Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[O:6][C:7]=1[CH3:8].[O:18]=[CH:19][C:20]1[CH:28]=[CH:27][C:25]([OH:26])=[C:22]([O:23][CH3:24])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:24][O:23][C:22]1[CH:21]=[C:20]([CH:28]=[CH:27][C:25]=1[O:26][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[O:6][C:7]=1[CH3:8])[CH:19]=[O:18]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1oc(-c2cccc([N+](=O)[O-])c2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1nc(-c2cccc([N+](=O)[O-])c2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-(3-nitrophenyl)-1,3-oxazole (2.67 g), vanillin (1.52 g), anhydrous potassium carbonate (1.38 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was dried over anhydrous magnesium sulfate, and filtered through a silica gel column. The filtrate was concentrated and the residue was washed with diethyl ether-hexane to give 3-methoxy-4-{[5-methyl-2-(3-nitrophenyl)-1,3-oxazol-4-yl]methoxy}benzaldehyde as colorless crystals (3.58 g, yield 97%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 179-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11]I)=[CH:4][CH:3]=1.[C:13](=[O:16])([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][S:8][C:5]2[CH:6]=[C:13]([OH:16])[CH:2]=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(SCCCI)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Oc1cccc(SCCCSc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.2 %

Procedure:
A mixture of 12.6 g of monothioresorcinol, 31.3 g of 1-(4-chlorophenylthio)-3-iodopropane (prepared from 4-chlorothiophenol and 1-bromo-3-chloropropane followed by replacement of chlorine by iodine with sodium iodide in acetone), 16.6 g of potassium carbonate and 60 ml of acetone was stirred at room temperature for 24 hours, then the solvent was removed by distillation under reduced pressure, methylene chloride was added, the solution was washed several times with water and dried, and then 14.5 g of 3-(4-chlorophenylthiopropylthio)phenol were isolated by chromatography on silica gel using methylene chloride as mobile phase. This product was stirred together with 9.5 g of 6-chloromethyl-4-methyl-2-pyrone, 10.4 g of potassium carbonate and 60 ml of acetone at 50° C. for 31 hours, then the solvent was removed by distillation under reduced pressure, the residue was taken up in methylene chloride, and the solution was washed several times with water, dried and chromatographed on silica gel. 11.2 g of the main fraction were heated with 50 g of 2-aminopyridine at 75° C. for 65 hours, and a total of 12 g of hydroxylamine hydrochloride was added in several portions. The residue was then taken up in methylene chloride, and the organic phase was extracted by shaking with dilute hydrochloric acid and several times with water and was dried, and the solvent was removed by distillation. The residue amounted to 9.9 g. Treatment with methanol resulted in 2.7 g of pure hydroxypyridone of melting point 102° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[Cl:12].C([Li])CCC.CN(C)[CH:20]=[O:21]>C1COCC1.[Cl-].[NH4+]>[Cl:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:20]=[O:21])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc2nccc(Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
To a solution of 6-bromo-4-chloro-quinoline (3.0 g, 12.37 mmol) in THF (60 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (5.95 mL, 14.84 mmol, 1.1 equiv.) at −70° C. During the addition, the color of the solution was turned to red and it was stirred for 1 h at this temperature. Then, a solution of dimethylformamide (1.91 mL, 24.74 mmol) in THF (10 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 2 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude brown solid which was purified by using a Biotage silica gel column chromatography to obtain 0.6 g (25% yield) of 4-chloro-quinoline-6-carbaldehyde as a white solid: EI-HRMS m/e calcd for C10H6ClNO (M+) 187.0633, found 187.0638.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1F)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH3:21][O:22][CH2:23][C@H:24]([NH2:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[NH:26][C@H:24]([CH3:25])[CH2:23][O:22][CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1F
