Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S[C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.C[O-].[Na+].CO>CO.[Ni]>[N:7]1[C:6]2[NH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][CH:2]=1
Reactant: O=c1[nH]c(S)nc2[nH]ccc12
Agent: [Ni]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]cnc2[nH]ccc12
Temperature: 50 °C
Yield: 66.5 %

Procedure:
In methanol (714 ml) was suspended 2-mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (15.06 g) followed by addition of 28% sodium methoxide/methanol (18.4 ml). While this solution was stirred at 50° C., Raney nickel was added until disappearance of the starting compound had been verified by TLC. The catalyst was then filtered off and the filtrate was neutralized with 1N-HCl (90 ml). The solvent was then distilled off under reduced pressure and the resulting precipitate was collected by filtration, rinsed serially with water, methanol and ether, and dried to provide the title compound (8.1 g). 1H-NMR (DMSO-d6) 8: 6.44(1H,d,J=3.0Hz), 7.03(1H,d,J=3.OHz), 7.83(1H,s), 11.80(1H,brs).
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26](O)=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C[O:33][C:34](=[O:48])[C@@H:35]([NH2:47])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=1>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26]([NH:47][C@@H:35]([CH2:36][C:37]4[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=4)[C:34]([OH:33])=[O:48])=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(C(C)(C)C)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(C[C@H](NC(=O)c2cc3ccc(Oc4ccc(C(C)(C)C)cc4)cc3c(CC3CCCC3)n2)C(=O)O)cc1
Yield: 98.1 %

Procedure:
50 mg (0.12 mmol) of 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (Example 419) was reacted with (2S)-amino-3-(4-tert-butyl-phenyl)-propionic acid methyl ester HCl (36.8 mg, 0.14 mmol) as described in general procedure A. The resulting ester was hydrolyzed as described in general procedure C to afford 71.4 mg of the title compound as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH:13]=3)=[C:10]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30](OC)(OC)OC>>[CH2:20]([N:19]1[C:14]2[CH:13]=[C:12]([C:11]3[N:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH:8]=[N:9][C:10]=3[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:17]=[CH:16][C:15]=2[N:18]=[CH:30]1)[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CNc1cc(-c2c(-c3ccccc3)ncn2C2CCCCC2)ccc1N
Reactant: COC(OC)OC
Product: CC(C)Cn1cnc2ccc(-c3c(-c4ccccc4)ncn3C3CCCCC3)cc21
Temperature: 25 °C
Yield: 73 %

Procedure:
Heat a mixture of 1-(cyclohexyl)-4-phenyl-5-(3-(isobutylamino)-4-aminophenyl)-1H-imidazole (83 mg, 0.21 mmol) and 3 mL trimethyl orthoformate at 120° C. for 6 hours. Cool to room temperature and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 3:1 ethyl acetate:hexanes to provide the title compound (73%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:12](O)=[O:13])[C:6]([C:9](O)=[O:10])=[CH:7][CH:8]=1.B.CO>C1COCC1>[OH:13][CH2:12][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:8]=[CH:7][C:6]=1[CH2:9][OH:10]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(C(F)(F)F)cc1CO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
To a solution of 4-trifluoromethylbenzene-1,2-dicarboxylic acid (5.85 g, 25 mmol) in THF (50 mL) at −78° C. was added borane in THF (1.0 M, 75 mL) and the mixture was stirred for 10 minutes. The mixture was then allowed to warm to room temperature and stirred overnight. Methanol (30 mL) was added and solvents were evaporated. The mixture was partitioned between ether and aqueous hydrochloric acid (1N). The organic layer was washed with brine and concentrated sodium bicarbonate solution. After the evaporation of solvents, colorless oil was obtained as (2-hydroxymethyl-4-trifluoromethyl-phenyl)-methanol (5.15 g). 1H-NMR (CDCl3) □ 7.58 (m, 2H), 7.51 (s 1H), 4.79 (s, 4H), 2.88 (m, 2H).
Reaction SMILES: [CH2:1]([OH:5])[C:2](=[CH2:4])[CH3:3].Cl[C:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:8].N1C=CC=CC=1.[Cl-].[NH4+]>C1COCC1>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([O:9][C:7](=[O:8])[O:5][CH2:1][C:2]([CH3:3])=[CH2:4])=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C=C(C)CO
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methallyl alcohol [CAS No. 513-42-8] (5 g) and 4-nitrophenyl chloroformate [CAS No. 7693-46-1] (12.6 g) were dissolved in THF (70 mL), and pyridine (6.69 mL) was added to the resulting mixture under ice-cooling, after which the resulting mixture was stirred overnight at room temperature. To the reaction mixture, ice and saturated aqueous ammonium chloride solution were added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (10.5 g).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[C:12]([C:22]#[N:23])=[N:13][C:14]([C:17](OCC)=[O:18])=[C:15]([OH:16])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+]>C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[C:12]([C:22]#[N:23])=[N:13][C:14]([C:17]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:18])=[C:15]([OH:16])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(-c3ccc(Br)o3)noc2c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2onc(-c3ccc(Br)o3)c12
Temperature: 25 °C
Yield: 22.3 %

