Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][N:19]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:32]1[C:40]2[C:35](=[CH:36][C:37](O)=[CH:38][CH:39]=2)[CH2:34][CH2:33]1.CNC1C=CC=C(NC)N=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][N:19]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[C:7]([C:11]([O:13][C:37]2[CH:36]=[C:35]3[C:40](=[CH:39][CH:38]=2)[CH2:32][CH2:33][CH2:34]3)=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1cccc2c1ccn2-c1ccccc1C#N
Reactant: Oc1ccc2c(c1)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: CNc1cccc(NC)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc(Cl)c(C(=O)Oc2ccc3c(c2)CCC3)n1Cc1cccc2c1ccn2-c1ccccc1C#N
Temperature: 25 °C

Procedure:
To a mixture containing 2-butyl-4-chloro-1-[[1-(2-cyanophenyl)-1H-indol-4-yl]methyl]-1H-imidazole-5-carboxylic acid (903 mg, 2.03 mmol, prepared as described in part C of Example 9), 5-indanol (307 mg, 2.29mmol), 2,6-dimethylaminopyridine (50.8 mg, 0.416 mmol) and triethylamine (0.377 mL, 2.70 mmol) in 9 mL of dichloromethane cooled in an ice bath was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (519 mg, 2.70 mmol). The stoppered reaction mixture was allowed to warm to ambient temperature overnight, then diluted with methylene chloride and rinsed with water and saturated aqueous sodium chloride solution. The organic extract was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 1.83 g of crude product. Flash chromatography on 75 g of silica gel eluted with 8:2, hexanes:ethyl acetate gave 1.03 g of the title A compound.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3cccnc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)sc2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(3-methylthieno[3,2-b]pyridin-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (330 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (291 mg, 94%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:6]=[CH:5]2.C([Li])CCC.CN(C)[CH:29]=[O:30]>O1CCCC1>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:29]=[O:30])[CH:3]=2)[N:8]=1
Reactant: CN(C)C=O
Reactant: COc1ccccc1CNc1ccc2cc(Br)ccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1CNc1ccc2cc(C=O)ccc2n1
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
(6-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (2.0 g, 5.83 mmol) was dissolved in 100 mL tetrahydrofurane. n-Butyllithium solution (1.6 M in hexane, 9.1 mL, 14.6 mmol) was slowly added at −78° C. The reaction mixture was allowed to warm to −10° C. and stirred at this temperature for 45 min. The reaction mixture was then cooled again to −78° C. and dimethylformamide (1.07 g, 14.6 mmol) was added. The mixture was then slowly warmed up and quenched with 200 mL water at 5° C. The solvent was evaporated off. The residue was extracted three times with ethyl acetate (200 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). 2-(2-Methoxy-benzylamino)-quinoline-6-carbaldehyde was obtained as a light yellow solid (683 mg, 40%), MS: m/e=293.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[C:9]([OH:12])[C:8]([Cl:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:15](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]2[O:11][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:12][C:9]=2[C:8]([Cl:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: ClC(Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc(Cl)c(O)c(O)c1Cl
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(Cl)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Yield: 28.2 %

Procedure:
2,5-Dichloro-3,4-dihydroxybenzoic acid (1 g, 4.48 mmol) and dichlorodiphenylmethane (2.12 g, 9.96 mmol) are dissolved in toluene (40 ml) and heated to reflux for 24 hours. After cooling the solvent is evaporated and the residue is purified by column chromatography on silic agel (100 g, dichloromethane then 5% methanol in dichloromethane eluant) to yield the acid as white crystals (490 mg, 28%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].Br.[NH2:7][C:8]1[C:13]([CH2:14]Br)=[CH:12][C:11]([Br:16])=[CH:10][N:9]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:7][C:8]1[C:13]([CH2:14][NH:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:12][C:11]([Br:16])=[CH:10][N:9]=1
Reactant: Nc1ncc(Br)cc1CBr
Reactant: COCCN
Agent: Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCNCc1cc(Br)cnc1N
Reaction time: 8 h
Yield: 89.6 %

Procedure:
2-Methoxyethylamine (1.49 mL, 17.16 mmole) was added to a solution of 2-amino-5-bromo-3-(bromomethyl)pyridine hydrobromide (1.49 g, 4.29 mmole) and DIEA (2.24 mL, 12.87 mmole) in CH2Cl2 (10 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and the solution was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to afford the title compound (1.00 g, 90%) as a light brown liquid after drying in vacuo: MS (ES) m/e 260/262 (M+H)+.
Reaction SMILES: C(=O)([S:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[N:13]=[CH:12]2)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[F:24][C:21]1[CH:20]=[CH:19][C:18]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([SH:8])=[CH:17][CH:16]=3)[CH:12]=[N:13]2)=[CH:23][CH:22]=1
Reactant: O=C(Sc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Fc1ccc(-n2ncc3cc(S)ccc32)cc1

Procedure:
To S-1-(4-fluorophenyl)-1H-indazol-5-yl benzothioate (0.046 g, 0.13 mmol) in methanol (3 mL), potassium carbonate (0.011 mL, 0.20 mmol) was added and the mixture was stirred at r.t. for 2 h. water was than added, 1N HCl (2 ml) and extracted with EtOAc (2*20 ml), dried, evaporated and then purified on HPLC. The relevant fractions were collected freeze dried and analysed by LC/MS.
Reaction SMILES: O1CCCC1.N.[C:7](#[N:16])[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[H][H]>[Co].O>[C:8]1([CH2:7][NH2:16])[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(C#N)cc1
Reactant: [H][H]
Agent: [Co]
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(CN)cc1
Temperature: 120 °C

Procedure:
A stirred autoclave was charged with 400 ml. tetrahydrofuran (THF), 100 ml. ammonia, 50 g. terephthalonitrile (TPN) and 6.0 g. cobalt supported catalyst and various amounts of water. The autoclave was heated to 120° C. Hydrogen was introduced rapidly until the selected pressure was reached. The absorption of hydrogen started immediately and additional hydrogen was added to keep the pressure at the selected level. The course of the reaction was monitored by measuring the volume of hydrogen consumed and by periodic withdrawal of a small sample of the reaction mixture for analysis. When the analysis indicated that all of the terephthalonitrile had reacted, the agitation was stopped and the reactor was cooled rapidly and vented. The reaction mixture was filtered to recover the catalyst and then was flash evaporated to remove solvent. The residual oil was flash distilled at about 100° C. and 0.5 mm Hg. to give practically pure p-xylylene diamine. A small amount of high boiling residue remained in the distillation pot. Results of experiments conducted with various amounts of water and at 1500 and 2500 psig are listed in Table I.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[NH2:17][CH2:18][C:19](OCC)=[O:20]>N1C=CC=CC=1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2=[C:2]([CH:7]=1)[NH:1][C:19](=[O:20])[CH2:18][N:17]=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cc(Br)ccc1C(=O)c1ccccc1
Reactant: CCOC(=O)CN
Solvent: c1ccncc1
Product: O=C1CN=C(c2ccccc2)c2ccc(Br)cc2N1
Yield: 50.8 %

Procedure:
(2-Amino-4-bromophenyl)(phenyl)methanone (1.75 g, 10 mmol), ethyl 2-aminoacetate (2.23 g, 16 mmol) and pyridine (40 mL) were stirred together at 80° C. for about 3 days. The pyridine was evaporated and the residue was triturated in 5% methanol in ethyl acetate to afford title compound 354 (1.6 g, 51%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C@H:11]1([NH2:18])[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([NH2:18])[CH2:12][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
A N,N-dimethylacetamide (30 ml) solution containing 4-nitrofluorobenzene (1.69 g) and trans-1,4-cyclohexanediamine (4.1 g) was stirred at 144-C for 3 days. After cooling, an aqueous saturated potassium carbonate solution was added to the reaction solution, and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous potassium carbonate, and then, the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: chloroform-methanol-ammonia (90:10:1)), and the solvent was removed to obtain trans-N-(4-nitrophenyl)-1,4-cyclohexanediamine (Reference Example 3-41 in Table 5) (2.31 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[F:19].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:9]2[CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[NH:10][C:8]=2[CH:7]=[CH:6][C:5]=1[F:19])=[O:20]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cc(N=Cc2cccc(Br)c2)ccc1F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(F)ccc2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a stirred mixture solution of 5-[(3-bromo-benzylidene)-amino]-2-fluoro-benzoic acid methyl ester (51.7 g, 153.8 mmol) and ytterbium(III) triflate hydrate (14.3 g, 23.1 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (14 mL, 153.8 mmol) and water (2.8 mL, 153.8 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-6-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (63.0 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrFNO3 (M+H)+: 409.27, observed: 390.0 & 392.0.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].S(Cl)(=O)(=O)N.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+].[Cl-]>CN1C(=O)CCC1.C(O)=O>[C:13]1([O:19][S:2](=[O:3])(=[O:4])[NH2:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: NS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O=CO
Solvent: CN1CCCC1=O
Product: NS(=O)(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A three necked round bottom equipped with a reflux condenser was charged with chlorosulfonyl isocyanate (5.25 ml, 0.06 mol) and cooled to 0° C. Formic acid (2.25 mL, 0.06 mol) was added dropwise with rapid stirring with rapid gas evolution observed. Upon complete addition of formic acid, the reaction was let warm to room temperature. After 2 h, the resultant reaction vessel containing the solid sulfamoyl chloride was cooled to 0° C. and phenol (1.88 g, 0.02 mol) dissolved in NMP (25 mL) was added dropwise via an addition funnel. The reaction was let warm to room temperature. After 3 h stirring, the reaction mixture was poured into cold saturated aqueous NaCl (120 mL) and extracted with EtOAc. After removal of the separated organic solvent, the crude product was purified by column chromatography on silica (35% EtOAc/hexane) to provide sulfamic acid phenyl ester (2.8 g, 81%): LCMS found 173.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Cl:1][C:2]1[C:3]([C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2
Reactant: OB(O)c1cccnc1
Reactant: COc1nc2cc(Cl)c(Cl)c(I)c2nc1OC
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1nc2cc(Cl)c(Cl)c(-c3cccnc3)c2nc1OC
Yield: 29.2 %

