Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:9]=[CH:10][C:3]=12
Reactant: Brc1ccnc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (15 g, 76 mmol) in N,N-dimethyformamide (300 mL) was added NaH (95%, 3.96 g, 99 mmol) at 0° C. The mixture was allowed to warm up to room temperature and was stirred for another 30 minutes. Benzenesulfonyl chloride (11.78 mL, 91 mmol) was added. After stirring at room temperature for 16 hours, the reaction mixture was quenched with aqueous NaHCO3 solution and was extracted with ethyl acetate (three times with 450 mL). The combined organic layers were washed with water, dried over MgSO4, and filtered. The filtrate was concentrated and the residue was separated by flash chromatography on silica gel (Teledyne CombiFlash Rf, 5% of ethyl acetate in dichloromethane) to provide the title compound. MS (ESI+) m/z 337 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:6]=[CH:5]2.[C:17](OC(=O)C)(=[O:19])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:17]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:6]=[CH:5]2)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)Oc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
A mixture of 2.2 g. of 6-hydroxy-2-naphthyl-α-methylacetic acid, 50 ml. of acetic anhydride, and 100 mg. of p-toluenesulfonic acid is stirred for four hours at 50° C. The mixture is evaporated, water is added, and the mixture is extracted with diethyl ether which is washed with water to neutrality, dried over sodium sulfate, and evaporated to yield 6-acetoxy-2-naphthyl-α-methylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[CH:24]3)=[O:20])[CH:17]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]=[CH:26][CH:25]=[CH:24]4)=[O:20])[CH:17]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1NC(=O)c1ccc2ncccc2c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1NC(=O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Using an analogous procedure to that described in Example 4, 6-chloropyrid-3-ylcarbonyl chloride was reacted with N-(5-amino-2-methylphenyl)quinoline-6-carboxamide in the presence of triethylamine. The reaction mixture was stirred at ambient temperature for 16 hours and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound; Mass Spectrum: M−H− 415.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][NH:30][CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=[C:23]([C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=2[F:42])[S:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:51](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][N:30]([CH3:51])[CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=[C:23]([C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=2[F:42])[S:22]1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nc2c(s1)CNCC2)(c1ccccc1)c1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3ccccc3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-4,5,6,7-tetrahydrothiazol[5,4-c]pyridine (0.157 g, 0.225 mmol) in 5 mL DCE was added formaldehyde (0.067 mL, 37 wt % in water, 0.901 mmol) followed by sodium triacetoxyborohydride (0.052 g, 0.248 mmol). The resulting suspension was stirred vigorously at room temperature overnight, then treated with saturated Na2CO3 solution (30 mL) and stirred for 10 minutes. The mixture was extracted with EtOAc (3×30 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (0-1% MeOH/DCM) to afford the desired product as a bright yellow foam, 0.119 g, 74%.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[CH2:28]([O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35](F)=[C:34]([F:39])[CH:33]=1)[CH3:29].C(OCC)(=O)C>CC(N(C)C)=O>[F:39][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][C:35]=1[O:7][C:8]1[CH:9]=[C:10]([C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=2)=[O:12])[CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:31]([O:30][CH2:28][CH3:29])=[O:40]
Reactant: C[C@@H](CO)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CCOC(=O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)CO)cc(C(=O)Nc3ccn(C)n3)c2)c(F)c1
Temperature: 115 °C
Yield: 31 %

Procedure:
Cesium carbonate (8.3 g, 25.4 mmol) was added to a mixture of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (3.7 g, 12.7 mmol) and ethyl-3,4-difluorobenzoate (2.36 g, 12.7 mmol) in dimethylacetamide (60 mL) and the stirred mixture heated at 115° C. for 3 hours. The mixture was allowed to cool to RT and ethyl acetate (100 mL) added. The mixture was washed with water (5×40 mL), brine (40 mL), dried (MgSO4), filtered, and reduced in vacuo. The residue was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired compound (1.8 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:28])[C:9]([C:15]2[C:16]([F:27])=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:29])[CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[C:37]([O:39][CH3:40])=[O:38]>>[CH3:40][O:39][C:37]([C:36]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:28])[C:9]([C:15]3[C:16]([F:27])=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=4[CH:26]=3)([OH:14])[C:10]([F:12])([F:11])[F:13])=[C:4]([Cl:29])[CH:3]=2)=[CH:32][C:31]=1[F:30])=[O:38]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1cc2c(cc1F)OCC(=O)N2C)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3cc4c(cc3F)OCC(=O)N4C)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-7-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid to give the title compound as a colorless solid. MS (m/e)=570.3 [M+H+].
Reaction SMILES: [Na].[CH3:2][C:3]([CH3:16])([CH:10](Cl)[CH:11]=[C:12]([Cl:14])[Cl:13])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]>C(O)C.C(OCC)C.Cl>[CH3:2][C:3]1([CH3:16])[CH:10]([CH:11]=[C:12]([Cl:14])[Cl:13])[CH:4]1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)(C)C(Cl)C=C(Cl)Cl
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Reaction time: 2 h
Yield: 87 %

