Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[N:11](O)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]([OH:58])[CH2:36][NH:37]C2C=CNC(=O)C=2C2NC(C3C=CC=CC=3)=C(CC)N=2)[CH:32]=[CH:33][CH:34]=1.Cl.C(O)(=O)C>[Cl-].[Ti+3].[Cl-].[Cl-]>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]([OH:58])[CH2:36][NH:37][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: COc1nccc(I)c1-c1ncc(-c2ccc(N3CCOCC3)cc2)n1O
Reactant: CCc1nc(-c2c(NCC(O)c3cccc(Cl)c3)cc[nH]c2=O)[nH]c1-c1ccccc1
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: CC(=O)O
Product: O=c1[nH]ccc(NCC(O)c2cccc(Cl)c2)c1-c1ncc(-c2ccc(N3CCOCC3)cc2)[nH]1

Procedure:
2-(4-Iodo-2-methoxy-pyridin-3-yl)-5-(4-morpholin-4-yl-phenyl)-imidazol-1-ol (0.049 g, 0.102 mmol) was reacted as described for the synthesis of 4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-3-(4-ethyl-5-phenyl-1H-imidazol-2-yl)-1H-pyridin-2-one except that the compound was first treated with titanium(III) chloride LCMS (+ESI, M+H+) m/z 463) and then hydrochloric acid/acetic acid. The title material was obtained (0.007 g, 14%) as a yellow solid. HPLC 85% (220 nm), LCMS (+ESI, M+H+) m/z 492; 1H NMR (400 MHz, methanol-d4) δ (ppm): 3.18 (4H, br t), 3.65 (1H, br dd), 3.74 (1H, br dd), 3.87 (4H, m), 5.02 (1H, m), 6.26 (1H, d, J=7.5 Hz), 7.02 (2H, d, J=8.6 Hz), 7.22-7.56 (7H, m), 7.74 (1H, d, J=7.9 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][N:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[O:13][CH3:14].[CH3:23][C:24]1[CH:29]=[C:28]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)[CH:27]=[CH:26][C:25]=1[C:36]1[CH:41]=[CH:40][C:39]([C:42](O)=[O:43])=[CH:38][CH:37]=1>>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[C:10]([NH:12][C:42]([C:39]2[CH:38]=[CH:37][C:36]([C:25]3[CH:26]=[CH:27][C:28]([C:30]4[N:34]=[C:33]([CH3:35])[O:32][N:31]=4)=[CH:29][C:24]=3[CH3:23])=[CH:41][CH:40]=2)=[O:43])[CH:9]=[CH:8][C:7]=1[O:13][CH3:14])[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16]
Reactant: COc1ccc(N)cc1N(CCN(C)C)C(=O)OC(C)(C)C
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1N(CCN(C)C)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from N,N-dimethyl-N'-t-butyloxycarbonyl-N'-(5-amino-2-methoxyphenyl)ethylenediamine (D21, 0.37 g, 0.0012 mole) and 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) biphenyl-4-carboxylic acid (EP 0533268 A1) (0.34 g, 0.0012 mol) using the method of Example 1 (0.40 g, 57%)
Reaction SMILES: [NH2:1][C:2](=[N:33][O:34][C:35](OCC(CC)CCCC)=[O:36])[C:3]1[CH:4]=[C:5]2[C:22](=[CH:23][CH:24]=1)[O:21][C:8]1([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH2:7][CH:6]2[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C1(C)C(C)=CC=CC=1>[Si:26]([O:25][CH:6]1[C:5]2[C:22](=[CH:23][CH:24]=[C:3]([C:2]3[NH:1][C:35](=[O:36])[O:34][N:33]=3)[CH:4]=2)[O:21][C:8]2([CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:12][CH2:13]2)[CH2:7]1)([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:28])[CH3:27]
Reactant: CCCCC(CC)COC(=O)ON=C(N)c1ccc2c(c1)C(O[Si](C)(C)C(C)(C)C)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O[Si](C)(C)C(C)(C)C)c1cc(-c3noc(=O)[nH]3)ccc1O2
Temperature: 25 °C

