Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:18])([CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7]C)=[O:6]>O1CCCC1.CO.Cl.C(OCC)(=O)C>[CH3:3][C:4]([CH3:18])([CH2:9][O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(C)(C)COCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(COCc1ccccc1)C(=O)O
Reaction time: 8 h
Yield: 93 %

Procedure:
Adapting procedures or variations thereof according to Rega et al., Eur. J. Org. Chem. 2007, 6, 934-942; Woo et al., J. Org. Chem. 2004, 69(25), 8984-8986; and Abiko et al., Tetrahedron Lett 1986, 27(38), 4537-40, 3.4 mL of an ten molar (10 M) aqueous solution of sodium hydroxide (NaOH) (34.0 mmol) was added to a solution of 3.7 g (16.9 mmol) of methyl-2,2-dimethyl-3-(phenylmethoxy)propanoate (26a) in a mixture of 15 mL of tetrahydrofuran (THF) and 5 mL of methanol (MeOH). The solution was vigorously stirred overnight at room temperature. Upon completion of the reaction, the reaction mixture was further diluted with one molar (1.0 M) hydrochloric acid (HCl) and ethyl acetate (EtOAc) and the phases were separated. The aqueous phase was extracted two additional times with ethyl acetate (EtOAc) and the combined organic extracts were washed with brine. The organic solution was dried over anhydrous magnesium sulfate (MgSO4), filtered, and the solvents and benzyl alcohol were removed under reduced pressure using a rotary evaporator. The crude material was used in the next step without further purification. Three-point-three (3.3) g (93% yield) of the title compound (26b) was obtained as a colorless solid. 1H NMR (400 MHz, CDCl3): δ=1.10 (s, 6H), 3.40 (s, 2H), 4.47 (s, 2H), 7.26-7.35 (m, 5H) ppm. The analytical data was consistent with the proposed structure.
Reaction SMILES: [N-:1]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[C:16](=O)([O-:18])[O-:17].[Ca+2:20]>O>[N-:1]([S:2]([C:5]([F:8])([F:6])[F:7])(=[O:4])=[O:3])[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10].[Ca+2:20].[N-:1]([S:2]([C:5]([F:8])([F:6])[F:7])(=[O:4])=[O:3])[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10].[C:16](=[O:18])=[O:17]
Reactant: O=C([O-])[O-]
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Ca+2]
Solvent: O
Product: O=C=O

Procedure:
Trifluoromethanesulfonimide ((CF3SO2)2NH, hereinafter HTFSI) was dissolved in water to make a 1 mol/l (1M) solution. Calcium carbonate (CaCO3) was added to the solution with stirring to a molar ratio of 2:1 (HTFSI:CaCO3). A reaction of calcium carbonate and HTFSI produced calcium bistrifluoromethanesulfonimide, carbon dioxide and water as shown below: CaCO3+HTFSI=Ca(TFSI)2+CO2+H2O
Reaction SMILES: [CH3:1][NH:2][S:3]([CH:6]=[CH2:7])(=[O:5])=[O:4].Br[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2.C(N(CC)CC)C>C(O)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)(=[O:5])=[O:4]
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C=CS(=O)(=O)NC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CNS(=O)(=O)/C=C/c1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 221.2 %

Procedure:
A mixture of N-methylethenesulphonamide (45 g), 5-bromoindole (60 g), palladium acetate (0.9 g), tri-o-tolylphosphine (18.6 g) and triethylamine (90 mL) in isopropanol (300 mL) was heated at 85° under nitrogen for 18 h. The reaction mixture was cooled to ambient temperature, filtered and the filter-cake washed with isopropanol (30 mL). The combined washings and filtrate were concentrated in vacuo to give a yellow-brown solid (160 g). This material was purified by column chromatography on silica gel. Eluting initially with ethyl acetate/cyclohexane (1:1) followed by ethyl acetate provided the product (26.4 g, 36% of theory) as a yellow powder.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([NH:19][C:20]1[CH:30]=[C:29]2[C:23]([C:24]([Cl:35])=[C:25]([O:31][CH2:32][CH2:33][CH3:34])[O:26][C:27]2=[O:28])=[CH:22][CH:21]=1)=[O:18])CC1C=CC=CC=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:36](N[C@H](C(N[C@H](C(NC1C=C2C(C(Cl)=C(OCCC)OC2=O)=CC=1)=O)C)=O)C)(=O)[C:37]1C=CC=C[CH:38]=1.C(N[C@H](C(NC1C=C2C(C(Cl)=C(OCC)OC2=O)=CC=1)=O)C(C)C)(OC(C)(C)C)=O.C(N[C@H](C(NC1C=C2C(C(Cl)=C(OCC)OC2=O)=CC=1)=O)C)(OC(C)(C)C)=O>>[C:1]([NH:8][C@H:9]([C:17]([NH:19][C:20]1[CH:30]=[C:29]2[C:23]([C:24]([Cl:35])=[C:25]([O:31][CH2:32][CH2:33][CH3:34])[O:26][C:27]2=[O:28])=[CH:22][CH:21]=1)=[O:18])[CH:37]([CH3:38])[CH3:36])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CCCOc1oc(=O)c2cc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)ccc2c1Cl
Reactant: CCCOc1oc(=O)c2cc(NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)c3ccccc3)ccc2c1Cl
Agent: CCOc1oc(=O)c2cc(NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc2c1Cl
Agent: CCOc1oc(=O)c2cc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)ccc2c1Cl
Product: CCCOc1oc(=O)c2cc(NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc2c1Cl

