Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[CH2:4][O:5][CH3:6].[Cl-].[NH4+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1>CN(C)C=O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:4][O:5][CH3:6])[CH:12]=1
Reactant: COc1cccc(O)c1
Reactant: COCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCOc1cccc(OC)c1
Reaction time: 0.33 h
Yield: 96.3 %

Procedure:
In N,N-dimethylformamide (50 mL) was dissolved 3.68 g (29.7 mmol) of commercially available 3-methoxyphenol, 1.81 g (45.4 mmol) of 60% sodium hydride was added to the solution in an ice bath, and the resulting mixture was stirred in an ice bath for 20 minutes. To the mixture was gradually added dropwise in an ice bath 4.05 mL (53.3 mmol) of chloro(methoxy)methane, and the resulting mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 4.81 g (28.6 mmol, Yield: 96.3%) of 1-methoxy-3-(methoxymethoxy)benzene.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:13])[C@H:10]([CH3:12])O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:14]([O:21][CH2:22][C@@H:23]1[C@@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][NH:25][CH2:24]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Si:14]([O:21][CH2:22][C@@H:23]1[C@@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][N:25]([C@H:10]([CH3:12])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:13])[CH2:24]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Product: C[C@H](C(=O)OCc1ccccc1)N1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c2ccccc2)C1
Yield: 66.3 %

Procedure:
The title compound was prepared from 242 mg (1.3 mmol) of (S)-lactic acid, benzyl ester (from EXAMPLE 7, Step A) and 310 mg (1.0 mmol) of 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidine (from EXAMPLE 1, Step E) using a procedure analogous to that described in EXAMPLE 1, Step G to provide 301 mg (62%) of the title compound: RF: 0.47 (4:1 v/v hexanes/EtOAc). 1H NMR (300 MHz) δ 0.0 (s, 6H), 0.85 (s, 9H), 1.41 (d, J=6.0 Hz, 3H), 2.41-3.62 (m, 9H), 5.17 (s, 2H), 7.16-7.38 (m, 10H).
Reaction SMILES: C[OH:2].[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1O)=[CH2:4]>C1(C)C=CC=CC=1>[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:2])=[CH:7][CH:6]=1)=[CH2:4]
Reactant: CO
Reactant: C=Cc1ccccc1O
Solvent: Cc1ccccc1
Product: C=Cc1ccc(O)cc1

Procedure:
The procedure of Example 6 was repeated except that no methanol was added to the starting crude vinylphenol and the alkali aqueous solution. A toluene solution of p-vinylphenol having the same purity (99.1 wt%) as in Example 6 was obtained as a product. However, for 60 hours after the extraction operation a large amount of scale deposited on the inner wall of the extraction tower and line 8, and, as a result, it was impossible to further continue the operation.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH3:29])[C:7]([C:10](=S)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C[O:31][C:32](=[O:46])[C:33](=[N+]=[N-])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]2[O:41][CH2:42][O:43][C:37]=2[CH:36]=1>CCOCC>[CH2:1]([C:5]1[N:6]([CH3:29])[C:7](/[C:10](/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH2:20][C:21]([OH:23])=[O:22])=[C:33](\[CH2:34][C:35]2[CH:40]=[CH:39][C:38]3[O:41][CH2:42][O:43][C:37]=3[CH:36]=2)/[C:32]([OH:46])=[O:31])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C(=S)c2ccc(OC)cc2OCC(=O)OC(C)(C)C)n1C
Reactant: COC(=O)C(Cc1ccc2c(c1)OCO2)=[N+]=[N-]
Solvent: CCOCC
Product: CCCCc1ncc(/C(=C(\Cc2ccc3c(c2)OCO3)C(=O)O)c2ccc(OC)cc2OCC(=O)O)n1C

Procedure:
The freshly prepared 2-n-butyl-1-methyl-5-(2-t-butoxycarbonylmethoxy-4-methoxythiobenzoyl)-1H-imidazole (206 mg, 0.49 mmol) was dissolved in ether (2 ml) and methyl-2-diazo-3-(3,4-methylenedioxyphenyl)propionate as prepared in Example 1(g) (117 mg, 0.50 mmol) was added under argon. After standing at ambient temperature for 1 week, several drops of hexanes were added to the Et2O solution and the resulting white ppt (162 mg) was collected by filtration to afford the (2RS,3RS) isomer of the title compound. Further addition of hexanes and cooling afforded the (2RS,3SR) isomer as a pale pink solid (60 mg). The filtrate containing the title mixture of thiiranes was chromatographed on silica gel to afford complete separation. (167 mg, (2RS,3RS) isomer; 116 mg (2RS,3SR) isomer; 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH:40]1([NH2:47])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>O1CCCC1>[CH:40]1([NH:47][C:18](=[O:20])[C@@H:17]2[CH2:21][CH2:22][CH2:23][N:16]2[C:14](=[O:15])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: NC1CCCCCC1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCCC1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 67.4 %

