Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:7]([CH3:14])[C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[C:22](=[O:29])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[NH2:23]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:23][C:22](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:3][CH:4]=3)[O:9][C:8]([CH3:13])([CH3:12])[C:7]=2[CH3:14])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: CC1=C(c2ccc(F)cc2)c2ccc(Cl)cc2OC1(C)C
Product: CC1=C(c2ccc(F)cc2)c2ccc(NC(=O)OC(C)(C)C)cc2OC1(C)C

Procedure:
The compound obtained in (3) described above (100 mg) and tert-butyl carbamate (125 mg) were treated in the same manner as Reference Example 5(4) to give the titled compound (126 mg) as a pale brown powder.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]([CH2:9][C:10](O)=[O:11])#[N:8].[CH2:13]([O:15][C:16]([C:18]1[C:22]([C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=2)=[CH:21][S:20][C:19]=1[NH2:31])=[O:17])[CH3:14]>C(Cl)Cl.CN(C=O)C>[CH2:13]([O:15][C:16]([C:18]1[C:22]([C:23]2[CH:24]=[C:25]([CH3:30])[CH:26]=[C:27]([CH3:29])[CH:28]=2)=[CH:21][S:20][C:19]=1[NH:31][C:10](=[O:11])[CH2:9][C:7]#[N:8])=[O:17])[CH3:14]
Reactant: CCOC(=O)c1c(-c2cc(C)cc(C)c2)csc1N
Reactant: N#CCC(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2cc(C)cc(C)c2)csc1NC(=O)CC#N
Temperature: 25 °C

Procedure:
To a stirred suspension of PCl5 (0.74 g, 3.5 mmol) in CH2Cl2 (10 mL) was added a solution of cyanoacetic acid (0.3 g, 3.5 mmol) in CH2Cl2 (5 mL) and DMF (1 mL) dropwise via syringe at room temperature and the reaction mixture was heated at reflux for 1 hour. The reaction was cooled to room temperature and a solution of 2-Amino-4-(3,5-dimethyl-phenyl)-thiophene-3-carboxylic acid ethyl ester (0.78 g, 2.8 mmol) in CH2Cl2 (5 mL) was added via canula over 5 minutes. The reaction was then heated at reflux for 2.5 h, cooled to 0° C. and quenched by slow addition of sat. aq. Na2CO3 (10 mL) until basic (pH 9–10). The mixture was extracted with ethyl acetate (3×30 mL) and the combined organic layers were washed with water (25 mL), brine (15 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as a yellow solid. MS (ESI) m/e 341.0 (M−H); 1H NMR (300 MHz, CDCl3): δ ppm 12.02 (s, 1H), 7.26 (s, 1H), 6.97 (s, 1H), 6.91 (s, 2H), 6.67 (s, 1H), 4.15 (q, 4H, J=7.12), 3.68 (s, 2H), 2.33 (s, 6H), 0.98 (t, 3H, J=7.12).
Reaction SMILES: [CH:1]1([NH:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:19][C:20]([CH3:25])([CH3:24])[C:21](Br)=[O:22]>>[Br:19][C:20]([CH3:25])([CH3:24])[C:21]([N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])=[O:22]
Reactant: CC(C)(Br)C(=O)Br
Reactant: O=C(NNC1CCCCC1)OCc1ccccc1
Product: CC(C)(Br)C(=O)N(NC(=O)OCc1ccccc1)C1CCCCC1

