Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C@@H:14]([CH2:25][S:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(N(CC)CC)C.[NH2:47][C@@H:48]1[CH2:63][C:62]2=[CH:64][CH:65]=[C:59]([CH:60]=[CH:61]2)[O:58][CH2:57][CH2:56][CH2:55][CH2:54][O:53][CH2:52][C@H:51]([CH:66]([CH3:68])[CH3:67])[NH:50][C:49]1=[O:69]>CN(C=O)C>[CH2:33]([O:32][C:30]([NH:29][CH2:28][CH2:27][S:26][CH2:25][C@H:14]([NH:13][C:1]([NH:47][C@@H:48]1[CH2:63][C:62]2=[CH:61][CH:60]=[C:59]([CH:65]=[CH:64]2)[O:58][CH2:57][CH2:56][CH2:55][CH2:54][O:53][CH2:52][C@H:51]([CH:66]([CH3:67])[CH3:68])[NH:50][C:49]1=[O:69])=[O:2])[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])=[O:31])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](N)C(=O)N1
Reactant: N[C@@H](CSCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CSCCNC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
A solution of 166 mg (1.02 mmol) of 1,1′-carbonyldiimidazole in 8 ml of DMF was mixed with 515 mg (1.02 mmol) of the trifluoroacetate from step B and 0.57 ml (415 mg, 4.10 mmol) of triethylamine. A solution of 328 mg (1.02 mmol) of (9S,12R)-12-amino-9-isopropyl-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-11-one (1-1E) in 8 ml of DMF was added to this mixture under argon, and the mixture was stirred at RT overnight. The reaction mixture was then concentrated and separated by preparative HPLC. The required fractions were combined and freed of acetonitrile. The resulting aqueous solution was extracted with ethyl acetate, and the organic phase was dried over sodium sulfate, filtered and concentrated. 222 mg of the title compound were obtained.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][C:6]=1[C:15]([C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:15]([C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][CH:21]=1)=[O:16])=[C:5]2[CH2:4][C:3]([OH:23])=[O:2]
Reactant: COC(=O)Cc1c(C(=O)c2cccn2C)[nH]c2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cn1cccc1C(=O)c1[nH]c2ccc(Cl)cc2c1CC(=O)O
Temperature: 25 °C
Yield: 16 %

Procedure:
A mixture of methyl[5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetate (Example 251, 250 mg, 0.79 mmol) and potassium carbonate (900 mg, 6.4 mmol) in methanol-water (1:1, 40 ml) was heated at reflux temperature for 1 h. After cooling to room temperature, the mixture was concentrated. The residue was neutralized with 2N aqueous HCl and extracted with ethyl acetate (50 ml×2) The combined extracts were dried (MgSO4) and concentrated. The residual solids were recrystallized from ethyl acetate/hexane to afford 40 mg (23%) of the title compound as pale yellow solids.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][CH2:19]O)[C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:23]>>[ClH:23].[CH2:1]([N:8]([CH2:18][CH2:19][Cl:23])[C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1N(CCO)Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: Cl
Product: NC(=O)c1ccccc1N(CCCl)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[Benzyl(2-hydroxyethyl)amino]benzamide (10 g) was added at 0° to 50 ml SOCl2, stirred 71/2 hours at room temperature and left overnight. The mixture was concentrated on the rotovap, ethyl acetate added and the solid filtered to give 11 g product, m.171-4°.
Reaction SMILES: [OH-].[Na+].C[C@:4]1([C:16]([O-:18])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C1COCC1.CO>[C:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@@H:4]1[C:16]([OH:18])=[O:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC[C@]1(C)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 8 h
Yield: 64 %

Procedure:
1N NaOH (1.2 ml, 1.2 mmol, 1.2 eq) was added to a stirred solution of (R)-1-tert-butyl 2-methylpyrrolidine-1,2-dicarboxylate (0.267 g, 1.0 mmol, 1 eq) in 4 ml of 3:1 THF/MeOH. After stirring overnight the solvent was removed in vacuo. The residue was dissolved in saturated aqueous NaHCO3 and extracted with Et2O (×2). The aqueous layer was adjusted to pH {tilde over ( )} 4 with 1N HCl and extracted with EtOAc (×4). The combined EtOAc fractions were dried over Na2SO4. The inorganics were filtered off, and the solvent removed in vacuo yielding 0.1615 g (0.64 mmol, 64% yield) of (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid.
Reaction SMILES: [H-].[Na+].[C:3]([O:8][CH2:9][CH3:10])(=O)[CH:4]([CH3:6])O.[C:11](#[N:14])C=C.[OH2:15]>O1CCCC1>[C:11]([CH:4]1[CH2:3][O:8][CH:9]([CH3:10])[C:6]1=[O:15])#[N:14]
Reactant: C=CC#N
Reactant: CCOC(=O)C(C)O
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1OCC(C#N)C1=O
Yield: 89 %

