Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[CH3:33][S:34]([CH2:37][CH2:38][NH2:39])(=O)=[O:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[CH:17]3[C:12]([C:13]4[CH:28]=[CH:27][C:26]([C:29]([NH:39][CH2:38][CH2:37][S:34]([CH3:33])=[O:35])=[O:31])=[CH:25][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CS(=O)(=O)CCN
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCOCC2)cc1Cl
Agent: Cl
Product: CS(=O)CCNC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCOCC1

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 36 and 2-(methylsulfonyl)ethanamine hydrochloride according to Method F. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25-1.32 (m, 2H), 1.41 (ddd, J=24.50, 12.42, 4.43 Hz, 1H), 1.51-1.57 (m, 1H), 1.87-1.99 (m, 2H), 2.25-2.33 (m, 1H), 2.87-3.00 (m, 1H), 3.04 (s, 3H), 3.08-3.21 (m, 3H), 3.38 (t, J=6.85 Hz, 2H), 3.61-3.79 (m, 5H), 4.82 (dd, J=9.80, 3.63 Hz, 1H), 7.18-7.23 (m, 1H), 7.44 (s, 1H), 7.71 (d, J=8.59 Hz, 1H), 7.73-7.77 (m, 1H), 7.78 (s, 1H), 8.08 (d, J=8.06 Hz, 1H), 8.79 (t, J=5.50 Hz, 1H); HRMS m/z 541.1702 (M+H).
Reaction SMILES: ClC1C=CC=C(Cl)C=1C[O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:22])[CH:11]=[C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[O:13]2)=[CH:8][CH:7]=1>CO.[Pd]>[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:22])[CH:11]=[C:12]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[O:13]2)=[CH:8][CH:7]=1
Reactant: O=c1cc(N2CCOCC2)oc2cc(OCc3c(Cl)cccc3Cl)ccc12
Agent: [Pd]
Solvent: CO
Product: O=c1cc(N2CCOCC2)oc2cc(O)ccc12
Reaction time: 40 h
Yield: 56.2 %

Procedure:
To a mixture of 7-(2,6-dichlorobenzyloxy)-2-(morpholin-4-yl)-chromen-4-one (6.60 g, 16.2 mmol) (299) and 10% Pd/C (150 mg) was added methanol (150 ml), under nitrogen. The suspension was stirred under an atmosphere of hydrogen for 40 h. The catalyst was removed by filtration through Celite, washing with methanol. The solvent was removed by evaporation in vacuo to provide an off-white solid. This was treated with fresh catalyst, re-suspended in methanol under nitrogen and stirred under an atmosphere of hydrogen for a further 72 h. The catalyst was removed by filtration through Celite, washing with methanol. The filtrate was evaporated in vacuo and the crude product re-crystallised from methanol to provide 2.26 g (9.1 mmol, 57%) of the desired compound as a white solid. mp>250° C. (decomp). 1H NMR (200 Mhz, d6-DMSO) δ 3.78 (4H, m); 3.86 (4H, m); 6.15 (1H, s); 7.05-7.13 (2H, m); 7.93 (1H, d); 11.3 (1H, bs). ESMS m/z=247 (M+), 190, 105.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)=[CH:6][CH:7]=1.[C:19]([NH:22][NH2:23])(=O)[CH3:20]>C(O)CCC>[CH3:20][C:19]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:23][N:22]=1
Reactant: CC(=O)NN
Reactant: Fc1ccc(-c2ccc(Cl)nn2)cc1C(F)(F)F
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3ccc(F)c(C(F)(F)F)c3)nn12

Procedure:
As described in Example 36, 3-chloro-6-[4-fluoro-3-(trifluoromethyl)phenyl]pyridazine is reacted with acetic acid hydrazide in n-butanol to give the product of the example.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]([S:18][C:19]3[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[C:21]([Cl:30])[C:20]=3[Cl:31])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.O.[OH-].[Li+]>CN(C=O)C.O.C(OCC)(=O)C>[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]([S:18][C:19]3[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([N:36]4[CH2:37][CH2:38][CH:33]([OH:32])[CH2:34][CH2:35]4)=[O:28])=[C:21]([Cl:30])[C:20]=3[Cl:31])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)([OH:3])=[O:5]
Reactant: CCOC(=O)C1CCN(c2cccc(Sc3ccc(/C=C/C(=O)O)c(Cl)c3Cl)c2)CC1
Reactant: OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C1CCN(c2cccc(Sc3ccc(/C=C/C(=O)N4CCC(O)CC4)c(Cl)c3Cl)c2)CC1
Reaction time: 15 h
Yield: 79.5 %

