Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22]([OH:24])=O)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:40]1[CH2:51][C:50](=[O:52])[CH2:49][C@H:41]1[C:42]([NH:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=O)(C)(C)C>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22]([N:40]1[CH2:51][C:50](=[O:52])[CH2:49][C@H:41]1[C:42]([NH:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:24])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Product: CC(C)(C)NC(=O)[C@@H]1CC(=O)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1

Procedure:
A procedure similar to that described in Example 1 was repeated, except that (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 1) and 1-t-butoxycarbonyl-N-t-butyl-4-oxo-L-prolinamide (prepared as described in Preparation 3) were used as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound as colorless powdery crystals, melting at 116°-120° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[NH:10][C:9]([CH2:11][N:12]3[CH:17]=[CH:16][C:15]4[C:18]([C:21](=[O:31])[C:22]5[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=5[F:30])=[CH:19][NH:20][C:14]=4[C:13]3=[O:32])=[N:8][C:5]2=[N:6][CH:7]=1.C(OC([N:40]1[CH:44]=[CH:43][CH:42]=[C:41]1B(O)O)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C.O>[NH:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[C:2]1[CH:3]=[C:4]2[NH:10][C:9]([CH2:11][N:12]3[CH:17]=[CH:16][C:15]4[C:18]([C:21](=[O:31])[C:22]5[C:23]([F:30])=[CH:24][C:25]([F:29])=[CH:26][C:27]=5[F:28])=[CH:19][NH:20][C:14]=4[C:13]3=[O:32])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(c1c(F)cc(F)cc1F)c1c[nH]c2c(=O)n(Cc3nc4ncc(Br)cc4[nH]3)ccc12
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: O=C(c1c(F)cc(F)cc1F)c1c[nH]c2c(=O)n(Cc3nc4ncc(-c5ccc[nH]5)cc4[nH]3)ccc12
Temperature: 135 °C
Yield: 8.2 %

Procedure:
A microwavable vial was charged with 6-[(6-bromo-1H-imidazo[4,5-b]pyridin-2-yl)methyl]-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (20 mg, 0.04 mmol), [1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]boronic acid (12.6 mg, 0.06 mmol), cesium carbonate (39 mg, 0.119 mmol), bis(triphenylphosphine)palladium(II) chloride (2.8 mg, 3.98 umol) and acetonitril/water (0.6/0.2 ml). The vial was sealed, purged by 3 cycles of freeze-pump-thaw. The resultant suspension was heated to 135° C. by microwave irradiation for 15 min. LCMS showed complete consumption of the starting material and formation of the desired product. The reaction mixture was diluted with acetonitrile, and filtered through a 0.45 micron membrane filter and then concentrated to dryness under reduced pressure. The crude reaction mixture was purified by HPLC on Xbridge (C18 5u particle size, 30×75 mm) preparative column eluting with a linear gradient of 15-40% acetonitrile/water (0.01% NH4OH) at 70 ml/min. to give the title compound (1.6 mg, 8%). MS (ESI): m/z 489 (M+H). 1H-NMR (500 MHz, d6-DMSO): δ 11.35 (br. s, 1H), 8.61 (s, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.58 (d, 1H), 7.36 (m, 2H), 7.00 (d, 1H), 6.86 (s, 1H), 6.54 (s, 1H), 6.11 (s, 1H), 5.47 (s, 2H),
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7](O)=[O:8])=[O:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O:46][P:47](=[O:74])([O:71]CC)[O:48][CH2:49][C@@H:50]([N:56]([S:61]([C:64]1[CH:69]=[CH:68][C:67]([NH2:70])=[CH:66][CH:65]=1)(=[O:63])=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])[CH2:51][CH2:52][CH2:53][CH2:54][NH2:55])C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:7](=[O:8])[NH:55][CH2:54][CH2:53][CH2:52][CH2:51][C@H:50]([N:56]([S:61]([C:64]1[CH:65]=[CH:66][C:67]([NH2:70])=[CH:68][CH:69]=1)(=[O:62])=[O:63])[CH2:57][CH:58]([CH3:60])[CH3:59])[CH2:49][O:48][P:47]([OH:71])([OH:46])=[O:74])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(OCC)OC[C@H](CCCCN)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)NCCCC[C@@H](COP(=O)(O)O)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 139.6 %

Procedure:
(2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid ((example 1, step E) 0.9 g, 3 mmol) was activated in DMF (5 mL) with EDAC (1.7 g, 9 mmol) and HOBt (1.2 g, 9 mmol). To the solution was added 1.17 g of (2S)-phosphoric acid 6-amino-2-[(4-amino -benzenesulfonyl)-isobutyl-amino]-hexyl ester diethyl ester (1X) (example 3, step B) and the mixture stirred for 3 h. 20 g of Amberlite XAD-2 resin was then added and the beads were left to soak for 10 min. The resin was transferred into a glass filter and washed thoroughly with distilled water (400 mL) and 200 mL of 1M NaHCO3. The beads were then washed with 4×50 ml portions of MeOH then EtOAc 200 mL. The organic phase was evaporated. The residue was adsorbed onto silica gel and passed through a short silica gel column (EtOAc) to yield 2.4 g (83%) of white solid after evaporation.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1.Br.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:39][C:40]5[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=5)[C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: BrCc1ccncc1
Agent: Br
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ccncc3)C(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (35 mg, 0.07 mmol) in dry DMF (1 ml) was added sodium hydride (7 mg, 0.18 mmol) and 4-(bromomethyl)pyridine.HBr (23 mg, 0.09 mmol) under nitrogen. The resulting mixture was stirred for 1 hour at room temperature. A saturated solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3×10 ml) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 80% EtOAc in cyclohexane) to give the title compound (21 mg, 50%). 1H NMR (500 MHz, CDCl3): 8.54 (2H,s), 7.19-7.12 (9H,m), 6.97 (1H,S), 6.93-6.91 (2H,m), 5.11 (2H, s), 4.98 (1H, br s), 4.95 (2H, s), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.75-1.70 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:21]2[CH:33]=[CH:32][C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C:21]2[CH:33]=[CH:32][C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=2)=[CH:3][C:4]=1[NH:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: CC(C)Nc1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NC(C)C)c3)cc2s1
Temperature: 100 °C
Reaction time: 1.67 h
Yield: 35 %

Procedure:
5-bromo-2-chloro-N-isopropylpyridin-3-amine (127.6 mg, 0.511 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (191.5 mg, 0.602 mmol), potassium carbonate (317.8 mg, 2.299 mmol), and Pd(dppf)C12-DCM complex (42.9 mg, 0.0526 mmol) were suspended in 1,2-dimethoxyethane (2.0 ml) and water (0.5 ml). Argon was bubbled through the suspension for about 15 seconds, and then the flask was fit with a reflux condensor and placed in a preheated oil bath (100° C.) and stirred under argon for 100 minutes. The reaction was cooled to room temperature, concentrated, and treated with DCM and MeOH. These organic washings were decanted, concentrated, treated with water, and filtered. The solid was washed with water and the filtrate was discarded. Solid also washed with MeOH and Et2O, but the filtrate and solid contain product. The solid and filtrate were combined, concentrated, and purified on a silica gel column (25:1 to 20:1 DCM/MeOH to 15:1 DCM/2 N ammonia in MeOH) to afford N-(6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (64.5 mg, 35% yield). MS (ESI pos. ion) m/z: 361. Calculated exact mass for C17H17ClN4OS 360.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:26])[CH:10]2[NH:14][C:15](=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][CH:18]=2)[C:7]=1[C:27]([OH:29])=[O:28])(=[O:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+]>CO>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:26])[CH:10]2[NH:14][C:15](=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:30]=[N+:31]=[N-:32])=[CH:19][CH:18]=2)[C:7]=1[C:27]([OH:29])=[O:28])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CCl)cc3)C2SC1
Agent: [Na+]
Solvent: CO
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CN=[N+]=[N-])cc3)C2SC1

Procedure:
A warm solution of 1 g of 3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid and 2 g. of sodium azide in 80 ml of methanol was refluxed for 4 hours after which the solvent was removed under high vacuum at room temperature. The residue was triturated with 80 ml of benzeneacetone (2:1) to give 3-[(Acetyloxy)methyl]-7-[[2-[4-(azidomethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid. M.P. 135°-136° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:26])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:27]([O:29]C)=[O:28])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].O>CO.C(Cl)(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:26])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:27]([OH:29])=[O:28])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ccc4c3)c(N3CCCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@H]1CCCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution of (S)-methyl 2-(1H-indol-5-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate (79 mg, 0.20 mmol) in methanol (15 mL) and CHCl3 (5 mL) was added NaOH (24 mg, 0.60 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (15 mL) and adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by filtration to afford (S)-2-(1H-indol-5-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (70 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8](O)[CH3:9].C(N(S(F)(F)[F:28])CC)C>ClCCl>[Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8]([F:28])[CH3:9]
Reactant: CCN(CC)S(F)(F)F
Reactant: CSc1ccc(C(C)Nc2ncnc(C(C)O)c2Cl)cc1
Solvent: ClCCl
Product: CSc1ccc(C(C)Nc2ncnc(C(C)F)c2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 80 ml of dichloromethane was dissolved 4.7 g of 5-chloro-6-(1-hydroxyethyl)-4-[1-(4-methylthiophenyl)ethylamino]pyrimidine, and to the mixture was added dropwise 2.6 g of diethylaminosulfur trifluoride under ice cooling. The mixture was stirred at room temperature for 1 hour.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1F)[CH3:2].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)c1ccccc1F
Reactant: NCc1ccc(F)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccccc1NCc1ccc(F)cc1
Temperature: 120 °C

Procedure:
To a stirred solution of commercially available 2-Fluoro-benzoic acid ethyl ester (1 g, 6.01 mmol) and 4-Fluoro-benzylamine (0.828 g, 6.62 mmol) in dry N,N′-dimethylformamide (10 mL) in a screw cap vial was added diisopropylethylamine (0.854 g, 6.62 mmole, 1.1 mL). The resulting solution was heated to 120° C. for 4 hours. Reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 2-(4-Fluoro-benzylamino)-benzoic acid ethyl ester as a clear liquid (1.23 g, 75%, LCMS calc M+H 274, obs M+H 274).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:30][Si](C)(C)C>C(Cl)Cl.CN(C)C=O.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH2:30])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(N)=O)cc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67.7 %

Procedure:
A mixture of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (400 mg, 1.07 mmol) in methylene chloride (4 mL) cooled to 0° C. was treated with N,N-dimethylformamide (2 drops) followed by oxalyl chloride (100 μL, 1.18 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 1 h. The resulting reaction mixture was then treated dropwise with 1,1,1,3,3,3-hexamethyldisilazane (680 μL, 3.21 mmol) and subsequently stirred at 25° C. for 15 h. The reaction mixture was then diluted with methylene chloride (20 mL) and methanol (20 mL). The organic layer was washed with a 5% aqueous sulfuric acid solution (1×40 mL) and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (271 mg, 68%) as a white foam. The white foam was used without further purification: mp 60-63° C.; EI-HRMS m/e calcd for C15H20BrNO3S (M+) 373.0347, found 373.0348.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[C:42][CH:43]=[C:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[N:36]=1>C(Cl)Cl.CN(C=O)C>[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[C:42][CH:43]=[C:44]2[CH2:45][CH2:46][N:47]([C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:48][CH2:49]2)[N:36]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(C#CC=C2CCN(C(=O)c3ccccc3[N+](=O)[O-])CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution 2-nitrobenzoic acid (42.6 mg, 0.25 mmol) in CH2Cl2 (2 mL) and DMF (0.5 mL) stirred at 0-5° C., was added 1-hydroxybenzotriazole (50 mg, 0.322 mmol) and, after 30′, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (62 mg, 0.323 mmol). Afterwards, the Compound of Example 3 (53 mg, 0.25 mmol) was added. The reaction mixture was stirred at r.t. for 2 h and kept overnight at the same temperature. After dilution with water and 1 N NaOH, the organic layer was separated and washed with water, dried over Na2SO4 and evaporated to dryness in vacuo. Purification by flash chromatography (CHCl3-1.4 N MeOH/NH3 100:0.1) yielded the title compound (82 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.Br[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Fc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(F)cc2)C1
Yield: 81.9 %

Procedure:
Under a nitrogen atmosphere, a toluene solution (4 mL) of tert-butyl (R)-piperidin-3-yl-carbamate (500 mg, 2.50 mmol), 4-bromo-1-fluorobenzene (0.250 mL, 2.28 mmol), 2-(di-tert-butylphosphino)biphenyl (136 mg, 0.500 mmol), tris(dibenzylideneacetone)dipalladium (0) (104 mg, 0.130 mmol), and sodium tert-butoxide (307 mg, 3.50 mmol) was stirred at 100° C. for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (hexane/ethyl acetate=100/0→70/30 (v/v)) to obtain the title compound (550 mg, yield 82%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([CH3:11])[C:3]=1[C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH:20](OCC)(OCC)[O:21][CH2:22][CH3:23]>C(OC(=O)C)(=O)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([CH3:11])[C:3]=1[C:12]([C:13](=[CH:20][O:21][CH2:22][CH3:23])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: CCOC(=O)CC(=O)c1c(C)c(F)c(F)c(F)c1F
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A solution of 8.1 g (29.1 mmol) of ethyl 3-(2, 3,4,5-tetrafluoro-6-methylphenyl)-β-oxopropanoate, 7.2 g (43.3 mmol) of triethyl orthoformate, and 70 mL of acetic anhydride was refluxed for 3.5 hours. The solution was cooled to room temperature and concentrated under high vacuum to give 9.1 g of the title compound. The product was used as is in the next step.
Reaction SMILES: OO.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][N:5]=1.Br[C:12]([F:19])([F:18])[C:13](OCC)=[O:14].S(=O)(=O)(O)O>CS(C)=O.O.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2]>[F:18][C:12]1([F:19])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([F:10])[CH:8]=2)[NH:3][C:13]1=[O:14]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Nc1ccc(F)cn1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CS(C)=O
Solvent: O
Product: O=C1Nc2ncc(F)cc2C1(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.3 %

Procedure:
Hydrogen peroxide (30% aqueous solution, 0.984 mL, 9.63 mmol) was added dropwise to a stirred mixture of 2-amino-5-fluoropyridine (0.540 g, 4.82 mmol), ferrocene (0.090 g, 0.482 mmol), and ethyl bromodifluoroacetate (1.862 mL, 14.45 mmol) in DMSO (24 mL) under an argon atmosphere. The mixture was stirred at room temperature for 18 h. Sulfuric acid (0.514 mL, 9.63 mmol) was added, and the reaction mixture was stirred at room temperature for another 24 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel column chromatography eluting with EtOAc in hexanes to yield the title compound (0.248 g, 1.318 mmol, 27.4% yield) as a brown solid. M+1: 189.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH:9]([CH2:24][CH2:25][CH:26]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:10](N2C(C3C=CC=CC=3)COC2=O)=[O:11])=[CH:4][CH:3]=1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.O.O.O.[F-].C([NH+](CCCC)CCCC)CCC.C(O)(=O)C>COC(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:42]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[C:10](=[O:11])[CH:9]2[CH2:24][CH2:25][CH:26]([O:34][Si:35]([C:38]([CH3:40])([CH3:41])[CH3:39])([CH3:37])[CH3:36])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC(C(=O)N1C(=O)OCC1c1ccccc1)C(Nc1ccc(F)cc1)c1ccc(Br)cc1)c1ccc(F)cc1
Agent: CCCC[NH+](CCCC)CCCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [F-]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(Br)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.34 g of 3-[2-[(4-bromophenyl)-(4-fluorophenylamino)methyl]-5-(tert-butyl-dimethylsilanyloxy)-5-(4-fluorophenyl)pentanoyl]-4-phenyloxazolidin-2-one are suspended in 70 ml of tert-butyl methyl ether. 3.8 ml of bis(trimethylsilyl)acetamide and 144 mg of tributylammonium fluoride trihydrate are then added. The reaction mixture is stirred at room temperature overnight, and 0.7 ml of glacial acetic acid are then added. The reaction mixture is concentrated using a rotary evaporator and the residue is purified by column chromatography (SiO2; ethyl acetate/heptane 1:4). The product is obtained as a clear oil. C30H34BrF2NO2Si (586) MS (ESI): M+-131
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][N:23]=[CH:24]2.Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH:24]1[C:25]2[C:20](=[C:19]([NH:18][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:16]#[N:17])[CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][N:23]=1
Reactant: Nc1cccc2cnccc12
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3cccc4cnccc34)c2cc1OC
Temperature: 200 °C
Yield: 28 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3-carbonitrile, 0.288 g of 5-aminoisoquinoline, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol was heated under nitrogen in a sealed tube at 200° C. for 2 hours. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 0.100 g of 4-(isoquinolin-5-ylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 140° C. (decomposed); mass spectrum (EI, m/e): M 356.1279.