Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[C:3]([O:8]C)=[CH:4][CH:5]=[CH:6][CH:7]=1>CO>[C:1]([OH:11])(=[O:10])[C:2]1[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:8]
Reactant: COc1ccccc1C(=O)O
Solvent: CO
Product: O=C(O)c1ccccc1O
Temperature: -80 °C
Reaction time: 0.33 h

Procedure:
Salicylic acid was extracted and analyzed by HPLC using a modification of the methods described in Meuwly et al., 1993. For salicylic acid analysis, 0.3 to 0.5 gFW leaf tissue from E. orontii-infected leaves (7 dpi) was frozen in glass tubes with liquid nitrogen and either used directly or stored at −80° C. The frozen tissue was ground in liquid nitrogen to a fine powder using a chilled glass rod. Three ml of 90% methanol and 250 ng o-anisic acid (internal standard) were added to each sample. Samples were vortexed, sonicated for 20 minutes, and centrifuged for 20 minutes at 3000 rpm in a table-top centrifuge. The supernatant was transferred to a new tube, and the pellet was re-extracted with 2 ml of 90% methanol. The two supernatants were combined, divided into two portions of equal volumes (for total SA and free SA measurements), vacuum dried, and frozen at −80° C. For total SA, 500 μl β-glucosidase (80 U/ml in 100 mM sodium acetate, pH 5.2; Sigma, St. Louis, Mo.) was added to each sample. The samples were sonicated for 5 minutes, vortexed, covered with foil, and incubated for 90 minutes at 37° C. For both total and free SA samples, 2.5 ml 5% trichloroacetic acid was added, and the samples were vortexed, sonicated for 5 minutes, and centrifuged at 3000 rpm for 15 minutes. The supernatant was extracted twice with 2.5 ml of a 1:1 (v/v) mixture of ethyl acetate:cyclopentane. The organic phases were combined, vacuum dried, and frozen at −80° C. Just prior to loading samples on the HPLC, each was resuspended in 250 μl of 20% methanol, vortexed, sonicated for 5 minutes, and filtered through a 0.22 μm nylon filter.
Reaction SMILES: O=C1C2C=CC=CC=2C(=O)[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:20][S:21]([C:24]2[S:25][C:26]([Cl:29])=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[O:19])=[CH:14][CH:13]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[NH2:3][C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:20][S:21]([C:24]2[S:25][C:26]([Cl:29])=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[O:19])=[CH:14][CH:13]=1
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)s1)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)NS(=O)(=O)c2ccc(Cl)s2)cc1

Procedure:
A 74 mg portion (0.21 mmol) of [4-(1,3-dioxobenzo[c]azolidin-2-yl)phenyl]-N-[(5-chloro(2-thienyl))sulfonyl]-carboxamide, 192 mg (0.84 mmol) of tin dichloride dihydrate were combined and dissolved in 1.4 mL of EtOAc. The mixture was refluxed for 4 h, filtered through celite, and concentrated in vacuo to afford a solid which was purified on silica gel eluting with 10% MeOH/CH2Cl2 to give a quantitative yield of the titled compound. ES-MS (M+H)+=317 (Cl).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[CH2:14][S:13][C:12]1=[S:17].[CH:18](=O)[CH2:19][CH2:20][CH2:21][CH3:22]>C(O)(=O)C.N1CCCCC1.C(COC)OC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[C:14](=[CH:18][CH2:19][CH2:20][CH2:21][CH3:22])[S:13][C:12]1=[S:17]
Reactant: CCCCC=O
Reactant: O=C1CSC(=S)N1N=c1sc2ccccc2s1
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: C1CCNCC1
Product: CCCCC=C1SC(=S)N(N=c2sc3ccccc3s2)C1=O

Procedure:
A slurry of 2.0 g of 3-[(1,3-benzodithiol-2-ylidene)amino]-2-thioxo-4-thiazolidinone (see example 37), valeraldehyde (10 ml, excess) and acetic acid/piperidine (2:1) (10 drops) in anhydrous glyme (400 ml) is heated at reflux for 18 hours. The reaction mixture is chilled in an ice bath and the resultant precipitate collected by filtration. This precipitate (1.6 g) is recrystallized from 50 ml of dimethylformamide to yield 1.1 g of the title compound, melting point 210°-212° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:11]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C:25](=[O:29])[CH2:24][CH2:23]4)[CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[C:11]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C:25](=[O:29])[CH2:24][CH2:23]4)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc(-c3ccc4c(c3)CCC4=O)c(-c3ccncc3)o2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCc2cc(-c3cc(-c4ccc(O)cc4)oc3-c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of the product of Step 4 (100 mg, 0.26 mmol) in dichloromethane (2 ml) was treated at 0° C. with boron tribromide (1.3 ml of a 1M solution in dichloromethane, 1.3 mmol) and stirred at room temperature for 1 hour. The reaction mixture was poured into saturated sodium bicarbonate solution extracted into dichoromethane, dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in methanol/dichloromethane and applied to an SCX column eluting with methanol and then a mixture of 0.880 ammonia/methanol (1:9). The basic fractions were combined and concentrated in vacuo to afford the title compound (65 mg, 70%); MS(ES+) m/e 368 [M+H]+.
Reaction SMILES: C([O:8][CH2:9][C:10]([CH2:24][S:25]CC1C=CC=CC=1)([CH2:15][S:16]CC1C=CC=CC=1)[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.OCC(CO)(C(C)(C)C)CS>>[CH2:11]([C:10]([CH2:9][OH:8])([CH2:24][SH:25])[CH2:15][SH:16])[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CC(COCc1ccccc1)(CSCc1ccccc1)CSCc1ccccc1
Agent: CC(C)(C)C(CO)(CO)CS
Product: CC(C)CC(CO)(CS)CS

Procedure:
2-i-Butyl-2-hydroxymethyl-propan-1,3-dithiol was prepared from 1-benzyloxy-2,2-di-benzylthiomethyl-4-methyl-pentane in a manner analogous to that described for the sysnthesis of 2,2-di-hydroxymethyl-3,3-dimethyl-butan-1-thiol.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17].[OH-].[Na+]>O1CCCC1>[C:15]([O:7][CH:3]1[CH2:4][CH2:5][CH2:6][S:1][CH2:2]1)(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)C(=O)Cl
Reactant: OC1CCCSC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC1CCCSC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
Freshly distilled tetrahydrothiopyran-3-ol (8.97 g, 75.3 mmol) and triethylamine (10.6 mL, 75.5 mmol) were dissolved in anhydrous tetrahydrofuran (THF) (40 mL) and cooled to 0° C. Methacryloyl chloride (8.1 mL, 83.2 mmol) was then added slowly, dropwise. The reaction then was warmed slowly to room temperature. After stirring overnight, 30 mL DIW were added and the mixture was made basic with 5 M NaOH. The THF then was removed by rotary evaporation and the product was extracted with diethyl ether (3×40 mL). The ether extracts were combined and washed with 0.1 M NaOH, followed by DIW before being dried over sodium sulfate and filtered. The product was then concentrated by rotary evaporation and dried in vacuo to afford tetrahydro-2H-thiopyran-3-yl methacrylate as a light orange liquid (7.63 g, 54%). 1H NMR (600 MHz, CDCl3, ppm) δ 6.08 (s, 1H), 5.54 (s, 1H), 4.94 (m, 1H), 2.78 (m, 1H), 2.62 (m, 1H), 2.49 (m, 1H), 2.47 (m, 1H), 2.14 (m, 1H), 1.99 (m, 1H), 1.91 (s, 3H), 1.85 (m, 1H), 1.49 (m, 1H). 13C NMR (150 MHz, CDCl3, ppm) δ 166.61, 136.69, 125.62, 71.21, 32.26, 31.82, 28.10, 27.43, 18.43.
Reaction SMILES: C(O[C:6](=[O:23])[CH2:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:20]C)(OC)[CH2:16][Br:17])[CH:10]=1)(C)(C)C.C(OC(=O)[NH:30][C:31]1[CH:36]=[C:35]([N:37]([CH3:39])[CH3:38])[C:34]([Cl:40])=[CH:33][C:32]=1[NH2:41])(C)(C)C>C1(C)C=CC=CC=1>[Br:17][CH2:16][C:15]([C:11]1[CH:10]=[C:9]([C:8]2[CH2:7][C:6](=[O:23])[NH:41][C:32]3[CH:33]=[C:34]([Cl:40])[C:35]([N:37]([CH3:38])[CH3:39])=[CH:36][C:31]=3[N:30]=2)[CH:14]=[CH:13][CH:12]=1)=[O:20]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: COC(CBr)(OC)c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Solvent: Cc1ccccc1
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(C(=O)CBr)c1)=N2
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-oxo-3-[3-(2-bromo-1,1-dimethoxy-ethyl)-phenyl]-propionic acid tert-butyl ester (2.34 g) (Example K28) and (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J2) (1.57 g) in toluene (16 mL) was heated to 100° C. for 5 h. The solvent was evaporated in vacuum and the crude product was purified by chromatography on silica gel using CH2Cl2/AcOEt (1:20) as eluent. A solution of the purified material (2.4 g) in CH2Cl2/TFA (1:1, 30 mL) was stirred at 20° C. for 15 min and then evaporated. The residual oil was dissolved in AcOEt and the solution was washed with 1N HCl and with brine, dried and evaporated. The residue was crystallized from AcOEt/Et2O to give 4-(3-bromoacetyl-phenyl)-8-chloro-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one as light-brown solid.
Reaction SMILES: [ClH:1].C([O:6][CH:7](OCCCC)[C@H:8]([CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:39])[NH2:38])[NH:9][C:10](=[O:32])[C@H:11]([CH3:31])[NH:12][C:13](=[O:30])[C@@H:14]1[CH2:18][CH2:17][C:16](=[O:19])[N:15]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])CCC.Cl.[OH-].[Na+]>C(#N)C>[ClH:1].[CH2:23]([O:22][C:20]([N:15]1[C:16](=[O:19])[CH2:17][CH2:18][C@H:14]1[C:13]([NH:12][C@H:11]([C:10]([NH:9][C@H:8]([CH:7]=[O:6])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:38])[NH2:39])=[O:32])[CH3:31])=[O:30])=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@H](C)NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: C[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N[C@H](C=O)CCCNC(=N)N
Yield: 55.9 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-pyroglutamyl-L-alanyl-L-argininal dibutylacetal hydrochloride (0.22 g, 0.35 mmol) in acetonitrile (35 ml) was added 1N hydrochloric acid aqueous solution (17.5 ml). The mixture was reacted at 36° C. for 1.5 hour with stirring. After completion of the reaction, pH of the reaction mixture was adjusted to 4.8 with 1N sodium hydroxide aqueous solution. The solvent was distilled off under reduced pressure and chloroform-methanol (20:1) was added to the residue. Insoluble matters were removed by filtration. After the filtrate was concentrated, the residue was recrystallized from chloroform-hexane to give 0.10 g (57%) of N-benzyloxycarbonyl-L-pyroglutamyl-L-alanyl-L-argininal hydrochloride.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=[C:2]=[O:3].[Cl:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]2[CH:24]=[N:23][N:22]=[C:21]2[C@H:25]2[CH2:29][CH2:28][CH2:27][NH:26]2)=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]2[CH:24]=[N:23][N:22]=[C:21]2[C@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:2]([NH:1][C:4]2[CH:5]=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:9]=2)=[O:3])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Clc1ccc(Cn2cnnc2[C@H]2CCCN2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCC[C@@H]1c1nncn1Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a stirring solution of 1-isocyanato-4-(trifluoromethyl)benzene (46.3 mg, 0.2474 mmol) in 8 mL of CH2Cl2 at 0° C. was slowly added a solution of (R)-4-(4-chlorobenzyl)-3-(pyrrolidin-2-yl)-4H-1,2,4-triazole (0.050 g, 0.1903 mmol) in dichloromethane (2 mL). The resulting mixture was stirred 0° C. for 30 minutes, then at room temperature overnight. The reaction mixture was concentrated in vacuo. Flash chromatography purification ((Hex/EtOAc with 10% of MeOH) afforded the desired product (68 mg, 79.4%).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[CH:21][CH:20]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2].N1([C:34](N2C=CN=C2)=[O:35])C=CN=C1>CN(C=O)C.CCOC(C)=O>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:28]=[CH:27][C:22]([C:23]4[O:24][C:34](=[O:35])[NH:26][N:25]=4)=[CH:21][CH:20]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(C(=O)NN)cc3)c2n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4n[nH]c(=O)o4)cc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
To a solution of (S)-4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzohydrazide (Example 9, Step 2; 91 mg, 0.239 mmol) in DMF (2 mL) was added di(1H-imidazol-1-yl)methanone (40.7 mg, 0.251 mmol). The reaction mixture was allowed to stir for 1 hour at ambient temperature, then dissolved in EtOAc, washed with water and brine, and concentrated. The resulting solid was suspended in dichloromethane, filtered, washed with dichloromethane, then concentrated to give crude product. The residue was purified by silica gel chromatography (0-5% MeOH in dichloromethane) to afford 42.8 mg (44%) of (S)-5-(4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1,3,4-oxadiazol-2(3H)-one. LCMS (APCI+) m/z 407.5 [M+H]+.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1OS(C1C=CC(C)=CC=1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+].CCOCC>CN(C=O)C>[N:26]([C@H:3]1[C@@H:2]([F:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)=[N+:27]=[N-:28]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H](N=[N+]=[N-])C1
Temperature: 128 °C
Reaction time: 18 h
Yield: 54.1 %

Procedure:
A mixture of trans-tert-butyl 4-fluoro-3-(tosyloxy)piperidine-1-carboxylate (3.95 g, 10.6 mmol) and NaN3 (1.72 g, 26.4 mmol) in DMF (30 mL) was stirred at 128° C. (bath) for 18 hours. After cooling to room temperature, ether (100 mL) was added. The mixture was washed with brine (2×50 mL), dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (hexane:ethyl acetate 4:1) to give cis-tert-butyl 3-azido-4-fluoropiperidine-1-carboxylate (1.40 g, 54%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]#[C:28][C:29]1[C:30]([O:39][CH3:40])=[CH:31][C:32]([O:37][CH3:38])=[C:33]([CH:36]=1)[CH:34]=O.C[O-].[Li+]>CN(C=O)C.CO>[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]#[C:28][C:29]1[C:30]([O:39][CH3:40])=[CH:31][C:32]([O:37][CH3:38])=[C:33](/[CH:34]=[CH:2]/[C:1]([C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)(=[O:12])=[O:11])=[CH:8][CH:9]=2)=[O:3])[CH:36]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccccn2)cc1
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1N
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(OC)c(/C=C/C(=O)c2ccc(S(=O)(=O)Nc3ccccn3)cc2)cc1C#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
Ex-57A: A solution of 4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A, 451 mg, 1.63 mmol) and 5-(2-aminophenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 459 mg, 1.63 mmol) in DMF (10.0 mL) and MeOH (5.0 mL) was treated with lithium methoxide (248 mg, 6.52 mmol). The reaction mixture was stirred at room temperature for 3 h under nitrogen, quenched with water (50 mL), and extracted with (3:1) ethyl acetate/THF (4×30 mL). The combined organic phase was brined, dried over sodium sulfate, and concentrated to a yellow oil. The crude material was purified by column chromatography (2–5% MeOH in dichloromethane) to give 735 mg (65%) of 4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}-N-pyridin-2-yl-benzenesulfonamide as a yellow oil. 1H-NMR (300 MHz, DMSO-d6) 8.21 (d, 2H, J=7.5), 8.18 (s, 1H), 8.00 (m, 4H), 7.81 (d, 1H, J=15.0 Hz), 7.74 (t, 2H, J=7.5 Hz), 7.17 (m, 2H), 7.05 (t, 2H, J=7.2 Hz), 6.80 (m, 3H), 6.52 (t, 1H), J=7.5 Hz), 5.43 (d, 1H, J=6.9 Hz), 3.96 (s, 3H), 3.95 (s, 3H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[CH3:29][O:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35](=[O:41])[CH2:36][S:37][CH2:38]2)=[CH:33][CH:32]=1.CN(P(N(C)C)(N(C)C)=O)C.C([C:55]([O:57][CH3:58])=[O:56])#N.[NH4+].[Cl-]>C1COCC1>[CH3:58][O:57][C:55]([CH:36]1[C:35](=[O:41])[C:34]2[C:39](=[CH:40][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)[CH2:38][S:37]1)=[O:56]
Reactant: COc1ccc2c(c1)CSCC2=O
Reactant: COC(=O)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: COC(=O)C1SCc2cc(OC)ccc2C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
A 2.0 M solution of LDA in heptane/THF/ethylbenzene (1.61 mL, 3.21 mmol) was added in a dropwise manner to a solution of 7-methoxy-isothiochroman-4-one (0.50 g, 2.57 mmol) in THF (50 mL) at −78° C. under N2. After 30 min at −78° C. HMPA (0.46 g, 2.57 mmol) and methyl cyanoformate (0.27 g, 3.21 mmol) were added and the yellow solution was allowed to stir at −78° C. for 30 min. The solution was then allowed to warm to room temperature and a saturated solution of NH4Cl (100 mL) was added. The slurry was extracted with EtOAc (3×75 mL) and the organic extracts were combined, dried (MgSO4) and concentrated under reduced pressure to provide a bright yellow oil. The oil was purified on silica using medium pressure chromatography (9:1 petroleum ether/EtOAc) to provide 7-methoxy-isothiochroman-4-one-3-carboxylic acid methyl ester as a bright yellow oil (0.51 g, 78%). 1H-NMR (300 MHz, CDCl3) δ 3.73 (s, 2H), 3.83 (s, 3H), 3.85 (s, 3H), 6.67 (d, J=3 Hz, 1H), 6.45 (dd, J=3, 8.7 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 12.52 (s, 1H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[N:34][C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[OH:45])=[N:36]2)=[CH:31][CH:30]=1.[OH:52][C@H:53]([CH2:57][CH:58]([CH3:60])[CH3:59])[C:54](O)=[O:55].C(N(CC)CC)C>CN(C=O)C>[OH:52][C@H:53]([CH2:57][CH:58]([CH3:60])[CH3:59])[C:54]([N:49]1[CH2:50][CH2:51][N:46]([C:33]2[C:32]3[C:37](=[CH:38][C:29]([CH3:28])=[CH:30][CH:31]=3)[N:36]=[C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[OH:45])[N:34]=2)[CH2:47][CH2:48]1)=[O:55]
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)C[C@@H](O)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(C)C)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
Under an N2 atmosphere, BOP (138 mg, 0.31 mmol) was added in a single portion to a stirring solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (100 mg, 0.31 mmol), (R)-2-hydroxy-4-methylpentanoic acid (41 mg, 0.31 mmol), and triethylamine (43 μL, 0.31 mmol) in DMF (0.5 ml). After stirring the mixture for 1 h at room temperature, it was partitioned between H2O and ether. The organic phase was washed with H2O (3×20 mL), dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 20% EtOAc and 80% CH2Cl2 gave (R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one as a light yellow solid (89 mg, 60%). LC/MS: m/z 435.1 (M+H)+ at 2.93 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, CDCl3) δ 8.46 (dd, J=7.9, 1.7 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.41-7.37 (m, 1H), 7.30 (dd, J=8.5, 1.5 Hz, 1H), 7.06-7.04 (m, 1H), 6.98-6.94 (m, 1H), 4.51-4.45 (m, 1H), 4.04-3.80 (m, 6H), 3.72-3.62 (m, 3H), 2.56 (s, 3H), 2.12-1.99 (m, 1H), 1.57-1.49 (m, 1H), 1.38-1.32 (m, 1H), 1.05 (d, J=6.6 Hz, 3H), 1.00 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[CH:33][N:32]=1.CCN(C(C)C)C(C)C>>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=2)=[N:32][CH:33]=1)(=[O:39])[CH3:38]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(=O)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(C(C)=O)cn2)cc1
Yield: 35.3 %

Procedure:
A mixture of ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate (1.05 g; 2.57 mmol), 2-chloro-5-acetyl-pyridine (0.40 g; 2.57 mmol) and DIEA (0.36 g; 2.83 mmol) was heated in a pressure tube at 180C for 5 hr. Upon cooling, the residue was chromatographed using 20% ethyl acetate-hexane mixtures to afford ethyl 2-[4-(2-{(5-acetylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (0.48 g; 35% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.ClCCl.[CH3:12][N:13](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.[Zn]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[N:13])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(Cl)nc1
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cl)cn1
Temperature: 25 °C
Yield: 46 %

Procedure:
Slurry 2,5-dichloropyridine (6 g, 40.5 mmol), zinc cyanide (2.9 g, 24.7 mmol), zinc (dust) (116 mg, 1.8 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (720 mg, 0.98 mmol) in anhydrous DMF (40 mL). Heat the mixture to reflux under a nitrogen atmosphere for 4.5 h. Cool the mixture to room temperature, dilute with EtOAc (300 mL), wash with aqueous 10% sodium chloride (3×75 mL). Collect organic layer, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1 gradient) to obtain the desired intermediate (2.6 g, 46%). GC-MS m/z: 138 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH3:30])=[C:21]([C:23]([O:25]CCCC)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH3:30])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)oc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCO[C@@H]1CN(c2nc(C(=O)O)c(C)o2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 50.3 %

Procedure:
The same operation as in Example (91d) was performed using butyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (112i) (0.2 g, 0.42 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (2 mL) and THF (3 mL), to obtain 90 mg of the title compound as a colorless solid (51%).
Reaction SMILES: ClCCl.[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(N(CC)CC)C>[CH3:23][S:24]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:26])=[O:25]
Reactant: CCCCCCCCC=CCCCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCC=CCCCCCCCCOS(C)(=O)=O

Procedure:
To a mixture of 250 ml. of dichloromethane, 25 g. 1-hydroxyoctadec-9-ene and 16.7 g. of triethylamine cooled in an ice-salt bath to -10° C. is added dropwise, over 15 minutes, 18.9 g. of methanesulfonyl chloride. The mixture is cooled at -10° C. to -15° C. for 30 minutes and then washed with 300 ml. each of cold water, 10% hydrochloric acid, sodium carbonate solution and with saturated sodium chloride solution. The organic layer is dried with magnesium sulfate and concentrated in vacuo to give a pale yellow oil.