Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:21][O:22][C:23](=[O:50])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][C:33]2[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([O:43][CH:44]([CH3:46])[CH3:45])=[C:35]([CH:47]=O)[C:34]=2[CH3:49])=[CH:27][CH:26]=1>O1CCCC1>[CH3:21][O:22][C:23](=[O:50])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][C:33]2[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([O:43][CH:44]([CH3:45])[CH3:46])=[C:35]([CH:47]=[CH2:1])[C:34]=2[CH3:49])=[CH:27][CH:26]=1
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(C=O)c2C)cc1
Solvent: C1CCOC1
Product: C=Cc1c(C)c(C#Cc2ccc(CC(=O)OC)cc2)cc(C(C)(C)C)c1OC(C)C
Yield: 38 %

Procedure:
A solution of methylidene triphenyl phosphorane [5 mL of 0.1M solution, 0.5 mmol, generated from methyl triphenylphosphonium bromide (2.5 g, 7 mmol) and 1.6M n-butyllithium solution in hexanes (2.9 mL, 4.7 mmol) in 50 mL of tetrahydrofuran] was added to a solution of [4-(5-tert-butyl-3-formyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 144, 0.052 g, 0.13 mmol) in tetrahydrofuran (1 mL). After 1 h the reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a clear oil that after flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent afforded the title compound (0.02 g, 39%).
Reaction SMILES: Br[CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1O.[C:14]([NH2:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.[K+].[Br-].C[O:26]C1C=CSC=1>>[OH:26][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[NH:22][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1
Reactant: CC1(C)Oc2ccsc2C(O)C1Br
Reactant: COc1ccsc1
Reactant: NC(=O)c1cccnc1
Agent: [Br-]
Agent: [K+]
Product: CC1(C)Oc2ccsc2C(NC(=O)c2cccnc2)C1O

Procedure:
The title compound was prepared as described for Example 3 starting with 6-bromo-5,6-dihydro-7-hydroxy-5,5-dimethyl-7H -thieno[3,2-b]pyran (4.0 g, 15.2 mmol) and nicotinamide (3.7 g, 30.4 mmol) to give 1.1 g (24%): m.p. 248°-49° C.; IR (KBr): 3329, 3312,1648, 1594, 1569 cm-1 ; MS: m/z 305 (MH+); 1 1H NMR (CDCl3) 6 9.02 (s, 1H), 8.79 (d, J=5,6 Hz, 1H), 8.14 (d, J=5,6 Hz, 1H), 7.44 (m, 1H), 7.18 (d, J=5.4 Hz, 1H), 6.64 (d, J=5.4 Hz, 1H), 6.55 (d, J=5,6, 1H), 5.20 (m, 1H), 4.46 (brs, 1H), 3.81 (d, J=9.4 Hz, 1H), 1.50 (s, 3H), 1.36 (s, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)(=O)=O.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(O)C>[CH3:18][N:17]1[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)=[CH:8][CH:9]=2)=[CH:14][CH:15]=[N:16]1
Reactant: OB(O)c1cccnc1
Reactant: Cn1nccc1-c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Cn1nccc1-c1ccc(-c2cccnc2)cc1
Yield: 143.2 %

Procedure:
A mixture of 4-(1-methyl-1H-pyrazol-5-yl)phenyl trifluoromethanesulfonate (200 mg), 3-pyridylboronic acid (88 mg), bis(triphenylphosphine)palladium(II) dichloride (14 mg), potassium carbonate (135 mg), dimethylformamide (1.4 mL) and ethanol (0.70 mL) was reacted in a microwave reactor (80° C., 25 minutes). Thereafter, water was added to the reaction solution, and the obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration, so as to obtain the title compound (220 mg) in the form of a light yellow oily substance.
Reaction SMILES: C([O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[CH:7]=[C:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)C>CO.[OH-].[Na+]>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:7]/[CH:6]=[CH:5]/[C:4]([OH:23])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 95 %

