Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]([O:14]CC)=[O:13])[C:7]2=[O:17].[OH-].[Na+]>[Pd].C(O)C>[O:17]=[C:7]1[C:6]2[C:11](=[CH:2][CH:3]=[CH:4][C:5]=2[C:18]([F:21])([F:19])[F:20])[NH:10][CH:9]=[C:8]1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ccc(C(F)(F)F)c2c1=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
Ethyl 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate (500 mg, 1.56 mmol) was dissolved in NaOH (16 mL of 2.0 M, 31 mmol) and ethanol (3 mL) and heated to 100° C. for 2 h. The clear, light yellow solution was cooled to 50° C., the reaction mixture was degassed with N2, and then treated with 10% Pd/C (65 mg, 0.03 mmol). The reaction mixture was heated at 70° C. for 3 h under an atmosphere of H2. The reaction mixture was cooled and then filtered, acidified with conc. HCl until a white precipitate was formed, then allowed to stir overnight. The reaction mixture was filtered, washed with water and dried with CH3CN to yield a white powder (350 mg, 87%). 1H NMR (400 MHz, DMSO-d6) δ 15.26 (s, 1H), 13.68 (s, 1H), 8.98 (s, 1H), 8.16-8.09 (m, 1H), 8.08-7.97 (m, 2H).
Reaction SMILES: CO.[C:3]([O:7][C:8]([O:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:19]([N+:30]([O-])=O)[CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>[C].[Pd].C(OCC)(=O)C>[NH2:30][C:19]1[CH:18]=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH:12]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)(C)OC(=O)Oc1cccc(-c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)Oc1cccc(-c2ccc(C(=O)OC(C)(C)C)c(N)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To a mixed solution of methanol 18 mL and ethyl acetate 18 mL of tert-butyl 4-(3-(tert-butoxycarbonyl)oxyphenyl)-2-nitrobenzoate 3.5 g was added 5% palladium-carbon 0.70 g, and it was stirred under hydrogen atmosphere at room temperature for 3 hours and 30 minutes. The solvent was removed under reduced pressure after insoluble matter was filtrated to give tert-butyl 2-amino-4-(3-(tert-butoxycarbonyl)oxyphenyl)benzoate 3.2 g of yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH2:12].[CH3:13][N:14]([CH3:20])[CH2:15][CH2:16][N:17]=[C:18]=[S:19]>>[CH3:13][N:14]([CH3:20])[CH2:15][CH2:16][NH:17][C:18]([NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]1[O:5][CH:4]=[N:3][C:2]=1[CH3:1])=[S:19]
Reactant: CN(C)CCN=C=S
Reactant: Cc1ncoc1CCNCCN
Product: Cc1ncoc1CCNCCNC(=S)NCCN(C)C

Procedure:
By the procedure of Example 40(a)(ii), N-[2-(4-methyl-5-oxazolyl)ethyl]ethylenediamine [prepared by reacting ethylenediamine with 5-(2-chloroethyl)-4-methyloxazole] is reacted with 2-dimethylaminoethyl isothiocyanate to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH2:22]([N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:33]3[CH:32]=[N:31][N:30]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:34]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(CCc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(Br)cnc32)cc1
Yield: 44 %

Procedure:
Using similar reaction conditions as described in step-i of example-1,5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 1) (400 mg, 0.838 mmol) was coupled with 1-phenethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 59) (250 mg, 0.838 mmol) using sodium carbonate (266 mg, 2.515 mmol) and Pd(PPh3)2Cl2 (30 mg, 0.041 mmol) in toluene/ethanol/water (20/10/5 ml) to afford 191 mg (44% yield) of the pure product after column purification using 20% ethyl acetate in hexane as eluent. MS: m/z=521.1 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH:9]=[CH2:10])[N:6]=[C:5]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[H][H]>[Pd].C(O)C>[CH2:9]([C:7]1[N:6]=[C:5]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]2)[N:4]([CH2:3][CH2:2][OH:1])[CH:8]=1)[CH3:10]
Reactant: C=Cc1cn(CCO)c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1cn(CCO)c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Add 10% palladium on carbon (2.10 g) in ethanol (50 mL). Then add a solution of tert-butyl 4-(1-(2-hydroxyethyl)-4-vinyl-1H-imidazol-2-yl)piperidine-1-carboxylate (20.00 g, 62.22 mmol) in ethanol (200 mL). Cycle through nitrogen and vacuum three times, then hydrogen and vacuum three times. Allow to stir at room temperature under 1 atmosphere hydrogen. After two hours, filter through Celite®. Wash with methanol. Concentrate the filtrate in vacuo to give a light yellow solid as the title compound (20.00 g, 99%). MS (ES) m/z=324 [M]+.
Reaction SMILES: Br[Zn]C[Zn]C[Zn]Br.[CH2:8]1OCCC1.[C:13]([Si:17]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[O:18][CH:19]1[CH2:23][CH:22]([OH:24])[C:21](=O)[CH:20]1[CH2:26][O:27][C:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:16])([CH3:15])[CH3:14]>O1CCCC1.Cl[Ti](Cl)(Cl)Cl>[C:13]([Si:17]([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[O:18][CH:19]1[CH2:23][CH:22]([OH:24])[C:21](=[CH2:8])[CH:20]1[CH2:26][O:27][C:28]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](OC1CC(O)C(=O)C1COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Br[Zn]C[Zn]C[Zn]Br
Product: C=C1C(O)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 50 %

