Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH:27]3[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1.CCN(C(C)C)C(C)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>C(Cl)Cl>[F:39][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH:27]3[CH2:32][CH2:31][CH2:30][N:29]([S:50]([CH3:49])(=[O:52])=[O:51])[CH2:28]3)[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCCNC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCCN(S(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N1-(3-piperidinyl)-1,3-propanediamine (155 mg, 0.28 mmol) and DIPEA (1 mL) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (0.5 mL) at 0° C. The resulting mixture was stirred for 16 hrs at room temperature. After dilution with water, the organic layer was separated, and the aqueous layer was further extracted with CH2Cl2 (3×15 mL). The combined organic fractions were dried over Na2SO4, and the solvent removed under vacuum. The residue was chromatographed on alumina eluting with CH2Cl2/MeOH (97:3) to give partially pure material, which was further purified by chromatography on silica eluting with CH2Cl2/MeOH (97:3) to give N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N1-[1-(methylsulfonyl)-3-piperidinyl]-1,3-propanediamine (125 mg, 72% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O-:11])[C:5]([N+:8]([O-])=O)=[N:6][CH:7]=1.[Na+]>C(O)C.[Pt](=O)=O>[NH2:8][C:5]1[C:4]([OH:11])=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1ncc(F)cc1[O-]
Agent: O=[Pt]=O
Agent: [Na+]
Solvent: CCO
Product: Nc1ncc(F)cc1O
Reaction time: 0.5 h
Yield: 11.7 %

Procedure:
A suspension of sodium 5-fluoro-2-nitro-pyridin-3-olate (7.3 g) and platinum(IV) oxide (0.092 g) in ethanol (20 ml) at 25° C., was hydrogenated under 3.5 atm at 25° C. for 30 minutes. The resulting black suspension was filtered through a pad of Dicalite Speed Plus (Acros Chemicals) and hydrogen chloride 4M in dioxane (4.26 ml) was added to the filtrate. The suspension was filtered and concentrated to a black oil, which was triturated in diethyl ether, the precipitate was collected by filtration and dried to afford the crude 2-amino-5-fluoro-pyridin-3-ol (0.607 g) hydrochloride salt. NMR Spectrum: (DMSOd6) 7.23 (dd, 1H), 7.65 (dd, 1H), 7.82 (bs, 2H), 12.23 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.COC1C=CC2[S:28]C3C(=CC=CC=3)NC=2C=1>>[CH3:1][O:2][C:3]1[C:8]2[S:28][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)Nc1ccccc1S2
Reactant: COc1cccc(Nc2ccccc2)c1
Product: COc1cccc2c1Sc1ccccc1N2

Procedure:
The conversion rate of the 3-methoxydiphenylamine is 91%, and the chemical yield of 2-methoxyphenothiazine is 91%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:27][O:28][CH2:29][CH3:30])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:39][CH2:38][CH2:37][C:36]3=[O:40])=[CH:5][C:4]=2[N:3]=1.[ClH:41]>>[ClH:41].[ClH:41].[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:27][O:28][CH2:29][CH3:30])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:39][CH2:38][CH2:37][C:36]3=[O:40])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCCN4CCCC4=O)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cl
