Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])([OH:3])=[O:2].[Na+].[CH2:6]([O:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH3:17])=[O:10])[CH3:7].ClC(O[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O>C1COCC1.ClCCl.O>[CH2:6]([O:8][C:9]([C:11]1[S:15][C:14]([NH:16][O:2][C:1]([O:4][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:3])=[N:13][C:12]=1[CH3:17])=[O:10])[CH3:7]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1sc(N)nc1C
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(NOC(=O)OCc2ccccc2)nc1C
Reaction time: 2 h
Yield: 48 %

Procedure:
A 3 M aq. NaHCO3 solution (10 mL, 30 mmol) was added to a stirred solution of ethyl-2-amino-4-methyl-thiazole-5-carboxylate (372 mg, 2 mmol) in THF (20 mL) at 0-5° C. Benzyl chloroformate (500 μL) was added. After 2 h, additional benzyl chloroformate (500 μL) and the biphasic solution was stirred for an additional 2 h at 0-5° C. The mixture was diluted with dichloromethane (50 mL) and water (30 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated. The residue was chromatographed on a silica gel column. Elution with 10% EtOAc in hexanes followed by 20% and 30% EtOAc in hexanes afforded the title compound (310 mg, 48%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.O=[CH:20][C:21]([Cl:24])([Cl:23])[Cl:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[CH:20]2[C:21]([Cl:24])([Cl:23])[Cl:22])[CH:5]=[CH:6][CH:7]=1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Cc1ccc(NCCNc2cccc(Cl)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCN(c3cccc(Cl)c3)C2C(Cl)(Cl)Cl)cc1
Yield: 35.6 %

Procedure:
A mixture consisting of 12.2 gm of N-(3-chlorophenyl)-N'-(4-methyl-phenyl)-ethylenediamine, 9 gm of chloral, 100 ml of toluene and 1.2 gm of p-toluenesulfonic acid was heated at its boiling point for 45 minutes in a vessel equipped with a water trap. Thereafter, the reaction mixture was filtered while still hot, and the filtrate was evaporated in vacuo. The oily residue was allowed to cool and was then triturated with a little glacial acetic acid, whereupon crystallization occurred. The crystals were collected by suction filtration, washed with cold methanol, and recrystallized from ethanol, yielding 6.5 gm of the compound of the formula ##STR14## which had a melting point of 34°-36° C.
Reaction SMILES: [OH-].[K+].C/C=C/[CH2:6][C@H:7]([C@@H:9]([OH:16])[C@H:10]([NH:14][CH3:15])[C:11]([OH:13])=[O:12])[CH3:8]>>[OH:16][CH:9]([CH:7]([CH3:8])[CH3:6])[C@@H:10]([C:11]([OH:13])=[O:12])[NH:14][CH3:15]
Reactant: C/C=C/C[C@@H](C)[C@@H](O)[C@H](NC)C(=O)O
Agent: [K+]
Agent: [OH-]
Product: CN[C@H](C(=O)O)C(O)C(C)C