Procedure:
A mixture of 6,7-dichloro-2,3-dimethoxy-5-iodoquinoxaline (Preparation 108, 0.2 g, 0.519 mmol), 3-pyridylboronic acid (Rec. Trav. Chim. Pays-Bas. 84, 439 (1965)) (0.077 g, 0.623 mmol), tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.026 mmol) and potassium carbonate (0.143 g, 1.038 mmol) in 1,4-dioxane (12 mL) and water (4 mL) was heated under reflux for 16 hours. After being cooled, the mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (20 mL) and water (20 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (1:0 changing to 99:1, by volume) to afford the title compound (0.051 g, 29%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:15][C:3]=1[C:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])=[O:5].C(O)C.[BH4-].[Na+]>O>[CH3:12][C:11]1[CH:10]=[C:9]([CH3:13])[CH:8]=[C:7]([CH3:14])[C:6]=1[CH:4]([C:3]1[CH:15]=[C:16]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH:17]=[CH:18][C:2]=1[CH3:1])[OH:5]
Reactant: Cc1cc(C)c(C(=O)c2cc(-n3ccnc3)ccc2C)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(C(O)c2cc(-n3ccnc3)ccc2C)c(C)c1
Temperature: 50 °C
Reaction time: 10 h
Yield: 78.9 %

Procedure:
To a suspension of 7.3 g of 2-methyl-5-(1-imidazolyl)-2',4',6'-trimethylbenzophenone is 50 ml of ethanol is added a solution of 1 g of sodium borohydride in 10 ml of water. After the mixture is stirred at 50° C. for 10 hours, the reaction mixture is poured into ice-cold water. The crystals precipitated are filtered off and recrystallized from ethanol to give 5.8 g of α-(2,4,6-trimethylphenyl)-2-methyl-5-(1-imidazolyl)benzenemethanol as white crystals, melting at 190°-191° C.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][C:14]3[CH:18]=[CH:17][O:16][CH:15]=3)SCCCS2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[OH:20].O>Cl[Hg]Cl>[O:16]1[CH:17]=[CH:18][C:14]([CH2:13][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:20])=[CH:15]1
Reactant: c1ccc(C2(Cc3ccoc3)SCCCS2)cc1
Reactant: CO
Agent: Cl[Hg]Cl
Solvent: O
Product: O=C(Cc1ccoc1)c1ccccc1

Procedure:
3-(2-Phenyl-[1,3]dithian-2-ylmethyl)-furan (11.5 g, 41 mmol) was suspended in 9:1 methanol/water (v/v) (150 mL) with slight heating. A solution of HgCl2 (22.3 g, 82 mmol) in methanol/water (50 mL) and solid HgO (8.0 g, 36.9 mmol) was added, and the mixture was heated at reflux under a nitrogen atmosphere for 6-7 h. The reaction mixture was filtered through celite to remove solids, and then concentrated. The resulting aqueous mixture was extracted with ethyl acetate, the combined organic extracts were washed with water, dried over sodium sulfate, and evaporated. The crude product was purified by flash column chromatography using 2% ethyl acetate in hexane as eluent. Yield: 5.7 g, 75%.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[C:31]([O:30][CH3:29])=[O:40])=[CH:11][CH:10]=1
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(O)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Yield: 69.4 %

