Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].O.[Cl:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:20])[CH:26]=1)=[O:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Clc1cccc([Mg]Br)c1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](CCC(=O)c1cccc(Cl)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (2.0 g) in tetrahydrofuran (100 mL), 3-chlorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 17.1 mL) was added dropwise at −40° C. over 20 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 2.5 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[C:8](/[C:10](=[CH:16]\OCC)/[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9]>C1(C)C=CC=CC=1>[C:8]([C:10](=[CH:16][NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9]
Reactant: Nc1cccnc1
Reactant: CCO/C=C(\C#N)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CNc1cccnc1
Temperature: 25 °C

Procedure:
A mixture of pyridin-3-amine (C-1) (10.0 g, 106.3 mmol, 1.0 eq) and (E)-ethyl 2-cyano-3-ethoxyacrylate (C-2) (21.5 g, 127 mmol, 1.2 eq) in toluene (40 mL) is stirred at reflux under argon for 5 h and then allowed to cool to RT. The precipitate is collected by filtration, rinsed with a mixture of petroether and ethyl acetate (v/v=2:1, 3×10 mL), and then dried in vacuo to afford the product, ethyl 2-cyano-3-(pyridin-3-ylamino)acrylate (C-3).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:8]2[C:7](=[O:23])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][NH:2][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:28][CH:29]=4)[CH:5]=3)[N:10]=[C:9]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2ccc(CNC(=O)c3ccc(OC(F)(F)F)cc3)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.4 mmol) in acetonitrile (10 mL), was added 4-trifluoromethoxy-benzoyl chloride (0.34 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.63 mL, 3.6 mmol). The mixture was stirred at room temperature for one hour. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-4-trifluoromethoxy-benzamide as an off-white solid (500 mg, 71% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.40 min (99.5%); mp, 165-167° C.; 1HNMR (DMSO-d6) δ 2.15-2.20 (m, 1H, CHH), 2.56-2.88 (m, 6H, CHCH2, CH3), 4.60 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.458-8.04 (m, 7H, Ar), 9.28 (t, J=5 Hz, 1H, CH2NH), 11.02 (s, 1H. NH); 13C NMR (DMSO-d6) δ 20.90, 23.40, 30.60, 42.35, 56.53, 119.93 (q, JC-F=257 Hz), 120.01, 120.67, 123.87, 126.62, 129.56, 133.19, 134.17, 134.07, 137.97, 145.83, 150.35, 154.61, 160.43, 165.06, 169.45, 172.59. LCMS MH=489; Anal Calcd For C22H19N4O5F3+1.1H2O: C, 54.36; H, 4.20; N, 11.02; F, 11.21. Found: C, 54.40; H, 3.89; N, 10.67; F, 11.06.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[C:7]3[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:8]=3[N:9]=[C:2]12.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[C:7]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:22][CH3:23])=[O:15])=[CH:10][C:8]=3[N:9]=[C:2]12
Reactant: CCO
Reactant: O=C(O)c1ccc2c(c1)nc1n2CCNC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2c(c1)nc1n2CCNC1
Yield: 84 %

Procedure:
In ethanol (200 ml), 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylic acid (2.94 g, 13.53 mmol) prepared in the Step 38-1-4 was suspended. Concentrated sulfuric acid (10 ml) was added thereto, and the mixture was heated under reflux for 72 hours. After being allowed to cool, the mixture was concentrated under a reduced pressure. The concentrate was neutralized with a saturated sodium bicarbonate solution and 25% ammonia water and then subjected to extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The concentrate was purified by silica gel column chromatography (chloroform:methanol=10:1) to give the title compound (2.78 g, 84%) as a light-yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12](O)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.CS(Cl)(=O)=O.[CH2:21]([N:23](CC)CC)C.[C-]#N.[Na+]>C1COCC1.CN1CCCC1=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([C:21]#[N:23])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)C2)cc1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: N#CC1CCN(c2ccc(N)cc2)C1

