Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].C[Li].[CH3:14]COCC.[C:19](=[NH:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[NH4+]>O1CCCC1>[CH3:14][C:19]([NH2:30])([CH2:20][CH2:21][CH2:22][CH3:23])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOCC
Reactant: CCCCC(=N)c1ccccc1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(C)(N)c1ccccc1
Reaction time: 3 h
Yield: 55.7 %

Procedure:
A suspension of MeCeCl2 was prepared as described in Example 1 from 7.5 g (20 mmol) of cerium chloride heptahydrate, 40 mL of tetrahydrofuran, and 14 mL of 1.4M methyllithium in ether (20 mmol). To this was added below -60° a solution of 1.35 g (8.4 mmol) of valerophenone imine in 5 mL of tetrahydrofuran. The mixture was stirred in a dry ice-acetone bath for 3 hours, treated below -40° slowly with 12 mL of conc. ammonium hydroxide solution, and allowed to come to room temperature. Celite™ was added, the mixture was filtered, and the solids were washed several times with methylene chloride. The dried organic layer of the filtrates was concentrated. The crude product (1.39 g) still contained ca. 10% unreacted imine as shown by 1H NMR spectroscopy. The product was dissolved in toluene and stirred with 3% phosphoric acid for 2 hours. The toluene layer was washed twice with water, and the combined aqueous phases were washed once with toluene and made basic with conc. ammonium hydroxide solution. Extraction with methylene chloride and short-path distillation of the crude product gave 0.83 g (56%) of the title compound., distilling at a bath temperature of 110° (0.005 mm). 1H NMR (in CDCl3) ∂ 0.8 (t, J=7 Hz, 3H), 1.0-1.3 (m, 4H); 1.4 (s, 3H), 1.5 (br, 2H), 1.6-1.8 (m, 2H), 7.2-7.5 (m, 5H). The hydrochloride had mp 153°-156° after crystallization from acetonitrile.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.Br[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[F:37].[C:38]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].CC([O-])(C)C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:41]([O:40][C:38]([N:45]1[CH2:50][CH2:49][N:48]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][C:28]=2[F:37])[CH2:47][CH2:46]1)=[O:39])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccc2ccccc2c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc3ccccc23)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 36.3 %

