Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=O)[CH3:18])=[C:12]([N+:20]([O-])=O)[CH:11]=1.C(O)(=O)C.[H][H]>[Pd].C(O)C>[CH3:18][C:17]1[NH:20][C:12]2[CH:11]=[C:10]([C:9](=[O:23])[NH:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:15]=[CH:14][C:13]=2[N:16]=1
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2[nH]1
Yield: 67.3 %

Procedure:
Five-percent palladium on carbon (0.10 g) was added to a mixture of 1.00 g of crude N-(2-pyridylmethyl)-4-acetylamino-3-nitrobenzamide, 8 ml of acetic acid and 12 ml of ethanol, and the solution was stirred in a hydrogen atmosphere at 80° C. for 7 hours. The solid material was separated through filtration, and the filtrate was concentrated. Ethyl acetate was added to the residue for crystallization. The crystals were separated through filtration, and were dried to give 0.57 g of 2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (252).
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][CH:22]=NN=2)=[CH:16][CH:15]=1.C([O-])([O-])=[O:26].[Cs+].[Cs+].CI>C1COCC1>[CH3:7][N:6]1[CH:2]=[C:3]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:21][CH3:22])=[O:26])=[CH:16][CH:15]=2)[N:4]=[C:5]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(-c3nnco3)cc2)c1I
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cn(C)c(-c3ccccn3)n2)cc1
Reaction time: 0.08 h
Yield: 60.9 %

Procedure:
Methyl 4-(2-pyridin-2-yl-1H-imidazol-4-yl)benzoate (from Step 1, 19.55 g, 70 mmol) was dissolve in THF (160 mL), to which was added Cs2CO3 (29.6 g, 91 mmol) at 0° C. After stirring for 5 min, MeI (11 mL, 175 mmol) was added. After stirring overnight at rt, the reaction was quenched with aq NH4Cl. The product was extracted with EtOAc and the organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was subject to silica column chromatography (0-20% EtOAc in hexanes) to give 12.5 g of methyl 4-(1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl)benzoate. LCMS: m/z 294 (M+H)+.
Reaction SMILES: I[CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([NH2:16])[C:10]([CH3:15])=[C:11]([CH:12]([CH3:14])[CH3:13])[C:5]=2[O:4]1.[C:19]1([CH:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[NH2:16][C:9]1[C:10]([CH3:15])=[C:11]([CH:12]([CH3:14])[CH3:13])[C:5]2[O:4][C:3]([CH2:2][N:30]3[CH2:31][CH2:32][CH:27]([NH:26][CH:25]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:28][CH2:29]3)([CH3:18])[CH2:7][C:6]=2[C:8]=1[CH3:17]
Reactant: c1ccc(C(NC2CCNCC2)c2ccccc2)cc1
Reactant: Cc1c(N)c(C)c(C(C)C)c2c1CC(C)(CI)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c(N)c(C)c(C(C)C)c2c1CC(C)(CN1CCC(NC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 91.9 %

Procedure:
A suspension of 2,3-dihydro-2-(iodomethyl)-7-isopropyl-2,4,6-trimethyl-5-benzofuranamine (1.1 g), N-(diphenylmethyl)-4-piperidinamine (1.4 g) and potassium carbonate (0.83 g) in N,N-dimethylacetamide (6 mL) was refluxed for 4.5 hours. The mixture was diluted with water and the product was extracted twice with ethyl acetate. The combined organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtrated and evaporated in vacuo. The residue was purified with basic silica gel column chromatography (hexane:ethyl acetate=20:1 to 5:1) and recrystallized from hexane/ethyl acetate to afford 1.4 g of the title compound. Yield 91%.
Reaction SMILES: [NH2:1]CC(N1CCC(C)CC1)=O.[CH2:12]([O:19]C1(OC)C=CC(C(O)=O)=CC1OC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:12]([NH2:1])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1CCN(C(=O)CN)CC1
Reactant: COC1C=C(C(=O)O)C=CC1(OC)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2-amino-1-(4-methylpiperidin-1-yl)ethanone represented by Formula 120 (24 mg, 0.15 mmol) was slowly added to 4-benzyloxy-3,4-dimethoxybenzoic acid represented by Formula 89 (48.72 mg, 0.17 mmol) prepared in Preparative Example 1 and diisopropylethylamine (0.11 mL, 0.61 mmol) in DMF (3 mL) at room temperature. After cooling the reaction mixture to 0° C. and adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 58.41 mg, 0.15 mmol) thereto, the mixture was agitated for 24 hours. The reaction solvent was removed under reduced pressure and chloroform (5 mL) was added to the remaining concentrate to prepare a solution. The solution was washed with a potassium carbonate solution, followed by separation to form an organic layer. After drying the organic layer with sodium sulfate (Na2SO4), the solvent was removed again under reduced pressure and the concentrate mixture was recrystallized using chloroform and hexane, resulting in a benzamide compound represented by Formula 37 as a desired product (VVZ-040; 27.2 mg, 42% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C:13]1[N:17]=[CH:16][NH:15][C:14]=1[CH:18]=O>>[Cl:1][C:2]1[C:3]2[C:10](=[CH:18][C:14]3[NH:15][CH:16]=[N:17][C:13]=3[CH3:12])[C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: Cc1nc[nH]c1C=O
Product: Cc1nc[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Yield: 76.9 %

