Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[Cl:25][C:26]1[CH:27]=[C:28]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:29][N:30]1[C:38]2[C:33](=[C:34]([O:39][CH2:40]CO)[CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[C:43]([O:45][CH3:46])=[O:44]>ClCCl>[Cl:25][C:26]1[CH:27]=[C:28]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:29][N:30]1[C:38]2[C:33](=[C:34]([O:39][CH2:40][CH2:20][Br:24])[CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[C:43]([O:45][CH3:46])=[O:44]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1cc2c(OCCO)cccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc2c(OCCBr)cccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
Triphenylphosphine (0.55 g) was added in small portions over 2 hours to a stirred solution of carbon tetrabromide (0.47 g) and methyl N-(3,4-diclilorobenzyl)-4-(hydroxyethyloxy)indole-2-carboxylate (0.28 g) in dichloromethane (10 ml). The reaction was stirred for 3 hours at room temperature, concentrated in vacuo and the residue purified by column chromatography using dichloromethane as eluent to give methyl N-(3,4-dichlorobenzyl)-4-(bromoethyloxy)indole-2-carboxylate as a white solid (0.29 g, 90%); NMR d (CD3SOCD3) 3.80 (s, 3H), 3.89 (t, 2H), 4.46 (t, 2H), 5.80 (s, 2H), 6.62 (d, 1H), 6.88 (dd, 1H), 7.17 (d, 1H), 7.25 (t, 1H), 7.30-7.36 (m, 2H), 7.52 (d, 1H), M/z (+) 456, 458 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)[CH3:18]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(I)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(I)cc1
Yield: 90 %

Procedure:
4-Iodophenylacetic acid (3 g), ethanol (20 mL) and conc. H2SO4 (5 mL) were refluxed overnight. Ca. 15 mL ethanol was then evaporated, the residue was extracted with dichloromethane (3×100 mL), the combined organic extracts were washed with sat. aq. NaHCO3, dried over Na2SO4 and evaporated in vacuo to afford 2.97 g (90%) of 121JP58 as a yellow oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH3:23])[C:14]=2[C:18]([F:21])([F:20])[F:19])[C:9]=1[C:24]([N:26]([CH3:32])[CH2:27][C:28]([O:30]C)=[O:29])=[O:25])[CH2:4][CH2:5][CH3:6]>C1COCC1.CO>[CH2:3]([O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH3:23])[C:14]=2[C:18]([F:21])([F:20])[F:19])[C:9]=1[C:24]([N:26]([CH3:32])[CH2:27][C:28]([OH:30])=[O:29])=[O:25])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1ccc2c(C(F)(F)F)c(OC)ccc2c1C(=O)N(C)CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1ccc2c(C(F)(F)F)c(OC)ccc2c1C(=O)N(C)CC(=O)O
Yield: 69.1 %

Procedure:
Aqueous sodium hydroxide (2.5N, 2.7 mL, 1.2 eq) was added to a stirred solution of N-[[2-butoxy-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-methylglycine, methyl ester (2.35 g, 5.50 mmol) in THF (22 mL) and methanol (6 mL) at room temperature. After 11/2 hours the organic solvents were removed and the residue was taken up in water (250 mL). The aqueous phase was acidified to pH 1 with 10% HCl, then extracted with ethyl acetate. The extracts were combined, dried over MgSO4, and concentrated to give a solid which was triturated with petroleum ether to provide the title compound as a white solid (1.57 g, 69%), m.p. 152°-155° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]([NH:13][C:14](=[O:17])[CH2:15]Cl)([CH2:11][OH:12])[CH2:9][OH:10])[CH:7]=1.CC(C)([O-])C.[K+].Cl.O>CC(O)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([CH2:11][OH:12])[NH:13][C:14](=[O:17])[CH2:15][O:10][CH2:9]2)[CH:7]=1
Reactant: O=C(CCl)NC(CO)(CO)c1cc(Br)ccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1COCC(CO)(c2cc(Br)ccc2F)N1

