Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH3:10][O:11][CH2:12][CH2:13]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:10][O:11][CH2:12][CH2:13][N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1
Reactant: COCCBr
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCN1CCC(=O)CC1

Procedure:
To a solution of 4-piperidone monohydrate hydrochloride salt (2.2 g, 14.32 mmol, 1 eq) in acetonitrile, 2-bromoethyl methyl ether (5.9 ml, 28.6 mmol, 2 eq), and K2CO3 (2 eq) was added and heated at reflux overnight. Reaction extracted into dichloromethane (50 ml), washed with water (2×50 ml), dried (MgSO4), and evaporated in vacuo to give 1-(2-methoxy-ethyl)piperidin-4-one as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH2:13](O)[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:13]1[CH2:14][O:15][C:5]2([CH2:4][CH2:3][C:2]([CH3:1])([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6]2)[O:8]1
Reactant: OCCO
Reactant: COC(=O)C1(C)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C1(C)CCC2(CC1)OCCO2
Yield: 100 %

Procedure:
Methyl 1-methyl-4-oxocyclohexanecarboxylate (30 g) was dissolved in benzene (300 ml). Ethylene glycol (30 ml) and p-toluenesulfonic acid monohydrate (1 g) were added, and the mixture was refluxed for 4 hours. The water which formed during the heating was removed by using a water trap. After cooling, the mixture was washed with water and dryed (MgSO4). The solvent was distilled off to give methyl 4,4-ethylenedioxy-1-methylcyclohexanecarboxylate as an oil (37.8 g, 100%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:22]1[CH:40]=[CH:39][C:25]([N:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:24][CH:23]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:27]1([N:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]2[CH:39]=[CH:40][C:22]([N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:9]=[CH:10][C:11]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:12][CH:13]=3)=[CH:23][CH:24]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc(N(c3ccccc3)c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc2)cc1
Yield: 55.6 %

Procedure:
To a stirred solution of N1,N4-diphenylbenzene-1,4-diamine (6.5 g, 20.0 mmol) in toluene (400 mL), 4-bromo-N,N-diphenylaniline (7.9 g, 30.1 mmol) was added and the solution was degassed with nitrogen for 15 minutes. Palladium (II) acetate (45 mg, 0.2 mmol), triphenylphosphine (210 mg, 0.8 mmol) and sodium tert-butoxide (2.9 g, 30.1 mmol) were added and degassed with nitrogen for another 15 minutes. The reaction was refluxed overnight. The reaction mixture was filtered through Celite®, washed with toluene and the filtrate was concentrated under vacuum. It was then column chromatographed with hexane to 50% toluene/hexane to obtain 5.6 g (48%) of the desired product as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[CH2:11]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]=[CH:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl>C(OCC)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:17][CH2:18]2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: CCCCCC1C=CC(=O)CC1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCC1=CCC(O)(c2ccc(OC)cc2)CC1

Procedure:
A solution of 6.5 g of p-bromoanisole in 20 ml of anhydrous diethyl ether was added dropwise under stirring at 15°-20° C. to 1 g of magnesium metal powder, followed by reaction at room temperature for 1 hour so that a Grignard reagent was formed. After 5 g of 4-pentylcyclohexenone were added under stirring at -10° to 0° C. to the thus-formed Grignard reagent, they were reacted at room temperature for additional 1 hour. After the completion of the reaction, diluted hydrochloric acid was added dropwise to the reaction mixture, followed by the extraction of the reaction mixture with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The diethyl ether was distilled off under reduced pressure, whereby 4-(4-methoxyphenyl)-4-hydroxy-1-pentylcyclohexene was obtained as a crude reaction product.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([N:9]=O)=[N:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][CH:12]([CH2:21][CH3:22])[CH2:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C(O)(=O)C>[CH3:11][CH:12]([CH2:21][CH3:22])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:18]=[N:9][C:7]2[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=2)=[CH:19][CH:20]=1
Reactant: O=Nc1ncc([N+](=O)[O-])s1
Reactant: CCC(C)Cc1ccc(N)cc1
Solvent: CC(=O)O
Product: CCC(C)Cc1ccc(N=Nc2ncc([N+](=O)[O-])s2)cc1

