Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.[NH2:39][C:40]1[CH:41]=[CH:42][C:43]([NH:46][C:47](=[O:49])[CH3:48])=[N:44][CH:45]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:47]([NH:46][C:43]1[N:44]=[CH:45][C:40]([NH:39][C:35]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:33])([CH3:34])[CH3:32])[NH:17]2)=[O:36])=[CH:41][CH:42]=1)(=[O:49])[CH3:48]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(=O)Nc1ccc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cn1
Yield: 89.2 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.16 g, 0.28 mmol) was reacted with N-(5-amino-pyridin-2-yl)-acetamide (Aldrich) (0.12 g, 0.79 mmol), HATU (0.1 g, 0.26 mmol) and iPr2NEt (0.2 g, 1.5 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-acetylamino-pyridin-3-yl)-amide as a white solid (0.15 g, 89%).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17](O)[C:16]3[C:11](=[CH:12][C:13]([O:20][CH3:21])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:20][CH3:21])=[CH:14][CH:15]=2)[N:10]=[C:9]([C:6]2[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[CH:18]=1
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)cc(-c3nc(C(C)C)cs3)nc2c1
Temperature: 0 °C
Yield: 64 %

Procedure:
A suspension of 1.3 g (4.3 mmol) of 2-(4-Isopropylthiazol-2-yl)-7-methoxyquinolin-4-ol, product of step F, in 60 mL of POCl3 was heated to reflux for 2 h. The solvent was removed in vacuo, the residue diluted with ice cold water and the mixture adjusted to pH 9 while cooling to 0° C. This aqueous solution was extracted several times with EtOAc. The combined EtOAc extracts were washed once with brine, pH 4 buffer, dried (MgSO4), and concentrated to afford 0.89 g (64%) of 4-Chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinoline as a yellow solid: 1H NMR (500 MHz, CDCl3) δ ppm 1.38 (d, J=7 Hz, 6H), 3.19 (m, 1H), 3.98 (s, 3H), 7.06 (s, 1H), 7.26 (m, 1H), 7.47 (d, J=2 Hz, 1H), 8.10 (d, J=9 Hz, 1H), 8.31 (s, 1H). LC-MS m/e 319 (retention time: 2.20, method A).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:20][NH2:21]>C(Cl)Cl.CN(C=O)C.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([NH:21][CH3:20])=[O:6]
Reactant: CN
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-5-nitrobenzoic acid (17.7 g) and oxalyl chloride (2 equiv.) in 250 mL of anhydrous CH2Cl2 was added a few drops of DMF, and the mixture was stirred for 2 hrs at room temperature. It was concentrated in vacuo, then reconcentrated in vacuo twice from 400 mL of toluene to remove excess oxalyl chloride. The residue was dissolved in 100 mL of anhydrous THF. In a separated flask methylamine (3 equiv.) was dissolved in 100 ml of anhydrous THF and cooled to 0° C. Then the acid chloride solution was added dropwise, causing a white solid to precipitate. The mixture was allowed to stir at room temperature for 16 hrs, and the solids were removed by filtration. The filtrate was concentrated in vacuo to provide a white solid, which was triturated with diethyl ether, collected by filtration to yield 3-bromo-N-methyl-5-nitrobenzamide. NMR (300 MHz, DMSO-d6) δ 9.92 (m, 1H), 8.64 (s, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 2.81 (d, 3H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.CN(C)C=O.C(N(CC)CC)C.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[S:28]>O>[Cl:1][C:2]1[C:3]([C:27](=[S:28])[N:26]([CH3:30])[CH3:25])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: CN(C)C(=S)Cl
Reactant: Oc1ccc2ccncc2c1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=S)c1ccc2ccncc2c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (122 g., 0.68 m.) 8-chloro-7-hydroxyisoquinoline in 180 ml. of dimethylformamide was added (450 g., 4.5 m.) triethylamine followed by (140 g., 0.87 m) dimethylthiocarbamoyl chloride. The mixture was stirred for four hours at room temperature and then poured into 5400 ml. of water. The resulting solid was collected by filtration, dried, dissolved in chloroform, dried with sodium sulfate and evaporated to yield 8-chloro-7-dimethylthiocarbamoylisoquinoline.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][C@@H:11]([NH2:14])[CH2:10]2)=[CH:6][CH:5]=1.[CH2:17]([O:19][C:20](=[O:29])[C:21]1[CH:26]=[C:25]([Cl:27])[C:24](Cl)=[N:23][CH:22]=1)[CH3:18].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[Cl:27][C:25]1[C:24]([NH:14][C@@H:11]2[CH2:12][CH2:13][N:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:16][CH:15]=3)[CH2:10]2)=[N:23][CH:22]=[C:21]([CH:26]=1)[C:20]([O:19][CH2:17][CH3:18])=[O:29]
Reactant: N[C@@H]1CCN(Cc2ccc(F)cc2)C1
