Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:16]([CH3:18])([CH3:17])[C:15](=[O:19])[N:14]1[CH:20]1[CH:27]2[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2)=[O:12])(=O)C.O.C(=O)(O)[O-].[Na+].O>CO.O1CCCC1>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:16]([CH3:17])([CH3:18])[C:15](=[O:19])[N:14]1[CH:20]1[CH:27]2[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2)=[O:12]
Reactant: CC(=O)Oc1ccccc1C(=O)N1N(C2C3CC4CC(C3)CC2C4)C(=O)C1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 73.1 %

Procedure:
A solution of 2-{[4,4-dimethyl-3-oxo-2-(adamantan-2-yl)-1,2-diazetidin-1-yl]carbonyl}phenyl acetate (15.0 mg, 0.0378 mmol) prepared in Example 137 in methanol-tetrahydrofuran was dropped with saturated sodium bicarbonate water (0.5 mL), and the resultant was stirred at room temperature for 4.5 hours. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=2:1), and the title compound (9.80 mg, 73.7%) was obtained as a white crystalline powder.
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:8][CH:7](C(OC)=O)[C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2].Cl>O>[C:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:8][CH2:7][C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1CC(C#N)(c2ccccc2F)CCC1=O
Agent: Cl
Solvent: O
Product: N#CC1(c2ccccc2F)CCC(=O)CC1
Yield: 40.1 %

Procedure:
Methyl 5-cyano-5-(2-fluorophenyl)-2-oxocyclohexane-1-carboxylate (D19, 30.66 g, 0.11 mol) was stirred at reflux in c. HCl (500 ml) for 17 h, cooled, diluted with water (500 ml), and extracted with ethyl acetate. This organic portion was extracted with potassium carbonate solution, dried (Na2SO4) and evaporated to give 4-cyano-4-(2-fluorophenyl)cyclohexanone (9.58 g, 38%) as a yellow foam. The alkaline extract was re-acidified with c. HCl, and the product isolated by extraction with ethyl acetate, drying (Na2SO4) and evaporation. This gave the title compound (16.36 g, 62%) as a colourless gum.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[CH2:16][C:11]3[C:12]4[C:13]2=[C:4]([CH2:5][CH2:6][C:7]=4[CH:8]=[CH:9][CH:10]=3)[CH:3]=1.CC1(C)C(C)(C)OB(C2C3C(C(C4C=CC=CC=4)=C4C=2C=CC=C4)=CC=CC=3)[O:19]1.C([O-])([O-])=O.[K+].[K+].C1COCC1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[C:14]2[C:16](=[O:19])[C:11]3[C:12]4=[C:13]2[C:4](=[CH:5][CH:6]=[C:7]4[CH:8]=[CH:9][CH:10]=3)[CH:3]=1
Reactant: CC1(C)OB(c2c3ccccc3c(-c3ccccc3)c3ccccc23)OC1(C)C
Reactant: Brc1cc2c3c(c1)Cc1cccc(c1-3)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=c1c2cccc3ccc4cc(Br)cc1c4c32
Temperature: 100 °C