Procedure:
At the same time, an elegant asymmetric glycine enolate reaction was developed by Evans and Weber for the synthesis of MeBmt and other chiral amino acids. [See Evans, D. A. and Weber, A. E., J. Am. Chem. Soc. 108:6757 (1986)]. The approach was also applied to prepare MeLeu(OH) [see FIG. 6]. In the reaction sequence, the chiral glycine synthon isothiocyanate was obtained from corresponding chloroacetate and followed by azide replacement in 56% yield. The isothiocyanate chiral auxiliary was condensed with isobutyraldehyde under stannous triflate mediated aldol reaction (-78° C. for 4 h) to give the aldol adduct in 63% yield (>90% e.e). Transesterification with a solution of magnesium methoxide in methanol at room temperature for 3 min gave the methyl ester in 78-82% yield. The yield of the bis-methylation was low, 52% as compared to 76% of Evans in MeBmt synthesis. Two epimers are usually obtained in a ratio of 1:5, which was not found by Evans for the MeBmt synthesis. The 1H NMR spectra of the epimers were compared as shown in Table 4 and FIG. 7. Hydrolysis of the desired trans-oxazolidinone with 2N KOH under reflux gave the pure β-hydroxy-N-methylleucine (see 1H NMR spectra in FIG. 8) after chromatographic purification over Sephadex LH-20.
Reaction SMILES: CN(C=O)C.[NH:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:7]([C:15]([OH:17])=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[CH2:33]([NH2:37])[CH:34]([CH3:36])[CH3:35]>C(N(CC)CC)C>[NH:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:7]([C:15]([NH:37][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
In a DMF solution containing a mixed anhydride prepared from 2.0 g of Boc-Phe-OH, 1.15 ml of triethylamine and 1.08 ml of isobutyl chloroformate, 1.50 ml of isobutylamine was added under ice cooling and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 51 (Process 1) to give 1.91 g of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=1)#[N:12].C(N(CC)CC)C>ClCCl>[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[CH:21][C:22]([CH:25]=[O:26])=[CH:23][CH:24]=1)#[N:12]
Reactant: N#Cc1ccccc1-c1ccc(CO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1-c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of 53 ml of oxalyl chloride in 2 l of dichloromethane is cooled to -60°. A solution of 88 ml of dimethyl sulfoxide in 150 ml of dichloromethane is added dropwise at this temperature and the mixture is then stirred for 2 minutes. After this, a solution of 117 g of 2'-cyano-4-hydroxymethyl-biphenyl in 1 l of dichloromethane is added dropwise at -60°. After the addition has ended (after about 5 minutes), the mixture is stirred for 15 minutes. After this, 390 ml of triethylamine are added dropwise. The mixture is stirred at -60° for 2 minutes, then allowed to warm to room temperature and poured onto water. The mixture is extracted with dichloromethane, and the organic phase is washed in succession with dilute hydrochloric acid and brine, dried and concentrated. The residue is suspended in hexane, the suspension is filtered with suction, the filter cake is washed, and the product thus obtained is dried at 60° in a high vacuum (elemental analysis: 80.7% C; 4.5% H; 6.7% N; 7.7% O).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3.[C:25]([Cu])#[N:26].[CH3:28][N:29]1C(=O)CCC1>>[C:28]([C:2]1[CH:7]=[C:6]([C:25]#[N:26])[CH:5]=[CH:4][C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)#[N:29]
Reactant: Cc1ccc2[nH]c3c(cc(-c4ccc(Br)cc4Cl)c(=O)n3C)c2c1
Reactant: N#C[Cu]
Reactant: CN1CCCC1=O
Product: Cc1ccc2[nH]c3c(cc(-c4ccc(C#N)cc4C#N)c(=O)n3C)c2c1

Procedure:
0.6 g of 3-(2-chloro-4-bromophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one is dissolved in 15 ml of NMP. 0.27 g of CuCN is added and then the mixture is heated at reflux for 5 hours. The reaction medium is poured onto CH2Cl2 and washing is carried out with a saturated NaCl solution. Purification is carried out by chromatography on a silica column eluted with an AcOEt/petroleum ether (v/v; 75/25) mixture and then pure AcOEt. The fractions recovered are washed with a 1N HCl solution to remove an NMP residue. 50 mg of the expected compound are obtained in the form of a powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.C(N(C(C)C)CC)(C)C.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>ClCCl.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]([C:24](=[O:27])[CH2:25][CH2:26][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[CH2:7][CH2:6]2
Reactant: C1COCCN1
Reactant: C=CC(=O)Cl
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CCN1CCOCC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (1.0 g, 5.15 mmol) and polymer-bound diisopropyl ethylamine (4.20 g, 15.46 mmol) in dichloromethane (200 mL) was added acryloyl chloride (0.51 g, 5.67 mmol) via a dropwise addition. After stirring overnight at rt, the solids were removed by vacuum filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure, and stored under vacuum for several hours. A portion of the crude mixture (0.4 g, 1.61 mmol) was redissolved in absolute ethanol (25 mL) and to this was added morpholine (0.41 g, 4.84 mmol). After heating at 60° C. for 3 hr, the reaction was concentrated under reduced pressure and solids were recrystallized from ethyl acetate/hexanes to provide 5-(methyloxy)-1-[3-(4-morpholinyl)propanoyl]-6-nitro-2,3-dihydro-1H-indole (0.44 g, 54%). ESIMS (M+H)+=336.
Reaction SMILES: [Cl:1][C:2]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:5]2[O:6][CH2:7][CH2:8]C(C#N)(O[Si](C)(C)C)[C:4]=2[CH:3]=1.[C:23]([OH:26])(=[O:25])[CH3:24]>>[ClH:1].[Cl:1][C:2]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:5]2[O:6][CH2:7][CH2:8][CH:24]([C:23]([OH:26])=[O:25])[C:4]=2[CH:3]=1
Reactant: CC(=O)O
Reactant: C[Si](C)(C)OC1(C#N)CCOc2c1cc(Cl)c1ccccc21
Product: Cl
Product: O=C(O)C1CCOc2c1cc(Cl)c1ccccc21

