Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:17])([F:16])[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]([CH3:37])[N:35]=[C:34]([C:38]3[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:45])[N:33]=2)=[CH:28][C:27]=1[Cl:46]>O>[Cl:45][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]([F:44])[C:38]=1[C:34]1[N:33]=[C:32]([C:29]2[CH:30]=[CH:31][C:26]([CH2:25][O:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:7]([F:16])([F:17])[F:6])=[CH:14][CH:13]=3)=[C:27]([Cl:46])[CH:28]=2)[N:36]([CH3:37])[N:35]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ccc(OC(F)(F)F)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To 30 ml of N,N-dimethylformamide are added 4-trifluoromethoxy phenol (0.33 g) and potassium carbonate (0.25 g) and 5-(4-bromomethyl-3-chlorophenyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (0.70 g) is added thereto at room temperature with stirring, which is stirred at 120° C. for 1 hour. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with toluene. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.83 g of desired compound (refractive index: 1.5701).
Reaction SMILES: [N+:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])([O-:3])=[O:2].CC(O[C:17]([CH3:19])=O)=O>CCOCC>[CH:7]1[CH:8]=[CH:9][C:17](/[CH:19]=[C:4](/[N+:1]([O-:3])=[O:2])\[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])=[CH:4][CH:5]=1
Reactant: O=C(C[N+](=O)[O-])c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: O=C(/C(=C\c1ccccc1)[N+](=O)[O-])c1ccccc1

Procedure:
Condensation of α-nitroacetophenone (Compound 6) with N-methyl benzylidene imine (Compound 7) under the conditions detailed by Dornow et al., Ann., 588:40 (1954) (1.1 equiv. Ac2O, Et2O, reflux, 3 hours, 88 percent) provided (E)α-nitrochalcone (Compound 8) as the exclusive olefin isomer detected in the reaction mixture (Scheme 3). Treatment of Compound 8 with freshly cracked cyclopentadiene (9.0 equiv. 45° C., CH2Cl2 24 hours, 81 percent) provided a single predominant Diels-Alder adduct, Compound 9, derived from a [4+2] cycloaddition reaction through a transition state with the nitro substituent endo to the diene. Less than 1-3 percent of the diastereomeric exo adduct was detected. Notably, this Diels-Alder reaction proceeds almost exclusively to provide the sterically less favored adduct, Compound 9, presumably a consequence of a strong endo directing effect of the polarized nitro substituent. Use of cyclohexadiene in the place of cyclopentadiene provides the corresponding bicyclo[2.2.21]octane derivative.
Reaction SMILES: [CH2:1]([O:6][C:7]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(N=C=NC2CCCCC2)CCCCC1.[F:43][C:44]1[C:49](O)=[C:48]([F:51])[C:47]([F:52])=[C:46]([F:53])[C:45]=1[F:54]>C(OCC)(=O)C>[CH2:1]([O:6][C:7]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27][C:49]4[C:48]([F:51])=[C:47]([F:52])[C:46]([F:53])=[C:45]([F:54])[C:44]=4[F:43])=[O:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCCCCOC1(c2ccc(-c3ccc(C(=O)O)cc3)cc2)C=CC=CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCCOC1(c2ccc(-c3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc3)cc2)C=CC=CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 4"-(n-pentyloxy)-[1,1':4',4"-terphenyl]-4-carboxylic acid (10.5 mmol) and dicyclohexylcarbodiimide (10.5 mmol) in ethyl acetate at 0° C. is added pentafluorophenol (11.5 mmol). The mixture is stirred at 25° C. for a period of 18 h, producing a precipitate. The mixture is filtered. The filtrate is washed with water and brine and dried with magnesium sulfate. The solvent is removed in vacuo to obtain pentafluorophenyl 4"-(n-pentyloxy)-[1,1':4',4"-terphenyl]-4-carboxylate, C30H23F5O3, M.W.=526.5.
Reaction SMILES: [Na].C(O)C.[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1)[CH3:6].Br[CH:15]([CH2:17][CH2:18][CH2:19][C:20]([O:23][CH3:24])([CH3:22])[CH3:21])[CH3:16]>O>[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH:15]([CH3:16])[CH2:17][CH2:18][CH2:19][C:20]([O:23][CH3:24])([CH3:22])[CH3:21])=[CH:9][CH:8]=1)[CH3:6]
Reactant: CCc1ccc(S)cc1
Reactant: COC(C)(C)CCCC(C)Br
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCc1ccc(SC(C)CCCC(C)(C)OC)cc1
Reaction time: 0.67 h

