Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](Cl)(Cl)[C:7]1=[O:17])[CH3:2].[OH-].[Na+].Cl.C(OCC)(=[O:26])C>CS(C)=O>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:26])[C:7]1=[O:17])[CH3:2]
Reactant: CCOC(CN1C(=O)C(Cl)(Cl)c2ccccc21)OCC
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(CN1C(=O)C(=O)c2ccccc21)OCC
Reaction time: 0.75 h

Procedure:
To a solution of 31 g of 1-(2,2-diethoxyethyl)-3,3-dichloroindolin-2-one in 200 ml of dimethyl sulfoxide was added dropwise 50 ml of an aqueous solution of 14.5 g of sodium hydroxide in such a manner that the reaction temperature might not exceed 20° C., followed by stirring at the same temperature for 45 minutes. To the mixture was slowly added 15.5 ml of concentrated hydrochloric acid, followed by stirring at room temperature for 1.5 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and an aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 25 g of the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][C:6]2([CH2:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:20]=[CH:21]/[C:22](O)=[O:23])[CH:15]=3)[O:10]2)[CH2:5]1)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:39][O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1>C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][C:6]2([CH2:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:20]=[CH:21]/[C:22]([NH:39][O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)=[O:23])[CH:15]=3)[O:10]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: NOC1CCCCO1
Reactant: CC(=O)N1CCCC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)N1CCCC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(±)-(E)-3-[1′-Acetyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid (crude compound from STEP B, 590 mg) was dissolved in DCM (30 ml) and TEA (0.498 ml, 3.59 mmol). EDC (513 mg, 2.68 mmol) and HOBt (362 mg, 2.68 mmol) were added and the mixture was stirred for 10 min at RT. NH2OTHP (251 mg, 2.15 mmol) was added and the solution was stirred overnight at RT and was then partitioned between 5% NaHCO3 and DCM. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude mixture was purified by column chromatography (eluent: DCM/MeOH 99:1 to 97:3) to give (±)-(E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide that was dissolved in DCM and treated with 4 M HCl in dioxane for 3 h. The precipitate was collected by filtration and washed with DCM to give (±)-(E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide as pale yellow powder (404 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[N:13]([CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:14]=[C:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)=O)C>C1COCC1.CCOC(C)=O>[C:31]([O:30][C:28](=[O:29])[NH:27][CH2:26][CH2:25][N:13]1[C:12]([CH2:10][OH:9])=[CH:16][C:15]([CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:14]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CCNC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCn1nc(COc2ccccc2)cc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
A 1M solution of lithium aluminum hydride in THF (6.98 mL, 6.98 mmol) was added dropwise to a stirred solution of 2-(2-tert-butoxycarbonylamino-ethyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (2.72 g, 6.98 mmol) in THF (47 mL) under N2 at 0° C. The mixture was stirred at room temperature for 1 hour and diluted with AcOEt. Na2SO4.10H2O was added at 0° C. and the mixture was stirred for 15 minutes at this temperature, filtered through a pad of diatomaceous earth and then washed with additional AcOEt. The solvents were evaporated in vacuo to yield [2-(5-hydroxymethyl-3-phenoxymethyl-pyrazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (2.5 g, 76% yield) as a white solid that was used in the next step without further purification.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]([C:16]1[C:23]([F:24])=[C:22]([F:25])[C:19]([CH2:20][OH:21])=[C:18]([F:26])[C:17]=1[F:27])[CH:14]=[CH2:15].[C:28]([C:30]([CH3:40])=[CH:31][C@@H:32]1[C@@H:34]([C:35](O)=[O:36])[C:33]1([CH3:39])[CH3:38])#[N:29]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:28]([C:30]([CH3:40])=[CH:31][C@@H:32]1[C@@H:34]([C:35]([O:21][CH2:20][C:19]2[C:18]([F:26])=[C:17]([F:27])[C:16]([CH2:13][CH:14]=[CH2:15])=[C:23]([F:24])[C:22]=2[F:25])=[O:36])[C:33]1([CH3:39])[CH3:38])#[N:29]
Reactant: C=CCc1c(F)c(F)c(CO)c(F)c1F
Reactant: CC(C#N)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C=CCc1c(F)c(F)c(COC(=O)[C@@H]2[C@@H](C=C(C)C#N)C2(C)C)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Under a nitrogen atmosphere, 0.23 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added to a mixture of 0.20 g of 4-allyl-2,3,5,6-tetrafluorobenzyl alcohol, 0.16 g of (1R)-trans-3-(2-cyano-1-propeny)-2,2-dimethylcyclopropanecarboxylic acid, 0.05 g of 4-dimethylaminopyridine and 4 ml of anhydrous chloroform, and the mixture was stirred at room temperature for 3 hours. Thereafter, the reaction mixture was poured into ice water, followed by extraction with ethyl acetate two times. Ethyl acetate layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.32 g of 4-allyl-2,3,5,6-tetrafluorobenzyl(1R)-trans-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylate represented by the following formula:
Reaction SMILES: O[CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.C1(=O)[NH:23]C(=O)C2=CC=CC=C12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH2:23][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:4]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)COc1cccc2c1CCC(CO)C2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)COc1cccc2c1CCC(CN)C2
Reaction time: 2 h
Yield: 61.1 %

Procedure:
To a solution of methyl (2-hydroxymethyl-l,2,3,4-tetrahydronaphthalen-5-yl)oxyacetate (1.15 g), phthalimide (1.22 g) and triphenylphosphine (2.17 g) in tetrahydrofuran (50 ml) was added diethyl azodicarboxylate (1.6 ml) at -20° C. After stirred for 2 h, the mixture was quenched by addition of water. The mixture was extracted with ether. The extract was washed with a saturated aquous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated. To a solution of the obtained residue in ethanol (30 ml) was added hydrazine monohydrate (0.7 ml) at room temperature. The mixture was stirred overnight. The mixture was quenched by addition of water (20 ml) and evaporated. The residue was crystallized from 2N hydrochloric acid (20 ml) to give the title compound (700 mg) having the following physical data.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].N#N>CCO.C(Cl)Cl.[Pd]>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:2]2
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Agent: [Pd]
Agent: N#N
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (Step b, 18 g, 68 mmol) in EtOH (200 mL) stirred under N2 was introduced Pd/C 10% (2 g). The N2 atmosphere was replaced by H2 and the mixture was vigourously stirred at RT under H2 atmosphere (balloon) overnight. The mixture was diluted with DCM and filtered. The catalyst was washed several times with DCM. The solvents were removed under vacuum. The solid residue was suspended in EtOH and the filtered to give ethyl 6-methoxyquinoline-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Br:9])[CH:6]=[CH:7][CH:8]=1.[C:10](Cl)(=[O:13])[CH:11]=[CH2:12].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:9][C:5]1[CH:6]=[CH:7][C:8]([C:10](=[O:13])[CH:11]=[CH2:12])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc(Br)cc1OC

Procedure:
3-methoxybromobenzene (0.5 mL), acryloyl chloride (110 mg), and aluminium chloride (160 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (8.0 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.C(=O)([O-])[O-:26].[K+].[K+].Cl>O1CCOCC1.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10](/[CH:9]=[CH:8]/[C:6]2[N:5]=[CH:4][NH:3][C:2](=[O:26])[CH:7]=2)=[CH:11][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc(/C=C/c2cc(Cl)ncn2)cc1
Agent: C1CN2CCN1CC2
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1cc(/C=C/c2ccc(Cl)cc2)nc[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of (E)-4-chloro-6-(4-chlorostyryl)pyrimidine Part A (120 mg, 0.48 mmol), DABCO (107 mg, 0.96 mmol), and potassium carbonate (660 mg, 4.78 mmol) in Dioxane (0.4 mL) and Water (4 mL) was stirred at 60° C. overnight. The reaction was cooled to RT, acidified with 10% HCl, extracted with EtOAC, dried (Na2SO4), and concentrated. The product was triturated with DCM to afford the desired product (E)-6-(4-chlorostyryl)pyrimidin-4(3H)-one 20B (108 mg, 0.46 mmol, 97% yield) as a light yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=O)[CH2:9]1>O1CCCC1.N>[CH3:7][C:8]1([CH3:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH2:10][CH2:9]1
Reactant: CC1(C)CC(=O)Nc2ccccc21
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1(C)CCNc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of aniline (4.43 g) in chloroform (20 ml), a solution of 3,3-dimethylacryloyl chloride (2.65 ml) in chloroform (10 ml) was added dropwise and heated under reflux for 1.5 hours. After insoluble materials were filtered off and washed with chloroform, the filtrate was washed sequentially with 1M aqueous hydrochloric acid and saturated aqueous sodium bicarbonate. The filtrate was dried over anhydrous magnesium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was converted into a powder form by addition of n-hexane, and then collected by filtration to give 3-methyl-N-phenylbut-2-eneamide (4.11 g) as a colorless powder. 3-Methyl-N-phenylbut-2-eneamide thus obtained (2.06 g) was melted at 130° C., to which aluminum chloride powder (1.88 g) was then added and stirred at 130° C. for 0.5 hours. After the reaction temperature was reduced to 85° C., aluminum chloride powder (0.27 g) was added and stirred at 85° C. for 1 hour. After cooling at room temperature, the reaction mixture was poured into ice-cold water and extracted with diethyl ether, and the organic layer was washed with brine. The aqueous layer was extracted with chloroform, and the resulting organic layer was combined with the organic layer obtained earlier, dried over anhydrous magnesium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 1:1), and the solvent was distilled off under reduced pressure. The residue was converted into a powder form by addition of n-hexane, and then collected by filtration to give 4,4-dimethyl-3,4-dihydroquinolin-2(1H)-one (1.01 g) as a colorless powder. A suspension of lithium aluminum hydride (0.43 g) in tetrahydrofuran (5 ml) was heated under reflux, to which a solution of 4,4-dimethyl-3,4-dihydroquinolin-2(1H)-one thus obtained (1.01 g) in tetrahydrofuran (10 ml) was then added dropwise and heated under reflux for 3.5 hours. The reaction mixture was allowed to stand overnight at room temperature, diluted with 28% aqueous ammonia under ice cooling, and then filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=19:1 to 4:1) to give the titled compound, i.e., 4,4-dimethyl-1,2,3,4-tetrahydroquinoline (0.84 g) as a light-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:18]1[C:28]2[CH:27]=[CH:26][C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[CH:23]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:29]1[C:25]2[CH:26]=[CH:27][C:28]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH:23]([CH:33]3[CH2:34][CH2:35][N:36]([C:6](=[O:7])[C:5]4[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:37][CH2:38]3)[C:24]=2[CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)N1CCC(C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 106.7 %

Procedure:
0.64 gram (4.03 millimoles) of p-fluorobenzoyl chloride, 1.84 grams (18.2 millimoles) of triethylamine, 0.22 gram (1.82 millimoles) of 4-dimethylaminopyridine was added at ambient temperature to a solution of 1.00 gram (3.63 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine in 40 milliliters of dry methylene chloride while protected from atmospheric moisture and the mixture stirred for a total of about 50 minutes. About 10 grams of ice was added to the reaction mixture to quench the reaction and the resulting biphasic mixture stirred and allowed to warm to room temperature. The aqueous and organic phases were separated and the organic phase washed successively with 5 percent hydrochloric acid, aqueous bicarbonate and brine. The washed solution was dried over magnesium sulfate, the drying agent then filtered off and the solvent vaporized in vacuo to obtain 1.54 grams of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-(p-fluorobenzoyl)piperidine residue which crystallized in a few hours at ambient temperature. Recrystallization from toluene produced white needles. The product had a melting point of 150°-151° C. Elemental analyses indicated presence of solvent of crystallization; the results calculated for 1 mole of toluene of crystallization were as follows:
Reaction SMILES: C(O[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)C#C.[CH2:11]([Li])[CH2:12][CH2:13][CH3:14]>CCCCCC.O1CCCC1>[CH3:14][C@:13]12[CH2:12][CH2:11][C@H:5]3[C@@H:5]([CH2:11][CH2:12][C:13]4[C@@H:10]3[CH2:9][CH2:8][CH2:7][CH:14]=4)[C@@H:10]1[CH2:9][CH2:8][C@@H:7]2[OH:6]
Reactant: C#CCOC1CCCCO1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1CC[C@@H]2O