Product: CCOCc1nc2c(N)nc3cc(OCCCN4CCCC4=O)ccc3c2n1CCCCN
Temperature: 25 °C

Procedure:
A solution of tert-butyl 4-{4-amino-2-(ethoxymethyl)-7-[3-(2-oxopyrrolidin-1-yl)propoxy]-1H-imidazo[4,5-c]quinolin-1-yl}butylcarbamate (prepared as described in Example 397, 2.90 g, 5.23 mmol) in 4 M ethanolic hydrogen chloride was heated at reflux for 2 hours. The solution was allowed to cool to room temperature and a precipitate formed that was isolated by filtration to afford 2.52 g of 1-(3-{[4-amino-1-(4-aminobutyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)pyrrolidin-2-one dihydrochloride as a white powder, mp>250° C. 1H NMR (300 MHz, DMSO-d6) δ 13.92 (s, 1H), 9.30-8.40 (br s, 2H), 8.15 (d, J=9.2 Hz, 1H), 8.13-8.00 (m, 3H), 7.30 (d, J=2.5 Hz, 1H), 7.20 (dd, J=9.1, 2.4 Hz, 1H), 4.83 (s, 2H), 4.65-4.60 (m, 2H), 4.10 (t, J=6.1 Hz, 2H), 3.60 (q, J=7.0 Hz, 2H), 3.41-3.37 (m, 4H), 2.87-2.76 (m, 2H), 2.22 (t, J=8.0 Hz, 2H), 2.04-1.85 (m, 6H), 1.81-1.70 (m, 2H), 1.19 (t, J=7.0 Hz, 3H);
Reaction SMILES: [OH:1][C:2]([PH:5](=[O:8])[O:6][CH3:7])([CH3:4])[CH3:3].O[C:10](P(O)O)([CH3:12])[CH3:11]>O>[OH:1][C:2]([PH:5](=[O:8])[O:6][CH2:7][CH:10]([CH3:12])[CH3:11])([CH3:4])[CH3:3]
Reactant: CC(C)(O)P(O)O
Reactant: CO[PH](=O)C(C)(C)O
Solvent: O
Product: CC(C)CO[PH](=O)C(C)(C)O
Temperature: 5 °C

Procedure:
The methyl (1-hydroxy-1-methylethyl)phosphinate prepared as described immediately above is heated with water (11) on a steam bath for 8 hours until conversion to 1-hydroxy-1-methylethylphosphonous acid is complete (monitored by 31P nmr). The water is removed on a rotary evaporator and the residue is completely dried by co-evaporation with toluene. A sample of this phosphonous acid (4.6 g, 0.037M), isobutyl alcohol (3.02 g, 0.041M) and dimethylaminopyridine (0.5 g, 0.0041M) is stirred at 5° C. in tetrahydrofuran. Dicyclohexylcarbodiimide (8.4 g, 0.041M) is added portionwise over 30 minutes. On completion of the reaction (31P nmr), ether (50 ml) is added and the precipitated dicyclohexyl urea is filtered off.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][CH:6]2[CH:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[O:4]1.CC(C)([O-])C.[K+].Cl[C:39]1[N:47]=[CH:46][CH:45]=[CH:44][C:40]=1[C:41]([OH:43])=[O:42]>CN(C=O)C>[CH3:12][C:9]1([CH3:11])[O:10][CH:6]2[CH:5]([N:13]3[CH:21]=[N:20][C:19]4[C:14]3=[N:15][CH:16]=[N:17][C:18]=4[NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])[O:4][CH:3]([CH2:2][O:1][C:39]3[N:47]=[CH:46][CH:45]=[CH:44][C:40]=3[C:41]([OH:43])=[O:42])[CH:7]2[O:8]1
Reactant: CC1(C)OC2C(CO)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1
Reactant: O=C(O)c1cccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC2C(COc3ncccc3C(=O)O)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
To a stirred solution of 1-[9-(6-hydroxymethyl-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl]-3-phenyl-urea (43 mg, 0.1 mmol) in dry N,N′-dimethylformamide (1 mL) at 23° C. was added potassium tert-butoxide (45 mg, 0.4 mmol). After 30 min, 2-chloronicotinic acid (60 mg, 0.4 mmol) was added to the solution. The resulting mixture was stirred at 23° C. for 15 h and then quenched with water (1 mL), suspended in ethyl acetate (50 mL), washed with brine (3×), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. Preparative reverse-phase HPLC was used to obtain the pure compound (15 mg, 27% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 10.15 (s, 1H), 9.16 (s, 1H), 8.65 (s, 1H), 8.05 (dd, J=8.5 Hz, 3.5 Hz, 1H), 7.94 (dd, J=9.0 Hz, 3.0 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.32 (t, J=12.5 Hz, 2H), 7.05 (t, J=12.5 Hz, 1H), 6.96 (dd, J=12.5 Hz, 8.5 Hz, 1H), 6.25 (d, J=6.0 Hz, 1H), 5.80 (t, J=7.5 Hz, 1H), 5.10 (dd, J=9.0 Hz, 2.5 Hz, 1H), 4.67 (m, 1H), 4.53 (dd, J=20.0 Hz, 4.0 Hz, 1H), 4.36 (dd, J=20.0 Hz, 4.0 Hz, 1H), 1.59 (s, 3H), 1.38 (s, 3H). MW calculated for C26H25N7O7 (MH+) 548, found 548 by LCMS.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].O1CCCC1.Cl>O.C(O)C>[F:25][C:2]([F:1])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
A mixture of ethyl 4-[5-(4-trifluoromethylphenyl)-2-thienyl]benzoate (0.941 g), 1 M aqueous sodium hydroxide solution (7.5 ml), tetrahydrofuran (25 ml) and ethanol (25 ml) as stirred at 60° C. for 1 hr. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid (25 ml) was added. The crystals were collected by filtration and recrystallized from ethanol to give 4-[5-(4-trifluoromethylphenyl)-2-thienyl]benzoic acid (0.583 g, yield 67%) as a yellow crystalline powder. melting point: 284–285° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.C(Cl)Cl.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:26])[CH3:25]>>[C:24]([N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1)(=[O:26])[CH3:25]
Reactant: O=C1CCNc2cccnc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(=O)c2ncccc21

Procedure:
To a solution of 2,3-dihydro-1,5-naphthyridin-4(1H)-one (1 eq.) and DCM (0.2 eq.) is added DIEA (2.2 eq.) and acetyl chloride (1.2 eq.). The reaction is monitored by TLC. The reaction is washed with water, brine, dried over MgSO4, concentrated in vacuo, and purified by column chromatography to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(Cl)Cl.CN(C=O)C>[O:29]1[CH2:30][CH2:31][N:26]([C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:27][CH2:28]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To stirred solution of 3-nitrobenzoic acid (5 g, 29.9 mmol) in DCM: DMF (30 ml, 29:1) was added oxalyl chloride (3.14 ml, 35.9 mmol) dropwise at RT. Resulting reaction mixture was stirred for 1 h. The mixture was concentrated and the residue was dissolved in DCM (25 ml), the reaction mixture was cooled to 0° C. and triethylamine (6.26 ml, 44.9 mmol) and morpholine (3.13 ml, 35.9 mmol) were added and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated under vacuum and the residue was diluted with cold water, the solid separated out was filtered and washed with n-hexanes and dried under vacuum to give the product (4.9 g).
Reaction SMILES: C[C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4](C)(C)N1.C1([C:17](C2C=CC=CC=2)([PH2:39]=[O:40])[N:18]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:19](=[O:29])[C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2F)C=CC=CC=1>C1COCC1.[Cl-].[NH4+]>[C:6]1([P:39]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:10]=2)([CH:17]2[C:21]3[C:20](=[CH:25][C:24]([O:26][CH3:27])=[CH:23][CH:22]=3)[C:19](=[O:29])[N:18]2[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)=[O:40])[CH:5]=[CH:4][CH:10]=[CH:2][CH:7]=1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: COc1ccc(CN(C(=O)c2cc(OC)ccc2F)C([PH2]=O)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)c3cc(OC)ccc3C2P(=O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 40.7 %

Procedure:
To a cooled solution (−78° C.) of 2,2,6,6-tetramethylpiperidine (5.7 g, 40.3 mmol) in THF (60 mL) BuLi (25 mL, 1.6 M in hexanes, 40.3 mmol) was added. To the resulting mixture a solution of N-(diphenyl-phosphinoylmethyl)-2-fluoro-5-methoxy-N-(4-methoxy-benzyl)-benzamide (9.2 g, 18.3 mmol) in THF (55 mL) was added at such a rate to maintain the temperature below −70° C. and maintained at this temperature for 30 min. The reaction mixture was then allowed to warm up to RT over 5 h, and diluted with ammonium chloride (200 mL). The product was then extracted with diethyl ether and the combined extracts washed with brine. The residue was then evaporated and purified by chromatography (SiO2, Hexane:Acetone 1:1) to afford the title product (3.6 g, 41%) as a light yellow solid. MS m/e=484.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:28]4[CH:29]=[CH:30][C:25]([C:23]([O:22][CH2:20][CH3:21])=[O:24])=[CH:26][CH:27]=4)=[CH:3][CH:4]=3)[O:9][CH:10]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(-c2coc(-c3ccc(Br)cc3)n2)cc1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccc(-c3nc(-c4ccc(C)cc4)co3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of Example 186B (140 mg, 0.45 mmol) in ethylene glycol dimethyl ether (7.0 mL) at room temperature was treated with tetrakis(triphenylphosphine)palladium (26 mg, 0.02 mmol), stirred for 5 minutes, treated with a solution of Example 186A (104 mg, 0.54 mmol) in ethanol (1.5 mL), stirred for 5 minutes, treated with 2M sodium carbonate (1.1 mL, 2.23 mmol), heated to reflux, and stirred for 4 hours. The reaction mixture was cooled to room temperature and concentrated. The concentrate was dissolved in water (20 mL) and extracted with diethyl ether (4×20 mL). The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate/hexanes to provide the desired product. MS (DCI) m/e 384 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.18-8.16 (m, 2H), 8.09-8.06 (m, 4H), 7.97-7.89 (m, 4H), 7.30-7.28 (m, 2H), 4.35 (q, 2H), 2.34 (s, 3H), 1.35 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[ClH:17].O1CCOCC1>C(O)C>[ClH:17].[NH:2]=[C:1]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: C1CCNC1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: N=C(c1ccc(C(=O)O)cc1)N1CCCC1
Temperature: 35 °C

Procedure:
4-Cyanobenzoic acid (10.0 g, 68.0 mmol) was dissolved in anhydrous ethanol (10 ml) and 4N hydrochloric acid/1,4-dioxane 90 ml, and the mixture was stirred in a closed system at room temperature for two nights, and further stirred in an open system for at 35° C. 3 hours. The solvent was evaporated under reduced pressure, and the obtained residue was suspended in anhydrous ethanol (100 ml), and pyrrolidine (11.4 ml, 136 mmol) was added thereto, and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration, and washed with diethyl ether containing a small amount of 4N hydrochloric acid/1,4-dioxane, and the crystals were collected by filtration to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[CH3:12].[CH3:13][C:14]1[C:18]([CH3:19])=[C:17]([CH3:20])[NH:16][N:15]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:15]2[C:14]([CH3:13])=[C:18]([CH3:19])[C:17]([CH3:20])=[N:16]2)=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(B(O)O)cc1C
Reactant: Cc1n[nH]c(C)c1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccc(-n2nc(C)c(C)c2C)cc1C
Yield: 52.6 %

Procedure:
A mixture of 4-methoxy-3-methyl-phenylboronic acid 10 g, 3,4,5-trimethyl-1H-pyrazole (described in Reference Preparation example 49) 7.3 g, copper(II) acetate 18.4 g, pyridine 10.0 g, molecular sieves 4 A 20.0 g and acetonitrile 300 ml was stirred with heating under reflux for thirty hours. The reaction mixture was filtered through Celite and was concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(4-methoxy-3-methyl-phenyl)-3,4,5-trimethyl-1H-pyrazole 7.3 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C=O)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
Mix 5-hydroxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (2.8 g, 10 mmol) and Dess-Martin periodinane (5.1 g, 12 mmol) in dichloromethane (50 mL) in an ice-bath. Stir the mixture overnight at room temperature. Dilute with dichloromethane (50 mL) and quench it with premixed sodium thiosulfate (1.5 g) in 5% aqueous sodium bicarbonate solution (50 mL). Filter the slurry through a filtering agent and separate the organic layer. Dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound (2.2 g, 79%).