Procedure:
To 3.5 g. of sodium in 150 ml. of ethanol is added 18.8 g. of p-ethylphenyl mercaptan. The mixture is stirred for about 40 minutes and then 30 g. of 2-bromo-6-methoxy-6-methylheptane is added. The reaction mixture is heated under reflux for about 35 minutes, allowed to cool and then diluted with water. The reaction is worked up by extraction with ether, washing with water and drying over magnesium sulfate to yield 5-methoxy-1,5-dimethylhexyl p-ethylphenyl sulfide which can be purified by chromatography. ##STR15##
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[Na].C(O)(=O)[CH2:22][C:23](CC(O)=O)(C(O)=O)[OH:24]>C(O)C>[N+:17]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:2]=1[O:24][CH2:23][CH3:22])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7])([O-:19])=[O:18]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=C(Nc1ccccc1)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Na]
Solvent: CCO
Product: CCOc1ccc(C(=O)Nc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Fluoro-3-nitro-N-phenyl-benzamide from Example 9 (2.34 g, 9 mmol) was added all at once to a solution prepared by dissolving sodium metal (2.29 g, 100 mmol) in ethanol (100 mL). The reaction mixture was stirred 1 hour at room temperature, then citric acid solution (10% aqueous, 4 mL) was added, and the mixture allowed to stand overnight. The reaction mixture was then concentrated to dryness and the residue chromatographed on silica gel using hexane/ethyl acetate, 1:1, as eluant to afford the product as an orange solid (1.09 g); m.p. 189-190° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][C:16](=[O:18])[O:15][O:14][C@H:13](/[CH:19]=[CH:20]/[CH2:21][CH2:22][S:23]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:12][C:11](=[O:43])[NH:10][C@H:9]([CH:44]([CH3:46])[CH3:45])[C:8](=[O:47])[NH:7][C@H:6]([CH3:48])[C:5](=[O:49])[NH:4][C@@H:3]1[CH:50]([CH3:52])[CH3:51].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C@H:2]1[CH2:17][C:16](=[O:18])[O:15][O:14][C@H:13](/[CH:19]=[CH:20]/[CH2:21][CH2:22][SH:23])[CH2:12][C:11](=[O:43])[NH:10][C@H:9]([CH:44]([CH3:46])[CH3:45])[C:8](=[O:47])[NH:7][C@H:6]([CH3:48])[C:5](=[O:49])[NH:4][C@@H:3]1[CH:50]([CH3:52])[CH3:51]
Reactant: CC(C)[C@H]1NC(=O)[C@@H](C)NC(=O)[C@@H](C(C)C)NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OOC(=O)C[C@@H]1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H]1NC(=O)[C@@H](C)NC(=O)[C@@H](C(C)C)NC(=O)C[C@@H](/C=C/CCS)OOC(=O)C[C@@H]1O
Reaction time: 1 h

