Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:28]([N:31](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN.O1CCCC1>CN(C)C=O.O>[CH:1]1([CH2:6][CH:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:31][CH3:28])=[O:17])=[CH:13][N:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
A solution of 6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid (prepared as in Example 46, 125 mg, 0.31 mmol), N,N-diisopropylethylamine (0.10 mL, 0.61 mmol), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (142 mg, 0.32 mmol) in N,N-dimethylformamide (15 mL) at 25° C. was treated dropwise with a 2.0M solution of methylamine in tetrahydrofuran (0.16 mL, 0.32 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-N-methyl-nicotinamide (83 mg, 64%) as white solid: mp 229.1-231.7° C.; FAB-HRMS m/e calcd for C21H23Cl2N3O2 (M+H)+ 420.1245, found 420.1247.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:12]=[C:13]([N:15]=[N+:16]=[N-:17])[CH:14]=1)=[O:8])[CH3:5].[C:25]([Si](C)(C)C)#[CH:26]>CN(C=O)C>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[CH:12]=[C:13]([N:15]2[CH:26]=[CH:25][N:17]=[N:16]2)[CH:14]=1)=[O:8])[CH3:5]
Reactant: C#C[Si](C)(C)C
Reactant: COCC(C)NC(=O)c1cc(N=[N+]=[N-])cc(-c2ccc(C)cc2)c1
Solvent: CN(C)C=O
Product: COCC(C)NC(=O)c1cc(-c2ccc(C)cc2)cc(-n2ccnn2)c1
Yield: 49.8 %

Procedure:
A solution of 5-azido-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (488 mg, 1.5 mmol), ethynyltrimethylsilane (4.5 mmol, 0.64 mL) in DMF (6 mL) was heated to 110° C. for 16 hours. The mixture was cooled and filtered, and the filtrate was purified by preparative HPLC to afford 262 mg of 4′-methyl-5-[1,2,3]triazol-1-yl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide as white solid (50%). MS (M+H)=351.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:38])[N:24]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][C:26]([OH:28])=O)([CH3:4])([CH3:3])[CH3:2].C1C=NC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.[C:59]([O:63][C:64](=[O:75])[C:65]1[CH:73]=[C:72]([NH2:74])[CH:71]=[C:67]([C:68]([OH:70])=[O:69])[CH:66]=1)([CH3:62])([CH3:61])[CH3:60].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:59]([O:63][C:64](=[O:75])[C:65]1[CH:73]=[C:72]([NH:74][C:26](=[O:28])[CH2:25][N:24]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:23](=[O:38])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:39])[CH:71]=[C:67]([C:68]([OH:70])=[O:69])[CH:66]=1)([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)CC(=O)O
Reactant: CC(C)(C)OC(=O)c1cc(N)cc(C(=O)O)c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)CC(=O)Nc1cc(C(=O)O)cc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
17-[(2-tert-Butoxycarbonyl-ethyl)-carboxymethyl-carbamoyl]-heptadecanoic acid tert-butyl ester (0.130 g) was dissolved in dry DCM (5 ml). HOAt (0.36 mg) and DIC (0.045 ml) was added the mixture was refluxed for 1 h under nitrogen. The reaction mixture was cooled to room temperature and 5-amino-isophthalic acid mono t-Butyl ester (60 mg) was added. After stirring for 1 h DIPEA (0.050 ml) was added, the orange reaction mixture turns yellow. After stirring for 2 days, the reaction mixture was concentrated. The residue was redissolved in EtOAc and extracted with 0.1 N HCl (2×) and brine (1×), dried (Na2SO4), and concentrated to give an sirup, which solidifies on standing. 5-{2-[(2-tert-Butoxycarbonyl-ethyl)-(17-tert-butoxycarbonyl-heptadecanoyl)-amino]-acetylamino}-isophthalic acid mono-tert-butyl ester was obtained in a quantitative yield (214 mg), contaminated with an impurity. HPLC/MS 775 (M), rt 7.64 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[S:13][C:14]([C:23]4[N:27]=[CH:26][N:25]([CH:28]5[CH2:33][CH2:32][CH2:31][CH2:30][O:29]5)[N:24]=4)=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=3)=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[C:36]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>COCCOC.O>[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[C:36]=1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[S:13][C:14]([C:23]4[N:27]=[CH:26][N:25]([CH:28]5[CH2:33][CH2:32][CH2:31][CH2:30][O:29]5)[N:24]=4)=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=3)=[C:9]([CH3:11])[N:10]=2)[CH:7]=1
