Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6]1)=[O:4].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:4]
Reactant: COC(=O)C1(c2cccc(F)c2)CCC=CCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(c2cccc(F)c2)CCCCCC1
Yield: 99.2 %

Procedure:
1-(3-Fluoro-phenyl)-cyclohept-4-enecarboxylic acid methyl ester (Example 12b) (1.09 g) was dissolved in methanol (20 mL), palladium on carbon (50 mg) added and mixture stirred under 4 atm of hydrogen overnight. The solution was filtered and evaporated to afford the sub-titled compound (1.09 g).
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[CH2:6]O)/[CH2:3]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[CH2:20]([N:27]1[CH2:6][CH:5]=[C:2]([CH3:3])[CH2:1]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: C/C(=C\CO)CO
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1=CCN(Cc2ccccc2)C1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a solution containing 40.8 g (0.4 mol) of E-2-methyl-2-butene-1,4-diol, 83.8 g (0.8 mol) of triethylamine, and 416.6 g of ethyl acetate in a round flask reactor, methanesulfonyl chloride was added dropwise with stirring for 30 min. at about 5° C. using an ice-bath. After addition, the mixture was allowed to react with stirring for 2 hours at room temperature. To the mixture, 171.7 g (1.6 mol) of benzylamine was added continuously dropwise with stirring for 30 min. at ambient temperature. After 2 hours of stirring, the crystallized solid was removed by filtration; 42.0 g of 35% HCl (aq) was added to the filtrate, and then excess benzylamine hydrochloride was removed by filtration or extraction. After the solvent was evaporated under reduced pressure, 54.2 g of 1-benzyl-3-methyl-3-pyrroline (yield 78.2%) was obtained.
Reaction SMILES: [CH2:1]([N:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH2:17]Cl>C(OCC)C>[Cl-:14].[CH2:10]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:17][C:16]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]=1[Cl:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCN(CCCC)CCCC
Reactant: ClCc1ccc(Cl)cc1Cl
Solvent: CCOCC
Product: CCCC[N+](CCCC)(CCCC)Cc1ccc(Cl)cc1Cl
Product: [Cl-]

Procedure:
Eighteen and fifty-four one-hundredths parts of tributylamine and 19.54 parts of 2,4-dichlorobenzyl chloride were placed in a 250 ml. glass stoppered flask. 70.8 parts of diethyl ether was added and the flask tightly stoppered and allowed to react at room temperature. After a considerable time an oil began to form and after 2 to 3 months, the product began to crystallize. At the end of six months, the crystals were filtered, washed with hexane and dried under vacuum. 16.7 parts of tributyl-2,4-dichlorobenzylammonium chloride was obtained, the compound having 3.33% nitrogen, the calculated value for nitrogen (for C19H32Cl3N) is 3.69%.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:8]=2)=[C:4]([F:23])[CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([N:34]=[C:35]=[O:36])=[O:33])=[CH:27][CH:26]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1>C1COCC1>[F:23][C:4]1[CH:3]=[C:2]([NH:1][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[N:8]=1
Reactant: Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)n2)c(F)c1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)n2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of 4-(4-amino-2-fluorophenoxy)-N-(4-fluorophenyl)pyrimidin-2-amine (10 mg, 0.032 mmol) in THF (1 mL) was cooled in an ice bath and treated with a solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example of 11, 228 μL, 0.064 mmol) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the residue triturated with isopropyl ether to give the title compound (15 mg, 93%) as a white solid. 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.56 (s, 1H), 9.68 (s, 1H), 8.39 (d, 1H, J=5.7 Hz), 7.76 (dd, 1H, J=13.5, 2.1 Hz), 7.43 (br s, 2H), 7.46-7.35 (m, 6H), 7.18 (dd, 2H, J=8.8, 8.8 Hz), 6.57 (d, 1H, J=5.4 Hz), 3.76 (s, 2H); MS(ESI+) m/z 492.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:28]=[CH:27][C:18]([CH:19](O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C1(P([N:43]=[N+:44]=[N-:45])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:28]=[CH:27][C:18]([CH:19]([N:43]=[N+:44]=[N-:45])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(O)c2ccccc2)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(N=[N+]=[N-])c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
Compound 2 (0.600 g, 1.61 mmol) was dissolved in toluene (15 mL), and diphenylphosphoryl azide (0.696 mL, 3.23 mmol) and DBU (0.483 mL, 3.22 mmol) was added to the solution, followed by stirring at 60° C. for 4 hours. The reaction mixture was diluted with toluene, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain [4-(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)phenyl]phenylmethylazide (0.590 g, yield 92%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=O)=O)=[CH:22][CH:21]=3)=[CH:18][C:17]([CH:30]([F:32])[F:31])=[N:16]2)=[CH:11][CH:10]=1)(=O)[NH2:7]>CN(C)C=O>[C:6]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([S:26][CH3:29])=[CH:22][CH:21]=3)=[CH:18][C:17]([CH:30]([F:32])[F:31])=[N:16]2)=[CH:13][CH:14]=1)#[N:7]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)F)nn2-c2ccc(C(N)=O)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CSc1ccc(-c2cc(C(F)F)nn2-c2ccc(C#N)cc2)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 114.7 %

Procedure:
A solution of phosphorus oxychloride (1.7 g) in N,N-dimethylformamide (20 ml) was stirred at 5° C. for 30 minutes. To the solution was added 1-(4-carbamoylphenyl)-3-(difluoromethyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (2 g). The resulting mixture was stirred at 5° C. for 2 hours, poured into ice-water, and extracted with a mixture of tetrahydrofuran and ethyl acetate. The extract was washed with water, dried, and evaporated to give an oil of 1-(4-cyanophenyl)-3-(difluoromethyl)-5-[4-(methylthio)phenyl]pyrazole (2.0 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CCCCCC>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:19]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[O:11])=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH3:30]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCCCCNCc1ccc(CCCC)cc1
Solvent: CCCCCC
Product: CCCCCCCN(Cc1ccc(CCCC)cc1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1.55 g of 2,4-diflurophenylisocyanate in hexane was added to a solution of 2.61 g of N-heptyl-4-butylbenzenemethanamine in 15 ml of hexane and the solution was stirred at room temperature for 4 hours, then evaporated. The residual oil was distilled to yield 1-[(4-butylphenyl)methyl]-1-(n-heptyl)-3-[2,4-difluorophenyl]urea as a colorless oil, bp 160°-165° C./120μ.
Reaction SMILES: O[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.CS([Cl:31])(=O)=O>>[Cl:31][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(NCc1ccc(CO)cc1)c1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCc1ccc(CCl)cc1)c1ccccn1
Yield: 45.2 %

Procedure:
Reaction of pyridine-2-sulfonic acid 4-hydroxymethyl-benzylamide (140 mg, 0.50 mmol), Et3N (88 uL, 0.60 mmol), and MsCl (47 uL, 0.60 mmol) for 2 h at reflux followed by column chromatography on silica gel (CH2Cl2/MeOH 99:1) gave the title compound (67 mg, 45%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 4.28 (d, 2H, J=6.0 Hz), 4.54 (s, 2H), 5.17 (br s, 1H), 7.23-7.49 (m, 4H), 7.47-7.52 (m, 1H), 7.88 (ddd, 1H, J=7.5, 7.5, 1.7 Hz), 7.97 (d, 2H, J=7.5 Hz), 8.69 (d, 1H, J=4.8 Hz). ES-MS m/z 319 (M+Na).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]2[S:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH2:4]1.[Cl:18][C:19]1[N:20]=[C:21]([C:26](O)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:18][C:19]1[N:20]=[C:21]([C:26]([NH:1][CH2:2][CH:3]2[CH2:6][N:5]([C:7]3[S:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=3)[CH2:4]2)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25]
Reactant: CCOC(=O)c1sc(N2CC(CN)C2)nc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1sc(N2CC(CNC(=O)c3nc(Cl)c(CC)[nH]3)C2)nc1C
Yield: 55.8 %

Procedure:
The same operation as in Example (221c) was performed using ethyl 2-[3-(aminomethyl)azetidin-1-yl]-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (233c) (51 mg, 0.20 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (52 mg, 0.30 mmol), WSC hydrochloride (115 mg, 0.60 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol) and N-methylmorpholine (0.04 mL, 0.40 mmol), to obtain 46 mg of the title compound as a white solid (56%).
Reaction SMILES: [CH:1]1([CH2:4]O)[CH2:3][CH2:2]1.[NH:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1.O.C(OCC)(=O)C>[CH:1]1([CH2:4][N:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: OCC1CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NN(CC1CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 486.4 %

