Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.S(Cl)([Cl:25])=O>CN(C=O)C>[Cl:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(O)ncnc2cc1OCCCN1CCCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1

Procedure:
A mixture of 4-hydroxy-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.7 g, 5 mmol) and thionyl chloride (25 ml) containing DMF (0.2 ml) was heated at reflux for 3 hours. Excess thionyl chloride was removed by evaporation and by azeotroping with toluene (×2). The residue was suspended in ether and 10% aqueous solution of sodium hydrogen carbonate was added to the mixture. The organic layer was separated, dried (MgSO4) and the solvent removed by evaporation to give 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.94 g, quantitative).
Reaction SMILES: [C:1]([C:3](=[CH:9][NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1)[C:4](OCC)=[O:5])#[N:2].[NH:18]1C(C2C(=O)N3C=CC=CC3=NC=2)=N[N:20]=[N:19]1>>[CH3:17][C:15]1[CH:14]=[CH:13][N:12]2[C:4](=[O:5])[C:3]([C:1]3[NH:2][N:20]=[N:19][N:18]=3)=[CH:9][N:10]=[C:11]2[CH:16]=1
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Reactant: CCOC(=O)C(C#N)=CNc1cc(C)ccn1
Product: Cc1ccn2c(=O)c(-c3nnn[nH]3)cnc2c1
Yield: 16 %

Procedure:
The title compound (16% yield, m.p. 307° with decomposition) was prepared from ethyl 2-cyano-3-(4-methyl-2-pyridylamino)acrylate in a manner similar to that described for the preparation of 3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]-pyrimidin-4-one in Example 2.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1>N1C=CC=CC=1>[CH:14]1([C:17]([NH:1][C:2]2[S:3][C:4]3[CH:10]=[C:9]([S:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:18])[CH2:16][CH2:15]1
Reactant: N#CSc1ccc2nc(N)sc2c1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: N#CSc1ccc2nc(NC(=O)C3CC3)sc2c1
Yield: 99.7 %

Procedure:
The 2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl thiocyanate was prepared in a manner similar to the method described in Example 18b, but using 2 g of commercial 2-amino-6-thiocyanatobenzothiazole and 1.21 g of cyclopropanecarboxylic acid chloride in 20 cm3 of pyridine after reaction for 5 h at 20° C. 2.65 g of 2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl thiocyanate are thus obtained in the form of a yellow powder, the characteristics of which are as follows:
Reaction SMILES: [C:1]1(/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][O:17][C:11]=3[CH2:10]2)=[O:8])=[CH:3][CH:2]=1.[CH3:26][NH:27][CH3:28].[CH2:29]=O>C(O)(=O)C>[CH3:26][N:27]([CH2:29][C:16]1[O:17][C:11]2[CH2:10][N:9]([C:7]([C:4]3[CH:3]=[CH:2][C:1](/[CH:18]=[CH:19]/[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:6][CH:5]=3)=[O:8])[CH2:14][CH2:13][C:12]=2[CH:15]=1)[CH3:28]
Reactant: O=C(c1ccc(/C=C/c2ccccc2)cc1)N1CCc2ccoc2C1
Reactant: C=O
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)c1ccc(/C=C/c3ccccc3)cc1)CC2
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a solution of 0.200 g (0.607 mmol) of (E)-6-(4-stilbenecarbonyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 20 ml of acetic acid, 0.082 ml (0.91 mmol) of 50% aqueous dimethylamine and 0.074 ml (0.91 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 90 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate, and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform/methanol=25/1) to yield the desired product.
Reaction SMILES: C(OC([C@@H:8]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=1)[CH2:9][N:10]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([N+:33]([O-:35])=[O:34])=[C:20]([CH:22](C(OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=2)=[N:13][N:12]=1)=O)(C)(C)C.[Cl-].[Li+].[OH2:56].CS(C)=O>[Cl-].[Na+].O.CCOC(C)=O>[C:39]([O:38][C:36]([N:10]([CH2:9][C@@H:8]([NH:10][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:56])[CH2:43][C:44]1[CH:45]=[CH:46][C:47]([C:50]([F:52])([F:53])[F:51])=[CH:48][CH:49]=1)[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([N+:33]([O-:35])=[O:34])=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=2)=[N:13][N:12]=1)=[O:37])([CH3:41])([CH3:42])[CH3:40]
Reactant: O
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(-c2nnc(N(C[C@H](Cc3ccc(C(F)(F)F)cc3)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(-c2nnc(N(C[C@H](Cc3ccc(C(F)(F)F)cc3)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a 500 mL round bottom flask was added diethyl 2-(5-(5-((S)-2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)propyl-boc-amino)-1,3,4-thiadiazol-2-yl)-2-nitrophenyl)malonate (3.60 g, 4.60 mmol), lithium chloride (0.390 g, 9.21 mmol), distilled water (0.0830 g, 4.60 mmol) and 50 mL DMSO. The reaction mixture was heated to 100° C. and stirred at this temperature for 3 hours. LC-MS indicated the reaction was not complete. Another 4 equivalents of LiCl was added. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled to ambient temperature, and 200 mL EtOAc and 200 mL brine were added. The organic portion was separated. The aqueous portion was extracted with EtOAc. The combined organic portions were washed with brine and dried over sodium sulfate. The crude mixture (3.40 g) was used in the following reaction without further purification.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[C:17]#[N:18])C.N>CO.[Ni]>[CH:16]1[C:11]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4](=[O:3])[NH:18][CH2:17][C:12]=2[CH:13]=[N:14][CH:15]=1
Reactant: CCOC(=O)c1ccccc1-c1ccncc1C#N
Agent: [Ni]
Agent: N
Solvent: CO
Product: O=C1NCc2cnccc2-c2ccccc21

