Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])([O-])=O.C(N(CC)CC)C.[CH3:30][O:31][CH2:32]Cl>CN(C=O)C.C(=O)([O-])O.[Na+]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:30][O:31][CH3:32])=[O:21]
Reactant: COCCl
Reactant: O=C(O)CCCCCCc1ccc2ccccc2c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCOC(=O)CCCCCCc1ccc2ccccc2c1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.3 %

Procedure:
7-(1-Nitro-2-naphthyl)heptanoic acid (2 g) and triethylamine (2.02 g) were dissolved in DMF (10 ml) followed by addition of chloromethyl methyl ether (0.802 g), and the mixture was stirred at room temperature for 20 hours. This reaction mixture was diluted with cold saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to dryness. Using the residue, 10% palladium-on-carbon (0.23 g), and ethanol (23 ml), a catalytic hydrogenation reaction was carried out at atmospheric temperature and pressure for 18 hours. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure to provide methoxymethyl 7-(1-amino-2-naphthyl)heptanoate (2.1 g).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[C:14](=[N:23]O)[CH:13]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([N+:35]([O-:37])=[O:36])=[CH:32][CH:33]=2)[C:28]([CH3:39])([CH3:38])[C:27]1=[CH2:40]>C1(C)C=CC=CC=1>[CH3:25][N:26]1[C:27]2([O:22][C:15]3[C:16]4[C:21]([C:12]([C:9]5[CH:8]=[CH:7][C:6]([N:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)=[CH:11][CH:10]=5)=[CH:13][C:14]=3[N:23]=[CH:40]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:28]([CH3:38])([CH3:39])[C:29]2[C:34]1=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=2
Reactant: O=C1C(=NO)C=C(c2ccc(N3CCCC3)cc2)c2ccccc21
Reactant: C=C1N(C)c2ccc([N+](=O)[O-])cc2C1(C)C
Solvent: Cc1ccccc1
Product: CN1c2ccc([N+](=O)[O-])cc2C(C)(C)C12C=Nc1cc(-c3ccc(N4CCCC4)cc3)c3ccccc3c1O2
Yield: 8 %

Procedure:
From 4-(4-pyrrolidinophenyl)-1,2-naphthoquinone-2-oxime and 1,3,3-trimethyl-2-methylene-5-nitroindoline. Yield=8%, m.p.=259.5-261.5° C., λmax=592 and 470 (sh.) nm in PhMe upon irradiation.
Reaction SMILES: N1C(C)=CC(C)=CC=1C.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].[C:22](Cl)(=[O:26])[C:23]([CH3:25])=[CH2:24]>ClCCl>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22](=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: C=C(C)C(=O)Cl
Reactant: OCCCCCCCCCCBr
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCCCCCBr
Temperature: 0 °C
Reaction time: 15 h
Yield: 69.9 %

Procedure:
2,4,6-Collidin (12.3 ml, 92.7 mmol, 1.1 eq.) was added to a solution of 10-bromodecanol (20.0 g, 84.3 mmol) in anhydrous dichloromethane (200 ml). After cooling the mixture to 0° C. methacrylic acid chloride (16.5 ml, 168.6 mmol, 2 eq.) was slowly added dropwise and the reaction mixture was stirred for 1 h at 0° C. and at for 15 h room temperature. The reaction mixture was then washed with water (100 ml) and cold 1N HCl (100 ml). The combined organic phases were dried with anhydrous sodium sulphate. After removal of the solvent under reduced pressure the obtained crude product was purified by column chromatography (eluent: hexane/dichloromethane 8:2). 18.0 g (70% yield) of the product was obtained as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][S:19]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(N)cc1OC
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(F)cc2)cc1OC
Reaction time: 8 h