Procedure:
The compound 2 (1.0 g, 1 eq., 2.02 mmol), 4,4,5,5-tetramethyl-2-(10-phenyl-anthracene-9-yl)-[1,3,2]dioxaborolane (0.77 g, 1 eq., 2.02 mmol), tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.1 eq., 0.2 mmol), 2M K2CO3 (1 ml, 1 eq., 2.02 mmol), and tetrabutylammoniumbromide (0.65 g, 1 eq., 2.02 mmol) were put into a 100 ml round bottom flask under an argon gas atmosphere, and THF (50 ml) and toluene (20 ml) were added thereto. The reaction mixture was refluxed at 100° C. for 16 hours. When the reaction solution turned dark brown, water was added, and the resultant solution was extracted with ethylacetate. The extracted organic phase was dried over anhydrous magnesium sulfate and filtered to remove a solvent. The residue was dissolved in a trace amount of toluene and purified on a silica gel column. The resultant solid was recrystallized from toluene and methanol to give a material 1 represented by Formula 18 (0.71 g, 52%). 1H NMR (300 MHz, CDCl3, δ): 8.11 (s, 2H), 7.98 (s, 3H), 7.81 (s, 2H), 7.75-7.10 (m, 13H), 1.93 (m, 4H), 1.21 (m, 20H), 0.87 (m, 6H), 0.65 (broad s, 4H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([O:20][CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=1.Cl.[NH2:34][CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[F:1][C:2]([F:31])([F:32])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([O:20][CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:34][CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:27])=[CH:24][CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: O=C(O)c1ccc(COc2cc(-c3ccc(OC(F)(F)F)cc3)cc3ccccc23)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc(COc2cc(-c3ccc(OC(F)(F)F)cc3)cc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a DMF solution (2 mL) of the intermediate from Step D (35 mg, 0.08 mmol) was added tert-butyl β-alaninate hydrochloride (30 mg, 0.16 mmol) DIEA (0.06 mL, 0.35 mmol) and BOP (53 mg, 0.12 mmol). The solution was stirred at room temperature for ca. 30 minutes. The solution was then partitioned between ethyl acetate and aqueous 1N HCl. The organic phase was washed with aqueous 1N HCl (3×), brine; dried over MgSO4 and filtered to give tert-butyl N-{4-[({3-[4-(trifluoromethoxy)phenyl]-1-naphthyl}oxy)methyl]benzoyl}-β-alaninate. LCMS1 4.50 min. (M+H)=566. The tert butyl group was removed by treatment with 1/1 DCM/TFA for 1 hour. The crude acid was purified by reverse phase HPLC to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.57 (s, 1H); 8.31 (d, J=8.1 Hz, 1H); 7.92 (m, 1H); 7.89 (d, J=8.3 Hz, 2H); 7.82 (d, J=8.7 Hz, 2H); 7.70 (m, 3H); 7.56-7.49 (m, 2H); 7.39 (d, J=8.1 Hz, 2H); 7.24 (s, 1H); 5.46 (s, 2H); 3.69-3.65 (m, 2H); 2.68-2.66 (m, 2H). LCMS1 3.97 min. (M+H)=510
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([O:24]C(=O)C)[CH:23]=1)[C:8]([NH:10][C:11]1[N:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1)=[O:9])(=O)C.C[O-].[Na+].Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[OH:4][C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([OH:24])[CH:23]=1)[C:8]([NH:10][C:11]1[N:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1)=[O:9]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OC(C)=O)cc(OC(C)=O)c2)nc1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)c2cc(O)cc(O)c2)nc1
Yield: 75.6 %

