Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([CH:16]=[N:17]O)[CH:15]=[C:5]2[C:4]1=[O:19])[CH3:2].O.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(OC(=O)C)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([C:16]#[N:17])[CH:15]=[C:5]2[C:4]1=[O:19])[CH3:2]
Reactant: CCn1c(=O)c2cc(C=NO)cn2c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCn1c(=O)c2cc(C#N)cn2c2ccccc21
Yield: 77.4 %

Procedure:
A mixture of 2.5 g (9.8 mmole) of the product of Step A in 40 ml of acetic acid anhydride was refluxed for 3 hours and was then poured into a mixture of water-sodium carbonate-ethyl acetate. The decanted organic phase was washed once with water, dried, filtered and evaporated to dryness. The residue was triturated with ether to obtain 1.8 g of 4,5-dihydro-5-ethyl-4-oxopyrrolo-[1,2-a]-quinoxaline-2-carbonitrile in the form of buff needles melting at 237°-239° C.
Reaction SMILES: C(Cl)CCl.C(N(C(C)C)CC)(C)C.C(N)C1C=CC=CC=1.[CH3:22][C:23]1[CH:39]=[CH:38][C:26]([C:27]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]2[C:35](O)=O)=[O:28])=[CH:25][CH:24]=1.[CH2:40]([NH:47][C:48]([C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][C:51]=1[NH-:57])=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:40]([N:47]1[C:48](=[O:49])[C:50]2[C:51](=[CH:52][C:53]([Cl:56])=[CH:54][CH:55]=2)[N:57]=[C:35]1[CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][N:29]1[C:27](=[O:28])[C:26]1[CH:38]=[CH:39][C:23]([CH3:22])=[CH:24][CH:25]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Cc1ccc(C(=O)N2CCCCC2C(=O)O)cc1
Reactant: [NH-]c1cc(Cl)ccc1C(=O)NCc1ccccc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: NCc1ccccc1
Product: Cc1ccc(C(=O)N2CCCCC2c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 47 %

Procedure:
Formula 205 where T is a covalent bond; W, X, Y and Z are —C═; U—V is —N(R6)—CReRf—CRgRh—; R1, R2, R4 and Ra to Rh are H; Rand R6 is p-methyl-benzoyl: A mixture of the compound of Formula 203 (2.66 g, 6.7 mmol), 1M NaOH (27 mL), methanol (54 mL), and dioxane (36 mL) was stirred at room temperature for 7 hours. The solvents were evaporated and the residue portioned between dichloromethane (75 mL), saturated NaCl (50 mL), and concentrated HCl (3 mL). The layers were separated and the organic layer dried over MgSO4 and concentrated under vacuum to give the corresponding compound of Formula 204, 4-chloro-2-[1-(4-methyl-benzoyl)-piperidine-2-carbonyl]amino}-benzoic acid, which was carried forward without further purification. This crude product was redissolved in dichloromethane and treated with EDC (3.84 g, 20 mmol), and diisopropylethylamine (3.50 mL, 20 mmol). After stirring 20 minutes, benzylamine (2.20 mL, 20 mmol) was added and the mixture stirred overnight at room temperature. The mixture was washed with water (2×50 mL) and 1M HCl, dried over MgSO4, filtered and concentrated under vacuum to give 1.5 g (47% yield) of the desired product of Formula 205, 1-(4-methyl-benzoyl)-piperidine-2-carboxylic acid (2-benzylcarbamoyl-5-chloro-phenyl-amide, a crude product that was found to be 80% pure by reverse phase HPLC. The product was taken on without further purification. LRMS (MH+) m/z 491.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][OH:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][O:17][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)CN(CCO)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COCCN(CC(=O)OCC)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of ethyl N-(tert-butoxycarbonyl)-N-(2-hydroxyethyl)glycinate (1.2 g) in THF (17 mL) was added ethyl bromoacetate (0.8 ml) under ice-cooling, and the mixture was stirred for 5 min. To this solution was added sodium hydride (288 mg), and the mixture was stirred under ice-cooling for 5 min, and at room temperature for 60 min. The reaction mixture was ice-cooled again, ice water was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (788 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([Br:20])[CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Br:20][C:18]1[CH:17]=[C:11]([CH:10]=[C:9]([NH:8][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C(Cl)CCCCl
Reactant: CCOC(=O)c1cc(N)cc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(Br)cc(NC(=O)CCCCl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
4-Chlorobutyryl chloride (636 mg, 505 μl, 4.5 mmol) was added to a solution of ethyl 3-amino-5-bromobenzoate (1.0 g, 4.1 mmol) and triethylamine (455 mg, 630 ul, 4.5 mmol) in dichloromethane (25 ml) at 0° C. After complete addition the reaction mixture was stirred at room temperature for 30 minutes, then diluted with ethyl acetate (50 ml). The solution was washed with 2M HCl, saturated NaHCO3, water and brine. The organic phase was dried and evaporated to give the title compound as a pale yellow solid (1.35 g, 94%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[CH3:18][CH:19]([CH3:22])[CH:20]=O>>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:10][CH2:18][CH:19]([CH3:22])[CH3:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)c1ccccc1
Product: CC(C)CNC[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Yield: 91.1 %