Procedure:
A mixture of N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide (6.34 g, 18.62 mmol) and potassium tert.-butoxide (2.09 g, 18.62 mmol) in 62 ml tBuOH was refluxed for 30 min. 19 ml 1 N HCl and water were added and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried with MgSO4 and evaporated. The crude product was recrystallized in Hex/EtOAc to provide the title compound as an off-white solid.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](Cl)=[O:19])=[CH:13][CH:12]=1>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:18](=[O:19])[CH2:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:3][CH:2]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: COc1ccccc1
Product: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1

Procedure:
1-(4-Methoxyphenyl)-2-(4-methoxyphenyl)ethanone was prepared from anisole and 4-methoxyphenylacetyl chloride (prepared by heating the commercially available carboxylic acid in thionyl chloride and subsequent concentration) using the method described in step A of Example 9. After step A, the product was chromatographed on silica gel using 3:2 hexane/EtOAc as eluant. 1-(4-methoxyphenyl)-2-(4-methoxyphenyl)ethanone was converted to the title compound following the procedures described in steps C-E of Example 1, except for the following modifications: 1) in step C, the acidic hydrolysis reaction, after dilution with H2O, was extracted 2× with Et2O prior to basification, extraction 3× with EtOAc and isolation of the desired amine after concentration; and 2) the prep HPLC purification of step D utilized 65% solvent B as eluant.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:11]=2[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:21][O:22][CH2:23]Cl.CCOCC.O>CN(C)C=O>[C:1]1([C:7]2[S:8][C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][C:11]=2[O:12][CH2:21][O:22][CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cc(-c2ccccc2)sc1-c1ccccc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COCOc1cc(-c2ccccc2)sc1-c1ccccc1
Reaction time: 0.33 h
Yield: 87.7 %

Procedure:
To a stirred, ice cooled solution of 2,5-diphenyl-3-hydroxythiophene (0.12 g, 0.5 mmol) in dried N,N-dimethylformamide (2 ml) was added sodium hydride (30 mg of a 60% suspension in mineral oil). When the initial vigorous reaction subsides (ca. 4 minutes), the mixture was allowed to stir at ambient temperatures for 20 minutes and then recooled. Chloromethyl methyl ether (0.055 ml, 0.7 mmol) was then added all at once. After stirring cold for ca. 30 minutes, the mixture was allowed to stir at ambient temperatures for ca. 4 hours and then added to a stirred ether/water mixture. The ether layer was washed 3 times with water, dried over sodium sulfate, filtered, concentrated to a residue, and chromatographed on silica gel (methylene chloride/hexane), to yield 0.13 g of (II). M.S.: M+ =296; NMR: consistent. ##STR27##
Reaction SMILES: [F:1][C:2]([F:21])(S(C1C=CC=CC=1)(=O)=O)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)[OH:4].C(O)C.[Na].CO>O1CCCC1.Cl.O>[F:1][CH:2]([F:21])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)[OH:4]
Reactant: Cc1ccc(C(O)C(F)(F)S(=O)(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(O)C(F)F)cc1
Yield: 49 %

Procedure:
A solution of 2.0 g (6.4 mmol) of 2,2-difluoro-1-(4-methylphenyl)-2-phenylsulfonylethanol and 1.9 mL (32 mmol) of absolute ethanol in 20 mL of dry tetrahydrofuran was treated with 0.74 g (32 mmol) of sodium spheres. After 90 minutes 1 mL of methanol followed by 1 mL of water were added to decompose unreacted sodium, and the mixture was poured into 100 mL of IN HCl. The resulting aqueous mixture was extracted with three 50 mL portions of dichloromethane. Combination, drying (MgSO4), and concentration of the organic layers afforded an orange liquid which was short path distilled to give 0.54 g (49% yield) of 2,2-difluoro-1-(4-methylphenyl)ethanol; bp 58° C. at 0.6 torr (lit 60°-62° C. at 0.5-0.6 torr; DePuy et al., J. Org. Chem., 1974, 39, 878); mass spectrum (70 eV) m/e (relative intensity) 172 (17, M +), 121 (100), 93 (68), 91 (75), 77 (64), 65 (25), 51 (46), 39 (24).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([OH:20])=[C:13]3[C:18]=2[NH:17][C:16](=[O:19])[CH2:15][CH2:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>C(O)C>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([O:20][CH2:27][CH:29]3[O:31][CH2:30]3)=[C:13]3[C:18]=2[NH:17][C:16](=[O:19])[CH2:15][CH2:14]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCC1CO1
Reactant: O=C1CCc2c(O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1CCc2c(OCC3CO3)ccc(OCc3ccccc3)c2N1
Yield: 89.1 %

