Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:15][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23]>C(O)C>[CH2:22]([NH:23][CH2:1][CH:2]([OH:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:1][CH:2]([OH:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NCCCCCCN
Reactant: CCCCCCCCCCCCC1CO1
Solvent: CCO
Product: CCCCCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-tetradecene oxide (91.8 g.) and hexamethylenediamine (25 g.) and recrystallization of the resulting product (71 g., m.p. 118°-121° C.) from ethanol gave N,N'-(1,6-hexylene)-bis[2-hydroxytetradecylamine] (I: R= CH3 (CH2)11, R' = H, X== (CH2)6, Z= H) (55.3 g., m.p. 122°-126° C.).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[CH3:19][NH:20][NH2:21]>O>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:20]([CH3:19])[NH2:21])[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Reactant: CNN
Solvent: O
Product: CN(N)c1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Yield: 79.1 %

Procedure:
A mixture of 275 mg of 2,6-dichloro-4-phenylquinazoline (compound No. Ia1-3) and 461 mg of monomethylhydrazine was stirred at 85° C. for 30 minutes. The resulting reaction product was cooled and 200 ml of water was added thereto. Precipitated crystals were collected by filtration and the collected product was purified by column chromatography (ethyl acetate) to obtain 225 mg of the titled compound. Mp. 155.9° C. 1H NMR (CDCl3): 3.52 (3H, s), 4.65 (2H, s), 7.54-7.63 (5H, m), 7.70-7.74 (2H, m), 7.80 (1H, d, J=2.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.Cl.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl>>[Cl:19][C:18]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=3)=[N:6][C:5]=2[CH:17]=1
Reactant: CN(C)CCCl
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Agent: Cl
Product: CN(C)CCn1c(-c2ccc(C=O)cc2)nc2cc(Cl)c(Cl)cc21

Procedure:
5,6-Dichloro-1-(2-dimethylaminoethyl)-2-(4-formylphenyl)benzimidazole was prepared from 5,6-dichloro-2-(4-formylphenyl)benzimidazole obtained in Example 13 and 2-(dimethylamino)ethyl chloride hydrochloride by following General Procedure 3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:22])[C:19](N)=[O:20])=[CH:17][C:11]=3[C:10](=[O:23])[CH2:9][C:8]=2[CH:24]=1)[CH3:2].[OH-:25].[Na+].O.Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:22])[C:19]([OH:25])=[O:20])=[CH:17][C:11]=3[C:10](=[O:23])[CH2:9][C:8]=2[CH:24]=1)[CH3:2]
Reactant: CCOc1ccc2c(c1)CC(=O)c1cc(C(C)C(N)=O)ccc1S2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ccc2c(c1)CC(=O)c1cc(C(C)C(=O)O)ccc1S2
Temperature: 0 °C
Yield: 37 %

Procedure:
A mixture of 70 mg of 2-(10,11-dihydro-8-ethoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide, 800 mg of sodium hydroxide, 5 ml of water and 5 ml of ethanol was refluxed for 3 hours. After the completion of the reaction, the solvent was removed by distillation to obtain a residue, to which was added ice water, and the mixture was acidified with 10% hydrochloric acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a residue, which was chromatographed over silica gel and eluted with chloroform/benzene (4/1), thereby obtaining 26 mg (yield: 37%) of 2-(10,11-dihydro-8-ethoxy-11-oxodibenzo-[b,f]thiepin-2-yl)-propionic acid as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH:9]2O)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=1)[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(F)cc(F)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(F)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a mixture of 2-(3,5-difluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (5.34 g, 14.8 mmol) and triethylsilane (20 mL) at 25° C. was added trifluoroacetic acid (5 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 2-(3,5-difluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.0 g, 41%) as a white solid: LC/MS m/e calcd for C20H21F2NO2 (M+H)+: 346.4, observed: 346.1.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO>[C:1]([O:5][C:6]([CH2:8][CH:9]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:19]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)CC(C(=O)O)c1ccc(OCc2ccccc2)cc1
Yield: 84.2 %