Procedure:
Using general procedure A, ((R)-2-amino-1-phenyl-ethyl)-carbamic acid tert-butyl ester (472 mg, 2.00 mmol) and 2-methylpropionaldehyde (181 μL, 2.00 mmol) afforded ((R)-2-(2-methylpropyl)amino-1-phenyl-ethyl)-carbamic acid tert-butyl ester (533 mg, 91%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13](=[O:17])[C:14]([OH:16])=[O:15])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O-:21])(=O)[CH3:19].[K+].Cl.[C:24](Cl)(=O)C(Cl)=O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13](=[O:17])[C:14]([O:16][CH2:19][CH2:18][O:21][CH3:24])=[O:15])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(=O)Nc1nc(-c2ccccc2)cs1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: COCCOC(=O)C(=O)Nc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6.2 g of N-(4-phenyl-thiazol-2-yl)-oxamic acid (prepared from the ethyl ester by hydrolyzing with aqueous potassium acetate and liberating the acid with dilute hydrochloric acid), in 25 ml of dry toluene, are heated with 20 ml of oxalyl chloride for 2 hours at 60° C. After distilling off the excess oxalyl chloride under reduced pressure, a solution of 5 ml of ethylene glycol monomethyl ether, 3.5 ml of triethylamine and 20 ml of toluene is added dropwise. The mixture is stirred for a further 3 hours at room temperature and is then left to stand overnight. The precipitate is filtered off, washed with methanol and water and recrystallized from ethanol. 3.7 g of the compound of the formula I, with R1 =C6H5 and R2 =CH2CH2OCH3, of melting point 118°-120° C., are obtained.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:15]=[CH:16]/[I:17])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>O1CCCC1>[I:17]/[CH:16]=[CH:15]/[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CCCOc1ccccc1/C=C/I
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCCCOc1ccccc1/C=C/I
Temperature: 0 °C
Yield: 54.3 %

Procedure:
A solution of 250 mg of 4-[2-[(E)-2-iodovinyl]-phenoxy]butyric acid ethyl ester in 5 ml of tetrahydrofuran is instilled into a suspension of 80 mg of lithium aluminum hydride at 0° C. with stirring and under argon atmosphere. Then, it is stirred for an hour with ice cooling, the mixture is decomposed under argon atmosphere with ice water, shaken out with diethyl ether, dried (Na2SO4) and concentrated by evaporation. 120 mg of 4-[2-[(E)-2-iodovinyl]-phenoxy]-butan-1-ol is obtained as a yellow oil, which is further reacted as a crude product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[CH2:8]([N:10]([CH2:13][CH3:14])[CH2:11]C)[CH3:9].CN(C)C(Cl)=[O:18]>C1C=CC=CC=1>[CH2:8]([N:10]([CH2:13][CH3:14])[C:11](=[O:18])[O:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:9]
Reactant: CN(C)C(=O)Cl
Reactant: CCN(CC)CC
Reactant: Oc1cccnc1
Solvent: c1ccccc1
Product: CCN(CC)C(=O)Oc1cccnc1
Yield: 94.7 %

