Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:3]([NH:5][C@@H:6]([CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:7]([OH:17])[C:8]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])=[O:4].[CH:31]1[CH:36]=[C:35]2[C:37]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45](O)=[O:46])[C:38]=3[C:39](=[O:40])[C:34]2=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH2:20]([O:19][CH2:18][CH:6]([NH:5][C:3](=[O:4])[C@H:2]([NH:1][C:45]([C:41]1[C:38]2[C:39](=[O:40])[C:34]3[C:35](=[CH:36][CH:31]=[CH:32][CH:33]=3)[C:37]=2[CH:44]=[CH:43][CH:42]=1)=[O:46])[CH2:27][CH:28]([CH3:29])[CH3:30])[CH:7]([OH:17])[C:8]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CNC(=O)C(O)[C@H](COCc1ccccc1)NC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)c1cccc2c1C(=O)c1ccccc1-2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)C(O)C(COCc1ccccc1)NC(=O)[C@@H](CC(C)C)NC(=O)c1cccc2c1C(=O)c1ccccc1-2
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Ethyl 2-[(3S)-3-[(2S)-2-amino-4-methylpentanoyl]amino-4-(benzyloxy)-2-hydroxyl butanoyl]aminoacetate (500 mg, 1.2 mmole), 9-Fluorenone-1-Carboxylic acid (266 mg, 1.2 mmole), and HBTU (587 mg, 1.6 mmole) were dissolved in DMF (10 mL). Et3N (330 ul, 2.4 mmole) was added and stirring was continued overnight. DMF was removed under reduced pressure. The residue was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation. Purification by chromatography (silica, EtOAc, Rf=0.3) afforded ethyl 2-(4-(benzyloxy)-2-hydroxy-3-[((2R)-4-methyl-2-[(9-oxo-9H-1-fluorenyl)carbonyl]aminopentanoyl)amino]butanoylamino)acetate as a white solid (641 mg, 85%).
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:3][CH2:4][C:5]([O:7]C(C)(C)C)=[O:6].CO.[OH-].[Na+:22]>O1CCCC1>[OH:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+:22]
Reactant: Cc1ccccc1C(O)CCC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1C(O)CCC(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of t-butyl 4-hydroxy-4-(2-methylphenyl)butanoate, thought to be the (R)-enantiomer, (0.5 g) in tetrahydrofuran (3 mL) and methanol (3 mL) is treated with aqueous sodium hydroxide solution (5 N; 0.5 mL) and stirred at ambient temperature for 8 hours. The reaction mixture is concentrated to dryness. The resulting residue is treated with isopropanol (10 mL) and stirred for 30 minutes, and the resulting precipitate is collected and washed with isopropyl ether, to give sodium 4-hydroxy-4-(2-methylphenyl)butanoate, thought to be the (R)-enantiomer, (300 mg) in the form of a white solid, m.p. above 250° C.; 25[α]D=+34° (c=0.01; CH3OH); [NMR(DMSO-d6) (300 MHz):- 1.58-1.75 (m,2H),2.11(m,2H),2.22(s,3H),4.75(m,1H),7.05-7.48 (m.4H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH2:20])[CH:14]=1.O>CN(C=O)C>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH:20][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])[CH:14]=1
Reactant: CN1CC(=O)NC1=NC(=O)O
Reactant: Cc1cc(C)nc(N)c1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(NC(=O)N=C2NC(=O)CN2C)c1
Temperature: 55 °C
Yield: 38 %

Procedure:
A mixture of 3.0 g (12.8 mM) of the phenyl carbamate 8, and 1.6 g (12.8 mM) of 4,6-dimethyl-2-aminopyridine in 50 ml of anhydrous DMF was heated at 55° C. for 8 hrs., cooled, and poured into 200 ml water. The resulting precipitate was collected and recrystallized from ethyl acetate to give 1.3 g of the above urea as a light yellow solid, m.p. 192°-193° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.CC(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1>O>[F:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:12]=[C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=3)=[CH:4][CH:3]=2)=[CH:37][CH:38]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(O)cc2)no1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(OCc3ccc(F)cc3)cc2)no1)C(C)C

Procedure:
To methyl 2-(3-(4-hydroxyphenyl)isoxazole-5-carboxamido)-3-methylbutanoate (150 mg) in, acetone (3 ml), potassium carbonate (78 mg) was added and stirred. To this 1-(bromomethyl)-4-fluorobenzene (0.07 ml) was added and the reaction mixture was refluxed for 2 hours and then cooled reaction. The mixture was filtered and filtrate was concentrated to obtain pale brown residue. To this residue, water was added and extracted with EtOAc. Organic layer was collected and dried over Na2SO4 and concentrated to obtain off white solid, which was crystallized using DCM-Petroleum ether to obtain the title compound as white solid. Yield: 170 (84%); MS (ES+): m/z 427 (M+1); 1HNMR (DMSO-d6; 300 MHz): δ 9.18 (d, 1H), 7.88 (d, 2H), 7.68 (s, 1H), 7.53 (m, 2H), 7.23 (m, 2H), 7.18 (d, 2H), 5.17 (s, 2H), 4.31 (m, 1H), 3.67 (s, 3H), 2.22 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8](F)=[O:9].[F-:11].[K+].[C:13]([Si](C)(C)C)([F:16])([F:15])[F:14]>>[F:11][C:2]1([C:8]([OH:9])([C:13]([F:16])([F:15])[F:14])[C:13]([F:16])([F:15])[F:14])[CH2:3][CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2
Reactant: O=C(F)C1CC2C=CC1C2
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: [F-]
Agent: [K+]
Product: OC(C(F)(F)F)(C(F)(F)F)C1(F)CC2C=CC1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 107 %

Procedure:
A 100 ml three-necked flask equipped with a thermometer, cooling tube having a 3-way cock and dropping funnel was charged with 27.7 g (168 mmol) of 5-norbornene-2-carboxylic acid fluoride (mixture of endo-form and exo-form) synthesized in Preparation Example 1 and 28 g (482 mmol) of potassium fluoride and was cooled in ice bath in nitrogen gas atmosphere. While maintaining the inside temperature of the flask at 3° to 10° C., 62 g (436 mmol) of CF3SiMe3 was added over two hours with stirring. After increasing the flask temperature to room temperature, stirring was carried out overnight. Then the reaction solution was poured into ice water, followed by extracting with diethylether. After washing an organic phase with water, diluted hydrochloric acid and then saturated sodium bicarbonate solution, the organic phase was dried with calcium chloride. Then refining was carried out by distillation under reduced pressure and 50 g (yield: 80%) of (2-fluoro-5-norbornene-2-yl)-1,1,1,3,3,3-hexafluoro-2-propanol (NB-2) was obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)(C)(C)C.CCOCC>[N:13]1([C:2]2[C:3]3[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N#Cc1c[nH]c2ncnc(Cl)c12
Reactant: C1CCNCC1
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: N#Cc1c[nH]c2ncnc(N3CCCCC3)c12
Temperature: 25 °C
Yield: 42.5 %

Procedure:
To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (54 mg/0.3 mmol) (prepared by the method of Townsend, et. al., J. Am. Chem. Soc., 1969, 91, 2102) suspended in 3.0 mL tert-Butanol was added piperidine (59 μL/0.60 mmol). The resulting mixture was then heated at reflux for 2.5 h and after cooling to room temperature, was transferred to a separatory funnel and diluted with ether (20 mL). The solution was extracted 2×10 mL with 1N HCl, the combined aqueous layers were adjusted to pH 7 with 2 N potassium hydroxide (KOH) solution forming a precipitate which was collected by filtration, washed with water and dried under reduced pressure to give 29 mg (42%) of the title compound as a colorless solid. Mp 209-211° C.; 1H NMR (400 MHz) (acetone-d6)δ: 1.72-1.74 (m, 6H), 3.72-3.79 (m, 4H), 8.12 (s, 1H), 8.29 (s, 1H). LRMS: 228 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][CH2:11][CH2:12][CH:13]2[O:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:4][C:3]=1[O:20][CH3:21].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:27][C:28]=1C>>[CH3:9][O:8][C:7]1[CH:6]=[C:5]([CH2:10][CH2:11][CH2:12][CH:13]2[O:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])[CH:4]=[C:3]([O:20][CH3:21])[C:2]=1[O:1][CH2:23][C:24]1[N:25]=[C:26](/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:27][CH:28]=1
Reactant: COc1cc(CCCC2OC(=O)NC2=O)cc(OC)c1O
Reactant: Cc1oc(/C=C/c2ccccc2)nc1CCl
Product: COc1cc(CCCC2OC(=O)NC2=O)cc(OC)c1OCc1coc(/C=C/c2ccccc2)n1

Procedure:
In substantially the same manner as in Working Example 9, 5-[3-(4-hydroxy-3,5-dimethoxyphenyl)propyl]-2,4-oxazolidinedione was reacted with 4-chloromethyl-5-methyl-2-[(E)-styryl]oxazole to obtain 5-[3-[3,5-dimethoxy-4-[2-[(E)-styryl]-4-oxazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.94-95° C.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C([Li:12])CCC.[CH3:13][CH:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]([O:17][CH3:18])=[O:16].C=C1CC1.C(Br)C=C.CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[CH:1]([N-:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Li+:12].[CH3:13][CH:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]([O:17][CH3:18])=[O:16]
