Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13]/[CH:14]=[CH:15]/[CH2:16][N:17]([CH2:19][C:20]#[N:21])[CH3:18])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-:27].[K+].[K+].OO.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13]/[CH:14]=[CH:15]/[CH2:16][N:17]([CH3:18])[CH2:19][C:20]([NH2:21])=[O:27])=[CH:10][CH:9]=2)=[O:7])=[CH:24][CH:25]=1
Reactant: CN(CC#N)C/C=C/COc1ccc(C(=O)c2ccc(Br)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C/C=C/COc1ccc(C(=O)c2ccc(Br)cc2)cc1)CC(N)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 314.6 %

Procedure:
A suspension of 0.4 g of (E)-[[4-[4-(4-bromo-benzoyl)-phenoxy]-but-2-enyl]-methyl-amino]-acetonitrile (Ex. 2j) and 0.04 g of potassium carbonate in 3 ml of dimethyl sulphoxide is cooled to 0° C. and treated with 1 ml of 30% hydrogen peroxide solution. The reaction mixture is warmed to room temperature and stirred overnight. For the working up, the mixture is treated with 10 ml of water and the separated crystals are filtered off and washed with water. There is obtained 0.38 g of (E)-2-[[4-[4-(4-bromo-benzoyl)-phenoxy]-but-2-enyl]-methyl-amino]-acetamide, MS: m/e 372 (M+-H2NCO, 1Br).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11](O)=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[OH-].[Na+]>C1COCC1>[OH:12][CH2:11][C:4]1[CH:3]=[C:2]([OH:1])[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=1
Reactant: O=C(O)c1cc(O)cc(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCc1cc(O)cc(CO)c1
Yield: 106.8 %

Procedure:
To a solution of 5-hydroxyisophthalic acid 1 (30 g, 0.17 mol) in THF (1 L) at room temperature was added slowly a solution of BH3 (800 mL, 1 M in THF). The resulting heterogeneous mixture was warmed to reflux overnight. The reaction mixture was cooled to room temperature whereupon 0.8 L of 1M HCl was carefully added. The resulting homogenous solution was concentrated in vacuo and the residues were treated with NaOH (42 g, 1.05 mol). Water was removed from the solution via concentration in vacuo and the residues were extracted with EtOAc (3×350 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give 28 g (93%) of triol 2 as thick colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)c1cncc(Br)c1
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: CN(C)C=O
Product: CCOC(=O)c1cncc(-c2ccccc2OC)c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of ethyl 5-bromonicotinate (2.29 g, 10 mmol), prepared as reported in the Journal of Medicinal Chemistry 1995, 38, 1608-28, 2-methoxy phenyl boronic acid (1.22 g, 10 mmol), Pd(PPh3)4 (5% mol), K2CO3 (5 g) in DMF/water (3/1) is stirred at 50° C. for 12 hours. The reaction mixture is then pored on water (150 mL). The aqueous phase is extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water (3×200 mL). The organic phase is dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([CH2:12][CH2:13][NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17][CH2:18][C:19](Br)=[O:20].N1C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:18][C:19]([NH:14][CH2:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)=[O:20]
Reactant: O=C(Br)CBr
Reactant: NCCc1ccc(Oc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CBr)NCCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.2 %

Procedure:
4-phenoxyphenethylamine (213.28 amu, 2.5 g, 1 eq, 10.8 mmol, 1.09 g/mL, 2.3 mL) added to a 3-necked flask. Bromoacetyl bromide (201.86 amu, 1.1 eq, 11.8 mmol, 2.4 g, 2.317 g/mL, 1.03 mL), pyridine (79.10 amu, 5 eq, 4.27 g, 0.978 g/mL, 54 mmol, 4.4 mL) added along with 50 mL CH2Cl2. Reaction stirred for 2 hours at RT. CH2Cl2 removed and mixture taken up in 200 mL EtOAc. Organic layer washed with brine and water (200 mL each). Organics seperated, dried sodium sulfate, and rotovaped to give 1.56 g material. MS [EI+] 334 (M+H)+, MS [EI−] 332 (M−H)+
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][Si](C)(C)C)[CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CCO.C(Cl)Cl>[C:7]([C:3]1[CH:2]=[C:1]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=1)#[CH:8]
Reactant: C[Si](C)(C)C#Cc1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: ClCCl
Product: C#Cc1cccc(-c2ccccc2)c1
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of (1,1′-biphenyl-3-ylethynyl)(trimethyl)silane (4.74 g, 18.96) in 1/1 EtOH/CH2Cl2 (60 mL) is added Cs2CO3 (6.78 g, 20.85 mmol) at room temperature. After stirring for 1 h, the insoluble material is filtered off and the filtrate is concentrated. The crude material is purified by chromatography (silica gel, 100% hexane) to give the title compound (3.07 g, 91%) as an oil. MS (+) EI: 178 M+.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[C:3]=1[OH:13].[N+]([C:17]1C=C(C(F)(F)F)C=CC=1Cl)([O-])=O.C[O-].[Na+].NC1C=C(C(F)(F)F)C=CC=1OC.F[B-](F)(F)F>>[F:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[CH:2][C:3]=1[O:13][CH3:17]
Reactant: Nc1cc(C(F)(F)F)cc(F)c1O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: COc1ccc(C(F)(F)F)cc1N
Agent: C[O-]
Agent: F[B-](F)(F)F
Product: COc1ccc(C(F)(F)F)cc1F