Procedure:
A solution of methyl (R/S)-α-t-butoxycarbonylmethyl-4-benzyloxyphenylacetate (5.92 g, 16 mmol) 48a in MeOH (50 mL) was treated with 1 N LiOH (32 mL) for 3 hours and MeOH was removed by concentration in vacuo. EtOAc was added and the solution was acidified with citric acid to pH 3. The organic layer was separated and the water solution was extracted with EtOAc one more time. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to afford the acid (4.8 g, 84%) as a solid. MS (CI—NH3): (M+H)+=357.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:4]=2[N:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1.[CH3:21]B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[CH3:21][C:2]1[C:3]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:4]=2[N:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1
Reactant: CB(O)O
Reactant: O=C1CCc2c(Cl)nc(/C=C/c3ccccc3)nc2N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(/C=C/c2ccccc2)nc2c1CCC(=O)N2
Temperature: 140 °C
Yield: 79.2 %

Procedure:
4-Chloro-2-[(E)-2-phenylethenyl]-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (0.434 g, 2.05 mmol) was dissolved in DMF (5 mL) and added to a microwave vial. MeB(OH)2 (0.273 g, 4.56 mmol), Pd(Ph3P)2Cl2 (0.107 g, 0.152 mmol) and K2CO3 (1.05 g, 7.61 mmol) were added and the vial was capped. The reaction was heated at 140° C. in the microwave for 10 minutes. The reaction was concentrated onto silica gel and purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the desired product as an off-white solid (0.431 g, 74%).
Reaction SMILES: [OH-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[OH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:13]=[CH:14][CH:15]=1>CS(C)=O>[C:18]([CH:17]1[CH2:4][CH:16]1[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([OH:9])[CH:11]=1)(=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(C=Cc1cccc(O)c1)c1ccccc1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(c1ccccc1)C1CC1c1cccc(O)c1
Temperature: 15 °C
Yield: 99 %

Procedure:
To a 250 ml round bottom flask equipped with magnetic stirrer, nitrogen inlet, thermometer and addition funnel was charged 0.71 g (0.0178 moles) of 60% sodium hydroxide (oil suspension) and 50 mls of anhydrous DMSO. With stirring, under a nitrogen atmosphere, the trimethylsulfoxonium iodide (3.9 g, 0.0178 moles) was added in one portion, and the reaction was stirred at ambient temperature for 30 minutes. The mixture was then cooled to 15° C., and a solution of 3-hydroxychalcone (2.0 g, 0.0089 moles) was added dropwide in 10 mls of DMSO. The reaction was stirred for 1 hour at 15.10 C., then allowed to warm to ambient temperature, and stirred for an additional 16 hours. The reaction mixture was the quenched with 100 mls of 0.1N HCl, and extracted with 3×100 mls of ethyl ether. The combined ether extracts were washed successively with 2×100 mls of water, and 100 mls of saturated aqueous sodium chloride solution. The ether extract was then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure with a rotary evaporator at 45° C. to afford 2.1 g of the tital compound, 2-benzoyl-1-(3-hydroxyphenyl)cyclopropane, as a thick yellow oil. 100% crude yield.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[CH:23]=[N:24][N:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=23)[C:19]2[C:32](=[O:42])[N:33](C(OC(C)(C)C)=O)[CH2:34][C:18]=2[C:17]=1[F:43])=O)(C)(C)C.[ClH:44]>C(O)(C)C>[ClH:44].[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[CH:23]=[N:24][N:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=23)[C:19]2[C:32](=[O:42])[NH:33][CH2:34][C:18]=2[C:17]=1[F:43]
Reactant: Cc1ccn2ncc(-c3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)c2c1
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccn2ncc(-c3nc(N[C@@H]4CCCC[C@@H]4N)c(F)c4c3C(=O)NC4)c2c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a solution of tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclo-hexyl)amino)-7-fluoro-4-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (110 mg, 0.185 mmol) in isopropanol (10 mL) at 65° C. was added concentrated HCl (0.268 mL, 3.21 mmol) dropwise. The reaction mixture was stirred at 65° C. overnight and then slowly cooled. The solids were filtered and dried to give an HCl salt of the title compound as a pale yellow solid (75 mg, 94%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.49 (br s, 1H) 1.61-1.82 (m, 1H) 1.96 (d, J=8.79 Hz, 1H) 2.44 (s, 3H), 4.33-4.45 (m, 2H) 6.81 (d, J=6.35 Hz, 1H) 6.88 (dd, J=7.02, 1.83 Hz, 1H) 7.90 (br s, 2H) 8.20 (s, 1H) 8.37 (s, 1H) 8.66 (d, J=7.02 Hz, 1H) 9.33 (s, 1H). [M+H] calc'd for C21H23FN6O, 395. found, 395.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:34]=[CH:33][C:24]([CH:25]=[C:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[C:23]([CH3:35])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]>CO>[CH2:1]([C:3]([C:21]1[CH:34]=[CH:33][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[C:23]([CH3:35])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:18])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(C=C2SC(=O)NC2=O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Solvent: CO
Product: CCC(CC)(c1ccc(CC2SC(=O)NC2=O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Yield: 36.6 %

