Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CC(C)([O-])C.[K+]>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([O:34][C:2]2[N:3]=[C:4]([N:8]3[C:16]4[C:11](=[CH:12][C:13]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][CH:15]=4)[CH2:10][CH2:9]3)[N:5]=[CH:6][N:7]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1ncnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc(N3CCc4cc(S(C)(=O)=O)ccc43)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
11a was dissolved in THF. 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (40 mg, 1 eq) and potassium tert-butoxide (22 mg, 1 eq) were added and the mixture was stirred at room temperature for 3 h, then was quenched with water. The mixture was extracted with ethyl acetate twice, and the organic layer was washed with water and dried over sodium sulfate. The solvent was evaporated and the residue taken up in methanol and dichloromethane and purified by preparative HPLC to give 11-1, LCMS 476.2 (MH+), tR=3.68 (Method 6).
Reaction SMILES: B.CSC.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:14](=O)[C@@H:13]([CH2:22][C:23](O)=[O:24])[O:12][C@H:11]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]4[O:32][CH2:33][CH2:34][O:35][C:27]=34)[C:10]=2[CH:36]=1>O1CCCC1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH2:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:14][C@@H:13]([CH2:22][CH2:23][OH:24])[O:12][C@H:11]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]4[O:32][CH2:33][CH2:34][O:35][C:27]=34)[C:10]=2[CH:36]=1
Reactant: CC(C)(C)CN1C(=O)[C@@H](CC(=O)O)O[C@H](c2cccc3c2OCCO3)c2cc(Cl)ccc21
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)CN1C[C@@H](CCO)O[C@H](c2cccc3c2OCCO3)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.5 %

Procedure:
Borane-methyl sulfide complex (2.0M in tetrahydrofuran; 5.9 mL, 11.8 mmol) was added to a solution of the ethyl ester of trans-7-chloro-5-(2,3-ethylenedioxyphenyl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetic acid (1.44 g, 2.95 mmol; Example 1D) in tetrahydrofuran (4.4 mL) under a nitrogen atmosphere. The reaction was stirred at ambient temperature for 18 hours and then cooled to 0° C. and quenched by slow addition of methanol. Once gas evolution ceased, an additional amount of methanol was added and the resulting mixture stirred 1 hour. The reaction mixture was then concentrated and the resulting residue taken up in water and extracted with ethyl acetate (3×). The combined organics were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography (3:1 hexanes/ethyl acetae) to give 835 mg (66%) of the title compound as a white solid.
Reaction SMILES: [N:1]1([CH:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])OCC)=[C:9]([CH:19]=[N:20][CH3:21])[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)C.[BH4-].[Na+]>CO>[N:1]1([CH:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]2[CH:8]=[C:9]3[C:10](=[CH:11][CH:12]=2)[NH:13][C:14](=[O:18])[N:20]([CH3:21])[CH2:19]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1C=NC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CN1Cc2cc(C(c3ccccc3)n3ccnc3)ccc2NC1=O
Reaction time: 7 h
Yield: 20.1 %

Procedure:
To a stirred mixture of 1.7 parts of ethyl [4-[(1H-imidazol-1-yl)phenylmethyl]-2-[(methylimino)methyl]phenyl]carbamate and 31.6 parts of ethanol were added 1 part of sodium tetrahydroborate (portionwise) and 55.3 parts of methanol. After stirring for 7 hours at 40°-50° C., the reaction mixture was evaporated. The residue was taken up in water (to which 0.29 parts of acetic acid were added) and the whole was basified with NH4OH. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 /CH3OH 95:5). The eluent of the desired fraction was evaporated and the residue was crystallized from ethyl acetate, yielding 0.3 parts (20.1%) of 3,4-dihydro-6-[(1H-imidazol-1-yl)phenylmethyl]-3-methyl-2(1H)-quinazolinone; mp. 173.8° C. (comp. 23).
Reaction SMILES: C[N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH:24]([CH3:30])[NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH:24]([CH3:30])[N:25]2[C:16](=[O:18])[CH2:15][C:3]1[NH:2][C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: CC1Cc2c(F)cccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1Cc2c(F)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 29.2 %

