25]1.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[CH:3]12[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]([CH2:10]3)[CH:2]1[NH:11][C:12]([N:24]1[CH2:27][CH:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:25]1)=[O:23])[CH2:9]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CN(C(=O)NC2C3CC4CC(C3)CC2C4)C1
Yield: 45.3 %

Procedure:
To a stirred solution of 4-nitrophenyl (2-adamantyl)carbamate (40 mg, 0.12 mmol) in CH2Cl2 (2 mL) was added tert-butyl azetidin-3-ylcarbamate (40 mg, 0.23 mmol), followed by i-Pr2NEt (0.05 mL, 0.28 mmol). The mixture was stirred over the weekend and applied to a 10-mL ChemElut cartridge prewetted with 5% aq HCl (6 mL). The cartridge was eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was applied to 2-g silica SPE cartridge which was eluted sequentially with 0, 25, 50, 75, 100 and 100% EtOAc in hexanes (15 mL of each) to afford six fractions. Fraction 4 was concentrated to provide tert-butyl 1-(2-adamantylcarbamoyl)azetidin-3-ylcarbamate (19 mg, 43%). LC-MS Method 1, tR=1.74 min, m/z=350, 294; 1H NMR (CDCl3) 1.45 (s, 9H), 1.60-1.95 (14H), 3.75 (m, 2H), 3.89 (m, 1H), 4.22 (m, 2H), 4.39 (d, 1H), 4.46 (1H), 5.06 (1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:29])[CH2:15][N:16]2[CH:19]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][C:17]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:29])[CH2:15][N:16]2[CH:19]([S:20]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:38])[CH2:18][C:17]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(CN1C(=O)CC1SCc1ccccc1)NCCCCCCc1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CN1C(=O)CC1S(=O)Cc1ccccc1)NCCCCCCc1ccccc1
Reaction time: 1 h
Yield: 20.3 %

Procedure:
A solution of N-(6-phenylhexyl)-4-benzylthio-2-oxoazetidin-1-yl acetamide (18.0 g, 43.8 mmol) in dichloromethane (500 ml) was cooled to -70° C. and a solution of m-chloroperbenzoic acid (6.7 g, 43.8 mmol) in dichloromethane (500 ml) added dropwise with stirring over 60 min. After a further 3 h at -60° C., the reaction mixture was shaken with a mixture of saturated aqueous sodium sulphite and saturated sodium hydrogen carbonate. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to a solid which was titurated with ether and filtered. Two recrystallisations from ethyl acetate gave (4R,SR/4S,SS) N-(6phenylhexyl)-4-benzylsulphinyl-2-oxoazetidin-1-yl acetamide (3.8 g, 20%) mp 138-140° C.
Reaction SMILES: [CH:1]1([CH3:15])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([O:10][CH2:11][C:12](O)=[O:13])[CH2:2]1.S(Cl)([Cl:18])=O>>[CH:1]1([CH3:15])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([O:10][CH2:11][C:12]([Cl:18])=[O:13])[CH2:2]1
Reactant: CC1CCC(C(C)C)C(OCC(=O)O)C1
Reactant: O=S(Cl)Cl
Product: CC1CCC(C(C)C)C(OCC(=O)Cl)C1
Yield: 107.4 %

Procedure:
0.771 g (3.6 mmol) of (-)-menthoxyacetic acid is stirred under reflux with 2.1 g of thionyl chloride for 4 to 5 h. The thionyl chloride is first removed from the solution by distillation under reduced pressure. 3 ml of dry benzene are then added in order to remove residual thionyl chloride by means of vacuum distillation. 0.9 g of the title compound is obtained.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[N:30][CH:29]=1>>[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:2]2[S:6][C:5]([NH:7][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=3[C:18]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[O:9])=[N:4][CH:3]=2)=[N:30][CH:29]=1
Reactant: COC(=O)c1ccc(S)nc1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: COC(=O)c1ccc(Sc2cnc(NC(=O)Nc3ccc(C)cc3C(=O)C3CCCC3)s2)nc1
Yield: 20.1 %

Procedure:
6-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-nicotinic acid methyl ester (100 mg, 20%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 6-mercapto-nicotinic acid methyl ester (340 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[CH:13]=[N:12][C:11]=2[CH:16]([CH3:18])[CH3:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Li])CCC.CCCCCC.CN(C)[CH:32]=[O:33].CCCCCC>O1CCCC1>[CH3:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH:32]=[O:33])=[N:12][C:11]=2[CH:16]([CH3:18])[CH3:17])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)ncn2C)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C)cc(Sc2c(C(C)C)nc(C=O)n2C)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
In 16 ml of dry tetrahydrofuran was dissolved 800 mg (3.1 mmol)of 5-(3,5-dimethylphenylthio)-4-isopropyl-1-methyl-1H-imidazole (X=Y=Me)(10). This solution was cooled to -78° C. and 2.2 ml of n-butyllithium-n-hexane (1.66 molar)was added dropwise under nitrogen. After 5 minutes, 680 mg (9.3 mmol) of dry N,N-dimethylformamide was added and the reaction was further conducted at the same temperature for 15 minutes. This reaction mixture was poured in ice-water and extracted with diethyl ether. The organic layer was washed with water and dried over sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:5)to provide 644 mg (yield 73%)of Compound I-6. mp 93 to 94° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1.C[O-].[Na+].[Cl-].[NH4+:13]>CO>[ClH:1].[Cl:1][C:2]1[S:6][C:5]([C:7]([NH2:13])=[NH:8])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)s1
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N=C(N)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 205.9 %

