Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@@H:4]([CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])[C@@H:3]1[C:10](O)=[O:11].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[C@@H:4]([CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])[C@@H:3]1[C:10]([Cl:16])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@@H](CC(Cl)(Cl)Cl)[C@@H]1C(=O)O
Solvent: c1ccccc1
Product: CC1(C)[C@@H](CC(Cl)(Cl)Cl)[C@@H]1C(=O)Cl
Yield: 77 %

Procedure:
Into 50 ml of water were dissolved 11.0 g of sodium hydroxide, followed by the addition of 50.0 g of ethyl cis, trans-2,2-dimethyl-3-(2,2,2-trichloroethyl) cyclopropanecarboxylate and about 100 ml of ethanol as a solvent. This mixture was stirred at room temperature for one day. To the reaction mixture was further added a solution of 8.0 g sodium hydroxide in 15 ml of water and the mixture was stirred at room temperature for two days. The resultant reaction mixture was distilled under reduced pressure to remove ethanol and extracted with diethyl ether to recover the unreacted ethyl cis, trans-2,2-dimethyl-3-(2,2,2-trichloroethyl) cyclopropanecarboxylate. Then, the alkaline aqueous layer was acidified by the addition of hydrochloric acid and extracted with diethyl ether. The ethereal layer was dried over anhydrous magnesium sulfate and distilled to remove diethyl ether. By the above procedure there were obtained 45.2 g of cis, trans-2,2-dimethyl-3-(2,2,2-trichloroethyl) cyclopropanecarboxylic acid. To 45.2 g of the carboxylic acid were added 131 g of thionyl chloride and 150 g of benzene and the mixture was heated under reflux overnight. The reaction mixture was then distilled under reduced pressure to remove the low-boiling fraction. The resultant residue was purified by distillation under reduced pressure to obtain 37.2 g of cis, trans-2,2-dimethyl-3-(2,2,2-trichloroethyl) cyclopropanecarboxylic acid chloride which displayed the following NMR spectrum [yield 77% based on the ethyl cis, trans-2,2-dimethyl-3-(2,2,2-trichloroethyl) cyclopropanecarboxylate].
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#N.[OH2:12].S(=O)(=O)(O)[OH:14]>>[Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]([OH:14])=[O:12]
Reactant: O
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: O=S(=O)(O)O
Product: O=C(O)c1cc(F)c(Cl)nc1Cl

Procedure:
The known compound, 2,6-dichloro-5-fluoronicotinonitrile (60 g) was heated at 65°-75° C. for 1 hour in concentrated sulfuric acid. After addition of water, the mixture was further heated at 100°-110° C. for 2 hours to give 2,6-dichloro-5-fluoronicotinic acid (59.8 g), m.p. 155°-156° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[O:14][C:7]2=[C:8]([NH2:13])[N:9]=[CH:10][C:11]([I:12])=[C:6]2[CH:5]=1.CI.[CH3:17][N:18]([CH:20]=O)[CH3:19]>>[Cl:3][C:4]1[O:14][C:7]2=[C:8]([NH:13][CH3:17])[N:9]=[CH:10][C:11]([I:12])=[C:6]2[CH:5]=1.[Cl:3][C:4]1[O:14][C:7]2=[C:20]([N:18]([CH3:17])[CH3:19])[N:9]=[CH:10][C:11]([I:12])=[C:6]2[CH:5]=1
Reactant: Nc1ncc(I)c2cc(Cl)oc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C)c1ncc(I)c2cc(Cl)oc12
Product: CNc1ncc(I)c2cc(Cl)oc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %
Yield: 17 %