Procedure:
4-Chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (1 eq.) was condensed with 5-methyl-3H-imidazole-4-carbaldehyde (1 eq.) at room temperature to give (76.9%) of 4-chloro-5-(5-methyl-3H-imidazol-4-ylmethylene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[N:33]1[CH2:38][CH2:37][CH:36](OS(C)(=O)=O)[CH2:35][CH2:34]1>CN(C)C=O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:36]3[CH2:37][CH2:38][N:33]([C:28]4[N:27]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:34][CH2:35]3)[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Reactant: CS(=O)(=O)OC1CCN(c2ncccn2)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OC3CCN(c4ncccn4)CC3)cc12

Procedure:
6-(1-Pyrimidin-2-yl-piperidin-4-yloxy)-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime was prepared using the procedure described in example 85A, starting from 6-Hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime (example 127B) and methanesulfonic acid 1-pyrimidin-2-yl-piperidin-4-yl ester (example 169B) in dimethylformamide.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[C:27]([OH:34])[C:26]=2[CH2:35][CH2:36][CH3:37])[C:10]=1[CH2:38][CH2:39][CH3:40])C.[OH-].[Na+]>CO>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])=[C:10]([CH2:38][CH2:39][CH3:40])[C:11]=1[O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[C:27]([OH:34])[C:26]=1[CH2:35][CH2:36][CH3:37])(=[O:17])[CH3:16]
Reactant: CCCc1c(OCCOCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCOCCOc2c(C(C)=O)ccc(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Reaction time: 6 h
Yield: 81.6 %

Procedure:
To a solution of 0.526 g (0.0009 mol) of 4-[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester in 23 ml of methanol was added 23 ml (0.023 mol) of 1N sodium hydroxide. The mixture was stirred at 25° for 6 hours and the methanol was removed in vacuo. The aqueous solution was acidified to pH 3, the precipitate was dissolved in ethyl acetate and washed with sodium chloride solution. The oil obtained on concentration of the ethyl acetate was purified by column chromatography, eluting with 50% ethyl acetate-hexane and ethyl acetate to yield 0.4 g (80% yield) of 4-[4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]butanoic acid as a pale yellow oil which solidified (melting point 52°-58°).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:25])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([C:23]#[N:24])([CH3:22])[CH3:21])[CH:15]=2)[CH:8]=[CH:9][C:10]=1[CH3:11])=[O:4].CCN(C(C)C)C(C)C.[C:35]1([C:41]([SH:54])([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[C:23]([C:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][C:7]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:5]([C:3](=[O:4])[CH2:2][S:54][C:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:6]=1)=[O:25])([CH3:22])[CH3:21])#[N:24]
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 70.9 %

