Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:13][NH:14][CH:15]([C:31](=[O:37])[NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O.[ClH:46]>C(Cl)Cl.C(OCC)C>[ClH:46].[ClH:46].[NH2:7][CH:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:13][NH:14][C@@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:22]=1)[C:31]([NH:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:37]
Reactant: CC(C)CC(CNC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC(N)CN[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Reaction time: 0.42 h
Yield: 61 %

Procedure:
To a solution of (1-{[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylamino]-methyl}-3-methyl-butyl)-carbamic acid tert-butyl ester (0.4 g, 0.76 mmol, Example 7, Step B) in CH2Cl2 (7.5 mL) was added trifluoroacetic acid (2.5 mL) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 25 minutes, then concentrated in vacuo. The viscous oil obtained was dissolved in 40 mL of CH2Cl2 and successively washed with saturated aqueous NaHCO3 solution (2×40 mL), brine (2×40 mL), and was dried over Na2SO4. The CH2Cl2 solution of free amine was concentrated in vacuo to afford the crude product as a viscous oil which was then dissolved in 10 mL of ethyl ether. To this solution was added saturated HCl solution in ethyl ether until no more white precipitate formed. Filtration and drying overnight under vacuum afforded 0.23 g (61%) of titled compound as a yellow solid; mp 228-230° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[O:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CN([C:16]([O:20][N:21]1N=NC2C=CC=C[C:22]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNOC>CN(C=O)C.C(=O)(O)[O-].[Na+]>[CH3:16][O:20][N:21]([CH3:22])[C:10]([C:8]1[O:9][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=1)=[O:12]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CS(=O)(=O)c1ccc(C(=O)O)o1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(S(C)(=O)=O)o1
Reaction time: 0.17 h

Procedure:
To a solution of 5-methanesulfonyl-furan-2-carboxylic acid (1.1 g, 5.8 mmol) in DMF (20 mL) was added HBTU (2.8 g, 8.7 mmol) and DIPEA (3.2 mL, 17.4 mmol). After stirring for 10 minutes, N,O-dimethylhydroxylamine hydrochloride (0.85 g, 0.71 mmol) was added. After 18 hours, the mixture was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (4×25 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 5-methanesulfonyl-furan-2-carboxylic acid methoxy-methyl-amide.
Reaction SMILES: [I:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11]CC)=O)=O)=[CH:4][CH:3]=1.[NH:16]([C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17]>C(O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[CH:8]=[C:9]([OH:11])[N:16]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=2)=[CH:14][CH:15]=1
Reactant: NNc1ncccn1
Reactant: CCOC(=O)CC(=O)c1ccc(I)cc1
Solvent: CCO
Product: Oc1cc(-c2ccc(I)cc2)nn1-c1ncccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
Ethyl 4-iodobenzoylacetate (10 mmol, manufactured by Aldrich) and ethanol (10 mL) were charged in a 100 mL round-bottom flask to which a solution of 2-hydrazinopyrimidine (10 mmol, manufactured by Aldrich) in ethanol (10 mL) was then added. After being stirred at 100° C. for 8 hours, the reaction liquid was cooled at room temperature. The resulting solid was filtered, washed with ethanol and hexane, and then dried under vacuum to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH:7][CH:8]2[CH2:11][CH:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9]2)=[N:5][N:6]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH:32]([C:38](=O)[CH2:39][CH2:40][CH3:41])[C:33](OCC)=[O:34])=[C:27]([F:43])[CH:26]=1)#[N:18].N12CCCN=C1CCCCC2>C(N(CC)C1C=CC=CC=1)C.C(OCC)(=O)C>[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2[C:33](=[O:34])[N:7]([C@@H:8]3[CH2:9][C@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11]3)[C:4]3[N:5]([N:6]=[C:2]([CH3:1])[N:3]=3)[C:38]=2[CH2:39][CH2:40][CH3:41])=[C:27]([F:43])[CH:26]=1)#[N:18]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Reactant: CCOC(=O)C1CC(Nc2nnc(C)[nH]2)C1
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](C(=O)OCC)C2)c2nc(C)nn12