Procedure:
3,4-Dimethoxyaniline(1.01 g, 6.99 mM) was added to a solution of 4-Fluorobenzenesulfonyl chloride (1.50 g, 7.69 mM) in anhydrous pyridine(10 ml). The reaction was stirred overnight. The reaction was quenched with 1N HClaq. (20 ml) and washed with ethyl acetate(3×20 ml). The organic extracts were combined, dried(sodium sulfate), solids filtered off and concentrated. The desired product was isolated using silica gel flash chromatography of 1.30 g as a yellow solid. H1 NMR(CDCl3) δ 3.79(s, 3H), 3.86(s, 3H), 6.50(d, 1H), J=4.71 Hz), 6.68(d, 1H, J=2.64 Hz), 6.71 (d, 1H, J=2.76 Hz), 7.11 (d, 2H, J=8.67 Hz), 7.75(m, 2H). MS(ES) m/z 328.9; (M+NH4+); HRMS for (MH+) C14H14SFNO4: 260.1511.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1.Cl.[OH-].[Na+]>C(O)C>[F:27][C:24]([F:25])([F:26])[C:20]1[CH:19]=[C:18]2[C:23]([C:14]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([N:2]([CH3:12])[CH3:1])=[O:11])=[CH:5][CH:6]=3)=[CH:15][CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: CN(C)C(=O)c1ccc(N)cc1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)C(=O)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1

Procedure:
A mixture of 0.1 mole of N,N-dimethyl-p-aminobenzamide, 0.1 mole of 4-chloro-7-trifluoromethylquinoline, 8 ml. of concentrated hydrochloric acid and 500 ml. of absolute ethanol is heated at reflux for 19 hours, after which 100 ml. of 2.5N sodium hydroxide is added. The mixture is cooled and filtered and the filter cake is recrystallized from methanol. There is thus obtained p-[(7-trifluoromethyl-4-quinolyl)amino]-N,N-dimethylbenzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][C:19]([NH2:21])=O)[CH:14]=3)[C:9]2=[O:22])=[CH:5][CH:4]=1.N1C(Cl)=NC(Cl)=NC=1Cl>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][C:19]#[N:21])[CH:14]=3)[C:9]2=[O:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2CCc3cc(CC(N)=O)ccc3C2=O)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(CN2CCc3cc(CC#N)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
To a suspension of 1.3 g of 2-[2-(4-Methoxy-benzyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-acetamide in 5 mL of THF and 10 mL of DMF was added 370 mg of cyanuric chloride and after stirring at room temperature for 0.5 hour, the reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with 5% sodium bicarbonate, followed by brine and then dried over sodium sulfate. Purification by flash chromatograpy on silica gel column using 75% ethyl acetate in hexane as eluent afforded 1.2 g of [2-(4-Methoxy-benzyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-acetonitrile.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1.[Cl-].[NH4+]>C1COCC1>[CH3:15][C:14]([CH3:16])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: BrCCCCCOC1CCCCO1
Reactant: CCOC(=O)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (1.78 mL) in dry THF (10 mL) at 0° C. under nitrogen was treated dropwise with n-butyl lithium (2.5M in hexanes, 5.09 mL) to generate a pale yellow solution which was stirred at 0° C. for 30 minutes then cooled to −78° C. and treated dropwise with ethyl isobutyrate (1.55 mL). The solution was stirred at −78° C. for 45 minutes then a solution of 2-(5-bromopentyloxy)tetrahydro-2H-pyran (example 285, step a) (3.20 g) in dry THF (1 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 10 minutes then was allowed to warn to room temperature overnight. The reaction mixture was cooled to 0° C. then treated with saturated aqueous ammonium chloride solution (3 mL) and extracted with ethyl acetate. The aqueous phase was extracted with ethyl acetate (×2) and the combined organic phase was washed with water, saturated aqueous sodium bicarbonate solution and brine then dried over sodium sulfate, filtered and evaporated. Purification was by silica gel chromatography eluting with 0-5% ethyl acetate in cyclohexane to afford the subtitled compound as colourless liquid. Yield 2.22 g.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[N:11]=[C:12]3[N:22]([CH:23]=2)[CH2:21][CH2:20][O:19][C:18]2[C:13]3=[CH:14][C:15]([CH:24]([OH:26])[CH3:25])=[CH:16][CH:17]=2)[N:5]([CH:7]([CH3:9])[CH3:8])[CH:6]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:26][CH:24]([C:15]1[CH:14]=[C:13]2[C:18]([O:19][CH2:20][CH2:21][N:22]3[C:12]2=[N:11][C:10]([C:4]2[N:5]([CH:7]([CH3:9])[CH3:8])[CH:6]=[C:2]([CH3:1])[N:3]=2)=[CH:23]3)=[CH:17][CH:16]=1)[CH3:25])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cn(C(C)C)c(-c2cn3c(n2)-c2cc(C(C)O)ccc2OCC3)n1
Solvent: ClCCl
Product: Cc1cn(C(C)C)c(-c2cn3c(n2)-c2cc(C(C)OS(C)(=O)=O)ccc2OCC3)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of 1-{4-[4-methyl-1-(propan-2-yl)-1H-imidazol-2-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-13-yl}ethan-1-ol (10 mg, 0.028 mmol) in DCM (2 mL) at 0° C. was added TEA (14 mg, 0.139 mmol) and methanesulfonyl chloride (6.0 mg, 0.053 mmol). The reaction mixture was further stirred at 0° C. for 2 h. TLC showed the reaction was completed. After being quenched with aqueous NaHCO3 (5 mL), the resultant mixture was extracted with DCM (3×5 mL), washed with brine (2×5 mL). The organic phase was dried over Na2SO4 and concentrated to give 1-{4-[4-methyl-1-(propan-2-yl)-1H-imidazol-2-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethyl methanesulfonate (12 mg, 100% yield), which was directly used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C2C=CC=CC=2)C=CC([C:20](=[O:28])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=CC=1>>[O:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: O=C(Cc1ccccc1)c1ccc(-c2ccccc2)cc1
Reactant: Brc1ccc(N2CCOCC2)cc1
Product: O=C(Cc1ccccc1)c1ccc(N2CCOCC2)cc1
Yield: 36 %

