Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:3][C:4]=1[N+:11]([O-:13])=[O:12])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(C)=O)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1-(4-Hydroxy-2-nitrophenyl)ethanone (Carbocore, 181 mg, 1.00 mmol), ethyl 2-bromoacetate (183 mg, 1.10 mmol), potassium carbonate (138 mg. 1.00 mmol) and DMF (5 mL) were combined in a 20 mL glass vial and stirred at 60° C. for 2 hours, at which point LC-MS analysis showed a clean complete reaction. The reaction mixture was diluted with water and extracted with EtOAc, washed with sat. NaCl aq. The reaction was repeated using 1-(4-Hydroxy-2-nitrophenyl)ethanone (0.802 g, 4.43 mmol), ethyl 2-bromoacetate (0.813 g, 4.87 mmol), potassium carbonate (0.612 g. 4.43 mmol) and DMF (25 mL), and worked up in the same way. The combined EtOAc extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, affording ethyl 2-(4-acetyl-3-nitrophenoxy)acetate (TU3205-034) as a dark yellow oil MS (ESI+): calcd. 268.07. found 268.10 (MH+). H-NMR (400 MHz, CDCl3): 1.317 (3H, t, J=7.2 Hz), 2.512 (3H, s), 4.294 (2H, q, J=7.2 Hz), 4.722 (2H, s), 7.192 (1H, dd, J=8.4 Hz, 2.4 Hz), 7.455 (1H, d, J=8.4 Hz), 7.462 (1H, d, J=2.8 Hz). C-NMR (100 MHz, CDCl3): 14.133, 29.695, 61.922, 65.499, 110.105, 119.735, 129.461, 130.154, 147.793, 159.356, 167.474, 198.352.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2>N.O.CO.[Ni]>[N:1]1[C:2]([C:10]2[CH:11]=[C:12]([CH2:13][NH2:14])[CH:15]=[CH:16][CH:17]=2)=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2
Reactant: N#Cc1cccc(-c2cn3ncccc3n2)c1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CO
Product: NCc1cccc(-c2cn3ncccc3n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Raney-Ni (cat.) and NH3.H2O (4˜5 drops) were added to the solution of 3-(imidazo[1,2-b]pyridazin-2-yl)benzonitrile (25 mg) in MeOH. The mixture was stirred vigorously at room temperature for 1 h under hydrogen and the Raney-Ni was then removed. The filtration was concentrated in vacuo to give the (3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)methanamine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:10][CH:11]([CH3:16])[C:12]([O:14]C)=[O:13])=[CH:5][C:4]=1[C:22]([F:25])([F:24])[F:23])#[N:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:17][C:18]([F:21])([F:19])[F:20])[CH2:10][CH:11]([CH3:16])[C:12]([OH:14])=[O:13])=[CH:5][C:4]=1[C:22]([F:23])([F:25])[F:24])#[N:2]
Reactant: COC(=O)C(C)CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Temperature: 75 °C
Yield: 92.9 %

Procedure:
A solution of methyl 3-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]-2-methylpropanoate (0.056 g, 0.152 mmol) in 1:1 THF/MeOH (6 mL) was treated with NaOH (1N, 1 mL, 1.0 mmol) and heated at 75° C. for 30 min. Upon cooling, the mixture was partitioned between EtOAc and 0.1N HCl. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (0.050 g, 94% yield): 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.8 Hz, 1H), 7.06 (d, J=2.6 Hz, 1H), 6.92 (dd, J=8.8, 2.6 Hz, 1H), 4.20-4.02 (m, 2H), 3.87 (dd, J=15.6, 9.0 Hz, 1H), 3.56 (dd, J=15.6, 5.0 Hz, 1H), 3.0-2.9 (m, 1H), 1.29 (d, J=7.1 Hz, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+].Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([CH3:30])[N:22]=1.C([O-])(O)=O.[Na+]>CS(C)=O>[CH3:30][C:23]1[C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=[C:21]([N:11]2[CH2:12][CH2:13][C@@H:9]([N:5]3[CH2:6][CH2:7][CH2:8][C@@H:4]3[CH3:3])[CH2:10]2)[N:22]=1
Reactant: C[C@@H]1CCCN1[C@H]1CCNC1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 98.4 %