Procedure:
One equivalent of 5-nitro-2-nitroso-thiazole was dissolved in a minimum quantity of glacial acetic acid and one equivalent of (+)-4-(2-methylbutyl)aniline (ex. 4) was added. The solution was allowed to react overnight and the resultant coupled helichromic dye was recovered by precipitation with water. Chromatography on alumina afforded the pure dye compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]2[S:8][C:9]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)=[C:14]([C@H:23]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]([O:26][CH3:27])=[O:25])[C:13]([CH3:33])=[CH:12][C:10]=3[N:11]=2)[S:5][CH:6]=1.[CH:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([CH3:36])[CH3:35]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.[OH-].[K+].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[C:29]([O:28][C@@H:23]([C:14]1[C:13]([CH3:33])=[CH:12][C:10]2[N:11]=[C:7]([C:4]3[S:5][CH:6]=[C:2]([N:40]4[CH2:41][CH2:42][N:37]([CH:34]([CH3:36])[CH3:35])[CH2:38][CH2:39]4)[N:3]=3)[S:8][C:9]=2[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:24]([O:26][CH3:27])=[O:25])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)N1CCNCC1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3nc(Br)cs3)sc2c1-c1ccc(Cl)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3nc(N4CCN(C(C)C)CC4)cs3)sc2c1-c1ccc(Cl)cc1
Temperature: 105 °C

Procedure:
In a 5 mL microwave reaction tube, (S)-methyl 2-(2-(4-bromothiazol-2-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (50 mg, 0.08 mmol), isopropylpiperazine (34 mg, 3 eq.), Bis(tri-t-butylphosphine)palladium(0) (3 mg, 15%), cetyltrimethylammonium bromide (4 mg, 0.5 eq.) were charged with 1 mL toluene, then 1 drop of 50% KOH aqueous solution (excess) was added. The reaction was heated to 105° C. for 1 hour. Reaction mixture was purified by HPLC (0.1% TFA in ACN and water) to give desired product. LCMS-ESI+: calc'd for C31H38ClN4O3S2: 613.2 (M+H+); Found: 613.4 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][CH2:39][NH2:40]>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:40][CH2:39][CH2:38][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[Cl:31])[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: NCCc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccccc3Cl)n2)c1

Procedure:
Intermediate 4 was coupled to 2-(2-chloro-phenyl)-ethylamine following procedure F and the resulting product deprotected by procedure G. LC-MS showed the product had the expected M+H+ of 474. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.8 (m, 1H) 8.18 (m, 4H) 7.6 (m, 6H) 4.45 (s, 2H) 3.95 (m, 2H) 3.4 (m, 2H) 3.18 (m, 4H) 3.0 (m, 2H) 2.9 (s, 3H) 1.75 (m, 2H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](O)(=[O:13])[CH2:10][CH2:11][CH3:12].Cl.[Cl-].[Na+].O>ClCCCl.[Cl-].[Cl-].[Zn+2]>[C:9]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])(=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: Oc1cccc(O)c1
Reactant: CCCC(=O)O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCC(=O)c1ccc(O)cc1O
Temperature: 150 °C

