Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[S:17][CH:18]=[C:19]([C:21]3[C:25](=[CH2:26])[S:24][CH:23]([C:27]([O:29][CH3:30])=[S:28])[CH:22]=3)[N:20]=2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:31]CC(C1C=C(C(OC)=S)SC=1C)=O.O(C1C=CC(NC(N)=S)=CC=1)C1C=CC=CC=1>>[BrH:31].[O:2]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:22]=[C:23]([C:27]([O:29][CH3:30])=[S:28])[S:24][C:25]=3[CH3:26])[N:20]=2)=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Reactant: C=C1SC(C(=S)OC)C=C1c1csc(Nc2ccc(Oc3ccccc3)cc2)n1
Agent: Br
Agent: NC(=S)Nc1ccc(Oc2ccccc2)cc1
Product: COC(=S)c1cc(-c2csc(Nc3ccc(Oc4ccccc4)cc3)n2)c(C)s1
Yield: 88 %

Procedure:
Methyl 4-(2-{[4-phenoxyphenyl]amino}(1,3-thiazol-4-yl))-5-methlylthiothiophene-2-carboxylate hydrobromide: Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (200 mg, 0.64 mmol) was allowed to react with 4-phenoxyphenylthiourea (158 mg) as described in Example 154, step (a) to give 300 mg (88% yield) of methyl 4-(2-{[4-(phenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide. Mass Spectrum (ESI) m/z calcd. for C22H18N2O3S3, 454.6 (M+H), found 455.2.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:22])[NH:5][C:6]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][N:7]=1)[CH3:2].[O-]CCCC.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:64]1[CH:69]=[CH:68][N:67]([CH3:70])[C:66](=[O:71])[CH:65]=1>O1CCOCC1.CO>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[N:7]=[CH:8][C:9]([C:10]([NH:12][C:64]2[CH:69]=[CH:68][N:67]([CH3:70])[C:66](=[O:71])[CH:65]=2)=[O:11])=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=1)=[O:22])[CH3:2]
Reactant: Cn1ccc(Br)cc1=O
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(N)=O)cn1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: CCCC[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)Nc2ccn(C)c(=O)c2)cn1
Temperature: 120 °C
Reaction time: 48 h
Yield: 25 %

Procedure:
Compound 61 (20 mg, 0.067 mmol) was suspended in dry dioxane (2 mL) with the sodium butoxide (13 mg, 0.13 mmol), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (6 mg, 0.01 mmol), 4-bromo-1-methyl-pyridin-2-one (25 mg, 0.13 mmol) and tris-(dibenzylidineacetone)dipalladium(0) (6 mg, 0.007 mmol). The mixture was placed under N2 and heated in a microwave for 1 h at 120° C. The mixture was left at RT over 2 days. The mixture was transferred to a flask with MeOH and the solvent removed. The residue was suspended in 10% MeOH/DCM and applied to a silica column, eluting with EtOAc/heptane, followed by MeOH/DCM gradient, to afford Compound 134 (6.8 mg). 1H NMR (400 MHz, DMSO) δ 10.27 (s, 1H), 9.70 (s, 1H), 9.14 (s, 1H), 8.54 (s, 1H), 7.88 (s, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.47-7.35 (m, 2H), 7.34-7.21 (m, 3H), 7.21-7.11 (m, 1H), 6.87 (d, J=2.3 Hz, 1H), 6.58 (dd, J=7.5, 2.4 Hz, 1H), 3.37 (s, 3H), 3.19-3.09 (m, 2H), 1.06 (t, J=7.2 Hz, 3H), [M+H]+ m/z=407.13.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].O1CCO[CH2:14][CH2:13]1.Cl>C(O)C>[N+:1]([C:4]1[S:8][C:7]([C:9]([O:11][CH2:13][CH3:14])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])s1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc([N+](=O)[O-])s1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
5 g of 5-nitrothiophene-2-carboxylic acid was stirred in 100 ml of ethanol. 20 ml of dioxane containing 4 M of hydrogen chloride was added to the obtained mixture, and they were stirred at 60° C. for 2 days. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8](N[C@H](C(NCC(O)=O)=O)CS)=[O:9])[C:3]([OH:5])=[O:4].[O:21]=[C:22]([C@H:24]([CH2:26][C:27]1[CH:34]=[C:32]([OH:33])[C:30]([OH:31])=[CH:29][CH:28]=1)[NH2:25])[OH:23]>>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:6][CH2:7][C:8]([NH:25][C@@H:24]([CH2:26][C:27]1[CH:34]=[C:32]([OH:33])[C:30]([OH:31])=[CH:29][CH:28]=1)[C:22]([OH:23])=[O:21])=[O:9].[C:3]([O-:5])(=[O:4])[CH3:2]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Product: CC(=O)[O-]
Product: N[C@@H](CCC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O)C(=O)O