Procedure:
To a solution of (2R,3′S)-2-methyl-[1,3′]bipyrrolidinyl dihydrochloride (1.59 g, 7 mmol) in DMSO (24 mL) was added K2CO3 (3.87 g, 28 mmol) and 2-chloro-6-methyl-5-nitropyridine (1.81 g, 10.5 mmol) and then heated to 90° C. for 8 hours. The reaction was cooled to rt and NaHCO3 (aq) (200 mL) was added. The solution was extracted with EtOAc (2×250 mL). The combined organic extracts were washed with NaHCO3 (aq) (200 mL), H2O (200 mL), and brine (150 mL), dried over K2CO3, filtered and concentrated to obtain a residue which was then purified by flash column chromatography (0% to 5% MeOH/CH2Cl2) to afford 2 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12](OC)=[O:13])[CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CC(C[AlH]CC(C)C)C>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[N:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: COC(=O)c1cnc(C(F)(F)F)c(Br)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: ClCCl
Product: OCc1cnc(C(F)(F)F)c(Br)c1
Temperature: 0 °C
Yield: 54 %

Procedure:
To a solution of methyl 5-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate (for a synthesis see Preparation 12(b)) (698 mg, 2.457 mmol) in DCM (20 ml) stirred under N2 at 0° C. was added DIBAL-H (1.5 M solution in toluene, 4.91 ml, 7.37 mmol) dropwise. The reaction mixture was stirred at 0° C. for 3 h and at room temperature overnight. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The residue was treated with a 1N HCl solution and extracted twice with EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced. The crude material was purified by Flashmaster chromatography on a 10 g silica gel cartridge using hexane/EtOAc 95:5 as eluent to afford [5-bromo-6-(trifluoromethyl)-3-pyridinyl]methanol (297 mg, 54%) no pure enough to be used in the next step. The title compound was re-purified by preparative HPLC (column XTerra 30×150 mm, gradient elution: 30 to 80% CH3CN/H2O, uv detection 254 nm) to give the title compound (157 mg, 24%).
Reaction SMILES: CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:43][CH2:44][C:45]([NH:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[O:46].[Br:53][C:54]1[CH:62]=[C:61](/[CH:63]=[CH:64]/[CH:65]([C:70]2[CH:75]=[C:74]([Cl:76])[C:73]([OH:77])=[C:72]([Cl:78])[CH:71]=2)[C:66]([F:69])([F:68])[F:67])[CH:60]=[CH:59][C:55]=1[C:56](O)=[O:57]>C(Cl)Cl>[Br:53][C:54]1[CH:62]=[C:61](/[CH:63]=[CH:64]/[CH:65]([C:70]2[CH:71]=[C:72]([Cl:78])[C:73]([OH:77])=[C:74]([Cl:76])[CH:75]=2)[C:66]([F:69])([F:68])[F:67])[CH:60]=[CH:59][C:55]=1[C:56]([NH:43][CH2:44][C:45](=[O:46])[NH:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[O:57]
Reactant: NCC(=O)NCC(F)(F)F
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(O)c(Cl)c2)C(F)(F)F)cc1Br
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(O)c(Cl)c2)C(F)(F)F)cc1Br)NCC(F)(F)F
Reaction time: 12 h
Yield: 50.9 %

Procedure:
DIPEA (0.20 mL, 1.26 mmol), PyBOP (245 mg, 0.47 mmol) and 2-amino-N-(2,2,2-trifluoroethyl)acetamide (90 mg, 0.47 mmol) were added to a stirred solution of (E)-2-bromo-4-(3-(3,5-dichloro-4-hydroxyphenyl)-4,4,4-trifluorobut-1-enyl)benzoic acid (200 mg, 0.42 mmol, 66% purity) in CH2Cl2 (5 mL) at ambient temperature. The resulting mixture was then stirred for 12 h. The reaction mixture was diluted with CH2Cl2, washed with 1N HCl, followed by saturated sodium bicarbonate solution, brine solution and water. The organic layer was dried (Na2SO4), filtered, concentrated under vacuum. The residue was purified by column chromatography on silica (100-200 mesh) eluting with 30% EtOAc in petroleum ether to give the title compound as light green solid (130 mg, 52%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([N:15]([CH3:33])[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[N:22](COCC[Si](C)(C)C)[CH:23]=[CH:24][C:17]=23)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(Cl)Cl.CO.[OH-].[Na+]>O>[CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([N:15]([CH3:33])[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[NH:22][CH:23]=[CH:24][C:17]=23)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1N(C)c1ccnc2c1ccn2COCC[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1N(C)c1ccnc2[nH]ccc12
Yield: 79 %

Procedure:
A solution of N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-1-[2-(trimethylsilyl)ethoxy]methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine (0.065 g, 0.00014 mol) in trifluoroacetic acid (0.6 mL, 0.008 mol) and methylene chloride (3 mL, 0.05 mol) was stirred overnight. The solvent volume was reduced by roto-vap 3× azeotroped with MeOH. The resulting orange oil was stirred in methanol (1.5 mL, 0.037 mol) and 1.00 M of sodium hydroxide in water (0.5 mL) overnight. Solvents were removed under vacuum and the remaining solid was stirred in ethyl acetate and water. The organic phase was washed with sat. NaCl and the solvent was removed under vacuum to give 37 mg of an orange oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:9][C:8]([F:11])([F:10])[C:5]1[N:4]=[CH:3][C:2](/[CH:14]=[CH:13]/[C:12]([O:16][CH3:17])=[O:15])=[CH:7][N:6]=1
Reactant: C=CC(=O)OC
Reactant: FC(F)(F)c1ncc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cnc(C(F)(F)F)nc1
Temperature: 130 °C
Yield: 97.7 %

Procedure:
A mixture of 5-bromo-2-(trifluoromethyl)pyrimidine (900 mg, 3.97 mmol), methyl 2-propenoate (0.533 mL, 5.95 mmol), Pd(OAc)2 (44.5 mg, 0.198 mmol), tri-o-tolylphosphine (241 mg, 0.793 mmol) and TEA (1.105 mL, 7.93 mmol) in DMF (6 mL) under argon was heated at 130° C. for 1 h. After cooling to room temperature, water (40 mL) was added to the reaction mixture and then extracted by EA (3×50 mL). The organic phase was washed with brine, dried over MgSO4 and evaporated in vacuo to afford the title compound (900 mg, 3.88 mmol, 98% yield) as a yellow solid. LCMS: rt=2.67 min, [M+H+]=233
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([C:5]([OH:7])=[O:6])[NH2:4].C(N(CC)CC)C.[C:15]([O:19][C:20](ON=C(C1C=CC=CC=1)C#N)=[O:21])([CH3:18])([CH3:17])[CH3:16].O>O1CCOCC1>[C:15]([O:19][C:20]([NH:4][C@H:3]([C:5]([OH:7])=[O:6])[CH2:2][Cl:1])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: N[C@@H](CCl)C(=O)O
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCl)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a solution of 1.0 g (6.25 mmol) of 3-chloro-L-alanine and 1.3 mL of triethylamine in 50% aqueous 1,4-dioxane were added 1.69 g (6.90 mmol) of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile with stirring at room temperature. After 2 hours, the reaction mixture was poured into 20 mL of water and extracted twice with ethyl acetate. The organic layer was washed twice with water and then with saturated brine, dried over anhydrous magnesium sulfate and evaporated to give 0.66 g (40.5%) of white solid. Recrystallization from a mixture of ethyl acetate and n-hexane afforded 0.58 g of the pure product (35.6%) melting at 123°-124° C., with decomposition, and having the structural formula: ##STR55## The identity of the product was confirmed by IR and NMR analyses.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([CH:10]=[O:11])[C:4]=1[OH:12])=[O:2].[CH:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(#N)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([C:3]1[CH:8]=[C:7]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:6]=[C:5]([CH:10]=[O:11])[C:4]=1[OH:12])=[O:2]
Reactant: C#CCCCCCCCCCC
Reactant: O=Cc1cc(Br)cc(C=O)c1O
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCCCCCCCCCC#Cc1cc(C=O)c(O)c(C=O)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 45.5 %

Procedure:
2,6-Diformyl-4-bromophenol (2.50 g, 10.9 mmol), 1-dodecyne (2.00 g, 12.0 mmol), CuI (65 mg, 0.33 mmol), and bis(triphenylphosphine)palladium)II) dichloride were suspended in degassed acetonitrile (MeCN) (5 mL) and degassed benzene (1 mL). The yellow suspension was sparged with argon for 30 min and degassed Et3N (1 mL) was added. The resulting brown suspension was sealed in a pressure vial, warmed to 80° C. and held there for 12 h. The mixture was then partitioned between EtOAc and KHSO4 solution. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated under reduced pressure. The dark yellow oil was purified by column chromatography on silica gel (25% Et2O in hexanes) to give 1.56 g (46%) of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2([CH2:3][OH:2])[CH2:6][CH2:7]2)[CH:9]=1
Reactant: COC(=O)C1(c2cccnc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(c2cccnc2)CC1
Reaction time: 2 h