Procedure:
To a solution of 9 (24.7 mg, 0.035 mmol) in CH2Cl2 (1.4 mL) was added triethylsilane (28 μL, 0.175 mmol) followed by the dropwise addition of TFA (0.35 mL, 25% v/v). After stirring for 1 h the reaction mixture was concentrated in vacuo and put under high vacuum for 2 h to give the crude thiol 10. At 0° C. to a solution of thiol 10 in CH2Cl2 (0.45 mL) was added diisopropylethylamine (30 μL, 0.172 mmol) followed by acetyl chloride (2.43 μL, 0.034 mmol) in CH2Cl2 (0.1 mL). After stirring for 2 h 10 min 1M HCl (1 mL) was added followed by EtOAc (10 mL) the layers were separated and the organic layer was washed with sat. brine (10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography (eluent 1:0-98:2-96:4-94:6-92.8 CH2Cl2/MeOH) gave the product 11 (7.3 mg, 0.014 mmol, 41%) as a white solid: Rf 0.47 MeOH/CH2Cl2 (1:9).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[NH:4][N:3]=1.C(SCCSCCSC1N=C2N(N=1)[C:36]([OH:39])=[CH:35][C:34]([CH3:40])=N2)CCCCC>>[CH2:11]([S:10][CH2:9][CH2:8][S:7][C:5]1[N:6]=[C:2]2[N:3]([N:4]=1)[C:36]([OH:39])=[CH:35][C:34]([CH3:40])=[N:1]2)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCSCCSc1nc(N)n[nH]1
Reactant: CCCCCCSCCSCCSc1nc2nc(C)cc(O)n2n1
Product: CCCCCCSCCSc1nc2nc(C)cc(O)n2n1

Procedure:
Compound 13 was prepared from Compound 6, using a procedure analogous to that described previously for Compound 20. The crude product was recrystallized from ethyl acetate to give a white solid, m.p. 125.5°-126° C. Analysis: Calculated for C14H22N4OS2 : C, 51.50; H, 6.79; N, 17.16. Found: C, 50.87; H, 6.62; N, 17.04.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:13][CH2:12][S:11][C:10]([NH2:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CN(C)CC.[CH:21]([OH:24])(C)[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH3:15])[CH2:13][CH2:12][S:11][C:10]([NH:14][C:21](=[O:24])[CH3:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)O
Reactant: CC1(c2cccc(Br)c2)CCSC(N)=N1
Agent: CCN(C)C
Product: CC(=O)NC1=N[C@](C)(c2cccc(Br)c2)CCS1
Yield: 35 %

Procedure:
4-(3-bromo-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-ylamine (20 g, 61 mmole) is purified by HPLC chiral separation [Column: 8×32 cm chiralpak AD; Eluent: 60:40:0.2 (isopropyl alcohol: heptanes: dimethylethylamine); Flow: 350 mL/min at UV 260 nm]. The second eluting isomer is isolated to provide the enantiomerically enriched title compound (35% Yield): MS (m/z): 327, 329 (M+1)
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N+:20]([O-])=O)[C:11]=1[OH:23]>C(O)C.O>[NH2:20][C:12]1[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=[C:10]([Cl:9])[C:11]=1[OH:23]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(Cl)c1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(C(F)(F)F)cc(Cl)c1O
Reaction time: 2 h

Procedure:
Solid sodium dithionite (10 g) was added in portions to a stirred solution of 2-chloro-6-nitro-4-trifluoromethylphenol (4.5 g) in a mixture of ethanol (20 ml) and water (30 ml). The solution was stirred for 2 hours, left overnight, filtered, and evaporated. The residue was mixed with toluene and the toluene removed under reduced pressure. The residue was extracted with boiling chloroform (3×100 ml) and the chloroform extracts evaporated to give a yellow oil identified as the required substituted phenol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:12]2[S:11][CH2:17][C:15](=[O:16])[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(=S)N1
Reactant: NCCc1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NCCc2cccc(F)c2)=N1

Procedure:
Similar procedure as described in example 1f was used, starting from 2-(3-fluoro-phenyl)-ethylamine, rhodanine (2-thioxo-thiazolin-4-one) and DIEA to give 2-[2-(3-fluoro-phenyl)-ethylamino]-thiazol-4-one. LC-MS m/e 239 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:29])([CH3:28])[C@@H:17]([OH:27])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].N1C=CN=C1.[Si:36](Cl)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:29])([CH3:28])[C@@H:17]([O:27][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 70 °C
Reaction time: 20 h
Yield: 80.3 %

Procedure:
3β-Hydroxy-4,4-dimethylchol-5-en-24-oic acid methyl ester (19.1 g) is suspended in 390 ml of N,N-dimethylformamide (hereinafter designated DMF) and 39 g of imidazol and 34.6 g of tert-butyldimethylsilyl choride is added. The reaction mixture is stirred at 70° C. for 20 hours. After aqueous work-up, a crude product 23.9 g is isolated. Crystallization from tetrahydrofurane/methanol (hereinafter tetrahydrofurane and methanol are designated THF and MeOH, respectively) yields 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-chol-5-en-24-oic acid methyl ester (19.55 g). Melting point: 144-146° C. 1H-NMR (CDCl3, 300 MHz): δ=5.52 (1H, m); 3.66 (3H, s); 3.18 (1H, m); 0.89 (9H, s); 0.02 (6H, m).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:15][C:16]1[NH:17][C:18]([CH3:28])=[CH:19][C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[N:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[CH3:15][C:16]1[NH:17][C:18]([CH3:28])=[CH:19][C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)[N:22]=1
Reactant: OB(O)c1ccc(F)c2ccccc12
Reactant: Cc1cc(-c2cccc(Br)n2)c(C)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2cccc(-c3ccc(F)c4ccccc34)n2)c(C)[nH]1
Yield: 700.4 %

Procedure:
To a 50 mL round-bottomed flask equipped with condenser and N2 inlet were added 404 mg (2.13 mmol) 4-fluoronaphthalene-1-boronic acid, 534 mg (2.13 mmol) 2-(2,5-dimethylpyrrolyl)-6-bromopyridine, 902 mg (8.51 mmol) sodium carbonate, 150 mg tetrakistriphenylphosphine, 10 mL ethanol, and 2 mL water. The reaction was refluxed overnight, cooled, poured into water, and extracted into ethyl acetate. After combining with another run on a larger scale, the combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluant to afford 4.72 g (85%) of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([Cl:10])[C:3]=1[N+:11]([O-])=O>CCOC(C)=O.[Pd]>[Cl:10][C:4]1[C:5]([O:8][CH3:9])=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH2:11]
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)c(N)c1Cl
Reaction time: 8 h
Yield: 104.1 %

Procedure:
To a solution of 1,3-dichloro-4-methoxy-2-nitro-benzene (550 mg, 2.5 mmol, 1.0 eq) in EtOAc (20 mL) was added Pd/C (10% Pd, 50 mg) and the reaction was stirred under a hydrogen atmosphere overnight. The catalyst was removed by filtration and the filtrate was evaporated in vacuo to give the title compound (500 mg, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:22]O)[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:22][Br:25])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)CC[C@@H](CO)NC(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@@H](CBr)NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
A solution of tert-butyl(4S)-4-{[(benzyloxy)carbonyl]amino}-5-hydroxypentanoate (5.0 g, 15.5 mmol) in dichloromethane (50 ml) was cooled to 0° C. and carbontetrabromide (6.15 g, 18.5 mmol) was added thereto. At the same temperature triphenylphosphine (5.68 g, 21.7 mmol) was divided to five portions and they were added to the reaction mixture for every 2 minutes and the mixture was stirred for 30 minutes. The solvent was removed in vacuo. To the residue was added diethyl ether and mixture was stirred. After removal of the resulting crystall by filtration, the filtrate was condensed in vacuo and the residue was purified with silica gel chromatography to give tert-butyl(4S)-4-{[(benzyloxy)carbonyl]amino}-5-bromopentanoate (4.5 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8]([OH:10])=O)=[C:4]([CH3:14])[CH:3]=1.[NH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)=[O:10])=[C:4]([CH3:14])[CH:3]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: Cc1cc(Cl)ccc1OC(C)C(=O)O
Product: Cc1cc(Cl)ccc1OC(C)C(=O)N1CCCc2ccccc21
Yield: 46 %

Procedure:
The title compound was synthesized according to General Procedure D using 2-(4-chloro-2-methylphenoxy)propanoic acid and compound 3 to yield 57 (350 mg, 46%): MS (APCI): m/z 330 [M+H]+. Anal. Calcd. for C19H20ClNO2: C, 69.19; H, 6.11; N, 4.25. Found: C, 69.09; H, 6.10; N, 4.31.
Reaction SMILES: C([Mg]Cl)CCC.C([Li])CCC.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1.[CH:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.CCCCCC.C(O)(=O)C>[Br:19][C:17]1[CH:18]=[C:13]([C:21]2([CH:22]=[CH:23][CH:24]=[CH:25][CH2:26]2)[CH2:20][OH:27])[CH:14]=[N:15][CH:16]=1
Reactant: Brc1cncc(Br)c1
Reactant: O=Cc1ccccc1
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCC1(c2cncc(Br)c2)C=CC=CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
n-Butylmagnesium chloride (3.49 mmol) in 2.05M tetrahydrofuran solution (1.70 mL) was added to ice-cooled n-butyllithium (6.99 mmol) in 1.52M hexane (4.60 mL). The mixture was stirred at 0° C. for 15 minutes to give a suspension. The suspension was added to a tetrahydrofuran solution (25 mL) containing 3,5-dibromopyridine (2.37 g, 10.0 mmol) over a period of 10 minutes or more, while keeping the temperature below −5° C., to give an orange suspension. The suspension was stirred at −10° C. for one hour, and benzaldehyde (1.35 mL, 13.3 mmol) was added thereto. The resultant mixture was stirred at 0° C. for 30 minutes, and then 1M acetic acid solution (15 mL) was added. The reaction mixture was extracted twice with ethyl acetate (20 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride (10 mL), dried over magnesium sulfate and was purified by flash column chromatography on silica gel in a developing solvent system of hexane-ethyl acetate (5:1, v/v) to give the title compound (1.647 g, 59% yield) as a colorless oil.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17](=[NH:21])OCC)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH3:25]>C(O)C>[F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([NH2:21])=[NH:25])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N
Reactant: CCOC(=N)c1cccc(OCc2ccccc2)c1
Agent: F[B-](F)(F)F
Solvent: CCO
Product: N=C(N)c1cccc(OCc2ccccc2)c1
Temperature: -70 °C
Reaction time: 69 h

Procedure:
A suspension of 8.57 g of ethyl m-benzyloxybenzimidate tetrafluoroborate in ethanol (120 ml) was cooled to −70° C. and then treated with liquid ammonia (100 ml). The cooling bath was removed and the reaction mixture stirred for 69 h until the reaction was complete (TLC analysis). The solvent was removed in vacuo to give the desired m-benzyloxybenzamidine tetrafluoroborate as a white solid, mp 125°-127° C., that was essentially pure and used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]([O:41][Si](C)(C)C(C)(C)C)[C:12]1[N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[CH2:21][N:22]([CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[C:26]=1[Cl:35])=[O:24].[F-]>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]([OH:41])[C:12]1[N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[CH2:21][N:22]([CH2:36][CH2:37][CH:38]([CH3:39])[CH3:40])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[C:26]=1[Cl:35])=[O:24]
Reactant: COc1ccc(OC)c(C(O[Si](C)(C)C(C)(C)C)c2c(CN(CCC(C)C)C(=O)c3ccc(OC)c(OC)c3Cl)nc3ccccn23)c1
Agent: O=C([O-])O
Agent: [F-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(OC)c(C(O)c2c(CN(CCC(C)C)C(=O)c3ccc(OC)c(OC)c3Cl)nc3ccccn23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 390 mg (0.56 mmol) of N-({3-[(2,5-dimethoxyphenyl) (1,1,2,2-tetramethyl-1-silapropoxy)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl) (2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide in 12 mL THF is treated with 0.70 mL (0.7 mmol) 1M tetabutylammonium fluoride in THF. The mixture is stirred at room temperature for 1 hr, diluted with 15 mL sat. NaHCO3 and extracted with 3×15 mL ether. The combined organics are washed with 25 mL water and 25 mL brine. The resulting organic layer is dried over anhydrous MgSO4 and the solvent removed in vacuo to give the crude material. A small sample of the residue is prep-plate chromatographed (9% MeOH/CH2Cl2/0.5% NH4OH) to afford N-({3-[(2,5-dimethoxyphenyl)hydroxymethyl](imidazolo[1,2-a]pyridin-2-yl)}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M++1) 584.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:21][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=[CH:10][C:2]=1[F:1]
Reactant: CC(C)Oc1cc(C(=O)O)c(F)cc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC(C)C)c(O)cc1F

