Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([C:11]([OH:13])=[O:12])([F:10])([F:9])[F:8]>>[CH:1]1([O:13][C:11](=[O:12])[C:7]([F:10])([F:9])[F:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: C1CCCCC1
Product: O=C(OC1CCCCC1)C(F)(F)F
Yield: 17 %

Procedure:
Activation of cyclohexane was also investigated in two experiments. Under anhydrous conditions, slow addition of Cu(I) dissolved in CF3CO2H to a solution of Cu(II) dissolved in CF3CO2H/C6H12 in air and gave a 17% yield of cyclohexyltrifluoroacetate. A 19.2% yield of this ester was obtained when solid Cu2O was stirred in the Cu(II) solution under a 100% O2 atmosphere. The yields are comparable even under widely varying conditions. Also, the yields are higher than for methane activation, probably due primarily to easier activation of a secondary hydrogen atom, aided by a higher solution concentration of cyclohexane (0.4M compared to about 0.01M).
Reaction SMILES: O[Li].O.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:30]([F:33])([F:32])[F:31])[O:16][N:15]=[C:14]([C:17]3[S:29][C:20]4=[N:21][CH:22]=[C:23]([C:25]([O:27]C)=[O:26])[CH:24]=[C:19]4[CH:18]=3)[CH2:13]2)[CH:8]=[C:9]([Cl:11])[CH:10]=1.Cl>O.C1COCC1>[Cl:11][C:9]1[CH:8]=[C:7]([C:12]2([C:30]([F:32])([F:31])[F:33])[O:16][N:15]=[C:14]([C:17]3[S:29][C:20]4=[N:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=[C:19]4[CH:18]=3)[CH2:13]2)[CH:6]=[C:5]([Cl:4])[CH:10]=1
Reactant: COC(=O)c1cnc2sc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc2sc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2c1
Reaction time: 12 h
Yield: 73.7 %

Procedure:
Add a solution of LiOH—H2O (76 mg, 2 mmol) in water (0.5 mL) to a solution of methyl 2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thieno[2,3-b]pyridine-5-carboxylate (237 mg, 0.5 mmol) in THF (3 mL). Stir the mixture at temperature for 12 hours. After addition of 10 mL of water, acidify the mixture with concentrated HCl to PH=6˜7. Extract the resultant mixture with ethyl acetate (3×10 mL). The combined organic layers are washed brine, dried over anhydrous Na2SO4 and concentrated under vacuum to afford 2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]thieno[2,3-b]pyridine-5-carboxylic acid as pale yellow solid (170 mg, 73.9%), which is used in next step without further purification. MS (m/z): 461 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>CN(C=O)C.C(Cl)Cl>[CH2:16]([C:7]1([CH2:5][CH2:4][CH2:3][CH:11]=[CH2:10])[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:12])[CH2:17][CH2:18][CH:19]=[CH2:20]
Reactant: C=CCCCBr
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCCCC1(CCCC=C)Cc2cc(OC)ccc2C1=O
Reaction time: 6 h

Procedure:
To a solution of 5-methoxy-1-indanone (2.5 g, 15.4 mmol) in DMF (20 mL) at rt was added NaH (1.8 g, 61% in oil, 46.2 mmol) and 5-bromo-1-pentene (5.48 mL, 46.2 mmol). After 6 h at rt, the solution was diluted with CH2Cl2 and quenched with saturated aqueous NH4Cl. The slurry was dried with MgSO4 and filtered through a plug of silica and rinsed with 10% EtOAc in hexanes. The filtrate was concentrated and provided crude 2,2-di(4-pentenyl)-5-methoxy-1-indanone.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[CH3:24][O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH2:28].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH3:24][O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH:28][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 73.1 %

Procedure:
In 100.4 g of acetic acid, 25.1 g (0.1 mole) of N-benzyloxycarbonyl-L-aspartic anhydride was suspended and 22.7 g (0.1 mole) of L-phenylalanine methyl ester sulfate was added with stirring at 5°-10° C. Successively 17.6 g (0.21 mole) of sodium acetate was added at the same temperature. The reaction was carried out for 4 hours with stirring at the same temperature. Thereafter 87.1 g of water was added to the reaction mixture to adjust the concentration of organic carboxylic acid to 53.5% by weight. After cooling to 0°-5° C., precipitated crystals were filtered, washed and dried. Crystals of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained. The yield was 31.2 g (73.1% yield on L-phenylalanine methyl ester sulfate).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[C:28]([O:32][C:33]([N:35]([CH3:40])[CH2:36][C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:37](=[O:38])[CH2:36][N:35]([CH3:40])[C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:31])[CH3:29])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00014 mol), 2-[(tert-butoxycarbonyl)(methyl)amino]acetic acid (0.0033 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0034 g, 0.000175 mol), N,N′-diisopropylethylamine (0.033 g, 0.00026 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous N,N-dimethylformamide (6 mL) was stirred for eighteen hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield tert-butyl N-(2-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-oxoethyl)-N-methylcarbamate. The solid was dissolved in dichloromethane (2 mL) and a 25% solution of trifluoroacetic acid in dichloromethane (4 mL) was slowly added to the reaction at 0° C. The reaction mixture was stirred for 5 hours at room temperature. The solvent was removed under reduced pressure. A 5 N aqueous solution of sodium hydroxide was added to pH 11 at 0° C. The water phase was extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with water (1×60 mL) and brine (1×60 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-(dimethylamino)-1-ethanone acetate (0.022 g, 0.00004 mol).
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C@@H:16]([CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18]>>[CH2:36]([O:35][CH2:34][C@H:16]([NH:15][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(O)CCCCc1ccccc1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CCCCc1ccccc1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 46.2 %

