Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24](=[O:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.[C:41](=O)([O:47]C(C)(C)C)[O:42][C:43]([CH3:46])([CH3:45])[CH3:44]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:43]([O:42][C:41](=[O:47])[NH:23][S:20]([C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:7]2[C:6]([C:24](=[O:27])[CH2:25][CH3:26])=[C:5]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[C:8]2=[O:12])=[CH:19][CH:18]=1)(=[O:21])=[O:22])([CH3:46])([CH3:45])[CH3:44]
Reactant: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(=O)(=O)NC(=O)OC(C)(C)C)cc1

Procedure:
To a mixture of 4-(6-bromo-1-oxo-4-phenyl-3-propionyl-1H-isoquinolin-2-ylmethyl)benzenesulfonamide (2.0 g), triethylamine (1.1 ml), 4-dimethylaminopyridine (0.23 g) and methylene chloride (40 ml) was added di-t-butyl carbonate (1.1 ml) at room temperature with stirring, and the mixture was stirred at the same temperature for 1 hr. After the completion of the reaction, the reaction mixture was washed with 1N hydrochloric acid, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=3/1-1/1), crystallized from hexane/ethyl acetate=3/1 to give the title compound (2.0 g) in pale-pink crystals. 1H NMR (CDCl3) δ: 0.46 (3H, t, J=6.9 Hz), 1.37 (9H, s), 1.62 (2H, q, J=6.9 Hz), 5.42 (2H, s), 7.14 (1H, br), 7.24-7.30 (2H, m), 7.39 (2H, d, J=8.4 Hz), 7.29-7.51 (4H, m), 7.69 (1H, dd, J=1.8, 8.4 Hz), 7.95 (2H, d, J=8.4 Hz), 8.41 (1H, d, J=8.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[OH-].[Na+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O>C(O)C>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:9])[CH:4]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Cc1cc(O)ccc1Cl
Reactant: CCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCOc1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
In 200 g of ethanol were dissolved 71.2 g (0.5 mol) of 4-chloro-3-methylphenol and 22 g (0.55 mol) of sodium hydroxide. To the solution at 70° C., 90.8 g (0.55 mol) of n-hexyl bromide was added dropwise. The solution was allowed to ripen for 4 hours and cooled to room temperature, after which 120 g of water was added. The oily matter was separated therefrom and concentrated by a rotary evaporator, followed by vacuum distillation (boiling point 115-117° C./0.3 Torr), yielding 102 g of 4-n-hexyloxy-2-methylphenyl chloride.
Reaction SMILES: Br[C@@H:2]([CH2:6][OH:7])[C:3]([OH:5])=O.N12CCCCC1C=NCCC2.C1CCN2C(=NCCC2)CC1.C(O)(=O)[C@@H]1OC1.C1(N=C=NC2CCCCC2)CCCCC1.[Cl-].[CH2:52]([NH2+:55][CH2:56][S:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[CH:53]=[CH2:54]>O1CCCC1.C(Cl)Cl>[CH2:52]([N:55]([CH2:56][S:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:3](=[O:5])[C@@H:2]1[O:7][CH2:6]1)[CH:53]=[CH2:54]
Reactant: O=C(O)[C@@H](Br)CO
Reactant: C=CC[NH2+]CSc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1=NCCCN2CCCCC12
Agent: O=C(O)[C@H]1CO1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCN(CSc1ccccc1)C(=O)[C@H]1CO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Analogously to Example 5, 8.45 g (50 mmol) of 2-(S)-bromo-3-hydroxypropionic acid in 200 ml of tetrahydrofuran is converted using 15.2 g (100 mmol) of 1,5-diazabicyclo[5.4.0]undec-5-ene into the DBU salt of (R)-glycidic acid. To the latter there are added in situ in methylene chloride at room temperature, 10.31 g (50 mmol) of dicyclohexyl carbodiimide and then, at 0°, 10.75 g (50 mmol) of N-allyl-N-phenylthiomethylammonium chloride. The resulting mixture is stirred for a further 3 hours at room temperature. The crystalline dicyclohexylurea is filtered off with suction, methylene chloride is added to the filtrate and the whole is washed with phosphate buffer having a pH of 8.0. The crude product obtained from the organic phase by drying over sodium sulphate and concentration by evaporation in vacuo is chromatographed over 500 g of silica gel using toluene/ethyl acetate (9:1) and the pure title compound is obtained in the form of a colourless oil.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][C:9]([C:11]([CH3:13])=[CH2:12])=[CH2:10]>C1(C)C=CC=CC=1>[CH3:8][C:9]1[CH2:10][C@H:2]2[C:1]([O:6][C:4](=[O:5])[C@H:3]2[CH2:12][C:11]=1[CH3:13])=[O:7]
Reactant: C=C(C)C(=C)C
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: CC1=C(C)C[C@H]2C(=O)OC(=O)[C@H]2C1
Yield: 92 %

Procedure:
Maleic anhydride (9.8 g, 0.10 mol) and 2,3-dimethylbutadiene (9.84 g, 0.12 mol) were mixed in toluene (50 ml) for 24 h at 50° C. The solution was allowed to cool, the solvent removed in vacuo and the residue recrystallised from petroleum ether (40° C.-60° C.) to yield the title compound in 92% yield. N.m.r: δH (90 MHz, CDCl3) 2.60 (m,2H), 2.14 (m,4H), 1.74 (s,6H).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:22])/[C:13](/I)=[CH:14]\[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][S:43]([C:46]1[CH:51]=[CH:50][C:49](Br)=[CH:48][CH:47]=1)(=[O:45])=[O:44].[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][O:11][C:12](=[O:22])/[C:13](/[C:49]1[CH:50]=[CH:51][C:46]([S:43]([CH3:42])(=[O:45])=[O:44])=[CH:47][CH:48]=1)=[CH:14]/[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: COC(=O)/C(I)=C\C1CCCCC1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C1CCCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
