Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[Cl:10][C:11]1[CH:46]=[CH:45][C:14]([C:15]([C:17]2[CH:18]=[C:19]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:36]=3)[S:20][C:21]=2[C:22]2[N:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=2)=[O:16])=[CH:13][CH:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:16])([CH:3]2[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]2)[C:17]2[CH:18]=[C:19]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:36]=3)[S:20][C:21]=2[C:22]2[N:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[N:23]=2)=[CH:45][CH:46]=1
Reactant: CC(=O)Nc1cc(-c2cc(C(=O)c3ccc(Cl)cc3)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Reactant: CN1CCC(Cl)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2cc(C(O)(c3ccc(Cl)cc3)C3CCN(C)CC3)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Temperature: 45 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
A 25 mL round bottom flask charged with magnesium turnings (23.0 mg, 0.947 mmol) was flame-dried. To the flask was added tetrahydrofuran (1.00 mL) and a drop of 1,2-dibromoethane. The mixture was heated to 45° C. for 10 min and cooled to rt. To the mixture was added 4-chloro-N-methylpiperidine (126 mg, 0.947 mmol). The reaction was stirred at 35° C. under an atmosphere of nitrogen for 12 hrs. The mixture turned cloudy, and magnesium turnings eventually disappeared, as the reaction progressed. To a solution of N-{4-[4-(4-chlorobenzoyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide (113 mg, 0.204 mmol) in tetrahydrofuran (1.00 mL) was added the pre-prepared Grignard reagent solution dropwise at 0° C. In 3 hrs, the reaction was warmed to rt. In another 3 hrs, the reaction was quenched with water and distributed between NaHCO3(aq) saturated solution and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layer was dried and concentrated. Purification on a silica gel column (gradient elution, 1-20% MeOH) provided N-(4-{4-[(4-chlorophenyl)(hydroxy)(1-methylpiperidin-4-yl)methyl]-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl}pyridin-2-yl)acetamide as a yellow solid (59.0 mg, 44.3% yield). LCMS: (AA) ES+ 653, 655; NMR (400 MHz, CDCl3) δ 8.77-8.66 (s, 1H), 8.60-8.49 (s, 1H), 8.31-8.23 (d, J=5.3 Hz, 1H), 8.15-8.08 (m, 2H), 7.66-7.60 (s, 1H), 7.34-7.23 (m, 3H), 7.17-7.08 (d, J=8.7 Hz, 2H), 5.45-5.38 (s, 2H), 3.63-3.51 (m, 2H), 3.49-3.44 (s, 3H), 3.02-2.90 (d, J=10.8 Hz, 1H), 2.90-2.78 (d, J=11.2 Hz, 1H), 2.28-2.20 (m, 4H), 2.20-2.09 (m, 1H), 2.07-1.95 (m, 1H), 1.96-1.78 (m, 2H), 1.76-1.58 (qd, J=12.7, 3.8 Hz, 1H), 1.16-1.07 (d, J=12.5 Hz, 1H), 0.99-0.85 (m, 2H), 0.02-1-0.04 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[NH:9]1[CH:13]=[N:12][C:11]([S:14]([CH2:17][CH:18]2[CH2:20][CH2:19]2)(=[O:16])=[O:15])=[N:10]1.Cl>N1C=CC=CC=1>[CH:18]1([CH2:17][S:14]([C:11]2[N:12]=[CH:13][N:9]([C:4]([N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:5])[N:10]=2)(=[O:15])=[O:16])[CH2:19][CH2:20]1
Reactant: CCN(CC)C(=O)Cl
Reactant: O=S(=O)(CC1CC1)c1nc[nH]n1
Agent: Cl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1cnc(S(=O)(=O)CC2CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Diethylcarbamoyl chloride (1.55 ml; 11.8 mmol) was added to cyclopropylmethyl 1,2,4-triazol-3-yl sulfone (2.07 g; 11.1 mmol) in dry pyridine (10 ml) under dry nitrogen. The resulting solution was stirred at room temperature overnight. The resulting mixture was poured into cold 2M hydrochloric acid (40 ml) and the cloudy solution extracted into ethyl acetate (3×50 ml). The extracts were combined, washed with saturated brine (50 ml), dried (Na2SO4), filtered and evaporated to afford 3-(cyclopropylmethylsulfonyl)-N,N-diethyl-1,2,4-triazole-1-carboxamide (3.10 g; 98%) as white crystals, m.p. 68°-74° C., (Found, C: 46.23; H: 6.24; N: 19.60; S: 11.29. C11H18N4O3S requires C: 46.14; H: 6.34; N: 19.57; S: 11.20%) NMR - d(CDC13; 60 MHz) 0.2-0.9 (4H, m), 0.9-1.5 (7H, m), 3.3 (2H, d, J= 7 Hz), 3.6 (4H, q, J=7 Hz) and 8.9 (1H, s). IR vmax (CHCl3) 3040, 1710, 1440, 1340, 1270, 1180, 1150, 1030, 870 and 635 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N:27](S(C)(=O)=O)[S:28]([CH3:31])(=[O:30])=[O:29])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.O[Li].O.[OH-].[Na+].Cl>O1CCCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc3nc2-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2nc3ccc(NS(C)(=O)=O)cc3nc2-c2ccc(OC)cc2)cc1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
To a solution of N-(2,3-bis(4-methoxyphenyl)quinoxalin-6-yl)-N-(methylsulfonyl)methanesulfonamide (143.64 mg, 0.28 mmol, 1.00 equiv, 90%) in tetrahydrofuran/MeOH (1:1, 10 mL) was added LiOH H2O (58.5 mg, 1.39 mmol, 5.00 equiv). This was followed by the dropwise addition of a solution of sodium hydroxide (56 mg, 1.40 mmol, 5.00 equiv) in water (2 mL). The resulting solution was stirred for 1 h at 35° C. in an oil bath. The pH was adjusted to 7-8 with 1N HCl. The resulting mixture was concentrated in vacuo and washed with methanol, resulting in 46.5 mg (37%) of N-(2,3-bis(4-methoxyphenyl)quinoxalin-6-yl)methanesulfonamide as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:17][C:18](I)([F:20])[F:19].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:18]([F:20])([F:19])[F:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: FC(F)(F)I
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCN(Cc2ccccc2)CC1C(F)(F)F
Reaction time: 0.25 h

Procedure:
1-benzylpiperidin-4-one (12 g, 63.5 mmole) was added to the stirred suspension of sodium hydride (3.0 g, 127.0 mmole) in tetrahydrofuran (100 ml) at −5° C. The reaction mixture was stirred for 15 min, trifluoromethyl iodide (25 g, 127.0 mmole) was bubbled over a period of 4 hr at −5° C. and stirring continued for 1 hr. The resulting mixture was stirred for 16 hr at ambient temperature, saturated sodium sulphate solution (20 ml) was added and diluted with ethyl acetate (200 ml). Ethyl acetate layer was separated, dried (Na2SO4) and concentrated to furnish crude product, which was purified through column chromatography. Elute from hexane afforded l-benzyl-3-trifluoromethylpiperidin-4-one as oil and 20% ethyl acetate in hexane gave the unreacted 1-benzylpiperidin-4-one (9.5 g). Yield 2.1 g (44%, based on reacted 1-benzyl piperidin-4-one), C13H14F3NO, m/z 258 (M+1), PMR (CDCl3): 2.54 (2H, m, H6), 3.02 (2H, m, H2), 3.6 (3H, m, H3 & H5), 4.36 (2H, s, N—CH2), 7.28 (5H, m, ArH).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=2)[N:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=C(C(C)C)C(C2C(C)=C(C)C(C)=C(C)C=2P(C)C)=C(C)C=1)(C)C.[OH-:48].[K+].ClCCl>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO>[CH2:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=2)[N:12]=[CH:11][C:10]=1[OH:48])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2ncc(Br)c(NCc3ccccc3)c2n1
Reactant: [OH-]
Agent: [Pd]
Agent: Cc1cc(C(C)C)cc(C(C)C)c1-c1c(C)c(C)c(C)c(C)c1P(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2ncc(O)c(NCc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.8 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.011 mmol, 0.04 eq) is added at room temperature to a stirred solution of benzyl-(3-bromo-6-methoxy-[1,5]naphthyridin-4-yl)-amine (100 mg, 0.29 mmol, 1.0 eq) in dioxane (6 mL) and water (3 mL), followed by (4′,6′-diisopropyl-3,4,5,6,2′-pentamethyl-biphenyl-2-yl)-dimethyl-phosphane (8 mg, 0.016 mmol, 0.06 eq). After 10 minutes stirring at room temperature, a solution of potassium hydroxide (82 mg, 1.46 mmol, 5.0 eq) in water (3 mL) is added and the resulting mixture is stirred at 105° C. for 16 hours. The reaction mixture is cooled down to room temperature, extracted with ethyl acetate (3×10 mL) and water (10 mL) and the pH is adjusted to 6 by the addition of a 1N hydrochloric acid aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to give the crude product that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 5:1, v/v) to afford 4-benzylamino-6-methoxy-[1,5]naphthyridin-3-ol as a light yellow solid (30 mg, 36% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)cc1NS(C)(=O)=O
Yield: 15 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl) methane sulfonamide (150 mg, 0.232 mmol) was hydrolyzed with lithium hydroxide (49 mg, 1.162 mmol) in THF/Methanol/Water (15/6/4 mL) to yield 17 mg (15% yield) after purification by preparative TLC (Silicagel-1000 micron) using 2% methanol in chloroform as eluent. 1H NMR (CD3OD, 400 MHz): δ 8.446-8.441 (d, 1H), 8.327-8.322 (d, 1H), 8.215 (s, 1H), 7.936 (s, 1H), 7.746-7.741 (d, 1H), 7.643 (s, 1H). 7.577-7.551 (m, 1H), 7.398-7.364 (m, 1H), 7.21-7.188 (d, 1H), 7.210-7.188 (d, 1H), 7.137-7.118 (d, 1H), 7.067-7.026 (m, 2H), 5.426 (s, 2H), 3.98 (s, 3H), 3.002 (s, 3H). MS: m/z=491.8 (M+1), HPLC: 97.01% in method A.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].F[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26]>CS(C)=O>[F:24][C:22]1[CH:21]=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[C:18]([CH:23]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(=O)c1c(N)sc2cc(C)ccc12
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2cc(C)ccc12
Yield: 71.2 %

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-amino-6-methylbenzo[b]thiophene-3-carboxylate (4.5 g), 2,4-difluoronitrobenzene (3.1 g) and dimethyl sulfoxide, ethyl 2-(5-fluoro-2-nitroanilino)-6-methylbenzo[b]thiophene-3-carboxylate (5.1 g) was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:35])[C:16]2[CH:21]=[CH:20][C:19]([CH:22](O)[CH3:23])=[C:18]([O:25][CH2:26][CH2:27][C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C(OC(C1(NC(=O)C2C=CC(C(O)C)=C(OCCC3C=C(C)C=CC=3)C=2)CC2C(=CC=CC=2)C1)=O)C.C(N(S(F)(F)[F:78])CC)C>C(Cl)Cl>[F:78][CH:22]([C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:5]2([C:3]([OH:2])=[O:4])[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:35])=[CH:17][C:18]=1[O:25][CH2:26][CH2:27][C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)[CH3:23]
Reactant: COC(=O)C1(NC(=O)c2ccc(C(C)O)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Reactant: CCN(CC)S(F)(F)F
Agent: CCOC(=O)C1(NC(=O)c2ccc(C(C)O)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Solvent: ClCCl
Product: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)ccc2C(C)F)c1

Procedure:
The mixture of 2-[4-(1-hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid methyl ester and 2-[4-(1-hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid ethyl ester obtained in example 9 (50 mg) was dissolved in DCM, and diethylaminosulfur trifluoride (33 mg, 0.204 mmol) was added in two portions (second portion after 3.5 h). After complete conversion as detected by HPLC, the mixture was partitioned between EA and a saturated aqueous sodium hydrogencarbonate solution and the aqueous phase extracted with EA. The combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness. The residue was stirred with a HEP/diethyl ether mixture, filtered, and dried in vacuo. The obtained ester was hydrolyzed in analogy to example 2 to give 12 mg of the title compound.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[CH2:29]([O:31][C:32]1[C:33]([CH3:41])=[C:34]([CH2:39]O)[CH:35]=[N:36][C:37]=1[CH3:38])[CH3:30].O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:29]([O:31][C:32]1[C:33]([CH3:41])=[C:34]([CH2:39][N:15]=[N+:16]=[N-:17])[CH:35]=[N:36][C:37]=1[CH3:38])[CH3:30]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOc1c(C)ncc(CO)c1C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1c(C)ncc(CN=[N+]=[N-])c1C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
Diphenylphosphoryl azide (0.59 ml, 2.7 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.41 ml, 2.7 mmol) were added dropwise in that order to a solution of (5-ethoxy-4,6-dimethyl-3-pyridyl)methanol (0.415 g, 2.29 mmol) in toluene (5 ml) at room temperature, and the mixture was stirred for 16 hours. After confirming completion of the reaction by thin layer chromatography, the mixture was poured into water and extraction was performed with ethyl acetate. The extract was washed with saturated aqueous NaCl and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (447 mg, 95%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][Li].Cl>O1CCCC1>[CH3:9][C:8]([CH3:11])([OH:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: CC(=O)c1ccccc1O
Reactant: [Li]C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1ccccc1O
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A solution of 10.0 ml (11.31 g, 83.1 mmol) of 2′-hydroxyacetophenone and 50 ml of tetrahydrofuran was placed in an ice bath and treated with 120.0 ml (168.0 mmol) of 1.4 M methyllithium in tetrahydrofuran, which was added dropwise over 30 minutes. The reaction mixture first became cloudy and then cleared up. After stirring for 18 hours, the solution was acidified with 4% aqueous hydrochloric acid. The layers were separated. The organic phase was washed with 30 ml of brine, dried over sodium sulfate, and concentrated. A total of 12.05 g of 2-(dimethylhydroxymethyl)phenol was isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.ClOC(C)(C)C.C(O[C:22](=[S:25])[CH2:23][CH3:24])C.Cl>C(Cl)Cl.C(OCC)C.O.C(N(CC)CC)C>[C:8]([C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][CH:4]=1)[NH:1][C:22](=[S:25])[CH:23]2[CH3:24])(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCOC(=S)CC
Reactant: CCCC(=O)c1ccc(N)cc1
Agent: CC(C)(C)OCl
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCC(=O)c1ccc2c(c1)C(C)C(=S)N2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8.15 g of p-aminobutyrophenone are dissolved in 300 ml of methylene chloride and the solution is cooled to -30° under nitrogen. 5.96 g of tert-butyl hypochlorite are then added dropwise and, in the course of this, the mixture is slowly cooled to -65°. Stirring is then carried out for 10 minutes at -65°, 7.37 g of methylthioacetic acid ethyl ester are added dropwise, the mixture is left for one hour at -65°, 5.55 g of triethylamine are added, and the mixture is slowly allowed to warm to room temperature. 100 ml of water are then added, the organic layer is separated off and subsequently washed with 100 ml of water, the aqueous phases are extracted twice with methylene chloride, and the organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness by evaporation under reduced pressure. The residue obtained by concentration by evaporation is dissolved in 200 ml of diethyl ether, 25 ml of 2N hydrochloric acid are added and the mixture is stirred overnight at room temperature. The mixture is then diluted with 50 ml of water, the organic phase is separated off, the aqueous phase is washed with 100 ml of diethyl ether, the organic phases are combined, washed with a mixture of 50 ml of water and 10 ml of 2N hydrochloric acid, dried over magnesium sulphate and concentrated to dryness by evaporation, and the residue is suspended in diethyl ether, filtered with suction and dried under reduced pressure. 5-Butyryl-3-methylthiooxindole having a melting point of 133°-136° is obtained.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7](Cl)[C:3]=1[C:4]([OH:6])=[O:5].OO.C1CCCCCCC=1.[C:22]([O-])([OH:24])=[O:23].[Na+]>CC#N.CCOCC.O>[C:22]([OH:24])(=[O:23])[CH2:2][CH2:10][CH2:9][CH2:8][CH2:7][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: O=C([O-])O
Agent: C1=CCCCCCC1
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: O=C(O)CCCCCCC(=O)O
Reaction time: 0.33 h
Yield: 47 %

Procedure:
To a mixture of [Mn2O3(Me3-TACN)4] (PF6)2.H2O (8.1 mg, 10 μmol, 0.1 mol %) and 2,6-dichlorobenzoic acid (57.3 mg, 0.30 mmol, 3.0 mol %) in CH3CN (7 ml) was added H2O2 (30 μl of a 50% aq. solution, 0.53 mmol) at room temperature and the resulting mixture was stirred for 20 min. Subsequently cyclooctene (1.16 g, 10 mmol) was added together with CH3CN (2 ml) and water (1 ml). H2O2 (2.83 ml of a 50% aq. solution, 50 mmol, 5.0 equiv.) was then added at room temperature using a syringe pump (0.07 ml/h). New batches of [Mn2O3(Me3-TACN)2] (PF6)2.H2O (8.1 mg, 10 μmol, 0.1 mol % per batch) were added to the reaction mixture 17, 25 and 40.5 hours after the addition of H2O2 had commenced. When the addition of H2O2 was completed, the mixture was stirred for additional 1 hour. Water (10 ml) and Et2O (10 ml) were added and the pH of the aqueous layer was set to pH >9 by adding some saturated NaHCO3 (aq.). The organic layer was separated and the aqueous layer was washed with Et2O (3×15 ml). The pH of the aqueous layer was subsequently set to pH <2 with some 10% HCl (aq.) and was extracted with Et2O (3×20 ml). The combined organic extracts were dried over anhydrous Na2SO4. The solvents were removed in vacuo yielding 868 mg of a solid with a purity of circa 95% (determined by 1H NMR), 47% yield of suberic acid. 1H NMR (400 MHz, acetone-d6) δ 1.34-1.39 (m, 4H), 1.56-1.63 (m, 4H), 2.28 (t, J=7.4, 4H). N.B. NMR showed other compounds as well, including 2,6-dichlorobenzoic acid.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](O)=[O:36])=[O:29])([CH3:26])([CH3:25])[CH3:24].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.O.C(OCC)(=O)C>[O:16]=[C:9]1[N:10]2[CH2:15][CH2:14][N:13]([C:35]([C:34]3[CH:33]=[C:32]([CH2:31][NH:30][C:28](=[O:29])[O:27][C:23]([CH3:25])([CH3:24])[CH3:26])[CH:40]=[CH:39][CH:38]=3)=[O:36])[CH2:12][CH:11]2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:8]1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cccc(C(=O)N2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.4 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.20 g, 0.67 mmol), 3-[[(tert-butoxycarbonyl)amino]methyl]benzoic acid (0.17 g, 0.67 mmol), 1-hydroxybenzotriazole (0.10 g, 0.74 mmol) and triethylamine (69 mg, 0.68 mmol) in acetonitrile (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g, 1.0 mmol), and the mixture was stirred at room temperature for 15 hours. To the reaction solution were added ethyl acetate and water. The separated organic layer was washed with saturated brine, dried over sodium sulfate, and then concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1 to 3:7) to obtain the title compound (0.27 g, yield 75%).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C-:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:7][CH:6]=1.[CH-:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.[Fe+2:23].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO.CCOCC>[C:4]([C:5]1[CH:10]=[CH:9][C:8]([C-:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:7][CH:6]=1)#[CH:3].[CH-:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.[Fe+2:23]
Reactant: C[Si](C)(C)C#Cc1ccc(-[c-]2cccc2)cc1
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#Cc1ccc(-[c-]2cccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
A solution of 3 (1.5 g, 4.2 mmol) in anhydrous THF/MeOH (2:1, 30 mL) was treated with K2CO3 (1.2 g, 8.4 mmol) and the mixture was stirred at rt for 30 min. The solvent was removed under reduced pressure affording an orange solid. The residue was dissolved in ether (50 mL), washed with H2O (3×50 mL), dried (MgSO4) and filtered. The solvent was removed under reduced pressure. Purification by column chromatography (silica, petroleum ether/ethyl ether, 10:2) afforded an orange solid (1.0 g, 90%): mp 104-106° C.; 1H NMR δ 3.11 (s, 1H), 4.04 (s, 5H), 4.35 (t, J=2.4 Hz, 2H), 4.65 (t, J=2.4 Hz, 2H), 7.42 (s, 4H); 13C NMR δ 66.5, 69.3, 69.7, 84.0, 94.1, 105.5, 120.3, 125.7, 132.1, 140.3; FAB-MS obsd 286.0460, calcd exact mass 286.0445 (C18H14Fe). Physical properties concur with published data (Simionescu et al. (1976) J. Organomet. Chem., 113: 23-28).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])=[O:2].[CH3:15][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:2][CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])[CH3:15]
Reactant: COC(=O)c1ccc(C=O)c(OC)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)O)c(OC)c1
Reaction time: 1 h

Procedure:
To a mixture of methyl 4-formyl-3-methoxybenzoate (3.30 g) and THF (30 mL) was added dropwise methyl magnesium bromide (3 M diethyl ether solution, 3.60 mL) under ice-cooling. After dropwise addition, the mixture was stirred for 1 hour under ice-cooling. A saturated aqueous ammonium chloride solution was added thereto to stop the reaction, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over an aqueous anhydrous sodium sulfate solution. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 4-(1-hydroxyethyl)-3-methoxybenzoate (1.92 g).