Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:14]=[C:15]([CH3:23])[C:16]4[O:20][N:19]=[C:18]([CH3:21])[C:17]=4[CH:22]=3)[C:11](=[O:24])[C:10](=O)[CH:9]2[C:26](=O)[CH2:27][CH3:28])=[CH:4][CH:3]=1.[NH:30]([CH2:32][CH2:33][OH:34])[NH2:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:10](=[N:31][N:30]([CH2:32][CH2:33][OH:34])[C:26]=3[CH2:27][CH3:28])[C:11](=[O:24])[N:12]2[C:13]2[CH:14]=[C:15]([CH3:23])[C:16]3[O:20][N:19]=[C:18]([CH3:21])[C:17]=3[CH:22]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)C1C(=O)C(=O)N(c2cc(C)c3onc(C)c3c2)C1c1ccc(Cl)cc1
Reactant: NNCCO
Product: CCc1c2c(nn1CCO)C(=O)N(c1cc(C)c3onc(C)c3c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 79 using 5-(4-chlorophenyl)-1-(3,7-dimethylbenzo[d]isoxazol-5-yl)-4-propionylpyrrolidine-2,3-dione (Step 9.1) and 2-hydrazinylethanol. tR: 1.04 min (LC-MS 2); ESI-MS: 451 [M+H]+ (LC-MS 2).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][C:8]3[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][NH:13][CH2:14][CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:21](Cl)(=[O:23])[CH3:22]>>[C:21]([N:13]1[CH2:14][CH2:15][C:7]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=3[NH:9][C:8]=2[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12]1)(=[O:23])[CH3:22]
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1c(C)cccc21
Reactant: CC(=O)Cl
Product: CCOC(=O)C1=CN(C(C)=O)CCc2c1[nH]c1c(C)cccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A using ethyl 7-methyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and acetyl chloride; 1H-NMR (CDCl3): δ 10.50 (1H, br s), 8.12 (1H, br s), 7.36 (1H, d), 7.01 (2H, m), 4.39 (2H, q), 4.01 (2H, m), 3.16 (2H, m), 2.53 (3H, s), 2.39 (3H, s), 1.43 (3H, t); MS (ES): 313 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:12][C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[NH:1][C:20]([NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21]
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(C(F)(F)F)cc1O
Product: O=C(Nc1ccccc1)Nc1ccc(C(F)(F)F)cc1O
Yield: 71.2 %

Procedure:
N-[2-Hydroxy-4(trifluoromethyl) phenyl]-N'-phenyl urea was prepared from 2-amino-5-trifluoromethylphenol (150 mg, 1.09 mmol) and phenyl isocyanate(1.09 mmol) according to the procedure in General method A. The product was purified by precipitation from methylene chloride and filtering to afford the titled compound (230 mg, 87% ). mp: °C.; 1H NMR (DMSO-d6): δ 9.45 (s, 1H, NH), 8.50 (s, 1H, NH), 8.31 (d, 1H, J=10.0 Hz), 7.45 (d, 2H, J=10.0 Hz), 7.29 (t, 2H, J=6.67 Hz), 7.10 (m, 2H), 6.99 (t, 1H, J=6.67 Hz). EI-MS m/z 296 (M+). Anal. (C14H11N2O2F3)C, H, N.
Reaction SMILES: N1SC=C2C=C(N)C=CC=12.[C:11]1([C:17]2[N:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[S:26]([C:30]1[CH:31]=[C:32]([NH-:36])[CH:33]=[CH:34][CH:35]=1)(=[O:29])(=[O:28])[NH2:27]>>[S:26]([C:30]1[CH:31]=[C:32]([NH:36][C:23]([C:20]2[CH:21]=[N:22][C:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:18][CH:19]=2)=[O:25])[CH:33]=[CH:34][CH:35]=1)(=[O:28])(=[O:29])[NH2:27]
Reactant: [NH-]c1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Agent: Nc1ccc2nscc2c1
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnc(-c3ccccc3)nc2)c1

Procedure:
Following procedures similar to those of Example 8 but substituting 3-amino-benzenesulfonamide (0.3 mmol) for 2,2-dioxo-2,3-dihydro-1H-2lamda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl-pyrimidine-5-carboxylic acid (3-sulfamoyl-phenyl-amide as a solid. MS: 355 (M+H).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH:4]=[CH2:5].C(OC(Cl)=O)C.C(N(CC)CC)C.Cl.[CH2:22]([O:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[CH2:22]([O:29][NH:30][C:1](=[O:7])[CH2:2][CH2:3][CH:4]=[CH2:5])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NOCc1ccccc1
Reactant: C=CCCC(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCCC(=O)NOCc1ccccc1

Procedure:
This compound was prepared in several steps. 4-pentenoic acid (1.2.6.4) was reacted with ethylchloroformate in the usual way to obtain the active mixed anhydride. To a solution of the mixed anhydride in chloroform was added triethylamine and O-benzylhydroxylamine hydrochloride to obtain O-benzyl-4-pentenohydroxamic acid (1.2.6.5). The double bond was oxidized using osmium tetroxide/N-methylmorpholine oxide to give the diol (1.2.6.6). The terminal hydroxyl group was then protected with t-butyldimethylsilylchloride in the usual way to yield (1.2.6.7). The secondary hydroxyl group was tosylated using pyridine/p-toluenesulfonyl chloride. Cyclization of (1.2.6.8) to the corresponding pyrrolidone (1.2.6.9) was effected by using sodium carbonate in methanol. The protecting silyl group was removed by treatment with tetraethylammonium fluoride. The title compound (1.2.6.3) was prepared by reacting the latter compound (1.2.6.10) with pyridinelp-toluenesulfonyl chloride in the usual way.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[C:13]([C:24]([OH:26])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[C:13]([C:24]([N:39]3[CH2:40][CH2:41][CH:36]([C:33]4[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=4)[CH2:37][CH2:38]3)=[O:26])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: COc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc(OC)cc4)CC3)cnc12
Yield: 0.1 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(2-fluoro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.5 g, 1.40 mmol) obtained in Example 90, step 2 and 4-(4-methoxyphenyl)piperidine hydrochloride (0.38 mg, 1.67 mmol), the title compound (0.58 mg, 78%) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.C([O-])([O-])=O.[K+].[K+].[Br:23][CH2:24][CH2:25][CH2:26]Br>CC#N>[Br:23][CH2:24][CH2:25][CH2:26][O:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1
Reactant: BrCCCBr
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(OCCCBr)cc2)OC1(C)C
Temperature: 70 °C
Yield: 86.9 %

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (CAS #269409-70-3) (10.5 g, 47 mmol) was dissolved in dry CH3CN (200 mL) and dry, pulverized K2CO3 (10.4 g, 75 mmol) was introduced. 1,3-dibromopropane (38.1 mL, 375 mmol) was added dropwise, and the reaction mixture was heated at 70° C. for 7 h under a nitrogen atmosphere. The cooled reaction mixture was filtered and the filtrate was evaporated to an oily residue, which was applied to a column of silica gel. Elution initially with hexanes, gradually increasing polarity to a mixture of hexanes/ethyl acetate (25:1, 20:1 and 10:1) as eluent, provided the title compound (13.93 g, 86%) which crystallized on standing to a white solid, m.p. 62-65° C.
Reaction SMILES: C(O[C:4]1(O[Si](C)(C)C)[CH2:6][CH2:5]1)C.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:4]1([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=3)[CH2:22][CH2:23]2)[CH2:5][CH2:6]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1ccc(N2CCN(C3CC3)CC2)cc1
Temperature: 62.5 °C
Yield: 100 %

Procedure:
A mixture of [(1-ethoxycyclopropyl)oxy]trimethylsilane (4.5 mL. 22.4 mmol, 2 eq.), 1-(4-nitrophenyl)piperazine (2.32 g, 11.1 mmol, acetic acid (6.4 mL, 5 eq.), molecule sieves (3 A, 5 g), and sodium cyanoborohydride (2.1 g, 33.3 mmol, 3 eq.) in dry methanol (50 mL) is heated at 60-65° C. for 4 h. The reaction mixture is filtered, and the filtration is evaporated. The residue is dissolved in DCM (200 mL) and the resulting solution is washed with 2 N NaOH (100 mL), brine (100 mL×2), dried over MgSO4, and evaporated to provide a yellow solid (2.75 g, 100%). The compound is used in the next reaction without further purification. 1H NMR (300 MHz, DMSO-d6), δ 8.02 (d, J=9.6 Hz, 2H), 7.00 (d, J=9.6 Hz, 2H), 3.38-3.42 (m, 4H), 2.60-2.68 (m, 4H), 1.60-1.67 (m, 1H), 0.40-0.46 (m, 2H), 0.35-0.38 (m, 2H). LCMS-ESI (m/z): calcd for C13H17N3O2, 247.1; [M+H]+ found, 248.4.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([O:16][CH3:17])[C:9]([O:14][CH3:15])=[C:10]([CH:13]=1)[C:11]#[N:12].CON(C)[C:21](=[O:37])[CH:22]([O:35][CH3:36])[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31]([CH3:34])=[N:32][N:33]=2)=[CH:25][CH:24]=1>>[CH3:15][O:14][C:9]1[C:8]([O:16][CH3:17])=[CH:7][C:6]([C:2]2[O:1][C:5]([C:21](=[O:37])[CH:22]([O:35][CH3:36])[C:23]3[CH:24]=[CH:25][C:26]([C:29]4[O:30][C:31]([CH3:34])=[N:32][N:33]=4)=[CH:27][CH:28]=3)=[CH:4][CH:3]=2)=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: COc1cc(-c2ccco2)cc(C#N)c1OC
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)o2)cc(C#N)c1OC
Temperature: 25 °C
Yield: 13 %

Procedure:
The method used for the final coupling step of Example 12 was followed for the reaction of 5-(furan-2-yl)-2,3-dimethoxybenzonitrile and N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide except that the reaction was performed at −40 to −25° C. then warmed to room temperature. Purification by chromatography (20-100% EtOAc-hexanes) provided 2,3-dimethoxy-5-(5-(2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetyl)furan-2-yl)benzonitrile (0.040 g, 13% yield). MS: m/z 460.2 [M+H]+.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH:4]([NH2:12])[CH2:3][CH2:2]1.[CH3:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:17]=1[N:25]=[C:26]=[O:27])[CH3:15]>C(OCC)(=O)C>[CH3:15][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:23])[CH3:24])[C:17]=1[NH:25][C:26]([NH:12][CH:4]1[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2][CH2:3]1)=[O:27])[CH3:13]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: NC1CCOc2ccccc2C1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NC1CCOc2ccccc2C1
Reaction time: 20 h
Yield: 51.7 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-benzoxepin-4-amine (0.95 g, 5.8 mmol) in 50 ml of ethyl acetate was added 1.18 g (5.8 mmol) of 2,6-bis(1-methylethyl)phenyl isocyanate. The resulting mixture was stirredat room temperature for 20 hours. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried to yield 1.1 g of N-[2,6-bis(1-methylethyl)phenyl]-N'-(2,3,4,5-tetrahydrobenzoxepin-4-yl)urea, mp 184°-186° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH2:55]([O:57][C:58]([C:60]1[S:64][C:63]([NH2:65])=[N:62][CH:61]=1)=[O:59])[CH3:56]>C(Cl)Cl>[CH2:55]([O:57][C:58]([C:60]1[S:64][C:63]([NH:65][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:62][CH:61]=1)=[O:59])[CH3:56]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: CCOC(=O)c1cnc(N)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cnc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Yield: 98 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (300 mg, 1.01 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (717 mg, 1.62 mmol), triethylamine (420 μL, 3.03 mmol), and 2-amino-thiazole-5-carboxylic acid ethyl ester: (279 mg, 1.62 mmol) in methylene chloride (10 mL) was stirred at 25° C. under nitrogen for 14 h. The reaction mixture was partitioned between water and methylene chloride. The organic layer was sequentially washed with a 1N aqueous hydrochloric acid solution (1×10 mL), water (1×10 mL), and a saturated aqueous sodium bicarbonate solution (1×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 10/11 hexanes/ethyl ether) afforded 2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylic acid ethyl ester (448 mg, 98%) as a white solid: mp 100-103° C.; EI-HRMS m/e calcd for C21H26N2O5S2(M+) 450.1283, found 450.1285.
Reaction SMILES: O=[C:2]1[NH:7][C:6]([NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:5][C:4]2[NH:18][C:19]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:20][C:3]1=2.C1(N(C)C)C=CC=CC=1.O=P(Cl)(Cl)[Cl:38]>CC#N>[Cl:38][C:2]1[C:3]2[CH:20]=[C:19]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:18][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCC(=O)Nc1nc2[nH]c(CN3CCCC3)cc2c(=O)[nH]1
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: CCCCCCCC(=O)Nc1nc(Cl)c2cc(CN3CCCC3)[nH]c2n1

Procedure:
A solution of octanoic acid (4-oxo-6-pyrrolidin-1-ylmethyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide (0.36 g 1 mmol; J. Chem. Soc. Perkin Trans. 1 1998, 1637), BnNEt3Cl (0.70 g, 2 mmol), PhNMe2 (0.25 mL) and POCl3 (0.86 mL, 6 mmol) in CH3CN (5 mL) was heated to 100° C. for 40 min and concentrated. The residue was poured into ice water and neutralized with 2N NaOH, extracted with EtOAc (50 mL×3), and evaporated to give octanoic acid (4-chloro-6-pyrrolidin-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide as a crude (0.33 g) which was used without purification. HPLC Rt: 6.737 min. 1H-NMR (CDCl3): δ 11.60 (br s, 1H), 10.20 (br s, 1H), 6.38 (s, 1H), 3.86 (s, 2H), 2.90 (m, 2H), 2.70 9s, 4H), 1.86 (s, 4H), 1.78 (t, 2H), 1.32–1.29 (m, 8H), 0.90 (t, 3H).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Br[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reactant: Cc1sc(-c2ccccc2)nc1CBr
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3)sc2C)c1)C(=O)O
Yield: 1 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-bromomethyl-5-methyl-2-phenyl-thiazole, the title compound was obtained in 1% yield as a yellow oil. MS: (M+H)+ 421.2.
Reaction SMILES: CO[C:3]1[CH:12]=CC=C2[C:4]=1CC(NCCCCN1C(=O)C3(CCCCC3)CC1=O)CO2.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[CH3:36][O:37][C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1[CH2:40][CH:41]([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH:53]1[C:57]3([CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]3)[C:56](=[O:63])[NH:55][C:54]1=[O:64])[CH2:42][O:43]2.C(O)(=O)C(O)=O>>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[CH2:4]([N:48]([CH2:49][CH2:50][CH2:51][CH2:52][CH:53]1[C:57]2([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62]2)[C:56](=[O:63])[NH:55][C:54]1=[O:64])[CH:41]1[CH2:40][C:39]2[C:44](=[CH:45][CH:46]=[CH:47][C:38]=2[O:37][CH3:36])[O:43][CH2:42]1)[CH2:3][CH3:12]
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)CC3(CCCCC3)C1=O)CO2
Reactant: COc1cccc2c1CC(NCCCCC1C(=O)NC(=O)C13CCCCC3)CO2
Agent: O=C(O)C(=O)O
Product: CCCN(CCCCC1C(=O)NC(=O)C12CCCCC2)C1COc2cccc(OC)c2C1

Procedure:
Using the procedure described in Example 10, but replacing the compound of Example 9 by the compound of Example 28, the product of the title is obtained. It is salified with oxalic acid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Br:7][C:8]1[CH:13]=[C:12]([C:14]2[C:23]3[C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[O:26][C:22]=3[C:21]([Br:31])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[CH:19]3)[CH:11]=[C:10]([Br:32])[C:9]=1[OH:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:6][O:5][C:3](=[O:4])[CH2:2][O:33][C:9]1[C:8]([Br:7])=[CH:13][C:12]([C:14]2[C:23]3[C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[O:26][C:22]=3[C:21]([Br:31])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[CH:19]3)=[CH:11][C:10]=1[Br:32]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3oc4ccccc4c23)cc1Br
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3oc4ccccc4c23)cc1Br
Reaction time: 21 h
Yield: 54.6 %

Procedure:
Methyl bromoacetate (0.554 mL, 5.8 mmol) was added to a stirred, room temperature suspension of 2, 6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]furan-11yl)-phenol (1.6 g, 2.92 mmol), potassium carbonate (0.81 g, 5.8 mmol) and dimethylformamide (7 mL). After 21 h, the reaction mixture was added to water and filtered. The solid was taken up in THF and silica gel was added. The solvent was removed. The adsorbate was flash chromatographed (9:1 petroleum ether:ethyl acetate as eluent) to provide the title compound as a white solid (0.987 g, 55%): mp 188-189° C.: NMR (DMSO-d6); δ8.37 (d, J=8 Hz, 1 H), 7.91 (s, 2 H), 7.84 (d, J=8 Hz, 1 H), 7.80 (ddd, J=8, 7, 1 Hz, 1 H), 7.70 (d, J=8 Hz, 1 H), 7.64-7.58 (m, 2 H), 7.31 (t, J=8 Hz, 1 H), 6.92 (d, J=8, 1 H), 4.88 (s, 2 H), 3.80 (s, 3 H); MS (EI): [M+], 3 bromine isotope pattern, 616 (30%), 618 (100%) 620 (100%) 622 (30%); Anal. Calc. for C25H15Br3O4: C, 48.50, H, 2.44, N, 0.00. Found: C, 48.53, H, 2.29, N, 0.00.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:45])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:46]([O:53][C:54]1C(C(O)=O)=NC(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)=N[C:59]=1O)[C:47]1C=CC=CC=1.[Si](OCCNC1CCOCC1)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:45]1[CH2:59][CH2:54][O:53][CH2:46][CH2:47]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C(O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCNC1CCOCC1
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)C1CCOCC1

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (350) from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (345) (300 mg, 0.66 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(tetrahydro-pyran-4-yl)-amine (8j) (257 mg, 0.99 mmol). The yield was 320 mg, 70%, of a colorless sticky mass.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH:14]1([C:20]([N:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(C1CCCCC1)N1CCN(Cc2ccccc2)CC1
Reaction time: 0.75 h
Yield: 74 %

Procedure:
To a solution of 21.2 g (0.12 mole) of 1-benzylpiperazine in 100 ml of CHCl3 was added dropwise over a period of 30 minutes a solution of 15.0 g (0.10 mole) of cyclohexanecarbonyl chloride in 50 ml of CHCl3. The mixture was allowed to stand at room temperature during 45 minutes and was made basic with 5 g of sodium hydroxide in 50 ml of water. The nonaqueous layer was separated, dried over sodium sulphate and concentrated. The residue was distilled b.p. 150°-56° C. at 0.1-0.2 mmHg to give 21.2 g of 1-cyclohexanecarbonyl-4-benzylpiperazine.
Reaction SMILES: CC([N:5]([C@H:9]([CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18]Br)=[CH:13][CH:12]=1)[C:6](=[O:8])[O-:7])(C)C.[NH2:33][C:34]1[C:39]([CH:40]([OH:42])[CH3:41])=[CH:38][CH:37]=[CH:36][N:35]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[CH2:21][C@@H:9]([NH:5][C:6](=[O:8])[O:7][C:11]([CH3:16])([CH3:12])[CH3:10])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:33]=[C:34]3[C:39]([CH:40]([OH:42])[CH3:41])=[CH:38][CH:37]=[CH:36][N:35]3[CH:18]=2)=[CH:15][CH:16]=1
Reactant: CC(O)c1cccnc1N
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H](Cc1ccc(C(=O)CBr)cc1)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(O)c1cccn2cc(-c3ccc(C[C@@H](CN4C(=O)c5ccccc5C4=O)NC(=O)OC(C)(C)C)cc3)nc12
Yield: 174.7 %

Procedure:
A mixture of 1,1-dimethylethyl{(1S)-2-{4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (1.90 g, 3.79 mmol), 1-(2-amino-3-pyridinyl)ethanol (0.523 g, 3.79 mmol), and solid sodium bicarbonate (0.398 g, 4.72 mmol) in isopropanol (24 mL) was refluxed for 3.0 h. The mixture was concentrated in vacuo and the residue dissolved in ethyl acetate, washed with water and saturated sodium chloride, dried (Na2SO4), and concentrated to give the title compound (1.79 g, 87%) as a light pink solid. MS (ES+) m/e 541 [M+H]+.
Reaction SMILES: [C:1]([C:4]1([O:9]/[N:10]=[C:11](/[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)\[C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5]1)([OH:3])=O.[CH3:21][O:22][NH2:23].C(Br)(Br)Br>CS(C)=O>[CH3:21][O:22][NH:23][C:1]([C:4]1([O:9][N:10]=[C:11]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3]
Reactant: CON
Reactant: COC(=O)/C(=N\OC1(C(=O)O)CCCC1)c1ccco1
Solvent: CS(C)=O
Solvent: BrC(Br)Br
Product: CONC(=O)C1(ON=C(C(=O)OC)c2ccco2)CCCC1
Yield: 75 %

Procedure:
This compound was prepared from methyl Z-2-(carboxycyclopent-1-yloxyimino)-2-(fur-2-yl)acetate and methoxyamine as described in Preparation 7(c) νmax (CHBr3) 3400, 3350 (--NH--), 1740 (--CO2R), 1686 cm-1 (--CONH--), τ(DMSO d6), 6.4 (--OMe), --0.88 (--CONHO), 7.7-8.7 (cylopentyl), 2.1, 3.1, 3.3 (furyl), 6.1 (--CO2Me). Yield 75%
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)[CH:7]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Clc1cc(Nc2ccc3[nH]ccc3c2)ncn1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 37.5 %

Procedure:
4,6-Dichloropyrimidine (5.89 g, 40 mmol), 5-aminoindole (6.27 g, 47 mmol) and N,N-diisopropylethylamine (20.6 ml, 0.12 mol) were dissolved in N-methylpyrrolidone (80 ml), and the reaction mixture was stirred at 50° C. for 2.5 hours. The reaction mixture was partitioned between ethyl acetate and water; the aqueous layer was subjected to re-extraction with ethyl acetate; and the combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure; a small amount of ethyl acetate was added to the residue to crystallize; and the crystals were filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (3.70 g, 15 mmol, 38%) as white crystals.