Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:33])[C:14]1[CH:19]=[C:18]([CH:20]=C)[C:17]([F:22])=[C:16]([F:23])[C:15]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=1[F:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:35].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Si:1]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:33])[C:14]1[CH:19]=[C:18]([CH:20]=[O:35])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=1[F:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=Cc1cc(C(=O)NOCCO[Si](C)(C)C(C)(C)C)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCONC(=O)c1cc(C=O)c(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 50.9 %

Procedure:
N-[2-(t-Butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-vinyl-benzamide (6.35 g, 10.7 mmol) prepared in Process A was dissolved in a mixed solvent of THF (100 ml) and water (30 ml). Aqueous solution of osmium tetroxide (0.1 mM, 2 ml, 0.2 mmol), and sodium metaperiodate (9.0 g, 42.1 mmol) were added at 10° C., and the mixture was stirred at room temperature for 17 hours. Insoluble material was removed through a celite column, and the solution was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (300 g, n-hexane/ethyl acetate (5:1)) to give N-[2-(t-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-formyl-benzamide (3.24 g, 51%) as a brown solid.
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:15]=[C:14]([C:16]2[C:25]3[C:26]4[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=4[S:28][C:24]=3[C:23]([Br:33])=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[CH:21]3)[CH:13]=[C:12]([Br:34])[C:7]=1[O:8][CH2:9][C:10]#[N:11].C[Si]([N:39]=[N+:40]=[N-:41])(C)C>O>[Br:5][C:6]1[CH:15]=[C:14]([C:16]2[C:25]3[C:26]4[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=4[S:28][C:24]=3[C:23]([Br:33])=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[CH:21]3)[CH:13]=[C:12]([Br:34])[C:7]=1[O:8][CH2:9][C:10]1[NH:41][N:40]=[N:39][N:11]=1
Reactant: N#CCOc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: C[Al](C)C
Solvent: O
Product: Brc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(Br)c1OCc1nnn[nH]1
Temperature: 80 °C

Procedure:
Trimethylaluminum (2.55 mL, 3.84mmol, 2.0 M solution in toluene) was added to [2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenoxy]-acetonitrile (0.615 g, 1.02 mmol) under a dry nitrogen atmosphere. Trimethylsilyl azide (0.510 mL, 3.84 mmol) was then added and the solution was heated in a 80° C. oil bath. After 16.5 h the reaction mixture was cooled to room temperature and water was cautiously added. The mixture was partitioned between dilute aqueous HCl and ethyl acetate. The layers were separated and the 2% phosphoric acid in methanol washed silica gel was added to the organic phase. The solvent was removed and the adsorbate was flashed using 2% phosphoric acid in methanol washed silica gel (eluent:gradient: 4:1 to 7:3 petroleum ether:ethyl acetate) to provide the title compound as a white solid, which was recrystallized from cyclohexane (0.365 g, 55%): mp 243-245° C.: NMR (DMSO-d6); δ8.29 (d, J=8 Hz, 1H), 8.09 (d, J=8 Hz, 1 H), 7.89 (s, 2 H), 7.80 (ddd, J =8, 7, 1 Hz, 1 H), 7.66-7.57 (m, 2 H), 7.55 (ddd, J=8, 7, 1 Hz, 1 H), 7.40 (ddd, J=8, 7, 1 Hz, 1 H), 6.71 (d, J=8 Hz, 1 H), 5.64 (s, 2 H), 1.34 (cyclohexane, 0.3 mole eq); MS (EI): [M+], 3 bromine isotope pattern, 642, 644, 646, 648; Anal. Calc. for C24H13Br3N40S.0.33 C6 H12: C, 46.39, H, 2.55, N, 8.32. Found: C, 46.28, H, 2.43, N, 7.90.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=2[C:24]([F:27])([F:26])[F:25])[N:12]=1)=[O:9].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P([CH:49]2[CH2:54][CH2:53]CCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:53]1([C:20]2[CH:21]=[CH:22][C:17]([CH2:16][N:13]3[CH:14]=[CH:15][C:11]([NH:10][C:8]([C:7]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]=4[F:1])=[O:9])=[N:12]3)=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:54][CH2:49]1
