Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].[N:16]1([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3([C:37]#[N:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1.O>C1COCC1>[N:16]1([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3([C:37]4[NH:38][C:7]5=[N:6][CH:5]=[CH:4][N:3]=[C:2]5[CH:1]=4)[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][CH:26]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cnccn1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1cnc2[nH]c(C3(c4ccc(OCCCN5CCCC5)cc4)CCOCC3)cc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
A solution of 2-methyl-pyrazine (580 μL, 6.4 mmol) in THF (4 mL) was added to 4.7 mL of 1.5M lithium diisopropylamide:THF complex in hexanes at −40° C. and the resulting deep red solution stirred at −40° C. for 0.5 hours. A solution of 4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (1.00 g, 3.2 mmol) in THF (5 mL) was added at −40° C. and the reaction mixture stirred at this temperature for 0.5 hours, then at room temperature for 18 hours. A further 1 equivalent of lithium diisopropylamide complex was then added and the reaction mixture stirred at reflux for 24 hours. The mixture was cooled to room temperature, water (10 mL) added and the mixture concentrated in vacuo. The residue was partitioned between water (60 mL) and DCM (2×60 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1, by volume) to provide the title compound (65 mg, 6%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 1.74-1.80 (m, 6H), 2.00 (m, 2H), 2.42-2.55 (m, 6H), 2.60 (t, 2H), 3.80 (m, 4H), 4.00 (t, 2H), 6.60 (s, 1H), 6.86 (d, 2H), 7.21 (d, 2H), 8.05 (d, 1H), 8.39 (d, 1H). HRMS ESI+ m/z 407.2437 [MH]+.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([NH2:31])[S:30][C:26]=2[CH:25]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:31][C:29]3[S:30][C:26]4[CH:25]=[C:24]([CH3:23])[CH:33]=[CH:32][C:27]=4[N:28]=3)=[O:20])=[CH:21][CH:22]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: Cc1ccc2nc(N)sc2c1
Product: Cc1ccc2nc(NC(=O)c3ccc(S(=O)(=O)N4CCCc5ccccc54)cc3)sc2c1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 6-methylbenzo[d]thiazol-2-amine (43 mg, 0.26 mmol) using method B. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(6-methylbenzo[d]thiazol-2-yl)benzamide as a white solid. Yield: 34 mg (28%). 1H-NMR: 8.21 (d, J=8.5 Hz, 2H), 7.81 (s, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.68 (br s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.29 (dd, J=8.0, 1.0 Hz, 1H), 7.24-7.19 (m, 1H), 7.13-7.06 (m, 2H), 3.84-3.80 (m, 2H), 2.47-2.41 (m, 5H), 1.66-1.59 (m, 2H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1([NH:13][C:14]([C:16]2[CH:20]=[CH:19][O:18][CH:17]=2)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].CCOCC>O1CCCC1>[O:18]1[CH:19]=[CH:20][C:16]([C:14]([NH:13][C:7]2([C:5]([OH:6])=[O:4])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:15])=[CH:17]1
Reactant: COC(=O)C1(NC(=O)c2ccoc2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(NC1(C(=O)O)CCCCC1)c1ccoc1
Yield: 96.7 %

Procedure:
450 ml of 2N aqueous sodium hydroxide solution was added to a solution of 75.4 g (300 mmol) of 1-[(3-furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester in 450 ml of tetrahydrofuran, and the mixture was refluxed under heating for 3 hours. After ether was added to the reaction solution to wash, the aqueous layer was neutralized by concentrated hydrochloric acid and extracted with ethyl acetate. After the obtained organic layer was washed with saturated brine and it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 68.8 g (97%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[C:9]([Cl:19])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:20][N:21]1[C:25]([OH:26])=[CH:24][C:23]([CH3:27])=[N:22]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[C:9]([Cl:19])[CH:8]=[CH:7][C:3]=1[C:4]([O:26][C:25]1[N:21]([CH3:20])[N:22]=[C:23]([CH3:27])[CH:24]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)c(OCCn2cnnn2)c1Cl
Reactant: Cc1cc(O)n(C)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=O)c2ccc(Cl)c(OCCn3cnnn3)c2Cl)n(C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.7 %

