Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:4])(=[O:3])=[O:2].O1CCOCC1.S(=O)(=O)=O.[CH2:15]([OH:19])[CH:16]([CH3:18])[CH3:17]>ClC(Cl)C>[CH2:15]([O:19][S:1](=[O:3])(=[O:2])[OH:4])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CO
Reactant: O=S(=O)=O
Solvent: C1COCCO1
Solvent: CC(Cl)Cl
Product: CC(C)COS(=O)(=O)O

Procedure:
609 g sulfur trioxide-dioxane addition product, which contained 143.9 g (1.8 mols) sulfur trioxide and was dissolved in 400 g dichloroethane, was reacted with 137.1 g (1.85 mols) isobutanol, and a solution of sulfuric acid monoisobutylester in dichloroethane was obtained. 66 g of this solution, which contained 49 g (0.32 mol) sulfuric acid monoisobutylester, was added dropwise within 1 hour to 59.5 g (0.33 mol) dichlorophenylphosphane. The whole was initially heated for a short while to 30° C. and then cooled with water to maintain the reaction temperature at 20° C. Next, the reaction mixture was stirred for 4 hours at room temperature, stripped under a vacuum of 1 mm mercury and at a temperature of up to 30° C. 79 g of a brown, medium-viscous crude product was obtained. 31P-NMR-spectroscopy indicated that 41% of the phosphorus used was present in the crude product in the form of benzenephosphonic acid isobutylester chloride.
Reaction SMILES: NO.C([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][N:7]=1)(=O)N.N.OO.[N-:18]=[N+]=[N-].NC(OCC)=O>>[NH2:18][C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][N:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: NC(=O)c1nsc2ccccc12
Agent: CCOC(N)=O
Agent: N
Agent: NO
Product: Nc1nsc2ccccc12

Procedure:
3-Amino-1,2-benzisothiazoles have hitherto been manufactured by other methods, since they differ in structure from the above benzisothiazoles. U.S. pat. No. 3,692,795 described a reaction of compounds of the formula ##STR1## with hydroxylamine in the presence of organic solvents at an elevated temperature, followed by hydrolysis of the resulting N-acyl-3-amino-1,2-benzisothiazoles in the presence of excess acid at the reflux temperature, treatment of the reaction mixture with alkali and extraction of the end product with, for example, ether. 3-Amino-1,2-benzisothiazole has also been prepared, using a 5-stage synthesis (Berichte der deutschen Chemischen Gesellschaft, 58 (1925), 2,095), using thionaphthene-2,3-dione, a compound difficult to obtain, as the starting material; the reaction stages comprise the manufacture of 3-carbamyl-1,2-benzisothiazole by reacting the thionaphthene-2,3-dione with ammonia and hydrogen peroxide, manufacture of the hydrazide, azide and urethane and, finally, decomposition to give 3-amino-benzisothiazole.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](N)=O)=[C:5]([SH:13])[CH:4]=1.[C:14](O)(=O)C>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]=[C:10]([CH3:14])[S:13][C:5]=2[CH:4]=1
Reactant: CC(=O)O
Reactant: NC(=O)Nc1ccc(Cl)cc1S
Agent: [Na]
Solvent: O
Product: Cc1nc2ccc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.3 %

Procedure:
112.25 parts of the sodium salt of 4-chloro-2-mercaptophenylurea, which salt is obtainable according to Example 6 of European Pat. No. 0,039,483, are suspended in 450 parts of glacial acetic acid in an autoclave. The pressure vessel is closed and heated slowly to 150° C.-160° C. in the course of 2 hours, a pressure of about 5 bar being established. The water formed is discharged continuously via a pressure release valve. The reaction is complete after 5 hours. The autoclave is cooled to room temperature and opened, the reaction mixture is allowed to run into 1000 parts of water, and the precipitated 6-chloro-2-methylbenzothiazole is isolated by filtration, washed neutral and dried in vacuo at 40° C. 85.6 parts of a product of the formula ##STR21## of melting point 85° C.-86° C. are obtained; this corresponds to a yield of 93.3% of theory, based on sodium salt employed.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[CH2:15][CH2:16][CH2:17][N:18]=[C:7]3[C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH2:19](Br)[CH:20]=[CH2:21]>>[N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[N:10]([CH2:21][CH:20]=[CH2:19])[C:9](=[O:14])[N:8]3[CH2:15][CH2:16][CH2:17][N:18]=[C:7]3[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C2=NCCCN12
Reactant: C=CCBr
Product: C=CCN1C(=O)N2CCCN=C2c2cc([N+](=O)[O-])ccc21

