Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([OH:17])[CH:16]=[C:12]2[CH:11]=[N:10][N:9]=1.[I:18]Cl.O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([OH:17])[C:16]([I:18])=[C:12]2[CH:11]=[N:10][N:9]=1
Reactant: Oc1cc2cnnc(-c3ccccc3F)n2n1
Reactant: ClI
Solvent: O
Solvent: CC(=O)O
Product: Oc1nn2c(-c3ccccc3F)nncc2c1I
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 95 %

Procedure:
To a stirred mixture of 7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazin-2-ol (0.5014 g, 2.18 mmol) in glacial acetic acid (10 ml) was added dropwise a 1.0 M solution of iodine monochloride in glacial acetic acid (3.26 ml, 3.26 mmol) and the mixture was stirred at room temperature for a total of 1.25 h. Water (40 ml) was then added and the resulting solid was collected by filtration, washed with water, and dried under vacuum at 60° C. to yield 0.7345 g (95%) of the title compound as a pale brown solid; 1H NMR (360 MHz, d6 -DMSO) δ 7.42-7.49 (2H, m), 7.71 (1H, m), 7.79 (1H, m), 9.26 (1H, s), 12.48 (1H, s); MS (ES+) m/e 357 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.OC[N:39]1[C:47](=[O:48])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]1=[O:49].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH2:31][N:39]2[C:47](=[O:48])[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:49])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C1c2ccccc2C(=O)N1CO
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCN4C(=O)c5ccccc5C4=O)cc3C)c2cc1OC
Yield: 59 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-(hydroxymethyl)-1,3-isoindolinedione (41 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (48 mg, yield 57%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)=[O:7])[N:3]=[CH:2]1.[CH2:20]([Mg]Br)[CH3:21]>CCOCC>[NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)([OH:7])[CH2:20][CH3:21])[N:3]=[CH:2]1
Reactant: CC[Mg]Br
Reactant: COc1ccc2cc(C(=O)c3c[nH]cn3)ccc2c1
Solvent: CCOCC
Product: CCC(O)(c1ccc2cc(OC)ccc2c1)c1c[nH]cn1

Procedure:
In a similar manner to that described in Example 1-(iv), the reaction of (1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone (0.60 g) with a solution of ethyl magnesium bromide in ether (3.0 M, 2.4 ml) was carried out to give the titled compound (0.28 g) as a colorless solid.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:30]2[CH2:35][C@H:34]([CH3:36])[O:33][C@H:32]([CH3:37])[CH2:31]2)=[C:22]([F:29])[C:23](F)=C([CH:27]=1)C#N)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[C:44]([NH:47][OH:48])(=O)[CH3:45].C[N:50](C=O)C>CCOC(C)=O>[NH2:50][C:44]1[C:45]2[CH:27]=[C:20]([CH2:19][OH:18])[C:21]([N:30]3[CH2:31][C@H:32]([CH3:37])[O:33][C@H:34]([CH3:36])[CH2:35]3)=[C:22]([F:29])[C:23]=2[O:48][N:47]=1
Reactant: CN(C)C=O
Reactant: CC(=O)NO
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C#N)c(F)c2F)C[C@H](C)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2c(CO)cc3c(N)noc3c2F)C[C@H](C)O1
Reaction time: 12 h

Procedure:
To an ice-bath cooled and stirred solution of 5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3-difluorobenzonitrile (Intermediate 6, 500 mg, 0.96 mmol) in DMF was added t-BuOK (161 mg, 1.4 mmol) followed by acetohydroxamic acid (108 mg, 1.4 mmol). The mixture was brought to room temperature and stirred for 12 hours. The reaction mixture was diluted with EtOAc and washed successively with 1 N HCl (1×250 mL), water and brine. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified over silica gel flash column using a gradient of ethyl acetate in pet. ether to give the title compound as a white solid. Yield: 200 mg, (70%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1(=[O:17])[NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)=O>O.C1(C)C=CC=CC=1>[C:24]([N:16]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:17])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1CCCCCN1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCCCN1C(=O)c1ccccc1
Temperature: 25 °C
Yield: 88 %

Procedure:
The comparison involves using soda instead of the Hunig base: 226.3 g of ε-caprolactam, 159.0 g of sodium carbonate and 1290 g of toluene are introduced into a 4 1 l flask. Under reflux, 281.1 g of benzoyl chloride are added dropwise over the course of 2 h at a rate such that CO2 evolution proceeds in a controlled manner. The mixture is then refluxed for a further 4 h. The reaction mixture is cooled to room temperature using water cooling (for about 15 min.), admixed with 500 g of water and vigorously stirred, and the aqueous phase is then separated off in a separating funnel. The toluene phase that remains is evaporated in a rotary evaporator at a temperature of 60° C. and residual toluene is removed in a vacuum drying oven, giving pale oil, which crystallizes upon cooling. M.p.: 69° C. The N-benzoylcaprolactam is obtained in a yield of 88% and a purity of 98%. The CO2 produced must be collected and disposed of separately.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:25])[C:8]2[CH:9]=[C:10]([F:24])[C:11]([F:23])=[C:12]3[O:17][CH2:16][C:15]4([CH2:21][CH2:20][CH2:19][CH2:18]4)[N:14]([CH:22]=1)[C:13]=23)=[O:5])C>C(O)(=O)C.O.OS(O)(=O)=O>[F:24][C:10]1[C:11]([F:23])=[C:12]2[O:17][CH2:16][C:15]3([CH2:21][CH2:20][CH2:19][CH2:18]3)[N:14]3[CH:22]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:25])[C:8]([CH:9]=1)=[C:13]23
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC21CCCC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC21CCCC1
Temperature: 0 °C
Yield: 86.1 %

Procedure:
A solution of ethyl-9′,10′-difluoro-7′-oxospiro[cyclopentane-1,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylate (13.2 g, 38 mmol) in a mixture of acetic acid/water/H2SO4 (8:6:1 v/v, 75 mL) was heated under reflux for 2 h. The reaction mixture was poured into ice water. A precipitate formed and was collected by filtration, washed with water and then dried to give the title compound (10.5 g, 32.7 mmol, 86%) as a light yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[O:17])=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:28])[C:3]([OH:29])=[O:2])=[CH:10][CH:9]=1)=[O:17]
Reactant: COC(=O)C(=O)c1ccc(OCCCNC(=O)c2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(OCCCNC(=O)c2ccc3ccccc3c2)cc1
Yield: 58.7 %

Procedure:
A mixture of 4-[[3-(2-naphthoylamino)propyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.76 g) in hot methanol (10 mL) and sufficient tetrahydrofuran to dissolve the solids was treated with 1N sodium hydroxide (4.0 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was mixed with water, acidified with excess 2N hydrochloric acid, and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from acetone-hexane provided 0.43 g of 4-[[3-(2-naphthoylamino) propyl]oxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 169°-170° C.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].[F:13][CH:14]([F:49])[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]1[N:27]2[CH:28]=[C:29]([C:32]3[CH:33]=[N:34][C:35]([C:38]4[CH2:43][CH2:42][CH:41]([C:44]([O:46][CH3:47])=[O:45])[CH2:40][CH:39]=4)=[N:36][CH:37]=3)[CH:30]=[CH:31][C:26]2=[N:25][C:24]=1[CH3:48]>CS(C)=O.C(Cl)Cl>[F:49][CH:14]([F:13])[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]1[N:27]2[CH:28]=[C:29]([C:32]3[CH:33]=[N:34][C:35]([C:38]45[CH2:7][CH:43]4[CH2:42][CH:41]([C:44]([O:46][CH3:47])=[O:45])[CH2:40][CH2:39]5)=[N:36][CH:37]=3)[CH:30]=[CH:31][C:26]2=[N:25][C:24]=1[CH3:48]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C1CC=C(c2ncc(-c3ccc4nc(C)c(Cc5ccccc5OC(F)F)n4c3)cn2)CC1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)C1CCC2(c3ncc(-c4ccc5nc(C)c(Cc6ccccc6OC(F)F)n5c4)cn3)CC2C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
A solution of trimethylsulfoxonium iodide (176 mg, 0.79 mmol) and potassium tert-butoxide (85 mg, 0.75 mmol) in DMSO (2 mL) was stirred at 50° C. for 45 minutes. A solution of methyl 4-[5-(3-{[2-(difluoromethoxy)phenyl]methyl}-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidin-2-yl]cyclohex-3-ene-1-carboxylate (prepared in an analogous manner to that described for Example 39, 100 mg, 0.2 mmol) in DMSO (2 mL) was added and the mixture was stirred at 50° C. for 4 h, then at room temperature for 3 days. The reaction mixture was diluted with DCM (10 mL) and washed with water (3×3 mL). The aqueous washes were combined and further extracted with DCM (2×3 mL). The organic extracts were combined, dried over sodium sulfate and evaporated. The resulting crude brown residue was diluted with DCM (3 mL) and washed with 1N aqueous NaOH solution (3×1 mL). The organic phase was dried over sodium sulfate and evaporated. The resulting pale brown residue was purified by preparative TLC, eluting with 1% MeOH in DCM, to afford the title compound (38.3 mg, 37%) as an off-white solid. Method B HPLC-MS: MH+ m/z 519, RT 1.80 minutes.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](SC)=[CH:16][CH:15]=1)=[O:13].[CH2:22]([O:24][C:25](Cl)=[O:26])[CH3:23]>O1CCCC1>[CH2:22]([O:24][C:25](=[O:26])[CH2:11][C:12](=[O:13])[C:14]1[CH:19]=[CH:18][C:17]([CH3:1])=[CH:16][CH:15]=1)[CH3:23]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CSc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Lithium bis(trimethylsilyl)amide (20% in tetrahydrofuran, 203.6 ml, 217 mmol) was added dropwise to a stirred solution of 4-methylthioacetophenone (20.2 g, 121 mmol) in dried tetrahydrofuran (300 ml) at −20° C. and stirring was continued for 1 hour at −20° C. Ethylchloroformate (19.8 g, 182 mmol) was added dropwise to the stirred reaction mixture at −20° C. and stirring was continued for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethylacetate. The organic extract was washed with water, brine, dried over anhydrous sodium sulphate and concentrated to dryness in vacuum. The crude product thus obtained was purified by column chromatography to yield the title compound as viscous oil (16.45 g, 56.8%). 1H-NMR (DMSO-d6): δ 1.15–1.19 (t, 3H), 2.54 (s, 3H), 4.07–4.11 (q, 2H), 4.13 (s, 2H), 7.36–7.39 (d, 2H), 7.85–7.88 (d, 2H). MS m/z: 239 (M+). Preparation 4 Synthesis of 2-amino-6-(4-methylphenyl)-1,3-oxazin-4-one
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[C:30](F)=[CH:31][C:32]([F:55])=[C:33]([S:35]([N:38]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])[C:39]2[S:43][N:42]=[CH:41][N:40]=2)(=[O:37])=[O:36])[CH:34]=1>CS(C)=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C:30]2[CH:31]=[C:32]([F:55])[C:33]([S:35]([N:38]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=3[O:53][CH3:54])[C:39]3[S:43][N:42]=[CH:41][N:40]=3)(=[O:36])=[O:37])=[CH:34][C:29]=2[Cl:28])=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)ccc2O)CC1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(Cl)cc3C3CCN(C(=O)OC(C)(C)C)CC3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
To a solution of tert-butyl 4-(5-chloro-2-hydroxyphenyl)piperidine-1-carboxylate (Preparation 231, 0.500 g, 0.0014 mol) and potassium carbonate (0.579 g, 0.00419 mol) in dimethyl sulfoxide (5.0 mL) was added 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 333, 0.644 g, 0.0014 mol). The mixture was stirred at room temperature under nitrogen for 1.5 hours before diluting with ethyl acetate (10.0 mL) and water (10.0 mL). The aqueous layer was extracted with ethyl acetate (3×10.0 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel column) eluting with ethyl acetate:heptane (gradient 0:1 to 35:65, by volume) to afford 1.03 g of tert-butyl 4-[5-chloro-2-(2-chloro-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}-5-fluorophenoxy)phenyl]piperidine-1-carboxylate as a white solid. This material was dissolved in dichloromethane (5.0 mL), trifluoroacetic acid (1.0 mL) added and reaction stirred for 16 hours at room temperature under nitrogen. Methanol (5.0 mL) was added to afford a white precipitate. This suspension mixture was filtered through a Celite™ pad and washed with methanol. The filtrate was concentrated in vacuo and the residue was diluted with methanol (2.0 mL), dichloromethane (2.0 mL) and saturated aqueous sodium bicarbonate (4.0 mL) and stirred for 1 hour at room temperature to afford a white solid. The suspension was filtered and the solid washed with water and diethyl ether. The collected solid was recrystallised from hot acetonitrile and ethanol (1:1 v/v) to afford the title compound as a white solid, 0.1929 mg, 27% yield.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][N:6]([CH3:23])[C:7]([C:9]1[S:17][C:16]2[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=2[C:10]=1[O:20][CH2:21][CH3:22])=[O:8])[CH3:2].[CH2:26](Br)[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:24]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([CH3:23])[C:7]([C:9]1[S:17][C:16]2[CH:15]=[C:14]([CH3:18])[N:13]([CH2:26][C:27](=[O:28])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:12](=[O:19])[C:11]=2[C:10]=1[O:20][CH2:21][CH3:22])=[O:8])[CH3:25]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOc1c(C(=O)N(C)CCN(CC)CC)sc2cc(C)[nH]c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1c(C(=O)N(C)CCN(CC)CC)sc2cc(C)n(CC(=O)c3ccccc3)c(=O)c12
Temperature: 60 °C
Reaction time: 15 h
Yield: 12.9 %

Procedure:
A mixture of the compound of Example 145 (300 mg, 0.821 mmol), phenacyl bromide (196 mg, 0.985 mmol), potassium carbonate (272 mg, 1.97 mmol) and DMF (5 mL) was stirred at 60° C. for 15 hr. After cooling, the mixture was diluted with water (10 mL), and extracted with ethyl acetate. The extract was washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/hexane=1/9 to 10/0) to give the title compound (51.2 mg, 13%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.I[CH2:23][CH2:24][CH3:25]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[N:9]1[CH2:23][CH2:24][CH3:25]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3F)c(=O)c12
Reactant: CCCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c2c(c(=O)n1-c1ccccc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
A mixture of a (4S,7R)-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 12; 150 mg, 0.52 mmol) and 1-iodopropane (103 μL, 1.05 mmol) in N,N-dimethylformamide (2 mL) in a microwave reaction tube was heated to 100° C. and stirred for 18 h. The reaction mixture was allowed to cool, diluted with saturated sodium bicarbonate, and extracted twice with ethyl acetate. The organic extracts were combined, washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO CombiFlash® Sg100c chromatography system with an Isco 12 g column, eluting with 25-100% ethyl acetate/hexanes to give (4S,7R)-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1-propyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (59.7 mg, 35%) as an orange oil. ES(+)-MS (M+H) 329.
Reaction SMILES: [OH-:1].[K+:2].O=C[C@@H:5]([C@H:7]([C@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[OH:6]>CO.O>[O:1]=[C:5]([O-:6])[C@H:7]([C@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8].[K+:2]
Reactant: [OH-]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)CO
Yield: 573.9 %

Procedure:
Air was sparged at 100 mL/min through a rapidly stirred solution of potassium hydroxide (41.9 g, 65.5 mmol) and D-galactose (45.0 g, 25.0 mmol) in a mixture of methanol/water (375 mL/180 mL) at 60 psi in a Parr bomb (1 L). The temperature was maintained at 35°-36° C. throughout the reaction. After sparging for 24 hours (h), methanol (50 mL) was added and sparging continued for a total of 45 h. The reaction mixture was cooled and vented. The bomb was opened and the light yellow mixture was filtered to remove a small amount of solids. The bomb and filter were rinsed with water (5 mL) in which most of the solids dissolved. The filtrate was stirred and diluted with methanol (850 mL). Crystallization occurred after approximately 500 mL of methanol had been added. After stirring for 4 h, the crystals were collected by filtration and vacuum dried to provide 29.3 g (57% yield) of potassium D-lyxonate 1 as a white solid: DISC mp 171.25° C.; Analysis calculated for C5H9O6K: C, 29.41; H, 4.44. Found: C, 28.86; H, 4.16. This white solid material was used in Example 2 without further purification.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].C(O)(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:30]([N:32]1[C:44]2[CH:43]=[CH:42][C:41]([NH2:45])=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11](=[O:13])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:8]([C:18]([NH:45][C:41]2[CH:42]=[CH:43][C:44]3[N:32]([CH2:30][CH3:31])[C:33]4[C:38]([C:39]=3[CH:40]=2)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: O=C(O)c1ccccc1
Product: C=CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 2, starting from (2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, benzoic acid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained after column chromatography as an off-white solid as a mixture of E/Z-isomers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:17][O:18][C:19](=[O:29])[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[NH2:28].CCCCCC>CCOC(C)=O>[CH3:17][O:18][C:19](=[O:29])[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[NH:28][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:12]
Reactant: CC(C(=O)O)c1ccc(Br)cc1
Reactant: COC(=O)c1c(N)cc(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Product: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(Br)cc1
Yield: 47 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-bromo-phenyl)-propionic acid (11.7 g, 48.3 mmol), SOCl2 (35.0 mL, 480 mmol), and 2-amino-4,6-dichloro-benzoic acid methyl ester (10.1 g, 45.9 mmol). After normal workup, the pure objective compound (9.31 g, 55%) was obtained as white solid by a flash column chromatography (n-hexane:EtOAc=10:1): 1H NMR (200 MHz, CDCl3) δ 1.58 (d, J=7.1 Hz, 3H, CH3), 3.75 (q, J=7.1 Hz, 1H, CH), 3.81 (s, 3H, CO2CH3), 7.15 (d, J=2.0 Hz, 1H, ArH), 7.20-7.53 (m, 4H, ArH), 8.41 (d, J=1.7 Hz, 1H, ArH), 9.16 (br s, 1H, NH).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C(=O)(O)[O-].[Na+]>COC(O)C>[Br:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:17]#[N:18])[CH:24]=[CH:25][CH:26]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Reactant: Nc1cccc(Br)c1
Agent: COC(C)O
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Yield: 15.3 %

Procedure:
A solution of 5.2 g (19.7 mmol) of 4-chloro-7-methoxy-6-nitro-quinoline-3-carbonitrile and 3.7 g (21.7 mmol) of 3-bromo aniline in 130 ml of methoxyethanol was refluxed under nitrogen for 4 hours. The reaction mixture was poured into dilute sodium bicarbonate solution. Solid was collected and washed with water and dried in air. The solid was chromatographed on silica gel eluting with chloroform-ethyl acetate 9:1. Solvent was removed from product fractions giving 1.2 g of 4-[(3-bromophenyl)amino]-7-methoxy-6-nitro-quinoline-3-carbonitrile as a yellow solid: mass spectrum (electrospray, m/e): M+H 399.0, 402.0.