Procedure:
To a cooled (−78° C.) solution of 7-2 (76 g, 398 mmol) in 500 mL THF was added LiAlH4 (1.0M, 250 mL, 250 mmol) gradually. The reaction mixture was stirred for 2 hr and quenched sequentially with 9.5 mL H2O, 9.5 mL 15% NaOH, and 28.5 mL H2O. The mixture was stirred overnight. Celite (50 g) was added and the mixture stirred for 20 min and filtered through a silica gel plug and concentrated to afford the desired product 7-3 as an oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH2:21][CH3:22])([O-:20])=[O:19]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[C:21]([CH3:22])[N+:18]([O-:20])=[O:19]
Reactant: CC[N+](=O)[O-]
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc(C=C(C)[N+](=O)[O-])c(OC)c1
Reaction time: 12 h

Procedure:
A solution consisting of 25 g of 2,4-dimethoxybenzaldehyde (Aldrich) in 200 ml of nitroethane was treated with 0.5 g anhydrous ammonium acetate and held on a steam bath for 12 hours. The solvent was removed in vacuo from the mixture yielding 22.3 g of yellow crystals, m.p. 80°-81° C., upon cooling in 50 ml of methanol.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>ClCCl>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[N:6]=[CH:5]2
Reactant: C1=COCCC1
Reactant: Ic1ccc2[nH]ncc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Ic1ccc2c(cnn2C2CCCCO2)c1
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a mixture of 5-iodo-1H-indazole (0.90 g, 3.69 mmol) and 3,4-dihydro-2H-pyran (1.57 g, 18.7 mmol) in dry dichloromethane (20 mL), was added p-TsOH (0.08 g, 0.41 mmol) at room temperature. The resulting mixture was stirred overnight. Upon completion, saturated aqueous NaHCO3 (30 mL) was added slowly into the reaction mixture. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜5% EtOAc in petroleum ether) affording the title compound (1.0 g). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (s, 1H), 8.08 (s, 1H), 7.67 (dd, 1H), 7.61 (d, 1H), 5.85 (dd, 1H), 3.88-3.85 (m, 1H), 3.78-3.72 (m, 1H), 2.41-2.29 (m, 1H), 2.05-1.95 (m, 2H), 1.77-1.72 (m, 1H), 1.61-1.56 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.O>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(Br)c2)CC1
Temperature: 25 °C
Yield: 45 %

Procedure:
2-Bromo-4-fluoronitrobenzene (949 mg, 4.31 mmol) was added in two portions to neat N-methypiperazine (8 mL) at 0° C. and allowed to warm to room temperature. The reaction was heated to 60° C. for 1 h, and then it was diluted with 50 mL of EtOAc and poured into H2O (50 mL). The layers were separated and the organic layer was washed with satd aq NaHCO3, dried (Na2SO4), and concentrated in vacuo to afford 580 mg (45%) of the title compound as a yellow solid: Mass spectrum (ESI, m/z): Calcd. for C11H14BrN3O2, 300.0 (M+H). found 300.1.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=2)[N:10]=[C:9]([O:18][CH3:19])[C:8]=1[CH2:20][C:21]1[CH:29]=[CH:28][C:24]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:22]=1.[CH3:30][C:31]1[C:36]([C:37]([C:39]2[N:43]([CH3:44])[N:42]=[N:41][CH:40]=2)=[O:38])=[CH:35][CH:34]=[C:33]([CH3:45])[N:32]=1>C1COCC1>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:37]([C:36]3[C:31]([CH3:30])=[N:32][C:33]([CH3:45])=[CH:34][CH:35]=3)([C:39]3[N:43]([CH3:44])[N:42]=[N:41][CH:40]=3)[OH:38])[CH:15]=2)[N:10]=[C:9]([O:18][CH3:19])[C:8]=1[CH2:20][C:21]1[CH:29]=[CH:28][C:24]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:22]=1
Reactant: Cc1ccc(C(=O)c2cnnn2C)c(C)n1
Reactant: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(N(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(N(C)C)cc1
Reaction time: 0.03 h