Procedure:
7-(Boc-phenylalanyl)amino-4-chloro-3-propyloxyisocoumarin, 7-(benzoylalanylalanyl)amino-4-chloro-3-propyloxyisocoumarin, 7-(Boc-valyl)amino-4-chloro-3-ethoxyisocoumarin and 7-(Boc-alanyl)amino-4-chloro-3-ethoxyisocoumarin can be prepared by the same procedure.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:38])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:19][CH2:18][CH2:17][CH:16]([O:20][CH2:21][C:22]3[C:23]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])=[N:24][O:25][C:26]=3[CH:27]3[CH2:29][CH2:28]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)C>O1CCOCC1>[CH:27]1([C:26]2[O:25][N:24]=[C:23]([C:30]3[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=3[Cl:36])[C:22]=2[CH2:21][O:20][CH:16]2[CH2:17][CH2:18][CH2:19][N:13]([C:10]3[CH:9]=[CH:8][C:7]([C:6]([OH:38])=[O:5])=[CH:12][CH:11]=3)[CH2:14][CH2:15]2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)c1ccc(N2CCCC(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2CCCC(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)CC2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution 2M of lithium hydroxide (283 μL, 566 μmoles) is added to a solution of 4-{4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-azepan-1-yl}-benzoic acid ethyl ester (isomer A, 60 mg, 113 μmoles) in 1,4-dioxane (2 mL) and the mixture is stirred at 90° C. overnight. The organic solvent is removed and HCl (1M) is added until the solution reaches pH 3-4. The solid is filtered and purified via flash chromatography (12 g silica) eluting with a gradient of dichloromethane:ethyl acetate from 10% to 20% to provide the title compound (50 mg, 88%) as a white solid. ES/MS m/z 501.0 (M+1).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.COCCOC>[C:16]1([C:2]2[C:3]3[C:8]([CH:9]=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Temperature: 80 °C
Reaction time: 9 h
Yield: 400.7 %

Procedure:
5.4 g (21.1 mmol) of 9-bromoanthracene, 2.6 g (21.1 mmol) of phenylboronic acid, 60 mg (0.21 mmol) of palladium acetate(II) (Pd(OAc)2), 10 mL (20 mmol) of an aqueous potassium carbonate (K2CO3) solution (2 mol/L), 263 mg (0.84 mmol) of tri(o-tolyl)phosphine (P(o-tolyl)3), and 20 mL of 1,2-dimethoxyethane (abbr.: DME) were mixed and stirred for 9 hours at 80° C. After the reaction, the precipitated solid was recovered by suction filtration, dissolved into toluene, and filtered through florisil, Celite®, and alumina. The filtrate was washed with a saturated aqueous sodium chloride solution and then dried with magnesium sulfate. After natural filtration, the filtrate was concentrated, thereby obtaining 21.5 g of objective 9-phenylanthracene as a light-brown solid with a yield of 85%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16]C)=[O:15])[C:9]2=[O:18])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[C:9]2=[O:18])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (crude 2.45 g, 12 mmol) and 6 N aq. NaOH (2.5 mL) in methanol (60 mL) was stirred at rt for 4 h. To the reaction mixture was added conc. HCl (1 mL) slowly with stirring at rt, and the precipitated solid was filtered, washed with a small amount water and dried to obtain the desired acid product (2.1 g, 1st crop) as a yellow solid. The filtrate solution was concentrated in vacuo, and the residue was mixed with water (50 mL), washed with EtOAc (2×130 mL) The organic layers were dried over MgSO4, and concentrated in vacuo. The residue was triturated with a small amount of ether to obtain the 2nd crop of acid product (195 mg, total 2.30 g, 82%). 1H NMR (DMSO-d6) δ 8.47 (dd, 1H, J=7.2, 2.2Hz), 8.19 (dd, 1H, J=6.6, 1.7Hz), 7.62-7.60 (m, 2H), 7.42 (t, 2H, J=8.8 Hz), 6.78 (t, 1H, J=7.1 Hz); MS(ESI+) m/z 234.2 (M+H)+.
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)C.[OH-].[Na+].[C:22]([CH2:25][C:26](=[O:28])[CH3:27])(=[O:24])[CH3:23]>>[C:16]([C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]=1[OH:15])[CH2:4][CH:25]([C:26](=[O:28])[CH3:27])[C:22](=[O:24])[CH3:23])([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(=O)CC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(C)=O
Yield: 37 %