Procedure:
Ethyl 3-(5-bromofuran-2-yl)-4-cyano-7-hydroxyisoxazolo[4,5-c]pyridine-6-carboxylate (42 mg, 0.11 mmol) and glycine (334 mg, 4.44 mmol) were added to sodium methoxide solution (6.7 mL, 3.33 mmol, 0.5 M in MeOH) and the mixture was refluxed for 48 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was redissolved in a minimum amount of water, and 0.25 M hydrochloric acid was added until pH was 3. The resulting precipitate was isolated by filtration and dried under vacuum to give 21 mg of crude solid. The solid was dissolved in 10 mL of saturated sodium bicarbonate solution and washed with hexanes and EtOAc. The aqueous layer was acidified to pH 3 and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated to afford 10 mg of the title compound. MS: (−) m/z 405.21, 407.18 (M−1, 79Br/81Br).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:16][NH:17][CH3:18]>O>[CH3:16][N:17]([CH3:18])[C:2]1[N:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Reactant: CNC
Solvent: O
Product: COC(=O)c1cnc(N(C)C)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of 2.5 g (10.43 mmol) of methyl 6-chloro-4-(trifluoromethyl)nicotinate and 18.4 ml (146 mmol) of a 40% solution of dimethylamine in water is heated at 100° C. for 1 hour. A precipitate is subsequently collected by filtering the cooled mixture and is washed with 150 ml of water. After drying under reduced pressure, 2.3 g of the expected compound are isolated.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14]O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:18]>>[CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][Cl:18])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cc(Cc2ccccc2)ccn1
Reactant: O=S(Cl)Cl
Product: ClCc1cc(Cc2ccccc2)ccn1
Yield: 100.7 %

Procedure:
A solution of 4-benzyl-2-(hydroxymethyl) pyridine (2.85 g, 14.6 mmol) in SOCl2 (7.50 mL, 102 mmol) was stirred at 25° C. for 30 min. and was concentrated under reduced pressure. The crude compound was diluted with EtOAc (100 mL), washed with NaHCO3 (2×100 mL), dried over Na2SO4 and was concentrated under reduced pressure to afford the title compound as a dark oil (3.2 g, 98%): 1H NMR (CDCl3) δ4.00 (s, 2H), 4.66 (s, 2H), 7.08 (d, J=5.1 Hz, 1H), 7.18 (d, J=7.2 Hz, 2H), 7.20-7.40 (m, 4H), 8.46 (d, J=5.1 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[CH:9][CH:10]=[C:11]([C:17]1C=C[CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5].F[B-](F)(F)F.CN(C)C(C(OCC)=O)=CC=[N+](C)C.CC[O-].[Na+].C(SCC(OCC)=O)CCC>C(O)C>[CH3:23][N:2]([CH3:1])[C:3](=[CH:9][CH:10]=[C:11]([CH2:17][CH2:18][CH2:19][CH3:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5]
Reactant: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CCCCSCC(=O)OCC
Agent: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CC[O-]
Solvent: CCO
Product: CCCCC(=CC=C(C(=S)OCC)N(C)C)C(=O)OCC

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (10 g), a 2M ethanolic solution of sodium ethylate (17.5 cc) and ethyl (n-butylthio)acetate (6.16 g) in ethanol (60 cc). Diethyl 2-dimethylamino-5-n-butylthio-2,4-hexadienedioate (10 g) is thereby obtained in the form of an orange-red oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: C(S)C.[H-].[Na+].[CH2:6]([O:10][C:11]([C:13]1[S:17][C:16]2[CH:18]=[C:19]([O:24]C)[C:20]([O:22][CH3:23])=[CH:21][C:15]=2[C:14]=1[OH:26])=[O:12])[CH2:7][CH2:8][CH3:9].[NH4+].[Cl-]>CN(C=O)C>[CH2:6]([O:10][C:11]([C:13]1[S:17][C:16]2[CH:18]=[C:19]([OH:24])[C:20]([O:22][CH3:23])=[CH:21][C:15]=2[C:14]=1[OH:26])=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOC(=O)c1sc2cc(OC)c(OC)cc2c1O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCS
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1sc2cc(O)c(OC)cc2c1O
Yield: 76.7 %

Procedure:
4.45 ml (60 mmol) ethanethiol and 2.62 g (60 mmol, 60%) NaH were stirred for 15 mins. at room temperature in 100 ml DMF. 9.31 g (30 mmol) XIII were added to the resulting solution, followed by refluxing for 4 h. After hydrolysis with 25 ml saturated NH4Cl solution, the solvents were removed in vacuo, the residue was taken up in 500 ml ethyl acetate and washed with water. After drying over Na2SO4, flash chromatography (250 g SiO2, n-hexane:ethyl acetate=2:1+1% acetic acid), pre-adsorption: 25 g SiO2/CHCl3) yielded 6.89 g (23 mmol, 78%) XVI.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]1([NH:34][CH:35]([CH:39](O)[CH3:40])[C:36]([O-:38])=[O:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[C:28]1([NH:34][CH:35]([CH:39]([Cl:1])[CH3:40])[C:36]([OH:38])=[O:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(O)C(Nc1ccccc1)C(=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Cl)C(Nc1ccccc1)C(=O)O
Reaction time: 8 h

Procedure:
To a solution of N-chlorosuccinimide (1.24 g) and dry THF (60 ml), stirring at RT, is slowly added triphenylphosphine (2.43 g) in 50 ml of THF. Then the m-phenoxybenzyl ester of 2-phenylamino-3-hydroxybutanoate (3.5 g) in 30 ml of THF is added slowly. The reaction mixture is stirred overnight. The reaction is then concentrated under reduced pressure. The residue (oil) is taken up in ether, washed with water, dried over magnesium sulfate and evaporated to yield the m-phenoxybenzyl ester of 2-phenylamino-3-chloro-butanoic acid, MS m/e 395 (M+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Cl)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O-:24].[Na+].CO>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:24][CH3:23])[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1Cc1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc(C)n2Cc2ccccc2)n2c(C)nnc12
Temperature: 150 °C

Procedure:
A suspension of 6-benzyl-4-chloro-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (10.0 mg, 0.0322 mmol, from Example 228, Step 7) in 25 wt % solution of NaOMe in MeOH (1.3 mL, 5.6 mmol, Aldrich) was heated at 150° C. in the microwave for 3 hours. The reaction was purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (0.7 mg, 7%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:18][C:19]([NH2:21])=[S:20].II>C(O)(C)C.CCOC(C)=O>[NH2:21][C:19]1[S:20][CH:2]=[C:1]([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=2)[N:18]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1ccc(NC(=O)OCC(C)C)cc1
Agent: II
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)COC(=O)Nc1ccc(-c2csc(N)n2)cc1
Yield: 51 %

Procedure:
To a solution of the product of the preceding section (a) (19 g, 80.75 mmol) in isopropanol (120 mL) was added thiourea (24.6 g, 323 mmol) and iodine (20.5 g, 161.5 mmol). The resulting mixture was heated at reflux for 7 h, then diluted with EtOAc, washed serially with H2O and saturated aqueous NaHCO3. The resulting solution was then treated with 4N aqueous HCl and Et2O and stirred vigorously. The precipitate was filtered and washed with Et2O. The collected solid was then treated with saturated aqueous NaHCO3 and extracted serially with EtOAc and CH2Cl2. The combined organic extracts were washed with H2O and brine, then dried (MgSO4) and concentrated under reduced pressure to yield 2-methylpropyl N-{4-(2-amino-4-thiazolyl)-phenyl}carbamate (12 g, 51% yield) as a pale yellow solid: 1H NMR (400 MHz, DMSO-d6) δ9.63 (s, 1H), 7.70 (d, 2H, J=8.9 Hz), 7.46 (d, 2H, J=8.7 Hz), 6.99 (s, 2H), 6.84 (s, 1H), 3.88 (d, 2H, J=6.9 Hz), 1.95 (m, 1H), 0.99 (d, 6H, J=6.9 Hz); MS (FAB) m/z 292 (MH)+. This product was used as such in the next reaction (section (c)).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=2)=[O:21])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl.O>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)=[CH:24][CH:23]=2)=[O:21])=[CH:7][CH:8]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(C(F)(F)F)cc3)sc2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(C(F)(F)F)cc2)sc2cc(O)ccc12
Temperature: -78 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
The product of Example 19 (480 mg, 0.89 mmol) was dissolved in anhydrous CH2Cl2 (15 mL), cooled to -78° C., and treated with a 1.0 M CH2Cl2 solution of boron tribromide (0.8 mL, 0.8 mmol). The mixture was allowed to warm to room temperature, stirred overnight, and treated with additional boron tribromide (1.75 mL, 1.75 mmol) in 2 portions. After 72 h, the mixture was diluted with 75 mL of water and extracted with CH2Cl2 (2×75 mL). The organic layers were washed with 2 N sodium hydroxide and the resultant aqueous layer was acidified and extracted with CH2Cl2 (75 mL). The combined organic layers were dried (Na2SO4), concentrated, and purified via radial chromatography (2:1:0.1 hexane:ethyl acetate:MeOH, under an ammonia atmosphere) to provide 110 mg (24%) of the title product as an amorphous green solid: 1H NMR d 1.45 (m, 2H), 1.63 (m, 4H), 2.57 (m, 4H), 2.79 (t, J=4.9 Hz, 2H), 4.08 (t, J=4.9 Hz, 2H), 6.59 (d, J=8.6 Hz, 2H), 6.77 (d, J=8.7 Hz, 1H), 7.15 (s, 1H), 7.33 (d, J=8.7 Hz, 1H), 7.42 (s, 4H), 7.64 (d, J=8.6 Hz, 2H), 8.18 (b, 1H); HRMS (FD+) m/e calc'd. for C29H27F3NO3S (MH+): 526.1664, found: 526.1669; Anal. calc'd for C29H26F3NO3S.H2O: C, 64.07; H, 5.20; N, 2.57. Found: C, 63.67; H, 5.12; N, 2.89.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH3:17])[CH:3]=1.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH2:26][NH:25][CH2:24][CH2:23]2.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH3:8][C:6]1[C:5]([NH:9][C:10](=[O:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH3:17])[CH:3]=[C:2]([N:25]2[CH2:24][CH2:23][C:22]3[C:27](=[CH:28][CH:29]=[C:20]([C:19]([F:18])([F:31])[F:30])[CH:21]=3)[CH2:26]2)[N:7]=1
Reactant: Cc1cc(Br)nc(C)c1NC(=O)CC(C)(C)C
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(C(F)(F)F)ccc3C2)nc(C)c1NC(=O)CC(C)(C)C
Temperature: 100 °C
Yield: 62.4 %

Procedure:
In a tube, a mixture of 1d (0.374 g, 1.25 mmol), 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline (0.301 g, 1.5 mmol) in toluene (15 ml) was degassed by nitrogen flow for 15 minutes. To this mixture was added tris(dichlorobenzylidenacetone)palladium (0) (0.037 g, 0.04 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.06 g, 0.15 mmol) and potassium tert-butoxide (0.336 g, 3.0 mmol). The tube was heated under microwave irradiation (Biotage Initiator®) for 6 hour at 100° C. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, concentrated and chromatographed to yield the title compound (0.326 g, 0.78 mmol, 63%). 1H NMR (CDCl3, 400 MHz) δ 1.14 (s, 9H), 2.19 (s, 3H), 2.27 (s, 2H), 2.35 (s, 3H), 2.91 (t, J=6.2 Hz, 2H), 3.82 (t, J=6.2 Hz, 2H), 4.62 (s, 2H), 6.39 (s, 1H), 6.55 (bs, 1H), 6.98 (d, J=7.2 Hz, 2H), 7.24 (s, 1H).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][CH:8]([NH:13][C:14](=[O:35])[CH:15]([CH2:19][C:20]([N:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:17][CH3:18])[C:9](=[O:12])[CH2:10][F:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:33]1[C:34]2[N:22]([C:20](=[O:21])[CH2:19][CH:15]([CH2:16][CH2:17][CH3:18])[C:14]([NH:13][CH:8]([C:9](=[O:12])[CH2:10][F:11])[CH2:7][C:6]([OH:36])=[O:5])=[O:35])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)O)C(=O)CF
Reaction time: 2 h
Yield: 5.6 %