Procedure:
As described under 3D, 460 mg of 7G is produced from 442 mg of 7F with 1.30 ml of 2-(2-propinyloxy)tetrahydro-2H-pyrane and 5.36 ml of a 15% solution of butyllithium in hexane in 70 ml of tetrahydrofuran.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:17](I)[CH2:18][CH3:19]>CC(C)=O.[Ag]=O>[CH2:17]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:10]1)[CH2:18][CH3:19]
Reactant: FC(F)(F)c1cccc(C2CCCNC2)c1
Reactant: CCCI
Agent: O=[Ag]
Solvent: CC(C)=O
Product: CCCN1CCCC(c2cccc(C(F)(F)F)c2)C1

Procedure:
A mixture of 4.6 g of the product of Step A in 25 ml of acetone was stirred until dissolution occured and then 2.5 g of silver oxide were added thereto. The mixture was cooled on an ice bath and 2.5 ml of propyl iodide were added dropwise over 5 minutes. The temperature went back to room temperature and the mixture was stirred for 16 hours and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 85-10-5 cyclohexane-chloroform-triethylamine mixture and evaporation to dryness under reduced pressure yielded 4.3 g of N-propyl-3-(m-trifluoromethylphenyl)-piperidine.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:10]([OH:21])[N:9]([CH:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[C:8]2=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29](O)(=[O:31])[CH3:30]>C(OC(=O)C)(=O)C.C(OCC)(=O)C>[C:29]([N:24]1[CH2:25][CH2:26][CH2:27][CH:22]([N:9]2[C:10]([OH:21])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:12](=[O:13])[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]2=[O:28])[CH2:23]1)(=[O:31])[CH3:30]
Reactant: CC(=O)O
Reactant: O=C(O)CNC(=O)c1c(O)n(C2CCCNC2)c(=O)n(C2CCCCC2)c1=O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCCC(n2c(O)c(C(=O)NCC(=O)O)c(=O)n(C3CCCCC3)c2=O)C1
Yield: 31 %

Procedure:
A solution of N-{[3-cyclohexyl-6-hydroxy-2,4-dioxo-1-(3-piperidinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine (500 mg, 1.26 mmoles) in acetic acid (5.0 mL) and acetic anhydride (5.0 mL) was heated at 130° C. for 2 hours. The mixture was cooled, diluted with ethyl acetate and washed with 1 molar hydrochloric acid (×3), dried and evaporated. Flash chromatography (dichloromethane to 4% methanol-0.1% acetic acid in dichloromethane) and recrystallization from ethanol-water gave the title compound (170 mg, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.17 (s, 1 H), 4.46-4.73 (m, 2 H), 4.25-4.46 (m, 1H), 4.13 (d, J=5.56 Hz, 2 H), 3.67-3.92 (m, J=4.55 Hz, 1 H), 3.24-3.43 (m, 1 H), 2.94 (t, J=12.63 Hz, 1 H), 2.34-2.48 (m, 1 H), 2.25 (m, 2 H), 1.97, 2.02 (2×s, 3 H), 1.69-1.87 (m, 4 H), 1.62 (m, 3 H), 1.41-1.57 (m, 1 H), 1.19-1.37 (m, 2 H), 0.97-1.18 (m, 1 H)
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:24])[CH:18]=1>CN(C=O)C.CCOC(C)=O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:19]([Cl:24])[CH:18]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1cc(Br)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
415 mg (3.00 mmol) K2CO3 and 170 mg (1.00 mmol) N-(2-chloroethyl)-pyrrolidine-hydrochloride is added to a solution of 207 mg (1.00 mmol) 4-bromo-2-chloro-phenol in 5 mL DMF and the mixture is stirred for 24 h at RT. The reaction mixture is diluted with 50 mL EtOAc, extracted once with 30 mL water and twice with 30 mL semisaturated NaHCO3 solution. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. Further purification is carried out by column chromatography on silica gel (gradient: DCM to DCM/MeOH 9:1).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[CH:10]([CH:24]3[O:28][CH2:27][CH2:26][O:25]3)[CH2:9][CH2:8][C@@:7]4([OH:29])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:3][CH2:2]1.N1C=CN=C1.[CH:35]([Si:38]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])Cl)([CH3:37])[CH3:36].O>C(Cl)Cl>[CH:35]([Si:38]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[O:20][C:15]1[CH:16]=[CH:17][C:18]2[CH2:19][C@H:6]3[N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:23][CH2:22][C@:12]45[C:13]=2[C:14]=1[O:21][C@H:11]4[CH:10]([CH:24]1[O:25][CH2:26][CH2:27][O:28]1)[CH2:9][CH2:8][C@@:7]35[OH:29])([CH3:37])[CH3:36]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1ccc2c3c1O[C@H]1C(C4OCCO4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)[Si](Oc1ccc2c3c1O[C@H]1C(C4OCCO4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314)(C(C)C)C(C)C

