Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[N+:30]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([N+:42]([O-:44])=[O:43])[CH:41]=1)[C:36]([OH:38])=O)([O-:32])=[O:31]>>[N+:42]([C:40]1[CH:39]=[C:35]([CH:34]=[C:33]([N+:30]([O-:32])=[O:31])[CH:41]=1)[C:36]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:38])([O-:44])=[O:43]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: Cl
Product: CN(C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3,5-dinitrobenzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3,5-dinitrobenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 558 (M-H)-.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:27]([NH2:30])[CH2:28][CH3:29]>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:30][CH2:27][CH2:28][CH3:29])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCCN
Solvent: CC#N
Product: CCCNC[C@H]1COc2ccc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [(2R)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.4 g, 0.9 mmol), propan-1-amine (1 ml) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and on a small silica plug (DCM/MeOH). Yield: 0.2 g, 90%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 228° C. MS m/z (rel. intensity, 70 eV) 285 (M+, 2), 79 (3), 73 (5), 72 (bp), 70 (5). [α]=−73° (MeOH).
Reaction SMILES: O1CCOCC1.Cl.[CH3:8][O:9][C:10]([C:12]1[N:13]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([O:41]C(C)(C)C)=[O:40])=[CH:35][CH:34]=2)[C:14](=[O:31])[C:15]2[C:20]([C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:19][C:18]([C:28](=[O:30])[NH2:29])=[CH:17][CH:16]=2)=[O:11]>>[CH3:8][O:9][C:10]([C:12]1[N:13]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]([OH:41])=[O:40])=[CH:37][CH:38]=2)[C:14](=[O:31])[C:15]2[C:20]([C:21]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:19][C:18]([C:28](=[O:30])[NH2:29])=[CH:17][CH:16]=2)=[O:11]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(C(N)=O)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1c(-c2ccccc2)c2cc(C(N)=O)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a 4N-hydrochloric acid dioxane solution (5 ml) was added 2-(4-tert-butoxycarbonylbenzyl)-6-carbamoyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (140 mg), and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure, and the obtained crystals were washed with methanol to give the title compound (86 mg).
Reaction SMILES: [NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19](C)[C:20](=O)OC(C)(C)C)[CH2:11][C@H:10]2[O:28][CH3:29])=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1.Cl>CC(O)C>[NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH3:20])[CH2:11][C@H:10]2[O:28][CH3:29])=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCCN(C)C(=O)OC(C)(C)C)C[C@H]1OC
Agent: Cl
Solvent: CC(C)O
Product: CNCCCCN1CC[C@H](NC(=O)c2cc(Cl)c(N)cc2OC)[C@H](OC)C1
Yield: 78.7 %

Procedure:
A mixture of (1,1-dimethylethyl) cis-[4-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]butyl]methylcarbamate and 250 parts of 2-propanol, saturated with hydrochloric acid was stirred and refluxed for 15 minutes. The reaction mixture was evaporated and the residue was taken up in trichloromethane. The organic layer was washed with water, saturated with ammonium hydroxide, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 33 parts (78.7%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-(methylamino)butyl]-4-piperidinyl]benzamide; mp. 129.3° C. (interm. 9).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])/[C:9]1=[O:32])=O)(C)(C)C.[F:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:49])=[C:38]([CH:40]=[N:41][C:42]([O:44][Si](C)(C)C)=[CH2:43])[CH:39]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:32])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:43][C:42](=[O:44])[NH:41][CH:40]3[C:38]3[CH:39]=[C:34]([F:33])[CH:35]=[CH:36][C:37]=3[CH3:49])[C:11]2=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cc(Cl)ccc2OCS(C)(=O)=O)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCS(C)(=O)=O)C12C(=O)Nc1cc(Cl)ccc12
Yield: 5.8 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-6-chloro-3-(5-chloro-2-methanesulfonylmethoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (600 mg, 1.2 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (5 mmol) in toluene to give the title compound as a white solid (40 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=3)[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N+:24]([O-])([OH:26])=[O:25]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=3)[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc2cnn(-c3ncc(C(F)(F)F)cc3Cl)c2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc2cnn(-c3ncc(C(F)(F)F)cc3Cl)c2cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 70.7 %

Procedure:
To a solution of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-6-nitroindazole [Compound No. 3] (10 g) in conc. sulfuric acid (100 g), fuming nitric acid (3.2 g) was added dropwise while cooling with ice, and the resultant mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into ice water, and precipitated crystals were collected by filtration, washed and dried. The crystals were purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5,6-dinitroindazole (8.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][C@@H:8]2[C@@H:12]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:11][C@@H:10]([N:18]3[CH:25]=[C:24]([F:26])[C:22](=[O:23])[NH:21][C:19]3=[O:20])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:29]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)[CH2:30][CH3:31].C(N(CC)CC)C>O1CCOCC1>[C:15]([O:14][CH2:13][C@H:12]1[O:11][C@@H:10]([N:18]2[CH:25]=[C:24]([F:26])[C:22](=[O:23])[N:21]([C:37](=[O:38])[C:36]3[CH:35]=[CH:34][C:33]([O:32][CH2:29][CH2:30][CH3:31])=[CH:41][CH:40]=3)[C:19]2=[O:20])[CH2:9][C@@H:8]1[O:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccc(Cl)cc1
Reactant: CCCOc1ccc(C(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCOc1ccc(C(=O)n2c(=O)c(F)cn([C@H]3C[C@H](OCc4ccc(Cl)cc4)[C@@H](COC(C)=O)O3)c2=O)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 35.9 %