Reactant: Cc1nc2ccc(Br)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: COc1cccc(F)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COc1cccc(F)c1-c1ccc2nc(C)c(-c3nc(-c4ccccc4)c(-c4ncn(C5CCCCO5)n4)s3)n2c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a suspension of 6-bromo-2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine (157 mg, 0.3 mmol) obtained in Example 117-B(i) in DME (10 mL) and water (2 mL) were added (2-fluoro-6-methoxyphenyl)boronic acid (102 mg, 0.6 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (51 mg, 0.06 mmol) and cesium carbonate (293 mg, 0.9 mmol) under a nitrogen atmosphere, and the mixture was stirred at 95° C. for 2 h. The reaction mixture was allowed to cool to rt, and then were added water (40 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (40 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (EtOAc/hexane=10/90→50/50) to give the title compound (156 mg, 92%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5](N)=[C:4]([F:11])[CH:3]=1.N([O-])=O.[Na+].C(Cl)Cl.[Br-:19]>Br.O.C(OCC)(=O)C>[Br:19][C:5]1[CH:7]=[C:8]([O:9][CH3:10])[C:2]([Cl:1])=[CH:3][C:4]=1[F:11]
Reactant: COc1cc(N)c(F)cc1Cl
Reactant: [Br-]
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(Br)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of 4-chloro-2-fluoro-5-methoxyaniline (25.0 g, 0.143 mol) in 10% HBr (250 mL) was cooled to 0° C. and a solution of sodium nitrite (15.0 g, 0.218 mol) in water (20 mL) was slowly added. Methylene chloride (50 mL) and curpric bromide (30.0 g, 0.244 mol) were added slowly and then the mixture was warmed to ambient temperature and stirred for 1 hour. The reaction mixture was filtered through a bed of celite and extracted with methylene chloride (2×100 mL) and the combined organic phases were dried (sodium sulfate) and concentrated. Chromatography of the dark oil (5% ethyl acetate in hexanes) gave 1-bromo-4-chloro-2-fluoro-5-methoxybenzene (16.6 g, 0.070 mol): 1H NMR (CDCl3): δ 7.20 (m, 1H) 7.05 (dd, 1H), 4.00 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([N+]([O-])=O)=[N:10][C:9]=3[N:8]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.O(Cl)[Cl:24].O>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([Cl:24])=[N:10][C:9]=3[N:8]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: ClOCl
Reactant: O=c1c2[nH]c([N+](=O)[O-])nc2n(CC2CC2)c(=O)n1CC1CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2[nH]c(Cl)nc2n(CC2CC2)c(=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,3-Di-cyclopropylmethyl-8-nitro xanthine (6 g, 0,023 mol) was dissolved in dimethylformamide (20 ml) and reacted with phosporous oxychloride (14 g) for 1 hour at 120° C. The mixture was then treated with water and stirred for 1 hour at room temperature. The precipitate was filtered off, dissolved in ethyl acetate, dried over anhydrous sodium sulphate and the solvent was removed in vacuo, yield 2.5 g (40%), m.pt. 220° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.C=O.[C:23](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(#N)C.O>[CH3:23][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])[CH:7]=2)[C:2]([CH3:20])([CH3:1])[CH2:3][CH2:4]1
Reactant: CCCCCC(CO)c1ccc2c(c1)NCCC2(C)C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: CCCCCC(CO)c1ccc2c(c1)N(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
A solution of 2-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptan-1-ol (from Example 5.5, step 6) (2.52 g, 9.15 mmole) in 35 mL of acetonitrile was cooled to 0° C. and treated with 6.68 mL of a 37% formaldehyde solution, 5.82 g of sodium triacetoxyborohydride and 2.36 mL of acetic acid. The reaction mixture was stirred at 0° C. for 30 minutes then at room temperature for four hours, diluted with 50 mL of water and extracted with two 50 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes) to yield 2.39 g of 2-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptan-1-ol as a pale yellow oil.