Procedure:
A third intermediate compound, 1-(2-Fluoro-naphthalen-1-yl)-piperazine, was produced as follows: A solution of Pd(OAc)2 (44.8 mg, 0.2 mmol) and 2-(dicyclohexylphosphino)biphenyl (70.0 mg, 0.2 mmol) was degassed by bubbling N2 for 20 min. 1-Bromo-2-fluoro-naphthalene (0.448 g, 2 mmol) and 1-Boc-piperazine (0.446 g, 2.4 mmol) were added followed by the addition of NaOtBu (0.27 g, 2.8 mmol). The mixture was warmed up to 80° C. and kept at this temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel to give 4-(2-fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.24 g, 40%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:63][CH:64]([F:81])[O:65][C:66]1[CH:67]=[C:68](B2OC(C)(C)C(C)(C)O2)[CH:69]=[CH:70][CH:71]=1>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:63][CH:64]([F:81])[O:65][C:66]1[CH:71]=[C:70]([C:16]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=2[CH:3]2[CH2:4][CH2:5][CH2:6][C:2]2([CH3:25])[CH3:1])[CH:69]=[CH:68][CH:67]=1
Reactant: CC1(C)OB(c2cccc(OC(F)F)c2)OC1(C)C
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C2CCCC2(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cccc(OC(F)F)c2)c(C2CCCC2(C)C)c1
Temperature: 75 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
A stirred mixture of 66.11F (0.48 g, 1.26 mmol), ground S-Phos (104.8 mg, 0.255 mmol), palladium acetate (29.1 mg, 0.130 mmol), and potassium phosphate tribasic (0.6727 g, 3.17 mmol) in dry DMF (5.0 mL) was purged with argon and placed under vacuum (repeated three times). Before heating, 66.11B (0.512 g, 1.89 mmol) was added via syringe, and then the mixture was heated to 75° C. After 16 hours, the reaction was cooled to room temperature, diluted with water and extracted three times with EtOAc. The combined organic layers were washed twice with brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was purified on silica gel (0-20% EtOAc in hexanes) to yield 66.11G as a colorless oil (308.9 mg, 65%). 1H NMR (500 MHz, CDCl3) δ ppm 8.11 (1H, d, J=1.7 Hz), 7.90 (1H, dd, J=7.9, 1.8 Hz), 7.44 (1H, m), 7.28 (1H, m), 7.16 (2H, m), 7.07 (1H, s), 6.57 (1H, t, J=75 Hz), 3.97 (3H, s), 3.10 (1H, t, J=9.4 Hz), 2.13 (2H, m), 1.90 (1H, m), 1.73 (1H, m), 1.61 (1H, m), 1.38 (1H, ddd, J=12.6, 9.4, 7.6 Hz), 0.75 (3H, s), 0.58 (3H, s).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([N:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]2=[O:33])=[N:23][C:22]=1[CH3:34])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([N:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:2][C:3]3[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=3)=[CH:28][C:27]2=[O:33])=[N:23][C:22]=1[CH3:34])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: CC(C)c1nc(CCl)cs1
Product: Cc1nc(-n2ccc(OCc3csc(C(C)C)n3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 36 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 4-(chloromethyl)-2-isopropylthiazole in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 36% yield: 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=8.1 Hz, 1H), 7.34-7.23 (m, 5H), 7.21 (s, 1H), 6.28-6.20 (m, 1H), 6.10-6.04 (m, 2H), 5.12 (s, 2H), 4.59 (d, J=5.6 Hz, 2H), 3.38-3.27 (m, 1H), 2.68 (s, 3H), 1.45-1.35 (m, 6H); MS (ES+) m/z 481.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:16])[CH3:15]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-hydroxy-4-nitrobenzoic acid (16.84 g) in acetic anhydride (60 mL) was heated under reflux overnight. After cooling, the reaction solution was concentrated in vacuo, water and tetrahydrofuran were added to the residue, and the mixture was stirred at room temperature for 4 hours. The aqueous solution was extracted with ethyl acetate, the organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was suspended in diisopropyl ether, the resultant precipitates were collected by filtration and washed with diisopropyl ether to give the titled compound (13.75 g) as a colorless powder.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.N1CCCCC1>CO>[CH:15](=[C:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12](=[O:14])[CH3:13])[CH:6]=2)[C:2]1=[O:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)Nc1ccc2c(c1)CCC2=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CO
Product: CC(=O)Nc1ccc2c(c1)CC(=Cc1ccccc1)C2=O

Procedure:
A mixture of N-(1-oxoindan-5-yl)acetamide (10.0 g, obtained from the Maybridge Chemical Co. Ltd), benzaldehyde (6.73 g), glacial acetic acid (1.06 g) and piperidine (10.8 g) was heated to 90° C. under nitrogen. Methanol (200 ml) was added and the mixture was cooled and then filtered to give N-(2-benzylidene-1-oxo-indan-5-yl)acetamide (13.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[NH:12])[CH3:11].C(=O)(O)[O-].[Na+].Br[CH2:19][C:20](=O)[C:21]([F:24])([F:23])[F:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:19]=[C:20]([C:21]([F:24])([F:23])[F:22])[N:12]=[C:10]1[CH3:11]
Reactant: O=C(CBr)C(F)(F)F
Reactant: CC(=N)Nc1c(Cl)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1nc(C(F)(F)F)cn1-c1c(Cl)cccc1Cl
Temperature: 105 °C