Reactant: COC[C@@H](C)N
Agent: O=C([O-])O
Agent: [Na+]
Product: COC[C@@H](C)Nc1cc(F)ccc1C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
A mixture of 2,4-difluoro-benzoic acid tert-butyl ester (30 g, 140.05 mmol) and (R)-2-methoxy-1-methyl-ethylamine (100 mL) was stirred at 65° C. for 2 days. A satured solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3 times). The organic phase was washed twice with water then with brine, dried over sodium sulfate filtered and evaporated to dryness to obtain a crude, which was purified by column chromatography on silica gel (exane/ethyl acetate 9:1). The title compound (33.38 g, 84%) was obtained as oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[C:13]([O:22][CH3:23])[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:25]>O1CCOCC1>[NH2:25][C:6]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[C:13]([O:22][CH3:23])[CH:12]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N
Reactant: COc1cc(NC(=O)c2c(Cl)ncnc2Cl)ccc1-c1cnco1
Solvent: C1COCCO1
Product: COc1cc(NC(=O)c2c(N)ncnc2Cl)ccc1-c1cnco1
Temperature: 0 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
4,6-Dichloro-N-(3-methoxy-4-(oxazol-5-yl)phenyl)pyrimidine-5-carboxamide (844 mg, 2.01 mmol) was dissolved in dioxane (10 ml) and cooled in an ice bath. Ammonia solution (1.44 ml, 7N in MeOH) was added dropwise and the mixture was stirred at 0° C. for 20 min and 4 h at room temperature. After dilution with ethyl acetate, this organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvents evaporated under reduced pressure, to yield a solid as a residue (788 mg, 86% purity, 98% yield) which was used in the next synthetic step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[O:17])[N:14]([CH3:16])[CH3:15])[N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:15][N:14]([CH3:16])[C:13]([C:11]1[N:12]=[C:8]([NH2:7])[S:9][CH:10]=1)=[O:17]
Reactant: CN(C)C(=O)c1csc(NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)c1csc(N)n1
Temperature: 0 °C

Procedure:
To a stirred solution of (4-dimethylcarbamoyl-thiazol-2-yl)-carbamic acid tert-butyl ester (150 mg, 0.53 mmol) in dichloromethane (1 mL) at 0° C. was added trifluoroacetic acid (2.5 mL, 32 mmol) and the mixture stirred at 0° C. until all of the starting material had been consumed. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate (2×), brine, dried over sodium sulfate and concentrated in vacuo to give crude 2-amino-thiazole-4-carboxylic acid dimethylamide as a viscous colorless oil which was used without further purification (85 mg, 90%).
Reaction SMILES: CC(=[O:5])CC.[CH3:6][CH:7]1[CH2:12][CH:11]([O:13][CH2:14][C:15](Cl)=[O:16])[CH:10]([CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:8]1.CO>N1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][CH:7]1[CH2:12][CH:11]([O:13][CH2:14][C:15]([OH:5])=[O:16])[CH:10]([CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:8]1
Reactant: CCC(C)=O
Reactant: CC1CCC(C(C)C)C(OCC(=O)Cl)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Solvent: c1ccncc1
Product: CC1CCC(C(C)C)C(OCC(=O)O)C1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
2-L-menthoxyacetyloxy-2-butene is prepared from 2-butanone, L-menthoxyacetyl chloride, and pyridine catalyst. A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5 mL), (PPh3)2PdCl2 (0.05 mmol), CH3OH (0.5 mmol), and 2-L-menthoxyacetyloxy-2-butene (0.5 mmol). The reactor is sealed, pressurized to 1000 psig with CO, and stirred for 24 hours at 100° C. The product mixture, isolated after removal of gas from the reactor vessel, contains a diastereomeric mixture of methyl 2-L-menthoxyacetyloxy-L-2-methylbutyrate and methyl 2-L-menthoxyacetyl-D-2-methylbutyrate. The diastereomers are separated by preparative gas chromatography using an SE-30 liquid phase column. Each diastereomer is hydrolyzed separately by treatment with 2N HCl (aq) for 2 hours at 100° C. to give pure L- and D-2-methyl-2-hydroxybutyric acid, methanol, and L-menthoxyacetic acid.
