Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=3)=[N:7][C:6]=12.[CH2:25]([Sn](CCCC)(CCCC)C=C)[CH2:26]CC.C([O-])([O-])=O.[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C.C1COCC1.O.ClCCl.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>[C:11]1([C:9]2[C:8]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=3)=[N:7][C:6]3[N:5]([N:4]=[CH:3][C:2]=3[CH:25]=[CH2:26])[CH:10]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=Cc1ccc(-c2nc3c(Br)cnn3cc2-c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: C=Cc1cnn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc12

Procedure:
400 mg 4-(3-bromo-6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (prepared as described above), 504 mg tributyl(vinyl)stannane, 176 mg tetraethylammonium chloride, 147 mg K2CO3 and 19 mg Pd(PPh3)2Cl2 were suspended in 10 mL THF under a nitrogen atmosphere. The mixture was heated (microwave irradiation) to 110° C. for 45 min. This mixture was worked up by diluting with water and extraction with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated to yield the crude product, which was purified by chromatography on silica gel (ethyl acetate/dichloromethane).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCC(C(OCC)=O)C1.[F:31]C1C=CC(C(Cl)=O)=CC=1>>[F:31][C:5]1[CH:4]=[CH:3][C:2]([C:1]([N:9]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[O:8])=[CH:7][CH:6]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Agent: CCOC(=O)C1CCCNC1
Product: CCOC(=O)C1CCCN(C(=O)c2ccc(F)cc2)C1

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with ethyl nipecotate (230.9 mg; 1.47 mmol) and commercially available 4-fluorobenzoyl chloride (173 μl; 1.47 mmol). The crude product was distilled at 220° C./0.1 torr, giving ethyl 1-(4-fluorobenzoyl)-3-piperidinecarboxylate (283.4 mg) as a light yellow oil. MS m/z (positive ion) 581 (dimer+Na+; 50), 302 (M+Na+; 100), 280 (MH+; 95), 234 (45), 229 (25), 158 (50), 122.5 (60).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].[F:15]C1C=CC=C([N+]([O-])=O)C=1C(O)=O>>[F:15][C:11]1[CH:2]=[CH:3][CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[C:6]=1[C:7]([NH:9][CH3:10])=[O:8]
Reactant: O=C(O)c1c(F)cccc1[N+](=O)[O-]
Reactant: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Product: CNC(=O)c1c(F)cccc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the procedure for Compound 102B (5-fluoro-N-methyl-2-nitrobenzamide) using 2-fluoro-6-nitrobenzoic acid. 1H NMR (CDCl3, 400 MHz): δ=3.09 (d, J=5.05 Hz, 3H), 7.45 (td, J=8.34, 1.01 Hz, 1H), 7.56 (td, J=8.27, 5.43 Hz, 1H), 7.94 (dt, J=8.08, 1.01 Hz, 1H). MS (ES+): m/z 199.05 [MH+] (TOF, polar).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[OH:27]>>[F:26][C:24]1[CH:23]=[CH:22][C:21]([OH:27])=[C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=1
Reactant: Nc1cc(F)ccc1O
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cc(F)ccc1O
Yield: 62.3 %

Procedure:
The product is prepared according to the procedure described in Stage 1 of Example 2, using 1 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 466 mg of 2-amino-4-fluorophenol in place of the 2,4-difluoroaniline. 795 mg of N-(5-fluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[CH3:9][S:10][C:11](SC)=[C:12]([C:16](=O)[CH3:17])[C:13](=[O:15])[CH3:14].C(OCC)(=O)C>[Cl-].[Na+].O>[CH3:17][C:16]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:8]=[C:11]([S:10][CH3:9])[C:12]=1[C:13](=[O:15])[CH3:14]
Reactant: NNc1ccccn1
Reactant: CSC(SC)=C(C(C)=O)C(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1nn(-c2ccccn2)c(C)c1C(C)=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of pyridin-2-yl-hydrazine (1.0 equivalent) and 3-(bis-methylsulfanyl-methylene)-pentane-2,4-dione (1.0 equivalent) was stirred at 60° C. overnight. To the reaction mixture was added ethyl acetate and brine, the organic phase was washed by brine twice, dried over magensium sulfate, and filtered. The organic solvent was removed under reduced pressure to provide the title compound.
Reaction SMILES: C([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]([OH:21])=O)=[CH:11][CH:10]=1)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CCSC)N.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:54][O:55][C:56](=[O:79])[C@H:57]([CH2:75][CH2:76][S:77][CH3:78])[N:58](C(=O)C1C=CC(N)=CC=1)[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60]>C(Cl)Cl.CCN(CC)CC>[CH3:54][O:55][C:56](=[O:79])[C@H:57]([CH2:75][CH2:76][S:77][CH3:78])[N:58]([C:19]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([NH2:8])=[CH:10][CH:11]=1)=[O:21])[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60]
Reactant: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)[C@@H](N)CCSC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)c2ccccc12
Yield: 63.6 %

