Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[C:14]([F:15])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:16])[C:5]=1[CH3:17])=[N+]=[N-].C(OCC)C.O.[OH-].[Na+]>CO>[NH2:1][C:4]1[C:14]([F:15])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:16])[C:5]=1[CH3:17]
Reactant: CCOC(=O)c1cc(F)c(N=[N+]=[N-])c(C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cc(F)c(N)c(C)c1F
Reaction time: 0.5 h

Procedure:
In 60 ml of methanol was suspended 14.2 g of stannous chloride, and to this suspension was dropwise added a solution of 10.0 g of ethyl 4-azido-2,5-difluoro-3-methylbenzoate in 20 ml of methanol at room temperature over one hour, after which the resulting mixture was stirred at the same temperature for 30 minutes. The methanol was removed by distillation under reduced pressure, and to the residue obtained were added 300 ml of diethyl ether and 100 ml of water, after which the pH was adjusted to 12.5 with 2N aqueous sodium hydroxide solution. The organic layer formed was separated, washed with water and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure to obtain 8.91 g of yellow, oily ethyl 4-amino-2,5-difluoro-3-methylbenzoate.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:37][CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH3:8][CH:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:37][CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][O:11][CH3:12]
Reactant: CS(=O)(=O)OCC1CCOCC1
Reactant: COCC(C)Oc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCC(C)Oc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 54.3 %

Procedure:
To a solution of 2-{[1-methyl-2-(methoxy)ethyl]oxy}-8-(methoxy)-9H-purin-6-amine trifluoroacetic acid salt (500 mg) in dry N,N-dimethylformamide (4.5 ml) at room temperature and under nitrogen was added potassium carbonate (0.75 g) in one go. The reaction was stirred at 60° C. for 1.5 hours. Tetrahydro-2H-pyran-4-ylmethyl methanesulfonate (0.29 g) was added in one go and the reaction heated at 90° C. for 3 hours. The reaction was cooled to room temperature and then diluted with ethyl acetate (20 ml) and washed with water (15 ml). The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (10-45%) to afford the title compound as a viscous clear oil (260 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[N:7][C:8]=1Cl.Cl[C:24]([O:26][CH3:27])=[O:25].C(Cl)(=O)C1C=CC=CC=1>>[C:16]([N:13]1[CH2:14][CH2:15][C@H:12]1[CH2:11][O:10][C:5]1[CH:6]=[N:7][CH:8]=[C:3]([CH2:2][NH:1][C:24]([O:26][CH3:27])=[O:25])[CH:4]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CN)c1
Reactant: COC(=O)Cl
Solvent: O=C(Cl)c1ccccc1
Product: COC(=O)NCc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Yield: 94 %

Procedure:
Following the general procedure of Example 92c, substituting 5-aminomethyl-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 205b for 5-aminomethyl-3-(1-BOC-2-(S)-azetidinylmethoxy)-6-chloropyridine and methyl chloroformate for benzoyl chloride therein, the title compound (0.23 g, 94%) was prepared: 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.20-2.41 (m, 2H), 3.72 (s, 3H), 3.87 (t, J=7.5 Hz, 2H), 4.15 (dd, J=2.5, 10.0 Hz, 1H), 4.33-4.39 (m, 3H), 4.55 (m, 1H), 7.10 (s, 1H), 8.17 (s, 1H), 8.27 (d, J=1.5 Hz, 1H); MS (CI/NH3) m/z 352 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])[C:5]([CH2:11]O)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.S(Cl)([Cl:26])=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])[C:5]([CH2:11][Cl:26])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1CO)C(=O)OC
Solvent: ClCCl
Product: COC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1CCl)C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
(S)-Dimethyl 2-((7-chloro-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (2.0 g, 5.9 mmol) was dissolved in dichloromethane (35 mL). Thionyl chloride (5.0 mL) was added to the mixture. Reaction stirred at room temperature for 1.5 hours. Mixture was concentrated. Residue was dissolved in ethyl acetate. Mixture was washed twice with aqueous sodium bicarbonate and once with brine. Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as amber solid in 89% yield. MS m/e (M+H)+=359.1.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[NH:6][C:7]([CH:28](OCC)[O:29]CC)=[C:8]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])C.Cl>CC(C)=O>[CH:4]([C:5]1[NH:6][C:7]([CH:28]=[O:29])=[C:8]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:3]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1ccccc1Cl
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C=O)=C(C(=O)OCC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.5 %