Procedure:
To a mixture of cyclopropylmethanol (10.1 g, 140 mmol), di-tert-butyl hydrazine-1,2-dicarboxylate (6.50 g, 28.0 mmol) and triphenylphosphine (44.1 g, 168 mmol) in tetrahydrofuran (100 mL) was added di-tert-butyl azodicarboxylate (38.7 g, 168 mmol) in portions. The mixture was stirred at room temperature for 3 hours then diluted with water and ethyl acetate. The organic extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% hexane in ethyl acetate gradient) to yield di-tert-butyl 1-(cyclopropylmethyl)hydrazine-1,2-dicarboxylate (39 g, 97% yield). 1H NMR (300 MHz, CDCl3) δ ppm 0.16-0.27 (m, 2H), 0.40-0.54 (m, 2H), 0.94-1.09 (m, 1H), 1.47 (s, 9H), 1.48 (s, 9H), 3.31 (d, J=6.10 Hz, 2H), 6.38 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([O:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[C:10]([C:29]#[N:30])=[N:9]2)=[C:4]([F:31])[CH:3]=1.[ClH:32].O1CCOCC1.CCOCC>C(Cl)Cl>[ClH:32].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([O:15][CH:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[C:10]([C:29]#[N:30])=[N:9]2)=[C:4]([F:31])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Br)cc3F)nc2C#N)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1nn(-c2ccc(Br)cc2F)c(=O)cc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a stirring solution of tert-butyl 4-(1-(4-bromo-2-fluorophenyl)-3-cyano-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (493 mg, 1.0 mmol) in DCM (5 mL) at room temperature under argon was added 4 M HCl in dioxane (1.25 mL, 5.0 mmol). The reaction mixture was stirred at room temperature overnight. Et2O (10 mL) was added to the reaction mixture. The solid product was collected by filtration and further washed with ether (2 mL×2). After drying under vacuum for 2 hours, 334 mg (85%) of 1-(4-bromo-2-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt was obtained as an off-white solid. MS (ESI) 393 (M+H).
Reaction SMILES: [CH3:1][C:2]1([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=2)[C:19]2[C:18]3[CH:17]=[CH:16][C:15]([OH:20])=[CH:14][C:13]=3[O:12][CH2:11][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:21])=[CH:5][C:4]=2[O:3]1.[CH3:37][C:38]([CH3:43])([CH3:42])[C:39](Cl)=[O:40].[C:44]([O-:47])(O)=O.[Na+]>ClCCl>[CH3:37][C:38]([CH3:43])([CH3:42])[C:39]([O:20][C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[C:2]([CH3:1])([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:24][CH:23]=4)[O:3][C:4]4[CH:5]=[C:6]([O:21][C:44](=[O:47])[C:2]([CH3:22])([CH3:19])[CH3:1])[CH:7]=[CH:8][C:9]=4[C:10]=3[CH2:11][O:12][C:13]=2[CH:14]=1)=[O:40]
Reactant: O=C([O-])O
Reactant: CC1(c2ccc(OCCN3CCCCC3)cc2)Oc2cc(O)ccc2C2=C1c1ccc(O)cc1OC2
Reactant: CC(C)(C)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)OC(C)(c1ccc(OCCN3CCCCC3)cc1)C1=C2COc2cc(OC(=O)C(C)(C)C)ccc21
Reaction time: 0.08 h

