Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][C:17]([C:23]([O:25]CC)=[O:24])=[CH:16][C:15]=3[CH:28]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].O.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1.C(O)CO>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:21])(=[O:22])[CH2:19][CH2:18][C:17]([C:23]([OH:25])=[O:24])=[CH:16][C:15]=3[CH:28]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCS3(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: OCCO
Solvent: O
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Ethyl 7-(4-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxlate (1.0 g, 2.497 mmol) was dissolved in 15 ml of a mixed solution of tetrahydrofuran/ethylene glycol =2/1. Crystals were formed by adding 8.5 ml of water. Potassium carbonate (690 mg, 4.994 mmol) was added and the mixture was heated under reflux for 3.25 hours. Under reflux, 3.5 ml of a 3N hydrochloric acid was dropped to form crystals. After cooling, the mixture was stirred at 20-30° C. for 45minutes and for 1 hour while cooling in ice. After filtration, the residue was washed with 10 ml of a mixed solution of tetrahydrofuran/methanol/water=1/1/3. After vacuum drying (40° C.), 858 mg (Yield 92%) of 7-(4-propoxyphenyl)-1, 1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid was obtained as pale yellowish white crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]([CH3:14])[CH2:12][C:11](=O)[CH2:10][CH:9]1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>CO.O>[CH2:1]([N:8]1[CH:13]([CH3:14])[CH2:12][C:11](=[N:18][OH:19])[CH2:10][CH:9]1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CC(=O)CC(C)N1Cc1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1CC(=NO)CC(C)N1Cc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
10 g of 1-benzyl-2,6-dimethyl-4-piperidone (prepared from benzylamine and ethyl crotonate in analogy to Bull. Chem. Soc. Japan 31 (1958) 418) are dissolved in 60 ml of methanol and this solution is added dropwise to a solution of 3.8 g of hydroxylamine hydrochloride and 4.5 g of sodium acetate in 150 ml of water. The mixture is stirred at 60° C. for 2 h and cooled to 0° C., and the oxime which has separated out is filtered off with suction. Drying results in 5.2 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:13]([O:15]CC)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].C(O)C.[OH-].[Na+]>C1COCC1>[CH3:3][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:1]
Reactant: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)nc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3ccc(S(C)(=O)=O)cc3)nc21

Procedure:
The title compound was prepared in the same manner as described for intermediate 58 using ethyl 1-(1-methylethyl)-6-[4-(methylsulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (260 mg, 0.671 mmol), Ethanol (4 mL), THF (1 mL) and sodium hydroxide (2N, 1.118 mL, 3.36 mmol). The final product was collected as 231 mg (96%). LCMS E-S (M+H)=360.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (d, J=6.8 Hz, 6 H), 3.30 (s, 3 H), 5.34-5.49 (m, 1 H), 8.11 (d, J=8.6 Hz, 2 H), 8.30 (s, 1 H), 8.44 (s, 1 H), 8.51 (d, J=8.6 Hz, 2 H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[OH-].[Na+].CO>[C:19]1([CH:18]=[CH:2][C:1]([C:4]2[CH:5]=[CH:6][C:7]([CH:10]=[C:11]3[S:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])=[CH:8][CH:9]=2)=[O:3])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc(C=C2SC(=O)NC2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1NC(=O)C(=Cc2ccc(C(=O)C=Cc3ccccc3)cc2)S1
Reaction time: 72 h
Yield: 29.8 %

Procedure:
A solution of 5-(4-acetylphenylmethylene)thiazolidine-2,4-dione (1.0 g, 4.0 mmol) and benzaldehyde (0.62 ml, 6.1 mmol) in 1N NaOH (14 ml) and methanol (25 ml) was stirred for 1 hour at 0° C. and then at room temperature for 3 days, the precipitate was collected and dissolved in water, and this solution was acidified with 2N HCl and extracted with ethyl acetate (2×30 ml). The combined extracts were washed with brine (30 ml), dried over sodium sulfate and concentrated in vacuo, leaving the free acid form of title product (0.4 g, 29%) as a yellow solid. The latter was converted to sodium salt according to the method of Example 42.
Reaction SMILES: O[CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1.S(Cl)([Cl:14])=O>>[Cl:14][CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1
Reactant: O=S(Cl)Cl
Reactant: OCn1nnc2ccccc21
Product: ClCn1nnc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
1-Chloromethyl benzotriazole was prepared using the procedure outlined in JACS 74, 3869 (1952). Solid 1-hydroxymethyl benzotriazole (45.0 parts) was stirred mechanically and thionyl chloride (130 parts) was added dropwise at a fairly rapid rate so that the slurry could be agitated while immersed in an ice bath. A nitrogen sweep was employed so that the gasses evolved could be bubbled through a dilute sodium hydroxide solution. After all of the thionyl chloride had been added, the mixture was allowed to warm to room temperature. The mixture was heated to 40° C. and gas evolution became vigorous and the caked-up solid dissolved to yield a clear, pale yellow solution. The mixture was warmed to 65° C. where it was held for 60 minutes. Excess thionyl chloride was distilled off slowly and when distillation ceased, the mixture was cooled to 35°-40° C. and 100 parts of methanol was added to scavenge any residual thionyl chloride. The solution was warmed to reflux and the precipitated solid was broken up with a stirring rod. After 15 minutes at reflux the solution was cooled in an ice bath for 30 minutes and the pale brown solid was filtered and dried in a vacuum oven. The yield of 1-chloromethyl benzotriazole was 41.6 parts (82.9% yield), m.p. 137°-139° C., literature 136°-8° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14]O)[C:10](=[O:16])[O:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][Cl:19])[C:10](=[O:16])[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-n2oc(=O)n(CO)c2=O)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-n2oc(=O)n(CCl)c2=O)cc1

Procedure:
2-(4-Methylphenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione (0.03 mole) dissolved in chloroform (40 ml) and thionyl chloride (0.06 mole) dissolved in chloroform (10 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is stripped of solvent under reduced pressure, leaving a residue. This residue is dissolved in toluene, and the toluene solution is stripped of solvent and unreacted starting materials to yield the desired product 2-(4-methylphenyl)-4-chloromethyl-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[OH:12][C:13]1[C:18](=[O:19])[CH:17]=[CH:16][N:15]([CH3:20])[C:14]=1[CH:21](O)[C:22]([F:25])([F:24])[F:23].CCN(CC)CC.[CH3:34][NH:35][CH2:36][C:37]#[CH:38]>C(#N)C>[OH:12][C:13]1[C:18](=[O:19])[CH:17]=[CH:16][N:15]([CH3:20])[C:14]=1[CH:21]([N:35]([CH3:34])[CH2:36][C:37]#[CH:38])[C:22]([F:25])([F:24])[F:23]
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Reactant: C#CCNC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC#N
Product: C#CCN(C)C(c1c(O)c(=O)ccn1C)C(F)(F)F
Reaction time: 2 h
Yield: 46.4 %

Procedure:
To 20 mL acetonitrile cooled in an ice-water bath was added DMF (0.42 mL, 5.4 mmol) followed by oxalyl chloride (0.47 mL, 5.4 mmol) dropwise. To this resulting suspension was added 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (1.0 g, 4.5 mmol) in one portion. The mixture was then stirred for 2 h. Then, Et3N (2.50 mL, 17.9 mmol) was added to this reaction mixture followed by N-methyl propargylamine (0.75 mL, 9.0 mmol). The reaction mixture was stirred at RT for overnight. The solid was filtered off, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography on silica gel (5% MeOH in CH2Cl2 as eluant) to afford the title compound, Apo7057 (570 mg) as an orange powder. Yield=46.4%; 1H NMR (400 MHz, DMSO+a few drops of D2O) δ (ppm): 7.6 (br. s., 1H), 6.25 (d, J=7.1 Hz, 1H), 5.15 (br. s., 1H), 3.87 (s, 3H), 3.37-3.67 (m, 2H), 3.23 (br. s., 1H), 2.32 (br. s., 3H); MS m/z 275 [M+1]+, 206 (100%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[C:19]([CH3:20])=[C:18]([CH3:21])[S:17][C:15]=2[N:16]=1>>[Cl:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[C:19]([CH3:20])=[C:18]([CH3:21])[S:17][C:15]=2[N:16]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Product: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
Following the procedure of Example 1, the reaction of 4-fluorobenzylamine with 2,4-dichloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[N:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]2[O:23][CH2:24][O:25][C:19]=2[CH:18]=1)=O.C(=O)([O-])O.[Na+]>C(O)C>[CH2:24]1[O:23][C:20]2[CH:21]=[CH:22][C:17]([C:15]3[N:12]=[C:9]4[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH:1]5[CH2:2][CH2:3]5)=[N:11][N:10]4[CH:14]=3)=[CH:18][C:19]=2[O:25]1
Reactant: Nc1ccc(OCC2CC2)nn1
Reactant: O=C(CBr)c1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: c1cc2c(cc1-c1cn3nc(OCC4CC4)ccc3n1)OCO2