Procedure:
17-(cyclopropylmethyl)-4,5a-epoxy-3,14-dihydroxy-6-(1,3-dioxolan-2-yl)morphinan (3.85 g, 10 mmol) was dissolved in 20 ml of methylene chloride, then imidazole (0.68 g, 10 mmol) and triisopropylchlorosilane (1.92 g, 10 mmol) were added with stirring. The whole system was refluxed to react for 4 hours. After the reaction was complete, water was added for extraction and then extracted with methylene chloride for 3 times. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated for crystallization to afford a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1.[O:37]1[CH:41]=[CH:40][C:39]([NH2:42])=[N:38]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:42][C:39]4[CH:40]=[CH:41][O:37][N:38]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(Br)c(C)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Br)c(C)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 0.33 h
Yield: 90.8 %

Procedure:
A solution of perfluorophenyl 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (3.508 g, 4.87 mmol), isoxazol-3-amine (0.540 ml, 7.31 mmol) and THF (48.7 ml) was cooled in an ice-bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in THF) (12.18 ml, 12.18 mmol) was added dropwise. After 20 min, additional portions of 3-aminoisoxazole (0.1 mL) and LHMDS solution (2 mL) were added. After 5 min, the mixture was diluted with 1N aq. HCl and EtOAc. The layers were separated, and the organic layer was washed with 1N aq. HCl. The aq. layers were combined and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was concentrated from DCM, and then taken up in DCM. The resulting suspension was sonicated and filtered. The collected solid was washed with DCM (2×), dried under a stream of N2 (g), then dried under vacuum to give 1-(4-bromo-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (2.169 g, 4.42 mmol, 91% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) □=11.66 (br. s., 1 H), 8.72 (d, J=1.8 Hz, 1 H), 8.35 (d, J=2.2 Hz, 1 H), 8.21 (d, J=9.6 Hz, 1 H), 7.83 (dd, J=2.2, 8.9 Hz, 1 H), 7.52 (s, 1 H), 7.34 (d, J=0.4 Hz, 1 H), 6.78 (d, J=9.6 Hz, 2 H), 6.43 (d, J=1.9 Hz, 1 H), 3.67 (s, 3 H); 2.31 (s, 3 H). m/z (ESI) 489.9 (M+H)+.
Reaction SMILES: Cl[C:2]([CH:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([C:7](=[O:14])[NH:8][C:9]2=[O:13])[CH2:5]1)=[O:3].[CH2:15]([OH:17])[CH3:16]>>[C:2]([CH:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([C:7](=[O:14])[NH:8][C:9]2=[O:13])[CH2:5]1)([O:17][CH2:15][CH3:16])=[O:3]
Reactant: O=C(Cl)C1CC2CC(C1)C(=O)NC2=O
Reactant: CCO
Product: CCOC(=O)C1CC2CC(C1)C(=O)NC2=O
Reaction time: 8 h

Procedure:
A mixture of 7-chlorocarbonyl-3-azabicyclo[3.3.1]nonane-2,4-dione (2 g) and absolute ethanol (25 ml) was left overnight at room temperature and evaporated to leave the desired compound which was used in the next step without purification.