Reaction SMILES: CC(OC1C=CC=C([N+]([O-])=O)C=1)(C(OCC)=O)C(OCC)=O.CO[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[CH2:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([N+:45]([O-])=O)[CH:43]=2)[CH:38]=[N:37]1)[C:28]([O:30][CH3:31])=[O:29]>>[NH2:45][C:42]1[CH:43]=[C:44]2[C:39]([CH:38]=[N:37][N:36]2[CH2:35][C:34]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:40][CH:41]=1
Reactant: COC(=O)c1ccc(Cn2ncc3ccc([N+](=O)[O-])cc32)c(OC)c1
Agent: CCOC(=O)C(C)(Oc1cccc([N+](=O)[O-])c1)C(=O)OCC
Product: COC(=O)c1ccc(Cn2ncc3ccc(N)cc32)cc1

Procedure:
In like manner to the reduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, methyl 3-methoxy-4-[(6-nitroindazol-1-yl)methyl]benzoate was reduced to provide methyl 4-[(6-aminoindazol-1-yl)methyl]benzoate. 1H NMR (CDCl3): δ 7.88 (s, 1H), 7.53 (d, (d, 1H, J=8.8 Hz), 7.51 (d, 1H, J=8.8 Hz), 7.50 (d, 1H, J=1.7 Hz), 6.67 (d, 1H, J=8.8 Hz), 6.56 (dd, 1H, J=1.7 and 8.8 Hz), 6.45 (d, 1H, J=1.2 Hz), 5.50 (s, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 3.79 (br s, 2H).
Reaction SMILES: Cl.[NH2:2][C@@:3]([CH3:18])([CH2:15][CH2:16][CH3:17])[C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:5].[F:19][C:20]([F:42])([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:21][C@H:22]([NH:26][C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28])[C:23](O)=[O:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[O:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=[C:6]1[C:4]([C@:3]([NH:2][C:23]([C@@H:22]([NH:26][C:27]([N:29]1[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1)=[O:28])[CH2:21][C:20]([F:42])([F:19])[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:24])([CH3:18])[CH2:15][CH2:16][CH3:17])=[O:5]
Reactant: CCC[C@](C)(N)C(=O)c1nc2ccccc2o1
Reactant: O=C(O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCC[C@](C)(NC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1)C(=O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of (S)-2-amino-1-benzoxazol-2-yl-2-methyl-pentan-1-one hydrochloride (80.6 mg, 0.3 mmol), (S)-4,4-difluoro-2-[(morpholine-4-carbonyl)-amino]-5-phenyl-pentanoic acid (0.102 mg, 0.3 mmol), EDCI (69 mg, 0.36 mmol), HOBT (48.6 mg, 0.36 mmol) and Diisopropyl ethylamine (0.2 mL) in DMF is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate, washed with cold 1N HCl, saturated NaHCO3 and then saturated NaCl solution. The organic phase is dried over magnesium sulfate and solvent evaporated under reduced pressure to give the crude product. Purification by Silica gel column chromatography, eluting with ethyl acetate and heptane mixture gives morpholine-4-carboxylic acid {(S)-1-[(S)-1-(benzoxazole-2-carbonyl)-1-methyl-butylcarbamoyl]-3,3-difluoro-4-phenyl-butyl}-amide (82%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([Cl:26])=[O:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 3 h

Procedure:
In a 100-ml, three-necked, round-bottomed flask equipped with a magnetic stirrer, an oil bath, and a condenser topped with a drying tube were placed 1.69 g of 4-benzyloxy-4'-biphenylcarboxylic acid, 34 ml of thionyl chloride, and one drop of dimethylformamide. After stirring the solution for three hours under reflux, the thionyl chloride was distilled off, then 75 ml tetrachloromethane was added and distilled. The brown solid was dissolved in 500 ml hot dichloromethane, and the solution was treated with charcoal and filtered through Celite. The solids were washed with hot dichloromethane, and the filtrate was evaporated, to yield the following compound. ##STR26##
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][CH3:6].Cl[C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17]>CS(C)=O.O>[CH2:3]([O:7][C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17])[CH2:4][CH2:5][CH3:6]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 30 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution prepared by diluting 8.6 g (2.0 eq.) of 60% sodium hydride with 200 mL of dimethylsulfoxide, 16.0 g (2.0 eq.) of 1-butanol was added, and the mixture was allowed to react for one hour at 60° C. The reaction liquid was cooled to 30° C., and then a liquid containing 17.0 g of 4-chlor-2,3-dimethylpyridine-1-oxide dissolved in dimethylsulfoxide (70 mL) was added dropwise. The mixture was allowed to react for 3 hours at 40 to 50° C., and was left to stand overnight at room temperature. 15 mL of water was added to the reaction liquid, and the mixture was concentrated, to obtain a residue in the form of a black paste. Subsequently, the residue was dissolved in 500 mL of water, and then the aqueous solution was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and was concentrated to dryness under reduced pressure. The obtained residue was purified on a silica gel column, to obtain 20.3 g of 4-butoxy-2,3-dimethylpyridine-1-oxide.