Procedure:
6.4 g (0.02 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline were dissolved in 75 ml of dry tetrahydrofuran and the solution was cooled to -10° C. 2.54 ml (0.02 mol) of N-ethylmorpholine and 2.62 ml (0.02 mol) of isobutyl chloroformate were added and the solution was stirred at -10° C. for 20 minutes. A solution of 2.25 g (0.02 mol) of cycloheptylamine in 25 ml of dry tetrahydrofuran was then added. The mixture was stirred at 0° C. for 1 hour and then left to stand at room temperature for 16 hours. The mixture was then evaporated and the residue extracted twice with 50 ml of ethyl acetate each time. The combined ethyl acetate extracts were washed successively with 1-N hydrochloric acid, water, 5% sodium bicarbonate solution and water and then dried over magnesium sulphate. Evaporation yielded an oil which solidified upon trituration with petroleum ether. The solid was recrystallised from ethyl acetate/petroleum ether to yield 5.6 g (67.5%) of N-benzyloxycarbonyl-L-alanyl-L-proline cycloheptylamide of melting point 110°-113° C.; [α]D20 =-92.4° (c=1.05% in methanol).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35](F)[CH:36]=1)[C:32]#[N:33]>CN1C(=O)CCC1>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C:35]1[CH:34]=[C:31]([CH:30]=[C:29]([Br:28])[CH:36]=1)[C:32]#[N:33])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(Cl)cccc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Br)cc(Oc2cccc(-c3c(Cc4ccccc4)cnc4c(Cl)cccc34)c2)c1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 18.4 %

Procedure:
3-(3-benzyl-8-chloroquinolin-4-yl)phenol (0.100 g, 0.289 mmol) was taken into NMP (1 mL) and to this was added NaH (0.0127 g, 0.318 mmol, 60% dispersion in oil) and stirred for 15 minutes. 3-Bromo-5-fluorobenzonitrile (0.116 g, 0.578 mmol) was added and the reaction was heated at 160° C. overnight. The reaction was cooled and quenched with water followed by extraction with ether. After drying and concentration the product was purified via Prep HPLC using 10-100% v acetonitrile in water as the eluent to yield 0.028 g of product. MS (ESI) m/z 526 ([M+H])+.
Reaction SMILES: [CH2:1]([NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[C:17](OCC)(=[O:21])[C:18]([O-])=[O:19].CC(C)([O-])C.[K+].Cl>C1COCC1>[CH2:1]([N:5]1[C:18](=[O:19])[C:17]([OH:21])=[C:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[S:6]1(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: CCCCNS(=O)(=O)Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCN1C(=O)C(O)=C(c2ccc(Cl)cc2)S1(=O)=O
Temperature: 150 °C
Yield: 60 %

Procedure:
The reaction was done in two vials. In each vial: N-butyl-1-(4-chlorophenyl)methanesulfonamide (0.5 g, 1.91 mmol) was dissolved in THF (3 mL). Ethyl oxalate (0.335 g, 2.29 mmol) was added. The mixture was cooled in an ice-bath. Potassium tert-butoxide (0.28 g, 2.48 mmol)) was added under nitrogen atmosphere. The mixture was heated in a microwave reactor at 150° C. for 10 mins. It was then cooled in an ice-bath. HCl (10%, ca.1 mL) was added, pH˜1. The mixtures of the two vials were combined and evaporated to remove THF. It was then extracted with DCM (20 mL). The extract was dried (MgSO4) and evaporated. Column chromatography (ISOLUTE SI, 20 g/70 mL) of the residue, eluting with heptane, then EtOAc:heptane (20:80), gave fraction A (0.9 g, containing ca. 60% of the title compound) and fraction B (0.035 g, the title compound). 1H NMR (400 MHz, THF-d8): δ 7.92 (d, 2H), 7.50 (d, 2H), 3.68 (t, 2H), 1.82-1.76 (m, 2H), 1.49-1.39 (m, 2H), 0.97 (t, 3H). 13C NMR (100 MHz, THF-d8): 159.2, 146.7, 135.4, 129.8, 129.4, 125.6, 117.7, 39.8, 31.2, 20.6, 13.7. Mass Spectrum: M−H+ 314.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([Cl:15])[N:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([Cl:15])[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[N:7]=1
Reactant: CCOC(=O)Cc1c(Cl)nc(Cl)nc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(Cl)nc(Cl)nc1NCc1ccc(OC)cc1
Temperature: 60 °C
Yield: 45.5 %