Procedure:
8-Phenylmethoxy-3,4-dihydro-5-hydroxycarbostyril (32.5 g) was dissolved in ethanol (300 mL). Potassium carbonate (25 g) and epichlorohydrin (45 g) were added to the solution, and the mixture heated under reflux for four hours. After cooling, the ethanol was evaporated and water added. The aqueous solution was then extracted with methylene chloride, the resulting solution was washed with water, dried over sodium sulfate and the methylene chloride was evaporated under reduced pressure. The residue was worked up with diisopropyl ether (10 mL), yielding 35 g of 8-phenylmethoxy-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril, m.p. 106°-108° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]3[CH:19]=[C:20]([CH2:31][C:32]([OH:34])=[O:33])[CH:21]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:23]=3[OH:24])[NH:15]2)=[CH:11][C:10]=1[C:35](=[NH:38])[NH:36]O>C(O)(=O)C.[Pd]>[C:35]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:9]=1[Cl:8])[NH:15][C:14]([C:18]1[CH:19]=[C:20]([CH2:31][C:32]([OH:34])=[O:33])[CH:21]=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:23]=1[OH:24])=[CH:13]2)(=[NH:36])[NH2:38]
Reactant: N=C(NO)c1cc2cc(-c3cc(CC(=O)O)cc(-c4ccccc4)c3O)[nH]c2cc1Cl
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: N=C(N)c1cc2cc(-c3cc(CC(=O)O)cc(-c4ccccc4)c3O)[nH]c2cc1Cl
Reaction time: 1.5 h

Procedure:
Acetic anhydride (1.1 eq, 0.77 ml, in 7 ml of AcOH) was added drop wise to a stirring solution of 3 g of 18 in 34 ml of acetic acid at ambient temperature under N2 over several minutes. HPLC 15 minutes thereafter indicated formation of a hydrophobic product. A catalytic amount of Pd/C (10% w/w) was added to the reaction mixture and teh reaction vessel then was charged with H2 (atm.). The reaction mixture was agitated for about 1.5 h. The agitated reaction mixture was passed through a celite pad (rinsed with ACOH). The filtrate was diluted with ethyl acetate to yield a precipitate. The colid was isolated and dried in vacuo to yield 2.05 g of the crude amdidine.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4](=[O:6])[CH3:5].O1[CH2:11][CH2:10][CH2:9][CH2:8]1.C([Li])CCC.ClC/C=C\CCl>O.C(Cl)Cl.CCCCCC>[CH3:1][S:2][C:3]1([S:4](=[O:6])[CH3:5])[CH2:11][CH:10]=[CH:9][CH2:8]1
Reactant: C1CCOC1
Reactant: CSCS(C)=O
Agent: ClC/C=C\CCl
Agent: [Li]CCCC
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: CSC1(S(C)=O)CC=CC1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Formaldehyde dimethyl mercaptal S-oxide (3.170g) was dissolved in 30 ml. of tetrahydrofuran, and at -15° C., 20 ml. of an n-hexane solution (1.3 millimols/milliliter) of n-butyl lithium was added. The mixture was stirred for 30 minutes at -15° to -5° C., and then 1.455g of cis-1,4-dichloro-2-butene was added. The mixture was stirred for 2.5 hours at -70° C. and then for 1.5 hours at room temperature. Methylene chloride (100 ml) and 30 ml. of water were added, and the mixture was shaken. The organic phase was separated, and the aqueous phase was extracted four times with 50 ml. of methylene chloride each time. The extract and the organic phase were combined, and dried with anhydrous sodium sulfate. The dried mixture was concentrated at reduced pressure, and the residue was separated by column chromatography (Florisil, eluted with methylene chloride and ethyl acetate) to afford 1.560 g of 3-cyclopentenone dimethyl mercaptal S-oxide and a light yellow oily substance in a yield of 76%.
Reaction SMILES: [NH2:1][N:2]1[C:13](=[O:14])[C:12]2[C:15]3[N:4]([CH:5]([CH3:18])[CH2:6][O:7][C:8]=3[C:9](F)=[C:10]([F:16])[CH:11]=2)[C:3]1=[O:19].[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>C(#N)C>[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:31][CH2:30][N:29]([C:9]2[C:8]3=[C:15]4[C:12]([C:13](=[O:14])[N:2]([NH2:1])[C:3](=[O:19])[N:4]4[CH:5]([CH3:18])[CH2:6][O:7]3)=[CH:11][C:10]=2[F:16])[CH2:28]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CC1COc2c(F)c(F)cc3c(=O)n(N)c(=O)n1c23
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1COc2c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c(F)cc3c(=O)n(N)c(=O)n1c23
Yield: 104.1 %

