Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=O.[CH2:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([C:3](=[O:5])[C@H:2]([OH:1])[CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)C[C@@H](O)C(=O)O
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](O)C(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution (0-5° C.) of (R)-α-hydroxyisocaproic acid (64.5 g, 0.5 mol), 1-benzylpiperazine (88 g, 0.5 mol) and triethylamine (71 ml, 0.5 mol) in CH2Cl2 (850 ml) was added in portions HOBt (68 g, 0.5 mol) and EDCI.HCl (96 g, 0.5 mol). The reaction mixture was stirred at room temperature overnight. The organic layer was washed with water (3×) and once with brine, dried over Na2SO4, and filtered, and the solvent was removed in vacuo. Crude (R)-1-(4-benzyl-piperazin-1-yl)-2-hydroxy-4-methyl-pentan-1-one (132 g, 91%) was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.O=[C:32]1[CH2:37][CH2:36][CH:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:34][CH2:33]1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:32]1[CH2:37][CH2:36][CH:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:34][CH:33]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)CC1CCC(=O)CC1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Product: CCOC(=O)CC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
Trifluoromethanesulfonic anhydride (11.9 mL, 70.86 mmol) was added portionwise to a solution of 2,6-di-tert-butyl-4-methylpyridine (18.19 g, 88.58 mmol) in DCM (250 mL). A solution of ethyl 2-(4-oxocyclohexyl)acetate (10.88 g, 59.05 mmol, CAS 58012-34-3) in DCM (100 mL) was then added dropwise and the reaction mixture was allowed to stir open to air and at room temperature overnight. The reaction mixture was washed with water, saturated Na2CO3, saturated brine, dried over MgSO4 and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (16.05 g, 86%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([I:13])=[CH:11][C:10]([N:14]3C(C)=CC=C3C)=[N:9]2)=[CH:4][CH:3]=1.[Cl-].O[NH3+].C(N(CC)CC)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([I:13])=[CH:11][C:10]([NH2:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C)n1-c1cc(I)n(-c2ccc(Cl)cc2)n1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1cc(I)n(-c2ccc(Cl)cc2)n1
Temperature: 95 °C
Reaction time: 86 h
Yield: 55.5 %

Procedure:
To a suspension of 1-(4-chlorophenyl)-3-(2,5-dimethylpyrrol-1-yl)-5-iodo-1H-pyrazole (4.19 g) in ethanol/water (2/1, 72 ml) were sequentially added hydroxylammonium chloride (14.64 g) and triethylamine (2.9 ml) at room temperature, and the mixture was stirred at 95° C. for 86 hours. This reaction mixture was cooled to room temperature, and concentrated under reduced pressure. To the resulting residue was added an 8M aqueous solution of sodium hydroxide, and then the mixture was extracted with ethyl acetate. This organic layer was sequentially washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to give the titled compound (1.87 g).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH:10]=[CH:9][N:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl-].[NH4+].C(O)C.CN(C)C=O>[Fe].O>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:12]=2)=[CH:19][CH:18]=1
Reactant: CCCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCC(=O)Nc1cc(Oc2ccc(N)cc2)ccn1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A mixture of 0.6 g of 2-butyrylamino-4-(4-nitrophenoxy)pyridine, 1.2 g of iron powder, 2.8 g of ammonium chloride, 10 ml of ethanol, 10 ml of dimethylformamide and 5 ml of water was vigorously stirred at 100° C. for 10 minutes. The reaction was filtered with celite, the solvent was distilled off under reduced pressure, and then water was added to the filtrate and extraction was performed with ethyl acetate. The extract was dried over magnesium sulfate and the solvent distilled off under reduced pressure to obtain 0.6 g of the target substance as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][C@H:9]2[C:15]([O:17]C)=[O:16])=[CH:4][CH:3]=1.[OH-].[Li+].Cl.[Cl-].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][C@H:9]2[C:15]([OH:17])=[O:16])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CCC(=O)C[C@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CC[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Temperature: 25 °C

Procedure:
A stirred mixture of methyl trans-2-(4-chlorophenyl)-4-oxocyclohexanecarboxylate (1.05 g, 3.94 mmol) and 1 N lithium hydroxide (5.91 mL, 5.91 mmol) in tetrahydrofuran (5 mL) was heated at reflux for approximately 1 h. After cooling to room temperature, the reaction mixture was poured into 1 N hydrochloric acid/brine (1:1) and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude title compound was used without further purification in the subsequent reaction.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-])=O)=[CH:7][CH:8]=2)[N:3]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C(O)C.[Pd]>[NH2:12][C:6]1[CH:5]=[C:4]2[C:9]([C:10](=[O:11])[N:2]([CH3:1])[N:3]2[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[CH:8][CH:7]=1
Reactant: Cn1c(=O)c2ccc([N+](=O)[O-])cc2n1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: Cn1c(=O)c2ccc(N)cc2n1C(=O)OC(C)(C)C

Procedure:
A solution of 715 mg (2.4 mmol) of tert-butyl 2-methyl-6-nitro-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate in 30 ml of ethanol was hydrogenated in the presence of 52 mg of palladium (10% on activated carbon) at RT and standard pressure. The reaction mixture was then filtered through Celite and the filtrate was concentrated under reduced pressure and dried. Yield: 668 mg (100% of theory)
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]=2[CH:16]=1.[I-:17].[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O.C(O)(=O)C>[I:17][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]=2[CH:16]=1
Reactant: Cn1c(=O)oc2ccc(N)cc21
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(=O)oc2ccc(I)cc21
Reaction time: 0.17 h
Yield: 55.8 %

Procedure:
A solution of sodium nitrite (4.62 g) in water (40 mL) was added dropwise over a period of 15 minutes at 0° C. to a solution of 5-amino-3-methyl-3H-benzooxazol-2-one (10 g) in acetic acid (400 mL). Stirring was continued for 10 minutes at 0° C. A solution of potassium iodide (11.12 g) in water (40 mL) was added dropwise over a period of 15 minutes. Stirring was continued for 1 hour at 0° C. Sodium pyrosulfite (1.0 g) was added to the reaction mixture. Stirring was continued for 10 minutes. The reaction mixture was then evaporated to dryness. The residue was dissolved in CH2Cl2 and the solution was poured into sat. Na2CO3 (pH 9) and 0.2 M sodium pyrosulfite solution and extracted two times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless solid (9.35 g, 55%). MS (m/e)=275.9 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>[Cu]>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([O:20][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[CH:18][CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: COc1ccc(Br)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(Oc2ccc(C(C)(C)C)cc2)cc1
Temperature: 210 °C

Procedure:
The starting material is prepared as follows: 4-Bromoanisole (28.06 g, 0.15 mol), 4-tert-butylphenol (27.04 g, 0.18 mol), potassium carbonate (6.9 g, 0.05 mol) and copper powder (0.2 g, 3 mmol) are combined under nitrogen and heated at 210° C. for 2.5 hours. The mixture is then cooled and treated with 1N NaOH to pH 12. Three extractions with ether are carried out. The combined extracts are dried (MgSO4) and evaporated. The residue is distilled under vacuum to yield 4-(p-tert-butylphenoxy)anisole, b.p. 220° C./20 mmHg. A mixture of the product (18.55 g, 68.5 mmol) and pyridinium hydrochloride (500 g, 4.33 mol) is heated at 230° C. for 2 hours under nitrogen, then cooled to room temperature and partitioned between water and ether. The aqueous layer is extracted with ether, the extract is dried (MgSO4) and evaporated to give 4-(p-tert-butylphenoxy)phenol as an oil. Such is converted to 5-(p-tert-butylphenoxy)salicylaldehyde, which is then converted to 3-(N-hydroxyaminomethyl)-6-(p-tert-butylphenoxy-2H-1-benzopyran as described hereinabove.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1.Br.C(=O)(O)[O-].[Na+]>>[C:16]1([CH2:15][CH2:14][N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(C2CCCN2CCc2ccccc2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1cccc(C2CCCN2CCc2ccccc2)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
2-(3-Methoxyphenyl)-1-(2-phenylethyl)pyrrolidine and 48% hydrobromic acid (15 ml) were warmed to 105° C. for 3.5 hrs and cooled to ambient temperature. The reaction mixture was neutralized with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (2 times). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, ether). The appropriate fractions were collected and concentrated to afford 1.1 g (96%) of 3-[1-(2-phenylethyl)-2-pyrrolidinyl]phenol.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:25][S:26][CH2:27][C@H:28]([O:44][C:45](=[O:57])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:29][O:30][C:31](=[O:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:3](=[O:24])[NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([P:16](=[O:23])([O:20]CC)[O:17]CC)([F:15])[F:14].C[Si](Br)(C)C>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:25][S:26][CH2:27][C@H:28]([O:44][C:45](=[O:57])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:29][O:30][C:31](=[O:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:3](=[O:24])[NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([P:16](=[O:17])([OH:23])[OH:20])([F:15])[F:14]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCC(F)(F)P(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCC(F)(F)P(=O)(O)O)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diethyl(12R,16R)-12-amino-16-(dodecanoyloxy)-1,1-difluoro-11,19-dioxo-4,7,18-trioxa-14-thia-10-azatriacontylphosphonate (1 eq) in DCM (0.1 M) was added trimethylsilyl bromide (10 eq). The reaction mixture was then stirred at room temperature overnight and concentrated. The crude mixture was purified by reverse phase high performance liquid chromatography (HPLC) with C4 column eluting with a gradient of 40-100% MeCN/10 mM NH4OAc (95:5) in 10 mM NH4OAc (pH 9) to give (12R,16R)-12-amino-16-(dodecanoyloxy)-1,1-difluoro-11,19-dioxo-4,7,18-trioxa-14-thia-10-azatriacontylphosphonic acid. 1H NMR (CDCl3): δ 8.47 (br s, 1H), 5.10-5.23 (m, 1H), 4.32 (dd, 1H), 4.18-4.26 (m, 1H), 4.12 (dd, 1H), 3.68-3.86 (m, 2H), 3.44-3.68 (m, 6H), 3.20-3.36 (m, 1H), 2.96-3.16 (m, 2H), 2.76-2.85 (m, 1H), 2.68-2.76 (m, 1H), 2.21-2.38 (m, 4H), 2.12-2.07 (m, 2H), 1.52-1.65 (m, 4H), 1.36-1.15 (m, 32H), 0.87 (t, 6H). LRMS [M+H]=805.5.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:14])[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Reactant: COC(=O)c1ccc(CN)cc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CN2C(=O)C(Cl)=C(c3ccccc3)C2=O)cc1

Procedure:
A solution of 3-chloro-4-phenylfuran-2,5-dione (0.24 mmol, 50 mg) and methyl 4-(aminomethyl)benzoate (0.24 mmol, 40 mg) in glacial acetic acid (1 mL) was heated in a microwave reactor at 120° C. for two min. After cooling, the solvent was evaporated at reduced pressure. The crude product was used without purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[CH:8]=[C:9]1[O:13][CH2:12][NH:11][C:10]1=[O:14])([CH3:4])([CH3:3])[CH3:2].ClS([N:27]=[C:28]=[O:29])(=O)=O>C1(C)C=CC=CC=1>[C:28]([N:11]1[C:10](=[O:14])[C:9](=[CH:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[O:13][CH2:12]1)(=[O:29])[NH2:27]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(C=C2OCNC2=O)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C=C2OCN(C(N)=O)C2=O)cc(C(C)(C)C)c1O
Temperature: 90 °C
Yield: 63.9 %

Procedure:
To a suspension of 5-(3,5-di-tert-butyl-4-hydroxybenzylidene)oxazolidin-4-one (100 mg, 0.33 mmole) suspended in dried toluene (0.5 ml), 32 μl of chlorosulfonyl isocyanate (0.363 mmole) was added under nitrogen atmosphere with stirring and the mixture was dissolved for 2 min. After the solution colored to brown, it was heated at 90° C. for 10 min. and toluene was evaporated under reduced pressure. A mixed solution (0.8 ml) of acetic acid and water (2:1) was added thereto, and the mixture was heated at 90° C. under nitrogen atmosphere for 10 min. The resulting mixture was poured into ice-water, which was subjected to extraction with dichloromethane, then the organic layer was washed with water, dried over sodium sulfate, and evaporated. The obtained residue was separated by using silica gel chromatography (toluene:ethyl acetate=1:1), and recrystallized from ether-n-hexane, whereby 73 mg of the objective compound was obtained in 64% yield. The physical constants are described on Table 1.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[C:5]#[N:6].[OH-:22].[K+]>>[CH3:1][O:2][N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[C:5]([NH2:6])=[O:22]
Reactant: CON=C(C#N)c1ccccc1COc1cccc(Cl)c1
Reactant: [OH-]
Agent: [K+]
Product: CON=C(C(N)=O)c1ccccc1COc1cccc(Cl)c1
Temperature: 80 °C
Yield: 58 %

Procedure:
7.0 g (23 mmol) of 2-methoxyimino-2-[2-(m-chlorophenoxymethyl)-phenyl]acetonitrile were added to a mixture of 50 ml of glycol and 10 ml of a 25% by weight aqueous solution of potassium hydroxide, and the reaction mixture was then heated at 80° C. for 2 hours. The solid was then separated off, washed with methyl tert-butyl ether and dried. Yield: 58%;
Reaction SMILES: [CH3:1][C@@H:2](CCCC1C=CC=CC=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][C@@H:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:6][CH3:7])[O:8][CH3:9]
Reactant: BrCCCCCc1ccccc1
Reactant: COP(=O)(CC(=O)[C@@H](C)CCCc1ccccc1)OC
Product: COP(=O)(CC(=O)[C@@H](C)CCCCCc1ccccc1)OC

Procedure:
(S)-Dimethyl (3-methyl-2-oxo-8-phenyloctyl)phosphonate was prepared in the same manner as the second alternative preparation of (S)-(+)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i)) using the same sequence of reactions except that (5-bromopentyl)benzene was used instead of (3-bromopropyl)benzene. The crude product was purified by silica gel chromatography. Elution with ethyl acetate-heptane (50:50 v/v) afforded the title compound (1.06 g) as a colorless oil; TLC Rf 0.22 (solvent system: 50:50 v/v ethyl acetate:heptanes); MS (ESI+) m/z 327.1 (M+H)+; 1H-NMR (CDCl3) δ 7.27-7.24 (m, 2H), 7.19-7.14 (m, 3H), 3.79-3.76 (m, 6H), 3.13 (s, 1H), 3.08 (s, 1H), 2.76-2.68 (m, 1H), 2.61-2.56 (m, 2H), 1.68-1.56 (m, 4H), 1.35-1.28 (m, 4H), 1.09 (d, J=6.96 Hz, 3H); [α]Tλ=α/cl, [α]21.9D=0.074/(0.01534 g/1.5 mL)(0.5)=+14.10° (c=1.02, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=C(O)Cc1ccccc1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccccc1F
Yield: 68.5 %

Procedure:
o-Fluorophenylacetic acid (35.9 g; 0.233 mmol) was stirred in 40 ml of thionyl chloride for 24 hours at room temperature. Volatile material was removed in vacuo to obtain a yellow, mobile liquid. The liquid was distilled in vacuo to obtain 27.45 g (68.5%) of o-fluorophenylacetyl chloride as a colorless liquid, b.p. 85° C. (4 mm Hg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[NH:13][C@@H:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][S:10]2)=[C:4]([CH3:18])[CH:3]=1.[CH2:19](Br)[CH:20]([CH3:22])[CH3:21]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:13]([CH2:19][CH:20]([CH3:22])[CH3:21])[C@@H:12]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:11][S:10]2)=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(F)ccc1N=C1N[C@@H](CC(C)C)CS1
Reactant: CC(C)CBr
Product: Cc1cc(F)ccc1N=C1SC[C@H](CC(C)C)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-Fluoro-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-fluoro -2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-fluoro-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14](C(=O)C(Cl)(Cl)Cl)[CH2:13]2)(=[O:9])=[O:8].[OH-].[K+].C(O)(=O)C>CCO.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13]2)(=[O:9])=[O:8]
Reactant: O=C(N1Cc2ccc(S(=O)(=O)Nc3nccs3)cc2C1)C(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=S(=O)(Nc1nccs1)c1ccc2c(c1)CNC2

Procedure:
2-(2,2,2-Trichloro-acetyl)-2,3-dihydro-1H-isoindole-5-sulfonic acid thiazol-2-ylamide (0.10 g, 0.23 mmol) and KOH (0.03 g, 0.46 mmol) were stirred in a mixture of EtOH (0.5 mL) and H2O (0.13 mL) for 19 h at room temperature. The solution was acidified with acetic acid and concentrated in vacuo. The white solid was used in the next step without further purification. LC/MS (10-99% CH3CN), M/Z: M+1 obs=282.3; tR=2.62 min.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:7]=[C:8]([CH:42]=[CH:43][CH:44]=2)[C:9]([NH:11][C:12]2[S:13][C:14]3[CH2:41][CH2:40][CH2:39][CH2:38][C:15]=3[C:16]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)=[CH:22][CH:21]=2)=[O:18])=[O:10])[CH2:3][CH2:2]1.Cl[C:46]1[N:51]=[CH:50][C:49]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:48][N:47]=1>>[CH:1]1([N:4]([CH2:5][C:6]2[CH:44]=[CH:43][CH:42]=[C:8]([C:9](=[O:10])[NH:11][C:12]3[S:13][C:14]4[CH2:41][CH2:40][CH2:39][CH2:38][C:15]=4[C:16]=3[C:17](=[O:18])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]4[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=4)=[CH:22][CH:21]=3)[CH:7]=2)[C:46]2[N:47]=[CH:48][C:49]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:50][N:51]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnc(Cl)nc1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CNC5CC5)c4)sc4c3CCCC4)cc2)cc1
Product: CCOC(=O)c1cnc(N(Cc2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)C2CC2)nc1
Yield: 98.5 %

Procedure:
By using 250 mg of methyl 4-{2-[4-({[2-({3-[(cyclopropylamino)methyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate and 153 mg of ethyl 2-chloropyrimidine-5-carboxylate as starting materials, the reaction similar to Preparation Example 30 was performed, thereby obtaining 307 mg of ethyl 2-{cyclopropyl[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl}-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl]amino}pyrimidine-5-carboxylate.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)=[C:9]([F:18])[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:26]([O:28]CC)=[CH2:27])CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=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>[F:18][C:9]1[CH:8]=[C:7]([C:26](=[O:28])[CH3:27])[CH:12]=[CH:11][C:10]=1[C:13]1[N:14]=[CH:15][S:16][CH:17]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(Oc1ccc(-c2cscn2)c(F)c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2cscn2)c(F)c1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a stirred solution of 3-fluoro-4-(1,3-thiazol-4-yl)phenyl trifluoromethanesulfonate (1.45 g, 4.43 mmol) in dioxane (42 ml) was added tributyl(1-ethoxyvinyl)tin (1.92 g, 5.32 mmol), tetrakis(triphenylphosphine)palladium (512 mg, 0.44 mmol), lithium chloride (466 mg, 11.0 mmol), and the mixture was heated at reflux temperature for 16 hours. The reaction mixture was cooled down to room temperature, and diluted with ethyl acetate. The whole was washed with saturated potassium fluoride aqueous solution, and the precipitate was removed by filteration through celite. The resulting solution was extracted with ethyl acetate. The organic layer was concentrated in vacuo. To the residue was added THF (20 ml), 2N HCl aqueous solution (20 ml), and the mixture was heated at reflux temperature for 8 hours. The reaction mixture was cooled down to room temperature, made neutral by addition of NaHCO3, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:5) to give title compound (666 mg, 68% yield).