Procedure:
A solution of N-(3-(2-bromoacetyl)-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 113 (1.127 mmol, 450 mg), DIPEA (1.352 mmol, 0.224 mL) and triphenylmethyl mercaptan (1.240 mmol, 343 mg) in DMF (5 ml) was stirred overnight at room temperature. Evaporated to dryness. Purification by chromatography (0-10% ethyl acetate in Toluene) gave 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(2-(tritylthio)acetyl)phenyl)benzamide 114 (475 mg, 70.9%). NMR (400 MHz, CDCl3) 1.80 (s, 6H), 2.38 (s, 3H), 3.55 (s, 2H), 7.31-7.15 (m, 10H), 7.39 (d, J=2.3 Hz, 1H), 7.42 (m, 3H), 7.44 (m, 3H), 7.56 (t, J=7.8 Hz, 1H), 7.72 (m, 2H), 7.74 (m, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.99 (t, J=1.9 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.C(=O)(O)[O-].[Na+].[CH3:35][C:36]1[N:37]([CH2:41][CH2:42][CH2:43][NH2:44])[CH:38]=[CH:39][N:40]=1>C(Cl)Cl>[CH3:35][C:36]1[N:37]([CH2:41][CH2:42][CH2:43][NH:44][C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=23)=[O:18])[CH:38]=[CH:39][N:40]=1
Reactant: Cc1nccn1CCCN
Reactant: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nccn1CCCNC(=O)c1cccc2oc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
A 100-mL one-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 2-phenylbenzoxazole-4-carboxylic acid (0.190 g, 0.79 mmol), DMF (0.588 g, 8.00 mmol) and anhydrous methylene chloride (15 mL). The resulting solution was treated with oxalyl chloride (1.46 g, 11.5 mmol) dropwise over 5 min and stirred at ambient temperature under nitrogen for 2 h. After this time, the reaction mixture was evaporated to a solid residue which was dissolved in anhydrous methylene chloride (15 mL). The resulting solution was treated with sodium bicarbonate (0.672 g, 8.00 mmol) and stirred at ambient temperature under nitrogen for 15 min. After this time, a solution of 3-(2-methylimidazol-1-yl)propylamine (0.332 g, 2.39 mmol) in anhydrous methylene chloride (5 mL) was added and the mixture stirred for a further 20 h. The reaction mixture was then diluted with methylene chloride (50 mL) and washed with 10% aqueous potassium carbonate (10 mL) followed by water (20 mL). The organic phase was dried over sodium sulfate, filtered and evaporated to a solid residue which was further purified by preparative HPLC to give 0.040 g (14% yield) of N-[3-(2-methylimidazol-1-yl)propyl]-2-phenylbenzoxazole-4-carboxamide as a white solid: mp 145-148° C.; 1H NMR (300 MHz, CD3OD) δ 8.33 (m, 2H), 8.03 (dd, J=7.8, 0.9 Hz, 1H), 7.86 (dd, J=8.2, 0.9 Hz, 1H), 7.69-7.59 (m, 4H), 7.52 (t, J=8.0 Hz, 1H), 7.38 (d, J=2.1 Hz, 1H), 4.32 (t, J=7.1 Hz, 2H), 3.67 (t, J=7.1 Hz, 2H), 2.65 (s, 3H), 2.31 (m, 2H); MS (ESI) m/z 361 [M+H]+.
Reaction SMILES: Cl.[CH2:2]1[CH2:6][O:5][CH2:4][CH2:3]1>CO.[OH-].[K+]>[C:2]([C:3]1[CH:4]=[C:6]([OH:5])[CH:2]=[CH:3][CH:4]=1)#[CH:6]
Reactant: C1CCOC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1cccc(O)c1
Reaction time: 2 h
Yield: 70 %