Procedure:
Methyl 6-[(3,5-di-acetoxybenzoyl)amino]-3-pyridinecarboxylate (6 g, 16.1 mM) was stirred at ambient temperature in THF (50 ml) and sodium methoxide solution (14.8 ml of 25% in methanol, 64.4 mM) added slowly. The resultant solution was stirred for one hour, poured into 1M hydrochloric acid and the pH adjusted to pH=4 with sodium bicarbonate solution, extracted with ethyl acetate, extracts combined, washed with brine and dried over anhydrous magnesium sulphate. The solvent was removed by distillation under reduced pressure to give a yellow solid. This solid was triturated with hot methanol, filtered, to give methyl 6-[(3,5-dihydroxybenzoyl)amino]-3-pyridinecarboxylate as a pale yellow solid (3.51 g, 77%); H1 NMR δ (d6-DMSO) 3.85 (3H s) 6.41 (1H s) 6.80 (2 H d)8.28 (2 Hm)8.85 (1 Hd)9.52 (2 H s)
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[S:16]([CH3:19])(=[O:18])=[O:17])[C:10]([OH:12])=[O:11].[I-].[Na+].O[CH2:23][CH:24]([CH2:26]O)O>O>[CH3:19][S:16]([C:15]1[C:7]2[N:6]=[CH:26][CH:24]=[CH:23][C:8]=2[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1)(=[O:18])=[O:17]
Reactant: OCC(O)CO
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1N
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)c2cccnc12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
38 ml of water and 102 g of concentrated sulfuric acid were heated to 110° C. At 95° C., 0.25 mol of 3-amino-4-methylsulfonylbenzoic acid was added. The mixture was then heated to 140° C., and 0.8 g of sodium iodide and 0.3 mol of glycerol were added. The reaction temperature was then increased to 150° C. While the mixture was heated to and stirred at 150° C. (1 hour), 47 g of distillate were collected. After cooling, the reaction mixture was carefully admixed with 200 ml of water and diluted with a further 800 ml of water. Using 20% strength aqueous sodium hydroxide solution, the pH was adjusted to 13 and the mixture was filtered and adjusted to pH 3.5 with sulfuric acid. This procedure was repeated. A precipitate was formed which was filtered off with suction. The filtrate was adjusted to pH=2 and the resulting precipitate was filtered off with suction, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[CH2:18][CH2:19][O:20][CH2:21][CH:22]=3)[S:10][C:11]=2[C:12]([O:14]CC)=[O:13])=[CH:4][CH:3]=1.O1CCCC1.CO.[OH-].[Li+].Cl>CCOC(C)=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[CH2:18][CH2:19][O:20][CH2:21][CH:22]=3)[S:10][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(C2=CCOCC2)nc1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1sc(C2=CCOCC2)nc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
In a round bottom flask equipped with a stir bar, a solution of ethyl 4-(4-chlorobenzyl)-2-(3,6-dihydro-2H-pyran-4-yl)-1,3-thiazole-5-carboxylate (109 mg, 0.300 mmol) in tetrahydrofuran (3.33 mL, 41.1 mmol) and methanol (1.67 mL, 41.1 mmol) was treated with lithium hydroxide (1.0M in water, 2.40 mL, 2.40 mmol). The mixture was stirred at room temperature overnight. pH was adjusted to −3 via addition of 1N aqueous HCl solution, and the reaction was then diluted with EtOAc and transferred to separatory funnel. The layers were separated, and the aqueous layer was extracted 2× with EtOAc. Combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography (gradient elution, 0 to 10% MeOH in DCM) afforded 4-(4-chlorobenzyl)-2-(3,6-dihydro-2H-pyran-4-yl)-1,3-thiazole-5-carboxylic acid (100) (53 mg, yield 53% as a white powder. LCMS: (FA) ES+ 336; 1H NMR (400 MHz, DMSO) δ 13.52 (bs, 1H), 7.35-7.31 (m, 2H), 7.27-7.23 (m, 2H), 6.82-6.79 (m, 1H), 4.40 (s, 2H), 4.24-4.22 (m, 2H), 3.77 (t, J=5.4, 2H), 2.50-2.45 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2F)=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=NO)c2cc(C(F)(F)F)ccc2F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2noc3ccc(C(F)(F)F)cc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.1 %

Procedure:
A solution of 4-[(2-Fluoro-5-trifluoromethyl-phenyl)-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester (4.969 g, 0.013 M) in anhydrous THF (59 mL) was treated with Potassium tert-butoxide (13.4 mL of a 1M solution in THF, 0.0133 M -1.05 eq). The mixture was stirred at ambient temperature for 1 hour and then heated to 65° C. for 2 hours. The THF was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with H2O (50 mL) and brine (50 mL) respectively. It was then dried over MgSO4, filtered and concentrated to give a solid (5 g) which was purified on silica ˜120 g, (eluting with ethylacetate/heptane (30:70) to give the product as a white solid (2.69 g, 57%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][C:3]1=[O:9].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:23][C:24]1[CH:38]=[CH:37][C:27]([C:28]2[CH:29]=[CH:30][C:31]([CH2:35][CH3:36])=[C:32]([Pb+3])[CH:33]=2)=[CH:26][CH:25]=1.CN(C1C=CC=CN=1)C.C(Cl)(Cl)Cl>ClCCl.Cl.C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:38]=[CH:37][C:27]([C:28]2[CH:33]=[CH:32][C:31]([CH2:35][CH3:36])=[C:30]([CH:4]3[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]3=[O:8])[CH:29]=2)=[CH:26][CH:25]=1
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)CCC(C)(C)C1=O
Temperature: 80 °C

