Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](Cl)[CH:4]([C:10]([Cl:13])([CH3:12])[CH3:11])[CH2:5][C:6]([O:8][CH3:9])=[O:7].C(=O)(O)[O-].[Na+]>>[Cl:13][C:10]([CH3:12])([CH3:11])[CH:4]([CH:3]=[O:2])[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(C(Cl)OC)C(C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CC(C=O)C(C)(C)Cl

Procedure:
The solution of Step A was poured into an iced aqueous sodium bicarbonate solution and the mixture was extracted with methylene chloride. The organic phase was evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 4-1 hexane-ethyl acetate mixture yielded 600 mg of methyl 4-chloro-4-methyl-3-formyl-pentanoate which crystallized at -20° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15](S)=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].OO.[OH-].[Na+]>C(Cl)Cl.CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH:15]=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(S)n1-c1ccc(F)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cncn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.6 %

Procedure:
To a suspension of 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (737 mg, 1.9 mmol) in DCM (4 mL) at 0° C. was added a solution of 0.6 mL H2O2(35% wt.) in HOAc (2 mL). After stirring 40 min, the mixture was allowed to warm to room temperature. After stirring 6 h, the reaction mixture was neutralized to pH 9 using 2N NaOH and was extracted with DCM. The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by chromatography (silica, 0-95% EtOAc/Hex) to give 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole as a white solid (455 mg, 69% yield).
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3]([CH3:5])=O.[CH2:7]([SH:11])[CH2:8][CH2:9][SH:10]>C(Cl)(Cl)Cl>[CH3:5][C:3]1([CH:2]([Cl:6])[Cl:1])[S:11][CH2:7][CH2:8][CH2:9][S:10]1
Reactant: SCCCS
Reactant: CC(=O)C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC1(C(Cl)Cl)SCCCS1
Temperature: 0 °C
Yield: 80 %

Procedure:
In a three-necked flask equipped with a magnetic stirrer and having a nitrogen blanket at the inlet and outlet, are added 13.97 grams (0.11 mole) of 1,1-dichloroacetone, 10.8 grams (0.10 mole) of 1,3-propanedithiol and 50 milliliters of chloroform. The reaction mixture is cooled to 0° C. A slow steam of hydrogen chloride gas is then bubbled through the solution for approximately five minutes. Upon the reaction mixture reaching saturation, the mixture is allowed to set at room temperature for approximately thirty minutes. The solvent is then evaporated and a crude 2-methyl-2-dichloromethyl-1,3-dithiane derivative is expected in a yield of approximately 80–90%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1ccnc(NC(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(CCC(=O)O)ccn1
Temperature: 25 °C
Reaction time: 21 h
Yield: 38.1 %

Procedure:
Methyl 3-{2-[(tert-butoxycarbonyl)amino]-4-pyridyl}propanoate (30.65 g, 0.11 mol) dissolved in methanol (200 ml) was added with 1 N aqueous sodium hydroxide (164 ml) and stirred at room temperature for 21 hours. After the solvent was evaporated under reduced pressure and the residue was washed with diethyl ether, the resulting aqueous layer was added with concentrated hydrochloric acid until pH of the layer became 1. The solution was washed with ethyl acetate, and the resulting aqueous layer was neutralized by further adding sodium hydroxide. The solution was extracted with chloroform:methanol=10:1, and the resulting organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 11.16 g (38%) of the title compound as yellow crystals without purification.
Reaction SMILES: [C:1](=[O:21])([O:19][CH3:20])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([C:12]#[C:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:5][C:4]=1[CH3:18].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C(O)(=O)C.O.[Fe]>[C:1](=[O:21])([O:19][CH3:20])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([C:12]#[C:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:5][C:4]=1[CH3:18]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(C#CCN(C)C)cc1C
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)Oc1cc(N)c(C#CCN(C)C)cc1C
Temperature: 60 °C
Yield: 79 %

Procedure:
To a solution of 4-(3-(dimethylamino)prop-1-ynyl)-2-methyl-5-nitrophenyl methyl carbonate (120 mg; 0.41 mmol) in ethanol (2.7 mL) and glacial acetic acid (1.5 mL) was added Fe (92 mg, 1.64 mmol). The mixture was heated at 60° C. for 1 h and then cooled to room temperature. The mixture was diluted with water and carefully neutralized with solid Na2CO3. The resulting solution was extracted with ethyl acetate. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% ethyl acetate/hexanes) to provide 5-amino-4-(3-(dimethylamino)prop-1-ynyl)-2-methylphenyl methyl carbonate (85 mg, 79% yield). LC/MS m/z 218.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[CH3:25]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:24]([CH3:25])=[C:19]([F:18])[CH:20]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1ccc(-c2cc(Cl)cc3c(C)c4n(c23)CCNC4=O)cc1F

Procedure:
The title compound, off-white solid (69 mg, 81%), MS (ISP) m/z=343.4 [(M+H)+], mp 225° C., was prepared in accordance with the general method of example 1 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 3-fluoro-4-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([NH:11][C@@H:12]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[C:22]([F:31])[CH:21]=2)[C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:10])=[N:6][C:7]=1[OH:8].Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.CCOC(C)=O>C1COCC1.CCCCCC>[F:31][C:22]1[CH:21]=[C:20]([C@@H:12]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[NH:11][C:9]([C:5]2[N:6]=[C:7]3[O:8][C:33](=[O:35])[NH:1][C:2]3=[CH:3][CH:4]=2)=[O:10])[CH:25]=[CH:24][C:23]=1[O:26][C:27]([F:28])([F:30])[F:29]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)nc1O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1ccc2[nH]c(=O)oc2n1
Temperature: -78 °C

Procedure:
To a cooled (−78° C.), stirred mixture of (S)-5-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-6-hydroxypicolinamide (400 mg, 0.00098 mol) in THF (4 mL) was added TEA (1.31 mL, 0.0090 mol, Spectrochem, India) and triphosgene (323 mg, 0.0010 mol, Spectrochem, India) in one lot and the reaction mixture was stirred for 2 h at the same temperature. The reaction was slowly warmed to room temperature overnight. After completion of the reaction (monitored by TLC, 50% EtOAc in hexane), the reaction mixture was quenched with water (2 mL) and extracted with EtOAc (2 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and purified by column chromatography, silica (60-120 mesh) using 50-60% EtOAc in petroleum ether as an eluent, and subsequently purified further using Prep TLC plates, mobile phase 50% EtOAc in hexane to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 12.40 (s, 1H), 9.53 (d, J=7.2 Hz, 1H), 8.59 (d, J=4.4 Hz, 1H), 7.90-7.80 (m, 2H), 7.61-7.53 (m, 4H), 7.35 (d, J=8.8 Hz, 1H), 6.54 (d, J=7.2 Hz, 1H). MS (ESI, positive ion) m/z: 467.1 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:22]([NH:24][N:25]([C:30](=[O:37])[CH:31]([O:33]C(=O)C)[CH3:32])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CO.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:22]([NH:24][N:25]([C:30](=[O:37])[CH:31]([OH:33])[CH3:32])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(=O)OC(C)C(=O)N(CC(C)C)NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C(C)O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A solution of 1.11 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(2(RS)-acetoxypropionyl)-2′-isobutyl-4-methylvalerohydrazide in a mixture of 8 ml of methanol and 4 ml of water was treated with 0.524 g of potassium carbonate. The mixture was stirred at room temperature for 2 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried over anhydrous magnesium sulphate and was evaporated to give a foam. Trituration of this foam with diethyl ether gave 0.71 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(2(RS)-hydroxypropionyl)-2′-isobutyl-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].[CH3:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>[OH-].[Na+].CCOCC>[CH3:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:10][C:8](=[NH:9])[S:7][CH3:6])=[O:17])=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CSC(=N)NC(=O)c1ccc(C)cc1
Reaction time: 8 h

Procedure:
A solution of 2-methyl-2-thiopseudourea sulfate (6.9 g, 0.025 mol) in 30 ml of sodium hydroxide (4%) was added a solution of 4-methylbenzoyl chloride (3.4 g, 0.022 mol) in ether (10 ml) at room temperature. The reaction mixture was stirred overnight and the precipitated solid was filtered, washed with water, later hexanes and dried under high vacuum. N-(4-methylbenzoyl)-S-methylisothiourea: yield 4.60 g (quantitative); purity 98% (HPLC); 1H-NMR (CD3OD) δ 2.4 (s, 3H, CH3), 2.6 (s, 3H, SMe), 7.2 (d, 2H, ArH), 8.1 (d, 2H, ArH).
Reaction SMILES: [Cl-].ClC1N(C)CC[NH+]1C.[NH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[C:38]([O:45]C(=O)C)[CH:37]=2)[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)(Cl)Cl.C(Cl)Cl>[N:14]1[CH:15]=[CH:16][C:11]([NH:10][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=3[CH3:49])=[CH:37][C:38]=2[OH:45])=[CH:12][CH:13]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(OC(C)=O)c2)=C(C)C1=O
Reactant: Nc1ccncc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3ccncc3)c(O)c2)=C(C)C1=O
Yield: 7 %

Procedure:
2-Chloro-1,3-dimethylimidazolinium chloride (43 mg, 0.257 mmol), 4-aminopyridine (24 mg, 0.257 mmol) and triethylamine (26 mg, 0.257 mmol) were added to a methylene chloride solution (5 ml) of 4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (64 mg, 0.171 mmol) in a nitrogen atmosphere and the resulting solution was stirred all the night through. The reaction solution was diluted with chloroform, then washed with water and dried, and the solvent was removed by distillation. Subsequently, an aqueous saturated sodium hydrogencarbonate solution (10 ml) was added to a methanol solution (4 ml) of the obtained residue and the resulting solution was stirred for 1 hour. The reaction solution was extracted with ethyl acetate, then washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (methylene chloride:methanol=30:1) to obtain the titled compound (5 mg, 0.012 mmol, 7.2%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([S:10][CH2:11][C:12]1[N:13]=[N:14][N:15]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1)(=O)C.Cl>O1CCCC1>[C:17]([N:15]1[CH:16]=[C:12]([CH2:11][SH:10])[N:13]=[N:14]1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(=O)SCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: SCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 76.5 %

Procedure:
To a suspension of litium aluminum hydride (1.07 g: 28.2 mMol.) in tetrahydrofuran (100 ml) under ice cooling is added 4-acetylthiomethyl-1-trityl-1,2,3-triazole (7.50 g: 18.8 mMol.), and the mixture is stirred at room temperature for 40 minutes. To the reaction mixture is added aqueous tetrahydrofuran dropwise, and the mixture is neutralized with 10% hydrochloric acid. The solution is filtered and the filtrate is diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated. The residue is crystallized from ether and washed with ether to give 1-trityl-1,2,3-triazol-4-ylmethylmercaptan (5.14 g) as white crystals. Yield: 77%. mp. 140° to 141° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Br)[CH3:2].[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][O:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:21][CH:20]=1)[CH3:2]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Ethylbromoacetate (4.17 g, 25 mmol) was added to a mixture of 4-benzyloxyphenol (5.00 g, 25 mmol) and K2CO3 (3.50 g, 25 mmol) in DMF (75 mL) and stirred for 20 hours at ambient temperature. The mixture was then concentrated in vacuo and the residue partitioned between water and EtOAc. The aqueous phase was further extracted with 2×50 mL of EtOAc and the combined extracts were washed with 2×50 mL of water and dried over Na2SO4. Concentration of the organic solution in vacuo left 7.00 g (97%) of product as a white solid. m.p. 65–68° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[O:7][CH:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=1.[C:13](Cl)(=O)[C:14](Cl)=O.C(O)C.C(N(CC)CC)C>O1CCCC1.CN(C)C=O>[CH2:13]([O:9][C:8]([C:5]1[CH:4]=[C:3]([Si:2]([CH3:12])([CH3:11])[CH3:1])[O:7][CH:6]=1)=[O:10])[CH3:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[Si](C)(C)c1cc(C(=O)O)co1
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
5-Trimethylsilyl-3-furancarboxylic acid (4.1 g) (synthesized in accordance with the method described in Tetrahedron Lett., 25, 4451 (1984)) was dissolved in tetrahydrofuran (100 ml), and N,N-dimethylformamide (3 drops) was added. Oxalyl chloride (3.0 g) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Ethanol (100 ml) and triethylamine (4.7 g) were added, and the resulting mixture was stirred at room temperature for 15 hours. The mixture as concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-trimethylsilyl-3-furancarboxylic acid ethyl ester (3.0 g) as oil. 5-Trimethylsilyl-3-furancarboxylic acid ethyl ester (3.0 g) was dissolved in acetonitrile (15 ml), and sulfuryl chloride (2.0 g) in acetonitrile (5 ml) was added dropwise. The mixture was stirred at room temperature for 30 minutes, poured into ice water and extracted with diethyl ether. The extract was washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-chloro-3-furancarboxylic acid ethyl ester (1.9 g) as oil. 5-Chloro-3-furancarboxylic acid ethyl ester (1.9 g) was dissolved in ethanol (15 ml), and 1N aqueous sodium hydroxide (12 ml) was added. The mixture was stirred at room temperature for 1.5 hour and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magensium sulfate and concentrated under reduced pressure. Precipaitated crystals were collected by filtration and washed with hexane to give 5-chloro-3-furancarboxylic acid (1.1 g) as crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([O:17]C)=[O:16])[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[C:5]([CH3:19])[CH:4]=[N:3]1.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([OH:17])=[O:16])[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[C:5]([CH3:19])[CH:4]=[N:3]1
Reactant: CCCc1sc(C(=O)OC)cc1-c1c(C)cnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1sc(C(=O)O)cc1-c1c(C)cnn1C
Yield: 100 %

Procedure:
A solution of methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (0.184 g, 0.66 mmol) in 6N sodium hydroxide (2.2 ml, 13.22 mmol) and tetrahydrofuran (6.6 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (180 mg, 0.66 mmol, 100% yield) as a yellow oil: LCMS (ES) m/e 265 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:9])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Oc1cccc(CO)c1
Reaction time: 2 h
Yield: 95 %

Procedure:
To m-isopropoxybenzaldehyde (38 g, 0.23 mol) in 500 mL of ethanol was added slowly sodium borohydride (12.2 g, 0.32 mol) over a period of 1 h and the mixture was stirred for 2 h, filtered, and concentrated to 100 mL of its volume. The above mixture was diluted with 50 mL of water, neutralized with sulfuric acid solution with cooling, and was extracted with ether (4×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 36.32 g (95%) of m-isopropoxybenzyl alcohol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6](N)[CH:5]=1.N([O-])=O.[Na+].NC(N)=O.C([O-])(=O)C.[Na+].[SH:26][CH2:27][C:28]([OH:30])=[O:29]>Cl.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([S:26][CH2:27][C:28]([OH:30])=[O:29])[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Reactant: O=C(O)CS
Agent: CC(=O)[O-]
Agent: Cl
Agent: NC(N)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Cl)c(SCC(=O)O)c1

Procedure:
4-Chloro-3-aminobenzoic acid methyl ester (7.0 g) was suspended in a mixture of hydrochloric acid (1 M, 85 mL) and water (170 mL). A solution of sodium nitrite (2.59 g) in water (40 mL) was slowly added to the suspension at 0-5° C. temperature. After 40 min stirring at 0-5° C. solid urea (3.8 g) was added and dissolved by stirring. After 5 min a cold solution containing sodium acetate (12.7 g) and mercaptoacetic acid (13.0 mL) in water (85 mL) was added. Ethyl acetate (300 mL) was added and the solution was then refluxed for 60 min. The mixture was cooled and ethyl acetate (100 ml) and hydrochloric acid (6 M, 50 mL) were added. The organic phase was separated and the product extracted from it to potassium bicarbonate solution (1 M, 200 mL). The solution was acidified with 6 M hydrochloric acid and then extracted with ethyl acetate (200 mL). The ethyl acetate extract was dried with sodium sulphate and evaporated to dryness to give impure 4-chloro-3-[(carboxymethyl)thio]benzoic acid methyl ester (15.5 g). This intermediate was mixed with potassium bicarbonate solution (1 M, 160 mL) and then potassium permanganate solution (0.33 M in 0.42 M acetic acid, 750 mL) was slowly added at 20-30° C. (until the color of the permanganate was permanent). After 2 h stirring at 20-30° C., the residual permanganate was decolorized with saturated sodium pyrosulfite solution. The mixture was filtrated and the filtrate was acidified with hydrochloric acid (6 M) and the product was extracted with ethyl acetate. The extract was dried with sodium sulphate and evaporated to dryness (yield 3.5 g) 1H-NMR (400 MHz, DMSO-d6) d=3.93 (s, 3H), 4.70 (s, 2H), 7.93 (d, J=11.1 Hz,1 H), 8.26 (dd, J=11.1 Hz, 2.8 Hz, 1H), 8.51 (d, J=2.8 Hz, 1H), 12.5 (b, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25]O)=[CH:24][C:19]=2[O:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:25][C:23]2[CH:22]=[CH:21][C:20]3[O:16][CH2:17][O:18][C:19]=3[CH:24]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Reactant: OCc1ccc2c(c1)OCO2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCc2ccc3c(c2)OCO3)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.9 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.0 g, 4.8 mmol), benzo[1,3]dioxol-5-yl-methanol (1.4 g, 9.5 mmol), and polymer-supported triphenyl phosphine (3.0 g, 9.5 mmol) in THF (30 mL) in an ice-bath was slowly added diisopropyl azodicarboxylate (1.9 mL, 9.5 mmol) and stirred at r.t. overnight. The mixture was filtered and the filter was washed with ethyl acetate (10 mL). The filtrate was evaporated and the residue was purified by flash column chromatography (EtOAc/Hexane) to give 3-(benzo[1,3]dioxol-5-ylmethoxy)-phthalic acid dimethyl ester (1.7 g, 102% crude yield). The product was used in the next step without further purification.