Procedure:
To a stirred solution of PdCl2(PPh3)2 (46 mg, 0.04 mmol), CuI (15 mg, 0.08 mmol), and Et3N (0.303 g, 0.42 mL, 3 mmol) in 10 mL of THF under nitrogen was added 3-iodophenol (0.440 g, 2 mmol) by syringe. The reaction mixture was cooled to 0° C., and trimethylsilylacetylene (0.206 g, 0.30 mL, 2.1 mmol) was added dropwise over 30 min. The reaction mixture was stirred at room temperature overnight and was filtered through Celite to remove Pd and Cu catalysts. Column chromatography (n-hexane/Acetone 6:1) yielded 3-(2-(trimethylsilyl)ethynyl)phenol (380 mg, 2.0 mmol, >99%) as a light brown oil. This compound was diluted with THF (6 mL) and MeOH (6 mL), and 10% aqueous KOH (6 mL) was added. After stirring for 2 hr, the reaction mixture was neutralized by 1 N HCl and evaporated, extracted with CH2Cl2, and dried (Na2SO4). Column chromatography (n-hexane/acetone 5:1) yielded 3-ethynylphenol (162.8 mg, 70%) as a yellow oil.
Reaction SMILES: C([O:4][C@H:5]1[C@H:11]([O:12]C(=O)C)[C@@H:10]([O:16]C(=O)C)[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37](=[N:44][O:45][CH3:46])[C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:47][O:48]C(=O)C)[CH2:7][O:8]2)(=O)C.C1COCC1.O.O[Li].O>CO.C(OC(=O)C)C>[CH3:46][O:45][N:44]=[C:37]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C:23]2[CH:22]=[C:21]([C@@:9]34[O:20][C@@:6]([CH2:47][OH:48])([CH2:7][O:8]3)[C@@H:5]([OH:4])[C@H:11]([OH:12])[C@H:10]4[OH:16])[CH:26]=[CH:25][C:24]=2[Cl:27])=[CH:34][CH:33]=1
Reactant: CON=C(COc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1)c1ccccc1
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CON=C(COc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of compound (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-(2-(methoxyimino)-2-phenylethoxy)benzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (170 mg, 0.23 mmol) in MeOH:THF:H2O (0.7 mL, 0.5 mL, 0.17 mL), LiOH.H2O (14.7 mg, 0.35 mmol) was added at 0° C. The reaction mixture was stirred for 1 h at r.t. After completion of the reaction as confirmed by TLC, solvent was evaporated in vacuo. The residue obtained was diluted with ethylacetate (100 mL), washed with water (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, MeOH:DCM) to afford the title compound (80 mg, 0.14 mmol, 61.8%).
Reaction SMILES: [OH-].[K+].C(OC([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([S:19][CH:20]1[S:24][C:23](=[O:25])[NH:22][C:21]1=[O:26])[CH:13]=[CH:12]2)=O)C>CO>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([S:19][CH:20]1[S:24][C:23](=[O:25])[NH:22][C:21]1=[O:26])[CH:13]=[CH:12]2
Reactant: CCOC(=O)Oc1ccc2cc(SC3SC(=O)NC3=O)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1NC(=O)C(Sc2ccc3cc(O)ccc3c2)S1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Potassium hydroxide (2.47 g, 44.0 mmol) was added to a suspension of 5-[(6-ethoxycarbonyloxy-2-naphthalenyl)thio]-2,4-thiazolidinedione (8.0 g, 22 mmol) in methanol (50 mL) at 25° C. After 30 minutes, the resulting solution was acidified to pH=1 with and then extracted with ethyl acetate (3×). The combined extracts were dried (magnesium sulfate) and concentrated to give 5-[(6-Hydroxyl-2-naphthalenyl)thio]-2,4-thiazolidinedione as a powder (6.4 g, 99% yield): mp 182°-183° C. (chloroform/ethyl acetate); 1H NMR (DMSO-d6, 400 MHz) δ 6.07 (s, 1 H CH). 7.1-8.0 (m, 6 H, ArH). Analogue 35 was prepared similarly, with the use of 3 molar equivalents of potassium hydroxide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([F:10])[F:9].C([Li])CCC.CN(C)[CH:18]=[O:19].[Cl-].[NH4+]>O1CCCC1.O>[F:9][CH:8]([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:18]=[O:19]
Reactant: FC(F)c1ccccc1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccccc1C(F)F
Temperature: -78 °C
Reaction time: 3 h

Procedure:
After dissolving 1-bromo-2-difluoromethylbenzene (3.23 g) in tetrahydrofuran (65 ml), the mixture was cooled to −78° C. After then adding n-butyllithium (2.64 M solution in hexane, 6.5 ml) and stirring for 30 minutes, N,N-dimethylformamide (2.4 ml) was added and stirring was continued for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (991 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH:52]=[C:51](B(O)O)[CH:50]=[N:49]2)=[CH:44][CH:43]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C@H:28]([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([C:51]4[CH:50]=[N:49][N:48]([C:45]5[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=5)[CH:52]=4)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: OB(O)c1cnn(-c2ccc(F)cc2)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4cnn(-c5ccc(F)cc5)c4)ccc3F)[C@@H](F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 75 %

Procedure:
In a manner analogous to that described in Example 9 a), the cross coupling reaction of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(4R,5R)-4-(5-bromo-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.3) with 1-(4-fluorophenyl)-1H-pyrazol-4-ylboronic acid (CAS [1072945-89-1]) and tetrakis(triphenylphosphine)-palladium(0) as the catalyst yielded the title compound (75% yield) as a white foam. MS (ISP): m/z=689.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5](=[C:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH2:15][CH3:16])[O:10][C:9]1=[O:17])[CH2:6][CH3:7])[CH3:2].C(Cl)(Cl)Cl.CC(C)=[O:24]>O.[Hg]>[CH2:1]([O:3][NH:4][C:5]([CH:8]1[C:13](=[O:14])[CH:12]=[C:11]([CH2:15][CH3:16])[O:10][C:9]1=[O:17])([OH:24])[CH2:6][CH3:7])[CH3:2]
Reactant: CC(C)=O
Reactant: CCONC(CC)=C1C(=O)C=C(CC)OC1=O
Agent: [Hg]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCONC(O)(CC)C1C(=O)C=C(CC)OC1=O