Procedure:
A mixture of the N,N-dimethyl-2,6-di-t-butyl-4-aminomethylphenol (10.5 g, 40 mmols), sodium hydroxide (3.6 g, 90 mmols) and acetylacetone (24 mLs, 10% solution) was refluxed for 3 hours. Acetylacetone was distilled under reduced pressure to afford an oily residue of the 3-(3',5'-di-t-butyl-4'-hydroxybenzyl)-2,4-pentanedione compound (37% by VPC).
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.C1(C2C3C=CC=CC=3N([CH2:57][C:58](C3CCCC3)=[O:59])C(=O)N(CC(O)=O)N=2)CCCCC1.C(OC(=O)CN1C2C(=CC=C(N)C=2)C=C1)C.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH2:58]([O:59][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:57]
Reactant: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CCOC(=O)Cn1ccc2ccc(N)cc21
Agent: COC(=O)c1cccc(N)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 22, step a) and (6-amino-indol-1-yl)-acetic acid ethyl ester were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (DMSO-d6) 9.65 (1H, s), 7.67 (1H, s), 7.58-7.47 (2H, m), 7.39 (1H, d), 7.28-7.15 (3H, m), 6.97 (1H, d), 6.31 (1H, d), 4.75-4.55 (4H, m), 4.30 (1H, br d), 3.95 (1H, br d), 3.00-2.88 (2H, m), 1.98-1.40 (14H, m), 1.35-1.10 (4H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 58.53; H, 6.80; N, 10.01%; C33H37N5O5.C7H17NO5.2.0H2O requires C, 58.95; H, 7.17; N, 10.31%.
Reaction SMILES: C([NH:3][C@@H:4]1[C:17](=[O:18])[N:6]2[C:7]([C:14]([OH:16])=[O:15])=[C:8]([CH2:11][S:12][CH3:13])[CH2:9][S:10][C@H:5]12)=O.[ClH:19]>O1CCOCC1>[ClH:19].[NH2:3][C@@H:4]1[C:17](=[O:18])[N:6]2[C:7]([C:14]([OH:16])=[O:15])=[C:8]([CH2:11][S:12][CH3:13])[CH2:9][S:10][C@H:5]12
Reactant: CSCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Agent: Cl
Solvent: C1COCCO1
Product: CSCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Yield: 90 %