Procedure:
A solution of 0.2 g (0.75 mmol) of 5-amino-8,9-difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dione (Example 24h), 0.58 g (2.0 mmol) of (S)-3-pyrrolidinylcarbamic acid tert-butyl ester (J. Med. Chem., 1992; 35:1764), 0.5 g (0.5 mmol) of triethylamine and 20 mL of acetonitrile is heated at reflux for 18 hours. The solvent is removed in vacuo and the residue is partitioned between dichloromethane-water. The organic layer is washed with water, dried (MgSO4) and concentrated in vacuo. The residue is chromatographed over flash grade silica gel (230-400 mesh) eluting with dichloromethane/ethanol (95:5) to give 0.34 g of the title compound, mp 114-116° C.
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[NH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:6](=[S:21])[CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[NH:3]1
Reactant: Cn1[nH]c(C(F)(F)F)cc1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cn1[nH]c(C(F)(F)F)cc1=S
Yield: 105.7 %

Procedure:
5.25 g of 1-methyl-3-(trifluoromethyl)pyrazol-5-one (8-4) and 10.23 g of Lawesson's reagent were suspended in 300 ml of anhydrous toluene. The suspension was heated under reflux for 6 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to produce 4.87 g of 1-methyl-3-(trifluoromethyl)pyrazol-5-thione (8-5).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[N:16][C:17]([CH3:23])=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=2)[C:10]([CH3:25])([CH3:24])[CH2:9]1)=O)(C)(C)C.Cl>CO>[CH3:24][C:10]1([CH3:25])[C:11]([C:14]2[CH:15]=[N:16][C:17]([CH3:23])=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=2)=[CH:12][CH2:13][NH:8][CH2:9]1
Reactant: Cc1ncc(C2=CCN(C(=O)OC(C)(C)C)CC2(C)C)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Product: Cc1ncc(C2=CCNCC2(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl-3′,3′,6-trimethyl-5-nitro-3′,6′-dihydro-3,4′-bipyridine-1′(2′H)-carboxylate (1.30 g, 3.70 mmol) in MeOH (30 mL) was added hydrochloric acid (4.0 M in 1,4-dioxane, 40 mL). The reaction mixture was allowed to stir for 2 h at rt. The reaction mixture was concentrated to give 3′,3′,6-trimethyl-5-nitro-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine as the hydrochloride salt (1.12 g, 100%) as a white solid. LCMS (FA): Rt=0.89 min, m/z=248.3 (M+H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1O.[OH-].[K+].Cl>C(O)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C:9]1[CH2:10][CH2:11][C:12](=[O:13])[C:14]=1[CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC[C@H](O)/C=C/C1=C(C/C=C\CCCC(=O)O)C(=O)CC1
Temperature: 10 °C