Procedure:
8.7 g (0.2 mol) of sodium hydride are suspended in 100 ml of tetrahydrofuran and the suspension is stirred at room temperature for 90 minutes with 23.6 g (0.2 mol) of ethyl lactate. 9.5 g (0.18 mol) of acrylonitrile are then added dropwise at 60° C. and the mixture is refluxed for 90 minutes. The mixture is poured into 200 ml of water and washed twice with 100 ml of ether each time. The aqueous phase is adjusted to pH 1 with 2-N hydrochloric acid and extracted three times with 150 ml of ether each time. The dried and concentrated ether phases give 20.1 g (89%) of 4-cyano-2-methyltetrahydrofuran-3-one of boiling point 116°-118° C./14 mmHg; IR: 2250 (CN), 1780 (C=O); NMR (CDCl3): 1.37 ppm doublet (CH3); 3.4-4.9 ppm multiplet.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:24][C:23](=O)[O:22][C:20](=[O:21])[CH2:19]2)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH2:24][C:23]2[NH:10][C:4]3[CH:3]=[C:2]([F:1])[C:7]([F:8])=[CH:6][C:5]=3[N:9]=2)[CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:17]=1.[ClH:11]
Reactant: Nc1cc(F)c(F)cc1N
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Product: Cl
Product: O=C(O)CC(Cc1nc2cc(F)c(F)cc2[nH]1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.4, starting from commercial 4,5-difluoro-1,2-phenylenediamine and 3-(4-chlorophenyl)glutaric anhydride, 3-(4-chlorophenyl)-4-(5,6-difluoro-2-benzimidazolyl)butanoic acid•HCl was obtained as light greyish solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][C:10]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])=[C:11]([Cl:13])[CH:12]=1)[CH3:2].[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:14]([C:17]#[N:18])([CH3:15])[CH3:16])=[C:11]([Cl:13])[CH:12]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1cnc(C(C)(C)C#N)c(Cl)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCc1cnc(C(C)(C)C#N)c(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of 3-[5-chloro-6-(cyano-dimethyl-methyl)-pyridin-3-yl]-acrylic acid ethyl ester (0.74 g, 2.65 mmol) from step 3 above was added ethanol (10 mL) and Pd(OH)2/C (0.37 g). The reaction was placed under a hydrogen atmosphere using a balloon filled with hydrogen. The slurry was stirred vigorously for 1 hour. The reaction was filtered to remove all of the solids, and the liquid was concentrated to an white solid which was used in next reaction without further purification. 1H NMR (400 MHz, CDCl3): δ 1.25 (t, J=7.7 Hz, 3 H), 1.85 (s, 6 H), 2.62-2.66 (m, 2 H), 2.92-2.98 (m, 2H), 4.15 (q, J=14, 7.7 Hz, 2 H), 7.61 (d, J=2 Hz, 1 H), 8.3 (d, J=2 Hz, 1 H). ESIMS (MH+): 289.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:8]([Cl:14])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=O)C>Cl>[NH2:4][C:5]1[CH:6]=[C:7]([C:15]([F:18])([F:16])[F:17])[C:8]([Cl:14])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Product: Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]