Procedure:
0.4 Part of metallic sodium was dissolved in 20 parts of anhydrous ethanol, and 2.7 parts of ethyl 3,3-dimethyl-4,6,6-trichloro-5-hexenoate was added to the solution. The mixture was agitated for 2 hours under reflux of ethanol. The liquid reaction mixture was diluted with about 50 parts of diethyl ether and neutralized with dried hydrogen chloride gas. The precipitated crystal of sodium chloride was removed by filtration and low-boiling-point substances were removed from the filtrate by distillation. The residue was then subjected to distillation under reduced pressure to obtain 2.1 parts of ethyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-carboxylate having a boiling point of 72° - 73° C. under 0.3 mm Hg. The yield was 87%. The properties of the product were in agreement with those of ethyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-carboxylate described in Example 1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH3:11][C:12]1([CH3:30])[O:16][N:15]=[C:14]([S:17][CH2:18][C:19]2[C:20]([C:26]([F:29])([F:28])[F:27])=[N:21][N:22]([CH3:25])[C:23]=2F)[CH2:13]1.O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:23]1[N:22]([CH3:25])[N:21]=[C:20]([C:26]([F:28])([F:27])[F:29])[C:19]=1[CH2:18][S:17][C:14]1[CH2:13][C:12]([CH3:30])([CH3:11])[O:16][N:15]=1
Reactant: Oc1ccccc1Cl
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1Oc1ccccc1Cl
Reaction time: 1 h
Yield: 68.2 %

Procedure:
0.2 g (8.3 mmoles) of sodium hydride (purity: 60%) was added, with ice-cooling, to a solution of 0.44 g (3.4 mmoles) of 2-chlorophenol dissolved in 30 ml of N,N-dimethylformamide. The mixture was stirred for 1 hour. Thereto was added 0.7 g (2.2 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline. The resulting mixture was stirred at 120 to 130° C. for 5 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.63 g (yield: 66.7%) of 3-(5-(2-chlorophenoxy)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as a yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:20](=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCCCCCCCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A mixture of 12-tert-butoxycarbonylaminododecanoic acid (3) (320 mg, 1.01 mmol) and 1,1′-carbonyldiimidazole (181 mg, 1.12 mmol) in anhydrous CH2Cl2 (10 mL) was stirred at room temperature for 2 hours. Then N-tert-butoxycarbonylpiperazine (227.0 mg, 1.22 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 66 hours. After this time, the solvent was removed by rotary evaporation and the resulting residue was purified with Biotage silica gel column chromatography, eluting with 5% to 36% ethyl acetate/hexanes, to afford the desired amide 10 (462.0 mg, 94%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.25 (m, 14H), 1.42 (s, 9H), 1.47 (s, 9H), 1.62 (m, 2H), 2.30 (t, 2H), 3.10 (m, 2H), 3.42 (m, 6H), 3.60 (m, 2H), 4.49 (br, 1H). m/z (ESI) 484 [C26H49N3O5+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1.[CH3:13][C:14](O)([CH3:16])[CH3:15].OS(O)(=O)=O>FC(F)(F)C(O)=O>[C:14]([N:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])=[N:12][N:11]=[N:10]1)([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)O
Reactant: Brc1ccccc1-c1nnn[nH]1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1nnnc1-c1ccccc1Br
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a solution of 5-(2-bromophenyl)-1H-tetrazole (7.9 g, 0.035 mol) in trifluoroacetic acid (35 mL) was added tBuOH (5.2 g, 0.070 mol) and H2SO4 (1.0 mL, 0.0175 mol). After 18 h, the solution was concentrated and the residue was taken up in EtOAc. The mixture was washed with water, 2.5N NaOH, water, dried (MgSO4), and concentrated. Purification by flash chromatography (20% EtOAc/hexane) gave 6.6 g (67%) of product as a pale yellow oil.
Reaction SMILES: CO[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[CH2:14])=[CH:5][CH:4]=1.CO[C:17]([C:19]#CC(OC)=O)=O.CCCCCC.CCOC(C)=O>[N+](C1C=CC=CC=1)([O-])=O>[CH:11]1[C:12]2[CH:3]=[CH:4][C:5]3[C:6](=[CH:13][CH:14]=[CH:17][CH:19]=3)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: C=Cc1ccc(OC)c2ccccc12
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCCCCC
Product: c1ccc2c(c1)ccc1ccccc12
Yield: 61.2 %