Procedure:
To a mixture of enantiomer 1 of 5-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzylidene)-thiazolidine-2,4-dione (0.35 g, 0.71 mmol) and MeOH (10 mL) is added Mg (0.17 g, 7.1 mmol). The solution is heated at a reflux for 4 hours. The solution is filtered thru Celite®, rinsed with MeOH (2 mL), and the solution concentrated. The residue is purified by ISCO (15%-30% EtOAc gradient) to furnish the title compound (0.13 g, 0.26 mmol, 37%).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[C:27]([C:28]2[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=2)=[C:15]2[N:16]=[C:17]([CH3:26])[N:18]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:19](=[O:20])[C:14]2=[N:13]1>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[C:27]([C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)=[C:15]2[N:16]=[C:17]([CH3:26])[N:18]([CH2:21][C:22]([F:25])([F:23])[F:24])[C:19](=[O:20])[C:14]2=[N:13]1
Reactant: COc1ccc(-c2c3nc(C)n(CC(F)(F)F)c(=O)c3nn2-c2ccccc2Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nc2c(-c3ccc(O)cc3)n(-c3ccccc3Cl)nc2c(=O)n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 66.9 %

Procedure:
BBr3 (3 ml, 1 M solution in CH2Cl2) was added to a solution of 2-(2-chlorophenyl)-3-(4-methoxyphenyl)-5-methyl-6-(2,2,2-trifluoroethyl)-2,6-dihydropyrazolo[4,3-d]pyrimidin-7-one (4A-11, 545 mg, 1.21 mmol) in CH2Cl2 (20 ml) at room temperature. The reaction mixture was stirred for 2.5 h, quenched with MeOH (2 ml), and concentrated under vacuum. The residue was redissolved in MeOH (2 ml) and heated under reflux for 0.8 h, cooled to room temperature, and concentrated under vacuum. The residue was purified on a Chromatotron using 4 mm plates and 50% EtOAc/hexanes to give an impure mixture of the desired product (352 mg). A second purification on a Chromatotron using 1 mm plates and 50% EtOAc/hexanes yielded the desired product 6A-1 (55 mg) as an oil: MS (m/z) 435.4 (M+H)+; 1H NMR (400 MHz, CDCl3): δ 7.63–7.53 (m, 5H), 7.52–7.42 (m, 3H), 5.00–4.80 (br m, 2H), 2.66 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([F:25])[CH:21]=2)[N:16]([CH2:27][CH3:28])[C:15]1=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]([F:25])[CH:21]=2)[N:16]([CH2:27][CH3:28])[C:15]1=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Reactant: C1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCCC3)cc21
Yield: 91.3 %

