Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@@H]1C2N=CN=C(N3CCN(C(OC(C)(C)C)=O)CC3)C=2[C@H](C)C1.CCN(S(F)(F)F)CC.[F:34][C@H:35]1[C:39]2[N:40]=[CH:41][N:42]=[C:43]([N:44]3[CH2:49][CH2:48][N:47](C(OC(C)(C)C)=O)[CH2:46][CH2:45]3)[C:38]=2[C@H:37]([CH3:57])[CH2:36]1.[ClH:58]>C(Cl)Cl.O1CCOCC1>[ClH:58].[ClH:58].[F:34][C@H:35]1[C:39]2[N:40]=[CH:41][N:42]=[C:43]([N:44]3[CH2:45][CH2:46][NH:47][CH2:48][CH2:49]3)[C:38]=2[C@H:37]([CH3:57])[CH2:36]1
Reactant: C[C@@H]1C[C@@H](F)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: CCN(CC)S(F)(F)F
Agent: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](F)c2ncnc(N3CCNCC3)c21
Temperature: -20 °C
Reaction time: 1.67 h
Yield: 96 %

Procedure:
tert-Butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.843 g, 2.521 mmol) was dissolved in methylene chloride (40 mL) and cooled to −20° C. The solution was treated with DAST (0.9992 mL, 7.562 mmol) and stirred at −20° C. for 100 minutes. After 3 hours, the reaction was quenched with ice and then warmed to ambient temperature. The mixture was separated. The aqueous phase (pH of about 1) was extracted with methylene chloride (2×), and the combined organics were washed with 6% NaHCO3 (2×), dried over Na2SO4, and concentrated to a dark oil (0.91 g). This material was chromatographed on SiO2 (Biotage 40S, load with eluant) and eluted with 2:1 hexane/EtOAc. The desired tert-butyl 4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.6138 g, 72%) was recovered cleanly. tert-Butyl 4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.6138 g, 1.825 mmol) was dissolved in dioxane (5 mL) and cooled to 0° C. A solution of HCl in dioxane (11.40 mL, 45.61 mmol; 4M) was added dropwise, and then the reaction mixture was allowed to warm to ambient temperature while stirring for 60 hours. The reaction mixture was concentrated in vacuo, re-suspended in MeOH and re-concentrated (3×). The residue was dissolved in MeOH (3.7 mL) and added dropwise to a rapidly stirring flask containing ether (100 mL). The white solid was filtered under a blanket of nitrogen gas, washed with ether and dried under nitrogen gas to give (5R,7R)-7-fluoro-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride as a white solid (539 mg, 96%). LC/MS (APCI)+ m/z 237.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][CH:9]=[N:10]2)=[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:4]=1.[C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH3:30])[CH:25]=[C:24]2[CH:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1)#[N:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][CH:9]=[N:10]2)=[C:5]([N:13]2[CH2:18][CH2:17][N:16]([C@@H:34]3[CH2:33][CH2:32][C@H:31]([C:24]4[C:23]5[C:27](=[CH:28][CH:29]=[C:21]([C:19]#[N:20])[CH:22]=5)[N:26]([CH3:30])[CH:25]=4)[CH2:36][CH2:35]3)[CH2:15][CH2:14]2)[CH:4]=1
Reactant: Cn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Reactant: COc1cc(N2CCNCC2)c2nccnc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(N2CCN([C@H]3CC[C@@H](c4cn(C)c5ccc(C#N)cc54)CC3)CC2)c2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-methoxy-5-piperazin-1-yl-quinoxaline (160 mg, 0.66 mmol), 4-(5-cyano-1-methyl-1H-indol-3-yl)-cyclohexanone (170 mg, 0.66 mmol), and sodium triacetoxyborohydride (210 mg, 0.98 mmol) in dichloroethane (30 mL) was added acetic acid (0.1 mL, 1.3 mmol) and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (100 mL) then extracted in CH2Cl2 (75 mL) and EtOAc (100 mL). The organic fractions were combined, dried over Na2SO4, concentrated, filtered and chromatographed (5% MeOH/EtOAc) affording 120 mg (38%) of the cis isomer as a bright yellow solid: mp 226-229° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]([NH2:24])=[O:23].Br[CH2:26][CH:27]1[CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.[Cl-].[Na+].O>[CH:27]1([CH2:26][N:13]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:12]=2[N:4]([CH2:3][O:2][CH3:1])[C:5]([C:22]([NH2:24])=[O:23])=[CH:6]3)[CH2:29][CH2:28]1
Reactant: COCn1c(C(N)=O)cc2cccc(NS(=O)(=O)c3cccs3)c21
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCn1c(C(N)=O)cc2cccc(N(CC3CC3)S(=O)(=O)c3cccs3)c21
Temperature: 85 °C
Reaction time: 20 h
Yield: 71.4 %