Procedure:
1-methoxy-4-vinyl naphthalene 18.42 g (0.1 mol) and acetylene dicarboxylic acid dimethyl ester 28.42 g (0.2 mol) were dissolved in nitrobenzene, 200 ml, and they were reacted for 7 hours at the temperature of 130° C. After cooling, nitrobenzene was escaped in vapor under a reduced pressure condition, silica gel column chromatography (developing solvent n-hexane: an acetic acid ethyl=9:1) process was performed to residual elements, crude material, 23.08 g, was obtained. Further, objective phenanthrene compounds, 19.85 g (yield 61.2%) was obtained by recrystallizing from n-butanol. A melting point was 150.2 to 151.0° C. An infrared absorption spectrum of this phenanthrene compound is shown in FIG. 4.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B1OC(C)(C)C(C)(C)O1)[CH3:2].I[C:20]1[CH:21]=[C:22]2[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:26]([CH3:33])[C:23]2=[N:24][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(OCC)(=O)C.O1CCOCC1>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:20]1[CH:21]=[C:22]2[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:26]([CH3:33])[C:23]2=[N:24][CH:25]=1)[CH3:2]
Reactant: CCSc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1c(C(F)(F)F)nc2cc(I)cnc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCSc1ccccc1-c1cnc2c(c1)nc(C(F)(F)F)n2C
Temperature: 100 °C
Reaction time: 4 h
Yield: 103.7 %

Procedure:
A mixture of 0.37 g of 2-ethylsulfanylphenylboronic acid pinacol ester, 0.46 g of 6-iodo-3-methyl-2-trifluoromethyl-3H-imidazo[4,5-b]pyridine, 0.03 g of tris(dibenzylideneacetone)dipalladium(0), 0.08 g of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylphenyl, 0.74 g of tripotassium phosphate, 0.1 ml of water and 10 ml of 1,4-dioxane was stirred at 100° C. for 4 hours. Ethyl acetate and water were added to the cooled reaction mixture, and the mixture was filtered. The filtrate was extracted with ethyl acetate and then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.49 g of 6-(2-ethylsulfanylphenyl)-3-methyl-2-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound of Present Invention 24).
Reaction SMILES: [ClH:1].C(C1C=CC([N:10]([CH2:18][C:19]2[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:20]=2[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)C(=O)OC(C)(C)C)=C(C)C=1)#N.O1[CH2:43][CH2:42]OCC1>>[ClH:1].[NH2:10][CH:18]([C:19]1[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:20]=1[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=1)[C:22]1[CH:21]=[CH:20][C:19]([C:18]#[N:10])=[CH:24][C:42]=1[CH3:43]
Reactant: Cc1cc(C#N)ccc1N(CC1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O)C(=O)OC(C)(C)C
Reactant: C1COCCO1
Agent: Cl
Product: Cc1cc(C#N)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O
Temperature: 25 °C

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane, 5.50 mL, 22.0 mmol) is added to a solution of tert-butyl (4-cyano-2-methylphenyl)(6-oxo-2-(3-(trifluoromethyl)phenylamino)cyclohex-1-enyl)methylcarbamate (intermediate 51, 1.57 g, 3.14 mmol) in 1,4-dioxane (10 mL), and the mixture is stirred at room temperature over night. All volatiles are removed under reduced pressure, and the residue is treated with tert-butyl methyl ether. The precipitate is filtered and dried. Yield: 1.18 g; ESI mass spectrum [M+H]+=400; Retention time HPLC: 0.56 min (X012_S01).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH2:22]1[C:24]2([CH2:28][CH2:27][NH:26][CH:25]2[C:29]([NH2:31])=[O:30])[CH2:23]1.Cl.C1C2(CC(C(N)=O)NC2)C1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][CH2:28][C:24]4([CH2:22][CH2:23]4)[CH:25]3[C:29]([NH2:31])=[O:30])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: NC(=O)C1NCCC12CC2
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Agent: NC(=O)C1CC2(CC2)CN1
Product: NC(=O)C1N(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)CCC12CC2