Procedure:
Pyrrolidine (0.06 mL, 0.72 mmol) was added to a solution of 3-benzyloxy-1-ethyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example C, 0.2 g, 0.6 mmol) and triethylamine (0.17 mL, 1.2 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 3 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform, washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.21 g of the title compound as a solid, mp 174-176° C.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1>C(Cl)Cl.CO.C(Cl)Cl.O=[Mn]=O>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH:10]=[O:11])=[CH:12][CH:13]=2)=[CH:4][N:3]=[CH:2]1
Reactant: OCc1ccc(-c2cnco2)cc1
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: O=Cc1ccc(-c2cnco2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the 4-(oxazol-5-yl)benzyl alcohol (prepared as described by Tanaka, A.; Terasawa, T.; Hagihara, H.; Sakuma, Y.; Ishibe, N.; Sawada, M.; Takasugi, H.; Tanaka, H. J. Med. Chem. 1998, 41, 2390–2410) (0.23 g, 1.31 mmol) in CH2Cl2/MeOH (20:1, 10.5 mL) was added activated MnO2 (1.01 g, 11.6 mmol) and the mixture stirred at room temperature overnight. The reaction was then diluted with CH2Cl2 (10 mL) and filtered through Celite®, washing with CHCl3. The filtrate was concentrated to give the crude aldehyde as a beige solid (0.164 g) which used without further purification in the next reaction. 1H NMR (CDCl3) δ 7.52 (s, 1H), 7.82 (d, 2H, J=9 Hz), 7.95 (d, 2H, J=9 Hz), 7.99 (s, 1H), 10.02 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2/[C:30](=[CH:35]\[O:36][CH3:37])/[C:31]([O:33][CH3:34])=[O:32])[CH:18]=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:17]1[N:22]=[CH:21][N:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2/[C:30](=[CH:35]\[O:36][CH3:37])/[C:31]([O:33][CH3:34])=[O:32])[CH:18]=1)#[N:2]
Reactant: N#Cc1ccccc1O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Temperature: 105 °C

Procedure:
A mixture of 2-cyanophenol (39.7 g), potassium carbonate (62.2 g), polyethylene glycol 400 (60.0 g), (E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (98.3 g) and toluene (130 g) was heated at 105° C. for 16 hours. (E)-methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate was produced (89.5 area %).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[OH-:13].[Na+].O>CS(C)=O>[Cl:9][C:6]1[C:7]([F:8])=[C:2]([OH:13])[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][CH:5]=1
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(Cl)c(F)c1Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Cl)c(F)c1O
Reaction time: 20 h
Yield: 35.5 %

Procedure:
10.5 g (0.05 mol) of 2,4-dichloro-3-fluoronitrobenzene was dissolved in 30 ml of dimethyl sulfoxide, and 8 ml of a 10% aqueous solution of sodium hydroxide was added to the mixture, followed by stirring the mixture at a temperature of 60° to 70° C. for 20 hours. After completion of the reaction, 200 ml of water was added thereto and the unreacted starting material was removed by extraction with diethyl ether. The aqueous layer was made acidic with acetic acid and extracted with diethyl ether. The ether extract was dried over sodium sulfate and the ether was distilled off. The resulting residue was purified by silica gel (100 g) column chromatography using chloroform as an eluant to provide 3,4 g (35.5% yield) of 3-chloro-2-fluoro-6-nitrophenol with m.p. 73° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[NH:19])[C:10]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[CH:13]=[N:12][CH:11]=2)[CH:3]=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:19]=[C:9]([C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[CH:15]=3)[N:8]=[C:4]2[CH:3]=1
Reactant: N=C(Nc1cc(Cl)ccn1)c1cncc(C2CC2)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccn2nc(-c3cncc(C4CC4)c3)nc2c1
Temperature: 150 °C

