Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=O)[CH2:3]1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Li+].[Cl-].[CH3:27][C@@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[NH:29]1>C1COCC1>[CH3:27][C@@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[N:29]1[C:8]([CH:4]1[CH2:5][CH2:6][CH2:7][C:2](=[O:1])[CH2:3]1)=[O:10]
Reactant: O=C1CCCC(C(=O)O)C1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)C1CCCC(=O)C1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Racemic 3-oxocyclohexanecarboxylic acid (1.0 g, 7.03 mmol) was dissolved in THF (27.1 mL). To this solution was added triethylamine (1.9 mL, 13.5 mmol) followed by pivaloyl chloride (0.8 mL, 6.5 mmol) at −20° C. The resulting mixture was stirred at −20° C. for 1 h. After that, LiCl (0.252 g, 5.9 mmol) and (4R,5S)-4-methyl-5-phenyloxazolidin-2-one (0.959 g, 5.4 mmol) were added to the solution at −20° C. The reaction mixture was warmed to room temperature and stirred overnight, before the reaction was quenched with 0.2 N HCl. The THF was removed and the resulting mixture was partitioned by 0.2 N HCl and EtOAc. The organic layer was collected and washed with brine, dried (MgSO4) and concentrated. The resulting residue was purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×250 mm, isocratic elution with Method 1-MeOH/water containing 0.1% trifluoroacetic acid as defined above, 51% B over 30 min, 25 mL/min, 220 nM: the first peak (retention time=15.3 min) was (4R,5S)-4-methyl-3-((S)-3-oxocyclohexanecarbonyl)-5-phenyloxazolidin-2-one, Int-8A, (LCMS=302.0 [M+H]+), and the second peak (retention time=19.6 min) was (4R,5S)-4-methyl-3-((R)-3-oxocyclohexanecarbonyl)-5-phenyloxazolidin-2-one, Int-8B, LCMS=324.1 [M+Na]+ by comparison to the R-3-oxocyclohexanecarboxylic acid case (Aust. J. Chem., 34:2231 (1981)).
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.[C:37]([O:41][C:42]([NH:44][C@@H:45]([CH:49]([CH3:51])[CH3:50])[C:46](O)=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38].Cl.CN(C)CCCN=C=NCC.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][C:46](=[O:47])[C@@H:45]([NH:44][C:42]([O:41][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:43])[CH:49]([CH3:51])[CH3:50])[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
The solution of 300 mg (0.59 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-1 3-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one in 3 ml of pyridine was admixed with 14 mg of 4-dimethylaminopyridine, 383 mg of (S)-2-tert-butoxycarbonylamino-3-methylbutanoic acid and 130 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and the mixture was stirred at 23° C. for 16 hours. The mixture was poured into water and extracted repeatedly with dichloromethane, and the combined organic extracts were washed with water and saturated sodium chloride solution and dried over sodium sulphate. The residue obtained after filtration and solvent removal was purified by chromatography. 314 mg (75%) of the title compounds were isolated as a colourless foam.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4]S.COC(OC)CCl.[Na].[CH2:16]([SH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([S:23][C:3]([O:6][CH3:7])([O:2][CH3:1])[CH3:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(CS)OC
Reactant: SCc1ccccc1
Agent: COC(CCl)OC
Agent: [Na]
Product: COC(C)(OC)SCc1ccccc1

Procedure:
Several processes for making 2-mercaptoacetaldehyde dimethylacetal (I, R1 =R2 =CH3) are reported by Parham et al., J. Am. Chem. Soc. 75, 2065-2069 (1953). These processes involve reaction of 2-chloroacetaldehyde dimethyl acetal with (1) benzylmercaptan sodium salt to produce benzyl-(1,1-dimethoxy ethyl)sulfide which was then reduced with sodium/ammonia to the desired acetal; (2) sodium sulfide to form 1,1,1',1'-tetramethoxyethyl disulfide followed by reduction of said disulfide using sodium/ammonia or lithium aluminum hydride; and (3) sodium polysulfide to give a mixture of polysulfides which was reduced with sodium/ammonia. A fourth process described in said reference comprises the action of potassium hydrosulfide on diethyl or dimethyl bromoacetal to produce the corresponding dialkyl mercaptoacetal.
Reaction SMILES: C1O[C:4]([CH:7]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9][C:8]2=[O:18])([NH:5]O)[O:3]C1.Cl>CO>[OH:3][C:4]1[C:7]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9][C:8]=2[O:18][N:5]=1
Reactant: COC(=O)N1CCC(=O)C(C2(NO)OCCO2)CC1
Agent: Cl
Solvent: CO
Product: COC(=O)N1CCc2onc(O)c2CC1
Temperature: 80 °C
Yield: 58.4 %