Procedure:
The product is prepared by following the procedure described in example 29c using 0.22 g of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (prepared in step 2c of example 4c), 0.11 g of (−)-4-fluoro-2-methyl-2,3-dihydro-1H-indole [reference example 8c, step 6c], and 0.19 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 120 μl of pyridine and 3.0 ml of N,N-dimethylformamide. 79 mg of (+)-2-{2-[4-fluoro-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7]2.CO>O1CCCC1>[F:1][C:2]([F:14])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH:9]([OH:13])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cc(OC(F)(F)F)ccc21
Solvent: C1CCOC1
Solvent: CO
Product: OC1CCc2cc(OC(F)(F)F)ccc21
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 28.6 %

Procedure:
(2S)-1-(1,3,2-Dioxaborolan-2-yloxy)-3-methyl-1,1-diphenylbutan-2-amine (33 mg, 0.1 mmol) obtained in a similar manner to the method of European Journal of Organic Chemistry, 1999, p. 1775 (Eur. J. Org. Chem. 1999, 1775) was suspended in tetrahydrofuran (5 mL), and then thereto was added borane dimethylsulfide complex (10 mol/L, 0.1 mL, 1 mmol) at room temperature. The mixture was stirred at the same temperature for 20 minutes, and then thereto was added in divided portions 5-trifluoromethoxyindan-1-one (0.217 g, 1 mmol) obtained in a similar manner to the method of U.S. Pat. No. 6,159,996 over 1 hour, and the mixture was stirred at room temperature overnight. The mixture was cooled to 5° C., and then thereto was added methanol (2 mL). The mixture was stirred at the same temperature for 1 hour, and then the reaction solution was concentrated, and then thereto was added chloroform. The chloroform solution was poured into saturated aqueous ammonium chloride solution, and extracted with chloroform three times, and the organic layer was washed with saturated brine. The resultant was dried over magnesium sulfate, and then concentrated. To the resulting residue were added diethyl ether and hexane, and the generated white solid was filtered off. The filtrate was concentrated to give a crude 5-(trifluoromethoxy)indan-1-ol (62.5 mg). The resultant was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][N:10]([CH3:39])[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]3[O:25][C:26]4[C:31]([CH:32]([C:33](=[CH2:38])[C:34]([O:36][CH3:37])=[O:35])[C:22]3=[CH:21][CH:20]=2)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:15][CH:14]=1)=[O:12]>CS(C)=O>[CH3:39][N:10]([CH3:9])[C:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:24]=[C:23]3[O:25][C:26]4[C:31]([CH:32]([C:33]5([C:34]([O:36][CH3:37])=[O:35])[CH2:4][CH2:38]5)[C:22]3=[CH:21][CH:20]=2)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:17][CH:18]=1)=[O:12]
Reactant: C[S+](C)(C)=O
Reactant: C=C(C(=O)OC)C1c2ccccc2Oc2nc(-c3ccc(C(=O)N(C)C)cc3)ccc21
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1(C2c3ccccc3Oc3nc(-c4ccc(C(=O)N(C)C)cc4)ccc32)CC1
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
Sodium hydride (5.2 mg, 0.13 mmol, 60% in mineral oil) was added to a solution of trimethyl sulfoxonium iodide (28.7 mg, 0.13 mmol) in DMSO (1 mL) at room temperature. After 30 min at room temperature, the mixture was added to a solution of the product from Step 3 (45 mg, 0.109 mmol) in DMSO (1 mL). The resultant mixture was stirred at room temperature for 10 min and quenched with saturated NaHCO3 (1 mL). After addition of ethyl acetate (80 mL), the mixture was washed with water (2×10 mL), brine (10 mL), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (silica, 50-100% ethyl acetate in hexanes) to provide methyl 1-(2-(4-(dimethylcarbamoyl)phenyl)-5H-chromeno[2,3-b]pyridin-5-yl)cyclopropanecarboxylate (12 mg, 26%). MS (ES+) m/z: 429 (M+H).
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]>>[F:12][C:13]1[CH:18]=[C:17]([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]4)[CH2:3]2)[CH2:9]3)[CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1F
Reactant: BrC12CC3CC(CC(C3)C1)C2
Product: COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1F
Yield: 83.3 %