Procedure:
Preparation analogously to Example 29 from 10-nitro-6-oxo-2,3,4,5,6,7-hexahydropyrimido-[1,2-c]-quinazoline and allyl bromide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH:8]([CH2:14]Br)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>>[N:1]12[CH2:6][CH2:5][N:4]([CH2:3][CH2:2]1)[CH2:14][CH:8]2[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C1CNCCN1
Reactant: CCOC(=O)C(Br)CBr
Product: CCOC(=O)C1CN2CCN1CC2

Procedure:
reacting piperazine and ethyl 2,3-dibromopropanoate to form ethyl 1,4-diazabicyclo[2.2.2]octane-2-carboxylate;
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[S:32]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]3[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=3[N:10]=2)[CH2:15][CH2:16]1)=[S:32]
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: S=C=Nc1ccccc1Cl
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccccc4Cl)CC3)nc21

Procedure:
Pipemidic acid (56 mg, 0.184 mmol) and 2-chlorophenylisothiocyanate (20 μL, 0.153 mmol) were used. Purification on silica yielded compound 17 in Table 1, below (72 mg, 99%). 1H NMR (300 MHz, CDCl3) δ 9.34 (s, 1H), 8.68 (s, 1H), 7.75 (d, J=8.10 Hz, 1H), 7.44 (d, J=8.00 Hz, 1H), 7.37-7.27 (m, 2H), 7.15 (t, J=7.67 Hz, 1H), 4.35 (q, J=7.15 Hz, 2H), 4.29-4.01 (m, 8H), 1.50 (t, J=7.20 Hz, 3H) ppm.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[C:19]([F:20])=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[C:16]([F:30])[CH:15]=1>>[Cl:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=2)=[C:16]([F:30])[CH:15]=1
Reactant: CC1(C)OB(c2cc(F)c(Cl)cc2F)OC1(C)C
Reactant: COC(=O)c1c(Cl)ccnc1C
Product: COC(=O)c1c(-c2cc(F)c(Cl)cc2F)ccnc1C
Yield: 24 %

Procedure:
Prepared as described in Example 16, Part D by carrying out a Suzuki coupling between methyl 4-chloro-2-methylnicotinate (prepared as described in Example 14, Part A) and 2-(4-chloro-2,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (prepared as described in Example 16, Part A-Part C) to afford methyl 4-(4-chloro-2,5-difluorophenyl)-2-methylnicotinate (3 g, 4.13 mmol, 24% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.60 (d, J=5.2 Hz, 1H), 7.36 (m, 1H), 7.20 (m, 2H), 3.74 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[CH2:5][C:3](=[O:4])[CH2:2]1.Cl[CH:9]1[NH:14][C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:12][CH:11]=[C:10]1[CH3:22].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:12]=[C:11]([CH:5]3[C:3](=[O:4])[CH2:2][CH2:1][C:6]3=[O:7])[C:10]([CH3:22])=[CH:9][N:14]=2)=[CH:20][CH:19]=1
Reactant: O=C1CCC(=O)C1
Reactant: CC1=CN=C(c2ccc(Cl)cc2)NC1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cnc(-c2ccc(Cl)cc2)nc1C1C(=O)CCC1=O
Temperature: 150 °C
Reaction time: 0.01 h
Yield: 27 %

Procedure:
To a microwave vial was added 1,3-cyclopentadione (0.5 g, 5.1 mmol), 6-Chloro-2-(4-chloro-phenyl)-5-methyl-1,6-dihydro-pyrimidine (1.04 g, 4.3 mmol), palladium acetate (58 mg, 0.26 mmol), 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (183 mg, 0.38 mmol), potassium phosphate tribasic (2.49 g, 11.7 mmol) and 1,4-dioxane (10 ml). This was heated in the microwave for 30 minutes at 150° C. on a normal setting with a pre-stir of 25 seconds. The resulting slurry was diluted with ethyl acetate (10 ml) and 2M hydrochloric acid (10 ml) before filtering through celite. The filter cake was washed with further ethyl acetate (10 ml) and 2M hydrochloric acid (10 ml). The resulting biphasic mixture was separated and the aqueous layer was extracted with further ethyl acetate (2×10 ml). The combined organic layers were then dried with magnesium sulphate, filtered and stripped to dryness to yield a dark yellow solid. This was purified by normal phase chromatography (gradient system of 100% dichloromethane−5% methanol:dichloromethane) to give 2-[2-(4-Chloro-phenyl)-5-methyl-pyrimidin-4-yl]-cyclopentane-1,3-dione as a yellow solid (348 mg, 1.16 mmol, 22% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[C@H:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:20][C:21](=O)[C:22]([F:25])([F:24])[F:23])C>C(O)C>[CH2:1]([O:8][C:9](=[O:17])[C@H:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[NH:11][C:21](=[O:20])[C:22]([F:25])([F:24])[F:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@@H](CCC(=O)O)C(=O)OCc1ccccc1
Solvent: CCO
Product: O=C(O)CC[C@H](NC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
100 g (421.5 mmol) of L-glutamic acid-mono-benzyl ester is dissolved in a mixture that consists of 1000 ml of trifluoroacetic acid ethyl ester/500 ml of ethanol, and it is stirred for 24 hours at room temperature. It is evaporated to the dry state, and the residue is crystallized from diisopropyl ether.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4](=[O:29])[C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[C:7]([F:27])[C:6]=1[F:28].[OH-].[Na+]>CO.O1CCCC1.O>[F:11][C:10]1[C:9]([F:12])=[C:8]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[C:7]([F:27])=[C:6]([F:28])[C:5]=1[C:4](=[O:29])[C:3]([OH:30])=[O:2]
Reactant: COC(=O)C(=O)c1c(F)c(F)c(OCCOc2ccc3ccccc3c2)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1c(F)c(F)c(OCCOc2ccc3ccccc3c2)c(F)c1F
Yield: 38.3 %

Procedure:
A solution of 2,3,5,6-tetrafluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from dichloromethane-hexane provided 0.185 g of purified 2,3,5,6-tetrafluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a yellow solid, mp 146°-148° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:13]C)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([I:12])=[CH:7]2.Br.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([I:12])=[CH:7]2
Reactant: COc1cc(Br)c2ncc(I)cc2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc(Br)c2ncc(I)cc2c1

Procedure:
A mixture of 8-bromo-3-iodo-6-methoxyquinoline (0.92 g) and conc HBr (11 ml) is heated at reflux during 3 days until no starting material can be detected. After addition of 2 M aq NaOH to reach pH 5 the mixture is extracted with ethyl acetate, the organic phase washed with brine and dried over anhydrous Na2SO4 Evaporation of the organic phase gives 8-bromo-3-iodo-6-hydroxyquinoline as a crude product which is used as such in the next step. 1H NMR (DMSO-d6) δ ppm: 10.50 (1H, br s); 8.9 (1H, d); 8.73 (1H, d); 7.70 (1H, d); 7.15 (1H, d). (M+1)+: 350/352.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:5](=[CH:6][C:7]([N+:19]([O-:21])=[O:20])=[C:8]([CH3:18])[C:9]=2[C:15]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:16])[N:4]=1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Reactant: C1CNCCN1
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)N3CCNCC3)c2nc1OC
Reaction time: 2 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and piperazine 138 mg (1.60 mmol). Reaction was continued for 2 hours, and the crude product was eluted through a flash column (8% methanol in chloroform): 250 mg (86%), mp 150-152° C.; 1H NMR (CDCl3): δ 8.30 (s, 1H), 4.05 (s, 3H), 3.96 (s, 3H), 3.81 (t, 4H, J=4.9, 5.1 Hz), 2.96 (t, 4H, J=5.1, 4.9 Hz), 2.54 (s, 3H), 1.84 (br s, 1H); MS (APCI): m/z 362 (M+H). Anal. Calcd. for C16H19N5O5: C, 53.18; H, 5.30; N, 19.38. Found: C, 53.08; H, 5.22; N, 18.82.
Reaction SMILES: [CH:1]([C@:3]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:44])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH2:43][C:27]4([CH2:30][C:29]([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:28]4)[CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[NH2:55][CH2:56][CH2:57][CH2:58][N:59]1[CH2:64][CH2:63][S:62](=[O:66])(=[O:65])[CH2:61][CH2:60]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[O:65]=[S:62]1(=[O:66])[CH2:61][CH2:60][N:59]([CH2:58][CH2:57][CH2:56][NH:55][CH2:1][C@:3]23[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:4]2[C@@H:5]2[C@@:18]([CH3:21])([CH2:19][CH2:20]3)[C@@:17]3([CH3:22])[C@@H:8]([C@:9]4([CH3:44])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]3[CH2:43][C:27]5([CH2:30][C:29]([C:31]([O:33][CH:34]([CH3:35])[CH3:36])=[O:32])([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[CH2:28]5)[CH:26]=3)=[CH:11][CH2:10]4)[CH2:7][CH2:6]2)[CH2:64][CH2:63]1
Reactant: NCCCN1CCS(=O)(=O)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To a solution of diisopropyl 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylate (100 mg, 0.146 mmol) from Step 3 in DCE (2 mL) was added acetic acid (0.017 mL, 0.291 mmol) and 4-(3-aminopropyl)thiomorpholine 1,1-dioxide (56.0 mg, 0.291 mmol). The mixture was stirred at RT for 2 h, then to the mixture was added sodium triacetoxyborohydride (154 mg, 0.728 mmol) and it was stirred for 24 hours. The mixture was diluted with 7 mL of sat. NaHCO3 and extracted with dichloromethane (3×7 mL). The organic layers were combined and dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified over a silica gel column eluted with mixture of ethyl acetate and hexanes. The fractions containing the expected product were combined to give the title compound as a white solid (90 mg, 71.6% yield). MS: m/e 863.9 (M+H)+, 3.03 min (method 2). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.85 (s, 1H), 5.54-5.43 (m, 1H), 5.14-4.96 (m, 2H), 4.68 (d, J=2.0 Hz, 1H), 4.57 (s, 1H), 3.12-2.90 (m, 9H), 2.83-2.63 (m, 7H), 2.63-2.50 (m, 4H), 2.42 (td, J=11.0, 5.8 Hz, 1H), 2.28-2.17 (m, 1H), 2.13-2.03 (m, 1H), 1.98-1.29 (m, 17H), 1.27-1.18 (m, 16H), 1.13 (s, 3H), 1.09-1.00 (m, 10H), 0.97 (s, 3H), 0.84-0.75 (m, 3H).
Reaction SMILES: [C:1]([O:9][C:10]1[C:11](=[O:21])[C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][Si:23]([CH:26](C)[C:27](O)=O)([CH3:25])[CH3:24].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>C(#N)C.O.C(OCC)C.[N+]([O-])([O-])=O.[Ag+]>[C:1]([O:9][C:10]1[C:11](=[O:21])[C:12]2[C:17]([C:18](=[O:20])[C:19]=1[CH2:27][CH2:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)[Si](C)(C)C
Reactant: O=C(OC1=CC(=O)c2ccccc2C1=O)c1ccccc1
Agent: [Ag+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: C[Si](C)(C)CCC1=C(OC(=O)c2ccccc2)C(=O)c2ccccc2C1=O
Temperature: 65 °C
Yield: 46.4 %

Procedure:
2-Benzoyloxy-1,4-naphthoquinone (1.39 g, 5 mmol), trimethylsilylpropionic acid (1.09 g, 7.5 mmol) and silver nitrate (523 mg, 3 mmol) were suspended in 40 ml aqueous acetonitrile (1:1) and then heated to 65° C. Ammonium persulphate (1.71 g, 7.5 mmol) in 20 ml water was added slowly and dropwise over 30 minutes to the mixture. The reaction mixture was stirred at this temperature for a further hour and then cooled, diluted with diethyl ether and the aqueous phase removed. The organic extract was washed with saturated sodium bicarbonate solution, then brine and dried over anhydrous magnesium sulphate. After concentration in vacuo, the crude material was chromatographed using petroleum ether/ethyl acetate as eluent to give 2-benzoyloxy-3-(2'-trimethylsilylethyl)-1,4-naphthoquinone (879 mg) which was recrystallised from methanol, m.pt.: 92-95° C. NMR peaks at: 184.4, 178.2, 150.3, 142.6, 134.0, 133.8, 132.1, 130.9, 126.6, 126.6; 18.8, 16.2; -2.0; 163.8, 128.0, 128.7, 130.4, 134.2 (PhCO).
Reaction SMILES: [OH:1][CH:2]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=[O:11])[C:5]([CH3:12])=[CH:4][CH:3]1[O:13][CH3:14].[C:15]1(=[O:25])[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.CC1C=CN=C(N)C=1C.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[C:18]([C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[C:15]([O:1][CH:2]1[C:8]([CH3:9])([CH3:10])[CH2:7][C:6](=[O:11])[C:5]([CH3:12])=[CH:4][CH:3]1[O:13][CH3:14])=[O:25])([OH:20])=[O:19]
Reactant: COC1C=C(C)C(=O)CC(C)(C)C1O
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cc1ccnc(N)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COC1C=C(C)C(=O)CC(C)(C)C1OC(=O)c1ccccc1C(=O)O
Temperature: 90 °C
Yield: 53 %

Procedure:
To a solution of 5-hydroxy-4-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU154) obtained in Example 4 (1.98 g, 10 mM) in pyridine (10 ml), phthalic anhydride (1.78 g, 12 mM) and dimethyl aminopyridine (0.05 g) were added and warmed to 90° C. for three hours, left to cool, poured onto ice-water, alkalified with potassium carbonate and extracted with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was crystallized from a mixed solvent of ethyl acetate and hexane to obtain 1.80 g (53%) of 5-(2-carboxybenzoyloxy)-4-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU218) as colorless plates. Melting point: 158.0° to 158.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][CH2:14][Cl:15].[Cl-].[NH4+]>[Fe].CO>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][CH2:14][Cl:15])[NH2:8]
Reactant: O=[N+]([O-])c1ccc(OCCCCl)c(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ccc(OCCCCl)c(Br)c1

Procedure:
2-bromo-1-(3-chloropropoxy)-4-nitrobenzene (1.3 g), ammonium chloride (1.3 g) and iron (1.3 g) were added to a mixed solvent of methanol (8 mL) and distilled water (4 mL), and the mixture was heated under reflux for 2 hours. The reaction mixture was filtered through cerite, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, and washed with distilled water and saturated brine. The organic phase was dried with anhydrous sodium sulfate, concentrated and dried to obtain the target substance (0.92 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Li]CCCC.CN(CCN(C)C)C.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH:38]=[O:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[NH4+].[Cl-]>C1COCC1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH:38]([OH:39])[C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a −78° C. solution of 1-bromo-4-trifluoromethylbenzene (32.9 g, 146 mmol) in anhydrous THF (500 mL) was added n-BuLi (2.5M in Hexanes, 63.4 mL, 158 mmol) dropwise. The mixture was stirred at −78° C. for 1 hour. TMEDA (22.1 mL, 146 mmol) was added followed by 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (26.0 g, 122 mmol) and the mixture was stirred at −78° C. for 1.5 hours. Saturated aqueous NH4Cl (5000 mL) was added and the mixture was warmed to room temperature. The phases were separated and the aqueous phase was extracted with EtOAc (2×300 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude material was crystallized (CH2Cl2/Hexanes) to give 4-[hydroxy-(4-trifluoromethylphenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (29.0 g). The mother liquor was purified by column chromatography to give further product (3.8 g) as a white solid (combined yield: 32.8 g, 75%). 1H NMR (CDCl3) δ 1.15-1.32 (m, 3H), 1.44 (s, 9H), 1.68-1.81 (m, 1H), 1.89 (d, 1H, J=13.8 Hz), 1.98 (br s, 1H), 2.54-2.68 (m, 2H), 4.12 (br s, 2H), 7.43 (d, 2H, J=8.7 Hz), 7.62 (d, 2H, J=8.7 Hz).
Reaction SMILES: [NH:1]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C@H]2CC[C@H](CC(OC)=O)CC2)=[CH:9][CH:8]=1)=[O:5])[NH2:2].COC(=O)C(NC1C=CC([S:37]([C:40]([CH3:46])([CH3:45])[C:41]([O:43][CH3:44])=[O:42])(=[O:39])=[O:38])=CC=1)=O>>[NH:1]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([S:37]([C:40]([CH3:46])([CH3:45])[C:41]([O:43][CH3:44])=[O:42])(=[O:39])=[O:38])=[CH:11][CH:12]=1)=[O:5])[NH2:2]
Reactant: COC(=O)C(=O)Nc1ccc(S(=O)(=O)C(C)(C)C(=O)OC)cc1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Product: COC(=O)C(C)(C)S(=O)(=O)c1ccc(NC(=O)C(=O)NN)cc1

Procedure:
The procedure described for Intermediate 43 (part iv) was followed starting with methyl 2-[(4-{[methoxy(oxo)acetyl]amino}phenyl)sulphonyl]-2-methylpropanoate to give the title compound; 1H NMR δ 1.56 (s, 6H), 3.67 (s, 3H), 4.77 (s, 2H), 7.77 (d, 2H), 8.11 (d, 2H); MS m/e (M+Na)+ 366.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[N:13]O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[C:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([NH2:13])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ON=C1CCC(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: NC1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
To a solution of 4-phenylcyclohexanone oxime (0.310 g, 1.64 mmol) in THF (3 ml) was added 1M lithium aluminum hydride in THF (3.44 ml, 3.44 mmol), and the reaction was heated to reflux for 4 hours. The reaction was allowed to cool to ambient temperature, and water (0.131 ml), 1M NaOH (0.131 ml) and additional water (0.393 ml) were added, and the reaction was stirred for 30 minutes. The reaction was diluted with EtOAc and filtered. The filtrate was concentrated to yield 100 mg of the title compound (34.8% yield) as a 1:1 mixture of cis and trans isomers.