Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH:31](C(OCC)=O)[C:32]([O:34]CC)=[O:33]>CN(C=O)C>[CH3:18][C:16]1[C:15]([CH3:19])=[CH:14][C:10]2[C:11](=[O:12])[O:13][C:31]([C:32]([OH:34])=[O:33])=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]=2[CH:17]=1
Reactant: Cc1cc(C(=O)O)c(C(=O)c2ccccc2)cc1C
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Cc1cc2c(-c3ccccc3)c(C(=O)O)oc(=O)c2cc1C
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 2-benzoyl-4,5-dimethylbenzoic acid (11.4 g), acetone (300 ml), DMF (10 ml), potassium carbonate (6.83 g) and diethyl bromomalonate (12.84 g) was stirred at room temperature for 60 hours. After the solvent was distilled off, ethyl acetate was added to the residue. This mixture was washed with water and dried, after which the solvent was distilled off. To the residue were added acetic acid (180 ml) and hydrochloric acid (180 ml), followed by heating at 110° C. for 5 hours. After the reaction mixture was concentrated, water was added to the concentrate, followed by extraction with ethyl acetate. The extract was washed with water and then dried, after which the solvent was distilled off, to yield colorless crystals, which were recrystallized from ethyl acetate-isopropyl ether, to yield 6,7-dimethyl-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:39]O>>[CH3:39][O:2][C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:3]
Reactant: CO
Reactant: O=C(O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Yield: 54 %

Procedure:
A mixture of 1-(7-carboxyheptyl)-2,4,5-triphenyl-imidazole (0.5 g), concentrated sulphuric acid (2 ml) and methanol (100 ml) was heated at reflux for 24 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (50 ml), washed with water (50 ml), saturated NaHCO3 solution (50 ml), water (50 ml), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Column chromatography on silica gel eluted with a dichloromethane:methanol gradient gave 1-(7-methoxycarbonylheptyl)-2,4,5-triphenylimidazole (0.28 g, 54%) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](S(Cl)(=O)=O)=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][CH:3]=1.C1([OH:27])C2C(=CC=CC=2)C=CN=1.BrN1C(=O)CCC1=O>CC#N>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:27])[NH:4][CH:3]=1
Reactant: Oc1nccc2ccccc12
Reactant: O=S(=O)(Cl)c1ccc2c(Br)cnc(Cl)c2c1
Agent: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: O=c1[nH]cc(Br)c2ccccc12

Procedure:
4-Bromo-1-chloro-7-isoquinolinesulphonyl chloride ##STR198## A suspension of isoquinolinol (10 g, 68.9 mmol) in MeCN (250 ml) at 50° C., was treated with N-bromosuccinimide (12.6 g, 70.8 mmol) whereupon almost complete solution occurred before a thick white precipitate was formed. After heating under reflux for 3 h, the reaction mixture was cooled in ice and the solid filtered, washed with MeCN, and dried to afford 4-bromo-1-(2H)-isoquinolone (7.6 g, 34.0 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH3:13]>O1CCCC1CCO.[Pd]>[F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH3:11])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(C)c([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: OCCC1CCCO1
Product: COc1cc(C)c(N)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.2 %

Procedure:
To a solution of 2-fluoro-5-methyl-4-nitroanisole (100 mg) in tetrahydrofuran-ethanol (1/1, 3 mL) was added 10% palladium on carbon powder (56.5 wt % aqueous, 30 mg) under cooling with ice, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite (registered trademark). The filtrate was concentrated under reduced pressure to obtain the title compound (84.8 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].COC(=O)C(CC1C=CC=CC=1)[C:11]1[C:19]2[C:14](=[C:15]([CH2:20][CH3:21])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1.[O:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:20]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][C:12]([CH:32]([CH2:33][C:34]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)[CH2:31][OH:30])=[CH:11]2)[CH3:21]
Reactant: CCc1cccc2c(C(Cc3ccccc3)C(=O)OC)c[nH]c12
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1cccc2cc(C(CO)Cc3ccccc3)[nH]c12
Temperature: 0 °C
Yield: 96 %

Procedure:
To a stirred suspension of lithium aluminum hydride (0.702 g, 18.5 mmol) in 80 mL of anhydrous tetrahydrofuran under nitrogen at 0° C. was slowly added (about 1.5 hours) a solution of 7-ethyl-α-(phenylmethyl)-1H-indole-3-acetic acid methyl ester (prepared in Step 2) (5.17 g, 16.8 mmol) in 30 mL of anhydrous tetrahydrofuran. The resulting dark red mixture was heated under reflux for 2 hours. It was cooled to 0° C., and quenched by the dropwise addition of 40 mL of water. The precipitated aluminum salts were removed by filtration and washed with ether. The layers of the filtrate were separated, and the aqueous layer was washed with ether. The combined ether layers were washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated to give the desired alcohol as a brown oil (4.51 g, 96%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:14]Br>C(O)(=O)C>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:4]([C:1](=[O:3])[CH2:2][Br:14])=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)CBr)cc1

Procedure:
The starting material, methyl 4-acetylbenzoate, is commercially available. Bromination at the α-position to the ketone is achieved with bromine in acetic acid to provide the desired 4-(2-bromo-acetyl)-benzoic acid methyl ester. Subsequent treatment of 4-(2-bromo-acetyl)-benzoic acid methyl ester with potassium fluoride in the presence of 18-crown-6 at 90° C., provides 4-(2-fluoro-acetyl)-benzoic acid methyl ester after column chromatography. Repeated bromination at the α-position to the ketone is achieved with bromine in acetic acid to provide the desired 4-(2-bromo-2-fluoro-acetyl)-benzoic acid methyl ester. Formation of the thiazole is typically carried out by heating 4-(2-bromo-2-fluoro-acetyl)-benzoic acid methyl ester with 4-methylpiperazine-1-carbothioamide at 70° C. for 2 hours. On cooling, the desired 4-[5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzoic acid methyl ester precipitates out. Deprotection of the methyl ester is carried out using a lithium hydroxide solution and the desired acid, 4-[5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzoic acid is generally obtained in good yield as the dihydrochloride salt on workup with hydrochloric acid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[O:12])[C:4](=[O:26])[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:45]=[CH:44][C:38]([O:39][CH2:40][CH2:41][CH2:42][OH:43])=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO>[OH:43][CH2:42][CH2:41][CH2:40][O:39][C:38]1[CH:44]=[CH:45][C:35]([C:2]2[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)=[O:12])[C:4](=[O:26])[CH:3]=2)=[CH:36][CH:37]=1
Reactant: CC1(C)OB(c2ccc(OCCCO)cc2)OC1(C)C
Reactant: CC(CCn1ccc(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(CCn1ccc(-c2ccc(OCCCO)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 80 °C

Procedure:
4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, which may be prepared as in Preparation 2A (301 mg, 0.622 mmol), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propan-1-ol (212 mg, 0.762 mmol), potassium carbonate (434 mg, 3.11 mmol), and tris(dibenzylideneacetone)dipalladium(0) (56.8 mg, 0.062 mmol) were combined into a flask, placed under vacuum and opened to nitrogen. Degassed dimethoxyethane (2.0 mL) and methanol (2.0 mL) were added and the reaction was heated at 80° C. under nitrogen for 16 hours. The reaction was cooled and diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate, filtered and evaporated in vacuo onto silica gel. Chromatography on silica gel with a dichloromethane-methanol gradient (1%-25%) eluted 4-(4-(4-(3-hydroxypropoxy)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as a yellow oil (120 mg, 36.9%). LCMS 521 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[C:15]1[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[N:19][CH:20]=1.[C@H]1(N)CCCC[C@@H]1N.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.[Cu]I.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[N:7]([C:15]3[CH:20]=[N:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: CC1(C)NC(=O)c2cc(F)ccc21
Reactant: OCc1cncc(Br)c1
Agent: [Cu]I
Agent: N[C@H]1CCCC[C@@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)c2ccc(F)cc2C(=O)N1c1cncc(CO)c1
Yield: 90.8 %

