Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH:9](O)[CH2:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[S:20]([O:23]Cl)(=O)=[O:21].C(OCC)(=O)C.CCCCCC.C(Cl)[Cl:38]>>[C:1]1([C:7]2[CH2:8][CH:9]([S:20]([Cl:38])(=[O:23])=[O:21])[CH2:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OCl
Reactant: ClCCl
Reactant: OC1CC(c2ccccc2)=C(c2ccccc2)C1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=S(=O)(Cl)C1CC(c2ccccc2)=C(c2ccccc2)C1
Reaction time: 8 h

Procedure:
3,4-Diphenyl-3-cyclopenten-1-ol (5.91 g) was dissolved in the mixture of 70 mL of methylene chloride and 50 mL of pyrridine. To this reaction mixture was added 4 mL of CH3SO3Cl. After stirring overnight and reaction mixture was washed with 1 M of HCl, H2O and NaHCO3. Solution was dried over Mg2SO4 and then filtered. Solvent removal gave brown solid. About 8 mL of ethyl acetate was added followed by 150 mL of hexane producing off-white crystalline solid). After stirring overnight solid was collected on the frit, washed with 10 mL of hexane and then dried under reduced pressure to give 4.0 g of product.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:9]1([CH2:15][C:16](=[O:20])[C:17]([O-:19])=[O:18])[CH:14]=CC=C[CH:10]=1.[C:21]1([C:27](C)([OH:31])[C:28]([OH:30])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.S(=O)(=O)(O)O>>[C:28]([OH:30])(=[O:29])[C@@H:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:31].[OH:20][C@H:16]([CH2:15][CH:9]([CH3:14])[CH3:10])[C:17]([O-:19])=[O:18]
Reactant: CC(O)(C(=O)O)c1ccccc1
Reactant: O=C([O-])C(=O)Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)C[C@@H](O)C(=O)[O-]
Product: O=C(O)[C@H](O)c1ccccc1
Reaction time: 9 h

Procedure:
In an electrochemical cell, 25 ml of a solution of 100 mM potassium phosphate buffer at pH 7.0, 4 mM methylviologen and 40 mM phenylpyruvate were reduced with 0.5 mg of 2-oxoacid reductase according to Example 3 at a voltage of -700 mV, against a standard calomel electrode. The current of 5.8 mA decreased sharply after 9 hours. According to HPLC analysis, the reaction solution contained 88% of the phenyllactic acid expected. The solution was acidified to pH 1.8 with dilute sulfuric acid and then extracted with ether. The crystalline residue (78% of theory) was converted to the sodium salt, which had a specific rotation of [α]RT 589=21.1° (0.09 millimole/ml of H2O). A pure commercial preparation of (2S)-sodium phenyllactate gave a value of -21.4°, measured under the same conditions. (R)-mandelic acid and (R)-2-hydroxy-4-methylpentanoate were prepared by a similar method.
Reaction SMILES: O.[OH-].[Li+].[OH:4][C@H:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][C:7]([O:9]C)=[O:8].Cl>C1COCC1.O.C(OCC)C>[OH:4][C@H:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@@H](O)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Lithium hydroxide monohydrate (1.98 g, 47.2 mmol) was added to a solution of (R)-methyl 3-hydroxytetradecanoate (42, 8.17 g, 31.5 mmol) in THF (66 mL) and water (66 mL) and stirred at room temperature for 2 h. The mixture was then diluted with diethyl ether (1 L) and the pH adjusted to ˜3 with a solution of hydrochloric acid (1 N). The solution was then extracted with diethyl ether (200 mL), and the organic fractions were combined and dried over Na2SO4. Na2SO4 was removed by filtration and the filtrate was concentrated in vacuo to provide (R)-3-hydroxytetradecanoic acid (36, 7.59 g, 98%) as an off-white solid. 1H NMR (CDCl3) δ 3.99-3.94 (m, 1H), 2.45-2.39 (m, 2H), 1.47 (br s, 3H), 1.29 (br s, 17H), 0.89 (t, J=7.0 Hz, 3H).
Reaction SMILES: N=[C:2]([C:8]1[CH:9]=[CH:10][C:11]([Br:14])=[N:12][CH:13]=1)[C:3](OCC)=O.[N:15]#[N:16].C([CH:21]([CH2:26][CH2:27][CH3:28])[C:22]([NH:24]N)=O)CCC>CO>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:2][C:3]2[N:16]([CH2:3][CH2:2][CH2:8][CH3:13])[N:15]=[C:22]([CH2:21][CH2:26][CH2:27][CH3:28])[N:24]=2)=[CH:13][N:12]=1
Reactant: CCCCC(CCC)C(=O)NN
Reactant: N#N
Reactant: CCOC(=O)C(=N)c1ccc(Br)nc1
Solvent: CO
Product: CCCCc1nc(Cc2ccc(Br)nc2)n(CCCC)n1
Yield: 79.7 %

