Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].[CH3:20]O>>[CH3:20][O:13][C:12](=[O:14])[C@@H:11]1[CH2:15][CH2:16][CH2:17][N:10]1[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8]
Reactant: CO
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Yield: 96 %

Procedure:
To a solution of 25 g (0.15 mol) of L-Proline methyl ester hydrochloride in 500 mL of CH2Cl2 was added 70 mL (0.5. mol) of triethylamine with stirring to give copious white precipitate. The mixture was filtered and the filtrate cooled to 0° C. (ice bath) with stirring. To the cooled solution was added a solution of 20 mL (0.15 mol) of benzenesulfonyl chloride in 50 mL of CH2Cl2 dropwise over fifteen minutes. The addition funnel was rinsed with an additional 25 mL of CH2Cl2, and the cloudy, colorless mixture was allowed to warm to room temperature with stirring overnight. The solution was washed 2× with 400 mL of 1N HCl, 2× with 400 mL of 1N NaOH, 1× with brine, then dried (MgSO4), filtered, and concentrated to a pale yellow solid. This material was recrystallized three times from ethyl acetate/hexanes to give 38.2 g (0.142 mol, 95%) of N-(benzenesulfonyl)-Proline methyl ester (MW=269) as broad white needles (TLC vs. 2:1 hexanes/ethyl acetate, Rf=0.35). M/z=270.2 (M+H+). N-(benzenesulfonyl)-Proline: To a solution of 38.2 g (0.142 mol) of the above methyl ester in 500 mL methanol was added 140 mL (0.28 mol) of freshly-prepared 2M aqueous LiOH with stirring to give a colorless solution. This was stirred overnight, after which HPLC showed no starting material. The solution was reduced by 50% in vacuo and partitioned between 1N HCl and CH2Cl2 (200 mL each). The phases were separated and the aqueous layer was washed again with CH2Cl2. The organic phases were combined, dried (MgSO4), and concentrated to a white solid. This was recrystallized twice from ethyl acetate/hexanes to give 34.7 g (0.136 mol, 96%) of the title compound as fine white needles. M/z=256.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.C(N(CC)CC)C.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:26])=[O:25])[CH:9]=[CH:10][C:3]=12
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ccnc2[nH]ccc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ccnc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.4 %

Procedure:
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (Ark Pharm, 5.023 g, 32.92 mmol) in DCM (150 mL), DMAP (418.1 mg, 3.422 mmol) was added, followed by triethylamine (4.984 g, 49.25 mmol) and benzenesulfonyl chloride (6.904 g, 39.09 mmol). After stirring at room temperature for 15 h, the mixture was washed with 1 M HCl (100 mL). The organic layer was washed with saturated aq. NaHCO3 (100 mL) and brine (100 mL), then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a pale yellow solid (9.39 g, 97%). LCMS calc. for C13H10ClN2O2S (M+H)+: m/z=293.0. found 293.0.
Reaction SMILES: [CH3:1][C:2]([F:7])([CH3:6])[C:3](=[O:5])[CH3:4].[Br-:8].[Br-:9].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:8][CH:4]([Br:9])[C:3](=[O:5])[C:2]([F:7])([CH3:6])[CH3:1]
Reactant: CC(=O)C(C)(C)F
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(F)C(=O)C(Br)Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
To a stirred solution of 3-methyl-3-fluoro-2-butanone (0.1031 g, 0.990 mmol) in anhydrous dichloromethane (5 ml) under nitrogen was added solid pyridinium tribromide (0.7035 g, 1.98 mmol) and the mixture was stirred at room temperature for 18 h. The mixture was then diluted with dichloromethane (5 ml), washed with dilute aqueous sodium hydrogensulfite (10 ml), then saturated aqueous NaCl (10 ml), dried (Na2SO4) and evaporated under low vacuum with no heat. The residue was purified by flash chromatography [silica gel, 5% Et2O/petroleum ether (40-60° C.)] to afford 0.1869 g (72%) of the title compound as a colourless oil: 1H NMR (360 MHz, CDCl3) δ 1.65 (6H, d, J 21.5 Hz), 6.51 (1H, d, J 1.5 Hz).
Reaction SMILES: O1CCCC1.[CH:6]1([OH:10])[CH2:9][CH2:8][CH2:7]1.[H-].[Na+].[Br:13][C:14]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:17]2[CH:18]=[N:19][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21](=[O:22])[C:16]=2[C:15]=1[CH2:40]Br>O>[Br:13][C:14]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:17]2[CH:18]=[N:19][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21](=[O:22])[C:16]=2[C:15]=1[CH2:40][O:10][CH:6]1[CH2:9][CH2:8][CH2:7]1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc2c(c(COC3CCC3)c(Br)n2COCC[Si](C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
To 10 ml of dehydrated tetrahydrofuran solution containing 0.89 g (12 mmol) of cyclobutanol was added 0.25 g (6.2 mmol) of sodium hydride (60% dispersed material in mineral oil) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the mixture was further added 0.70 g (1.2 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one obtained in Reference example 25-(a), and the mixture was stirred at 45° C. for 1 hour. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 561 mg of the title compound as a pale yellowish oil. (Yield: 82%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:25][CH:24]1[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC1Cc1ccccc1

Procedure:
Intermediate 1 was coupled with 2-Benzyl-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 479.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C@@H:7]1[C@@H:11]([CH3:12])[O:10][C:9](=[O:13])[NH:8]1>N1C=CC=CC=1>[Cl:3][CH2:6][C@@H:7]1[C@@H:11]([CH3:12])[O:10][C:9](=[O:13])[NH:8]1
Reactant: O=S(Cl)Cl
Reactant: C[C@H]1OC(=O)N[C@@H]1CO
Solvent: c1ccncc1
Product: C[C@H]1OC(=O)N[C@@H]1CCl
Temperature: 25 °C

Procedure:
Thionyl chloride (5.07 ml, 69.4 mmol) was added to a mixture of (4R,5R)-4-(hydroxymethyl)-5-methyloxazolidin-2-one (1.82 g, 13.88 mmol) in pyridine (35 mL) at 0° C. and the mixture was allowed to warm to room temperature for one hour. The mixture was then heated to 60° C. for one hour, allowed to cool to room temperature and then concentrated under reduced pressure. The crude oil was purified by column chromatography on silica to afford (4S,5R)-4-(chloromethyl)-5-methyloxazolidin-2-one. 1H NMR (500 MHz, CDCl3) δ 6.23 (s, 1H), 4.50 (qd, J=6.3, 4.6 Hz, 1H), 3.74-3.63 (m, 1H), 3.59-3.48 (m, 2H), 1.48 (d, J=6.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1.C=O.O.[C:29]([O:32][CH2:33]C)(=O)[CH3:30]>C(O)C>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:24]=[CH:25][C:2]([NH:1][CH2:33][O:32][CH2:29][CH3:30])=[N:3][CH:4]=2)=[CH:11][CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(C)=O
Reactant: Nc1ccc(C(=O)NCc2ccc(OCc3ccccc3)cc2)cn1
Agent: C=O
Solvent: O
Solvent: CCO
Product: CCOCNc1ccc(C(=O)NCc2ccc(OCc3ccccc3)cc2)cn1
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of the resulting 6-amino-N-(4-benzyloxy-benzyl)-nicotinamide (200 mg, 0.556 mmol) in ethanol (10 mL) were added 5,5-dimethylimidazophospho-2,4-dione (85 mg, 0.66 mmol) and 37% formaldehyde aqueous solution (1 mL), and the solution was stirred for 1 hour under reflux. Water and ethyl acetate were added to the reaction solution, which was then partitioned, and the organic layer was washed twice. NH silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption, purification was carried out by NH silica gel column chromatography (ethyl acetate), and the title compound (95 mg, 0.243 mmol, 40%) was obtained as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].C(Cl)Cl.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1>O>[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][C:25]=1[C:5]([C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[S:2][CH3:1])=[O:6]
Reactant: Cc1ccc(C)cc1
Reactant: CSc1ccccc1C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CSc1ccccc1C(=O)c1cc(C)ccc1C
Yield: 46 %

Procedure:
To a mixture of 1.2 g 2-(methylthio)benzoyl chloride (B) and 1.55 g AlCl3 at 0° C. was added slowly 20 ml DCM. The mixture was stirred 5 minutes at ambient temperature before 7.8 g p-xylene was added slowly. The reaction was stirred 30 minutes at ambient temperature before water was added slowly. The mixture was extracted with DCM (2×50 ml). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Flash silica chromatography (hexane:ethyl acetate 85:15) afforded 0.758 g product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C-:12]#[N:13].[Na+]>CO>[C:12]([CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])#[N:13]
Reactant: [C-]#N
Reactant: O=C(O)c1cccc(CBr)c1
Agent: [Na+]
Solvent: CO
Product: N#CCc1cccc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromomethylbenzoic acid (2.29 g, 10 mmol) in methanol (30 mL) is added sodium cyanide (0.49 g, 10 mmol) and the mixture is stirred at 70° C. for 2 hrs. The solvent is removed under reduced pressure and water is added to the residue. The mixture is extracted with ether and the organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by column chromatography using CH2Cl2 as eluent to give 3-cyanomethylbenzoic acid.
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH:7]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:39]=[N:38][C:20]5[N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:22]6[CH:27]=[N:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=6[C:19]=5[CH:18]=4)=[CH:13][CH:12]=3)[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH:40]1[N:44]=[CH:43][N:42]([C:45](N2C=NC=C2)=[S:46])[CH:41]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:28]([C:25]1[N:26]=[CH:27][C:22]2[N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:36])[CH3:37])[C:20]3[N:38]=[CH:39][C:17]([C:14]4[CH:15]=[CH:16][C:11]([CH2:10][N:9]5[CH:7]6[CH2:6][CH2:5][CH:4]5[CH2:3][CH:2]([O:1][C:45]([N:42]5[CH:41]=[CH:40][N:44]=[CH:43]5)=[S:46])[CH2:8]6)=[CH:12][CH:13]=4)=[CH:18][C:19]=3[C:23]=2[CH:24]=1)#[N:29]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(-c3ccc(CN4C5CCC4CC(O)C5)cc3)cnc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(-c3ccc(CN4C5CCC4CC(OC(=S)n4ccnc4)C5)cc3)cnc21
Yield: 96.6 %

Procedure:
A solution of 3-[4-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-ylmethyl)-phenyl]-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (155 mg, 0.29 mmol), DMAP (5 mg, catalytic) and N,N′-thiocarbonyldiimidazole (455 mg, 8.76 mmol) in DCM (10 mL) was heated under reflux for 12 h. The cooled reaction mixture was purified by flash chromatography (silica, 50 g column, Biotage, 0-5% MeOH in DCM) to afford the title compound as a white solid (182 mg, 97%). 1H NMR (CDCl3, 300 MHz): 9.28-9.25 (m, 1H), 9.04 (dd, J=7.0, 2.2 Hz, 1H), 8.69-8.66 (m, 1H), 8.51 (d, J=1.0 Hz, 1H), 8.47-8.39 (m, 1H), 7.81-7.61 (m, 5H), 7.15-7.10 (m, 1H), 6.12 (s, 2H), 4.35 (s, 2H), 3.76-3.61 (m, 4H), 2.32-2.17 (m, 4H), 2.13-1.93 (m, 5H), 1.08-0.96 (m, 2H), 0.00 (s, 9H). LCMS (Method B): RT=3.13 min, M+H+=650.
Reaction SMILES: [C:1]([C:5]([F:20])([C:16]([F:19])([F:18])[F:17])[O:6][C:7]([F:15])([C:11]([F:14])([F:13])[F:12])[C:8](F)=[O:9])([O:3]C)=[O:2].C[Si](C)(C)[O-:23].[K+:26]>CCOCC>[F:15][C:7]([C:11]([F:14])([F:13])[F:12])([O:6][C:5]([F:20])([C:16]([F:17])([F:18])[F:19])[C:1]([O-:3])=[O:2])[C:8]([O-:9])=[O:23].[K+:26].[K+:26]
Reactant: COC(=O)C(F)(OC(F)(C(=O)F)C(F)(F)F)C(F)(F)F
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=C([O-])C(F)(OC(F)(C(=O)[O-])C(F)(F)F)C(F)(F)F
Yield: 97.9 %

Procedure:
The procedure of Example 1 was followed using ~95% pure 4-carbomethoxyperfluoro-2-methyl-3-oxapentanoyl fluoride (12.5 g, 39 mmol), potassium trimethylsilanolate (10 g, 78 mmol), and dry ether (300 mL). Dipotassium perfluoro-2,4-dimethyl-3-oxa-1,5-pentanedioate (14.6 g, 98% yield) was isolated as a white solid: 19F NMR (D2O) δ -78.8 (m, CF3, 6F), -124.1 (m, CF, 1F), -130.3 ppm (m, CF, 1F). Anal. Calcd. for C6F8K2O5 : C, 18.85; F, 39.76; K, 20.46. Found: C, 17.45; F, 37.65, 37.53; K, 21.50, 21.30.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[N:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:29]([O:31]C)=[O:30])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([C:7]2[C:16]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[N:24]=[CH:25][CH:26]=[CH:27][N:28]=4)[CH2:21][CH2:22]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:29]([OH:31])=[O:30])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ncccn4)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ncccn4)CC3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-phenyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate (192 mg, 0.41 mmol, 1.00 equiv, 90%) in methanol (10 mL), a solution of sodium hydroxide (80 mg, 2.00 mmol, 5.00 equiv) in water (2 mL). The resulting solution was stirred overnight at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 80 mg (47%) of 2-phenyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].CS(O[CH2:20][CH2:21][CH2:22][C:23]#[CH:24])(=O)=O>O1CCCC1>[CH3:1][C:2]([CH2:24][CH2:23][CH2:22][C:21]#[CH:20])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: C#CCCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCCC(C)(C(=O)OCC)C(=O)OCC

Procedure:
A solution of diethyl methylmalonate (Aldrich Chemical Company, 35.6 ml) in dry tetrahydrofuran (200 ml) was added, dropwise, to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 9.1 g) in tetrahydrofuran (50 ml) under nitrogen. After the addition was complete, the mixture was heated to gentle reflux for 1 hour and then allowed to cool before a solution of pent-4-ynyl methanesulphonate (35.2 g) in tetrahydrofuran (50 ml) was added. The resulting mixture was heated to gentle reflux for a further 2 hours. The bulk of the solvent was then removed in vacuo and the residue was partitioned between diethyl ether and water. The organic phase was separated and washed with water and brine before drying over anhydrous magnesium sulphate and evaporation under reduced pressure. Distillation gave diethyl 2-methyl-2-(pent-4-ynyl)malonate (45.8 g) as a colourless oil (b.p. 92°-97°, 0.5 mm Hg).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].[CH3:18]O>C(OCC)(=O)C>[OH:2][CH:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=1)[CH3:18]
Reactant: CC(C)(C)C(=O)Nc1cccc(C=O)n1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(O)c1cccc(NC(=O)C(C)(C)C)n1
Reaction time: 3 h
Yield: 80 %

Procedure:
To solution of N-(6-formylpyridin-2-yl)-2,2-dimethylpropanamide (3.0 g, 14.9 mmol) in methanol (10 mL) was added sodium borohydride (1.37 g, 37.1 mmol) and stirred for 3 hours. The mixture diluted with ethyl acetate (50 mL). The mixture was washed with aqueous hydrochloric acid (2×30 mL, 0.1 N) and saturated sodium bicarbonate (2×50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford the above-titled intermediate as a white solid (2.49 g, 80%). 1H NMR (400 MHz, CDCl3), δ: 8.16 (d, J=8.3 Hz, 1H), 8.00 (br s, 1H), 7.71 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.5 Hz, 1H), 4.05-3.96 (m, 2H), 1.35 (s, 9H); LRMS (ESI): m/z: 209.2.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:4][N:3]=1.CS(O[CH:17]1[CH2:20][CH2:19][CH2:18]1)(=O)=O.C(N(CCCC)CCCC)CCC>C(OCC)C>[CH:20]1([CH2:17][N:4]2[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:6][C:2]([CH3:1])=[N:3]2)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: CS(=O)(=O)OC1CCC1
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOCC
Product: CCOC(=O)c1cc(C)nn1CC1CC1
Yield: 54.3 %

Procedure:
A mixture comprising 2.1 g of ethyl 3-methyl-1H-pyrazole-5-carboxylate, 2.1 g of cyclobutyl methanesulfonate and 2.6 g of tri-n-butylamine was allowed to react at 110 ° C. for three hours without using any solvent. Then the reaction mixture was allowed to cool and diethyl ether was added thereto. The obtained mixture was successively washed with 1 N hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by column chromatography (eluent: hexane : ethyl acetate=14 : 1). Thus 0.5 g of the aimed ethyl 1-cyclobutyl-3-methyl-1H-pyrazole-5-carboxylate (compound No. 1001) (yield: 17.6 %) and 1.54 g of ethyl 1-cyclopropylmethyl-3-methyl-1H-pyrazole-5-carboxylate(yield: 54.3 %) were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[Br:22])=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2].[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:28][C:5]1[C:6]([CH2:25][CH2:26][CH3:27])=[C:7]([CH:23]=[CH:24][C:4]=1[C:1](=[O:3])[CH3:2])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[Br:22])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Br)ccc(C(C)=O)c1O
Solvent: c1ccncc1
Product: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Br)ccc(C(C)=O)c1OC(C)=O

Procedure:
In a mixture of pyridine (10 ml) and acetic anhydride (10 ml) was dissolved 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-bromobenzoic acid (2 g). The solution was heated at 100° to 120° C. for 14 hours, which was then concentrated. The residue was dissolved in chloroform. The solution was washed with dilute hydrochloride acid, which was then dried on sodium sulfate. From the resultant was removed the solvent by evaporation, and the residue was chromatographed on a column of silica gel. Elution was conducted with hexane-ethyl acetate (3:1), (2:1), (1:1) and ethyl acetate in that order. Ethyl acetate fractions were combined and concentrated. The residue was crystallized from chloroform-hexane to give 4-[3-(3-acetoxy-4-acetyl-2-propylphenoxy)propoxy]-3-bromobenzoic acid (1.0 g), m.p. 155°-156° C.
Reaction SMILES: [CH:1]1([S:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:15]S(O)(=O)=O.OO>C(Cl)Cl>[CH:1]1([S:7]([CH2:10][CH2:11][C:12]([O:14][OH:15])=[O:13])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=S(=O)(O)O
Reactant: O=C(O)CCS(=O)(=O)C1CCCCC1
Agent: OO
Solvent: ClCCl
Product: O=C(CCS(=O)(=O)C1CCCCC1)OO
Temperature: 25 °C
Yield: 61 %

Procedure:
To a 150 mL beaker equipped with a support clamp, ice bath, alcohol thermometer, mechanical stirrer, and dropping funnel were charged 22.03 g (0.1 mole) of powdered 3-(cyclohexylsulfonyl)propionic acid and 29.8 mL of 82 wt. % aqueous H2SO4. After a few minutes mixing at ambient temperature, a uniform slurry was obtained. To the dropping funnel was charged a solution prepared by adding 33.3 mL of 95.5% H2SO4 to 17.0 mL of 50% H2O2 (0.3 mole, 3 fold excess) with stirring and cooling to maintain ≤30° C., with final cooling to 25° C. With agitation, the mixture in the dropping funnel was added to the beaker over a 10 minute period, the temperature rising to 27° C. The ice bath was not applied because the heat evolution was so small. The mixture was agitated for another 130 minutes, the temperature gradually declining to 26.5° C. Most of the solids dissolved. The mixture was then contacted with ten 25-30 mL portions of methylene chloride at ambient temperature in an effort to recover the product by direct extraction into the methylene chloride. The combined extracts were washed with pH 5 phosphate buffer solution, then washed with water, partially evaporated, mixed with a weighed amount of boric acid, and dried. The weight and active oxygen analysis of this product showed that only 3.57 g of the organic product had been recovered by extraction (~15% of theory) and that its activity was 91.1% of that for the pure peracid. The crude reaction product remaining after methylene chloride extraction was mixed with 100 mL of cold pH 5 buffer with agitation and ice cooling, resulting in immediate formation of a large amount of white solids. The slurry was filtered at 15°-20° C. and the solids were washed on the filter with two 100 mL portions of cold buffer followed by 100 mL cold water. The resulting product was mixed with boric acid and dried and then blended uniformly with most of the product recovered by extraction. The resulting final product weighed about 30 g and had an active oxygen content of 3.27% (boric acid content roughly 47%). The calculated active yield was 61% of theory. (Equipment, analysis, and yield calculation were as described in Example 3.)