Procedure:
To a suspension of Example 412C (150 mg, 0.31 mmol) in DMF (3 mL) was added 4-hydroxypiperidine (63 mg, 0.62 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide (120 mg, 0.62 mmol), HOBt (84 mg, 0.62 mmol) and triethylamine (87 μL, 0.62 mmol) at room temperature. The mixture was stirred at the same temperature for 15 hours. Ethyl acetate was added, the mixture was washed with brine, water, and was concentrated. The residual oil was dissolved in THF (3 mL), and was added lithium hydroxide monohydrate (26 mg, 0.62 mmol) in water (1.5 mL). After stirring for 15 hours, the solution was separated by HPLC (Zorbax C-18) to give the title compound (132 mg, 55%). 1H NMR (300 MHz, DMSO-d6) δ 1.32 (m, 2H), 1.65 (m, 2H), 1.75 (m, 2H), 1.92 (m, 2H), 2.43 (m, 1H), 2.86 (t, J =10.6 Hz, 2H), 3.15 (m, 1H), 3.32 (m, 1H), 3.71 (m, 3H), 3.95 (m, 2H), 6.73 (d, J=8.5 Hz, 1H), 6.94 (d, J=7.2 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 7.13 (s, 1H), 7.24 (d, J=15.2 Hz, 1H), 7.37 (t, J=8.1 Hz, 1H), 7.72 (d, J=15.2 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H); MS (ESI+) m/z 535, 537 (M+H)+. Anal. calcd for C26H28N2Cl2SO4 0.25 TFA: C, 56.43; H, 5.05; N, 4.97. Found: C, 56.37; H, 5.00; N, 4.91.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[N:9]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Br:17][C:11]1[CH:12]=[CH:13][C:8]([NH:7][CH2:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][C:10]=1[F:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1cccc(NCc2ccc(Cl)cc2)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: Fc1nc(NCc2ccc(Cl)cc2)ccc1Br
Reaction time: 2 h

Procedure:
To (4-chloro-benzyl)-(6-fluoro-pyridin-2-yl)-amine (536, 1.03 g, 4.35 mmol) in acetonitrile (30.0 mL), under an atmosphere of nitrogen, N-bromosuccinimide (0.820 g, 4.61 mol) was added slowly. After 2 hours, the reaction was poured into a solution of sodium thiosulfate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and crystallized with ethyl acetate and hexane to give a white solid (537, 1.10 g, 80.1%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:3]=1>CO.[C].[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:3]=1
Reactant: Cc1ccnc(/C=C/C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccnc(CCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
tert-Butyl (E)-3-(4-methyl-2-pyridyl)-2-propenoate (1.9 g, 8.5 mmol) was dissolved in methanol (80 ml), and 10% palladium-carbon (200 mg) was added thereto. The mixture was stirred under hydrogen atmosphere at room temperature for 3 hrs. Palladium-carbon was filtered off, and the filtrate was concentrated to give the titled compound (1.8 g, 90%).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH2:16])=[O:15])=[O:7])[CH:3]([CH3:5])[CH3:4].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH2:16])=[O:15])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CCCNC(N)=O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H](N)C(=O)N[C@@H](CCCNC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58 %