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: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: CS(=O)(=O)Cl
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: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:13]1[C:12]2[C:17](=[CH:18][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:21])([F:20])[F:1])=[CH:10][CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2cc(-c3ccccc3C(F)(F)F)ccc12
Product: FC(F)(F)c1ccccc1-c1ccc2c(Cl)ccnc2c1

Procedure:
Heat a mixture of 7-(2-trifluoromethyl-phenyl)-quinolin-4-ol (50 mg, 0.17 mmol) in POCl3 (10 mL) at 90° C. for 16 hours. Evaporate the POCl3, and add ice (100 g) followed by careful addition of saturated NaHCO3. Extract with EtOAc, dry (Na2SO4), and evaporate to provide 4-chloro-7-(2-trifluoromethyl-phenyl)-quinoline as a tan solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][NH:5][C:4]2[N:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][N:19]=1.[H-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:17][C:18]1[N:19]=[CH:20][C:21]([CH2:24][N:5]2[C:4]3[N:13]=[CH:14][CH:15]=[CH:16][C:3]=3[C:2](=[O:1])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6]2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1n[nH]c2ncccc2c1=O
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(Cc2ccc(Cl)nc2)c2ncccc2c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate (1.00 g, 4.56 mmol) and 2-chloro-5-(chloromethyl)pyridine (813 mg, 5.02 mmol, 1.1 equiv) were combined in degassed N,N-dimethylformamide and cooled to 0° C. Sodium hydride (219 mg, 5.47 mmol, 1.2 equiv) was added portionwise over 5 minutes and the mixture was stirred for an additional 1 hour at 0° C. The mixture was warmed to ambient temperature, stirred for 1 hour and poured into sodium bicarbonate (150 mL, aqueous saturated). The aqueous layer was extracted with ethyl acetate (2×150 mL) and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound as a white solid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.CS(O[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[N:28]=[C:29](/[CH:32]=[CH:33]/[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:30][CH:31]=2)=[CH:21][CH:20]=1)(=O)=O>>[C:34]1(/[CH:33]=[CH:32]/[C:29]2[O:30][CH:31]=[C:27]([CH2:26][O:25][C:22]3[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][CH2:16][CH2:15][N:1]4[C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=[CH:2]4)=[CH:24][CH:23]=3)[N:28]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CS(=O)(=O)OCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: c1ccc2[nH]cnc2c1
Product: C(=C/c1nc(COc2ccc(CCCCn3cnc4ccccc43)cc2)co1)\c1ccccc1
Yield: 36 %

Procedure:
In substantially the same manner as in Working Example 8, benzimidazole was allowed to react with 4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl methanesulfonate to give 1-[4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl]benzimidazole. The yield was 36%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 148-149° C.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C@@H:6]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N:15]([CH2:22][C:23]2[C:27]3[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=3[S:25][N:24]=2)[C:14]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Li+]>O1CCOCC1.O>[CH3:33][C:28]1[C:27]2[C:23]([CH2:22][N:15]3[C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:21]=4[N:13]([C@@H:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:5][C:4]([OH:35])=[O:3])[C:14]3=[O:34])=[N:24][S:25][C:26]=2[CH:31]=[C:30]([CH3:32])[CH:29]=1
Reactant: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2nsc3cc(C)cc(C)c23)c2cnccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c2c(Cn3c(=O)n([C@H](CC(=O)O)c4ccccc4)c4ccncc43)nsc2c1
Reaction time: 4 h
Yield: 86.2 %

Procedure:
To a solution of (R)-3-[3-(4,6-dimethyl-benzo[d]isothiazol-3-ylmethyl)-2-oxo-2,3-dihydro-imidazo[4,5-c]pyridin-1-yl]-3-phenyl-propionic acid ethyl ester (10 mg, 0.021 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added lithium hydroxide (LiOH) (0.9 mg, 0.042 mmol) at room temperature. The solution was stirred at the same temperature for 4 hours. The solution was concentrated and water was added to the residue. The solution was acidified by 12N HCl in an ice-bath. The solution was concentrated and the residue was purified by preparative TLC with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (8.3 mg, 88%): LCMS, M++1, m/z: 459.13 as a white solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]\[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=1)[C:10]([O:12]C)=[O:11])=O.O.[NH2:19]N>C(O)C>[NH:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=2)[C:10]([OH:12])=[O:11])=[N:19]1