Procedure:
2-Fluoro-4-hydroxy-5-isopropyloxybenzoic acid (5.7 g) is dissolved in methanol (200 mL) and concentrated sulfuric acid (1 mL) and heated at 70° C. for 5 hours. The solution is concentrated and the resultant oil subjected to mplc on silica gel using petroleum ether: ethyl acetate (4:1 v/v) as eluent to give methyl-2-fluoro-4-hydroxy-5-isopropyloxybenzoate (5.7 g). [NMR (CDCl3) 7.38 (d, 1H, J=7 Hz), 6.67 (d, 1H, J=12 Hz), 4.85 (m, 1H), 3.9 (s, 3H), 1.3 (d, 6H, J=7 Hz)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O:17][C:18]([C:20]1[S:21][CH:22]=[C:23]([CH2:25]Cl)[N:24]=1)=[O:19])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:25][C:23]3[N:24]=[C:20]([C:18]([OH:19])=[O:17])[S:21][CH:22]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)c1nc(CCl)cs1
Product: O=C(O)c1nc(COc2ccc(-c3ccc(Cl)cc3)cc2)cs1

Procedure:
4-(4′-Chloro-biphenyl-4-yloxymethyl)-thiazole-2-carboxylic acid was prepared using general procedure B from 4-chloro-4′-hydroxybiphenyl (available from TCI America, Portland, Oreg.) and 4-chloromethyl-thiazole-2-carboxylic acid ethyl ester (Intermediate 4). Yield: 71 mg. Mass spectrum (ES) MH+=346.
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([S:10][CH2:11][CH:12]=[CH2:13])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][N:15]([CH3:19])[C:16](Cl)=[O:17]>N1C=CC=CC=1>[CH3:14][N:15]([CH3:19])[C:16]([N:7]1[C:8]([S:10][CH2:11][CH:12]=[CH2:13])=[N:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]1)=[O:17]
Reactant: CN(C)C(=O)Cl
Reactant: C=CCSc1nnc(C(C)(C)C)[nH]1
Solvent: c1ccncc1
Product: C=CCSc1nc(C(C)(C)C)nn1C(=O)N(C)C
Yield: 87 %

Procedure:
A solution of 56 g (0.284 mol) of 3-tert.butyl-5-allylthio-4H-1,2,4-triazole and 31.2 g (0.29 mol) of dimethylcarbamyl chloride in 300 ml of pyridine was maintained at reflux temperature for 16 hrs. After the pyridine was removed at reduced pressure on the rotary evaporator, water was added followed by chloroform. The organic layer was washed with successive portions of dilute hydrochloric acid, water and brine, then dried over Na2SO4. The solvent was removed in vacuo to give 66.3 g of an oil, nD26 1.5126.