Procedure:
After 1g of 3-(1-ethoxyaminopropylidene)-6-ethyl-3,4-dihydro-2H-pyrane-2,4-dione was dissolved in 50ml of acetone containing 5% of water, it was irradiated with high-pressure mercury arc for a day. Chloroform was added to the residue after the distillation of acetone and the insoluble crystal was obtained by filtration of chloroform solution containing the residue. The crude product was recrystallized from the mixture of benzene and petroleum ether, and thereby 0.6g of 3-(1-ethoxyamino-1-hydroxypropyl)-6-ethyl-3,4-dihydro-2H-pyrane-2,4-dione having a melting point of 63° to 64°C as a white plate was obtained.
Reaction SMILES: [CH3:1]/[C:2](/O[Si](C)(C)C)=[N:3]\[Si:4]([CH3:7])([CH3:6])[CH3:5].[CH2:13](NCC)[CH3:14]>>[CH2:2]([N:3]([Si:4]([CH3:7])([CH3:6])[CH3:5])[CH2:13][CH3:14])[CH3:1]
Reactant: CCNCC
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Product: CCN(CC)[Si](C)(C)C
Temperature: 55 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
In a 500 ml four-neck flask equipped with a stirrer, a reflux condenser, a dropping funnel and a thermometer, 290.3 g (1.43 mol) of N,O-bis(trimethylsilyl)acetamide was placed, and thereto was added dropwise 94.9 g (1.3 mol) of diethylamine from the dropping funnel over a 1-hour period. During the addition, the temperature of the reaction system was kept within the range of 20° C. to 60° C. to make the reaction be proceeding. At the conclusion of the addition, the temperature was raised to 50-60° C. and kept there for 2 hours, whereby the reaction was matured. Then, the reaction product was subjected to vacuum distillation. As the result of this procedure, 152 g of diethylaminotrimethylsilane was obtained as a fraction having a boiling point of 60° C. under the pressure of 80 mmHg. The yield was 90%.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[N:6]1)[CH2:2][CH:3]=[CH2:4].B1C2CCCC1CCC2.Br[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][C:30]2[N:31]=[C:32]([CH:35]=[CH:36][C:37]3[CH:42]=[CH:41][C:40]([S:43]([F:48])([F:47])([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[O:33][CH:34]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[F:45][S:43]([F:44])([F:46])([F:47])([F:48])[C:40]1[CH:41]=[CH:42][C:37]([CH:36]=[CH:35][C:32]2[O:33][CH:34]=[C:30]([CH2:29][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH2:4][CH2:3][CH2:2][CH2:1][N:5]4[CH:9]=[CH:8][N:7]=[N:6]4)=[CH:21][CH:22]=3)(=[O:28])=[O:27])[N:31]=2)=[CH:38][CH:39]=1
Reactant: C=CCCn1ccnn1
Reactant: O=S(=O)(Cc1coc(C=Cc2ccc(S(F)(F)(F)(F)F)cc2)n1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(Cc1coc(C=Cc2ccc(S(F)(F)(F)(F)F)cc2)n1)c1ccc(CCCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A solution of 1-but-3-enyl-1H-[1,2,3]triazole (80 mg, 0.65 mmol) in anhydrous THF (5 ml) was treated with 9-BBN (0.5 M in THF, 2.86 ml, 1.43 mmol) at 0° C. and stirred for 2 h at room temperature. This mixture was added to a solution of 4-(4-bromo-benzenesulfonylmethyl)-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole (345 mg, 0.65 mmol), [Pd(dppf)Cl2] (57 mg, 0.07 mmol) and aqueous cesium carbonate (3M, 0.65 ml, 1.95 mmol) in N,N-dimethyl formamide (4 ml) and stirred for 3 h at 70° C. After cooling to room temperature ethyl acetate (100 ml) was added and the solution washed with water (2×50 ml). The organic layer was concentrated and the crude product purified by flash column chromatography (ethyl acetate) and crystallization from diethyl ether to yield 1-[4-(4-{2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazol-4-ylmethanesulfonyl}-phenyl)-butyl]-1H-[1,2,3]triazole as white solid (213 mg, 57%).