Procedure:
To a solution of (IV) (12.0 g; 0.044 mol) in methanol (45 mL) was added at 80° C. concentrated hydrochloric acid (45 mL). After continued heating at 80° C. for 15 min, the reaction mixture was evaporated to ca. 40 mL and then extracted with chloroform (3×100 mL). The combined organic phases were dried (MgSO4), filtered and evaporated. The residue was recrystallized from ethyl acetate to give (III) (5.45 g; 58%), M.p. 127.0°-128.0° C. Anal. C9H12N2O4.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].CC(C)([O-])C.[K+].Cl[C:12]1[C:17]([C:18]#[N:19])=[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([C:26]#[N:27])=[C:14]([S:28][CH2:29][C:30]2[N:31]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[S:33][CH:34]=2)[N:13]=1>CN(C=O)C>[Cl:41][C:38]1[CH:37]=[CH:36][C:35]([C:32]2[S:33][CH:34]=[C:30]([CH2:29][S:28][C:14]3[C:15]([C:26]#[N:27])=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:17]([C:18]#[N:19])=[C:12]([O:4][CH2:1][CH2:2][CH3:3])[N:13]=3)[N:31]=2)=[CH:40][CH:39]=1
Reactant: CCCO
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccccc2)c1C#N
Reaction time: 0.25 h

Procedure:
37 μl (0.501 mmol) of 1-propanol are initially charged in 2 ml of DMF, 20 mg (0.184 mmol) of potassium tert-butoxide are added and the mixture is stirred for 15 minutes, after which 100 mg (0.167 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulphanyl)-4-phenylpyridine-3,5-dicarbonitrile, dissolved in 2 ml of DMF, are added. The reaction mixture is stirred at room temperature for one hour and then purified by preparative HPLC (acetonitrile/water: 10:90→95:5, with 0.1% TFA added). This gives 13 mg (15% of theory) of the target compound.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:30])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:14][CH:13]=2)[CH:6]=1.[Li+].[OH-].C1(C)C=CC=CC=1.CO>O1CCCC1>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[CH:10]=[CH:9][CH:8]=2)=[O:30])=[CH:13][CH:14]=1
Reactant: COC(=O)Cc1cccc(C(=O)c2ccc(OCc3ccc4ccccc4n3)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(O)Cc1cccc(C(=O)c2ccc(OCc3ccc4ccccc4n3)cc2)c1
Yield: 75.5 %

Procedure:
To a solution of the ester (5 g, 12.16 mmole) of Step G, in dry tetrahydrofuran (66 mL) is added 1N-LiOH (37 mL, 37 mmole) and the mixture is stirred under nitrogen at room temperature for 2.5 hours (TLC, toluene-MeOH 9:1). The tetrahydrofuran is evaporated and the residue is diluted with water, acidified (to pH 6.5) with 10% acetic acid and extracted with ethyl acetate (3×). The extracts are washed with brine, dried (MgSO4) and evaporated to dryness. The crude product (4.94 g, pale yellow solid) is recrystallized from ethyl acetate to provide 3.65 g (75%) of the pure title compound (white solid, m.p. 146°-147° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:27]2([OH:34])[CH2:32][CH2:31][NH:30][CH2:29][C@@H:28]2[OH:33])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[CH:14][C:13]2=[CH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[N:12]2[N:11]=1.[F:35][CH2:36][CH2:37]I.C(=O)(O)[O-].[Na+].C(#N)C>>[F:35][CH2:36][CH2:37][N:30]1[CH2:31][CH2:32][C@@:27]([C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]3[N:15]=[CH:14][C:13]4=[CH:16][CH:17]=[C:18]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[O:25][CH3:26])[N:12]4[N:11]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)([OH:34])[C@@H:28]([OH:33])[CH2:29]1
Reactant: FCCI
Reactant: COc1cc([C@@]2(O)CCNC[C@@H]2O)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1cc([C@@]2(O)CCN(CCF)C[C@@H]2O)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Yield: 41.1 %

Procedure:
A mixture of (±)-(3S,4S)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidine-3,4-diol (42.00 mg, 0.0910 mmol), 1-fluoro-2-iodo-ethane (18.99 mg, 0.109 mmol), and sodium bicarbonate (9.174 mg, 0.109 mmol) in acetonitrile (1.000 mL, 19.15 mmol) was heated to reflux for overnight. After evaporation of volatiles under reduced pressure, the product was isolated by preparative reverse phase hplc (Gilson). Free base was obtained by catch/release work-up on acidic resin cartridge (Strata-X-C from Phenomenex) to afford (±)-(3S,4S)-1-(2-fluoro-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidine-3,4-diol as a yellow foam (19 mg, 41%). 1H-NMR (CDCl3) δ 8.66 (s, 1H), 8.36 (d, J=8.4 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.45 (m, 2H), 7.11 (m, 3H), 7.01 (d, J=4.6 Hz, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.83 (d, J=4.6 Hz, 1H), 4.67 (m, 1H), 4.56 (m, 1H), 4.19 (dd, J=10.0; 4.8 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.00 (m, 1H), 2.85 (m, 1H), 2.75 (m, 3H), 2.55 (m, 1H), 2.44 (m, 1H), 2.07 (m, 1H), 1.90 (br s, 1H), 1.87 (m, 1H); LC/MS (ESI+): 508.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([NH:14][C@H:15]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1)=[O:13])[N:6]=[CH:5]2.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([NH:14][C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)=[O:13])[N:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)c2ncc3cc(Cl)ccc3n2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(N[C@H]1CCNC1)c1ncc2cc(Cl)ccc2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl 3-(6-chloroquinazoline-2-carboxamido)pyrrolidine-1-carboxylate (0.086 g, 0.23 mmol, 1 eq) in 1 mL of p-dioxane was added a solution of 4.0 M HCl in dioxane (0.29 mL, 1.2 mmol, 5 eq). After stirring at 60° C. for 1 h, the mixture was concentrated to provide (S)-6-chloro-N-(pyrrolidin-3-yl)quinazoline-2-carboxamide which was carried on without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].[CH2:14](Br)[CH:15]=[CH2:16].CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH2:16]([O:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CC(C)=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1[N+](=O)[O-]
Temperature: 55 °C
Yield: 93.2 %

Procedure:
A mixture of 2,5-dinitrophenol (7.36 g, 40 mmol), allyl bromide (4.84 g, 40 mmol), acetone (75 mL), 1methylpyrrolidinone (3 mL) and potassium carbonate (11.0 g, 80 mmol) was heated to 50-60° C. for 22 h. The mixture was cooled to room temperature and filtered and the solid rinsed with ethyl acetate. The filtrate was concentrated and recrystallized from isopropanol-hexane (1:1) to give 2-allyloxy-1,4-dinitrobenzene as yellow crystals (8.36 g, mp 66.5-68° C.).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH:28]([C:37]1([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:39][CH2:38]1)[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)(C(C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH:28]([C:37]2([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:39][CH2:38]2)[CH2:27][OH:26])=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NC1(C(CO[Si](C)(C)C(C)(C)C)Cc2ccc(Cl)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(CO)Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
TBAF (2.80 g, 8.86 mmol) was added to a stirred solution of tert-butyl 1-(1-(tert-butyldimethylsilyloxy)-3-(4-chlorophenyl)propan-2-yl)cyclopropylcarbamate (1.95 g, 4.43 mmol) in THF (80 mL). The mixture was stirred at room temperature for 2 hours. Saturated NH4Cl solution was added to the reaction. The mixture was extracted with ether. The combined organic layer was washed with brine, dried and concentrated. The residue was purified by column (hexane:EtOAc, 20:1 to 4:1) to give tert-butyl 1-(1-(4-chlorophenyl)-3-hydroxypropan-2-yl)cyclopropylcarbamate (1.25 g, 87%) as a white solid. LCMS: 325.9 [M+H+] (APCI+); Rf: 3.75 min.
Reaction SMILES: [S:1]1[C:5]([C:6](=[O:8])[CH3:7])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[S:1]1[C:5]([C:6](=[O:8])/[CH:7]=[CH:15]/[N:16]([CH3:18])[CH3:17])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: CC(=O)c1cc2ccccc2s1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1cc2ccccc2s1
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of 1-(benzo[b]thiophen-2-yl)ethanone (1 g) in dimethoxy-N,N-dimethyl-methanamine (10 mL) was refluxed for 6 h and then cooled to rt. The precipitate was filtered and washed with diethyl ether to afford the title compound (1.1 g, 84%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][CH2:16][CH:17]([C:20]([O:22]C)=[O:21])[CH2:18][CH2:19][C:13]=3[O:12][N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[K+].O>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]3[CH2:15][CH2:16][CH:17]([C:20]([OH:22])=[O:21])[CH2:18][CH2:19][C:13]=3[O:12][N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)C1CCc2onc(-c3ccc(C(C)C)cc3)c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1ccc(-c2noc3c2CCC(C(=O)O)CC3)cc1
Temperature: 20 °C
Reaction time: 68 h
Yield: 73.4 %

Procedure:
0.286 g (0.00091 mol) of methyl 5,6,7,8-tetrahydro-3-(4-isopropylphenyl)-4H-cyclohept[d]isoxazole-6-carboxylate was dissolved in 15 ml of methanol, 0.15 g (0.0027 mol) of potassium hydroxide and 2 ml of water were added and the mixture was stirred at 20° C. for 68 hours. The methanol was removed by evaporation. Water was added and the mixture was extracted once with diethyl ether. The aqueous layer was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with sodium chloride solution and dried over magnesium sulfate. Evaporation gave a residue which was crystallized from methylcyclohexane to give 200 mg of 5,6,7,8-tetrahydro-3-(4-isopropylphenyl)-4H-cyclohept[d]isoxazole-6-carboxylic acid of melting point 109°-111° C.
Reaction SMILES: C(O[C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:12][CH:11]=1)C.[NH3:29]>>[C:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][CH2:18][CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][NH:6][CH2:5][C:4](=[O:28])[NH2:29])=[CH:15][CH:14]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: CCOC(=O)CNCCOc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Reactant: N
Product: CC(C)(C)OC(=O)NCCCCc1ccc(OCCNCC(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2 (0.27 g, 0.685 mmol) dissolved in 7 N methanolic ammonia (25 mL) was stirred in a sealed tube at room temperature overnight. After this time, TLC analysis indicated that the reaction was complete. The reaction mixture was concentrated and further dried under vacuum to afford the desired product 3 (0.25 g, quantitative yield) as a yellow viscous oil which was used directly without further purification. m/z (ESI) 366.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][CH:14](O)[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl>O1CCCC1.CCOCC>[CH3:13][CH:14]([O:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([F:1])=[CH:3][C:4]=1[CH3:12])[CH3:15]
Reactant: CC(C)O
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(F)c([N+](=O)[O-])cc1OC(C)C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
A solution of 4-fluoro-2-methyl-5-nitrophenol (D16) (0.85 mmol, 145 mg) in tetrahydrofuran (5 mL) was treated with 2-propanol (0.85 mmol, 51.1 mg, 1 eq), diphenyl-2-pyridylphosphine (1.28 mmol, 335.7 mg, 1.5 eq) and di-tert-butyl azodicarboxylate (1.28 mmol, 293.5 mg, 1.5 eq) under argon at room temperature. The mixture was stirred for 3 h then a solution of hydrogen chloride in ether (1M) was added and the mixture was stirred for 1 h. A gummy precipitate appeared. The mixture was concentrated under reduced pressure and the residue was dissolved in ether, washed twice with 5M aqueous hydrogen chloride solution for 30 min then washed twice with 10% aqueous sodium carbonate solution. The organic (ether) phase was dried and concentrated under reduced pressure to give a residue which was purified by chromatography on silica (ethyl acetate/petrol ether) to give the title compound as a pale yellow solid (0.53 mmol, 115 mg, 63% yield).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]#[C:4][C:5]([F:8])([F:7])[F:6].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[N:20][OH:21])[CH3:19])=[CH:14][CH:13]=1.CO.CC(C)([O-])C.[K+]>O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[N:20][OH:21])[CH3:19])=[C:16]([C:4]([C:5]([F:8])([F:7])[F:6])=[CH:3][C:2]([F:10])([F:9])[F:1])[CH:17]=1
Reactant: FC(F)(F)C#CC(F)(F)F
Reactant: CC(=NO)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=NO)c1ccc(Cl)cc1C(=CC(F)(F)F)C(F)(F)F

Procedure:
Hexafluoro-2-butyne is slowly bubbled through a 55°-60° C. solution of p-chloroacetophenone oxime (17.0 g, 0.10 mol), methanol (80 mL) and potassium tert-butoxide (1.12 g, 0.01 mol) over a 5 hour period. The solvent is removed in vacuo to obtain a liquid which is poured into water and extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give an oil. The oil is chromatographed using silica gel and eluted with ethylacetate in methylene chloride to 5% ethyl acetate in methylene chloride to give p-chloro-0-[1,2-bis(trifluoromethyl)vinyl]acetophenone oxime, vinyl-(Z) as a yellow liquid (21.5 g, 65%) and 2-(p-chlorophenyl)-4,5-trans-bis(trifluoromethyl)-1-pyrrolin-5-ol as a white solid (2.35 g, mp 152.5°-153° C., 7%).
Reaction SMILES: [Na].[CH3:2][N:3]1[S:7](=[O:9])(=[O:8])[NH:6][C:5](=[O:10])[CH:4]1[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].[F:16][C:17]1[N:22]=[C:21]([F:23])[C:20]([F:24])=[C:19](F)[C:18]=1[F:26].C1OCCOCCOCCOCCOC1>C(#N)C>[F:23][C:21]1[C:20]([F:24])=[C:19]([N:6]2[C:5](=[O:10])[CH:4]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:3]([CH3:2])[S:7]2(=[O:9])=[O:8])[C:18]([F:26])=[C:17]([F:16])[N:22]=1
Reactant: CC(C)CCC1C(=O)NS(=O)(=O)N1C
Reactant: Fc1nc(F)c(F)c(F)c1F
Agent: C1COCCOCCOCCOCCO1
Agent: [Na]
Solvent: CC#N
Product: CC(C)CCC1C(=O)N(c2c(F)c(F)nc(F)c2F)S(=O)(=O)N1C
Yield: 40.6 %

Procedure:
To a mixture of the sodium salt of 5-methyl-4-(3-methylbutyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1 g; 4.13 mmol, prepared by treatment with sodium methoxide), pentafluoropyridine (0.54 ml, 4.97 mmol), and 0.91 g (4.13 mmol) of 15-Crown-5 suspended in 30 ml of acetonitrile was refluxed for 17 hours. The mixture was cooled, concentrated in vacuo, and the residue extracted with methylene chloride, and the organic layer was washed with water (3x) and brine. After drying over sodium sulfate, the organic layer was concentrated in vacuo and a crude product was purified by flash chromatography (10% ethyl acetate in hexane) to afford 0.62 g (41%) of 2-(2,3,5,6-tetrafluoro-4-pyridyl)-5-methyl-4-(3-methylbutyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: R1 =(CH2)2CH(CH3)2 ; R2 =H; R3 =CH3), as a solid, m.p. 80.5°-81.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2].[O:19](S(C(F)(F)F)(=O)=O)[S:20]([C:23]([F:26])([F:25])[F:24])(=O)=[O:21].Cl>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:21])=[O:19])=[CH:11][C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCOC(=O)C(OCC)c1c(F)cc(O)cc1F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(OCC)c1c(F)cc(OS(=O)(=O)C(F)(F)F)cc1F
Temperature: 0 °C
Yield: 97.9 %

Procedure:
A solution of (RS)-(2,6-difluoro-4-hydroxy-phenyl)-ethoxy-acetic acid ethyl ester (500 mg) in pyridine (5 ml) was placed under N2 and cooled to 0° C. Tf2O (813 mg) was added and the resulting solution was left to stir in the ice bath. After 18 h the reaction mixture was poured on a mixture of 50 ml 1 N HCl and ice. The product was extracted with AcOEt. The organic layer was washed with more 1 N HCl (50 ml), water (50 ml) and brine (30 ml). The aqueous layers were extracted with more AcOEt. After drying (MgSO4) the solvent was evaporated to obtain 738 mg (98%) of (RS)-(2,6-difluoro-4-trifluoromethanesulfonyloxy-phenyl)-ethoxy-acetic acid ethyl ester. Yellow oil. MS 393.4 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([CH2:25][OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].Cl>C1(C)C=CC=CC=1.CN(C)CCN(C)C.O1CCCC1>[CH3:40][S:41]([O:26][CH2:25][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:27])[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:32])=[C:18]2[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CO)ccc2c1=O
Agent: CN(C)CCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(COS(C)(=O)=O)ccc2c1=O
Yield: 101 %

Procedure:
To a mixture of tert-butyl[6-(hydroxymethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.33 g, 0.75 mmol), triethylamine (0.18 mL, 1.1 mmol), N,N,N′,N′-tetramethyletylenediamine (0.011 mL, 0.075 mmol), toluene (6 mL) and tetrahydrofuran (6 mL) was added dropwise a solution of methanesulfonyl chloride (0.088 mL, 1.1 mmol) in toluene, (4 mL) under ice-cooling. The mixture was stirred under ice-cooling for 30 min, the reaction mixture was poured into 0.1N hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL). The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl)methyl methanesulfonate (0.39 g, 100%) as colorless powder.