Procedure:
Lead tetra acetate (0.684 g, 0.0015 mol) was added to a solution of N-(4-chloropyridin-2-yl)-5-cyclopropylnicotinimidamide (42-1; 0.280 g, 0.001 mol) in toluene (30 mL) in a 40 mL microwave vial at RT. The reaction mixture was heated to 150° C. for 2 h under microwave irradiation. It was cooled to RT then diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was purified by silica gel column chromatography to afford the title compound. 1H NMR (400 MHz, DMSO) δ 9.08-9.02 (t, J=7.2 Hz, 2H), 8.52 (s, 1H), 8.10-8.05 (d, J=18.4 Hz, 2H), 7.32-7.31 (d, J=6.8 Hz, 1H), 2.08 (s, 1H), 1.07-1.05 (d, J=10.4 Hz, 2H), 0.82-0.81 (d, J=4.4 Hz, 2H). MS (M+1): 271.7.
Reaction SMILES: C(O[C:4](=[O:26])[C@H:5]([CH3:25])[NH:6][CH2:7][C:8]([NH:10][C:11]1[C:12]2[C:17]([N:18]=[C:19]3[C:24]=1[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])C.[NH2:27][C:28](N)=[O:29].O>CN1CCCC1=O>[CH3:25][C@@H:5]1[N:6]([CH2:7][C:8]([NH:10][C:11]2[C:12]3[C:17]([N:18]=[C:19]4[C:24]=2[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[C:28](=[O:29])[NH:27][C:4]1=[O:26]
Reactant: NC(N)=O
Reactant: CCOC(=O)[C@H](C)NCC(=O)Nc1c2c(nc3ccccc13)CCCC2
Solvent: O
Solvent: CN1CCCC1=O
Product: C[C@H]1C(=O)NC(=O)N1CC(=O)Nc1c2c(nc3ccccc13)CCCC2
Temperature: 80 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
In 9 ml of N-methylpyrrolidone, was dissolved 3.9 g of the compound obtained in Example 38, and 2.64 g of urea was further added thereto. The reaction was carried out at 160° C. for one hour. The reaction mixture was cooled to 80° C. and 100 ml of water was added. The precipitated crystals were collected by filtration and dissolved in a mixture of 5 ml of methanol and 150 ml of chloroform. The solution was dried over anhydrous sodium sulfate and evaporated to dryness. The obtained product was recrystallized from ethanol-ethyl acetate to obtain 2.44 g of the titled compound having the melting point of 260° to 263° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][CH:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH:13]1[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C@H:12]2[C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][C@H:13]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CN(c2ccccc2)C(=O)C1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
To a solution of p-chlorobenzoyl chloride (247 mg, 1.41 mmol) in CH2Cl2 (4 ml) was added a solution of aminopyrrolidinone of Example S (350 mg, 1.41 mmol) and triethylamine (0.4 ml, 2.82 mmol) in CH2Cl2 (4 ml) and the resulting solution was stirred for 18 h at room temperature. Concentration in vacuo gave an oil which was chromatographed on silica gel eluting with 5/95 EtOH/CH2Cl2 to give the title compound (378 mg, 68%) as a solid. Anal calcd for C20H19N2O4Cl: C, 62.10; H, 4.95; N, 7.24. Found: C, 62.07; H, 5.05; N, 7.18. MS calcd for C20H19N2O4Cl 386, found 386. DSC=215.2°-216.8° C. at 144.3 J/g.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[O:17][N:16]=[C:15]([CH2:18][O:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1>ClCCl>[Cl:4][C:14]1[C:15]([CH2:18][O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[N:16][O:17][C:13]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=1
Reactant: CS(=O)(=O)OCc1cc(-c2cccc(Cl)c2)on1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCc1noc(-c2cccc(Cl)c2)c1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Sulfuryl chloride (1 ml) was added to methanesulfonic acid 5-(3-chloro-phenyl)-isoxazole-3-ylmethyl ester (200 mg, 0.70 mmol) and then stirred at 60° C. overnight. The reaction mixture was diluted with dichloromethane, washed saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to afford methanesulfonic acid 4-chloro-5-(3-chloro-phenyl)-isoxazol-3-ylmethyl ester (219 mg, 97%, light brown solid). 1H NMR (CDCl3) d (ppm): 8.07 (m, 1H), 7.92 (m, 1H), 7.50 (m, 2H), 5.38 (s, 2H), 3.16 (s, 3H).