Procedure:
Following the procedure of Example 2, 6-chloro-4-cyano-4-trimethylsilyloxy-3,4-dihydro-2H-naphtho[1,2-b]pyran (0.52 g.), stannous chloride dihydrate (1.94 g.) were reacted in glacial acetic acid (5 ml.) and concentrated hydrochloric acid (5 ml.) to form 6-chloro-3,4-dihydro-2H-naphtho[1,2-b]pyran-4-carboxylic acid. Recrystallization from ethyl acetate-hexane yielded 0.23 g. of product, m.p. 141°-142° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[C:21]([C:24]([O:26][CH3:27])=[O:25])[CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[CH:28]=[CH:29][CH:30]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=C(Cl)[O:35][C:36](Cl)(Cl)[Cl:37].C(N(CC)CC)C.[CH3:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>ClCCl>[ClH:37].[CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[C:21]([C:24]([O:26][CH3:27])=[O:25])[CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:28]([C:36]([N:52]5[CH2:53][CH2:54][N:49]([CH3:48])[CH2:50][CH2:51]5)=[O:35])=[CH:29][CH:30]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc2c(c1)N(C(=O)c1ccc(C3CCCCC3)cc1)Cc1cccn1C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)N(C(=O)c1ccc(C3CCCCC3)cc1)Cc1ccc(C(=O)N3CCN(C)CC3)n1C2
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 10-(4-cyclohexylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylate of Step C (3.38 mmol) in dichloromethane (20 mL) was treated with diphosgene (1.1 equiv.) and triethylamine (1.5 equiv.) and stirred at room temperature overnight. The solvent was then removed in vacuo and the residue was dissolved in dichloromethane (20 mL), and then treated with triethylamine (1.5 equiv) and 1-methylpiperazine (1.5 equiv). The reaction mixture was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was first chromatographed on silica gel eluting with 2% methanol in dichloromethane, and then chromatographed again eluting with 2% methanol in ethyl acetate to provide the title compound as a white crystalline solid, m.p. 166–168° C. This was converted to the hydrochloride salt by treatment of the free base in anhydrous ethanol with anhydrous hydrogen chloride in dioxane (1.1 equiv.). The salt so obtained was a white crystalline solid, m.p. 203° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[H-].[Na+].C(OP([CH2:26][C:27]([O:29]CC)=[O:28])(OCC)=O)C.CN(C)C=O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:6][CH:7]=1
Reactant: Cn1ncc(C=O)c1-c1ccc(F)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc(/C=C/C(=O)O)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
A mixture of 5-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (350 mg), sodium hydride (60% in oil, 120 mg), ethyl diethylphosphonoacetate (673 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the precipitated solids were collected by filtration. After drying with airflow, the solids were dissolved in a mixed solvent of tetrahydrofuran (10 ml) and ethanol (10 ml). A 1N aqueous sodium hydroxide solution (5 ml) was added and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into a 10% aqueous citric acid solution and the precipitated solids were collected by filtration, washed with water and dried with airflow to give (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (354 mg, 84%) as crystals. Recrystallization thereof from methanol-isopropyl ether gave colorless prism crystals. melting point: 212-213° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:12]=[C:11]([Cl:13])[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:9]([N:19]([CH3:21])[CH3:20])[N:8]=2)=[CH:4][CH:3]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:57]1[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:60]=[CH:59][C:58]=1[C:67](O)=[O:68].O>CN(C=O)C>[Cl:13][C:11]1[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:9]([N:19]([CH3:20])[CH3:21])[N:8]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:67]([C:58]3[CH:59]=[CH:60][C:61]4[C:66](=[CH:65][CH:64]=[CH:63][CH:62]=4)[CH:57]=3)=[O:68])=[CH:23][CH:22]=2)[N:12]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(N)cc2)nc1N(C)C
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N(C)C

Procedure:
To a mixture of methyl [2-(4-aminobenzyl)-4-chloro-6-(dimethylamino)pyrimidin-5-yl]acetate (0.090 g, 0.30 mmol) and PyBOP (0.187 g, 0.36 mmol) in anhydrous DMF (1 mL) at room temperature was added 2-naphthoic acid (0.062 g, 0.36 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours at which time water was added and the resulting aqueous phase was extracted with EtOAc. The combined organic extracts was sequentially washed with 0.5N HCl, saturated NaHCO3, and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give methyl {4-chloro-6-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate as a colorless oil.
Reaction SMILES: C([CH2:3][C:4]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=1)([CH3:8])[C:5]([OH:7])=[O:6])C.[NH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[SH:29]>CO>[CH3:8][C:4]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[S:29][C:20]3[CH:21]=[CH:22][C:23]([C:25]([F:26])([F:27])[F:28])=[CH:24][C:19]=3[N:18]=2)=[CH:14][CH:15]=1)([CH3:3])[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: CCCC(C)(Oc1ccc(C=O)cc1)C(=O)O
Solvent: CO
Product: CC(C)(Oc1ccc(-c2nc3cc(C(F)(F)F)ccc3s2)cc1)C(=O)O

Procedure:
A solution including Compound 97c (1.0 eq.) and 2-amino-4-trifluoromethylbenzenethiol (1.0 eq.) was stirred in a methanol solvent at room temperature. After methanol was removed, the precipitate was filtered, and washed with cold methanol to obtain a solid target product.
Reaction SMILES: [Mg].Br[CH:3]([CH3:5])[CH3:4].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[C:16]#N.S(=O)(=O)(O)[OH:19]>C(OCC)C>[CH:3]([C:16]([C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1)=[O:19])([CH3:5])[CH3:4]
Reactant: N#Cc1ccc2ccccc2c1
Reactant: CC(C)Br
Reactant: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)C(=O)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A Grignard reagent prepared by using 0.61 g of magnesium, 3.6 g of 2-bromopropane and 18 ml of anhydrous diethyl ether, was dropwise added to a mixture comprising 3.0 g of 2-naphthonitrile and 20 ml of anhydrous diethyl ether. After completion of the dropwise addition, the mixture was reacted for 12 hours under reflux. The reaction mixture was put into ice water, and 6N sulfuric acid was added to bring the mixture to be weakly acidic, followed by stirring for 0.5 hour. The mixture was extracted with ethyl acetate, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/n-hexane=1/50) to obtain 1.14 g of 2-naphthyl isopropyl ketone. The NMR spectrum data of this product is as follows.
Reaction SMILES: [O:1]=[C:2]1[N:10]2[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:12][N:13]=[C:9]2[N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2.C1C(=O)N([Br:31])C(=O)C1>C1COCC1>[Br:31][C:5]1[NH:4][C:3]2[C:2](=[O:1])[N:10]3[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:12][N:13]=[C:9]3[N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:7]=2[N:6]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CCC(=O)O)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCC(=O)O)nnc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
The mixture of 3-(5-oxo-9-pentyl-6,9-dihydro-5H[1,2,4]triazolo[4,3-a]purin-3-yl)propanoic acid (203 mg, 0.64 mmole) and NBS (125.8 mg, 7.0 mmol) in THF (25 ml) was stirred at 70° C. for 2 hours. After evaporation of solvent, the residue was purified by preparative LC-MS to afford 60.2 mg (23.7%) of the desired product (60.2 mg, 23.7%) as white solid. LCMS calculated for C14H18BrN6O3(M+H): 397.1; found: 371.1.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([OH:28])=[CH:20][N:19]=1>>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:28][C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[N:19][CH:20]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Fc1cc(-c2ccc(C(F)(F)F)cc2)ncn1
Reactant: Oc1cncc2ccccc12
Product: FC(F)(F)c1ccc(-c2cc(Oc3cncc4ccccc34)ncn2)cc1