Procedure:
To a solution of diethyl 2,6-bis(diethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.7 g) in acetone (17 ml) was added 6N-hydrochloric acid (1.5 ml) and stirred at room temperature for 3 hours. After removing the solvent, the residue was extracted with diethyl ether and the extract was washed with water and dried. The dolvent was removed from the extract to give diethyl 2,6-diformyl-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.35 g). The product was recrystallized from diethyl ether to give pure yellowish granules, m.p. 85° to 86° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:11][CH2:10]1)(C)(C)C.Cl>C(Cl)(Cl)Cl.O1CCOCC1>[NH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CNS(=O)(=O)c2cccc3ccccc23)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: NC[C@H]1CC[C@H](CNS(=O)(=O)c2cccc3ccccc23)CC1

Procedure:
A suspension of trans-{4-[(naphthalene-1-sulfonylamino)-methyl]-cyclohexylmethyl}-carbamic acid tert-butyl ester (25 g) in chloroform (300 ml) is treated with a 4N HCl solution in dioxane (300 ml) at 0° C. After completion, the reaction mixture is concentrated in vacuo, the residue is taken up in a 1N sodium hydroxide solution and dichloromethane. After extraction with dichloromethane, the organics are dried over sodium sulfate and concentrated to 18.5 g of trans-naphthalene-1-sulfonic acid (4-aminomethyl-cyclohexylmethyl)-amide as a white powder melting at 157-162° C. Rf (C3) 0.36.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1.[I:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([OH:25])=[C:20]([CH3:26])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.CCCCCC>[I:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=3)[N:3]=2)=[C:20]([CH3:26])[CH:19]=1
Reactant: Cc1cc(I)cc(C)c1O
Reactant: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(I)cc(C)c1Oc1ccnc(Nc2ccc(C#N)cc2)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A mixture of 4-(4-chloro-pyrimidin-2-ylamino)benzonitrile (Ludovici, et al. ibid) 2 (600.0 mg, 2.60 mmol), 4-iodo-2,6-dimethylphenol (Chabrier, et al., Ibid) (838.0 mg, 3.38 mmol) and cesium carbonate (2.20 g, 6.76 mmol) in dry DMF (12 mL) was heated to 90° C. (Zhang, et al., Tetrahedron Lett., 2002, 43, 8235-8239). After 3 hours, TLC (EtOAc/hexane=50:50) revealed a more polar product and consumption of compound 2. The mixture was poured into water (100 mL) and the product extracted into EtOAc (3×50 mL). The combined extracts were washed with brine (50 mL) followed by water (2×50 mL), and then dried over (Na2SO4) and the solvent evaporated in vacuo to furnish a residue that was subjected to silica-gel column chromatography using EtOAc/hexane (50:50) as eluent to produce 3 as a white solid (982.0 mg, 2.22 mmol, 85%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([CH:11]=O)[C:7]([F:10])([F:9])[F:8])[CH3:2].[F:14][C:15]([F:29])([F:28])[C:16]1[CH:17]=[C:18]([C@H:22]2[O:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.FC(F)(F)C1C=C([C@@H]2CO2)C=CC=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.ClCCl>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([CH2:11][N:24]1[CH2:25][CH2:26][O:27][C@H:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:28])([F:29])[F:14])[CH:17]=2)[CH2:23]1)[C:7]([F:10])([F:9])[F:8])[CH3:2]
Reactant: CCOC(=O)CC(C=O)C(F)(F)F
Reactant: FC(F)(F)c1cccc([C@@H]2CNCCO2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: FC(F)(F)c1cccc([C@@H]2CO2)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CC(CN1CCO[C@H](c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A mixture of the unpurified racemic 4,4,4-trifluoro-3-formyl-butyric acid ethyl ester from above (step b), 0.498 g (2.15 mmol) of (R)-2-(3-trifluoromethyl-phenyl)-morpholine [prepared from (R)-2-(3-trifluoromethyl-phenyl)oxirane in a similar manner to that described in Example 4 (steps b-e)], 0.162 g (2.7 mmol) of acetic acid and 8 mL of dichloromethane was stirred at room temperature. After 30 min, 0.913 g (4.3 mmol) of sodium triacetoxyborohydride was added. The mixture was stirred overnight at room temperature and then diluted with ethyl acetate and washed successively with 0.5 M sodium carbonate solution, water and then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexanes-ethyl acetate (90:10) to give 0.592 g (66%) of 4,4,4-trifluoro-3-[(R)-2-(3-trifluoromethyl-phenyl)-morpholin-4-ylmethyl]-butyric acid ethyl ester as an oil. Used as is in the next step
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[N:9]=[C:10]([CH2:12]O)[S:11][C:7]=2[CH:6]=1)=[O:4].P(Br)(Br)[Br:17].O>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[N:9]=[C:10]([CH2:12][Br:17])[S:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2nc(CO)sc2c1
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc2nc(CBr)sc2c1
Temperature: 120 °C
Yield: 38.4 %

Procedure:
To a solution of 2-Hydroxymethyl-benzothiazole-6-carboxylic acid methyl ester (0.08 g, 0.40 mmol) in 5 ml of toluene and 1 ml of DMF was added PBr3 (0.06 ml, 0.60 mmol). The reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (0.044 g, 36%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[C:10]1([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[O:9][C:8]2=[O:17].[C:18]1([C:24]2[CH:25]=[N:26][C:27]([NH:30][C:31](=O)[O:32]C3C=CC=CC=3)=[N:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[C:10]1([CH2:11][CH2:12][N:13]([C:31]([NH:30][C:27]3[N:26]=[CH:25][C:24]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:29][N:28]=3)=[O:32])[CH2:14][CH2:15]1)[O:9][C:8]2=[O:17]
Reactant: O=C1OC2(CCNCC2)c2c(F)cccc21
Reactant: O=C(Nc1ncc(-c2ccccc2)cn1)Oc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1OC2(CCN(C(=O)Nc3ncc(-c4ccccc4)cn3)CC2)c2c(F)cccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A mixture of 7-fluorospiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (150 mg), phenyl N-(5-phenyl-2-pyrimidinyl)carbamate (170 mg) and triethylamine (0.24 mL) in chloroform (2 mL) was stirred at 60° C. for 2 hours. The reaction mixture was diluted with ethyl acetate. The whole was washed with 10% citric acid aqueous solution, saturated aqueous sodium bicarbonate and saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the reaction mixture left a residue, which was recrystallized from ethyl acetate to give the subject compound (202 mg) as colorless crystals (melting point 244-246° C.).
Reaction SMILES: [CH2:1]1[CH:8](N)[C:6](=[O:7])[NH:5][C:3](=[O:4])C1.Cl.[Br:11][CH2:12][C:13]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C.CN(C)C=[O:36]>>[Br:11][CH2:12][C:13]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].[N+:23]([C:21]1[CH:20]=[CH:19][CH:14]=[C:13]([CH3:12])[C:22]=1[C:6]([OH:7])=[O:36])([O-:25])=[O:24].[Br:11][N:5]1[C:6](=[O:7])[CH2:8][CH2:1][C:3]1=[O:4]
Reactant: CN(C)C=O
Reactant: NC1CCC(=O)NC1=O
Agent: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cccc([N+](=O)[O-])c1C(=O)O
Product: O=C1CCC(=O)N1Br

Procedure:
This compound can be prepared according to the methods described in U.S. Pat. Nos. 6,281,230 and 5,635,517, the entireties of which are incorporated herein by reference. For example, the compound can be prepared through catalytic hydrogenation of 3-(4-nitro-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione. 3-(4-Nitro-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione can be obtained by allowing 2,6-dioxopiperidin-3-ammonium chloride to react with methyl 2-bromomethyl-4-nitrobenzoate in dimethylformamide in the presence of triethylamine. The methyl 2-bromomethyl-4-nitrobenzoate in turn is obtained from the corresponding methyl ester of nitro-ortho-toluic acid by conventional bromination with N-bromosuccinimide under the influence of light.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:16][CH:15]=1.[N:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:21][C:22]([C:31]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)([OH:33])[CH3:32])=[CH:23][N:24]=2)=[CH:18][CH:19]=1
Reactant: CC(=O)c1ccncc1
Reactant: Clc1ccc(-c2nccs2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(Cl)cc2)s1
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
To a solution of diisopropylamine (0.2 mL, 1.538 mmol) in dry THF (5 mL), was added 1.6M n-BuLi in hexanes (0.96 mL, 1.538 mmol) slowly at −78° C. The reaction mixture was stirred for 30 min, 2-(4-chlorophenyl)thiazole (0.2 g, 1.025 mmol) in THF (10.0 mL) added, the mixture stirred for 30 min, a solution of 1-(pyridin-4-yl)ethanone (0.17 mL, 1.538 mmol) in THF (5.0 mL) added, and the mixture was stirred for 2 hours at −78° C. The reaction mixture was quenched with saturated NH4Cl (50 mL) solution and extracted with EtOAc (2×100 mL). The organic layer was washed with water (2×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (1% methanol in dichloromethane) to obtain 1-(2-(4-chlorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol as off-white solid (0.1 g, 31% yield) in 99.9% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (d, 2H), 7.87 (d, 2H), 7.82 (s, 1H), 7.51-7.47 (m, 4H), 6.66 (s, 1H), 1.92 (s, 3H); LC-MS m/z calculated for [M+H]+ 317.04. found 317.4.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C@@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N.[CH3:18]O>>[ClH:3].[CH3:18][O:15][C:14](=[O:16])[C@@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:5]
Reactant: O=S(Cl)Cl
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: CO
Agent: N
Product: COC(=O)[C@H](N)Cc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled solution of methanol (500 ml), was charged thionyl Chloride (50 ml, 0.681 moles) at 5° C.±3° C. under nitrogen atmosphere. D-Phenyl alanine (50 grams, 0.301 moles) was added at 5° C.±3° C. and further stirred for 30 minutes. The temperature was raised to 25° C. The reaction mass was further stirred for 12 hours and concentrated at 50° C. under reduced pressure to obtain residue. Basified with aqueous ammonia, extracted with dichloromethane (250 ml×2), dried over sodium sulphate and concentrated to obtain D-phenyl alanine methyl ester hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]2[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=2)=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].OO.C(=O)([O-])[O-:28].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]2[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=2)=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]([NH2:8])=[O:28]
Reactant: O=C([O-])[O-]
Reactant: Cn1nccc1-c1cc(Cl)ccc1Oc1cc(F)c(C#N)cc1Cl
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1nccc1-c1cc(Cl)ccc1Oc1cc(F)c(C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.1 %

Procedure:
To a solution of 5-chloro-4-[4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]-2-fluorobenzonitrile (Preparation 19, 290 mg, 0.801 mmol) in DMSO (0.8 mL) was added hydrogen peroxide (545 μL, 16 mmol) followed by potassium carbonate (221 mg, 1.60 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was then purified directly using trilution reverse phase chromatography to furnish the title compound (320 mg, 105%).
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].[CH3:16][SnH:17]([CH3:19])[CH3:18]>[Hg].C1(C)C=CC=CC=1>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH2:2][Sn:17]([CH3:19])([CH3:18])[CH3:16])(=[O:5])=[O:4])=[CH:7][CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: C=CS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: C[SnH](C)C
Agent: [Hg]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(S(=O)(=O)CC[Sn](C)(C)C)cc1
Yield: 68.9 %

Procedure:
An 80 ml, two-necked, pyrex glass Schlenk reaction tube containing a Teflon coated magnetic stir bar was swept thoroughly with nitrogen and maintained in an air-free condition. The tube was charged with 9.5 g (42.5 mmoles) of 4-t-butylphenyl vinyl sulfone, 7.0 g (42.5 mmoles) of trimethyltin hydride and 10 ml. of toluene, stoppered, and placed in a 20°C water bath. The tube was irradiated for 35 hours by a 100 watt mercury vapor lamp which was situated in a large test tube and placed in the same bath 5-10 cm. from the reaction tube. Solvent was stripped off at reduced pressure on a rotary evaporator. Recrystallization of the solid product from cyclohexane gave 11.4 g of 2-(4-t-butylphenylsulfonyl)ethyltrimethylstannane, m.p. 118°-120°C. The presence of both the sulfonyl and trimethyltin groups was indicated by the strong infrared absorption bands at 1310 cm-1, 1262 cm-1, 1145 cm-1 (--SO2 --) and 770 cm-1 ((CH3)3Sn) using a KBr disc. Nuclear magnetic resonance spectroscopy (NMR) showed the following:
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([CH:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH:28]=[CH2:29])[CH:24]=4)[C:19]3=O)=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.O.[NH2:34][NH2:35]>O1CCOCC1>[C:1]1([C:7]2[C:11]([C:12]([F:13])([F:15])[F:14])=[C:10]([C:16]3[NH:34][N:35]=[C:19]4[C:18]=3[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([CH:28]=[CH2:29])[CH:22]=[CH:21][C:20]4=3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NN
Reactant: C=Cc1ccc2c(c1)CCC(C(=O)c1onc(-c3ccccc3)c1C(F)(F)F)C2=O
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)CCc1c-2n[nH]c1-c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 90 °C
Reaction time: 14 h
Yield: 74.7 %

Procedure:
To 2-(3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl)-6-vinyl-3,4-dihydronaphthalen-1(2H)-one (Preparation 22A, 0.25 g, 0.608 mmol) in a 50 mL round bottom flask was added methanol (2 mL) followed by hydrazine hydrate (0.040 mL, 0.790 mmol) at room temperature. Dioxane (2 mL) was added and the homogenous reaction mixture was heated at 90° C. for 1 h. The reaction mixture was stirred at room temperature for 14 h, concentrated under reduced pressure, azeotroped with methanol (2×10 mL, water bath heated to ˜60° C.) and kept under high vacuum for 15 min to yield 3-phenyl-4-(trifluoromethyl)-5-(7-vinyl-4,5-dihydro-2H-benzo[g]indazol-3-yl)isoxazole (0.24 g, 0.454 mmol, 74.6% yield) as a thick oil. LC/MS M+1=408.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[F:35])#[N:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:29]4[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[C:27]([F:35])[CH:28]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(C#N)c(F)c4)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-cyano-3-fluoro-phenylboronic acid following a procedure analogous to that described for Example 1; the reaction is conducted at 150° C. LC (method 4): tR=1.84 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[CH2:5]1[C:14]2[C:9](=CC=CC=2)[CH:8]=[CH:7][CH2:6]1.[OH2:15].II.[C:18]([OH:21])(=O)[CH3:19]>C([O-])(=O)C.[Ag+]>[C:1]1([OH:4])[C:2]2[CH2:19][C@H:18]([OH:21])[C@H:5]([OH:15])[CH2:6][C:7]=2[CH:8]=[CH:9][CH:14]=1
Reactant: CC(=O)O
Reactant: O
Reactant: C1=Cc2ccccc2CC1
Agent: [Ag+]
Agent: CC(=O)[O-]
Agent: II
Product: Oc1cccc2c1C[C@H](O)[C@H](O)C2

Procedure:
The corresponding cis isomer of formula II can be prepared by dissolving a dihydronaphthalene acetate of formula X in acetic acid and water (from 92 to 98% acetic acid, preferably 96% acetic acid), and then treating the solution with silver acetate and iodine and heating under nitrogen (as described for the preparation of the trans-isomer) to form the cis-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol having the formula ##STR16## after basic hydrolysis. A compound of formula XV can be converted to the 2,3-cis-1,2,3,4-tetrahydro-5-[2,3-(epoxy)propoxy]-2,3-naphthalenediol, which in turn can be converted to the 2,3-cis-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(alkylamino)-propoxy]-2,3-naphthalenediol in a manner similar to that described with respect to the preparation of the corresponding trans isomer.