Procedure:
To a room temperature solution of Fmoc-Val-Cit (2.18 g, 4.4 mmol, U.S. Pat. No. 6,214,345 to Firestone et al.) in anhydrous DMF (10 mL) was added DEA (10 mL). The reaction mixture was stirred at ambient temperature for 20 minutes. The reaction mixture was concentrated in vacuo to thick oil, and then was added drop wise to a flask containing diethyl ether (˜500 mL) to precipitate the crude product. The white precipitate was collected by filtration and washed with ethyl acetate (2×250 mL). After drying material in vacuo, it was dissolved in DMSO (30 mL), and maleimidocaproic acid-N-hydroxysuccinimide ester (1.42 g, 1.05 eq, Molecular Biosciences, Inc., Boulder Colo.) was added, followed by the addition or DIEA (0.843 mL, 1.1 eq). The reaction mixture was stirred ˜6 h, the DMSO solution was concentrated in vacuo to a volume of ˜2 mL. Product was purified on a semi-preparative HPLC system (stationary phase: C12, mobile phase: 0.1% TFA/H2O/MeCN) to give 1.19 g (2.55 mmol, 58% yield). ES-MS m/z 468.23 [M+H]+. 1H NMR (d6-DMSO) □: 8.15 (d, J=7.2 Hz, 1H), 7.75 (d, J=9.2 Hz, 1 H), 7.00 (s, 1 H), 5.93 (br s, 1 H), 5.38 (br s, 1 H), 4.21 (dd, J1=6.8 Hz, J2=2.148, 1 H), 4.1 (m, 1 H), 2.94 (br s, 2 H), 2.22-2.05 (m, 2 H), 1.93 (q, J=6.8, 1 H), 1.68 (m, 1 H), 1.6-1.2 (m, 7 H), 1.17 (t, J=7.6, 2 H), 0.86-0.80 (dd, J1=6.8 Hz, J2=9.0, 6 H).
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:15])[CH3:14])[C:3](=[O:5])[CH3:4].[OH-].[K+].[H][H]>[Cr]([O-])([O-])=O.[Cu+2].C(O)(CC)C>[CH3:1][CH:2]([CH2:6][CH2:7][CH:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:15])[CH3:14])[CH:3]([OH:5])[CH3:4]
Reactant: [H][H]
Reactant: CC(=O)C(C)=CCC1CC=C(C)C1(C)C
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Agent: [K+]
Solvent: CCC(C)O
Product: CC1=CCC(CCC(C)C(C)O)C1(C)C
Temperature: 25 °C

Procedure:
Into a one-liter stainless steel autoclave was charged 350 g (1.7 moles) of 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-3-en-2-one, 26.3 g (7.5 wgt-%) of copper chromite, 0.1 g (0.03 wgt-%) of potassium hydroxide and 250 ml of sec.-butyl alcohol. The mixture was stirred and heated to 160° C under 300 psi hydrogen pressure and was hydrogenated until the hydrogen uptake ceased. The mixture was cooled to ambient temperature. The autoclave was vented and then the reaction mixture removed and filtered through a thin pad of Filter-cel®. The solvent was removed from the filtrate by distillation to a pot temperature of 75° C at 10-15 mm. The residual viscous oil was fractionally distilled to give 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol (a mixture of diastereomers). Yield 310 g (87% theory); bp 103°-106° C (1.0 mm); nD20 1.4730; mol wt. 210 (ms); nmr, 0.5δ, 0.8, 0.9 and 1.0 (6H, 4s, geminal dimethyl groups of the various diastereomers in the mixture), 1.0-1.1 (3H, d, buried under the CH3 singlets), 1.12 and 1.15 (3H, 2d, J=6.5 Hz, carbinol methyl groups of the various diastereomers in the mixture), 1.2-1.5 (6H, broad complex), 1.6 (3H, broad s, olefinic CH3), 1.7 (1H, s, hydroxyl H/exchanged by D2O, 1.8-2.4 (2H, broad complex, allylic methylene), 3.7 (1H, broad multiplet, carbinyl H), 5.2 (1H, broad multiplet, olefinic H); ir, 3360, 3040, 790 cm-1.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:33])[C@H:21]([CH3:32])[NH:22][C:23](=[O:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[F:34]C1C=CC(CC(O)=O)=CC=1>>[F:34][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C:23]([NH:22][C@H:21]([C:20]([NH:19][C@@H:3]2[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C@@H:4]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:33])[CH3:32])=[O:31])=[CH:30][CH:29]=1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Reactant: O=C(O)Cc1ccc(F)cc1
Product: C[C@H](NC(=O)Cc1ccc(F)cc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (113) was used except that 4-fluorophenylacetic acid (77 mg) was used instead of phenylacetic acid to afford the title compound as a 1:1 mixture with the 2S,3R diastereomer (134 mg), white solid, m.p. 130-140° C. 1H NMR (300 MHz, CDCl3) δ 0.97 (d, 1.5H, J=5 Hz), 1.07 (d, 1.5H, J=5 Hz), 3.43 (two peaks, 2H), 4.52 (m, 0.5H), 4.57 (m, 0.5 H), 4.93 (t, 1H, J=6 Hz), 5.11 (t, 1H, J=6 Hz), 5.78 (dd, 1H, J=7 Hz, J=10 Hz), 6.05 (d, 0.5H, J=8 Hz), 6.21 (d, 0.5 Hz, J=8 Hz), 6.33 (d, 0.5h, J=6 Hz), 6.66 (d, 0.5H, J=7 Hz), 6.88-7.60 (m, 13H), 7.96 (s, 1H). MS APCI, m/z=484 (M+Na). LC/MS: 2.10 min.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][C:6]2[C:16]([C:19]([O:21]C)=[O:20])=[CH:17][S:18][C:5]1=2>CO.O1CCOCC1.O>[O:3]=[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:7][C:6]2[C:16]([C:19]([OH:21])=[O:20])=[CH:17][S:18][C:5]1=2
Reactant: COC(=O)c1csc2c(=O)cc(-c3ccccc3)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1csc2c(=O)cc(-c3ccccc3)oc12
Temperature: 22.5 °C
Yield: 93.6 %