Procedure:
N-BOC-4-amino-1-naphthoic acid (0.46 g, 1.60 mmol), methionine methyl ester hydrochloride (0.35 g, 1.76 mmol), EDCI (0.43 g, 1.76 mmol), HOBT (0.24 g, 1.76 mmol) and Et3N (0.27 ml) in CH2Cl2 (6.4 ml) were reacted as described for N-BOC-4-aminobenzoyl methionine methyl ester in Example 1. After workup and recrystallization from ethyl acetate and hexanes, 0.44 g (63.6%) of pale pink crystals were obtained. mp 131-132° C.; 1H NMR (CDCl3) 1.57 (9H, s), 2.11-2.21 (4H, m), 2.29-2.41 (1H, m), 2.65 (2H, t, J=7.1 Hz), 3.83 (3H, s), 4.99-5.06 (1H, m), 6.68 (1H, d, J=8.0), 7.02 (1H, s), 7.56-7.59 (2H, m), 7.69 (1H, d, J=7.9 Hz), 7.87-7.90 (1H, m), 8.02 (1H, d, J=7.9 Hz), 8.44-8.48 (1H, m); 13C NMR (CDCl3) 15.56, 28.31, 30.19, 31.65, 52.06, 52.64, 81.17, 115.82, 120.18, 125.79, 126.37, 126.53, 127.18, 131.02, 135.65, 152.93, 169.04, 172.40; HRMS calc. for C22H28N2O5S, 432.1719; found 432.1702; m/z (FAB) 433 (M+1).
Reaction SMILES: [CH3:1]I.[H-].[Na+].[F:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][CH2:17][CH:18]3[NH:21][C:22]3[CH:23]=[C:24]([CH:33]=[CH:34][CH:35]=3)[O:25][CH2:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1>CN(C)C=O>[F:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][CH2:17][CH:18]3[N:21]([CH3:1])[C:22]3[CH:23]=[C:24]([CH:33]=[CH:34][CH:35]=3)[O:25][CH2:26][C:27]([O:29][CH:30]([CH3:31])[CH3:32])=[O:28])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CI
Reactant: CC(C)OC(=O)COc1cccc(NC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)COc1cccc(N(C)C2CCc3ccc(-c4cccc(F)c4)cc32)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
Methyl iodide (17 mg, 0.122 mmol) and sodium hydride (60% dispersion of mineral oil, 1.1 mg, 0.045 mmol) were added to a solution of isopropyl 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)amino)phenoxy)acetate (17 mg, 0.041 mmol) and dimethylformamide (2 mL) in a 50 mL round bottom flask at room temperature. The mixture was then heated to 50° C. and allowed to stir overnight. The solution was quenched with saturated ammonium chloride (25 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (1×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by preparative TLC (1000 mm thickness, 30% ethyl acetate/hexanes) to afford 12 mg (68%) of isopropyl 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)phenoxy)acetate.
Reaction SMILES: [ClH:1].C([NH:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:12]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[C].[Pd]>[ClH:1].[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH:13]2[CH2:14][CH2:15][CH:11]([CH2:10][NH2:9])[CH2:12]2)=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: COc1ccc(C2CCC(CNCc3ccccc3)C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(C2CCC(CN)C2)cc1
Reaction time: 2 h
Yield: 93.9 %