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(N[C@@H]2CCN(Cc3ccc(F)cc3)C2)c(Cl)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of (3R)-1-(4-fluorobenzyl)-3-pyrrolidinamine dihydrochloride (3.5 g) in DMF (35 ml) was added 5,6-dichloronicotinic acid ethyl ester (3.38 ml) and K2CO3 (6.34 g), the mixture was stirred at 100° C. for 4 hours under N2 atmosphere. The mixed solution was poured into a mixture of water (250 ml) and AcOEt (250 ml). The organic layer was separated, washed with water twice and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt:hexane=1:2 to give ethyl 5-chloro-6-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}nicotinate (3.75 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH:11]([OH:13])[C:10]2[CH:14]=[CH:15][S:16][C:9]=2[S:8]1(=[O:18])=[O:17])[CH3:2].[CH:19]([O:21][CH2:22][CH3:23])=[CH2:20].C(=O)(O)[O-].[Na+]>C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:19]([O:21][CH:22]([O:13][CH:11]1[C:10]2[CH:14]=[CH:15][S:16][C:9]=2[S:8](=[O:17])(=[O:18])[N:7]([CH2:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH2:12]1)[CH3:23])[CH3:20]
Reactant: C=COCC
Reactant: CCOCCCN1CC(O)c2ccsc2S1(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCCCN1CC(OC(C)OCC)c2ccsc2S1(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
A solution of the product from Step B (13.0 g, 44.77 mmol) and p-toluenesulfonic acid (0.20 g) in THF (250 mL) was cooled in an ice bath and ethyl vinyl ether (4.7 mL, 49.24 mmol) was added slowly; this mixture was stirred at room temperature for 18 hr. Sodium bicarbonate (2.0 g) was added and the mixture stirred for 30 min, washed with water (3×75 mL), saturated aqueous sodium chloride (100 mL) and dried (MgSO4). The mixture was evaporated to a residue which was filtered through silica gel with 3:1 hexane/ethyl acetate to give a pale yellow oil (7.53 g, 46%) which was used in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(CC(F)(F)C(F)F)c1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(CC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
While stirring zinc chloride (1.22 g, 8.92 mmol) in diethyl ether (30 ml), sodium borohydride (0.68 g, 17.8 mmol) was added at room temperature, and the mixture was stirred as it was for 2 hrs. Insoluble material in the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. A solution of ethyl 3-(4-fluorophenyl)-2-[3-(2,2,3,3-tetrafluoropropyl)benzyl]-3-oxopropionate (1.849 g, 4.462 mmol) in diethyl ether (20 ml) was added to the obtained solution under ice-cooling, and the mixture was stirred as it was for 20 min. To the reaction solution was added dilute hydrochloric acid by small portions to decompose excess zinc borohydride, and the mixture was extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give the objective substance.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24]4[CH:27]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=5)[S:29][C:23]=4[C:22]3=[O:37])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.Cl.O1CCOCC1>ClCCl>[ClH:36].[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:28]2[S:29][C:23]3[C:22](=[O:37])[N:21]([C:18]4[CH:17]=[N:16][C:15]([O:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:20][CH:19]=4)[CH2:26][CH2:25][C:24]=3[CH:27]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N3CCc4cc(-c5ccc(Cl)cc5)sc4C3=O)cn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: O=C1c2sc(-c3ccc(Cl)cc3)cc2CCN1c1ccc(OC2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add 4-{5-[2-(4-chloro-phenyl)-7-oxo-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-pyridin-2-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (5.41 g, 10.02 mmol) to a solution of 1:1 MeOH:dichloromethane (80 mL). Then add 4M HCl in dioxane (18.53 mL, 74 mmol) and stir at RT overnight. Filter the reaction and wash with dichloromethane. Dry thoroughly to yield the title compound quantitatively. MS/ES m/z (35Cl) 440.0 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[C:22]1[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:23]=1[O:31][CH3:32])(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[CH:28]([C:26]1[CH:25]=[CH:24][C:23]([O:31][CH3:32])=[C:22]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]=2[CH2:11][NH:10][CH2:9][C@@H:8]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH2:7])[CH:27]=1)([CH3:30])[CH3:29]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNC[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNC[C@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl[(1R)-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)-1-phenylethyl]carbamate (150 mg, 0.277 mmol) containing minor impurities in CH2Cl2 (10 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 2 hours and then poured into 1 N NaOH (25 mL). The mixture was extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by flash chromatography with 0 to 10% MeOH/CH2Cl2 afforded (1R)—N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1-phenylethane-1,2-diamine. Rf=0.27 (10% MeOH/CH2Cl2). LCMS=443.4 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]2[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:13]=[C:14]([CH2:15][C:16]([O:18]C)=[O:17])[C:3]1=2.[OH-].[Na+].Cl>CO>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]2[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:13]=[C:14]([CH2:15][C:16]([OH:18])=[O:17])[C:3]1=2