Procedure:
A mixture of 1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.0 g), (bromomethyl)cyclopropane (456 mg), potassium carbonate (1.13 g) and N,N-dimethylformamide (5 ml) was stirred at 85° C. for 20 hr. The reaction mixture was diluted with ethyl acetate and saturated brine. The organic layer was washed with aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated. The residue was subjected to basic silica gel column chromatography, and eluted with ethyl acetate-hexane mixture (2:1) to give the title compound (820 mg, yield 72%) as an amorphous form.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[CH:11][CH:12]=1)C.[OH-].[Na+]>C(O)C>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[N:9]=[CH:8][C:7]([CH2:6][CH2:5][C:4]([OH:20])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccccc2F)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1ccc(-c2ccccc2F)nc1
Temperature: 47.5 °C
Reaction time: 1 h

Procedure:
11.5 g (0.042 mol) of 3-[6-(2-fluoro-phenyl)-pyridin-3-yl]-propionic acid ethyl ester were dissolved in 230 ml ethanol, 7.7 ml of a 32% sodium hydroxide solution were added, and the mixture stirred at 45 to 50° C. for 1 h. After evaporation to dryness, the remaining solid was taken up in 100 ml of water, the pH was adjusted to 2.5 to 3 with 2 N hydrochloric acid, and the precipitated product was filtered off with suction. The solid was rinsed with water and dried. Yield 10.0 g.
Reaction SMILES: N[C:2]1[C:3]2[N:4]([N:10]=[C:11]([S:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=2)[C:5]([Cl:9])=[CH:6][C:7]=1[Cl:8].N(OC(C)(C)C)=O.O1CCCC1>CCOCC>[CH2:14]([S:13][C:11]1[N:12]=[C:3]2[CH:2]=[C:7]([Cl:8])[CH:6]=[C:5]([Cl:9])[N:4]2[N:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1c(Cl)cc(Cl)n2nc(SCc3ccccc3)nc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1cc(Cl)n2nc(SCc3ccccc3)nc2c1

Procedure:
8-Amino-2-benzylthio-5,7-dichloro[1,2,4]triazolo[1,5-a]pyridine (25.8 g, 0.079 mol), t-butyl nitrite (18.9 mL, 16.4 g, 0.158 mol) and tetrahydrofuran (1.5 L) were combined and heated at reflux with stirring. Gas evolution began immediately and stopped after a few minutes, but the reaction was heated at reflux for an hour. The volatiles were removed by evaporation under reduced pressure and the residue obtained was chromatographed on silica gel eluting with dichloromethane. The product fractions were concentrated by evaporation under reduced pressure and the residue obtained was mixed with ether. The insoluble solid material was collected by filtration. The ether filtrate was concentrated by evaporation under reduced pressure and the residue was rechromatographed on silica gel eluting with 10 percent ethyl acetate in hexane. The product fractions were concentrated by evaporation under reduced pressure and the residue obtained was combined with the insoluble solid material obtained before to obtain 12.2 g (50 percent of theory) of the title compound as a red-brown powder melting at 88°-89° C.
Reaction SMILES: C([O:3][C:4](=[O:15])/[C:5](/O)=[CH:6]/[C:7](=[O:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])C.Cl.[NH2:17]O.[OH-].[Na+].Cl>CCO>[CH3:10][C:9]([CH3:12])([CH3:11])[CH2:8][C:7]1[O:13][N:17]=[C:5]([C:4]([OH:3])=[O:15])[CH:6]=1
Reactant: NO
Reactant: CCOC(=O)/C(O)=C/C(=O)CC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)Cc1cc(C(=O)O)no1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (Z)-2-hydroxy-6,6-dimethyl-4-oxo-hept-2-enoic acid ethyl ester (298.5 g, 1.39 mol) in EtOH (1600 ml) is added hydroxylamine hydrochloride (106.5 g, 1.53 mol) and the resulting solution is stirred at room temperature for 24 h. 2N aq sodium hydroxide (1740 ml, 3.48 mol) is added to the reaction and the resulting solution is stirred at rt for 2 h. The reaction mixture is acidified with 6N aq hydrochloric acid, concentrated to about 3 L, and extracted with EtOAc (2000 ml). The combined organic layers are washed with brine, dried over magnesium sulfate and concentrated. The resulting solid is washed with ether and dried to afford the product.
Reaction SMILES: C(O[C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:11][C:12]=1I)=O)C.C[O:19][CH:20]1[CH:24]=[CH:23]C(OC)[O:21]1.C(N(C(C)C)CC)(C)C.CN(C=O)C>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[F:17][C:14]([F:15])([F:16])[C:9]1[CH:8]=[C:7]2[C:12]([C:23]([CH2:24][C:20]([OH:21])=[O:19])=[CH:4][NH:6]2)=[CH:11][CH:10]=1
Reactant: COC1C=CC(OC)O1
Reactant: CCOC(=O)Nc1cc(C(F)(F)F)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)Cc1c[nH]c2cc(C(F)(F)F)ccc12
Temperature: 80 °C
Reaction time: 20 h
Yield: 6.3 %