Procedure:
To a solution of resorcinol (1.5 g) and butyric acid (2.9 mL) in 1,2-dichloroethane (45 mL) was added ZnCl2 (3.22 g) and the mixture then heated at 150° C. under nitrogen for 5 hr. The reaction mixture was cooled, poured onto 1N HCl/brine and extracted (3×EtOAc). After washing with 0.1N K2CO3, then twice with brine, the organic layer was dried and evaporated. Chromatography of the residue (silica gel; hexane/EtOAc 2:1) afforded the title product as a solid.
Reaction SMILES: [F:1][C:2]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:20])=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13](O)=[C:8]2[CH:7]=[CH:6]1.N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[I-:47].[Na+].Cl.[O-]S([O-])(=S)=O.[Na+].[Na+].O>C(#N)C>[F:1][C:2]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:20])=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]([I:47])=[C:8]2[CH:7]=[CH:6]1
Reactant: [I-]
Reactant: CCOC(=O)c1c(C)nc2c(ccn2Cc2cccc(F)c2F)c1O
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1c(C)nc2c(ccn2Cc2cccc(F)c2F)c1I
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
To a solution of ethyl 1-(2,3-difluorobenzyl)-4-hydroxy-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (9.0 g, 24.69 mmol) in acetonitrile (120 mL) was added pyridine (2.60 mL, 32.1 mmol) and the mixture was cooled to 0° C., then triflic anhydride (5.42 mL, 32.1 mmol) was added dropwise in ˜15 min. After stirring at ambient temperature for 1.5 h the mixture was charged with sodium iodide (18.50 g, 123 mmol) and hydrochloric acid (10.70 mL, 32.1 mmol) (3M/water) and heated to 70° for 1.5 h. The mixture was allowed to cool to ambient temperature and then 20% Na2S2O3/water (350 mL) was added followed by ice-water and the mixture was stirred for 30 min then filtered. The solid was washed with water and dried in vacuo for 18 h to provide ethyl 1-(2,3-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (10 g, 19.73 mmol, 80% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (t, J=7.12 Hz, 3 H), 2.66 (s, 3 H), 4.48 (q, J=7.22 Hz, 2 H), 5.53 (s, 2 H), 6.39 (d, J=3.71 Hz, 1 H), 6.75-6.89 (m, 1 H), 6.97 (m, J=8.02, 8.02, 4.93, 1.66 Hz, 1H), 7.03-7.16 (m, 1 H), 7.22 (d, J=3.71 Hz, 1 H); LCMS (m/z) ES+=457 (M+1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:20]=1[CH:21]=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>ClCCl>[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:20]=1[CH2:21][OH:22])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1cc(I)ccc1OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Product: OCc1cc(I)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
100 ml of a 1M diisobutylaluminum hydride solution in dichloromethane are added to a solution, cooled to 0° C., of 33.98 g (100.5 mmol) of 2-benzyloxy-5-iodobenzaldehyde (Example 2A) in 200 ml of dichloromethane. After stirring at 0° C. for 2 h, a saturated potassium sodium tartrate solution is added while cooling (highly exothermic reaction), and the reaction mixture is stirred for a further 2 h. After the separation of the phases, the organic phase is washed twice with water and once with a saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent is evaporated in vacuo. 31.8 g (93% of theory) of product are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[N:8]=[CH:9]2)([O-])=O>C(O)(=O)C.O.[Fe]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[N:8]=[CH:9]2
Reactant: COC(=O)c1cc2c([N+](=O)[O-])cccc2cn1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc2c(N)cccc2cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product of Example 71A (10.33 g, 44.5 mmol) in acetic acid/water (3/1) (320 mL) was treated with iron powder (5.06 g, 90.7 mmol). After stirring for 16 hours at room temperature, the reaction mixture was filtered the filtrate concentrated under reduced pressure to approximately half the original volume. The mixture was then extracted with dichloromethane (3×200 mL). The organic fractions were combined, dried (MgSO4), and the filtrate concentrated under reduced pressure to afford crude material. A precipitate formed in the aqueous phase after sitting for several hours. This was filtered to afford additional crude material. The crude material was purified by column chromatography (2% methanol/CH2Cl2) to provide the title compound. MS (ESI+) m/z 203 (M+H)+; MS (ESI−) m/z 201 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 3.92 (s, 3H), 6.34 (s, 2H), 6.96 (dd, J 1.0, 7.8, 1H), 7.31 (d, J 8.1, 1H), 7.51 (t, J 7.9, 1H), 8.82 (s, 1H), 9.15 (s, 1H); Anal. Calcd for C11H10N2O2: C, 65.34; H, 4.99; N, 13.85. Found: C, 65.03; H, 4.95; N, 13.65.
Reaction SMILES: [C:1]1([CH:7]([N:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[H-].[Na+].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]1([CH:7]([N:9]2[CH2:12][CH:11]([O:13][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:10]2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1ccccn1
Reactant: CC(c1ccccc1)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(c1ccccc1)N1CC(Oc2ccccn2)C1
Temperature: 65 °C
Yield: 14.3 %