Reactant: COC(=O)c1ccnc(C(=O)/C=C\N(C)C)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccnc(-c2cc[nH]n2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a 2 L three-necked flask was added (Z)-methyl 2-(3-(dimethylamino)acryloyl)isonicotinate (0.894 mol), hydrazine hydrate (48.8 g), anhydrous ethanol (1 L). The suspension was stirred at 20° C. overnight. The solvent was removed in vacuo. The residue was taken up in concentrated hydrochloric acid (600 mL) and heated to reflux for 2 hours. The mixture was cooled to ambient temperature. The resultant precipitate was filtered, washed with water, ethanol and acetone and dried to give 78.6 g of the title compound as a brown solid. 1HNMR (DMSO-d6/D2O) δ ppm 8.80 (d, 1H), 8.50 (s, 1H), 7.91 (d, 1H), 7.87 (dd, 1H), 7.15 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH2:14][C:15]4[S:16][C:17]([C:20]5[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=5)=[CH:18][C:19]=4[C:12]=3[N:11](COCC[Si](C)(C)C)[N:10]=2)=[CH:5][CH:4]=1.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH2:14][C:15]4[S:16][C:17]([C:20]5[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=5)=[CH:18][C:19]=4[C:12]=3[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4cccc(N)c4)cc2-3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4cccc(N)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 95.7 %

Procedure:
3-[6-(4-Methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-phenylamine (0.36 g, 0.7 mmol) was dissolved in MeOH and treated with concentrated HCl (0.26 mL, 7.0 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 3-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-phenylamine (0.26 g, 0.67 mmol) as yellow solid in 96% yield.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][C@@H:19]([C:28]1[CH:29]=[CH:30][C:31]([Cl:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[O:20][Si](CC)(CC)CC.Cl.O1CCOCC1>O1CCCC1>[ClH:39].[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][C@@H:19]([C:28]1[CH:29]=[CH:30][C:31]([Cl:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:33]=1)[OH:20]
Reactant: CC[Si](CC)(CC)O[C@@H](CNCCOc1ccc2c(c1)[nH]c1ccccc12)c1ccc(Cl)c(NS(C)(=O)=O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate 108 (73.2 mg) was dissolved in anhydrous tetrahydrofuran (4.2ml), whereto 4 N hydrogenchloride/1,4-dioxane (240 μl ) was added and the mixture was agitated at room temperature for 1 hour. The deposited precipitate was taken out and washed with tetrahydrofuran, whereupon it was dried under a reduced pressure at 40° C., whereby the above-identified compound was obtained (36.3 mg).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)[C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-n2c(C(=O)N3CCOCC3)cc3cc(OC4CCN(C(C)C)CC4)ccc32)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone (intermediate 2) and 4-methoxyphenylboronic acid. The title compound was obtained in 56% yield as yellow foam. MS (m/e): 478.2 (MH+, 100%).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[N:11]=[N:10][C:9]([CH:12]([OH:14])[CH3:13])=[N:8]2)[CH:2]=1.[H-].[Na+].[CH:18]1([N:21]2[C:25](S(C)(=O)=O)=[N:24][N:23]=[C:22]2[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH2:20][CH2:19]1>>[CH:18]1([N:21]2[C:25]([O:14][CH:12]([C:9]3[N:10]=[N:11][N:7]([C:3]4[CH:2]=[C:1]([CH3:15])[CH:6]=[CH:5][CH:4]=4)[N:8]=3)[CH3:13])=[N:24][N:23]=[C:22]2[C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)[CH2:20][CH2:19]1
Reactant: Cc1cccc(-n2nnc(C(C)O)n2)c1
Reactant: CS(=O)(=O)c1nnc(-c2ccncc2)n1C1CC1
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(-n2nnc(C(C)Oc3nnc(-c4ccncc4)n3C3CC3)n2)c1
Yield: 2 %

Procedure:
The title compound (7.8 mg, 19%, clear oil) was prepared from 1-(2-m-tolyl-2H-tetrazol-5-yl)-ethanol (1 mmol), sodium hydride (1.5 mmol) and 4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol). 1H NMR (CDCl3) δ (ppm): 8.73 (d, 2H), 7.93 (m, 2H), 7.78 (d, 2H), 7.45 (t, 1H), 7.33 (d, 1H), 6.62 (q, 1H), 3.22 (m, 1H), 2.49 (s, 3H), 2.05 (d, 3H), 1.14 (m, 2H), 1.00 (m, 2H).