Procedure:
The title compound was prepared from 1-fluoro-2-methoxybenzene (10 mL) and 1-bromoadamantane (3.25 g, 15.25 mmol) according to the step 1 of the example 5, which was given 1-(3-fluoro-4-methoxyphenyl)adamantane (5.05 g, 83.3% yield).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[C:4]([OH:6])=[O:5].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Cl>[OH-].[Na+]>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:2][CH:3]([OH:7])[C:4]([OH:6])=[O:5])=[CH:11][CH:10]=1
Reactant: O=C(O)C(O)CCl
Reactant: Oc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(O)COc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.8 g (14.7 mmoles)3-chlorolactic acid and 3.4 g p-chlorophenol in 15 ml 3.3 N sodium hydroxide was stirred under reflux for two hours. The mixture was cooled to room temperature and acidified to pH=3, with concentrated hydrochloric acid. The resulting white crystals were filtered and dissolved in hot water and the hot solution was adjusted to pH=1 with concentrated sulfuric acid. Upon cooling the product, 3-(p-chlorophenoxy)-lactic acid was collected as clear crystals, 0.7 g, m.p. 135° to 136° C.; Edelson, et al. Biochem Pharmacol 18, 2331 (1969) reported m.p. 137° to 138° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][OH:8].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][O:8][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(Br)cc1CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a solution of 2.17 g (10.0 mmol) of 5-bromo-2-methoxybenzyl alcohol in 10 mL of N,N-dimethylformamide was added 1.36 g (20.0 mmol) of imidazole, then 2.26 g (15.0 mmol) of tert-butyldimethylsilyl chloride. The reaction was stirred at ambient temperature for 30 min, and poured into 100 mL of water. The aqueous suspension was extracted with diethyl ether (3×15 mL), then the combined ether layers were back extracted with 1 M HCl (2×15 mL), saturated NaHCO3(aq.) (2×15 mL), and brine (1×15 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 95:5 hexanes:ethyl acetate to give 2.91 g (88%) of the titled compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[Br:1][C:2]1[C:3]([NH2:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)=[N:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: Nc1c(Br)cnc(Cl)c1[N+](=O)[O-]
Solvent: CCO
Product: CN1CCN(c2ncc(Br)c(N)c2[N+](=O)[O-])CC1
Temperature: 130 °C
Yield: 64.9 %

Procedure:
A 20 mL microwave reaction tube was charged with 5-bromo-2-chloro-3-nitropyridin-4-amine (1.0 g, 3.9 mmol), N-methylpiperazine (0.78 g, 7.8 mmol) and anhydrous ethanol (15 mL). The resulting solution was heated at 130° C. for 1 h in a Biotage microwave reactor. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 10% MeOH in CH2Cl2, to afford 0.80 g (64%) of the product as a white solid. MS m/z: 316 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:19](COC)[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)(=[O:22])=[O:21])[C:5]([C:8](=[O:18])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[F:17])=[N:6][CH:7]=1.Cl>O.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)(=[O:22])=[O:21])[C:5]([C:8](=[O:18])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[F:17])=[N:6][CH:7]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1c(F)cccc1OC)S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(F)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
N-[5-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (180 mg, 0.313 mmol) was magnetically stirred in water (1.0 mL) and 4N HCl in dioxane (2.5 mL) and heated at 85° C. for 7 h. The reaction was subsequently concentrated and the residue was neutralized (pH 7) with aqueous sodium bicarbonate and extracted with EtOAc (3×80 mL). The extracts were dried (MgSO4), filtered, and chromatographed on silica gel using EtOAc-hexane (gradient, 0:100 to 50:50) to provide N-[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide: MS m/z 489.1 (M+H); 511.0 (M+Na).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:10])=[N:4][C:5]([CH2:9][Br:18])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C)c(Br)c(C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CBr)nc(C)c1Br
Temperature: 25 °C
Yield: 36.8 %

