Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@H:9]1[CH2:21][O:22][CH2:23][C:24](=[O:26])[NH2:25])=O)(C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:24]([CH2:23][O:22][CH2:21][C@@H:9]1[CH2:10][C@@H:11]([OH:13])[CH2:12][NH:8]1)(=[O:26])[NH2:25]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COCC(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NC(=O)COC[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (2S,4R)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2-(carbamoylmethyloxymethyl)pyrrolidine (0.60 g) in a mixture of trifluoroacetic acid (3 ml) and anisole (0.6 ml) was stirred at ambient temperature for 1 hour. The mixture was concentrated under reduced pressure to give (2S,4R)-2-(carbamoylmethyloxymethyl)-4hydroxypyrrolidine. To a solution of the compound obtained above in a mixture of water (20 ml) and tetrahydrofuran (20 ml) was dropwise added a solution of 4-nitrobenzyloxycarbonyl chloride (0.50 g) in tetrahydrofuran (5 ml) under icecooling with stirring, keeping the pH between 8.5-9.5 with 1N aqueous sodium hydroxide. The mixture was stirred at the same condition for 1 hour and extracted with ethyl acetate (50 ml). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (1:99 and then 2:98 V/V) to give (2S,4R)-2-(carbamoylmethyloxymethyl)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.32 g).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.CS(O[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([F:37])[CH:31]=1)(=O)=O>CN(C=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][N:19]2[CH:20]=[CH:21][C:16]([C:14]3[CH:13]=[CH:12][N:11]=[C:10]([NH:9][CH:6]4[CH2:7][CH2:8][O:3][CH2:4][CH2:5]4)[N:15]=3)=[CH:17][C:18]2=[O:22])=[CH:31][C:32]=1[F:37]
Reactant: O=c1cc(-c2ccnc(NC3CCOCC3)n2)cc[nH]1
Reactant: CS(=O)(=O)OCCc1ccc(Cl)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1CCc1ccc(Cl)c(F)c1
Reaction time: 0.25 h

Procedure:
NaH (11.1 mg, 0.277 mmol; 60% oil dispersion) neat as a solid was added to a stirred suspension of 4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (75.4 mg, 0.277 mmol) in DMF (700 L) at room temperature under nitrogen. After 15 minutes, a clear solution had formed. A solution of 4-chloro-3-fluorophenethyl methanesulfonate (105 mg, 0.416 mmol) in of DMF (700 μL) was then added dropwise. After stirring overnight, the reaction was quenched by addition of saturated ammonium chloride solution (1 mL). The mixture was partitioned between ethyl acetate (30 mL) and water (30 mL). The organics were isolated and washed with water (3×30 mL) and with brine (30 mL). The organics were isolated, dried (MgSO4), filtered and concentrated. The crude product was loaded onto a Biotage 12M column with 2.5/97.5 methanol/ethyl acetate and eluted. The undesired O-alkylated product eluted first and was not collected. Product containing fractions then eluted and were pooled and concentrated to an oil that eventually solidified, 1-(4-chloro-3-fluorophenethyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (20 mg, 17%). 1H NMR (400 MHz, CDCl3) δ 8.38 (d, 1H), 7.30 (dd, 1H), 7.18 (br s, 1H), 7.02 (d, 1H), 6.98 (dd, 1H), 6.90 (m, 2H), 6.66 (dd, 1H), 5.17 (br d, 1H), 4.16 (t, 2H), 4.12 (m, 1H), 4.00 (m, 2H), 3.57 (m, 2H), 3.08 (t, 2H), 2.06 (m, 2H), 1.58 (m, 2H); m/z (APCI-pos) M+1=430.1.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:2]/[C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Reactant: COC(OC)N(C)C
Product: CCOC(=O)c1ccc(C(=O)/C=C/N(C)C)cc1

Procedure:
A mixture of ethyl 4-acetylbenzoate (3.00 g, 15.62 mmol) and N,N-dimethylformamide dimethyl acetal (6.2 g, 52.10 mmol) was refluxed for 18 hours, cooled and concentrated to give ethyl 4-[(2E)-3-(dimethylamino)prop-2-enoyl]benzoate quantitatively. A solution of ethyl 4-[(2E)-3-(dimethylamino)prop-2-enoyl]benzoate, potassium carbonate (3.55 g, 25.74 mmol), and 4-(amidinoamino)benzamide (3.10 g, 12.87 mmol) in ETOH (120 mL) was refluxed for 18 hours. The mixture was cooled, filtered, and washed with ETOH, water, then ether respectively to give ethyl 4-{2-[(4-carbamoylphenyl)amino]pyrimidin-4-yl}benzoate (2.60 g, 46% yield). This compound was refluxed for 2 hours in ETOH (30 mL), water (20 mL), and NaOH (0.640 g, 16 mmol). The reaction mixture was cooled, acidified to pH 3, and filtered to give 1.00 gram (42% yield) of the titled compound. HPLC/ES-MS (20-100% acetonitrile): R.T. 4.7 min. (Method A); (m/z) 335 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[CH3:28][N:29]([CH3:48])[S:30]([C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)(=[O:32])=[O:31].C(=O)(O)[O-].[Na+].O>COCCOC.O>[CH3:28][N:29]([CH3:48])[S:30]([C:33]1[CH:34]=[CH:35][C:36]([C:2]2[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[O:16])[C:5]3[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=3[N:7]=2)=[CH:37][CH:38]=1)(=[O:31])=[O:32]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reactant: CN(C)S(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(S(=O)(=O)N(C)C)cc3)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Yield: 81.4 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (75 mg, 0.19 mmol) and N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (90 mg, 0.29 mmol) in DME/water (3 ml:1 ml). PdCl2 (dppf)-CH2Cl2 adduct (7.9 mg, 0.009 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (48.7 mg, 0.58 mmol) was added, the vessel was sealed, and the reaction mixture was irradiated (microwave) at 150° C. for 30 min. After cooling, 2 mL of water was added and solids that precipitated were filtered. DCM/MeOH (1:1) was added, the mixture was pre-absorbed on silica gel and purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated product was treated with EtOH/EtOAc (1:1), the solids filtered and washed with EtOAc and DCM, and then dried to afford the title compound (83 mg, 78%) as a white solid. LCMS E-S (M+H)=537.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.79 (t, J=4.93 Hz, 1H) 8.47 (m, J=8.59 Hz, 2H) 7.90 (m, J=8.59 Hz, 2H) 7.80 (s, 1H) 5.89 (s, 1H) 5.28 (quin, J=6.69 Hz, 1H) 4.40 (d, J=5.05 Hz, 2H) 2.66 (s, 6H) 2.47 (s, 3H) 2.25 (s, 3H) 2.12 (s, 3H) 1.53 (s, 3H) 1.51 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:16]=1)[CH2:7][N:8]([CH2:14][CH3:15])[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10].[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:24]=[C:25]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:16][C:6]=2[CH2:7][N:8]([C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH2:14][CH3:15])[C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH3:19]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCN(Cc1cc(Br)ccc1I)C(=O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2CN(CC)C(=O)C2CC2)c1
Temperature: 75 °C

Procedure:
Cyclopropanecarboxylic acid (5-bromo-2-iodo-benzyl)-ethyl-amide (6.0 g, 14.7 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (5.2 g, 16.2 mmol), and potassium carbonate (5.09 g, 36.8 mmol) were combined in DME (50 mL) and water (20 mL) under nitrogen. The mixture was purged with nitrogen, and then tetrakis(triphenylphosphine)palladium(0) (0.85 g, 0.74 mmol) was added, and the reaction was heated to 75° C. The reaction was monitored by analytical LCMS and an additional portion of the boronic ester (0.500 g, 1.56 mmol) was added to push the reaction to completion. When the starting material was consumed, the mixture was cooled to room temperature and diluted with ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-25% ethyl acetate in hexanes) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[NH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Li]CCCC>C(Cl)Cl.C1COCC1.CN(C=O)C>[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:6](=[O:8])[CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:10])[F:9])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)CCCC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CCCC(F)(F)F)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 5,5,5-trifluoropentanoic acid (14.76 g, 95 