Procedure:
To a refluxing solution of 3-pyridinol (9.7 g, 0.10 mol) and triethylamine (17.0 mL, 0.12 mol) in anhydrous benzene (300 mL) was slowly added a solution of N,N-dimethylcarbamyl chloride (14.4 mL, 0.11 mol) in anhydrous benzene (50 mL). After heating at reflux for 12 hours, the resultant mixture was filtered, and the salt was washed with benzene (3×10 mL). The filtrate was concentrated and distilled under reduced pressure to provide 18.4 g (95% yield) of the title compound as a light yellow oil (lit.: bp 91-93° C./3.5 mmHg, Millner, O. E, Jr.; Stanley, J. W; Purcell, W. P. J. Med. Chem. 1974, 17, 13). TLC Rf 0.57 (10:1 CHCl3 /MeOH). MS (DCI/NH3) m/e 212 (M+NH4)+, 195 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.44 (d, J=0.9 Hz, 1H, ArH), 8.43 (dd, J=4.8, 1.8 Hz, 1H, ArH), 7.53 (ddd, J=7.5, 1.8, 0.9 Hz, 1H, ArH), 7.30 (dd, J=7.5, 4.8 Hz, 1H, ArH), 3.43 (q, J=7.2 Hz, 2H, NCH2), 3.40 (q, J=7.2 Hz, 2H, NCH2), 1.27 (t, J=7.2 Hz, 3H, CH3), 1.21 (t, J=7.2 Hz, 3H, CH3).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1C(O)=O.B.[CH3:14][OH:15]>O1CCCC1>[O:1]1[C:5]2[C:6]([CH2:14][OH:15])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)C1Cc2ccccc2O1
Reactant: CO
Agent: B
Solvent: C1CCOC1
Product: OCc1cccc2c1OCC2
Temperature: 25 °C

Procedure:
2,3-Dihydrobenzofuran carboxylic acid (5.047 g) in tetrahydrofuran at −10° C. was treated dropwise with a solution of 1.0 M borane.tetrahydrofuran (20 mL). The temperature was allowed to warm to room temperature overnight, treated with additional 1.0 M borane.tetrahydrofuran (10 mL), and stirred at room temperature for 2 hours. The mixture was cooled to 5° C., slowly treated with methanol (20 mL), and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate (2×), saturated sodium chloride, dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes:ethyl acetate, 3:2) to provide the title compound. MS (DCI/NH3) m/z 168 (M+NH4)+; 1H NMR (CDCl3) δ 3.21 (t, 2H), 4.60 (t, 2H), 4.68 (s, 2H), 6.83 (t, 1H), 7.08 (dd, 1H), 7.14 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH:11]([OH:18])[C:12]([N+:15]([O-])=O)([CH3:14])[CH3:13])=[CH:7][CH:6]=1>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH:11]([OH:18])[C:12]([NH2:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1
Reactant: COCCc1ccc(OCC(O)C(C)(C)[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COCCc1ccc(OCC(O)C(C)(C)N)cc1

Procedure:
19 g of 1-[4-(2-methoxyethyl)-phenoxy]-3-nitro-3-methyl-butan-2-ol are hydrogenated at 60° C. and under a pressure of 6 bar in a mixture of 250 ml of ethanol and 50 ml of glacial acetic acid in the presence of 4 g of palladium-on-charcoal (10% Pd). After the mixture has been filtered and the solvent has been evaporated off, the residue is rendered alkaline with 2N NaOH and the mixture is extracted with CH2Cl2. The organic phase is washed with water and dried with Na2SO4 to give, after evaporation, 15 g of the amine, which is converted into the hydrochloride with ethanol hydrochloric acid. Melting point: 120°-122° C. (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[O-])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH3:17][O:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=1[C:27](=O)C(OCC)=O.[NH4+].[Cl-:35]>CCOCC.CCCCC.C1COCC1>[Cl:35][C:27]1([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:19]=2[O:18][CH3:17])[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[NH:8][C:9]1=[O:11]
Reactant: O=C([O-])Nc1ccc(Cl)cc1
Reactant: [Cl-]
Reactant: CCOC(=O)C(=O)c1cccc(OC)c1OC
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1cccc(C2(Cl)C(=O)Nc3ccc(Cl)cc32)c1OC
Temperature: -20 °C
Reaction time: 3 h