Procedure:
Proceeding as in Example 1, but substituting 5-phenylpentanoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 104, (S)—N-(3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-yl)-5-phenylpentanamide (3 mg, 46.2%).
Reaction SMILES: C([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:13]=2)[C:8](=[O:20])[C:7]([C:21]([O:23]CC)=[O:22])=[CH:6]1)(C)(C)C>C(O)C.Cl.C(OCC)C>[O:20]=[C:8]1[C:9]2[C:14](=[N:13][C:12]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)=[CH:11][CH:10]=2)[NH:5][CH:6]=[C:7]1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCCC3)ccc2c1=O
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)c1c[nH]c2nc(N3CCCC3)ccc2c1=O

Procedure:
A solution of Example 74A (63.2 mg) in ethanol (2.5 mL) and 6M HCl (2.5 mL) was heated in a sealed tube at 130° C. for 18 hours then cooled, diluted with diethyl ether, and filtered. NMR (300 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.22 (m, 1H), 6.80 (m, 1H), 3.55 (m, 4H), 2.00 (m, 4H).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[N:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH3:20])=[CH:15][CH:14]=1>>[N:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=3[C:2](=[O:3])[O:4][C:5]2=[O:12])[CH3:20])=[CH:15][CH:14]=1
Reactant: CC(O)c1ccncc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: CC(c1ccncc1)n1c(=O)oc(=O)c2ccccc21

Procedure:
Prepared by a similar procedure as described for preparation 7A, starting from isatoic anhydride and (+/−)-1-(4-pyridyl)ethanol (Fluka). 13C-NMR (DMSO-d6) δ 159.0, 149.8, 148.6, 140.6, 136.5, 129.8, 123.6, 121.2, 115.7, 112.9, 53.1, 15.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([CH:13]([CH3:15])[CH3:14])[C:6]([S:16][C:17]1[NH:21][C:20]([C:22]([F:25])([F:24])[F:23])=[N:19][N:18]=1)=[N:5]2.[CH2:26](N(CC)CC)C.IC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([CH:13]([CH3:15])[CH3:14])[C:6]([S:16][C:17]1[N:21]([CH3:26])[C:20]([C:22]([F:23])([F:24])[F:25])=[N:19][N:18]=1)=[N:5]2
Reactant: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Sc1nnc(C(F)(F)F)[nH]1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Sc1nnc(C(F)(F)F)n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the above 6,7-dichloro-2-isopropyl-3-(5-trifluoromethyl-4H-1,2,4-triazol-3-ylsulfanyl)quinoxaline (78 mg, 0.19 mmol) in tetrahydrofuran (5 ml) was added triethylamine (0.05 ml, 0.38 mmol) followed by addition of iodomethane (0.02 ml, 0.29 mmol). The reaction was stirred under nitrogen overnight at room temperature. Purification by flash column chromatography using ethyl acetate:hexanes 1:10 afforded the title compound.
Reaction SMILES: Cl[C:2]1[N:11]2[C:12](=[O:21])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=[C:10]2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C(N(C(C)C)CC)(C)C.[BH4-].[Na+]>[Pd].O>[C:15]1([N:13]2[C:12](=[O:21])[N:11]3[CH2:2][NH:3][C:4]4[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=4[C:10]3=[N:14]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=c1n(-c2ccccc2)nc2c3c(nc(Cl)n12)CCCC3
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1n(-c2ccccc2)nc2n1CNC1=C2CCCC1