A mixture of zinc dust (2.6 g, 40 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (3 mL) under argon was treated with 1,2-dibromoethane (0.37 g, 2 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (217 mg, 2 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (5.88 g, 20 mmol) in dry tetrahydrofuran (5 mL) over 5 min. During the addition, the temperature rose to 50° C. The reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (10 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (270 mg, 0.5 mmol) and triphenylphosphine (520 mg, 2 mmol) in dry tetrahydrofuran (25 mL) was stirred at 25° C. under argon for 10 min and then treated with 4-bromophenyl methyl sulfone (4.23 g, 18 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 50° C. for 24 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (150 mL), and the organic compound was extracted into ethyl acetate (3×100 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/2 hexanes/ethyl acetate) afforded (E)-3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-acrylic acid methyl ester (5.79 g, 99%) as a low melting white solid: EI-HRMS m/e calcd for C17H22O4S (M+) 322.1238, found 322.1236.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[NH2:12])(=[O:5])=[O:4].[C:13](N1C=CN=C1)(N1C=CN=C1)=[S:14]>O1CCOCC1.CN(C=O)C>[CH3:1][N:2]1[C:13](=[S:14])[NH:12][C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[S:3]1(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1cnccc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CN1C(=S)Nc2ccncc2S1(=O)=O
Reaction time: 0.5 h

Procedure:
A solution of N-methyl-4-aminopyridine-3-sulfonamide (de Tullio et al., Tetrahedron 1995, 3221-3234) (5.0 g) and thiocarbonyidiimidazole (7.5 g) in dioxane (30 mL) and DMF (15 mL) was heated at 90° C. for 2 h. The solvents were removed by distillation under reduced pressure. The residue was dispersed in 0.6N NaOH (20 mL) and stirred for 30 min. The alkaline solution was treated with charcoal, filtered, and the filtrate was adjusted to pH 4-5. The precipitate was collected by filtration, washed with water and dried (yield: 4 g); m.p. 195°-198° C. (Compound IV).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.NC(N)=[O:13].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N+:6]([O-:13])[CH:7]=1
Reactant: NC(N)=O
Reactant: O=C(O)c1ccc(Br)cn1
Agent: OO
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(O)c1ccc(Br)c[n+]1[O-]
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a suspension of 5-bromopicolinic acid (25.0 g) and urea-hydrogen peroxide adduct (20.0 g) in acetonitrile (200 mL) was added trifluoroacetic anhydride (50 mL) at 0° C., and the mixture was stirred for 30 min. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from diethyl ether to give the title compound (19.6 g) as white crystals.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:32])[N:25]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].C1COCC1.[CH3:39][N:40]1[CH2:45][CH2:44][N:43]([C:46]2[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=2)[CH2:42][CH2:41]1>CCOC(C)=O.CCCCCC>[CH3:39][N:40]1[CH2:41][CH2:42][N:43]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH3:32])[N:25]=[C:26]([C:28]([CH3:30])([CH3:29])[CH3:31])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:33])=[CH:48][CH:47]=2)[CH2:44][CH2:45]1
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(NC=C3C(=O)Nc4cc(C(=O)c5cccc(NC(=O)c6cc(C(C)(C)C)nn6C)c5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 29 %

Procedure:
A small screw cap test tube was charged with 5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 128 mg, 0.288 mmol) and THF (3.0 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (54.8 mg, 0.286 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜40 mL). The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (˜10 mL) to afford the title compound in 29% yield (0.051 g, 0.083 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Cl:1][C:2]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1Cl
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
2,5-dichlorobenzoic acid (5 g, 26.2 mmol) was added to cooled conc. H2SO4 (50 mL) at −10° C. in small portions. After 10 minutes nitrating mixture {prepared by mixing Conc. HNO3 (2.5 mL) with conc.H2SO4 (10 mL)} was added drop wise at −10° C. The resulting reaction mixture was stirred at −10° C. for 2 h. On completion, the reaction mixture was poured into ice cold water and a solid precipitated. The solid was collected by filtration, washed with water and dried under vacuum to give 2,5-dichloro-3-nitrobenzoic acid (3.4 g, 65%).
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[C:15]2[C:6]([S:7][C:8]3[C:9]([C:17]4[O:18][C:19]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:20][C:21](=[O:23])[CH:22]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14]2)=[CH:5][CH:4]=1.[BrH:30]>C(Cl)(Cl)Cl>[Br:30][CH2:2][C:3]1[CH:16]=[C:15]2[C:6]([S:7][C:8]3[C:9]([C:17]4[O:18][C:19]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:20][C:21](=[O:23])[CH:22]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14]2)=[CH:5][CH:4]=1
Reactant: Br
Reactant: O=c1cc(-c2cccc3c2Sc2ccc(CO)cc2C3)oc(N2CCOCC2)c1
Solvent: ClC(Cl)Cl
Product: O=c1cc(-c2cccc3c2Sc2ccc(CBr)cc2C3)oc(N2CCOCC2)c1
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 2-(7-Hydroxymethyl-9H-thioxanthen-4-yl)-6-morpholin-4-yl-pyran-4-one (3)(240 mg, 0.59 mmol) in chloroform (10 mL) was saturated with hydrogen bromide by bubbling hydrogen bromide gas through the reaction mixture until the solution became cloudy. After 18 hours, hydrogen bromide gas was again bubbled through the reaction mixture. The reaction mixture was washed with saturated NaHCO3 and water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The brown coloured solid was dried under vacuum at 50° C. to give the crude title compound (assumed 100%) which was used without any further purification. m/z (LC-MS, ESP): 470.2 [M+H]+ (1:1, bromine isotope ratio present), R/T=3.86 mins
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:14][N:15]3[N:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:14][N:15]3[N:19]=[C:18]([NH2:20])[CH:17]=[N:16]3)[S:12][CH:13]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2csc(Cn3ncc([N+](=O)[O-])n3)n2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Temperature: 75 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-4-nitro-2H-[1,2,3]triazole (145 mg, 0.49 mmol), iron powder (83 mg, 1.46 mmol) and NH4Cl (132 mg, 2.44 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 75° C. for 1 h. The reaction mixture was filtered while hot and the filter cake rinsed with EtOH. The filtrate was concentrated under reduced pressure and the residue partitioned between CH2Cl2 (10 mL) and aq. 1M NaOH (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a yellow oil (120 mg, 92%). LC-MS-conditions 02: tR=0.68 min, [M+H]+=268.05.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[C:17]1[N:16]=[C:15]([N:9]2[C:10]([C:11]([F:14])([F:13])[F:12])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(Cl)n2)c1C(F)(F)F
Reactant: COc1ccc(C)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3OC)n2)c1C(F)(F)F
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a flask containing the title compound from Example 1 Step A (1.50 g, 4.69 mmol) were added 2-methoxy-5-methylphenyl boronic acid (0.779 g, 4.69 mmol) and trans-dichlorobis(triphenylphosphine) palladium (II) (329 mg, 0.469 mmol). Acetonitrile (12 mL) and sodium carbonate (11.7 mL, 1.0 M aqueous, 11.7 mmol) were added, and the resulting mixture was degassed via nitrogen sparge. The reaction mixture was stirred at 70° C. for 18 h, then was allowed to cool to room temperature and was poured into water. The mixture was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by chromatography on silica gel (0 to 20% EtOAc in hexanes, then 20 to 100% EtOAc in hexanes) provided compound the title compound: LCMS m/z 406.4 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.91 (t, J=8.0 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.19 (dd, J=8.0, 2.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 3.87 (s, 3H), 2.35 (s, 3H), 1.40 (t, J=7.0 Hz, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:11]2[N:12]=[C:13]([CH3:15])[S:14][C:10]=2[CH:9]=[C:8]([F:16])[CH:7]=1>S(=O)(=O)(O)O>[Cl:5][C:6]1[C:11]2[N:12]=[C:13]([CH3:15])[S:14][C:10]=2[C:9]([N+:1]([O-:4])=[O:2])=[C:8]([F:16])[CH:7]=1