Procedure:
To a solution of ethyl 2-(2,4,6-trichloropyrimidin-5-yl)acetate (43.3 g, 160.7 mmol) in N,N-dimethylformamide (500 mL) was added 4-Methoxybenzylamine (24.2 g, 176.8 mmol) and N,N′-diisopropylethylamine (24.9 g, 192.9 mmol), the reaction mixture was heated to 60° C. for 1 h. Quenched with water, extracted with ethyl acetate, and the organic extracts were combined, washed with hydrochloride (1 N), brine, dried over anhydrous sodium sulfate, evaporated and purified by silica gel chromatography to afford the as a pale-yellow solid (27.1 g, yield 45.6%). 1H NMR (400 MHz, CDCl3) δ ppm 7.29 (dd, J=6.0, 3.9 Hz, 1H), 6.93-6.85 (m, 1H), 6.14 (s, 1H), 4.63 (d, J=5.3 Hz, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.83 (s, 3H), 3.62 (s, 2H), 1.23 (t, J=7.1 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][N:5]=1)(=O)[CH3:2].[BH4-].[Na+].[OH2:13]>CO>[OH:13][CH2:2][CH:1]=[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][NH:5]1
Reactant: O
Reactant: CC(=O)c1ccc(Br)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC=C1C=CC(Br)=CN1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
2-acetyl-5-bromopyridine (1 g, 5.0 mmol) (Bioorg. Med. Chem., 13, 2005, 6763-6770.) is dissolved in methanol (10 mL), and stir at room temperature. NaBH4 (0.57 g, 15 mmol) is added in batches and stir at room temperature for 10 minutes. TLC (petroleum ether/ethyl acetate=10:1) is used to monitor the reaction. Once the reaction is completed, add water (15 mL) into the reaction solution, and stir for 0.5 hours. After that, methanol is evaporated, extract with dichloromethane (25 mL×3), merge the organic phases, followed by anhydrous Na2SO4 drying and filtering. The solvent is evaporated to obtain 0.93 g of oily liquid (Compound 42-A). The yield is 91.9%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH3:7][O:8][CH2:9][CH2:10]Cl.C(N(CC)CC)C>>[CH3:7][O:8][CH2:9][CH2:10][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: Cc1ncc[nH]1
Reactant: COCCCl
Solvent: CCN(CC)CC
Product: COCCn1ccnc1C
Reaction time: 72 h

Procedure:
In an autoclave of 100 mL, 2-methylimidazole (19.2 g, 200 mmol) was made reacted with chloroethyl methyl ether (22.7 g, 240 mmol) at 140 deg C. for 72 hours. Brown liquid that was obtained was washed with 120 mL of a compound liquid of ethanol and ether (volume ratio thereof is 1:5), and then made reacted with triethylamine (20.2 g, 200 mmol) in the autoclave of 100 mL at 130 deg C. for 24 hours. Solid salts that was formed was removed by filtration, and residue (filtrate) was subjected to reduced-pressure distillation by using a Vigreux column of 20 cm. The obtained product was a transparent liquid which has a boiling point of 160-163 deg C. when a pressure is 10 Pa. 1H-NMR measurement of obtained amine was performed, and it was confirmed that chemical shifts, δ (ppm), are 6.95 (d, 1H), 6.72 (d, 1H), 4.07-4.04 (t, 2H), 3.62-3.60 (t, 2H), 3.27(s, 3H), and 2.29 (s, 3H), and 1-(2-methoxyethyl)-2-methyl imidazole was synthesized.
Reaction SMILES: [C:1]([N:3]=[CH:4][NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1O)#[N:2].S(Cl)(C)(=O)=O>N1C=CC=CC=1>[C:1]([N:3]=[CH:4][NH:5][C:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[CH:7]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC=NC#N)[C@@H]1O
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC1(C)C=C(NC=NC#N)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.7 %

Procedure:
To a solution of trans-4-[N-(cyanoiminomethyl)amino]-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (1.08 g) in dry pyridine (5.4 ml) was added mesyl chloride (0.77 ml) under ice-water cooling. The reaction mixture was stirred for 2 hours and 20 minutes at ambient temperature and evaporated. The residue was suspended in toluene (26 ml) and thereto was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.89 ml). The reaction mixture was stirred at 70° C. for 50 minutes and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and then washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to a column chromatography on silica gel (28 g) and eluted with a mixture of ethyl acetate and n-hexane (1:4→1:1). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was recrystallized from 50% aqueous ethanol to give 4-[N-(cyanoiminomethyl)amino]-2,2-dimethyl-2 H-1-benzopyran-6-carbonitrile (0.38 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:14]([O:13][CH:10]1[CH2:9][CH2:8][N:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[CH2:12][CH2:11]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Cn1ccnc1N1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cn1ccnc1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(1-Methyl-1H-imidazol-2-yl)piperidin-4-ol (0.200 g, 1.10 mmol), tert-Butyldimethylsilyl chloride (0.333 g, 2.21 mmol), 4-Dimethylaminopyridine (30 mg, 0.2 mmol), 1H-Imidazole (225 mg, 3.31 mmol) and DCM (6.0 mL, 94 mmol) was stirred at ambient temperature for 1 h. The reaction mixture was diluted with DCM to ≈60 mL, washed with sat. NaHCO3 solution, water, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel [Isco Combiflash, 2.5 g loading column/12 g column, eluting with DCM→5% MeOH in DCM]. Fractions containing the title compound were combined and dried in vacuo overnight, giving the title compound as yellow oil. 1H NMR (400 MHz, CDCl3): δ=6.77 (d, J=1.2 Hz, 1H), 6.65 (d, J=1.4 Hz, 1H), 3.85 (tt, J=8.0, 3.8 Hz, 1H), 3.47 (s, 3H), 3.28-3.21 (m, 2H), 2.91 (br ddd, J=12.0, 9.0, 3.0 Hz, 2H), 1.92-1.84 (m, 2H), 1.73-1.64 (m, 2H), 0.90 (s, 9H), 0.07 (s, 6H). MS (ES+): m/z=296.29 (100) [MH+]. HPLC: tR=3.22 min (verypolar—5 min, ZQ3). UV: λmax≈240 nm.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH3:11])([CH3:10])[C:8]#[N:9])[CH:3]=1.C(C1C=C(N[C:21](=[O:29])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)ON=1)(C)C>>[C:8]([C:7]([C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:29])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:6][N:5]=1)([CH3:11])[CH3:10])#[N:9]
Reactant: CC(C)(C#N)c1cc(N)on1
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Product: CC(C)(C#N)c1cc(NC(=O)Oc2ccccc2)on1
Yield: 40 %

Procedure:
Prepared from 2-(5-aminoisoxazol-3-yl)-2-methylpropanenitrile (130 mg, 0.861 mmol) according to the method described for phenyl 3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to afford phenyl 3-(2-cyanopropan-2-yl)isoxazol-5-ylcarbamate as a colorless solid (93 mg, 40%). 1H NMR (300 MHz, CDCl3) δ 7.82 (brs, 1H), 7.41-7.46 (m, 2H), 7.32 (m, 1H), 7.18-7.21 (m, 2H), 6.29 (s, 1H), 1.83 (s, 6H); LC-MS (ESI) m/z 272 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:25]3[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])=[CH:27][CH:26]=3)[C:16]=2[C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:25]3[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)[C:16]=2[C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(OCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl 4-{2-{6-(4-tert-butylbenzenesulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yloxy]ethoxy}phenoxyacetate (1.25 g) in dichloromethane (120 ml) are added anisole (2.09 g) and trifluoroacetic acid (20 ml) under ice-cooling. The mixture is stirred at room temperature for five hours, washed with water, and extracted with 10% aqueous sodium hydroxide solution. The aqueous layer is washed with chloroform, and acidified with 10% hydrochloric acid under ice-cooling. The mixture is extracted with ethyl acetate, and the extract is washed, dried, and evaporated to remove the solvent. The residue is crystallized from ethyl acetate/diisopropyl ether to give 4-{2-[6-(4-tert-butylbenzenesulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yl-oxy]ethoxy}phenoxyacetic acid (1.14 9).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:25]1([CH2:31][CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[OH:39][C:38]1[CH:2]=[C:1]([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)[O:3][C:35](=[O:36])[C:34]=1[S:33][CH2:32][CH2:31][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)c1ccncc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccncc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4-acetylpyridine (2.50 g, 20.63 mmol), lithium bis(trimethylsilyl)amide (5.17 g, 30.94 mmol), chlorotrimethylsilane (3.92 mL, 30.94 mmol), THF (200 mL), and diethyl ester of [(2-phenylethyl)thio]-propanedioic acid (1.00 g, 3.37 mmol). m.p. dec. 149-152° C.; 1H NMR (400 MHz, DMSO-d6) δ2.78 (t, 2 H), 3.04 (t, 2 H), 6.98 (s, 1 H), 7.20 (m, 5 H), 7.74 (d, 2 H), 8.74 (d, 2 H).
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:9]([OH:11])=O)[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[NH2:44][C@H:45]([C:54]([O:56][CH3:57])=[O:55])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=1.Cl.C(N1CCOCC1)C>CN(C)C=O>[NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:9]([NH:44][C@H:45]([C:54]([O:56][CH3:57])=[O:55])[CH2:46][C:47]1[CH:48]=[CH:49][C:50]([OH:53])=[CH:51][CH:52]=1)=[O:11])[CH2:3][O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(C)(C)OC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](COC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A mixture of Boc-Ser(But)-OH (26 g), dicyclohexylcarbodiimide (28.3 g) and 1-hydroxybenzotriazole (18.6 g) in dimethylformamide (200 ml) was stirred at ice-bath temperature for 60 min and at room temperature for 60 min. A solution of H-Tyr-OMe hydrochloride (23.6 g) and N-ethylmorpholine (14.36 ml) in dimethylformamide (160 ml) was added to the above mixture. The resulting mixture was stirred at room temperature overnight and filtered. The filtrate was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with 5% aqueous citric acid, water, saturated sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, and evaporated to give 39 g of Boc-Ser(But)-Tyr-OMe as an amorphous solid. This dipeptide was crystallized from diethyl ether-hexane to a mp of 109°-111° C.; Anal. Calcd for C22H34N2O7 : C, 60.26% H, 7.82% N, 6.39% and Found: C, 60.68% H, 7.87% N, 6.37% and nmr (CDCl3) δ 1.17 (s, 9H), 1.44 (s, 9H) and 3.67 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CN1CCNCC1.[CH:17](=[O:26])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[OH:26][CH:17]1[CH2:18][CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=2)[O:9]1
Reactant: OCc1ccc(O)cc1
Reactant: O=C/C=C/c1ccccc1
Agent: CN1CCNCC1
Solvent: Cc1ccccc1
Product: OCc1ccc2c(c1)C(c1ccccc1)CC(O)O2
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.4 %

Procedure:
4-(Hydroxymethyl)phenol (2.515 kg, 20.26 mol, 1 eq) was stirred with N-methylpiperazine (5.06 kg, 50.52 mol, 2.5 eq) in toluene (17.74 kg, 20.5 L, 8.15 mL/g) and then heated to reflux. trans-Cinnamaldehyde (3.35 kg, 25.35 mol, 1.25 eq) was then added over 2 hours maintaining the reaction mixture at reflux. The transfer line was washed with toluene (0.9 Kg, 0.35 ml/g). Once the addition was complete the reaction mixture continued to be heated at reflux for 19 h. Then some toluene was distilled off, reducing the volume to approximately 18.5 L. The mixture was then allowed to cool to room temperature and EtOAc was added (13.5 Kg 15 L, 6 mL/g). The organic phase was washed with HCl 2M (46.4 kg, 46.4 L 18.5 mL/g). The phases were separated, and ethyl acetate (27.1 kg, 30 L, 12 ml/g) was added to dilute the organic layer. The organic phase was washed with 1M HCl (17.75 kg, 17.75 L 7.1 mL/g), 5% w/w NaHCO3 (17.5 L, 7 mL/g) and water (25 L, 10 mL/g). The phases were separated, and toluene (6.5 Kg, 7.5 L, 3 ml/g) was added to the organic layer, and the mixture was distilled to approximately 8 L. Additional toluene (7 kg) was charged followed by ethyl acetate (3.9 L). The mixture was heated to reflux then cooled to 22° C. at 1° C./minute, then stirred for 20 hrs. The suspension was cooled to 2° C. and granulated for 2 hrs. The slurry was filtered and the cake was washed with cold toluene (2×4.3 Kg, 5 L). The resulting pale tan solid was dried in vacuum for 68 h at 40° C., to provide 2.76 Kg of product (2-hydroxy-4-phenyl-3,4-dihydro-2H-chromen-6-yl)methanol (53.4% yield) which was used in the following example without purification: