Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11](=[O:14])([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1CCl.O>CS(C)=O>[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:11][O:14][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:10]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CC(=O)c1ccccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(COCc1ccc(Cl)cc1Cl)c1ccccc1
Reaction time: 24 h
Yield: 93.4 %

Procedure:
o-Hydroxyacetophenone (40.85 g, 300 mmole) was dissolved in dimethyl sulfoxide (150 ml) and potassium carbonate (49.0 g, 355 mmole) was added to the mixture. Then, 2,4-dichlorobenzyl chloride (65.9 g, 337 mmole) was added dropwise with stirring. Stirring was continued at room temperature for 24 hours and water (225 ml) was added dropwise over 1 hour. After stirring at room temperature for additional 1 hour, the precipitated crystals were filtered off, washed with water (200 ml×3) and recrystallized from methanol to obtain the title compound (82.7 g, 93.4%), m.p. 83°-85° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](F)[CH:3]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13].Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:15][CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CC(C)N
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)Nc1cc(Br)ccc1C(=O)O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2-fluorobenzoic acid (1 g) in pyridine (5 ml) was added isopropylamine (1.94 ml) at room temperature and the mixture was stirred at 100° C. overnight. The mixture was poured into aqueous hydrochloric acid (1N) and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give 4-bromo-2-(isopropylamino)benzoic acid (218 mg).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][C:10]=1[O:17][CH2:18][CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].P(Br)(Br)[Br:21].C([O-])(O)=O.[Na+]>>[Br:21][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:10]([O:17][CH2:18][CH3:19])[CH:11]=1
Reactant: BrP(Br)Br
Reactant: CCOc1cc(CO)ccc1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1cc(CBr)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of (4-(tert-butyldimethylsilyloxy)-3-ethoxyphenyl)methanol (12.5 g, 44.4 mmol, 1.0 equiv.) in CH2CI2 (45 mL), PBr3 (5.0 mL, 53.2 mmol, 1.2 equiv.) was added at 0° C., and the mixture was stirred at 0° C. for 30 min. After slow addition of sat. aq. NaHCO3-solution, the aqueous layer was extracted with CH2Cl2 (2×). The combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated to yield 14.5 g (94%) of (4-(bromomethyl)-2-ethoxyphenoxy)(tert-butyl)dimethylsilane as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[CH:3][C:4]([NH:6][C:7]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[S:8])=[O:5].[C:15](=O)([O-])[O-].[Na+].[Na+].IC>O1CCCC1>[CH3:15][S:8]/[C:7](=[N:6]\[C:4](=[O:5])[CH:3]=[C:2]([CH3:14])[CH3:1])/[N:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)=CC(=O)NC(=S)N1CCCC1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CS/C(=N\C(=O)C=C(C)C)N1CCCC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 48.7 %

Procedure:
A mixture of 3-methyl-N-(pyrrolidine-1-carbonothioyl)but-2-enamide (230 mg, 1.08 mmol, Eq: 1.00), sodium carbonate (121 mg, 1.14 mmol, Eq: 1.05) and iodomethane (769 mg, 339 μl, 5.42 mmol, Eq: 5) in tetrahydrofuran (7 ml) was stirred for 18 hours at 70° C. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using heptane/ethyl acetate 50-100% as eluent affording 3-methyl-but-2-enoic acid 1-methylsulfanyl-1-pyrrolidin-1-yl-meth-(Z)-ylideneamide (119 mg/48.5%) as a light yellow liquid. MS: m/e=227.1 (M+H+)
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH3:10])=[N:5][S:6][C:7]=1[C:8]#[N:9].NC(N)=S.C[S:16]([C:19]1[CH2:23][C:22]([CH3:25])([CH3:24])[O:21][N:20]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:24][C:22]1([CH3:25])[O:21][N:20]=[C:19]([S:16][CH2:2][C:3]2[C:4]([CH3:10])=[N:5][S:6][C:7]=2[C:8]#[N:9])[CH2:23]1
Reactant: Cc1nsc(C#N)c1CBr
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Agent: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1nsc(C#N)c1CSC1=NOC(C)(C)C1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
4-Bromomethyl-5-cyano-3-methyl-isothiazole (50% purity) (0.65 g, 1.5 mmol) was dissolved in ethanol (30 ml) and thiourea (242 mg, 3.2 mmol) was added. The mixture was stirred at room temperature until the solids were dissolved. 3-Methane-sulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (540 mg, 3.2 mmol) and potassium carbonate (440 mg, 3.2 mmol) were added and the mixture was heated under reflux for 1 hour. The solids were removed by filtration and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product (0.25 g, 62% yield). 1H-NMR (400 MHz, CDCl3): 1.44 (6H, s, Me), 2.6 (3H, s, Me), 2.8 (2H, s, CH2), 4.4 (2H, s, CH2).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[C:17](=[O:23])[CH2:18][CH2:19][C:20]=2[O:21][CH3:22])=[C:11]([CH3:24])[CH:10]=1)C1C=CC=CC=1.[H][H].[CH2:27]([OH:29])[CH3:28]>[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH3:24])[C:12]([C:16]2[C:17](=[O:23])[CH:18]([CH2:14][CH:9]3[CH2:10][CH2:11][O:29][CH2:27][CH2:28]3)[CH2:19][C:20]=2[O:21][CH3:22])=[C:13]([CH3:15])[CH:14]=1
Reactant: COC1=C(c2c(C)cc(OCc3ccccc3)cc2C)C(=O)CC1
Reactant: CCO
Reactant: [H][H]
Agent: [Pd]
Product: COC1=C(c2c(C)cc(O)cc2C)C(=O)C(CC2CCOCC2)C1

Procedure:
To a solution of 2-(4-benzyloxy-2,6-dimethylphenyl)-3-methoxycyclopent-2-enone (1.50 g, 3.59 mmol) in ethanol (10 ml) is added 5% palladium on carbon (0.150 g), and the suspension is stirred for 4 hours under a 4 bar hydrogen atmosphere. The reaction mixture is then filtered through diatomaceous earth, and the filtrate is concentrated in vacuo then purified by flash column chromatography to afford 2-(4-hydroxy-2,6-dimethylphenyl)-3-methoxy-5-(tetrahydropyran-4-ylmethyl)cyclopent-2-enone.
Reaction SMILES: CI.[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:18])[NH:13][C:14](=[S:17])[NH:15][CH:16]=2)=[CH:6][CH:5]=1.[OH-].[Na+].[C:21](O)(=O)C>O>[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:18])[NH:13][C:14]([S:17][CH3:21])=[N:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (13.79 g) was added to a stirred solution of 5-(6-methyl-3-pyridylmethyl)-2-thiouracil (22.66 g) and sodium hydroxide (8.0 g) in water (250 ml), and the mixture was heated at 70° for 1 hour and stirred at room temperature overnight. Acetic acid was added until pH 5 and the volume of the mixture was evaporated to a volume of 50 ml. The solid was filtered off and was recrystallised from ethanol-acetic acid to give 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone (10.16 g) m.p. 197°-197.5°.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23](OC)[C:22](C(OCC)=O)=[C:21]([CH2:32][C:33]3[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=3)[N:20]=2)[CH2:8][C@H:7]1[CH2:47][CH3:48])=[O:5])[CH3:2].[OH-].[Na+].C(O)(=O)C[C:53](CC(O)=O)([C:55]([OH:57])=[O:56])[OH:54]>CO>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:20]=[C:21]([CH2:32][C:33]3[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[C:35]([C:43]([F:45])([F:46])[F:44])[CH:34]=3)[C:22]([O:54][CH2:53][C:55]([OH:57])=[O:56])=[CH:23][N:24]=2)[CH2:8][C@H:7]1[CH2:47][CH3:48])=[O:5])[CH3:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCOC(=O)c1c(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(N[C@H]2C[C@@H](CC)N(C(=O)OCC)c3ccc(OC)nc32)nc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OCC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-ethoxycarbonyl-methoxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (128 mg) is dissolved in methanol (3 ml), then thereto is added 1M aqueous sodium hydroxide solution (2 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is added 10% aqueous citric acid solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=19:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-carboxymethoxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (100 mg). MS (m/z): 658 [M+H]+
Reaction SMILES: [C:1]([C:3](=[N:9]O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].CCCCCCC.II>C(O)(=O)C.CCOC(C)=O.[Pt]>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([NH2:9])[C:1]#[N:2])[CH3:8]
Reactant: CCOC(=O)C(C#N)=NO
Agent: [Pt]
Agent: II
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCCC
Product: CCOC(=O)C(N)C#N
Yield: 141.1 %

Procedure:
Combine ethyl cyanoglyoxylate-2-oxime (20.0 g, 141 mmol) and 5% Pt/C (2.0 g, 10% wt. load) in acetic acid (120 mL) and EtOAc (60 mL) and hydrogenate under 40 psi H2 overnight until the reaction is complete by TLC (5:1/heptane:EtOAc, I2 stain). Carefully filtered the spent catalyst using partial vacuum through glass fiber paper, and rinse with HOAc/EtOAc without allowing the cake to dry out. Concentrate the filtrate in vacuo on a rotovapor to an oil, leaving 25.5 g (96%) of crude amino-cyano-acetic acid ethyl ester as the HOAc salt. Partition a portion (13.0 g) of the HOAc salt between EtOAc (70 mL) and-water (35 mL). Stir the biphasic solution and add dropwise aqueous 5N NaOH (1 6.5 mL) to adjust the pH to 8.0–8.2. Separate the layers, and extract the aqueous layer with more EtOAc (3×25 mL). Combine the organic layer, dry (MgSO4), filter, and concentrate the filtrate to dryness in vacuo on a rotovapor at low bath temperature (30–35° C.) to afford 5.68 g (65%) crude amino-cyano-acetic acid ethyl ester which was used immediately in the next reaction.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:25])[C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[C:9]([O:11]N1C(=O)CCC1=O)=O)[CH:2]=[CH2:3].Cl.[CH3:27][NH:28][O:29][CH3:30].C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][C:5](=[O:25])[C:6]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:8]([C:9](=[O:11])[N:28]([O:29][CH3:30])[CH3:27])[CH:7]=1)[CH:2]=[CH2:3]
Reactant: CNOC
Reactant: C=CCOC(=O)c1cc(C(=O)ON2C(=O)CCC2=O)cc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)c1cc(C(=O)N(C)OC)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (7(b)) (2.00 g), N,O-dimethylhydroxylamine hydrochloride (0.62 g), triethylamine (0.86 ml) and dichloromethane (60 ml) was stirred at 50 for 30 min and then allowed to warm to ambient temperature and stirred for a further 16 h. The mixture was poured onto a flash column and eluted with ethyl acetate/hexane (40:60) to give 3-(N-methyl-methoxycarbamoyl)-5-nitro benzoic acid allyl ester (7(c)) as a yellow oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])(=O)=O>C1(C)C=CC=CC=1>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:43]
Reactant: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Reactant: CCOC(=O)CCCCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 0 °C
Yield: 43.8 %

Procedure:
Sodium hydride (3.225 g or a 60% oil dispersion, 80.6 mmol) was suspended in 80 ml of anhydrous toluene, placed under a nitrogen atmosphere and cooled in an ice bath. A solution of the non-polydispersed alcohol 16 (27.3 g, 73.3 mmol) in 80 ml dry toluene was added to the NaH suspension. The mixture was stirred at 0° C. for thirty minutes, allowed to come to room temperature and stirred for another five hours, during which time the mixture became a clear brown solution. The non-polydispersed mesylate 17 (19.21 g, 80.6 mmol) in 80 ml dry toluene was added to the NaH/alcohol mixture, and the combined solutions were stirred at room temperature for three days. The reaction mixture was quenched with 50 ml methanol and filtered through basic alumina. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, gradient elution: 3/1 ethyl acetate/hexanes to ethyl acetate) to yield the non-polydispersed product as a pale yellow oil (16.52 g, 44%). FAB MS: m/e 515 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH:15](N)([CH3:17])[CH3:16]>CN(C=O)C>[CH:15]([NH:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([CH3:17])[CH3:16]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)Nc1cccc([N+](=O)[O-])c1C#N
Temperature: 50 °C
Yield: 35.7 %

Procedure:
To a solution of 2,6-dinitrobenzonitrile (0.58 g, 3.00 mmol) in DMF (6 mL) was added isopropylamine (0.71 g, 12.00 mmol) and the reaction mixture was stirred at 50° C. under nitrogen for ten minutes. After cooling to room temperature, dilution with H2O and extraction with EtOAc, solvents of the combined organic phases were evaporated and the residue was purified by flash chromatography (Biotage system, 80 g silicagel column) using a Hexane/EtOAc (3:2) solution as eluant, to give 2-(isopropylamino)-6-nitrobenzonitrile (0.22 g, 35%). 1H NMR (400 MHz, DMSO-d6) δ 1.20 (d, J=6.4 Hz, 6H), 3.85-3.80 (m, 1H), 5.94 (d, J=8.0 Hz, NH), 7.26 (d, J=9.0 Hz, 1H), 7.42 (d, J=9.0 Hz, 1H), 7.60 (t, J=8.8 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([P:14]([CH2:18][CH3:19])([CH2:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>C(Cl)Cl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[CH2:16]([P:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)([CH2:18][CH3:19])=[O:15])[CH3:17]
Reactant: CCP(=O)(CC)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCP(=O)(CC)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-tert-butyloxycarbonylpiperazine (1.0 g, 5.34 mmol) was dissolved in 5 mL of THF: water (1:1) and cooled in an ice bath. Triethylamine (1.45 mL, 10.68 mmol), followed by diethylchlorophosphate (1.16 mL, 8.01 mmol) in 5 mL of ether were added, and stirred at 0° C. for 1 hour and at room temperature for 2 hours. Solvents were removed and 40 mL of ethyl acetate was added to the residue. The ethyl acetate layer was washed with brine (30 mL×3) and dried over anhydrous sodium surf ate. After filtered, the filtrate was concentrated in vacuo to yield 1.5 g of N-tert-butyloxycarbonyl--N'-diethylphosphoryl-piperazine in 88% yield as an oil. MS m/z M+H=323, M+NH4 =340. H1 -NMR (in CDCl3) δ=1.32 (t, 6H, 2×CH3), 1.48 (s, 9H, Boc), 3.1 (m, 4H, piperazine), 3.37 (t, 4H, piperazine), 4.05 (m, 4H, 2×OCH2). The obtained N-tert-butyloxycarbonyl--N'-diethylphosphoryl-piperazine (1.5 g, 4.66 mmol) was dissolved in I 0 mL of 10% trifluoroacetic acid in methylene chloride and stirred at room temperature for 30 minutes. Solvent and trifluoroacetic acid were removed to obtain 1.6 g of N-diethylphosphorylpiperazine trifluoroacetic acid salt in quantitative yield. MS m/z M+H=223, H1 -NMR (in MeOH-d4) δ=1.35 (m, 6H, 2×CH3), 3.19 (m, 4H, piperazine), 3.37 (m, 4H, piperazine), 4.05 (m, 4H, 2×OCH2).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.CS[C:15](SC)=[CH:16][N+:17]([O-:19])=[O:18].[NH2:22][C@H:23]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]([CH2:30][C:31]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:32])[C:24]1=[O:38]>C(O)C>[N+:17]([CH:16]=[C:15]([NH:22][C@H:23]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]([CH2:30][C:31]([N:33]2[CH2:34][CH2:35][CH2:36][CH2:37]2)=[O:32])[C:24]1=[O:38])[NH:8][C:7]1[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=1)([O-:19])=[O:18]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: N[C@H]1CCCCN(CC(=O)N2CCCC2)C1=O
Solvent: CCO
Product: O=C(CN1CCCC[C@H](NC(=C[N+](=O)[O-])Nc2ccc(OC(F)(F)F)cc2)C1=O)N1CCCC1
Temperature: 80 °C
Reaction time: 14 h
Yield: 56.2 %

Procedure:
A mixture of 4-(trifluoromethoxy)aniline (20 mg, 0.11 mmol) and 1,1-bis(methylthio)-2-nitroethylene (19 mg, 0.12 mmol) in ethanol (0.25 mL) was heated at 80° C. for 5 h. To the mixture was added 1-[[(3S)-3-aminohexahydro-2-oxo-1H-azepin-1-yl]acetyl]pyrrolidine (27 mg, 0.11 mmol). The resulting solution was stirred at 80° C. for 14 h, and the mixture was then concentrated in vacuo. The residue was purified by preparative HPLC (YMC-PACK ODSA S5 (30×250 mm); flow rate 25 mL/min; gradient time 55 min) to furnish the title compound as a white solid (30 mg, 55%): MS (ESI, pos. ion spectrum) m/z 486; HPLC (method A) tR 3.59 min.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:19])([F:18])[CH2:12][CH2:13][B-](F)(F)F>>[F:10][C:11]([F:19])([F:18])[CH2:12][CH2:13][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: F[B-](F)(F)CCC(F)(F)F
Reactant: O=Cc1ccc(Br)cc1
Product: O=Cc1ccc(CCC(F)(F)F)cc1
Yield: 89.4 %

Procedure:
The compound was synthesized as in Example 3.1 using 4-bromobenzaldehyde (250 mg, 1.35 mmol) in place of 5-bromo-2-formylfuran and 3,3,3-trifluoropropyltrifluoroborate (455 mg, 2.23 mmol) in place of hexylboronic acid to give 4-(3,3,3-trifluoropropyl)benzaldehyde (244 mg, 89%). Used without further characterization.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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>[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:25]=2)[CH2:20][CH2:21]1
Reactant: O=C1CN(c2nncc3cc(Br)ccc23)CCN1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
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: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCNC(=O)C3)nncc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 4-(6-bromophthalazin-1-yl)piperazin-2-one (0.10 g, 326 μmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (98mg, 326 μmol), and tetrakis(triphenylphosphine)palladium (19 mg, 16 μmol) in 5 mL DME/EtOH (4:1) was treated with 2M potassium carbonate (488 μl, 977 μmol). The resulting mixture was warmed up to 90° C. and stirred for 1 h under nitrogen. The mixture was cooled to room temperature, and the crude product was purified via flash chromatography (silica gel) eluting with a gradient of 4% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give the title compound (0.11 g) as a pale yellow solid. Found MS(ES+): 402(M+H)+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=[O:3].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1)=[O:3]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: COC(=O)c1ccc(NC(=O)c2ccccc2N)cc1
Temperature: 140 °C
Yield: 78 %

Procedure:
Isatoic anhydride (4.0 g, 24.5 mmol) and methyl 4-aminobenzoate were combined and heated at 140° C. for 4 hours. The reaction was cool to room temperature and purified by flash chromatography on silica gel, eluting with 90-100% CH2Cl2 in heptane, to afford methyl 4-(2-aminobenzamido)benzoate (5.2 g, 78%). 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylbenzaldehyde (1.0 g, 3.30 mmol) and anhydrous CuCl2 (1.3 g, 9.90 mmol) were added to a solution of methyl 4-(2-aminobenzamido)benzoate (0.900 g, 3.30 mmol) in anhydrous EtOH (70 mL) and heated to reflux for 6 hours, before being cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 5% MeOH in CH2Cl2, followed by further purification on silica gel, eluting with 30-100% EtOAc in heptane, afforded the title compound as a white solid (0.500 g, 34%). 1H-NMR (300 MHz, DMSO-d6): δ 8.18 (dd, J=7.9, 1.1 Hz, 1H), 7.88-7.93 (m, 3H), 7.75 (d, J=6.7 Hz, 1H), 7.57-7.62 (m, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.03 (s, 2H), 4.82 (t, J=5.5 Hz, 1H), 3.84 (s, 3H), 3.60-3.72 (m, 4H), 2.07 (s, 6H). MS (APCI) m/z: 445 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].Br.[Br:32][CH2:33][CH2:34][NH2:35].C(N(CC)CC)C>C1COCC1>[Br:32][CH2:33][CH2:34][NH:35][S:27]([C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18](=[O:19])[CH2:17][CH2:16][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=2)=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)c1cc(CCC(=O)Nc2ccc(S(=O)(=O)Cl)cc2)cc(C(C)(C)C)c1O
Reactant: NCCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CCC(=O)Nc2ccc(S(=O)(=O)NCCBr)cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.6 %

Procedure:
To a stirred suspension of 4-[3-(3,5-di-tert-butyl-4-hydroxy-phenyl)-propionylamino]-benzenesulfonyl chloride (4.38 g, 0.0097 mol) and 2-bromoethylamine hydrobromide (2.11 g, 0.0103 mol) in THF (30 g) at 0-2° C. under nitrogen was added dropwise a solution of triethylamine (2.01 g, 0.0199 mol) in THF (9 g). When addition was complete, the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered and the filtrate was spin evaporated in vacuo. The residue was chromatographed over silica (toluene/acetone 75:25) to give 2.7 g of N-[4-(2-bromoethylsulfamoyl)-phenyl]-3-(3,5-di-tert-butyl -4-hydroxy-phenyl)-propionamide as a white crystalline solid, mp 153-155° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[Cl:13][CH2:14][C:15](Cl)=[O:16]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:13][CH2:14][C:15]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc2ccc(O)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1cccc2ccc(O)cc12
Reaction time: 2 h

Procedure:
To a solution of 8-amino-2-naphthol (8.00 g, 50.3 mmol) in 500 mL of EtOAc and 500 mL of saturated NaHCO3 solution at 0° C. was added chloroacetyl chloride (4.40 mL, 55.2 mmol). After 2 hours, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The titled product was obtained as a dark brown solid which was used in the next reaction without further purification.