Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:8]2=[N:9][CH:10]=[C:11]([F:14])[C:12](I)=[C:7]2[CH:6]=[CH:5]1)(=O)C.[CH2:15]([N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[C:19]([C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[N:18]1)[CH3:16].C(=O)(O)[O-].[Na+].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.CN(C)C=O>[CH2:15]([N:17]1[CH:21]=[C:20]([C:12]2[C:11]([F:14])=[CH:10][N:9]=[C:8]3[NH:4][CH:5]=[CH:6][C:7]=23)[C:19]([C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[N:18]1)[CH3:16]
Reactant: CC(=O)n1ccc2c(I)c(F)cnc21
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
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: O
Solvent: CN(C)C=O
Product: CCn1cc(-c2c(F)cnc3[nH]ccc23)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 100 °C
Yield: 80 %

Procedure:
A mixture of 1-acetyl-5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridine (0.822 mmol), 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.15 mmol), tetrakis(triphenylphosphine)palladium(0) (0.041 mmol), sodium bicarbonate (2.47 mmol), water (2 mL) and N,N-dimethylformamide (6 mL) were heated to 100° C. in a sealed tube for 16 h. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The combined extracts were dried over sodium sulfate filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% ethyl acetate/hexanes) to give the title compound as a yellow solid (80%). ESMS [M+H]+: 352.2
Reaction SMILES: [OH:1][C:2]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)([C:10]([OH:12])=[O:11])[CH2:3][C:4](=[N:8][OH:9])[C:5]([OH:7])=[O:6].Cl.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O>[OH:1][C@:2]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)([C:10]([OH:12])=[O:11])[CH2:3][C:4](=[N:8][OH:9])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)C(CC(O)(Cc1c[nH]c2ccccc12)C(=O)O)=NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C(C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)=NO
Yield: 72.7 %

Procedure:
44.7 g (0.131 mol) of the ammonium salt of 4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid was dissolved in 500 ml of water at 25° C. The resulting aqueous solution was adjusted to pH 2, using 25.5 g of 36% hydrochloric acid. The acidic solution was extracted in 1300 ml of ethyl acetate. The ethyl acetate solution was rinsed with 200 ml of aqueous saturated sodium chloride. 500 ml of aqueous sodium carbonate solution (13.9 g (0.131 mol) of sodium carbonate) was added to the resulting ethyl acetate solution, for agitation to separate the aqueous alkaline solution from ethyl acetate. 23.1 g of 36% hydrochloric acid was added to the resulting aqueous alkaline solution to adjust the solution to pH 2. (R)-(+)-1-phenylethylamine of 6.99 g (57.6 mmol) is dropwise added to the resulting acidic solution, for agitation at 25° C. for one hour. The resulting crystal was filtered and dried under reduced pressure, to obtain the (R)-(+)-1-phenylethylaine salt (21.8 g; 47.8 mmol) of (4S)-4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid (at a yield of 72.7% and optical purity of 87.4%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1.O>CN(C)C=O>[CH3:1][N:2]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:17][CH:18]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CBr)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2ccc(CN(C)c3ccccc3)cc2)cc1
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
N-Methylaniline (57 mg, 0.53 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 60% sodium hydride (21 mg, 0.53 mmol) was added under ice-cooling. The reaction mixture was stirred for 30 min., and methyl 4-[[4-(bromomethyl) phenyl]methoxy]benzenepropanoate (0.15 g, 0.41 mmol) was added. The mixture was stirred at room temperature for 3 hrs, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=18:1) to give the title compound (74 mg, yield 45%) as a yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:11][CH2:12][C@H:13]([O:16]S(C)(=O)=O)[CH2:14]O)=[CH:9][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:11][CH2:12][C@@H:13]2[CH2:14][O:16]2)=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC[C@@H](CO)OS(C)(=O)=O)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CC[C@@H]2CO2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a stirred, ice-cold solution of 559 mg (1.73 mmol) of the mesylate (18) in 10 ml of THF was added 76 mg (1.90 mmol) of a 60% dispersion of sodium hydride (NaH) in mineral oil. After 1 hour, the ice bath was removed and the reaction was stirred at room temperature. After stirring for 18 hours, another 35 mg (0.88 mmol) of a 60% dispersion of NaH was added. After 4 days of stirring, the reaction mixture was diluted with EtOAc, washed with 0.5N HCl and then with saturated NaCl, dried (MgSO4), and concentrated under reduced pressure. The resulting crude residue was flash-chromatographed on silica gel, eluting CH2Cl2. Consequently, 322 mg (82%) of the desired epoxide (19) was obtained as a colorless oil.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[C:20]([OH:34])[CH:19]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:9]([O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])=[C:20]([O:34][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:19]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Oc1ccc(C(=O)OCc2ccccc2)c(O)c1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Benzyl bromide (0.80 mL) was added to a mixture of benzyl 4-benzoyloxy-2-hydroxybenzoate (2.23 g) and cesium carbonate (2.29 g) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was stirred at 50° C. for 3 hrs, and water was added. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure liquid silica gel column chromatography (eluent: n-hexane/ethyl acetate=6/1) to afford benzyl 4-benzoyloxy-2-benzyloxybenzoate (2.87 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:26]2[CH:25]=[C:24]([C:23]3[CH2:22][C:21](=[O:37])[NH:20][C:9]4[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)ccc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(OCC(F)(F)F)ccc2N1

