Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:23])[CH:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]#[N:15])[N:13]=1)=[S:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:14]([C:12]1[N:13]=[C:9]([N:8]2[C:3](=[O:23])[CH:4]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:5][C:6]2=[S:7])[S:10][CH:11]=1)#[N:15]
Reactant: COC(=O)C(Cc1ccccc1)NC(=S)Nc1nc(C#N)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1csc(N2C(=O)C(Cc3ccccc3)NC2=S)n1
Temperature: 25 °C
Yield: 13.2 %

Procedure:
A solution of N-[[(4-cyano-2-thiazolyl)amino]thioxomethyl]-DL-phenylalanine methyl ester (1.42 g, 4.10 mmol) and p-toluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a Dean-Stark trap for 24 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl ether-hexanes to provide 170.1 mg (10%) of the titled product:
Reaction SMILES: Cl.[NH:2]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C@H:6]([CH3:15])[CH2:5]1)[NH2:3].CCN(C(C)C)C(C)C.CN(/[CH:28]=[C:29](/[C:40](=O)[C:41]([F:44])([F:43])[F:42])\[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])C.CCOC(C)=O.CCCCCC>CCO>[CH2:13]([O:12][C:10]([C@H:7]1[CH2:8][CH2:9][C@H:4]([N:2]2[C:40]([C:41]([F:44])([F:42])[F:43])=[C:29]([C:30]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH:28]=[N:3]2)[CH2:5][C@H:6]1[CH3:15])=[O:11])[CH3:14]
Reactant: CCOC(=O)[C@H]1CC[C@H](NN)C[C@H]1C
Reactant: CN(C)/C=C(\C(=O)OCc1ccccc1)C(=O)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)OCc3ccccc3)c2C(F)(F)F)C[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a 250-mL round-bottomed flask was added (1S,2R,4S)-ethyl 4-hydrazinyl-2-methylcyclohexanecarboxylate hydrochloride (4.00 g, 16.90 mmol) and DIPEA (4.43 ml, 25.3 mmol) in EtOH (84 ml). Then a solution of (Z)-benzyl 2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate (5.09 g, 16.90 mmol) in EtOH (84 ml) was added dropwise into the reaction mixture. The overall reaction mixture was allowed to stir under inert atmosphere, while at ambient temperature overnight. The progress of the reaction was monitored by LC/MS and TLC (30% EtOAc/hexane) which showed mostly desired material LCMS (ESI) m/z 461.2 (M+Na)+, without any starting material remaining. The reaction mixture was concentrated in-vacuo. The crude material was purified by chromatography through an Interchim (25 micron) silica-gel column (200 g), eluting with a gradient of 0-30% EtOAc in hexane, to provide benzyl 1-((1S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (5.631 g, 12.84 mmol, 76% yield) as light-yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.32-7.45 (m, 5H), 5.30 (s, 2H), 4.55-4.65 (m, 1H), 4.02-4.15 (m, 2H), 2.65 (td, J=4.50, 11.54 Hz, 1H), 2.13 (dt, J=4.50, 12.42 Hz, 1H), 1.95-2.04 (m, 2H), 1.73 (d, J=4.89 Hz, 3H), 1.16-1.23 (m, 3H), 0.92 (d, J=7.04 Hz, 3H); LCMS (ESI) m/z 461.2 (M+Na)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[C:5]=1[OH:12])[CH:2]=[CH2:3]>ClCCl.CC#N.CC#N.Cl[Pd]Cl>[Br:11][C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:4](/[CH:1]=[CH:2]/[CH3:3])[C:5]=1[OH:12]
Reactant: C=CCc1cc(F)cc(Br)c1O
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: ClCCl
Product: C/C=C/c1cc(F)cc(Br)c1O
Yield: 90.2 %

Procedure:
To a solution of 2-allyl-6-bromo-4-fluorophenol (7.14 g, 0.0309 mol) in anhydrous dichloromethane (100 mL) at room temperature under nitrogen was added bis(acetonitrile)dichloropalladium (II) (0.4 g, 1.54 mmol) and the reaction mixture heated to reflux for 1 hour. Additional bis(acetonitrile)dichloropalladium (II) (0.1 g, 0.39 mmol) was added and heating to reflux continued for 1 additional hour. The cooled reaction mixture was then concentrated under reduced pressure to afford a brown semi-solid. Purification by flash chromatography using a solvent gradient of 0 to 2% ethyl acetate in hexane gave 6.44 g (90%) of 2-bromo-4-fluoro-6-[(1E)-prop-1-enyl]phenol as a white solid. MS (ESI) m/z 229 ([M−H]−).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[C:25]1[NH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[C:32](C(OC)=O)[CH:31]=2)=[CH:28][N:29]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)(O)[O-].[Na+]>O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:25]1[NH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:33]3[CH:32]=[CH:31][C:30]([C:27]4[NH:26][C:25]([CH:21]5[CH2:22][CH2:23][CH2:24][N:20]5[C:18]([O:17][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:19])=[N:29][CH:28]=4)=[CH:35][CH:34]=3)=[CH:32][CH:31]=2)=[CH:28][N:29]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Temperature: 80 °C
Yield: 105 %

Procedure:
To the solution of 245-{4-bromo-3-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (142 mg, 0.27 mmol) and 2-{5-[3-Methoxycarbonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (125 mg, 0.25 mmol) in 1,2-dimethoxyether (2.3 ml) and water (0.7 ml) was added sodium bicarbonate (63 mg, 0.75 mmol), followed by Pd(PPh3)4 (12 mg) and PdCl2(dppf)CH2Cl2 (12 mg). The mixture was heated at 80° C. for 20 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 4,4′-bis-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-2-[(tert-butoxycarbonyl-methyl-amino)-2′-carboxylic acid dimethyl ester (82 mg). m/z: 826 (M+H)+, 413.6 (M+2H)+/2.
Reaction SMILES: C([O:8][C:9]1[CH:39]=[CH:38][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:37])[C:21]([CH2:34][CH2:35][CH3:36])([CH2:31][CH2:32][CH3:33])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][C:25]([F:30])=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1.C(OC1C=CC2NC(C3C(=O)C(CCC)(CCC)C4C(C=3O)=CC=CC=4)=NS(=O)(=O)C=2C=1)C1C=CC=CC=1>>[F:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[C:21]([CH2:34][CH2:35][CH3:36])([CH2:31][CH2:32][CH3:33])[C:20](=[O:37])[C:19]([C:14]1[NH:13][C:12]3[CH:38]=[CH:39][C:9]([OH:8])=[CH:10][C:11]=3[S:16](=[O:17])(=[O:18])[N:15]=1)=[C:28]2[OH:29]
Reactant: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2cc(F)ccc21
Agent: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(O)ccc3N2)=C(O)c2cc(F)ccc21

Procedure:
The title compound was prepared according to the procedure of Example 2G, substituting the compound of Example 15A for the compound of Example 2F. 1H NMR (300 MHz, DMSO-d6): δ 0.57 (m, 2 H) 0.68 (m, 6 H) 0.89 (m, 2 H) 2.01 (dd, J=12.13, 8.82 Hz, 2 H) 2.17 (m, 2 H) 7.18 (m, 2 H) 7.62 (m, 2 H) 7.83 (m, 2 H) 10.41 (s, 1 H) 13.46 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[O:12][CH2:13][C:14]([F:17])([F:16])[F:15].Cl[Sn]Cl.[OH-].[Na+].CC(=O)OCC>CO.Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:11])[C:3]=1[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[NH2:8]
Reactant: O=[N+]([O-])c1cc(Cl)c(OCC(F)(F)F)c(Cl)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(Cl)c(OCC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a solution of 1,3-dichloro-5-nitro-2-(2,2,2-trifluoroethoxy)benzene (1.90 g, 6.55 mmol) in MeOH (20 mL) and 12 N HCl (20 mL) at rt, SnCl2 (3.72 g, 19.66 mmol) was slowly added to it and then the reaction mixture was stirred overnight at rt. To the reaction mixture was slowly added 3N NaOH to pH=10 and then extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (6:1) to provide 3,5-dichloro-4-(2,2,2-trifluoroethoxy)aniline (1.60 g, yield 94%) as pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC1C=CC(C(C)(C)C)=CC=1)(=O)C>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: CC(=O)OCc1ccc(C(C)(C)C)cc1
Product: Cc1ccc(C(C)(C)C)cc1
Yield: 12 %

Procedure:
If the material discharged from the electrolysis is worked up similarly to Example 1, 120.3 g of p-tert.-butylbenzaldehyde and 144.1 g of p-tert.-butylbenzyl acetate are obtained in addition to 13.2 g of unconverted p-tert.-butyltoluene. This corresponds to a yield of 75.5% and a current efficiency of 51.4%.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]([O:17][C:18](=[O:30])[NH:19][CH2:20][CH2:21][CH:22]([OH:29])[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)([CH3:16])[CH3:15].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:16][C:14]([O:17][C:18](=[O:30])[NH:19][CH2:20][CH2:21][CH:22]([O:29][C:33]1[CH:34]=[C:35]([C:38]([F:40])([F:41])[F:39])[CH:36]=[CH:37][C:32]=1[Cl:31])[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)([CH3:13])[CH3:15]
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(Oc1cc(C(F)(F)F)ccc1Cl)c1cccnc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 79.5 %

Procedure:
Diethyl azodicarboxylate (0.71 ml, 4.47 mmol) was added to a solution of [3-hydroxy-3-(3-pyridinyl)propyl]carbamic acid 1,1-dimethylethyl ester (Example 58(b)) (291 mg, 1.15 mmol), 2-chloro-5-trifluoromethylphenol (232 mg, 1.18 mmol) and triphenylphosphine (455 mg, 1.73 mmol) in tetrahydrofuran (6 ml) at 0° C. and stirred at 20° C. for 18 h. The reaction was concentrated in vacuo and the residue purified by chromatography on silica, eluting with petrol—diethyl ether to afford the sub-title compound (394 mg, 79%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(OCC)C>[CH2:17]([O:10][C:7]1[CH:8]=[CH:9][C:2]([Br:1])=[C:3]([CH:6]=1)[CH:4]=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1cc(O)ccc1Br
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=Cc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a suspension of 2-bromo-5-hydroxybenzaldehyde (100 mg, 0.50 mmol), potassium carbonate (138 mg, 1.00 mmol), and tetrabutylammonium iodide (18 mg, 0.05 mmol) in 1.0 mL of dry N,N-dimethylformamide was added benzyl bromide (89 μL, 0.74 mmol) at 0° C. After being stirred at room temperature overnight, the reaction mixture was diluted with diethyl ether, and the solution was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain the title compound as a colorless oil (140 mg, 97%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[Cl:35])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[S:25]([C:22]1[CH:21]=[CH:20][C:19]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=3)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]=2[CH3:18])=[CH:24][CH:23]=1)(=[O:26])=[O:27]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3ccc(Cl)cc3Cl)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
Lithium hydroxide monohydrate (0.009 g, 0.22 mmol) was added to a stirred solution of {4-[4-(2,4-dichlorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.028 g, 0.054 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(2,4-dichlorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.018 g, 66%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.49 (br. s., 1 H) 8.37 (d, J=7.82 Hz, 1 H) 8.09 (d, J=7.82 Hz, 2 H) 8.01 (dd, J=9.00, 6.70 Hz, 1H) 7.96 (s, 1 H) 7.91 (s, 1 H) 7.83 (d, J=8.80 Hz, 1 H) 7.54 (d, J=7.82 Hz, 2 H) 7.39 (t, J=8.00 Hz, 1 H) 6.63 (d, J=10.76 Hz, 1 H) 3.84 (s, 2 H) 2.05 (s, 3 H) MS calcd. for C25H16Cl2FO4S [(M−H)−] 501, obsd. 501.2.
Reaction SMILES: [CH2:1]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:22]1[CH2:28][S:25](=[O:27])(=[O:26])[O:24][CH2:23]1>CC(C)=O>[CH2:1]([N:17]1[CH:21]=[CH:20][N+:19]([CH2:23][CH2:22][CH2:28][S:25]([O-:27])(=[O:26])=[O:24])=[CH:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=S1(=O)CCCO1
Reactant: CCCCCCCCCCCCCCCCn1ccnc1
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCn1cc[n+](CCCS(=O)(=O)[O-])c1
Temperature: 25 °C

Procedure:
12.3 g of N-hexadecylimidazole was dissolved in 80 ml of acetone, and the mixture was cooled in an ice-water bath. Into the resultant, a solution in which 5.13 g of 1,3-propanesultone was dissolved in 80 ml of acetone was dripped, and after the dripping was completed, the resultant was stirred at room temperature. After the completion of the reaction, the resultant was filtered to obtain a precipitate. The precipitate was dried under reduced pressure, whereby 15.4 g of 3-(3-hexadecyl-1-imidazolio)-1-propanesulfonate (M-1) represented by the chemical formula (M-1) was obtained.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([O:11][C:12]1[N:13]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:14]([CH3:17])=[CH:15][N:16]=1)[CH3:10].C(OCC)(=O)C>CC#N.O.C(=O)([O-])[O-].[Na+].[Na+]>[Br:8][C:15]1[N:16]=[C:12]([O:11][CH2:9][CH3:10])[N:13]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=2)[C:14]=1[CH3:17]
Reactant: CCOc1ncc(C)n1-c1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOc1nc(Br)c(C)n1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of NBS (5.16 g, 29 mmol) in MeCN (60 mL) was added to a stirred solution of 2-ethoxy-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-imidazole (7.92 g, 29 mmol) in MeCN (115 mL) at such a rate that the internal temperature of the mixture did not exceed 25° C. (a RT cooling bath was used). After 0.5 h the mixture was diluted with water (50 mL) and saturated sodium carbonate (aq) (50 mL). Ethyl acetate (50 mL) was added. The mixture was stirred vigorously then the phases were separated. The organic phase was washed with saturated brine (50 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was taken into dichloromethane and filtered through a 25 g Si II SPE cartridge. The cartridge was washed with DCM and 10% EtOAc in DCM.
Reaction SMILES: CN1CCOCC1.[NH:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:9]([C:20]([OH:22])=O)[CH2:10][S:11][CH2:12][C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1.C(OC(Cl)=O)C(C)C.[NH2:38][C@H:39]([CH2:43][OH:44])[C@@H:40]([CH3:42])[OH:41].Cl>C1COCC1.CN(C=O)C>[NH:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:9]([C:20]([NH:38][C@H:39]([CH2:43][OH:44])[C@@H:40]([CH3:42])[OH:41])=[O:22])[CH2:10][S:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1
Reactant: C[C@@H](O)[C@H](N)CO
Reactant: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CO)[C@@H](C)O)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
2.1 ml N-methylmorpholine are added with stirring to a solution of 6.3 g Boc-Cys(MBzl)-OH in 50 ml THF, followed by drop-wise addition at -15° C. of 2.4 ml chloroformic acid isobutyl ester. After stirring for 5 minutes at -15° C. a solution of 3.3 g H-Thr-ol hydrochloride and 4.1 ml N-methylmorpholine in 30 ml DMF, pre-cooled to -10° C. is added. The reaction mixture is stirred for 2 hrs. at 0° C. and for a further 2 hrs. at room-temperature. 50 ml 10% KHCO3 -solution are added and the whole concentrated under vacuum. After dilution with AcOEt, washing 3× with 2 N citric acid, 3× with KHCO3 -solution and 1× with NaCl solution, the organic phase is dried over Na2SO4 and evaporated under vacuum to yield the title compound:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>[B].B#[Ti]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Oc1ccccc1
Agent: B#[Ti]
Agent: [B]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated with 14.1 g of a powdered titanium diboride from H. C. Starck at 140° C. After 2 hours' reaction time, phenol conversion was 27.7%, wherein 0.06 g of phenyl chloroformate and 43.9 g of diphenyl carbonate were formed. Selectivity for carbonates was approximately 99%.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](OS(C)(=O)=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([S:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:1])([F:10])[F:11])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: FC(F)(F)c1ccccc1S
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccc2C(F)(F)F)CC1
Temperature: 80 °C
Yield: 62.6 %

Procedure:
To a stirred solution of 2-trifluoromethylbenzenethiol (0.637 g, 0.00358 mole) in DMF (5 mL) was added cesium carbonate (1.396 g, 0.00429 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 0.00358 mole). The reaction mixture was heated at 80° C. overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed brine solution, dried over sodium sulfate, filtered and concentrated. The resulting residue was washed with hexane to afford 0.81 g (99%) of 4-(2-trifluoromethyl-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 362.13 (M+1)+, 99%. A solution of 4-(2-trifluoromethyl-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (0.81 g, 0.00224 mole) in dioxane.HCl (2 mL) was stirred at ambient temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with hexane twice to afford 0.604 g (90%) of 4-(2-trifluoromethyl-phenylsulfanyl)-piperidine hydrochloride which was used in the next step without further purification. LCMS: 262.08 (M+1)+, 95.07%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23]([NH:25][C:26]4[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([O:35][CH3:36])[CH:27]=4)=[O:24])[NH:12][C@H:11]3[CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:5]2=[CH:4][CH:3]=1.CC[N:45]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].C(N(CC)CC)C>CN(C)C=O.O>[C:30]([C:29]1[CH:33]=[CH:34][C:26]([NH:25][C:23]([CH:13]2[NH:12][CH:11]([CH2:37][C:38]([CH3:40])([CH3:41])[CH3:39])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:42])[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:24])=[CH:27][C:28]=1[O:35][CH3:36])(=[O:31])[NH2:45]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)O
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)C2NC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)ccc1C(N)=O
Temperature: 80 °C

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-2-methoxy-benzoic acid prepared in Example 16 (55 mg, 0.09 mmol) in N,N-dimethylformamide (2 mL) was added EDCI (34 mg, 0.18 mmol), HOBt (24 mg, 0.18 mmol), NH4Cl (48 mg, 0.9 mmol), and triethylamine (18 mg, 0.18 mmol) sequentially. The reaction mixture was heated at 80° C. for 1 h. The mixture was poured into water, then extracted with ethyl acetate three times. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (25% to 100% EtOAc in hexanes) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-3-methoxy-phenyl)-amide as a off white solid (Yield, 35 mg, 64%)
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4]1.C(=O)([O-])O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([C:3]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:4][CH2:5]1)=[O:1]
Reactant: CC(C)(C)OC(=O)C1(CO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(C=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Step 3 To a stirred suspension of tert-butyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (0.16 g, 0.929 mmol) and sodium hydrogen carbonate (0.312 g, 3.72 mmol) in DCM (5.57 mL) at room temperature was added Dess-Martin periodinane (0.788 g, 1.86 mmol). The mixture was stirred at room temperature for 1 hour before it was quenched by the addition of a 1:1 mixture of saturated NaHCO3 solution and saturated Na2S2O3 solution. After stirring for an additional 1 hour the phases were separated and the aqueous phase was extracted into DCM (×2). Combined organic extracts were dried (Na2SO4), filtered and concentrated giving tert-butyl 1-formylcyclopropane-1-carboxylate which was used without further purification, 0.141 g.