Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:5]([CH3:10])([CH2:8][OH:9])[CH2:6][OH:7])([CH2:3][CH3:4])[CH3:2].[CH3:11][CH:12]1[CH:17]=[C:16]([CH3:18])[CH2:15][CH2:14][CH:13]1[CH:19]=O>>[CH:1]([C:5]1([CH3:10])[CH2:8][O:9][CH:19]([CH:13]2[CH2:14][CH2:15][C:16]([CH3:18])=[CH:17][CH:12]2[CH3:11])[O:7][CH2:6]1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)C(C)(CO)CO
Reactant: CC1=CC(C)C(C=O)CC1
Product: CCC(C)C1(C)COC(C2CCC(C)=CC2C)OC1

Procedure:
An aqueous NaOH solution (30%, 420 g) was added at room temperature into a stirred mixture of 2,3-dimethyl pentanal (325 g, prepared as above in EXAMPLE II) and aqueous formaldehyde solution (CH2O) (30%, 722 g) while the reaction temperature was allowed to rise up to about 80° C. due to the exothermic reaction. After the addition was completed, the reaction mixture was cooled to about 40° C. The organic phases was separated and fractionally distilled to afford 2-sec-butyl-2-methyl-propane-1,3-diol (277 g). 2-sec-Butyl-2-methyl-propane-1,3-diol was reacted with 2,4-dimethyl-cyclohex-3-enecarbaldehyde to afford 5-sec-butyl-2-(2,4-dimethyl-cyclohex-3-enyl)-5-methyl-[1,3]dioxane according to previous disclosure (See, for example, U.S. Pat. No. 6,444,637).
Reaction SMILES: [O:1]([C:8]([O:10][CH2:11][CH2:12][N:13]([CH2:15][CH2:16][O:17][C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[CH3:14])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](#N)C.[CH3:30][O:31][S:32]([O:35]C)(=[O:34])=[O:33]>CCOCC>[CH3:30][O:31][S:32]([O-:35])(=[O:34])=[O:33].[O:1]([C:8]([O:10][CH2:11][CH2:12][N+:13]([CH2:15][CH2:16][O:17][C:18]([O:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19])([CH3:27])[CH3:14])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: COS(=O)(=O)OC
Reactant: CN(CCOC(=O)Oc1ccccc1)CCOC(=O)Oc1ccccc1
Solvent: CCOCC
Product: COS(=O)(=O)[O-]
Product: C[N+](C)(CCOC(=O)Oc1ccccc1)CCOC(=O)Oc1ccccc1

Procedure:
To a 1000 ml three-necked round-bottomed flask fitted with a reflux condenser, magnetic stirrer, internal thermometer, addition funnel, and argon inlet are added N,N-bis[2-((phenoxycarbonyl)oxy)ethyl]-N-methylamine (100.00 g, 0.278 mol), acetonitrile (270 ml), and dimethylsulfate (35.93 g, 0.278 mol) over 10 min. After addition is complete, the mixture is heated to reflux for 2 h. The cooled mixture is treated with ether (500 ml). The product precipitates from the mixture after approximately 15 min to give 4 as a white powder, 126.26 g (93%): mp 85°-87° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:48][C:49](Br)=[CH:50][CH:51]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:48][C:49]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=4)[CH:14]=[C:13]([C:27]([F:28])([F:29])[F:30])[N:12]=3)[CH:10]=2)=[CH:50][CH:51]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (Example G.12) (0.570 g, 0.88 mmol), commercially available 5-bromo-thiophene-2-sulfonic acid tert-butylamide (0.295 g, 0.99 mmol), tetrakis(triphenylphosphine)palladium (0.061 g, 0.046 mmol) in toluene (6 mL) was heated under reflux conditions for 16 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (290 mg, 57%). MS (ISP) 575.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)=[O:4].[N+](C1C=CC=C([N+]([O-])=O)C=1)([O-])=O.[F:30]OC(F)(F)F>FC(Cl)(Cl)Cl>[F:30][C:10]12[CH2:11][CH:12]3[CH2:14][CH:8]([CH2:7][C:6]([O:5][C:3](=[O:4])[C:2]([F:16])([F:17])[F:1])([CH2:13]3)[CH2:15]1)[CH2:9]2