Procedure:
Glutathione and L-DOPA were incubated with a partially purified preparation of sheep kidney γ-glutamyl transpeptidase. γ-Glutamyl-DOPA was isolated from the incubation mixture by preparative ion exchange chromatography on a Dowex-1 (acetate) column. 6.14 of glutathione (0.02 mole) and 1.97 g of L-DOPA (0.01 mole) were dissolved in 200 ml of 1 M Tris (base) solution. 2.5 ml of γ-glutamyl transpeptidase solution (100 units/ml) were added and the flask was flushed with nitrogen to protect DOPA from oxidation and the mixture was incubated at 37° for 6 hours. L-γ-glutamyl-L-3,4-dihydroxyphenylalanine (γ-glutamyl-DOPA) was isolated by ion exchange chromatography as in Example 1. It emerges from the column when approximately 2 liters of the eluent passed through the column. Unreacted. glutathione, free glutamate and cysteinylglycine emerge from the column in earlier fractions.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].[Li]CCCC.CN([CH:19]=[O:20])C.CCOC(C)=O>CCOCC>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([F:10])=[C:2]([CH:7]=1)[CH:19]=[O:20]
Reactant: Fc1cc(F)c(Br)cc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=Cc1cc(Br)c(F)cc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,5-dibromo-2,4-difluorobenzene (17.5 g, 64.2 mmol) in ether (100 mL) at −78° C. was added n-BuLi (2.5 M solution, 30.8 mL, 77 mmol) over a period of 5 min, and the reaction mixture was stirred at −78° C. for 30 min. Then DMF (9.94 mL, 148 mmol) was added in one portion, and the mixture was stirred at −78° C. for 30 min. The reaction mixture was worked up with EtOAc/sat. NH4Cl, and the crude product was purified by silica gel chromatography eluting with 0-10% EtOAc/Hexanes to give the title compound as a slightly yellow oil (8.5 g, 60% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 10.26 (s, 1H), 8.14 (t, J=7.5 Hz, 1H), 7.05 (dd, J=9.8, 8.0 Hz, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:14]=2)=[CH:11][N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[S:9][C:10]([C:13]2[CH:14]=[C:15]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:16]=[CH:17][CH:18]=2)=[CH:11][N:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 69.7 %

Procedure:
To a suspension of tert-butyl[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]carbamate (56 mg, 0.128 mmol) in CH2Cl2 (2 mL) at room temperature, under nitrogen, was added trifluoroacetic acid (0.197 mL, 2.56 mmol). The mixture was stirred at room temperature for 17 hours and concentrated to dryness. The residue was partitioned between ethyl acetate and 5% NaHCO3. The aqueous layer was extracted twice with ethyl acetate and the combined organic fractions were washed with water and brine, dried over Na2SO4 and concentrated. The product was purified by column chromatography on silica gel (ethyl acetate/dichloromethane) to afford N-[3-(2-amino-1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)-pyrimidin-2-amine (30.1 mg, 69.7%) as a beige solid. APCI [M+H]+ m/z 338.1 1H NMR (400 MHz, Acetone-d6): δ 9.21 (br s, 1H); 8.82 (d, J=4.9 Hz, 1H); 8.12 (s, 1H); 7.67 (d, J=8.2 Hz, 1H); 7.37 (s, 1H); 7.33 (t, J=8.0 Hz, 1H); 7.24 (d, J=4.9 Hz, 1H); 7.18 (d, J=7.8 Hz, 1H); 6.48-6.41 (m, 2H). rhSYK activity=+++
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.O=[CH:12][C@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14].Cl>O1CCOCC1.C1C=CC=CC=1>[CH2:4]1[CH2:5][CH2:6][C:1]2([O:14][C@@H:13]([C@H:15]3[O:16][C@@H:21]4[O:22][C:1]5([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[O:20][C@H:19]4[C@H:17]3[OH:18])[CH2:12][O:7]2)[CH2:2][CH2:3]1
Reactant: O=C1CCCCC1
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccccc1
Solvent: ClCCl
Product: O[C@@H]1[C@@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1[C@H]1COC2(CCCCC2)O1
Temperature: 65 °C
Reaction time: 7 h
Yield: 92.6 %

Procedure:
To a mixed solution of 150 ml of cyclohexanone and 120 ml of dichloromethane were added 10.0 g of D-mannose, 200 mg of cupric acetate monohydrate and 1 ml of a 2 mole/l solution of hydrogen chloride in dioxane, and the mixture was stirred for 7 hours under reflux in a warm-water bath at 65° C. The refluxing solvent was continuously dried with 20 g of molecular sieves 3A which was placed between the reaction vessel and the cooling tube. After the conclusion of the reaction, the reaction solution was diluted with benzene, washed with aqueous sodium hydrogen-carbonate and water, and dried over anhydrous magnesium sulfate. When the solvent and cyclohexanone were distilled off under reduced pressure, there was obtained 17.5 g (92.6%) of 2,3:5,6-di-O-cyclohexylidene-α-D-mannofuranose as a residue. The compound, when recrystallized from hexane, showed a melting point of 122° to 124° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[OH:11])[CH2:3][CH2:2]1.CC(C)([O-])C.[Na+].[OH:18][C:19]1[CH:24]=[C:23]([Cl:25])[N:22]=[N:21][C:20]=1Cl.Cl>C1(C)C=CC=CC=1.O.C(O)(C)(C)C>[Cl:25][C:23]1[N:22]=[N:21][C:20]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:19]([OH:18])[CH:24]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
A mixture of 114.76 g (purity: 95.9%; 743 mmol) of 2-cyclopropyl-6-methylphenol and 70.0 g of t-butanol was charged into an autoclave, and 72.8 g (purity: 98.0%; 743 mmol) of sodium t-butoxide was added to the mixture over one hour, and then stirred at 70° C. for 30 minutes. The resultant solution was cooled to 40° C., and then 25.0 g (purity: 98%; 148.6 mmol) of 4-hydroxy-3,6-dichloropyridazine was added to the solution. Then, the resultant mixture was heated from 40° C. to 140° C. to effect a reaction for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 750 g of pure water and 574 g of toluene were added to the cooled mixture and stirred for 30 minutes. Then, 41.7 g (400 mmol) of a 35% aqueous hydrochloric acid solution was added dropwise to the mixture, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. 287 g of toluene was added to the resultant aqueous phase and stirred at room temperature for 30 minutes, and then an organic phase was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was added dropwise to 20.5 g (196 mmol) of a 35% aqueous hydrochloric acid solution at 0° C. to deposit solids, followed by filtration. The resultant solids were washed with pure water and dried under a reduced pressure, and dissolved in an organic solvent and quantitatively determined by an HPLC internal standard analysis method, which showed that 41.2 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (purity: 85.4%; yield: 87.0%) and 29 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 1.4%) were obtained.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:14])[NH:7][C:8]([CH:11]2[CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[C:15]([CH:19]1[CH2:24][CH2:23][CH:22]([C:25](Cl)=[O:26])[CH2:21][CH2:20]1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([CH:19]1[CH2:20][CH2:21][CH:22]([C:25]([NH:1][CH:2]([C:5]2[C:6](=[O:14])[NH:7][C:8]([CH:11]3[CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH2:3][CH3:4])=[O:26])[CH2:23][CH2:24]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCC(N)c1nnc(C2CC2)[nH]c1=O
Reactant: CC(C)(C)C1CCC(C(=O)Cl)CC1
Product: CCC(NC(=O)C1CCC(C(C)(C)C)CC1)c1nnc(C2CC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 250 mg (1.29 mmol) 6-(1-aminopropyl)-3-cyclopropyl-1.2,4-triazin-5(4H)-one, 260 mg (1.29 mmol) 4-tert-butyl-cyclohexanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH:25]=O)=[CH:17]1.[CH3:27][C:28]1[CH:32]=[CH:31][S:30][C:29]=1[CH:33]=O>>[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH2:25][N:2]2[C:33]([C:29]3[S:30][CH:31]=[CH:32][C:28]=3[CH3:27])=[C:4]3[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]3=[O:15])=[N:1]2)=[CH:17]1
Reactant: Cc1ccsc1C=O
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: O=Cc1csc2ccccc12
Product: Cc1ccsc1-c1c2c(=O)n(C)c(=O)n(CC(C)C)c2nn1Cc1csc2ccccc12

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 1-benzothiophene-3-carbaldehyde, followed by 3-methylthiophene-2-carbaldehyde. Mass: 464.85 (M+H).
Reaction SMILES: CON(C)[C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[C:7]([CH3:15])[CH:6]=1.[CH3:18][Mg]Br.C(OCC)C.Cl>C1COCC1.CCOC(C)=O>[CH3:15][C:7]1[CH:6]=[C:5]([C:4](=[O:16])[CH3:18])[CH:10]=[CH:9][C:8]=1[C:11]([F:14])([F:13])[F:12]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)c(C)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(F)(F)F)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-methoxy-3,N-dimethyl-4-trifluoromethyl-benzamide from step 7 (16.90 g, 68.36 mmol) in THF (280 mL) at −5° C. was added a 3 M methylmagnesium bromide solution in diethyl ether (45.6 mL, 136.7 mmol). The mixture was stirred at 0° C. for 1 h, then was warmed up to 23° C. and stirring was continued at 23° C. for further 1.5 h under nitrogen atmosphere. Then 1 N HCl (100 mL) was added drop wise to the mixture and stirring was continued for 30 min. The mixture was diluted with EtOAc and the aqueous layer was separated, the organic layer was washed with brine and dried over MgSO4. Removal of the solvent in vacuum left the title compound as a light brown liquid (12.87 g, 93.1%), which was used without further purification. MS (EI) 202.1 [M].
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1)[C:10]([N:12]([C@H:22]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:23](O)=[O:24])[C@@H:13](C(OC)=O)[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])=[O:7])(C)(C)C.C(N(C(C)C)CC)(C)C.[P].[F:52][C:53]([F:57])([F:56])[CH2:54][NH2:55]>CN(C)C=O>[CH2:41]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH:33]1[C@H:9]1[NH:8][C:6](=[O:7])[C@@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:12]([C@H:22]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:23]([NH:55][CH2:54][C:53]([F:57])([F:56])[F:52])=[O:24])[C:10]1=[O:11]
Reactant: NCC(F)(F)F
Reactant: COC(=O)[C@@H](CC(C)C)N(C(=O)[C@H](NC(=O)OC(C)(C)C)C1Cc2ccccc2C1)[C@@H](C(=O)O)c1ccc(F)cc1
Agent: [P]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)NCC(F)(F)F)c1ccc(F)cc1
Reaction time: 0.03 h

Procedure:
A solution of (2R)-{[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl][(1R)-1-(methoxycarbonyl)-3-methylbutyl]amino}(4-fluorophenyl)ethanoic acid (73 mg) in N,N-dimethylformamide (2 ml) was sequentially treated with diisopropylethylamine (51 μL), phosphorus, (1-hydroxy-1H-benzotriazolato-O)tri-1-pyrrolidinyl-(T-4)-hexafluorophosphate (80 mg) and then after 2 minutes, 2,2,2-trifluoroethylamine (25 μl). This reaction mixture was stirred for 2 hours before being partitioned between 2M aqueous hydrochloric acid and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine before being dried over magnesium sulphate and evaporated in vacuo. The residue was dissolved in 4M hydrogen chloride in dioxane and stirred for 7 hours at room temperature. The reagent was removed in vacuo and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The separated organic fraction was washed with brine before being dried over magnesium sulphate and evaporated in vacuo. The crude material was purified by column chromatography (silica) eluting with methanol: dichloromethane (1% to 3%) to furnish ((2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide (10 mg)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.[W].CC(N=NC(C#N)(C)C)(C#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][Br:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(F)c1
Yield: 80 %

Procedure:
A mixture of methyl 3-fluoro-4-methylbenzoate (4.3 g), N-bromosuccinimide (4.5 g) and AIBN (20 mg) in carbon tetrachloride was irradiated with a 100 W Tungsten lamp at reflux for 1 hour. The mixture was filtered through diatomaceous earth, and evaporated to give methyl 3-fluoro-4-(bromomethyl)benzoate (5.0 g).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]([F:18])=[CH:13][CH2:14][CH2:15][CH2:16]Cl>CN(C)C=O>[Cl:11][C:12]([F:18])=[CH:13][CH2:14][CH2:15][CH2:16][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(Cl)=CCCCCl
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(Cl)=CCCCSCc1ccccc1
Temperature: 25 °C
Yield: 64.2 %