Procedure:
2,4-Dichloro-3-[2-(1H-tetrazol-1-yl)ethoxy]benzoyl chloride (0.60 g) was dissolved in tetrahydrofuran (5 ml), this solution was added dropwise to a tetrahydrofuran (5 ml) solution of 1,3-dimethyl-5-hydroxypyrazole (0.22 g) and triethylamine (0.23 g) at 5° C. and the mixture was stirred at room temperature for 6 hours. After the reaction, the mixture was extracted with ethyl acetate (100 ml) and then washed with diluted hydrochloric acid and an aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off to obtain the desired 5-{2,4-dichloro-3-[2-(1H-tetrazol-1-yl)ethyloxy]-benzoyloxy}-1,3-dimethylpyrazole (0.65 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:24]([OH:26])=O)[CH:15]=1)[CH2:5][CH2:6][O:7]2.[CH3:27][NH:28][CH2:29][CH2:30][OH:31]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:24]([N:28]([CH2:29][CH2:30][OH:31])[CH3:27])=[O:26])[CH:15]=1)[CH2:5][CH2:6][O:7]2
Reactant: CNCCO
Reactant: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)O)cc2[nH]1
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N(C)CCO)cc2[nH]1
Yield: 40 %

Procedure:
The title compound was prepared as a white solid (50 mg, 40% yield for 3 steps) from 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-2-methyl-1H-benzimidazole-6-carboxylic acid (100 mg, crude, STEP 4 in Example 4) and 2-(methylamino)ethanol (63 mg, 0.83 mmol) by the same manner in STEP 5 of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH:3]=1.I[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N:12]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)OC(C)C
Reactant: COC(=O)CCCI
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CCCN(C(=O)OC(C)C)c1cc(Br)ccc1C(=O)OC
Temperature: 25 °C
Yield: 62.9 %

Procedure:
Heat a suspension of methyl 4-bromo-2-isopropoxycarbonylaminobenzoate (19.2 g, 60.7 mmol), methyl 4-iodobutyrate (16.4 mL, 121 mmol) and cesium carbonate (39.6 g, 121 mmol) in N,N-dimethylformamide (240 mL) under nitrogen at 80° C. for 24 h. Cool the mixture to room temperature and pour into a saturated ammonium chloride solution (500 mL) and extract with ethyl acetate (3×200 mL). Combine the organic extracts and wash with water (2×400 mL), brine (100 mL), then dry the solution over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to provide the title compound as an orange oil (15.9 g, 63%): APCI MS 416 (M+H
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][Cl:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH3:14].C(N(CC)CC)C.Cl>C(#N)C.CO.CCOCC>[ClH:12].[CH2:13]([O:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:11][CH2:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH3:14]
Reactant: O=S(=O)(CCCl)c1ccccc1
Reactant: CCOCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOCC
Product: CCOCCCNCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.2 %