Procedure:
A mixture of 6-fluoro-3,3-dimethyl-2,3-dihydro-isoindol-1-one (intermediate A-20 [B], 35.8 mg, 0.2 mmol), (5-bromo-pyridin-3-yl)-methanol (74.8 mg, 0.4 mmol), CuI (3.8 mg, 0.02 mmol), (1S,2S)-cyclohexane-1,2-diamine (4.5 mg, 0.04 mmol) and Cs2CO3 (130 mg, 0.4 mmol) were dissolved in dioxane (5 mL). The reaction mixture was subjected to microwave reaction at 140° C. for 1 hour before it was poured into H2O (50 mL) and extracted with EtOAc (2×25 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (52 mg, 92%) as a solid. MS: 287.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=O)=[CH:5][CH:4]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH:14]1([C:12]2[C:7]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=3)[CH2:9][CH2:10][N:11]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc(CCNC(=O)C2CCCCC2)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(C1CCCCC1)=NCC2
Yield: 36.1 %

Procedure:
N-[2-(4-methoxyphenyl)ethyl]cyclohexanecarboxamide (5.56 g) was dissolved in toluene (120 mL), and diphosphorus pentoxide (3.0 g) and phosphorus oxychloride (6.0 mL) were sequentially added thereto, followed by stirring under heating at reflux for 5.5 hours. The reaction mixture was left to cool and then the solvent was evaporated. An aqueous 8 M potassium hydroxide solution, water and chloroform were added to the resulting residue to completely dissolve the insoluble materials to achieve a pH of around pH 8, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 1-cyclohexyl-7-methoxy-3,4-dihydroisoquinoline (1.87 g).
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH3:26])[C:10](=[O:25])[C:11]3[CH:21]=[C:20]([CH2:22][CH:23]=C)[CH:19]=[N:18][C:12]=3[N:13]([CH2:16][CH3:17])[C:14]=2[N:15]=1.[BH4-].[Na+].[NH4+].[Cl-]>C(Cl)Cl.CO>[CH3:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH3:26])[C:10](=[O:25])[C:11]3[CH:21]=[C:20]([CH2:22][CH2:23][OH:1])[CH:19]=[N:18][C:12]=3[N:13]([CH2:16][CH3:17])[C:14]=2[N:15]=1
Reactant: C=CCc1cnc2c(c1)C(=O)N(C)c1ccc(C)nc1N2CC
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: CCN1c2ncc(CCO)cc2C(=O)N(C)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A stream of O3 was introduced into a cold (−78° C.) solution of 5,11-dihydro-2,5-dimethyl-11-ethyl-8-(2-propenyl)-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (187 mg, 0.6 mmol) and Sudan III in CH2Cl2 (3 mL) and MeOH (3 mL). When the pink solution turned brown, O2 was bubbled through the solution for 10 min. NaBH4 (57 mg, 1.52 mmol) was then added and the solution was allowed to warm to room temperature. After 30 min, an additional amount of NaBH4 (20 mg) was added. After 2 h, aqueous saturated NH4Cl was then added and the mixture stirred for 20 min. The solution was concentrated if under reduced pressure and extracted with CH2Cl2 (3×). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc:Hexane 6:4) to give the title compound (111 mg, 58% yield) as a white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]#[CH:22].Cl>C(OCC)(=O)C.O.O1CCCC1.CN(C)C=O>[CH2:22]([NH:11][CH:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:1])([F:12])[F:13])[CH2:6][CH2:7]1)[C:21]#[CH:20]
Reactant: C#CCBr
Reactant: NC1CCN(C(=O)C(F)(F)F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNC1CCN(C(=O)C(F)(F)F)CC1
Reaction time: 0.83 h

Procedure:
To a solution of 0.50 g of 1-(trifluoroacetyl)piperidin-4-amine in 10 mL of a mixed solvent of N,N-dimethylformamide and tetrahydrofuran (1:1), 0.41 g of potassium carbonate, 0.42 mL of propargyl bromide were added, and the mixture was heated under reflux while stirring for 2 hours. Thereto were added water and ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.60 g of N-(2-propyn-1-yl)-1-(trifluoroacetyl)piperidin-4-amine as a crude product (crude product A). On the other hand, to a solution of 0.70 g of 1-(trifluoroacetyl)piperidin-4-amine in 7.2 mL of a mixed solvent of N,N-dimethylformamide and tetrahydrofuran (1:1), 0.59 g of potassium carbonate, and 0.30 mL of propargyl bromide were added, and the mixture was heated under reflux while stirring for 1 hour 50 minutes. Thereto were added water and ethyl acetate, and mixed with 0.60 g of the crude product A obtained above, and the mixture was adjusted to pH 1 with 6 mol/L hydrochloric acid. The aqueous layer was separated, and washed with ethyl acetate, ethyl acetate was added thereto, and the aqueous layer was saturated with potassium carbonate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.0 g of N-(2-propyn-1-yl)-1-(trifluoroacetyl)piperidin-4-amine as a brown oily substance.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][N:12]([CH:14]2[CH2:19]CN(C3C=NC(OC)=CC=3)C[CH2:15]2)[CH2:11][C@H:10]1[NH:28][C:29](=[O:44])[CH2:30][NH:31][C:32](=[O:43])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1)[C:2]1C=CC=C[CH:3]=1.O[C@@H]1CN(C2C[CH2:55][O:54][CH2:53]C2)C[C@H]1NC(=O)CNC(=O)C1C=CC=C(C(F)(F)F)C=1.C(OC(NC1C(O)CN(C(OCC2C=CC=CC=2)=O)C1)=O)(C)(C)C.C(Br)C=C.C(Br)C1C=CC=CC=1>>[CH2:1]([O:8][C@@H:9]1[CH2:13][N:12]([CH:14]2[CH2:15][CH2:55][O:54][CH2:53][CH2:19]2)[CH2:11][C@H:10]1[NH:28][C:29](=[O:44])[CH2:30][NH:31][C:32](=[O:43])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:41])([F:40])[F:42])[CH:34]=1)[CH:2]=[CH2:3]
Reactant: COc1ccc(N2CCC(N3C[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)[C@H](OCc4ccccc4)C3)CC2)cn1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CN(C2CCOCC2)C[C@H]1O
Agent: BrCc1ccccc1
Agent: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CC1O
Solvent: C=CCBr
Product: C=CCO[C@@H]1CN(C2CCOCC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1

Procedure:
The title compound was synthesized in similar fashion to rel-N-[2-({(3R,4R)-4-(benzyloxy)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide, rel-N-(2-{[(3R,4R)-4-hydroxy-[1-tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide was substituted for benzyl rac-(3R,4R)-3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-1-carboxylate and allyl bromide was substituted for benzyl bromide. The title compound was isolated as a white solid. 1H-NMR (CDCl3) δ: 1.56 (m, 2H), 1.76 (m, 2H), 2.34-2.48 (m, 2H), 2.80 (m, 2H), 3.30-3.42 (m, 3H), 3.84 (m, 1H), 3.93-4.03 (m, 3H), 4.13 (m, 2H), 4.18 (m, 1H), 4.34 (m, 1H), 5.14 (m, 1H), 5.26 (m, 1H), 5.87 (m, 1H), 6.66 (b, 1H), 7.13 (b, 1H), 7.57 (t, J=7.4 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 8.05 (d, J=7.7 Hz, 1H), 8.09 (s, 1H). MS m/z: 456 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][CH:6]([OH:14])[CH2:7][NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][NH2:11].[Cl:19][C:20]1[N:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=1>C1C=CC=CC=1>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][CH:6]([OH:14])[CH2:7][NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][NH:11][C:23]1[N:22]=[N:21][C:20]([Cl:19])=[CH:25][CH:24]=1
Reactant: Cc1ccccc1OCC(O)CNC(C)(C)CN
Reactant: Clc1ccc(Cl)nn1
Solvent: c1ccccc1
Product: Cc1ccccc1OCC(O)CNC(C)(C)CNc1ccc(Cl)nn1
Temperature: 110 °C
Yield: 67.8 %

