Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[OH-].[K+].[K].Br[CH2:12][Cl:13]>CCO.CC#N>[Cl:13][CH2:12][S:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1
Reactant: ClCBr
Reactant: Cc1nnc(S)s1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Product: Cc1nnc(SCCl)s1
Temperature: 0 °C
Yield: 164.4 %

Procedure:
2-Mercapto-5-methyl-1,3,4-thiadiazole (41.4 g, 313 mmol) was added to an ice-bath cooled (5° C.) aqueous solution of 85% KOH (20.7 g, 313 mmol) in EtOH (160 mL). The ice bath was removed and the mixture stirred until complete dissolution occurred (30 min). The solvent was then evaporated to leave a viscous oil which solidified. The resulting potassium salt was dissolved in CH3CN (200 mL), and the solution was cooled in an ice bath and treated with bromochloromethane (121 g, 939 mmol). The ice in the bath was allowed to melt and the mixture was further stirred at R.T. for 25 h. The reaction mixture was partitioned between EtOAc and H2O. The organic phase was dried (MgSO4) and evaporated. The residue was purified by passing through a pad of silica gel, eluted first with CH2Cl2 and then with 5% CH3CN/CH2Cl2 to afford 93.0 g (76.0%) of 2-[(chloromethyl)-thio]-5-methyl-1,3,4-thiadiazole.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH2:17][CH3:18])[CH:3]=1.C([Li])CCC.C[O:25]B(OC)OC.Cl.OO>O1CCCC1.C1(C)C=CC=CC=1>[CH2:17]([C:4]1[CH:3]=[C:2]([OH:25])[CH:7]=[C:6]([CH3:8])[C:5]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:18]
Reactant: CCc1cc(Br)cc(C)c1OCc1ccccc1
Reactant: COB(OC)OC
Agent: Cl
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1cc(O)cc(C)c1OCc1ccccc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Then, 35.6 g of 4-bromo-2-ethyl-6-methyl-1-benzyloxybenzene was dissolved in 250 ml of tetrahydrofuran, and 69 ml of n-butyl lithium solution (in hexane; 1.69 mol/liter), while stirring at -70° C. After further stirring at -70° C. for 2 hours, a solution of 12.1 g of trimethoxyboron dissolved in 50 ml of tetrahydrofuran was added dropwise to the reaction mixture. After completion of the dropwise addition, the reaction mixture was returned to room temperature, stirred for 1 hour, and then poured into ice water. The mixture was made weak acidic by the addition of 10% hydrochloric acid, and extracted twice with 500 ml of diethyl ether. The ether layers was combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated to give a residue. To the residue was added 120 ml of toluene, and 33 ml of 30% aqueous hydrogen peroxide was added dropwise, while heating at 70° C. under stirring. After heating under reflux for 1 hours, the reaction mixture was returned to room temperature, washed once with water, twice with 10% aqueous ferrous ammonium sulfate and then once with water. The toluene layer was dried over anhydrous magnesium sulfate, and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 26.2 g of 3-ethyl-4-benzyloxy-5-methylphenol (93% yield).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[F-].[K+]>C1(C)C=CC=CC=1>[CH3:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:18]1[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Br
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a solution of 2-bromo-1,3-dimethyl-5-nitro-benzene (1 g, 4.3 mmol) in toluene (20 mL) is added palladium tetrakis triphenylphosphine (0.5 g, 0.43 mmol), 4-trifluoromethyl phenyl boronic acid (1.65 g, 8.7 mmol), and potassium fluoride (0.75 g, 12.9 mmol). The reaction is purged with nitrogen three times and heated to reflux under nitrogen. At the reflux temperature, water (5 mL) is added to the reaction and the reaction is allowed to reflux under nitrogen. The reaction is monitored by HPLC, and upon completion, allowed to cool to room temperature. The reaction is diluted with ethyl acetate and Celite® is added, followed by water. This mixture is then filtered through a pad of Celite®. The solution is poured into a separatory funnel and the organic layer is washed with water and brine. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by flash column chromatography eluting with ethyl acetate/hexanes to afford 0.68 g of the titled compound as a yellow solid. 1H-NMR.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>[N+](C1C=CC=CC=1)([O-])=O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 180 °C
Yield: 100.6 %