Procedure:
A solution of n-butyllithium (2.5 M in hexanes, 0.27 mL, 0.66 mmol) was added dropwise by syringe to a stirring solution of 4-((4-chloro-6-iodo-2-methoxyquinolin-3-yl)methyl)-N,N-dimethylaniline (300 mg, 0.663 mmol, Intermediate 24: step c) in dry THF (5 mL) at −78° C. After 2 minutes, a solution of (2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (143 mg, 0.663 mmol, Intermediate 19: step b) in dry THF (1 mL) was added dropwise by syringe. After 3 minutes, the flask was removed from the cooling bath and allowed to warm. After 5 minutes, the flask was placed into an ice-water bath. After 15 minutes, water (5 mL) and ethyl acetate (25 mL) were added. The biphasic mixture was partitioned between half-saturated aqueous sodium chloride solution (20 mL) and ethyl acetate (25 mL). The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Silica gel (4 g) was added to the filtrate and the solvents were removed by rotary evaporation to provide a free-flowing powder. The powder was loaded onto a silica gel column. Elution with 30% ethyl acetate-hexanes initially, grading to 90% ethyl acetate-hexanes provided the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.03 (s, 1H), 7.83-7.78 (m, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.23-7.17 (m, 2H), 7.00-6.90 (m, 3H), 6.68-6.61 (m, 2H), 4.19 (s, 2H), 4.11 (s, 3H), 3.92 (s, 3H), 3.45 (s, 1H), 2.88 (s, 6H), 2.55 (s, 3H), 2.39 (s, 3H); MS (ESI): mass calcd. for C30H31ClN6O2, 542.2. m/z found, 543.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C@H:10]([CH2:11][CH2:12][OH:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[NH:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.ClCCl.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:15]1([C:2]2[CH:3]=[CH:4][C:5]3[C@H:10]([CH2:11][CH2:12][OH:13])[O:9][CH2:8][CH2:7][C:6]=3[CH:14]=2)[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1
Reactant: OCC[C@@H]1OCCc2cc(Br)ccc21
Reactant: C1CSCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OCC[C@@H]1OCCc2cc(N3CCSCC3)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-((1S)-6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol (0.26 g, 0.99 mmol) was dissolved in dry toluene (10 mL) and degassed. Thiomorpholine (0.14 mL, 1.48 mmol), tris(dibenzylideneacetone)dipalladium (51 mg), (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (77 mg) and sodium tert-butoxide (0.126 g, 1.3 mmol) were added and the mixture heated under reflux with stirring, under a nitrogen atmosphere, for 24 h. The reaction was cooled to room temperature, diluted with dichloromethane, filtered through celite and washed with water. The organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica, to yield the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13]CC)=O.[N:21]1([C:27](=[NH:29])[NH2:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([OH:13])=[N:28][C:27]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:29][C:16]=1[OH:18]
Reactant: CCOC(=O)C(C(=O)OCC)c1nc2ccccc2s1
Reactant: N=C(N)N1CCOCC1
Solvent: Cc1ccccc1
Product: Oc1nc(N2CCOCC2)nc(O)c1-c1nc2ccccc2s1

Procedure:
A mixture 1,3-diethyl 2-(1,3-benzothiazol-2-yl)propanedioate (3.00 g, 10.23 mmol, 1.00 equiv), and morpholine-4-carboximidamide (1.33 g, 10.30 mmol, 1.00 equiv) in Toluene (30 mL) was heated for 20 h at 120° C. under an inert atmosphere of nitrogen. After cooling down, the white solid was collected by filtration, washed with a mixture solution of Dichloromethane/Methanol and dried in an IR oven to afford the title compound. as a white solid. MS m/z [M+H]+ (ESI): 331.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([OH:21])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:44]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C.O>[C:10]([O:14][C:15](=[O:16])[NH:17][CH2:18][C:19]([N:54]1[CH2:55][CH2:56][N:51]([CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:52][CH2:53]1)=[O:21])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
DIPEA (22.14 g, 171.3 mmol) was added to a stirred solution of tert-butoxycarbonylamino-acetic acid (10 g, 57.1 mmol) in DMF (40 mL). HOBT (9.25 g, 68.5 mmol) and EDCI.HCl (12.61 g, 68.5 mmol) were then added at room temperature. After 2 minutes N-benzylpiperazine (12.1 g, 68.5 mmol) was added, and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 13.4 g (70.5% yield) of [2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester as white powder. 1H NMR (CDCl3): δ 7.3 (m, 5H), 5.5 (bs, 1H), 4.0 (d, 2H), 3.7-3.6 (t, 2H), 2.5 (s, 2H), 3.4 (t, 2H), 2.4 (s, 4H), 1.3 (s, 9H).