Procedure:
(ii) A solution of 7β-formamido-3-methylthiomethylceph-3-em-4-carboxylic acid (6.4 g.) in dioxan (50 ml.) was treated with 50% aqueous hydrochloric acid (7 ml.). After 2 hours at room temperature the mixture was freeze-dried. The resulting material was washed with ethyl acetate and ether, and dried to give 7β-amino-3-methylthiomethylceph-3-em-4-carboxylic acid, hydrochloride (5.95 g., 90%) as a white amorphous solid, [α]D + 58.4° (C 1, 3% NaHCO3), λmax. (0.1 M pH 6 phosphate buffer) 265.5 nm. (ε 7,650), νmax. (Nujol) 1782 (β-lactam), 1715 and 1682 (carboxyl) cm-1, τ (D2O - NaHCO3) 6.59 (C-7 H 1-proton doublet, J 4.5 Hz) 6.91 (C-6 H 1-proton doublet, J 4.5 Hz), 6.2 and 6.67 [C-2 H2 two 1-proton doublets (branches of a quartet), J 18 Hz], 6.24 and 6.7 [C-3 CH2 two 1-proton doublets (branches of a quartet), J 13 Hz], and 7.98 (3-proton singlet, CH3S).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].CC(O)(C)C.[H][H]>CC([C@@H](N)C(N)(C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1)C.COC1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C(C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC(OC)=NC=2OC)=C(OC)N=1.Cl[Ru]Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Agent: Cl[Ru]Cl
Agent: CC(C)(C)[O-]
Agent: COc1cc(P(c2ccccc2)c2ccccc2)c(-c2c(P(c3ccccc3)c3ccccc3)cc(OC)nc2OC)c(OC)n1
Solvent: CC(C)(C)O
Solvent: CO
Product: Cc1cc(Nc2nc([C@@H](O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 50 °C
Reaction time: 18 h
Yield: 1066.7 %

Procedure:
A stirred mixture of compound 1 (418 mg, 1.2 mmol) and (R)—P-Phos RuCl2 (R)-DAIPEN (5.4 mg, 0.0048 mmol) at room temperature was subjected to five cycles pressurizing with nitrogen to 40 psi and then depressurizing. Then KOtBu/tBuOH (1 M, 14.4 μL, 0.0144 mmol) in 9:11-PrOH/H2O (4 mL) was added and the mixture was subjected to five cycles of pressurizing with nitrogen to 40 psi and then depressurizing. The stirred mixture was then subjected to ten cycles of pressurizing with hydrogen to 435 psi and then depressurizing. The mixture was then stirred at 900 rpm under hydrogen (435 psi) at 50° C. for 18 hrs. The mixture was allowed to cool to room temperature and vented carefully. MeOH (8 mL) was added, and a sample (0.2 mL) was analyzed by chiral HPLC and LCMS (Phenomenex Luna C18) eluted with a gradient of CH3CN in 0.1% aq. HOAc. The above procedure was carried out in analogous fashion in an additional 12 runs. Samples of the required specification (>98%, >95% enantiomeric excess) were combined and filtered through celite, washing with MeOH. The filtrate was concentrated to dryness and further dried under high vacuum overnight to afford compound 3 as an off-white solid (4.48 g, 12.8 mmol). 1H NMR (300 MHz, DMSO-d6) δ 12.13 (br s, 1H), 10.38 (br s, 1H), 8.59 (d, J=7.7 Hz, 1H), 7.70-7.98 (m, 2H), 7.45-7.64 (m, 3H), 7.06-7.24 (m, 2H), 6.45 (s, 1H), 5.80 (s, 1H), 5.67 (s, 1H), 2.26 (s, 3H); LC-MS (ESI) m/z: 350 (M+H)+. Analysis by chiral HPLC showed a 96.7% enantiomeric excess of the earlier eluting enantiomer.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Cl:11][C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:12]([Cl:11])=[O:14]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Commercially available 1,2,3,4-tetrahydroisoquinoline (50 mg) was dissolved in chloroform (10 ml), and triphosgene (111 mg) was added to the solution. The mixture was stirred at room temperature for 2 hr. The solvent was removed by distillation to give 1,2,3,4-tetrahydro-2-isoquinolinecarbonyl chloride. 1,2,3,4-Tetrahydro-2-isoquinolinecarbonyl isothiocyanate was prepared using this compound as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 1,2,3,4-tetrahydro-2-isoquinolinecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (78 mg, yield 94%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[O:11][CH3:12].P(Br)(Br)[Br:14]>CCOCC>[Br:14][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[O:11][CH3:12]
Reactant: BrP(Br)Br
Reactant: COc1ccc(CO)c(OC)c1
Solvent: CCOCC
Product: COc1ccc(CBr)c(OC)c1

Procedure:
A solution of 0.537 g of 1-hydroxymethyl-2,4-dimethoxybenzene in 5 ml of ether is cooled to -10° C., under a nitrogen atmosphere, and a solution of 0.1 ml of phosphorus tribromide in 2 ml of ether is added dropwise. The 1-bromomethyl-2,4-dimethoxybenzene thus obtained is stored in solution at -30° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[O:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][OH:15].C1C=CC=CC=1>>[C:1]([OH:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:8])=[O:5].[O:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][OH:15].[O:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][OH:15]
Reactant: O=C1C=CC(=O)O1
Agent: OCC1COCCO1
Solvent: c1ccccc1
Product: O=C(O)/C=C\C(=O)O
Yield: 82 %

Procedure:
Following the procedure of Example 2, a mixture of 98 grams (1 mole) of maleic anhydride, 354 grams (3.0 moles) of 1,4-dioxanemethanol and 50 milliliters of benzene affords an 82 percent yield of bis-1,4-dioxanemethanol maleate.
Reaction SMILES: N(CCO)(CCO)CC[OH:4].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH:13]=[CH:12]1.O.[N:19]([CH2:26][CH2:27][OH:28])([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>O>[C:11]([OH:16])(=[O:17])/[CH:12]=[CH:13]\[C:14]([OH:4])=[O:15].[N:19]([CH2:26][CH2:27][OH:28])([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]
Reactant: O=C1C=CC(=O)O1
Solvent: OCCN(CCO)CCO
Solvent: O
Product: O=C(O)/C=C\C(=O)O
Temperature: 50 °C

Procedure:
Triethanolamine (99% pure, Aldrich) and water as specified in Table 2 was added into a 500 ml beaker for each of the following examples. The beaker was heated to 50° C. on a hot plate with magnetic agitation. A preweighed amount of maleic anhydride briquett (100%, Huntsman) was then added to the triethanolamine water solution. After all the maleic anhydride was dissolved, the mixture was cooled and was ready for further blending.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12]O>S(=O)(=O)(O)O>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(O)cc1
Yield: 80 %

Procedure:
A solution of 15 gm (0.1 mole) of 4-hyroxyphenylacetic acid in 500 mL methanol and 2 mL concentrated sulfuric acid was placed in a Soxhlet extractor charged with 3A molecular sieves. The solution was heated to reflux for 72 hours, and the sieves were exchanged at 24-hour intervals. The reaction medium was then evaporated to an oil which was dissolved in 100 mL toluene and extracted with 3×100 mL water. The toluene phase was dried over magnesium sulfate, treated with activated charcoal and evaporated to provide 13 gm (80% yield) of a yellow oil. The NMR spectrum was consistent with the assigned structure and this material was used in the next reaction step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH2:15][CH:16]2[CH2:21][CH2:20][C:19]([CH:23]([OH:25])[CH3:24])([OH:22])[CH2:18][CH:17]2[C:26]([O:28]CC2C=CC=CC=2)=O)[CH:4]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.C1CCCCC=1>CN(C)C1C=CN=CC=1.[Pd].N1C=CC=CC=1>[OH:25][CH:23]([C:19]1([OH:22])[CH2:20][CH2:21][CH:16]2[CH:17]([C:26](=[O:28])[C:4]3[C:5]([CH2:15]2)=[C:6]([O:13][CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=3[O:2][CH3:1])[CH2:18]1)[CH3:24]
Reactant: COc1cc(CC2CCC(O)(C(C)O)CC2C(=O)OCc2ccccc2)c(OC)c2ccccc12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1=CCCCC1
Solvent: CC(=O)OC(C)=O
Product: COc1c2c(c(OC)c3ccccc13)C(=O)C1CC(O)(C(C)O)CCC1C2
Yield: 66.1 %

Procedure:
Operation as described in Example 6, 0.44 g of 1-(1,4-dimethoxy-3-naphthylmethyl)-2-benzyloxycarbonyl-4-(1-hydroxyethyl)-4-hydroxyl-cyclohexane, prepared as described in Example 11, was treated with acetic anhydride in presence of 4-dimethylamino-pyridine and pyridine. The corresponding acetate was treated with cyclohexene in the presence of 10% by weight palladium-on-carbon in order to remove the benzyl group. The acid was cyclized by treatment with a mixture of trifluoroacetic anhydride and trifluoroacetic acid at 0° C. Finally the removal of the acetyl O-protecting groups by treatment with sodium methylate afforded. after purification by chromatography on a silica gel column, 0.225 g of the title compound (overall yield 66%); IR (film): 3450 cm-1 (OH), 1675 cm-1 (C=O, benzylic ketone). PMR (CDCl3): inter alia δ 1.3 (d, J=4 Hz, CH3 --CH), 1.6-3.5 (m, 3H), 3.85 (s, OCH3), 3.90 (s, OCH3), 7.2-8.4 (m, four aromatic H).