Reaction SMILES: N.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=2)[N:6]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH2:24][CH3:25])[N:4]=1.C1COCC1.C(#[N:33])C>O>[NH2:33][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=2)[N:6]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH2:24][CH3:25])[N:4]=1
Reactant: CC#N
Reactant: CCSc1ccccc1-c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CCSc1ccccc1-c1nc(N)c2ccc(C(F)(F)F)cc2n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
4.5 ml of a 28% aqueous ammonia solution was added to a mixture of 500 mg of 4-chloro-2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline, 8 ml of THF and 5 ml of acetonitrile, and the mixture was stirred at 50° C. for 2 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 396 mg of 4-amino-2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline (Compound of Present Invention 5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([O:7][C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([C:15]3[N:16]=[C:17]([NH:20][C:21](=[O:31])[C:22]4[CH:27]=[CH:26][N:25]=[C:24]([N+:28]([O-])=O)[CH:23]=4)[S:18][CH:19]=3)=[C:10]([CH3:32])[CH:9]=2)=[CH:5][CH:4]=1>C(O)C.[Pd]>[NH2:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][N:25]=1)[C:21]([NH:20][C:17]1[S:18][CH:19]=[C:15]([C:11]2[C:10]([CH3:32])=[CH:9][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:34][CH:33]=3)=[CH:13][C:12]=2[CH3:14])[N:16]=1)=[O:31]
Reactant: COc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccnc([N+](=O)[O-])c4)n3)c(C)c2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccnc(N)c4)n3)c(C)c2)cc1
Reaction time: 8 h
Yield: 61.6 %

Procedure:
A mixture of N-(4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl)-2-nitroisonicotinamide (0.20 g, 0.40 mmol) and Pd/C (0.15 g, 10% w/w) in ethanol (10 mL) was stirred under H2 overnight. The reaction was filtered through diatomaceous earth and concentrated under reduced pressure to provide 2-amino-N-(4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (0.11 g) as yellow solids in 59% yield: 1H NMR (500 MHz, DMSO-d6) δ 7.88-7.89 (m, 1 H), 7.10-7.11 (m, 2 H), 6.95-6.97 (m, 2 H), 6.62 (s, 1 H), 5.76 (s, 1 H), 3.29 (s, 3 H), 2.03 (s, 6 H); ESI-MS: m/z 446.6 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:14]([OH:16])=O)=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:2].[Na].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.O[N:42]=[C:43]([C:45]1[CH:62]=[CH:61][C:48]([CH2:49][N:50]2[CH2:53][CH:52]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:51]2)=[CH:47][CH:46]=1)[NH2:44].N1C=CC=CC=1C1C(C(F)(F)F)=C(C2ON=C(C3C=CC(CN4CC(C(O)=O)C4)=CC=3)N=2)ON=1>C(#N)C>[CH2:1]([C:3]1[C:4]([C:14]2[O:16][N:44]=[C:43]([C:45]3[CH:46]=[CH:47][C:48]([CH2:49][N:50]4[CH2:51][CH:52]([C:54]([O:56][C:57]([CH3:58])([CH3:60])[CH3:59])=[O:55])[CH2:53]4)=[CH:61][CH:62]=3)[N:42]=2)=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:2]
Reactant: CCc1c(C(=O)O)noc1-c1ccccn1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)cc2)C1
Agent: O=C(O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Agent: On1nnc2ccccc21
Agent: [Na]