Reactant: O=C(OC12CC3CC(CC(C3)C1)C2)C(F)(F)F
Reactant: FOC(F)(F)F
Agent: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Solvent: FC(Cl)(Cl)Cl
Product: O=C(OC12CC3CC(CC(F)(C3)C1)C2)C(F)(F)F
Yield: 45.9 %

Procedure:
A solution of 1-trifluoroacetoxyadamantane (1.0 g, 4.0 mmole, prepared by reacting adamantan-1-ol with trifluoroacetic anhydride in dry pyridine) in fluorotrichloromethane (10 ml), containing m-dinitrobenzene (80 mg, 0.48 mmole), was treated with trifluoromethyl hypofluorite (4.5 mmole) at -25° for 24 hours, air being admitted to the reaction vessel during this time. The product was recovered in a similar manner to that described in Example 3 and was chromatographed on silica (100 g). Elution with chloroform:hexane (1:5) afforded unreacted starting material (152 mg), while elution with chloroform: hexane (1:4) gave liquid 3-fluoro-1-trifluoroacetoxyadamantane (489 mg) which appeared homogeneous by g.l.c. This product sublimed at 70° (bath)/1 mm Hg to give a crystalline solid m.p. 28°-32°; vmax (film) 1780 cm-1 ; PMR 1.5-2.6 (m, adamantyl protons); FMR φ*+76.2 (s, CF3COO--) and +133.5 (broad s) ppm.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)(=O)=O.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[F:30][C:21]([F:20])([F:29])[C:22]1[CH:23]=[CH:24][C:25]([S:28][CH:6]2[CH2:7][CH2:8][CH:9]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:10][CH2:11]2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(OS(C)(=O)=O)CC1
Reactant: FC(F)(F)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCC(Sc2ccc(C(F)(F)F)cc2)CC1
Temperature: 130 °C
Yield: 43 %

Procedure:
4-[(tert-Butoxycarbonyl)amino]cyclohexyl methanesulfonate (0.7 g, 2.39 mmol), 4-(trifluoromethyl)thiophenol (1.28 g, 7.16 mmol) and K2CO3 (1.32 g, 9.54 mmol) was dissolved in THF (21 ml) and the reaction mixture was heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was diluted with water (300 ml) and extracted with EtOAc (2×150 ml). The combined organic phases were dried over Na2SO4, filtrated and evaporated. The residue was purified by silica gel column chromatography using a 85:15 mixture of heptane:EtOAc to give the title compound (0.386 g, 43%) as a 50:50 mixture of cis and trans isomers. 1H-NMR (CDCl3, 500 MHz): δ 7.55-7.50 (m, 4H), 7.45-7.40 (m, 4H), 4.70-4.23 (m, 2H), 3.69-3.36 (m, 3H), 3.16-3.05 (m, 1H), 2.13-2.04 (m, 4H), 1.95-1.64 (m, 9H), 1.54-1.40 (m, 1H), 1.45 (ds, 18H), 1.30-1.15 (m, 2H); 13C-NMR (CDCl3, 125 MHz): δ 155.4, 141.1, 140.7, 130.5, 129.9, 128.6, 128.5, 128.2, 126.0, 125.9, 125.9, 125.9, 125.4, 123.2, 79.5, 49.1, 47.9, 44.8, 43.8, 33.4, 32.0, 29.2, 29.1, 28.6.
Reaction SMILES: C([Li])CCC.[C:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:8])[CH3:7].[Cl:16][CH:17]([C:20]1[O:25][C:24](=[O:26])[C:23]2[CH:27]=[CH:28][CH:29]=[C:30]([C:31]([F:34])([F:33])[F:32])[C:22]=2[N:21]=1)[CH2:18][CH3:19].Cl>CCCCCC.O1CCCC1.O>[Cl:16][CH:17]([CH2:18][CH3:19])[C:20]([NH:21][C:22]1[C:30]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](=[O:26])[CH2:7][C:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:8])=[O:25]
Reactant: CCC(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Reactant: CC(=O)Nc1ccccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCC(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2ccccn2)cccc1C(F)(F)F
Temperature: -70 °C
Yield: 19.4 %

Procedure:
314.3 ml of a 1.4M solution of n-butyllithium in hexane were added to a solution of 30 g of 2-acetylamino pyridine in 886 ml of tetrahydrofuran. After cooling to -70° C., a solution of 32 g of 2-(1-chloropropyl)-8-trifluoromethyl-4H-3,1-benzoxazine-4-one [prepared by the process of Example 10 of Belgian Pat. No. 896,941] in 230 ml of tetrahydrofuran was added and the solution was poured into 500 ml of 2N hydrochloric acid and 600 ml of water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried and concentrated to dryness under reduced pressure. The residue was taken in ethyl ether, separated and dried to obtain 9.1 g of 2-[(2-chloro-1-oxobutyl)-amino]-β-oxo-N-(2-pyridinyl)-3-trifluoromethyl benzene propanamide melting at 137° C.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[Na][Na].[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1>>[C:1]([C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:4][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:18][CH:19]=1)([OH:3])=[O:2]
Reactant: O=C1OCc2ccccc21
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: [Na][Na]
Product: O=C(O)Cc1ccc(OCc2ccccc2C(=O)O)cc1

Procedure:
Those 6,11-dihydro-11-oxodibenz[b,e]oxepins of this invention wherein the substituent at the 2-position is 4-hydroxy-3-pyrrolin-2,5-dione-3-yl may be prepared according to the following general reaction scheme: ##STR9## wherein R2 and R3 are as previously defined, by treating an appropriately substituted R2 and/or R3 phthalide with the disodium salt of p-hydroxyphenylacetic acid at 170°-250° C. for 2-3 hours to obtain the corresponding 4-(2-carboxybenzyloxy)phenylacetic acid. The disodium salt of p-hydroxyphenylacetic acid is formed by treating the acid with aqueous sodium hydroxide and evaporating the mixture to dryness. The phthalide is then added and the reaction is carried out as described above. The carboxybenzyloxyphenylacetic acid so produced then is cyclized by stirring with trifluoroacetic anhydride in a pressure bottle at 70°-80° C. for 1-3 hours. The intermediate R2 and/or R3 substituted 6,11-dihydro-11-oxodibenzo[b,e]oxepin-2-acetic acid trifluoroacetic acid mixed anhydride then is treated with base and acidified in order to obtain the free acid. The free acid then is treated with thionyl chloride followed by ammonia to form the corresponding acetamide which is treated with diethyl oxalate in dimethylformamide in the presence of potassium t-butoxide to form the desired R2 and/or R3 substituted 2-(4-hydroxy-Δ3 -pyrrolin-2,5-dione-3-yl)-6,11-dihydro-11-oxodibenz[b,e]oxepin of formula VI.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=4)[NH:14][C:13]=3[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:26][C:27]([O:29]CC)=[O:28].[ClH:32]>C1COCC1.CCO.[OH-].[Na+]>[Cl:32][C:8]1[CH:7]=[C:6]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=3)[N:14]([CH2:26][C:27]([OH:29])=[O:28])[C:13]=2[CH3:22])[C:5]2[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1ccc2[nH]c(C)c(-c3ccnc4cc(Cl)ccc34)c2c1
Reactant: Cl
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc2c(c1)c(-c1cc(Cl)nc3ccccc13)c(C)n2CC(=O)O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
7-chloro-4-(2,5-dimethyl-1H-indol-3-yl)quinoline (370 mg) was dissolved in dry THF (8 ml), and maintained under a nitrogen atmosphere. The reaction was cooled to −5° C. before slowly adding NaH (53 mg, 60% dispersion in mineral oil) portion-wise. Allowed the mixture to warm to RT and stirred for 40 minutes. The mixture was cooled to 0° C. before adding ethyl bromoacetate (0.147 ml) dropwise. After stirring for 1 hour at 15° C., the reaction was diluted with EtOH (5 ml) and 10% aqueous NaOH solution (3 ml). Stirring over night at RT converted the ethyl ester to the acid. Acidified with 1M aqueous HCl and extracted with EtOAc (×3). The combined organics were washed with water and brine then dried (Na2SO4) and the solvent was evaporated under reduced pressure. Further purification was by solid phase extraction using NH2 sorbent (6.5 g), eluting CH3CN and 20% AcOH/CH3CN. The solvent was evaporated under reduced pressure and the residue was azeotroped using toluene. This gave the title compound (378 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[OH:12])[O:8][C:7](=[O:14])[CH:6]=[C:5]2[CH3:15].Cl.[NH:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:18]([NH2:20])=[NH:19].Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[NH:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][C:6]2[C:7](=[O:14])[O:8][C:9]3[C:4]([C:5]=2[CH3:15])=[CH:3][C:2]([F:1])=[C:11]([OH:12])[C:10]=3[F:13])=[O:26])=[CH:23][CH:22]=1)[C:18]([NH2:20])=[NH:19]
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: Cc1cc(=O)oc2c(F)c(O)c(F)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(OC(=O)c2ccc(NC(=N)N)cc2)c(=O)oc2c(F)c(O)c(F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a pale yellow solution of 6,8-difluoro-7-hydroxy-4-methylcoumarin (Compound 5, 0.13 g, 0.61 mmol) in THF (5 mL) under air at room temperature is added a solution of 4-guanidinobenzoic acid hydrochloride (132 mg, 0.61 mmol) in 4 mL water, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC; 125 mg, 0.65 mmol). The resulting solution is stirred at room temperature overnight, followed by the addition of more EDC (100 mg). After two hours, TLC analysis indicates the starting materials are consumed. Volatiles are removed in vacuo, and a portion of the residue (0.61 g of pale yellow powder) is purified by chromatography on SEPHADEX LH-20 resin using water:dioxane (1:1) as eluant to give nonfluorescent Compound 35 as a colorless powder: Rf =0.30 (MeCN:H2O:AcOH 90:5:5). Upon treatment with ammonia vapor, a TLC spot corresponding to Compound 35 becomes blue fluorescent.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].C1COCC1.[CH3:12][C:13]1[C:14]([NH:24][C:25](=[O:27])[CH3:26])=[CH:15][C:16]2[CH2:17][CH2:18][CH2:19][C:20](=O)[C:21]=2[CH:22]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH3:12][C:13]1[C:14]([NH:24][C:25](=[O:27])[CH3:26])=[CH:15][C:16]2[CH2:17][CH2:18][CH2:19][C:20](=[CH2:1])[C:21]=2[CH:22]=1
Reactant: CC(=O)Nc1cc2c(cc1C)C(=O)CCC2
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C1CCCc2cc(NC(C)=O)c(C)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
In a mechanically stirred 50 L vessel, Et2O (12.5 L) was added to methyltriphenylphosphonium bromide (1.81 kg, 5.06 mol). KOtBu (566 g, 5.06 mol) was added. The mixture was heated to reflux for about 1 h. THF (5 L) was added followed by addition of N-(3-methyl-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (75) (475 g, 2.19 mol). The mixture was warmed to reflux overnight. The reaction was diluted with Et2O (5 L). The resulting mixture was cooled to rt and then poured into water (30 L). After stirring for about 1 h at rt, the layers were left standing to separate. The aqueous layer was removed and the organic mixture was filtered rinsing with Et2O. The solids were dried in vacuo to afford N-(3-methyl-5-methylene-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (76) (284 g, 60% yield). 1H NMR (300 MHz, DMSO): δ 9.24 (s, 1H), 7.49 (s, 1H), 7.24 (s, 1H), 5.48 (m, 1H), 4.86 (m, 1H), 2.65 (m, 2H), 2.49 (m, 2H), 2.35 (s, 3H), 2.06 (s, 3H), 1.75 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:19])[C:4]([CH2:11][CH2:12][CH:13]([CH3:18])[CH2:14][CH2:15][CH2:16][OH:17])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[CH3:20][C:21](C)=O.S(=O)(=O)(O)[OH:25]>O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:10][C:5]1[C:6](=[O:9])[C:7]2[C:2]([C:3](=[O:19])[C:4]=1[CH2:11][CH2:12][CH:13]([CH3:18])[CH2:14][CH2:15][C:16]([OH:25])=[O:17])=[CH:1][CH:21]=[CH:20][CH:8]=2
Reactant: CC(C)=O
Reactant: O=S(=O)(O)O
Reactant: CC1=C(C)C(=O)C(CCC(C)CCCO)=C(C)C1=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: CC1=C(CCC(C)CCC(=O)O)C(=O)c2ccccc2C1=O
Reaction time: 0.17 h

Procedure:
To 0.05 part of 2,3,5-trimethyl-6-(6'-hydroxy-3'-methylhexyl)-1,4-benzoquinone (Formula (III) wherein R=H3C) obtained in Reference Example 4 in 300 volume parts of acetone is added, at 0°C, 10 volume parts of solution prepared by dissolving 267 parts of chromium trioxide in 230 volume parts of 98 % sulfuric acid and diluting the solution with water to make a total of 1000 volume parts. The mixture is stirred for 10 minutes and, following the dilution with 2000 volume parts of water extracted with 300 volume parts of diethyl ether. The solvent is distilled off and the residue is recrystallized from ligroine. The described procedure gives 0.05 part of 2,3,5-trimethyl-6-(5'-carboxy-3'-methylpentyl)-1,4-benzoquinone (Formula (I), wherein R=H3C; Z=H) as yellowish needles melting at 58°C-61°C.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC)(=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[SH:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[S:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22](=[O:30])[N:21]=2)[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cc(C2CCCN2C(=O)c2ccccc2)ccn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCCC1c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 83.8 %

Procedure:
4-(1-Benzoyl-2-pyrrolidinyl)-2-pyridinecarbonitrile (0.42 g, 1.5 mmol) and methyl thiosalicylate (1.03 g, 6.1 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 14 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (4:1, v/v) were collected and concentrated to give the titled compound (0.52 g, 82%) as amorphous crystals.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][S:10]1(=[O:20])=[O:19].O.CCOC(C)=O>CN(C=O)C>[Br:8][C:17]1[CH:16]=[CH:15][C:14]2[NH:9][S:10](=[O:19])(=[O:20])[CH2:11][CH2:12][C:13]=2[CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=S1(=O)CCc2ccccc2N1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=S1(=O)CCc2cc(Br)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
NBS (1.5 g, 8.2 mmol) was added to a solution of 3,4-dihydro-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.5 g, 8.2 mmol) in DMF (15 mL). The reaction mixture was stirred overnight at ambient temperature followed by addition of water (200 mL) and EtOAc (100 mL). The two layers were separated and the aqueous phase was extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (200 mL×3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane=1:3) to afford 6-bromo-3,4-dihydro-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.7 g, 79% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11](=[NH:22])[NH:12][C:13]2[C:18]([Br:19])=[CH:17][C:16]([F:20])=[CH:15][C:14]=2Br)[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:22][C:14]3[CH:15]=[C:16]([F:20])[CH:17]=[C:18]([Br:19])[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(C(=N)Nc2c(Br)cc(F)cc2Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2nc3c(Br)cc(F)cc3[nH]2)c1
Temperature: 80 °C
Yield: 16.6 %

Procedure:
A mixture of 1-[N-(2,6-dibromo-4-fluoro-phenyl)-carbamimidoyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.134 g, 0.290 mmol), CuI (6.00 mg, 0.0290 mmol), Cs2CO3 (0.464 g, 1.43 mmol), and DMF (2 mL) was heated to 80° C. for 1 h. The mixture was cooled to 23° C., diluted with EtOAc (3 mL), filtered through Celite®, and rinsed with EtOAc. The filtrate was washed with aqueous 1M HCl and water, dried (MgSO4), filtered, and concentrated under reduced pressure. Dichloromethane was added and the resulting precipitate was collected by filtration to yield the titled compound (17.0 mg, 17%). MS (ESI/CI): mass calcd. for C13H10BrFN4O2, 353.2; m/z found, 354.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.86 (s, 1H), 8.95 (s, 1H), 8.36 (s, 1H), 7.45 (dd, J=9.6, 2.3 Hz, 1H), 7.32 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: S1C=C[CH:3]=[C:2]1[C@:6]1(O[C@H](CO)[C@@H:11]([O:12][C@@H:13]2[O:30][C@H](COCC3C=CC=CC=3)[C@H](OC(=O)C)[C@H](OC(=O)C)[C@H:14]2OC(=O)C)[C@H:9](O)[C@@:8]1([C@@H:48]1O[C@@H](C)[C@@H](OCC2C=CC=CC=2)[C@@H](OCC2C=CC=CC=2)[C@@H]1OCC1C=CC=CC=1)NC(=O)C)O.CN(S(F)(F)F)C.BrN1C(=O)CCC1=O>ClCCl>[C:13]([O:12][CH2:11][CH3:9])(=[O:30])[CH3:14].[CH3:3][CH2:2][CH2:6][CH:8]([CH3:48])[CH3:9]
Reactant: CC(=O)N[C@]1([C@@H]2O[C@@H](C)[C@@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[C@@H](O)[C@H](O[C@@H]2O[C@H](COCc3ccccc3)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@@H](CO)O[C@]1(O)c1cccs1
Agent: CN(C)S(F)(F)F
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCCC(C)C
Product: CCOC(C)=O
Temperature: 25 °C

Procedure:
Compound [18] (0.25-6.2 g, 0.2-4.91 mmol) is taken up in dry dichloromethane (3-85 ml) and, at -78° C., dimethylaminosulfur trifluoride (0.08-1.93 g, 0.6-14.73 mmol) and N-bromosuccinimide (0.05-1.23 g, 0.28-6.87 mmol) are added, and the mixture is warmed to room temperature. After washing with saturated sodium bicarbonate solution, the mixture is concentrated and the byproducts of the reaction are removed by silica gel chromatography (stepwise gradient: ethyl acetate/isohexane) giving compound [22] (0.33-6.47 g, 0.72-14.4 mmol, about 80% yield). The reaction product is dissolved in dichloromethane and, at -78° C., o-nitrobenzyl alcohol (0.08-1.88 g, 0.5-12.28 mmol), 4 Å molecular sieves (0.1-7.5 g), silver trifluoromethanesulfonate (0.18-4.42 g, 0.7-17.19 mmol) and hafnocene dichloride (0.27-6.53 g, 0.7-17.19 mmol) are added, and the mixture is allowed to warm to room temperature. Filtration is followed by washing with saturated sodium bicarbonate solution and concentration. The crude product obtained in this way is purified by chromatography on silica gel (dichloromethane/methanol gradient) and dissolved in dry methanol (3-80 ml), and catalytic amounts of sodium methylate (prepared from 0.001-0.09 g of sodium methylate (prepared from 0.001-0.09 g of sodium in 0.2-2.5 ml of methanol) are added. After the reaction is complete, the mixture is neutralized with an acidic ion exchanger (0.2-6.5 g Amberlite IR-120, H+ -form). Evaporation results in compound [23]. FAB-MS: M+H+ =1186. NMR data consistent with Nicolaou et al., J. Am. Chem. Soc. 114:3127 (1992) and C. W. Hummel, Ph.D. Dissertation, University of California, San Diego (1993).