Procedure:
1-(4-Nitrophenyl)pyrroidin-3-ol and methanesulfonyl chloride were allowed to undergo the reaction in THF in the presence of triethylamine. The resulting compound and sodium cyanide were allowed to undergo the reaction in 1-methyl-2-pyrrolidone under heating. The resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 1-(4-aminophenyl)pyrrolidine-3-carbonitrile. NMR2: 1.48 (9H, s), 3.12-3.19 (2H, m), 6.46-6.50 (2H, m).
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])(=[O:3])[CH3:2].[NH2:29][CH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37]([NH2:41])=[N:36][CH:35]=[CH:34]2.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:41][C:37]1[C:38]2[C:33](=[CH:32][C:31]([CH2:30][NH:29][C:13]([C@@H:9]3[CH2:10][CH2:11][CH2:12][N:8]3[C:6](=[O:7])[C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[O:15])=[CH:40][CH:39]=2)[CH:34]=[CH:35][N:36]=1
Reactant: NCc1ccc2c(N)nccc2c1
Reactant: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A mixture of 1-(2-(R)-acetylamino-3-biphenyl-4yl-propionyl)-pyrrolidine-2-(S)-carboxylic acid (0.120 g), 6-aminomethyl-isoquinolin-1-ylamine (0.058 g), N-methyl morpholine (0.11 mL) and 0.100 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 4.5 mL of dry N,N-dimethyl formamide was stirred for 3 h at ambient temperature. The mixture was concentrated and the remaining residue was purified by silica chromatography (dichloro-methane/methanol 8/2) to give 0.120 g (70%) of the title compound as a light yellow solid. (+)-APCI-MS: 536 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])[C:3]=1[CH3:21].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:33]([NH2:34])=[CH:32][C:31]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:30][N:29]=2)[CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[N:25]1([C:28]2[C:33]([NH:34][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][C:15]4=[O:20])[C:3]=3[CH3:21])=[CH:32][C:31]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[CH:30][N:29]=2)[CH2:24][CH2:23][O:22][CH2:27][CH2:26]1
Reactant: Cc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure H using 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperidin-2-one (35.0 mg, 0.113 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give 1-(4-((2,5-di-4-morpholinyl-3-pyridinyl)-amino)-5,7-difluoro-3-methyl-2-quinolinyl)-2-piperidinone. 1H NMR (CDCl3) δ ppm 8.01 (1H, br. s.), 7.60 (1H, d, J=2.5 Hz), 7.47 (1H, d, J=9.8 Hz), 6.99 (1H, ddd, J=13.7, 8.6, 2.5 Hz), 6.51 (1H, br. s.), 4.33 (1H, br. s.), 3.83-4.01 (4H, m), 3.77-3.83 (4H, m), 3.48-3.59 (1H, m), 3.41 (2H, br. s.), 3.16 (4H, br. s,), 2.89-3.07 (2H, m), 2.50-2.61 (2H, m), 1.88-2.19 (7H, m). Mass Spectrum (ESI) m/e=539.2 (M+1).
Reaction SMILES: [C:1]1([C@@H:7]([O:11][CH3:12])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([C@@H:7]([O:11][CH3:12])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO[C@@H](C(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CO[C@@H](CO)c1ccccc1

Procedure:
72 g of (R)-2-phenyl-2-methoxyacetic acid (prepared according to the method described in J. Chem. Soc., 1962, p. 1519), are reduced with 16.5 g of lithium aluminum hydride in 300 ml of tetrahydrofuran.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:19][S:20][CH2:21][CH2:22][CH2:23][OH:24].[Br:25][C:26]1[CH:45]=[CH:44][C:29]([NH:30][C:31]2[C:40]3[C:35](=[CH:36][C:37](O)=[C:38]([O:41][CH3:42])[CH:39]=3)[N:34]=[CH:33][N:32]=2)=[C:28]([F:46])[CH:27]=1.C(P(CCCC)CCCC)CCC>C(Cl)Cl>[Br:25][C:26]1[CH:45]=[CH:44][C:29]([NH:30][C:31]2[C:40]3[C:35](=[CH:36][C:37]([O:24][CH2:23][CH2:22][CH2:21][S:20][CH3:19])=[C:38]([O:41][CH3:42])[CH:39]=3)[N:34]=[CH:33][N:32]=2)=[C:28]([F:46])[CH:27]=1
Reactant: CSCCCO
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCCSC
Temperature: 5 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
1,1′-(Azodicarbony)dipiperidine (1.56 g, 6.2 mmol) followed by 3-(methylthio)-1-propanol (0.32 ml, 3 mmol) was added to a mixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (225 mg, 7.0 mmol), (prepared as described for the starting material in Example 48), and tributylphosphine (1.42 mL 6.1 mmol) in methylene chloride (20 ml) at 5° C. The mixture was stirred at 5° C. for 1 hour and then for 18 hours at ambient temperature. The insolubles were removed by filtration and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/methanol (100/0 increasing to 95/5) to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-methylthiopropoxy)quinazoline (400 mg, 50%).
Reaction SMILES: FCC(CF)(CF)[C:4]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[C:18]([CH3:24])[CH:17]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)[OH:5].[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:23][N:22]([C:19]1[CH:20]=[CH:21][C:16]([C:4]([OH:5])([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=2)[C:12]([F:15])([F:14])[F:13])=[CH:17][C:18]=1[CH3:24])[S:35]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:37])=[O:36]
Reactant: CNc1ccc(C(O)(c2cccc(C(F)(F)F)c2)C(CF)(CF)CF)cc1C
Reactant: O=S(=O)(Cl)c1ccccc1
Product: Cc1cc(C(O)(c2cccc(C(F)(F)F)c2)C(F)(F)F)ccc1N(C)S(=O)(=O)c1ccccc1

Procedure:
The title compound was prepared from 2,2,2-trifluoromethyl-1-(3-methyl-4-methylaminophenyl)-1-(3-trifluoromethyl-phenyl)-ethanol (Step A) and benzenesulfonyl chloride using the procedure described in Example 1, Step D. 1H-NMR (CDCl3) δ 2.41 (s, 3H), 3.15 (s, 3H), 6.64 (d, J=8.4 Hz, 1H), 7.18 (brs, 1H), 7.42 (brs, 1H), 7.52–7.56 (m, 3H), 7.63–7.67 (m, 3H), 7.73 (d, J=8.5 Hz, 2H), 7.82 (s, 1H). Mass Spectrum (CI+) m/e=526.0 (M+23).
Reaction SMILES: [C:1]([N:4]1[CH:9]=[C:8]([CH:10]=O)[CH2:7][CH2:6][C@H:5]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([N:4]1[CH2:9][C@@H:8]([CH3:10])[CH2:7][CH2:6][C@H:5]1[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N1C=C(C=O)CC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1C[C@@H](C)CC[C@H]1C(=O)OC(C)(C)C
Yield: 109.7 %