Procedure:
A mixture of 5-chloro-2-phenyl-7,8,9,10-tetrahydro-1,2,4-triazolo[4,3-c]quinazolin-3-one (150 mg, 0.5 mmol), diisopropylethylamine (130 ml, 0.74 mmol) and 10% Pd-C (30 mg) was hydrogenated under H2 balloon for 1 hour. The reaction was filtered through Celite. NaBH4 (30 mg, 0.79 mmol) was added to the filtrate and the mixture was heated to reflux temperature. The reaction was poured into water and extracted with CH2Cl2 (3×50 ml). The combined organic layers were dried over Na2 SO4 and evaporated under reduced pressure. The residue was triturated with ethanol and filtered to afford 2-phenyl-5,6,7,8,9,10-hexahydro-1,2,4-triazolo[4,3-c]-quinazolin-3-one (Compound 31), m.p. 158°-159° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14](Cl)=[O:15].C1(C)C=CC=CC=1.[CH2:24]([OH:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:9])[CH3:10])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14]([O:36][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:15]
Reactant: CCCCCCCCCCCCO
Reactant: Cc1cc(C(C)(C)C)c(O)cc1CC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOC(=O)Cc1cc(O)c(C(C)(C)C)cc1C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Into a 500-ml four-necked flask, were charged 24.1 g of 2-methyl-4-t-butyl-5-hydroxyphenylacetyl chloride, 300 ml of toluene and 50 ml of pyridine. After replacing air in the reactor by nitrogen, 18.7 g of dodecyl alcohol was added to the mixture at 30° to 40° C., and then the reaction was continued at 30° to 40° C. for about 8 hours. After completion of the reaction, pyridine was neutralized with diluted hydrochloric acid, and the reaction mixture was washed with water, dried over anhydrons sodium sulfate and then freed from the solvent under reduced pressure to obtain 33.2 g (85% yield) of viscous dodecyl 2-methyl-4-t-butyl-5-hydroxyphenylacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](O)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1.P(Cl)(Cl)([Cl:14])=O.C(N(CC)C1C=CC=CC=1)C>C(#N)C>[Cl:14][C:4]1[C:3]([O:2][CH3:1])=[CH:8][N:7]=[C:6]([S:9][CH3:10])[N:5]=1
Reactant: COc1cnc(SC)nc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Solvent: CC#N
Product: COc1cnc(SC)nc1Cl