Procedure:
2.4 ml (1.26 mmol) of 20% suspension Nysted reagent and 6.4 ml of tetrahydrofuran were added dropwise to a reactor successively and cooled to 0° C. 0.14 ml (1.26 mmol) of TiCl4 was added thereto dropwise, and the resulting mixture was stirred. The reaction mixture was cooled to −40° C., and a solution which had been prepared by dissolving 0.527 g (0.842 mmol) of 3-(tert-butyl-diphenyl-silanyloxy)-5-hydroxy-2-trityloxymethyl-cyclopentanone (a compound of formula (2)) obtained in Example 2 in 2.4 ml of tetrahydrofuran was added thereto. The reaction mixture was stirred at room temperature for 3.5 hrs. After completion of the reaction, the reaction mixture was cooled to −20° C., quenched by adding 25 ml of 1N hydrochloric acid, and extracted with 25 ml of dichloromethane to separate an organic layer. The organic layer was washed with 20 ml of 4% sodium bicarbonate solution and 20 ml of brine successively, dried over anhydrous sodium sulfate, filtered, and condensed. The residue thus obtained was isolated by HPLC to obtain 0.184 g of the title compound (yield: 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:17])[C:11]2[CH2:15][O:14][C:13](=[O:16])[CH:12]=2)[CH:5]=[N:6][C:7]=1[Cl:8].C(N(CC)CC)C.[Cl:25]N1C(=O)CCC1=O>C(#N)C>[Cl:25][C:12]1[C:13](=[O:16])[O:14][CH2:15][C:11]=1[N:10]([CH2:9][C:4]1[CH:5]=[N:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:17]
Reactant: CN(Cc1cnc(Cl)c(Cl)c1)C1=CC(=O)OC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(Cc1cnc(Cl)c(Cl)c1)C1=C(Cl)C(=O)OC1
Reaction time: 1 h
Yield: 84.3 %

Procedure:
162 mg (0.59 mmol) of 4-[[(5,6-dichloropyridin-3-yl)methyl](methyl)amino]furan-2(5H)-one (10) are dissolved in 20 ml of acetonitrile, and 90 μl (0.65 mmol) of triethylamine and 158 mg (1.19 mmol) of N-chlorosuccinimide are added at room temperature. After 1 hour of stirring, the mixture is concentrated under reduced pressure. Purification of the residue by column chromato-graphy on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (2:1) gives 153 mg (67% of theory) of 3-chloro-4-[[(5,6-dichloropyridin-3-yl)methyl](methyl)amino]furan-2(5H)-one.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]=1[CH3:23])[CH:3]=[C:4](C(OC)=O)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[Li+].O.CN1CCCC1=O.Cl>>[CH3:1]/[C:2](/[CH2:13][CH2:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]=1[CH3:23])=[CH:3]\[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(=CC(C)CCC1=C(C)CCCC1(C)C)C(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)C/C=C(\C)CCC1=C(C)CCCC1(C)C
Temperature: 130 °C
Yield: 100.9 %

Procedure:
Conjugated malonate 3a (0.5 g, 1.5 mmol), anhydrous lithium chloride (93 mg, 2.2 mmol) and water (53 mg, 3 mmol) in N-methyl-pyrrolidone (2.9 g, 29 mmol) are heated under stirring to 130° C. After 4 h at this temperature the mixture is poured upon 2 M HCl and extracted with tent-butyl methyl ether. The combined organic layers are washed with conc. NaHCO3, conc. NaCl and dried over MgSO4. After filtration and evaporation of the solvent the crude product (0.64 g) is bulb-to-bulb-distilled to give 0.4 g of 4a at 120° C./0.1 mbar. E/Z ratio 82:18. Analytical data of the E-isomer: 1H-NMR (400 MHz, CDCl3): δ 1.0 (s, 6 H), 1.4 (m, 2 H), 1.55 (m, 2 H), 1.6 (s, 3 H), 1.7 (s, 3 H), 1.9 (m, 2 H), 2.1 (4 H), 3.05 (d, 2 H), 3.7 (s, 3 H), 5.35 (t, 1 H) ppm. 13C-NMR (400 MHz, CDCl3): δ 16.35 (t), 19.5 (t), 19.8 (q), 27.5 (t), 28.6 (q, 2 C), 32.8 (t), 33.5 (t), 34.95 (s), 39.8 (t), 40.0 (t), 51.6 (q), 115.0 (d), 127.1 (s), 136.9 (s), 139.9 (s), 172.9 (s). MS (EI): m/z (%) 264 (M+, 4), 249 ([M-15]+, 1), 190 (3), 175 (3), 138 (10), 137 (100), 136 (21), 121 (12), 106 (11), 95 (73), 81 (45), 55 (19), 41 (21). Retention times (GC): 9.47 (Z), 9.56 (α,β), 9.62 (E) min. The mass spectra of the E- and Z-isomers are identical. IR (film): 2972 (m), 2865 (m), 1738 (s), 1434 (m), 1258 (m), 1199 (m), 1148 (m).
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10][O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])[N:8]=1)([CH3:3])[CH3:2].[NH2:22][C@H:23]([C@@H:31]([OH:51])[CH2:32][C@@H:33]([NH:41][C:42]([O:44][CH2:45][C:46]1[S:50][CH:49]=[N:48][CH:47]=1)=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10][O:11][C:12]([NH:14][C@H:15]([C:19]([NH:22][C@H:23]([C@@H:31]([OH:51])[CH2:32][C@@H:33]([NH:41][C:42]([O:44][CH2:45][C:46]2[S:50][CH:49]=[N:48][CH:47]=2)=[O:43])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[CH:16]([CH3:17])[CH3:18])=[O:13])[N:8]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1nc(CCOC(=O)N[C@H](C(=O)O)C(C)C)cs1
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Product: CC(C)c1nc(CCOC(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1

Procedure:
Using the procedure of Example 1U, but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((2-(2-isopropyl-4-thiazolyl)ethoxy)carbonyl)valine and replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-2-amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane provided, after purification by silica gel chromatography using 99:1 CHCl3 :CH3OH, 50 mg (30%) of the desired compound (Rf 0.3, 95:5 CHCl3 :CH3OH) as a solid, mp 159-160° C. Mass spectrum: (M+H)+ =722 HRMS. Exact mass calcd for C37H47N5O6S2 : 722.3046. Found: 722.3036.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9](Cl)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([CH3:30])[C:22]=1[S:23]([CH2:26][N+:27]([O-:29])=[O:28])(=[O:25])=[O:24])[NH2:19].C(=O)([O-])[O-].[Ca+2].O>O1CCCC1>[CH3:30][C:21]1[CH:20]=[C:18]([NH:19][S:9]([C:8]2[CH:13]=[CH:14][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:11])=[O:10])[CH:17]=[C:16]([CH3:15])[C:22]=1[S:23]([CH2:26][N+:27]([O-:29])=[O:28])(=[O:25])=[O:24]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(C)c(S(=O)(=O)C[N+](=O)[O-])c(C)c2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 7.2 %

Procedure:
2.9 g (12.4 mmol) of N-acetylsulphanilyl chloride are added portionwise to a mixture, maintained under a nitrogen atmosphere, of 2.0 g (8.19 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline and 1.6 g (16.0 mmol) of calcium carbonate in 40 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for 6 h at room temperature and is then refluxed for 2 h, after which it is poured into 200 ml of water. The mixture is extracted 3 times with methylene chloride. The combined organic extracts are washed with water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The oily residue obtained is crystallized by trituration from a mixture of hexane and ethyl acetate. These crystals are washed with a mixture of methylene chloride and methanol at room temperature and then with a mixture of hexane and ethyl acetate at reflux, and finally with ethanol at room temperature, to give 0.26 g (7.2%) of N-[4-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenylsulphamoyl]phenyl]acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]([NH:19]C(OC(C)(C)C)=O)[CH2:13][O:14][S:15](=[O:18])(=[O:17])[NH2:16])[C:6]=2[CH:27]=1.O1CCOCC1.Cl.C(OCC)(=O)C>CO>[ClH:1].[NH2:19][CH:12]([CH2:13][O:14][S:15](=[O:17])(=[O:18])[NH2:16])[CH2:11][O:10][C:7]1[C:6]2[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][N:8]=1
Reactant: CC(C)(C)OC(=O)NC(COc1noc2ccc(Cl)cc12)COS(N)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(COc1noc2ccc(Cl)cc12)COS(N)(=O)=O

Procedure:
To a solution of 0.4 g of 5-chloro-3-(2-tert-butoxycarbonylamino-3-sulfamoyloxypropoxy)-1,2-benzoisoxazole in 10 ml of methanol is added 5 ml of a dioxane solution (3.2N) of hydrogen chloride at room temperature and they are subjected to reaction at the same temperature for 24 hours, after which the solvent is removed by distillation under reduced pressure. To the residue obtained is added 10 ml of ethyl acetate, and the crystals precipitated are collected by filtration, to obtain 0.24 g of colorless, crystalline 3-(2-amino-3-sulfamoyloxypropoxy)-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 150.5°-152.5° C. (decomp.).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[O:28][N:27]=4)=[O:24])=[CH:18][CH:17]=3)=[O:14])=[N:11][CH:12]=2)[CH2:3]1.Cl.[C:36](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=C(OC4CCNCC4)C=CN=3)=CC=2)C=1)(C)(C)[CH3:37]>>[C:31]([C:29]1[O:28][N:27]=[C:26]([NH:25][C:23](=[O:24])[NH:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH:4]4[CH2:5][N:2]([CH2:36][CH3:37])[CH2:3]4)=[CH:12][N:11]=3)=[CH:21][CH:20]=2)[CH:30]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CNC4)cn3)cc2)no1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3cc(OC4CCNCC4)ccn3)cc2)no1
Agent: Cl
Product: CCN1CC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)C1
Yield: 34 %

Procedure:
N-(4-(3-(5-tert-Butylisoxazol-3-yl)ureido)phenyl)-5-(1-ethylazetidin-3-yloxy)picolinamide (13 mg, 34%) was prepared as an off-white powder using a procedure analogous to that described in Example 2, substituting 5-(azetidin-3-yloxy)-N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)picolinamide hydrochloride from Step 2 of this example for N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-4-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 2. LC-MS (ESI) m/z 479 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.51 (s, 1H), 8.81 (s, 1H), 8.32 (br. s., 1H), 8.08 (d, J=8.29 Hz, 1H), 7.81 (d, J=8.29 Hz, 2H), 7.49 (d, J=8.85 Hz, 1H), 7.42 (d, J=7.54 Hz, 2H), 6.50 (s, 1H), 4.99 (t, J=4.71 Hz, 1H), 3.61-3.82 (m, 2H), 2.99 (t, J=5.93 Hz, 2H), 2.46 (br. s., 2H), 1.30 (s, 9H), 0.90 (t, J=6.97 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[N:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[Sn](CCCC)(CCCC)CCCC>CN(C)C(=O)C>[N:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cnccn5)cc43)n2)CC1
Temperature: 150 °C
Yield: 68.2 %

Procedure:
A solution of tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-2-pyridyl]piperazine-1-carboxylate (40 mg, 0.096 mmol) and palladium(0)tetrakis(triphenylphosphine) (11 mg, 0.0095 mmol) in N,N-dimethylacetamide 1 mL was added (2-pyrazinyl)tributyltin (0.064 mL, 0.19 mmol). The reaction mixture heated at 150° C. for 45 min in biotage microwave. The reaction mixture was filtered through celite and concentrated. The crude product was diluted with EtOAc then washed with water. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 20% EtOAc) to give tert-butyl 4-[6-(6-pyrazin-2-ylpyrazolo[4,3-c]pyridin-1-yl)-2-pyridyl]piperazine-1-carboxylate 30 mg 67% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:16])=[C:6]([CH:12]([OH:15])[C:13]#[N:14])[CH:7]=[C:8]([CH2:10][CH3:11])[CH:9]=1)[CH3:2].[CH3:17][OH:18].[ClH:19]>C(OCC)C.O1CCOCC1>[ClH:19].[CH2:1]([O:3][C:4]1[C:5]([F:16])=[C:6]([CH:12]([OH:15])[C:13](=[NH:14])[O:18][CH3:17])[CH:7]=[C:8]([CH2:10][CH3:11])[CH:9]=1)[CH3:2]
Reactant: CO
Reactant: CCOc1cc(CC)cc(C(O)C#N)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOc1cc(CC)cc(C(O)C(=N)OC)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 118E (630 mg, 2.93 mmol) in anhydrous diethyl ether (10 mL) at 0° C. was added MeOH (1.2 mL) and 4.0 N HCl in dioxane (2.9 mL). The mixture was stirred at 0° C. for 30 min and then at rt over night. Solvent was removed to give methyl 2-(3-ethoxy-5-ethyl-2-fluorophenyl)-2-hydroxyacetimidate HCl salt. To this salt in CH2Cl2 (5.0 mL) was added H2O (8.0 mL). The mixture was stirred at rt for 30 min, then extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried and concentrated. The crude was purified by column chromatography to give 118F (632 mg, 89% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.20 (t, J=7.69 Hz, 3H) 1.43 (t, J=7.03 Hz, 3H) 2.58 (q, J=7.76 Hz, 2H) 3.76 (s, 3H) 4.04-4.13 (m, 2H) 5.37 (s, 1H) 6.68-6.81 (m, 2H).
Reaction SMILES: C[C:2]1[C:3](=[O:17])[CH2:4][CH2:5][N:6]2[C:11]=1[CH2:10][CH2:9][C:8]1[CH:12]=[C:13](C)[CH:14]=[CH:15][C:7]2=1.COC=CC(O[Si](C)(C)C)=C.C([O-])(O)=O.[Na+]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:5]1[N:6]2[CH:11]([CH2:2][C:3](=[O:17])[CH:4]=1)[CH2:10][CH2:9][C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]2=1
Reactant: CC1=C2CCc3cc(C)ccc3N2CCC1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C=C(C=COC)O[Si](C)(C)C
Agent: O=C([O-])O
Solvent: ClCCl
Product: O=C1C=CN2c3ccccc3CCC2C1
Reaction time: 1 h
Yield: 25.1 %

Procedure:
To a stirred solution of compound 4 [(QW)n=H, R3=R4=H] (4 g, 14.42 mmol) of the example 3, in 75 ml of anhydrous CH2Cl2 under argon at −10° C. is added, dropwise in 7 min, 28.84 ml of a 1M solution of TiCl4 in CH2Cl2 maintaining the temperature below −5° C. Then 1-methoxy-3-(trimethylsilyloxy)-1-3-butadiene (compound 6, R1=MeO, R2=H, R6=H) (3.29 ml, 17.3 mmol) is added by syringe at 0° C., and the reaction was left aside at room temperature for 1 h. The reaction mixture is added, cautiously, with 100 ml of NaHCO3 satured solution, and then stirred for 30 min. The organic layer is separated, washed with water, filtered on Celite and dried over Na2SO4. After removal of the solvent the crude product is purified by flash column chromatography (eluant light-petroleum ether/ethyl acetate 1:4) affording 0.72 g (25% yield) of the expected product (white crystals, m.p.: 135-137° C.).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH2:14][OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][C:24]=1[CH3:30].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:18][O:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:15][CH2:14][C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:16])([F:1])[F:17])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[CH:25][C:24]=1[CH3:30]
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: COC(=O)CCc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)CCc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1C
Reaction time: 8 h

Procedure:
To a solution of [5-(4-Trifluoromethyl-phenyl)-thiophen-2-yl]-methanol (0.063 g, 0.232 mmole) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.045 g, 0.232 mmole) in toluene (2 mL) at room temperature, is added tributylphosphine (0.087 mL, 0.348 mmole) followed by a solution of 1,1′-(azodicarbonyl)-dipiperidine (0.088 g, 0.348 mmole) in toluene (2 mL). The reaction is stirred overnight, and then diluted with hexane (10 mL). The precipitate is removed through filtration and the filtrate is concentrated, loaded to a silica gel column, eluted with ethyl acetate in hexane (0-15%) and concentrated to provide the titled compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:22][C:23]([F:29])([F:28])[S:24]([NH2:27])(=[O:26])=[O:25]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:17]=[C:16]([CH2:18][NH:27][S:24]([C:23]([F:29])([F:28])[F:22])(=[O:26])=[O:25])[CH:15]=[N:14][CH:13]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Product: Cn1c(-c2cncc(CNS(=O)(=O)C(F)(F)F)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and trifluoromethanesulfonamide are processed according to the method described in Example 170 to give N-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-C,C,C-trifluoromethanesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.78 (s, 3H), 4.56 (s, 2H), 7.37 (dd, J=8.5, 1.9 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 8.09 (t, J=2.1 Hz, 1H), 8.78 (d, J=2.3 Hz, 1H), 8.83 (d, J=2.0 Hz, 1H), 10.16 (br. s., 1H). HRMS (ESI) m/z 429.0412 [(M+H)+ Calcd for C17H13ClF3N4O2S: 429.0400].