Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl)([O-:15])=[O:14]>O>[CH3:7][N:8]([CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[N+:13]([O-:15])=[O:14])[S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: CNS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(Cc1ccccc1[N+](=O)[O-])S(C)(=O)=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
171 a) To a suspension of potassium carbonate (1.2 g, 8.7 mmol) in was added N-methyl-methanesulfonamide (0.70 g, 6.4 mmol) followed by o-nitrobenzylchloride (1.0 g, 5.8 mmol). The mixture was heated at 50° C. for 18 hours. The mixture was cooled to room temperature and diluted with water (50 mL) and stirred for 30 minutes. The resulting precipitate was filtered and rinsed with water. The solid was dissolved in dichloromethane (25 mL), dried over magnesium sulfate, filtered, evaporated under reduced pressure then placed under high vacuum for 2 hours. N-Methyl-N-(2-nitro-benzyl)-methanesulfonamide was isolated as an orange-brown solid (1.12 g, 78%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.07 (d, J=8.0 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.70 (t, J=7.4 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 4.73 (s, 2H), 2.96 (s, 3H), 2.88 (s, 3H). MS=245 (MH)+. 171 b) N-(2-Amino-benzyl)-N-methyl-methanesulfonamide was prepared from N-methyl-N-(2-nitro-benzyl)-methanesulfonamide (1.12 g, 4.58 mmol) in a manner analogous to
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:9]([O:11][C:12](=[O:22])[C:13]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:14])[CH3:10].C(OC(=O)C(CC1C=CC=CC=1)C(O)=O)C.[Na]>C(O)C>[CH2:9]([O:11][C:12](=[O:22])[CH:13]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:14][P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[O:8])[CH3:10]
Reactant: CCOP([O-])OCC
Reactant: C=C(Cc1ccccc1)C(=O)OCC
Agent: CCOC(=O)C(Cc1ccccc1)C(=O)O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1)CP(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of diethylphosphite (6.9 g) and 2-benzylacrylic acid ethyl ester (9.5 g) (prepared according to the procedure of C. Mannich and K. Risert Ber. (1924), 57, 1116 from benzylmalonic acid mono ethyl ester) was added, with stirring at ambient temperature under an atmosphere of nitrogen, a solution of sodium (1.15 g) in ethanol (20 ml). Following the initial exothermic reaction stirring was continued for 48 hr. The solvent was evaporated in vacuo and the residual gum partitioned between ether (100 ml) and 5% CA (50 ml). The ether solution was shaken once more with 5% CA (50 ml), dried (MgSO4) and the residue distilled, collecting the fraction (3.7 g) m.p. 58°-72°/0.02-0.03 mm). The structure of the product was confirmed by NMR and Mass spectroscopy.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:8]1(O)[CH2:13][CH2:12]C[CH2:10][CH2:9]1>C([Sn](=O)CCCC)CCC.CO>[C:1]([O:6][CH:7]1[CH2:12][CH2:13][CH2:8][CH2:9][CH2:10]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: OC1CCCCC1
Reactant: C=C(C)C(=O)OC
Agent: CCCC[Sn](=O)CCCC
Solvent: CO
Product: C=C(C)C(=O)OC1CCCCC1
Yield: 72 %

Procedure:
Using a reflux apparatus equipped with a 20-plates Oldershaw column as the distillation column, a 3-liter four-necked flask with a side arm was charged with 1,401 g (14 moles) of methyl methacrylate, 701 g (7 moles) of cyclohexanol, 12.6 g of dibutyltin oxide, and 1.18 g (corresponding to 0.1% of the theoretical yield of the product) of MTX as a polymerization inhibitor. This mixture was subjected to an ester exchange reaction. The methanol formed as a by-product during reaction was removed from the system together with the methyl methacrylate. The resulting reaction product was purified by simple distillation using an empty column having a length of 20 cm, so that 848 g of cyclohexyl methacrylate was obtained. During the course of the reaction and distillation, polymerization occurred neither in the reactor nor the column. However, the cyclohexyl methacrylate thus obtained was slightly colored and had a color number (APHA) of 140.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12]3[CH:13]=[C:14]([CH3:20])[C:15](Br)=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12]3[CH:13]=[C:14]([CH3:20])[C:15]([CH3:24])=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2c(cc1Br)cc1n2[C@H](C)CN(C(=O)OC(C)(C)C)C1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc2cc3n(c2cc1C)[C@H](C)CN(C(=O)OC(C)(C)C)C3
Yield: 63.4 %

Procedure:
To a solution of 1.18 g (R)-8-bromo-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester in 12 ml dioxane were added 0.36 g tetrakistriphenylphosphinpalladium, 1.29 g potassium carbonate and 0.39 trimethylboroxine and the mixture was heated 1 h at reflux. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was washed with 10% sodium bicarbonate, 10% citric acid and brine, dried over magnesium sulfate and purified by chromatography on silica gel with hexane:ethyl acetate=3:1 to yield 0.62 g (R)-4,7,8-trimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester as slightly yellow foam. MS: (M+H)=315.4
Reaction SMILES: I[Si](C)(C)[CH3:3].[C:6]([C:11]1[C:12](=[O:30])[CH2:13][CH:14]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH2:26][O:27][CH3:28])[C:19]=2[CH3:29])[CH2:15][C:16]=1[OH:17])(=[O:10])[CH2:7][CH2:8][CH3:9]>C(#N)C>[C:6]([C:11]1[C:16](=[O:17])[CH2:15][CH:14]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH2:26][O:27][CH2:28][CH3:3])[C:19]=2[CH3:29])[CH2:13][C:12]=1[OH:30])(=[O:10])[CH2:7][CH2:8][CH3:9]
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(COC)c2C)CC1=O
Reactant: C[Si](C)(C)I
Solvent: CC#N
Product: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(COCC)c2C)CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
Iodotrimethylsilane (0.5 ml) was added to a solution of 2-butyryl-3-hydroxy-5-(3-methoxymethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (1.50 g; 4.36 mmole) (see Example 36) in dry acetonitrile (10 ml) under nitrogen and the mixture was stirred at room temperature for 15 minutes. The solvent was evaporated and the residue was stirred with an ethanolic potassium hydroxide solution at room temperature for 15 hours. The solution was poured into dilute hydrochloric acid and then extracted with diethyl ether. The ether extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Purification by column chromatography over silica gel (eluant dichloromethane) gave 2-butyryl-5-(3-ethoxymethyl-2,4,6-trimethylphenyl)-3-hydroxycyclohex-2-en-1-one (1.32 g; 84.7%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14](O)=[O:15])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][OH:15])[CH:3]=1
Reactant: O=C(O)c1cc(Br)ccc1-c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cc(Br)ccc1-c1ccccc1
Temperature: 0 °C
Yield: 64.5 %

Procedure:
4-bromobiphenyl-2-carboxylic acid (5.71 g, 20.61 mmol) was dissolved in THF (50 mL) and cooled to 0° C. 1.0M borane tetrahydrofuran complex (41.2 mL, 41.2 mmol) was added dropwise over 15 min. and allowed to warm up to r.t. overnight. The reaction was diluted with EtOAc and washed with water, sat. ammonium chloride, and then brine. The organic layer was collected, dried over MgSO4, filtered and evaporated to give the crude product. The crude product was purified by flash chromatography on the Biotage (5-35% EtOAc:Hex) to give (4-bromobiphenyl-2-yl)methanol (3.5 g, 13.30 mmol, 65% yield) as a light orange oil. LCMS: rt=1.43 min.; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.60 (d, J=5.77 Hz, 2H) 7.15 (d, J=8.28 Hz, 1H) 7.29-7.35 (m, 2H) 7.36-7.46 (m, 3H) 7.48 (dd, J=8.28, 2.01 Hz, 1H) 7.75 (d, J=2.01 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26](=[O:30])[N:27]([CH3:29])[N:28]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:22][C:23]2[CH:24]=[CH:25][C:26](=[O:30])[N:27]([CH3:29])[N:28]=2)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cn1nc(N)ccc1=O
Reactant: CCOC(=O)c1nn(C)c(C)c1C(O)c1ccc(Cl)cc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(C)c(C)c1C(Nc1ccc(=O)n(C)n1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy with the procedure described in Step 1.4 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (Step 28.2) and 6-amino-2-methylpyridazin-3(2H)-one (Step 32.1). tR: 4.25 min (HPLC 1); tR: 0.94 min (LC-MS 2); ESI-MS: 416 [M+H]+ (LC-MS 2); Rf=0.43 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1>CN(C=O)C>[N:1]1([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2cccn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
Under nitrogen atmosphere, a solution of pyrazole (743 mg) in DMF (10 mL) was cooled to 0° C., and thereto was added NaH (480 mg, 60%). The mixture was stirred at 0° C. for 10 minutes, and stirred at room temperature for one hour. Methyl 4-(bromomethyl)benzoate (2.50 g) was added to the mixture, and the mixture was stirred at room temperature for 2 hours. To the mixture was added ice water (50 mL), and extracted three times with ethyl acetate-toluene, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=10/1→3/1) to give methyl 4-(1H-pyrazol-1-ylmethyl)benzoate (2.17 g, 92%).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[C:13]([S:17][Na])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[C:13]([S:17][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)S[Na]
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Ethyl 4-fluorobenzoate (1.5 g, 8.9 mmol) and tert-butylsulfanylsodium (2.00 g, 17.8 mmol) were combined in N,N-dimethylformamide (10 mL). The reaction mixture was heated at 80° C. for 2 hours. A large amount of precipitate formed and an additional 15 mL of N,N-dimethylformamide was added and the reaction mixture was stirred for an additional 20 hours at 80° C. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was discarded, and the water layer was made acidic with 4M hydrochloric acid. The water layer was extracted two times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, and evaporated to dryness to yield 4-(tert-butylthio)benzoic acid as a colorless oil. ESI-MS m/z calc. 210.3, found 211.1 (M+1)+. Retention time: 1.74 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Si:9]([O:16][CH2:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C(OCC)(=O)C.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]>[Si:9]([O:16][CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([C:2]2[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=2)[CH2:22][CH2:23]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCNCC1
Reactant: Clc1ccc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCC1CCN(c2ccc(Cl)nc2)CC1
Temperature: 80 °C
Yield: 8.9 %

Procedure:
5-Bromo-2-chloropyridine (1.00 g, 5.20 mmol), 4-((t-butyldimethylsilyloxy)-methyl)piperidine (284), (1.19 g, 5.20 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.0952 g, 0.104 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.180 g, 0.312 mmol), and sodium t-butoxide (0.749 g, 7.79 mmol) were dissolved in 40 mL dioxane under argon. The reaction was heated at 80° C. for 17 hours. The resulting solution was cooled an taken up in ethyl acetate (125 mL) and washed with aqueous K2CO3, (10%, 100 mL) water (100 mL1), and brine (100 mL). The organic phase was dried (MgSO4) and evaporated to give an orange oil. Silica gel chromatography (gradient elution hexanes/0-10% ethyl acetate) afforded compound 281 as a white solid (158 mg, 9%).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH:14]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-:37].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH:14]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[CH2:15][F:37])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCC(Oc2cnn(C(C)(C)C)c(=O)c2Cl)c2ccc(C(C)(C)C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(C(CF)Oc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 15 ml round bottom flask charged with 2-tert-butyl-4-chloro-5-(2-p-toluenesulfonyloxy-1-(4-tert-butylphenyl)-1-ethyl)oxy-3(2H)-pyridazinone (0.2 g, 0.375 mmol) is added 3.75 ml of tetrabutylammonium fluoride solution (1M in THF, 3.75 mmol). The mixture is first stirred at room temperature for 15 minutes after which it is heated for 15 minutes at 100° C. The solution is then cooled to room temperature and to it is added dichloromethane followed by water. The layers were separated and the organic layer is washed with water and then dried. The organic layer is then concentrated and subjected to purification using silica gel flash chromatography (ethyl acetate/hexanes) to obtain the above compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O.CN(C)C=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:21])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Yield: 98.5 %

Procedure:
To a mixture of 5.0 g (21.9 mmol) of 4-benzyloxy-benzoic acid in 25 mL of dichloromethane (DCM) was added dropwise 10 mL (114 mmol) of oxalyl chloride, followed by 5 □L of dimethylformamide (DMF cat) and the reaction mixture was heated at reflux for 3 h, and concentrated to give 5.32 g (98%) of desired 4-benzyloxy-benzoyl chloride as a yellow solid as indicated by 1H NMR. The product was used without any further purification in the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:40]([O:42]CC)=[O:41])[CH2:9][CH:8]([CH2:10][C:11]2[CH:12]=[C:13]3[C:19]4([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]4)[CH2:18][N:17]([C:31]([O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])=[O:32])[C:14]3=[CH:15][CH:16]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][C:19]2([C:13]3[C:14](=[CH:15][CH:16]=[C:11]([CH2:10][CH:8]4[CH2:9][C:6]([C:4]([OH:5])=[O:3])([C:40]([OH:42])=[O:41])[CH2:7]4)[CH:12]=3)[N:17]([C:31]([O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])=[O:32])[CH2:18]2)[CH2:20]1)=[O:25])([CH3:29])([CH3:28])[CH3:30]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(Cc2ccc3c(c2)C2(CCN(C(=O)OC(C)(C)C)C2)CN3C(=O)OCC[Si](C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CC3CC(C(=O)O)(C(=O)O)C3)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.8 %

Procedure:
1-(2-(Trimethylsilyl)ethyl) 1′-tert-butyl 5-((3,3-bis(ethoxycarbonyl)cyclobutyl)methyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (20.8 mg, 0.033 mmol) was dissolved in ethanol (1 mL). Thereafter, an 8 N aqueous solution of sodium hydroxide (0.5 mL) was added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at room temperature for 4 hours. Thereafter, a 1 N aqueous solution of hydrochloric acid was added to the reaction solution, and the thus obtained mixture was neutralized and was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo, to obtain 3-((1′-(tert-butoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy) carbonyl)spiro[indoline-3,3′-pyrrolidin]-5-yl)methyl)cyclobutane-1,1-dicarboxylic acid (19.3 mg, quant.) in the form of a colorless oily product.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([C:11]1C(O)=[C:13]2[C:17](=[C:18]([CH3:20])[CH:19]=1)[N:16]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15](=[O:28])[C:14]2(C)[CH3:29])[CH:9]=[CH2:10]>N1C=CC=CC=1>[C:5]([O:4][C:1]1[C:11]([CH2:8][CH:9]=[CH2:10])=[CH:19][C:18]([CH3:20])=[C:17]2[C:2]=1[C:14]([CH3:29])([CH3:13])[C:15](=[O:28])[N:16]2[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:7])[CH3:6]
Reactant: C=CCc1cc(C)c2c(c1O)C(C)(C)C(=O)N2Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=CCc1cc(C)c2c(c1OC(C)=O)C(C)(C)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.5 g (50.9 mmol) of acetic anhydride was added to a solution of 8.2 g (25.5 mmol) of 5-allyl-1-benzyl-2,3-dihydro-4-hydroxy-3,3,7-trimethyl-1H-indol-2-one and 250 mg (2.0 mmol) of N,N-dimethylaminopyridine in 80 ml of pyridine under cooling with ice, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water, washed with 10% hydrochloric acid, washed with water, and dried. The solvent was evaporated and the residue was purified by column chromatography (silica gel, 5:1 mixture of n-hexane and ethyl acetate) to obtain 8.0 g (yield, 85.2%) of colorless needles of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[C:3]=1[CH:24]([CH2:29][CH2:30][CH3:31])[C:25]([O:27]C)=[O:26].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[C:3]=1[CH:24]([CH2:29][CH2:30][CH3:31])[C:25]([OH:27])=[O:26]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc2c(c1)OCO2)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc2c(c1)OCO2)CCCC3
Temperature: 60 °C
Yield: 57.8 %

Procedure:
To a solution of methyl [2-methyl-4-(benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.300 g; 0.686 mmol) in methanol (6.9 mL) was added a solution of sodium hydroxide 5 N (1.4 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was crystallized from a mixture ethyl acetate-heptane to furnish 0.168 g (58%) of the title compound as a light yellow solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[S:18](=[O:21])(=[O:20])[CH2:19][C:10]=3[C:9]([C:22](O)=[O:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>C(Cl)Cl.CN(C=O)C.Cl>[N:31]1([C:22]([C:9]2[C:10]3[CH2:19][S:18](=[O:20])(=[O:21])[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]=3[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:23])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: C1COCCN1
Reactant: O=C(O)c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1ccccc1-2
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide (150.00 mg; 0.44 mmol; 1.00 Eq) is suspended in DCM (4.00 ml) and 2 drops of DMF and then Oxalyl chloride (3 mL) is added dropwise. The reaction mixture is stirred at room temperature for 30 min. The solution is evaporated to dryness. The residue is suspended in DCM (4.00 ml) and morpholine (350.00 μL; 4.02 mmol; 9.12 Eq) is added dropwise. The reaction mixture is stirred at rt for 30 min then diluted with aq. solution of HCl 0.05 M. The two layers are separated. The aqueous layer is extracted with DCM (2×). The organic layers are washed with a saturated solution of NaHCO3 and brine, dried over MgSO4 and evaporated to give foam. The foam is recrystallised in EtOH to the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.04-8.01 (m, 1H), 7.67-7.53 (m, 7H), 6.85-6.82 (m, 1H), 4.91 (s, 2H), 3.98-3.94 (m, 2H), 3.68-3.61 (m, 6H). UPLC/MS: (ES+): 410.1, (ES−): 408.1. HPLC (max plot) 100.0%; Rt 3.36 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](=O)(O)[O-].[K+].CI>CN(C)C=O.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)ccc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 102.4 %

Procedure:
To a solution of 2-bromo-5-methoxybenzoic acid (15.0 g) in dimethylformamide (100 ml) were added potassium bicarbonate (7.83 g) and methyl iodide (8.12 ml) and the mixture was stirred for 20 hours at room temperature. The reaction mixture was diluted with water and was extracted with a mixture of ethyl acetate and hexane (1/1). The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=8:1) to give the title compound (16.3 g) having the following physical data.