Procedure:
The 2-amino-4-trifluoromethylphenols (XI) required for the reaction sequence just described may be prepared by conventional methods. Thus 2-amino-6-fluoro-4-trifluoromethylphenol may be prepared from 2-nitro-4-trifluoromethylchlorobenzene by reacting the latter with sodium methoxide to give 2-nitro-4-trifluoromethylanilsole, and reducing this compound to 2-amino-4-trifluoromethylanisole. The latter compound may be diazotised and converted to its fluorborate salt and heated to give 2-fluoro-4-trifluoromethylanisole. This may then be nitrated to form 2-fluoro-6-nitro-4-trifluoromethyl anisole, which is then reduced to give 2-amino-6-fluoro-4-trifluoromethylanisole. Finally the latter compound is heated with a dimethylating agent, for example an excess of pyridine hydrochloride to give 2-amino-6-fluoro-4-trifluoromethylphenol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([CH:11]([CH3:13])[CH3:12])[C:3]=1[OH:14].I[CH2:16][CH2:17][CH3:18].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[C:4]([CH:11]([CH3:13])[CH3:12])[C:3]=1[O:14][CH2:16][CH2:17][CH3:18]
Reactant: CC(C)c1cc(Br)c(O)c(C(C)C)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1c(Br)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 64 h
Yield: 95.5 %

Procedure:
A mixture of 2-bromo-4,6-diisopropyl-phenol (Intermediate 2, 14.5 g, 56 mmol), 1-iodopropane (16.5 mL, 169 mmol), and K2CO3 (38.6 g, 280 mmol) in acetone (100 mL) was stirred at room temperature for 64 h. The solvent was removed in vacuo, and the residue was taken up in CHCl3 and filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash column chromatography on silica gel (hexanes) to yield the title compound as a colorless oil (16.0 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](Cl)(C)=O>CO.CC(=O)OCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(O)c1cc(O)cc(Br)c1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(O)cc(Br)c1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
To a flask containing 3-bromo-5-hydroxybenzoic acid (2.0 g, 9.2 mmol) in anhydrous MeOH (10 mL) at 0° C. under N2 was added AcCl (912 μL, 12.9 mmol). The reaction mixture was allowed to warm to room temperature overnight. The mixture was diluted with EA and washed with NaHCO3. The organic layers were dried and concentrated to provide 2.1 g (97%) of methyl 3-bromo-5-hydroxybenzoate as a white solid. LCMS-ESI (m/z) calculated for C8H7BrO3: 231.04; found 232.9 [M+H]+, tR=3.06 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)=O)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].B.Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(CC2CCNC2)CC1
Yield: 17.2 %

Procedure:
To a stirred solution of tert-butyl 3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)carbonyl]pyrrolidine-1-carboxylate (3.39 g, 7.19 mmol) in THF (60 ml) was added a 1M solution of borane in THF (21.6 ml, 21.6 mmol) and the reaction heated to reflux for 4 hours. The cooled reaction mixture was then cautiously quenched by addition of methanol then solvents removed in vacuo to give a white solid. To this was then added saturated HCl in methanol (150 ml) and heated to reflux for 1 hour. The reaction mixture was then evaporated to dryness, partitioned between 2M NaOH and DCM, extracted twice, combined organics dried (Na2SO4), filtered and evaporated to a colorless oil. This was then purified on Isco™ Companion (40 g column: 20% methanolic ammonia/DCM) to give the product N-(3,4-dichlorophenyl)-4-(pyrrolidin-3-ylmethyl)piperazine-1-carboxamide as a white foam (444 mg, 1.24 mmol, 17%).
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1([CH2:24][N:25]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])C2C=CC=CC=2N=N1.O>C1COCC1.[Zn]>[CH2:33]([N:25]([CH2:24][C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)CCN(Cc1ccccc1)Cn1nnc2ccccc21
Reactant: CCOC(=O)C(F)(F)Br
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCN(Cc1ccccc1)CC(F)(F)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To a solution of 1H-benzotriazole (2.38 g) in methanol (20 mL) were added ethyl N-benzyl-β-alaninate (4.14 g) and aqueous formaldehyde solution (37%, 2 mL) at room temperature. The reaction mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give ethyl N-(1H-benzotriazol-1-ylmethyl)-N-benzyl-β-alaninate (5.60 g). To a mixture of zinc powder (1.74 g) in anhydrous THF (16 mL) was added chlorotrimethylsilane (1.58 g) under nitrogen atmosphere, and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added ethyl bromodifluoroacetate (2.97 g) at room temperature, and then a solution of ethyl N-(1H-benzotriazol-1-ylmethyl)-N-benzyl-β-alaninate (4.50 g) in THF (8 mL) was added thereto at room temperature. The reaction mixture was stirred at room temperature for 18 hr, and added to water. The insoluble substance was removed by the filtration, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (3.23 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32](C4CCCN4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH3:39][C:40]([CH3:42])=O>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:22]=4[NH:31][C:32]([CH:40]4[CH2:42][CH2:5][N:9]([CH:8]([CH3:10])[CH3:7])[CH2:39]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCCN4)ncn3)cccc2s1
Reactant: CC(C)=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCN(C(C)C)C4)ncn3)cccc2s1

