Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:20]([O:22]C)=[O:21])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1>CO.O>[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:20]([OH:22])=[O:21])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][CH:11]=1
Reactant: COC(=O)c1cccc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(C(=O)O)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
6N Sodium hydroxide (260 mL) is added slowly at room temperature to a solution of 183 g of methyl 6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylate in 1200 mL of methanol. The reaction mixture is heated under gentle reflux for 2.5 hours, cooled to room temperature and diluted with 300 mL of water. The reaction mixture is evaporated under reduced pressure (110-120 mbar/40° C.) to a suspension of about 750 mL which is filtered through the filter agent Celite® 521, and the filter cake is washed sequentially with 250 mL of water and 250 mL of heptane. The organic layer is separated and the aqueous layer is washed with 250 mL of heptane. The aqueous layer is acidified with 500 mL of 4N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed with water and filtered through the filter agent Celite® 521. The ethyl acetate solution (ca. 1000 mL) is evaporated under reduced pressure (110-120 mbar/40° C.) to a volume of 600 mL to which is added heptane (3125 mL). The suspension is then heated to reflux until a clear solution is obtained, the solution is cooled to 0° C. and the resulting solid is filtered off to yield 6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.O[C:17]1[C:25]([CH3:26])=[C:24]2[C:20]([C:21](=[O:27])[O:22][CH2:23]2)=[C:19]([O:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:18]=1[CH2:39]/[CH:40]=[C:41](\[CH3:48])/[CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45].C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:26][C:25]1[C:17]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[C:18]([CH2:39]/[CH:40]=[C:41](\[CH3:48])/[CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:19]([O:28][S:29]([C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=[O:31])=[O:30])=[C:20]2[C:24]=1[CH2:23][O:22][C:21]2=[O:27]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)CC/C(C)=C/Cc1c(O)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC/C(C)=C/Cc1c(OS(=O)(=O)C(F)(F)F)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2

Procedure:
Trifluoromethanesulfonic anhydride (10.57 g) was added to a solution of methyl (E) 6-(1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate in methylene chloride (500 ml) and pyridine (5 ml) at 0° C. After 6 hours the reaction was added to excess aqueous sodium bicarbonate. The organic solution was dried and evaporated to afford methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-trifluoromethanesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12](=[O:14])[CH3:13]>CO.C(Cl)(Cl)Cl>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])cc1C(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(N)cc1C(C)=O

Procedure:
The above-identified compound (2.13 g) was obtained by processing Intermediate 72 (2.50 g) through reaction and after-treatment in accordance with the procedures of the step C of Example 63. Rf=0.38 (methanol/chloroform of 1/19).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:26][NH:27][O:28][CH3:29].CCOC(C)=O>C(Cl)Cl>[CH3:29][O:28][N:27]([CH3:26])[C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:12]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
2-{[(tert-Butoxy)carbonyl]amino}acetic acid (5.00 g, 28.5 mmol) was dissolved in DCM (50 mL), CDI (5.09 g, 31.4 mmol) was added and the reaction mixture was stirred for 1 h. N,O-dimethylhydroxylamine hydrochloride (3.06 g, 31.4 mmol) was added and the reaction mixture was stirred for 16 h. EtOAc (150 mL) was added and the reaction mixture was washed with 1 M aq HCl (50 mL), sat aq NaHCO3 (2×50 mL), dried (Na2SO4) and concentrated in vacuo to give the crude title compound (5.13 g, 82%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[CH:10][C:3]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ccnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (3.05 g, 20 mmol, prepared according to Thibault, C. et al. Org. Lett. 2003, 5, 5023) in DMF (50 mL) at −40° C. under N2, was added NaH (60% in mineral oil, 880 mg, 22 mmol). The mixture was stirred at rt for 15 min, then cooled to −40° C. To this solution was added (2-(chloromethoxy)ethyl)trimethylsilane (3.67 g, 22 mmol). The resulting mixture was stirred at rt overnight. The mixture was diluted with EtOAc, washed twice with 10% LiCl, and dried over MgSO4. The title compound was purified by flash column chromatography (silica gel, eluding with hexane, followed by Et2O) to give the desired product (5.6 g, quantitiatve yield) as an oil. LC/MS(ESI+) m/z 283 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([C:6]1(O)[C:15]2[CH:14]=[N:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[CH2:5].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:19][N:2]([CH3:1])[CH2:3][C:4]([C:6]1[C:15]2[CH:14]=[N:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]=1)=[CH2:5]
Reactant: C=C(CN(C)C)C1(O)CCCc2cc(OC)ncc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C=C(CN(C)C)C1=CCCc2cc(OC)ncc21

