Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][C@@H:38]([N:42]1[C@H:47]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)[C@@H:46]([C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[CH:56]=2)[CH2:45][C@@:44]([CH2:63][C:64]([OH:66])=[O:65])([CH3:62])[C:43]1=[O:67])[CH:39]1[CH2:41][CH2:40]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[Cl:61][C:57]1[CH:56]=[C:55]([C@@H:46]2[C@@H:47]([C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=3)[N:42]([C@@H:38]([CH:39]3[CH2:40][CH2:41]3)[CH2:37][OH:36])[C:43](=[O:67])[C@:44]([CH2:63][C:64]([OH:66])=[O:65])([CH3:62])[CH2:45]2)[CH:60]=[CH:59][CH:58]=1
Reactant: CC(C)(C)[Si](OC[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@]1(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of tetrabutylammonium fluoride, (1.0 M in THF, 0.453 mL, 0.453 mmol) was added to a solution of 2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 251, Step E, 108 mg, 0.151 mmol) in THF (4 ml) and the reaction was stirred at ambient temperature for 20 hours. Analysis by LC-MS showed incomplete reaction so an extra 0.225 ml of tetrabutylammonium fluoride solution was added and the reaction was stirred for another 26 hours. The mixture was diluted in ethyl acetate then washed with water and sat. aq. NaCl solution. The organic layer was dried over sodium sulfate and concentrated. Purification by RP-HPLC (Sunfire Prep C18 OBD 10 μm column, gradient elution of 10% MeCN in water to 80% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) afforded the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:34]([O:36]C)=[O:35])=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[C:19]([C:29](=[O:32])[NH:30][CH3:31])[C:18]=3[CH:33]=2)=[CH:12][CH:13]=1.[CH3:38]O.[OH-].[Na+].Cl>C(OCC)(=O)C.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:34]([OH:36])=[O:35])=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)=[C:19]([C:29](=[O:32])[NH:30][CH3:31])[C:18]=3[CH:33]=2)=[C:12]([CH3:38])[CH:13]=1
Reactant: CO
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3ccc(-c4ccccc4Cl)c(C(=O)OC)c3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(-c4ccccc4Cl)cc3C)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
To a 25 mL round-bottomed flask was added methyl 2′-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylate (43.8 mg, 0.079 mmol), methanol (1 mL), THF (1 mL) and 8 equivalents of a 1M solution of sodium hydroxide (0.63 mL, 0.63 mmol). The mixture was stirred at room temperature for 48 hours. The crude product was diluted with 20 mL of ethyl acetate, made acidic with 0.5M HCl, extracted, washed with brine, dried over sodium sulfate, filtered and evaporated to dryness giving 47.2 mgs (96% yield) of 2′-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-5-methylbiphenyl-2-carboxylic acid as yellow solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. LCMS m/z 500.2 (M+H), Rt=3.426 min., 90% purity.
Reaction SMILES: [NH2:1][C:2](=[O:41])[CH2:3][C:4]1[CH:40]=[CH:39][CH:38]=[CH:37][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:36]=[CH:35][C:22]([CH2:23][N:24]([CH2:32][CH2:33][OH:34])C(=O)OC(C)(C)C)=[CH:21][CH:20]=2)[N:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:34][CH2:33][CH2:32][NH:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:10]2[N:9]=[C:8]([CH2:7][CH2:6][C:5]3[CH:37]=[CH:38][CH:39]=[CH:40][C:4]=3[CH2:3][C:2]([NH2:1])=[O:41])[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=2)=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CNCCO)cc2)ncc1C(F)(F)F
Yield: 23.3 %

Procedure:
A solution of tert-butyl 4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl(2-hydroxyethyl)carbamate (A75) (0.301 g, 0.525 mmol) and trifluoroacetic acid (1.0 mL) in DCM (10 mL) was stirred at room temperature for 22 hours. The volatiles were removed in vacuo and 2 M aqueous sodium hydroxide solution (20 mL) added to the residue. The resulting suspension was sonicated for several minutes then filtered, washing the filter cake with water. Semi preparative HPLC of the filter cake gave the title compound 19 as a white solid (58 mg, 23%); 1H NMR (300 MHz, d4-MeOH) δ 8.61 (s, 1H), 8.53 (s, 1H), 7.83 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.6 Hz, 2H), 7.29-7.19 (m, 4H), 4.19 (s, 2H), 3.82 (t, J=5.2 Hz, 2H), 3.68 (s, 2H), 3.22-3.10 (m, 6H). LCMS-B: rt 5.313 min; m/z 474 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH2:20][O:21][CH3:22])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:29])[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH2:20][O:21][CH3:22])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: COC[C@H]1CCCN1c1c(C(C)=O)cc(Cl)c2cccnc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COC[C@H]1CCCN1c1c(C(C)N)cc(Cl)c2cccnc12
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]quinolin-7-yl}ethanone (14 mg, 0.044 mmol) and ammonium acetate (33.8 mg, 0.439 mmol) in methanol (0.25 mL,) and acetonitrile (0.25 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling, sodium cyanoborohydride (5.52 mg, 0.0878 mmol) was added to the resultant mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C17H23ClN3O(M+H)+: m/z=320.2; found: 302.1.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][S:13][C:14]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2[Cl:34])=[CH:19][C:15]=1[C:16](Cl)=[O:17].O>CN(C)C=O>[CH3:12][S:13][C:14]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][C:25]=2[Cl:34])=[CH:19][C:15]=1[C:16]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:17]
Reactant: CSc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1C(=O)Cl
Reactant: O=C1NC(=O)c2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1C(=O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of phthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-methylthio-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-methylthio-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl]phthalimide.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16](C=O)[CH2:15][CH2:14]1.Cl.C(Cl)(Cl)Cl>CO>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: O=CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: c1ccc2[nH]c(SCCN3CCNCC3)nc2c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 137.2 %

Procedure:
1-[2-(benzimidazol-2-ylthio)ethyl]-4-formylpiperazine (1.92 kg) was suspended in methanol (4.5 kg), and 12N hydrochloric acid (2.9 kg) was added, and the mixture was stirred at 40° C. for 3 hours. To the reaction solution was added chloroform (17 kg), and the precipitated crystals were collected by filtration. The crystals were washed with chloroform to give 2.38 kg of 1-[2-(benzimidazol-2-ylthio)ethyl]piperazine.3 hydrochloride (yield 97%) as colorless crystalline powder.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.CC(C)([O-])C.[K+].I[C:17]1[N:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1.O>O1CCCC1>[Br:23][C:20]1[CH:19]=[N:18][C:17]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[N:22][CH:21]=1
Reactant: Brc1cnc(I)nc1
Reactant: OC1CN2CCC1CC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1cnc(OC2CN3CCC2CC3)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) in tetrahydrofuran (10 ml) was treated with potassium tert-butoxide (Aldrich, 224 mg, 2 mmol) at ambient temperature for 1 hour. The mixture was treated with 2-iodo-5-bromo-pyrimidine (TCl, 568 mg, 2 mmol), stirred at room temperature for 1 hour, treated with water (5 mL), and extracted with chloroform:isopropyl alcohol (10:1) (3×20 mL). The extracts were combined and concentrated. The title compound was purified by chromatography (SiO2, CH2Cl2: MeOH: NH3H2O, 90:10:2, Rf. 0.20) as oil (210 mg, yield, 71%). 1H NMR (MeOH-d4, 300 MHz) δ 1.56–1.68 (m, 1H), 1.70–1.90 (m, 2H), 2.05–2.30 (m, 2H), 2.79–3.06 (m, 5H), 3.40–3.48 (m, 1H), 5.11 (m, 1H), 8.64 (s, 2h) ppm. MS (DCl/NH3) m/z 284 (M+H)+, 286 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCOc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CCOc1ccccc1
Temperature: 25 °C
Yield: 1589.1 %

Procedure:
To demonstrate the methyl ester, as well as the ethyl ester, may be used to make members of composition 7, we illustrate the preparation of the corresponding methyl ester of composition 7 in which the Et group is replaced by Me and X is O. A solution of 3-phenoxypropionic acid (10.0 g, 0.060 mol) and p-toluenesulfonic acid (0.6 g, 0.0033 mol) in methanol (250 mL) was heated at reflux through 3 Å molecular sieve for 36 hours under N2 in a flask equipped with a Soxhlet extractor and a condenser. The solution was allowed to cool to room temperature and then was concentrated to a volume of 50 mL, diluted with water (50 mL), and extracted with ether (2×75 mL). The combined organic layers were washed with 5% aqeuous NaHCO3 (75 mL), H2O (75 mL), and brine (75 mL). After drying (Na2SO4) the solution, the solvent was removed (vacuum). Vacuum distillation gave 9.45 grams (87.1%) of the title ester as a colorless liquid: by 85°-87° C./0.1 mm (literature reports 85° C./0.4 mm; see C. E. Rehberg and M. D. Dixon [J. Am. Chem. Soc. 72, 2205 [1972]): IR (neat) 1740-1750 cm-1 (C=O); 1H NMR (DCCl3) δ 2.78 [s, 2H, CH2CO2CH3 ], 3.70 [s, 3H, OCH3 ], 4.23 [2H, OCH], 6.84-7.02 and 7.18-7.35 [m, 5H, ArH]; 13C NMR (DCCl3) ppm 34.3 [H2CCO2 ], 51.7 [CH3 ], 63.2 [Ar--OCH2 ]; Ar--C [114.5, 120.8, 129.2, 158.3, 171.1].
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+]>O1CCOCC1.O.O>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:18][CH:19]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(CC(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(CC(=O)O)cc1

Procedure:
3.3 g (9.5 mmol) of methyl 2-[4-(2-butyl-4-chloro-5-formyl-imidazol-1-yl-methyl)-phenyl]-acetate are dissolved in 100 ml of dioxane/water (1:1) at 0° C. and a solution of 0.44 g (10.4 mmol) of lithium hydroxide monohydrate in 5 ml of water is added dropwise with stirring. After stirring at room temperature for 3 h, the mixture is concentrated to a half, diluted with water, washed with diethyl ether, and the aqueous phase is acidified with 1N hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulphate and concentrated.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[O:10][N:9]=[CH:8][C:7]=1[C:11](Cl)=[O:12].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:11]([C:7]2[CH:8]=[N:9][O:10][C:6]=2[CH3:5])=[O:12])=[CH:17][CH:16]=1
Reactant: Clc1ccccc1
Reactant: Cc1oncc1C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1oncc1C(=O)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of aluminium chloride (16 g) and 5-methylisoxazole-4-carbonyl chloride (5.0 g) in dry chlorobenzene (50 ml) was stirred in an atmosphere of nitrogen for 16 hours. The mixture was heated to 80° C. for 1.5 hours. The cooled mixture was quenched with excess ice and extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with water (3×500 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was purified by chromatography on silica eluted with a mixture of ethyl acetate and cyclohexane (1:20) to give 4-(4-chlorobenzoyl)-5-methylisoxazole (compound 9, 5.2 g) as a yellow solid mp 65°-66° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:19](OCC)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>CCOCC>[CH2:17]([O:16][C:3]([CH:4]([C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:15])[CH3:18]
Reactant: CCOC(=O)c1cccnc1
Reactant: CCOC(=O)CCCCCCC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)CCCCCC(C(=O)OCC)C(=O)c1cccnc1
Temperature: 0 °C

Procedure:
To a suspension of 16 g of 50% sodium hydride in 450 ml of ether is added dropwise 92.2 g of diethyl suberate and 27.3 ml (30.2 g) of ethyl nicotinate at room temperature, under nitrogen. The reaction mixture is heated at reflux temperature overnight, and, after cooling, 400 ml of ice water is added. The ether layer is separated (discarded) and the aqueous adjusted to pH 5 with 1N hydrochloric acid and extracted with ether (3×250 ml). The ether layer is dried and concentrated to give ethyl 7-ethoxycarbonyl-7-nicotinoylheptanoate as an oil. A solution of this ester in 300 ml of 1M sulfuric acid is heated for 12 hours at reflux temperature. The reaction solution is cooled by an ice bath and adjusted to pH=4.5-5.0 with saturated sodium bicarbonate solution. A white solid is collected and, after washing with water and air-drying, is recrystallized from ethanol to give 7-nicotinoylheptanoic acid, m.p. 113°-115°.
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([NH:23][C:24](=[O:35])[C@@H:25]([NH:27]C(=O)OC(C)(C)C)[CH3:26])[C:6]([NH:8][C@@H:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([C@@:12]2([CH3:15])[CH2:14][O:13]2)=[O:11])=[O:7])[CH2:3][CH2:2]1.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[OH:42][C:36]([C:38]([F:41])([F:40])[F:39])=[O:37].[NH2:27][C@@H:25]([CH3:26])[C:24]([NH:23][C@@H:5]([CH2:4][CH:1]1[CH2:3][CH2:2]1)[C:6]([NH:8][C@@H:9]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:10]([C@@:12]1([CH3:15])[CH2:14][O:13]1)=[O:11])=[O:7])=[O:35]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC1CC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)N[C@@H](CC1CC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Reaction time: 0.5 h

Procedure:
To tert-butyl ((S)-1-(((S)-3-cyclopropyl-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (380 mg, 0.779 mmol) was added DCM (2.5 mL) and TFA (2.5 mL). The mixture was allowed to stand at ambient temperature for 30 min before it was concentrated to provide (S)-2-((S)-2-aminopropanamido)-3-cyclopropyl-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide TFA salt (377 mg, quant.) as a yellow oil that was carried forward without further purification. MS (EI) for C23H29F3N3O5, found 388.3 [M-TFA]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]([NH:19]C(=O)C2C=CC=CC=2)=[S:18])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]([NH2:19])=[S:18])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(=S)Nc1cc(Br)cc(OCc2ccccc2)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=S)Nc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 69.5 °C
Yield: 78.1 %

Procedure:
To a solution of N-[(3-benzyloxy-5-bromo-phenyl)carbamothioyl]benzamide (648 g, 1.47 mol) in THF (12 L) was added NaOH solution (300 g, 7.5 mol in 3 L H2O) at rt. The reaction mixture was heated up to 69 to 70° C. overnight. After completion of reaction (by TLC), the THF layer was decanted off and the aqueous layer extracted with EtOAc (3×2 L). The combined organic layer (THF+EtOAc) was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was treated with mixture of Et2O and hexane (5:95, 3.0 L), filtered, washed with hexane and dried under high vacuum to obtain the desired product (387 g, 78%).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:21](OC)=[O:22])[C:17](OC)=[O:18])=[CH:12][CH:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C1COCC1>CO>[OH:18][CH2:17][CH:16]([C:13]1[CH:14]=[CH:15][C:10]([C:8]([O:7][C:3]([CH3:4])([CH3:6])[CH3:5])=[O:9])=[CH:11][CH:12]=1)[CH2:21][OH:22]
Reactant: COC(=O)C(C(=O)OC)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(C(CO)CO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of NaBH4 (1.23 g, 32.4 mmol) in MeOH (20 ml) was added a solution of dimethyl [4-(tert-butoxycarbonyl)phenyl]malonate (2.00 g, 6.49 mmol) in 3:2 MeOH:THF (18 mL). The reaction was stirred at room temperature for 2 h. It was then quenched with saturated NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Flash chromatography (0-10% MeOH/CH2Cl2) afforded tert-butyl 4-[2-hydroxy-1-(hydroxymethyl)ethyl]benzoate as a colorless solid. 1H NMR (CDCl3, 600 MHz) δ 7.93 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.2 Hz, 2H), 3.99 (ddd, J=10.8, 7.4, 5.1 Hz, 2H), 3.93 (dt, J=10.7, 5.2 Hz, 2H), 3.13 (tt, J=7.6, 5.5 Hz, 1H), 2.14 (t, J=5.3 Hz, 2H), 1.56 (s, 9H). MS: cal'd 275 (MH+), exp 275 (M)H+).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:28](=[O:44])[N:29]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH3:30])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)C)(C)(C)C.C(=O)([O-])O.[Na+].C(=O)([O-])O>ClCCl>[CH3:43][S:40]([NH:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][CH2:31][N:29]([CH3:30])[C:28](=[O:44])[C@H:16]([NH:14][CH3:13])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)(=[O:42])=[O:41]
Reactant: CN(CCc1ccccc1NS(C)(=O)=O)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 78.4 %

Procedure:
At 0° C., trifluoroacetic acid (1.5 ml) was added to a solution of N-((1R)-1-(N-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl-ester (245 mg, 0.45 mmol) in dichloromethane (1.5 ml). The reaction mixture was stirred for 1.75 h at 0° C. Dichloromethane (5 ml) and a saturated aqueous solution of sodium hydrogen carbonate (6 ml) were added successively. Solid soidum hydrogen carbonate was added until pH 7 was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (3×50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (30 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 155 mg of (2R)-N-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[Cl:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][N:29]=[C:30]([CH2:31][CH3:32])[C:23]=12.C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[N:28]([CH:1]([O:3][CH2:4][CH3:5])[CH3:2])[N:29]=[C:30]([CH2:31][CH3:32])[C:23]=12
Reactant: CCc1n[nH]c2nccc(Cl)c12
Reactant: C=COCC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(C)n1nc(CC)c2c(Cl)ccnc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Ethyl vinyl ether (3.7 mL) and (+)-10-camphorsulfonic acid (0.162 g) were sequentially added to a solution of compound (3c) (2.36 g) in THF (13.0 mL), followed by stirring at 50° C. for 30 min. After cooling, the reaction solution was distributed between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain compound (3d) (3.01 g, 91%) as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([OH:10])[CH:3]=1.[H-].[Na+].[CH2:13]([O:15][C:16](=[O:27])[C:17](P(OCC)(OCC)=O)=[CH2:18])[CH3:14]>O1CCCC1>[CH2:13]([O:15][C:16]([C:17]1[CH2:18][O:10][C:4]2[C:5]([CH:6]=1)=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)=[O:27])[CH3:14]
Reactant: O=Cc1ccc(Cl)cc1O
Reactant: C=C(C(=O)OCC)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2ccc(Cl)cc2OC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
4-Chloro-2-hydroxybenzaldehyde (Acta. Chem. Scand., vol. 53, p. 258 (1999)) (510 mg) was dissolved in tetrahydrofuran (40 mL), and sodium hydride (60% in oil, 157 mg) was added thereto, followed by stirring at room temperature for 2 hours. To the reaction mixture was added a solution of 2-diethylphosphonoacrylic acid ethyl ester (J. Org. Chem., vol. 43, p. 1256 (1978)) (769 mg) in tetrahydrofuran (10 mL), and the thus-obtained mixture was stirred at room temperature for 2 hours, followed by heating under reflux overnight. After the reaction mixture was cooled to room temperature, the mixture was partitioned between water and diethyl ether. The organic layer was dried over sodium sulfate anhydrate, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), to thereby give the title compound (247 mg).