Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12](O)=[O:13])[C:8]=1[C:15]([F:18])([F:17])[F:16].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:27]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12]([F:27])=[O:13])[C:8]=1[C:15]([F:18])([F:17])[F:16]
Reactant: O=C(O)c1noc(-c2ccccn2)c1C(F)(F)F
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(F)c1noc(-c2ccccn2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a solution of 5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-3-carboxylic acid (54.3 mg, 0.210 mmol) and pyridine (0.037 mL, 0.463 mmol) in dichloromethane (2 mL) was added cyanuric fluoride (0.021 mL, 0.252 mmol). The reaction mixture was stirred at room temperature for 2 hrs., diluted with dichloromethane (2 mL), and washed with ice water (1 mL). The aqueous layer was extracted with dichloromethane (2×1 mL), and the combined organic layers were washed with brine (1 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 5-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride (0.048 g, 0.185 mmol, 88% yield). The product had an HPLC retention. time=2.50 min. (The product reacted readily with methanol and a small portion was characterized as the methyl ester)—Column: YMC S5 COMBISCREEN® 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:15]C1COCCO1>>[Br:15][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(=O)Cc1ccc(C(C)=O)cc1
Reactant: BrC1COCCO1
Product: COC(=O)Cc1ccc(C(=O)CBr)cc1

Procedure:
Prepared from methyl 4-acetyl-phenylacetate and bromodioxane.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12](Cl)(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1>[C:12]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC(=O)Cl
Reactant: COC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: CCCCCC(=O)Nc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anhydrous pyridine (10 mL) was added dropwise hexanoyl chloride (550 μl) at 0° C. After 5 min the temperature was allowed to warm up to rt. After 90 min aminomethyl resin (Polymers Laboratories PL-AMS, 1.93 mmol/g, 720 mg) was added and the resulting mixture was stirred overnight at rt. After filtration and rinsing the resin, water (125 mL) was added to the filtrate and a white solid precipated out. Filtration and washing with water gave a solid which was dried under vacuo at 60° C. overnight. The title compound (699 mg) was obtained as a white solid (85%) in 96.9% purity by HPLC (MaxPlot detection between 230 and 400 mn).
Reaction SMILES: C[Si](I)(C)C.[CH2:6]([O:8][C:9]([C:11]1[N:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[C:13]2[C:18]([CH:19]=1)=[C:17]([Cl:20])[C:16]([O:21]C)=[CH:15][CH:14]=2)=[O:10])[CH3:7].CO>C(Cl)(Cl)Cl>[Cl:31][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[Cl:30])[CH2:23][N:12]1[C:13]2[C:18](=[C:17]([Cl:20])[C:16]([OH:21])=[CH:15][CH:14]=2)[CH:19]=[C:11]1[C:9]([O:8][CH2:6][CH3:7])=[O:10]
Reactant: CCOC(=O)c1cc2c(Cl)c(OC)ccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)c1cc2c(Cl)c(O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Yield: 54.5 %