Procedure:
To a cooled (0° C.) suspension of sodium hydride (15 mg, 0.37 mmol) in DMF (200 μL) was added dropwise a solution of 2-chloro-4-iodo-furo[2,3-c]pyridin-7-ylamine (100 mg, 0.340 mmol) in DMF (1 mL). After 5 min, methyl iodide (23 μL, 0.37 mmol) was added and the reaction stirred at room temperature for 2 h. The reaction was then quenched with water (30 mL). The quenched mixture was extracted with dichloromethane (2×10 mL). The combined organic fractions were washed with water (1×10 mL) and brine (1×10 mL), dried over sodium sulfate, filtered, and concentrated. Purification by ISCO chromatography (5 to 25% ethyl acetate:heptane) afforded 18 mg (17%) of 2-chloro-4-iodo-N-methylfuro[2,3-c]pyridin-7-amine and 44 mg (40%) of 2-chloro-4-iodo-N,N-dimethylfuro[2,3-c]pyridin-7-amine as off-white white solids.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C:12]2[S:22][C:21]3[N:23]4[C:14](=[CH:15][N:16]=[C:17]4[CH:18]=[CH:19][CH:20]=3)[CH:13]=2)=[O:11])[CH2:5][CH2:4]1.C(N(CC)CC)C.I[CH2:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(O)C.O>[C:36]1([CH2:35][CH2:34][CH2:33][CH2:32][N:3]2[CH2:4][CH2:5][CH:6]([NH:9][C:10]([C:12]3[S:22][C:21]4[N:23]5[C:14](=[CH:15][N:16]=[C:17]5[CH:18]=[CH:19][CH:20]=4)[CH:13]=3)=[O:11])[CH2:7][CH2:8]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: ICCCCc1ccccc1
Reactant: O=C(NC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC1CCN(CCCCc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C

Procedure:
To a solution of 72.5 mg (1.94 mM) of N-(piperidin-4-yl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.4 ml (10.0 mM) of triethylamine in ethanol (7 ml) was added 0.61 g (2.33 mM) of 1-iodo-4-phenylbutane at room temperature and the mixture was refluxed under nitrogen for 6 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and concentrated. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 30%) and recrystallization from ethyl acetate to provide the title compound as light-purple crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=1>CN(C=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])=[N:14][CH:15]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: CN1CC(=O)NC1=NC(=O)O
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccc(Cl)cn1

Procedure:
A mixture of 2.3 g. (10 mM) of the phenyl carbamate 8 and 3.0 g. (23 mM) of 2-amino-5-chloropyridine in 25 ml of anhydrous DMF was heated at 45°-50° C. for 2 hrs., cooled and filtered. The collected solid was washed successively with cold DMF, ethyl acetate, and ether to give 1.6 g of the above urea as a yellow solid, m.p. 250°-251° C. (dec.).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[NH2:14][NH2:15]>C(O)C>[C:9]([O:8][C:6](=[O:7])[NH:5][CH2:4][C:3]([NH:14][NH2:15])=[O:2])([CH3:12])([CH3:11])[CH3:10]
Reactant: NN
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(=O)NN
Temperature: 60 °C
Reaction time: 5.5 h
Yield: 75.9 %

Procedure:
The title compound was prepared essentially in accordance with the procedures of Tetrahedron Letters, Vol 36, No. 37 P6591-6594 as set forth herein. Under a nitrogen atmosphere in a round bottom flask, tert-butoxycarbonylamino-acetic acid methyl ester (2.0 mL, 13.5 mmol) is dissolved in absolute ethanol (50 mL) and anhydrous hydrazine (0.45 mL, 14.3 mmol) is added. The resulting mixture is heated in an oil bath at 60° C. for 3 hours then 80° C. for 5.5 hours. The reaction mixture is evaporated and the residue partitioned between water (50 mL) and dichloromethane (50 mL). The aqueous layer is extracted with dichloromethane (2×10 mL). The combined dichloromethane extracts are washed with water (2×30 mL). The dichloromethane layer is dried over magnesium sulfate and evaporated to give a solid that is triturated with diethyl ether to give hydrazinocarbonylmethyl-carbamic acid tert-butyl ester (1.94 g, 76% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])=[CH:4][C:3]=1[F:16].C(N(CC)CC)C.[N+:24]([C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25].Cl>C(Cl)Cl.CO>[N+:24]([C:27]1[CH:28]=[C:29]([S:33]([O:14][CH2:13][C@@H:11]2[O:10][C:9](=[O:15])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:16])[CH:4]=3)[CH2:12]2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25]
Reactant: O=C1O[C@@H](CO)CN1c1ccc(Br)c(F)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: O=C1O[C@@H](COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CN1c1ccc(Br)c(F)c1
Temperature: 0 °C
Yield: 95.1 %