Procedure:
5-Methoxy-2-methylsulfanyl-pyrimidin-4-ol (250 mg) is dissolved in acetonitrile (7 ml) and thereto are added phosphorus oxychloride (0.7 ml) and N,N-diethyl aniline (460 μl) and the mixture is heated under reflux for 5.5 hours. The reaction solution is evaporated azeotropically with toluene three times, and to the residue are added aqueous citric acid solution and chloroform, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) to give 4-chloro-5-methoxy-2-methylsulfanyl-pyrimidine (260 mg). MS (m/z): 191/193 [M+H]+
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=1[C:8]([OH:10])=[O:9]>S(=O)(=O)(O)O>[F:5][C:6]1[C:7]([C:8]([OH:10])=[O:9])=[C:11]([CH3:15])[C:12]([N+:1]([O-:4])=[O:2])=[CH:13][CH:14]=1
Reactant: Cc1cccc(F)c1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c([N+](=O)[O-])ccc(F)c1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of nitric acid (6.96 mL, 156 mmol) in sulfuric acid (44 mL) was added a solution of 2-fluoro-6-methylbenzoic acid (16 g, 104 mmol) in concentrated sulfuric acid (150 mL) at −15° C., and the mixture was stirred at 0° C. for 30 min. The reaction solution was poured into ice water (500 mL), and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound as a crudely purified product (20.7 g, yield 100%).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.N1C=CC=CC=1.[CH3:39][C:40]([CH3:45])([CH3:44])[C:41](Cl)=[O:42]>C1COCC1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:41](=[O:42])[C:40]([CH3:45])([CH3:44])[CH3:39])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C(C)(C)C)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 mmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, a solution of 2,2-dimethylpropanoyl chloride (20 mg, 164 mmol, 2.5 eq.) in abs. THF (1 ml) was added in two portions. Once analysis of the reaction by HPLC showed substantial conversion (12 h), the reaction mixture was concentrated under reduced pressure and directly purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (26.9 mg, 81% of theory).
Reaction SMILES: [C:1]1([N:7]2[C:13](=[O:14])[CH2:12][C:11](=[O:15])[NH:10][C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:31][C:32]([N:34]([C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33]>CN(C=O)C.C1COCC1>[C:41]([N:34]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:32](=[O:33])[CH2:31][N:10]1[C:11](=[O:15])[CH2:12][C:13](=[O:14])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:19]=[CH:18][CH:17]=[CH:16][C:9]1=2)([CH3:42])([CH3:43])[CH3:44]
Reactant: CC(C)(C)N(C(=O)CBr)c1ccccc1
Reactant: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a stirred solution of 600 mg (2.38 mmol) 1-Phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2,4-dione in 16 mL DMF is added 2.62 mL (2.62 mmol, 1.1 equiv) of 1M Sodium bis(trimethylsilyl)amide in THF at ambient temperature and stirred 0.5 h. To this solution is added 707 mg (2.62 mmol, 1.1 equiv) 2-Bromo-N-tert-butyl-N-phenyl-acetamide, prepared as in Part A, in 4 mL DMF and stirred 18 h at ambient temperature. The solvent is removed in vacuo and the residue taken into 50 mL EtOAc, washed successively with H2O (30 mL), 1N HCl (30 mL), satd. NaHCO3 (30 mL), and brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo to a brown oil. The crude product is purified by flash chromatography on 40 g silica gel eluted successively with EtOAc/Hexanes (2:3, 500 mL), (1:1, 750 mL). Appropriate fractions were combined and concentrated in vacuo to give 748 mg (1.69 mmol) of N-tert-Butyl-2-(2,4-dioxo-5-phenyl-2,3,4,5,-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-phenyl-acetamide as a white foam: 1H NMR (CDCl3, 300 MHz) δ7.45-7.21 (m, 12H), 7.08 (t, 1H), 6.90 (m, 1H), 4.30 (d, 1H, J=16.4), 3.85 (d, 1H, J=16.6), 3.59 (d, 1H, J=12.0), 3.49 (d, 1H, J=11.9), 1.43 (s, 9H); TLC Rf =0.24 (EtOAc/Hexanes, 1:1).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](=O)([O:27]C(C)(C)C)[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>C(#N)C>[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([C:21]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:27])[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC=C(c2ccccc2)CC1
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
To a solution of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (354.6 g) in acetonitrile (12 L) was added triethylamine (366.9 g) at 20° C. in a water-bath, and the mixture was stirred for 15 minutes. To the reaction solution was added dropwise a solution of di-t-butyl carbonate (474.5 g) in acetonitrile (700 ml) at 15˜19° C. in a water-bath, and further thereto was added N,N-dimethylamino-pyridine (11.06 g). The mixture was stirred at room temperature for 12 hours, and the solvent was removed by evaporation under reduced pressure. The obtained residue was diluted with methylene chloride (10 L), and washed with 1M hydrochloric acid (×3) and 5% saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium hydrogen sulfate, and the solvent was evaporated under reduced pressure to give a crude product (470.6 g). The obtained crude product was purified by silica gel column chromatography (methylene chloride/methanol=1/0→50/1) to give the title compound (456.8 g).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[N:20][CH:21]=1.[OH:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O.O>ClCCl>[Br:15][C:16]1[CH:17]=[C:18]([NH:22][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[OH:23])[CH:19]=[N:20][CH:21]=1
Reactant: O=Cc1ccccc1O
Reactant: Nc1cncc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1ccccc1CNc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
295 mg (1.4 mmol, 1.4 eq) of sodium triacetoxyborohydride are added to a solution of 173 mg (1 mmol, 1 eq) of 5-bromopyridin-3-ylamine (starting material 1) and 122 mg (1 mmol, 1 eq) of 2-hydroxybenzaldehyde (starting material 2) in 20 ml of dichloromethane. The solution is stirred at room temperature for 24 h. The medium is poured into water and stirred for 2 h. The aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with water, and then dried over sodium sulphate. The residue is chromatographed on silica gel (80/20 heptane/ethyl acetate). 2-[(5-Bromopyridin-3-ylamino)methyl]phenol is obtained in the form of a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:3])[CH3:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[C:1](=[O:3])[CH:2]=[CH:16][N:17]([CH3:19])[CH3:18]
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1ccc2ccccc2c1
Yield: 76 %

Procedure:
2'-Acetonaphthone (10 0 g, 58 mmol, [93-08-3]) was dissolved in 20 mL of N,N-dimethylformamide dimethylacetal [4637-24-5] and the mixture was heated under reflux for 14 hours. The mixture was then cooled, concentrated, and the crystalline residue was recrystallized from cyclohexane to give the title product as orange crystals (9.88 g, 76%). mp 100° -101° . Calc'd for C15H15NO: C 79.97%, H 6.71 %, N 6.22%; found: C 79.71%, H 6.76%, N 6.51%. NMR (CDCl3): 8.40 (s, 1 H); 8.00-7.83 (m, 5 H); 7.54-7.51 (m, 2 H); 5.86 (d, 1 H); 3.33-2.83 (br d, 6 H). Mass spec 226 (M +H+).
Reaction SMILES: C1(O[C:8](=[S:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH2:35][CH2:34]2)=[S:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=S)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=S)N2CCN(c3ccccc3OC)CC2)c(OC)nc1C
Yield: 93 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.