Procedure:
A solution of ethyl 3-[(5-methyl-4H-1,2,4-triazol-3-yl)amino]cyclobutanecarboxylate (7.85 g), ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (23.15 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.62 mL) in N,N-diethylaniline (70 mL) was stirred at 180° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=85/15→65/35 (volume ratio)] to give the title compound as a pale-yellow amorphous compound (3.91 g, 21%).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[S:7][C:6]=1[C:17]([NH2:19])=[O:18])=[O:3].Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:11]=2)[S:7][C:6]=1[C:17]([NH2:19])=[O:18])=[O:3]
Reactant: ClCCN1CCCCC1
Reactant: NC(=O)Nc1cc(-c2cccc(O)c2)sc1C(N)=O
Product: NC(=O)Nc1cc(-c2cccc(OCCN3CCCCC3)c2)sc1C(N)=O

Procedure:
Prepared by the method of Example 9(b) using the product of Example 6 and N-(2-chloroethyl)piperidine.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:30][CH2:31][O:32][Si](C(C)(C)C)(C)C)=[N:9]1)=O)(C)(C)C.Cl>>[OH:32][CH2:31][CH2:30][NH:29][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])[CH:12]=2)[NH:8][N:9]=1
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(NCCO[Si](C)(C)C(C)(C)C)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Agent: Cl
Product: CC1=C(C#N)C(c2ccc3[nH]nc(NCCO)c3c2)C(C#N)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
A mixture of crude 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-indazole-1-carboxylic acid tert-butyl ester (165 mg) and HCl (4M solution in THF, 2 mL) was stirred overnight at room temperature. The mixture was partitioned between dilute aqueous sodium hydrogen carbonate solution (0.5%, 40 mL) and EtOAc (40 mL). The organic extract was dried (Na2SO4), concentrated and the residue purified by chromatography on silica gel to give 1,4-dihydro-4-[3-[(2-hydroxyethyl)amino]-1H-indazol-5-yl]-2,6-dimethyl-3,5-pyridinedicarbonitrile (66 mg) (Cpd. No. 118, Table 2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.Cl>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1cc(Br)ccc1F
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CCC(=O)O)ccc1F
Temperature: 62 °C
Reaction time: 0.5 h