Reaction SMILES: [NH2:1]C1SC(C)=NN=1.C(O[C:13]1[C:21](OC)=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1OC)CCC.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:17]([NH2:1])(=[O:18])[C:16]1[CH:20]=[CH:21][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1nnc(N)s1
Reactant: CCCCOc1c(OC)cc(C(=O)O)cc1OC
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:
A compound represented by Formula 110, that is, 2-amino-5-methyl-1,3,4-thiadiazole (314.6 mg, 2.73 mmol, purchased from TCI Co.) was slowly added to 4-n-butoxy-3,5-dimethoxybenzoic acid represented by Formula 90 (772 mg, 3.04 mmol) prepared in Preparative Example 2 and diisopropylethylamine (1.64 mL, 10.92 mmol) in DMF (15 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, 1.15 g, 3.04 mmol) thereto, the mixture was agitated at room temperature for 24 hours. The reaction solvent was removed under reduced pressure and chloroform (30 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. The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) using silica gel (SiO2), resulting in a benzamide compound represented by Formula 24 as a desired product (VVZ-025; 545.7 mg, 56.8% yield).
Reaction SMILES: Br.[NH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=O)[CH2:7]Br.[C:13]([NH2:16])(=[S:15])[CH3:14].CN(C)C=O.[OH-].[Na+]>O>[CH3:14][C:13]1[S:15][CH:7]=[C:6]([C:5]2[CH:10]=[CH:11][CH:12]=[C:3]([NH2:2])[CH:4]=2)[N:16]=1
Reactant: CC(N)=S
Reactant: Nc1cccc(C(=O)CBr)c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(N)c2)cs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
A mixture of 3-amino-phenacyl bromide hydrobromide (11.78 g), thioacetamide (3 g) and dimethylformamide (20 ml) was stirred at room temperature for 24 hours and then poured into water (100 ml). The resulting solution was made alkaline with 10% sodium hydroxide, and the precipitate was filtered off and dried to give 6 g of 2-methyl-4-(3-amino-phenyl)-thiazole; M.p. 134°-137° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CO>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=2)[O:7][CH:12]=1)[CH3:19]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CO
Product: CCOC(=O)Cc1coc(-c2ccc(O)cc2)n1
Temperature: 110 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of 4-hydroxybenzamide (25.2 g, 0.18 mol) and ethyl chloroacetoacetate (90 mL) is heated to 110° C. After 1 h, more ethyl chloroacetoacetate (30 mL) is added, and continue to heat for 3 h more. The mixture is cooled to approximately 60° C., and MeOH is added. The mixture is filtered and dried to yield the title compound (36.6 g, 80%) as an off-white solid. MS (m/e): 248.3 (M+1)
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:14]([NH:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=1)=[O:19])[CH3:15].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][CH2:9][C:10]([N:16]([CH2:14][CH3:15])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=1)=[O:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CCNCC(=O)c1ccc(F)c(C)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC(=O)c1ccc(F)c(C)c1)C(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
2.9 g benzyloxy-acetyl chloride was added to 3.7 g 2-ethylamino-1-(4-fluoro-3-methyl-phenyl)-ethanone hydrochloride and 5 mL triethylamine in 40 mL dichlormethane. The reaction was stirred 3 h at RT. The reaction was diluted with dichlormethane, washed with water, 1 mol/L aqueous hydrochloride acid and with 5% aqueous potassium carbonate solution. The organic layer was dried and evaporated to yield 5.2 g of the desired product. Rt: 0.91 min (method J), (M+H)+: 344