mmol) and DMF (0.146 mL) in DCM (50 mL) was slowly added oxalyl chloride (8.27 mL, 95 mmol). After 2 h, the mixture was concentrated to dryness. A separate flask was changed with (S)-4-benzyloxazolidin-2-one (16.75 g, 95 mmol) in THF (100 mL) and then cooled to −78° C. To the solution was slowly added n-BuLi (2.5M, 37.8 mL, 95 mmol) over 10 min, stirred for 10 min, and then a solution of the above acid chloride in THF (50 mL) was slowly added over 5 min. The mixture was stirred for 30 min, and then warmed to room temperature. The mixture was quenched with saturated aqueous NH4Cl, 10% aq LiCl was then added, and the mixture was extracted with Et2O. The organic layer was washed with saturated aqueous NaHCO3 then with brine, dried (MgSO4), filtered and concentrated to dryness. The residue was purified by SiO2 chromatography (ISCO, 330 g column, eluting with a gradient from 100% hexane to 100% EtOAc) to afford the product Intermediate S-6B; (25.25 g, 85%): 1H NMR (400 MHz, CDCl3) δ ppm 7.32-7.39 (2H, m), 7.30 (1H, d, J=7.05 Hz), 7.18-7.25 (2H, m), 4.64-4.74 (1H, m), 4.17-4.27 (2H, m), 3.31 (1H, dd, J=13.35, 3.27 Hz), 3.00-3.11 (2H, m), 2.79 (1H, dd, J=13.35, 9.57 Hz), 2.16-2.28 (2H, m), 1.93-2.04 (2H, m).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:16]=O)=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:7]=1.[O:18]=[C:19]1[CH2:23][CH2:22][S:21][CH2:20]1>>[Br:1][C:2]1[C:3]([CH:16]=[C:20]2[C:19](=[O:18])[CH2:23][CH2:22][S:21]2)=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:7]=1
Reactant: O=C1CCSC1
Reactant: COC(=O)C(C)c1cc(Br)c(C=O)cc1OC
Product: COC(=O)C(C)c1cc(Br)c(C=C2SCCC2=O)cc1OC
Yield: 33.3 %

Procedure:
By using methyl 2-(5-bromo-4-formyl-2-methoxyphenyl)propionate (540 mg) obtained in Example 48 and 3-oxothiolane (370 mg), the title compound (230 mg, 35%) was obtained in the same manner as that of Example 1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH2:34][CH2:33]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>CO.C(OCC)(=O)C.O1CCOCC1>[CH3:30][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:43][C:42]3[CH:41]=[CH:40][C:39]([CH2:38][N:35]4[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]4)=[CH:45][CH:44]=3)[CH:3]=2)[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[N:15]2
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Nc5ccc(CN6CCN(C)CC6)cc5)c4)n3n2)cc(OC)c1OC
Temperature: 140 °C
Yield: 41.5 %

Procedure:
To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (40 mg, 0.085 mmol), 4-[(4-methylpiperazin-1-yl)methyl]aniline (20.9 mg, 0.102 mmol), (S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl ((S)-BINAP) (15.9 mg, 0.026 mmol), Tris(dibenzylidineacetone)dipalladium (0) (7.8 mg, 0.008 mmol) and sodium t-butoxide (11.4 mg, 0.12 mmol) was added 1,4-dioxane (1.5 mL). In a sealed reaction vessel, the mixture was heated with microwave radiation at 140° C. for 60 minutes. After cooling to room temperature, diluted mixture with methanol (5 mL) and ethyl acetate (5 mL) followed by filtration over celite. Removed solvent under reduced pressure and diluted brown residue in DMSO (1.0 mL). Injected (2×0.5 mL) on an Agilent reverse phase prep LC subjected to a gradient elution using acetonitrile(0.1% Formic acid):water(0.1% Formic acid) (10:90 to 90:10). The appropriate fractions were combined and concentrated under reduced pressure to give 5-methyl-7-[3-({4-[(4-methylpiperazin-1-yl)methyl]phenyl}amino)phenyl]-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.021 g) as a yellow solid. 1H NMR (CDCl3): δ8.78 (s, 1H), 8.47 (s, 1H), 8.09 (dd, J=1.9, 1.8 Hz, 1H), 8.0-7.98 (m, 1H), 7.33 (dd, J=7.9, 7.8 Hz, 1H), 7.19 (ddd, J=7.9, 2.2, 0.8 Hz, 1H), 7.16-7.14 (m, 2H), 7.11 (s, 1H), 7.07-7.05 (m, 2H), 6.94 (m, 2H), 3.82 (s, 9H), 3.53 (s, 2H), 2.90-2.54 (m, 14H). MS m/z 595 (M+1).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:31]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35](=[O:42])[NH:36]2)[CH2:10][N:11]([CH3:30])CCCC#CC1C=CC(NC(=O)C(F)(F)F)=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrC[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][CH2:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=1>>[OH:41][C:38]1[CH:39]=[CH:40][C:31]([C@H:9]([CH2:10][NH:11][CH2:30][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][CH2:53][CH2:54][C:55]2[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=2)[O:8][Si:1]([CH3:3])([CH3:2])[C:4]([CH3:6])([CH3:7])[CH3:5])=[C:32]2[C:37]=1[NH:36][C:35](=[O:42])[CH:34]=[CH:33]2
Reactant: O=[N+]([O-])c1ccc(CCCCOCCCCCCBr)cc1
Reactant: CN(CCCC#Cc1ccc(NC(=O)C(F)(F)F)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCOCCCCc1ccc([N+](=O)[O-])cc1)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 102, using Intermediate 52 in place of Intermediate 45. ES/MS calcd. for C33H50N3O6Si+ 612.4. Found m/z=612.5 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:17]([OH:19])=O)=[CH:11][N:12]([CH3:16])[C:13](=[O:15])[CH:14]=2)=[C:4]([F:20])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:42]1([CH2:45][O:46][NH2:47])[CH2:44][CH2:43]1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH:42]1([CH2:45][O:46][NH:47][C:17]([C:10]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[F:20])=[CH:14][C:13](=[O:15])[N:12]([CH3:16])[CH:11]=2)=[O:19])[CH2:44][CH2:43]1
Reactant: NOCC1CC1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NOCC2CC2)c(Nc2ccc(Br)cc2F)cc1=O
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
A mixture of 4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.078 g, 0.229 mmol), EDCI (0.13 g, 0.69 mmol), and HOBt (0.093 g, 0.69 mmol) in DMF (5 mL) was stirred for 30 minutes. O-Cyclopropylmethyl-hydroxylamine (0.060 g, 0.69 mmol) was added followed by Et3N (0.096 mL, 0.69 mmol). After 1 hour, the reaction mixture was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated to yield 83 mg (89%) clean desired product. MS APCI (+) m/z 410, 412 (M+, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 9.42 (s, 1H), 8.10 (s, 1H), 7.67 (d, 1H), 7.43 (m, 2H), 3.70 (d, 2H), 3.35 (s, 3H), 1.11 (m, 1H), 0.54 (m, 2H), 0.27 (m, 2H).
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:8]=2[N:9]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)#[N:2]
Reactant: CCCCNc1ccc2nc(Cl)sc2c1
Reactant: [C-]#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCNc1ccc2nc(C#N)sc2c1
Temperature: 120 °C

Procedure:
Potassium cyanide (18 mg) and 2-chloro-6-butylaminobenzothiazole (18 mg) were dissolved in 1 ml DMSO and heated to 120° C. for 4 h. After cooling to room temperature, the reaction was poured into 0.2M potassium phosphate, pH 4.5. The aqueous layer was extracted with ethyl acetate three times, washed with water, and dried over sodium sulfate. The solvent was removed by rotary evaporation and the residue purified by silica gel chromatography (20% ethyl acetate in hexanes). 1H-NMR (d6-DMSO): δ 7.84 (d, 1H, J=8.8 Hz), 7.14 (d, 1H, J=2.4 Hz), 6.99 (dd, 1H, J=2.4, 9.2 Hz), 6.67 (br t, 1H), 3.06 (m, 2H), 1.55 (m, 2H), 1.39 (m, 2H), 0.90 (t, 3H, J=7.4 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:21]1([S:24](Cl)(=[O:26])=[O:25])[CH2:23][CH2:22]1>C(Cl)Cl.CN(C1C=CN=CC=1)C.[NH4+].[Cl-].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:24]([CH:21]3[CH2:23][CH2:22]3)(=[O:26])=[O:25])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Brc1ccc(N2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(C1CC1)N1CCN(c2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(4-bromophenyl)piperazine (1 g, 4.15 mmol) was dissolved in DCM (40 ml) and cooled in 0° C. Then DMAP (0.051 g, 0.415 mmol), triethylamine (0.723 ml, 5.18 mmol), and cyclopropanesulfonyl chloride (0.641 g, 4.56 mmol) were added. The reaction was stirred 1 h at rt, then diluted with DCM and saturated NH4Cl/water (1:1). The aqueous phase was separated, extracted with DCM (×2) and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give the desired product. LC-MS: calculated for C13H17BrN2O2S 346.02 observed m/e: 346.88 (M+H)+ (Rt 1.16/2 min).