Procedure:
26 mL of 0.6N sodium hydroxide was added to a solution of 3.82 g of Compound 1F in 174 mL of methanol and 87 mL of dioxane at 50° C. while stirring. The mixture was stirred at 50° C. for an additional 20 minutes, cooled to 20-25° C., then diluted with 280 mL of water, filtered and acidified with 1N hydrochloric acid to pH=1. The suspension of that formed precipitate gel was stirred at 60° C. for 2 hours, until a heavier filtrable solid was obtained. This solid was filtered and dried to yield 3.4 g of the title compound, which was suitable for use in the next reaction step without further purification. It was crystallized from ethanol to yield the analytical sample, melting at 282-283° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[NH:22][N:21]=[C:20]([C:23]([NH:25][CH2:26][C:27]([OH:29])=O)=[O:24])[CH:19]=1.COC1C=CC=CC=1C(=O)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[NH:72][CH:73]1[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]1>CN(C=O)C.O>[Cl:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[NH:72][CH:73]1[CH2:78][CH2:77][N:76]([C:27](=[O:29])[CH2:26][NH:25][C:23]([C:20]2[CH:19]=[C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][CH3:10])[NH:22][N:21]=2)=[O:24])[CH2:75][CH2:74]1
Reactant: COc1ccccc1-c1cc(C(=O)NCC(=O)O)n[nH]1
Reactant: Clc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: COc1ccccc1C(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(C(=O)NCC(=O)N2CCC(Nc3ccccc3Cl)CC2)n[nH]1
Reaction time: 0.03 h
Yield: 65.1 %

Procedure:
DIPEA (99 mg, 0.76 mmol) was added to a stirred solution {[5-(2-methoxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (60 mg, 0.22 mmol) (prepared by the method used for the synthesis of Intermediate 30, starting from (2′-methoxy)acetophenone) in DMF (2.0 mL) followed by HOBt (34 mg, 0.25 mmol) and EDCI.HCl (49 mg, 0.25 mmol). After 2 minutes of stirring, (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (54 mg, 0.22 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine and concentrated. The residue was purified washing with diethyl ether to afford 67 mg (43.5% Yield) of 5-(2-methoxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 468.2, 98.33%. 1H NMR (300 MHz, DMSO-d6): δ13.6 (S, 1H), 8.05 (m, 1H), 7.7 (m, 1H), 7.35 (m, 1H), 7.24 (m, 1H), 7.12 (m, 2H), 7.0 (m, 2H), 6.82 (m, 1H), 4.85 (d, 1H), 4.3 (d, 1H), 4.1 (d, 2H), 3.9 (s, 3H), 3.85 (m, 1H), 3.6 (m, 1H), 3.1 (m, 1H), 2.7 (m, 1H), 1.9 (m, 2H), 1.4 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.Cl[CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2
Reactant: ClCCCN1CCCCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCCN1CCCCC1
Temperature: 95 °C
Reaction time: 2 h
Yield: 9.7 %

Procedure:
A suspension of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g, 0.6 mmol), (prepared as described in Example 4), 1-(3-chloropropyl)piperidine (0.12 g, 0.72 mmol) and potassium carbonate (0.125 g, 0.9 mmol) in DMF (5 ml) was stirred at 95° C. for 2 hours. After cooling, the precipitate was filtered. The filtrate was diluted with methylene chloride and purified by column chromatography eluting with methanol/ethyl acetate/methylene chloride (1/4/5) followed by methanol/methylene chloride (1/9) followed by methanol saturated with ammonia/methylene chloride (1/9). The fractions containing the expected product were combined and evaporated to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)cinnoline (27 mg, 10%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:38])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][C:18]([O:21][CH2:22][CH3:23])=[N:19][CH:20]=3)[N:14]=1)[N:11]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10](=[O:31])[C:9]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:8]2)=O.[NH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:24]([N:11]1[C:12]2[C:7](=[C:6]([OH:38])[C:5]([C:3]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:2])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][C:18]([O:21][CH2:22][CH3:23])=[N:19][CH:20]=2)[CH:8]=[C:9]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:10]1=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOc1ncc(-c2nc(C(=O)OC)c(O)c3cc(-c4ccccc4)c(=O)n(Cc4ccccc4)c23)cn1
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1ncc(-c2nc(C(=O)NCCC(=O)O)c(O)c3cc(-c4ccccc4)c(=O)n(Cc4ccccc4)c23)cn1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
A mixture of 1-benzyl-8-(2-ethoxy-pyrimidin-5-yl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (58 mg, 0.11 mmol), β-alanine (818 mg, 9.13 mmol) and NaOMe solution (13.7 mL, 6.85 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-70% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 38 mg of the title compound as a light yellow solid. MS: (+) m/z 566.38 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[NH:17][C:18]([C:20]1[C:21](Cl)=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[O:19])[CH2:14]2.[CH:28]1([SH:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[CH:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][CH:7]([CH2:14]3)[CH:8]1[NH:17][C:18]([C:20]1[C:21]([S:33][CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[O:19])[CH2:10]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(Cl)nc1Cl
Reactant: SC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(Cl)nc1SC1CCCC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Anhydrous Sodium carbonate (2.201 mL, 52.58 mmol) was added in one portion to N-(2-adamantyl)-2,6-dichloro-pyridine-3-carboxamide (5.7 g, 17.53 mmol) and cyclopentyl mercaptan (1.885 mL, 17.53 mmol) in DMF (50 mL) under nitrogen. The resulting suspension was stirred at 60° C. for 6 hours.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([F:10])([F:9])[F:8])=[O:4].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2([C:36]([F:39])([F:38])[F:37])[O:23][N:22]=[C:21]([C:24]3[S:35][C:27]4=[N:28][CH:29]=[C:30]([C:32](O)=[O:33])[CH:31]=[C:26]4[CH:25]=3)[CH2:20]2)[CH:15]=[C:16]([Cl:18])[CH:17]=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>>[Cl:18][C:16]1[CH:15]=[C:14]([C:19]2([C:36]([F:38])([F:37])[F:39])[O:23][N:22]=[C:21]([C:24]3[S:35][C:27]4=[N:28][CH:29]=[C:30]([C:32]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH2:6][C:7]([F:10])([F:9])[F:8])=[O:33])[CH:31]=[C:26]4[CH:25]=3)[CH2:20]2)[CH:13]=[C:12]([Cl:11])[CH:17]=1
Reactant: O=C(O)c1cnc2sc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2c1
Reactant: NCC(=O)NCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)c1cnc2sc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2c1)NCC(F)(F)F
Yield: 34.8 %

Procedure:
Stir a mixture of 2-Amino-N-(2,2,2-trifluoro-ethyl)-acetamide (156 mg, 1 mmol), 2-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-thieno[2,3-b]pyridine-5-carboxylic acid (160 mg, 0.24 mmol), HATU (150 mg, 0.39 mmol) and DIPEA (0.2 mL) at room temperature for 10 hours. After removal of solvent, purify the mixture by preparative-HPLC to afford 2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)thieno[2,3-b]pyridine-5-carboxamide as a white solid (50 mg, 34.78%). MS (m/z): 599 (M+1). 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 8.51 (s, 1H), 7.52 (s, 2H), 7.44-7.41 (m, 2H), 7.22 (s, 1H), 6.64 (s, 1H), 4.27 (d, J=5.2, 2H), 4.17 (d, J=16.8, 1H), 4.04-3.95 (m, 2H), 3.80 (d, J=16.08, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:31]OC1C=CC=CC=1NC.O1C2C=CC(C3(C(NC4C=CC=C(Br)N=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])[CH3:31])[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1Nc1cccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)n1
Reactant: CNc1ccccc1OC
Agent: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OCO3)CC1
Product: COc1ccccc1N(C)c1cccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)n1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-((2-methoxyphenyl)(methyl)amino)pyridin-2-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-(2-methoxyphenylamino)pyridin-2-yl)cyclopropanecarboxamide by reacting 2-methoxy-N-methylaniline with 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.Cl[C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])=[O:14].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:13](=[O:14])[O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])[N:10]=2)[N:7]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cn2nc(Cl)ccc2n1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cn2nc(Cl)ccc2n1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine-2-amine (561 g, 3.3 mmol) in dimethylacetamide (11 ml) was added 2,2,2-trichloroethyl chloroformate (0.506 ml, 3.66 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction solution, and a solid was separated by filtration, which was washed with water to give 724 mg (63.3%) of the desired product as a solid.