Procedure:
The title compound was prepared from 4-fluoro-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example 169(a) and isoquinolin-4-ol (MonomerChem) analogous to the conditions described in Example 169(b). Mp: 206–211° C. MS (ESI, pos. ion) m/z: 368.2 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.O.Cl>C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:6])[CH:2]=[CH2:3]
Reactant: c1c[nH]cn1
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COS(C)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cn1ccnc1
Temperature: 72.5 °C
Reaction time: 7 h
Yield: 65.9 %

Procedure:
A mixture of (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-(methanesulfonyloxy)methylpyrrolidine (8.73 g) and imidazole (4.16 g) was stirred at 70-75° C. for 7 hours. After cooling, the reaction mixture was dissolved in ethyl acetate (30 ml), water (30 ml) and conc. hydrochloric acid (8.0 ml) with stirring. The aqueous layer was separated, adjusted to pH 9.0 with 10% aqueous sodium hydroxide and extracted twice with ethyl acetate (50 ml). The extract was dried over anhydrous magnesium sulfate and evaporated in vacuo to give (2S,4R)-1-allyloxycarbonyl-2-(imidazol-1-yl)methyl-4-methanesulfonyloxypyrrolidine (5.30 g).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:34])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[K+]>O.CO>[CH3:8][C:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:34])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3ccccc3OC)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccccc1C(=O)NCCc1ccc(-c2ccc(OC(C)(C)C(=O)O)cc2)cc1

Procedure:
4gm (8.6 millimols) of ethyl 2-methyl-2-{4-[2-(2-methoxy-benzamido)-ethyl]-biphenyl-4'-oxy}-propionate were hydrolized at room temperature over a period of 12 hours with a solution of 1gm (17.2 millimols) of potassium hydroxide in 5 ml of water and 95 ml of methanol. After distilling off the methanol, 100 ml of water were added, and the mixture was extracted with ether. The pH of the aqueous phase was adjusted to between 1 and 2 with 2 N hydrochloric acid, and the acid mixture was extracted with chloroform. The combined chloroform extracts were dried over sodium sulfate and evaporated to dryness, and the residue was recrystallized from ether. Yield: 3.2 gm (86% of theory); m.p. 133° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=2)=[CH:5][C:4]=1OS(C(F)(F)F)(=O)=O.[CH:28]([O:30]CCCC)=[CH2:29].C1(C(C2C=CC=CC=2)(P)CC)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:28]([C:4]1[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:30])[CH3:29]
Reactant: COC(=O)Cc1cccc(-c2ccc(OC)c(OS(=O)(=O)C(F)(F)F)c2)c1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCC(P)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(-c2ccc(OC)c(C(C)=O)c2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
357 mg of Methyl (4′-methoxy-3′-trifluoromethanesulfonyloxybiphenyl-3-yl)acetate was dissolved in 3 ml of N,N-dimethylformamide, then 0.45 ml of butyl vinyl ether, 10 mg of palladium acetate, 20 mg of diphenyl phosphinopropane and 1 ml of triethylamine were added thereto, and the mixture was stirred at 80° C. overnight in a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, to give 184 mg of the title compound in the 4:1 hexane-ethyl acetate fraction.