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]#[CH:12])[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.Br[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C.[Cu]I.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[N:7]2[CH:8]=[C:9]([C:11]#[C:12][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[N:10]=[C:6]2[C:5]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[N:4][CH:3]=1
Reactant: Brc1ccc2ccccc2n1
Reactant: C#Cc1cn2c(Br)cnc(N3CCOCC3)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cnc(N2CCOCC2)c2nc(C#Cc3ccc4ccccc4n3)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of compound 80a (200 mg, 0.7 mmol) and 2-bromoquinoline (0.800 mg, 4 mmol) in dry DMF (5 mL) and DIEA (0.7 mL, 4 mmol) under an Argon gas atmosphere, CuI (12 mg, 0.06 mmol) and (Ph3P)2PdCl2 (46 mg, 0.06 mmol) were added. The reaction was stirred at rt overnight, poured into water (50 mL) and extracted with DCM (3×30 mL). The combined organic extracts were washed with water (20 mL), brine (2×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-50% EtOAc/heptanes) to give compound 80b as an off-white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H16BrN5O: 434.0 (M+H). found: 434.2.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:9][CH:10]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][C:12](Cl)=[O:13].Cl>O>[CH3:9][CH:10]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][C:12]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13]
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Reactant: CC(C)(C)OO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)OOC(C)(C)C)CC(C)(C)C
Yield: 98.2 %

Procedure:
Before the start of the reaction, the loop reactor is filled with a solution of 25.7% by weight of tert-butyl hydroperoxide and 15.0% by weight of potassium hydroxide in water. Initially 20.2 kg/h of a solution of 70% by weight of tert-butyl hydroperoxide in water, 18.2 kg/h of a solution of 45% by weight of potassium hydroxide in water, 16.2 kg/h of water and 19.2 kg/h of 3,5,5-trimethylhexanoyl chloride are then fed to the loop reactor. Cooling with cooling water keeps the internal temperature at 25° C. in the loop reactor and in the stirred cell reactor. The partial neutralization is effected with 27.6 kg/h of 4% by weight hydrochloric acid at a temperature of 15° C. The organic phase is extracted with 23.6 kg/h of a 20% by weight aqueous solution of potassium hydroxide. This affords 26.2 kg/h of aqueous extract comprising 9.6% by weight of tert-butyl hydroperoxide and 18.0% by weight of potassium hydroxide, which are feeded into the loop reactor. From the time at which aqueous extract is recycled into the loop reactor, the metered addition of the feedstocks is changed to 16.6 kg/h of a solution of 70% by weight of tert-butyl hydroperoxide in water, 7.8 kg/h of a solution of 45% by weight of potassium hydroxide in water and 4.8 kg/h of water. After the extraction, the organic phase is washed with 33.8 kg/h of a solution of 3% by weight of sodium sulphite and 1% by weight of sulphuric acid, and dried by stripping at 34° C. and 47 mbar. 24.6 kg/h of tert-butyl peroxy-3,5,5-trimethylhexanoate with a purity of 99.9% are obtained (98.2% yield based on 3,5,5-trimethylhexanoyl chloride).