Procedure:
A solution of racemic PGE2 (200 mg.) in 100 ml. of 50% aqueous ethanol containing 10 grams of potassium hydroxide is kept at 25° C. for 10 hours under nitrogen. Then, the solution is cooled to 10° C. and neutralized by addition of 3 normal hydrochloric acid at 10° C. The resulting solution is extracted repeatedly with ethyl acetate, and the combined ethyl acetate extracts are washed with water and then with saturated aqueous sodium chloride solution, dried, and evaporated to give racemic PGB2.
Reaction SMILES: [Li+].[Cl-].Br[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.C([Sn](CCCC)(CCCC)[C:19]1[S:23][C:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:21][CH:20]=1)CCC.CN(C=O)C>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>[N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([C:19]3[S:23][C:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[N:21][CH:20]=3)[CH:13]=2)[CH:8]=[N:9][CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(=O)OC(C)(C)C)s1
Reactant: Brc1ccc2cncnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2ccc3cncnc3c2)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
To a stirred mixture of flame-dried LiCl (45 mg, 1052 μmol), 7-bromoquinazoline (22 mg, 105 μmol), and Pd(Ph3P)4 (6.1 mg, 5.3 μmol), was added a solution of tert-butyl 5-(tributylstannyl)thiazol-2-ylcarbamate (77 mg, 158 μmol) in DMF (1.50 mL, 19372 μmol). The resulting mixture was stirred at 80° C. overnight. The mixture was concentrated, and the crude residue was dissolved in DCM and mixed with SiO2. The solvent was evaporated, and the residue was purified with flash column chromatography (pure DCM→5% MeOH in DCM) followed by washing with ether to obtain the desired product tert-butyl 5-(quinazolin-7-yl)thiazol-2-ylcarbamate (16 mg, 46%) as a pale yellow solid. LCMS (API-ES) m/z (%): 329.4 (100%, M++H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][CH2:13][C@H:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[O:29]1C[CH2:32][CH2:31][CH2:30]1.C(Cl)(=O)C=C>O>[C:30]([O:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:14][CH2:13]2)[CH2:16][CH2:17]1)(=[O:29])[CH:31]=[CH2:32]
Reactant: O[C@H]1CC[C@H]([C@H]2CC[C@H](c3cccc(F)c3F)CC2)CC1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)O[C@H]1CC[C@H]([C@H]2CC[C@H](c3cccc(F)c3F)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
First, 1.44 g of trans-4-[trans-4-(2,3-difluorophenyl)cyclohexyl]cyclohexanol, 0.61 g of triethylamine, and 20 ml of dry tetrahydrofuran were placed in a 100 ml flask. Then, 0.53 g of acryloyl chloride was added dropwise to the mixture under ice water cooling. The resultant mixture was allowed to warm to room temperature and stirred overnight. Water was added to the reaction mixture, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: benzene/hexane=1/2) and recrystallized from hexane to obtain 0.91 g of trans-4-[trans-4-(2,3-difluorophenyl)cyclohexyl]cyclohexyl acrylate (Y: 53.3%). The compound thus obtained had a purity of 98.8% by GC and 99.4% by HPLC. Furthermore, the phase transition temperature of this compound was as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:6](=[O:18])[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[C:12]([OH:16])[CH:11]=[CH:10][C:9]=2[F:17].[CH3:24][O:25][C:26](=[O:30])[CH:27](Br)[CH3:28]>>[CH3:24][O:25][C:26](=[O:30])[CH:27]([O:16][C:12]1[CH:11]=[CH:10][C:9]([F:17])=[C:8]2[C:13]=1[C:14]([CH3:15])=[C:5]([CH2:4][C:3]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=1[Cl:1])[C:6](=[O:18])[NH:7]2)[CH3:28]
Reactant: Cc1c(Cc2ccc(Cl)cc2Cl)c(=O)[nH]c2c(F)ccc(O)c12
Reactant: COC(=O)C(C)Br
Product: COC(=O)C(C)Oc1ccc(F)c2[nH]c(=O)c(Cc3ccc(Cl)cc3Cl)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 34d using 3-(2,4-dichlorobenzyl)-8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one and 2-bromopropionic acid methyl ester.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:13]4[CH:14]=[C:15]([NH:20][C@H:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[CH3:22])[C:16]([C:18]#[N:19])=[CH:17][C:12]=4[N:11]=[CH:10]3)[CH:5]=2)[CH2:3][CH2:2]1.[H][H]>[Pd].CO.Cl>[NH2:19][CH2:18][C:16]1[C:15]([NH:20][C@H:21]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH3:22])=[CH:14][C:13]2[N:9]([C:6]3[CH:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[NH:8][N:7]=3)[CH:10]=[N:11][C:12]=2[CH:17]=1
Reactant: [H][H]
Reactant: C[C@H](Nc1cc2c(cc1C#N)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C[C@H](Nc1cc2c(cc1CN)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Reaction time: 30 h
Yield: 64.8 %