Procedure:
140 mg (0.529 mmol) of the t-butyl (S)-N-acetyl-5-formyl-1,2,3,4-tetrahydropyridine-2-carboxylate obtained in Synthesis Example 14 was dissolved in 20 mL of ethanol, followed by the addition of 5% Pd/C (140 mg). It was treated in a hydrogen atmosphere of 3 kg/cm2 by the use of mediumpressure catalytic reduction equipment to conduct hydrogenation. The catalyst was removed by filtration and the filtrate was concentrated to give 140 mg of the title compound.
Reaction SMILES: N1CCCCC1.C1C2C(COC([NH:24][CH2:25][C@@H:26]([C:50]([O:52][CH3:53])=[O:51])[NH:27][C:28](=[O:49])[C:29]3[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][C:39]4[CH:47]=[CH:46][CH:45]=[C:44]5[C:40]=4[CH:41]=[CH:42][NH:43]5)=[O:36])=[CH:31][C:30]=3[Cl:48])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C)C=O>[NH2:24][CH2:25][C@@H:26]([C:50]([O:52][CH3:53])=[O:51])[NH:27][C:28](=[O:49])[C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][C:39]2[CH:47]=[CH:46][CH:45]=[C:44]3[C:40]=2[CH:41]=[CH:42][NH:43]3)=[O:36])=[CH:31][C:30]=1[Cl:48]
Reactant: COC(=O)[C@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Cl
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COC(=O)[C@H](CN)NC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
Piperidine (88 μL, 0.89 mmol) was added to a solution of 3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine, methyl ester (116 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL). The solution was stirred at room temperature for 30 min and then the solvent was evaporated. The resulting white solid was triturated with ether five times and dried in vacuo to give 3-amino-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine, methyl ester as an off-white solid (59 mg, 81%). N,N-Dimethylformamide (5 mL) was added, followed by HOAT (23 mg, 0.17 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol), and thiophene-2-carboxylic acid (18 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 18 h. Water was added, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered, evaporated, and chromatographed (40-80% ethyl acetate/hexanes) to give 3-[(thiophene-2-carbonyl)amino]-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine, methyl ester (58 mg, 78%). A solution of lithium hydroxide monohydrate (13 mg, 0.32 mmol) in tetrahydrofuran/methanol/water (3:1:1) was added, and the solution was stirred at room temperature for 20 min. The solvent was evaporated and the residue was purified by HPLC to give 3-(thiophene-2-carbonyl)amino-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine (45 mg, 80% from ester, 48% for three steps) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:23]([C:25]3[S:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:24])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:43])[O:41][CH3:42]>C(Cl)Cl>[CH3:32][O:31][C:4]1[CH:3]=[C:2]([O:1][C:40]([O:41][CH3:42])=[O:43])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][O:22][C:23]([C:25]2[S:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[O:24])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])([CH3:19])[CH:12]=[C:11]2[CH3:20]
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccc(-c2ccc3c(c2COC(=O)c2ccc(C)s2)C(C)=CC(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(5-methylthiophen-2-ylcarbonyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-2, 31.7 mg, 0.0705 mmol) was dissolved in anhydrous methylene dichloride (1 mL), triethylamine (30 μL, 0.22 mmol) and methyl chlorocarbonate (10 μL, 0.13 mmol) were added thereto, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (26.8 mg) as a pale yellow amorphous product. (Yield 79%)
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[O:7]=[S:8]1(=[O:32])[C:13]2[CH:14]=[C:15]([O:18][C:19]3[CH:20]=[C:21]([C:25](=[N:27][OH:28])[NH2:26])[CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:12]=2[N:11]2[CH2:29][CH2:30][CH2:31][C:10]2=[N:9]1.N1C=CC=CC=1>CN(C=O)C>[O:32]=[S:8]1(=[O:7])[C:13]2[CH:14]=[C:15]([O:18][C:19]3[CH:20]=[C:21]([C:25](=[N:27][O:28][C:2]([O:4][CH2:5][CH3:6])=[O:3])[NH2:26])[CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:12]=2[N:11]2[CH2:29][CH2:30][CH2:31][C:10]2=[N:9]1
Reactant: NC(=NO)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)ON=C(N)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reaction time: 0.5 h

Procedure:
65 μl (0.65 mmol) of ethyl chloroformate are added dropwise to a solution, cooled to 0° C., of the product obtained in Step A (244 mg, 0.65 mmol) in 1.5 ml of DMF and 59 μl (0.72 mmol) of pyridine. Stirring is carried out at 0° C. for 30 minutes and precipitation of the reaction mixture is brought about using water. The precipitate is filtered off to yield the title product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:13])[CH3:12])=[O:4].[C:20]([O:23][C@H:24]1[CH2:29][C@H:28]([CH3:30])[CH2:27][CH2:26][C@H:25]1[C:31](Cl)=[O:32])(=[O:22])[CH3:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])(O)=O.[Na+]>ClCCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:9]=1[N:10]([CH:11]([CH3:13])[CH3:12])[C:31]([C@@H:25]1[CH2:26][CH2:27][C@@H:28]([CH3:30])[CH2:29][C@@H:24]1[O:23][C:20](=[O:22])[CH3:21])=[O:32])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Reactant: CC(=O)O[C@H]1C[C@H](C)CC[C@H]1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@@H]1CC[C@@H](C)C[C@@H]1OC(C)=O)C(C)C
Temperature: 90 °C
Reaction time: 20 h
Yield: 48.1 %