Procedure:
A mixture of 3-bromo-2,4,6-trimethylpyridine (15.6 g), NBS (13.9 g) and benzoyl peroxide (567 mg) was heated under reflux in a carbon tetrachloride solvent (300 mL) for two hours. The reaction mixture was cooled to room temperature and then filtered, and the filtration residue was washed with carbon tetrachloride. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 10%) to give the title compound (8.00 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[CH3:8].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>C(O)(=O)C>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][CH3:10])=[CH:3][C:2]=1[N:1]1[CH:13]=[CH:17][CH:16]=[CH:15]1
Reactant: COC1CCC(OC)O1
Reactant: COc1ccc(C)c(N)c1
Solvent: CC(=O)O
Product: COc1ccc(C)c(-n2cccc2)c1
Temperature: 25 °C

Procedure:
A solution of 88.4 g (0.64 mole) of 3-amino-4-methylanisole in 1.4 liters of glacial acetic acid is heated to 106° and, at this temperature, 114 g (0.86 mole) of 2,5-dimethoxytetrahydrofuran are added in the course of 30 minutes. The mixture is then immediately cooled to room temperature and concentrated in a vacuum rotary evaporator. Distillation of the residue in a high vacuum yields 4-methyl-3-(pyrrol-1-yl)-anisole, b.p. 93°-95°/0.04 torr. Rf (toluene/ethyl acetate=10:1):0.57.
Reaction SMILES: [C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17][C:18](O)=[O:19])=[C:13]([CH3:23])[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.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17][C:18]([N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)=[O:19])=[C:13]([CH3:23])[CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CN1CCNCC1
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCCC(=O)O
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCCC(=O)N1CCN(C)CC1
Yield: 94.5 %

Procedure:
The title compound was prepared from 3-(4-(adamantan-1-yl)-2-methylphenoxy)propanoic acid (0.2 g, 0.63 mmol) and 1-methylpiperazine (0.063 g, 0.63 mmol) according to the example 1, which was given 3-(4-(adamantan-1-yl)-2-methylphenoxy)-1-(4-methylpiperazin-1-yl)propan-1-one as a white solid (0.236 g, 93.6% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[C:19](/[C:21]([OH:23])=[O:22])\[CH3:20])[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:9]([CH3:29])[NH:8][C:7]=1[CH3:30])=[O:5])[CH3:2].[CH2:31](Br)[CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[C:19](\[CH3:20])/[C:21]([O:23][CH2:31][CH3:32])=[O:22])[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:9]([CH3:29])[NH:8][C:7]=1[CH3:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1/C=C(\C)C(=O)O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1/C=C(\C)C(=O)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
A suspension of Compound A (4 g), ethyl bromide (1 g) and potassium carbonate (30 g) in dimethylformamide (60 ml) was stirred at room temperature for 6 h. The mixture was poured into water and extracted with ethyl acetate, then washed thoroughly with water and dried over Na2SO4. Evaporation of the solvent gave an oil which was triturated with petrol and recrystallized from petrol ether to give the title compound as a white solid (3.2 g). M.p. 105°-106°.
Reaction SMILES: C([Li])(CC)C.[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]1[O:16][CH2:15][CH2:14][CH2:13][O:12]1.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].O>C1COCC1>[O:16]1[CH2:15][CH2:14][CH2:13][O:12][CH:11]1[C:7]1[O:6][C:10]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1coc(C2OCCCO2)c1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCCO2)o1
Temperature: -20 °C
Reaction time: 2.5 h

Procedure:
200 ml of sec-butyllithium (1.3M solution in cyclohexane, 260 mmol) were added dropwise to a solution of 34.4 g of 2-(2-furyl)-1,3-dioxane (224 mmol, obtainable from furfural and propane-1,3-diol) in 320 ml of THF at −70° C. in the course of 20 minutes. The solution was warmed at −20° C. for 30 minutes and then cooled again to −78° C. A solution of 60.8 ml of tributylstannyl chloride in 160 ml of THF was then added dropwise in the course of 30 minutes, after which the mixture was allowed to warm to room temperature. After 2.5 hours, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated and the residue was distilled (boiling point0.8 1 80° C.). 93 g were obtained.
Reaction SMILES: [CH2:1]1[CH2:8][O:7][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2]1.[CH3:9][CH:10]([C:16]([CH3:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(O[K])(C)(C)C>C(O)(C)(C)C>[CH2:14]([O:13][C:11]([C:10]([CH3:9])([C:16](=[O:17])[CH3:18])[CH2:8][CH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])=[O:12])[CH3:15]
Reactant: O=S1(=O)CCCCO1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: CC(C)(C)O[K]
Solvent: CC(C)(C)O
Product: CCOC(=O)C(C)(CCCCS(=O)(=O)O)C(C)=O
Yield: 75 %

Procedure:
0.35 ml (3.47 mmol) of 1,4-butane sultone were added to a mixture of 0.49 ml (3.47 mmol) ethyl 2-methylacetoacetate and 513 mg (4.2 mmol) of tert-BuOK in 12 ml tert-butanol and refluxed for 15 hours. The formed precipitate was filtered and washed with hexane to yield 730 mg of 5-ethyloxycarbonyl-5-methyl-6-oxo-1-heptanesulfonic acid. δH (200 MHz, DMSO-d6): 4.12 (2H, q, 7.1, 14.2 Hz, OCH2), 3.97 (2H, t, 5.8 Hz, CH2SO3H), 2.10 (3H, s, COCH3), 1.78-1.41 (4H, m, CH2), 1.24-1.01 (2H, m, CH2), 1.22 (3H, s, CCH3), 1.17 (3H, t, 7.3 Hz, CH2CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=[C:11]([CH:14]=O)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:20][OH:21]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=[C:11]([CH:14]=[N:20][OH:21])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NO
Reactant: O=CC1=NOC(c2cc(Cl)cc(Cl)c2)(C(F)(F)F)C1
Solvent: O
Solvent: CCO
Product: ON=CC1=NOC(c2cc(Cl)cc(Cl)c2)(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3-carbaldehyde (2 g) in EtOH (4 mL) and H2O (2 drops), was added aqueous NH2OH (50% in water, 0.48 mL). The solution was stirred at room temperature for 3 hours then allowed to stand at room temperature for 16 hours. Then the solution was stirred again and more hydroxylamine (0.04 mL) was added. After 3 hours, the reaction was quenched by addition of water. After extraction with ethylacetate, the organic phase was separated, dried over magnesium sulfate and concentrated to give 2.02 g of a yellow solid which was used in the next step without further purification. 1H-NMR (CDCl3, 400 MHz) shows a mixture of diastereoisomers: 8.07 and 7.94 (s, 1H), 7.43-7.38 (m, 3H), 3.88 (d, 1H), 3.50 (d, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:10](Cl)(=[O:12])[CH3:11].[Cl-].Cl>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:12])[CH3:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCO2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCO2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
2,3-Dihydrobenzofuran (10 g, 83.2 mmol) was dissolved in dichloromethane (400 mL), added sequentially with acetyl chloride (11.8 mL, 167 mmol) and alminium chloride (33.3 g, 250 mmol) at −10° C., and the mixture was stirred at −10° C. for 0.5 hours. The reaction solution was added 5% aqueous solution of hydrochloric acid, extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. 1-(2,3-Dihydrobenzofuran-5-yl)ethanone (13.4 g (yield 99%)) was obtained as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:14]=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]2)=[CH:4][C:3]=1[O:16][CH3:17].C([O-])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27]Br>C(#N)C>[Br:24][CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:14]=[O:15])[CH:9]=[CH:10][CH:11]=[CH:12][CH2:13]2)=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: BrCCCBr
Reactant: COc1cc(C2(C=O)C=CC=CC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C2(C=O)C=CC=CC2)ccc1OCCCBr
Yield: 13.2 %

Procedure:
A mixture of 1-(4-hydroxy-3-methoxyphenyl)phenyl-methanone (14 g, 61.4 mmol), K2CO3 (13 g, 92.1 mmol), and 1,3-dibromopropane (28 g, 86 mmol) in acetonitrile (400 ml) was heated at reflux for 4 hours. The reaction was followed by thin layer chromatography. At the end of the reaction, the inorganics were filtered off and the solvent was removed on a rotary evaporator. The residue was purified on a flash chromatographic column (SiO2, 140 g, eluted with 4:1 hexane:dichloromethane, 1,2 l) to give a partially solidified material: 15.44 g (72%). Recrystallization twice from ethanol gave 2.84 g of 1-[4-(3-bromopropoxy)-3-methoxyphenyl]phenylmethanone as white crystals, m.p.=88°-89° C.