Procedure:
A mixture of 3-acetamido-6-chloro-4-nitrobenzotrifluoride (780 mg, 2.76 mmol) in concentrated HCl (3 mL) was refluxed overnight and it was extracted by ethyl acetate (2×3 mL). The extract was dried over Mg2SO4 and evaporated to give 517 mg (78%) of 3-amino-6-chloro-4-nitrobenzofluoride. 1H NMR (CDCl3): δ6.205 (s, 2H); 7.206 (s, 1H); 8.263 (s, 1H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13](=[O:20])[C:14](=[N+:18]=[N-:19])[C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:21][OH:22].C(Cl)(Cl)Cl.O>C(N(CC)CC)C>[N+:18](=[C:14]([C:15](=[O:17])[CH3:16])[C:13](=[O:20])[CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([O:22][CH3:21])(=[O:4])=[O:3])=[CH:6][CH:7]=1)=[N-:19]
Reactant: CO
Reactant: CC(=O)C(=[N+]=[N-])C(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COS(=O)(=O)c1ccc(CCC(=O)C(=[N+]=[N-])C(C)=O)cc1

Procedure:
6-(4-Chlorosulfonylphenyl)-3-diazo-2,4-hexanedione (2.0 g, 6.4 mmol) obtained in Example 3, (3) was stirred in triethylamine (1.5 ml), methanol (2.5 ml) and chloroform (8 ml) for 6 h at 10°-15° C., then the mixture was poured into H2O and extracted thrice with chloroform. The organic extract was washed with H2O, dried over anhydrous MgSO4 and evaporated under reduced pressure. The residue was chromatographed on silica gel (Wako Gel C-200, manufactured by Wako Pure Chemical Industries, Ltd.) with chloroform as eluent to give the title compound as a pale yellow viscous oil; yield: 730 mg.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:8][C:7]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:6]1.[Li+].[OH-].Cl>O1CCOCC1.O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[N:5]([CH2:4][C:3]([OH:24])=[O:2])[N:6]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.3 %

Procedure:
30.8 g of (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid methyl ester was dissolved in 250 mL dioxane and a solution of 2.4 g LiOH in 250 mL of water was added. The mixture was stirred for 24 h at RT. Then, HCl-solution was added and the precipitate was filtered to give 29 g of the desired product. Rt: 1.28 min (method B), (M+H)+: 316
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[N:34]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.O>CN(C)C=O>[OH:16][CH:15]([CH2:17][N:42]1[CH2:43][CH2:44][CH:39]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:40][CH2:41]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC1CO1
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC(O)CN1CCC(N2CCCC2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (39 mg) and 4-(1-pyrrolidinyl)piperidine (41 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (38 mg, yield 73%).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:17])[C:13]=1[C:14]([NH2:16])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>O>[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:17])[C:13]=1[C:14](=[S:19])[NH2:16]
Reactant: NC(=O)c1c(Cl)cncc1Cl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: NC(=S)c1c(Cl)cncc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
Into a 3000-mL three-necked round bottom flask equipped with a condenser, mechanical stirrer under an atmosphere of nitrogen was added pyridine (1500 mL), then 3,5-dichloro-4-pyridine-carboxamide (92.9 g., 0.486 mole) (which dissolved), and tetraphosphorus decasulfide (237 g., 0.535 moles)(which had almost dissolved then a bright yellow precipitate formed and an exotherm heated the mixture to 60° C.). The slurry was allowed to stir for 1 hr (temperature had dropped to 45° C.) and then the temperature was then raised and when it reached 100° C. all of the solids had dissolved and continued heating to 118° C. and was maintained at 115° C. for 4 hr. The mixture was poured into water (3750 mL) carefully as gas began to evolve and the temperature of the aqueous solution rose to approximately 45° C. and was allowed to sit at room temperature over two nights. To the resulting mixture was added water (6000 mL) and was extracted with methylene chloride (3×2000 mL), washed with water (3×1000 mL) and the solvent removed in vacuo to give a brownish yellow liquid, with much pyridine present. The vacuum pump was connected to the rotary evaporator to remove the residual pyridine. The residue (brown solid) was triturated with diethyl ether (3×1500 mL), treated with decolorizing carbon and the solvent removed in vacuo to give a solid which contained pyridine. The yellow solid was slurried in water (2×200 mL) and dried in vacuo at 60° C. to give 63.2 g of a light yellow solid (62.8% yield): mp 186-187° C.; TLC[50/50 ethyl acetate/hexanes] showed amide at Rf=0.31 and thioamide Rf=0.53; 1H NMR (DMSO-d6) d 10.6 (s, b, 1H), 10.0 (s, b, 1H), 8.6 (s, 2H).
Reaction SMILES: Cl.[Br-].[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[C:17]3=[C:18]([CH2:21][N+](CC)(CC)CC)[CH:19]=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[F:10].Cl.[Cl:30][CH2:31][CH2:32][NH:33][CH2:34][CH2:35][Cl:36].CCN(C(C)C)C(C)C>CC#N>[Cl:30][CH2:31][CH2:32][N:33]([CH2:21][C:18]1[CH:19]=[CH:20][N:16]2[C:17]=1[C:12]([NH:11][C:6]1[CH:7]=[CH:8][C:9]([F:10])=[C:4]([Cl:3])[CH:5]=1)=[N:13][CH:14]=[N:15]2)[CH2:34][CH2:35][Cl:36]
Reactant: CC[N+](CC)(CC)Cc1ccn2ncnc(Nc3ccc(F)c(Cl)c3)c12
Reactant: ClCCNCCCl
Agent: Cl
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Fc1ccc(Nc2ncnn3ccc(CN(CCCl)CCCl)c23)cc1Cl
Temperature: 60 °C