Procedure:
A solution of [3S/R, (2R)]-3-[2-(2-carbazol-9-yl-2-oxo-ethyl)-pentanoylamino]-5-fluoro-4-oxo-pentanoic acid tert-butyl ester (1.43 g, 2.88 mmol) in anhydrous DCM (20 ml) was treated with a solution of TFA (10 ml) in anhydrous DCM (10 ml) with stirring. The mixture was stirred at 0° C. for 2 h then at room temperature for 2 h. The mixture was concentrated under reduced pressure and then the residue was dissolved in dry DCM. This process was repeated several times in order to remove excess trifluoroacetic acid. The off-white solid was recrystallized from Et2O/40/60 hexanes to give the title compound as a white powder (71 mg): IR (solid) 1746, 1689, 1641, 1541, 1436, 1374, 1284, 1207, 1160 cm-1; 1H NMR (400 MHz, d6-DMSO) δ 0.80-1.00 (3H, m), 1.20-1.76 (4H, m), 2.30-2.90 (2H, m), 2.95-3.24 (1H, m), 3.26-3.59 (2H, m), 4.25-4.79 (1.5H, m), 5.02-5.43 (1.5H, m), 7.36-7.58 (4H, m), 8.10-8.30 (4H, m), 8.54-8.91 (1H, m); 13C NMR (100 MHz, DMSO) δ 14.31, 20.03, 20.13, 21.92, 22.51, 34.36, 34.77, 41.20, 41.62, 44.06, 51.77, 52.84, 83.45, 85.22, 116.70, 120.54, 123.91, 124.01, 127.85, 126.01, 138.20, 172.15, 172.36, 172.96, 173.00, 175.32, 175.48, 202.60, 203.10; 19F (376 MHz, DMSO) δ −226.68, −226.73, −231.21, −232.95, −233.38, −233.52.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:19])[CH2:14][C:15](=[N:17]O)[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:19][N:17]=[C:15]([CH3:16])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CC(=O)[C@@H]1CCCN1Cc1ccccc1)=NO
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc([C@@H]2CCCN2Cc2ccccc2)on1
Temperature: 25 °C

Procedure:
To a solution of 878 mg 1-((S)-1-Benzyl-pyrrolidin-2-yl)-butane-1,3-dione 3-oxime in 50 ml dichloromethane were added 0.52 ml methanesulfonyl chloride and 0.94 ml triethylamine at 0° C. The solution was allowed to warm to RT within 5 h. The reaction mixture was extracted with 1 M HCl (3×), the aqueous extracts were neutralized with solid NaHCO3 and extracted with dichloromethane (3×) to give the crude product which was purified by chromatography on silica using ethyl acetate/heptane 1/2 as eluent.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)[C:4](=[O:26])[CH:3]=1.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29].O>CN(C)C(=O)C>[F:24][C:22]([F:25])([F:23])[CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([N:5]2[C:4](=[O:26])[C:3]3[CH2:29][CH2:28][C:27](=[O:30])[NH:1][C:2]=3[N:7]=[C:6]2[CH2:8][CH2:9][C:10]([F:13])([F:11])[F:12])=[CH:19][CH:18]=1
Reactant: Nc1cc(=O)n(-c2ccc(OCC(F)(F)F)cc2)c(CCC(F)(F)F)n1
Reactant: C=CC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C1CCc2c(nc(CCC(F)(F)F)n(-c3ccc(OCC(F)(F)F)cc3)c2=O)N1
Reaction time: 0.17 h

Procedure:
A solution of 6-amino-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(3,3,3-trifluoropropyl)pyrimidin-4(3H)-one (1.0 g) in N,N-dimethylacetamide (30 mL) was heated to 60° C., acryloyl chloride (0.85 mL) was added thereto, and the mixture was stirred for 10 min. To the reaction mixture was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), diolpropylsilane-bonded silica gel column chromatography (ethyl acetate/hexane) and then silica gel column chromatography (ethyl acetate/hexane). The obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (0.72 g) as a solid. The solid (487 mg) was recrystallized from ethyl acetate to give the title compound (300 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]([NH:16][S:17]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[CH:29]=O)(=[O:19])=[O:18])([CH3:15])([CH3:14])[CH3:13].N1CCCC1>CO>[C:12]([NH:16][S:17]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1/[CH:29]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)(=[O:19])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)NS(=O)(=O)COc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)NS(=O)(=O)COc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 87.8 %

Procedure:
To the mixture of 6-chlorooxindole (3.05 g, 10 mmol) and N-tert-butyl-C-(4-chloro-2-formyl-phenoxy)-methanesulfonamide (1.65 g, 10 mmol)) in methanol (20 mL) was added pyrrolidine (1.41 g, 20 mmol) dropwise. The mixture was then heated at 70° C. for 1 h. After cooled to 4° C., the mixture was filtered and the precipitate was collected, dried to give the title compound (4 g).