Procedure:
A mixture of 51.4 g (0.253 mole) of 2-chloroethyl phenyl sulfone, 50.2 g (0.417 mole) of 3-ethoxy-1-propanamine, and 33.0 g (0.327 mole) of triethylamine in 400 ml of acetonitrile was stirred at room temperature for 20 hr. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride phase was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. This was dissolved in methanol, an excess of ethereal hydrogen chloride was added and ether was added. A precipitate was collected to give 49.2 g (63.2%) of white crystalline solid, m.p. 169°-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S(=O)(c1cccc(Cl)c1)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Yield: 64.3 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-[(3-chlorophenyl)sulfonyl]piperidine (150 mg, 0.58 mmol) was reacted with 2-chloro-5-(trifluoromethyl)pyridine (211 mg, 1.16 mmol), DIEA (0.3 ml, 1.74) and 1,4-dioxane (0.2 ml) to afford the title compound (151 mg), a white solid, in 64% yield.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8]([O:11]S(C)(=O)=O)(=[O:10])=[O:9].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[C:27]1[C:28](=[O:46])[NH:29][C:30](=[O:45])[C:31]=1[C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]([CH2:41][CH2:42][CH2:43]O)[N:33]=1.Cl>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[C:27]1[C:28](=[O:46])[NH:29][C:30](=[O:45])[C:31]=1[C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]([CH2:41][CH2:42][CH2:43][O:11][S:8]([CH3:7])(=[O:10])=[O:9])[N:33]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: Cn1cc(C2=C(c3nn(CCCO)c4ccccc34)C(=O)NC2=O)c2cc(Cl)ccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3nn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2cc(Cl)ccc21
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Pyridine (0.37 g, 4.62 mmol) and methanesulfonic anhydride (0.54 g, 3.08 mmol) were added to Compound 74 (0.67 g, 1.54 mmol) in THF (10 mL). The mixture was heated at 50° C. for 2 h, then cooled to rt. Another portion of THF (5 mL) was added, followed by 1N HCl (5 mL). The mixture was stirred for another 15 min, then extracted with EtOAc several times. The combined EtOAc layers were washed once with 1 N HCl (10 mL), water (2×20 mL) and saturated NaCl (20 mL), then dried (Na2SO4) and evaporated in vacuo to obtain 3-(5-chloro-1-methyl-1H-indol-3-yl)-4-[1-[3-[(methylsulfonyl )oxy]propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione as Compound 26a (0.73 g, 92%) as a reddish solid. ES-MS m/z 513 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]([CH3:15])([CH3:14])[C:10]([F:13])([F:12])[F:11])=[O:7].[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[I-].[Na+].C(N(CC)CC)C>O.C(OCC)(=O)C>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]([C:5]1[CH:4]=[C:3]([CH:18]=[CH:17][CH:16]=1)[CH2:2][N:22]1[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]1)=[O:7])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(NC(=O)c1cccc(CCl)c1)C(F)(F)F
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C(F)(F)F)c2)CC1
Yield: 97.6 %

Procedure:
3-(Chloromethyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide (3.10 mmol, 868 mg), tert-butyl piperazine-1-carboxylate (3.10 mmol, 578 mg), sodium iodide (3.10 mmol, 465 mg) and triethylamine (3.10 mmol, 0.433 mL) were all combined in actetonitrile (28 ml) and heated to reflux for 2 hours. After this time the reaction mixture was allowed to cool and ethyl acetate and water were added. The organic layer was separated, dried and concentrated under vacuum to yield the title compound (1.3 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[Cl:19])[CH:8]=[N:9]2)=[CH:4][N:3]=1.[CH:20]1([C:23]([NH2:25])=[O:24])[CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[C:7]1[CH:8]=[N:9][C:10]2[C:5]([CH:6]=1)=[CH:4][N:3]=[C:2]([NH:25][C:23]([CH:20]1[CH2:22][CH2:21]1)=[O:24])[CH:11]=2
Reactant: NC(=O)C1CC1
Reactant: Fc1ccc(Cl)c(-c2cnc3cc(Br)ncc3c2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2ncc(-c3cc(F)ccc3Cl)cc2cn1)C1CC1
Temperature: 90 °C
Yield: 43.9 %