Procedure:
A mixture of (E)-5,5-bis(4-chlorophenyl)-2,4-pentadienoic acid ethyl ester (7.5 g) in methanol (30 mL) and 2N sodium hydroxide solution (15 mL) was heated at reflux for 30 minutes. The crude solid obtained from the usual work up, was crystallized from ether-hexane to yield 6.55 g of (E)-5,5-bis(4-chlorophenyl)-2,4-pentadienoic acid, mp 213°-215° C. Recrystallization of a portion from 2-propanol furnished the analytical sample, mp 214°-215° C. Anal. Calculated for C17H12Cl2O2 : C, 63.97; H, 3.79; Cl. 22.21 Found: C, 63.80; H, 3.90; Cl, 21.99.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH:10]([CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=1.C(C(CCC)[O-])(C)(C)C.[K+].C(O)(C)(C)C>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([O:29][CH2:28][C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH:10]([CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1ccncc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1Cl
Agent: CCCC([O-])C(C)(C)C
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1OCc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
3′-Chloro-2-methyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (1.88 g, 6.0 mmol), pyridin-4-yl-methanol (1.35 g, 12.4 mmol) and a solution of 1M potassium tert-butyl butoxide in tert-butyl alcohol (14 mL, 14 mmol) were combined and stirred at room temperature overnight. The reaction mixture is diluted with H2O and washed with EtOAc (3×). The combined EtOAc extractions were washed with 6% NaHCO3 (2×), sat's NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography (4:1 hexanes:EtOAc, followed by 1:1 hexanes:EtOAc) to give 1.89 g (81%) of 2-methyl-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester. 1H NMR (CDCl3) 8.06 (d, 2H), 7.75 (d, 1H), 7.51 (d, 1H), 7.30 (d, 2H), 5.42 (s, 2H), 4.52 (m, 1H), 4.11-3.81 (complex m, 3H), 3.36-3.11 (complex m, 3H), 1.48 (s, 9H), 1.17 (d, 3H) ppm. LC-MS (MH+)=386.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9]O)(C)(C)C.[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C([Cl:59])(=O)C>O1CCCC1>[ClH:59].[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:9][CH2:8][NH2:7])=[CH:17][CH:16]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCN)cc1
Product: Cl
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
(2-Hydroxyethyl)carbamic acid tert-butyl ester (152.0 g, 0.942 mol) and 4-hydroxybenzoic acid methyl ester (174.0 g, 1.12 mol) were dissolved in tetrahydrofuran (2000 ml) and cooled to 0-5° C. Triphenylphosphine (292.8 g 1.116 mol) was added to the cooled mixture. A solution of diisopropyl azodicarboxylate (246.0 g, 1.218 mol) in tetrahydrofuran (400 ml) was added dropwise over a period of one to two hours keeping the reaction temperature below 10° C. After addition, the reaction was allowed to warm slowly to ambient temperature and stirred overnight. After completion of reaction, solvent was distilled under reduced pressure and the resulting oil was dissolved in ethanol (500 ml) and ethyl acetate (2000 ml). Acetyl Chloride (222.0 g, 2.826 mol) was added drop wise over fifteen minutes with the temperature allowed to rise to 40° C. The resulting suspension was stirred at 40° C. until completion of reaction. After completion of reaction, the resulting crystals were filtered on a coarse frit and washed with ethyl Acetate (300 mL). The material is dried in vacuo to to give of 4-(2-aminoethoxy)benzoic acid methyl ester hydrochloride (204.1 g) as a white crystalline solid.
Reaction SMILES: [S:1]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[C:4]([C:10]([OH:12])=[O:11])=[CH:3][CH2:2]1.[SH:13][C:14]1[N:18]([CH3:19])[N:17]=[N:16][N:15]=1.P(OC)(OC)O[CH3:22].Cl>O1CCCC1.C(Cl)Cl>[CH3:19][N:18]1[C:14]([S:13][CH2:22][C:3]2[CH2:2][S:1][C@@H:6]3[CH2:7][C:8](=[O:9])[N:5]3[C:4]=2[C:10]([OH:12])=[O:11])=[N:15][N:16]=[N:17]1
Reactant: Cn1nnnc1S
Reactant: COP(OC)OC
Reactant: O=C(O)C1=CCS[C@@H]2CC(=O)N12
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Reaction time: 3.5 h