Procedure:
To an oven dried three neck flask was added Mg turnings (355 mg, 14.6 mg-at.) catalytic amount of iodine, and 20 mL THF. To the resulting mixture was added dropwise 4-bromo-1-fluoro-2-methyl-benzene (1.0 g, 0.005 mol) with heating to ˜62° C. After completing the addition of the aryl bromide, the mixture was stirred for an additional 30 min at 62° C. The THF solution of the prepared aryl magnesium bromide was cooled to −70° C. and succinic anhydride (1.0 g, 0.01 mmol) added as a solution in 10 mL THF. The mixture was vigorously stirred with warming to rt over 3 h and then hydrolyzed by the addition of 30 mL of 1M HCl. The resulting mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were extracted with 5% aqueous K2CO3 (3×10 mL) and the combined aqueous layers acidified with 1M HCl to pH3. A milky colloidal suspension was extracted with ethyl acetate (3×30 mL) and the combined organic layers washed with brine (2×20 mL). The solvent was evaporated under reduced pressure and the crude product used directly in the next step without further purification.
Reaction SMILES: I.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:19])[C:13]=3[C:12]3=[N:20][O:21][C:22]([CH3:23])=[C:11]3[C:10]2=[O:24])[CH2:4]1.C(Cl)CCl.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH:48]1[CH:53]=[N:52][CH:51]=[C:50]([C:54]([NH:56][CH2:57][C:58](O)=[O:59])=[O:55])[CH:49]=1>CN(C=O)C>[Cl:19][C:14]1[C:13]2[C:12]3[C:11](=[C:22]([CH3:23])[O:21][N:20]=3)[C:10](=[O:24])[N:9]([CH:5]3[CH2:6][CH2:7][CH2:8][CH:3]([NH:2][C:58]([CH2:57][NH:56][C:54](=[O:55])[C:50]4[CH:49]=[CH:48][CH:53]=[N:52][CH:51]=4)=[O:59])[CH2:4]3)[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)CNC(=O)c1cccnc1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(N)C1)c1cccc(Cl)c21
Agent: I
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)CNC(=O)c3cccnc3)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(3-Amino-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin4-one hydroiodide (70 mg, 0.19 mmol) was combined with EDC (47 mg, 0.25 mmol), 1-hydroxy-7-azabenzo-triazole (34 mg, 0.25 mmol), N,N-diisopropylethyl amine (0.10 mL, 0.58 mmol), (5 mg, cat.), and nicotinuric acid (44 mg, 0.24 mmol) in DMF(6 mL) and the mixture stirred overnight at rt. The mixture was then concentrated in vacuo and the residue taken up in water and extracted with EtOAc. The combined extracts were dried over Na2SO4 and concentrated in vacuo. The residue was loaded onto a silica gel column and eluted with MeOH/CH2Cl2 which allowed for the recovery of 87 mg (92%) of the title compound as a white solid.
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]=[CH:6][C:7]1[CH:35]=[CH:34][C:10]([CH2:11][NH:12][C:13](=[O:33])[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24]N(CC4C=NC=CC=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)=[O:4].C(OC(=O)C=CC1C=CC(CNC(=O)C2C=CC(N3CCCC3)=CC=2)=CC=1)C>>[OH:1][NH:2][C:3]([CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][NH:12][C:13](=[O:33])[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[CH:34][CH:35]=1)=[O:4]
Reactant: O=C(C=Cc1ccc(CNC(=O)c2ccc(N3CCN(Cc4cccnc4)CC3)cc2)cc1)NO
Agent: CCOC(=O)C=Cc1ccc(CNC(=O)c2ccc(N3CCCC3)cc2)cc1
Product: O=C(C=Cc1ccc(CNC(=O)c2ccc(N3CCCC3)cc2)cc1)NO
Yield: 35 %

Procedure:
The titled compound was prepared as described in the process (1-3) by using the compound from the process (5-2).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][SiH:10]([Cl:12])[Cl:11]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:3]1([CH:2]([Si:10]([Cl:12])([Cl:11])[Cl:9])[CH3:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: Cl[SiH](Cl)Cl
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(c1ccccc1)[Si](Cl)(Cl)Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Into a 2-liter round-bottom flask fitted with a reflux condenser, addition funnel and magnetic stir bar, was charged styrene (410 g, 3.94 mols) and Bis(triphenylphosphine)palladium (II) dichloride (1.2 g, 0.3% wt). The reaction mixture was heated to 70° C. and then trichlorosilane (532.8 g, 3.94 mols) was added dropwise to the reaction mixture. During the addition, the reaction mixture was maintained between 80 to 110° C. After the addition was finished, the reaction mixture was kept at 70° C. for additional two hours. After distillation, >98% pure (1-phenylethyl)trichlorosilane (840 g, 99% purity) was obtained (collected at 78° C./3 mmHg). The product structure was characterized by GC-MS.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[NH2:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=2)=[C:27]([C:29](O)=[O:30])[N:28]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:29]([C:27]3[N:28]=[C:24]([NH2:23])[S:25][C:26]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=3)=[O:30])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1
Reactant: Cc1cccc(-c2sc(N)nc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: Cc1cccc(-c2sc(N)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-amino-5-(3-methyl-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[C:5]([C:6]([NH2:8])=O)=[C:4]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[O:20][CH3:21].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Br:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:16])[CH3:17])[C:5]([C:6]#[N:8])=[C:9]([CH3:12])[C:10]=1[I:11]
Reactant: COc1c(Br)c(I)c(C)c(C(N)=O)c1NC(=O)C(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COc1c(Br)c(I)c(C)c(C#N)c1NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
4-Dimethylaminopyridine (54.2 mg, 443 μmol) was added to a pyridine (40 ml) suspension of 4-bromo-2-(2,2-dimethylpropionylamino)-5-iodo-3-methoxy-6-methylbenzamide (I-5) (2.08 g, 4.43 mmol), followed by cooling at 0° C. To this, trifluoromethanesulfonic acid anhydride (2.25 ml, 13.3 mmol) was dropwise added, followed by stirring at room temperature for 2.5 hours, the reaction liquid was put into 1 N hydrochloric acid (200 ml), followed by extraction with ethyl acetate (200 ml×2). The organic layer was washed successively with 1 N hydrochloric acid (200 ml×2), saturated sodium bicarbonate water (50 ml), saturated brine (50 ml), then dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified twice by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain the entitled compound (1.86 g, quant.) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[C:13]([C:18]([NH2:20])=[O:19])[S:14][C:15]=2[S:16][CH3:17])(=[O:10])=[O:9])=[CH:4][C:3]=1Br.[C:22]1([CH3:37])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1C1C=CC=CC=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[C:13]([C:18]([NH2:20])=[O:19])[S:14][C:15]=2[S:16][CH3:17])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH3:37]
Reactant: CSc1sc(C(N)=O)cc1S(=O)(=O)c1cnc(N)c(Br)c1
Reactant: Cc1ccccc1-c1ccccc1B(O)O
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1sc(C(N)=O)cc1S(=O)(=O)c1cnc(N)c(-c2ccccc2C)c1
Yield: 32 %