Procedure:
Prepared from 4-(4-bromophenyl)morpholine following the procedure described in Intermediate 14, where the crude product was purified by column chromatography (PE:EtOAc=5:1) to afford Intermediate 25 (280 mg, yield 36%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[OH:34]>>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[N:7]=2)[CH:22]=[CH:21][C:20]=1[OH:34]
Reactant: C[C@H](Nc1cncc(Cl)n1)c1ccccc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(-c2cncc(N[C@@H](C)c3ccccc3)n2)ccc1O
Yield: 69.8 %

Procedure:
In a procedure analogous to Example 2, reaction of 6-chloro-N-[(1S)-1-phenylethyl]pyrazin-2-amine (717.3 mg, 3.07 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (845 mg, 3.38 mmol) furnished the product (689 mg, 70%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:6]([C:7]#[CH:8])[O:5][C:4](=[O:9])[NH:3]1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19](I)[CH:20]=2)[N:15]=[CH:14][N:13]=1.C(NC(C)C)(C)C>C1COCC1.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.[Cu](I)I>[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:8]#[C:7][CH:6]3[O:5][C:4](=[O:9])[NH:3][C:2]3([CH3:10])[CH3:1])[CH:20]=2)[N:15]=[CH:14][N:13]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: C#CC1OC(=O)NC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC1(C)NC(=O)OC1C#Cc1ccc2ncnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
A mixture of 4,4-Dimethyl-5-ethynyl-2-oxazolidinone (1.10 g, 7.90 mmol), 4-chloro-6-iodoquinazoline (1.63 g, 5.60 mmol), dichlorobis(triphenylphosphine)palladium(II) (200 mg, 0.28 mmol), copper iodide (53 mg, 0.28 mmol), and diisopropylamine (0.57 g, 5.60 mmol) in anhydrous THF (30 mL) was stirred at room temperature under nitrogen for 4 hours. After concentration, the residue was dissolved in CH2Cl2 (80 mL), washed with aqueous NH4Cl and brine, dried over sodium sulfate, and concentrated to give the crude product as brown oil. Purification by silica gel column using 50-70% EtOAc in hexane afforded 1.22 g (72%) of yellow solid: 1H NMR (CDCl3) δ 1.49 (s, 3H), 1.53 (s, 3H), 5.14 (s, 1H), 5.57 (br s, 1H), 7.95 (dd, 1H), 8.04 (d, 1H, J=8.8 Hz), 8.38 (d, 1H, J=2.0 Hz), 9.05 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[C:18]3=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]3[CH:16]=[CH:15][CH:14]=1)[CH:7]=[CH:6]2>C1COCC1.CO.[Pt](=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]1[C:18]3=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]3[CH2:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C3=CC=CN4CCS(=O)(=O)N=C34)ccc2c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2cc(C3CCCN4CCS(=O)(=O)N=C34)ccc2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-(6-methoxynaphthalen-2-yl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (218 mg) in THF (dry) (75 mL) and MeOH (75 mL) and the mixture was stirred at room temperature under hydrogen overnight and at 50° C. overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). The filtrate was concentrated and the residue was crystallized from MeCN-THF/IPE to give the title compound (153 mg) as colorless crystals.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1>ClCCl.O>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][C:14]=1[Br:1]
Reactant: BrBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(N)c(Br)c1
Reaction time: 18 h
Yield: 88 %

Procedure:
A solution of bromine (7.0 mL, 137.3 mmol) in dichloromethane is added dropwise to a cold (−10° C.) solution of ethyl 4-aminobenzoate (22.0 g, 133.3 mmol) in dichloromethane. The reaction mixture is allowed to come to room temperature, stirred for 18 h and diluted with water. The organic phase is separated, washed twice with brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (SiO2, 8/1 hexanes/EtOAc as eluent) to afford the title compound as a white solid, 28.6 g (88% yield), identified by HNMR and mass spectral analyses. MS m/e 242 (M−H)+; 1H NMR (400 MHz, DMSO-d6) δ 1.28 (t, J=7.01 Hz, 3 H), 4.22 (q, J=7.16 Hz, 2 H), 6.18 (brs, 2 H), 6.81 (d, J=7.91 Hz, 1H), 7.65 (dd, J=8.54, 1.98 Hz 1 H), 7.89 (d, J=1.83 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].O>C(Cl)Cl>[CH2:23]([O:22][C:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN1CCN(c2cccc3ccc(NC(=O)OCc4ccccc4)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.225 g, 0.933 mmol), benzyl chloroformate (0.147 mL, 1.03 mmol), and potassium carbonate (0.142 g, 1.03 mmol) were combined in a two phase mixture of methylene chloride (10 mL) and water (3 mL) and the mixture was stirred at room temperature overnight. Benzyl chloroformate (0.147 mL, 1.03 mmol) was added and the reaction was stirred 5 hours more. The reaction was diluted with methylene chloride and the phases were separated. The organic layer was washed with brine, dried over calcium sulfate and concentrated to a brown oil which was flash chromatographed on silica gel (1×4 inches). Gradient elution with ethyl acetate/hexane of from 50% to 100% followed by gradient ethanol/ethyl acetate elution of from 5% to 10% gave 0.29 g of a brown foam. This residue was recrystallized from ethyl acetate to give 0.095 g (27%) of the title product in two crops; mp 143°-144° C. Analysis calculated for C23H25N3O2 : C, 73.58; H, 6.71; N, 11.19. Found: C, 73.46; H, 6.71; N, 11.05.
Reaction SMILES: C([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][C:10]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)C1C=CC=CC=1.O>ClCCl>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C:10]2[S:11][C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:9]=2[OH:8])=[CH:24][CH:23]=1
Reactant: COc1ccc(Cc2sc(C(F)(F)F)cc2OCc2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Cc2sc(C(F)(F)F)cc2O)cc1
Reaction time: 0.08 h
Yield: 90.2 %

Procedure:
To a solution of (3-benzyloxy-2-(4-methoxybenzyl)-5-trifluoromethylthiophene (170.5 mg, 0.45 mmol) in dichloromethane (4.5 mL), a solution of boron tribromide-dimethylsulfide complex in dichloromethane (0.47 mL, 0.47 mmol) was added at −78° C. in a nitrogen stream. The reaction mixture was stirred at the same temperature for five minutes and then at 0° C. for 11 hours. To the reaction mixture, water was added and the resulting mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried (anhydrous sodium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (117.0 mg, 90%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH3:20])[CH:12]=[CH:11][C:10]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)O[O:31]1>CC(C)=O.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]2[CH:16]([CH2:17][CH2:18][CH2:19][CH3:20])[O:31]2)[CH:12]=[CH:11][C:10]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Reactant: CC1(C)OO1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCCC1OC1c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-[2-benzyloxy-4-((E)-hex-1-enyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (10 mg, 0.275 mmol) in acetone (10 mL) is added a solution of DMDO (0.56 mM, 4.9 mL, 0.413 mmol) in acetone. This mixture is stirred at RT for 1 h, at which point LCMS of the reaction shows clean conversion to the desired epoxide. The reaction mixture is diluted with EtOAc and concentrated 3× to fully remove the volatile DMDO. The remaining EtOAc is removed under reduced pressure to afford the title compound which is used directly in the next step.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].N1C=C(C#C[C:23]2[CH:24]=[C:25]([CH:47]=[CH:48][C:49]=2[CH3:50])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:31]([C:43]([F:46])([F:45])[F:44])[CH:30]=2)=[O:27])N2C=CN=CC=12.N#N.C(N(CC)C(C)C)(C)C>[Cu]I.CN(C=O)C>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:48]2[CH:47]=[C:25]([CH:24]=[CH:23][C:49]=2[CH3:50])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:31]([C:43]([F:46])([F:45])[F:44])[CH:30]=2)=[O:27])[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Reactant: C#Cc1cnc2ccccn12
Agent: [Cu]I
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2ccccn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
3-Ethynylimidazo[1,2-a]pyridine (37 mg, 0.26 mmol), 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (103.4 mg, 0.2 mmol), (prepared as in Example 2), Pd[(PPh3)4](11.6 mg, 5 mol %), and CuI (2.9 mg, 7.5 mmol %) was placed in a vial with rubber septum. The mixture underwent 3 cycles of vacuum/filling with N2, and DMF (1.5 ml) and N,N-diisopropylethylamine (53 mL, 0.3 mmol) was added. The mixture was stirred at rt for 16 h, and the reaction was quenched with H2O. EtOAc and more water were added for extraction. The combined organic layer was dried (Na2SO4), filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluent: 5% MeOH in methylene chloride, MeOH was pre-saturated with ammonia gas), giving the titled compound as an off-white solid (53%, 56 mg): MS (M+H)+ 532.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[NH:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl.O>[CH2:20]([N:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1c(Cl)ncnc1N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 4,6-dichloro-5-nitropyrimidine (7 g, 36 mmol) and TEA (10 mL, 72 mmol) in DCM (60 mL) at 0° C. under N2 was added Bn2NH in 10 mL dropwise over 2 hrs. Stirring was continued for 30 min before the reaction mixture was diluted with water (100 mL). The layers were separated and the aqueous layer was extracted with DCM (50 mL×3). The combined organic layer was washed with water (100 mL×2) and brine (100 mL×1), dried over Na2SO4 and concentrated in vacuo. N,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (12.8 g, 100%) was obtained as a brown slurry. LC-MS (ESI): m/z (M+1) 355.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1N.O.C(O)(=O)C.N([O-])=O.[Na+].[BrH:21]>[Cu](Br)Br>[Br:21][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[F:1]
Reactant: Br
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-fluoro-5-nitroaniline (25.90 g), 47% aqueous hydrogen bromide (100 ml), water (200 ml) and acetic acid (200 ml) was added dropwise an aqueous sodium nitrite (11.56 g) solution (100 ml), and the mixture was stirred at 0° C. for 1 h. This mixture was added at 0° C. to a solution of copper bromide (CuBr: 27.30 g) dissolved in 47% aqueous hydrogen bromide (100 ml) and the mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with ethyl acetate, dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chomatography (eluent: hexane). Crystallization from hexane gave the title compound (4.01 g) as colorless needle crystals.