Reaction SMILES: C1(NC([O:10][C@H:11]2[C@H:18]([OH:19])[CH2:17][O:16][C@@H:13]([O:14][CH3:15])[C@@H:12]2[OH:20])=O)C=CC=CC=1.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([O:20][C@@H:12]1[C@@H:11]([OH:10])[C@H:18]([O:19][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][O:16][C@H:13]1[O:14][CH3:15])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CO[C@@H]1OC[C@@H](O)[C@H](OC(=O)Nc2ccccc2)[C@H]1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1OC[C@@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a solution of methyl 3-O-phenylcarbamoyl-b-D-xylopyranoside (73.6 g, 0.26 mole) in DMF (300 ml) was added by portions 60% NaH in oil (36.0 g, 0.9 mole). After stirring at room temperature for 30 min, benzyl bromide (113 ml, 0.95 mole) was added dropwise to the reaction mixture. After the addition was completed, the stirring was continued for 3 hr. The reaction mixture was evaporated under reduced pressure and the oily residue was partitioned between ether (500 ml) and water (500 ml). The ether layer was dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure. The resulting amber viscous oil (150 g) was dissolved in 28% NaOMe--MeOH, (750 ml) and heated under reflux for 19 hrs. The reaction mixture was evaporated to dryness under reduced pressure. The oily residue was partitioned between ether (500 ml) and water (500 ml). The ether layer was washed with water (250 ml×2), and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel using CH2Cl2 /AcOEt (95:5) as an eluent to give methyl 2,4-di-O-benzyl-b-D-xylopyranoside (80.5 g, 90% yield) as amorphous powder; EI-MS: m/z 344 (M+); 1H-NMR (CDCl3)d: 2.54 (1H,d,J=2.5 Hz), 3.21 (1H,dd,J=7.5 & 9 Hz), 3.22 (1H,dd,J=10 & 12 Hz), 3.52 (3H,s), 3.49 (1H,m), 3.68 (1H,t,J=9 Hz), 3.93 (1H,dd,J=6 & 12 Hz), 4.25 (1H,d,J=7.5 Hz), 4.63 (1H,d,J=12 Hz), 4.66 (1H,d,J=11.5 Hz), 4.75 (1H,d,J=12 Hz), 4.90 (1H,d,J=12 Hz), 7.31 (10H,br.s).
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]2[N:11]=[N:12][N:13]([CH2:15][CH2:16][OH:17])[CH:14]=2)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[O:18](S(C1C=CC(C)=CC=1)(=O)=O)[S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=O)=[O:20]>C(Cl)Cl>[CH3:26][C:25]1[CH:27]=[CH:28][C:22]([S:19]([O:17][CH2:16][CH2:15][N:13]2[CH:14]=[C:10]([CH2:9][N:5]3[CH:6]=[CH:7][N:8]=[C:4]3[N+:1]([O-:3])=[O:2])[N:11]=[N:12]2)(=[O:20])=[O:18])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=[N+]([O-])c1nccn1Cc1cn(CCO)nn1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCn2cc(Cn3ccnc3[N+](=O)[O-])nn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.1 %

Procedure:
To a round bottom flask containing alcohol 11 (160 mg, 0.672 mmol), TEA (136 mg, 1.34 mmol) and DCM (5 mL) was added Ts2O (263 mg, 0.806 mmol). The reaction was stirred at RT for 4 hrs. TLC indicated that the reaction was complete. The reaction was concentrated in vacuo and purified on a silica gel cartridge using EtOAc:Hex as the eluent to afford 140 mg (53% yield) of 12 as a pale orange oil. Mass Spec (lo-res): Calc'd for C15H16N6O5S: 392.092; found: 393.10 (M+H).