Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[CH3:24][S:25][CH2:26][CH2:27][C:28](Cl)=O.C(N(CC)CC)C.CS(O)(=O)=O.[OH-].[Na+]>O1CCCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:28]([CH2:27][CH2:26][S:25][CH3:24])=[N:15][C:14]=2[CH:16]=1
Reactant: CSCCC(=O)Cl
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSCCc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 66.9 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (200 mg, 0.646 mmol) in tetrahydrofuran (5 mL) was added 3-(methylthio)propionyl chloride (98.5 mg, 0.711 mmol) and triethylamine (131 mg, 1.29 mmol), and this was stirred at room temperature for 7 hours. After the reaction was complete, water was added and this was extracted with ethyl acetate. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. To a solution of the residue obtained in dioxane (5 mL) was added methanesulfonic acid (0.5 mL), and this was heated to reflux for 3 hours. After the reaction was complete, 1M aqueous sodium hydroxide solution was added, and this was extracted with ethyl acetate. The organic layer obtained was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude crystals that were purified by silica gel column chromatography to yield the title compound (170 mg, 67% yield) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:5]([O:28][CH3:29])[C:4]=1B(O)O.[CH2:33]([O:35][C:36](=[O:57])[C@H:37]([CH2:49][C:50]1[CH:55]=[CH:54][C:53](Br)=[CH:52][CH:51]=1)[NH:38][C:39](=[O:48])[C:40]1[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:47])[CH3:34].C([O-])([O-])=O.[K+].[K+]>COCCOC.O>[CH2:33]([O:35][C:36](=[O:57])[C@H:37]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:25])[CH3:26])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:6][C:5]=2[O:28][CH3:29])=[CH:52][CH:51]=1)[NH:38][C:39](=[O:48])[C:40]1[C:41]([Cl:47])=[CH:42][CH:43]=[CH:44][C:45]=1[Cl:46])[CH3:34]
Reactant: CCOC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Yield: 97.9 %

Procedure:
A mixture of 2,6-dimethoxy-4-[(t-butyldiphenylsilyloxy)methyl]benzeneboronic acid (5.2 g), N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine ethyl ester (1.71 g), Pd(Ph3)4 (0.44 g) and K2CO3 (1.59 g) in DME/H2O (20 mL/0.5 mL) was heated at 80° C. for 24 h under N2. The mixture was worked up and purified in a similar procedure as described in Example 8-3) to yield 2.9 g of N-(2,6-dichlorobenzoyl)-4-[2,6-dimethoxy-4-[(t-butyldiphenylsilyloxy)methyl]phenyl]-L-phenylalanine ethyl ester. ESMS: m/z 770 (MH+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[F:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Cl.[Br:21]Br>ClC(Cl)=C(Cl)Cl.C(Cl)Cl.O>[Br:21][C:18]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[C:6]([F:5])[CH:19]=1
Reactant: Oc1ccc(Oc2ccccc2F)cc1
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)=C(Cl)Cl
Solvent: ClCCl
Product: Oc1ccc(Oc2ccc(Br)cc2F)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a 250 mL flask equipped with a nitrogen purge, mechanical stirrer, thermometer, condenser and gas scrubber was added 100 mL of perchloroethylene and 16 g (0.12 moles) of AlCl3. The slurry was heated to 60° C. and a solution of 20.4 g (0.10 moles) of 4-(2-fluorophenoxy)phenol in 100 mL of perchloroethylene was added slowly. During the addition HCl gas was given off as the complex with AlCl3 formed. At the end of the addition the temperature was 75° C. The clear, rose-colored solution was cooled to 13° C. with an ice-water bath. To the cooled, rapidly stirred solution was added a total of 16 g (0.1 moles) of liquid bromine dropwise over a 1 hour period at 12°-16° C. After stirring for an additional 30 min, 80 mL of water and 50 mL of methylene chloride were added and the layers were separated. The organic phase was further extracted with 2-50 mL portions of 10% aqueous HCl and then 2-50 mL portions of water. Stripping the solvent under vacuum gave 27.9 g (98.5%) yield of crude product. This crude product was recrystallized from 20 mL of perchloroethylene to give after precipitation, filtration, and drying, 24.2 g (88% yield) of 4-(4-bromo-2-fluorophenoxy)phenol, mp 81-83.5. The identity to the product was confirmed by C13NMR, IR and mixed mp with an authentic sample.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](=[N:15]O)[NH2:14])=[CH:11][CH:10]=1>CO>[C:1]([C:2]1[N:14]=[C:13]([C:12]2[CH:17]=[CH:18][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)[NH:15][CH:3]=1)([O:5][CH3:6])=[O:4]
Reactant: C#CC(=O)OC
Reactant: COc1ccc(C(N)=NO)cc1
Solvent: CO
Product: COC(=O)c1c[nH]c(-c2ccc(OC)cc2)n1
Reaction time: 8 h
Yield: 30.1 %

Procedure:
A solution of methyl propiolate (25.4 g, 0.3 mol), p-methoxybenzamidoxime (50 g, 0.3 mol) and CH3OH (700 ml) was heated at reflux with stirring. After 8 hours, the reaction mixture was concentrated to dryness, and the residue treated with diphenyl ether (300 ml) and heated at reflux. After 2.5 hours, the reaction mixture was poured in C6H14 (2 L) and allowed to stand. The C6H14 was decanted off and the residue chromatographed on silica gel. The product was eluted with 2% CH3OH--CHCl3 to yield 21 g (30%) of 63; m.p. 188°-90° C. (trituration with Et2O).