Procedure:
A mixture of 7-bromo-3-(2-chloro-5-fluorophenyl)-1,6-naphthyridine (40 mg, 0.1 mmol), cyclopropanecarboxamide (30 mg, 0.35 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (14 mg, 0.024 mmol), palladium acetate (5 mg, 0.024 mmol), and cesium carbonate (77 mg, 0.24 mmol) in 1,4-dioxane (1 mL) was heated at 90° C. for 1 hour. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (15 mg, 40%). 1H NMR (400 MHz, DMSO) δ 11.17 (s, 1H), 9.29 (s, 1H), 9.11 (d, J=2.2 Hz, 1H), 8.66-8.55 (m, 2H), 7.73 (dd, J=8.9, 5.2 Hz, 1H), 7.60 (dd, J=9.1, 3.1 Hz, 1H), 7.40 (td, J=8.5, 3.1 Hz, 1H), 2.18-2.06 (m, 1H), 0.96-0.81 (m, 4H). LCMS (Method E): RT=4.646 min, M+H+=342.0.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11]([OH:13])=O)(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[NH2:22]>>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11]([NH:22][C:21]1[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=[C:19]([C:18]([F:17])([F:30])[F:31])[CH:20]=1)=[O:13])(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(=O)C(C)C)cc1C(=O)O
Product: COc1ccc(C(=O)C(C)C)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 61.4 %

Procedure:
Using 5-isobutyryl-2-methoxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]=[C:11]([N:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:42])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:40])[F:39])[CH2:27][CH2:26]1)[CH2:12][NH:13][C:14](=[O:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1.C1[CH:44]=[CH:45][C:46]2[N:51](O)N=N[C:47]=2[CH:48]=1.CCN=C=NCCCN(C)C.C1(N)CCCC1>CN(C=O)C.O>[CH:46]1([NH:51][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([C:14]([NH:13][CH2:12][C:11](=[O:10])[N:25]3[CH2:26][CH2:27][N:28]([C:31](=[O:42])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:41])([F:40])[F:39])[CH2:29][CH2:30]3)=[O:24])=[CH:16][CH:17]=2)[CH2:45][CH2:44][CH2:48][CH2:47]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(C(=O)NC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 34.1 %

Procedure:
DIPEA (83.75 mg, 0.1 mL, 0.64 mmol) was added to a stirred solution of N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-terephthalamic acid (100 mg, 0.21 mmol) in DMF (1 mL). HOBT (29.26 mg, 0.21 mmol) and EDCI (41.4 mg, 0.21 mmol) were then added at room temperature. After 2 minutes, cyclopentylamine (18.39 mg, 0.21 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with 5% sodium bicarbonate solution followed by brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was recrystallized from a mixture of EtOAc and ether to afford 38 mg (33% yield) of N-cyclopentyl-N′-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-terephthalamide. LCMS Purity: 91.36%. 1H NMR (CDO3): δ 7.8-7.7 (m, 7H), 7.7-7.5 (m, 2H), 7.4-7.2 (m, 2H), 6.1 (d, 1H), 4.5-4.4 (q, 1H), 4.4-4.2 (m, 2H), 4.1-3.8 (m, 2H), 3.8-3.4 (m, 5H), 3.2 (m, 2H), 2.1 (m, 2H), 1.7 (m, 3H), 1.5 (m, 2H).
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[NH-:12].ClC1C2C(=CC=CC=2)[N:17]=[CH:16]C=1[NH-].Cl.NO>>[NH:17]1[C:2]2[C:11]3[N:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[CH:16]1
Reactant: [NH-]c1cnc2cccnc2c1Cl
Reactant: [NH-]c1cnc2ccccc2c1Cl
Agent: Cl
Agent: NO
Product: c1cnc2c(c1)ncc1nc[nH]c12

Procedure:
In step (7) of Reaction Scheme II, an N-(4-chloro[1,5]naphthyridin-3-yl)amide or N-(4-chloroquinolin-3-yl)amide of Formula XXXII is reacted with a hydroxylamine hydrochloride of Formula R1ONH2.HCl and cyclized to provide a 1H-imidazo[4,5-c][1,5]naphthyridine or a 1H-imidazo[4,5-c]quinoline of Formula XXXIII. The reaction can be carried out using the method described in step (3) of Reaction Scheme I.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:16]1[CH:17]=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:16]1[CH:17]=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: Oc1cnc2ccccc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc2ccccc2c1

Procedure:
A 2.77 g sample of (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol and 3 g of 3-hydroxyquinoline were reacted with triphenylphosphine and DEAD in 100 mL of THF according to the procedure of Example 14a, to give 2.5 g of the title compound. MS (DCI/NH3) m/e 329 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.67 (d, J=3 Hz 1H), 8.4 (d, J=7 Hz, 1H), 7.72 (dd, J=7, 1 Hz 1H), 7.56-7.40 (m, 3H), 4.24-3.94 (m, 3 H), 3.42 (bs 2H), 2.11-1.94 (m 3H), 1.92-1.86 (m 1H), 1.48 (s 9H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C[N:18](C)C=O.C(Cl)(=O)C(Cl)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH2:18])=[O:16])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 4'-Methyl[1,1'-biphenyl]-2-carboxylic acid, prepared as in European Patent Application 87-109919.8 Example 85-a, page 147, line 32 (20.0 g, 94.2 mmol) in dichloromethane (200 mL) at 0° C. was added dimethylformamide (0.5 mL) followed by oxalyl chloride (375 mL of 2.0 M solution in dichloromethane, 750 mmol). The rate of addition was adjusted to maintain the internal temperature below 10° C. When the addition was complete, the mixture was allowed to warm to 25° C. and was stirred at that temperature for two hours, after which it was concentrated in vacuo. The semisolid residue was added portionwise to concentrated ammonium hydroxide solution (250 mL) at 0° C., stirred for 15 minutes, and diluted with water (200 mL). The resulting white precipitate was collected, washed with water, and dried in vacuo over phosphorus pentoxide to give the title compound (18.7 g, 90%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([F:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[F:21][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ccccc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccccc1C1(F)CCNCC1
Reaction time: 1 h

Procedure:
4-Fluoro-4-(2-fluoro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.4 g, 1.35 mmol) was dissolved in a solution of hydrogen chloride in dioxane (4 M, 3 mL) and the mixture stirred for 1 hour. The solvent was evaporated under vacuum, and the resulting solid triturated from diethyl ether to give the title compound as a pale yellow solid (0.26 g) which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:23])[N:11]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:10]=1[C:37]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[O:38])C1C=CC=CC=1>CO.C(Cl)Cl.[Pd]>[CH2:42]([N:39]([CH2:40][CH3:41])[C:37]([C:10]1[N:11]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:12]([C:22]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])=[O:23])=[C:13]([OH:14])[C:9]=1[OH:8])=[O:38])[CH3:43]
Reactant: CCN(CC)C(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(CC)CC)n1-c1ccc(OC)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)C(=O)c1c(O)c(O)c(C(=O)N(CC)CC)n1-c1ccc(OC)cc1
Yield: 93 %

Procedure:
A solution of 3,4-bis(benzyloxy)-N2,N2,N5,N5-tetraethyl-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxamide UL1-046 (50 mg, 0.086 mmol) in methanol/DCM (4 mL/4 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 25° C. under H2 (full H2 mode). The output was concentrated in vacuo to afford N2,N2,N5,N5-tetraethyl-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxamide (UL1-003) (32 mg, 93%) as a light yellow solid: m/z 404 (M+H)+ (ES+); 402 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 2H), 6.96-6.88 (m, 2H), 6.87-6.81 (m, 2H), 3.72 (s, 3H), 3.27 (q, J=7.1 Hz, 8H), 0.96 (t, J=7.0 Hz, 12H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][C@@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1>>[Cl:8][C:7]1[C:2]([N:15]2[CH2:14][CH2:13][NH:12][C@H:11]([CH3:10])[CH2:16]2)=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: C[C@@H]1CNCCN1
Product: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1

Procedure:
2,3,5-Trichloro-pyridine (910 mg, 5.0 mmol, Aldrich) and (R)-(−)-2-methyl-piperazine (700 mg, 7.0 mmol, Aldrich) reacted under the conditions of Example 3a to give the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 247 (M+1).