Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[N:13]/[OH:14])/[CH2:7][C:8]32[CH2:12][CH2:11]3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[CH3:22][S:23]([O:14]/[N:13]=[C:6]1\[CH2:7][C:8]2([CH2:12][CH2:11]2)[C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: O/N=C1\CC2(CC2)c2cc(Br)ccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)O/N=C1\CC2(CC2)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
To a 0° C. solution of (E)-6′-bromospiro[cyclopropane-1,1′-inden]-3′(2′H)-one oxime (500 mg, 1.98 mmol) in THF (5 mL) was added triethylamine (332 μL, 2.38 mmol) followed by slow addition of MsCl (170 μL, 2.18 mmol). The reaction was stirred 10 minutes at 0° C. then concentrated. The residue was triturated from methanol (5 mL) to afford (E)-6′-bromospiro[cyclopropane-1,1′-inden]-3′(2′H)-one O-methylsulfonyl oxime (653 mg, 100% yield) as a white solid after drying under high vacuum. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.64 (d, J=8.4 Hz, 1H), 7.42 (dd, J=8.3, 1.6 Hz, 1H), 6.98 (d, J=1.5 Hz, 1H), 3.26 (s, 3H), 3.15 (s, 2H), 1.06-1.42 (m, 4H); MS (EI) m/z=331.2 [M+1]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[F:16][C:17]1([F:25])[CH2:22][CH2:21][CH:20]([CH2:23][NH2:24])[CH2:19][CH2:18]1>CCO>[F:16][C:17]1([F:25])[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:19][CH2:18]1
Reactant: NCC1CCC(F)(F)CC1
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Product: CC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c([N+](=O)[O-])c1

Procedure:
N-(4-Fluoro-3-nitrophenyl)acetamide (1.15 g, 5.84 mmol) and [(4,4-difluorocyclohexyl)methyl]amine hydrochloride (1.30 g, 7.59 mmol) were stirred in 30 mL of EtOH containing TEA (2.40 mL, 17.5 mmol) at 80° C. for 48 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4 solution, saturated aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The product was crystallized from EtOAc. The left over mother liquor was purified by silica gel flash chromatography using 2:1/hexanes:acetone as eluent. Yield: 1.50 g (78%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.33-1.47 (m, 2 H), 1.66-1.77 (m, 2 H), 1.77-1.86 (m, 1 H), 1.89-1.93 (m, 1 H), 1.93-1.97 (m, 1 H), 2.10-2.17 (m, 2 H), 2.18 (s, 3 H), 3.23 (dd, J=6.74, 5.76 Hz, 2 H), 6.83 (d, J=9.37 Hz, 1 H), 7.15 (s, 1 H), 7.80 (dd, J=9.18, 2.54 Hz, 1 H), 8.09 (d, J=2.54 Hz, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.[CH3:10][NH2:11]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:11][CH3:10])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CN
Product: CNCc1ccc(Br)cc1
Yield: 93.7 %

Procedure:
Following the procedure outlined for Example 488, 1-bromo-4-(bromomethyl)benzene (1.0 g, 4.0 mmol) was reacted with methanamine (620 mg, 20 mmol) to afford the desired product (750 mg, 93%) as a brown solid: ESI MS m/z 201 [C8H10BrN+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[CH2:8][N:9]1[C:13](=[O:14])[C:12]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[N:11]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10]1)=[O:4].Cl>O1CCOCC1>[O:14]=[C:13]1[C:12]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:11]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:10][N:9]1[CH2:8][C:7]1[CH:6]=[C:5]([CH:35]=[CH:34][CH:33]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C

Procedure:
To tert-butyl 3-(3-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.24 g, 0.5 mmol) was added 4M solution of HCl in dioxane (5 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated in vacuo to obtain methyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]1[CH2:8][C:7](=[O:9])[CH2:6][C:5](=[O:10])[CH2:4]1.[O:13](S(C(F)(F)F)(=O)=O)[S:14]([C:17]([F:20])([F:19])[F:18])(=O)=[O:15]>C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[S:14]([O:9][C:7]1[CH2:8][CH:3]([C:2]([F:11])([F:12])[F:1])[CH2:4][C:5](=[O:10])[CH:6]=1)(=[O:15])=[O:13]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CC(=O)CC(C(F)(F)F)C1
Solvent: ClCCl
Product: O=C1C=C(OS(=O)(=O)C(F)(F)F)CC(C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-(trifluoromethyl)cyclohexane-1,3-dione (1.0 eq) in DCM (0.23 M) was added TEA (1.2 eq) to give a clear solution. The mixture was cooled to 0° C. And then Tf2O (1.05 eq) in DCM was added dropwise. The reaction mixture was stirred at that temperature for 2 hours. The reaction mixture was diluted with DCM, and washed with water, aq. NaHCO3, brine, and was dried over MgSO4, filtered and concentrated to give 3-oxo-5-(trifluoromethyl)cyclohex-1-enyl trifluoromethanesulfonate, which was used to next step directly. LC/MS (m/z): MH+=313.0, Rt=1.02 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.Br[CH2:38][C:39]([NH2:41])=[O:40]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: NC(=O)CBr
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CC(N)=O)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (50 uL, 0.36 mmol) in DMF (1.5 mL), was added 2-bromo-acetamide (33 mg, 0.24 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to give 2-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)acetamide as a white solid: 1H NMR (400 MHz, MeOD-d4) δ 8.11 (s, 1H), 7.76 (d 1H), 7.09 (d, 1H), 6.27 (s, 1H), 4.0 (s, 2H), 3.75-3.73 (m, 2H), 3.22-3.13 (m, 3H), 2.34 (s, 3H), 2.30 (s, 3H), 2.04-2.00 (m, 4H); ESMS m/z 473.2 (M+H+).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]1[C:20]([Cl:21])=[CH:19][C:11]2[N:12]=[C:13](S(O)(=O)=O)[NH:14][C:10]=2[CH:9]=1>P(Cl)(Cl)(Cl)=O>[Cl:2][C:13]1[NH:14][C:10]2[CH:9]=[C:8]([Cl:7])[C:20]([Cl:21])=[CH:19][C:11]=2[N:12]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1nc2cc(Cl)c(Cl)cc2[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
A modified procedure of Balli and Kersting procedure described in Balli, H. et al., Justis Liebigs Am. Chem. 1:647 (1961), was followed. A one liter three neck roundbottom flask was fitted with an over head stirrer and a reflux condenser connected to a gas scrubber. To the flask was added in order, phosphorus oxychloride (80 mL), phosphorus pentachloride (104.0 g, 0.5M) and 5,6-dichlorobenzimidazole-2-sulfonic acid (9) (66.8 g, 0.25M). The resulting mixture was carefully heated until an exothermic reaction occurred. The heat source was removed. When the reaction had subsided, the mixture was carefully heated to reflux. After all gas evolution had ceased (5 hr) the mixture was protected from moisture and allowed to cool to 25° C. The resulting thick slurry was carefully added to cold H2O (2.5 L) containing some ice. Ice was added as needed. The aqueous mixture was allowed to stand for 18 hr at 5° C. while the product precipitated. The pH of the mixture was adjusted to pH 8 with conc. NH4OH then acidffied to pH 3 with glacial AcOH. The solid was collected by filtration, washed with H2O, then dried on the filter. The material was dissolved in THF, treated with charcoal, then filtered through Celite. The solvent was removed under reduced pressure. The solid residue was dried at 60° C. under reduced pressure for 18 hr to yield 39.9 g (72%) of 2,5,6-trichlorobenzimidazole (5). MP: 212°-214° C. (eff. then solidifies). See Kawashima, E. et al., Nucleic Acid Chemistry: Improved and New Synthetic Procedures, Method and Techniques, eds. Townsend, L. B. et al., Wiley Interscience New York, N.Y., Part IV p. 96 (1991). TLC: Rf =0.89 (EtOAc; SiO2). Recrystallization from benzene-hexane raises the melting point to 223°-224° C.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([F:28])[C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:9])=C>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([F:28])[C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:9]
Reactant: C=COCCONC(=O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Solvent: CO
Product: O=C(NOCCO)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Yield: 47.6 %

Procedure:
A solution of 8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-vinyloxy-ethoxy)-amide (200 mg, 0.39 mmol) in methanol (1 mL) was loaded onto an SCX-2 column. The column was washed with methanol (10 mL) then the product was then eluted with ammonia in methanol (20 mL, 2M), the appropriate fractions were concentrated in vacuo. The resultant residue was subjected to reverse phase preperative HPLC (10-90% acetonitrile/water 0.1% formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm). The resultant product was dissolved in ethyl acetate (5 mL) and washed with aqueous saturated sodium bicarbonate solution (10 mL). The aqueous fraction was extracted twice with ethyl acetate (2×10 mL) and the combined organics were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to yield the title compound as a white solid (88 mg, 39%). LCMS (Method A): RT=7.71 min, [M+H]+=475. 1H NMR (DMSO-d6): 8.20 (1H, s), 7.60 (1H, s), 7.57 (1H, dd, J=10.73, 1.96 Hz), 7.26 (1H, dd, J=8.43, 1.82 Hz), 6.82 (1H, d, J=11.14 Hz), 6.30 (1H, t, J=8.71 Hz), 3.65 (2H, t, J=4.77 Hz), 3.45 (2H, t, J=4.68 Hz).
Reaction SMILES: [F-].[Cs+].[CH2:3]([O:10][N:11]1[C:17](=[O:18])[N:16]2[CH2:19][C@H:12]1[CH2:13][CH2:14][C@H:15]2[C:20]1[CH:24]=[C:23]([Si](C)(C)C)[O:22][N:21]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CC#N.CCO>[CH2:3]([O:10][N:11]1[C:17](=[O:18])[N:16]2[CH2:19][C@H:12]1[CH2:13][CH2:14][C@H:15]2[C:20]1[CH:24]=[CH:23][O:22][N:21]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)c1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: CC#N
Product: O=C1N2C[C@@H](CC[C@H]2c2ccon2)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
CsF (230 mg, 1.512 mmol was added to a solution of (2S,5R)-6-(benzyloxy)-2-(5-(trimethylsilyl)isoxazol-3-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (187 mg, 0.504 mmol) in CH3CN/EtOH (15 mL, 3:1). After stirring at rt for 2 hrs, the reaction mixture was concentrated and the residue was dissolved in DCM (25 mL), washed with water (3×), and saturated sodium chloride, then, dried, and concentrated. The residue was purified by silica gel column chromatography (6:1 petroleum ether/EA) to afford (2S,5R)-6-(benzyloxy)-2-(isoxazol-3-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (116 mg, 77%) as a white solid. ESI-MS (EI+, m/z): 300 [M+H]+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[F:34][C:35]1[CH:36]=[C:37]([C:42]2([O:48][CH3:49])[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH:38]=[C:39]([OH:41])[CH:40]=1>C(OCC)(=O)C>[F:34][C:35]1[CH:40]=[C:39]([CH:38]=[C:37]([C:42]2([O:48][CH3:49])[CH2:43][CH2:44][O:45][CH2:46][CH2:47]2)[CH:36]=1)[O:41][C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Reactant: NS(=O)(=O)c1ccc(-c2oc(Cl)nc2-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1(c2cc(F)cc(Oc3nc(-c4ccccc4)c(-c4ccc(S(N)(=O)=O)cc4)o3)c2)CCOCC1
Yield: 34.7 %

Procedure:
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide from Step 3 (0.74 g, 2.2 mmol), N,N′-dimethylformamide (DMF) (20 mL), potassium carbonate (0.61 g, 4.4 ,mmol), and 4-(3-fluoro-5-hydroxyphenyl) -4-methoxy-3,4,5,6-tetrahydro-2H-pyran [prepared as described by G. C. Crawley, et al, J. Med. Chem., 35, 2600-2609 (1992)] (0.75 g, 7.5 mmol) were stirred at room temperature for 16.0 hours. The solution was diluted with ethyl acetate (100 mL), washed with 1N HCl, brine and water, dried over MgSO4 and concentrated. The residue was dissolved in ethyl acetate/hexanes (1:1) and filtered through silica. The eluant was concentrated and the residue was recrystallized from ethyl acetate/hexanes to afford 4-[2-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy]-4-phenyl-5-oxazolyl]benzenesulfonamide as a white solid (0.4 g, 35%): mp 159-161° C. 1H NMR (CDCl3) 300 MHz δ 7.9 (d, J=8.7 Hz, 2H) 7.72 (d, J=8.7 Hz, 2H) 7.6 (m, 2H) 7.4 (m, 3H) 7.24-7.30 (m, 2H) 7.0-7.1 (dt, J=9.5 Hz and J=1.8 Hz, 1H) 4.85 (bs, 2H) 3.85 (dd, J=9.9 Hz and J=1.8 Hz, 4H) 3.05 (s, 3H) 2.0 (m, 4H). Anal. Calc'd. for C27H25N2O6SF: C, 61.82; H, 4.80; N, 5.34. Found: C, 61.77; H, 4.82; N, 4.31.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[N:3]1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH2:18][C:17]2([CH3:25])[CH3:24])[N:11]=1.C1C(=O)N([Br:34])C(=O)C1>C(#N)C>[Br:34][C:13]1[C:12]([N:16]2[C:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][CH2:20][C:21]2([CH3:23])[CH3:22])=[N:11][C:10]([N:3]2[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]2([CH3:26])[CH3:1])=[CH:15][CH:14]=1
Reactant: CC1(C)CCCC(C)(C)N1c1cccc(N2C(C)(C)CCCC2(C)C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC1(C)CCCC(C)(C)N1c1ccc(Br)c(N2C(C)(C)CCCC2(C)C)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Reaction was performed under air. To a ice-cooled solution of 2,6-bis(2,2,6,6-tetramethylpiperidin-1-yl)pyridine (1 g, 2.8 mmol) in acetonitrile (100 ml) was added NBS (0.45 g, 2.5 mmol) portion-wise over 30 min. The reaction mixture was stirred at −0° C. for 2 h, until the color of the solution disappeared and then stirred overnight at room temperature. The reaction was quenched with water (100 mL) and the product extracted by ethylacetate. The product was purified by column chromatography on silica gel and obtained as white solid (Rf=0.6 in Ethylacetate:hexane=1:20, Yield=0.53 g (43.4%))
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:33][C:34]1([OH:38])[CH2:37][NH:36][CH2:35]1>>[Cl:19][C:16]([F:17])([F:18])[O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:36]3[CH2:37][C:34]([OH:38])([CH3:33])[CH2:35]3)=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: CC1(O)CNC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and 3-methylazetidin-3-ol to afford a white powder. HPLC (Condition 4) tR=4.8 min, UPLC-MS (Condition 3) tR=0.94 min, m/z=450 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.30 (s, 3H) 3.61 (s, 4H) 5.41 (s, 1H) 6.41 (br. s, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.74-7.90 (m, 3H) 7.99-8.09 (m, 1H) 8.70 (br. s, 1H) 10.21 (s, 1H) 12.90-13.18 (m, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:39])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH2:33]3)[CH:29]=1)=O)C.[CH2:40]([NH2:42])[CH3:41]>CO>[CH2:40]([NH:42][C:4]([C:6]1[C:7](=[O:39])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH2:33]3)[CH:29]=1)=[O:3])[CH3:41]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Reactant: CCN
Solvent: CO
Product: CCNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Cpd 1 (Example 1(g), 5 mg) in 1 mL of methanol was added 1 mL of ethylamine (2 M in methanol). The solution was stirred at 70° C. for 30 minutes. The solvent was evaporated and the product was purified by preparative HPLC as the formic acid salt (1 mg, yellow solid). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.71 (m, 1H), 9.35 (s, 1H), 8.83 (s, 1H), 8.24 (br, 1H), 7.69 (br, 1H), 7.42 (d, 1H), 7.27 (m, 3H), 7.17 (d, 1H), 6.67 (br, 2H), 3.50 (m, 2H), 3.25 (m, 4H), 3.03 (m, 4H), 2.92 (m, 4H), 2.55 (s, 3H), 2.22 (m, 2H), 1.27 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H33N7O2: 524.27 (M+H), Found: 524.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([Se:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][N:16]=3)[C:5]([O:26][CH2:27][CH2:28][CH3:29])=[CH:4][C:3]1=2.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1([CH3:30])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([Se:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=3)[C:5]([O:26][CH2:27][CH2:28][CH3:29])=[CH:4][C:3]1=2
Reactant: CCCOc1cc2c(cc1[Se]c1ccc(C(=O)OCC)cn1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1cc2c(cc1[Se]c1ccc(C(=O)O)cn1)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to that of Example 2, by reaction of 485 mg (1.02 mmol) of ethyl 6-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydro 2-naphthylselanyl)nicotinate with 385 mg (9.6 mmol) of sodium hydroxide in ethanol (20 ml), 444 mg (97%) of a white solid are obtained. m.p.: 220° C.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][N:6]1[C:10]([I:11])=[C:9]([I:12])[C:8]([I:13])=[C:7]1[I:14])C.O.[OH-].[Na+]>O1CCOCC1>[I:14][C:7]1[N:6]([CH2:5][C:4]([OH:15])=[O:3])[C:10]([I:11])=[C:9]([I:12])[C:8]=1[I:13]
Reactant: CCOC(=O)Cn1c(I)c(I)c(I)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cn1c(I)c(I)c(I)c1I
Yield: 96.8 %