Reactant: O=C(Nc1ccn(Cc2ccc(I)cc2C(F)(F)F)n1)c1ccncc1F
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccn(Cc2ccc(C3CC3)cc2C(F)(F)F)n1)c1ccncc1F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoro-N-(1-{[4-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-4-pyridinecarboxamide (for a preparation see Example 88)(40 mg, 0.082 mmol) in toluene (2 ml) was added potassium phosphate tribasic (52 mg, 0.245 mmol, Aldrich), tricyclohexyl phosphine (7 mg, 0.025 mmol, Aldrich), cyclopropyl boronic acid (21 mg, 0.244 mmol, Fluorochem), water (0.1 ml) and then palladium (II) acetate (6 mg, 0.027 mmol. ABCR). The resulting slight suspension was heated to 100° C. and stirred under nitrogen overnight. The reaction mixture was partitioned between DCM (10 ml) and water (10 ml). The phases were separated using a hydrophobic frit and the aqueous phase washed with DCM (10 ml). The organic phases were combined and the solvent removed in vacuo. The residue was dissolved in 1:1 MeOH:DMSO (1 ml) and purified by MDAP on Sunfire C18 column (Method B) using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a white solid (16 mg); LCMS: (System 4) MH+=405, tRET=2.98 min.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15](Cl)=[O:16])[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:15]([C:12]2[CH:13]=[C:14]3[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]3[CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:11]=2)=[O:16])=[CH:23][CH:24]=1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Cl)ccc12
Reactant: NCc1ccncc1
Product: CCc1nn(C2CCCC2)c2cc(C(=O)NCc3ccncc3)ccc12
Yield: 20.3 %

Procedure:
This compound was prepared according to the method of Example 15, using 51 mg (0.184 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl chloride and 20 μL (0.193 mmol, 1.05 equiv) 4-(aminomethyl)pyridine as starting materials, to give 13 mg (20%) of white crystals: mp 147-149° C.; HRMS calcd for C21H24N4O+H: 349.2028. Found: 349.2031.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[N:4]([C:10]2[C:11]([F:23])=[CH:12][C:13]3[S:17][C:16](=[O:18])[N:15](C(C)C)[C:14]=3[CH:22]=2)[C:3]1=[O:24]>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[N:4]([C:10]2[C:11]([F:23])=[CH:12][C:13]3[S:17][C:16](=[O:18])[NH:15][C:14]=3[CH:22]=2)[C:3]1=[O:24]
Reactant: Cc1cc(=O)n(-c2cc3c(cc2F)sc(=O)n3C(C)C)c(=O)n1C
Agent: O=S(=O)(O)O
Product: Cc1cc(=O)n(-c2cc3[nH]c(=O)sc3cc2F)c(=O)n1C
Temperature: 150 °C

Procedure:
34.94 g of 1,6-dimethyl-3-(6-fluoro-3-isopropyl-2-oxo-5-benzothiazolinyl)-2,4(1H,3H)-pyrimidinedione (see Example 49) are dissolved in 200 ml of concentrated sulphuric acid while stirring and gassing with nitrogen and the solution is heated to 150° C. for 45 minutes. The reaction mixture is cooled to 25° C. and poured on to 1 kg of ice, and the precipitated product is filtered off under suction and washed neutral with water. The filter cake is suspended in 500 ml of ethyl acetate at 60° C., the suspension is concentrated to 250 ml, the product, after cooling, is filtered off under suction, the filtrate is back-washed with ethyl acetate and dried at 50° C. under reduced pressure. In this manner there is obtained 1,6-dimethyl-3-(6-fluoro-2-oxo-5-benzothiazolinyl)-2,4-(1H,3H)-pyrimidinedione, m.p.>250° C.
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[CH2:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[CH:9]=2.[OH-].[Na+]>CO>[CH3:21][O:20][C:10]1[CH:9]=[C:8]2[C:13]([C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:22])=[O:2])[CH2:7]2)=[CH:12][CH:11]=1
Reactant: CCCCCC1=C(/C=C/C(=O)OC)Cc2cc(OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC1=C(/C=C/C(=O)O)Cc2cc(OC)ccc21
Yield: 73.4 %

Procedure:
As in Example 112, (E)-3-(6-methoxy-3-pentyl-1H-inden-2-yl)-2-propenoic acid methyl ester (6 g) in methanol (40 mL) was treated with 2N sodium hydroxide solution (20 mL) for 0.5 hours at reflux and worked up in the described manner. Crystallization of the crude product from ethyl acetate furnished 4.2 g of (E)-3-(6-methoxy-3-pentyl-1H-inden-2-yl)-2-propenoic acid. A sample was recrystallized from ethyl acetate-hexane to give the analytical specimen, mp 165°-166° C. Anal. Calcd for C18H22O3 : C, 75.50; H, 7.74 Found: C, 75.53; H, 7.83
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:49])[CH2:27][C:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[S:36][CH:37]=[C:38]([CH2:40][O:41]C3CCCCO3)[N:39]=2)[CH:30]=1)(C)(C)C>C1(C)C=CC=CC=1>[OH:41][CH2:40][C:38]1[N:39]=[C:35]([C:31]2[CH:30]=[C:29]([C:28]3[CH2:27][C:26](=[O:49])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[S:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
A mixture of (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J15) (0.145 g) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert.-butyl ester (Example K19) (0.23 g) in toluene (2 mL) was heated to 100° C. for 5 h. The mixture was cooled and evaporated in vacuum. A solution of the residue in a mixture of CH2Cl2 (2 mL) and TFA (2 mL) was stirred for 0.5 h at 20° C. The mixture was evaporated in vacuum, the residual oil was dissolved in AcOEt and the solution was washed with saturated NaHCO3 solution and with brine, dried over Na2SO4 and evaporated in vacuum. The residue was crystallized from CH2Cl2/hexane to give the title compound (0.04 g) as light-brown crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O-:11].[Na+]>CO>[Br:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a stirred solution of 5-bromo-2,4-dichloropyrimidine (500 mg, 2.19 mmol) in MeOH (5 mL) was added a 30% solution of sodium methoxide (0.40 mL, 2.26 mmol). The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in water (5 mL) and extracted with EA (3×5 mL). The combined organic layer was washed with brine, dried over MgSO4 and concentrated to afford 432 mg (88%) of 5-bromo-2-chloro-4-methoxypyrimidine as white solid. LCMS-ESI (m/z) calculated for C5H4BrClN2O: 223.4. found 224.2 [M+H]+, tR=7.66 min. (Method 2).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([O:17][CH3:18])[C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[H-].[Na+].[CH3:21][OH:22]>>[Cl:1][C:2]1[N:11]=[C:10]([O:22][CH3:21])[C:9]2[C:4](=[C:5]([O:17][CH3:18])[C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1cc2c(Cl)nc(Cl)nc2c(OC)c1OC
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COc1cc2c(OC)nc(Cl)nc2c(OC)c1OC
Yield: 97 %

Procedure:
5.00 g (17.3 mmol) of 2,4-dichloro-6,7,8-trimethoxyquinazoline was suspended in 100 ml of methanol, followed by the gradual addition of 1.5 g of sodium hydride. The obtained mixture was heated under reflux. After several hours, the reaction mixture was concentrated under a reduced pressure, followed by the addition of water. The crystal thus precipitated was recovered by filtration, washed with water and air-dried to give 4.80 g of the title compound as a pale-pink crystal.
Reaction SMILES: [N+:1]([O-])([O:3]C(=O)C)=[O:2].[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]([NH:29][C:30]2[C:35]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:33]=[C:32]([OH:39])[C:31]=2[CH:40]([CH3:42])[CH3:41])=[O:28])[CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>C(#N)C.O>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]([NH:29][C:30]2[C:35]([CH:36]([CH3:37])[CH3:38])=[CH:34][C:33]([N+:1]([O-:3])=[O:2])=[C:32]([OH:39])[C:31]=2[CH:40]([CH3:42])[CH3:41])=[O:28])[CH2:22][CH2:21]1
Reactant: CC(C)c1ccc(O)c(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Reactant: CC(=O)O[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)c1cc([N+](=O)[O-])c(O)c(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
Acetyl nitrate (145 mg, 0.75 mmol) was added to a solution of 2-[4-[2-(benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-(2,6-diisopropyl-3-hydroxyphenyl)acetamide (107 mg, 0.22 mmol) in acetonitrile (3 ml) with ice cooling followed by stirring for 10 minutes. The reaction solution was diluted with water, made alkaline by adding an aqueous solution of sodium bicarbonate thereto and extracted with chloroform twice. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a preparative thin layer chromatography (developing solvent, chloroform:methanol=20:1) and the resulting crude crystals were recrystallized from chloroform-ethyl acetate-hexane to provide 60 mg (yield 51%) of the desired compound as yellow powdery crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:12]([Cl:19])=[CH:11][CH:10]=2)=[CH:6][C:5]([CH3:20])=[C:4]([N+:21]([O-])=O)[CH:3]=1>C1(C)C=CC=CC=1.[Pt]>[Cl:1][C:2]1[C:7]([O:8][C:9]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:12]([Cl:19])=[CH:11][CH:10]=2)=[CH:6][C:5]([CH3:20])=[C:4]([CH:3]=1)[NH2:21]
Reactant: Cc1cc(Oc2ccc(Cl)c3c2CCCC3)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1cc(Oc2ccc(Cl)c3c2CCCC3)c(Cl)cc1N
Yield: 95.1 %

Procedure:
To a solution of 45.0 g of 4-chloro-5-(4-chloro-5,6,7,8-tetrahydro-1-naphthoxy)-2-nitrotoluene in 1200 ml of toluene was added 4.5 g of 5% platinum on carbon catalyst. This mixture was then changed to a 2 L stirred Parr pressure reactor. The reactor was flushed twice with nitrogen, then twice with hydrogen and then finally filled with hydrogen to a pressure of 250 psig. The internal pressure was maintained between 200 psig and 250 psig while the internal temperature was maintained between 40° and 45° C. during the course of the reaction. When hydrogen uptake ceased, the reaction mixture was removed from the reactor and filtered through celite. Removal of the toluene in vacuo afforded a yellow oil which slowly solidified. Recrystallization from a hexane-ethyl acetate mixture afforded 39.14 g of the desired aniline as white crystals. mp=180° C. NMR (CDCl3): 1.6-1.9 (m, 4H), 2.05 (s, 3H), 2.5-2.7 (m, 4H), 3.47 (broad s, 2H), 6.33 (d, J=8 Hz, 1H), 6.63 (s, 2H), 7.03 (d, J=8 Hz, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([C:10]1([C:23]([O:25][CH3:26])=[O:24])[CH2:15][CH2:14][N:13]([C:16](OC(C)(C)C)=O)[CH2:12][CH2:11]1)[CH3:9].C(=O)([O-])[O-].[Na+].[Na+].ClC1[N:39]=[CH:38][C:37]([B:40]([OH:42])[OH:41])=[CH:36][N:35]=1>O1CCOCC1.C(O)C>[CH2:8]([C:10]1([C:23]([O:25][CH3:26])=[O:24])[CH2:11][CH2:12][N:13]([C:16]2[N:39]=[CH:38][C:37]([B:40]([OH:42])[OH:41])=[CH:36][N:35]=2)[CH2:14][CH2:15]1)[CH3:9]
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCC1(C(=O)OC)CCN(c2ncc(B(O)O)cn2)CC1
Reaction time: 2 h
Yield: 60.6 %

Procedure:
TFA (8 mL) was added to a stirred solution of 1-tert-butyl 4-methyl 4-ethylpiperidine-1,4-dicarboxylate (0.61 g, 2.25 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred for 2 h, then the volatiles were removed by rotary evaporation and the residue was left on a high vacuum line for 1 h. The syrupy material thus obtained was dissolved in ethanol (8 mL), anhydrous sodium carbonate (0.72 g, 6.79 mmol) was added and the mixture was stirred for 10 minutes. (2-Chloropyrimidin-5-yl)boronic acid (0.37 g, 2.3 mmol) was added and the mixture was stirred at 80° C. for 7 h. The reaction mixture was filtered through celite, then the solvent was removed under vacuum, and water was added. The mixture was decanted and washed again with water, then the residual gum was freeze-dried, to give the title compound (0.4 g, 60%) as a pale yellow lyophilised solid, which was used without further purification. LCMS (pH 10) MH+ 294, RT 1.15 minutes.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([C:26]5[CH:31]=[CH:30][C:29]([S:32][CH:33]6[CH2:35][CH2:34]6)=[CH:28][CH:27]=5)[N:19]=[C:20]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[O:37]1CO1>ClCCl.CC(C)=O>[CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([C:26]5[CH:27]=[CH:28][C:29]([S:32]([CH:33]6[CH2:35][CH2:34]6)=[O:37])=[CH:30][CH:31]=5)[N:19]=[C:20]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CC(C)CNc1nc(-c2ccc(SC3CC3)cc2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Reactant: C1OO1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)CNc1nc(-c2ccc(S(=O)C3CC3)cc2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