Procedure:
The title compound was prepared by reacting N-(2-(6-(2-acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)pyrrolidine-2-carboxamide [Example 62(b)] with acetone under the conditions of Example 3(d). MS (ESI, pos. ion.) m/z: 585 (M+1).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[NH:29]N>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[N:29]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1cc(F)ccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1cc(F)ccc1F
Yield: 24 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 2,5-difluorophenylhydrazine according to the method described for Example 1 in 24% yield. MS: M=351.1 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:12][CH2:11][C:10]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:9]2)[N:3]=1.[CH2:17]([Mg]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Br)C1C=CC=CC=1.[Mg]>CC(P(C1C=CC=CC=1)C1C=CC=CC=1)C.C1C=CC(PC2C=CC=CC=2)=CC=1.[Cl-].[Ni].C(OCC)C.O1CCCC1>[CH2:17]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:12][CH2:11][C:10]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:9]2)[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: Brc1cccc(N2CCC3(C2)OCCO3)n1
Agent: [Ni]
Agent: BrCc1ccccc1
Agent: CC(C)P(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1ccc(Cc2cccc(N3CCC4(C3)OCCO4)n2)cc1

Procedure:
A mixture of 6.3 g of 2-bromo-6-(3,3-ethylenedioxypyrrolidine-1-yl)pyridine, 240 mg of 1,3-bis (diphenylphosphino)propanenickel (II) chloride and 20 ml of tetrahydrofuran was stirred in an ice bath in a nitrogen atmosphere. Into the mixture were added dropwise a diethyl ether solution of benzyl magnesium bromide prepared from 3.4 ml of benzyl bromide, 0.8 g of magnesium and 15 ml of diethyl ether, followed by stirring at room temperature overnight as it was. The reaction solution was partitioned between an aqueous saturated ammonium chloride solution and ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography using 5-10% ethyl acetate/hexane, to give 6.6 g of the target compound.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[F:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[CH3:32]>CCOC(C)=O>[Br:8][CH2:32][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:22]=1[F:21])[C:26]([O:28][CH3:29])=[O:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(F)c(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)c(CBr)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
NBS (14.60 g) and AIBN (2.89 g) were added to a solution of the product from step (i) (9.85 g) in EtOAc (200 mL). The resulting mixture was stirred at 80° C. for 20 h. After cooling the mixture was washed with sat. sodium thiosulphate, brine, dried, filtered and the solvent removed. The crude product was purified using chromatography, to give the subtitle compound, 5.30 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][C:20]([OH:22])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][CH:36]2[CH2:40][CH2:39][CH2:38][NH:37]2)=[CH:30][CH:29]=1)=[O:27])[CH3:24].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][C:20]([N:37]2[CH2:38][CH2:39][CH2:40][CH:36]2[C:35]#[C:34][C:31]2[CH:32]=[CH:33][C:28]([C:26]([O:25][CH2:23][CH3:24])=[O:27])=[CH:29][CH:30]=2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:11]
Reactant: CCOC(=O)c1ccc(C#CC2CCCN2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)c1ccc(C#CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3)c(OC)c2)cc1
Reaction time: 8 h
Yield: 60.9 %