Procedure:
The reaction of the keto group of the 6-alkoxy, and 6-cycloalkoxy 7-aza-1-tetralones with the lithium salt formed by adding butyl lithium to an appropriate halo substituted dimethylaminoalkene affords the corresponding N,N-dimethyl-N-(2-[5,6,7,8-tetrahydro-8-hydroxy-3-alkoxyisoquinol-8-yl]alk2-en-1-yl)amine, or the appropriate cycloalkyloxy derivative. Typically, 7-aza-6-methoxy-1-tetralone is contacted with a solution containing butyl lithium and 2-bromo-3-dimethylaminopropene to yield N,N-dimethyl-N-(2-[5,6,7,8-tetrahydro-8 -hydroxy-3-methoxyisoquinol-8-yl]prop-2-en-1yl)amine. The hydroxyl substituent is removed with a phosphorous oxyhalide, such as phosphorous oxychloride in pyridine or in concentrated sulfuric acid, to yield the N,N-dimethyl-N-(2-[5,6-dihydro-3-substituted-isoquinol-8-yl]alk-2-en-1-yl)amine. For example, N,N-dimethyl-N-(2-[5,6,7,8-tetrahydro-8-hydroxy-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine is contacted with phosphorous oxychloride in pyridine to obtain N,N-dimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl-]prop-2-en-1-yl)amine. Quaternarization of the amines with an alkyl halide, e.g. methyl iodide, yields the quaternary salts, which are subsequently reacted with silver oxide and then with 2-(lower alkyl)cyclopentane-1,3-dione to yield the appropriate 5,6-dihydro-3-substituted-8-[3-(2-methyl-1,3-dioxocyclopent-2-yl)alk-1-en-2-yl]isoquinoline. In that manner, the aforementioned N,N-dimethyl-N-(2[5,6-dihydro-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine is treated with methyl iodide to afford the corresponding trimethyl ammonium iodide. Subsequent treatment with silver oxide and 2-(lower alkyl)cyclopentane-1,3-dione produces 5,6-dihydro-3-methoxy-8-[3-( 2-methyl-1,3-dioxocyclopent-2-yl)prop-1-en-2-yl]isoquinoline. Cyclization of the diketones is effected conveniently with sulfuric acid to afford the corresponding dl-2-aza-3-substituted-11β-methylestra-1,3,5(10),8(14),9(11),15-hexaen-17-ones. Representative thereof is the formation of dl-2-aza-3-methoxy-11β-methylestra-1,3,5(10),8(14),9(11),15-hexaen17one upon contacting the aforementioned isoquinoine derivative with sulfuric acid.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:7]1(=[O:16])[N:6]([CH2:5][CH:4]=[O:3])[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]12
Reactant: CCOC(CN1C(=O)c2ccccc2C1=O)OCC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.5 %

Procedure:
A solution of 50.0 g (190 mmol) of 2-(phthalimido)acetaldehyde diethyl acetal in 300 mL of toluene was treated with 150 mL of 50% aqueous trifluoroacetic acid and the mixture was stirred vigorously at ambient temperature for 72 h. The solution was concentrated in vacuo and 100 mL of ethyl acetate was added. The white precipitate was filtered off and washed with ice-cold ethyl acetate (100 mL) to give 30.0 g (78%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-])=O)[CH:23]=3)[NH:18][CH:17]=2)=[CH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O.NN>CO.[Ni]>[NH2:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C:13]1[CH2:14][CH2:15][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:11][CH:12]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Yield: 93.6 %

Procedure:
A solution of compound 81 (0.5 g, 1.346 mmol) in dry methanol (20 mL) was treated with hydrazine hydrate (0.41 mL, 13.461 mmol) followed by Raney-Ni (0.1 g) and the resulting mixture was refluxed for 30 min. The reaction was brought to room temperature, filtered through celite bed, washed with CH2Cl2:methanol (1:1, 3×20 mL). The combined organic layer was evaporated and crude was purified by column chromatography (EtOAC: Hexanes, 1:1) to obtain compound 98 (0.43 g, 94%) as a foam. 1H NMR (DMSO-d6) δ: 1.38-1.41 (m, 11H), 1.76-1.86 (m, 2H), 2.14-2.42 (m, 2H), 2.73 (s, 3H), 4.05-4.15 (m, 1H), 4.49 (s, 2H), 6.00 (brs, 1H), 6.48 (dd, 1H, J=1.8, 8.2 Hz), 6.99 (d, 1H, J=1.5 Hz), 7.05 (d, 1H, J=8.4 Hz), 7.16 (d, 1H, J=2.7 Hz), 10.60 (s, 1H); ESI-MS m/z (%): 364 (M+Na+, 7), 342 (MH+, 11), 286 (100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.CCCCCC>N1C=CC=CC=1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 15 h
Yield: 85.9 %

Procedure:
To a well-stirred solution of 2-(R)-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (compound (2), 15 g, 75 mmol) in 42 mL of pyridine and 100 mL of dichloromethane at 0° C. was added a solution of 4toluenesulfonyl chloride (15.68 g, 82.55 mmol) in 75 mL of dichloromethane in a dropwise manner while maintaining the reaction temperature below 0° C. After the addition was complete, the temperature of the reaction was allowed to rise to ambient temperature (˜23° C.) and the reaction was stirred for 5 hours, at which time another 5 grams of 4-toluenesulfonyl chloride was added. The reaction was stirred for 15 hours. The reaction mixture was poured into 150 mL of a 2:1 mixture of dichloromethane and hexane. The mixture was washed twice with a mixture of 100 mL of saturated NaH2PO4 (pH=4.1) solution and water, and then washed with 500 mL of a mixture of 100 mL of Na2HPO4 and water. The organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography, eluting with 15% EtOAc in hexane to give a clear oil (22.9 g, 86% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C(=O)C.COC(C)(C)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 60 °C

Procedure:
At room temperature, to a 3-L pear-shaped evaporating flask was added methyl(4-hydroxyphenyl)acetate (202 g) and potassium carbonate (233 g) which were dissolved in N,N-dimethylacetamide (DMA) (1 L). To the solution was added benzyl chloride (117 mL) at room temperature and stirred. The solution was then heated to 60° C. and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with methyl tert-butylether (MTBE) (1.3 L) and added with water (3 L) and an organic layer was extracted. The resulting organic layer was washed three times with a 1 N sodium hydroxide aqueous solution, then with water and a saturated sodium chloride solution and then dried over anhydrous magnesium sulphate. The solvent was distilled off at reduced pressure to give the titled compound (245 g) having the following physical properties.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.F[C:13]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]>>[CH:21]([C:18]1[CH:19]=[CH:20][C:13]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)=[C:14]([CH:17]=1)[C:15]#[N:16])=[O:22]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D starting from 3-Trifluoromethyl-phenol and 2-Fluoro-5-formyl-benzonitrile.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.C([Li])CCCCC.CN(C)C=O.Cl>O1CCCC1>[NH:8]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[CH:15]=[CH:6]1
Reactant: Cc1cccnc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1cnc2[nH]ccc2c1
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-(tert-butoxycarbonylamino)-3-methylpyridine (Example 2a) (100 g) in anhydrous tetrahydrofuran and cooled to -15° C. was slowly added hexyllithium (2.8M, 350 ml) over 40 minutes, while maintaining the reaction temperature at -15° C. The reaction mixture was aged at -15° C. for 15 minutes and then allowed to warm to -5° C. Anhydrous dimethylformamide (40 ml) was added in one portion (temp. to 5° C.) and the resulting yellow suspension vigorously stirred at ambient temperature for 30 minutes. 5.5M Hydrochloric acid (900 ml) was added in one portion and the mixture heated at 45° C. for one hour. The mixture was cooled to 20° C. and the phases separated. The aqueous phase was covered with isopropyl acetate (500 ml), cooled to 5° C. and with vigorous stirring, neutralised by the addition of sodium hydroxide pellets (200 g, 5.0 mole). The phases were separated and the aqueous phase extracted with isopropyl acetate (500 ml). The organic phases were combined, washed with 2%w/w sodium metabisulphite (2×500 ml) and evaporated to residue (56.8 g, 91%w/w purity, 91%w/w assay yield (method 1)).
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([CH3:10])[CH2:5][CH:6]([OH:9])[CH2:7]O.CS([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=O)=O>CC1CCCCC1>[CH2:16]([O:15][CH:5]([N:4]([CH3:10])[CH3:3])[CH:6]([O:9][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:7])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CN(C)CC(O)CO
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: CC1CCCCC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC(C)C(OCCCCCCCC/C=C\C/C=C\CCCCC)N(C)C
Reaction time: 13 h

Procedure:
In a nitrogen atmosphere, methylcyclohexane (30 mL) and potassium hydroxide (3.1 g, 54.4 mmol) were added to a four-necked flask, and 3-(dimethylamino)-1,2-propanediol (0.72 g, 6.04 mmol: DAP) was dropped under agitation. Thereafter, linoleyl methane sulfonate (5.0 g, 14.5 mmol) was added, and agitation was performed at 40° C. for 13 hours. The reaction was terminated because remaining linoleyl methane sulfonate became 2.1% (degree of conversion: 68.0%, integrated value of isomer: 0.024).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(Cl)Cl>[C:19]1([C:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:1]2[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reaction time: 16 h
Yield: 94.6 %

Procedure:
To a solution of 76.5 g of ethyl isonipecotate and 81.5 ml of triethylamine in 750 ml of methylene chloride, 149 g of triphenylmethyl chloride dividied in three portions was added portionwise at room temperature, and the mixture was stirred for 16 hours. The reaction mixture was added with water and extracted with methylene chloride. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated. The resulting brown liquid was added with diisopropyl ether, and the precipitated crystals were collected by filtration and washed with diisopropyl ether to give 184 g of pale yellow crystals. Recrystallization from ethanol gave colorless prisms having the melting point of from 147.5 to 148.5° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[P:14](=[O:18])([OH:17])([OH:16])[OH:15].[CH3:19]O>>[P:14]([OH:18])([OH:17])([OH:16])=[O:15].[CH3:19][O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: CO
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=P(O)(O)O
Product: COC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 8 h
Yield: 61.1 %

Procedure:
The same esterification procedure as in Example 1 was followed with the exception that 165.2 g of L-phenylalanine and 165.2 g of methanol were used and that hydrochloric acid was replaced with 132.1 g of 89% phosphoric acid. The reaction was conducted at 60 ° C. for 8 hours, followed by cooling in order to deposit the crystals, which were collected by filtration and then dried to obtain 169.4 g (58.1% yield) of L-phenylalanine methyl ester phosphate having a purity of 95.1% and containing 0.3% of water and 3.0% of L-phenylalanine.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([CH3:16])=[CH2:15])[CH2:9][CH:8]=1.CN(CC1C2C=CC=CC=2NC=1)C>>[CH:11]1[C:10]([CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=[C:7]([CH3:6])[C:12]=1[OH:13]
Reactant: C=C(C)C1CC=C(C)C(=O)C1
Agent: CN(C)Cc1c[nH]c2ccccc12
Agent: O=S(=O)(O)O
Product: Cc1ccc(C(C)C)cc1O