Procedure:
A mixture of Compound 1E (50 mg, 0.1 mmol), bis-(2-chloroethyl)amine hydrochloride (18 mg, 0.1 mmol), DIEA (36 μl, 0.2 mmol) in CH3CN (0.5 ml) was heated to 60° C. for 3 h. The mixture was cooled to rt and concentrated to give Compound 133A which was used directly in next step. 133A had an analytical HPLC retention time=2.986 min. (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=416.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:51][CH2:52][C:53]([F:56])([F:55])[F:54])=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[O:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[Cl:67][C:68]1[CH:69]=[C:70]([CH:79]([CH3:81])[CH3:80])[C:71]2[O:75][C:74]([SH:76])=[N:73][C:72]=2[C:77]=1[CH3:78]>>[Cl:67][C:68]1[CH:69]=[C:70]([CH:79]([CH3:81])[CH3:80])[C:71]2[O:75][C:74]([S:76][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]4[C:39]([O:51][CH2:52][C:53]([F:54])([F:55])[F:56])=[N:40][C:41]([CH3:50])=[CH:42][C:43]=4[O:44][CH2:45][C:46]([F:48])([F:47])[F:49])=[O:36])[CH2:30][CH2:29]3)=[N:73][C:72]=2[C:77]=1[CH3:78]
Reactant: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCO)CC2)c(OCC(F)(F)F)n1
Reactant: Cc1c(Cl)cc(C(C)C)c2oc(S)nc12
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCSc3nc4c(C)c(Cl)cc(C(C)C)c4o3)CC2)c(OCC(F)(F)F)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole, to thereby yield the title compound as a colorless crystalline powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[S:39](Cl)(=[O:41])=[O:40]>>[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][N:23]([S:39]([C:30]4[CH:31]=[CH:32][C:33]5[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:29]=4)(=[O:41])=[O:40])[CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc5ccccc5c4)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B5*HCl) and naphthalene-2-sulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:19])=[CH:4][C:5]([CH3:18])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[CH:7]=1.[C:20]([O:23]C(=O)C)(=O)[CH3:21].[N+:27]([O-])([OH:29])=[O:28]>CC(O)=O>[Cl:1][C:2]1[C:3]([NH:19][C:20](=[O:23])[CH3:21])=[C:4]([N+:27]([O-:29])=[O:28])[C:5]([CH3:18])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:16])([F:17])[F:15])[CH:7]=1
Reactant: Cc1cc(N)c(Cl)cc1-c1ccccc1C(F)(F)F
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)Nc1c(Cl)cc(-c2ccccc2C(F)(F)F)c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
5-Chloro-2-methyl-2′-trifluoromethyl-biphenyl-4-ylamine (384 mg, 1.34 mmol, as prepared in the previous step) was placed in a 50 mL round-bottom flask equipped with a magnetic stir bar. Acetic anhydride (1.5 mL) was added. The mixture was stirred at rt for 1 h and then cooled to 0° C. To a 4 mL vial cooled at 0° C. was added AcOH (0.27 mL), acetic anhydride (0.31 mL), and nitric acid (0.45 mL). The nitrating mixture was added dropwise via pipette to the above-prepared solution, maintaining the temperature below 10° C. Upon completion of the addition, the mixture was stirred at 0° C. for 1 hour and poured onto ice. The resulting precipitate was isolated by filtration, washed with water, and dissolved in EtOAc. The solution was dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography using a 40-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 3:7, v/v over 30 min, yielding 301 mg (60%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 7.80 (d, J=7.8 Hz, 1H), 7.54-7.68 (m, 2H), 7.50 (s, 1H), 7.43 (s, 1H), 7.25 (d, J=7.6 Hz, 1H), 2.21 (s, 3H), 1.98 (s, 3H).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Cl:8][C:9]1[S:13][C:12]([S:14]([NH:17][C@H:18]([C:24]([OH:26])=[O:25])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])(=[O:16])=[O:15])=[CH:11][CH:10]=1>C1COCC1.CO>[CH3:1][O:25][C:24](=[O:26])[C@H:18]([CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])[NH:17][S:14]([C:12]1[S:13][C:9]([Cl:8])=[CH:10][CH:11]=1)(=[O:15])=[O:16]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCC(CC)[C@H](NS(=O)(=O)c1ccc(Cl)s1)C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)[C@H](NS(=O)(=O)c1ccc(Cl)s1)C(=O)OC
Yield: 94.9 %