Procedure:
To a slurry of 907 g (3.13 mol) of (5R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one in 4.5 L of CH2Cl2 in a 22 L round bottom flask was added 654 mL (4.69 mol, 1.50 equiv.) of triethylamine. The mixture was cooled to 0° C., and a solution of 832 g (34.75 mol, 1.20 equiv) of m-nitrobenzenesulfonyl chloride in 2 L of CH2Cl2 was added, keeping the temperature below 6° C. The mixture was sampled for HPLC, and an additional 55 g of solid m-nitrobenzenesulfonyl chloride was added to drive the reaction to completion. Hydrochloric acid (1M, 4.5 L) was added to the slurry. The solids were collected by filtration and washed with water. The phases in the filtrate were separated, and the aqueous later was extracted with 2×500 mL of CH2Cl2. The combined organic layers were concentrated and combined with the solids previously isolated, 2 L of CH2Cl2 and 2 L of methanol. This slurry was distilled on a rotary evaporator, keeping the volume at ˜5 L by adding methanol. The solids were collected by filtration, washed with 1 L of MeOH, and air dried to afford 1415 g (95%) of [(5R)-3-(4-bromo-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl 3-nitrobenzene sulfonate: TLC Rf=0.15 (50% EtOAc.hexanes); HPLC rt=5.68 min; mp 153-156°; [α]D=−76.6° C.=1, MeOH/CH2Cl2), 1H NMR (DMSO) δ8.77 (d, 1H, J=8.2 Hz), 8.71 (s,1H), 8.52 (d, 1H, 7.9 Hz), 8.14 (t, 1H, J=8.1 Hz), 7.85 (t, 1H, J=8.5 Hz), 7.73 (dd, 1H, J=2.3, 11.4 Hz), 7.40 (d, 1H, J=8.9 Hz), 5.12 (m, 1H), 4.68 (m, 2H), 4.28 (t, 1H, J=9.4 Hz), 3,89 (m, 1H); 13C NMR (DMSO) δ157.3 (s, JCF=242 hz), 152.4 (S), 147.2 (S), 138.3 (S, JCF=10 hz), 135.4 (S), 132.7 (D), 132.6 (D), 131.1 (D), 128.2 (D), 121.7 (D), 114.2 (D), 105.3 (D, JCF=29 Hz), 100.6 (s, JCF=20 Hz), 70.4 (t), 69.0 (d), 44.8 (t); Anal. calc'd for C16H12BrFN2O7S: C, 40.44; H, 2.55; N, 5.89; Br, 16.81; found: C. 40.22; H, 2.45; N, 5.86; Br, 16.60.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[NH:19][CH2:1][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Nc1nccs1
Product: O=C(OCc1ccccc1)N1CCC(CNc2nccs2)CC1

Procedure:
The title compound was prepared as described in EXAMPLE 25, except using benzyl 4-formyl-1-piperidinecarboxylate (300 mg, 1.21 mmol) and 2-amino-1,3-thiazole (133 mg, 1.33 mmol) as starting materials to give the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[S:10][CH2:9][CH2:8][C:7]2([CH3:15])[CH3:14])(=O)[CH3:2].CN(C)[CH:18]=[O:19].P(Cl)(Cl)([Cl:23])=O.C([O-])(=O)C.[Na+]>O>[CH3:14][C:7]1([CH3:15])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([C:1]([Cl:23])=[CH:2][CH:18]=[O:19])[CH:5]=2)[S:10][CH2:9][CH2:8]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCS2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)CCSc2ccc(C(Cl)=CC=O)cc21

Procedure:
In a 500 ml 4-necked round bottom flask fitted with a mechanical stirrer and a reflux condenser, 6-acetyl-4,4-dimethylthio-chroman (22 g) and dimethylformamide (38 ml) are added at a temperature in the range of from about 35° C. to about 95° C. under stirring. The reaction mixture is then cooled to a temperature in the range of from about −5° C. to about 0° C. Phosphorus oxychloride (17.2 g) is added to the reaction mixture dropwise over about 30 minutes. Following the addition of the phosphorous oxychloride, the reaction mixture is maintained at a temperature in the range of from about 10° C. to about 15° C. for about 8 hours to about 10 hours. After completion of the reaction as determined by TLC, the reaction mixture is added to cold water (100 ml) at a temperature of from about 0° C. to about 5° C. containing sodium acetate (25 g). The aqueous layer is extracted with dichloromethane (200 ml×3). The organic layer is washed with demineralized water (100 ml×3) until it becomes neutral.
Reaction SMILES: C(OC([NH:11][CH:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:13]1)=O)C1C=CC=CC=1.Br>C(O)(=O)C.C(OCC)C>[NH2:11][CH:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[C:14]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:13]1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-[(benzyloxycarbonyl)amino]-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (7.00 g, 18.2 mmol) in glacial acetic acid (200 mL), prepared as in Intermediate 6, is saturated with HBr gas. The reaction is warmed to 70° C. and held for 20 min. The temperature is raised to 80° C. and maintained for an additional 20 min. The resulting slurry is cooled to ambient temperature, diluted with anhydrous diethyl ether (200 ml), agitated for 0.5 hrs., filtered and washed with diethyl ether. The hydrobromide salt is dried at 60° C. under vacuum to provide the dihydrobromide salt (6.836 g, 16.5 mmol) of the title compound. The free base is obtained by partitioning the dihydrobromide (6.100 g, 14.3 mmol) between aqueous potassium carbonate (5% w/v, 50 mL) and a mixture of ethyl acetate, isopropanol and DCM. After separating the phases, the organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a solid. The product is dried under high vacuum to provide the title compound as a crystalline solid (3.69 g, 14.3 mmol). 1H NMR (300 MHz, d6-DMSO) δ=4.21 (s, 1H); 7.15-7.60 (m, 9H); 10.66 (s, 1H). TLC: Rf =0.33 (95:5 chloroform: methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N+:13]([O-])=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C[Si]([C:22]#[N:23])(C)C.CCN(CC)CC>C(#N)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[C:12]([C:22]#[N:23])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1ccc2c(cnn2-c2ccc(F)cc2)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: N#Cc1nccc2c1cnn2-c1ccc(F)cc1
Reaction time: 3 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridine 5-oxide (0.300 g, 1.31 mmol) in acetonitrile (10 mL) was added trimethylsilyl cyanide (TMSCN) (931 μL, 6.99 mmol) followed by Et3N (0.930 mL, 6.69 mmol) and the mixture was warmed at reflux. After 3 hours, the mixture was diluted with water and the solid collected by filtration washing with water. The flakey solid was then dissolved in methanol and concentrated to afford 1-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridine-4-carbonitrile.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]3=2)[CH:10]=[CH:9]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:9]2[CH2:8][C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=32)=[CH:25][CH:24]=1
Reactant: COc1ccc(I)cc1
Reactant: C1=Cc2ccc3ccccc3c2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(C2=Cc3ccc4ccccc4c3C2)cc1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
20 mnl of triethylamine, 3.32 g (20 mmole) of benzindene, 4.68 g (20 mmole) of p-methoxy-phenyl-iodide and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 ml of ethanol. The crystalline precipitate was isolated, washed with ethanol and dried under vacuum to obtain 2.9 g (54%) of the mixture of two isomers.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:30]4[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)=[CH:15][C:16]=1[CH3:21]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4ccc(N)nc4)c3)n2)ccc1Cl

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-3-methyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.41) (0.21 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a white solid (0.13 g, 60%). MS (ISP) 441.1 [(M+H)+]; mp 168.5° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1([NH2:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CS(C)=O>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Solvent: CS(C)=O
Product: Cc1ccc([N+](=O)[O-])c(Nc2ccccc2)c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A solution of 2-fluoro-4-methyl-1-nitrobenzene (1.0 g, 6.45 mmol) in DMSO (3 mL) was purged with a stream of nitrogen prior to addition of phenylamine (1.18 mL, 12.9 mmol) and then stirred in a sealed tube at 100° C. for 20 h. After cooling to RT, the reaction mixture was partitioned between EtOAc (125 mL) and water (150 mL). The organic layer was then washed with water (150 mL×3), followed by brine, then dried (Na2SO4) and concentrated in vacuo affording (5-Methyl-2-nitrophenyl)phenylamine as a red solid (1.5 g, quantitative). 1H NMR (DMSO, 400 MHz): δ 9.40 (1H, s), 8.03 (1H, d, J=8.70 Hz), 7.45-7.39 (2H, m), 7.35-7.30 (2H, m), 7.21 (1H, t, J=7.33 Hz), 6.98 (1H, s), 6.72-6.68 (1H, m), 2.24 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]([C:23]([F:26])([F:25])[F:24])[NH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18](SC)=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O[O:28][S:29]([O-:31])=O.[K+].[CH3:33]O>O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]([C:23]([F:24])([F:25])[F:26])[NH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:29]([CH3:33])(=[O:31])=[O:28])=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=S([O-])OO
Reactant: COc1ccc(-c2nc(C(F)(F)F)[nH]c2-c2ccc(SC)cc2)cc1F
Reactant: CO
Agent: [K+]
Solvent: O
Product: COc1ccc(-c2nc(C(F)(F)F)[nH]c2-c2ccc(S(C)(=O)=O)cc2)cc1F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4-(3-Fluoro-4-methoxyphenyl)-5-[4-(methylthio)phenyl]-2-(trifluoromethyl)-1H-imidazole 516 mg, 1.35 mmol) from step 4 was dissolved in methanol (10 mL) and cooled to 0° C. OXONE® (2.46 g, 4 mmol) in water (10 mL) was added. After the addition, the ice bath was removed and the reaction was stirred at ambient temperature for 3 hours. The mixture was extracted with chloroform (3×50 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography, affording 4-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole as a solid (98 mg): m.p. 228°-234° C. (DSC, 10° C./min.). The structure assignment was supported by NMR. Mass spectrum (EI, m/e): 414. Anal. Calc'd. for C18H14N2F4O3S: C, 52.17; H, 3.41; N, 6.76. Found: C, 52.30; H, 3.62; N, 6.53.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[C@@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:13][C:12]2=[O:19])=[O:10])=[CH:4][CH:3]=1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Na+].CC(O)=O>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:20])[C:9]([N:11]2[C@@H:15]([CH:16]([CH3:17])[CH3:18])[CH2:14][O:13][C:12]2=[O:19])=[O:10])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)Cc1ccc(Cl)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](C)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of (4S)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one (1.07 g, 3.81 mmol) in dry THF (30 mL) at −78° C. under argon, was added dropwise 1.0M solution of NaHMDS in THF (4.20 mL, 4.20 mmol) over a period of 10 min. After stirring at −78° C. for 1 h, Mel (1.19 mL, 19.1 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 1 h and −40° C. for 2 h, quenched with HOAc (11.4 mmol) in ether (20 mL), filtered over celite. The filtrate was concentrated in vacuo and the residue was dissolved in CH2Cl2 (50 mL) and washed with H2O following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (5%–10% EtOAc in hexane) to give 0.68 g (2.30 mmol, 60%) of (4S)-3-[(2S)-2-(4-chlorophenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCl3) δ 7.30–7.23 (m, 4H), 5.11 (q, 1H, J=7.9 Hz), 4.35 (quintet, 1H, J=3.7 Hz), 4.16–4.09 (m, 2H), 2.46–2.36 (m, 1H), 1.49 (d, 3H, J=7.3 Hz), 0.91 (apparent t, 6H, J=6.9 Hz); ESMS m/e: 296.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH3:15])[CH2:12][CH2:13][NH2:14])=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23].[CH3:34][C:35]1[NH:39][CH:38]=[N:37][C:36]=1[CH2:40][S:41][CH2:42][CH2:43][NH2:44]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][NH:14][C:22]([NH:44][CH2:43][CH2:42][S:41][CH2:40][C:36]2[N:37]=[CH:38][NH:39][C:35]=2[CH3:34])=[O:23])[CH3:15])=[CH:4][CH:3]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CN(CCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1[nH]cnc1CSCCNC(=O)NCCN(C)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.8 g (2.6 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.5 g (2.8 mmol) of 2-[[(5-methylimidazol-4-yl)methyl]thio]ethaneamine as starting materials. Working up by chromatography (eluant: ethyl acetate/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of a crystalline solid; m.p.(ether): 114° C.; MS (+FAB method): m/z (rel. int.[%])=501 ([M+H]+, 15), 95 (63), 230 (100); IR (KBr): 1640 cm-1 (C=O).
Reaction SMILES: [CH3:1][O:2]C1C2C=NC3NN=CC=3C=2N2N=CN=C2N=1.Cl[C:20]1[C:25]2[CH:26]=[N:27][C:28]3[N:32](CC)[N:31]=[CH:30][C:29]=3[C:24]=2[N:23]2[N:35]=[CH:36][N:37]=[C:22]2[N:21]=1.C(O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(O)C>[C:39]1([C:20]2[C:25]3[CH:26]=[N:27][C:28]4[NH:32][N:31]=[CH:30][C:29]=4[C:24]=3[N:23]3[N:35]=[C:36]([O:2][CH3:1])[N:37]=[C:22]3[N:21]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: OCc1ccccc1
Reactant: COc1nc2ncnn2c2c1cnc1[nH]ncc12
Reactant: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Solvent: CCO
Product: COc1nc2nc(-c3ccccc3)c3cnc4[nH]ncc4c3n2n1

Procedure:
By substituting the 5-chloro-8H-pyrazolo[4',3':5,6]-pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine of Example 15 for the 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido-[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine and benzyl alcohol for the ethanol in the procedure of Example 4, 5-phenyl-methoxy-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine is obtained.