Procedure:
The title compound was prepared from [2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example M53) (356 mg, 0.67 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (190 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:18][CH2:17]2)=[O:15])[CH2:3]1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>>[CH2:7]([N:5]1[C@H:4]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:20][CH2:21]2)=[O:15])[CH2:3][C@H:2]([NH:1][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][CH:40]=[C:32]([O:31][CH3:30])[CH:33]=2)[CH2:6]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(N)CN2Cc2ccccc2)CC1
Product: COc1cccc(C(=O)N[C@H]2C[C@@H](C(=O)N3CCN(c4ccccc4C#N)CC3)N(Cc3ccccc3)C2)c1
Yield: 8.2 %

Procedure:
As described for Example 89e, 2-[4-(4-amino-1-benzyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile (50.0 mg, 0.128 mmol) was converted, using 3-methoxy-benzoyl chloride instead of 2-chloro-benzoyl chloride, to the title compound (5.5 mg, 8.2%) as light yellow oil. MS m/e=524.3 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[O:9][C:8]2=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26]O>>[C:1]1([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([CH:18]=[CH:19][C:20]([O:22][CH3:26])=[O:21])=[CH:23][CH:24]=3)[O:9][C:8]2=[O:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: O=C(O)C=Cc1ccc(OCC2CN(c3ccccc3)C(=O)O2)cc1
Product: COC(=O)C=Cc1ccc(OCC2CN(c3ccccc3)C(=O)O2)cc1
Yield: 94 %

Procedure:
In 20 ml of methanol was dissolved 200 mg of 4-(3-phenyl-2-oxooxazolidin-5-yl)methoxycinnamic acid (compound 181) obtained in Example 27. Concentrated sulfic acid (0.05 ml) was added to the solution, and the mixture was refluxed with heating for 16 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was washed with water and methanol to give 195 mg of the title compound (compound 185) in a yield of 94%.
Reaction SMILES: [C:1]([CH2:3][C:4]1([C:17]([O:19]C)=O)[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].[H][H]>CO.N.O.[Ni]>[O:19]=[C:17]1[C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH2:3][CH2:1][NH:2]1
Reactant: [H][H]
Reactant: COC(=O)C1(CC#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1

Procedure:
A suspension of 1-tert-butyl 4-methyl 4-(cyanomethyl)piperidine-1,4-dicarboxylate (70.0 g, 247.9 mmol) and Raney Ni (60 g) in MeOH (1500 mL) and NH3.H2O (80 mL) was stirred at 2 MPa of hydrogen pressure at 50° C. for 18 h. The reaction mixture was filtered through a pad of CELITE® and the filtrate was concentrated under vacuum to give a crude product, which was washed with ethyl acetate (200 mL) to give the title compound. 1H-NMR (400 MHz, CDCl3) δ 6.05 (s, 1H), 4.0 (s, 2H), 3.37-3.34 (m, 2H), 3.02-2.96 (m, 2H), 2.08-2.05 (m, 2H), 1.88-1.87 (m, 2H), 1.51-1.41 (m, 11H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].C(#N)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH:9]=[CH:13][N:14]([CH3:16])[CH3:15]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CN(C)C=CC(=O)c1ccccc1Cl
Temperature: 83 °C
Yield: 101.7 %

Procedure:
To a 5 liter, 3-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser capped with a nitrogen inlet, and a heating mantle were added o-chloroacetophenone (305.8 g), N,N-dimethylformamide dimethyl acetal (707.0 g), and acetonitrile (dried over molecular sieves, 3.0 L) giving an orange solution. The mixture was heated gradually to reflux (83° C.) over 1.5 hours, then maintained at reflux for 18 hours. After the dark red solution was cooled to room temperature, the acetonitrile was evaporated, leaving a heavy red oil. The oil was redissolved in toluene (1L). The toluene was evaporated to afford the crude enamine which was further dried under high vacuum overnight to afford 2'-chloro-3-dimethylaminopropenophenone (422 g) which was used without further purification.
Reaction SMILES: CO[C:3](=[O:37])[CH:4]([CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[NH:5][C:6](=[O:30])[C@H:7]([CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[NH:8][C:9]([O:11][CH2:12]C1C=CC=CC=1)=[O:10].O.[NH2:39][NH2:40]>CN(C)C=O>[CH2:12]([O:11][C:9]([NH:8][C@H:7]([C:6]([NH:5][CH:4]([C:3]([NH:39][NH2:40])=[O:37])[CH2:31][C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[O:30])[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:10])[C:20]1[CH:29]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NN
Reactant: COC(=O)C(Cc1cccs1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: NNC(=O)C(Cc1cccs1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 967.8 %

Procedure:
A mixed solution of 1.0 g (194 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(2-thienyl)-DL-alanine methyl ester and 0.64 g (0.2 mmole) of 80% hydrazine hydrate in 10 ml of dimethylformamide was stirred for 2 hours at room temperature and then left standing overnight at room temperature. Dimethylformamide was removed by evaporation under reduced pressure. Water was added to the residue, and the mixture was stirred to form a powdery precipitate, which was collected by filtration, washed with a mixture of diethyl ether and hexane and dried to yield 1.0 g (100%) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(2-thienyl)-DL-alanine hydrazide melting at 163°-164° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[C:4]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:3]1[CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24].C([O-])([O-])=O.[K+].[K+].Br[CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:36][C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)[CH:9]=2)[C:4]([C:12](=[O:20])[C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[C:3]1[CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)c2ccc(Cl)cc2)c2ccc(O)cc2n1C
Reactant: BrCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1c(C(=O)c2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc2n1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 180 mg of the phenol from Step E in 5 mL of DMF were added 124 mg of milled K2CO3 followed by 150 mg of 2-(bromomethyl) quinoline. The mixture was stirred at R.T. for 18 h, poured onto 25% aq. NH4OAc and extracted with ethyl acetate. The extract was dried over Na2SO4 and evaporated to dryness to give an oil which was chromatographed on flash silica gel using ethyl acetate:hexane (30:70) as eluant to give the title compound as a foam.
Reaction SMILES: [CH:1]1([C:7]2([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:22][C:23]([NH:25][C@H:26]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:13]([C:7]1([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:8][CH2:9][N:10]([C:27](=[O:28])[C@H:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH2:11][CH2:12]1)(=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(=O)C1(C2CCCCC2)CCNCC1
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
0.44 g (1.9 mmol) of 1-(4-cyclohexylpiperidin-4-yl)butan-1-one, 0.56 g of (R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid (1.9 mmol), 0.4 g (2.1 mmol) of EDC and 0.282 g (2.1 mmol) of HOBt are dissolved in 4 ml of DMF. The mixture is stirred at room temperature for 2 hours. The solution is washed with aqueous 2.5% citric acid solution and extracted with ethyl acetate, and the organic phase is then washed with aqueous 10N sodium hydroxide solution. It is dried over sodium sulfate, filtered and concentrated. The crude product obtained is chromatographed on silica gel (eluent: 7/3 heptane/ethyl acetate). 0.43 g is obtained in the form of a colourless oil in a yield of 44%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[CH3:30][C:31]1([CH3:41])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][NH:33][CH2:32]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:30][C:31]1([CH3:41])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][N:33]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:16][CH2:15][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:19][CH2:18]3)[CH:21]=2)=[O:27])[CH2:32]1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: CC1(C)CNCc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4Cc5ccccc5C(C)(C)C4)ncn3)CC1)C(=O)N2

Procedure:
0.10 g mg (0.25 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 57 mg (0.35 mmol) 4,4-dimethyl-1,2,3,4-tetra-hydro-isoquinoline, 75 μL (0.53 mmol) TEA and 0.11 (0.30 mmol) TBTU were stirred in 1.1 mL DMF overnight at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[S:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]([O:10][CH3:11])=[O:9].CN1CCOCC1.[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH:21]=[C:22]=[CH2:23]>C(Cl)Cl>[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:4]2[CH2:5][CH2:6][S:7][C:2]([CH3:12])([CH3:1])[C@@H:3]2[C:8]([O:10][CH3:11])=[O:9])(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH:21]=[C:22]=[CH2:23]
Reactant: C=C=CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1NCCSC1(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=C=CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.2 %

Procedure:
To a solution of product from Example 23 (155 mg, 0.82 mmol) in methylene chloride (5 ml) was added N-methylmorpholine (0.180 ml, 1.64 mmol) followed by the product from Example 5 (200 mg, 0.82 mmol). The resulting mixture was stirred for 15 hours at room temperature. The solvent was removed in vacuo and the residue dissolved in ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated sodium bicarbonate, saturated sodium chloride and dried over anhydrous sodium sulfate. The crude residue was purified by flash chromatography to give 170 mg (52%) of the product.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[C:14]([OH:22])[CH:13]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1)(O)[C:31]#[CH:32]>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1([C:34]2[CH:35]=[CH:36][C:37]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:38][CH:39]=2)[O:22][C:14]2[CH:13]=[C:12]([C:10]3[S:11][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8][CH:9]=3)[C:21]3[C:16]([C:15]=2[CH:32]=[CH:31]1)=[CH:17][CH:18]=[CH:19][CH:20]=3
Reactant: C#CC(O)(c1ccc(N2CCCC2)cc1)c1ccccc1F
Reactant: Oc1cc(-c2ccc(-c3ccccc3)s2)c2ccccc2c1
Solvent: Cc1ccccc1
Product: Fc1ccccc1C1(c2ccc(N3CCCC3)cc2)C=Cc2c(cc(-c3ccc(-c4ccccc4)s3)c3ccccc23)O1

Procedure:
A stirred solution of 4-(5-phenyl-2-thienyl)-2-naphthol, (0.52 g, 1.73 mmol) and 1-(2-fluorophenyl)-1-(4-pyrrolidinophenyl)prop-2-yn-1-ol (0.51 g, 1.73 mmol) in toluene (50 ml) was warmed to 50° C. Acidic Al2O3 (1 g) was then added and the mixture heated to reflux for 1.5 h. After cooling, the solution was filtered, washed with hot toluene (100 ml) and the solvent removed. The resulting residue was then flash chromatographed eluting with EtOAc-hexane (1:9). The fractions were combined and the solvent removed. After precipitation from acetone-MeOH, the title compound (0.52 g, 52%) was collected as dark green crystals.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[C:35]([CH3:37])([CH3:36])[CH2:34][C:33]4[C:32]([C:38](O)=[O:39])=[C:31]([F:41])[CH:30]=[CH:29][C:28]=4[NH:27]3)[CH:21]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[C:35]([CH3:37])([CH3:36])[CH2:34][C:33]4[C:32]([C:38]([NH:9][S:6]([CH:3]5[CH2:5][CH2:4]5)(=[O:8])=[O:7])=[O:39])=[C:31]([F:41])[CH:30]=[CH:29][C:28]=4[NH:27]3)[CH:21]=2)=[CH:18][CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)(C)c1ccc(-c2cccc(C3Nc4ccc(F)c(C(=O)O)c4CC3(C)C)c2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2cccc(C3Nc4ccc(F)c(C(=O)NS(=O)(=O)C5CC5)c4CC3(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.7 %

Procedure:
To a suspension of 60% sodium hydride (75 mg, 1.86 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (242 mg, 1.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(4′-tert-butyl-biphenyl-3-yl)-6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (80 mg, 0.19 mmol) and 1,1′-carbonyldiimidazole (65 mg, 0.38 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(4′-tert-butyl-biphenyl-3-yl)-6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carbonyl]-amide (21 mg, 20%) as a white solid: LC/MS m/e calcd for C31H35FN2O3S (M+H)+: 535.70, observed: 535.1.