Procedure:
To 5.03 g of 7β-D-5-carboxy-5-phthalimidovaleramido)-3-cephem-4-carboxylic acid were added 100 ml of tetra-hydrofuran-methylene chloride mixture solution (1:2,v/v), 1.74 g of 5-mercapto-1-methyl-1H-tetrazole and 2.3 ml of trimethyl phosphite in sequence. The reaction was allowed to proceed at 18 to 22° C. for 3.5 hours while stirring. To the reaction solution was added 30 ml of 1N HCl, and the mixture was stirred for 30 minutes, which was concentrated under reduced pressure to about 30 ml. To the concentrate was added 30 ml of methylene chloride, to which was added 1N NaOH to render the pH to 5.6, followed by separating the organic layer from the aqueous layer. To the aqueous layer was added 30 ml of tetrahydrofuran-methylene chloride mixture solution (1:1,v/v), whose pH was changed to 2.0 with 2N HCl, then the organic layer was separated. The aqueous layer was subjected to extraction with 30 ml of the same mixture solution. The organic layers were combined, washed with saturated aqueous saline solution and dried on anhydrous magnesium sulfate, followed by concentration under reduced pressure. The concentrate was poured into 300 ml of ether and the precipitating matter was collected by filtration, washed with ether and dried to obtain 5.86 g (yield:97.4%) of 7β-D-5-carboxy-5-phthalimidovaleramido)-3-(1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:10])=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[CH3:11][C:12]1[C:13]([N:17]=[C:18]=[S:19])=[CH:14][S:15][CH:16]=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>C1COCC1>[NH2:10][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:9][C:18]([NH:17][C:13]1[C:12]([CH3:11])=[CH:16][S:15][CH:14]=1)=[S:19]
Reactant: COc1cccc(N)c1N
Reactant: Cc1cscc1N=C=S
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(NC(=S)Nc2cscc2C)c1N

Procedure:
is obtained analogously to the procedure described in example 25 a) from 3-methoxy-1,2-diaminobenzene and 4-methyl-3-thienyl isothiocyanate in anhydrous THF, followed by medium-pressure chromatography on silica gel using a mixture of 1 part of toluene and 1 part of ethyl acetate. Crystalline solid, m.p.: 148-153° C. Solidification of the melt and next m.p. at 260° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[N:4][C:5]([CH3:10])=[C:6]([Br:9])[C:7]=1[Cl:8].C([Mg]Cl)(C)C.C1COCC1.Cl[C:23](=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].CCOCC>C1COCC1.CCOC(C)=O>[Br:9][C:6]1[C:7]([Cl:8])=[C:2]([C:23](=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:3]([CH3:11])=[N:4][C:5]=1[CH3:10]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1nc(C)c(Br)c(Cl)c1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1c(C)nc(C)c(Br)c1Cl
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a stirred mixture of 3,5-dibromo-4-chloro-2,6-dimethylpyridine (14.94 g, 49.9 mmol) and Cu(I)Br Me2S (0.513 g, 2.495 mmol) in THF (50 mL) was added drop wise 2M iPrMgCl/THF (26.2 ml, 52.4 mmol) at −30° C. over 5 min. Then, the resulting slurry was warmed to −10° C. over 30 min and stirred for 30 min. The homogeneous brown reaction mixture was rapidly transferred via cannula to a solution of ethyl 2-chloro-2-oxoacetate (6.14 ml, 54.9 mmol, degassed for 5 min by bubbling N2 through the solution) in THF (50 mL) maintained at −30° C. The resulting reaction mixture was stirred (1.5 h) while warming to 0° C. Then, taken up in to Et2O (200 mL), washed with 1:1 sat Na2CO3/1M NH4Cl (3×50 mL), dried (MgSO4), filtered and concentrated to give brown viscous oil. Flash chromatography using 2.5, 5 and 7.5% EtOAc/Hex afforded ethyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (14.37 g, 44.8 mmol, 90% yield) as white solid. 1H NMR (400 MHz, CDCl3) δ 4.42 (q, J=7.0 Hz, 2H), 2.76 (s, 3H), 2.46 (s, 3H), 1.41 (t, J=7.2 Hz, 3H). LCMS (M+H)=322.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([Cl:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4].Cl.Cl.Cl.C1(NC(C2C3C=C(C4C(Cl)=CN=C([NH:47][CH2:48][CH2:49][CH2:50][N:51]5[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]5)N=4)SC=3C=CC=2)=O)CC1>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:47][CH2:48][CH2:49][CH2:50][N:51]4[CH2:52][CH2:53][N:54]([CH3:57])[CH2:55][CH2:56]4)[N:14]=3)[S:10][C:9]=2[CH:21]=1)=[O:4]
Reactant: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reactant: COC(=O)c1ccc2cc(-c3nc(Cl)ncc3Cl)sc2c1
Agent: Cl
Product: COC(=O)c1ccc2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)sc2c1