Procedure:
Aqueous 0.5M sulphuric acid (25 ml), Teric N100 emulsifying agent (a product of ICI; 2.5 g) and carvone (50 g) were stirred and the emulsion passed through the CMR four times (15.5 ml/min, 165°-75° C., 690-760 kPa). Analysis was again by GC after each pass. After four passes a conversion of 50% was obtained. This experiment was then repeated using 1M sulphuric acid, and was directly comparable with experiment (a) above, the variation being the addition of the emulsifying agent. After four successive passes, the percentage of carvacrol obtained was 32%, 63%, 73% and 83%, with negligible by-product formation.
Reaction SMILES: [CH2:1]([CH:9]1[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]1)[CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.[C:16]([OH:20])(=O)[CH2:17][OH:18]>O>[CH2:1]([CH:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:16](=[O:20])[CH2:17][OH:18])[CH2:6][CH2:7]1)[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:17](=[O:18])[CH2:16][OH:20])[CH2:11][CH2:10]1
Reactant: NC1CCC(CC2CCC(N)CC2)CC1
Reactant: O=C(O)CO
Solvent: O
Product: O=C(CO)NC1CCC(CC2CCC(NC(=O)CO)CC2)CC1
Yield: 86.8 %

Procedure:
4,4'-Methylenebis(cyclohexylamine) (25 g, 0.12 mole) and glycolic acid (18.2 g, 0.24 mole) were combined in a 250 ml round bottom flask heated in an oil bath. The solids were melted together with mixing and heated to 175° C. whereupon distillation of water occurred. After heating for 3 hours the evolution of water subsided and crystallization commenced. The solid was removed and recrystallized from methanol to yield 34 g (87%) of lustrous white needles; m.p. 208°-212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][N:13]1[CH2:17][CH2:16][CH:15](O)[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH:15]1[CH2:16][CH2:17][N:13]([CH3:12])[CH2:14]1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: CN1CCC(O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cc2Cl)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-chloro-4-nitrophenol (2.0 g) in tetrahydrofuran (60 mL) is added 1-methyl-3-pyrrolidinol (2.3 g), triphenyl phosphine (6.0 g), and diethylazo-dicarboxylate (3.6 mL) and the mixture is stirred at room temperature under an atmosphere of argon for 1.5 hours. The solution is then concentrated under reduced pressure, diluted with ethyl acetate, washed successively with 10% aqueous sodium hydroxide, water, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is chromatographed over silica gel (ethyl acetate then 10% methanol in dichloromethane is used as the eluant). Pooled product fractions are then recrystallized from hexanes to provide the desired product as a yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]3[O:14][CH2:13][CH2:12][O:11][C:8]=3[CH:9]=2)[C:4](=O)[NH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[Cl:18][C:4]1[C:5]2[C:10](=[CH:9][C:8]3[O:11][CH2:12][CH2:13][O:14][C:7]=3[CH:6]=2)[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc3c(cc12)OCCO3
Solvent: Cc1ccccc1
Product: Clc1ncnc2cc3c(cc12)OCCO3
Temperature: 125 °C
Yield: 94 %

Procedure:
According to the procedure described in Example 6A Step 5, a mixture of 7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4(3H)-one (1.114 g, 5.46 mmol) and POCl3 (10 mL) in toluene (10 mL) was heated at 125° C. for 5 hours to afford 4-chloro-7,8-dihydro-[1,4]dioxino[2,3-g]quinazoline as a solid (1.143 g, 94%). 1H NMR (300 MHz, CDCl3) δ 8.90 (s, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 4.46 (m, 4H).