Procedure:
To a mixture of 4,4-dimethyl-1,3-cyclohexanedione (0.21 g, 1.5 mmol), 4′-chloro-4-ethylbiphen-3-yllead triacetate (1.0 g, 1.7 mmol) and dimethylaminopyridine (0.93 g, 7.6 mmol) is added anhydrous chloroform (11 ml) and anhydrous toluene (2.8 ml). The reaction mixture is heated at 80° C. for 4 hours and then cooled to room temperature. The mixture is diluted with dichloromethane (50 ml) and 2M aqueous hydrochloric acid (50 ml) and filtered through diatomaceous earth. The filtrate is partitioned, the aqueous layer is extracted with dichloromethane (50 ml) and the organic extracts are combined, washed with 2M aqueous hydrochloric acid (50 ml), brine (50 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The crude product is purified by preparative reverse phase HPLC to give 2-(4′-chloro-4-ethylbiphen-3-yl)-4,4-dimethyl-1,3-cyclohexanedione.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](=[O:15])=O.[CH3:16][C@H:17]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:19](=[CH:20][CH2:21][C@@H:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@H:23]3[CH2:24][CH2:25][C:26]2=O)[CH2:18]1.CI>O1CCCC1.CCCCCC.C(Cl)(Cl)(Cl)Cl>[CH3:16][C@H:17]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:19](=[CH:20][CH2:21][C@@H:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@H:23]3[CH2:24][C@@H:25]([CH3:26])[C:13]2=[O:15])[CH2:18]1
Reactant: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](C)C[C@@H]32)C1
Reaction time: 0.25 h
Yield: 74 %

Procedure:
Diisopropyl amine (1.165 g, 11.5 mmol) was dissolved in dry tetrahydrofuran (30 mL) at -78° C. under N2. n-Butyl lithium (4.44 mL of a 2.6 M solution in hexane, 11.5 mmol) was added via syringe and the solution warmed to -23° C. (CO2, CCl4) for 0.25 h. 3β-Methylandrost-5-en-17-one (3.0 g, 10.4 mmol) in dry tetrahydrofuran (30 mL) was added via syringe and the solution stirred for 0.25 h. Methyl iodide (7.0 g, 49.33 mmol) in dry tetrahydrofuran (30 mL) was added dropwise and the mixture stirred at room temperature for 1.5 h. The solution was quenched with saturated ammonium chloride and the organic layer separated, dried over magnesium sulfate, filtered, and evaporated. The residual solid was chromatographed on flash silica gel (120 g) and eluted with 1/99 (v/v) ether hexane to give 3β, 16α-dimethylandrost-5-en-17-one (2.32 g, 74%). mp 109°-110° C. (recrystallized from methanol); NMR (CDCl3) δ5.29 (br s, J=5 Hz, 1H, H-6), 2.52 (m, 1-H, H-16), 1.07 (d J=8 Hz, 3H, C-16 Me), 0.99 (s, 3H, C-19 Me), 0.91 (s, 3H, C-18 Me); IR (KBr) 2900, 1730, 1450, 1430, 1370; MS 300 (M+,100), 285(62), 282(2), 272(12), 267(17), 229(20), 217(30), 159(17); Anal. Calcd for C21H32O: C, 83.93; H, 10.73. Found: C, 83.79; H, 10.52.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:31]=[CH:30][C:22]4[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[O:26][C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>CS(C)=O.CCOC(C)=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:19]3[CH:31]=[CH:30][C:22]4[C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[O:26][C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)OC(C)(C)OC2=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 57.5 %

Procedure:
To a solution of 7-[4-(4-butyl-phenylethynyl)-benzylamino]-2,2-dimethyl-benzo[1,3]-dioxin-4-one (1.16 g, 2.64 mmol) in DMSO (32 mL) was added sodium hydride (159 mg, 3.96 mmol, 55-65% in oil) and the resulting mixture was stirred 2 min at rt, then 1-bromohexane (559 μl, 3.96 mmol) was added. The red solution was stirred at rt for 2 hrs. The reaction mixture was poured in EtOAc (70 mL) and washed with an aqueous solution of HCl (2×30 mL, 0.1N) and water (6×30 mL). The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. The crude mixture was purified by flash chromatography on silicagel (c-Hex/EtOAc (6/1)) to give 795 mg (56%) of the title compound as a yellow oil. HPLC, Rt: 6.4 min (purity: 98.3%). M+(ESI): 524.5. 1H NMR (CDCl3) δ: 7.71 (d, J=8.7 Hz, 1H), 7.47 (d, J=8.3 Hz, 2H), 7.41 (d, J=7.9 Hz, 2H), 7.13 (m, 4H), 6.36 (m, 1H), 6.04 (m, 1H), 4.58 (s, 2H), 3.40 (t, J=7.7 Hz, 2H), 2.61 (t, J=7.7 Hz, 2H), 1.76-1.48 (m, 8H), 1.42-1.20 (m, 10H), 0.95-0.82 (m, 6H).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:19])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=O.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C.FC(F)(F)C(O)=O>CC(C)=O>[CH:20]1([N:26]2[C:4]([C:6]3[CH:11]=[CH:10][C:9]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:8][CH:7]=3)=[C:3]([CH3:19])[NH:2][C:27]2=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(N)C(=O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c(=O)n(C2CCCCC2)c1-c1ccc(Oc2ccccc2)cc1
Reaction time: 0.83 h

Procedure:
2-Amino-4'-phenoxypropiophenone hydrochloride (459 mg, 1.65 mmol) was suspended in acetone (30 ml) under ice-cooling, and cyclohexyl isocyanate (278 mg, 2.22 mmol) was added thereto. Triethylamine (476 mg, 4.71 mmol) was added, and the mixture was stirred for 50 minutes under ice-cooling. After addition of trifluoroacetic acid (1.5 ml), the mixture was stirred for 3 days at room temperature. The solvent was removed by evaporation in vacuo, and the residue was extracted with dichloromethane. The extract was washed successively with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. Evaporation of the solvent provided a crude product, which was purified by column chromatography (chloroform/ethanol=50/1 (v/v)) and recrystalization (ethyl acetate) to give the title compound. Yield: 520 mg (90%), m.p. 198° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4](=[O:19])[CH2:3]1.N(CCCC)(CCCC)CCCC.O.Cl>C(Cl)Cl.C(OCCCC)(C)=O>[OH:19][C:4]12[CH2:3][CH:2]([CH3:1])[CH2:17][C:16](=[O:18])[CH:15]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: CC1CC(=O)CCCCCCCCCCCC(=O)C1
Agent: Cl
Solvent: CCCCOC(C)=O
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: CC1CC(=O)C2CCCCCCCCCCC2(O)C1
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A solution of 3-methyl-1,5-cyclohexadecanedione (33) (1 g, 3.76 mmol) in CH2Cl2 (6 ml) was treated at 22-24° with a solution of ZrCl3OPr (36% in AcOBu) (3 g, 5.0 mmol). After 15 minutes the solution was treated at −10° C. with NBu3 (1.15 g, 1.48 ml, 6.2 mmol). After 60 minutes, the reaction mixture was poured into 15 ml water and 15 ml of a 2 N HCl solution were added. After extraction with 50 ml diethyl ether the combined organic phases were washed (saturated aqueous NaHCO3 solution, H2O), dried (Na2SO4) and the solvent was evaporated (crude 1.0 g). Flash chromatography, using SiO2 (100 g) and n-pentane/diethyl ether=6:4 as eluent, afforded 898 mg (yield: 90%) of (34).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11](I)=[CH:10]3)=[CH:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.C[N:27]([CH:29]=[O:30])C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:29]([NH2:27])=[O:30])=[CH:10]3)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 70 °C
Yield: 95 %

Procedure:
To a solution of 13-bromo-4-iodo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (5.0 g, 0.013 mol) in DMF (50 mL) was added hexamethyldisilazane (16 mL, 0.077 mol) and Pd(PPh3)2Cl2 (0.45 g, 0.639 mmol). After being purged with CO three times, the mixture was heated at 70° C. for 3 h. After removal of the solvent, water (100 mL) was added. The solid was collected by filtration, washed with water, and dried in vacuo to afford the title compound (3.8 g, 95% yield) as a yellow solid. LCMS m/z [M+H]+ 309.1.