A solution of 50 mg (100 μmol) N-cyclopropyl-4-{6-[4-(cyclopropylsulfanyl)phenyl]-8-(isobutylamino)imidazo[1,2-a]pyrazin-3-yl}benzamide in 5.0 mL dichloromethane was cooled to −30° C. and 1.16 mL of a 0.15 molar dioxirane solution in acetone were added. After 15 minutes of stirring the mixture was warmed to 23° C., the solvent removed and the residue was purified by chromatography to give 33.3 mg (59%) of the title compound. 1H-NMR (CDCl3): δ=0.67 (2H), 0.86-1.05 (5H), 1.06 (3H), 1.07 (3H), 1.25 (1H), 2.09 (1H), 2.28 (1H), 2.95 (1H), 3.56 (2H), 6.36 (1H), 6.54 (1H), 7.60 (1H), 7.63 (2H), 7.70 (2H), 7.94 (2H), 7.96 (1H), 8.02 (2H) ppm.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=1)([O-:5])=[O:4].[C:13](Br)([Br:16])([F:15])[F:14]>CN1CCCC1=O>[Br:16][C:13]([F:15])([F:14])[O:12][C:11]1[C:6]([N+:3]([O-:5])=[O:4])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: FC(F)(Br)Br
Reactant: O=[N+]([O-])c1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ncccc1OC(F)(F)Br
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
To a stirred solution of sodium hydride (856 mg, 21.41 mmol) in N-methylpyrrolidinone (20 mL) was added a solution of 2-nitropyridin-3-ol (2 g, 14.28 mmol) in N-methylpyrrolidinone (10 mL). The reaction mixture was stirred at 20° C. for 30 min followed by heating at 50° C. for another 30 min before cooling to 20° C. CF2Br2 (4.49 g, 21.41 mmol) was added dropwise and the resulting mixture was stirred at 20° C. for 18 h. Then CF2Br2 (8.99 g, 42.83 mmol) was added dropwise and the mixture was stirred at 20° C. for another 18 h. The reaction mixture was slowly quenched into saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (2×50 mL), brine (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 15% ethyl acetate in petroleum ether) affording product (890 mg, 23%): 1H NMR (400 MHz, chloroform-d) δ 8.53-8.51 (m, 1H), 7.99-7.97 (m, 1H), 7.72-7.69 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:9]([CH2:15][C:16]([F:23])([F:22])/[CH:17]=[CH:18]/[N+:19]([O-:21])=[O:20])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O.OP([O-])(O)=O.[K+]>C1COCC1>[C:27]([O:26][C:24]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C@H:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:15][C:16]([F:23])([F:22])[CH2:17][CH2:18][N+:19]([O-:21])=[O:20])=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)[C@H](CC(F)(F)/C=C/[N+](=O)[O-])N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=P([O-])(O)O
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CC(F)(F)CC[N+](=O)[O-])N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl(2S,5E)-2-[bis(tert-butoxycarbonyl)amino]-4,4-difluoro-6-nitrohex-5-enoate, from Step 4 (2.81 g, 6.40 mmol) in THF (64 mL) at 6° C. was added sodium borohydride (1.212 g, 32.0 mmol) followed by a slow addition of water (12.8 mL). The reaction mixture was stirred at room temperature for 4 hours, poured into 10% KH2PO4, and extracted with EtOAc (2×). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford 2.725 g of the title compound (colorless oil) that was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23]C(=O)OC(C)(C)C)[CH:18]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:31](O)([C:33](F)(F)F)=[O:32].CCN(C(C)C)C(C)C.C(Cl)(=O)C>C(Cl)Cl.C([O-])(O)=O.[Na+].C1COCC1>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:31](=[O:32])[CH3:33])[CH:18]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(CCOc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)Nc1cc(CCOc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of tert-butyl 4-(2-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-2-ylcarbamate (900 mg, 2.20 mmol) in DCM (10.0 mL) was added TFA (10.0 mL) and the reaction mixture was stirred at RT overnight. The resulting mixture was evaporated in vacuo and the residue subjected to SCX capture and release. The crude product so obtained was taken up into THF (8.0 mL) and DIPEA (660 μl, 3.8 mmol) and then acetyl chloride (147 μl, 2.06 mmol) were added. After stirring for 1 hr, the mixture was diluted with saturated aq. NaHCO3 (10.0 mL) and was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine and then dried, and evaporated in vacuo. The residue was taken up in a mixture of acetonitrile and a solution of NH3 in MeOH (7M, 1:1 v/v, 20 mL) and after 10 min was re-evaporated in vacuo. The residue was triturated with MeOH (10.0 mL) to afford N-(4-(2-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-2-yl)acetamide, as a yellow solid (570 mg, 74%): m/z 352 (M+H)+ (ES+).