Procedure:
A 500 mL flask was charged with 4.8 g (24 mmol) of N-(2,6-dichlorophenyl)acetamidine, sodium bicarbonate 4.03 g (48 mmol) and 250 mL anhydrous ethanol. 5 g (26.2 mmol) of 3-bromo-1,1,1-trifluoro-propan-2-one was added dropwise. After 1 h solid was filtered off and the filtrate was evaporated in vacuo to give a crude. A mixture of the crude and p-toluenesulfonic acid (668 mg, 3.5 mmol) in toluene was heated to 105° C. for 15 hours. The crude reaction mixture was washed into a separatory funnel with ethyl acetate and water. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo to give the crude product, which was then purified by column chromatography on silica eluting with EtOAc-Hexane (10:0 to 3:2) to afford 1-(2,6-dichloro-phenyl)-2-methyl-4-trifluoromethyl-1H-imidazole as a tan solid (0.9, 43%); 1H NMR (400 MHz, CDCl3): δ 7.52 (m, 2H), 7.43 (m, 1H), 7.19 (m, 1H), 2.2 (s, 3H); MS (ES): 295 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([OH:13])=O.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.[NH2:47][C:48]1[CH:49]=[C:50]([NH:55][C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=2)[CH:51]=[CH:52][C:53]=1[CH3:54]>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:47][C:48]1[CH:49]=[C:50]([NH:55][C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:64])([F:65])[F:66])[CH:58]=2)[CH:51]=[CH:52][C:53]=1[CH3:54])=[O:13]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Reactant: Nc1c(C(=O)O)sc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1sc2nccnc2c1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
A solution of 7-aminothieno[2,3-b]pyrazine-6-carboxylic acid 8 (32 mg, 0.164 mmol), HATU (74.8 mg, 0.197 mmol) and DIPEA (0.054 mL, 0.328 mmol) in DMF (2 mL) was stirred for 15 at rt. N-(3-amino-4-methylphenyl)-3-(trifluoromethyl)benzamide 67 (48.2 mg, 0.164 mmol) was added and stirred overnight at 80° C. The reaction mixture was poured in cold citric acid solution and the resulting precipitate was collected. Purification by HPLC gave the title compound 7-amino-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 70 (14 mg, 18%). NMR (400 MHz, DMSO-d6) 2.23 (s, 3H), 7.07 (s, 2H), 7.28 (d, J=8.2 Hz, 1H), 7.62 (dd, J=8.2 Hz and 2.0 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.31 (s, 1H), 8.78 (dd, J=5.1 Hz and 2.3 Hz, 2H), 9.48 (s, 1H), 10.49 (s, 1H). (m/z)=472 (M+H)+.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]2[C:9]([Sn](CCCC)(CCCC)CCCC)=[CH:10][CH:11]=[CH:12][C:7]2=[CH:6][N:5]=1)[CH3:2].Br[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[Cs+]>O1CCOCC1.C(OCC)C>[CH2:1]([S:3][C:4]1[N:8]2[C:9]([C:35]3[C:36]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:32]=[CH:33][CH:34]=3)=[CH:10][CH:11]=[CH:12][C:7]2=[CH:6][N:5]=1)[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc2cnc(SCC)n12
Reactant: Brc1cccc2ccccc12
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCSc1ncc2cccc(-c3cccc4ccccc34)n12
Temperature: 100 °C

Procedure:
To a solution of the title C compound, 3-ethylsulfanyl-5-tributylstannyl-imidazo-[1,5-a]pyridine (550 mg, 1.18 mmol) in 1,4-dioxane (8 mL), 1-bromonaphthalene (0.18 mL, 1.29 mmol) is added followed by tris(dibenzylidineacetone)dipalladium(0) (38 mg, 0.041 mmol), tri-t-butylphosphine (80 μL, 0.329 mmol) and cesium fluoride (396 mg, 2.6 mmol). The suspension is heated at 100° C. under nitrogen in a sealed tube for two days. The mixture is cooled, diluted with ethyl ether and filtered through a short silica plug. The solvent is evaporated under reduced pressure, and the residue is purified by flash column chromatography on silica using 10% ethyl acetate in hexanes to yield 3-ethylsulfanyl-5-naphthalen-1-yl-imidazo[1,5-a]pyridine as an amber oil: 1H-NMR (CDCl3) δ 8.01 (dd, J=7.5, 1.8, 1H), 7.93 (d, J=8.1, 1H), 7.61 (s, 1H), 7.58-7.47 (m, 4H), 7.41-7.32 (m, 2H), 6.78 (dd, J=9.0, 6.6, 1H), 6.51 (dd, J=6.6, 1.2, 1H), 2.66 (q, J=7.2, 2H), 0.86 (t, J=7.2, 3H), MS (M+1)+ 305.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:6]([CH2:12]Cl)=[N:7]2.[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:12][C:6]1[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:4](=[O:21])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1F
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2cccc(Cl)c2c(=O)n1-c1ccccc1F
Yield: 50 %

Procedure:
Prepared according to Procedure C using Intermediate 2k (210 mg, 0.650 mmol), adenine (97 mg, 0.715 mmol), K2CO3 (99 mg, 0.715 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 137 mg of a tan solid (50%), mp 295.6-295.8° C. (decomposes). 1H NMR (DMSO-d6) δ: 8.05 (s, 1H); 8.04 (s, 1H); 7.75 (t, J=7.6 Hz, 1H); 7.74 (t, J=7.9 Hz, 1H); 7.62-7.69 (m, 1H); 7.61 (d, J=7.6 Hz, 1H); 7.47-7.55 (m, 1H); 7.48 (d, J=7.8 Hz, 1H); 7.41 (d, J=8.0 Hz, 1H); 7.24 (br s, 2H); 5.19 (d, J=17 Hz, 1H); 5.03 (d, J=17 Hz, 1H). 13C NMR (DMSO-d6) ppm: 158.7, 157.6 (d, J=250 Hz), 156.2, 152.8, 152.4, 150.0, 149.2, 141.8, 135.4, 133.3, 132.5 (d, J=8.0 Hz), 131.0, 130.4, 127.3, 126.2 (d, J=3.5 Hz), 123.1 (d, J=14 Hz), 118.4, 117.6, 117.2 (d, J=19 Hz), 45.1. MS (ES): m/z 422.0 (M+). Anal. calcd. for C20H13ClFN7O.0.05C2H6O: C, 56.92; H, 3.16; Cl, 8.36; N, 23.12. Found: C, 56.79; H, 3.20; Cl, 8.46; N, 22.79.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:16])[O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)(=[O:3])[CH3:2].[CH2:17]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH3:18]>N1CCCCC1.C(#N)C>[CH2:17]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH:2][C:1]([C:4]2[C:5](=[O:16])[O:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=3)=[O:3])=[CH:22][CH:21]=1)[CH3:18]
Reactant: CCOc1ccc(C=O)cc1
Reactant: COc1ccc2cc(C(C)=O)c(=O)oc2c1
Solvent: C1CCNCC1
Solvent: CC#N
Product: CCOc1ccc(C=CC(=O)c2cc3ccc(OC)cc3oc2=O)cc1

Procedure:
A suspension of 2.18 g 3-acetyl-7-methoxycoumarin and 1.65 g p-ethoxybenzaldehyde in 100 ml alcohol was heated under reflux on a steam bath. Acetonitrile was added until solution was attained. Fifty drops of piperidine were added and the reaction mixture heated under reflux for 90 minutes. An additional fifty drops of piperidine were added and the solution was heated under reflux another hour. The product separated upon cooling and was washed with alcohol before being recrystallized from a mixture of alcohol and acetonitrile.
Reaction SMILES: BrCC1C=CC=CC=1/C(=C\OC)/C(OC)=O.[OH-].[Na+].[OH-].[K+].CC1C=CC=CC=1CC([O-])=O.[CH3:32][O:33]/[N:34]=[C:35](\[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][Br:47])/[C:36]([O:38][CH3:39])=[O:37].[CH3:48][O:49][N:50]=[C:51]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[CH2:62]Br)[C:52]([O:54][CH3:55])=[O:53].CC1C=CC=CC=1CC(OC)=O>C(C(C)=O)C.CC(C)=O>[CH3:32][O:33][N:34]=[C:35]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][Br:47])[C:36]([O:38][CH3:39])=[O:37].[CH3:48][O:49][N:50]=[C:51]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[CH3:62])[C:52]([O:54][CH3:55])=[O:53]
Reactant: CO/N=C(/C(=O)OC)c1ccccc1CBr
Agent: CO/C=C(/C(=O)OC)c1ccccc1CBr
Agent: COC(=O)Cc1ccccc1C
Agent: CON=C(C(=O)OC)c1ccccc1CBr
Solvent: CC(C)=O
Solvent: CCC(C)=O
Product: CON=C(C(=O)OC)c1ccccc1C

