Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:70])[NH:4][C@@H:5]([CH:67]([CH3:69])[CH3:68])[C:6](=[O:66])[N:7]1[CH2:11][CH2:10][CH2:9][C@@:8]1([C:63](=[O:65])[NH2:64])[C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[N:22]([C:23]3[S:24][C:25]4[CH2:31][CH2:30][CH2:29][CH2:28][C:26]=4[N:27]=3)[C@@H:21]([C:32]3[CH:37]=[CH:36][C:35]([C@:38]4([C:54](=[O:56])[NH2:55])[CH2:42][CH2:41][CH2:40][N:39]4[C:43](=[O:53])[C@@H:44]([NH:48][C:49](=[O:52])[O:50][CH3:51])[CH:45]([CH3:47])[CH3:46])=[C:34]([N+:57]([O-])=O)[CH:33]=3)[CH2:20][CH2:19]2)=[CH:14][C:13]=1[N+:60]([O-])=O>O1CCCC1.[Ni].O>[CH3:51][O:50][C:49](=[O:52])[NH:48][C@@H:44]([CH:45]([CH3:47])[CH3:46])[C:43](=[O:53])[N:39]1[CH2:40][CH2:41][CH2:42][C@@:38]1([C:54](=[O:56])[NH2:55])[C:35]1[CH:36]=[CH:37][C:32]([C@@H:21]2[N:22]([C:23]3[S:24][C:25]4[CH2:31][CH2:30][CH2:29][CH2:28][C:26]=4[N:27]=3)[C@@H:18]([C:15]3[CH:16]=[CH:17][C:12]([C@:8]4([C:63](=[O:65])[NH2:64])[CH2:9][CH2:10][CH2:11][N:7]4[C:6](=[O:66])[C@@H:5]([NH:4][C:3](=[O:70])[O:2][CH3:1])[CH:67]([CH3:69])[CH3:68])=[C:13]([NH2:60])[CH:14]=3)[CH2:19][CH2:20]2)=[CH:33][C:34]=1[NH2:57]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@@]1(C(N)=O)c1ccc([C@H]2CC[C@H](c3ccc([C@]4(C(N)=O)CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)c([N+](=O)[O-])c3)N2c2nc3c(s2)CCCC3)cc1[N+](=O)[O-])C(C)C
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@@]1(C(N)=O)c1ccc([C@H]2CC[C@H](c3ccc([C@]4(C(N)=O)CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)c(N)c3)N2c2nc3c(s2)CCCC3)cc1N)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Example 116E (0.59 g, 0.596 mmol) was dissolved in tetrahydrofuran (15 mL) and treated with Raney Nickel slurry in water (0.25 mL). The flask was evacuated and opened to a hydrogen balloon and stirred at ambient temperature for 1 hour. The solution was filtered through a silica plug and concentrated to dryness to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]=[O:22])[C:17]=3[CH:23]=2)[C:3]1=[O:24].[CH2:25](O)[CH:26]([OH:28])[CH3:27].C1(C)C=CC=CC=1.O>C(OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]4[O:28][CH:26]([CH3:27])[CH2:25][O:22]4)[C:17]=3[CH:23]=2)[C:3]1=[O:24]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Reactant: CC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC1COC(c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)O1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (0.500 g, 1.41 mmol), 1,2-propanediol (0.130 ml, 1.83 mmol), p-toluenesulfonic acid (0.0100 g, 0.0100 g, 0.071 mmol) and toluene is stirred at reflux with azeotropic removal of water overnight, cooled to room temperature, diluted with diethyl ether, washed twice with water and once with brine and dried over anhydrous magnesium sulfate. Concentration in vacuo affords a yellow oil, which is chromatographed on silica gel to afford the title compound as a yellow solid (0.510 g, 87.6%, mp 81-83° C.) which is identified by NMR spectral analysis.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:26]=[C:25]([CH:27]2[CH2:31][CH2:30][CH2:29][NH:28]2)[O:24][N:23]=1.C(N(C(C)C)CC)(C)C>C(O)CCCCC>[Cl:15][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)=[N:7][C:2]([N:28]2[CH2:29][CH2:30][CH2:31][CH:27]2[C:25]2[O:24][N:23]=[C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)[CH:26]=2)=[N:3][CH:4]=1
Reactant: c1ccc(-c2cc(C3CCCN3)on2)nc1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCCO
Product: Cc1cc(Nc2nc(N3CCCC3c3cc(-c4ccccn4)no3)ncc2Cl)n[nH]1
Yield: 109.5 %

Procedure:
A mixture of 2,5-dichloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Method 10 of WO 03/048133) (158 mg, 0.648 mmol), 2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidine (Method 12) (212 mg, 0.972 mmol) and di-isopropylethylamine (282 μL, 1.62 mmol) was stirred and heated at 140° C. in n-hexanol (7.0 ml) under nitrogen for 9 hours. The bulk of the hexanol was then removed by evaporation and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed with 1.0 molar phosphate buffer pH 4 (×2), then water and finally brine. The organic layer was dried (Na2SO4), filtered and evaporated and the crude product was absorbed onto a 10 g isolute SCX2 ion exchange column. The column was eluted with DCM/methanol (4:1) to remove neutrals and then with dichloromethane/2M methanolic ammonia (4:1) to elute the product. The purified product was dissolved in the minimum volume of DCM and to the stirred solution a slight excess of 1.0 M ethereal hydrogen chloride was added. Further diethyl ether was added and the solid product collected by filtration, washed with diethyl ether and dried to give the hydrochloride salt of the title compound (300 mg, 100%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]2[C:19]([N:20]=1)=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2.[CH3:25]N(C=O)C.[CH3:30][S-:31].[Na+]>O>[CH2:30]([S:31][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]2[C:19]([N:20]=1)=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[CH3:25]
Reactant: C[S-]
Reactant: Fc1cc(C(F)(F)F)ccc1-c1nc2cc(C(F)(F)F)cnc2s1
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: O
Product: CCSc1cc(C(F)(F)F)ccc1-c1nc2cc(C(F)(F)F)cnc2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-[2-fluoro-4-(trifluoromethyl)phenyl]-6-(trifluoromethyl)thiazolo[5,4-b]pyridine (0.18 g) and DMF (2 ml), sodium thiomethoxide (63 mg) was added under ice-cooling, and stirred at room temperature for 4 hours. Into the reaction mixture, water was poured, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.11 g of 2-[2-ethylsulfanyl-4-(trifluoromethyl)phenyl]-6-(trifluoromethyl)thiazolo[5,4-b]pyridine (hereinafter referred to as Present Compound 267).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[O:9]1[CH2:14][CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.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>[O:9]1[CH2:10][CH:11]=[C:12]([C:6]2[CH:7]=[C:2]([NH2:1])[CH:3]=[N:4][CH:5]=2)[CH2:13][CH2:14]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Nc1cncc(Br)c1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1cncc(C2=CCOCC2)c1
Temperature: 70 °C
Reaction time: 19 h

Procedure:
A stirred mixture of 3-amino-5-bromopyridine (0.25 g, 1.4 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.33 g, 1.6 mmol), tetrakis(triphenylphosphine)palladium (83.3 mg, 0.072 mmol), and 2.0M sodium carbonate (3.6 mL, 7.2 mmol) in toluene (3.0 mL) and EtOH (1.0 mL) was heated to 70° C. After 19 h, the reaction was cooled to rt then diluted with water. After extraction with EtOAc, the organic extraction was dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-35% EtOAc in hexanes) to afford a white solid as 5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.05 (1H, d, J=2.0 Hz), 7.96 (1H, d, J=2.7 Hz), 6.95 (1H, m), 6.10 (1H, tt, J=2.9, 1.5 Hz), 4.28 (2H, q, J=2.9 Hz), 3.90 (2H, t, J=5.5 Hz), 3.81 (1H, br. s.), 2.48 (2H, m). Mass Spectrum (pos.) m/e: 177.1 (M+1).
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[C:20]3[N:19]4[CH:21]=[CH:22][CH:23]=[C:18]4[C:17](=[N:24][OH:25])[C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[CH2:26]([OH:28])[CH3:27].O>C(O)(=O)C.[Zn]>[C:26]([OH:25])(=[O:28])[CH3:27].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[C:20]3[N:19]4[CH:21]=[CH:22][CH:23]=[C:18]4[CH:17]([NH2:24])[C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: CCO
Reactant: ON=C1c2cccc(-c3cnc4ccccc4c3)c2-n2cccc21
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: NC1c2cccc(-c3cnc4ccccc4c3)c2-n2cccc21
Reaction time: 1.5 h

Procedure:
In a 100 ml round-bottomed flask, a mixture of 277 mg of 5-quinolin-3-ylpyrrolo[1,2-a]indol-9-one oxime hydrochloride obtained according to the preceding stage, in 5 ml of acetic acid, 5 ml of ethanol and 5 ml of water, is stirred at ambient temperature. 58 mg of powdered zinc are added and the resulting mixture is left to stir for 1.5 hours. A further 58 mg of powdered zinc is added and the resulting mixture is left to stir for 3.5 hours. The reaction medium is filtered through clarcel, washing being carried out with 100 ml of methanol. The filtrate is evaporated to dryness under vacuum and chromatographed on silica gel (15-40 μm), elution being carried out with a gradient of methanol (2% to 7% v/v) in dichloromethane. 116 mg of 5-quinolin-3-yl-9H-pyrrolo[1,2-a]indol-9-ylamine acetate are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH3:20].[N:21]1[C:26]([CH:27]=[O:28])=[CH:25][CH:24]=[CH:23][C:22]=1C=O.O.O1CCOC[CH2:33]1>C(OC(=O)C)(=O)C.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=[CH:33][C:26]1([CH:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][NH:21]1
Reactant: O=Cc1cccc(C=O)n1
Reactant: Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Reactant: C1COCCO1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=CC1(C=Cc2nc3ccc(F)cc3c(=O)n2-c2ccccc2Cl)C=CC=CN1

Procedure:
A catalytic amount (about 100 mg) of anhydrous zinc chloride was added to a solution of 576 mg (2.0 mmol) of 3-(2-chlorophenyl)-6-fluoro-2-methyl-4(3H)-quinazolinone and 270 mg (2.0 mmol) of 2,6-pyridinedicarboxaldehyde in 20-25 mL of dioxane and 1.0 mL of acetic anhydride. The reaction mixture was heated at reflux under a nitrogen atmosphere for 3 hours until TLC indicated that the starting materials had been consumed. The cooled reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The combined extracts were dried with brine and magnesium sulfate, treated with decolonizing carbon and filtered and the solvent was removed to give the desired product. This was taken up in 2:1 ether/pentane and the crystals were filtered to give 266 mg of the product, 33%, m.p. 247-248° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[C:35]1([CH2:41][CH2:42][C:43](Cl)=[O:44])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([C:43](=[O:44])[CH2:42][CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCN(C(=O)CCc3ccccc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (80 mg, 0.22 mmol) in dichloromethane (4 ml) was added diisopropylethylamine (0.49 mmol, 81 μL) and 3-phenylpropionyl chloride (0.25 mmol). The reaction was stirred at room temperature for 16 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (43 mg) which was characterized by its mass spectrum: MS m/z (%): 491 ([M+H]+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:18][CH2:19][C@:20]([CH3:26])([OH:25])[C:21]([F:24])([F:23])[F:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[F:22][C:21]([F:24])([F:23])[C@:20]([OH:25])([CH3:26])[CH2:19][NH:18][C:14]([C:3]1[C:2]([NH2:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[C:5]([O:12][CH3:13])[N:4]=1)=[O:16]
Reactant: COc1nc(C(=O)O)c(N)cc1C(F)(F)F
Reactant: C[C@](O)(CN)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1nc(C(=O)NC[C@](C)(O)C(F)(F)F)c(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate D) (10 g, 42.3 mmol) and (S)-3-amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride (Intermediate RA) (7.60 g, 42.3 mmol) in NMP (400 ml) was added HATU (19.3 g, 50.8 mmol) followed by dropwise addition of DIPEA (22.19 ml, 127 mmol) over ˜1 hr. After stirring at room temperature for 30 min, the mixture was added to EtOAc (2 L), washed with 1M NaOH (2×1 L), water (1 L), brine (1 L), dried (MgSO4) and evaporated under reduced pressure to give the crude product as a dark brown oil. Purification by chromatography on silica eluting with a gradient of 1 to-25% of EtOAc in iso-hexane afforded a yellow oil. Recrystallisation of the oil from iso-hexane/DCM afforded 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide as a crystalline solid;
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:5]([NH2:17])=[N:4][CH:3]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([C@H:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:10])[C:18]([OH:19])=[N:17][C:5]2=[N:4][CH:3]=1
Reactant: C[C@H](Nc1nc(Br)cnc1N)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of (S)-6-bromo-N2-(1-phenylethyl)pyrazine-2,3-diamine (1.0 equiv) in refluxing anhydrous THF (5 volume equivalents) was added carbonyldiimidazole (CDl). Successive portions of CDl were added until the starting material was consumed (approx. 3.6 equiv total) as judged by TLC (50% EtOAc/Hexanes). After complete reaction, the mixture was cooled to room temperature and quenched by the careful addition of water until gas evolution had ceased. The mixture was diluted with 25 volume equivalents of EtOAc and washed with 3×7.5 volume equivalents of water and 1×7.5 volume equivalents of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Biotage MPLC 5%-40% EtOAc/Hexanes) provided the title compound (66%) as a white solid. LCMS m/z (APCI)=319.0, 321.0 (M+H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([C:39]2[CH:44]=[C:43]([Cl:45])[CH:42]=[C:41]([Cl:46])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([C:39]2[CH:40]=[C:41]([Cl:46])[CH:42]=[C:43]([Cl:45])[CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(-c2cc(Cl)cc(Cl)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2cc(Cl)cc(Cl)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 5.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogen carbonate (0.82 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(3,5-dichlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.49 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (1 mL), N,N′-carbonyldiimidazole (0.018 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.016 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.029 g, 5%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([Cl:22])[C:3]=1[CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([Cl:22])[C:3]=1[CH2:4][NH2:5]
Reactant: COc1cc(Cl)c(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(Cl)c(CN)c(Cl)c1
Product: Cl
Yield: 166.3 %

Procedure:
Treat a solution of 2-(2,6-Dichloro-4-methoxy-benzyl)-isoindole-1,3-dione (2.74 g, 8.18 mmol) in ethanol with hydrazine hydrate (0.61 g, 12.27 mmol) at 70° C. for 12 hours. Cool the reaction and filter the precipitate. Concentrate the filtrate and partition the residue with ethyl acetate and water. After drying the organic layer over sodium sulfate, filter and concentrate under vacuum. To the residue, add ethyl acetate (20 mL) and HCl (4 N in dioxane, 5 mL). Collect the white crystal by filtration and air dry to afford 1.65 g (84%) of the title compound. MS (m/z): 242 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH:28]([CH2:32][CH3:33])[C:29](=[O:31])[CH3:30].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:32]([CH:28]([N:23]1[C:22](=[O:26])[N:21]([C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:11][CH2:10][N:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)[CH:25]=[N:24]1)[C:29](=[O:31])[CH3:30])[CH3:33]
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Reactant: CCC(Br)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCC(C(C)=O)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Yield: 21.1 %

Procedure:
A mixture of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (0.05 mol) prepared as described in Eβ-A-0,006,711, 3-bromo-2-pentanone (0.073 mol) and K2CO3 (10 g) in DMF (200 ml) and toluene (200 ml) was stirred and refluxed overnight using a water separator. The solvent was evaporated. The residue was dissolved in CH2Cl2. The organic solution was washed, dried, filtered and the solvent was evaporated. The residue was crystallized from 2-propanol. The precipitate was filtered off and the filtrate was evaporated. The residue was triturated in DIPE, filtered off and dried, yielding 4.6 g of (±)-2-(1-ethyl-2-oxopropyl)-2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (intermn.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH3:15])[CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)=[O:5])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:31][NH:32][C:33](=[O:45])[C@H:34]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[NH2:35].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:31][NH:32][C:33](=[O:45])[C@H:34]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1)[NH:35][C:8](=[O:10])[CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH3:15]
Reactant: CCOC(=O)C(C)C(CC(C)C)C(=O)O
Reactant: CNC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(C)C(CC(C)C)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)NC
Temperature: 0 °C

Procedure:
A mixture of 3-(ethoxycarbonyl)-2-(2-methylpropyl)butanoic acid (7.5 g., 0.037 mol.) and dichloromethane (70 mls.) was stirred and cooled to 0° C. To the mixture was added dropwise a solution of N,N'-dicyclohexylcarbodiimide (7.6 g., 0.37 mol.) in dichloromethane (20 mls.) and the reaction mixture was allowed to warm to room temperature. A solution of O-methyl-L-tyrosine N-methylamide (7.7 g., 0.037 mol.) in dichloromethane (45 mls.) was added to the reaction mixture and the resulting mixture was stirred overnight at room temperature. A saturated sodium bicarbonate solution (100 mls.) was added to the reaction mixture and the resulting mixture was stirred for an additional hour. The reaction mixture was filtered and the organic layer recovered and then dried on anhydrous sodium sulfate. The solvent was removed by evaporation in vacuo to yield a sticky brown solid. The solid was purified by chromatography on normal phase silica eluting with 20% hexane in ethyl acetate to yield N-[3-(ethoxycarbonyl)-2-(2-methylpropyl)butanoyl]-O-methyl-L-tyrosine N-methylamide as a mixture of 4 diastereomers.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:5][CH:4]=1)#[N:2].CN(C)C=O.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)C(=O)C1.[CH:39]1[CH:44]=[CH:43][C:42]([CH:45]([NH2:50])[CH2:46][C:47]([OH:49])=[O:48])=[CH:41][CH:40]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:50][CH:45]([C:42]2[CH:43]=[CH:44][CH:39]=[CH:40][CH:41]=2)[CH2:46][C:47]([OH:49])=[O:48])=[O:15])=[CH:7][CH:8]=1)#[N:2]
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: N#Cc1ccc(CCCCC(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(CCCCC(=O)NC(CC(=O)O)c2ccccc2)cc1
Reaction time: 5 h
Yield: 49.2 %

Procedure:
To a solution of 5-(p-cyanophenyl)pentanoic acid (1.00g, 4.93 mmol), dimethylformamide (10 mL), and pyridine (2 mL) was added N,N'-disuccinimidylcarbonate (1.24 g, 4.85 mmol) and 4-dimethylaminopyridine (60 mg, 0.493 mmol) under an argon atmosphere at 23° C. After 5 h, DL-3-amino-3-phenylpropionic acid (0.814 g, 4.93 mmol) was added as a solid, followed immediately by N,N'-diisopropylethyl amine (0.627 g, 4.85 mmol). After 20 h at 23° C., the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (300 mL), washed with KHSO4 (2×50 mL), washed with brine (1×50 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (2 liters ethyl acetate: chloroform:acetic acid 50:50:0.5 followed by 2 liters of ethyl acetate:methanol:acetic acid 89:10:1) to afford 850 mg (50%) of the title compound (compound 6 of Scheme D). The product was verified by C NMR (CDCl3) delta 24.9, 29.9, 35.3, 35.7, 40.5, 49.7, 109.1, 118.9, 126.1, 127.4, 128.5, 129.0, 131.9, 140.5, 147.8, 173.4, 176.4.