Procedure:
Under nitrogen, a solution of 1.2 g (5 mmol) of imidate ester from step 6 and 850 mg (5 mmol) of N2 -butyl valeric acid hydrazide from step 2 in 25 mL of absolute methanol was stirred for 24 h at ambient temperature. The methanol was removed in vacuo and replaced with 25 mL of anhydrous toluene. The reaction vessel was equipped with a Dean-Stark trap and the reaction stirred at reflux for 48 h. Concentration in vacuo produced the crude product residue. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (60:40) gave 700 mg (40%) of 2-bromo-5-[(1, 3-dibutyl-1H-1,2,4-triazol-5-yl)methyl]pyridine as an oil: NMR (CDCl3) δ 0.88 (t, J=7Hz, 3H), 0.92 (t, J=7Hz, 3H), 1.25-1.75 (m, 8H), 2.67 (t, J=8Hz, 2H), 3.93 (t, J= 7Hz, 2H), 4.05 (s, 2H), 7.43 (s, 1H), 7.44 (s, 1H), 8.27 (s, 1H); MS (FAB)m/e (rel intensity) 353 (50), 351 (50), 297 (100), 295 (100), 215 (40), 160 (90), 158 (90), 138 (70).
Reaction SMILES: C([O:4][C:5]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11]([O:13]C)=[O:12])[C:6]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=O)C.C1(C)C=CC=CC=1.C(OO)(=O)C>O>[CH2:15]([C:6]12[C:5](=[O:4])[CH2:9][CH2:8][CH:7]1[CH2:10][C:11](=[O:13])[O:12]2)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC1=C(OC(C)=O)CCC1CC(=O)OC
Agent: CC(=O)OO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC12OC(=O)CC1CCC2=O
Reaction time: 2 h
Yield: 94.5 %

Procedure:
A 2000 ml three-necked round-bottom flask, equipped with a magnetic stirrer, nitrogen device, thermometer, dropping funnel and a reflux condenser was charged with 591.0 g of crude methyl 3-acetoxy-2-pentyl-2-cyclopentene-1-acetate and 70 g of toluene. At 26° C. 386.9 g (2.04 mol) 40% peracetic acid were added dropwise over a 5.3 h period. Stirring was continued for 2 h. 22.0 g (0.12 mol) of 40% peracetic acid were added over 30 min, and stirring was continued for another 2 h. 350 g of water were added and the water-layer (590.4 g) was separated. Three more washes were made with each 350 ml of water. The organic phase (1273.9 g) was evaporated to give 437.8 g of crude product which was vacuum distilled (0.4 hPa) to furnish 2 fractions, of which the first one (Bp=90-144° C.) was 172.55 g, containing 26.5% of product and the second one was 187.6 g, containing 95% of lactone. 1H-NMR: 0.88 (br t, J=6.7 Hz, Me); 1.15-1.45 (m, 6H); 1.67-1.87 (m, 3H); 2.14-2.63 of overlapping m, 4H); 2.84-2.97 (m, 2H). 13C-NMR: 13.9 (Me), 22.4, 22.6, 25.0, 31.9, 33.0, 35.7, 35.8 (CH2), 38.6 (CH), 89.0 (C), 175.0 (CO2), 210.9 (CO). MS: M+=210 (5): 154 (16), 139 (22), 112 (25), 111 (73), 99 (79), 98 (100), 83 (26), 71 (26), 55 (73), 43 (28).
Reaction SMILES: [OH:1][CH:2]([CH2:27][CH2:28][CH2:29][OH:30])/[CH:3]=[CH:4]/[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12]([CH3:14])=[O:13])=[CH:8][C:7]1([OH:26])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[OH:1][CH:2]([CH2:27][CH2:28][CH2:29][OH:30])/[CH:3]=[CH:4]/[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12]([CH3:14])(=[O:39])=[O:13])=[CH:8][C:7]1([OH:26])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)C1=CC(O)(CCCCOc2ccccc2)C(=C/C=C/C(O)CCCO)C1=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)C1=CC(O)(CCCCOc2ccccc2)C(=C/C=C/C(O)CCCO)C1=O
Reaction time: 2 h
Yield: 45.6 %

Procedure:
To a solution of 165 mg of 5-[(E)-4,7-dihydroxyheptenylidene]-4-hydroxy-2-methylsulfinyl-4-(4-phenoxybutyl)-2-cyclopentenone obtained in Example 104 dissolved in 30 ml of dichloromethane was added a solution 117 mg of 3-chloroperbenzoic acid in 5 ml of dichloromethane, and the mixture was stirred for 2 hours. The reaction mixture was poured onto saturated aqueous sodium thiosulfate, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed twice with saturated aqueous sodium hydrogencarbonate and with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. After filtration and concentration, the concentrate was subjected to chromatography to give 78 mg (yield 47%) of 5-[(E)-4,7-dihydroxy-2-heptenylidene]-4-hydroxy-2-methylsulfonyl-4-(4-phenoxybutyl)-2cyclopentenone
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[NH:4][C:5]([CH3:10])=[C:6]([CH2:8][CH3:9])[CH:7]=1.Cl[CH2:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.C(N(CC)CC)C>C(O)C>[S:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[CH2:13][NH:1][C:2]1[C:3](=[O:11])[NH:4][C:5]([CH3:10])=[C:6]([CH2:8][CH3:9])[CH:7]=1
Reactant: ClCc1nc2ccccc2s1
Reactant: CCc1cc(N)c(=O)[nH]c1C
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1cc(NCc2nc3ccccc3s2)c(=O)[nH]c1C
Yield: 77.8 %

Procedure:
A solution of 3-amino-5-ethyl-6-methyl-2-(1H)-pyridinone (152 mg, 1.0 mmol), 2-chloromethyl-1,3-benzthiazole (184 mg, 1.0 mmol) and triethylamine (0.14 mL, 1.0 mmol) in absolute ethanol (5 mL) was stirred at reflux for 24 hours. After filtering and concentrating under reduced pressure, the residue was flash chromatographed over silica gel. Elution with 4% MeOH- 96% CHCl3 gave 233 mg of product. Recrystallization from EtOH-water gave 77 mg of analytically pure product, mp 209°-210° C. Anal. Calcd for C16H17N3OS: C, 67.83; H, 6.05; N, 14.83. Found: C, 67.71; H, 6.03; N, 14.70.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[O:20][CH3:21].N1C=CC=CC=1.O>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])=[CH:14][C:13]=1[O:20][CH3:21]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1cc(C=O)ccc1F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(C=C2C(=O)OC(C)(C)OC2=O)ccc1F
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a solution of titanium (IV) chloride (11.1 g) in THF (50 mL) was added dropwise a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (4.26 g) and 4-fluoro-3-methoxybenzaldehyde (3.08 g) in THF (50 mL) at 0° C., and then a solution of pyridine (4.00 g) in THF (20 mL) was added dropwise. The reaction mixture was stirred for 1 hr, and water was added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (3.20 g) as a yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:28]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:7]([CH:32]1[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
Phenol (503 mg, 5.34 mmol) and triphenylphosphine (1.40 g, 5.34 mmol) were added to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (500 mg, 2.67 mmol; which may be prepared as described in Step 1) in anhydrous THF (13 mL) under nitrogen. The reaction mixture was cooled to 0° C. and DEAD (775 μL, 4.27 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure then diluted with dichloromethane and filtered. The filtrate was washed three times with NaOH 0.2N and brine, dried over Na2SO4 then concentrated. The residue was purified on column chromatography (eluent: pentane EtOAc 9/1) to give the title compound (175 mg, 25%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[SH:11].C(N(CC)CC)C.Cl[CH2:20][C:21](=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:21]1[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[S:11][CH:20]=1)[CH3:27]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1ccc([N+](=O)[O-])cc1S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1=CSc2cc([N+](=O)[O-])ccc2N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.6 %

Procedure:
A solution of 2-amino-5-nitro-benzenethiol (Example 8a, 4.1 g, 23.9 mmol) in tetrahydrofuran (60 mL) was treated with triethylamine (4.8 g, 47.8 mmol) and ethyl chloroacetoacetate (4.3 g, 26.3 mmol). The reaction mixture was stirred at 25° C. for 12 h, concentrated in vacuo, taken up in ethyl acetate, and heated at 80° C. for 3 h. The reaction mixture was allowed to cool to 25° C., washed with brine solution, dried over sodium sulfate, and concentrated in vacuo. The resulting brown solid was triturated with diethyl ether to afford the desired product, (7-nitro-4H-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (5.8 g, 20.7 mmol, 87% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.32 (t, 3H, J=7.1 Hz), 3.49 (s, 2H), 4.21 (q, 2H, J=7.0 Hz), 4.89 (s, 1H), 6.91 (d, 1H, J=8.7 Hz), 8.00 (dd, 1H, J1=9.5 Hz, J2=2.3 Hz), 8.12 (d, 1H, J=3.1 Hz), 10.95 (bs, 1H). LC-MS (ESI) calcd for C12H12N2O4S [M+H+] 281.05, found 281.23 [M+H+].
Reaction SMILES: [Br:1]Br.C(Cl)(Cl)Cl.[CH3:7][C:8]([C:10]1([CH3:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9].CO>BrBr.O>[CH3:16][C:10]1([C:8]([CH2:7][Br:1])=[O:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(=O)C1(C)CCCCC1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CC1(C(=O)CBr)CCCCC1
Reaction time: 0.17 h

Procedure:
A solution of 328 g. bromine in 300 ml. chloroform was added gradually to a stirred solution of 300 g. 1-methylcyclohexyl methyl ketone in 100 ml. methanol. After the addition of a few drops of bromine solution at 15° C. the reaction mixture was cooled and maintained between 0°-5° C. The reaction mixture was stirred for 10 minutes, after the addition of bromine had been completed, and then poured on to a mixture of crushed ice and water. The water layer was separated from the organic liquid and extracted with methylene chloride. The extract and the organic portion were combined and washed with water followed by a saturated solution of sodium bicarbonate and then finally with water. After drying over calcium chloride the liquid was evaporated and distilled to give bromomethyl 1-methylcyclohexyl ketone, b.p. 76°-78° C./0.1 mm Hg.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:24]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[C@H:25]([C:36](O)=[O:37])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:35])[NH:31][N+:32]([O-:34])=[O:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[NH:24]([C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[C@H:25]([C:36]([NH:22][CH2:21][C:20]([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:23])=[O:37])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:35])[NH:31][N+:32]([O-:34])=[O:33]
Reactant: NCC(=O)OCc1ccccc1
Reactant: N=C(NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)N[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: N=C(NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)OCc1ccccc1)N[N+](=O)[O-]
Reaction time: 4 h

Procedure:
353 g of tosylate of glycine benzyl ester (H-Gly-o-Bzl, Tosylate) are dissolved in 2 liters of DMF; 115 g of NEM then 353 g of Z-Arg(NO2)-OH and finally 500 g of BOP are added. The pH of the medium is adjusted to 7 with the aid of NEM and using pH indicating paper on samples of the reaction medium diluted with water. The reaction medium is stirred and the state of advance of the reaction followed by TLC. After 4 hrs., the reaction is complete and the medium evaporated to dryness in vacuo at 35°. The residue of evaporation is taken up in 2 liters of ethyl acetate and 2 liters of water. Under these conditions, a solid is obtained which is drained and washed successively in solid phase with a 5% aqueous solution of HKSO4 +K2SO4, with pure water, with a 5% aqueous solution of NaHCO3 and finally water.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([N:20]1[C:25](=[O:26])[C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:30][CH:29]=2)=[C:23]([CH2:42][CH2:43][CH2:44][CH3:45])[N:22]=[C:21]1[CH2:46][OH:47])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH2:13]([N:20]1[C:25](=[O:26])[C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[NH:3][C:4](=[O:7])[O:5][N:41]=3)=[CH:30][CH:29]=2)=[C:23]([CH2:42][CH2:43][CH2:44][CH3:45])[N:22]=[C:21]1[CH2:46][OH:47])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCc1nc(CO)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(CO)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.75 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C. for 30 min, 4′-{[1-benzyl-4-butyl-2-(hydroxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.50 g) was added, and the mixture was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.18 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.32 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.20 g, 35%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:23][O:22][CH2:21]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:30].[Na+].OP([O-])(O)=O.[Na+]>C(#N)C.O.C(O)(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:30])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:23][O:22][CH2:21]2)=[CH:15][CH:14]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(OC4COC4)cc3)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OC4COC4)cc3)cc12
Reaction time: 0.03 h
Yield: 38.5 %

Procedure:
To a solution of 6-chloro-5-[4-(oxetan-3-yloxy)phenyl]-1H-indole-3-carbaldehyde (100 mg, 0.34 mmol) in acetonitrile (4 mL) was added tert-butanol (4 mL), water (4 mL) and 2-methyl-2-butene (2.52 mL). The reaction mixture was stirred for 2 minutes and treated with sodium chlorite (620 mg, 9.25 mmol) and sodium phosphate monobasic (1.45 g, 9.29 mmol). The mixture was stirred at room temperature for 17 hours. The reaction was quenched with sodium sulfite and the mixture was concentrated in vacuo to give a residue, which was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na2SO4 and concentrated in vacuo to give a residue, which was purified by prep-HPLC to give 6-chloro-5-[4-(oxetan-3-yloxy)phenyl]-1H-indole-3-carboxylic acid (45 mg, 42%) as an off-white solid. MS (ES+) 343.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.07 (s, 1H), 7.92 (s, 1H), 7.62 (s, 1H), 7.35 (d, 2H), 6.87 (d, 2H), 5.35-5.32 (m, 1H), 4.97-4.94 (m, 2H), 4.61-4.58 (m, 2H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[NH:9][C:8](=[O:10])[CH:7]=[C:6]([CH3:11])[N:5]=1)[CH3:2].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([S:3][C:4]1[N:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[C:8](=[O:10])[CH:7]=[C:6]([CH3:11])[N:5]=1)[CH3:2]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCSc1nc(C)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCSc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 29.6 %

Procedure:
To a solution of 2-ethylthio-6-methylpyrimidin-4(3H)-one (6.1 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (10.6 g) in acetonitrile (120 mL) was added potassium carbonate (5.9 g), and the mixture was stirred at 50° C. for 12 hr. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (3.83 g, 30%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.Cl.Cl>O1CCCC1.C(Cl)Cl>[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH:22][C:11](=[O:13])[CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:17][CH:16]=1
Reactant: NCCOc1ccc(Cl)cc1
Reactant: COc1ccccc1CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccccc1CCC(=O)NCCOc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
3-(2-Methoxyphenyl)propionic acid (8.3 g, 46.2 mmol) was dissolved in tetrahydrofuran (20 mL), and 4-chlorophenoxyethylamine (10.3 g, 60.0 mmol) was added dropwise thereto at room temperature. Subsequently, a solution (10 mL) of WSC•HCl (11.5 g, 60.0 mmol) in methylene chloride was slowly added dropwise thereto under ice-cooling, followed by stirring overnight. Under ice cooling, diluted hydrochloric acid was added dropwise thereto, followed by extraction with chloroform. The organic layer was washed with brine, and the resultant mixture was subjected to drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=20/1), whereby the target compound was obtained (12.8 g, 83%).