Procedure:
N-(2,4-difluorobenzyl)-N-heptyl-3-(4-hydroxyphenyl)propanamide (195 mg, 0.501 mmol), 2-bromomethylbenzoic acid methyl ester (120.4 mg, 0.526 mmol) and anhydrous potassium carbonate (103 mg, 0.751 mmol) were mixed in acetonitrile (15 ml). The mixture was heated to reflux overnight and then evaporated to dryness. Water and ethyl acetate were added and the two phases were separated. The organic phase was dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using heptane/DCM (50:50), then DCM and then MeOH/DCM (0.5:99.5) as eluant gave 187 mg desired product, yield 69.5%.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:15](=[O:29])[CH:16]([NH2:28])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[CH3:31]C(C)([O-])C.[Na+].O>C1COCC1>[CH2:11]([O:10][C:8]([C:7]1[CH:12]=[CH:13][C:4]2[C:3](=[O:2])[NH:28][CH:16]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[C:15](=[O:29])[NH:14][C:5]=2[CH:6]=1)=[O:9])[CH3:31]
Reactant: COC(=O)c1ccc(C(=O)OC)c(NC(=O)C(N)CCCNC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)C(CCCNC(=O)OC(C)(C)C)NC2=O
Temperature: 60 °C
Reaction time: 15 h

Procedure:
The compound (303.8 mg) obtained in Example 14-2 and sodium t-butoxide (manufactured by Wako Pure Chemical Industries, Ltd.) (138.4 mg) were dissolved in anhydrous THF (6.0 ml) and the whole was stirred at 60° C. for 15 hours. After completion of the reaction, water was added thereto and the whole was subjected to extraction with chloroform.
Reaction SMILES: [C:1]([C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].ClC(OCC)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>>[F:26][C:25]([F:27])([F:28])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:9]([C:6]2([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:7][CH2:8]2)=[O:11])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1(C(=O)O)CC1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Yield: 50 %

Procedure:
1-Carboethoxycyclopropanecarboxylic acid (9.81 grams, 0.06 mole), ethyl chloroformate (6.73 grams, 0.06 mole) and 4-aminobenzotrifluoride (10.0 grams, 0.06 mole) were reacted sequentially in the presence of triethylamine (6.28 grams, 0.06 mole) in a manner similar to that described in Example XXXIII to give 10.25 grams (0.03 mole) of ethyl 1-(4-trifluoromethylphenylaminocarbonyl)cyclopropanecarboxylate having a melting point of 80.5° C.-82.0° C.
Reaction SMILES: [C@@H:1]12[CH2:7][C:6](=[CH:8][C:9]([OH:11])=[O:10])[C@@H:5]1[CH2:4][CH2:3][CH2:2]2.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:19][CH2:20]CCCCC>C(O)C.O>[C@@H:1]12[CH2:7][C:6](=[CH:8][C:9]([O:11][CH2:19][CH3:20])=[O:10])[C@@H:5]1[CH2:4][CH2:3][CH2:2]2
Reactant: O=C(O)C=C1C[C@H]2CCC[C@@H]12
Reactant: CCCCCCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C=C1C[C@H]2CCC[C@@H]12
Temperature: 75 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
The compound of Example 5 (10.5 Kg; 69.0 mol) was dissolved in absolute ethanol (52.5 L) and 98 wt % sulfuric acid (0.525 Kg; 5.36 mol) was added at 20–25° C. The reaction mixture was then heated to 75° C. over 0.5 hours and stirred for 24 hours. The reaction mixture was cooled to 10° C. and a 40 wt % solution of sodium hydroxide (3.17 L) diluted with demineralised water (28.6 L) was added slowly to maintain the reaction temperature below 20° C. n-Heptane (31.5 L) was added and the phases were separated. The aqueous phase was then extracted again with n-heptane (31.5 L). The combined organic phases were washed twice with demineralised water (63.0 L, then 31.5 L). The organic phase was separated to give the title compound (11.1 Kg) in 89% yield as an organic solution which is used directly in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted with 0.289g. of valeric acid chloride as in Example 1. The 0.590 g. of brownish colored turbid oil obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.518 g. of a colorless, turbid oil which crystallizes upon trituration. It is recrytallized from acetone-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl valerate obtained melts at 36.5°-36.9° and has a clearing point of 61.7°. UV (EtOH): ε 271 = 25800.