Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH2:10][C@@H:9]([NH:13]C(=O)OC(C)(C)C)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:21]>CO>[C:1]1([N:7]2[CH2:12][CH2:11][CH2:10][C@@H:9]([NH2:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:21]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccccc2)C1
Agent: Cl
Solvent: CO
Product: N[C@@H]1CCCN(c2ccccc2)C1

Procedure:
A solution of tert-butyl [(3R)-1-phenylpiperidin-3-yl]carbamate (133 mg, 0.483 mmol) in 3 M HCl in MeOH (3 ml) was heated to 70° C. for 3 hr. The reaction mixture was concentrated in vacuo to provide crude (3R)-1-phenylpiperidin-3-amine as the bis HCl salt, which was used as-is without further purification.
Reaction SMILES: C([O:5]O)(C)(C)C.[C:7]1([CH2:13][CH2:14][CH:15]=[CH:16][CH2:17][OH:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[O:5]1[C@@H:15]([CH2:14][CH2:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@@H:16]1[CH2:17][OH:18]
Reactant: CC(C)(C)OO
Reactant: OCC=CCCc1ccccc1
Product: OC[C@@H]1O[C@H]1CCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a 1L 3-neck round-bottom flask equipped with a mechanical stirrer, thermocouple and nitrogen inlet was added CH2C12 (350 mL), dried 4 Å molecular sieves (30 g) and L-(+)-diethyl tartrate (7.62 g, 0.037 mol). The resulting mixture was cooled to -20° C. and treated with Ti(O-i-Pr)4 (9.2 mL, 0.031 mol), followed by the addition of t-butylhydroperoxide (4.0 M in CH2Cl2, 182 mL, 0.78 mol) at a rate to maintain the temperature 2 -20° C. Upon complete addition, the reaction mixture was stirred for another 30 min, and then treated with a solution of the allylic alcohol (15) (50 g, 0.31 mol) in CH2C12 (30 mL) at a rate to maintain the temperature at -20° C. The reaction was stirred at the same temperature for 5 h, then filtered into a solution of ferrous sulfate heptahydrate (132 g) and tartaric acid (40 g) in water (400 mL) at 0° C. The mixture was stirred for 20 min, then transferred to a separatory funnel and extracted with t-BuOMe (2×200 mL). The combined organic phase was stirred with 30% NaOH solution containing NaCi, for 1 h at 0° C. The layers were again separated, and the aqueous phase extracted with t-BuOMe. The combined organic phase was washed with brine, dried over MgSO4 and concentrated to yield the title compound (52.8 g) as an amber oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:14][N:13]([C:15]2[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=2)[C:12](=[O:21])[C:11]1([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[N+:31]([O-])([OH:33])=[O:32].[OH-].[Na+]>O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:14][N:13]([C:15]2[C:19]([N+:31]([O-:33])=[O:32])=[CH:18][N:17]([CH3:20])[N:16]=2)[C:12](=[O:21])[C:11]1([CH3:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc(N2CC(COCc3ccccc3)C(C)(C)C2=O)n1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cn1cc([N+](=O)[O-])c(N2CC(COCc3ccccc3)C(C)(C)C2=O)n1

Procedure:
To a mixture of 4-((benzyloxy)methyl)-3,3-dimethyl-1-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one (459 mg) and acetic anhydride (3.0 mL) was added fuming nitric acid (0.12 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, water was added thereto, and the mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (343 mg).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][CH:11]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])[CH3:12])[CH:6]=[CH:7][CH:8]=1.ClC(C)[CH2:26][NH:27]C1C=CC=C(C(F)(F)F)C=1.CC1C=CC=C(C)C=1N.Cl.CC1C=CC=C(C)C=1N>>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH:11]([CH3:12])[N:13]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:21])[C:26]2=[NH:27])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(Cl)CNc1cccc(C(F)(F)F)c1
Reactant: Cc1cccc(C)c1NC(C)CNc1cccc(C(F)(F)F)c1
Agent: Cc1cccc(C)c1N
Agent: Cl
Product: Cc1cccc(C)c1N1C(=N)N(c2cccc(C(F)(F)F)c2)CC1C
Yield: 55.6 %

