Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]([NH2:16])[C:8]1[N:9]=[C:10]([NH:13][CH:14]=[O:15])[S:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25](Cl)(=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH:7]([C:8]1[N:9]=[C:10]([NH:13][CH:14]=[O:15])[S:11][CH:12]=1)[NH:16][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(N)c1csc(NC=O)n1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)NC(C(=O)OC(C)(C)C)c1csc(NC=O)n1
Temperature: -45 °C
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
In 100 ml of methylene chloride was dissolved 5.5 g (21.4 mmole) of 2-amino-2-(2-formylamino-1,3-thiazol-4-yl)acetic acid tert-butyl ester, and 2.165 g (21.4 mmole) of triethylamine was added thereto. Then, the mixture was cooled to -45° C. and a solution of 2.92 g (21.4 mmole) of ethyl chlorooxalate dissolved in 10 ml of methylene chloride was added dropwise thereto for 10 minutes. Then, a cooling bath was removed, and the mixture was stirred for 30 minutes. After the mixture was washed with water, it was dried over anhydrous magnesium sulfate and the solvent was evaporated to obtain 7.5 g of the oily title compound. (Yield: 98%)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:11])=[CH:5][NH:6]2.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:11])=[CH:5][N:6]2[CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1
Reactant: Cc1c[nH]c2cccc(Br)c12
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(C)c3c(Br)cccc32)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
4-Bromo-3-methyl-1H-indole (1.33 g) was dissolved in dimethylformamide (20 mL), and sodium hydride (0.33 g) was added thereto under ice-cooling. After stirring at 0° C. for 15 minutes, p-methoxybenzyl chloride (0.95 mL) was added thereto. The reaction solution was stirred under heating at 70° C. for 30 minutes and partitioned between ethyl acetate and 1M HCl aqueous solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate) to obtain compound (45a) (2.09 g, 99%) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23](O)=[O:24])[N:21]=1)=[CH:5]2.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:24])[N:21]=1)=[CH:5]2
Reactant: C1CCNCC1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Product: O=C(C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1)N1CCCCC1
Yield: 57 %

Procedure:
The compound (40 mg, 0.11 mmol) prepared in Example 27 and piperidine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (27 mg, Yield 57%).
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[O:3][CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]=1.C([Li:22])CCC>CCOCC.CCCCCC>[CH3:17][Si:2]([CH3:1])([CH3:16])[O:3][CH2:4][CH2:5][CH2:6][C-:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.[Li+:22]
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)OCCCC1=CCc2ccccc21
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)OCCC[c-]1ccc2ccccc21
Product: [Li+]
Reaction time: 2 h
Yield: 85 %

Procedure:
To 1.5 g (6.1 mmol) of [3-(3-trimethylsiloxypropyl)indene] in ether at −78° C, 2.44 ml (6.1 mmol) of a 2.5 M butyllithium solution in hexane was added. The immediate formation of a white solid was observed. The mixture was maintained under stirring for 2 h. Then, the solvent was removed under vacuum and the residue was washed twice with 25 ml of hexane to give a brown solid. (1.3 g, 5.2 mmol, yield 85%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[S:5][C:6]([CH2:9][OH:10])=[CH:7][N:8]=1.Cl[C:12]1[C:17]([CH3:19])([CH3:18])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[C:14](=[O:23])[CH:13]=1.Cl>O1CCCC1.O>[Br:3][C:4]1[S:5][C:6]([CH2:9][O:10][C:12]2[C:17]([CH3:18])([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[C:14](=[O:23])[CH:13]=2)=[CH:7][N:8]=1
Reactant: CC1(C)C(=O)C=C(Cl)C(C)(C)C1=O
Reactant: OCc1cnc(Br)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(=O)C=C(OCc2cnc(Br)s2)C(C)(C)C1=O
Yield: 53.8 %

