Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.C(N(CC)CC)C.[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:15]1([C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 15 °C
Reaction time: 19 h

Procedure:
To a stirred suspension of 4-imidazole carboxaldehyde (from Maybridge Chemicals, United Kingdom) (35.0 g, 364 mmol) and triethylamine (55.8 mL; 400 mmol) in dichloromethane (2 L), was added a solution of triphenylmethyl chloride in dichloromethane (600 mL) while maintaining the reaction temperature at approximately 15° C. with a cooling bath. The resultant solution was warmed to room temperature and stirred for 19 h. Washed the reaction solution with a solution of saturated brine and water (1:3.5; 3×600 mL), followed by brine (1×800 mL). Dried over sodium sulfate; filtered to remove drying agent; and removed solvent under vacuum to obtain the desired tritylated product (7) as an off-white solid. MP 186.5-194° C. [Trituration of this product with ether yielded a cream-colored powder with mp 195-197° C.]
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=1[CH2:22]Br>>[C:1]([O:5][C:6](=[O:9])[N:7]([CH2:22][C:14]1[C:15]([N+:19]([O-:21])=[O:20])=[CH:16][CH:17]=[CH:18][C:13]=1[Br:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(Br)c1CBr
Reactant: CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CN(Cc1c(Br)cccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of methyl-carbamic acid tert-butyl ester from Preparation 1 (5.347 g, 40.76 mmol) in 200 ml anhydrous dimethylformanide was added sodium hydride (2 g of a 60% suspension in mineral oil, 50 mmol) portion-wise at 0° C. The solution was stirred with a magnetic stirrer at 0° C. for 30 minutes, at which time the initial off-gassing had completed. 1-bromo-2-bromomethyl-3-nitro-benzene (12 g, 40.7 mmol) was added in one portion and the reaction mixture was stirred at 0° C. for an hour. The solution was allowed to warm to room temperature and the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extract with ethyl acetate and the combined organic fractions were washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give (2-bromo-6-nitro-benzyl)-methyl-carbamic acid tert-butyl ester as a yellow oil (11.761 g, 84%). MS: (M+H)+345.1.
Reaction SMILES: Cl.[Al].[Mg].[Cl].[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])[CH3:6]>>[C:8]1([CH:5]([OH:7])[CH3:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: [Al]
Agent: [Cl]
Product: CC(O)c1ccccc1
Yield: 95 %

Procedure:
Repeating the procedure of Example 2, 22.4 g (11.2 mmoles) of chlorine magnesium aluminum hydridochloride solution are reacted with 1.81 g (15 mmoles) of acetophenone. After the reaction product is worked up, 1 H-NMR spectroscopy confirms a 95% yield of 1-phenylethanol.
Reaction SMILES: C([Li])CCC.C(O[SiH](OCC)OCC)C.[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])[CH3:17].[OH-].[Na+]>[Cl-].[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Ti+2].O.CCOCC.O1CCCC1.O.CCCCCC>[CH3:17][CH:16]([OH:18])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccccc1
Agent: [Ti+2]
Agent: CCO[SiH](OCC)OCC
Agent: [Cl-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.5 %

Procedure:
To a dry Schlenk tube under argon was added 37.6 mg (0.15 mmol) of a titanocene dichloride and 3 mL of tetrahydrofuran. The slurry was cooled to -78° C. and a 1.64 M hexane solution of n-butyl lithium (190 μL, 0.3 mmol) was added. After stirring for 15 minutes, triethoxysilane (140 μL, 0.75 mmol) was added. The black mixture was allowed to warm to 0° C., then acetophenone (350 μL, 3.0 mmol), followed by more triethoxysilane (700 μL, 3.75 mmol) were added. The reaction mixture was allowed to stir for 6 hours at room temperature. The Schlenk tube was opened to air and 5 mL of water were added and allowed to stir at room temperature for 1 hour. A solution of 5 M NaOH (1 mL) was added and allowed to stir. When the reaction mixture had turned to a white slurry additional 5M NaOH and 5 mL of tetrahydrofuran were added. After stirring for 1 hour, the mixture was added to a water/ether mixture (150 mL each), shaken vigorously, and the layers were then separated. The aqueous layer was extracted with ether (2×50 mL) and the combined organic extracts were dried over MgSO4, filtered, and concentrated by rotary evaporation. The crude product was purified by flash chromatography (ether:hexane=1:2), which yielded 295 mg (80% yield) of sec-phenethyl alcohol.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O(C(C)(C)C)[Na].[C:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])[CH3:27]>C(O)(C)C>[CH3:27][CH:26]([OH:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)c1ccccc1
Agent: CC(C)(C)O[Na]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)O
Product: CC(O)c1ccccc1
Temperature: 30 °C
Reaction time: 16.5 h

Procedure:
Into a 100-mL stainless-steel autoclave was put 24.0 mg (0.03 mmol) of [CuCl((R,R)-SKEWPHOS)(PPh3)]n obtained in Example 27, triphenyl phosphine of the amount shown in Table 6 below, and 28.8 mg (0.30 mmol) of NaO-t-Bu, followed by replacing with nitrogen in the autoclave, and then 2.0 mL of isopropyl alcohol and 1.05 mL (9.0 mmol) of acetophenone were added. The reaction was carried out with stirring under a hydrogen pressure of 5 MPa at 30° C. for 16 to 17 hours to give 1-phenethyl alcohol which is a hydrogenated compound of acetophenone. The reaction mixture was analyzed by using GC. The results are shown in Table 6.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
2,5-Dichloropyridine (30 g, 203 mmol), phenylboronic acid (24.72 g, 203 mmol) and potassium carbonate (84 g, 608 mmol) were added to dimethoxyethane (500 mL) and water (100 mL). The reaction mixture was degassed with nitrogen for 20 min, and Pd(PPh3)4 (2.3 g, 2.0 mmol) was added and reaction mixture was allowed to reflux for 18 h. The reaction was cooled to room temperature, the aqueous layer removed and dimethoxyethane was concentrated to dryness by rotary evaporation under vacuum. The residue was dissolved in DCM and passed through a silica gel plug, eluting with DCM. The solvent was removed and the crude product was chromatographed on silica with 40/60 (v/v) DCM/hexane to 50/50 (v/v) DCM/hexane to yield 28 g (73%) of the product as a white solid (HPLC purity: 99.7%).
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].[F:17][C:18]1[CH:19]=C([Mg]Br)[CH:21]=[CH:22][CH:23]=1.[Cl-].[NH4+].O>C1COCC1>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(c1cccc(F)c1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 12 (23.45 g, 104 mmole) in absolute THF (100 ml) was added dropwise to a 1M solution of 3-fluorophenyl magnesium bromide in THF (208 ml, 208 mmole) under argon and while cooling with ice, and stirred for 20 hours at RT. To work up the reaction mixture saturated ammonium chloride solution (100 ml) and water (100 ml) were added while cooling with ice and the mixture was extracted with diethyl ether (3×100 ml). The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated by evaporation.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1C=CC=CC=1C(O)=O.[NH2:29][C:30]1[C:35]([C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)=[CH:34][C:33]([Cl:43])=[CH:32][N:31]=1.[NH4+].[Cl-]>CS(C)=O.[Cu]I>[Cl:43][C:33]1[CH:34]=[C:35]([C:36]2[CH:41]=[CH:40][C:39]([O:42][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=3)=[CH:38][CH:37]=2)[CH:30]([NH2:29])[NH:31][CH:32]=1
Reactant: Nc1ncc(Cl)cc1-c1ccc(O)cc1
Reactant: FC(F)(F)c1cc(Br)ccn1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: NC1NC=C(Cl)C=C1c1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
A mixture of 4-bromo-2-(trifluoromethyl)pyridine (282 mg), tripotassium phosphate (481 mg), picolinic acid (27.9 mg), copper (I) iodide (21.58 mg) and 4-(2-amino-5-chloropyridin-3-yl)phenol (250 mg) in DMSO (5 ml) was stirred at 140° C. under N2 overnight. The mixture was poured into sat. NH4Cl aq. and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (230 mg) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13]([Cl:15])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:9])=[O:8].[C:17](Cl)(=[O:19])[CH3:18]>CN(C)C(=O)C>[C:17]([NH:1][C:2]1[C:10]([I:11])=[C:6]([C:7]([Cl:9])=[O:8])[C:5]([I:12])=[C:4]([C:3]=1[I:16])[C:13]([Cl:15])=[O:14])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Yield: 90 %

Procedure:
5-Amino-2,4,6-triiodoisophthaloyl chloride (190 g,0.32 g-mole) prepared as in Example 1 is dissolved in 475 ml of N,N-dimethylacetamide (DMAc) (dried over molecular sieves), and the solution is stirred and cooled to 0°-3° C. Acetyl chloride (75.1 g, 68 ml, 0.96 g-mole) is added dropwise over a period of 100 minutes, keeping the temperature between 0° C. and 3° C. The ice bath is removed and the solution is stirred overnight at room temperature (20°-25° C.). An additional charge of acetyl chloride (8.5 g, 0.11 g-mole) is added, and the mixture is stirred overnight (23 hours). The product (a creamy white sold) precipitates during this time. The mixture is cooled to 0°-5° C. and filtered while cold. After rinsing with three 100-ml portions of hexane on the funnel, the solution is stirred with three 200-ml portions of cold hexane for 10 minutes each time, collected by suction filtration, and dried in a vacuum desiccator (183 g, 90% yield). The product shows one major spot by TLC analysis.
Reaction SMILES: [ClH:1].[CH3:2][O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[N:13]=[CH:12][N:11]=[C:10]2[NH:22][C:23]1[CH:24]=[C:25]([C:29]#[C:30]C(C)(O)C)[CH:26]=[CH:27][CH:28]=1.O.[OH-].[Na+].Cl>C(O)CCC>[ClH:1].[C:29]([C:25]1[CH:24]=[C:23]([NH:22][C:10]2[C:9]3[C:14](=[CH:15][C:16]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:7]([O:6][CH2:5][CH2:4][O:3][CH3:2])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:28]=[CH:27][CH:26]=1)#[CH:30]
Reactant: COCCOc1cc2ncnc(Nc3cccc(C#CC(C)(C)O)c3)c2cc1OCCOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[3-[[6,7-Bis(2-methoxyethoxy]-4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol, monohydrochloride, prepared as described above (32.34 g, 66.3 mmol), water (300 mL) and butan-1-ol (600 mL) were stirred together at room temperature to form a mixture. The pH of the mixture was adjusted to pH 10-12 with 50% aqueous sodium hydroxide solution to give two clear layers. The organic layer was separated from the aqueous layer and concentrated under atmospheric pressure, so that water was azeotropically removed from the butan-1-ol solution. The final volume of butan-1-ol solution was ˜300 mL. Anhydrous solid sodium hydroxide (0.13 g, 3.3 mmol) was added to the azeotropically dried butan-1-ol solution and the resultant mixture was heated under reflux at 115-120° C. for 24 hours. Butan-1-ol (150 mL) was removed by distillation and the concentrated reaction mixture cooled to 15-25° C. Concentrated hydrochloric acid (6.1 mL) and butan-1-ol (60 mL) were added to the cooled concentrate and the mixture was granulated overnight at 20-25° C. to establish crystallization. The title product crystals were isolated by filtration and dried under vacuum at 45-50° C. to remove butan-1-ol. Yield (21.0 g, 73.7%). Purity by HPLC 96.5%.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>O1CCCC1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 98 %

Procedure:
A solution of the ester of Step A (3.9 g, 15.2 mmol) in tetrahydrofuran (50 mL) was treated with 1 N sodium hydroxide (31 mL, 31 mmol) and then heated at reflux overnight. After cooling, the reaction mixture was concentrated in vacuo. The residue was acidified with 2N hydrochloric acid to give a white solid which was collected by filtration and dried under vacuum to provide the title compound (3.4 g, 98.0%) as a white solid, m.p. 250–254° C.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH2:2][C:3]#[CH:4].C([Li])CCC.[CH2:17]=[O:18]>C1COCC1>[O:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[O:5][CH2:1][CH2:2][C:3]#[C:4][CH2:17][OH:18]
Reactant: C#CCCOC1CCCCO1
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCC#CCCOC1CCCCO1
Temperature: -23 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a solution of 8.0 mL (51 mmol) of 2-(3-butynyloxy)tetrahydro-2H-pyran in 150 mL of THF under nitrogen atmosphere at −23° C. was added dropwise a solution of 33 mL (53 mmol) of 1.6M butyllithium in hexanes, maintaining the temperature at −23° C. The resulting solution was stirred at 0° C. for 2 h, recooled to −23° C. and 2.4 g (76.5 mmol) of paraformaldehyde was added in several portions. The mixture was stirred at −23° C. for 1 h and let warm to room temperature and stirred for 18 h. The reaction mixture was poured into a large excess of ice water and extracted with ether. The organics were washed with brine until neutral, dried over MgSO4, filtered and concentrated in vacuo. The residue was kugelrohr distilled to provide 7.26 g (77%) of 5-(tetrahydro-2H-pyran-2-yloxy)-2-pentyn-1-ol as a colorless liquid. El Mass Spec: 185.1 (M+H)+
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:21])=O.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1.CO>[CH:19]([N:14]1[CH2:15][CH2:16][CH2:17][N:11]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1][CH2:2][CH2:3]2)[CH2:12][CH2:13]1)([CH3:21])[CH3:18]
Reactant: c1ccc2c(c1)CCCC2N1CCCNCC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCCN(C2CCCc3ccccc32)CC1
Yield: 96.6 %

Procedure:
R(−) N-(1,2,3,4-tetrahydronaphthalen4-yl)homopiperazine (2.00 g; 8.7 mmol) in THF (50 ml), methanol (25 ml) and acetone (15.5 ml; 174 mmol) was reacted with sodium cyanoborohydride (1.1 g; 17.6 mmol) and acetic acid (1.0 ml) as in Example 14. Kugelrohr distillation gave the title compound (2.29 g), bp (air bath temperature) 165-175° C. at 180 mtorr; [α]D22−74° (c=0.64, methanol).
Reaction SMILES: BrC(C(OCC)=O)C(OCC)=O.C(N(CC)CC)C.[CH3:20][C:21]([CH3:33])([CH2:31][SH:32])[C:22]([NH:24][C@H:25]([C:28]([OH:30])=[O:29])[CH2:26][SH:27])=[O:23].Cl>C(Cl)Cl>[CH3:20][C:21]1([CH3:33])[CH2:31][S:32][S:27][CH2:26][C@@H:25]([C:28]([OH:30])=[O:29])[NH:24][C:22]1=[O:23]
Reactant: CC(C)(CS)C(=O)N[C@@H](CS)C(=O)O
Agent: CCOC(=O)C(Br)C(=O)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CSSC[C@@H](C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a solution of diethyl bromomalonate (10.5 g) and triethylamine (8.5 g) in methylene chloride (3.8 l), N-(2,2-dimethyl-3-mercaptopropionyl)-L-cysteine (9.5 g) dissolved in methylene chloride (0.3 l) was added dropwise under ice-salt cooling. After the addition, the reaction mixture was stirred for 30 minutes at the same temperature and for 30 minutes at room temperature. The mixture was acidified with 6N hydrochloric acid and washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Separated crystals were collected by filtration to give 6.1 g (65%) of the titled compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][C:45]2[CH:46]=[CH:47][C:42]([O:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:43][CH:44]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Triphenylphosphine (917 mg) was added to a solution of N-tert-butoxycarbonyl-4-hydroxypiperidine (A, 704 mg), 4-benzyloxyphenol (700 mg) and diethyl azodicarboxylate (609 mg) in tetrahydrofuran (20 mL) at room temperature. After stirring at room temperature for 14 hr, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9, v/v) to give the titled compound (703 mg) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.47 (s, 9H), 1.72 (m, 2H), 1.88 (m, 2H), 3.29 (ddd, J=3.9, 7.8, 12.5 Hz, 2H), 3.70 (m, 2H), 4.32 (quintet, J=3.9 Hz, 1H), 5.01 (s, 2H), 6.84-6.91 (m, 4H), and 7.32-7.43 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:20][O:21][CH2:22]Cl>O1CCCC1.ClCCl>[CH3:20][O:21][CH2:22][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: COCCl
Reactant: COC(=O)c1cc(O)no1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCOc1cc(C(=O)OC)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of 2.0 g (14.0 mmol) of methyl 3-hydroxy-5-isoxazole carboxylate and 29.2 ml (16.8 mmol) of N,N-diisopropylethylamine in 20 ml of tetrahydrofuran was treated with 1.27 ml of chloromethyl methyl ether. After being stirred at ambient temperature for 2 h, the solution was diluted with dichloromethane, washed with water, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography of the residue using 10% methanol in dichloromethane provided 129.6 mg (78%) of the desired compound as a white solid. 1H NMR (CDCl3) δ 3.57 (s, 3H), 3.96 (s, 3H), 5.37 (s, 2H), 6.64 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34][NH2:35])([CH3:29])([CH3:28])[CH3:27].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([NH:35][CH2:34][CH2:33][NH:32][C:31](=[O:36])[O:30][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)c(CC(=O)NCCNC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Yield: 75 %

Procedure:
a Fluorescent Indo-Coumarinyl Analog: Compound 27 cc, N-{2-(Coumarin-3-carboxylamido)ethyl}-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide, was synthesized by the method depicted in FIG. 6. Briefly, indomethacin was complexed with tert-Butyl-2-aminoethylcarbamate for 16 hours at room temperature in the presence of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCl), 1-hydroxybenzotriazole (HOBt), N,N-diisopropylethylamine (DIPEA), and N,N-dimethylformamide (DMF). A yellow solid of tert-Butyl 2-[2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamido]ethylcarbamate was produced as a yellow solid at 75% yield. This product was then dissolved in dichloromethane and treated with HCl (gas) for 2 hours at room temperature, producing N-(2-Aminoethyl)-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide hydrochloride as a brown solid with a yield of 98%, which was reacted with N,N-diisopropylethylamine (DIPEA) in dichloromethane for 5 minutes at room temperature prior to the addition of Coumarin-3-carboxylic acid, 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCl), 1-hydroxybenzotriazole (HOBt), and N,N-diisopropylethylamine (DIPEA) in dichloromethane. The reaction proceeded for 16 hours at room temperature and produced Compound 27 cc as a yellow solid (35% yield).
Reaction SMILES: COC(OC)C(CCCCCC)=CC1C=CC=CC=1.C([C@@H]([C@H](C(OC)=O)O)O)(OC)=O.[CH2:32](/[C:38](/[CH:46]1[O:50][C@@H:49]([C:51]([O:53][CH3:54])=[O:52])[C@H:48]([C:55]([O:57][CH3:58])=[O:56])[O:47]1)=[CH:39]/[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:32](/[C:38](/[CH:46]1[O:50][C@@H:49]([C:51]([O:53][CH3:54])=[O:52])[C@H:48]([C:55]([O:57][CH3:58])=[O:56])[O:47]1)=[CH:39]\[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCC/C(=C/c1ccccc1)C1O[C@@H](C(=O)OC)[C@H](C(=O)OC)O1
Agent: CCCCCCC(=Cc1ccccc1)C(OC)OC
Agent: COC(=O)[C@H](O)[C@@H](O)C(=O)OC
Product: CCCCCC/C(=C\c1ccccc1)C1O[C@@H](C(=O)OC)[C@H](C(=O)OC)O1

Procedure:
In a fashion similar to that described in Example 4, α-hexylcinnamaldehyde dimethyl acetal and dimethyl L-tartrate were condensed to provide a mixture of (E)-and (Z)-(4R,5R)-2-(1-hexyl-2-phenyl-1-ethenyl)-4,5-dicarbomethoxy-1,3-dioxolane in an approximate ratio of 90:10 Crystallization provided the pure E-isomer, mp 49°-50° C., [α]D25 -2.2 (c,0.2, methanol). 1H-NMR (CDCl3)δ7.35-7.26 (5H,m), 6.74 (1H,s), 5.84 (1H,s), 4.86 (1H,d,J=4.4 Hz), 4.70 (1H,d,J=4.4 Hz), 3.85 (3H,s), 3.80 (3H,s), 2.34-2.27 (2H,m), 1.58-1.55 (2H,m), 1.37-1.26 (6H,m), 0.93-0.87 (3H,m). IR (KBr)2900, 2840, 1730, 1430, 1340, 1200, 1100, 1060, 1030, 980, 950, 915, 870, 790, 750, 730, 690 cm-1. MS m/e (% abundance) 305 (4), 292 (17), 291 (100), 145 (18), 142 (25), 131 (73), 129 (76), 128 (26), 117 (74), 116 (17), 115 (51), 104 (29), 91 (57), 59 (31), 41 (25).