Procedure:
A mixture of 3-ethoxycarbonylamino-4-iodobenzotrifluoride (1.8 g), 2,5-dihydro-2,5-dimethoxyfuran (1.3 g), palladium acetate (60 mg), diisopropylethylamine (2.0 g), benzyltriethylammonium chloride (1.2 g) and DMF (15 ml) was stirred for 20 hours under a nitrogen atmosphere at 80° C. Water and ethyl acetate were added to the reaction mixture, the insoluble portion was filtered out with celite, and extraction was performed with ethyl acetate. The organic layer was collected and dried over sodium sulfate and then concentrated under reduced pressure. Dichloromethane (25 ml) and trifluoroacetic acid (1.5 ml) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate water was added to the reaction mixture and vigorously stirred therewith. The organic layer was collected and dried over sodium sulfate and then concentrated under reduced pressure. A (1-ethoxycarbonyl-6-trifluoromethyl-1H-indol-3-yl)acetic acid methyl ester component was purified from the obtained residue by silica gel column chromatography using a mixed solvent of hexane and ethyl acetate. A 2 N sodium hydroxide aqueous solution (1 ml) and methanol (1 ml) were added to the obtained (1-ethoxycarbonyl-6-trifluoromethyl-1H-indol-3-yl)acetic acid methyl ester, and the mixture was heated to reflux for one hour. Water was added to the reaction mixture, which was then rendered acidic with concentrated aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, to obtain 77 mg of the title compound as a colorless powder (5% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: BrCCCCCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution containing 2.00 g (8.96 mmol) of 9-bromo-1-nonanol in 20 mL of anhydrous THF were added 1.55 mL (12.60 mmol) of benzyl bromide followed by 677 mg (16.94 mmol) of a 60% suspension of NaH in mineral oil. The reaction mixture was stirred overnight under argon atmosphere at room temperature. The reaction mixture was carefully quenched with saturated aqueous sodium bicarbonate. The mixture was poured into 100 nit of water and extracted with two portions of 100 mL of ether. The combined organic solution was washed with a portion of 100 mL of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes and then with hexanes-ethyl acetate 4:1 gave the expected product as colorless oil: yield 2.54 g (90%). 1H-NMR (CDCl3) δ 7.86 (m, 5H), 4.51 (s, 2H), 3.47 (t, 2H, J=6.4), 3.40 (t, 2H, J=6.8), 1.85 (m, 2H), 1.62 (m, 2H), 1.39 (m, 10H); 13C-NMR (CDCl3) δ 138.70, 128.34, 127.62, 127.47, 72.86, 70.46, 34.02, 32.83, 29.76, 29.38, 29.36, 28.71, 28.15, 28.16