Procedure:
To 1.58 g of 1-(2-methylphenoxy)-3-(1,1-dimethyl-2-aminoethylamino)-2-propanol heated at 110° C. in an oil bath with stirring was added 934 mg of 3,6-dichloropyridazine little by little. After heating at 110° C. for 1 hour, the reaction mixture was dissolved in benzene, and extracted with 1N hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate, and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to give 1.55 g of 1-(2-methylphenoxy)-3-[1,1-dimethyl-2-(3-chloro-6-pyridazinylamino)ethylamino]-2-propanol as an oil.
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1C.C[O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:34][CH2:33]2)=[C:28]([CH3:46])[CH:27]=1>>[CH3:46][C:28]1[CH:27]=[C:26]([OH:25])[CH:31]=[CH:30][C:29]=1[N:32]1[CH2:33][CH2:34][N:35]([CH2:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:36][CH2:37]1
Reactant: COc1ccc(N2CCN(CCc3ccccc3)CC2)c(C)c1
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1C
Product: Cc1cc(O)ccc1N1CCN(CCc2ccccc2)CC1
Yield: 85.3 %

Procedure:
Production Example 10 was repeated except that 1-(4-methoxy-3-methylphenyl)-4-phenethylpiperazine was replaced with 1-(4-methoxy-2-methylphenyl)-4-phenethylpiperazine (512 mg), and the resulting crude product was purified on TLC (developer, chloroform: methanol=15:1) to provide 3-methyl-4-(4-phenethyl-piperazin-1-yl)phenol (417 mg).
Reaction SMILES: C(N(CC)CC)C.C(Cl)(=O)OCC.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:27]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[N:26][N:25]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:24](=[O:40])[C:23]=2[C:41](O)=[O:42])=[CH:18][CH:17]=1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:27]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[N:26][N:25]([CH2:36][CH:37]([CH3:38])[CH3:39])[C:24](=[O:40])[C:23]=2[CH2:41][OH:42])=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2nn(CC(C)C)c(=O)c(C(=O)O)c2-c2ccc(OC)cc2)cc1
Agent: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nn(CC(C)C)c(=O)c(CO)c2-c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 52.8 %

Procedure:
Triethylamine (278.7 mg) and ethyl chlorocarbonate (298.9 mg) were added under ice cooling to a solution of 5,6-bis(4-methoxyphenyl)-4-carboxy-2-isobutyl-2H-pyridazin-3-one (750 mg, 1.84 mmol) in tetrahydrofuran (8 ml), followed by stirring for 1 hour. The reaction mixture was filtered. Under ice cooling, sodium borohydride (277.8 mg) was added to the filtrate, followed by stirring for 1 hour. The mixture was stirred further at room temperature for 2 hours. The reaction mixture was concentrated, to which a saturated aqueous solution of ammonium chloride was added. After the mixture was extracted with ethyl acetate, the extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, successively, and was the dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was separated and purified by chromatography on a silica gel column and then crystallized from ethyl acetate-hexane, whereby the title compound (383.0 mg, yield: 52.9%) was obtained as colorless needles.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH:12](Br)Br)[CH:6]=1)[CH3:2].[OH:16]S(O)(=O)=O>CCO.O.O1CCOCC1.CCOC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH:12]=[O:16])[CH:6]=1)[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)c1ccc(Br)c(C(Br)Br)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Br)c(C=O)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
4-Bromo-3-dibromomethyl-benzoic acid ethyl ester (6.4 g, 16 mmol) was dissolved in EtOH (200 mL) and heated to 60° C. Silver nitrate (6.80 g, 40 mmol), prepared as a solution in H2O (50 mL), was added dropwise, resulting in a precipitate. After 1 hour, the mixture was decanted, and the precipitate was washed with EtOH (3×50 mL) and decanted after each wash. The combined EtOH solution was treated with 1N aqueous HCl (40 mL), which resulted in additional precipitate formation. The mixture was filtered, and the filtrate was concentrated and partitioned between EtOAc and H2O. The aqueous layer was separated and extracted with EtOAc, and the combined organic layers were concentrated. The crude material was dissolved in MeOH (100 mL) and treated with 2N aqueous H2SO4 (15 mL) for 1 hour at room temperature. After work-up, the crude material was purified by silica gel chromatography to give a mixture of the aldehyde and the dimethyl acetal. The mixture was dissolved in 1,4-dioxane and treated with 2N aqueous H2SO4 (80 mL), and stirred overnight at room temperature. The solution was diluted with EtOAc and H2O, and the organic layer was separated, dried, and concentrated to give 4-bromo-3-formyl-benzoic acid ethyl ester.