Reactant: Cc1nc2c(Cl)cc(F)cc2s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1nc2c(Cl)cc(F)c([N+](=O)[O-])c2s1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 7 ml of concentrated nitric acid in 6 ml of concentrated sulfuric acid was added to a solution of 10 g (50 mmol) of 4-chloro-6-fluoro-2-methylbenzothiazole in 35 ml of concentrated sulfuric acid. Stirring was carried out for 10 minutes, after which the mixture was poured into ice water. Thereafter, the suspended desired product was separated off and, for purification, was dissolved in 100 ml of 3:1 cyclohexane/ethyl acetate. After filtration over a bed of silica gel, 8 g of desired product was obtained from the remaining solution; mp.: 130° to 132° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH2:16])[C:5]2[N:6]([N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:7]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:5]2[C:4]([NH2:16])=[N:3][C:2]([C:22]3[CH:23]=[CH:24][C:19]([C:18]([F:29])([F:28])[F:17])=[CH:20][CH:21]=3)=[CH:7][N:6]2[N:8]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1nc(Br)cn2nc(-c3ccco3)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccc(C(F)(F)F)cc2)cn2nc(-c3ccco3)nc12
Temperature: 100 °C

Procedure:
A mixture of 6-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine (50 mg, 0.179; see Examples 1 and 2), 4-trifluoromethyl-phenyl boronic acid (0.196 mmol), Pd(dppf)Cl2 (7 mg, 0.009 mmol), and aqueous Na2CO3 (2 M, 330 μL) in DMF (2 mL) was degassed under N2 and then heated (at around 100° C.) for overnight. The reaction was filtered and then purified by HPLC (C18, H2O:MeCN gradient). 1H NMR (300 MHz, DMSO-d6) δ 6.77 (dd, J=3.4, 1.8 Hz, 1H), 7.19 (dd, J=3.4, 0.8 Hz, 1H), 7.70 (br. s, 2H), 7.87 (d, J=8.2 Hz, 2H), 7.93 (dd, J=1.8, 0.7 Hz, 1H), 8.31 (d, J=8.2 Hz, 2H), 8.8 (s, 1H). MS: m/z 346 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[C:44]([O:43][C:42](=[O:48])[NH:41][C@H:38]1[CH2:37][CH2:36][C@H:35]([NH:34][C:31]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=2[CH3:30])=[O:33])[CH2:40][CH2:39]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: Cc1c(C(=O)O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c2) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].CCN(CC)CC.[I:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[I:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:21]
Reactant: O=C(Cl)c1ccccc1I
Reactant: COc1ccccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1NC(=O)c1ccccc1I
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
To a solution of 2-methoxyaniline 5 (2.46 g, 20 mmol) in dry CH2Cl2 (50 mL) was added Et3N (6.14 mL, 44 mmols) at 0° C. and under dry N2 atmosphere. A solution 2-iodobenzoyl chloride 2 (5.33 g, 20 mmol) in dry CH2Cl2 (25 mL) was slowly added to the reaction mixture keeping the temperature at 0° C. After 15 min the reaction mixture was allowed to warm to room temperature and stirred overnight. Reaction mixture was diluted with CH2Cl2 (100 mL), washed with H2O (40 mL) and saturated aqueous NaCl solution (40 mL), dried (Na2SO4) and evaporated to yield a light pink solid. Recrystallization from ethyl acetate-hexanes (1:3) provided 3 as white needles (5.7 g). The filtrate was concentrated and the residue was purified by flash chromatography on silica, eluting with 15% ethyl acetate (EtOAc) in hexanes, to provide additional pure product (1.25 g). Total yield: 6.95 g, 98%; 1H NMR (400 MHz, CDCl3) δ 8.54 (dd, J=8.0, 2.0 Hz, 1H), 8.10 (br s, 1H), 7.92 (dd, J=8.0, 1.2 Hz, 1H), 7.52 (dd, J=7.6, 1.2 Hz, 1H), 7.43 (ddd, J=8.8, 7.6, 1.2 Hz, 1H), 7.17-7.09 (m, 2H), 7.03 (t, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.10, 148.29, 142.58, 140.30, 131.49, 128.52, 128.43, 127.58, 124.45, 121.33, 120.12, 110.25, 92.70, 55.92; MS (ESI): m/z 376.20 (M+Na)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.[NH2:10][OH:11]>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[N:10][OH:11])[CH2:4][CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: CN1CCC(=NO)CC1

Procedure:
1-Methyl-piperidin-4-one oxime was prepared from 1-methyl-piperidin-4-one and hydroxylamine hydrochloride using conditions of General Method 1. 1H NMR (400 MHz, DMSO-d6) δ 10.31 (1H, s), 2.45 (2H, t, 6.1 Hz), 2.38 (2H, t, 5.9 Hz), 2.31 (2H, t, J=6.0 Hz), 2.20 (2H, t, 6.4 Hz), 2.18 (3H, s).