Procedure:
A stirred mixture of 6-cyclopropylmethoxypyridazin-3-amine (110 mg), 2-bromo-1-(3,4-methylenedioxyphenyl]ethanone (162 mg), sodium hydrogen carbonate (84 mg, 1 mmol) and ethanol (5 mL) was heated under reflux for 3 hours. Sodium hydrogen carbonate (56 mg) was added and the mixture was refluxed for a further 0.5 hour. The mixture was evaporated. The residue was extracted with chloroform (50 mL) and the extract washed with saturated, aqueous, sodium chloride solution (50 mL), dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel. Elution with 1-3% methanol in dichloromethane afforded Compound 43 (162 mg). 1H n.m.r. (CDCl3) δ 0.33-0.43, m, 2H; 0.62-0.72, m, 2H; 1.22-1.44, m, 1H; 4.13, d, 2H; 6.0, s, 2H; 6.72, d, 1H; 6.86, d, 1H; 7.38, s, 1H; 7.40, d, 1H; 7.78, d, 1H; 7.90, s, 1H.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]([CH3:15])[C:10](=O)[CH:11]([CH3:13])[O:12][C:7]=2[CH:6]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:35]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]([CH3:15])[C:10](=[S:35])[CH:11]([CH3:13])[O:12][C:7]=2[CH:6]=1
Reactant: CC1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(C)C1=S

Procedure:
7-(2-Chloro-4-trifluoromethylphenoxy)-2,4-dimethyl-2H-1,4-benzoxazine-3 (4H)-one (2.5 g) prepared in Example 6 was dissolved in toluene (30 ml), and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (1.9 g) was added thereto, and the resultant mixture was refluxed for 2 hr. The solvent was distilled off in vacuo, and the residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=5/1) to prepare the title compound (2.9 g) as a colorless crystal.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[C:7](=[S:9])=[S:8].C(O)(=O)[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)N>ClCCCl.O1CCOCC1>[CH2:1]([O:6][CH:7]1[S:9][C:17]2[CH:16]=[CH:15][CH:14]=[CH:12][C:11]=2[S:8]1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: S=C=S
Reactant: CC(C)CCO
Reactant: Nc1ccccc1C(=O)O
Solvent: ClCCCl
Solvent: C1COCCO1
Product: CC(C)CCOC1Sc2ccccc2S1
Temperature: 80 °C
Yield: 40 %

Procedure:
42.1 g (0.36 mole) of isoamyl nitrile, 52.8 g (0.60 mole) of isoamyl alcohol and 150 ml of carbon disulfide were dissolved in 800 ml of 1,2-dichloroethane. The reaction solution was mildly heated under reflux at a temperature of about 80° C. A solution of 41.1 g (0.30 mole) of anthranilic acid in 100 ml of dioxane was added dropwise to the reaction solution over 1.5 hours. The reaction solution was further heated under reflux for an additional 30 minutes. The resulting mixture was washed successively with water, a saturated aqueous solution of sodium carbonate and water, and then dried over magnesium sulfate. The resulting organic solution was concentrated under reduced pressure. The residue was then purified through silica gel column chromatography (75 to 230 mesh; eluent: benzene) to obtain 28.8 g (yield: 40%) of the desired compound (V) as a pale yellow oil. The physical properties of the compound were as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]C)=[O:21])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[OH-].[Na+].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: COC(=O)Cc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 110 °C
Yield: 98.1 %

Procedure:
A solution of methyl 2-(4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)phenyl)acetate (1.3799 g, 3.54 mmol) in tetrahydrofuran (THF) (8 mL) and water (2 mL), was prepared and treated with sodium hydroxide (1.063 mL, 10.63 mmol). The reaction was then heated by microwaves to 110° C., for 30 minutes. After cooling, crude material from a test of the above reaction run on a smaller scale (˜40 mg) was combined with this mixture. The combined solution was then neutralised with 2M HCl and diluted with further water and ethyl acetate. The product was extracted into the organic phase and the organics separated (hydrophobic frit) then concentrated in vacuo to provide 1.3033 g of desired material. LCMS (M+1) 376, RT 1.24 mins.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:15])[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Reactant: COC(=O)CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCNC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
To a stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (0.3 g, 1.234 mmol) in DCM (5 ml) EDCI (0.284 g, 1.48 mmol) and HOBt (0.2 g, 1.48 mmol) were added at about 0° C., after 10 minutes methyl 3-aminopropanoate hydrochloride (0.254 g, 2.47 mmol) and Et3N (0.9 ml, 6.17 mmol) in DCM (5 ml) were added drop wise and the reaction mass was allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water and saturated NaHCO3 solution, then washed with aqueous 1N HCl, then washed with water and saturated brine, and the organic layer was concentrated under reduced pressure, the resulting crude was purified by silica gel column (100-200 mesh, elution 70% EtOAC in hexane) to afford the title compound as solid. Wt: 0.336 g; Yield: 88.9%; 1H NMR (300 MHz, CDCl3): δ 5.89 (brs, 1H), 4.79 (d, 1H, J=8.1 Hz), 3.88-3.73 (m, 1H), 3.70 (s, 3H), 3.59-3.42 (m, 2H), 2.54-2.51 (m, 2H), 2.39-2.20 (m, 2H), 2.11-1.99 (m, 1H), 1.43 (s, 9H), 1.26 (s, 3H), 0.87 (s, 3H); Mass: [M+Na]+ 351 (100%); IR (KBr, cm−1): 3359, 3319, 2973, 1737, 1696, 1667, 1539, 1454, 1366, 1271, 1254, 1176, 1051, 1024, 782, 683; M.R: 98.6° C.-100.2° C.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[NH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[NH2:16].CN1CCN(C)C2C=NC=CC1=2.[K+].[Br-]>C(O)C.CCOC(C)=O.CCCCCC>[CH:11]1[C:10]2=[N:9][C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][C:1]=3[N:16]=[C:15]2[CH:14]=[CH:13][N:12]=1
Reactant: Nc1ccncc1N
Reactant: O=C1CCCCC1=O
Agent: CN1CCN(C)c2cnccc21
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1cc2nc3c(nc2cn1)CCCC3
Temperature: 70 °C
Reaction time: 36 h

Procedure:
1,2-Cyclohexanedione (1.52 g, 13.93 mmol) was added to a suspension of 1.56 g (13.93 mmol) of 3,4-diaminopyridine in 50 ml of ethanol. The reaction mixture was subsequently heated at an oil bath temperature of 70° C. for 5 hours, then cooled to room temperature and the solvent was then distilled off on a rotary evaporator. The product obtained was purified by flash chromatography using ethyl acetate as eluent. This gave 1.84 g (71%) of a white solid which was stored in a refrigerator and processed further after 1-2 days. Allowing the solid to stand in an open flask in sunlight resulted in the color changing to greyish green. Rf=0.25 (EtOAc/hexane, 20:1). 1H NMR: (200 MHz, CDCl3): δ=2.05 (m, 4H, H-7,8), 3.18 (m, 4H, H-6,9), 7.79 (d, 3J=5.8 Hz, 1H), 8.72 (d, 3J=5.8 Hz, 1H), 9.38 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ=22.8 (CH2, C-7,8), 33.7 (CH2, C-6,9), 121.2 (CH), 136.9 (Cq), 144.1 (Cq), 146.8 (CH), 153.9 (CH), 156.8 (Cq) 159.9 (Cq) ppm. GC-MS (EI): RT 8.44 min, m/e (%) 186 (11), 185 (M+, 100), 184 (39), 183 (3), 182 (3), 171 (2), 170 (21), 169 (4), 158 (2), 157 (5), 156 (5) 131 (2), 104 (2), 103 (4), 78 (3), 76 (4), 67 (2), 64 (2), 51 (2), 50 (6); IR (KBr): ν=3435 (vs), 2947 (s), 2864 (m), 1594 (s), 1557 (w), 1461 (w), 1421 (m), 1385 (s), 1365 (w), 1330 (w), 1297 (m), 1211 (m), 1140 (w), 979 (m), 949 (w), 901 (m), 849 (m), 679 (w), 629 (w), 570 (w), 412 (w) cm−1. HRMS (EI): calculated for C11H11N3 185.0953 [M+], found: 185.0935
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20](O)=[O:21])[N:9]=2)=[CH:4][CH:3]=1.Cl.[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[F:34][C:25]([F:24])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH:32][C:20]([C:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:12][N:11]=2)=[O:21])[O:28][N:27]=1
Reactant: O=C(O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Reactant: NCc1nc(C(F)(F)F)no1
Agent: Cl
Product: O=C(NCc1nc(C(F)(F)F)no1)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylic acid (example W) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAS registry No. 944905-93-5; example AK) as starting materials; LC-MS (UV peak area/ESI) 100%, 482.0446 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][C@H:37]([OH:39])[CH3:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][C@H:37]([OH:39])[CH3:38])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: C[C@@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-1-amino-2-propanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.10 (d, J=6.32 Hz, 3 H), 1.55-1.65 (m, 4 H), 2.04 (t, J=5.79 Hz, 2 H), 3.15-3.28 (m, 2 H), 3.40-3.53 (m, 4 H), 3.81 (br. s., 1 H), 4.16 (s, 2 H), 4.39 (t, J=6.42 Hz, 2 H), 4.95 (d, J=3.58 Hz, 1 H), 7.11-7.17 (m, 2 H), 7.38-7.43 (m, 2 H), 8.20 (d, J=1.47 Hz, 1 H), 8.56 (d, J=1.68 Hz, 1 H), 10.42 (t, J=5.16 Hz, 1 H), 17.23 (s, 1 H); ES+ MS: 497 (M+H+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][N+:8]([O-])=[C:7]([CH3:12])[C:6]=1[CH3:13])[CH2:2][CH3:3].[C:14]([O:17]C(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:17][CH2:12][C:7]1[C:6]([CH3:13])=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:10]=[CH:9][N:8]=1)(=[O:16])[CH3:15]
Reactant: CCCOc1cc[n+]([O-])c(C)c1C
Reactant: CC(=O)OC(C)=O
Product: CCCOc1ccnc(COC(C)=O)c1C
Yield: 111.2 %