Procedure:
To a solution of 0.30 g of 3'-O-(4-chlorobenzyl)-5'-O-acetyl-2'-deoxy-5-fluorouridine in 30 ml of dioxane were added 0.44 g of 4-n-propoxybenzoyl chloride and 0.61 ml of triethylamine, and the mixture was stirred at 70° C. for 3 hours. The insolubles were removed by filtration, and the residue was dissolved in ethyl acetate. The solution was washed with water and dried. The ethyl acetate was distilled off, and the residue was placed on a silica gel column and eluted with chloroform-petroleum ether (1:1), thereby producing 0.15 g of the title compound in a yield of 36%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:22]=1)=[CH:5]2.[C:31](O)(=[O:34])[CH2:32][OH:33].C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][N:28]([C:32](=[O:33])[CH2:31][OH:34])[CH2:27][CH2:26]3)[N:22]=1)=[CH:5]2
Reactant: O=C(O)CO
Reactant: Clc1cc(NC2CCOCC2)c2[nH]c(C3=N[C@H](CCN4CCNCC4)CS3)cc2c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CO)N1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
The compound (23 mg, 0.05 mmol) prepared in Example 117 was dissolved in N,N-dimethylformamide (5 ml). Glycolic acid (15.1 mg, 0.2 mmol), triethylamine (28 ul, 0.2 mmol), EDC (45 mg, 0.23 mmol) and HOBT (40 mg, 0.29 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, 1N hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (5 mg, Yield 19%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:29])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:22])[CH:15]=2)=[CH:8][CH:7]=1.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO.O>[CH2:30]([NH:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:29])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH:15]=2)=[CH:10][CH:11]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(NC(=O)c3ccccc3)c2)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: O=C(Nc1cccc(C(=O)Nc2ccc([C@@H]3C[C@H]3NCc3ccccc3)cc2)c1)c1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-[(phenylcarbonyl)amino]benzamide hydrochloride (85.5 mg) in methanol (2 mL) were added benzaldehyde (21 μL) and sodium hydrogen carbonate (26.4 mg). The mixture was stirred at 70° C. for 1 hr, and ice-cooled to 0° C. and sodium borohydride (11.9 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and crystallized (hexane/ethyl acetate) to give the title compound (6.2 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C@@H:16]3[C@@H:20]([OH:21])[C@@H:19]([OH:22])[CH:18]([OH:23])[O:17]3)=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1.F[C:25](F)(F)C(O)=O>CO>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C@@H:16]3[C@@H:20]([OH:21])[C@@H:19]([OH:22])[CH:18]([O:23][CH3:25])[O:17]3)=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:8])(=[O:9])[N:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3OC(O)[C@H](O)[C@@H]3O)c21
Solvent: CO
Product: COC1O[C@H](COc2cccc3c2C(N)=NS(=O)(=O)N3)[C@@H](O)[C@H]1O
Yield: 100 %

Procedure:
To a solution of 4-Amino-5-(((2R,3S,4R)-3,4,5-trihydroxytetrahydrofuran-2-yl)methoxy)-1H-benzo[c][1,2,6]thiadiazine-2,2-dioxide (Example 212a) (7 mg, 0.020 mmol) in dry methanol (1 mL) was added trifluoroacetic acid 0.2 mL) and the mixture was refluxed overnight. The resulting solution was evaporated to dryness to provide the title compound as a white powder (7.28 mg, 100%, mixture of diastereomers˜4/1). 1H NMR (400 MHz, DMSO-d6): δ0 [3.17 (s, ¾H)], 3.22 (s, 3H), 3.81 (d, J=4.0 Hz, 1H), [3.93 (m, ½H)], 4.12 (m, 3H), 4.39 (m, 1H), 4.71 (s, 1H), [4.85 (d, J=4.0 Hz, ¼H)], 5.44 (br s, 2H), 6.65 (d, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.95 (s, 1H), 8.41 (s, 1H), 11.00 (s, 1H), [11.01 (s, ¼H)].
Reaction SMILES: [C:1]1([C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:25][CH2:26][CH:27]=[C:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]=2[CH2:32][O:31][C:30]2[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]1=2>C(O)(C)C>[OH:46][C:43]([C:41]1[CH:40]=[CH:39][C:30]2[O:31][CH2:32][C:33]3[N:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:28](=[CH:27][CH2:26][CH2:25][N:10]3[CH2:11][CH2:12][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([OH:13])[CH2:8][CH2:9]3)[C:29]=2[CH:42]=1)([CH3:45])[CH3:44]
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: OC1(c2ccccc2)CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(O)(c3ccccc3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 14 h
Yield: 49.6 %

Procedure:
To a solution of the 4-phenyl-piperidin-4-ol (0.212 g, 1.2 mmol) in isopropanol was added 2,6-lutidine (0.240 mL, 2.1 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.224 g, 0.6 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.140 g, 50%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([C:34]([F:45])([F:44])[F:33])[CH:40]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCN(C2CCCC2)CC1
Yield: 73 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (73%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:30]#[C:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)CCC.Cl>CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:30]#[C:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ncc2c(cc(C#Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 85 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (500 mg, 1.29 mmol), tributyl-phenylethynyl-stannane (0.54 mL, 1.54 mmol), and PdCl2(PPh3)2 (180 mg, 0.26 mmol) in 10 mL of DMF was heated at 120° C. for 2 h under N2 atmosphere. The mixture was cooled to r.t. and diluted with brine (10 mL) and EtOAc (40 mL). 1M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After the solvent was evaporated in vacuo, the crude residue was chromatographed (0-60% EtOAc/hexanes+2% AcOH) to give 450 mg of the title compound as a yellow solid. MS: (+) m/z 411.11 (M+1).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:23])[CH3:22])[C@@H:16]([CH3:24])[CH2:15][C@H:14]2[N:25]([C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1)[C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])=[O:10])C1C=CC=CC=1>C(O)C>[C:21]([N:17]1[C:18]2[C:13](=[CH:12][C:11]([C:9]([OH:10])=[O:8])=[CH:20][CH:19]=2)[C@H:14]([N:25]([C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[CH:34][CH:33]=2)[C:26](=[O:31])[C:27]([F:28])([F:30])[F:29])[CH2:15][C@@H:16]1[CH3:24])(=[O:23])[CH3:22]
Reactant: CC(=O)N1c2ccc(C(=O)OCc3ccccc3)cc2[C@H](N(C(=O)C(F)(F)F)c2ccc(N3CCOCC3)cc2)C[C@@H]1C
Solvent: CCO
Product: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](N(C(=O)C(F)(F)F)c2ccc(N3CCOCC3)cc2)C[C@@H]1C
Yield: 88.6 %

Procedure:
[Step 3] Reactions and treatments were carried out in the same manner as in Step 5 of Example 117, using 111.1 mg of (2S,4R)-1-acetyl-2-methyl-4-[2,2,2-trifluoro-N-(4-morpholinophenyl)acetamido]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid benzyl ester instead of ethyl (2S,4R)-1-acetyl-2-methyl-4-(4-nitrophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylate, and using ethanol instead of methanol. Thus, 83.5 mg (88.3%) of (2S,4R)-1-acetyl-2-methyl-4-[2,2,2-trifluoro-N-(4-morpholinophenyl)acetamido]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid was obtained as a pale yellow amorphous substance.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:8]([OH:10])=O)=[CH:6][N:7]=1)[CH3:2].Cl.[NH2:12][C@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)=[CH:25][CH:24]=1)[CH2:14][CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[Cl:35][C:31]1[CH:30]=[C:29]([C:26]2[CH:27]=[CH:28][C:23]([CH2:22][C@@H:13]([NH:12][C:8]([C:5]3[O:4][C:3]([CH2:1][CH3:2])=[N:7][CH:6]=3)=[O:10])[CH2:14][CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:24][CH:25]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CCc1ncc(C(=O)O)o1
Reactant: CCOC(=O)C(C)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cnc(CC)o1
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To a solution of 2-ethyloxazole-5-carboxylic acid (95 mg, 0.68 mmol) in DMF (2 mL) and DCM (2 mL) is added (4S)-ethyl 4-amino-5-(3′-chlorobiphenyl-4-yl)-2-methylpentanoate hydrochloride (215 mg, 0.56 mmol), HATU (321 mg, 0.84 mmol), and TEA (392 μL, 2.81 mmol). After stirring for 2 hours, the reaction is quenched with H2O, and the crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN) to give (4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-4-(2-ethyloxazole-5-carboxamido)-2-methylpentanoate (264 mg), HPLC retention time=0.71 minutes (condition B); MS (m+1)=469.3.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33].O.[NH2:37][NH2:38].C(=O)([O-])O.[Na+]>CN(C=O)C>[N+:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][C:24]1[C:3]2[C:4](=[O:23])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:21])([F:22])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:38][N:37]=1)([O-:34])=[O:33]
Reactant: NN
Reactant: O=C(Cc1ccccc1[N+](=O)[O-])c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccccc3[N+](=O)[O-])n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 115 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-hydroxy-3-(2-nitrophenylacetyl)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (450 mg, 0.93 mmol) produced in Synthesis Example 31 in DMF (4 mL) was added hydrazine monohydrate (purity of 80%, 148 μL), and the mixture was stirred at 110 to 120° C. for 3 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-nitrobenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (373 mg, yield 84%).