Procedure:
4-chlorophenylcarbamate in 100 ml of ether is cooled to −40° C. under an atmosphere of dry nitrogen, 80 ml of a 1.5 M solution of tert-butyllithium in pentane are added dropwise and the mixture is left stirring at −20° C. for 3 hours. The reaction mixture is cooled to −40° C., a solution of 14 g of the compound obtained in step A in 50 ml of THF is added over 1 hour and the mixture is left stirring for 4 days at RT. The reaction mixture is poured into saturated NH4Cl solution and the precipitate formed is spin-filtered off and dried. 10.2 g of the expected product are obtained and are used without further purification in the following step.
Reaction SMILES: [Li]CCCC.[Se:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[Se:12][CH:13]=[CH:14][CH:15]=1.CN(CCN(C)C)C.[CH3:24][Sn:25](Cl)([CH3:27])[CH3:26]>C1COCC1.CC#N>[CH3:24][Sn:25]([CH3:27])([CH3:26])[C:10]1[Se:6][C:7]([C:11]2[Se:12][C:13]([Sn:25]([CH3:27])([CH3:26])[CH3:24])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: c1c[se]c(-c2ccc[se]2)c1
Reactant: C[Sn](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CC#N
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1ccc(-c2ccc([Sn](C)(C)C)[se]2)[se]1
Temperature: 17 °C
Reaction time: 0.33 h

Procedure:
A solution of BuLi in hexanes (10.6 ml of a 1.6 M solution, 17 mmol) is added dropwise to a cooled (−78° C.) solution of 2,2′-biselenophene (2.00 g, 7.7 mmol) in THF (50 ml) and TMEDA (1.98 g, 17 mmol). On addition of the BuLi an immediate colour change is observed (dark red). After stirring for 20 min, the reaction mixture appeared dark yellow. The mixture is stirred for 6 h allowing to warm to 16-18° C. While warming the reaction mixture changed appearance to a green suspension. The reaction mixture is then cooled to −70° C. Trimethylstannyl chloride (3.38 g, 17 mmol) is added as a solid to the reaction mixture. After 10 min, the reaction mixture appeared brown. The reaction mixture is allowed to warm to room temperature overnight. The reaction is quenched with water (100 mL) and the mixture stirred for 1 h. Ethylacetate (100 mL) is added to the mixture. The layers are separated. The combined organic extracts are washed with water, brine and then dried (Na2SO4). After filtration the crude product is concentrated to yield a brown oil. MeCN is added and the mixture is stirred for 5 min. The mixture is recrystallized three times from acetonitrile. The material is used without further purification. MS (EI) 588 (M+).
Reaction SMILES: [CH2:1]([NH:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[NH:13][C:12]=1[C:21]([O:23]C)=[O:22])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].O.[OH-].[Li+]>O1CCCC1.O.C(OCC)(=O)C.O>[CH2:1]([NH:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[NH:13][C:12]=1[C:21]([OH:23])=[O:22])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CNc1c(C(=O)O)[nH]c2cc(Cl)ccc12)c1ccccc1
Temperature: 60 °C

Procedure:
Dissolve 3-[(phenacyl)amino]-2-carbmethoxy-6-chloroindole (480 mg, 1.46 mmol) in tetrahydrofuran/water (20 mL, 1/1). Add lithium hydroxide monohydrate (316 mg, 2.92 mmol). Seal the flask and warm to 60° C. for 3 hours. Dilute with ethyl acetate/water (50 mL/50 mL) and separate the organic phase. Acidify the aqueous phase and extract with ethyl acetate. Dry (MgSO4) the combined organic phases and concentrate in vacuo. Precipitate with hexane to give the title compound; first crop (289 mg, 63%) and second crop (74 mg, 16%); mp 205°-210° C. (dec).
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:17])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3][C:4]([OH:6])=O.[CH2:18]([CH2:20][NH2:21])[OH:19]>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:17])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3][C:4]([NH:21][CH2:20][CH2:18][OH:19])=[O:6]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Reactant: NCCO
Product: CC(C)=CCCC(C)=CCCC(C)=CC(=O)NCCO
Yield: 94 %

Procedure:
The procedure of Example 1 was repeated except that 4.7 g of 3,7,11-trimethyl-2,6,10-dodecatrienoic acid and 1.8 ml of ethanolamine were used as starting materials. 5.2 g (yield 94%) of the title compound was obtained as a colorless oil.
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22](#[N:25])[CH:23]=[CH2:24].C(N(CC)CC)C>O1CCOCC1>[CH2:2]([N:9]1[C@@H:14]2[C@H:23]([C:22]#[N:25])[CH2:24][C@@:10]1([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](=[O:15])[CH:12]=[CH:13]2)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=CC#N
Reactant: Oc1ccc[n+](Cc2ccccc2)c1-c1ccccc1
Agent: [Br-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#C[C@@H]1C[C@@]2(c3ccccc3)C(=O)C=C[C@@H]1N2Cc1ccccc1
Yield: 24 %

Procedure:
N-benzyl-3-hydroxy-2-phenylpyridinium bromide (20 g, 58.3 mmol), acrylonitrile (50 ml, 755 mmol) and triethylamine (20 ml, 143 mmol) were mixed and stirred at reflux for 20 hours in 1,4-dioxane (150 ml). The mixture was partitioned between saturated sodium hydrogen carbonate and ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated. The residue was chromatographed on silica gel eluting with 25, 35 and 45% diethyl ether/iso-hexanes to yield the title compound (4.4 g, 24%).
Reaction SMILES: [C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>>[C:31](/[CH:30]=[CH:29]/[C:28]([O-:35])=[O:34])([OH:33])=[O:32].[C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][NH+:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: C[NH+]1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: O=C([O-])/C=C/C(=O)O
Yield: 87.1 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and fumaric acid (0.41 g, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium (E)-3-carboxyacrylate as a crystalline white solid (1.14 g, 87% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH:10]1([CH2:15]O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:15][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: OCC1CCCC1
Reactant: Oc1cc(Br)cc(Br)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Brc1cc(Br)cc(OCC2CCCC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3,5-Dibromophenol (5.0 g; 19.8 mmol), cyclopentane-methanol (2.0 g; 19.9 mmol) and tributylphosphine (8.8 mL; 35.7 mmol) were dissolved in dry THF (250 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (9.01 g; 35.7 mmol) dissolved in dry THF (150 mL) was added to the reaction mixture, which was stirred at room temperature for 16 hours. The reaction mixture was filtered, evaporated to dryness and purified by flash chromatography (heptane→ethyl acetate:heptane 2:3). Yield: 5.68 g; 86%.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:9][C:8](=[O:10])[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=2)([CH3:12])[CH3:11])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: CC(C)(Oc1ccc(F)cc1)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)Oc3ccc(F)cc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Yield: 1959.2 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 719 mg of 2-(4-fluorophenoxy)-2-methylpropionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give1.26 g of the title compound as a colorless foam.
Reaction SMILES: O[C:2]1([C:27]([F:30])([F:29])[F:28])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([N:5]2[CH:6]=[C:2]([C:27]([F:28])([F:29])[F:30])[N:3]=[C:4]2[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)=[CH:8][CH:9]=1)(=[O:14])=[O:15]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(C(F)(F)F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
A mixture of 4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-(4-trifluoromethylphenyl)-4-trifluoromethyl-4,5-dihydro-1H-imidazole (10 mmol) and p-toluenesulfonic acid monohydrate (1 mmol) in toluene (100 mL) is heated to reflux for 72 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude residue is redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture is chromatographed on silica gel using toluene/ethyl acetate to give pure 1-[4-(methylsulfonyl)phenyl]-2-(4-trifluoromethylphenyl)-4-trifluoromethyl-1H-imidazole.
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[OH:26][CH2:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>>[Cl:25][C:22]1[S:21][C:20]([C:3]2[C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:27][OH:26])[CH:33]=3)=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])[N:4]=2)=[CH:24][CH:23]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Reactant: OCc1cccc(B(O)O)c1
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2cccc(CO)c2)c(-c2ccc(Cl)s2)n1

Procedure:
The title compound was prepared from 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione and 3-(hydroxymethyl)phenylboronic acid in a manner analogous to Example 269. MS (M+H)+ 472.