Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[C:9]1[CH3:29])(C)(C)C.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]([CH3:29])=[C:10]2[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[N:20]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=2)[N:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1c(-c2n[nH]c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Product: Cc1c(-c2nn(Cc3ccc(F)cc3)c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)O

Procedure:
The title compound was prepared from the product of example 16, step c) and 4-fluorobenzyl bromide using the procedure described in example 14. 1H NMR (DMSO-d6) δ 13.25 (bs, 1H), 8.41 (d, J=6.6 Hz, 1H), 7.94-7.87 (m, 2H), 7.58 (d, J=8.7 Hz, 1H), 7.52 (d, J=9.0 Hz, 1H), 7.45 (dd, J=5.7, 8.4 Hz, 2H), 7.24-7.10 (m, 4H), 5.44 (d, J=14.4 Hz, 1H), 5.38 (d, J=14.4 Hz, 1H), 5.14 (s, 2H), 2.24 (s, 3H); MS: ESI (negative): 474, 476 (M−H).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].C1COCC1.Cl[C:12]1[C:13]([C:19]([N:21]([CH3:33])[C:22]2[CH:27]=[CH:26][C:25]([S:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=1>O>[Cl:18][C:16]1[CH:17]=[C:12]([S:5][CH2:3][CH3:4])[C:13]([C:19]([N:21]([CH3:33])[C:22]2[CH:27]=[CH:26][C:25]([S:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)=[O:20])=[N:14][CH:15]=1
Reactant: CCS
Reactant: CN(C(=O)c1ncc(Cl)cc1Cl)c1ccc(SC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCSc1cc(Cl)cnc1C(=O)N(C)c1ccc(SC(F)(F)F)cc1
Reaction time: 1 h

Procedure:
1.03 g of 60% sodium hydride (oil-based) was added to a mixture of 1.82 mL of ethanethiol and 59 ml of THF under ice cooling, and the mixture was stirred for 1 hour under ice cooling. A mixture of 8.92 g of 3,5-dichloro-N-methyl-N-(4-trifluoromethylsulfanylphenyl)picolinamide and 59 ml of THF was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 7 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 9.02 g of 5-chloro-3-ethylsulfanyl-N-methyl-N-(4-trifluoromethylsulfanylphenyl)picolinamide (hereinafter, referred to as Compound of Present Invention 158).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[NH:17]1[CH2:22][CH:21]=[C:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[CH2:19][CH2:18]1.C(=O)(O)[O-].[K+].O>CN(C)C(=O)C>[CH3:16][C:3]1([CH2:2][N:17]2[CH2:18][CH:19]=[C:20]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][CH:24]=3)[CH2:21][CH2:22]2)[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CC=C(c3c[nH]c4ccccc34)CC1)O2
Yield: 82.4 %

Procedure:
A suspension of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (0.85 g), 3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (1.1 g) and potassium bicarbonate (0.83 g) in N,N-dimethylactamide (6 mL) was refluxed for 7.5 hours under nitrogen atmosphere. To the mixture water was added and the product was extracted twice with ethyl acetate. The combined extract was washed with water followed by saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from acetone/diisopropyl ether to provide 0.99 g of the title compound. Yield 82%.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CC(=O)CC>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: C1COCCN1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Solvent: CCC(C)=O
Solvent: O
Product: COc1ccccc1OCCCc1oc(N2CCOCC2)nc1-c1ccc(Cl)cc1
Yield: 82.4 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), morpholine (435 mg) and 2-butanone (10 ml) was stirred with heating under reflux for 2 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was washed with a 10% aqueous solution of citric acid (100 ml) and dried over anhydrous magnesium sulfate. After the organic layer was concentrated, the residue was recrystallized from ethyl acetate-hexane to give 4-(4-chlorophenyl)-2-(4-morpholinyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole as pale yellow prisms (353 mg, 82%). Melting point 81-82° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[N:9]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)[CH:10]=[C:11]([C:13]3[CH:27]=[CH:26][C:16]([O:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:15][CH:14]=3)[N:12]=2)[CH2:3][CH2:2]1.[CH:42](=O)[CH3:43].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:42]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[N:9]([C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=4)=[CH:32][CH:33]=3)[CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:26][CH:27]=3)[N:12]=2)[CH2:3][CH2:2]1)[CH3:43]
Reactant: CC=O
Reactant: CCN(CC)CCCOc1ccc(-c2cn(-c3ccc(Oc4ccc(Cl)cc4)cc3)c(CC3CCNCC3)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)CCCOc1ccc(-c2cn(-c3ccc(Oc4ccc(Cl)cc4)cc3)c(CC3CCN(CC)CC3)n2)cc1
Temperature: 25 °C

Procedure:
[3-(4-{2-(Piperidine-4-ylmethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine (Example 539) (0.1 mmol) was treated in anhydrous DCM (2 ml) with acetaldehyde (1.2 eq.,) followed by addition of Na(OAc)3BH (1.5 eq.). The reaction mixture was stirred at rt. Crude product was extracted into EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concenterated in vacuo to give desired product, which was purified by column chromatography on silica gel to afford 49 mg of Example 540.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(O)(=O)C.[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=[CH2:15].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CO>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:14][CH2:15][NH:4][C:3]1[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1cc(O)ccc1N
Reactant: C=Cc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(O)ccc1NCCc1ccccn1
Temperature: 25 °C
Yield: 25.8 %

Procedure:
A mixture of 50.0 g (0.4 mole) of 2-methyl-4-hydroxyaniline, 2.4 g of glacial acetic acid and 125.0 ml of anhydrous methyl alcohol was heated to reflux with stirring and 63.1 g (0.6 mole) of 2-vinylpyridine was added dropwise to the mixture. The resultant reaction mixture was maintained at reflux for approximately forty-eight hours, cooled to ambient temperature and added to a mixture of aqueous sodium bicarbonate and toluene. The water layer was separated from to toluene layer and the water layer was extracted a second time with toluene. The two toluene layers were combined, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solid, which crystallized from the toluene upon standing, was collected by filtration, washed with hexane and dried to obtain 23.6 g of N-[2-(2-pyridyl)ethyl]-2-methyl-4-hydroxyaniline (Formula VI: R1 =R9 =H; R2 =CH3 ; R11 =OH), a pale beige-colored solid which melted at 137.5° to 139.5° C. after recrystallization from toluene. Significant infrared maxima appeared at 3200 cm-1 (OH;m) and 1601 cm-1 (C=C;m). The nuclear magnetic resonance spectrum was in accord with the assigned structure.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[S:21]([N:18]1[CH2:19][CH2:20][CH:15]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:14]=2)[CH2:16][CH2:17]1)(=[O:22])=[O:23]
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccccc3Cl)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3ccccc3Cl)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.6 %

Procedure:
To a stirred solution of {4-[1-(2-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (90 mg, 0.19 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (40 mg, 0.95 mmol) in water (1 mL) and the reaction mixture was stirred for 24 h at room temperature. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {4-[1-(2-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid (40 mg, 46%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.36 (br. s., 1H), 8.03 (d, J=7.8 Hz, 1H), 7.88-7.99 (m, 2H), 7.67-7.79 (m, 3H), 7.61 (t, J=8.8 Hz, 1H), 7.40 (dt, J=8.7, 1.7 Hz, 1H), 7.35 (s, 1H), 3.88 (d, J=12.2 Hz, 2H), 3.72 (s, 2H), 3.46 (t, J=11.7 Hz, 1H), 3.04 (t, J=11.7 Hz, 2H), 1.88-1.96 (m, 2H), 1.64-1.79 (m, 2H); MS cald. for C23H22ClFNO4S [(M−H)−]: 462, obsd. 462.2.
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:35])[N:21]([NH:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>O1CCCC1.[Pd].[OH-].[OH-].[Pd+2]>[CH:32]1([CH2:31][NH:30][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]([OH:29])=[C:19]([C:14]3[NH:13][C:12]4[CH:36]=[CH:37][C:9]([OH:8])=[CH:10][C:11]=4[S:16](=[O:17])(=[O:18])[N:15]=3)[C:20]2=[O:35])[CH2:33][CH2:34]1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc2n1NCC1CC1
Agent: [Pd+2]
Agent: [Pd]
Agent: O=C[O-]
Solvent: C1CCOC1
Product: O=c1c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc2n1NCC1CC1
Yield: 52.2 %

Procedure:
The product of Example 320B (0.296 g, 0.57 mmol) in tetrahyrofuran (15 mL) was reacted with a catalytic amount of palladium hydroxide on carbon, a catalytic amount of 5% palladium on carbon, and ammonium formate (0.180 g, 2.85 mmol) at 60° C. for 2 hours. The warm reaction mixture was filtered through celite® (diatomaceous earth) and the filtrate was diluted with diethyl ether and the precipitate filtered and dried to give the title compound (0.127 g, 53%).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9](Cl)=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:25]([Li])[CH2:26][CH2:27][CH3:28]>O1CCCC1.CCCCCC>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:25][CH2:26][CH2:27][CH3:28])=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCc1c(SCc2ccc(C(C)(C)C)cc2)cnn(C(C)(C)C)c1=O
Temperature: 0 °C

Procedure:
To a solution of 0.73 g (0.002 mol) of the 2-t-butyl-5-(p-t-butylbenzylthio)-4-chloro-3(2H)-pyridazinone thus obtained dissolved in 20 ml of tetrahydrofuran was added 3.0 ml of a solution of 10% butyl lithium dissolved in hexane at -70° C. under stirring. The reaction temperature was gradually raised from -70° C. to room temperature, and then the reaction mixture was stirred at room temperature for one hour. The reaction mixture was poured into 50 ml of ice water and extracted with 50 ml of chloroform. The resulting chloroform layer was washed with 100 ml of water, dried over anhydrous sodium sulfate and freed of solvent by distillation to give 0.65 g of a crude product. The crude product was purified by preparative thin layer chromatography on silica gel (developer:benzene) to obtain 0.38 g of 2-t-butyl-4-butyl-5-(p-t-butylbenzylthio)-3(2H)-pyridazinone.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][F:9])[N:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:22])[CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.[C:30](Cl)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C)C=O.CN(C)C1C=CN=CC=1>[F:9][CH2:8][CH2:7][N:6]1[C:2]([NH:1][C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[C:3]([NH:10][C:11](=[O:22])[CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1cnn(CCF)c1N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1cnn(CCF)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 49.2 %

Procedure:
To a solution of tert-butyl (3-{[5-amino-1-(2-fluoroethyl)-1H-pyrazol-4-yl]amino}-3-oxopropyl)carbamate (2.3 g) in N,N-dimethylformamide (12 ml) were added triethylamine (1.48 g), 4-dimethylaminopyridine (35.6 mg) and trityl chloride (2.2 g) at room temperature. The reaction mixture was stirred for 2 hours, and water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Acetonitrile was added, and the precipitate was collected by filtration to give tert-butyl (3-{[1-(2-fluoroethyl)-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-oxopropyl)carbamate (2 g).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([C:6]1([N:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:18])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5].[CH3:26]I>CN(C)C=O>[CH2:19]([N:17]([CH3:18])[C:6]1([C:4]([NH:3][CH3:26])=[O:5])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:7]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CI
Reactant: CN(Cc1ccccc1)C1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)C1(N(C)Cc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60% dispersion in mineral oil) (351 mg, 8.78 mmol) was added to a solution of tert-butyl 3-(aminocarbonyl)-3-[benzyl(methyl)amino]azetidine-1-carboxylate (described in Example 74) (1.4 g, 4.39 mmol) in dimethylformamide (14 ml) at 0° C.). After 1 hour at room temperature the reaction mixture was cooled to 0° C. and methyl iodide (0.44 ml, 7.02 mmol) added dropwise. The reaction mixture was allowed to stir at room temperature overnight, evaporated and the residues purified by preparative HPLC (standard basic conditions) to give tert-butyl 3-[benzyl(methyl)amino]-3-[(methylamino)carbonyl]azetidine-1-carboxylate as a solid, (460 mg, 31%). 1H NMR Spectrum: (CDCl3) 1.45 (s, 9H), 2.23 (s, 3H), 2.87 (d, 3H), 3.56 (s, 2H), 4.05 (d, 2H), 4.20 (brs, 2H), 6.80 (brs, 1H), 7.28 (m, 3H), 7.35 (m, 2H); Mass Spectrum: (M+H)+ 334.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:10][C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[C:5]([F:16])=[C:4]([NH:17][NH2:18])[N:3]=1.[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:38]=[O:39])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][NH:18][C:26](=[O:27])[C@H:25]([CH2:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:29][N:30]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH:38]=[O:39])[C:5]([F:16])=[C:6]([N:8]([CH2:10][C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[N:7]=1
Reactant: CN(Cc1ccco1)c1nc(Cl)nc(NN)c1F
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CN(Cc1ccco1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c1F
Reaction time: 8 h
Yield: 77.6 %