Procedure:
To a suspension of 5-methyl-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,11-dihydro-chromeno[4,3-c]chromene-2,8-diol, prepared as om STEP C above, in dichloromethane (5 mL) (DCM) at 5° C. was added TEA (42 mg, 0.42 mmol) and the reaction mixture stirred for 5 min. Trimethylacetyl chloride (47 mg, 0.39 mmol) was then added to the reaction mixture and the mixture stirred at room temperature overnight. To the reaction mixture was then added saturated NaHCO3 (10 mL) and stirred for 1 h. The resulting mixture was extracted with DCM, washed with brine and dried over MgSO4. The organic layer was concentrated and the residue was purified via silica gel with 2% methanol in DCM as the eluent, to yield the title compound as a thick yellow oil.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Cl[C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.CN(C=O)C>O>[CH2:1]([S:3][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)c1ncccc1Cl
Reactant: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cccnc1C(=O)Nc1cccc(C(F)(F)F)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
0.86 g of sodium ethanethiolate was added to a mixture of 1.23 g of 3-chloro-N-(6-trifluoromethylpyridin-2-yl)picolinamide and 3 mL of DMF, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture cooled to room temperature was poured to water, and the precipitated solid was taken by filtration. The resulting solid was dissolved in ethyl acetate, and the mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.30 g of 3-ethylsulfanyl-N-(6-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 7).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[S:13]1C=CC=C1CC(O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:41][CH:42]([O:44]C(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[C:42](=[O:44])([S:13][CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:12])[CH3:41]
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: O=C(O)Cc1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)SCCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
tert-Butyl 3-hydroxypropylcarbamate (3.22 g, 18.37 mmol) in 100 ml of DCM at 0° C. was added thiolacetic acid (2.0 ml, 26.73 mmol) and triphenylphosphine (7.0 g, 26.73 mmol) under Ar. After stirred at 0° C. for 15 min, DIAD (6.0 ml, 28.93) was added. The mixture was stirred at 0° C. for 2 h then RT overnight. The mixture was concentrated, diluted with 120 ml of EtAc/Hexane (1:2), filtered through celite. The solution was washed with NaHCO3 (conc.)/NaCl (conc.) and 1 M NaH2PO4 respectively, dried over MgSO4, filtered, evaporated and purified on SiO2 chromatography eluted with EtAc/Hexane (1:7 to 1:6) to afford 3.22 g (75%) of the title compound. 1H NMR (CDCl3) 3.09 (t, 2H, J=6.5 Hz), 2.84 (t, 2H, J=6.9 Hz), 2.27 (s, 3H), 1.69 (dt, 2H, J=6.8, 13.5 Hz),1.38 (s, 9H); 13C NMR 196.35, 156.16, 79.50, 39.26, 30.79, 30.24, 28.61, 26.44; MS m/z+ 256.0 (M+Na).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[C:11]([CH2:13][Cl:14])[CH:10]=[C:7]([CH:8]=[O:9])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C(#N)C>[ClH:14].[C:1]([C:5]1[CH:12]=[C:11]([CH2:13][N:18]([CH2:19][CH3:20])[CH2:16][CH3:17])[CH:10]=[C:7]([CH:8]=[O:9])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CCl)cc(C=O)c1O
Reactant: CCNCC
Solvent: CC#N
Product: CCN(CC)Cc1cc(C=O)c(O)c(C(C)(C)C)c1
Product: Cl
Temperature: 30 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of 3-tert-butyl-5-chloromethylsalicylaldehyde (8)(226.5 mg, 1 mmol) in acetonitrile (60 mL), diethylamine (1 mmol) was added dropwise to give a greenish solution. The reaction was stirred at 30° C. overnight. After evaporation of volatiles, a green oil was obtained and it was used without any purification for the next step. Yield: 77%. Green oil. IR 3300, 2899, 1720. 1H-NMR δH (CDCl3, 300 MHz): 1.35 (9H, s, C(CH3)3), 1.45 (61-1, t, J=7.2 Hz, 2×CH2CH3), 3.43 (4H, q, J=7.2 Hz, 2×CH2CH3), 4.90 (2H, s, CCH2N), 7.57, 8.03 (2H, 2d, J=2.1 Hz, 2×HAr), 9.98 (1H, s, CHO), 12.00 (1H, br s, OH). δC(CDCl3, 75 MHz): 10.8, 28.3, 33.7, 45.8, 56.0, 119.5, 129.8, 130.3, 133.7, 137.0, 159.0, 195.9.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH3:18]>C(O)C>[NH:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:3]1[N:4]=[C:5]([NH2:18])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccc(Cl)c(-c2nc3ccccc3[nH]2)n1
Reactant: N
Solvent: CCO
Product: Nc1ccc(Cl)c(-c2nc3ccccc3[nH]2)n1
Reaction time: 16.67 h
Yield: 21 %

Procedure:
2-(3,6-Dichloro-pyridin-2-yl)-1H-benzoimidazole (20 mg; 0.076 mmol) was dissolved in ethanol (1.5 ml) and concentrated ammonia (2 ml) in a pressure tube. After 1000 minutes in a microwave at 140° C. and 200 psi, the solvents were removed and the residue dissolved in isopropyl alcohol (1 ml) and concentrated ammonia (1 ml) before microwaving as before. The solvents were evaporated and the residue chromatographed on silica gel with 80% ethyl acetate in heptane to give 6-(1H-benzoimidazol-2-yl)-5-chloro-pyridin-2-ylamine (4 mg, 21%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[NH:11].C[O:14][C:15](=O)/[C:16](/[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[C:17](\O)/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(OC(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=C(Cl)C=2Cl)N=1)=O)(C)(C)C>>[C:21]([O:20][C:18]([C:17]1[C:16]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:15]([OH:14])[N:12]=[C:10]([CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[Br:2])[N:11]=1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: N=C(N)Cc1ccccc1Br
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)c1nc(Cc2cccc(Cl)c2Cl)nc(O)c1OCc1ccccc1
Agent: Cl
Product: CC(C)(C)OC(=O)c1nc(Cc2ccccc2Br)nc(O)c1OCc1ccccc1
Yield: 83.3 %

Procedure:
5-Benzyloxy-2-(2-bromobenzyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (148) (28 g, crude) as a brown solid was synthesized from 2-(2-bromophenyl)-acetamidine hydrochloride salt (147) (17.76 g, 71.32 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (32.95 g, 106.98 mmol) following the procedure as described for 5-benzyloxy-2-(2,3-dichlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (130). The product was used without purification for further synthesis.
Reaction SMILES: OS(O)(=O)=O.[I:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[CH3:14])N.N([O-])=[O:16].[Na+].C(Cl)Cl>O.CCOC(C)=O>[I:6][C:7]1[CH:8]=[C:9]([OH:16])[CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: Cc1ccc(N)cc1I
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(O)cc1I
Temperature: 0 °C

Procedure:
A mixture of 8 mL of concentrated H2SO4, 12 mL of water, 3-iodo-4-methylaniline (5.00 g, 21.5 mmol) and 20 g of ice was stirred under ice-bath cooling until a paste resulted. To this paste was added slowly an ice-cold solution of NaNO2 (1.55 g, 22.4 mmol) in 3.5 mL of water and the resulting mixture stirred for 20 minutes while maintaining the temperature at <5° C. The resulting suspension was slowly added to a mixture of 26 mL of concentrated H2SO4 and 24 mL of water preheated to 80° C. This mixture was stirred at 80° C. for 15 min, then chilled in an ice-bath and poured onto 200 g of ice. The resulting mixture was extracted with 100 mL of EtOAc, and the organic extract washed with water, brine, dried (MgSO4) and evaporated to give a residue. The residue was adsorbed onto 15 g of SiO2 from CH2Cl2, loaded into a precolumn and subjected to MPLC through a 120 g column of SiO2 eluting with 5% EtOAc in hexanes (10 min) and then 10% EtOAc (20 min) to provide 3-iodo-4-methylphenol 1-1 as an oil. 1H NMR (300 MHz, DMSO-d6): δ 2.25 (s, 3H), 6.71 (dd, 1H, J=8, 2 Hz), 7.11 (d, 1H, J=8 Hz), 7.23 (d, 1H, J=2 Hz), 9.51 (s, 1H); LC-MS: calculated for C7H7IO 234.0, observed m/e 234.6 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12]O.O=S(Cl)Cl>C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(O)cc1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(O)cc1

Procedure:
A mixture of 4-hydroxyphenylacetic acid (9.12 g, 0.06 mol), methanol (50 mL) and SOCl2 (2 mL, 0.028 mol) was refluxed for 3 hours. The residue was cooled, diluted with ethyl acetate (20 mL), washed-first with aqueous 5% Na2CO3 solution and then twice with water (100 mL), then dried over anhydrous MgSO4, filtered and evaporated in vacuo to give methyl 4-hydroxyphenylacetate as an oil.