Procedure:
Using the method of Preparation E in 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide tri-hydrochloride, the title compound is synthesized from 2-(2,5-dichloro-pyrimidin-4-yl)-benzo[b]thiophene-6-carboxylic acid methyl ester and isolated as a white solid.
Reaction SMILES: Cl[C:2]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][CH:7]([NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[C:6]1=[O:33])=[O:3].[CH2:34]([NH2:36])[CH3:35]>>[C:27]1([CH2:26][O:25][C:23](=[O:24])[NH:22][CH:7]2[N:8]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]([CH2:4][C:2]([NH:36][CH2:34][CH3:35])=[O:3])[C:6]2=[O:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCN
Reactant: O=C(Cl)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Product: CCNC(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21

Procedure:
The products of Example 134 was carried out using equivalent amounts of 1,3-dihydro-1-chlorocarbonylmethyl-3(phenylmethyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one and ethylamine. The product was purified by chromatography on silica gel (hexane-ethyl acetate elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° : m.p. 149° C.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH2:5][CH:6]1[CH2:8][CH2:7]1)[C:3]#[N:4].CCN(C(C)C)C(C)C.[C:19](Cl)(=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([O:20][C:19](=[O:28])[NH:1][C:2]([C:3]#[N:4])([CH3:9])[CH2:5][CH:6]1[CH2:8][CH2:7]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(N)(C#N)CC1CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C#N)(CC1CC1)NC(=O)OCc1ccccc1
Temperature: 45 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
To a solution of 2-Amino-3-cyclopropyl-2-methyl-propionitrile (Example 66a, 5.01 g, 30.9 mmol) in dry THF (119 mL) was added DIEA (12.1 mL, 67.9 mmol) and benzyl carbonochloridate (CAN 501-53-1, 5.57 mL, 37.1 mmol). The reaction was stirred at 45° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethylacetate and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography eluting with a gradient of heptane/ethylacetate to yield the title compound (6.2, 60%) as a colorless oil. MS (ESI, m/z): 259.5 (M+H+).
Reaction SMILES: [C:1]([C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][C:6](O)=[O:7])#[N:2].C(Cl)(=O)C([Cl:24])=O>CN(C)C=O.ClCCl>[C:1]([C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][C:6]([Cl:24])=[O:7])#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#CC(CCC(=O)O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CC(CCC(=O)Cl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Dimethylformamide (1 drop) was added to a suspension of 4-cyano-4,4-diphenylbutanoic acid [(7.8 g, 29 mmol), WO97/24325] and oxalyl chloride (5.2 mL, 60 mmol) in dichloromethane (40 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo and the residue was azeotroped with toluene (3×50 mL) to afford the crude title compound. The material was used in preparation 60 without further purification.
Reaction SMILES: Cl.[N:2]1([C:8]2[C:13](/[CH:14]=[C:15]3/[C:16](=[O:21])[NH:17][C:18](=[O:20])[S:19]/3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31][C:32](O)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[O:20]=[C:18]1[NH:17][C:16](=[O:21])/[C:15](=[CH:14]/[C:13]2[C:8]([N:2]3[CH2:7][CH2:6][N:5]([C:32](=[O:33])[CH2:31][CH2:30][NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:4][CH2:3]3)=[N:9][CH:10]=[CH:11][CH:12]=2)/[S:19]1
Reactant: O=C1NC(=O)/C(=C/c2cccnc2N2CCNCC2)S1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCN(c2ncccc2/C=C2\SC(=O)NC2=O)CC1
Temperature: 50 °C