Procedure:
To 20.3 g of 4-propoxy-2,3-dimethylpyridine-1-oxide, 44.0 g (4.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 4 hours at 90° C. Acetic anhydride was distilled off, and then the resulting concentrated residue was purified on a silica gel column, to obtain 27.8 g of 2-acetoxymethyl-3-methyl-4-propoxy-pyridine as an oily matter.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][CH:7]([F:37])[C:8]1[N:12]([C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:16]=[C:15]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:14]=2)[C:11]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:10]=2[N:9]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[F:37][CH:7]([F:6])[C:8]1[N:12]([C:13]2[N:18]=[C:17]([N:19]3[CH2:20][CH2:21][N:22]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:23][CH2:24]3)[N:16]=[C:15]([CH:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:14]=2)[C:11]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:10]=2[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCOCC2)nc(N2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCOCC2)nc(N2CCN(S(C)(=O)=O)CC2)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60.9 %

Procedure:
Methanesulfonyl chloride (0.07 mL, 0.904 mmol) was added drop-wise to a mixture of the above amine (102 mg, 0.229 mmol) and powdered K2CO3 (253 mg, 1.83 mmol) in CH2Cl2 (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 5 min and allowed to warm to room temperature. After 5 hrs, additional K2CO3 (127 mg, 0.919 mmol) and methanesulfonyl chloride (0.04 mL, 0.517 mmol) were added and the mixture stirred at room temperature for another 16 hrs. Water was added and the layers were separated. The organic layer was dried (Na2SO4) and the solvent was removed under vacuum. Recrystallization from CH2Cl2/MeOH gave 2-(difluoromethyl)-4-methoxy-1-{4-[4-(methylsulfonyl)-1-piperazinyl]-6-tetrahydro-2H-pyran-4-yl-1,3,5-triazin-2-yl}-1H-benzimidazole (73 mg, 61%): mp (CH2Cl2/MeOH) 242-244° C.; 1H NMR (CDCl3) δ 8.00 (dd, J=8.4, 0.6 Hz, 1H), 7.55 (t, JHF=53.5, 1H), 7.40 (t, J=7.9 Hz, 1H), 6.86 (d, J=7.7 Hz, 1H), 4.14-4.09 (m, 6H), 4.06 (s, 3H), 3.56 (m, 2H), 3.37 (br s, 4H), 2.96 (m, 1H), 2.83 (s, 3H), 1.99 (ddd, J=12.1, 7.9, 4.0, 4H); Anal. Calcd. for C22H27F2N7O4S: C, 50.5; H, 5.2; N, 18.7. Found: C, 50.6; H, 5.4; N, 18.6%.