Procedure:
Benzyl 2-cyclohexylhydrazinecarboxylate and 2-bromoisobutyryl bromide were used for a similar reaction and treatment as Process 3 of Example 1, and benzyl 2-(2-bromoisobutyryl)-2-cyclohexylhydrazinecarboxylate was obtained as a white oil.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].C([O-])(O)=O.[Na+].[C:11]1([CH:17]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][N:27]1[CH2:28][CH2:29][N:24]([CH:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25][CH2:26]1
Reactant: ClCC1CO1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
To a mixture of epichlorohydrin (5.1 mL, 0.065 mL) in ethanol (13 mL) and anhydrous NaHCO3 (0.065 mol, 5,46 g) at 0° C., diphenylmethylpiperazine (16.4 g, 0.065 mol) in ethanol (250 mL) was added dropwise over 45 min at room temperature under N2. After 17 h the NaHCO3 was removed by filtration via a sintered glass funnel and the ethanol was removed from the filtrate in vacuo giving a white-yellow solid (21.5 g). This solid after trituration with Et2 (300 mL) gave a precipitate which was filtered and dried in vacuo to give the pure product (5.11 g, 22.8%) mp 114°-116° C. DCI/MS (M+1) 345. 400 MHz 1H NMR (CDCl3) δ: 7.2-7.4 (m, 10H), 4.2 (s, 1H), 3.9 (m, 1H), 3.55-3.7 (m, 2H), 2.7 (m, 2H), 2.45 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([N:49]4[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]4)=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[N:22](COCC[Si](C)(C)C)[S:21]3(=[O:35])=[O:34])=[CH:16][CH:15]=2)[CH:13]=1.I[CH2:57][CH3:58]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([N:49]4[CH2:54][CH2:53][N:52]([CH2:57][CH3:58])[C:51](=[O:55])[CH2:50]4)=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[NH:22][S:21]3(=[O:34])=[O:35])=[CH:16][CH:15]=2)[CH:13]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCNC(=O)C5)cc4)cc3)cc2)S1(=O)=O
Reactant: CCI
Product: CCN1CCN(c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)CC1=O

Procedure:
4-[4′-(4-(2,4-Dichloro-phenyl)-1-{4-[1,1,4-trioxo-5-(2-trimethylsilanyl-ethoxy methyl)-[1,2,5]thiadiazolidin-2-yl]-phenyl}-1H-imidazol-2-ylmethyl)-biphenyl-4-yl]-piperazin-2-one (17 mg, 0.02 mmol) was treated as described in general procedure L (using iodoethane) and general procedure W stepwise to give 4-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-1-ethyl-piperazin-2-one.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[N:21]=[C:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:23][C:24]=3[C:25]([F:28])([F:27])[F:26])=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[C:29]1([C:22]2[O:23][C:24]([C:25]([F:26])([F:27])[F:28])=[C:20]([C:18]([NH:17][C:14]3[CH:13]=[CH:12][C:11]([N:8]4[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]4)=[CH:16][CH:15]=3)=[O:19])[N:21]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(N2CCC(C(=O)O)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
The above 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid methyl ester (470 mg, 1 mmol) was dissolved in a mixture of methanol (7 mL) and THF (2 mL). To this solution was added 1N sodium hydroxide solution (3 mL). The mixture was stirred at room temperature for 4 hrs until all starting material was consumed. Solvents were evaporated and the residue was diluted with water (8 mL). The solution was filtered and the filtrate was acidified with 1N hydrochloric acid (3.5 mL). The yellow precipitate was filtered and dried in the air to give 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid (395 mg). 1H-NMR is consistent with the desired structure. LC-MS indicated a single peak (Rf=3.23 min). LRMS for C23H20F3N3O4 (m/e) calcd 459.14, obsd 460.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8](=[O:25])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH:10]=1.[CH2:31]([S-:33])[CH3:32].[Na+]>CS(C)=O>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8](=[O:25])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([S:33][CH2:31][CH3:32])[CH:18]=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH:10]=1
Reactant: CC[S-]
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCSc1ccc([N+](=O)[O-])c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide 14d (300 mg, 0.72 mmol, 1.00 equiv) in DMSO (5 mL), and sodium ethanethiolate (100 mg, 1.19 mmol, 1.70 equiv). The resulting solution was stirred for overnight at 90° C. in an oil bath. The mixture was concentrated under vacuum. The residue was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of dichloromethane and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 300 mg (crude) of N-(3-(trifluoromethyl)benzyl)-2-(5-(ethylthio)-2-nitrophenyl)isonicotinamide as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH:14]2[CH2:23][CH2:22][N:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15]2)=[O:11])=[CH:2]1.[C:24](Cl)(=[O:26])[CH3:25]>>[C:24]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH:14]2[CH2:23][CH2:22][N:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15]2)=[O:11])=[CH:2]1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Product: CC(=O)n1cc(C(=O)OCC2CCN3CCCCC3C2)c2ccccc21