Procedure:
Trimethylsilyldiazomethane (3.1 mL, 6.1 mmol) was added to a solution of N-[(5-chloro-2-thienyl)sulfonyl]-3-ethyl-L-norvaline (1.0 g, 3.1 mmol) in THF (20 mL) and MeOH (5 mL). After 2 h the mixture was concentrated to give N-[(5-chloro-2-thienyl)sulfonyl]-3-ethyl-L-norvaline methyl ester as a white solid (1.0 g, 99%). Mass Spectrum (−ESI): 338.00 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH:22]([O:25][CH2:26][CH2:27][CH2:28][NH2:29])([CH3:24])[CH3:23]>ClCCl>[CH:22]([O:25][CH2:26][CH2:27][CH2:28][NH:29][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: CC(C)OCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OCCCNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 25 °C
Yield: 84.5 %

Procedure:
4-Chloro-3-nitro[1,5]naphthyridine (4.1 g), dichloromethane (150 mL), triethylamine (4.1 mL, 29.5 mmol), and 3-isopropoxypropylamine (3.3 mL, 23.8 mmol) were combined. The reaction mixture was maintained at ambient temperature overnight and then quenched with water (100 mL). The phases were separated. The aqueous phase was extracted with dichloromethane (100 mL). The organic phases were combined, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide a yellow oil. The oil was purified by flash chromatography (silica gel eluting with 1:1 ethyl acetate:hexanes) to provide 4.8 g of N4-(3-isopropoxypropyl)-3-nitro[1,5]naphthyridin-4-amine as a yellow powder, m.p. 62.5-63.5° C. Analysis: Calculated for C14H18N4O3: %C, 57.92; %H, 6.25; %N, 19.30; Found: %C, 57.96; %H, 6.19; %N, 19.51. 1H NMR (300 MHz, CDCl3): δ 10.08 (broad s, 1H), 9.38 (broad s, 1H), 8.78 (m, 1H), 8.21 (dd, J=8.4,1.6 Hz, 1H), 7.64 (dd, J=8.4,4.1 Hz, 1H), 4.57 (broad s, 2H), 3.65-3.57 (m, 3H), 2.05 (t, J=5.6 Hz, 2H), 1.19 (d, J=6.0 Hz, 6H); MS (EI): m/e 290.1366 (290.1378 calc'd for C14H18N4O3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12]O[CH:10]=2)=[CH:5][CH:4]=1.[NH3:18].O>>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12][NH:18][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2coccc2=O)cc1
Reactant: N
Solvent: O
Product: COc1ccc(COc2c[nH]ccc2=O)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A suspension of 3-[(4-methoxybenzyl)oxy]-4H-pyran-4-one (6.2 g, 26.7 mmol) and 120 mL of NH3.H2O was sealed in a glass tube, and the mixture was stirred at 100° C. After 18 h, the reaction mixture was filtered and the collected solid was washed with MeOH to give 3-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one. 1H-NMR (DMSO, 400 MHz) δ 11.27 (s, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.30 (dd, J=8.4, 2.8 Hz, 2H), 6.90 (m, 2H), 6.13 (s, 1H), 4.8(s, 2H), 3.72 (s, 3H). MS (M+H)+ 232.0.