Procedure:
Compounds of formula IV (X is CH) are prepared by alkylation with methyl E-α-(2-bromomethylphenyl)-β-methoxyacrylate in the presence of a base, preferably NaOH or KOH, in a solvent, preferably acetone or methyl ethyl ketone. Methyl E-α-(2-bromomethylphenyl)-β-methoxyacrylate, as a single E isomer, can be prepared in two steps from 2-methylphenylacetate as described previously in U.S. Pat. No. 4,914,128, columns 3-4. Compounds of formula V (X=N) are prepared by the reaction with methyl E-2-(bromomethyl)phenylglyoxylate O-methyloxime in the presence of a base, preferably NaOH or KOH, in a solvent, preferably acetone or methyl ethyl ketone. Methyl 2-(bromomethyl)phenylglyoxylate O-methyloxime can be prepared as described in U.S. Pat. No. 4,999,042, columns 17-18 and 5,157,144, columns 17-18. Methyl 2-(bromomethyl)phenylglyoxylate O-methyloxime is prepared from methyl 2-methylphenyl-acetate by treatment with an alkyl nitrite under basic conditions to provide after methylation, methyl 2-methyl-phenylglyoxalate O-methyl oxime which can also be prepared from methyl 2-methyl-phenylglyoxalate by treatment with 2-hydroxylamine hydrochloride and methylation or by treatment with methoxylamine hydrochloride. ##STR17##
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[N:6]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[C:10]([C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([NH:1][S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[S:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=1)#[N:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1cccc(-c2csc(N)n2)c1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc(C#N)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
A mixture of 0.5 g of 3-(2-amino-thiazol-4-yl)-benzonitrile with 0.52 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 50 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 80 ml of 50% ethanol yielded 0.35 g of N-[4-(3-cyano-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=3)[C:31]([O:33]C)=[O:32])[CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=3)[C:31]([OH:33])=[O:32])[CH2:25][CH2:26]2)=[CH:39][CH:40]=1
Reactant: COC(=O)c1cccc(CN2CCC(Nc3cc(O)nc4ccc(C(c5ccc(Cl)cc5)c5ccc(Cl)cc5)cc34)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(CN2CCC(Nc3cc(O)nc4ccc(C(c5ccc(Cl)cc5)c5ccc(Cl)cc5)cc34)CC2)c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 3-[[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidin-1-yl]methyl]benzoate (80 mg, 0.13 mmol, 1.00 equip), methanol (20 mL), and 1M sodium hydroxide (20 mL). The resulting solution was stirred overnight at 30° C. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 5-6 with 10% HCl. The solids were collected by filtration to yield 3-[[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidin-1-yl]methyl]benzoic acid as a white solid.
Reaction SMILES: C(OP([CH:9]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[N:10]1[CH3:16])(=O)OCC)C.O.[OH-].[Li+].[CH:20]([CH:22]([N:26]([CH3:49])[C:27]([CH:29]([NH:34][C:35](=[O:48])[CH:36]([NH:46][CH3:47])[C:37]([CH3:45])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:38])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:23]([CH3:25])[CH3:24])=O>C(O)C.O>[CH3:47][NH:46][C@H:36]([C:35]([NH:34][C@H:29]([C:27]([N:26]([CH3:49])[C@H:22](/[CH:20]=[C:9]1\[N:10]([CH3:16])[C:11](=[O:15])[NH:12][C:13]\1=[O:14])[CH:23]([CH3:24])[CH3:25])=[O:28])[C:30]([CH3:31])([CH3:32])[CH3:33])=[O:48])[C:37]([CH3:38])([CH3:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CNC(C(=O)NC(C(=O)N(C)C(C=O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Reactant: CCOP(=O)(OCC)C1C(=O)NC(=O)N1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C1/C(=O)NC(=O)N1C)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
The yield, (3-methyl-2,5-dioxo-imidazolidin-4-yl)-phosphonic acid diethyl ester (0.915 g, 3.0 mmol) in ethanol (9 mL) is added to lithium hydroxide monohydrate (139 mg, 2.1 mmol) in 0.9 ml water to give a yellow solution. It is then added to N-{1-[(1-formyl-2-methyl-propyl)-methyl-carbamoyl]-2,2-dimethyl-propyl}-3-methyl-2-methylamino-3-phenyl-butyramide (˜1 mmol, from Reference Example 12) in 3 mL ethanol. The reaction mixture is stirred at room temperature for 60 hours. Solvent is evaporated. The residue is diluted with dichloromethane/water. The aqueous layer is extracted twice with dichloromethane. The combined organic extracts are washed with brine, dried oversodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed by reverse phase HPLC (0.01% trifluoroacetic acid in water/acetonitrile) to give the product as a white solid, N,beta,beta-trimethyl-L-phenylalanyl-N1,3-dimethyl-N1-{(1S)-2-methyl-1-[(Z)-(3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl]propyl}-L-valinamide: 25 mg (4%) MS (ES+): (M+H)=514.3
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.CCN(C(C)C)C(C)C.C(OCC)(=O)C>[CH2:14]([NH:21][C:6](=[O:8])[C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cccc([N+](=O)[O-])c1C(=O)NCc1ccccc1
Reaction time: 1 h
Yield: 75.5 %

Procedure:
2-Nitro-6-methylbenzoic acid (0.91 g) and benzylamine (0.53 g) were dissolved in NMP (5 mL) and DIPEA (3 mL). HATU (1.9 g) was added and the mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate and then brine. The organic solution was dried with magnesium sulfate, filtered and the solvent was removed under vacuum to give a light brown oil (1.01 g) that crystallized on standing.