Procedure:
The maleate salt of 1-(1-phenylethyl)-3-azetidinol (65 g, 0.22 mole) was partitioned between toluene and dilute sodium hydroxide and was extracted once with toluene. The organic layer was dried (sodium sulfate) and concentrated. The residue was dissolved in 125 ml of dimethylformamide and added dropwise to a stirred suspension of 9.6 g (0.24 mole) of sodium hydride (washed three times with isooctane) in 400 ml of dimethylformamide at 25°-35° C. The solution was heated to 65° C. and 35 g (0.22 mole) of 2-bromopyridine was added dropwise while heating to 75° C. The solution was stirred and heated at 90° C. for 1 hr followed by heating at 120° C. for 2.75 hr. The mixture was stirred at room temperature overnight and concentrated. The residue was partitioned between water and isopropyl ether. The organic layer was washed twice with water, dried (sodium sulfate), filtered and concentrated. Crude yield was 30 g. The residue was distilled to give 8 g of product, bp 128°-134° C./0.01 mm.
Reaction SMILES: [C:1]([O-:22])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Na+].C1C=CC(S(OC2C=CC(Cl)=CC=2Cl)(=O)=O)=CC=1.CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=O.CN1[C@H]2[C@@H](O)C[C@@H]1C[C@H](OC([C@@H](C1C=CC=CC=1)CO)=O)C2>>[C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)[O-]
Agent: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Agent: CN1[C@H]2C[C@H](OC(=O)[C@H](CO)c3ccccc3)C[C@@H]1[C@@H](O)C2
Agent: O=S(=O)(Oc1ccc(Cl)cc1Cl)c1ccccc1
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O

Procedure:
Finally, we investigated arachidonic acid-induced lipid peroxidation of the retinal suspension and any protection provided by the presence of anisodamine. Sodium arachidonate was freshly prepared with DPBS by ultrasonification. The experimental system consisted of 0.24 ml of the retinal suspension and, 0.03 ml anisodamine or DPBS for the control. To each tube, excluding the control, 0.03 ml of sodium arachidonate was added. The final concentration of sodium arachidonate was 0.25 mg/ml. The final concentration of anisodamine was 0.01 mg/ml. The malondialdehyde concentration was measured after incubation of the tubes at 37° C. for 30 minutes using the technique discussed previously.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:6][CH:5]([OH:7])[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:3]1[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>ClCCl.CN(C1C=CN=CC=1)C>[C:33]([O:7][CH:5]1[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:3]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:2]([CH3:25])([CH3:1])[O:6]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OC(O)C(c2cccc(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1OC(C)(C)C(c2ccc(S(C)(=O)=O)cc2)=C1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5,5-Dimethyl-3-(3-fluorophenyl)-2-hydroxy-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran (Example 1, 0.8 g) and triethylamine (2 mL) in dichloromethane (20 mL) was added DMAP (5 mg) and acetic anhydride (1 mL). The resulting mixture was stirred at room temperature for 10 min, then quenched with saturated aqueous NaHCO3. The mixture was extracted with CH2 Cl2 and the organic phase was dried over Na2SO4, filtered and evaporated. The resulting solid was swished in 1:1 EtOAc/hexanes to provide 0.5 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]([C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[F:19])([CH2:10][OH:11])[CH2:8][OH:9].C([O-])([O-])=O.[K+].[K+].CO>C(#N)C>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C:7]([NH:6][C:3](=[O:4])[CH2:2][Cl:1])([CH2:8][OH:9])[CH2:10][OH:11])[CH:17]=1
Reactant: O=C(Cl)CCl
Reactant: NC(CO)(CO)c1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: O=C(CCl)NC(CO)(CO)c1cc(Br)ccc1F
Reaction time: 2 h

Procedure:
A solution of chloro-acetyl chloride (6.39 ml, 80 mmol) in 10 ml ACN was added dropwise to a mixture of 2-amino-2-(5-bromo-2-fluoro-phenyl)-propane-1,3-diol (5.3 g, 20 mmol) and K2CO3 (11.1 g, 80 mmol) in 90 ml ACN while the temperature did not rise above 35° C. The mixture was stirred for 2 h. MeOH (40 ml, 99 mmol) were added and after 5 min stirring the mixture was filtered over celite and washed with MeOH. The filtrate was acidified with citric acid solution (10%, aqueous) (pH 4-5) and partly evaporated. The remaining aqueous layer was extracted with EtOAc. The organic layer was washed with NaHCO3 solution (10%, aqueous) and brine, dried with Na2SO4 and evaporated to provide the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:24]=3)[O:20][N:19]=2)[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][CH2:9][CH:10](OCC)[O:11]CC>O1CCOCC1.OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:24]=3)[O:20][N:19]=2)[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][CH2:9][CH:10]=[O:11]
Reactant: CCOC(COc1c(C)cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc1Cl)OCC
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: COc1cc(-c2nc(-c3cc(C)c(OCC=O)c(Cl)c3)no2)cc(C2CCCC2)n1
Yield: 118.6 %