Procedure:
A mixture of 3-methoxy-4-(N′-phenylureido)phenylacetic acid (180 mg, 0.6 mmol), 2-(2-(4-ethoxycarbonylphenyl)ethynyl)pyrrolidine (146 mg, 0.6 mmol), EDC (173 mg, 0.9 mmol), DMAP (73 mg, 0.6 mmol), and cat HOBt in DMF (10 mL) was stirred overnight. The mixture was poured into 1 N HCl and the solid was collected with suction. The residue was dissolved in CHCl3 and dried over MgSO4. After removal of the solvent, the residue was chromatographed on silica-gel with CHCl3—MeOH (10:1, v/v) as eluent to give 192 mg (61%) ethyl 4-[2-[1-[3-methoxy-4-(N′-phenylureido)phenylacetyl]-2-pyrrolidinyl]ethynyl]benzoate as a light yellow amorphous solid. 1H-NMR (CDCl3) δ1.38 (3 H, t, J=6.8 Hz), 1.98-2.24 (4 H, m), 3.48-3.89 (2 H, m), 3.53 (2 H, s), 3.62 (3 H, s), 4.33-4.40 (2 H, m), 4.78-5.04 (1 H, m), 6.77-8.00 (14 H, m).
Reaction SMILES: [CH3:1][C:2]([C:9]#[C:10][Se:11][C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:18]([CH3:24])([CH3:23])[CH2:17][CH2:16][C:15]([CH3:26])([CH3:25])[C:14]=2[CH:13]=1)=[CH:3][C:4]([O:6]CC)=[O:5].[Li+].[OH-]>C1COCC1>[CH3:1][C:2]([C:9]#[C:10][Se:11][C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:18]([CH3:24])([CH3:23])[CH2:17][CH2:16][C:15]([CH3:26])([CH3:25])[C:14]=2[CH:13]=1)=[CH:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C=C(C)C#C[Se]c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C#C[Se]c1cc2c(cc1C)C(C)(C)CCC2(C)C)=CC(=O)O

Procedure:
In a manner similar to that of Example 2, by reaction of 600 mg of ethyl 3-methyl-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylselenyl)-pent-2-en-4-ynoate with 600 mg of LiOH in 15 ml of THF, 410 mg (73%) of a yellow powder are obtained. m.p.: 175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9](N)=[C:8]([CH2:15][CH3:16])[CH:7]=2)=[CH:4][CH:3]=1.C(#N)C.N(OCCCC)=O.[BrH:29]>[Cu]Br>[Br:29][C:9]1[C:10]([CH2:12][CH3:13])=[CH:11][C:6]([C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:7][C:8]=1[CH2:15][CH3:16]
Reactant: Br
Reactant: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1N
Agent: [Cu]Br
Agent: CCCCON=O
Solvent: CC#N
Product: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1Br
Temperature: 25 °C

Procedure:
4′-Chloro-3,5-diethylbiphen-4-ylamine (9.6 g, 0.036 mol) is added to acetonitrile (95 ml) and stirred at room temperature until dissolution is complete. The reaction mixture is cooled to between −5° C. and 0° C., tent-butyl nitrite (5.7 ml, 0.044 mol) is added dropwise and the reaction mixture is maintained at between −5° C. and 0° C. for 30-40 minutes. The mixture is added slowly to a preheated (50° C.) suspension of copper (I) bromide (2.87 g, 0.02 mol) in hydrobromic acid (2.8 ml) and stirred at 50° C. for 10-15 minutes. The reaction mixture is cooled to room temperature, then poured into ice-cold water and extracted with ethyl acetate (3×250 ml). The organic extracts are washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to yield 4-bromo-4′-chloro-3,5-diethylbiphenyl (4.5 g).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17](Br)[CH:18]=[CH:19][C:12]=2[NH:11][C:10](=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=3)[CH:18]=[CH:19][C:12]=2[NH:11][C:10](=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(Cc2ccccc2)C(=O)c2cc(Br)ccc2N1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CN(Cc2ccccc2)C(=O)c2cc(-c3ccc(C(F)(F)F)cc3)ccc2N1
Temperature: 80 °C
Yield: 75.2 %

Procedure:
4-Benzyl-7-bromo-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (1.4 g, 4.05 mmol) was combined with 4-(trifluoromethyl)phenylboronic acid (0.77 g, 4.05 mmol), potassium carbonate (1 g) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (148 mg, 0.202 mmol) in 5 mL DMF. Water (3 mL) was added and the mixture was heated under nitrogen atmosphere at 80° C. for three hours. After cooling the mixture was diluted with ethyl acetate, washed with water and brine, dried with magnesium sulfate and evaporated. Purification by silica-gel chromatography (20-100% ethyl acetate in hexane) followed by recrystallization gave 4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (1.25 g, 75%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[N:38][N:37]=[CH:36]2)[CH:30]=1)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:36]=[N:37][N:38]=[CH:39]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CCOC(=O)CC(=O)c1cccc(-n2cnnc2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cnnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) (383 mg, 1.2 mmol) and 3-oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionic acid ethyl ester [CAS-No. 335255-97-5 ] (259 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow solid (290 mg).