Procedure:
eq-Quinolizidin-2-ylmethyl indole-3-carboxylate (E9b) was acylated with acetyl chloride using the method of Example 18. The product was chromatographed on silica gel eluting with ethyl acetate to give a pale yellow oil, which crystallised from ether to afford the title compound (E30) as a white solid mp 127°-129° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].C(N(CC)CC)C.[C:17](Cl)(Cl)=[S:18].[OH-].[K+]>CCOCC>[NH:9]1[C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:2][NH:1][C:17]1=[S:18]
Reactant: NCc1ccccc1N
Reactant: S=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: S=C1NCc2ccccc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 2-aminomethyl-phenylamine (6.35 g, 52 mmol) and triethylamine (16.8 ml, 120 mmol) in ether (150 ml) was added dropwise a solution of thiophosgene (4.6 ml, 60 mmol) in ether (40 mL), at −78° C. over 1 h. After warming to rt a precipitate was filtered, washed thoroughly with ether, dissolved in methanol (200 mL) and treated with solid KOH (6.7 g, 120 mmol). The mixture was stirred for 15 min, filtered, and the filtrate was concentrated under reduced pressure to obtaine a residue which was recrystallized from methanol/water to give an off-white solid 7.43 g (87%). 1H NMR (500 MHz, DMSO-D6) δ 4.35 (s, 1H) 6.92 (d, J=7.93 Hz, 1H) 6.96 (m, 1H) 7.08 (d, J=7.32 Hz, 1H) 7.15 (m, 1H) 8.59 (s, 1H) 10.36 (s, 1H). MS (ESI) m/z 165 (MH+); HPLC (Column YMC Xterra OSD 4.6×33 mm S 7) Rt 0.81 min; Purity (96%).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[CH:20]([NH:22][CH3:23])[CH3:21])=[CH:5][CH:4]=1.[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:22]([CH:20]([C:10]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[CH3:24])=[CH:4][CH:5]=3)[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH3:21])[CH3:23])(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC(C)c1nc2ccccc2c(=O)n1-c1ccc(N(C)C)cc1
Product: CC(c1nc2ccccc2c(=O)n1-c1ccc(N(C)C)cc1)N(C)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
In a similar manner as described above in Example 7, 3-(4-dimethylamino-phenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one, as prepared above in Paragraph L, was condensed with 4-tert-butylbenzenesulfonyl chloride to yield 4-tert-butyl-N-{1-[3-(4-dimethylamino-phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide; MS (ESI) 519 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:16])=[N:8][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH2:17](OC(C1C(O)=NC(CC)=NC=1)=O)[CH3:18].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:16][CH2:17][CH3:18])=[N:8][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)nc1O
Reactant: CCOC(=O)c1cnc(CC)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(C(C)(C)C)nc1OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of 4-hydroxy-2-tert-butyl-pyrimidine-5-carboxylic acid ethyl ester (3 g, 13.377 mmol, prepared in an analogous manner as described for the preparation of 2-ethyl-4-hydroxy-pyrimidine-5-carboxylic acid ethyl ester, Dostert, P. et al. Eur. J. Med. Chem. 1982, 17, 437-444) in dimethylformamide (10 mL) was added slowly to the suspension of sodium hydride (800 mg, 60% in mineral oil, Aldrich) in dimethylformamide cooled to 0° C. After the addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was stirred at room temperature for 4 h then quenched with saturated solution of ammonium chloride. It was extracted with ethyl acetate (2×). The organic extracts were washed with brine (1×), dried over anhydrous sodium sulfate and concentrated. Purification of the crude residue by flash column chromatography (120 g of silica gel, eluting with a gradient of 5-60% ethyl acetate in hexane gave 4-ethoxy-2-tert-butyl-pyrimidine-5-carboxylic acid ethyl ester (1.12 g, 30%).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([N:12]3[CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Cl:21])[CH:18]=4)[C:13]3=[O:22])[C:6]=2[CH2:5][CH2:4][CH2:3]1.CCN(CC)CC.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>C(Cl)Cl>[Cl:21][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:22])[N:12]([C:7]1[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[C:11]=3[CH:10]=[N:9][CH:8]=1)[CH2:20]2
Reactant: CCS(=O)(=O)Cl
Reactant: NC1CCCc2c1cncc2N1Cc2cc(Cl)ccc2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NC1CCCc2c1cncc2N1Cc2cc(Cl)ccc2C1=O
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(8-amino-5,6,7,8-tetrahydro-isoquinolin-4-yl)-5-chloro-2,3-dihydro-isoindol-1-one (156 mg, 0.5 mmol) and Et3N (210 uL) in DCM (10 mL) was added ethanesulfonyl chloride (48 uL mg, 0.5 mmol) at 0° C. and stirring continued at 0° C. for 1 h. The resulting mixture was extracted with EtOAc (2×50 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound. The residue was separated by prep-HPLC to give a racemic mixture of title compound (170 mg, 84%) as a light yellow solid. MS: 406.1 (M+H+).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][C:7]=2[C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[Cl:23][C:24]1[N:29]=[C:28]([C:11]2[CH:12]=[CH:13][C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[C:7]([CH:10]=2)[C:8]#[N:9])[CH:27]=[CH:26][N:25]=1
Reactant: CC1(C)OB(c2ccc(N3CCCC3)c(C#N)c2)OC1(C)C
Reactant: Clc1ccnc(Cl)n1
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: C1COCCO1
Product: N#Cc1cc(-c2ccnc(Cl)n2)ccc1N1CCCC1
Temperature: 100 °C
Yield: 381.1 %

Procedure:
Pyrrolidin-1-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (200 mg, 0.67 mmol), 2,4-dichloropyrimidine (120 mg, 0.81 mmol), tetrakis(triphenylphosphine)palladium(0) (78 mg, 0.07 mmol, 10 mol %) and sodium carbonate (213 mg, 2.01 mmol) were diluted with 1:1 1,4-dioxane-H2O (4.0 mL). The mixture was then heated at 100° C. in the microwave (300 W, stirring) for 10 minutes. The reaction was repeated four more times. The reaction mixtures were combined and the solvents evaporated in vacuo (Genevac™). The residue was partitioned between DCM (150 mL) and H2O (50 mL). The organic phase was washed with water (50 mL) and saturated brine solution (75 mL). The organic phase was then dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude product was purified by column chromatography (40-63 mesh silica gel, 70% isohexane-EtOAc) to provide the title compound as a yellow solid (727 mg, 76%); LC-MS, Rt=2.80 min (MeOH-FA method), m/z 285, 287 (MH+).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@:18]3(O)[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc(C[C@@H]2CCCC[C@]2(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 4 h
Yield: 59.6 %

Procedure:
A mixture of (1R,2S)-1-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2-(3-methoxybenzyl)cyclohexane (28 g) and p-toluene-sulfonic acid (2.5 g) in toluene (300 ml) was stirred for 4 hours under reflux. The solution was washed with water, saturated sodium hydrogencarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (S)-2-(4,5-diphenyloxazol-2-yl)-1-(3-methoxybenzyl)-2-cyclohexene (16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]([CH3:26])[CH3:25])[CH:18]=3)=[O:16])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:35]1([C:41]2([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][N:44]3[CH2:43][CH2:42][C:41]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45]3)[CH2:13][CH2:12][N:11]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]([CH3:25])[CH3:26])[CH:18]=3)=[O:16])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: CC(C)Oc1cccc(C(=O)CN2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)c1
Agent: Cl
Product: CC(C)Oc1cccc(C(=O)CN2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3-isopropoxy-phenacyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.6 mmol) and 4-phenylpiperidine-4-carboxylic acid amide hydrochloride (0.72 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:23])[N:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:32][OH:33].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:23])[N:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:17]=2)=[N:32]\[OH:33])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(CCC(=O)O)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(CCC(=O)O)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 3-{5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-2-oxo-2H-pyridin-1-yl}-propionic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI−): m/z=481.0 [M−H]−.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[CH:10]=[C:9]([NH2:12])[CH2:8][C:7]([CH3:14])([CH3:13])[C:6]=2[NH:5][C:4](=[O:15])[CH2:3]1.F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][CH:2]1[C:11]2[CH:10]=[C:9]([NH:12][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-:25])=[O:24])[CH2:8][C:7]([CH3:14])([CH3:13])[C:6]=2[NH:5][C:4](=[O:15])[CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC1CC(=O)NC2=C1C=C(N)CC2(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC1CC(=O)NC2=C1C=C(Nc1ccccc1[N+](=O)[O-])CC2(C)C

Procedure:
This compound, m.p. 205°14 211°, was prepared similarly to Preparation 20 using 3,4-dihydro-4,8,8-trimethyl-6-amino-2-(1H)-quinolone, 1-fluoro-2-nitrobenzene, and sodium carbonate as starting materials.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C@@H:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](OCC)=[O:18])=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=1[NH:30][C:31]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][N:32]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C@@H:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH:29][C:26]4[CH:27]=[CH:28][C:23]([CH3:22])=[C:24]([NH:30][C:31]5[N:36]=[C:35]([C:37]6[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=6)[CH:34]=[CH:33][N:32]=5)[CH:25]=4)=[O:18])=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)c1ccc2c(c1)CC[C@@H]2N1CCN(C)CC1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2ccncc2)n1
Product: Cc1ccc(NC(=O)c2ccc3c(c2)CC[C@@H]3N2CCN(C)CC2)cc1Nc1nccc(-c2ccncc2)n1

Procedure:
The title compound was prepared by condensation reaction between ethyl (1S)-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indene-5-carboxylate and 4-methyl-N(3)-(4-pyridin-4-ylpyrimidin-2-yl)benzene-1,3-diamine, according to the procedure described in Step C of EXAMPLE 11. MS (M+1)=520.27. 1HNMR (DMSO-d6, ppm): δ 10.14 (s, 1H); 9.04 (s, 1H); 8.07 (d, J=4.4 Hz, 2H); 8.55 (d, J=4.8 Hz, 1H); 8.06 (s, 1H); 8.04 (d, J=4.4 Hz, 2H); 7.78 (s, 1H); 7.75 (d, J=8.8 Hz, 1H); 7.45 (d, J=7.6 Hz, 1H); 7.44 (d, J=4.8 Hz, 1H); 7.35 (d, J=7.6 Hz, 1H); 7.18 (d, J=8.8 Hz, 1H); 4.31 (t, J=7.2 Hz, 1H); 2.0-3.0 (m, 10H); 2.19 (s, 3H); 2.12 (s, 3H); 2.04 (m, 2H).
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][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][CH3:22].O.[N+]([O-])([O-])=O.[Ag+:30]>C1C=CC=CC=1>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][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][CH3:22].[Ag+:30]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
3.4 g of behenic acid was dissolved in 100 ml of benzene at 60° C., and the temperature of this solution was adjusted to 60° C. 100 ml of water was added to the above solution with stirring to form an emulsion. 100 ml of an aqueous solution of silver ammonium complex, which was prepared by adding aqueous to about 80 ml of an aqueous solution containing 1.7 g of silver nitrate, and then adding water to the aqueous solution to make the total volume one liter, was then added to the above emulsion. Crystallites of silver behenate were obtained.