Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:18]=[CH:17][C:16](CO)=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:21]N1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(#N)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:18]=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(CO)cc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.6 %

Procedure:
To a solution of dl-N-t-butoxycarbonyl-p-hydroxymethylphenylglycine (3.0 g, 0.011 mole) and N-hydroxysuccinimide (1.25 g., 0.011 mole) in 10 ml dry tetrahydrofuran and 50 ml dry acetonitrile was added N,N'-dicyclohexylcarbodiimide (2.238 g., 0.011 mole). The mixture was stirred at room temperature overnight. The dicyclohexylurea was filtered off and the filtrate taken to dryness under reduced pressure. The resulting solid was triturated with ether and filtered to give the N-hydroxysuccinimide ester of N-t-butoxycarbonyl-p-hydroxyphenylglycine (3.4 g., 83 percent yield) m.p. 141°-148° dec.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.CN(C)[CH:23]=[O:24]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Fc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1c(F)cccc1Br
Temperature: -69 °C
Reaction time: 1.5 h
Yield: 96.3 %

Procedure:
A solution of n-butyllithium (2.5M in hexanes, 2.866 L, 7.17 mol) is added dropwise to a stirred solution of diisopropylamine (745.7 g, 7.37 mol) in tetrahydrofuran (1.630 L) such that the temperature is maintained in the range −60 to −78° C. The resulting suspension is stirred for 1.5 h at −75 to −78° C. A solution of 1-bromo-3-fluorobenzene (1.228 Kg, 7.02 mol) in tetrahydrofuran (2.40 L) is added slowly to the reaction mixture over 1.5 h. Stirring is continued for 30 min at −70 to −71° C. Dimethylformamide (511.3 g) is added over 1 h. The reaction mixture is allowed to warm to −15° C. and is quenched by the slow addition of acetic acid (1.965 L) over 20 min. TBME (5.20 L) and water (6.25 L) are added. The resultant solution is stirred vigorously and the layers are separated. The aqueous layer is extracted with TBME (1.965 L) twice and the combined organic layers are washed with 0.2 M hydrochloric acid (2×5.00 L), saturated aqueous sodium hydrogen carbonate solution (2×2.50 L) and water (3.50 L). The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a yellow crystalline solid (1.367 Kg, 96%). 1H NMR (CDCl3): δ 10.36 (s, 1H), 7.49 (d, 1H, 3=7.8 Hz), 7.45-7.37 (m, 1H), 7.15 (t, 1H, J=7.9 Hz).
Reaction SMILES: CO[C:3]([CH3:6])([CH3:5])[CH3:4].[F:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([F:14])[CH:13]=1>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:3]([C:13]1[C:8]([F:7])=[CH:9][C:10]([OH:15])=[CH:11][C:12]=1[F:14])([CH3:6])([CH3:5])[CH3:4]
Reactant: Oc1cc(F)cc(F)c1
Reactant: COC(C)(C)C
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)c1c(F)cc(O)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To a suspension of zirconium tetrachloride (1.17 g, 5 mmol) in DCM (10 ml) was added tert-butyl methyl ether (0.44 g, 5 mmol) at 0° C. After stirring for 30 minutes at 0° C., 3,5-difluorophenol (0.65 g, 5 mmol) in DCM was placed there and the mixture was stirred for 8 hours at 60° C. The reaction was quenched with saturated sodiumbicarbonate aqueous solution followed by addition of DCM. Then, organic layer was separated, dried over magnesium sulfate, evaporated in vacuo to give the residue which was purified through silica gel column chromatography eluting with hexane/EtOAc (20:1 to 4:1) to furnish 4-tert-butyl-3,5-difluorophenol as colorless oil (293 mg, 31%). 1H NMR (300 MHz, CDCl3): δ 1.42 (9H, t, J=2.2 Hz), 5.22 (1H, bs), 6.32 (2H, d, J=11.9 Hz).
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:31])=[C:14]([F:32])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6](OC(C)C)=[O:7].O.[CH2:34]([NH2:36])[CH3:35]>>[F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:31])=[C:14]([F:32])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([NH:36][CH2:34][CH3:35])=[O:7]
Reactant: CC(C)OC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Reactant: CCN
Solvent: O
Product: CCNC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of isopropyl 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (II(d)) (0.2 g, 0.45 mmol, 1.0 eq) in ethylamine (6 mL, 60-70% aqueous solution) was stirred at 100° C. overnight in a sealed tube. The reaction mixture was then cooled to room temperature and poured into water. The mixture was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 1:20 to 1:4, v/v) to give the title compound as a white solid (0.15 g, 80%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[Si:39]([O:46][CH2:47][CH2:48][CH2:49][N:50]1[CH:54]=[C:53](B2OC(C)(C)C(C)(C)O2)[CH:52]=[N:51]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Si:39]([O:46][CH2:47][CH2:48][CH2:49][N:50]1[CH:54]=[C:53]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:52]=[N:51]1)([C:42]([CH3:45])([CH3:43])[CH3:44])([CH3:40])[CH3:41]
Reactant: CC1(C)OB(c2cnn(CCCO[Si](C)(C)C(C)(C)C)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cnn(CCCO[Si](C)(C)C(C)(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, 0.2 mmol) was treated with 1-(3-(tert-butyldimethylsilyloxy)propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (180 mg, 0.49 mmol), tetrakistriphenylphosphine palladium (72 mg, 0.06 mmol) and aqueous solution of sodium carbonate (2M, 250 μl, 0.5 mmol) in DMF (3 ml). The reaction mixture was submitted at vacuum-argon cycles and stirred at 100° C. for 3 h. The reaction mixture was cooled down to room temperature and poured over ice, basified with potassium carbonate and extracted with ethyl acetate (×3). The organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified by normal phase using SP1® Purification System (0% to 50%, hexane-diethyl ether) to obtain 124 mg (69% yield) of the title compound. Purity: 85%.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.Br[C:16]1[C:17]([CH:38]([CH3:40])[CH3:39])=[N:18][N:19]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1>CN(C=O)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[N:19]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)[N:18]=[C:17]([CH:38]([CH3:40])[CH3:39])[C:16]=2/[CH:3]=[CH:2]/[C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:23]=1
Reactant: C=CC(=O)OCC
Reactant: CC(C)c1nn(-c2ccc3ccccc3n2)c(-c2ccc(F)cc2)c1Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(C(C)C)nn(-c2ccc3ccccc3n2)c1-c1ccc(F)cc1
Yield: 86.9 %