Procedure:
N-Benzyl-N-[3-(4-methoxyphenyl)cyclopentylmethyl]amine hydrochloride (6.30 g) was dissolved in acetic acid (130 ml), and 10% palladium-carbon (1.1 g) was added. After substituting the reaction vessel with hydrogen gas, hydrogen addition was carried out at normal pressure, 80° C. for 2 hours. After the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to produce light yellow crystals which were then washed with diethyl ether to give 4.31 g of 3-(4-methoxyphenyl) cyclopentylmethylamine hydrochloride (94.0%).
Reaction SMILES: C([O:6][C:7]([C:11]1[C:12]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[N:13][N:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=12)=[C:8]([CH3:10])[CH3:9])(=O)C(C)C.FC1C=CC(C2C=C3C=CC(C(F)(F)F)=CN3N=2)=CC=1.O.[OH-].[Na+]>C(OC(=O)C(C)C)(=O)C(C)C.OS(O)(=O)=O>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:12]2[C:11]([C:7](=[O:6])[CH:8]([CH3:9])[CH3:10])=[C:15]3[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][N:14]3[N:13]=2)=[CH:29][CH:28]=1
Reactant: CC(C)=C(OC(=O)C(C)C)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Agent: CC(C)C(=O)OC(=O)C(C)C
Agent: Fc1ccc(-c2cc3ccc(C(F)(F)F)cn3n2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)C(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Temperature: 142 °C
Yield: 68 %

Procedure:
1-(2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylprop-1-enyl isobutyrate. To 2.50 g (8.9 mmol) of 2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine in 43 ml of isobutyric anhydride was added conc. H2SO4 (5 drops). The mixture was stirred and heated at 142° C. overnight. The mixture was cooled to room temperature and poured into water (120 ml) at 0° C. The solution was then adjusted to pH 10 with 2N NaOH. The aqueous layer was extracted with Et2O (3×100 ml), dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography (3% EtOAc-hexane) to afford 2.54 g (68%) of the title compound) as an orange solid. Compound 1033.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N+:12]([O-])=O)[CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1OCC1CC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1OCC1CC1
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A mixture of 1-(cyclopropylmethoxy)-2-nitrobenzene (1.352 g, 7.00 mmol) and 10% Pd/C (0.140 g, 0.132 mmol) in MeOH (30 ml) was hydrogenated at 20 psi for 1 hour. The catalyst was filtered off, and the solvent was removed affording 2-(cyclopropylmethoxy)aniline (1.03 g, 6.31 mmol, 90% yield, MS/ESI+ 164.0 [MH]+) that was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[NH:6][CH:5]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Fc1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cccc(F)c23)CC1
Yield: 26.3 %