Procedure:
A 50 mL vial was charged with a magnetic spin bar, (Z)-5-((2-(piperazin-1-yl)pyridin-3-yl)methylene)thiazolidine-2,4-dione hydrochloride (Example 89) (0.125 g, 0.38 mmol), 3-(tert-butoxycarbonylamino)propanoic acid (0.109 g, 0.57 mmol), DMF (1.912 ml), and diisopropylethylamine (0.334 ml, 1.91 mmol). With stirring, HATU (0.291 g, 0.76 mmol) was added and the reaction was warmed to 50° C. for 3 h. The reaction was then diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extract was dried with MgSO4, filtered through a bed of Celite, and conc. in vacuo to yield the product which was purified via silica gel chromatography (80 g) using ethyl acetate/hexanes (1:1) as eluent to provide the title compound as an off white solid. (0.080 g, 45.3%); m/z 462.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[C:11]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:22](=[O:25])([O-])O.[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([O:25][CH3:22])[O:6][CH3:11])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(OC)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5 g of 3-Bromo-4-fluorobenzaldehyde was dissolved in 40 ml of methanol, and 7.8 g trimethyl o-formate and 0.42 g of p-toluene sulfonic acid were added thereto, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with water and sodium hydrogencarbonate, and extracted with ethylacetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated, to give 6.2 g of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9]>CO.[Pd]>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)/C=C/c1ccco1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCC1CCCO1
Temperature: 60 °C
Yield: 93.9 %

Procedure:
(E)-3-(Furan-2-yl)acrylic acid (10 g, 72.4 mmol) was treated with Pd/C (1 g) in MeOH (100 mL). The mixture was heated at 60° C. at 60 psi under H2 for 12 hrs. After filtering off the catalyst, the filtrate was concentrated to afford 9.8 g (93%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.42-1.56 (m, 1 H) 1.77-1.96 (m, 4 H) 1.93-2.07 (m, 1H) 2.41-2.56 (m, 2 H) 3.71-3.79 (m, 1 H) 3.82-3.94 (m, 2 H); MS (DCI/NH4+) m/z 145 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.C([O-])([O-])=O.[K+].[K+].[CH3:15][O:16][C:17](=[O:42])[C@H:18]([CH2:27][C:28]1[CH:33]=[CH:32][C:31](OS(C(F)(F)F)(=O)=O)=[CH:30][CH:29]=1)[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C1(C)C=CC=CC=1.CN(C=O)C.C1(C)C=CC=CC=1.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>[CH3:15][O:16][C:17](=[O:42])[C@H:18]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:32][CH:33]=1)[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21]
Reactant: OB(O)c1cccs1
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
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: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2cccs2)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 62.6 %

Procedure:
To a mixture of 2-thienylboronic acid (1.135 g) and anhydrous K2CO3 (2.23 g) in toluene/DMF (75 mL/7.5 mL) under N2 was added a solution of N-(tert-butoxycarbonyl)-O-(trifluoromethanesulfonyl)-L-tyrosine methyl ester (3.42 g) in 5 mL of toluene. Pd(PPh3)4 (1.4 g) was added and the mixture was heated at 80° C. for 24 h. After usual work-up as shown in Example 1 the crude material was purified by flash column chromatography (silica gel; eluent: EtOAc/hexane 1:3) to yield N-(tert-butoxycarbonyl)-4-(2-thienyl)-L-phenylalanine methyl ester(1.81 g). ESMS: m/z 362 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:5](Cl)=[N:6][C:7]([Cl:11])=[N:8][C:9]=1[Cl:10])([OH:3])=[O:2].C(N(CC)CC)C.[CH:20]1[CH:25]=[CH:24][C:23]([CH2:26][SH:27])=[CH:22][CH:21]=1>CN(C)C=O.O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:26]([S:27][C:5]1[C:4]([C:1]([OH:3])=[O:2])=[C:9]([Cl:10])[N:8]=[C:7]([Cl:11])[N:6]=1)[C:23]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1c(Cl)nc(Cl)nc1Cl
Reactant: SCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)c1c(Cl)nc(Cl)nc1SCc1ccccc1
Reaction time: 1 h

Procedure:
To a mixture of 5-carboxy-2,4,6-trichloropyrimidine (prepared in the above (1)) 100 mg, triethylamine 89 mg in dimethylformamide 3 ml is added at room temperature a 1.0M solution of benzylthiol in tetrahydrofuran 0.44 ml, and the mixture is stirred for 1 hour. The reaction mixture is diluted with a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-benzylthio-5-carboxy-2,6-dichloropyrimidine as a pale yellow oil.