Procedure:
Ethyl acrylate (4.9 mL, 45 mmoles) and bis-triphenyl phosphine palladium (II) chloride (0.25 g, 0.36 mmoles) were suspended in a 1:1 mixture of triethyl amine and DMF. This mixture was heated to reflux under an atmosphere of N2. When the suspension had completely dissolved, 2-[4-bromo-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]quinoline (3.70 g, 9.0 mmoles) was carefully added. The resulting yellow solution was refluxed for 16 hours, then cooled and partitioned between H2O and Et2O. The ether layer was dried over MgSO4, filtered, and evaporated to give a yellow solid which was recrystallized from hexanes to give 3.36 g (87%) of the title compound as a tan solid, mp 140°-143° C.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][NH:7][CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]1=2.N1C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45].[OH-].[Na+]>ClCCl.Cl>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[CH2:6][N:7]([CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]1=2)[C:44](=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(NCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (+/−) (3,5-Bis-trifluoromethyl-benzyl)-[1-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-amine (149 mg, 0.27 mmol) and pyridine (0.33 ml, 4 mmol) in dichloromethane (1.5 ml) at room temperature is added acetic anhydride (0.38 ml, 4.1 mmol) via dropwise addition over 2 minutes. The mixture is stirred at room temperature for 20 hours. The mixture is treated with 1N aqueous NaOH (4 ml) and stirred for 10 minutes, then diluted with 1N HCl (15 ml) and dichloromethane (15 ml). The organic layer is washed with water, dried (Na2SO4), and concentrated to a solid. Purification by silica gel column chromatography (eluent, 35% ethyl acetate in hexanes) gives the title compound as a solid. Mass spectrum (ES+): 585 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([NH:22][S:23]([C:26]4[CH:27]=[CH:28][CH:29]=[C:30]5[C:35]=4[N:34]=[CH:33][CH:32]=[CH:31]5)(=[O:25])=[O:24])=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)#[N:2].[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([NH:22][S:23]([C:26]4[CH:27]=[CH:28][CH:29]=[C:30]5[C:35]=4[N:34]=[CH:33][CH:32]=[CH:31]5)(=[O:25])=[O:24])=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)(=[NH:41])[NH2:2]
Reactant: N#Cc1ccc(CC(=O)N2CCc3ccc(NS(=O)(=O)c4cccc5cccnc45)cc3C2)cc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: N=C(N)c1ccc(CC(=O)N2CCc3ccc(NS(=O)(=O)c4cccc5cccnc45)cc3C2)cc1

Procedure:
Prepared analogously to Example 1e from 2-[(4-cyanophenyl)-acetyl]-7-(quinoline-8-sulphonylamino)-1,2,3,4-tetrahydro-isoquinoline and hydrochloric acid/ammonium carbonate in ethanol.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[C@H:10]1[C:15]([O:16]C)=N[C@H](C(C)C)C(OC)=[N:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.C1C[O:37][CH2:36]C1>CC#N>[NH2:11][C@@H:10]([C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=1)[C:15]([O:37][CH3:36])=[O:16]
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Reactant: C1CCOC1
Agent: Cl
Solvent: CC#N
Product: COC(=O)[C@@H](N)[C@@H](O[Si](C)(C)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Yield: 84 %

Procedure:
To a solution of (2S,5R)-2-((S)-(tert-butyldimethylsilyloxy)(4-(trifluoromethyl)phenyl)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (3.1 g, 6.6 mmol) in THF (15 mL) and CH3CN (30 mL) was added 0.25 N hydrochloric acid (53 mL, 13 mmol) at room temperature. The mixture was stirred over the weekend and then concentrated in vacuo. The residue was neutralized with saturated NaHCO3 and extracted with EtOAc three times. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-25%-50% EtOAc-hexane) to provide the product as colorless oil (2.1 g, 84%). LCMS (API-ES) m/z: 378 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:30][CH3:31])[CH2:22][O:23][CH2:24][C:25]3([C:28]#[N:29])[CH2:27][CH2:26]3)[C:11](=[O:32])[C@@H:10]([CH2:33][C:34]([OH:36])=[O:35])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:42]>CC(O)(C)C>[C:28]([C:25]1([CH2:24][O:23][CH2:22][C@@H:21]([N:12]2[C@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:9][C@H:10]([CH2:33][C:34]([OH:36])=[O:35])[C:11]2=[O:32])[CH2:30][CH3:31])[CH2:27][CH2:26]1)(=[O:42])[NH2:29]
Reactant: CC[C@@H](COCC1(C#N)CC1)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC[C@@H](COCC1(C(N)=O)CC1)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A solution of 10 mg (0.02 mmol) 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((1-cyanocyclopropyl)methoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid (Example 11) and potassium hydroxide (3.2 mg, 0.06 mmol) in t-BuOH (189 μL) was stirred at 85° C. for 24 h. The reaction was acidified (10% citric acid) and extracted (2×EtOAc). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification by reversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 35 to 75% acetonitrile +0.1% TFA in water +0.1% TFA, gradient elution) provided the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[C:14](O)(=[O:17])[C:15]#[CH:16].C1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:14]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:12]=[CH:13][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:17])[C:15]#[CH:16]
Reactant: Cc1ccc(OCCCCO)cc1
Reactant: C#CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C#CC(=O)OCCCCOc1ccc(C)cc1
Yield: 89.2 %

Procedure:
A mixture of 1 g of 4-(4-methylphenoxy)butanol, 1.1 g of propiolic acid, 0.005 g of p-toluenesulfonic acid and 25 ml of benzene was refluxed with stirring for six hours while water formed was removed by a Dean-Stark water separator. After the reaction was completed, the reaction solution was washed successively with a 5% aqueous sodium bicarbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue was subjected to silicagel column chromatography to yield 1.15 g of 4-(4-methylphenoxy)butyl propiolate (compound 11).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1.[Li]C(C)(C)C.[C:19](=[O:21])=[O:20]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:19]([OH:21])=[O:20])=[C:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1csc(-c2ccc(Cl)cc2)c1
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ccc(Cl)cc2)sc1C(=O)O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 74.9 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-4-methyl-thiophene (0.53 g, 1.85 mmol) in THF (25 mL) and cool to −78° C. Add t-BuLi (1.7 M, 2.3 mL, 3.88 mmol) dropwise. Stir the solution at −78° C. for 20 min. Cannulate the solution into a flask containing powdered dry ice (10 g). Stir the reaction and allow to warm to RT. Quench the reaction with saturated NH4Cl (10 mL), dilute with water (40 mL), and extract with EtOAc (2×50 mL). Dry the combined organic layers over Na2SO4, filter, and concentrate. Purify the crude material by washing with hexane (2×20 mL) to give 0.35 g (74%) of the title compound. LC-MS/ES m/z (35Cl) 251.0 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].[C:26](OC(=O)C)(=[O:28])[CH3:27]>CC(O)=O>[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1)=[O:8])(=[O:28])[CH3:27]
Reactant: Nc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
5-Amino-N-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxybenzamide (364.24 mg, 1 mmol) obtained in Example 31 was dissolved in acetic anhydride (0.09 ., 1 mmol), to which AcOH (3 ml) was added, followed by stirring at room temperature for 3 hours. The mixture was extracted by using ethylacetate. The extract was washed with saturated sodium hydrogen carbonate, and dried over MgSO4. After eliminating ethylacetate, the non-purified compound was purified by silica gel column chromatography (ethylacetate:hexane=1:1) to give 340 mg of the target compound (yield: 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)=[C:4]([F:18])[CH:3]=1.[I:19]I.N1C=CN=N1>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([I:19])=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:15])[F:16])[C:10]([CH3:17])=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: Cc1nn(-c2ccc(Cl)cc2F)c(=O)n1C(F)F
Reactant: II
Agent: O=S(=O)(O)O
Agent: c1c[nH]nn1
Product: Cc1nn(-c2cc(I)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 25 °C
Yield: 93 %

Procedure:
To a 250 mL roundbottom flask equipped with a mechanical stirrer and a thermometer was added 100 mL of 20% fuming sulfuric acid (oleum) (% wt/vol. triazole to solvent--28.7%), followed by 28.7 grams (0.104 mole--1.0 equiv.) of 1-(4-chloro-2-fluorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole. The mixture was vigorously stirred at ambient temperature to effect dissolution. The mixture was cooled in an ice-bath, and 26.3 grams (0.104 mole--1.0 equiv.) of iodine crystals were added. The reaction mixture was then warmed to ambient temperature, where it stirred for seven hours. After this time gas chromatographic (GC) and TLC analysis of the reaction mixture indicated that the reaction was almost complete. The reaction mixture was stirred at ambient temperature for an additional 16 hours. At the conclusion of this period a second GC analysis of the reaction mixture indicated 100% conversion of the triazole starting material. The reaction mixture was poured into 300 grams of ice, and the resulting mixture was extracted with two 250 mL portions of methylene chloride. The organic extracts were combined and washed with an aqueous 10% potassium carbonate solution, an aqueous 5% sodium bisulfite solution, and an aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding a white solid, which was dried to a constant weight, yielding 38.8 grams of 92% pure 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole (92.5% yield). GC analysis of the product indicated the presence of about 4% of an impurity. The 92% pure product was recrystallized from 300 mL of methanol, yielding 29.8 grams of 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole, m.p. 125-127° C. The mother liquor was concentrated under vacuum to yield a residue, which was recrystallized from 60 mL of methanol, yielding an additional 5.9 grams of 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(Cl)(=O)C>>[CH3:1][N:2]([CH:3]1[CH2:16][CH:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH2:14]2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reactant: O=C(Cl)c1ccccc1
Solvent: CC(=O)Cl
Product: CC1C2CCC3C4CCC5CC(N(C)C(=O)c6ccccc6)CCC5(C)C4CCC32CN1C

Procedure:
The title compound was prepared according to procedures described in Example 7C, except substituting Compound 172B for Compound 7B and benzoyl chloride for acetyl chloride. 1H NMR (CDCl3): δ 0.75 (s, 3 H) 0.85-2.00 (m, 26 H) 2.21 (m, 3 H) 2.80 (s, 3 H) 2.98 (s, 3 H) 3.46 (m, 1 H) 7.39 (m, 5 H); (M+H)+=449.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.[CH2:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:14].C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CCCCNCC
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CC)c1cc(C)nc(Cl)c1[N+](=O)[O-]

Procedure:
2,4-Dichloro-6-methyl-3-nitropyridine (1 g, 4.83 mmol), N-ethylbutylamine (0.75 mL, 5.55 mmol), and N,N-diisopropylethylamine (1 mL, 6 mmol) were stirred at 25° C. for 24 h and at reflux for 5 h. Then the mixture was stripped in vacuo and the residue was partitioned between EtOAc (75 mL), and water (50 mL). The organic layer was washed with water (30 mL), brine (30 mL), dried (MgSO4) and stripped in vacuo. The residue was chromatographed on silica gel (10%) EtOAc/hexanes eluent) to give the two regiomers 270 mg and 840 mg. The major regioisomer was characterized as the 4-adduct by nOe NMR experiments. minor: NMR (CDCl3) 6.56 (s, 1H), 3.30-3.42 (m, 4H), 2.38 (s, 3H), 1.49-1.59 (m, 2H), 1.23-1.35 (m, 2H), 1.15 (t, 3H, J=7.3 Hz), 0.92 (t, 3H, J=7.0 Hz); major: NMR (CDCl3) 6.52 (s, 1H), 3.28 (q, 2H, J=7.0), 3.18 (dd, 2H, J1 =7.3 Hz, J2 =8.1 Hz), 2.44 (s, 3H), 1.49-1.60 (m, 2H), 1.24-1.37 (m, 2H), 1.17 (t, 3H, J=7.3 Hz), 0.94 (t 3H, J=7.3 Hz).