Procedure:
85 g of 1-nitro-anthraquinone, redissolved in nitrobenzene and reprecipitated (88.2% pure), is heated to 180° C. with 145 ml of water in a 0.7 l stirred autoclave. A solution of 14.6 g of NH4Cl in 240 ml of 25% strength NH3 solution is pumped in over a period of 5 minutes. The mixture is allowed to react for a further hour and cooled and the product is filtered off. After drying, 75.4 g of 86.8% pure 1-amino-anthraquinone=97.4% of theory are obtained.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.N>>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: N
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
Crude 1-nitroanthraquinone (composition of organic substances: anthraquinone, 0.5 wt.%; 1-nitroanthraquinone, 82 wt.%; 2-nitroanthraquinone, 5 wt.%; 1,5-dinitroanthraquinone, 0.5 wt.%; other dinitroanthraquinones and others, 12 wt.%) was reacted with ammonia, and the reaction mass obtained was filtered to obtain crude 1-aminoanthraquinone wet cake.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[N+](C1C2C(=O)C3C(=C([N+]([O-])=O)C=CC=3)C(=O)C=2C=CC=1)([O-])=O.[N+](C1C2C(=O)C3C(=CC=CC=3[N+]([O-])=O)C(=O)C=2C=CC=1)([O-])=O.[OH-].[Na+]>>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Agent: [Na+]
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reaction time: 3 h

Procedure:
A 1-liter electromagnetically stirred cylindrical glass reactor was charged with 5.0 g of crude ;b 1-nitroanthraquinone having a purity of 81% and containing 8% of 1,5-dinitroanthraquinone, 4% of 1,8-dinitroanthraquinone and 7% of other dinitroanthraquinones as impurities (0.016 mole of 1-mitroanthraquinone), 100 g of a 4% aqueous solution of sodium hydroxide and 4.2 g (0.067 mole) of 80% hydrated hydrazine. The mixture was stirred at 80° to 100° C. for 3 hours to form a slurry of 1-aminoanthraquinone. The slurry was cooled to room temperature, and 0.1 g of 5% palladium-carbon was added. The inside of the reactor was purged with hydrogen, and the crude 1-mitroanthraquinone was hydrogenated at room temperature. The reaction was stopped when 0.016 mole of hydrogen was absorbed. The catalyst and insoluble materials were separated by filtration. The filtrate was oxidized with air at 20° to 30° C. for 2 hours with stirring to afford 3.2 g of 1-aminoanthraquinone having a purity of 98% and containing 1% of 1,8-diaminoanthraquinone and only traces of other diaminoanthraquinones as impurities. The yield of 1-aminoanthraquinone was 88% on a purity basis.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[SH-].[Na+]>O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Na+]
Agent: [SH-]
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 70 °C
Yield: 75.6 %

Procedure:
15 Parts of the nitroanthraquinone (1-nitroanthraquinone content: 74.3%) used in Example 1 was sufficiently pulverized and suspended in 279 parts of water at room temperature. Upon addition thereto of 30.7 parts of a 30.5% sodium hydrosulfide aqueous solution, there was generated a slight amount of heat and the solution color was turned into green. In the course of temperature rise to 95° C. for the period of 30 minutes, the reaction mixture became very viscous but the temperature rise was continued. During additional 4-hour agitation at 95°-98° C., there took place little advancement of the reduction reaction. The reaction mixture was cooled to 70° C., filtered, washed and dried to obtain 12.5 parts of an aminoanthraquinone containing 75.6% of 1-aminoanthraquinone. The obtained aminoanthraquinone crystals had the maximum length of 3-5μ, and a photograph thereof is shown in FIG. 3. The yield of 1-aminoanthraquinone as calculated in terms of purity was 96.2%. The amount of water used for the reaction was 20 times that of the nitroanthraquinone, but since the reaction mixture becomes too viscous in the course of temperature rise, it was difficult to lessen the water amount below such level. Also, the filtering rate was very low because of small size of crystals and there was required about 10 times as much time for filtration as required in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10]O)[CH:5]=[CH:6][C:7]=1[F:8].[BrH:12].S(=O)(=O)(O)O>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][CH2:10][Br:12]
Reactant: OCCc1ccc(F)c(F)c1
Reactant: Br
Agent: O=S(=O)(O)O
Product: Fc1ccc(CCBr)cc1F
Yield: 80.7 %

Procedure:
17.59 g (111 mmol) of 2-(3,4-difluorophenyl)ethanol, 16 ml (137 mmol) of hydrogen bromide, 6.8 ml (234 mmol) of conc. sulfuric acid were added in the order, and the mixture was heated under reflux for 3 hrs. The reaction mixture was poured onto an ice-bath, an organic layer and an aqueous layer were separated, the aqueous layer was extracted with ether, the extract combined with the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was distilled off, the solution condensed and purified by vacuum distillation to obtain 21.96 g (bp 68-70° C./2-4 Torr.) of oily product. The oily product was purified by column chromatography (elution solvent: hexane:ethyl acetate=3:1), the eluate was further purified by vacuum distillation to obtain 19.79 g of the title compound (81%, bp 73-75° C./4 Torr.) as oily product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O1CCCC1.[O-][Si]([O-])=O.[Mg+2]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: O=[Si]([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.3 %

Procedure:
Into a 1000-mL three-neck flask were added 28.3 g (0.10 mol) of p-bromoiodobenzene, 10.2 g (0.10 mol) of phenylacetylene, 701 mg (1 mmol) of bis(triphenylphosphine)palladium(II)dichloride, and 190 mg (1 mmol) of copper(I) iodide, and nitrogen substitution was carried out. Then, 350 mL of tetrahydrofuran and 18 mL of triethylamine were added thereto, and the mixture was stirred at room temperature for 12 hours. After the reaction, the reaction mixture was washed with a 3% hydrochloric acid aqueous solution, and an aqueous phase was extracted with ethyl acetate. The extract combined with an organic phase was washed with a saturated saline solution and then dried with magnesium sulfate. The mixture was filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855, the same product was used hereinafter), Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135, the same product was used hereinafter), and alumina, and a solid obtained by the concentration of the filtrate was recrystallized with hexane to give 15 g of the target product as a solid at a yield of 58%.
Reaction SMILES: [I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[CH:5]=[C:4]([I:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18](O)=[O:19])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1.S(Cl)([Cl:26])=O>[Zn]>[I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[CH:5]=[C:4]([I:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([Cl:26])=[O:19])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: CCc1c(I)cc(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I
Agent: [Zn]
Product: CCc1c(I)cc(I)c(-c2ccc(C(=O)Cl)c([N+](=O)[O-])c2)c1I

Procedure:
Freidel-Crafts acylation is performed on 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carboxylic acid (6) in the presence of AlCl3 and CH3COCl to yield 2′,4′,6′-triiodo-3′-acetyl-3-nitrobiphenyl-4-carboxylic acid (12). C 13 ⁢ H 6 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 ⁢ → C ⁢   ⁢ H 3 ⁢   ⁢ C ⁢   ⁢ O ⁢   ⁢ Cl Al ⁢   ⁢ Cl 3 ⁢ C 15 ⁢ H 8 ⁢ I 3 ⁢ N ⁢   ⁢ O 5 2′,4′,6′-triiodo-3′-acetyl-3-nitrobiphenyl-4-carboxylic acid (12) is then reacted with a zinc mercury amalgam and hydrochloric acid and heated to yield 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carboxylic acid (13). C 15 ⁢ H 8 ⁢ I 3 ⁢ N ⁢   ⁢ O 5 ⁢ → Δ Zn ( Hg ) ,   ⁢ H ⁢   ⁢ Cl ⁢ C 15 ⁢ H 10 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carboxylic acid (13) is reacted with thionyl chloride to yield 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carbonyl chloride (14). C 15 ⁢   ⁢ H 10 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 ⁢ → S ⁢   ⁢ O ⁢   ⁢ Cl 2 ⁢ C 15 ⁢   ⁢ H 9 ⁢ Cl ⁢ I 3 ⁢ N ⁢   ⁢ O 3 1,3,4,6-tetra-O-acetyl-D-glucosamine (9) is reacted with 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carbonyl chloride (14) to yield 2-nitro-4-(3′-ethyl-2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (15). C14H21NO9+C15H9ClI3NO3→C29H29I3N2O12 2-nitro-4-(3′-ethyl-2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (15) is treated with stannous chloride and hydrochloric acid to yield 2-amino-4-(3′-ethyl-2′,4′,6′-triiodophenyl)-benzoyl-D-glucosamine (16). C 29 ⁢   ⁢ H 29 ⁢ I 3 ⁢ N 2 ⁢ O 12 ⁢ → Sn ⁢   ⁢ Cl 2 ,   ⁢ H ⁢   ⁢ Cl ⁢ C 21 ⁢   ⁢ H 23 ⁢ I 3 ⁢ N 2 ⁢   ⁢ O 6 Example 2 is similar in general structure to Example 1, with the additional presence of a short alkyl chain attached to the radio-opaque tri-iodophenyl moiety at the C-3′ position to further increase lipophilicity of the molecule and enhance cell membrane permeability. The computed logP of Example 2 is 5.31.
Reaction SMILES: [H-].ClCC(=O)CC1SC=CC=1.[Cl:12][CH2:13][CH2:14][CH:15]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[OH:16]>>[Cl:12][CH2:13][CH2:14][C@@H:15]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[OH:16]
Reactant: OC(CCCl)c1cccs1
Agent: O=C(CCl)Cc1cccs1
Agent: [H-]
Product: O[C@@H](CCCl)c1cccs1

Procedure:
In this example, thiophene is used as the starting material to be acylated by Friedel-Crafts reaction so as to form 3-chloro-1-(2-thienyl)-propanone. Hydride reduction of this propanone forms racemic 3-chloro-1-(2-thienyl)-propan-1-ol. Racemic 3-chloro-1-(2-thienyl)-propan-1-ol is then resolved via enzymatic transesterification to form (S)-(−)-3-chloro-1-(2-thienyl)-propan-1-ol. Subsequently, the resulting chiral chloropropanol is aminated to form (S)-(−)-3-methylamino-1-(2-thienyl)-propan-1-ol with methylamine. In this process, the yield of enzymatic resolution is very low (35%). In addition, large excess, 20 equivalents, of methylamine is required for the amination reaction and the overall yield is low (24%), which renders this process economically less competitive.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CCCCCCC.[Br:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23](=[O:29])[CH:24]=[CH:25][O:26]2)=[CH:21][CH:20]=1>O1CCCC1>[Br:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23](=[O:29])[CH2:24][CH2:25][O:26]2)=[CH:21][CH:20]=1
Reactant: O=c1ccoc2cc(Br)ccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=C1CCOc2cc(Br)ccc21
Temperature: 25 °C
Yield: 78.5 %

Procedure:
A solution of diisobutylaluminum hydride in heptane (1.0 M, 60 mL, 60.0 mmol) was added dropwise to a solution of 7-bromo-4H-chromen-4-one (4.5 g, 20.0 mmol) in tetrahydrofuran at −78° C. under an atmosphere of argon over a period of 30 minutes. After 30 minutes the reaction was quenched with a mixture of silica gel (10 g), and water (10 mL). The mixture was allowed to warm to room temperature and was filter through celite and the tetrahydrofuran was removed under reduced pressure. The residue was taken up in chloroform (100 mL) and washed with sodium hydroxide (1N, 25 mL) and dried over sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluant of dichloromethane. The product containing fractions were combined and the solvent was removed under reduced pressure to provide 7-bromochroman-4-one (3.57 g, 15.7 mmol, 78%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO.[CH2:9]1[O:11][C@H:10]1[CH2:12]Cl.C[O-].[Na+]>C(O)C>[O:11]1[CH:10]([CH2:12][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:9]1
Reactant: C1COCCN1
Reactant: ClC[C@H]1CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: C1CN(CC2CO2)CCO1
Temperature: 250 °C
Yield: 96.4 %

Procedure:
To 1 L 3-neck round bottom flask, fitted with mechanical stirring, thermocouple and addition funnel, was charged morpholine (91.5 g, 91.5 ml, 1.05 mole, 1.0 eq.) and 200 ml of methanol. The solution was stirred rapidly while adding R-epichlorohydrin (100 g, 84.5 ml, 1.08 mole, 1.03 eq.) from the addition funnel over about 30 minutes. The temperature was monitored and when the pot temperature reached 27° C., the reaction was cooled with an ice water bath. The clear solution was stirred for 18 hours. The reaction was assayed by GC (dilute 5 drops of reaction mixture into 1 ml of ethanol and inject onto a 15 m DB-5 capillary GC column with the following run parameters, Injector 250° C., detector 250° C., initial oven temperature 28° C. warming to 250° C. at 10° C. per minute.) The reaction was complete with less than 3% morpholine remaining. The solution was cooled to 10° C. and a 25 wt. % solution of sodium methoxide in methanol (233 g, 1.08 mole, 247 ml) was added dropwise keeping the temperature less than 15° C. The resulting white slurry was stirred at 10-15° C. for 2 hours and checked by GC using the above conditions. None of the chlorohydrin could be observed. The mixture was concentrated on the rotoevaporator using 50° C. bath and full house vacuum. The resulting mixture was diluted with water (500 ml) and methylene chloride. The phases were separated and the aqueous phase washed with methylene chloride (500 ml). The combined organic layers were dried over sodium sulfate and concentrated to a clear, colorless oil. This provided 145 g, 97% yield of 1,2-epoxy-3-morpholin-4-ylpropane. 1H NMR (400 MHz, DMSO-d6) δ3.3 (dd, 4 H), 3.1 (m, 1 H), 2.6 (dd, 1 H), 2.5 (dd, 1 H), 2.4 (m, 4 H), 2.2 (dd, 2 H); 13C NMR (100 MHz, DMSO-d6) δ65.4, 60.1, 53.1, 48.9, 43.4.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH:11][CH3:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19](Cl)(Cl)=[O:20]>O>[I:1][C:2]1[CH:10]=[C:6]2[C:7]([O:9][C:19](=[O:20])[N:11]([CH3:12])[C:5]2=[CH:4][CH:3]=1)=[O:8]
Reactant: CNc1ccc(I)cc1C(=O)O
Reactant: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cn1c(=O)oc(=O)c2cc(I)ccc21
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a mechanically stirred solution of 5-iodo-N-methylanthranilic acid (40 grams 0.144 mol), potassium carbonate (19.95 grams, 0.144 mol), and 500 ml water at 0° C. was added phosgene (1.93M solution in toluene, 0.2 mol, 104 mL) over a period of 1 hr, the resulting slurry was stirred for an additional 3 hrs and the solids isolated by filtration, washing with water, and a small amount (70 mL) of ether. The solids were dried overnight in vacuo to yield 34 grams (78%) of 5-iodo-N-methylisatoic anhydride. 1H NMR (DMSO-d6) 8.18 (1H, bs, C6-H), 8.08 (1H, bd, 3JHH =8 Hz, C4-H), 7.12 (1H, d, 3JHH =8 Hz, C3-H), 3.42 (3H, s, NCH3).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16]>>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: ClCCCCCBr
Reactant: N#Cc1ccc(O)cc1
Product: N#Cc1ccc(OCCCCCCl)cc1
Yield: 90 %

Procedure:
In the fifth step, 4-hydroxy-benzonitrile (7) is reacted with 1-bromo-5-chloropentane, and thus, 4-(5-chloro-pentoxy)-benzonitrile (8) (yield: 90%) is obtained. As such, the reaction temperature is preferably maintained in the range from 20 to 82° C., and the reaction solvent is selected from polar solvents, including dichloromethane, acetonitrile, ethylacetate, lower alcohols such as methanol, ethanol or isopropanol, ethers such as tetrahydrofuran or 1,4-dioxane, dimethylformamide, or dimethylsulfoxide, and mixtures thereof. To ensure that the above reaction occurs under a basic condition, an inorganic base, including potassium carbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, sodium methoxide, or sodium ethoxide, and other base, may be used.
Reaction SMILES: [CH2:1](/[C:3](=[CH:6]\[CH2:7][C@@H:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:15])[CH3:14])/[CH:4]=[O:5])[CH3:2].CC1[C@@H]2C(C)(C)[C@@H](C2)CC=1>>[CH2:1](/[C:3](=[CH:6]\[CH2:7][C@@H:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:14])[CH3:15])/[CH2:4][OH:5])[CH3:2]
Reactant: CC/C(C=O)=C\C[C@@H]1CC=C(C)C1(C)C
Agent: CC1=CC[C@@H]2C[C@H]1C2(C)C
Product: CC/C(=C\C[C@@H]1CC=C(C)C1(C)C)CO

Procedure:
(E)-(S)-2-Ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-2-buten-1-al synthesized from (1R,5R)-α-pinene having an optical purity of 97% e.e. (available from Aldrich) was hydrogenated in the same manner as in Example 2 to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)c(F)c1
Temperature: 80 °C
Yield: 97 %

Procedure:
To 4-bromo-3-fluorobenzoic acid (2.00 g, 9.13 mmol) in methanol (12 ml) was added sulfuric acid (500 μl) and heated to 80° C. for 18 h then cooled to room temperature and concentrated. The residue was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and then concentrated to afford (2.07 g, 97%) of methyl 4-bromo-3-fluorobenzoate, which was used without further purification. 1H NMR (400 MHz, CD3OD): 7.80-7.73 (m, 3H), 3.91 (s, 3H). MS (EI) for C8H6BrFO2: 234 (MH+).