Procedure:
2.43 g of benzylmercaptan were mixed with 30 ml of N,N-dimethylformamide and then additioned with 0.7 g of NaH (55% in paraffin oil). Thereupon, at room temperature and under stirring, into this mixture were dripped 3 g of 1,5-dichloro-1-fluoro-pent-1-ene. The mixture was stirred for 5 hours at 25° C. After washing with water, extraction with ether, drying and evaporizing, there were obtained 3 g of raw product purified by chromatography in a column (cis-, trans- isomer mixture) and which had the following characteristics:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C(C)=CC=CC=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22](Cl)=[CH:21][CH:20]=1)([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.O>[CH:5]1[CH:6]=[CH:7][C:2]([NH:1][C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Temperature: 96 °C
Yield: 129.4 %

Procedure:
186 g of aniline, 60 ml of xylene, 4.5 g of 1,10-phenanthroline, 157.5 g of 4-nitrochlorobenzene, 2 g of CuO and 76.3 g of potassium carbonate are heated to 195° C. for 7 hours in a water separator. The reaction mixture is cooled to 96° C. After the precipitated salts have been separated off by filtration, the filter cake is thoroughly washed with 200 ml of hot xylene. The filtrate and the washing liquid are combined, and after the solution has been cooled to 0° C., 127 g of 4-nitrodiphenylamine of melting point 128°-130° C. crystallize out and are separated off by filtration. 93 g of aniline, 157.5 g of p-nitrochlorobenzene and 76.3 g of potassium carbonate are added to the mother liquor produced in this procedure, and the mixture is freed from excess xylene by distillation, and heated at 195° C. for 11 hours in a water separator. After the salts have again been filtered off, the filtrate is worked up by steam distillation, as described in Example 7. 277 g of 4-nitrodiphenylamine of melting point 107°-111° C. are obtained.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]([F:25])([C:17]1[CH:24]=[CH:23][C:20]([C:21]#N)=[CH:19][CH:18]=1)[C:13]([F:16])([F:15])[F:14].S(=O)(=O)(O)[OH:27].O>C(Cl)Cl>[F:11][C:12]([F:25])([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:27])=[CH:19][CH:18]=1)[C:13]([F:16])([F:15])[F:14]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(C(F)(F)C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diisobutylaluminum hydride solution (1 M in hexane, 5.0 mL, 5.0 mmol) was added at 0° C. to a solution of 4-pentafluoroethyl-benzonitrile (1.00 g, 4.52 mmol) in DCM (5 mL), then after 2 h another portion of diisobutylaluminum hydride solution (5 mL) was added and the reaction stirred at RT for 16 h, then carefully poured onto 50% aq. sulfuric acid solution (4 mL). Water (45 mL) was added, and the mixture is extracted three times with DCM. The organic layer was subsequently washed with brine and 1 M potassium sodium tartrate solution, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded crude 4-pentafluoroethyl-benzaldehyde (390 mg) as a yellow liquid, which was added at RT to a solution of 2-(4-chlorophenyl)ethylamine (269 mg, 1.73 mmol) in methanol (2 mL), then after 18 h sodium borohydride (65 mg, 1.73 mmol) was added at 0° C. After 1 h the reaction mixture was partitioned between ether and water, the organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (431 mg, 26%). Light yellow oil, MS (ISP) 364.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[F:10][CH:11]([C:17]([CH3:19])=O)[C:12](OCC)=[O:13].S(=O)(=O)(O)O.O>O1CCOCC1>[F:10][C:11]1[C:12](=[O:13])[O:4][C:3]2[C:5]([C:17]=1[CH3:19])=[CH:6][CH:7]=[C:8]([OH:9])[C:2]=2[CH3:1]
Reactant: Cc1c(O)cccc1O
Reactant: CCOC(=O)C(F)C(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(F)c(=O)oc2c(C)c(O)ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A solution of 2-methylresorcinol (3.23 g, 26.02 mmoles), ethyl 2-fluoro-acetoacetate [E. B. Banks, N. J. Lawrence, A. L. Popplewell, J. Chem. Soc., Chem. Commun, 343 (1994)] (3.85 g, 25.99 mmoles) in 0.5 mL of 1,4-dioxane was added dropwise, at 0° C. and under an inert atmosphere, to 25 mL of concentrated sulfuric acid. The reaction mixture was stirred for 1.5 hours, while the temperature was increased to 25° C. Cold water (100 mL) was added, the reaction mixture was stirred for 15 minutes and the resulting precipitate was collected by suction filtration, dried in vacuo, affording 4.56 g (84% yield) of 3-fluoro-4,8-dimethyl-7-hydroxycoumarin as a white solid. An analytical sample was obtained by recrystallisation from methanol:water: mp 260° C. (decomp.).