Procedure:
TO a solution of 23.2 g of compound B), 2,3,4,5-tetraiodopyrrol-1-acetic acid ethyl ester (35.32 mmol) , in 840 mL of a dioxane (750 mL) / H2O (90 mL) mixture, 36 mL of 1M NaOH (36 mmol) are quickly added (10 min) and the final solution is kept at room temperature for 4 h. The reaction mixture is treated with carbon Carbopuron 4N, filtered, then acidified with 37% HC1 (w/w) and diluted in 500 1 of H2O, to give a solid which is filtered and purified by chromatography (silica gel (product E. Merck item 9385): eluent: CHCl3 : MeOH : 25% NH4OH (w/w) =7.5:2:0.3 (v/v/v)). Fractions with similar purity are collected, evaporated and diluted with 200 mL of H2O. By acidifying the aqueous phase with 40 mL of 1M HCl , a solid precipitates, which is filtered, washed with H2O and dried under reduced pressure. 21.5 g of 2,3,4,5-tetraiodopyrrol-1-acetic acid(34.20 mmol) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:21])[F:22])=[CH:17][CH:16]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Product: FC(F)(F)Oc1ccc(-c2cc(Cl)ncn2)cc1

Procedure:
4-Chloro-6-(4-trifluoromethoxyphenyl)-pyrimidine was prepared by palladium-catalyzed arylation of 4,6-dichloropyrimidine and 4-trifluoromethoxyphenyl boronic acid: 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.14 (d, J=9.8 Hz, 2H), 7.74 (m, 1H), 7.36 (d, J=8.4 Hz, 2H); EIMS m/z 274 (M+).
Reaction SMILES: [NH2:1][S:2]([CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])(=[O:4])=[O:3].C(Cl)CCl.[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31][N:32]([CH3:61])[C@@H:33]1[CH2:40][N:39]2[C:41]3[CH:42]=[C:43]([C:54](O)=[O:55])[CH:44]=[CH:45][C:46]=3[C:47]([CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)=[C:38]2[C:37]2[CH:57]=[CH:58][CH:59]=[CH:60][C:36]=2[O:35][CH2:34]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:22]([O:26][C:27]([NH:29][CH2:30][CH2:31][N:32]([CH3:61])[C@@H:33]1[CH2:40][N:39]2[C:41]3[CH:42]=[C:43]([C:54]([NH:1][S:2]([CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[O:9])(=[O:3])=[O:4])=[O:55])[CH:44]=[CH:45][C:46]=3[C:47]([CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)=[C:38]2[C:37]2[CH:57]=[CH:58][CH:59]=[CH:60][C:36]=2[O:35][CH2:34]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: NS(=O)(=O)CCCC(=O)OCc1ccccc1
Reactant: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)CCCC(=O)OCc4ccccc4)cc3n2C1
Yield: 37 %

Procedure:
Benzyl 4-(aminosulfonyl)butanoate (1.3 eq)(prepared as described in step 1), DMAP (2.5 eq) and EDC (1.5 eq), were added to a solution of (7R)-7-[{2-[(tert -butoxycarbonyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (0.03 M) in DCM. The reaction was stirred under N2 at RT for 24h, before volatiles were removed in vacuo to leave the crude product as a yellow gum, which was purified by automated RP-HPLC (WATERS XTERRA column; MeCN/H2O/0.1% TFA gradient). Fractions containing the pure compound were combined and lyophilized to afford the product as a white powder (37%). (ES+) m/z 787 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](N)=[O:10])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[OH-:12].[Na+].Cl>>[NH2:1][C:2]1[C:3]([C:9]([OH:10])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: [OH-]
Reactant: NC(=O)c1ncc(Br)cc1N
Agent: Cl
Agent: [Na+]
Product: Nc1cc(Br)cnc1C(=O)O
Yield: 94 %

Procedure:
To a 100 mL round bottom flask, 3-amino-5-bromo-pyridine-2-carboxylic acid amide (1.05 g, 0.0049 mol) and aqueous sodium hydroxide solution (0.98 g in 10 mL water, 0.0245 mol) were added. The reaction mixture was stirred at reflux temperature for 5 hours. The volatiles were evaporated under reduced pressure to provide the residue. The residue was neutralized to pH 7.0, using 2N HCl at 0° C. to obtain the precipitate. The precipitate was filtered and dried to provide the title compound as light yellow solid (1 g, 95%). 1H NMR (300 MHz, DMSO-d6): δ 7.65 (d, J=2.1 Hz, 1H), 7.20 (d, J=2.1 Hz, 1H), 7.01-7.16 (br s, 2H); LC-MS (ESI): Calculated mass: 216.0; Observed mass [M+H]+: 217.0. (RT: 0.43 min).