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 80 mg, 281 μmol) was reacted with a mixture of 5-azaspiro[2.4]heptane-4-carboxamide hydrochloride and 5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (Example 151 d, 59.7 mg, 338 μmol) to obtain the title compound after preparative chiral HPLC (22 mg, 19%) as off-white solid, MS (ESI): m/e=407.3 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=1.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: CON(C)C(=O)c1ccc(O)cn1
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(OCCN(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a stirred solution of 5-hydroxy-N-methoxy-N-methylpicolinamide (1.0 eq), 2-(dimethylamino)ethanol (1.2 eq) and PPh3 (1.2 eq) in 5 mL anhydrous THF under nitrogen was added DIAD (1.2 eq) dropwise at 0° C. The reaction was stirred overnight at rt., quenched with water, and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (40% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([Br:14])=[CH:8][C:3]=1[C:4](OC)=[O:5].C([O-])=O.[NH4+].O.[CH:20]([NH2:22])=O>>[Br:14][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[O:12][CH3:13])[N:1]=[CH:20][NH:22][C:4]2=[O:5]
Reactant: COC(=O)c1cc(Br)c(OC)cc1N
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: COc1cc2nc[nH]c(=O)c2cc1Br
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of methyl 2-amino-5-bromo-4-methoxybenzoate (75 mg, 0.29 mmol) and ammonium formate (38 mg, 0.8 mmol) in formamide (1 mL) was heated at 165° C. for 18 h. The mixture was allowed to cool to room temperature then diluted with an excess of water. The solid formed was collected by filtration and washed with water then ethyl acetate and dried to give 6-bromo-7-methoxyquinazolin-4(3H)-one (53 mg, 72% yield) as a pale yellow solid. MS (EI) for C9H7BrN2O2: 255, 257 (MH+).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[C:32]([CH3:31])[CH:33]=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: Cc1cccc(B(O)O)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)c1
Yield: 94 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 3-methylphenylboronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless foam (94%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH:2]=[CH2:3].[CH3:10][O:11][SiH:12]([O:15][CH3:16])[O:13][CH3:14]>C(O)(C)C>[O:9]=[C:5]1[CH2:6][CH2:7][CH2:8][N:4]1[CH2:1][CH2:2][CH2:3][Si:12]([O:15][CH3:16])([O:13][CH3:14])[O:11][CH3:10]
Reactant: C=CCN1CCCC1=O
Reactant: CO[SiH](OC)OC
Solvent: CC(C)O
Product: CO[Si](CCCN1CCCC1=O)(OC)OC
Reaction time: 2 h
Yield: 74.3 %

Procedure:
To a 500 ml volume glass flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, there were added 125.2 g (1.0 mol) of 1-allyl-2-oxopyrrolidine and 0.5 g of 4% isopropyl alcohol solution of H2PtCl6. Trimethoxysilane (122.2 g; 1.0 mol) was dropwise added through the dropping funnel at a temperature ranging from 100° to 110° C. over 2 hours and the reaction mixture was allowed to stand at 100° C. for 30 minutes. The reaction solution was distilled to give 183.8 g of a compound having a boiling point of 123° to 125° C./2 mmHg in an yield of 74.3%.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:8]Cl>C(O)C>[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:8][NH:2][NH2:3]
Reactant: NN
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: Cc1cc(CNN)ccc1[N+](=O)[O-]
Yield: 96.6 %

Procedure:
To an ethanol solution (60 ml) of hydrazine monohydrate (5.00 g), an ethanol solution (20 ml) of 3-methyl-4-nitrobenzyl chloride (3.71 g) was added dropwise while refluxing it, and the mixture was continuously refluxed for 6 hours. After finishing the reaction, the solvent was distilled off and (3-methyl-4-nitrobenzyl)-hydrazine (3.50 g) was obtained.