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Br:24][C:25]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:26]=1[CH2:27]Br>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:27][C:26]3[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:25]=3[Br:24])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Fc1ccc(Br)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (2.0 g, 6.39 mmol) in THF (40 mL) at 0° C. was added NaH (285 mg, 60 w/w % in mineral oil, 7.13 mmol, 1.1 eq.) in one portion. The resulting foaming mixture was stirred in an ice bath. Additional THF (50 mL) was added into the reaction. The mixture was stirred at 0° C. for 30 min. A solution of 2-bromo-5-fluorobenzyl bromide (1.712 g, 6.39 mmol) in THF (20 mL) was added. The resulting mixture was stirred cold for 30 min and then allowed to warm to room temperature. The reaction was completed in 3 hours. The reaction was quenched with NH4Cl (aq., sat.,80 mL). Volatiles were removed in vacuo. The crude mixture was extracted with EtOAc and dried over Na2SO4. The residue was purified by flash chromatography on SiO2 (Biotage 40+M cartridge, EtOAc/hexane, gradient). (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one was obtained as a clear oil. LC-MS: 500.09 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 1H), 7.79 (s, 2H), 7.55 (dd, J=8.8, 5.2 Hz, 1H), 7.17 (dd, J=8.7, 4.5 Hz, 1H), 6.95 (m, 1H), 5.74 (d, J=8.0 Hz, 1H), 4.83 (d, J=15.8, 1H), 4.54 (d, J=16.0 Hz, 1H), 4.11 (m, 1H), 0.80 (d, J=6.6 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:32]=[CH:31][S:30][CH:29]=4)[CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO>[CH3:40][C:5]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:32]=[CH:31][S:30][CH:29]=4)[CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:11][CH:12]=1)[C:4]([OH:41])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3cccc(-c4ccsc4)c3)oc2C)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2cccc(-c3ccsc3)c2)nc1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
2-Methyl-3-(4-{2-[5-methyl-2-(3-thiophen-3-ylphenyl)oxazol-4-yl]ethoxy}phenyl)-2-phenoxypropionic acid ethyl ester (3.6 mmol) in MeOH (7 mL) was treated with 2N NaOH (7 mL) and warmed to 55° C. After 18 h, the mixture was concentrated under reduced pressure and then acidified with 5N HCl to pH=1. The solution was extracted with EtOAc and then the organic phases dried (Na2SO4), filtered and concentrated to a white solid. 1H NMR (400 MHz, DMSO-d6) δ8.15 (t, J=1.6 Hz, 1H), 7.98 (dd, J=2.8 Hz, J=1.6 Hz, 1H), 7.82–7.79 (m, 2H), 7.66 (dd, J=7.6 Hz, J=2.8 Hz, 1H), 7.59 (dd, J=6.4 Hz, J=1.2 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.24 (t, J=8.0 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 6.93 (t, J=7.6 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.79 (dd, J=7.6 Hz, J=1.2 Hz, 2H), 4.19 (t, J=6.4 Hz, 2H), 3.16 (d, J=13.2 Hz, 1H), 3.04 (d, J=13.2 Hz, 1H), 2.92 (t, J=6.4 Hz, 2H), 2.36 (s, 3H), 1.26 (s, 3H); MS (EI) 540.2 (M+H)+, 538.3 (M−M)−.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc(C(=O)O)cc1-c1ccnn1C
Yield: 64.2 %