Reactant: CC(C)NC(C)C
Reactant: [Li]CCCC
Agent: C=C1CC1
Agent: COC(=O)C(C)C(C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C=CCBr
Solvent: C1CCOC1
Product: CC(C)[N-]C(C)C
Product: [Li+]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of lithium diisopropylamide was prepared by treating diisopropylamine (40.91 g, 405 mmol) in dry THF (350 mL) with butyllithium in hexanes (2.5M, 154.4 mL, 386 mmol) at 0° C. for 15 min in a nitrogen atmosphere. Then a solution of methyl 2,3,3-trimethylbutyrate (38.88 g, 270 mmol) in THF (30 mL) was added slowly, and the mixture was stirred. Methyl 2,3,3-trimethylbutyrate was prepared as in Quast H, Meichsner G, Seiferling B (1986) "Photochemical formation of methylenecyclopropane analogs. XII. Synthesis of 3,5,5-trialkyl-3,5-dihydro-4H-1,2,3-triazol-4-ones" Liebigs. Ann. Chem., 1891-1899. After 45 min. of stirring, the temperature of the mixture was reduced to -78° C. and a solution of allyl bromide (51.30 g, 424 mmol) in THF (20 mL) and HMPA (40.3 mL, 232 mmol) was added over a period of 15 min. Stirring was continued for 2 h at -78° C. and the system was allowed to warm to room temperature (ca. 6 h). The reaction was quenched by addition of HCl (3N, 300 mL) at 0° C. The layers were separated and the aqueous phase was further extracted with ether (3×150 mL). The combined organic extract was washed sequentially with 100 mL portions of water, 5% Na2S2O3, saturated NaHCO3, water, and brine, and dried over MgSO4. The solvent was removed in vacuo to give 48.88 g of brown colored liquid, which upon two vacuum distillations, afforded olefinic ester (34.85 g, 70%) as a colorless liquid: bp 87°-89° C. (20 mmHg).
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:9]1[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CI.[Li+].[CH3:21]C([N-]C(C)C)C>C1COCC1>[C:1]([N:8]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@@:9]1([CH3:21])[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)[C@]1(C)C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of N-BOC-4(R)-hydroxyproline, methyl ester (Bachem, 17 g, 69 mmol) and MeI (276 mmol) in 250 mL of anhydrous THF at −30° C. was added LDA (Aldrich, 1.5 M in cyclohexane, 250 mmol). The reaction was allowed to warm up to rt over 4 h. The reaction was cooled to −30° C., and was quenched with saturated aqueous ammonium chloride (50 mL). The resulting mixture was partitioned between EtOAc and brine, and the product was extracted with EtOAc (3×100 mL). The combined extracts were dried over anhydrous MgSO4 and concentrated in vacuo. The solvent was removed in vacuo and the residue was purified by repeated flash column chromatography on silica gel eluted with 20:1 to 10:1 hexane/acetone to afford N-BOC-4(R)-hydroxy-2-methyl-(L)-proline, methyl ester (slower eluting and major isomer, 10 g, 58%). The stereochemistry was assigned by NMR comparisons with literature reports (Noe, C R et al Pharmazie 1996, 51, 800).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][CH:15]([CH3:17])[CH3:16])=[N:9][CH:10]=[N:11]2)=[CH:6][C:5]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH3:23][S:24][CH2:25][CH2:26][CH2:27]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O.C(OCC)(=O)C>[CH:15]([NH:14][C:8]1[C:7]2[C:12](=[CH:13][C:4]([O:3][CH2:27][CH2:26][CH2:25][S:24][CH3:23])=[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=2)[N:11]=[CH:10][N:9]=1)([CH3:17])[CH3:16]
Reactant: CSCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)c1cc2c(NC(C)C)ncnc2cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(NC(C)C)ncnc2cc1OCCCSC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
Sodium hydride (60%, 251 mg, 6.3 mmol) is introduced into N,N-dimethylformamide (13 ml), treated in portions with ethyl 7-hydroxy-4-(isopropylamino)quinazoline-6-carboxylate (1 g, 2.98 mmol) and subsequently stirred at room temperature for 30 minutes. After addition of a solution of 3-(methylthio)-1-(tosyloxy)propane (777 mg, 2.98 mmol) in N,N-dimethylformamide (8 ml), the mixture is stirred at 80° C. for one hour. After cooling, the batch is treated with water and ethyl acetate, and the organic phase is separated off and dried over sodium sulphate. The desired product is obtained after removing the solvents and preparative HPLC in 48% yield (548 mg).
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.O[C:23]1[CH:58]=[CH:57][C:26]([CH2:27][N:28]([CH2:49][C:50]([O:52]C(C)(C)C)=[O:51])[C:29](=[O:48])[C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:47])[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][C:23]3[CH:58]=[CH:57][C:26]([CH2:27][N:28]([CH2:49][C:50]([OH:52])=[O:51])[C:29](=[O:48])[C:30]4[CH:31]=[CH:32][C:33]([NH:36][C:37](=[O:47])[CH2:38][C:39]5[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=5)=[CH:34][CH:35]=4)=[CH:25][CH:24]=3)=[O:12])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)cc1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(OC(=O)c4ccc(C5CCCCC5)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
Prepared using General Procedures 2 and 8: To a stirring solution of 4-cyclohexylbenzoic acid (24 mg, 0.119 mmol) in DCM (0.5 mL) were added DMF (1 drop) and oxalyl chloride (0.011 mL, 0.127 mmol). The reaction mixture was stirred at room temperature for 2 h. To this mixture was added a solution of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-7 (40 mg, 0.079 mmol) and TEA (0.022 mL, 0.159 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 18 h then TFA (1 mL) was added. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to provide to afford 22.2 mg (44%) of 2-(N-(4-((4-cyclohexylbenzoyl)oxy)benzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido) acetic acid 39. LCMS-ESI (m/z) calculated for C38H38N2O7: 634; found 633 [M−H]−, tR=8.92 min (Method 4). 1H NMR (400 MHz, DMSO) δ 10.30 (s, 1H), 8.04 (d, J=7.7 Hz, 2H), 7.64 (d, J=8.2 Hz, 2H), 7.45 (t, J=7.0 Hz, 3H), 7.39-7.26 (m, 3H), 7.24 (d, J=8.4 Hz, 4H), 6.88 (d, J=8.1 Hz, 2H), 4.62 (d, J=36.7 Hz, 2H), 3.94 (d, J=31.7 Hz, 2H), 3.72 (s, 2H), 3.57 (s, 3H), 2.63 (t, J=10.7 Hz, 1H), 1.76 (dd, J=36.3, 11.5 Hz, 5H), 1.53-1.16 (m, 5H).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][S:3][CH:2]1[C:6]([O:8]CC)=O.Cl.[CH3:12][NH:13][O:14][CH3:15].C([Mg]Br)(C)C>C1COCC1>[CH3:15][O:14][N:13]([CH3:12])[C:6]([CH:2]1[S:1][CH2:5][CH2:4][S:3]1)=[O:8]
Reactant: CCOC(=O)C1SCCS1
Reactant: CNOC
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)C1SCCS1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A vigorously stirred slurry of ethyl 1,3-dithiolane-2-carboxylate (8, 1.50 mL, 10.5 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.57 g, 26.2 mmol) in THF (21 mL) was treated dropwise with isopropylmagnesium bromide (52.5 mmol, 26.3 mL, 2 M in THF) over 40 min at −78° C. under argon. The reaction mixture was stirred for 1 h at −78° C. under argon. The reaction mixture was quenched with saturated aqueous NH4Cl/H2O (1:1). The aqueous phase was extracted with ether (3×100 mL). The combined organic extract was washed (water, brine), dried (Na2SO4), concentrated and chromatographed [silica, EtOAc/hexanes (2:1)] to afford a yellow oil that solidified upon storage at 1° C. (985 mg, 49%). The characterization values (1H NMR, 13C NMR, ESI-MS) were consistent with those for the title compound prepared via a different synthetic route.43
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=O.C([CH2:21][C:22]([NH:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])=[O:23])(O)=O>C1(C)C=CC=CC=1>[OH:7][C:8]1[CH:9]=[C:10](/[CH:11]=[CH:21]/[C:22]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:23])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(C=O)cc1O
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1O
Temperature: 25 °C
Yield: 76.9 %

Procedure:
Piperidine (0.25 mL, 2.5 mmol) was added to a suspension of 3-hydroxy-4-methoxybenzaldehyde (0.39 g, 2.5 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.50 g, 2.2 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 3 h, then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (5.0 mL) and water (2.0 mL) at 40° C. and the solution was acidified with concentrated HCl. The precipitate was filtered, providing (E)-2-[[3-(3-hydroxy-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.53 g, 76%) as a yellow crystalline solid; mp 215-216° C., lit.5 219-222° C.; δH (500 MHz, DMSO-d6) 3.81 (s, 3H, OCH3), 6.59 (d, J=15.5 Hz, 1H, CH═CHCO), 6.80 (d, J5′,6=8.5 Hz, 1H, H5′), 7.10-7.13 (m, 2H, H2′, H6′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.47 (d, J=15.5 Hz, 1H, CH═CHCO), 7.60 (td, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 7.99 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.58 (d, J5,6=8.0 Hz, 1H, H6), 11.25 (s, 1H, NH), 13.56 (br s, 1H, CO2H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([CH2:16][CH3:17])[CH:10]=1.CC([O-])=O.[K+].[N:23](OCCC(C)C)=O.C1OCCOCCOCCOCCOCCOC1>C(Cl)(Cl)Cl>[C:5]([N:13]1[C:12]2[C:11](=[CH:10][C:9]([Br:8])=[CH:15][CH:14]=2)[C:16]([CH3:17])=[N:23]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cc(Br)ccc1N
Reactant: CC(C)CCON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(=O)n1nc(C)c2cc(Br)ccc21
Reaction time: 0.5 h

Procedure:
Acetic anhydride (4.73 ml) was added to the mixture of 4-bromo-2-ethylaniline (5.0 g) and KOAc (2.94 g) in CHCl3 (70 ml) and stirred for 30 min at reflux. Then isoamyl nitrite (6.65 ml) and 18-crown-6-ether (660 mg) was added to the reaction mixture and stirred for 12 h at reflux. The reaction mixture was diluted with CHCl3, washed with water, and dried over sodium sulfate. After filtration and concentration, the residue was purified by silica gel chromatography (hexane/ethyl acetate), and crystallized from mixed solvent of hexane and CHCl3 to give the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].C(O[C:20]1[CH:21]=[C:22]([CH:31]=[C:32]([N+]([O-])=O)[CH:33]=1)[C:23](OCCC(C)C)=O)CC(C)C.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:37]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH2:23][C:22]1[CH:21]=[CH:20][CH:33]=[CH:32][CH:31]=1)=[O:6])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(O)c1cc(O)cc([N+](=O)[O-])c1
Reactant: BrCc1ccccc1
Reactant: CC(C)CCOC(=O)c1cc(OCCC(C)C)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)cc([N+](=O)[O-])c1

Procedure:
Compound 12 was prepared from 3-hydroxy-5-nitrobenzoic acid (8), following the same protocol as for the synthesis of iso-pentyl 3-iso-pentyloxy-5-nitrobenzoate (9). Scale: 2 g (10.9 mmol) 8; 5.2 mL (43.6 mmol) benzyl bromide; 6.03 g (43.6 mmol) K2CO3; 15 mL DMF anhydrous. Crude yield: 6.5 g dark red oil. Column chromatography (hexanes/ethyl acetate, 9:1, Rf=0.5), purified yield: 2.58 g white solid (65%). 1H NMR (CDCl3) δ 8.49 (dd, J1=1.4 Hz, J2=2.0 Hz, 1H), 8.01-7.98 (m, 2H), 7.49-7.34 (m, 10H), 5.41 (s, 2H, PhCH2), 5.19 (s, 2H, PhCH2).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: Nc1ccc(C2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
DIPEA (1.631 mL, 9.36 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (1.389 g, 6.24 mmol) and 4-(piperidin-4-yl)aniline (1.21 g, 6.86 mmol) in DMF (30 mL). The resulting solution was stirred at 80° C. for 2 hours. The reaction mixture was evaporated to dryness, redissolved in DCM and purified by flash chromatography on silica gel, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to give 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]aniline (1.910 g, 84%) as a solid.