Procedure:
A stirred solution of 4-fluoroindole (400 mg, 3.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (650 mg, 3.3 mmol), and pyrrolidine (0.62 mL, 7.4 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue subjected to chromatography on silica gel with 20% ethyl acetate/hexanes to afford a yellow solid (250 mg, 27%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)/[C:29](=[N:33]/[OH:34])/[CH2:28][CH2:27][CH2:26]2.[C:35]1([C:41]2[O:45][N:44]=[C:43]([C:46](OC)=O)[C:42]=2[C:50]([F:53])([F:52])[F:51])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.S(Cl)(Cl)=O>C1COCC1.C(OCC)(=O)C.N1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]1=[N:33][O:34][C:46]([C:43]3[C:42]([C:50]([F:51])([F:52])[F:53])=[C:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:45][N:44]=3)=[C:28]1[CH2:27][CH2:26]2
Reactant: COc1ccc2c(c1)CCC/C2=N\O
Reactant: COC(=O)c1noc(-c2ccccc2)c1C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a fresh solution of lithium diisopropylamide made by adding butyllithium (6.64 mL, 16.6 mmol) to a stirred mixture of diisopropylamine (2.33 mL, 16.6 mmol) in THF (10 mL) at 0° C. was added a solution of (E)-6-methoxy-3,4-dihydronaphthalen-1(2H)-one oxime (I-2, 1.06 g, 5.53 mmol) in THF (4 mL) over 2 minutes. After complete addition, the reaction mixture turned orange-colored and was stirred for an additional 20 minutes. Methyl 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylate (I-5, 1.00 g, 3.69 mmol) in THF (4 mL) was then added over 5 minutes. The resulting reaction mixture turned dark brown and was stirred for thirty minutes at 0° C. The reaction mixture was allowed to warm to room temperature, quenched with conc. sulfuric acid (1.0 mL), and concentrated under vacuum. The residue was taken up in toluene (25 mL), filtered, and dried. To the filtrate was added pyridine (1.5 mL) and thionyl chloride (0.234 mL, 3.20 mmol), and the reaction mixture was heated at 110° C. for about 20 minutes. The residue was taken up in ethyl acetate (50 mL), stirred, and filtered. The filtrate was concentrated in vacuo to give a dark brown crude product mixture. This crude product was chromatographed on silica gel eluting with a 10% mixture of ethyl acetate in hexane to give 7-Methoxy-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (416 mg, 3.69 mmol, 27%) as a yellowish solid. The product had an HPLC ret. time=4.32 min (condition B). LC/MS M+1=413.15.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].Cl.[N:14]([O-])=O.[Na+]>O>[CH3:9][N:6]1[C:7]2[CH:8]=[N:14][NH:1][C:2]=2[C:3](=[O:12])[N:4]([CH3:11])[C:5]1=[O:10]
Reactant: Cc1c(N)c(=O)n(C)c(=O)n1C
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1c(=O)c2[nH]ncc2n(C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of Step 1 intermediate (4.0 g, 23.634 mmol) in a mixture of ice (24 g) and concentrated HCl (5 ml) was added a solution of sodium nitrite (1.42 g, 20.580 mmol) in water (5 ml). The resulting suspension was stirred below 10° C. for 30 min. The solid formed at this stage was removed by filtration and the filtrate was added slowly with continuous stirring to 20% aq. NaOH (20 ml) by maintaining the temperature below 10° C. After addition the basic solution was filtered and neutralized with hydrochloric acid (5 N HCl). The precipitate separated was filtered and dried to get 300 mg of the product as dark orange solid; 1H NMR (300 MHz, DMSO-d6): δ 3.45 (s, 3H), 3.52 (s, 3H), 7.53 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:12]=[CH:11]2)[C:7]([C:23]([F:26])([F:25])[F:24])=[CH:6][C:5]=1[N+:27]([O-])=O>O1CCCC1.[Pd]>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[N:12]=[CH:11]2)[C:7]([C:23]([F:26])([F:24])[F:25])=[CH:6][C:5]=1[NH2:27]
Reactant: COC(=O)c1cc(-n2cnc(-c3ccc(OC)cc3)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc(-n2cnc(-c3ccc(OC)cc3)c2)c(C(F)(F)F)cc1N
Yield: 93 %

Procedure:
1.470 g of 5-[4-(4-methoxy-phenyl)-imidazol-1-yl]-2-nitro-4-trifluoromethyl-benzoic acid methyl ester in 25 ml of tetrahydrofuran are hydrogenated in presence of 200 mg of palladium on carbon. After filtration of the catalyst the solution is evaporated to dryness and the residue purified by flash chromatography on silica (40-63 μm particle size) with dichloromethane/methanol 98:2, yielding 1.270 g of 2-amino-5-[4-(4-methoxy-phenyl)-imidazol-1-yl]-4-trifluoromethyl-benzoic acid methyl ester as a beige solid. 1H-NMR (DMSO-d6, 400 MHz): 3.80 s, 3H; 3.95 s, 3H; 6.95 d, J=10.4 Hz, 2H; 7.30 s, 2H; 7.40 s, 1H; 7.70 s, 1H; 7.75 s, 1H; 7.78 d, J=10.4 Hz, 2H; 7.80 s, 1H.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(C)c1O