Solvent: ClCCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(-c2nc(-c3ccc(CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1-c1ccccn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 4-ethyl-5-(pyridin-2-yl)isoxazole-3-carboxylic acid, sodium salt (22 mg), HOBt (27.8 mg, 0.181 mmol), and diisopropylethylamine (0.070 mL, 0.403 mmol) in acetonitrile (1 mL) was added EDC (45.4 mg, 0.237 mmol) and tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int. 1 (30.8 mg, 0.101 mmol). The reaction mixture was stirred at 80° C. for 4 h. and then concentrated under reduced pressure. The residue was diluted with ethyl acetate (3 mL), washed with a saturated aqueous solution of sodium bicarbonate, washed with water (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by preparative HPLC [Prep HPLC: Column: PHENOMENEX® S10 30×100 mm; Gradient time: 10 min; Flow rate=40 ml/min; Solvent A=10% MeOH—90% Water—0.1% TFA; Solvent B=90% MeOH—10% water—0.1% TFA; Start % B=20; Final % B=100.] afforded tert-butyl 1-(4-(5-(4-ethyl-5-(pyridin-2-yl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[N:18]=[C:17]([N:19]([CH3:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:16]=[C:15]([NH2:27])[N:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH:28]([NH2:31])([CH3:30])[CH3:29].CCN(C(C)C)C(C)C>CCO>[CH3:26][N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]1[N:16]=[C:15]([NH2:27])[N:14]=[C:13]([C:10]2[N:9]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([NH:31][CH:28]([CH3:30])[CH3:29])=[CH:3][CH:4]=3)[O:12][N:11]=2)[N:18]=1
Reactant: CC(C)N
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(Cl)nc3)n2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)Nc1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Yield: 27.3 %

Procedure:
A mixture of 6-[5-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-triazine-2,4-diamine (Intermediate 135, 0.100 g, 0.263 mmol), isopropylamine (0.087 mL, 1.052 mmol), DIPEA (0.091 mL, 0.525 mmol) in EtOH (1 mL) was heated 3 times under microwave conditions (first treatment: 100 W, 130 C, 40 min; second treatment: 100 W, 130 C, 45 min; third treatment: 100W, 130 C, 45 min). The reaction mixture was cooled down and concentrated under vacuum. The resulting dark oil was purified by preparative HPLC, to afford the title compound (29 mg, 27%).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Cl[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=1.O>CN(C)C=O>[I:3][C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:8]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccnc1-n1cc(I)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 243 mg, 6.07 mmol) was suspended in 4 mL anhydrous N,N-dimethylformamide. To this solution was added 4-iodo-1H-pyrazole (982 mg, 5.06 mmol) in 4 mL anhydrous N,N-dimethylformamide at 0° C. under nitrogen. The mixture was stirred at 0° C. for 15 min, and then allowed to warm to ambient temperature and stirred at the same temperature for 2 hrs. After this period of time, a solution of 2-chloro-3-trifluoromethyl-pyridine (1.01 g, 5.56 mmol) in 4 mL N,N-dimethylformamide was added and the mixture was heated at 90° C. for 5 hrs. After cooling off, the mixture was poured into water and extracted with ethyl acetate three times. The combined extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 2-(4-iodo-pyrazol-1-yl)-3-trifluoromethyl-pyridine as a white solid (1.406 g, 74% yield). The product was used for the next step without purification. 1H-NMR (400 MHz, CDCl3): δ 7.48 (dd, 1H, J=4.80, J=8.08), 7.79 (s, 1H), 8.21 (dd, 1H, J=1.52, J=8.08), 8.27 (s, 1H), 8.67 (dd, 1H, J=1.52, J=4.80).