Procedure:
An 18-mL vial was charged with 5-chlorothiophene-2-carbonitrile (1 g, 7 mmol, 1 eq.), methanol (5 ml), Sodium methoxide (25 w % in methanol, 151 mg, 0.7 mmol, 0.1 eq.) was added. The mixture was stirred at rt for 3 hr. and then ammonium chloride (470 mg, 8.8 mmol, 1.25 eq.) was added. The resulting mixture was stirred at rt for 48 hr. The volatile material was removed under reduced pressure and the residue was treated with ether. The solid was collected by filtration and washed with ether, dried. The crude product (1.42 g) thus obtained contains inorganic salt and was forwarded to the next step without any further purification.
Reaction SMILES: [C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15]1[C:14]3[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=3[S:12][CH2:11][C:10]2=1)([CH3:4])([CH3:3])[CH3:2].[OH:27][O:28][S:29]([O-:31])=O.[K+]>CO.O.C1COCC1>[C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15]1[C:14]3[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=3[S:12](=[O:27])[CH2:11][C:10]2=1)([CH3:4])([CH3:3])[CH3:2].[C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]1[C:14]3[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=3[S:29](=[O:31])(=[O:28])[CH2:11][C:10]2=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cn1c2c(c3cc(O[Si](C)(C)C(C)(C)C)ccc31)CSc1ccccc1-2
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c3c(c2c1)CS(=O)(=O)c1ccccc1-3
Product: Cn1c2c(c3cc(O[Si](C)(C)C(C)(C)C)ccc31)CS(=O)c1ccccc1-2
Temperature: 25 °C

Procedure:
A mixture of 8-(tert-Butyl-dimethyl-silanyloxy)-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (490 mg, 1.286 mmol), as prepared in Example 45, and OXONE (791 mg, 1.286 mmol) in MeOH (2 mL), H2O (2 mL) and THF (2 mL) was stirred at 25° C. After the solvent was removed in vacuo, the residue was partitioned between saturated NaHCO3 aqueous solution and CH2Cl2, the aqueous layer was extracted with CH2Cl2 and the organic layers were dried and concentrated to yield crude product. The crude product was purified by chromatography to yield 8-(tert-butyl-dimethyl-silanyloxy)-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene 5-oxide as a white solid, 11-methyl-5-oxo-6,11-dihydro-5H-5I4-thia-11-aza-benzo[a]fluoren-8-ol as a pale solid, and 8-(tert-butyl-dimethyl-silanyloxy)-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene 5,5-dioxide as a white solid respectively.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:32])O[C:20](=[O:31])[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[CH:9]1)(=[O:3])[CH3:2].C[Si](C)(C)[NH:35][Si](C)(C)C.CO>C(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:32])[NH:35][C:20](=[O:31])[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[CH:9]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CC(=O)OCCCn1cc(C2=C(c3ccccc3[N+](=O)[O-])C(=O)OC2=O)c2ccccc21
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCCn1cc(C2=C(c3ccccc3[N+](=O)[O-])C(=O)NC2=O)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A solution of 0.411 g of 3-[1-(3-acetoxypropyl)-3-indolyl]-4-(2-nitrophenyl)furan-2,5-dione in 50 ml of chloroform was treated with a mixture of 1.53 g of 1,1,1,3,3,3-hexamethyldisilazane and 0.3 g of methanol and the mixture was heated at 60° C. for 1 hour. A further 1.53 g of hexamethyldisilazane and a further 0.3 g of methanol were added and the heating was continued overnight before adding further 1.53 g of hexamethyldisilazane and 0.3 g of methanol. The mixture was heated for a further 1 hour. The solvents were removed under reduced pressure and the residue was chromatographed on silica gel with 5% methanol in dichloromethane to give 130 mg of 3-[1-(3-acetoxypropyl)-3-indolyl]-4-(2-nitrophenyl)-1H-pyrrole-2,5-dione, m.p. 77°-78° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:24][CH2:23]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][C:27]1([CH3:33])[O:31][C:30](=[O:32])[N:29]=[CH:28]1>>[CH:22]1([C:19]2[CH:20]=[CH:21][C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:29]5[CH2:28][C:27]([CH3:33])([CH3:26])[O:31][C:30]5=[O:32])=[CH:3][C:4]=4[F:25])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:24][CH2:23]1
Reactant: O=C(c1ccc(Br)cc1F)N1CCN(c2ccc(C3CC3)cn2)CC1
Reactant: CC1(C)C=NC(=O)O1
Product: CC1(C)CN(c2ccc(C(=O)N3CCN(c4ccc(C5CC5)cn4)CC3)c(F)c2)C(=O)O1
Yield: 43.2 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2-fluorophenyl)[4-(5-cyclopropylpyridin-2-yl)piperazin-1-yl]methanone (606 mg) described in Preparation Example 188 and 5,5-dimethyloxazolin-2-one (207 mg) described in Preparation Example 43, the title compound (284 mg) was obtained.