Procedure:
Into a 3-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-hydroxy-3-methylbenzoic acid (50 g, 328.63 mmol, 1.00 equiv) and methanol (800 mL). This was followed by the addition of thionyl chloride (20 mL) dropwise with stirring. The resulting solution was stirred overnight at 80° C. The resulting mixture was concentrated under vacuum. The residue was diluted with 1000 mL of ethyl acetate. The resulting mixture was washed with 2×800 mL of NaOH (cold). The resulting mixture was washed with 2×500 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 25 g (46%) of methyl 2-hydroxy-3-methylbenzoate as brown oil. 1H NMR (300 MHz, DMSO-d6) δ 2.19 (s, 3H), 3.90 (s, 3H), 6.83-6.88 (m, 1H), 7.41-7.44 (m, 1H), 7.64-7.66 (m, 1H), 10.87 (b, 1H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:23]([O:24][CH3:25])=[CH:22][C:10]2[NH:11][C:12](=[O:21])[C:13]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:14]=3[NH:15][C:9]=2[CH:8]=1)(=O)=O.[CH:28]([N:30]1[CH2:34][CH2:33][CH2:32][C:31]1=[O:35])=[CH2:29].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:13]2[C:12](=[O:21])[NH:11][C:10]3[CH:22]=[C:23]([O:24][CH3:25])[C:7]([C:28]([N:30]4[CH2:34][CH2:33][CH2:32][C:31]4=[O:35])=[CH2:29])=[CH:8][C:9]=3[NH:15][C:14]=2[CH:16]=1
Reactant: COc1cc2c(cc1OS(=O)(=O)C(F)(F)F)Nc1cc(Cl)ccc1C(=O)N2
Reactant: C=CN1CCCC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=C(c1cc2c(cc1OC)NC(=O)c1ccc(Cl)cc1N2)N1CCCC1=O
Temperature: 25 °C

Procedure:
A mixture of Example 516A, 1-vinyl-2-pyrrolidinone, Pd(dppf)Cl2-CH2Cl2, and triethylamine in DMF was heated at 110° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by column chromatography on silica gel using a solvent gradient that increased from 1 to 4% methanol in dichloromethane to give the title compound. MS (ESI) m/e 384 (M+H)+.
Reaction SMILES: CC1[N:3]([C:8]2[CH:12]=[C:11]([I:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[N:9]=2)C(C)=CC=1.[Cl-].O[NH3+].C(N(CC)CC)C>CCCCCC.C(OCC)(=O)C>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:10]1[C:11]([I:13])=[CH:12][C:8]([NH2:3])=[N:9]1
Reactant: Cc1ccc(C)n1-c1cc(I)n(-c2ccccc2F)n1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1cc(I)n(-c2ccccc2F)n1
Temperature: 90 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
To a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-(2-fluorophenyl)-5-iodo-1H-pyrazole (1.23 g) in ethanol/water (2/1, 18 ml) were sequentially added hydroxylammonium chloride (4.47 g) and triethylamine (0.9 ml) at room temperature, and the mixture was stirred at 90° C. for 24 hours. This reaction mixture was cooled to room temperature, concentrated under reduced pressure. To the resulting residue was added a 8M aqueous solution of sodium hydroxide, and then the mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1 to 1/1) to give the titled compound (0.61 g).
Reaction SMILES: OS(O)(=O)=O.[C:6]([OH:15])(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH2:9].[N+]([C:19]1[CH:28]=[CH:27][C:22]([CH:23]=[CH:24][CH:25]=O)=[CH:21][CH:20]=1)([O-])=O.[OH-].[K+]>CC(O)=O.O>[C:22]1([C:23]2[CH:24]=[CH:25][C:10]3[C:8](=[C:7]([C:6]([OH:15])=[O:14])[CH:13]=[CH:12][CH:11]=3)[N:9]=2)[CH:27]=[CH:28][CH:19]=[CH:20][CH:21]=1
Reactant: O=CC=Cc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cccc2ccc(-c3ccccc3)nc12
Temperature: 105 °C

Procedure:
A mixture of conc. H2SO4 (45 mL), water (5 mL), AcOH (5 mL), anthranilic acid (XI; R2 =H) (20.5 g) and H3AsO4 (80% w/w; 32 g) was heated with stirring to 105° C., and then treated with cinnamaldehyde (VIII; R1 =H) (25 g) at the rate which maintained the temperature at 105°-110° C. The reaction mixture was stirred for a further 3 h at 110°-115° C., then cooled and strongly basified with aqueous KOH. The aqueous layer was decanted from a quantity of tar, washed with CHCl3 and then acidified with AcOH. The resulting precipitate was chromatographed on SiO2 and eluted with a gradient of MeOH in CH2Cl2 to give a low yield of the desired acid, mp 160°-161° C., identical in all respects to the compound obtained in Example A. This compound was elaborated to compound 1 of Table I by the method outlined in Example A.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]([CH:31]=O)[CH:22]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:31][C:23]2[CH:22]=[N:21][C:30]3[C:25]([CH:24]=2)=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cnc2ccccc2c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cnc2ccccc2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available quinoline-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.60 min.; [M+H]+: 376.75 g/mol.