Procedure:
1-(3'-Trifluoromethylphenyl-amino)-2-(2',6'-dimethylphenyl-amino)-propane, applied as starting substance, is prepared by reacting N-(β-chloropropyl)-3-trifluoromethylaniline, a compound obtained as described in Example 23, point (b), with 2,6-dimethylaniline. The reaction is performed as described in Example 16, point (c) with the difference that crystalline 2,6-dimethylaniline hydrochloride is separated from the reaction mixture by trituration with ethyl acetate. The aimed product is obtained with a yield of 55.6%; m.p.: 95°-98° C. (dhydrochloride).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6](C(=O)C(F)(F)F)[C@@H:7]([CH3:19])[CH2:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:19])[CH2:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@H]1CN(C(=O)OC(C)(C)C)c2cc(Br)ccc2N1
Temperature: 70 °C
Yield: 96.4 %

Procedure:
A 500-mL round bottomed flask fitted with a nitrogen inlet, magnetic stir bar, and condenser was charged with (S)-tert-butyl 7-bromo-3-methyl-4-(2,2,2-trifluoroacetyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (13.10 g, 31.0 mmol), ethanol (130 mL), and half-saturated aqueous sodium bicarbonate solution (130 mL, 31.0 mmol). The reaction mixture was heated to 70° C. for 24 h and then cooled to room temperature. The ethanol was removed under reduced pressure, and the residue was extracted into dichloromethane (250 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 4:1 hexanes-ethyl acetate) to afford (S)-tert-butyl 7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (9.78 g, 97%) as a white solid. MS (ESI, pos. ion) m/z 327, 329 [M+1]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[CH3:6][C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:28][C@H:27]([CH2:29]O)[O:26][C:25]4=[O:31])=[CH:20][C:19]=3[F:32])=[CH:14][N:13]=2)=[N:10][N:11]=1>>[CH3:6][C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:28][C@H:27]([CH2:29][N:1]5[CH:5]=[CH:4][N:3]=[N:2]5)[O:26][C:25]4=[O:31])=[CH:20][C:19]=3[F:32])=[CH:14][N:13]=2)=[N:10][N:11]=1
Reactant: Cc1nnc(-c2ccc(-c3ccc(N4C[C@H](CO)OC4=O)cc3F)cn2)o1
Reactant: c1c[nH]nn1
Product: Cc1nnc(-c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)o1

Procedure:
The same procedure as in Example 24 was conducted, except for adding 1,2,3-triazole and using the compound 16 as a starting material, to obtain the title compound.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:4]=2[CH2:3]1.[N:20]1([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]2=[O:34])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[CH3:19][C:17]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][C:8]=3[CH:2]([N:23]3[CH2:24][CH2:25][N:20]([CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]4=[O:34])[CH2:21][CH2:22]3)[CH2:3][C:4]=2[CH:18]=1
Reactant: O=C1CCCCN1CCN1CCNCC1
Reactant: CSc1ccc2c(c1)C(Cl)Cc1cc(C)ccc1O2
Solvent: ClC(Cl)Cl
Product: CSc1ccc2c(c1)C(N1CCN(CCN3CCCCC3=O)CC1)Cc1cc(C)ccc1O2

Procedure:
A solution of 3 g. of 10-chloro-10,11-dihydro-2-methyl-8-methylthio-dibenz[b,f]oxepin and 5.73 g. of 1-[2-(1-piperazinyl)-ethyl]-2-piperidone in 18 ml. of chloroform is heated at reflux for 20 hours. The solvent is removed in vacuo. The residue is partitioned between benzene and 10% aqueous sodium carbonate solution. The benzene solution is extracted with dilute hydrochloric acid. The acid-aqueous solution is made alkaline with sodium bicarbonate and extracted with benzene. The benzene extract is washed several times with water, dried, evaporated in vacuo, and there is obtained 1-[2-{4-[10,11-dihydro-2-methyl-8-methylthio-dibenz[b,f]-oxepin-10-yl]-1-piperazinyl}-ethyl]-2-piperidone. The dihydrochloride is prepared in ethanol by the addition of an excess of alcoholic hydrogen chloride. By the addition of ether, there are obtained crystals having a melting point of 183°-185° C. (with decomposition). By re-dissolving the dihydrochloride in water, there is obtained the monohydrochloride having a melting point of 117°-120° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]>[Ni].CO>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CO
Product: CCN1CCN(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 98 %