Reactant: COC(=O)Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=O)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of methyl 2-[4-oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinolin-3-yl]acetate (5.47 g, 16.4 mmol) in methanol (150 mL), an aqueous 2N sodium hydroxide solution (15 mL) was added at 0° C., and the mixture was stirred at room temperature for 2 hours, and refluxed further for 3 hours. The solution was allowed to cool to room temperature, made acidic by the addition of an aqueous 2N hydrochloric acid solution, and the resulting precipitate was collected by filtration. The collected crude crystals were washed with water and dried to give the title compound (4.96 g, 95% yield).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:13])[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C(=O)N=C=O)(c1ccccc1)c1ccccc1
Reactant: OCCCCc1ccccc1
Product: CC(C(=O)NC(=O)OCCCCc1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound, yellow oil, MS: m/e=401.5 (M+H+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl isocyanate and 4-phenyl-butan-1-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][N:3]=1.[Cl:12][S:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])(=[O:15])=[O:14]>>[CH:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]([C:19]([C:18]2[CH:17]=[C:16]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:24]=[CH:23][CH:22]=2)=[O:20])[C:19]([C:18]2[CH:17]=[C:16]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:24]=[CH:23][CH:22]=2)=[O:20])=[N:3][CH:4]=1)([CH3:11])[CH3:10]
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)Oc1ccc(N)nc1
Product: CC(C)Oc1ccc(N(C(=O)c2cccc(S(=O)(=O)Cl)c2)C(=O)c2cccc(S(=O)(=O)Cl)c2)nc1

Procedure:
The entitled compound was produced according to the method of Reference Example 5 but using 2-amino-5-isopropoxypyridine and 3-(chlorosulfonyl)benzoyl chloride as the starting materials.
Reaction SMILES: S(O[C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:21]2[CH:26]=[CH:25][C:24](OS(C)(=O)=O)=[C:23]([N+:32]([O-:34])=[O:33])[CH:22]=2)([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])=[CH:8][C:7]=1[N+:35]([O-:37])=[O:36])(C)(=O)=O.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(#N)C>[NH:38]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([NH:32][C:23]3[CH:24]=[CH:25][CH:26]=[CH:21][CH:22]=3)=[C:23]([N+:32]([O-:34])=[O:33])[CH:22]=2)([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])=[CH:8][C:7]=1[N+:35]([O-:37])=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Nc1ccccc1
Reactant: CS(=O)(=O)Oc1ccc(C(c2ccc(OS(C)(=O)=O)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(C(c2ccc(Nc3ccccc3)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)ccc1Nc1ccccc1
Yield: 159.3 %

Procedure:
A solution of 60 g (0.103 mol) of 2,2-bis-(4-mesyloxy-3-nitrophenyl)-hexafluoropropane and 122.8 g (1.32 mol) of aniline in 400 ml of acetonitrile is heated under reflux for 24 hours. In the course of this the methanesulfonic acid salt of aniline is precipitated, and is removed by filtration with suction. The filtrate is freed from the solvent and from excess aniline by distillation under reduced pressure. Recrystallizing the residue from ethanol gives 47.3 g of 2,2-bis-(4-anilino-3-nitrophenyl)-hexafluoropropane (80% yield). M.p. 165-166° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][C@H:10]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]([NH:13][NH:14][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.S(Cl)(Cl)=O>CCOCC.C1COCC1>[CH2:20]([O:19][C:17]([C:15]1[O:16][C:11]([C@H:10]([NH:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:13][N:14]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C(=O)NNC(=O)[C@@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nnc([C@@H](Cc2ccccc2)NCC(=O)OC(C)(C)C)o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
1-((2R)-2-((tert-Butoxycarbonyl)methylamino)-3-phenylpropionyl)-2-ethoxycarbonylformylhydrazine (1.4 g, 3.55 mmol) was dissolved in ether (25 ml) and THF (10 ml). Pyridine (1.44 ml 17.75 mmol) was added, and the solution was cooled to 0° C. Thionyl chloride (0.3 ml, 3.90 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 2 h. The precipitation was filtered off. The solvent was removed in vacuo without warming. The residue was dissolved in toluene (25 ml) and the solution was warmed to reflux for 2 h. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (70 g) with ethyl acetate/dichloromethane 1:2 to give 721 mg of 5-((1R)-1-((tert-butoxycarbonyl)methylamino)-2-phenylethyl)-[1,3,4]oxadiazole-2-carboxylic acid ethylester.
Reaction SMILES: C(O[C:4](=[O:22])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Br:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:22])[C:18]2[C:13](=[C:14]([Br:21])[CH:15]=[CH:16][C:17]=2[O:19][CH3:20])[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1cc(OC)ccc1Br)C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2c(Br)ccc(OC)c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
2-[(2-Bromo-5-methoxy-phenylamino)-methylene]-malonic acid diethyl ester (9 g, 24.2 mmol) was slowly added to polyphosphoric acid (30 g) at 120° C. The mixture was stirred at this temperature for additional 30 min and then cooled to room temperature. Absolute ethanol (30 mL) was added and the resulting mixture was refluxed for 30 min. The mixture was basified with aqueous sodium bicarbonate at 25° C. and extracted with EtOAc (4×100 mL). The organic layers were combined, dried and the solvent evaporated to give 8-bromo-5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (2.3 g, 30%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>C(O)(=O)C>[N:15]1[CH:16]=[CH:17][C:12]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:14]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Clc1ccncc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(Nc2ccncc2)cc1

Procedure:
4-(4-Pyridinylamino)benzoic acid was prepared from 76.6 g of 4-aminobenzoic acid and 63.5 g of 4-chloropyridine in 240 ml of acetic acid, heated at reflux for 6 hours. With a work-up procedure similar to that of Example 33, there was obtained 50 g of product with the m.p. 322°-324° C.(decompn.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:13])[CH:10]([CH3:12])[CH3:11].Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:16]=1.CC(C)([O-])C.[Na+].Cl>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O>[C:26]([O:25][C:23]([NH:22][C:17]1[CH:16]=[C:15]([C:10]([CH3:12])([CH3:11])[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:13])[CH:20]=[CH:19][C:18]=1[F:21])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1ccccc1C(=O)C(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)C(C)(C)c1ccc(F)c(NC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
A mixture of 1-(2-methoxyphenyl)-2-methyl-1-propanone (0.58 g), 4-bromo-2-(tert-butoxycarbonylamino)-1-fluoro -benzene (0.94 g), palladium(II) acetate (37 mg), tri(tert -butyl)phosphine tetrafluoroborate (47 mg) and sodium tert-butoxide (0.78 g) in tetrahydrofuran (10 mL) was stirred at 60° C. under an argon atmosphere overnight. To the reaction mixture was added water, and the mixture was stirred for 10 minutes. The mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=95/5−85/15) to give 2-[3-(tert-butoxycarbonylamino)-4-fluorophenyl]-1-(2-methoxyphenyl)-2-methyl-1-propanone (0.91 g). To the obtained 2-[3-(tert-butoxycarbonylamino)-4-fluorophenyl]-1-(2-methoxyphenyl)-2-methyl-1-propanone (0.34 g) was added hydrochloric acid (4 mol/L ethyl acetate solution, 3 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the title compound (0.22 g).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:32]=[CH:33][C:34]=1[O:35]C(=O)C)[CH:8]=[CH:9][C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])=[CH:20][C:19]([CH3:30])=[CH:18][C:17]=2[CH3:31])=[O:11])(=O)C.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1CO.O.Cl>O>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]1[C:21]2[C:16](=[C:17]([CH3:31])[CH:18]=[C:19]([CH3:30])[CH:20]=2)[N:15]=[CH:14][C:13]=1[NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[CH:32]=[CH:33][C:34]([OH:35])=[C:5]([OH:4])[CH:6]=1
Reactant: CC(=O)Oc1ccc(C=CC(=O)Nc2cnc3c(C)cc(C)cc3c2-c2ccccc2Cl)cc1OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: OCC1COCCO1
Solvent: O
Product: Cc1cc(C)c2ncc(NC(=O)C=Cc3ccc(O)c(O)c3)c(-c3ccccc3Cl)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
A mixture of 3-(3,4-diacetoxycinnamoylamino)-4-(2-chlorophenyl)-6,8-dimethylquinoline (4.0 g), potassium carbonate (3.13 g) and dioxane-methanol-water (2:2:1, 50 ml) was stirred at room temperature for 3 hours in a stream of argon gas, then diluted with water. After being adjusted to pH 4 by addition of 2N hydrochloric acid, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was removed, and the residue was crystallized from isopropyl ether to give crystals of 4-(2-chlorophenyl)-3-(3,4-dihydroxycinnamoylamino)-6,8-dimethylquinoline (2.7 g, 80.4%). The crystals were recrystallized from ethyl acetate to afford pale yellowish prisms.