Reaction SMILES: [N-:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Na+].[Cl:7][C:8]1[O:12][C:11]([CH:13]2[C:18]3=[C:19]4[N:31]([CH3:32])[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[C:20]4=[C:21]([C:22]4[S:23][CH:24]=[C:25]([CH3:27])[N:26]=4)[N:17]3[CH2:16][CH:15]([CH2:36]O)[S:14]2)=[CH:10][CH:9]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[N:1]1([CH2:36][C@H:15]2[S:14][C@H:13]([C:11]3[O:12][C:8]([Cl:7])=[CH:9][CH:10]=3)[C:18]3=[C:19]4[N:31]([CH3:32])[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[C:20]4=[C:21]([C:22]4[S:23][CH:24]=[C:25]([CH3:27])[N:26]=4)[N:17]3[CH2:16]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[n-]cn1
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CO)SC3c2ccc(Cl)o2)n1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2C[C@@H](Cn2ccnc2)S[C@@H]3c2ccc(Cl)o2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium imidazolide (86 mg, 0.960 mmol) was added to a solution of racemic 10-(5-chlorofuran-2-yl)-8-(hydroxymethyl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione (115 mg, 0.240 mmol) (Example 17) in DCM (24 ml) at 0° C. The mixture was stirred for 30 minutes, then trifluoromethanesulfonic anhydride (0.049 ml, 0.288 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 3 hours. The mixture was diluted with DCM (10 ml) washed with water (30 ml) and brine (30 ml). The organic layer was passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-20% methanol/DCM, afford the title compound as a mixture of diastereomers.
Reaction SMILES: C([Li])CCC.C1([SiH3])C=CC=CC=1.[CH3:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH:15]=1.[H][H]>C1COCC1>[CH3:13][CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: CC1=CCCc2ccccc21
Reactant: [H][H]
Agent: [Li]CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: CC1CCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
In a dry sealable Schlenk flask under an argon atmosphere 0.059g (0.099 mmol) (S,S)-ethylene-1.2-bisη5 -4,5,6,7-tetrahydro-1-indenyl)titanium (S)-1,1'-binaphth-2,2'-diolate was dissolved in THF (10 mL). The vessel was degassed by exposure to vacuum (2'~10 sec), put under an atmosphere of hydrogen and subsequently cooled to 0° C. in an ice water bath. After equilibration, a solution of n-butyllithium (0.125 mL, 1.58 M in hexanes, 0.196 mmol, 1.96 equiv) was added and the mixture was allowed to stir for 10 min. Phenylsilane (0.033 mL, 0.259 mmol, 2.6 equiv) and 0.273 g (1.87 mmol, 19 equiv) 1-methyl-3,4-dihydronaphthalene were then added. The flask was sealed and the solution moved into a dry box and transferred to a Parr® high pressure reaction vessel containing a magnetic stir bar. The pressure vessel was sealed and moved to a fume hood where it was charged to 2150 psig with hydrogen and placed in an oil bath at 65° C. The reaction mixture was allowed to stir/br 184 h. The vessel was cooled to room temperature, vented and opened to air. The reaction mixture was worked up by partitioning between diethyl ether/hexane (1/4) and water and separating the layers. The organic extract was distilled at reduced pressure to yield 0.195 g (1.31 mmol, 70%) of 1-methyl-1,2,3,4-tetrahydronaphthalene with an ee of 70 %, determined polarimetrically.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]1[C:17]2([CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=[O:23])[CH2:16][CH2:15][CH2:14]1.[C:24](=O)([O:27]C)[O:25][CH3:26]>CCOCC>[O:23]=[C:18]1[CH:19]([C:24]([O:25][CH3:26])=[O:27])[CH2:20][CH2:21][CH2:22][C:17]21[CH2:13][CH2:14][CH2:15][CH2:16]2
Reactant: COC(=O)OC
Reactant: O=C1CCCCC12CCCC2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: COC(=O)C1CCCC2(CCCC2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (5.97 mL, 41.9 mmol) in ether (30 mL) was cooled to −78° C. and then was treated slowly with n-butyllithium (16.75 mL, 41.9 mmol). The mixture was stirred at −78° C. for 30 minutes; then this solution was transferred via cannula into a −78° C. solution of Example 10A (4.25 g, 27.9 mmol) in ether (30 mL). The mixture was stirred at this temperature for 30 minutes and then was treated with dimethyl carbonate (23.50 mL, 279 mmol). The resulting mixture was warmed to ambient temperature and stirred for 16 hours. The mixture was quenched with saturated ammonium chloride and diluted with ether (100 mL); then the layers were separated. The aqueous layer was extracted with additional ether, then the organic layers were combined, dried with magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel (100% hexane to 85:15 ethyl acetate/hexanes, eluant) to provide the title product. 1H NMR (300 MHz, CDCl3) δ 12.40-12.42 (m, 1H), 3.72-3.76 (m, 3H), 2.18-2.26 (m, 2H), 2.00-2.12 (m, 2H), 1.74-1.86 (m, 2H), 1.57-1.62 (m, 2H), 1.54-1.57 (m, 2H), 1.35-1.48 (m, 4H); MS (DCI+) m/z 211 (M+H)+.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:28])[NH:15][C:16]2[CH:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH:19]=[CH:18][C:17]=2[NH2:27])=[CH:10][CH:9]=1)(=[O:6])[O:4]C.[OH-].[Na+].C(O)(C(F)(F)F)=O>O1CCOCC1.CN(C=O)C>[CH3:1][O:2][P:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14](=[O:28])[NH:15][C:16]2[CH:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH:19]=[CH:18][C:17]=2[NH2:27])=[CH:12][CH:13]=1)(=[O:4])[OH:6]
Reactant: COP(=O)(Cc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COP(=O)(O)Cc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
[4-(2-Amino-5-thiophen-2-yl-phenylcarbamoyl)-benzyl]-phosphonic acid dimethyl ester (35 mg, 0.066 mmol) was made 0.25 M in dioxane and to this stirring solution was added 5N aqueous sodium hydroxide (26 μL, 0.132 mmol). The resulting solution was stirred at 80° C. overnight then diluted with DMF, acidified with TFA, and purified by HPLC (0-60% MeCN in water w/0.025% TFA) to afford the title compound: 1H NMR (DMSO-d6, 600 MHz) δ9.80 (s, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.48-7.50 (m, 1H), 7.31-7.42 (m, 4H), 7.26-7.28 (m, 1H), 7.04-7.06 (m, 1H), 6.88 (d, J=8.4 Hz, 1H), 3.52 (d, J=11.4 Hz, 3H), 3.18 (d, J=21.6 Hz, 2H). MS: cal'd 403 (MH+), exp 403 (MH+)
Reaction SMILES: [C:1]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(O)C.[OH-].[Na+:26]>O>[C:1]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([O-:20])=[O:19])=[CH:13][CH:12]=1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Na+:26]
Reactant: CC(C(=O)O)c1ccc(NC(=O)c2ccccc2O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)[O-])c1ccc(NC(=O)c2ccccc2O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A solution of 53.05 g (0.186 mol) of 2-(4-(N-salicyloyl)aminophenyl)propionic acid and 300 ml of ethanol was treated with 7.59 g (0.190 mol) of NaOH dissolved in 22 ml of water. The reaction mixture was stirred for 30 min at 25 C and for 30 min at 0° C. The resulting pale yellow solid was isolated by filtration to give 52.61 g of sodium 2-(4-(N-salicyloyl)aminophenyl)propionate.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11]1[O:13][CH2:12]1>C(O)(C)C>[OH:13][CH2:12][CH2:11][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: C1CO1
Reactant: O=C(O)c1ccc(O)cc1
Solvent: CC(C)O
Product: O=C(OCCO)c1ccc(O)cc1

Procedure:
Into an autoclave, 138 parts by weight of p-hydroxybenzoic acid, 1 part by weight of Na2CO2 and 300 parts by weight of isopropanol were charged, and at 90° C., 66 parts by weight of ethylene oxide was added thereto, and the reaction was conducted. After the reaction, the mixture was cooled, and the precipitate was collected by filtration and recrystallized twice from water to obtain 55 parts by weight of p-hydroxylbenzoic acid-β-hydroxyethyl ester ##STR88## having a melting point of 141° C. The structure was confirmed by 1H-NMR.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].CCN(C(C)C)C(C)C.[Cl:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)Cl>[Cl:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([NH:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])=[O:37]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](NC(=O)c1cccc(CCl)c1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a solution of (R)-2-Amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride (30.5 mg, 0.092 mmol) in DCM (1 mL) cooled to 0° C. was added DIEA (17.4 μL, 0.1 mmol) followed by 3-chloromethyl benzoylchloride (14.2 μL, 0.1 mmol). Upon completion of addition, the reaction mixture was allowed to warm slowly to rt. where it stirred overnight. After this time, the solution was diluted with dichloromethane and quenched by the addition of aqueous NaHCO3. The layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified via SiO2 chromatography to give the (R)-3-(chloromethyl)-N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)benzamide as a clear glassy solid (23.7 mg, 58% yield). MS found: 447.3 (M+), 449.3 (M+2).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C([N-:18]C(C)C)(C)C.[Li+].[Br-].[Mg+2].[Br-].[C:26](Cl)(=O)[CH2:27][CH2:28][CH2:29][CH3:30]>CCOCC>[CH2:11]([O:10][C:8](=[O:9])[C:7]1[CH:13]=[CH:14][C:4]([C:1]2[O:3][N:18]=[C:26]([CH2:27][CH2:28][CH2:29][CH3:30])[CH:2]=2)=[CH:5][CH:6]=1)[CH3:12]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Reactant: CCCCC(=O)Cl
Agent: [Br-]
Agent: [Li+]
Agent: [Mg+2]
Solvent: CCOCC
Product: CCCCc1cc(-c2ccc(C(=O)OCC)cc2)on1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
A solution of ethyl 4-acetylbenzoate (2.93 g, 15.3 mmol) in 25 mL ether was added to a solution of lithium diisopropylamide (0.805 M in THF-hexane, 20.85 mL, 16.79 mmol) in 200 mL of ether at −70° C. The mixture was stirred at −78° C. for 30 minutes, magnesium bromide etherate (3.94 g, 15.26 mmol) was added and the reaction mixture was stirred for 30 minutes followed by the addition of valeryl chloride (1.47 g, 12.2 mmol) in 3 mL ether. Stirring was continued at −78° C. for an additional 30 minutes. The mixture was allowed to come to room temperature, quenched by adding saturated ammonium chloride and acidified (pH=3.0) by adding 20% sulfuric acid. The mixture was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, concentrated, and the residue subjected to flash chromatography (silica gel/hexane-ethyl acetate 95:5) to afford the title compound (1.35 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](Br)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C-:15]#[N:16].[K+].Cl.C([OH:21])C>O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:21])[CH2:12][C:15]#[N:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1ccc(CC(=O)Br)cc1
Reactant: CCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)CC#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a stirred suspension of 1.0 g (3.61 mmol) (4-methanesulfonyl-phenyl)-acetyl bromide in 15 ml ethanol was added a solution of 0.47 g (7.22 mmol) potassium cyanide in 5 ml water. The mixture was then stirred at RT for 1 h, then acidified to ph=5-6 with aqueous HCl 1M and then extracted with ethyl acetate, The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford 0.29 g (37%) 3-(4-methanesulfonyl-phenyl)-3-oxo-propionitrile as a yellow solid. ES-MS m/e (%): 222 (M, 100).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8](O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.C(O)(C)(C)C>CO>[C:4]([OH:6])(=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:1]
Reactant: O=C(O)c1cc(O)ccc1O
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Solvent: CO
Product: O=C(O)c1ccccc1O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
While 100 g of 2,5-dihydroxybenzoic acid and 1441 g of 80% sulfuric acid are heated to 50° C., these are mixed. 144 g of tert-butyl alcohol is added to the mixed solution, and stirred at 50° C. for 30 minutes. Next, the operation is performed 3 times in which 144 g of tert-butyl alcohol is added to the mixed solution, and stirred at 50° C. for 30 minutes. The reaction solution is cooled to room temperature. The reaction solution is gradually poured into 1.00 kg of ice water, and a precipitate is filtered. The precipitate is washed with water, and further washed with hexane. The precipitate obtained here is dissolved in 200 mL of methanol, and again precipitated using 3.60 L of water. After filtration, the obtained product is dried at 80° C. to obtain 74.9 g of a salicylic acid intermediate product represented by the following formula (8).
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:8]=2[CH:7]=[C:6]([Cl:20])[C:5]=1[OH:21])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:30])C=1.O.[OH-].[Na+]>C(Cl)Cl>[Cl:20][C:6]1[C:5]2[O:21][CH:2]([CH2:3][OH:30])[CH2:1][C:4]=2[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:8]=2[CH:7]=1
Reactant: C=CCc1c(O)c(Cl)cc2c(-c3ccccc3F)noc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OCC1Cc2c(c(Cl)cc3c(-c4ccccc4F)noc23)O1
Temperature: 0 °C
Yield: 65 %

Procedure:
To the ice-cooled solution of 7-allyl-5-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole (9.5 g) in methylene chloride (200 ml), m-chloroperbenzoic acid (16.4 g) was added in small portions under agitaiton, and the solution was subsequently refluxed for 3 hours. After cooling the solution, water and 100 ml of an aqueous solution of 2N sodium hydroxide were added and the mixture was subjected to extraction with methylene chloride. The methylene chloride layer was washed with water and dried. By distilling off the solvent, 6.5 g of 5-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-methanol was obtained. m.p. 136°-139° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 319.
Reaction SMILES: [CH3:1][C@@:2]([S:42]([CH3:45])(=[O:44])=[O:43])([CH2:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH:30]3[CH2:33][CH:32]([O:34]C4CCCCO4)[CH2:31]3)=[CH:23][CH:22]=2)=[CH:17][C:16]1=[O:41])[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl>O1CCOCC1.CO.CCOCC>[OH:6][NH:5][C:3](=[O:4])[C@:2]([CH3:1])([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH:30]3[CH2:33][CH:32]([OH:34])[CH2:31]3)=[CH:23][CH:22]=2)=[CH:17][C:16]1=[O:41]
Reactant: C[C@@](CCn1ccc(-c2ccc(OCCC3CC(OC4CCCCO4)C3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@](CCn1ccc(-c2ccc(OCCC3CC(O)C3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To (2R)-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(4-{2-[3-(tetrahydro-2H-pyran-2-yloxy)cyclobutyl]ethoxy}phenyl)pyridin-1(2H)-yl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (386 mg, 0.597 mmol) was added 4 N hydrogen chloride in dioxane (6.0 mL) and methanol (0.60 mL). The reaction was stirred for 30 minutes and then evaporated in vacuo to give a yellow oil. The residue was dissolved in a minimal amount of methanol (0.50 mL) and diluted with ether to give a yellow precipitate. This suspension was stirred overnight at room temperature. The solid was allowed to settle and the liquid was decanted off. The solid was rinsed twice with ether and dried on a vacuum pump to give the title compound as a white solid (229 mg, 80.5%). 1H NMR (poor resolution in spectra) (400 MHz, METHANOL-d4) δ ppm 1.55-1.63 (m, 2H) 1.69-1.73 (m, 3H) 1.87-1.97 (m, 3H) 2.11 (t, J=6.83 Hz, 0H) 2.36-2.50 (m, 3H) 2.61-2.72 (m, 1H) 3.08-3.11 (m, 3H) 3.99-4.10 (m, 4H) 4.32-4.42 (m, 1H) 6.89-6.97 (m, 1H) 7.00-7.07 (m, 3H) 7.67-7.73 (m, 2H) 7.87 (t, J=10.54 Hz, 1H). LCMS 479.6 (M+1).