Procedure:
A suspension of 1-ethyl-4-(4-nitro-phenyl)-piperazine (Step 1.10) (6.2 g, 26.35 mmol) and Raney nickel (2 g) in MeOH (120 mL) was stirred for 7 h at rt, under a hydrogen atmosphere. The reaction mixture was filtered through a pad of celite and concentrated to afford 5.3 g of the title compound as a violet solid: ESI-MS: 206.1 [M+H]+; TLC: Rf=0.15 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [N+](C1C(C)=CC=C([N+]([O-])=O)C=1N)([O-])=O.[CH2:15]([C:17]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:20]([NH2:21])=[C:19]([N+:27]([O-:29])=[O:28])[C:18]=1[CH2:30]OC)[CH3:16]>>[CH2:15]([C:17]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:20]([NH2:21])=[C:19]([N+:27]([O-:29])=[O:28])[C:18]=1[CH3:30])[CH3:16]
Reactant: CCc1cc([N+](=O)[O-])c(N)c([N+](=O)[O-])c1COC
Agent: Cc1ccc([N+](=O)[O-])c(N)c1[N+](=O)[O-]
Product: CCc1cc([N+](=O)[O-])c(N)c([N+](=O)[O-])c1C

Procedure:
The above 2,6-dinitro-m-toluidine was dealkylated in a manner similar to that described for the preparation of 4-ethyl-α-methoxy-2,6-dinitro-m-toluidine. The desired product after recrystallization from hexane had m.p. 101°-101.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:16][C:17]([OH:19])=O)[CH:7]([CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][CH3:9])=[O:5])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:8]([CH:7]1[CH2:10][C:11]2[S:12][CH:13]=[CH:14][C:15]=2[C:17](=[O:19])[CH2:16][N:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH3:9]
Reactant: CCOC(=O)N(CC(=O)O)C(CC)Cc1cccs1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N1CC(=O)c2ccsc2CC1CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
To a solution of Compound 1036 (2.25 g, 7.885 mmol) in DCM (35 mL) was added 0.1 mL of DMF followed by addition of oxalyl chloride (1.502 g, 1.032 mL, 11.83 mmol). The reaction mixture was stirred at RT for 1 hour and the volatiles were removed in vacuo. The residue was taken up in benzene and the volatiles were again removed in vacuo (2×), followed by drying under vacuum. The residue was taken up in dry DCM (35 mL) and AlCl3 (3.679 g, 27.59 mmol) was added at RT. The mixture was stirred at RT for 1.5 hours and the reaction quenched with ethanol. The resulting solution was poured into ice water and extracted with DCM (2×). The combined organic layers were dried over Na2SO4, concentrated under vacuum, and the residue purified by silica gel chromatography, using a 5%-20% ethyl acetate/hexanes gradient as eluant, to produce ethyl 7-ethyl-4-oxo-7,8-dihydro-4H-thieno[2,3-d]azepine-6(5H)-carboxylate (Compound 1037, 671 mg).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8](F)[N:7]=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[N:5]=1.[CH2:16]([OH:18])[CH3:17]>>[NH2:3][C:4]1[N:9]=[C:8]([O:18][CH2:16][CH3:17])[N:7]=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[N:5]=1
Reactant: CCO
Reactant: Nc1nc(F)nc(OC(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Product: CCOc1nc(N)nc(OC(F)(F)F)n1
Reaction time: 0.25 h

Procedure:
2.3 g (0.093 mol) of 97% sodium hydride were added a little at a time to 300 ml of ethanol at 20-35° C. and dissolved by stirring for 15 minutes. Then, while stirring at 0° C., 18.5 g (0.093 mol) of 2-amino-4-fluoro-6-trifluoromethoxy-1,3,5-triazine were added over the course of 10 minutes, and the mixture was stirred at 0° C. for 1 hour and at 22° C. overnight. The residue from concentration under reduced pressure was taken up in methylene chloride, extracted with water and dried. Concentration yielded 17.9 g (85.9% of theory) of the title compound of melting point 69-71° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[S:25]([N:24]([CH3:29])[CH3:23])(=[O:27])=[O:26])=[CH:4][CH:3]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(Nc1ccc(Cl)cc1)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(c1cccnc1)N(c1ccc(Cl)cc1)S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 3.5 g. portion of 3-[1-(4-chlorophenylamino)ethyl]pyridine was dissolved in dichloromethane and 2.7 g. of potassium carbonate and 2.9 g. of dimethylsulfamoyl chloride were added. The mixture was stirred at ambient temperature for 3 days, and was then diluted with 25 ml. of additional dichloromethane and was extracted with water. The organic layer was dried over magnesium sulfate and evaporated to an oil, which was taken up in dichloromethane and chromatographed over silica gel, eluting with chloroform. The product-containing fractions were combined and evaporated to obtain about 0.3 g. of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH2:21][N:22]([C:29]([CH:26]2[CH2:28][CH2:27]2)=[O:30])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1ccc(C)cc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C)ccc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-5′-methyl-biphenyl-3-yl)-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[I:41])[CH:36]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH2:25]([O:32][C:33]1[CH:34]=[C:35](/[CH:36]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:38]=[CH:39][C:40]=1[I:41])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(I)c(OCc2ccccc2)c1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(I)c(OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
5.0 g (14.95 mmol, 1.8 eq) of methyl triphenylphosphoranylideneacetate are added to a solution of 3.25 g (8.2 mmol, 1 eq) of 3-benzyloxy-4-iodobenzaldehyde in 15 ml of toluene. The reaction mixture is stirred for 1 hour at 90° C. The solvent is evaporated off and the residual oil is then chromatographed on silica gel (8/2 heptane/ethyl acetate) and recrystallized from dichloromethane/heptane. 2.59 g of methyl (E)-3-(3-benzyloxy-4-iodophenyl)acrylate are obtained in solid form. Yield=68%
Reaction SMILES: [F:1][C:2]([F:17])([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)O.[H-].[Na+].[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C1COCC1>[F:1][C:2]([F:17])([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)[S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC(c1ccc[nH]1)C(F)(F)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)C(c2ccc[nH]2)C(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(2',2',3',3',4',4',4'-heptafluoro-1'-hydroxybutyl)pyrrole (2.6514 g, 10 mmol) dissolved in 25 ml of dry THF is transferred by canula to a suspension of sodium hydride (0.2640 g, 11 mmol) in 50 ml of THF. The mixture is stirred for 2 hours at room temperature. A solution of tosylchloride (11 mmol) in 10 ml of THF is added dropwise and the solution stirred overnight. The resulting suspension is evaporated almost to dryness and 50 ml of water is added. The mixture was extracted 3×50 mL with pentane and the organic layers were combined and dried over magnesium sulfate. The mixture is filtered and the solvent evaporated to yield the product 2-(2',2',3',3',4',4',4'-heptafluoro-1'-tosylbutyl)pyrrole.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=O>C(O)C>[CH3:11][C:9]1([C:8]([OH:13])=[O:12])[NH:1][CH:2]([C:5]([OH:7])=[O:6])[CH2:3][S:4]1
Reactant: CC(=O)C(=O)O
Reactant: N[C@@H](CS)C(=O)O
Solvent: CCO
Product: CC1(C(=O)O)NC(C(=O)O)CS1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
Under an argon atmosphere, L-cysteine (15 g) was dissolved in dry ethanol (35 mL), pyruvic acid (18.6 mL) was added thereto at room temperature, and the mixture was stirred for 3 hours. The resulting solid was collected by filtration under reduced pressure, and washed with ice-cooled ethanol to give 2-methylthiazolidine-2,4-dicarboxylic acid (diastereomer mixture) (23 g, yield 97%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[CH:5]=[C:4]([NH:10][C:11](=[O:32])[CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[CH:18][C:17]=2[C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH2:13][CH3:14])[C:3]=1[OH:33].[C:34](Cl)(=[O:39])[CH2:35][C:36](Cl)=[O:37].O.C(OCC)(=O)C>C1C=CC=CC=1>[Cl:9][C:6]1[C:7]2=[N:8][C:34](=[O:39])[CH2:35][C:36](=[O:37])[N:1]=[C:2]2[C:3]([OH:33])=[C:4]([NH:10][C:11](=[O:32])[CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[CH:18][C:17]=2[C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH2:13][CH3:14])[CH:5]=1
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c(N)c(N)c1O
Reactant: O=C(Cl)CC(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c2c(c1O)=NC(=O)CC(=O)N=2

Procedure:
In 250 ml of benzene was dissolved 17 g of the resulting 2,3-diamino-4-chloro-6-[2-(2,4-di-t-amylphenoxy)butanoylamino]phenol, and a solution of 5.8 g of malonyl dichloride in 100 ml of benzene was slowly added to the solution at room temperature while stirring. After the dropwise addition, the reaction mixture was stirred for 1 hour. Water and ethyl acetate were added to the reaction mixture to effect extraction. The extract was concentrated, and the residue was purified by silica gel column chromatography (chloroform/ethyl acetate=2/1 by volume) to obtain 4.2 g of the desired coupler (Coupler 3) having a melting point of 193° to 195° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Cl)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35.1 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (786 mg, 0.004 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (2.58 g, 0.020 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(3-chloro-phenoxy)-but-2-enoic acid ethyl ester (1.30 g, 0.004 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-2-[4-(3-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (530 mg, 33%) as a yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][CH2:13][CH2:14]O.C(N(CC)CC)C.[CH3:23][O:24][C:25](=[O:37])[C:26]1[C:27](=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=1)[C:28]([O:30][CH3:31])=[O:29].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:23][O:24][C:25](=[O:37])[C:26]1[C:27](=[C:32]([NH:36][CH2:14][CH2:13][O:12][CH3:11])[CH:33]=[CH:34][CH:35]=1)[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1cccc(N)c1C(=O)OC
Reactant: COCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COCCNc1cccc(C(=O)OC)c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.8 %

Procedure:
To a stirred solution of oxalyl chloride (1.75 ml, 20 mmol) in methylene chloride (20 ml) under a nitrogen atmosphere at −78° C. was added DMSO (1.42 ml, 20 mmol) in methylene chloride (10 ml) dropwise over 5 minutes. The mixture was stirred for 5 minutes followed by the dropwise addition of 2-methoxyethanol (1.58 ml, 20 mmol) in methylene chloride (10 ml) over 5 minutes. The mixture was stirred for 20 minutes followed by the dropwise addition of triethylamine (8.36 ml, 60 mmol) over 5 minutes. The resulting suspension was stirred for 30 minutes at −78° C. and then allowed to warm to room temperature. The reaction mixture was diluted with methylene chloride (20 ml). To this stirred mixture was added 3-amino-phthalic acid dimethyl ester (2.09 g, 10 mmol) and acetic acid (4.60 ml, 80 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 5 minutes followed by the addition of sodium triacetoxyborohydride (4.24 g, 20 mmol). The mixture was stirred for 3 h. The reaction mixture was diluted with methylene chloride (50 ml) and washed with water (3×100 ml), saturated aqueous sodium bicarbonate (2×100 ml), brine (100 ml), and dried (MgSO4). The solvent was evaporated in vacuo and the residue purified by chromatography (25% ethyl acetate/hexane) to give 2.24 g (84%) of product as an oil. 1H NMR (DMSO-d6) d 7.32 (t, J=8.0 Hz, 1H), 6.88-6.79 (m, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.62 (t, J=5.4 Hz, 2H), 3.41 (s, 3H), 3.35 (q, J=5.2 Hz, 2H).