Procedure:
A solution of tert-butyl 6-{amino[({[(2-ethylhexyl)oxy]carbonyl}oxy)imino]methyl}-4-{[tert-butyl(dimethyl)silyl]oxy}-spiro[chroman-2,4′-piperidine]-1′-carboxylate in 100 mL of xylene was stirred at 145° C. for 14 h. The reaction mixture was cooled to rt, and concentrated in reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of hexane-AcOEt (100/1-35/65) as an eluent to give the product as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[F:18][C:19]([F:29])([F:30])[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4C(F)(F)F)nc23)CC1
Yield: 96 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.053 mMol) 2-trifluoromethylbenzoyl chloride, 0.017 gm (96%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1)#[N:2].N.[H][H]>CO.[Ni].[Mo]>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Reactant: [H][H]
Agent: [Mo]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1
Temperature: 20 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
A solution of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate (Example 5), 8.2 kg (30.5 mol) in 100 L of methanol containing 15 kg of anhydrous ammonia was reacted with hydrogen gas under 50 pounds per square inch (psi) at 30° C. in the presence of a slurry of 8 kg of Raney nickel doped with 1% molybdenum. After 6 hours, uptake of hydrogen had ceased, the mixture was cooled to 20° C., the atmosphere was vented and exchanged for nitrogen, and the slurry was filtered, concentrated by distillation and distilled under vacuum to give 7.8 kg of 96% pure (4R-cis)-1,1-dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate as a clear oil; bp 125-135° C. at 0.5 mm Hg.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-].[Na+:9].S(OOS([O-])(=O)=O)([O-])(=O)=[O:11].[NH4+].[NH4+].OO.[Na]>>[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:11])=[O:5].[Na+:9].[Na+:9]
Reactant: O=C1C=CC(=O)O1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: OO
Agent: [NH4+]
Agent: [Na+]
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
An aqueous solution of sodium maleate was prepared by neutralizing maleic anhydride with an aqueous sodium hydroxide solution in a four-necked flask. The aqueous solution polymerization of this product was effected in the presence of ammonium persulfate and hydrogen peroxide at 100° C. for 5 h to obtain a dyeability-improving agent comprising sodium polymaleate having a molecular weight of 700.
Reaction SMILES: ClC1C(Cl)=C2C(CC(C3CCCC3)(C)C2=O)=CC=1OCC(O)=O.[CH2:24]([C:28]1([CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:36][C:35]2[C:30](=[C:31]([Cl:43])[C:32]([Cl:42])=[C:33]([O:37]CC(O)=O)[CH:34]=2)[C:29]1=[O:44])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([C:28]1([CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:36][C:35]2[C:30](=[C:31]([Cl:43])[C:32]([Cl:42])=[C:33]([OH:37])[CH:34]=2)[C:29]1=[O:44])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: CC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Product: CCCCC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O

Procedure:
By following substantially the procedure in Example 8, Step A, but substituting for (+)[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]acetic acid an equimolar quantity of (+)[(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]acetic acid, there is obtained (+)2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-one which is used in Step C without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:29])[C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C@H:14]([C:30]3[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:29])[C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C@H:14]([C:30]3[CH:35]=[CH:34][C:33]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:32][CH:31]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(C(=O)N(C)[C@@H]2CCN(C(=O)C3CCN(C(C)=O)CC3)C[C@H]2c2ccc(Br)cc2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N(C)[C@@H]2CCN(C(=O)C3CCN(C(C)=O)CC3)C[C@H]2c2ccc(-c3ccccc3)cc2)cc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 60.3 %

Procedure:
A mixture of the compound obtained in Example 239 (0.20 g), phenylboronic acid (0.066 g), dppf (0.040 g), Pd(OAc)2 (0.008 g) and potassium carbonate (0.050 g) in toluene (3 mL), water (0.3 mL) and DMF (1 mL) was stirred under an argon atmosphere at 100° C. for 10 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, and concentrated. The residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 65→95% ethyl acetate/hexane) to give the title compound (0.12 g, 61%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH:21](N1CCOCC1)=[O:22]>O1CCCC1>[O:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:21]=[O:22])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccc(COc2ccccc2)cc1
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(COc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 100.6 %

Procedure:
To a tetrahydrofuran solution (50 mL) of 1-bromo-4-phenoxymethyl-benzene (4.69 g, 17.8 mmol) described in Manufacturing Example 86-1-1 was added dropwise n-butyl lithium (16.8 mL, 1.59 M hexane solution, 26.7 mmol) at −78° C. After 40 minutes of stirring at −78° C., N-formylmorpholine (2.25 g, 19.6 mmol) was added to this mixture, which was then stirred for a further 30 minutes at that temperature. This mixture was partitioned into diethyl ether and water. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.8 g). This compound was used in the subsequent reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[C:12]1([C:18]2[N:19]=[C:20]([CH2:29][O:30][C:31]3[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=3)[O:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:18]2[N:19]=[C:20]([CH2:29][O:30][C:31]3[CH:32]=[CH:33][C:34]([CH:35]=[CH:5][C:3]([O:2][CH3:1])=[O:4])=[CH:37][CH:38]=3)[O:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=Cc1ccc(OCc2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Product: COC(=O)C=Cc1ccc(OCc2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1

Procedure:
Reaction of trimethyl phosphonacetate and 4-[(4,5-diphenyl-2-oxazolyl)methoxy]benzaldehyde according to the procedure of Example 21 provided the title compound, m.p. 159°-161° C.
Reaction SMILES: C[O:2][C:3](=O)[CH3:4].[CH:6]12[CH2:12]C([CH2:10][CH2:11]1)[CH:8]=[CH:7]2.C[O-].[Na+]>CO>[C:4]12([CH2:3][OH:2])[CH2:12][CH:6]([CH2:11][CH2:10]1)[CH:7]=[CH:8]2
Reactant: C1=CC2CCC1C2
Reactant: COC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OCC12C=CC(CC1)C2

Procedure:
subjecting norbornene methyl acetate (IIIB) to trans-esterification reaction in the presence of methanol and sodium methoxide at a temperature of from about 40° C. to about 50° C. to form norbornene methanol (IB):
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>N1C=CC=CC=1>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:22]([NH:21][CH2:19][CH3:20])=[O:23])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: CCN=C=O
Agent: Cl
Solvent: c1ccncc1
Product: CCNC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 50 °C
Yield: 77.5 %

Procedure:
To a stirred solution of 1-(2-tert-butylphenyl)piperazine dihydrochloride (0.12 g, 0.41 mmol) in pyridine (4.0 mL) was added ethyl isocyanate (0.036 g, 0.51 mmol) at room temperature and the reaction mixture was heated at 50° C. for 16 h. After this time, the reaction mixture was cooled to room temperature and concentration under reduced pressure. The residue was partitioned between ethyl acetate and 0.5 N hydrochloric acid (2×10 mL), separated and the organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 1:9 to 1:1 ethyl acetate/heptanes) to provide 4-(2-tert-butylphenyl)-N-ethylpiperazine-1-carboxamide (0.092 g, 77%) as a white solid, mp 196-198° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:13][OH:14])[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[Br:15][C:16]1[CH:17]=[N:18][C:19](Cl)=[N:20][CH:21]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:15][C:16]1[CH:17]=[N:18][C:19]([O:14][CH2:13][C:2]2([CH3:1])[O:6][C:5]3=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]3[CH2:3]2)=[N:20][CH:21]=1
Reactant: CC1(CO)Cn2cc([N+](=O)[O-])nc2O1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(COc2ncc(Br)cn2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
(2-Methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)-methanol (0.10 g, 0.50 mmol), 5-bromo-2-chloropyrimidine (0.16 g, 0.82 mmol) and NaH (˜30 mg, 60% in mineral oil) were suspended in 2 mL DMF and stirred at r.t. for 2 hours. The resulting mixture was diluted with 150 mL EtOAc, washed with 100 mL NaHCO3 and 100 mL water. The aqueous layer was re-extracted with 100 mL EtOAc. The organic layer was washed with brine and dried over Na2SO4. The concentrated residue was purified by column chromatography (DCM/MeOH, 0 to 3%) to give the title compound (152 mg, 83%) as a white solid. APCI MS m/z 356.6, 358.6 (M+H). 1H NMR (400 MHz, (CD3)2SO) δ 8.77 (s, 2H), 8.14 (s, 1H), 4.61 (s, 2H), 4.41 (d, J=11.1 Hz, 1H), 4.20 (d, J=11.1 Hz, 1H), 1.70 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([OH:22])=O)[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[F:30][C:31]([F:39])([F:38])[C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[F:29][CH:2]([F:1])[O:3][C:4]1[C:5]([O:23][CH2:24][CH2:25][CH:26]([CH3:27])[CH3:28])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([NH:37][C:34]2[S:35][CH:36]=[C:32]([C:31]([F:39])([F:38])[F:30])[N:33]=2)=[O:22])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)CCOc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Reactant: Nc1nc(C(F)(F)F)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)CCOc1c(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C(F)(F)F)cs2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 8 (300 mg, 0.710 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (128 mg, 0.781 mmol) in the presence of EDCI hydrochloride (272 mg, 1.42 mmol), DMAP (80 mg, 0.710 mmol) in a mixture of THF and DMF (1:1, 6 mL) to give 35 mg of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 0.86 (d, J=6.6 Hz, 6H), 1.56-1.65 (m, 2H), 1.77-1.86 (m, 1H), 3.95 (t, J=6.3 Hz, 2H), 7.20 (t, J=74.4 Hz, 1H), 7.22-7.30 (m, 2H), 7.46 (s, 1H), 7.57-7.64 (m, 2H), 7.76 (d, J=15.9 Hz, 1H), 8.05-8.12 (m, 2H), 13.03 (br s, 1H); APCI-MS (m/z) 573.23 (MH)+.
Reaction SMILES: [N+:1]([CH:4]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:5][C@@H:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:7][C:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][CH:4]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:5][C@@H:6]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[NH:7][C:8]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)C(C[C@H](NC(=O)Cc1ccccc1)C(=O)OC(C)(C)C)[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(N)C[C@H](NC(=O)Cc1ccccc1)C(=O)OC(C)(C)C

Procedure:
A solution of di t-butyl 4-nitrobenzylcarbonyl-L-glutamate (9.7 g) in ethyl acetate (200 ml) was hydrogenated over 30% Pd/C (900 mg). The mixture was then filtered through Celite and evaporated to yield a yellow oil (di t-butyl 4-aminobenzylcarbonyl-L-glutamate) which was used without further purification. NMR: 8.23(d)1H; 6.92(d)2H; 6.50(d)2H; 4.86(s)2H; 4.15(m)1H; 3.24(s)2H; 2.22(m)2H; 1.8(m)2H); 1.4(d)18H. Yield 8.2 g 90%.
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[CH:1]1([N:7]([CH2:25][CH:26]2[CH2:27][CH2:28]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:39]4[CH2:38][CH2:37][N:36]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:41][CH2:40]4)=[CH:21][CH:22]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(NC(=O)c3cc(N(CC4CC4)C4CCCCC4)ncn3)cc2)CC1

Procedure:
Following the general method as outlined in Example 73, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(4-formylphenyl)pyrimidine-4-carboxamide (Intermediate 24) and 1-boc-piperazine (Fluka), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: O=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1.[CH3:17][O:18][C:19](=[O:39])[CH2:20][CH2:21][CH2:22][CH:23]([C:25]1[N:30]=[C:29]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:28]([O:37][CH3:38])=[CH:27][CH:26]=1)[OH:24]>ClCCl.CCCCCC>[CH3:17][O:18][C:19](=[O:39])[CH2:20][CH2:21][CH2:22][C:23]([C:25]1[N:30]=[C:29]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:28]([O:37][CH3:38])=[CH:27][CH:26]=1)=[O:24]
Reactant: COC(=O)CCCC(O)c1ccc(OC)c(CCC(=O)OC)n1
Agent: O=[Cr](=O)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCC(=O)c1ccc(OC)c(CCC(=O)OC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
2.9 g of Collins reagent is added to a solution of 470 mg of 5-[3-methoxy-2-(2-methoxycarbonylethyl)-6-pyridyl]-(5RS)-5-hydroxypentanoic acid methyl ester in 50 ml of dichloromethane under argon atmosphere at 0° C., and the mixture is stirred for 2 hours at room temperature. Then, it is diluted with hexane, mixed with diatomaceous earth until paste formation, filtered on diatomaceous earth and rewashed with ethyl acetate. The filtrate is concentrated by evaporation, and the crude product is chromatographed on silica gel with hexane/0-10% ethyl acetate. 337 mg of 5-[3-methoxy-2-(2-methoxycarbonylethyl)-6-pyridyl]-5-oxopentanoic acid methyl ester of melting point 64°-66° C. is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C(=O)C)=[CH:9][C:8]=1[CH3:17])[CH3:2].[O-]CC.[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:17])[CH3:2]
Reactant: CCOC(=O)COc1ccc(OC(C)=O)cc1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)COc1ccc(O)cc1C
Temperature: 45 °C

Procedure:
A solution of ethyl[4-(acetyloxy)-2-methylphenoxy]acetate (intermediate 6, 148 g) in ethanol (1300 ml) was treated with sodium ethoxide (41.3 g) and the mixture heated to 45° C. for 2.5 hours. The mixture as cooled to 22° C. and concentrated hydrochloric acid added to give a neutral (pH 7) solution. The resulting mixture was concentrated and the residue dissolved in a mixture of t-butylmethyl ether, water and brine. The organic layer was separated, washed with brine and dried over sodium sulfate and filtered. The filtrate was concentrated to give a brown solid which was further purified by precipitation from a solution in dichloromethane (100 ml) on addition of cyclohexane (710 ml) to give the title compound as a brown solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])=[O:4].[OH-].[Na+]>C(#N)C>[C:14]1([S:11]([NH:10][C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3]([OH:4])=[O:2])(=[O:13])=[O:12])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccccc1
Temperature: 50 °C
Yield: 94.6 %

Procedure:
3-Benzenesulfonylaminothiophene-2-carboxylic acid methyl ester (1.5 g, 5.0 mmol) was dissolved in acetonitrile (10 mL) and treated with aqueous, sodium hydroxide solution (2N, 7.5 mL, 3 equivalents) at room temperature. The solution was warmed to 50° C. and monitored by thin layer chromatography. Upon completion of the reaction, the mixture was cooled and extracted once with diethyl ether. The ether layer was set aside. The aqueous layer was then acidified with aqueous HCl (2N, excess) before re-extracting twice with ethyl acetate. The combined organic layers were washed once with brine solution and dried over anhydrous sodium sulfate. The ethyl acetate was decanted and evaporated under reduced pressure to give of 3-benzenesulfonylaminothiophene-2-carboxylic acid (1.34 g, 95%) as a white powder.