Procedure:
A solution of 3-(3-chloro-4-(2,2-diethoxyethoxy)-5-methylphenyl)-5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazole (1.01 g, 2.01 mmol) in dioxane (15 mL) and 2 M aq. H2SO4 (5 mL) is stirred at 80° C. for 3 h. The mixture is extracted with EA (100 mL) and the org. extract is washed twice with brine (2×35 mL), dried over MgSO4, filtered and concentrated to give crude 2-(2-chloro-4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-6-methylphenoxy)acetaldehyde (1.02 g) as a yellow oil; LC-MS: tR=1.11 min, [M+H]+=428.19. Part of this material (345 mg, 0.806 mmol.) is dissolved in DCM (10 mL), methanol (10 mL) and acetic acid (0.7 ml) before β-alanine (72 mg, 0.806 mmol) is added. The mixture is degassed and put under argon before Na(BH3CN) (23 mg, 0.364 mmol) is added. The clear solution is stirred at rt for 2 h before the reaction is quenched by adding water (2 mL). The mixture is concentrated and the crude product is purified by prep. HPLC to give the title compound (77 mg) as a brownish solid; LC-MS: tR=0.95 min, [M+H]+=501.23; 1H NMR (CDCl3): δ 8.53 (s br, 2H), 7.83 (s, 1H), 7.67 (s, 1H), 7.33 (s, 1H), 7.07 (s, 1H), 4.20-4.30 (m, 2H), 3.95 (s, 3H), 3.39-3.49 (m, 2H), 3.25-3.36 (m, 2H), 3.12-3.22 (m, 1H), 2.64-2.75 (m, 2H), 2.32 (s, 3H), 2.02-2.12 (m, 2H), 1.78-1.91 (m, 4H), 1.68-1.78 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[C:11]([C:15]1[C:16](=[O:26])[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][C:19](=O)[CH:20]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:22]([C:17]1[C:16](=[O:26])[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:20][C:19](=[N:1][C:2]2[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=2)[CH:18]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: N#CCc1ccc(N)cc1
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Product: CC(C)(C)C1=CC(=Nc2ccc(CC#N)cc2)C=C(C(C)(C)C)C1=O

Procedure:
Using the method of Example 1, 4-aminobenzylcyanide was reacted with 2,6-di-tertiary-butyl-p-benzoquinone to give 2,6-di-tertiary-butyl-4-(4'-cyanomethylphenylimino)-2,5-cyclohexadiene-1-one, m.p. 26.5°-127.5° C. Following the reduction method of Example 1, Step B, the corresponding anilino phenylacetonitrile, m.p. 146°-147° C., was obtained. This was converted to 5-[4-(3,5-di-t-butyl-4-hydroxyanilino)benzyl]tetrazole, m.p. 212°-214° C. (dec), following the method of Example 30, but carried out at 110° C. for 48 hours.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:3]=[C:4]([C:9]3[N:10]([CH2:18][CH3:19])[C:11]4[CH:16]=[CH:15][N:14]=[CH:13][C:12]=4[N:17]=3)[C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nc(-c3ccc(OCc4ccccc4)cc3)cnc2N)nc2cnccc21
Temperature: 200 °C
Yield: 23.4 %

Procedure:
5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.032 g, 0.10 mmol) (made in example 2), 4-benzyloxy-phenylboronic acid (0.046 g, 0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of N,N-dimethylformamide and heated to 200° C. in the SmithSynthesizer microwave for 8 minutes. The reaction mixture was concentrated in vacuo and the residue purified by HPLC to give 0.0099 g of the title compound.