Procedure:
A mixture of Example 180C (29.4 g, 0.117 mol) and Raney®-nickel (30 g) in 2 L of methanol saturated with NH3 was stirred under H2 (50 psi) at 50° C. for 24 hours. After cooling and removal of the catalyst, the mixture was concentrated under reduced pressure to obtain the title compound which was used without further purification.
Reaction SMILES: C[CH:2]1[CH2:9][CH:8]2[CH:6]([O:7]2)[CH2:5][N:4]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])[CH2:3]1.[N-:19]=[N+:20]=[N-:21].[Na+].[NH4+].[Cl-].[CH3:25]O>O>[N:19]([CH:8]1[CH:9]([CH3:25])[CH2:2][CH2:3][N:4]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:11])=[O:12])[CH2:5][CH:6]1[OH:7])=[N+:20]=[N-:21]
Reactant: CC1CC2OC2CN(S(=O)(=O)c2ccccn2)C1
Reactant: CO
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: CC1CCN(S(=O)(=O)c2ccccn2)CC(O)C1N=[N+]=[N-]
Yield: 64 %

Procedure:
5-methyl-3-(pyridine-2-sulfonyl)-8-oxa-3-aza-bicyclo[5.1.0]octane (230 mg, 0.86 mmol) was dissolved in the mixture of 8 ml MeOH and 2 ml H2O. NaN3 (170 mg, 2.6 mmol) and NH4Cl (140 mg, 2.6 mmol) were added to the solution. The resulting mixture was refluxed overnight. After the removal of MeOH, the residue was diluted in EtOAc and washed with 10% NaHCO3 and brine. Purified on column chromatography gave the title compound (170 mg, yield 64%). MS (M+H+) 312.2; 1H-NMR (400 Hz, CDCl3): d=8.69(d, 1H), 8.04-7.94(m, 2H), 7.54 (m, 1H) 4.00-2.95 (m, 7H), 2.20(m, 1H), 1.90-1.74(m, 2H), 0.98(d, 3H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:31])[C:16]3[CH:21]=[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:19]=[CH:18][C:17]=3[N+:28]([O-])=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]>C(O)(=O)C.[Zn]>[NH2:28][C:17]1[CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:21][C:16]=1[C:15]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[N:10]=1)=[O:31]
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(N4CCCCC4)ccc3[N+](=O)[O-])n2)cc1C
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(N4CCCCC4)ccc3N)n2)cc1C
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-yl)-2-nitro-5-(piperidin-1-yl)benzamide (400 mg, 0.95 mmol, 1.00 equiv) in acetic acid (8 mL), and zinc (600 mg, 9.23 mmol, 9.96 equiv). The resulting solution was stirred for 1 h at 70° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The solution was adjusted to pH 8 with ammonia (2 mol/L). The resulting solution was extracted with 2×50 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 300 mg (81%) of 2-amino-N-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-yl)-5-(piperidin-1-yl)benzamide as a green solid.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[C:11]([OH:13])=[O:12])([O-:7])=[O:6].[CH3:21]COC(C)=O>CO>[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=1)[C:11]([O:13][CH3:21])=[O:12])([O-:7])=[O:6]
Reactant: CCOC(C)=O
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Yield: 100 %

Procedure:
Add thionyl chloride (2 mL) dropwise to the solution of 3-nitro-5-(trifluoromethyl)benzoic acid (1.5 g, 6.4 mmol) in methanol (20 mL), reflux for 5 hrs. TLC (PE:EtOAc=1:1) shows the reaction is complete. Concentrate under reduced pressure to give the crude product (1.8 g, 100%) which is used in next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.S([O-])(O)(=O)=O.[K+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)C(O)c1ccc(OC)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)C(C)=Cc1ccc(OC)cc1

Procedure:
A mixture of 71.8 g (0.30 mole) of ethyl β-(p-methoxyphenyl)-β-hydroxy-α-methylpropionate is refluxed with 41.0 g (0.30 mole) of potassium hydrogen sulfate in 718 ml of benzene for 1 hour. The insoluble white crystals formed are filtered off, washed with benzene and the solvent of the filtrate is removed on evaporation. This is dissolved in 700 ml of ether. The ether solution is washed with 4 × 100 ml of cold water until neutral followed by 80 ml of saturated sodium chloride solution, then it is dried over magnesium sulfate for 1.5 hours and filtered. The solvent is removed on an evaporator to give ethyl p-methoxy-α-methylcinnamate.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])(=O)C(C)=O.[Na+]>>[CH:7](=[CH:4][C:2](=[O:3])[C:1]([OH:6])=[O:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)C(=O)O
Reactant: O=Cc1ccccc1
Agent: CC(=O)C(=O)[O-]
Agent: [Na+]
Product: O=C(O)C(=O)C=Cc1ccccc1

Procedure:
Furthermore, the pyruvic acid compound (I) can also be produced, for example, in accordance with: (1) the process in which benzaldehyde and sodium pyruvate are condensed together to give benzalpyruvic acid, and the benzalpyruvic acid is then reacted with ethyl chloroformate to give ethyl benzalpyruvate, and the ethyl benzalpyruvate is then reduced [EP387058]; or (2) the process in which phenetyl bromide is reacted with carbon monoxide in the presence of a cobalt carbonyl catalyst [J. Mol. Cat., 88, 295(1994)]. The process for producing the pyruvic acid compound (I) as the starting material is not limited to these processes, either of which can be used as the production process for the starting material in the present invention.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH:7][C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)(C)c1ccccc1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)Nc1ccccc1C(C)(C)C
Temperature: -30 °C
Yield: 92.9 %

Procedure:
A 3-L, 3-necked round-bottomed flask, equipped with a mechanic stirrer and a thermal probe (under nitrogen) was charged with 2-tert-Butylaniline (109 g, 114 mL, 732 mmoles), triethylamine (81.4 g, 112 mL, 804 mmoles, 1.1 equiv.) and toluene (600 mL). The resulting mixture was stirred at a moderate speed at −30° C. An additon funnel was charged with Methyl chlorooxoacetate (100 g, 816 mmoles, 1.11 equiv.) with toluene (200 mL), and the mixture added to the reaction mixture at such a rate that the internal batch temperature is less than −20° C. After addition, the reaction was warmed to room temperature for an hour, quenched with water, then partitioned between EtOAc/water. The aqueous phase was extracted with EtOAc (200 mL), and the combined organic layers were washed successively with KHSO4 (200 mL), NaHCO3 (sat'd) (200 mL) and brine (200 mL), then dried the organic over MgSO4. The organic phase was concentrated by rotary evaporation, yielding the title compound as a pale yellow solid [Methyl 2-(2-tert-Butylphenylamino)-2-oxoacetate, 160 g, 93.1%]. MP 61.7–63.6° C. IR (KBr) 3409, 2954, 1736, 1724, 1530, 1299, 1166, 766 cm−1; 1H NMR (300 MHz, CDCl3): δ(ppm): 9.20 (br, 1H), 7.97 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.43 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.31–7.16 (m, 2H), 4.00 (s, 3H), 1.47(s, 9H). The product thus obtained can be used directly for the subsequent reaction.
Reaction SMILES: C([SiH](CC)CC)C.[Br:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([F:22])[CH:13]=1)=O>FC(F)(F)C(O)=O>[Br:8][CH2:9][CH2:10][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([F:22])[CH:13]=1
Reactant: CC(=O)Nc1ccc(C(=O)CBr)cc1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(CCBr)cc1F
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 56.3 %

Procedure:
Triethylsilane (1.60 mL, 10.017 mmol) was added via syringe to a stirred solution of N-[4-{2-bromo-acetyl)-2-fluoro-phenyl]-acetamide (1.1435 g, 4.172 mmol) in trifluoroacetic acid (14.0 mL) under nitrogen. The reaction was heated on an oil bath to 60° C. After 2.5 h, the reaction mixture was poured into ice water and allowed to warm to rt. The crude product was extracted with methylene chloride (2×75 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was crystallized from methanol and water to provide 0.6109 g (2.349 mmol) of the product as a white solid. Yield: 56%; MS (APCI): 260 [M+H]+, 262 [M+H+2]+; 1H NMR (400 MHz, CDCl3) δ 8.22 (dd, J=8.3, 8.5 Hz, 1H), 7.30 (br s, 1H), 6.93–6.97 (m, 2H), 3.51 (t, J=7.3 Hz, 2H), 3.10 (t, J=7.3 Hz, 2H), 2.20 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[OH:7])[CH3:2].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4](=[O:12])[C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[O:7][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH3:14]
Reactant: CCCCCCCCCCCCCCBr
Reactant: CCN(CC)C(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCOc1ccccc1C(=O)N(CC)CC

Procedure:
A mixture of 25 g of N,N-diethylsalicylamide, 38.5 ml of 1-bromotetradecane, 22.35 g of potassium carbonate and 400 ml of 2-butanone is heated at reflux temperature for 16 hours. The reaction is cooled, filtered and concentrated in vacuo. The concentrate is dissolved in chloroform, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:0-30% ethyl acetate/hexane) to give 42.5 g of the desired product as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:9][N:10]2[CH3:15].[C:25](O)(=O)[CH:26]=C>>[CH2:25]([O:19][C:18](=[O:20])/[CH:17]=[CH:16]/[C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][C:4]2[CH:21]=[CH:22][C:23]([F:24])=[C:2]([Cl:1])[CH:3]=2)[N:10]([CH3:15])[CH:9]=1)[CH3:26]
Reactant: C=CC(=O)O
Reactant: Cn1cc(/C=C/C(=O)O)c2c(Oc3ccc(F)c(Cl)c3)cccc21
Product: CCOC(=O)/C=C/c1cn(C)c2cccc(Oc3ccc(F)c(Cl)c3)c12

Procedure:
Synthesis of (E)-3-[4-(3-Chloro-4-fluoro-phenoxy)-1-methyl-1H-indol-3-yl]-acrylic acid, A38. Following the general procedure P-8, K-59G was hydrolyzed to acrylic acid A38. 1H NMR (DMSO-d6) 3.85 (s, 3H), 6.24 (d, J=16 Hz, 1H), 6.66 (d, J=8 Hz, 1H), 7.00 (m, 1H), 7.20 (dd, J=8 and 8 Hz, 1H), 7.25 (m, 1H), 7.35 (d, J=8 Hz, 1H), 7.43 (dd, J=9 and 9 Hz, 1H), 7.88 (d, J=16 Hz, 1H), 8.07 (s, 1H), 11.8 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>C(Cl)Cl>[OH:10][CH2:9][C:4]1[CH:3]=[C:2]([NH:1][C:12](=[O:11])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1cc(N)cc(CO)c1
Solvent: ClCCl
Product: Cc1cc(CO)cc(NC(=O)OC(C)(C)C)c1

Procedure:
To a solution of (3-amino-5-methylphenyl)methanol (1.0 g, 7.29 mmol) in CH2Cl2 (30 mL) was added BOC2O (1.75 g, 8.02 mmol) at room temperature. After 24 hours the mixture was concentrated. Flash column chromatography (30% EtOAc/hexanes) gave tert-butyl 3-(hydroxymethyl)-5-methylphenylcarbamate as a white solid. 1H-NMR (300 MHz, CDCl3) δ 7.20 (s, 1H), 7.18 (s, 1H), 6.85 (s, 1H), 6.45 (bs, 1H), 4.60 (s, 2H), 3.60 (bs, 2H), 2.32 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[N:13]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=[O:28])=CC=1.[Cl-]>O>[C:1]1([CH:7]2[NH:13][C:8](=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: ON=C1CCCCC1c1ccccc1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: O
Product: O=C1CCCCC(c2ccccc2)N1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 250 ml round-bottomed flask equipped with N2 inlet were added 7.33 g (38.8 mmol) 2-phenylcyclohexanone oxime (Chem. Ber., 55, 3664 (1922)) and 25 ml pyridine. The solution was cooled to 0° C., and 9.61 g (50.4 mmol) p-toluenesulfonyl chloride was added. The reaction was allowed to stir overnight as the ice melted, and then poured into water. Excess chloride was skimmed off the surface, and the reaction mixture was stirred at pH 4 for 3 hours. The precipitate was filtered, washed with water, and dried to a solid, 4.65 g (55%), mp 135°-137° C. (J. Am. Chem. Soc., 82, 4671 (1960) gives mp 139°-141° C.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>CO.ClCCl.C(OCC)C>[ClH:24].[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:15])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccccc2F)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(c1ccccc1F)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-Fluoro-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (891 mg) was dissolved in methanol (10 ml) and dichloromethane (5 ml), 2M HCl in diethyl ether (12.9 ml) was added and the reaction mixture was stirred at room temperature overnight, then cooled in ice bath, the resulted precipitate was filtered, washed with ether to yield 4-(2-fluoro-benzenesulfonyl)-piperazine hydrochloride salt (600 mg).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:27]([N:35]1[C:39](=[O:40])[C:38]([CH:42]([CH3:44])[CH3:43])([CH3:41])[N:37]=[C:36]1[C:45]1[N:54]=[CH:53][C:52]([CH3:55])=[CH:51][C:46]=1[C:47]([O:49][CH3:50])=[O:48])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:27]([N:35]1[C:39](=[O:40])[C:38]([CH:42]([CH3:44])[CH3:43])([CH3:41])[N:37]=[C:36]1[C:45]1[N:54]=[CH:53][C:52]([CH2:55][Br:1])=[CH:51][C:46]=1[C:47]([O:49][CH3:50])=[O:48])(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1cc(C)cnc1C1=NC(C)(C(C)C)C(=O)N1C(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(CBr)cnc1C1=NC(C)(C(C)C)C(=O)N1C(=O)c1ccccc1
Temperature: 70 °C
Yield: 35.5 %

Procedure:
Solid N-bromosuccinimide (22.98 g, 0.129 mol) and benzoyl peroxide (3.12 g, 0.0129 mol) are added to a 25° C. solution of 2-(1-benzoyl-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-methylnicotinic acid, methyl ester (46.2 g, 0.117 mol) in carbon tetrachloride. The reaction mixture is heated at 70° C. for 16 hours, cooled to room temperature, diluted with methylene chloride, washed sequentially with 5% sodium metabisulfite solution and water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give an oil. The oil is chromatographed using silica gel and hexanes/ethyl acetate (3:1) to (1:1) as eluant to give the title compound as a yellow solid (19.64 g, 35%), mp 88°-119° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[C:14]([N+]([O-])=O)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1.O>CN(C=O)C>[Br:11][C:12]1[CH:13]=[C:14]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ncc(Br)cc1Oc1ccc(F)cc1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
To a solution of 4-fluorophenol (0.49 g, 4.4 mmol) in DMF (10 mL) cooled to 0° C. was added 60% sodium hydride (0.19 g, 4.8 mmol) was added and the reaction was warmed to ambient temperature. 5-Bromo-3-nitropicolinonitrile (1.0 g, 4.4 mmol, solution in 5 mL DMF) and stirred for 3 hours. Poured into water, filtered, washed with water, and dried to yield the title compound (1.0 g, 78%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C@@:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:9](O)=[O:10].[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1>C(Cl)Cl.CN(C=O)C>[CH3:17][S:18][C:19]1[CH:20]=[CH:21][C:22]([S:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[N:31]([C:9](=[O:10])[C@:8]([OH:7])([CH3:16])[C:12]([F:15])([F:14])[F:13])[CH2:30][CH2:29]3)=[CH:23][CH:24]=1
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Reactant: CSc1ccc(Sc2ccc3c(c2)CCN3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1ccc(Sc2ccc3c(c2)CCN3C(=O)[C@@](C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
Oxalyl chloride (0.35 ml, 4.0 mmol) was added to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (0.58 g, 3.7 mmol) (Method A) in DCM (10 ml) containing DMF (1 drop). The mixture was stirred at ambient temperature for 18 hours and was then added to a solution of 5-(4-methylsulphanylphenylsulphanyl)indoline (1.03 g) (Method B) and 2,6-diphenylyridine (0.84 g, 3.64 mmol) in DCM (20 ml). The mixture was stirred for 16 hours, volatile material was removed by evaporation, and the residue was purified by flash column chromatography on silica gel eluting with 10-20% EtOAc/iso-hexane to give the title compound (0.935 g, 2.3 mmol) as a solid. NMR: 1.80 (s, 3H), 2.50 (s, 3H), 3.11-3.19 (m, 2H), 4.19-4.29 (m, 1H), 4.38-4.47 (m, 1H), 4.86 (s, 1H), 7.19-7.27 (m, 6H), 8.20 (d, 1H); m/z (+ve ESP): 414 (M+H)+.