Procedure:
Trimethylsilyliodide (0.6 ml) was added to a solution of ethyl-N-(3,4-dichlorobenzyl)-4-chloro-5-methoxyindole-2-carboxylate (190 mg) in chloroform (20 ml). The mixture was heated to 50 C. for 18 hours then poured into methanol (50 ml) and concentrated under vacuo. The residue was purified by column chromatography using isohexane-20% ethyl acetate/isohexane as eluent to yield the product as a yellow solid (100 mg,71%) NMR: δ (CDCl3) 1.39 (t, 3H), 4.35 (q, 2H), 5.72 (s, 2H), 6.84 (dd, 1H), 7.05-7.13 (m, 3H) 7.3 (d, 1H) 7.35 (s, 1H);m/z396.2/398.2 (M−H+)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:13])[C:7](=[CH:11][CH:12]=1)[C:8](O)=[O:9])([O-:3])=[O:2]>C1COCC1>[OH:9][CH2:8][C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[OH:13]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CO)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.0 g (54.6 mmol) of 4-nitrosalicylic acid are initially charged in 100 ml of THF. With ice-cooling, 109 ml of 1 M borane/THF complex are added, and the mixture is stirred at RT overnight. The mixture is concentrated and the precipitate is filtered off with suction. The solid is dissolved in ethyl acetate and dried over magnesium sulfate. After concentration and drying under high vacuum, the title compound is directly reacted further.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:48]=[CH:49][C:50]=1[C:51]([O:53]C)=[O:52])[CH2:5][NH:6][C:7](=[O:47])[CH:8]([S:19][S:20][CH:21]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH:39]=1)[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([O:34]C)=[O:33])=[C:28]([OH:36])[CH:27]=1)=[O:23])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH:24][C:22](=[O:23])[CH:21]([S:20][S:19][CH:8]([CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[C:7]([NH:6][CH2:5][C:4]2[CH:48]=[CH:49][C:50]([C:51]([OH:53])=[O:52])=[C:2]([OH:1])[CH:3]=2)=[O:47])[CH2:37][C:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[NH:40][CH:39]=2)=[CH:27][C:28]=1[OH:36])([OH:34])=[O:33]
Reactant: COC(=O)c1ccc(CNC(=O)C(Cc2c[nH]c3ccccc23)SSC(Cc2c[nH]c3ccccc23)C(=O)NCc2ccc(C(=O)OC)c(O)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(CNC(=O)C(Cc2c[nH]c3ccccc23)SSC(Cc2c[nH]c3ccccc23)C(=O)NCc2ccc(C(=O)O)c(O)c2)cc1O

Procedure:
Hydrolysis of 57 (0.28 g) with K2CO3 in MeOH/water at 50° C. for 5 hours, under nitrogen as above, gave an oil. Chromatography on silica gel, eluting with EtOAc:light petroleum (1:1) containing 1% AcOH, gave 2,2'-dithiobis[N-(4-carboxy-3-hydroxybenzyl)-3-(3-indolyl)propanamide] (58) [VI: n=2; R1 =R3 =H, R2 =(CH2)2CONHCH2Ph{3-OH, 4-COOH}] (72 mg, 27% mp (MeOH/dilute HCl) 160°-163.5° C. (dec).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>CO>[CH2:9]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCC(NCc2ccccc2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Combine trans-4-amino-cyclohexanol (2.0 g, 17.4 mmol) in methanol (75 mL) in a sealed tube then add benzaldehyde (1.85 mL, 18.23 mmol). Heat the reaction mixture at 70° C. while stirring for 2 h. Then let the reaction cool down and add sodium borohydride (2.46 g, 65.1 mmol) in portions. Stir overnight. Evaporate the solvent till ⅓ of the original volume. Partition the reaction mixture between EtOAc (50 mL) and water (40 mL). Reextract the aqueous layer with EtOAc (20 mL). Combine the organic layers and dry over sodium sulfate. Filter and concentrate to provide the title compound (3.5 g) that will be use directly in the next step.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[F:24][C:25]1[C:30]([CH3:31])=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1>>[F:24][C:25]1[N:26]=[CH:27][C:28]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([N:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)=[CH:14][CH:13]=4)=[N:9]3)=[CH:4][CH:3]=2)=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1cc(B(O)O)cnc1F
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Product: Cc1cc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cnc1F

Procedure:
[7-(6-Fluoro-5-methyl-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine and 2-fluoro-3-methylpyridine-5-boronic acid in an analogous manner to Example 1031b. Product isolated as a yellow solid (79 mg, 66%). m.p.=227-230° C.; LCMS (m/e) 405 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 8.62 (s, 1H), 8.56-8.49 (m, 1H), 7.51 (d, 2H, J=8.9 Hz), 6.99-6.90 (m, 3H), 6.83 (d, 1H, J=4.8 Hz), 6.68 (bs, 1H), 3.92-3.85 (m, 4H), 3.17-3.10 (m, 4H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2-].[Na+].[Cl:19][CH2:20][CH2:21][CH2:22]I.O>C1(C)C=CC=CC=1>[Cl:19][CH2:20][CH2:21][CH2:22][C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13]
Reactant: ClCCCI
Reactant: COc1ccc(C(C#N)C(C)C)cc1OC
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(C#N)(CCCCl)C(C)C)cc1OC
Temperature: 25 °C
Yield: 85.7 %

Procedure:
2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile (1.21 g, 5.52 mmol) was added to a suspension of sodium amide (0.59 g, 14.4 mmol) in toluene (12 ml). The mixture was then heated to reflux for 2 hours before the addition of 1-chloro-3-iodopropane (0.9 ml, 8.3 mmol). The mixture was cooled to room temperature over 80 minutes, and worked up by addition of water. The product was extracted with methyl-t-butyl ether (MTBE). After usual work-up, including drying the organic extract using MgSO4 and concentrating under reduced pressure the product was purified on column chromatography eluting with (ethyl acetate: light petroleum (b.p. 40 -60° C.) =1:2), to give 1.4g (82% yield) of the required product.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1.[H-].[Na+].Cl[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17].C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[N:3]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1nc(Br)[nH]c1Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(Br)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of 2-bromo-4,5-dichloro-1H-imidazole (2.16 g, 10 mmol) in THF (25 mL) was added dropwise to a suspension of NaH (440 mg of a 60% suspension in mineral oil, 11 mmol) in THF (20 mL) at 0° C. The mixture was stirred at RT for 2 h, cooled to 0° C. and {2-[(chloromethyl)oxy]ethyl}(trimethyl)silane (1.9 mL, 11 mmol) was added dropwise. The mixture was stirred at RT overnight. Saturated NaHCO3 was added and the aqueous layer was extracted with CH2Cl2. The organic layer was dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography (0-50% CH2Cl2/hexanes) to give the title compound (3.26 g, 95%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.26 (2H, s) 3.55-3.61 (2H, m) 0.88-0.94 (2H, m) −0.02 (9H, s). LCMS: m/z 346 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl.[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[C:13](=[O:19])[CH2:12]2.[OH-].[K+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:12]2[C:13](=[O:19])[CH:14]3[CH2:17][CH2:18][N:11]2[CH2:16][CH2:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CN2CCC1CC2
Reactant: O=Cc1cccc(Br)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2cccc(Br)c2)N2CCC1CC2

Procedure:
The manner in which 2-[(2-, 3-, and 4-substituted phenyl)methyl]-1-azabicyclo[2.2.2]octanes are synthesized can vary. For example, in one method, 3-bromobenzaldehyde can be subjected to an aldol reaction with 3-quinuclidinone hydrochloride (commercially available from Aldrich Chemical Company) using potassium hydroxide in methanol to give 2-[(3-bromophenyl)methylene]-1-azabicyclo[2.2.2]octan-3-one. The latter unsaturated ketone can be reduced by hydrogenation using palladium over charcaol to give 2-[(3-bromophenyl)methyl]-1-azabicyclo[2.2.2]octan-3-one. Depending upon the choice of hydrogenation catalyst, it may be necessary to use suitable inhibitors to suppress dihologenation. For suitable catalysts and inhibitors, see Rylander, Catalytic Hydrogenation in Organic Synthesis, pp. 125-126 (1979). The resulting ketone can be reduced under Wolff-Kishner conditions with hydrazine and base (or under modified Wolff-Kishner conditions with tosylhydrazine and sodium cyanoborohydride) to yield 2-[(3-bromophenyl)methyl]-1-azabicyclo[2.2.2]octane. Methods similar to those described by A. D. Yanina et al., Khim.-Farm. Zh. 21(7):808-811 (1987) can be used. The isomeric compounds, 2-[(2-bromophenyl)methyl]-1-azabicyclo[2.2.2]octane and 2-[(4-bromophenyl)methyl]-1-azabicyclo[2.2.2]octane can be prepared in a similar manner by replacing 3-bromobenzaldehyde with 2-bromobenzaldehyde and 4-bromobenzaldehyde, respectively in the above synthetic approach. Alternatively, 2-[(3-bromophenyl)methyl]-1-azabicyclo[2.2.2]octane can be prepared form the previously described 2-[(3-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane by conversion to the intermediate diazonium salt compound using sodium nitrite and acid at 0° C., followed by treatment with cuprous bromide under Sandmeyer reaction conditions. In a similar manner, 2-[(2-bromophenyl)methyl]-1-azabicyclo[2.2.2]octane and 2-[(4-bromophenyl)methyl]-1-azabicyclo[2.2.2]octane can be prepared from the corresponding amino compounds.
Reaction SMILES: C[O-].[Na+].C(=O)(O)O.[NH2:8][NH:9][C:10]([NH2:12])=[NH:11].[F:13][C:14]([F:26])([F:25])[C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18](OC)=O>CO>[F:13][C:14]([F:25])([F:26])[C:15]1[CH:16]=[C:17]([C:18]2[NH:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: N=C(N)NN
Reactant: COC(=O)c1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Product: Nc1nnc(-c2cccc(C(F)(F)F)c2)[nH]1
Temperature: 0 °C
Yield: 13.4 %

Procedure:
To a solution of sodium methanolate (1.05 g, 19.44 mmol, 4.00 equiv) in methanol (40 mL) at 0° C. was added aminoguanidine bicarbonate (2.66 g, 19.54 mmol, 4.00 equiv) in several batches. To this was added dropwise a solution of methyl 3-(trifluoromethyl)benzoate (1 g, 4.90 mmol, 1.00 equiv) in methanol (10 mL) with stirring at 0° C. The resulting solution was then stirred overnight at 75° C. in an oil bath. The reaction was then quenched with 10 mL of water/ice, the solution adjusted to pH 3-4 with hydrochloric acid (1 mol/L), and the solids were collected by filtration To afford 150 mg (13%) of 5-(3-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-amine as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[C:25]([Cl:32])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:23]C)=[C:9]([CH:22]=1)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:11].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[C:25]([Cl:32])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:23])=[C:9]([CH:22]=1)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:11]
Reactant: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
To a solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-N-nonyl-benzamide (173 mg, 0.36 mmol) in CH2Cl2 (3 ml) was added a solution of BBr3 (0.72 ml of a 1 M solution in CH2Cl2). The resulting mixture was stirred at RT for 1.5 h then quenched by addition of MeOH (1 ml) and water (10 ml). The resulting mixture was stirred at RT for 30 min then further diluted with 1 M HCl (10 ml) and extracted with CH2Cl2 (3×5 ml). The combined CH2Cl2 extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound of Step D (168 mg) as a viscous oil. The title product of Step D was used in the next step without further purification. MS (APCl−) Calc.: 468.1. Found: 467.2 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([OH:20])=O.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[CH3:21]/[C:16](/[CH:15]=[CH:14]/[CH:13]=[C:12](\[CH3:22])/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])=[CH:17]/[C:18]([NH:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[O:20]
Reactant: Nc1ccncc1
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C\C(=O)Nc2ccncc2)C(C)(C)CCC1
Yield: 86.6 %

Procedure:
Reaction of the reduced retinoic acid (0.83 g, 2.7 mmol) with 4-aminopyridine (0.26 g, 2.7 mmol) was conducted according to the general amide coupling procedure using DCC to obtain the product as a clear yellow oil (0.88 g, 85%). EIMS m/z: 387 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([CH2:22][CH2:23][O:24]C(=O)C)[C:18]2=[O:28])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[OH-].[NH4+]>C(#N)C>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([CH2:22][CH2:23][OH:24])[C:18]2=[O:28])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(=O)OCCN1CSC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)c1cc(C=C2SCN(CCO)C2=O)cc(C(C)(C)C)c1O
Reaction time: 90 h
Yield: 46.7 %

Procedure:
A solution of 85.2 g of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-3-[2-(acetyloxy)ethyl]-4-thiazolidinone from Example 26 in 1.5 l of acetonitrile was treated with 1 1 of concentrated ammonium hydroxide. The reaction mixture was allowed to stand for approximately 90 hours at room temperature. The solution was concentrated in vacuo and 500 ml of ethyl acetate were added, with the pH adjusted to 3.0 with concentrated hydrochloric acid. The layers were separated and the aqueous layer extracted with 250 ml of ethyl acetate. The combined organic layers were washed with 250 ml of a saturated sodium chloride solution and concentrated in vacuo. The residue was crystallized from 95 ml of hexane and 70 ml of ethyl acetate to provide 35.68 g of the desired subtitled intermediate, m.p. 131-135° C.
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N+:11]2[CH2:14][CH:15]=[CH2:16])=[CH:6][CH:5]=1.[OH-].[K+].[O:19]1CCOCC1>O.CCOC(C)=O>[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10](=[O:19])[N:11]2[CH2:14][CH:15]=[CH2:16])=[CH:6][CH:5]=1
Reactant: C1COCCO1
Reactant: C=CC[n+]1cccc2ccc(OC)cc21
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCn1c(=O)ccc2ccc(OC)cc21
Reaction time: 0.5 h
Yield: 51 %

Procedure:
7-(Methyloxy)-1-(2-propen-1-yl)quinolinium iodide (14.81 g; 45.43 mmol), KOH (11.20 g; 199.89 mmol) and K3-[Fe(CN)6] (32.78 g; 99.95 mmol) were stirred in 1:1 water: 1,4-dioxane (400 ml) at rt under Argon for 1 h. More KOH (1.1 g; 19.9 mmol) and K3-[Fe(CN)6] (3.28 g; 10.0 mmol) were added to the reaction and it was stirred under the same conditions for a further 0.5 h. EtOAc (500 ml) and water (500 ml) was then added. The layers were then separated and the combined organic layers were washed with water and then concentrated. The crude residue was then purified by column chromatography on silica gel using a 0-5% MeOH/DCM gradient to give the desired product (4.90 g; 51%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23]>O1CCCC1>[OH:1][C:2]1[C:7]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)c1c(O)cc(O)cc1O
Reactant: CC(C)=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1c(O)cc(O)c(CC=C(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
In 250 ml of anhydrous tetrahydrofuran was dissolved 50.0 g of 2',4',6'-trihydroxyacetophenone, and 123.1 g of anhydrous potassium carbonate was added to the solution and the mixture was stirred at room temperature for 30 minutes. Then, 37.2 g of 1-chloro3-methyl-2-butene was added dropwise to the mixture over a period of 20 minutes and reaction was carried out at room temperature for 24 hours. After the reaction, the reaction mixture was extracted with 2 l of ethyl acetate and the solvent was removed from the ethyl acetate layer by distillation, and the residue was recrystallized from a benzene/petroleum ether mixed solvent to obtain 38.6 g (yield=55.0%) of 2',4',6'-trihydroxy-3'-(3-methyl-2-butenyl)acetophenone in the form of a yellow prism.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.C(N(CC)CC)C.[Br:15][CH2:16][C:17](Br)=[O:18]>C(Cl)(Cl)Cl>[Br:15][CH2:16][C:17]([NH:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: Cc1cc(N)no1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)CBr)no1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-methyl-isoxazol-3-ylamine (4.0 g, 40.8 mmol) and triethylamine (6.8 ml, 50 mmol) in chloroform (20 ml) cooled to −40° C., is added bromoacetyl bromide (3.9 ml, 44.9 mmol) in chloroform (20 ml). The reaction mixture is stirred at −40° C. for 30 minutes and then allowed to warm to room temperature. The resultant suspension is filtered, washed with DCM and dried in vacuo to yield the titled compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[C:13]([C:15]1[CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:20]=1)#[N:14].Cl>CN(C=O)C>[NH:1]1[C:13]([C:15]2[CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:20]=2)=[N:14][N:3]=[N:2]1
Reactant: COC(=O)c1cc(C#N)cc(-c2ccccc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2ccccc2)cc(-c2nnn[nH]2)c1
Temperature: 100 °C
Reaction time: 9 h

Procedure:
Sodium azide (880 mg) and triethylamine hydrochloride (1.9 g) were added to a DMF (40 mL) solution of methyl 5-cyanobiphenyl-3-carboxylate (1.09 g), and stirred at 100° C. for 9 hours. With cooling with ice, diluted hydrochloric acid was added to it, the formed precipitate was taken out through filtration, washed with water, and dried to obtain the title compound as a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)(Cl)Cl.ClCCl>[CH3:1][C:2]1[N+:7]([O-:17])=[C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2c(n1)COC2=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c([n+]1[O-])COC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
A solution of 2-methyl-7H-furo[3,4-b]pyridin-5-one (150 mg, 1.0 mmol) in chloroform (5 mL) and dichloromethane (1 mL) is treated with m-chloroperoxybenzoic acid (258 mg, 1.5 mmol). The reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated and the residue is purified by chromatography (silica gel). The product containing fractions are concentrated to give the title compound as a solid (122 mg, 73%).