Procedure:
The procedure as in Example 1: step c was followed using 4-(6-amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid amide (25 mg, 0.06 mmol, Example 120: step a), o-tolyl phenyl boronic acid (33 mg, 0.25 mmol), Pd(PPh3)4 (14 mg, 0.01 mmol), aqueous Na2CO3 (2M, 0.4 mL), ethanol (0.4 mL) and toluene (0.8 mL). Purification by preparative SiO2 chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (7.4 mg, 32%) as a brown solid. ESI-MS (m/z): Calcd. for C18H17N3O3S3: 420.0 (M+H); found: 420.2.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>CN(C=O)C>[O:20]([C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=Cc1cc(C(F)(F)F)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a stirred solution of 2-chloro-5-(trifluoromethyl)benzaldehyde (500 mg, 2.40 mmol) in DMF (5 ml) was added phenol (226 mg, 2.40 mmol), K2CO3 (663 mg, 4.79 mmol). The reaction suspension was stirred at room temperature for 1 hr, then at 80° C. for 1.5 hr. The reaction mixture was neutralizing for acetic acid (0.5 ml), the solvent was removed. To the solid residue was added water and the mixture was extracted with CH2Cl2. The combined CH2Cl2 extracts were washed with sat. NaHCO3 aq., dried with MgSO4, and concentrated to give crude Compound 6 as a yellow oil. This was purified with chromatography to give pure Compound 6 as a yellow oil (466 mg, 72.9%)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C@@H:12]([OH:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:8][C:9]=1[Cl:10].[O:19]=[C:20]1[N:26]([CH:27]2[CH2:32][CH2:31][N:30]([C:33](Cl)=[O:34])[CH2:29][CH2:28]2)[CH2:25][CH2:24][C:23]2[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=2[NH:21]1>C1COCC1>[O:19]=[C:20]1[N:26]([CH:27]2[CH2:28][CH2:29][N:30]([C:33]([O:18][C@@H:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][C:6]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=3)=[O:34])[CH2:31][CH2:32]2)[CH2:25][CH2:24][C:23]2[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=2[NH:21]1
Reactant: CCOC(=O)[C@H](O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](Cc1ccc(Cl)c(Cl)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
450 mg (55% in mineral oil, 10.3 mmol) NaH were added batchwise to a solution of 2.6 g (9.9 mmol) ethyl(R)-3-(3,4-dichloro-phenyl)-2-hydroxy-propionate in 50 mL THF cooled to 0° C. and stirred for a further 30 min at this temperature. Subsequently 3.7 g (11.9 mmol) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonylchloride were added batchwise while being cooled and the reaction mixture was stirred overnight at RT. The reaction solution was evaporated down i.vac., the residue combined with DCM, the organic phase was separated off, washed with 10% citric acid solution and 15% K2CO3 solution and dried over Na2SO4. After the desiccant and solvent had been eliminated the product was obtained which was reacted without any further purification.
Reaction SMILES: [C:1]([O:9][C:10]1[C:11]([O:13][C@@H:14]([CH3:26])[C@H:15]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CCOC(C)=O.[Pd]>[C:1]([O:9][C@@H:10]1[CH2:16][C@@H:15]([O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:14]([CH3:26])[O:13][C:11]1=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: C[C@@H]1OC(=O)C(OC(=O)c2ccccc2)=C[C@H]1OC(=O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H]1OC(=O)[C@H](OC(=O)c2ccccc2)C[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
The compound (VIII) (6.1 g, 17.31 mmol) is dissolved in EtOAc (300 ml) and then 10%-Pd/C (400 mg) is added and is stirred for 3 hours at a room temperature after being substituted with hydrogen gas. The reactant is filtered by using celite 545. The solution is vacuum concentrated and then the compound (IX) (5.2 g, 85%) is isolated using flash column chromatography (toluene/EtOAc, 10:1, v/v).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=[O:13].C(Cl)(=O)C(Cl)=O.[CH3:21][C:22]([CH3:25])([O-])[CH3:23].[K+]>ClCCl.CN(C)C=O.O1CCCC1>[C:22]([O:13][C:12]([C:7]1[C:8]2[C:3](=[C:2]([Br:1])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=1)=[O:14])([CH3:25])([CH3:23])[CH3:21]
Reactant: CC(C)(C)[O-]
Reactant: O=C(O)c1cccc2c(Br)cccc12
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.8 %

Procedure:
To a suspension of 5-bromo-1-naphtoic acid (Example 9.1) (10.8 g) in dichloromethane (93 ml) containing 3 drops of dimethylformamide was added oxalyl chloride (4 ml) and the reaction mixture stirred at ambient temperature for 6 hours. The solution was concentrated to afford a white solid which was re-dissolved in tetrahydrofuran. The solution was cooled to 2° C. and a solution of potassium tert-butoxide (7.2 g) in tetrahydrofuran (148 ml) was added dropwise and the reaction mixture stirred at ambient temperature for 3 hours. The solution was poured onto ice and extracted with ethyl acetate. The combined organic extracts were washed with water, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate) to give 5-bromo-1-naphtoic acid tert-butyl ester (12 g). 1H-NMR (CDCl3, 400 MHz): 8.82 (d, 1H), 8.46 (d, 1H), 8.11 (d, 1H), 7.72 (d, 1H), 7.60 (m, 1H), 7.40 (m, 1H), 1.70 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:40])[CH:5]([C:10]1[CH:11]=[C:12]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[CH:13]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[Na+]>CO>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:34][CH:35]=2)[CH:13]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH:15]=1)[C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCCCC2Cc2ccccc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1CC1CCCCN1c1cc(-c2ccc(C(F)(F)F)cc2)cc(C(CC(C)C)C(=O)O)c1
Temperature: 60 °C

Procedure:
To a solution of 4-methyl-2-{5-[2-(2-methyl-benzyl)-piperidin-1-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid ethyl ester (12 mg, 0.02 mmol) in MeOH (1 mL) was added 3N NaOH (0.200 mL) and heated to 60° C. for 14 h. The reaction was concentrated in vacuo to remove MeOH. The thick liquid was acidified to pH=2 by 2N HCl. The resulting acidic solution was extracted with EtOAc. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by Gilson reverse phase column chromatography to obtain 4-methyl-2-{5-[2-(2-methyl-benzyl)-piperidin-1-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid.