Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]1(=O)[O:12][C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12>>[OH:4][CH2:3][C:2]([N:1]1[C:10](=[O:11])[C:9]2[C:8](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]1=[O:12])([CH3:6])[CH3:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(N)CO
Product: CC(C)(CO)N1C(=O)c2ccccc2C1=O
Yield: 32.9 %

Procedure:
2-Amino-2-methyl-1-propanol (4.46 g, 50 mmol) and phthalic anhydride (7.41 g, 50 mmol) were heated at 170° C. for 30 minutes. Icewater was added to the cooled reaction mixture and then the mixture was extracted three times with DCM. Organic phase was dried over Na2SO4, filtered and evaporated to dryness. Crude product was purified by CombiFlash (column: silica, eluent: 0-10% MeOH in DCM) to obtain 3.611 g (33%) of the title compound. LC-MS: M+1=220.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([S:35][CH3:36])[N:30]=2)=O)[N:15]([C:17](=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([S:35][CH3:36])[N:30]=3)=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:17](=[O:26])[N:15]2[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CSc1nccc(C(=O)N(C2CCN(C(=O)OC(C)(C)C)CC2)N(C)C(=O)Cc2ccc(F)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n(C)n2C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of 4-{N′-[2-(4-fluoro-phenyl)-acetyl]-N′-methyl-N-(2-methylsulfanyl-pyrimidine-4-carbonyl)-hydrazino}-piperidine-1-carboxylic acid tert-butyl ester, 10, (1.058 g, 2.05 mmol) in DMF (2 mL) at 0° C. is slowly added NaH (123 mg of a 60% dispersion in mineral oil, 3.07 mmol). The reaction mixture is stirred for 1 hour at 0° C. and then quenched with 0.1 N HCl. The aqueous layer is extracted three times with CH2Cl2 and the combined organic layers are dried (MgSO4), filtered and concentrated in vacuo. Purification over silica (20% MeOH/CHCl3) affords 0.743 g (73% yield) of the diesired product. ESI/MS: 500.2 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:15][CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].I[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][C:23]=1[CH2:33][CH2:34][CH3:35].[I-]>>[CH3:31][C:29]([CH3:30])([CH3:32])[CH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][O:14][C:11]2[CH:12]=[CH:13][C:7]3[O:6][C:5]([CH2:15][CH3:16])([C:3]([OH:2])=[O:4])[CH2:9][C:8]=3[CH:10]=2)=[C:23]([CH2:33][CH2:34][CH3:35])[CH:24]=1
Reactant: CCCc1cc(CC(C)(C)C)ccc1OCCCI
Reactant: CCC1(C(=O)OC)Cc2cc(O)ccc2O1
Agent: [I-]
Product: CCCc1cc(CC(C)(C)C)ccc1OCCCOc1ccc2c(c1)CC(CC)(C(=O)O)O2

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4, employing the phenol prepared in Step 1 and the intermediate prepared in Example 2, Step 2 as the iodide.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.[CH3:9]O>>[NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1
Reactant: CO
Reactant: O=C(O)c1c[nH]cn1
Product: COC(=O)c1c[nH]cn1
Temperature: 25 °C

Procedure:
112.09 g (1 mol) (1H-imidazol-4-yl)carboxylic acid are added to 1.3 l methanol. Dry HCl-gas is bubbled through the mixture which is heated under reflux for 4 hours. Cooling to room temperature and evaporation to 300 ml afford 98 g of the title compound as white crystals. Repeated evaporation leads to 46.5 g additional material (total: 144.5 g, 88.9%). An analytical sample is recrystallized from methanol, melting point: 173°-174° C. (ref.1) mp: 156° C.).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[CH3:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH2:22][CH2:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28][CH2:27]1)=O)=[CH:19][C:18]([F:38])=[CH:17][CH:16]=2.O>O1CCCC1>[CH3:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH2:22][CH2:23][CH2:24][N:26]1[CH2:31][CH2:30][N:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]1)=[CH:19][C:18]([F:38])=[CH:17][CH:16]=2
Reactant: Cc1[nH]c2ccc(F)cc2c1CCC(=O)N1CCN(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Cc1[nH]c2ccc(F)cc2c1CCCN1CCN(c2ccccc2)CC1
Reaction time: 4 h

Procedure:
To a stirred mixture of 21 g of lithium aluminum hydride and 100 ml of dry ether was added dropwise a solution of 67.5 g of 1-[β-(2-methyl-5-fluoro-3-indolyl)propionyl]-4-phenylpiperazine in 900 ml of tetrahydrofuran over a period of 90 minutes under gentle refluxing. Stirring and refluxing were continued for additional 4 hours and to the reaction mixture was added dropwise a mixture of water and tetrahydrofuran under cooling with ice. The resulting precipitate was filtered off and the filtrate was evaporated to dryness. Recrystallization of the residue from benzene gave 2-methyl-3-[γ-(4-phenylpiperazino)propyl]-5-fluoroindole having a melting point of 146.0°-147.0°C.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].BrC1C=CC(C(C)(C)C(OCC)=O)=CC=1>>[CH3:8][C:2]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)c1ccsc1
Agent: CCOC(=O)C(C)(C)c1ccc(Br)cc1
Product: CC(C)(C(=O)O)c1ccsc1

Procedure:
The title compound was prepared according to the method of Example 22B, substituting the product of Example 24A for the product of Example 22A.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])[CH2:4][CH2:3]1.[H][H]>[Pd].CCOC(C)=O.CO>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: COC(=O)/C=C/c1ccccc1NC1CCN(C)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccccc1NC1CCN(C)CC1

Procedure:
A suspension of (E)-methyl 3-(2-(1-methylpiperidin-4-ylamino)phenyl)acrylate (330 mg, 1.20 mmol) and palladium on carbon (10% wt, 128 mg, 0.12 mmol) in 20 mL EtOAc was stirred under a balloon of hydrogen overnight. The suspension was diluted with MeOH (50 mL) and filtered through a pad of celite. The celite pad was rinsed with 10 mL of MeOH. The filtrate was concentrated and the residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2. A light yellow oil was obtained (300 mg, 90.4%). 1H-NMR (CDCl3) δ 7.14-7.08 (m, 1H), 7.04-7.01 (m, 1H), 6.67-6.63 (m, 2H), 3.76-3.74 (m, 1H), 3.69 (s, 3H), 3.35 (brs, 1H), 2.82-2.77 (m, 4H), 2.65-2.60 (m, 2H), 2.31 (s, 3H), 2.19-2.06 (m, 4H), 1.61-1.49 (m, 2H). MS (ESI): 277.2 (M+1, 100%).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1)(=[O:3])[NH2:2].Cl.[Cl:11][CH2:12][C:13](=[NH:16])OC>CO>[ClH:11].[C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:13](=[NH:16])[CH2:12][Cl:11])[CH2:5]1)(=[O:3])[NH2:2]
Reactant: COC(=N)CCl
Reactant: NC(=O)C1CCCNC1
Agent: Cl
Solvent: CO
Product: N=C(CCl)N1CCCC(C(N)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 194.9 %

Procedure:
1.28 g of (3RS)-3-carbamoylpiperidine were added to a solution of 1.44 g of methyl 2-chloroacetimidate hydrochloride in 5 ml of anhydrous methanol, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then worked up in the same manner as in Example 3(1), giving 2.34 g of 2-[(3RS)-3-carbamoylpiperidin-1-yl]-2-iminoethylchloride hydrochloride.
Reaction SMILES: [C:1](#[N:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:4]#[N:5].C[O-].[Na+].[NH3:14]>CO>[NH:5]=[C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[NH:14])[NH:10]1
Reactant: N#Cc1ccccc1C#N
Reactant: N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N=C1NC(=N)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To 180 ml of methanol were fed 20 g of a phthalonitrile represented by the formula (XV) and 14 g of sodium methoxide. The mixture was stirred at room temperature for 1 hour while blowing ammonia gas thereinto and, then, refluxed with heating for 3 hours with stirring while blowing ammonia gas thereinto. After being cooled to room temperature, the resulting mixture was concentrated as much as possible. The concentrate was dissolved in 700 ml of chloroform and was washed well with water and with hot water. Water in the organic layer was removed with magnesium sulfate and toluene was removed by distillation. The residue was recrystallized from hexane to obtain 19.7 g (yield: 91.7%) of a compound having the following formula (XVI). ##STR38##
Reaction SMILES: [I-].[F:2][C:3]1[CH:4]=[C:5]([C@@H:11]2[CH2:16][O:15][CH2:14][C@@H:13]3[CH2:17][CH2:18][CH2:19][C:20](=[O:21])[N:12]23)[CH:6]=[C:7]([F:10])[C:8]=1[F:9].CN(C)CCN(C)C.II.S([O-])([O-])(=O)=S.[Na+].[Na+].[P:39]([O:46]CC)([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42]>C(OCC)(=O)C.C(Cl)Cl>[CH2:41]([O:40][P:39]([CH:19]1[C:20](=[O:21])[N:12]2[C@H:13]([CH2:14][O:15][CH2:16][C@H:11]2[C:5]2[CH:6]=[C:7]([F:10])[C:8]([F:9])=[C:3]([F:2])[CH:4]=2)[CH2:17][CH2:18]1)(=[O:46])[O:43][CH2:44][CH3:45])[CH3:42]
Reactant: O=C1CCC[C@H]2COC[C@@H](c3cc(F)c(F)c(F)c3)N12
Reactant: CCOP(OCC)OCC
Agent: CN(C)CCN(C)C
Agent: II
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C1CC[C@H]2COC[C@@H](c3cc(F)c(F)c(F)c3)N2C1=O
Temperature: 25 °C

Procedure:
In nitrogen atmosphere, trimethylsilyle iodide (0.188 mL) was added to a methylene chloride solution (6 mL) of (4R,9aS)-4-(3,4,5-trifluorophenyl)hexahydropyrido[2,1-c][1,4]oxazin-6-one (252 mg) and N,N,N′,N′-tetramethylethylenediamine (0.466 mL) at 0° C. The resulting reaction solution was stirred under ice-cooling for 30 min, and iodine (336 mg) was added thereto under ice-cooling. The resulting reaction solution was stirred under ice-cooling for 1 hr, and ethyl acetate and a saturated sodium thiosulfate aqueous solution were added thereto. The organic layer was separated, washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude iodinated substance. To the given crude iodinated substance, triethyl phosphite (3 mL) was added. The resulting mixture was stirred at 120° C. for 2 hr, allowed to cool to room temperature, and then concentrated under reduced pressure to give 372 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[C:13](=[O:16])([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:16][CH3:13])=[CH:7][CH:6]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccccc2OC)cc1
Temperature: 100 °C
Yield: 179.7 %

Procedure:
A mixture of 4-bromo benzoic acid ethyl ester (2.7 mL, 16.5 mmol), 2-methoxy boronic acid (2.5 g, 16.5 mmol) and sodium carbonate (7.7 g, 72.6 mmol) in toluene: ethanol:water (75 mL:37 mL:37 mL), was flushed with nitrogen for 1 hour. After addition of the tetrakis (triphenylphosphine)palladium (0) catalyst (0.96 g, 0.83 mmol), the reaction mixture was heated at 100° C. overnight. After cooling, the mixture was filtered through Celite which was then rinsed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification of the residue by flash chromatography with a solvent gradient from 25% to 50% dichloromethane in hexane provided the title compound (3.8 g, 89.9%) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.[F-].[Cs+].[CH3:23][N:24]1[C:28]2[CH:29]=[C:30]([Sn](CCCC)(CCCC)CCCC)[S:31][C:27]=2[CH:26]=[N:25]1.[SnH4]>O1CCOCC1>[CH3:20][N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])=[N:7][C:2]([C:30]3[S:31][C:27]4[CH:26]=[N:25][N:24]([CH3:23])[C:28]=4[CH:29]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(cnn2C)s1
Agent: [Cs+]
Agent: [F-]
Agent: [SnH4]
Solvent: C1COCCO1
Product: C[C@@H](Oc1nc(-c2cc3c(cnn3C)s2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Temperature: 67.5 °C
Reaction time: 2 h

Procedure:
Intermediate 2.06 (29 mg, 0.098 mmol), Pd-PEPPSI-IPent precatalyst (4 mg, 0.005 mmol), cesium fluoride (32 mg, 0.21 mmol) and powdered 4 Å molecular sieves (25 mg) were taken up in dioxane (1 mL) under Ar. 1-methyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole (46 μL, 0.13 mmol) was added and the resulting mixture was heated to 65-70° C. After 2 h, the reaction temperature was increased to 80° C. After 18 additional hours, additional Pd-PEPPSI-IPent precatalyst (3 mg, 0.004 mmol), CsF (35 mg, 0.23 mmol) and stannane (23 μL, 0.065 mmol) were added and the reaction was heated to 80° C. After an additional 3 h, additional Pd-PEPPSI-IPent precatalyst (5 mg, 0.006 mmol) was added and the reaction was stirred at 80° C. overnight. After 16 additional hours, the reaction mixture was partitioned between EtOAc and water. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography (MeOH in DCM) to provide (R)-4-((R)-1-(3-methyl-6-(1-methyl-1H-thieno[3,2-c]pyrazol-5-yl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.23. LCMS-ESI+ (m/z): [M+H]+ calcd for C19H21N6O2S: 397.1; found: 397.2. 1H NMR (400 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.70 (s, 1H), 7.63 (d, J=0.7 Hz, 1H), 7.35 (d, J=0.7 Hz, 1H), 5.74-5.65 (m, 1H), 5.53 (s, 1H), 4.06 (s, 3H), 4.02 (d, J=0.4 Hz, 3H), 3.66-3.58 (m, 1H), 3.45-3.39 (m, 1H), 3.02-2.88 (m, 1H), 2.63-2.48 (m, 2H), 1.52 (d, J=6.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 4 h
Yield: 90.1 %

Procedure:
To a solution of the 4-fluoro-3-nitrobenzoic acid (0.12 mol, 22.2 g) in 100 mL of anhydrous DCM was added 10 drops of anhydrous DMF. To this solution was added dropwise over 60 min, oxalyl chloride (0.144 mol, 12.6 mL). During the addition, the solid slowly dissolved to give rise to a yellow solution. The mixture was stirred for an additional 4 h and the solvent was stripped down to give a yellow oil. This oil was distilled under vacuum (110° C., 1.5 mm Hg) to give 4-fluoro-3-nitrobenzoyl chloride as a light yellow liquid (22.0 g, 90% yield).
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][C:12]([CH3:18])([CH3:17])[C:13](NN)=[O:14]>>[C:12]([C:13]([CH2:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4])=[O:14])([CH3:18])([CH3:17])[CH3:11]
Reactant: CC(C)(C)C(=O)NN
Reactant: O=C(CO)c1ccccc1
Product: CC(C)(C)C(=O)CC(=O)c1ccccc1

Procedure:
The desired product is prepared as described in Example 1 using 2-hydroxyacetophenone (19.0 g, 140 mmol) and trimethylacetic hydrazide (10 g, 96 mmol). Yield: 5.0 g, 84%. m.p. 43°-45° C. 1H NMR (CDCl3), δ=1.25 (s, 9H, 3×CH3); 2.58 (s, 3H, CH3); 7.21 (d, 1H, ArH); 7.45-7.49 (m, 1H, ArH); 7.55-7.59 (m, 1H, ArH); 7.89 (d, 1H, ArH).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][CH2:15]O)=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[Cl:3][CH2:15][CH2:14][CH2:13][NH:12][C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCNc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(NCCCCl)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Thionyl chloride (5.3 mL) was added to a solution of 3-(4-fluorophenylamino)propan-1-ol (2.37 g) in toluene (30 mL) at room temperature, and the reaction solution was stirred at 60° C. for five hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ice and a saturated sodium bicarbonate solution were added to the residue, followed by extraction with ethyl acetate (100 mL). Heptane (100 mL) was added to the resulting extract, and the solution was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=1:1) to obtain (3-chloropropyl)-(4-fluorophenyl)amine. Triethylamine (5.4 mL) and phenyl chlorocarbonate (1.9 mL) were added to a solution of (3-chloropropyl)-(4-fluorophenyl)amine (2.40 g) in THF (40 mL) at 0° C., and the reaction solution was stirred at room temperature for 12 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain phenyl (3-chloropropyl)-(4-fluorophenyl)carbamate (3.93 g). Hydrazine monohydrate (0.40 mL) was added to a solution of phenyl (3-chloropropyl)-(4-fluorophenyl)carbamate (500 mg) in ethanol (10 mL) at room temperature. The reaction solution was stirred at room temperature for one hour, stirred at 60° C. for one hour and heated under reflux for seven hours. Hydrazine monohydrate (0.40 mL) was added to the reaction solution, and the reaction solution was heated under reflux for 13 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 265 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH2:16]C)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([O:18][CH3:19])[CH:3]=1.[CH2:20](OC1C(OC)=CC=CC=1C(CC(C)C)CC(O)=O)C1C=CC=CC=1>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]([CH3:16])[CH3:20])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([O:18][CH3:19])[CH:3]=1
Reactant: CCCCC(CC(=O)OC)c1ccc(O)cc1OC
Reactant: COc1cccc(C(CC(=O)O)CC(C)C)c1OCc1ccccc1
Product: COC(=O)CC(CC(C)C)c1ccc(O)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 58A, but using 3-(2-benzyloxy-3-methoxyphenyl)-5-methylhexanoic acid (prepared as described in Preparation 30H), the title compound was obtained as an oily substance.
Reaction SMILES: B(F)(F)F.CCOCC.C(O[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])C.[Cl:20][CH2:21][C:22](=[O:24])[CH3:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:20][CH:21]([CH:13]([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])[C:22](=[O:24])[CH3:23]
Reactant: CC(=O)CCl
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(OCC)C(Cl)C(C)=O
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 57.1 %

Procedure:
A solution of BF3.Et2O (9.35 mL; 108 mmol; 2 eq.) in DCM (100 mL) was added dropwise at −30° C. over 50 minutes to diethoxymethoxy-ethane (18 mL; 108 mmol; 2 eq.). The reaction mixture was stirred at this temperature for a further 40 minutes then allowed to return to room temperature and was stirred at room temperature for 1 hour. After cooling down to −78° C., 1-chloro-propan-2-one (4.3 mL; 54 mmol; 1 eq.) was added dropwise followed by DIEA (28 mL; 162 mmol; 3 eq.) at such a rate to keep the temperature below −70° C. The resulting mixture was stirred at −70° C. for one hour then poured onto sat. aq. NaHCO3. The two layers were separated and the aqueous phase extracted with DCM. The combined organics were washed with cold diluted H2SO4 then water, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (6 g, 48%) as a brown oil which was used without further purification. 1H NMR (DMSO-d6) δ 4.81 (d, J=6.0 Hz, 1H), 4.64 (d, J=6.0 Hz, 2H), 3.70-3.44 (m, 4H), 2.25 (s, 3H), 1.30-1.17 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][CH:32]=[C:33]([C:35](O)([CH3:37])[CH3:36])[N:34]=3)[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][CH:32]=[C:33]([C:35]([CH3:37])=[CH2:36])[N:34]=3)[C@H:14]2[CH3:39])[CH:4]=[C:3]([C:2]([F:41])([F:40])[F:1])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1nc(C(C)(C)O)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)c1csc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Temperature: 80 °C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxy-1-methylethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (example 136) (9.5 mg, 0.015 mmol) in toluene (4 mL) was added p-toluenesulfonic acid monohydrate (20 mg, 0.105 mmol). The reaction was heated to 80° C. for 30 minutes and then cooled to room temperature, diluted with EtOAc (35 mL), and washed with saturated NaHCO3 and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(4-isopropenyl-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.55 (40% EtOAc/hexanes). LCMS=595.1 (M+1)+. 1H NMR (CD2Cl2, 500 MHz) δ 7.91 (s, 1H), 7.78-7.83 (m, 4H), 7.68 (d, J=8.5 Hz, 1H), 7.33 (s, 1H), 5.95 (d, J=0.9 Hz, 1H), 5.66 (d, J=8.0 Hz, 1H), 5.24 (m, 1H), 5.07 (d, J=16.4 Hz, 1H), 5.00 (d, J=16.3 Hz, 1H), 4.03 (m, 1H), 2.17 (s, 3H), 0.63 (d, J=6.4 Hz, 3H).