Procedure:
To 1-(5-cyclopropyl-1H-pyrazol-3-yl)-6-((S)-1-(4-fluorophenyl)ethylamino)-1H-benzo[d]imidazol-5-carbonitrile (Example 33, 1.25 g, 3.2 mmol) and 10% palladium on carbon (0.69 g, 0.65 mmol) in MeOH (40 ml) was added 15 drops of conc. HCl. The reaction was charged 45 psi hydrogen and shook for 30 hours. The solvent was removed. The residue was dissolved in EtOAc (200 ml), washed with saturated sodium bicarbonate (50 ml) and dried over sodium sulfate. After removal of solvent, the residue was purified by reverse-phase column chromatography (5-50% CH3CN in H2O) to give the title compound as an off-white solid (0.81 g, 61%). 1H NMR (400 MHz) 12.65 (s, 1H), 8.15 (s, 1H), 7.46 (m, 2H), 7.36 (s, 1H), 7.11 (m, 2H), 6.91 (d, J=5.6 Hz, 1H), 6.74 (s, 1H), 5.94 (s, 1H), 4.54 (m, 1H), 3.92 (s, 2H), 2.07-1.91 (m, 3H), 1.48 (d, J=6.4 Hz, 3H), 1.01 (m, 2H), 0.72 (m, 2H). MS: Calcd.: 390; Found: [M+H]+ 391.
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([CH3:12])([S:8][CH2:9][CH2:10][CH3:11])[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[NH:20][C:21]([NH:23][C:24]([O:26][CH3:27])=[O:25])=[S:22].[OH-].[Na+].[CH3:30]I>CC(C)=O.O>[NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([CH3:12])([S:8][CH2:9][CH2:10][CH3:11])[C:4]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:3]1[NH:20][C:21](=[N:23][C:24]([O:26][CH3:27])=[O:25])[S:22][CH3:30]
Reactant: CI
Reactant: CCCSC1(C)C=CC(=N)C(NC(=S)NC(=O)OC)=C1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCSC1(C)C=CC(=N)C(NC(=NC(=O)OC)SC)=C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
To a suspension of 1-imino(4-methyl)phenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (4.02 g; 0.01 mole) in acetone (60 ml) and water (20 ml) there is added 50% aqueous sodium hydroxide (0.8 g; 0.01 mole). The solution that forms within 10 min. is stirred at room temperature for 50 min. and to it there is added methyl iodide (1.42 g; 0.01 mole). The suspension that forms is stirred at room temperature for 1 hr. and is vacuum filtered. The filter cake is air dried to afford 1-imino(4-methyl)phenylmethyl-2-(3-carbomethoxy-S-methyl isothioureido)-4-propylthiobenzene (3.6 g; 86.6%), m.p. 113°-115° C.