Procedure:
A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (250 mg, 1.06 mmol) [Prepared in Example 99] in 6N sodium hydroxide (1.76 ml, 10.6 mmol) and tetrahydrofuran (5.290 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (151 mg, 0.68 mmol, 64% yield) as a white solid; LCMS (ES) m/z=223 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]2[N:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[NH:7][C:6]=2[CH:13]=1.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]2[N:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[N:7]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:13]=1
Reactant: BrCc1cccc2ccccc12
Reactant: CC(C)c1nc2c([N+](=O)[O-])cc(Br)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1nc2c([N+](=O)[O-])cc(Br)cc2n1Cc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 102.6 %

Procedure:
A mixture of 6-bromo-2-isopropyl-4-nitro-1H-benzo[d]imidazole (4.7 g), 1-(bromomethyl)naphthalene (4.01 g) and K2CO3 (4.55 g) in DMF (150 mL) was stirred at 80° C. for 2 h. It was cooled to room temperature and filtered. The filtrate was then poured into water (1 L). It was then filtered to afford a solid that was washed with water and then dried in-vacuo to afford the crude product (7.2 g). LC-MS: m/e=425 [M+1]+
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CC1C=CC2C(=CC=CC=2)C=1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[OH:32]>>[CH2:23]([O:32][C:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=1)[CH3:22].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[OH:32]
Reactant: c1ccc2ccccc2c1
Agent: Cc1ccc2ccccc2c1
Agent: Oc1ccc2ccccc2c1
Product: CCOc1ccc2ccccc2c1

Procedure:
Silylations of aryl alkyl ethers at elevated temperatures were conducted under the conditions applied to diaryl ethers to probe the cleavage selectivity of sp2 versus sp3 C—O bond. At the elevated temperatures of these experiments, the reaction of 2-methoxynaphthalene gave 2-naphthol as the major product in moderate yield (Scheme 1). GC-MS analysis of the crude reaction mixture indicated the presence of trace amounts of naphthalene along with 2-methylnaphthalene and further reduced species, including products of partial aromatic reduction. Compounds presumably derived from 2-naphthol silylation were also detected. Likewise, cleavage of 2-ethoxynapthalene under the same conditions gave 2-naphthol in slightly higher yield, but with the same or analogous side products. Sterically bulkier ethers were investigated to probe the versatility and possible mechanism of the C—O bond cleavage. Despite the large alkyl substituent adjacent to the ether oxygen, reaction of 2-neopentyloxynaphthalene provided 2-naphthol in approximately the same yield as with the less bulky substrates. Even 2-tert-butyloxynapthalene was cleaved to give the expected naphthol in 55% yield (Scheme 1). Control experiments performed at identical conditions but without triethylsilane provided 2-naphthol in cases of 2-ethoxy- and 2-tert-butyloxynapthalene albeit with substantially diminished yields. Since 2-methoxy- and 2-neopentyloxy-substrates remained intact in such silane-free cleavages, a b elimination mechanism is likely to be operative. When attempting to reduce 4-tert-butyl and 4-methyl anisoles under the standard conditions, the yields of the corresponding phenols were high, likely because of more challenging silylation of the substituted phenyl ring for the steric reasons (Scheme 2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1.O>CN(C=O)C>[F:23][C:22]([F:25])([F:24])[C:19]1[CH:20]=[CH:21][C:16]([O:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[N:17][CH:18]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 74.8 %

Procedure:
p-dihydroxybenzene 12.1 g (0.11 mol), anhydrous potassium carbonate 15.2 g (0.11 mol) were added to 500 mL of three-necked flask with DMF (200 mL) in sequence, the reaction mixture was then heated to 60° C., forming pale yellow turbid liquid, a solution of 2-chloro-5-(trifluoromethyl)pyridine 18.2 g (0.1 mol) in DMF (50 mL) was added dropwise to the above solution, after completion of addition for 15 min, then the mixture was heated to 90° C. and stirred for another 4 hours at this temperature. The reaction was monitored by thin-layer chromatography (TLC). After the reaction was completed, the reaction mixture was cooled to room temperature, then poured into water (300 mL) and extracted with ethyl acetate (2×300 mL). The organic phases were combined, washed with brine (2×200 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure and the residue was purified via silica gel column chromatography (Fluent: ethyl acetate/petroleum ether=1:8) to give the product (19.1 g) as a white solid in 75% yield.
Reaction SMILES: [CH3:1][C:2]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:12]=1[CH2:25][CH3:26])[C:3]#[N:4].[Br:32]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14]([Br:32])=[CH:13][C:12]=1[CH2:25][CH3:26])[C:3]#[N:4]
Reactant: CCCCCC(C)(C#N)CCCCCOc1cc(OCc2ccccc2)ccc1CC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCC(C)(C#N)CCCCCOc1cc(OCc2ccccc2)c(Br)cc1CC
Yield: 60 %

Procedure:
2-Methyl-2-n-pentyl-7-(2-ethyl-5-benzyloxyphenoxy)heptanenitrile and 1.1 equivalents of N-bromosuccinimide in carbon tetrachloride were stirred 1.5 hours, washed with aqueous sodium thiosulfate, washed with saturated sodium chloride, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane/ethyl ether providing the desired title intermediate in 60% yield, as an oil, NMR.