Procedure:
To a suspension of sodium hydride, 60% dispersion in mineral oil solution (1.6 g, 40 mmol) in tetrahydrofuran (50 ml) is added a solution of (2-bromothiazol-5-yl)methanol (6.75 g, 35 mmol) in tetrahydrofuran (50 ml) at 0° C. A solution of 5-chloro-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (7.0 g, 35 mmol) in tetrahydrofuran (50 ml) is then added and the reaction mixture is heated to reflux for 18 hours. The reaction mixture is poured into water, acidified to pH4 with dilute aqueous hydrochloric acid and extracted with ethyl acetate (4×50 ml). The combined organic layers are dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated to a brown oil. The crude product is purified by flash chromatography on silica gel to give 5-(2-bromothiazol-5-ylmethoxy)-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (6.75 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:14][C:13](=O)[C:12]3[CH:16]=[CH:17][S:18][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:13]1[C:12]2[CH:16]=[CH:17][S:18][C:11]=2[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc3sccc3c(=O)[nH]2)cc1
Product: COc1ccc(-c2cc3sccc3c(Cl)n2)cc1
Temperature: 120 °C
Yield: 67.7 %

Procedure:
6-(4-Methoxyphenyl)-5H-thieno[3,2-c]pyridin-4-one (9.1 g) was added to phosphorus oxychloride (90 g), and the mixture was heated at 120° C. for 3 hr. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and water. The organic layer was washed with water, an aqueous solution of saturated sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent was evaporate, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a white powder (6.6 g, yield; 73%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])[NH2:20]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:19]([C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=[O:24])[N:20]=1
Reactant: NNc1ccccc1C(=O)O
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Solvent: CCO
Product: O=C(O)c1ccccc1-n1nc(-c2ccccc2O)nc1-c1ccccc1O

Procedure:
4.8 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin4-one and 3.5 g of 2-hydrazinobenzoic acid are boiled under reflux for 4 h in 10 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from ethyl acetate/hexane. After drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid is obtained as colorless crystals of m.p. 132-138° C.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].C(O[CH2:17][CH3:18])C>>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C@H:18]1[CH:17]=[CH:5][C:1]2[C:2](=[CH:5][CH:1]=[CH:2][CH:3]=2)[C@@H:3]1[OH:4]
Reactant: CCOCC
Reactant: C1CCOC1
Reactant: Oc1ccccc1Br
Product: O[C@H]1c2ccccc2C=C[C@@H]1Oc1ccccc1Br
Temperature: 80 °C
Reaction time: 0.53 h

Procedure:
To a flame dried round-bottomed flask, [Rh(COD)Cl]2 (1.7 mg, 0.0035 mmol), (S)-(R)-PPF-PtBu2 (3.8 mg, 0.0069 mmol) and 1 (100 mg, 0.694 mmol) were added followed by addition of THF (2.5 mL) and 2-bromophenol (0.40 mL, 3.47 mmol). The mixture was heated at 80° C. for 24 hours, then poured into diethyl ether and extracted 3 times with 10% aqueous sodium hydroxide solution. The aqueous extracts were combined and back-extracted three times with diethyl ether. The combined ether extracts were washed with brine and dried with anhydrous sodium sulfate. The solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (5% ethyl acetate in hexanes) as a white crystalline solid 13 (75 mg, 37%). The ee was determined to be 81% by HPLC analysis on a CHIRALCEL OD column, λ=486 nm. Retention times in 1.5% isopropanol in hexanes were 22.8 min and 32.1 min (major). Rf=0.44 on silica (20% ethyl acetate in hexanes); mp 120-122° C. (Et2O); [α]25D=+254° (c=9.2, CHCl3). IR (KBr, cm−1) 3341 (br), 3071 (w), 2884 (w), 1581 (m), 1472 (s), 1358 (m), 1237 (s), 1028 (s), 987 (s), 780 (s), 689 (m), 569 (m); 1H NMR (400 MHz, CDCl3): δ7.67 (1H, d J=6.8 Hz), 7.58 (1H, dd, J=1.5, 7.9 Hz), 7.33-7.23 (3H, m), 7.14-7.12 (1H, m), 6.95(1H, dd, J=1.1, 8.2 Hz), 6.92-6.87 (1H, m), 6.52 (1H, dd, J=2.0, 9.9 Hz), 6.06 (1H, dd, J=1.8, 9.9 Hz), 5.32 (1H, d, J=11.0 Hz), 5.10 (1H, ddd, J=2.0, 2.0, 11.0 Hz), 2.85 (1H, d, J=3.2 Hz). 13C NMR (400 MHz, CDCl3): δ154.3, 135.4, 133.6, 131.8, 129.1, 128.6, 128.3, 128.0, 126.4, 126.0, 124.9, 122.9, 115.6, 113.5, 82.2, 72.5. HRMS calculated for (M-H2O)+ (C16H11OBr): 297.9993. Found: 297.9976.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[F:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>CCCCCC.C(OCC)(=O)C>[F:30][C:31]1[N:36]=[CH:35][C:34]([C:2]2[C:10]3[O:9][CH2:8][CH:7]([C:11]4[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=4)[C:6]=3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=2[CH3:29])=[CH:33][CH:32]=1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: OB(O)c1ccc(F)nc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccc(F)nc1)OCC2c1ccc(C(C)C)cc1
Yield: 58 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (6-fluoropyridin-3-yl)boronic acid, the title compound was synthesized in the same manner as in Example 101. Yield: 58%. Melting point: 135-137° C. (hexane-ethyl acetate).
Reaction SMILES: [H-].[Na+].CS(C)=O.[PH4+].FC([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O)(F)F>C(OCC)(=O)C>[C:13]1([CH:14]=[CH:14][C:13]2[CH:12]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Agent: [PH4+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 208.2 %

Procedure:
In a nitrogen atmosphere, 8.7 g of 55% sodium hydride dispersion are added to 100 ml of absolute dimethylsulphoxide and stirred at 80° C. for 45 minutes. After cooling to ambient temperature, a suspension of 98 g (0.2 mol) of phosphonium salt 4 is added dropwise and the reaction mixture is stirred for a further 10 minutes. Then 34.8 g of trifluoromethylbenzaldehyde are added dropwise and the mixture is stirred for 2 hours at ambient temperature. The mixture is then diluted with 400 ml of ethyl acetate and washed twice with water. The organic phase is dried and the residue is chromatographed (SiO2 column, eluant: dichloromethane). The main fraction is evaporated down in vacuo and the residue is recrystallised from isopropylether. 37.5 g (61% of theory) of stilbene of the type 8 are obtained in the form of crystals, m.p. 157°-158° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65](=[O:76])[C:66]1[CH:71]=[CH:70][C:69]([NH2:72])=[C:68]([O:73][CH2:74][CH3:75])[CH:67]=1>>[CH3:63][O:64][C:65](=[O:76])[C:66]1[CH:71]=[CH:70][C:69]([NH:72][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[C:68]([O:73][CH2:74][CH3:75])[CH:67]=1
Reactant: CCOc1cc(C(=O)OC)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(C(=O)OC)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, 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 trifluoroacetic acid prepared in Example 4 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 4-amino-3-ethoxy-benzoic acid methyl ester (0.21 g, 1.1 mmol) to give 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}-3-ethoxy-benzoic acid methyl ester as a white solid (Yield, 0.13 g, 29%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8]CNC1=O.[H-].[Na+].[CH3:12]I.[CH3:14][N:15]([CH3:18])[CH:16]=[O:17]>>[CH3:14][N:15]1[CH2:18][CH2:8][N:4]([CH2:3][CH2:2][O:1][CH3:12])[C:16]1=[O:17]
Reactant: CI
Reactant: CN(C)C=O
Reactant: O=C1NCCN1CCO
Agent: [H-]
Agent: [Na+]
Product: COCCN1CCN(C)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Reaction of 1-(2-hydroxyethyl)-2-imidazolidinone (13 g) in dry dimethylformamide (125 ml) with sodium hydride (50% suspension in paraffin oil 12 g) at 10° C. for 3 hours was followed by treatment with methyl iodide (35.5 g) over a period of one hour. The mixture was stirred at ambient temperature for 18 hours gave 1-methyl-3-(2-methoxyethyl)-2-imidazolidinone (b.p. 110°-114° C. at 0.4 mm).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@H:7]2[O:13][C@@H:12]([CH2:14][OH:15])[C@H:10]([OH:11])[C@@H:8]2[OH:9])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].OO.C([OH:22])C>[OH-].[NH4+]>[NH2:1][C:2]1[N:6]([C@H:7]2[O:13][C@@H:12]([CH2:14][OH:15])[C@H:10]([OH:11])[C@@H:8]2[OH:9])[N:5]=[CH:4][C:3]=1[C:16]([NH2:17])=[O:22]
Reactant: CCO
Reactant: N#Cc1cnn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c1N
Agent: OO
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cnn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
To a solution of (25) (4.60 g) in ammonium hydroxide (35 mL) was added 30% hydrogen peroxide (2 mL). The mixture was stirred in a pressure bottle at room temperature for 18 h, the pressure bottle was cooled, opened carefully and the volatile products were evaporated to dryness. The residue thus obtained was co-evaporated with ethanol (3×20 mL). The crude product on crystallization with ethanol/water gave pure compound 3.5 g (71%): 1H NMR (DMSO-d6) δ 3.57 (m, 2H, C5'CH2), 3.86 (q, 1H, C4'H), 4.11 (q, 1H, C3'H), 4.43 (q, 1H, C2'OH), 5.63 (d, 1H, J=3.99 Hz, C1',H), 6.51 (br s, 2H, NH2), 6.71 and 7.26 (2br s, 2H, CONH2) and 7.69 (s, 1H, C3H). Anal. Calc. for C9H14N4O5 (258.23): C, 41.86; H, 5.46; N, 21.69. Found: C, 41.57; H, 5.40; N, 21.61.
Reaction SMILES: [SH2:1].C([S:4][C:5](=N)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH2:13][CH2:14][C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])C.Cl.CCOCC>O1CCCC1.O>[Br:21][C:19]1[CH:18]=[CH:17][C:16]([O:22][CH3:23])=[C:15]([CH2:14][CH2:13][C:7]2[C:8]([Cl:12])=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([SH:4])=[S:1])[CH:20]=1
Reactant: CCSC(=N)c1cccc(Cl)c1CCc1cc(Br)ccc1OC
Reactant: S
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1CCc1c(Cl)cccc1C(=S)S
Temperature: 45 °C
Reaction time: 8 h

Procedure:
As shown in Scheme 9, hydrogen sulfide gas (2 mL) was condensed into a cooled (−78° C.) solution of 2.8 grams (6.8 mmol) of 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-thiobenzimidic acid ethyl ester and 13.6 mL (13.6 mmol) of 1.0 M HCl/ether in 100 mL of tetrahydrofuran. The reaction was heated to 45° C. and stirred overnight in a sealed tube. The reaction mixture was diluted with water and extracted with methylene chloride once, organic layer was washed with brine, dried (MgSO4), filtered and evaporated to give a crude orange oil. The oil was partially purified by chromatography through a short column of silica gel (eluting with 5:95 ethyl acetate/hexanes) which resulted in 1.8 g of an orange powder which was used directly.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:51][C:52]([F:67])([F:66])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[S:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[O:18]=[C:16]([N:63]1[CH2:62][CH2:61][CH:60]([S:59][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[C:52]([F:66])([F:51])[F:67])[CH2:65][CH2:64]1)[CH2:15][NH:14][C:12]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:11][N:10]=1)=[O:13]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: FC(F)(F)c1ccccc1SC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Sc2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a stirred solution of [(5-Phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.05 g, 0.00018 mol) in DMF (1 mL) was added DIPEA (0.0689 g, 0.00053 mol), HOBt (0.028 g, 0.00021 mol) and EDCI.HCl (0.0407 g, 0.00021 mol) at ambient temperature. After 2 minutes 4-(2-trifluoromethyl-phenylsulfanyl)-piperidine hydrochloride (0.063 g, 0.00021 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.068 g (78%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-phenylsulfanyl)-piperidin-1-yl]-ethyl}-amide. LCMS: 489.15 (M+1)+, 94.5%, 1H NMR (DMSO-d6): δ 13.8 (s, 1H), 8.0 (s, 1H), 7.8 (m, 4H), 7.65 (t, 1H), 7.5-7.3 (m, 4H), 7.1 (s, 1H), 4.3-4.05 (m, 3H), 3.9-3.6 (m, 2H), 3.2 (m, 1H), 2.9 (m, 1H), 1.9 (m, 2H), 1.6 (m, 1H), 1.4 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:34])[C:12]([CH3:33])=[C:13]([CH2:15][NH:16][C:17]3[C:18]([F:32])=[C:19]([CH:28]=[CH:29][C:30]=3[F:31])[O:20][CH2:21][C:22]([O:24]C(C)C)=[O:23])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Li+].[OH-]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:34])[C:12]([CH3:33])=[C:13]([CH2:15][NH:16][C:17]3[C:18]([F:32])=[C:19]([CH:28]=[CH:29][C:30]=3[F:31])[O:20][CH2:21][C:22]([OH:24])=[O:23])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(-c2ccc(F)c(F)c2)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2ccc(F)c(F)c2)cc(CNc2c(F)ccc(OCC(=O)O)c2F)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of isopropyl 2-[3-[[5-(3,4-difluorophenyl)-2,3-dimethyl-phenyl]methylamino]-2,4-difluoro-phenoxy]acetate (70 mg, 0.15 mmol, 1.0 eq) in a mixture of THF (1.5 mL) and MeOH (0.5 mL) was added LiOH (2M aqueous solution, 1.5 mL, 3.0 mmol). The reaction was stirred at room temperature for 1 h then the organic solvent was removed under reduced pressure. The remaining aqueous solution was diluted with water and the solution acidified to pH 4-5 with 3M HCl. The mixture was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a white solid (63 mg, 99%).
Reaction SMILES: [Na].C(C1C(C)=C([CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[C:15]([C:20](=[N:24][O:25][CH2:26][CH3:27])[CH2:21][CH2:22][CH3:23])=[C:14]2[OH:28])C=C(C)C=1C)(=O)C.[N+:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)([O-:32])=[O:31].[CH3:42][C:43]([CH3:45])=[O:44]>>[C:43]([C:45]1[C:13]([CH3:18])=[C:14]([CH:18]2[CH2:17][C:16](=[O:19])[C:15]([C:20](=[N:24][O:25][CH2:26][CH3:27])[CH2:21][CH2:22][CH3:23])=[C:14]([O:28][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=3)[CH2:13]2)[C:15]([CH3:16])=[CH:20][C:21]=1[CH3:22])(=[O:44])[CH3:42]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCC(=NOCC)C1=C(O)C(c2cc(C)c(C)c(C(C)=O)c2C)CCC1=O
Reactant: CC(C)=O
Agent: [Na]
Product: CCCC(=NOCC)C1=C(OC(=O)c2ccc([N+](=O)[O-])cc2)CC(c2c(C)cc(C)c(C(C)=O)c2C)CC1=O
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
The sodium salt of 5-(3-acetyl-2,4,5-trimethylphenyl-2-[1-(ethoxyimino)butyl]-3-hydroxy-cyclohex-2-en-1-one (0.13 g; 0.33 mmole) was dissolved in acetone and then 4-nitrobenzoyl chloride (0.06 g; 0.33 mmole) was added. The mixture was stirred for 15 minutes and then the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The product was purified by column chromatography over silica gel (eluant dichloromethane) to give 5-(3-acetyl-2,4,6-trimethylphenyl)-2-[1-(ethoxyimino)butyl]-3-(4-nitrobenzoyl)oxy-cyclohex-2-en-1-one (0.16 g; 93.6%) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[S:11]([O-])([O-:14])(=[O:13])=[S:12]>>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][C:5]=1[S:12][SH:11](=[O:14])=[O:13]
Reactant: CN(C)c1ccc(N)cc1
Reactant: O=S([O-])([O-])=S
Product: CN(C)c1ccc(N)c(S[SH](=O)=O)c1

Procedure:
In one embodiment, an N,N-dimethyl-1,4-diamino-benzene, 1, is oxidized in the presence of a thiosulfate and an oxidizing agent that is or comprises Cr(VI) to give a thiosulfonic acid S-{2-(amino)-5-(dimethylamino)-phenyl}ester, (a 2-amino-5-dimethyl-aminophenylthiosulfonic acid), 2, as illustrated in the following scheme: