Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].C(N(C(C)C)CC)(C)C.[Cl:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>ClCCl>[Cl:21][CH2:22][CH2:23][CH2:24][C:25]([NH:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[F:1])=[O:26]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCl)Nc1cc([N+](=O)[O-])ccc1F
Reaction time: 2 h

Procedure:
2-Fluoro-5-nitroaniline (500 mg, 3.2 mmol) and diisopropylethylamine (1.1 ml, 6.4 mmol) were stirred in dry dichloromethane (10 ml) under nitrogen. 4-Chlorobutyryl chloride was added drop-wise over 1 minute and the reaction was stirred for a further 2 hrs. The reaction mixture was partitioned between water (50 ml) and dichloromethane (50 ml). The organics were collected, dried (magnesium sulphate), concentrated in vacuo and the residue purified by flash column chromatography (SiO2) eluting with dichloromethane to give 537 mg of 4-chloro-N-(2-fluoro-5-nitro-phenyl)-butyramide as a white solid. This material was re-dissolved in dry tetrahydrofuran and cooled over an ice-bath. Sodium hydride (83 mg, 2 mmol) was added and the reaction was stirred at room temperature for 3 hr. The reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (50 ml). The organics were washed with water (50 ml), dried (magnesium sulphate) and concentrated in vacuo to give 430 mg of crude 1-(2-fluoro-5-nitro-phenyl)-pyrrolidin-2-one as a yellow solid. This material was suspended in diethyl ether (20 ml) and ethanol (2 ml). A solution of tin (II) chloride dihydrate in concentrated HCl (20 ml) was added drop-wise over 5 minutes and the reaction stirred at room temperature for 3 hrs. The reaction mixture was neutralised to pH 7 by addition of 2M sodium hydroxide (aq) and the resulting solution was extracted with dichloromethane (2×100 ml). The organic extracts were combined, dried (magnesium sulphate) and concentrated in vacuo to afford crude 1-(5-amino-2-fluoro-phenyl)-pyrrolidin-2-one (424 mg, 68%) as a yellow solid. HPLC retention time 3.3 min. Mass spectrum (ES+) m/z 195 (M+H).
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[Br:17][CH2:18][CH2:19][CH2:20]Br.C(OCC)(=O)C>CS(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][N:8]([N:6]1[CH:5]=[N:4][N:3]=[CH:7]1)[C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(N(CCCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1,3dibromopropane (5 mL) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 mL) and filtered through a layer of silica (ca. 5 cm). The silica was washed with more diethyl ether (ca. 100 mL) to remove the excess of 1,3-dibromopropane, the crude product was washed from the silica with acetone (120 mL). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a white solid. Yield: 792 mg (52%). 1H-NMR (400 MHz, d6-DMSO) δ=2.01 (tt, J=7.0, 6.6 Hz, 2H), 3.64 (t, J=6.6 Hz, 2H), 3.95 (t, J=7.0 Hz, 2H), 6.62 (d, J=9.0 Hz, 2H), 7.74 (d, J=9.0 Hz, 2H), 9.02 (s, 2H). 13C-NMR (100 MHz, d6-DMSO) δ=30.38, 32.13, 52.72, 103.17, 113.83, 119.74, 134.63, 144.14, 151.65. LRMS (FAB+): 306.0 (100, [M+H]+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([C:7]([SH:10])([CH3:9])[CH3:8])[NH2:6].[CH2:12]1CCN2C(=NCCC2)CC1.CI>CN(C=O)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([C:7]([S:10][CH3:12])([CH3:9])[CH3:8])[NH2:6]
Reactant: COC(=O)[C@H](N)C(C)(C)S
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](N)C(C)(C)SC
Reaction time: 1 h
Yield: 81 %

Procedure:
To a 0° C. solution of D-penicillamine methyl ester hydrochloride (0.250 g., 1.25 mmoles) in DMF (4 mL) was added DBU (0.382 ml., 2.56 mmoles), followed by methyl iodide (0.081 ml., 1.31 mmoles). After 1 hour, the solution was partitioned between brine and ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated. The residue was purified on silica, eluting with 6% methanol in dichloromethane to give S-methyl-D-penicillamine methyl ester as a colorless oil in 81% yield: 1H--NMR (CDCl3) δ 1.25 (s, 3H) 1.35 (s, 3H), 2.02 (s, 3H), 3.44 (s,1H), 3.72 (s, 3H); FAB HRMS:expected (M+H)=178.0902, found (M+H)=178.0905.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[F:1][C:2]1[CH:3]=[C:4]2[C:6]([C:12]([OH:11])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:19]=[N:5]2)=[CH:7][CH:8]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc(F)c1
Product: CCOC(=O)c1cnc2cc(F)ccc2c1O

Procedure:
Prepared as in Example 1c from 3-fluoroaniline and diethyl 2-(ethoxymethylene)malonate as a brown solid (51%). MS 236 (MH+).
Reaction SMILES: Br.[Br:2][CH:3]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][C:4]1=O.[C:11]([NH2:15])(=[S:14])[CH2:12][CH3:13]>C(O)C>[BrH:2].[CH2:12]([C:11]1[S:14][C:3]2[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][C:4]=2[N:15]=1)[CH3:13]
Reactant: O=C1CCNCCC1Br
Reactant: CCC(N)=S
Agent: Br
Solvent: CCO
Product: CCc1nc2c(s1)CCNCC2
Temperature: 25 °C

Procedure:
0.40 g (1.47 mmol) 5-bromo-azepan-4-one hydrobromide, 0.13 g (1.47 mmol) thiopropionamide and 3 mL ethanol were stirred under reflux for 3 hours. The reaction was allowed to cool to RT and was filtered. The filtrate was concentrated to dryness and dried.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O.O>[C:2]([O:6][C:7]([NH:9][C@H:10]([C:18]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])([CH3:3])([CH3:4])[CH3:5]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1
Reaction time: 6 h

Procedure:
To a solution of N-tert-butoxycarbonyl-L-phenylalanine hydrochloride (2.65 g) and aniline (1.02 g) in dimethylformamide (DMF, 50 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl) and hydroxybenzotriazole (HOBT, 1.5 g) at room temperature, and the mixture was stirred for 6 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous citric acid solution, water, a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure to give N-tert-butoxycarbonyl-L-phenylalanylaminobenzene. To a solution of the obtained compound in dichloromethane (20 ml) was added trifluoroacetic acid (10 ml) at room temperature, and the mixture was stirred for 1 hour. Toluene (10 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. A 1M hydrogen chloride-ether solution (10 ml) was added to the residue, and crystallization gave the title compound (1.45 g, yield 52%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CC(C)=O.O>[N:13]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[N+:14]=[N-:15]
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NCc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
A solution of p-bromomethylphenylacetic acid (3.64 g, 15.9 mmol) in acetone (100 ml) was treated with a solution of sodium azide (1.04 g, 16.0 mmol) in H2O (15 ml). The mixture was stirred at room temperature overnight (ca. 20 h). After evaporation of the acetone, the residual solution was cooled in an ice-bath. The white gelatinous precipitate that formed was collected, washed with cold water and dried yielding 2.175 g (11.4 mmol, 71.5%) of p-azidomethylphenylacetic acid as a white solid: 1Hmr (DMSO-d6) δ: 3.59 (2H, s,--CH2CO2), 4.42 (2H, s,--CH2N3) and 7.32 ppm (4H, s, aromatic Hs); ir (nujol) νmax : 2500-3400 (b, --CO2H), 2070 (s, --N3) and 1690 cm-1 (s, C=O).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)[CH3:2].Cl.[C:17]1([C:23]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:31]3[CH:27]([CH2:28][NH:29][CH2:30]3)[C:26](=[O:32])[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[C:33]1([C:23]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:31]3[CH:27]([CH2:28][N:29]([C:11](=[O:13])[CH2:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]([CH2:1][CH3:2])[CH2:14][CH3:15])[CH2:30]3)[C:26](=[O:32])[CH2:25][CH2:24]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCN(CC)c1ccccc1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)c1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
N,N'-Carbonyldiimidazole (0.86 g) is added to a solution of 2-diethylaminophenylacetic acid (1.1 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred at +5° C. for 30 minutes and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.73 g) and triethylamine (1.48 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 24 hours, then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 3 cm, height 40 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (30/80 by volume) and collecting 125 cc fractions. Fractions 12 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile (15 cc) and isopropyl ether (50 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[2-(2-diethylaminophenyl)acetyl]-4-perhydroisoindolone (1.6 g) is obtained in the form of white crystals melting at 160° C.
Reaction SMILES: [CH3:1][NH2:2].CS([C:7]1[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[C:9]([CH2:16][CH2:17][CH3:18])[N:8]=1)(=O)=O>>[CH3:1][NH:2][C:7]1[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[C:9]([CH2:16][CH2:17][CH3:18])[N:8]=1
Reactant: CN
Reactant: CCCc1cc(C(=O)O)nc(S(C)(=O)=O)n1
Product: CCCc1cc(C(=O)O)nc(NC)n1

Procedure:
A solution of 40% aq. methylamine (5 mL) and 2-methanesulfonyl-6-propyl-pyrimidine-4-carboxylic acid (150 mg, 0.614 mmol) is heated to 70° C. for 2 h. The reaction mixture is then evaporated and the crude compound is dissolved in 3N NaOH solution (10 mL). The aq. solution is washed with EtOAc (5 mL), is then adjusted to pH 3 with 25% aq. HCl and finally extracted with DCM (3×15 mL). The combined DCM extracts are dried over MgSO4, filtered and evaporated to give 2-methylamino-6-propyl-pyrimidine-4-carboxylic acid as a beige powder (128 mg); LC-MS: tR=0.56 min, [M+H]+=196.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.C1C=CC(P([N:35]=[N+:36]=[N-:37])(C2C=CC=CC=2)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([N:35]=[N+:36]=[N-:37])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(/C=C/C(=O)O)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cccc(/C=C/C(=O)N=[N+]=[N-])c1
Reaction time: 18 h
Yield: 87.9 %

Procedure:
To a solution of (E)-3-(3-methoxyphenyl)acrylic acid (15 g, 84 mmol) in benzene (100 ml) was added triethylamine (11.73 ml, 84 mmol) followed by DPPA (23.17 g, 84 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by conventional column chromatography (Silica gel, 60-120 mesh) using 10% ethyl acetate in pet ether as mobile phase to get the desire compound as white solid (15 g, 88%). 1H NMR (400 MHz, CDCl3): δ ppm 7.75-7.70 (d, J=20 Hz, 1H), 7.36-6.97 (m, 4H), 6.45-6.40 (d, J=20 Hz, 1H), 3.85 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:18](=[O:19])[N:17]([CH2:20]C=C)[C:16](=[O:23])[C:15]([CH3:24])=[N:14]1.BrCC=C.IC.ClC1C(OC(C)C)=CC(N2C(=O)N(CCCF)C(=O)C=N2)=C(F)C=1.ClC1C(OC(C)C)=CC(N2C(=O)NC(=O)C=N2)=C(F)C=1.ClCCCF>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:18](=[O:19])[N:17]([CH3:20])[C:16](=[O:23])[C:15]([CH3:24])=[N:14]1
Reactant: C=CCn1c(=O)c(C)nn(-c2cc(OC(C)C)c(Cl)cc2Cl)c1=O
Agent: CC(C)Oc1cc(-n2ncc(=O)[nH]c2=O)c(F)cc1Cl
Agent: CC(C)Oc1cc(-n2ncc(=O)n(CCCF)c2=O)c(F)cc1Cl
Agent: FCCCCl
Solvent: CI
Solvent: C=CCBr
Product: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2Cl)c(=O)n(C)c1=O

Procedure:
Compound 16, 2-[2,4-dichloro-5-(1-methylethoxy)phenyl]-6-methyl-4-(2-propenyl)-1,2,4-triazine-3,5(2H,4H)-dione, was also prepared by the method of Example IV using 3-bromo-1-propene rather than iodomethane in Step D. Similarly, Compound 50, 2-[4-chloro-2-fluoro-5-(1-methylethoxy)phenyl]-4-(3-fluoropropyl)-1,2,4-triazine-3,5(2H,4H)-dione, was prepared by treating Compound 17 (Example II D) with 1-chloro-3-fluoropropane.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([OH:14])=[CH:6][CH:5]=1.[O:15]([CH2:22][CH2:23][CH2:24]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(N(C)C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br:3][C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([O:14][CH2:24][CH2:23][CH2:22][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1nc(Br)ccc1O
Reactant: BrCCCOc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1nc(Br)ccc1OCCCOc1ccccc1
Temperature: 100 °C
Yield: 85.5 %

Procedure:
Sodium hydride (60% in mineral oil, 172 mg, 4.53 mmol) was added to a mixture of methyl 6-bromo-3-hydroxypicolinate (26B) (1.0 g, 4.31 mmol) and 3-phenoxypropyl bromide (927 mg, 4.31 mmol) in DMA (20 mL) at it. The mixture was heated to 100° C. for 1.75 hours, cooled, diluted with 10% citric acid and extracted with EtOAc. The organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of PE:EtOAc 100:0-75:25, to provide 1.35 g (86%) of the desired product methyl 6-bromo-3-(3-phenoxypropoxy)picolinate (26C): 1H NMR (300 MHz, CDCl3) δ 7.52 (1H, d), 7.27 (2H, m), 6.92 (2H, m), 4.25 (2H, t), 4.19 (2H, t), 3.92 (3H, s), 2.30 (2H, t).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]#[N:13].[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>ClCCl.N1C=CC=CC=1>[CH2:7]([N:6]1[C:2]([NH:1][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[F:14])=[C:3]([C:12]#[N:13])[C:4]([CH3:11])=[N:5]1)[CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CCCCn1nc(C)c(C#N)c1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCn1nc(C)c(C#N)c1NC(=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
5-Amino-1-butyl-3-methyl-1H-pyrazole-4-carbonitrile (10.0 g, 56 mmole) was dissolved in a mixture of dichloromethane/pyridine (45 ml/15 ml) and cooled to 0° C. 2-fluorobenzoyl chloride (8.87 g, 56 mmole) was added dropwise and the reaction mixture was stirred for 1 hour at 0° C., and at room temperature overnight. The solvent was removed under vacuum. The residue was taken up in ethyl acetate, washed with diluted hydrochloric acid, 0.1 M sodium hydroxide, and water, and dried over sodium sulfate (anh). The solvent was removed and the solid triturated in 30% ethyl acetate/hexanes. The product was filtered to obtain 4.16 g product (yield: 24%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:36][C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:40]([O:39][C:37](=[O:38])[CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)([CH3:42])[CH3:41]
Reactant: CC(C)OC(=O)CCl
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(O)c4)nc4ccccc34)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1

Procedure:
A suspension of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (120 mg, 0.26 mmol), isopropyl 2-chloroacetate (45 mL, 0.36 mmol), K2CO3 (125 μL, 0.24 mmol), in DMF (5 mL) stirred at RT for 2 h. Concentrated in vacuo to afford the crude tert-butyl 5-(2-(3-(2-isopropoxy-2-oxoethoxy)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate ( ). (0.26 mmol)
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17]>CCOCC>[Cl:17][CH2:16][C@@H:18]([OH:20])[CH2:19][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: ClC[C@@H]1CO1
Solvent: CCOCC
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and ferric chloride (12.6 g. 0.30 mol) were added to 100 mL of ether. The mixture was stirred at 25° C. for 30 minutes, (S)-epichlorohydrin (18.6 g, 0.2 mol) was then added and stirred for at 60° C. 8 hours. Filtered and the solvent was evaporated to provide 53 g of colorless oil in 92% yield. HPLC: 99%.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:23])[CH:6]=[CH:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].CCCC[C@@H](O)/C=C\C/C=C\C/C=C\C/C=C\CCCC(O)=O.C(CCO)CC/C=C\C/C=C\C/C=C\C/C=C\CCCC(O)=O>>[CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:23])/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCCCC(O)C=CCC=CCC=CCC=CCCCC(=O)O
Agent: CCCC[C@@H](O)/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: O=C(O)CCC/C=C\C/C=C\C/C=C\C/C=C\CCCCCO
Product: CCCCC(O)/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Reaction time: 0.33 h

Procedure:
Neutrophil adhesion: Isolated neutrophils were resuspended in M1 99 containing 1% BSA with a final concentration of 3×106 cells per ml. Cells suspensions (1 ml) were incubated with or without a test compound, 16(S)-HETE, 16(R)-HETE, or 20-HETE (concentrations 0.01 to 10 μM) for 10 min and then placed into gelatin-coated wells and further incubated for 20 min at 37° C. The wells were washed three times with 0.5 ml of solution M199 to remove non-adherent cells. The adherent cells were then removed by addition of 0.4 ml of 0.25% trypsin-EDTA in 0.1 M PBS to the gelatin-coated wells and incubation for 10 min at 37° C. The incubates were transferred and the wells were washed with 0.1 ml of M199 solution. The amount of cells in combined solutions was counted. In some experiments, the adhesion of neutrophils was stimulated by addition of 1 U/ml of thrombin to neutrophil suspension immediately prior to the transfer of cells to the wells. Experiments were performed in duplicates for each concentration of HETE. The inhibition of adhesion was expressed as percent of cells remaining in suspension (non-adherent) relative to control. The range of adherent PMNs in control incubations was 6 to 23%. This was increased two-fold in the presence of thrombin.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:13]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:21]3)=[CH:17][CH:16]=2)=[O:14])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].Br[CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45].[F-].[Cs+]>CC#N>[Br:1][C:2]1[S:3][C:4]([C:13]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:21]3[CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[C:39](=[O:40])[C:38]4[C:37](=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:36]3=[O:45])=[CH:17][CH:16]=2)=[O:14])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)[nH]c3c2)sc1Br
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Yield: 65 %

Procedure:
To a stirred solution of 4 (715 mg, 1.53 mmol), N-(4-bromobutyl)-phthalimide (888 mg, 3.15 mmol) in 20 mL CH3CN, CsF (1.24 g, 8.21 mmol) was added. The resulting mixture was refluxed for 5 hours and then concentrated in vacuo. MPLC purification (Hex:EtOAc/4:1) of the residue gave 5 as a yellow amorphous solid (666 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.78-7.65 (m, 6H), 7.58 (s, 1H), 7.48-7.39 (m, 5H), 6.57 (s, 1H), 4.30 (t, J=7.2 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 3.67 (s, 2H), 3.49 (t, J=6.8 Hz, 2H), 1.74-1.68 (m, 2H), 1.50-1.46 (m, 2H), and 1.26 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 187.33, 169.95, 168.50, 145.22, 144.25, 136.85, 135.71, 135.07, 134.18, 132.55, 132.15, 132.09, 130.69, 129.52, 128.96, 128.84, 128.74, 123.44, 121.48, 121.42, 120.53, 112.50, 103.12, 61.49, 43.67, 37.26, 35.37, 27.38, 25.81, and 14.44.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[C:8]([CH3:13])[C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2].[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH3:13])[C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1sc(Cl)c(C)c1C(N)=O
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1sc(Sc2ccccc2)c(C)c1C(N)=O
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Intermediate 6 (2-Acetylamino-5-chloro-4-methyl-thiophene-3-carboxylic acid amide) (1.16 g, 5 mmol) is mixed with benzenethiol (535 μL, 5.25 mmol) and Cs2CO3 (3.25 g, 10 mmol) in DMF (15 mL). The resulting mixture is stirred at 120° C. for 30 min, then diluted with water, affording a suspension which is left to stir at room temperature overnight. The solid is separated by filtration, the cake is dried, and the resulting solid is used as such.