Procedure:
2-Chloro-5-fluoro-N-(2-furanylmethyl)-6-hydrazino-N-methyl-4-pyrimidinamine (0.400 g) and (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (0.764 g, 1.770 mmol) were dissolved in DMF. NMM (0.65 mL, 5.912 mmol) was added, followed by HOAt (0.241 g, 1.772 mmol) and EDC (0.3396 g, 1.771 mmol). After stirring overnight, the reaction mixture was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(2-furanylmethyl)(methyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as an orange solid (0.6318 g). LCMS: (M+H)+=553.2.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([N:55]([CH:65]3[CH2:67][CH2:66]3)CC3C=CC(OC)=CC=3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[CH:50][C:49]=4[F:54])=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.C(OC([NH:84][C@@H:85]([CH3:89])[C:86](O)=[O:87])=O)(C)(C)C.C(O)(C(F)(F)F)=O>CN(C=O)C>[NH2:84][C@H:85]([C:86]([NH:28][C@H:29]1[CH2:30][CH2:31][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([NH:55][CH:65]3[CH2:67][CH2:66]3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[CH:50][C:49]=4[F:54])=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:33][CH2:34]1)=[O:87])[CH3:89]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)C2CC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](N)C(=O)N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
BOP (62.5 mg, 0.141 mmol) was added to a solution of 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 8B (20 mg, 0.047 mmol), DIEA (0.0062 mL, 0.035 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (17.83 mg, 0.094 mmol) in DMF (1 mL). The clear reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated down, dissolved in CH2Cl2 (0.50 mL) and TFA (0.545 mL, 7.07 mmol) and stirred at rt for 30 min. The reaction mixture was concentrated and purified with HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)) to isolate the title compound, 6-((trans-4-(L-alanylamino)cyclohexyl)amino)-8-(cyclopropylamino)-N-(3-fluoro-4-pyridinyl)imidazo[1,2-b]pyridazine-3-carboxamide (10 mg, 42.8%), as a white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.41 (M+H=496.3). 1H NMR (400 MHz, MeOD) δ ppm 8.85 (1H, t, J=6.55 Hz), 8.69 (1H, d, J=3.53 Hz), 8.48 (1H, d, J=6.04 Hz), 8.13 (1H, s), 6.11 (1H, s), 3.97 (1H, d, J=4.28 Hz), 3.87 (1H, q, J=7.13 Hz), 3.72 (1H, br. s.), 2.59 (1H, td, J=6.80, 3.53 Hz), 2.21 (2H, br. s.), 1.99 (2H, br. s.), 1.32-1.62 (7H, m), 0.78-0.96 (2H, m), 0.55-0.76 (2H, m).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]4[C:33]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[N:27]([S:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)(=[O:36])=[O:35])[CH:26]=4)[CH:23]=3)[C:18](=[O:43])[NH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(#N)C>ClCCl>[C:37]1([S:34]([N:27]2[C:28]3=[N:29][CH:30]=[CH:31][CH:32]=[C:33]3[C:25]([C:22]3[CH:23]=[C:24]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:43])[NH:17][N:16]=[C:15]4[CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:26]2)(=[O:35])=[O:36])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2n[nH]c(=O)c3ccc(-c4cn(S(=O)(=O)c5ccccc5)c5ncccc45)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: O=c1[nH]nc(CC2CCNCC2)c2cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncccc34)ccc12

Procedure:
A solution of EXAMPLE 9B (272 mg, 0.45 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (1 mL) at ambient temperature for 1 hour. Acetonitrile (10 mL) was added and the solution was concentrated on a rotary evaporator. The residue was purified by HPLC (Zorbax C-18, 0-100% gradient of acetonitrile in water containing 0.1% trifluoroacetic acid) to yield the title compound. MS (ESI) m/z 500 (M+H)+; 1H NMR (300 MHz, CD3OD) δ 1.49-1.66 (m, 2H), 2.01-2.16 (m, 2H), 2.26-2.37 (m, 1H), 2.93-3.05 (m, 2H), 3.10 (d, J=7.12 Hz, 2H), 3.39 (d, J=12.54 Hz, 2H), 7.41 (dd, J=8.14, 4.75 Hz, 1H), 7.55-7.61 (m, 2H), 7.64-7.72 (m, 1H), 8.18-8.24 (m, 3H), 8.24-8.27 (m, 1H), 8.33 (dd, J=7.97, 1.53 Hz, 1H), 8.39 (s, 1H), 8.45 (dd, J=4.92, 1.53 Hz, 1H), 8.47-8.52 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].BrCCC1C=CC2[O:39][CH2:40][O:41]C=2C=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[O:39]1[C:22]2[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][N:16]([C@H:25]3[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]3)[C:14](=[O:15])[NH:13][C:11]3[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=3)=[CH:24][C:23]=2[O:41][CH2:40]1
Reactant: BrCCc1ccc2c(c1)OCO2
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2ccc3c(c2)OCO3)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 5-(2-bromo-ethyl)benzo[1,3]dioxole and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[SH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20](OC)=[O:21]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:20](=[O:21])[CH2:19][S:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: COC(=O)CBr
Reactant: Nc1ccc([N+](=O)[O-])cc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CSc2cc([N+](=O)[O-])ccc2N1
Temperature: 50 °C
Yield: 73.8 %

Procedure:
To a stirred suspension of 2-amino-5-nitrobenzenethiol (Step 1, 29 g, 139.8 mmol) and potassium carbonate (115.93 g, 838.8 mmol) in dry DMF (150 mL) is added methyl bromoacetate (15.88 mL, 167.8 mmol). The reaction mixture is heated at 50° C. for 16 h at which time the reaction is quenched with ice and water (50 mL). The precipitate is filtered and dried under high vacuum to give the title compound as a yellow solid (21.69 g, 74%), MS m/z 211.5 (M+H)+.