Procedure:
To a solution of 3-Isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (136 mg, 0.50 mmol) in 1,2-dichloroethane (1.0 ml) was added (1R,2S,4R)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid chloride (119 mg, 0.54 mmol) dissolved in 1,2-dichloroethane (0.6 ml) followed by PPh3 (136 mg, 0.52 mmol). The resulting solution was stirred for 20 h at 90° C. and then cooled to room temperature. It was then diluted with ethyl acetate (10 ml) and a solution of saturated NaHCO3 (10 ml). The aqueous phase was separated and washed with ethyl acetate (2×10 ml) and the combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0% to 25% EtOAc/Hexane) to obtain 110 mg (45%) of (1R,2S,4R)-3-[Isopropyl-(2-Acetoxy-4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 1.5:1.0 mixture of rotamers 7.73-7.70 ppm (m, 2H, Haro); 7.69-7.63 ppm (m, 1H, Haro); 7.51-7.41 ppm (m, 4H, Haro); 7.13 ppm (s, 0.6H, Haro, major rotamer); 5.79 ppm (s, 0.4H, minor rotamer); 5.21 ppm (s, 0.6H, major rotamer); 4.95-4.88 ppm (m, 1H); 3.88 ppm (s, 1.8H, major rotamer); 3.87 ppm (s, 1.2H, minor rotamer); 2.40-2.36 ppm (m, 0.6H, major rotamer); 2.11 ppm (s, 3H); 1.78-0.77 ppm (m, 16H).
Reaction SMILES: [F:1][C:2]([F:29])([C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:3][CH2:4][CH2:5][CH2:6]OC1(C)C=CC(S([O-])(=O)=O)=CC1.[CH2:30](OC1C=CC2C(=CC=C(Br)C=2)C=1)[C:31]1C=CC=[CH:33][CH:32]=1>C1COCC1.[Cu]Br>[F:29][C:2]([F:1])([C:19]([F:27])([F:28])[C:20]([F:25])([F:26])[C:21]([F:22])([F:23])[F:24])[CH2:3][CH2:4][CH2:5][CH2:6][C:31]([CH:32]=[CH2:33])=[CH2:30]
Reactant: CC1(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C=CC(S(=O)(=O)[O-])=CC1
Reactant: Brc1ccc2cc(OCc3ccccc3)ccc2c1
Agent: [Cu]Br
Solvent: C1CCOC1
Product: C=CC(=C)CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyl)-tosylate (10), (1 equi) and copper (I) bromide (0.05 equi.) in THF (2 mL/mmole), a solution of buta-1,3-diene-2-magnesium chloride, prepared as described in (3), (38) (0.5M in THF) (1.3 equi.) was added at ice temperature over a period of 20 min. The reaction mixture was stirred at room temperature for 24 h, quenched with 5% aqueous ammonium chloride (1 mL/mmole), extracted with hexane, washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (hexane) gave 2-(5,5,6,6,7,7,8,8,8-nona fluoro-octyl)-buta-1,3-diene (39) a colorless oil (96%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[N:10]=1.C(N(CC)CC)C.[F-].[K+].Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[N:10]=1)=[O:4]
Reactant: Nc1cccc(Br)n1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cccc(Br)n1
Reaction time: 42 h
Yield: 383.9 %

Procedure:
Trimethylacetyl chloride (180.9 g, 1.500 mols) was added over 1 h to a mixture of 2-amino-6-bromo-pyridine (264.7 g, 1.530 mols), triethylamine (166.7 g, 1.650 mols) and toluene (1 L, KF=2 mg moisture/L) maintaining the temperature below 50° C. The mixture was aged at 25° C. for 42 h. A solution of 1M aqueous HCl (500 mL) was added and the biphasic mixture was filtered (after agitation for 5 min) through a pad of solka floc (10 g) which was washed with toluene (50 mL). The organic phase was separated from the filtrates and was washed with 1M aqueous HCl (2×500 mL), 2% aqueous NaCl (500 mL) and a mixture of saturated aqueous NaCl (250 mL) and saturated aqueous NaHCO3 (25 mL). The organic phase was dried over MgSO4 (10 g), filtered and evaporated to dryness to provide 380.7 g of crude title compound, which was diluted with toluene to give 1480.8 g of crude solution.