Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:3]=1[C:4](=[N:12][OH:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1F.C1C=CC=CC=1.[H-].[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C.C1(C)C=CC=CC=1.O>[O:13]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([C:3]2[CH:14]=[CH:15][C:16]([O:19][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:17]([Cl:18])[C:2]=2[Cl:1])=[N:12]1
Reactant: CCOC(=O)CBr
Reactant: ON=C(c1ccccc1F)c1ccc(O)c(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)COc1ccc(-c2noc3ccccc23)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 18.42 g (0.06 m) of 2,3-dichloro-4-hydroxy-2'-fluorobenzophenone oxime of Example 2C in 120 ml of DMF and 120 ml of benzene 3.6 g (0.15 m) of NaH is added. The mixture is brought to a temperature of 80°-85° C. and held there for 3 hours. The mixture is cooled to room temperature and a solution of 11 g (0.066 m) of ethyl bromoacetate in 20 ml of DMF is added dropwise. After addition the mixture is stirred for 1/2 hour. Water is added to decompose excess NaH. The mixture is extracted with ethylacetate, dried (Na2SO4) and evaporated to give 19 g. This is dissolved in toluene and chromatographed on silica gel with toluene as elutant. The product of ethyl 4-(1,2-benzisoxazol-3-yl)-2,3-dichlorophenoxyacetate is isolated from the column, 3.8 g (17%). An analytical sample is recrystallized from 95% ethanol, m.p. 88°-89° C.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[H-].[Na+].[Cl-].[NH4+]>O1CCCC1>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]([O:22][CH2:23][CH3:24])=[O:21])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(C(C)(C)C)cc1
Yield: 87.8 %

Procedure:
A mixture of 25.3 g of 4-t-butyl-benzoyl chloride, 30.9 g of diethyl malonate and 500 ml of tetrahydrofuran was stirred under cooling with ice and then stirred with 5.9 g of 55% sodium hydride for another 1 hour. To the reaction solution, 200 ml of aqueous ammonium chloride was added, and the tetrahydrofuran was removed by evaporation under reduced pressure. The residue was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 36.2 g of the title compound as a pale yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([F:27])[CH:14]=1.[OH-:28].[K+].Cl>O1CCOCC1.O.C(OCC)(=O)C.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].CC(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)C>[F:27][C:15]1[CH:14]=[C:13]([N:6]2[C:7]3[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]([OH:28])[C:3]=3[CH:4]=[N:5]2)[CH:18]=[CH:17][C:16]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [OH-]
Reactant: COc1cc(Br)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(O)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Temperature: 90 °C
Yield: 79 %

Procedure:
To a solution of 4-bromo-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-6-(methyloxy)-1H-indazole (D3) (176 mg, 0.41 mmol) in dioxane (5 mL) and water (5 mL) was added potassium hydroxide (92 mg, 1.64 mmol). The reaction mixture was degassed with argon and then treated with bis(1,1-dimethylethyl)[2′,4′,6′-tris(1-methylethyl)-2-biphenylyl]phosphane (10 mg, 0.02 mmol) and tris(dibenzylideneacetone)dipalladium (0) (8 mg, 0.009 mmol). After heating at 90° C. for 1 hour, the mixture was allowed to cool to room temperature and then diluted with ethyl acetate and water. The pH was adjusted to 7 by the addition of 1M hydrochloric acid. After separation of the layers, the aqueous phase was re-extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The product was purified by silica gel chromatography eluting with 5-70% ethyl acetate in hexane to yield the title compound (D4) (118 mg).
Reaction SMILES: P.II.C([O:6][C:7](=[O:22])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=O)=O)=[CH:12][C:11]=1[CH2:20][CH3:21])C.O>C(O)(=O)C>[CH2:20]([C:11]1[CH:12]=[C:13]([SH:16])[CH:14]=[CH:15][C:10]=1[O:9][CH2:8][C:7]([OH:22])=[O:6])[CH3:21]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1CC
Agent: II
Agent: P
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(S)ccc1OCC(=O)O

Procedure:
To a refluxing solution of PH3 (4.3 g, 126.5 mmol) and I2 (0.7 g, 2.6 mmol) in glacial acetic acid (30 ml) was added slowly a solution of (4-chlorosulfonyl-2-ethyl-phenoxy)-acetic acid ethyl ester (15 g, 48.9 mmol) in glacial acetic acid (20 ml). The reaction mixture was refluxed for 24 h. Water (10 ml) was added carefully and the mixture was refluxed for further 1 h after cooling, the reaction mixture was filtered and the filtrate diluted with water (100 ml). The mixture was extracted with dichloromethane (3×100 ml), and the organic phases were washed with water. After drying the dichloromethane phase was evaporated to give crude (2-ethyl-4-mercapto-phenoxy)-acetic acid in 10 g (96%) yield.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[C:20]=1[C:29]([O:31]C)=[O:30])(=[O:17])=[O:16])[CH3:2].[Li+].[I-]>N1C=CC=CC=1>[CH2:33]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[C:20]=1[C:29]([OH:31])=[O:30])(=[O:17])=[O:16])[CH3:34]
Reactant: CCN(CC)CCCCCc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCCC2
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCN(CC)CCC/C=C/c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2

Procedure:
A solution of Example 597A (310 mg, 0.6 mmol), and LiI (322 mg, 4 equiv.) in 6 mL of pyridine was reacted in two vials in a microwave at 150° C. for 35 minutes and concentrated. The concentrate was purified by preparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μm particle size) using a gradient of 10% to 95% acetonitrile/10 mM aqueous ammonium acetate over 12 minutes (15 minute run time) at a flow rate of 70 mL/min. The product was combined with a sample of Example 596B to provide 256 mg of a 5:4 mixture of Example 596B and Example 597B.
Reaction SMILES: [Se].CN(CCOC1C=CC(NS(C)(=O)=O)=CC=1)CCC1C=CC(NS(C)(=O)=O)=CC=1.Cl.[CH3:32][NH:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1.Cl[CH2:46][CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[CH:51][CH:50]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>[CH3:32][N:33]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)[CH2:46][CH2:47][O:48][C:49]1[CH:50]=[CH:51][C:52]([N+:55]([O-:57])=[O:56])=[CH:53][CH:54]=1
Reactant: O=[N+]([O-])c1ccc(OCCCl)cc1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(CCOc1ccc(NS(C)(=O)=O)cc1)CCc1ccc(NS(C)(=O)=O)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CN(CCOc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Temperature: 40 °C

Procedure:
In another embodiment, the competitive inhibitor is a selenium analog of dofetilide (N-[4-(2-[2-[4-(methanesulphonamido)phenoxy]-N-methylethylamino]ethyl)phenyl]methane-sulfphonamide). In one aspect of this embodiment, the selenium analog is di-seleno-dofetilide(n-[4-(2-[2-[4-(methaneselenodoioxamido)phenoxyl]-N-methylethylamino)ethyl)phenyl]-methane-selenodioxamide). Di-seleno-dofetilide may be synthesized according to the scheme shown in FIG. 3, which is based on the synthesis of dofetilide described in U.S. Pat. No. 6,124,363. First, N-methyl-2-(4-nitrophenyl)ethylamine hydrochloride (compound 310) is mixed with 4-(2-chloroethoxy)nitrobenzene (compound 320), anhydrous potassium carbonate, potassium iodide, tetra-n-butylammonium iodide and deionized water and heated under reflux for 3 hours. Next, the mixture is cooled to about 40° C., ethyl acetate is added, and the mixture is extracted with ethyl acetate and concentrated. Ethanol is then added to the extract to precipitate the product and the product is filtered to give N-Methyl-N-[2-(4-nitrophenoxy)ethyl]-4-nitrophenethylamine (compound 330). In the next step, compound 330 and 5% w/v palladium-on-carbon are added to methanol, stirred and hydrogenated at 60 p.s.i. to give N-Methyl-N-[2-(4-aminophenoxy)ethyl]-4-aminophethylamine (compound 340). Compound 340 is then added to acetonitrile, followed by triethylamine and methaneselenodioxy chloride. Sodium carbonate is then added to the reaction mixture and distilled. Next, sodium hydroxide is added to the mixture, followed by concentrated hydrochloric acid. The solid is the collected by filtration, washed with water, and dried to obtain di-seleno-dofetilide (compound 350).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([NH:11][C:12]([C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:36])([CH3:35])[O:29][SiH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:24][CH:23]=3)=[C:16]([F:37])[C:15]=2[F:38])=O)[C:5]=1[NH2:39]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:39]=[C:12]([C:14]3[C:15]([F:38])=[C:16]([F:37])[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([CH3:36])([CH3:35])[O:29][SiH2:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[CH:24][CH:23]=4)=[C:18]([F:21])[C:19]=3[F:20])[NH:11][C:6]=2[CH:7]=[C:8]([CH3:10])[CH:9]=1)=[O:40]
Reactant: COC(=O)c1cc(C)cc(NC(=O)c2c(F)c(F)c(-c3ccc(C(C)(C)O[SiH2]C(C)(C)C)cc3)c(F)c2F)c1N
Solvent: CC(=O)O
Product: COC(=O)c1cc(C)cc2[nH]c(-c3c(F)c(F)c(-c4ccc(C(C)(C)O[SiH2]C(C)(C)C)cc4)c(F)c3F)nc12

Procedure:
2-Amino-3-{[4′-(tert-butyl-dimethyl-silanyloxymethyl)-2,3,5,6-tetrafluoro-biphenyl-4-carbonyl]-amino}-5-methyl-benzoic acid methyl ester (2.4 g, 4.16 mmol) was dissolved in glacial acetic acid (75 mL) and stirred and refluxed for 4 hours. Progress of the reaction was monitored by TLC. Acetic acid was distilled under vacuum and the resulting residue was quenched with ice cold water. The precipitate was washed with water and dried (2.0 g, 84.03%) which was directly taken to the next step.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[Cl:20][C:21]1[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:20][C:21]1[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:22]=1[C:23]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=2)[CH:8]=1)=[O:24]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)c(Cl)c1
Yield: 69.2 %

Procedure:
2-Chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-4-(methylsulfonyl)benzamide was prepared in a similar manner as described herein from 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.025 g, 0.085 mmol), 2-chloro-4-(methylsulfonyl)benzoic acid, (0.03 g, 0.13 mmol), HATU (0.05 g, 0.13 mmol), DIPEA (0.025 mL, 0.13 mmol) and DMF (1 mL). The crude material was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.030 g, 69%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.20 (t, 1H), 8.02 (d, 1H), 7.92 (dd, 1H), 7.83 (d, 1H), 7.69 (d, 1H), 7.62 (d, 1H), 7.48 (d, 1H), 7.41 (t, 1H), 7.31 (dd, 1H), 7.23 (d, 1H), 4.46 (d, 2H), 3.30 (s, 3H). MS: m/z 508.9 (M+1).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[O:22][C:21]([C:23]([O:25]CC)=[O:24])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+]>C(O)C>[CH2:1]([NH:17][C:18]1[O:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)o1

Procedure:
A mixture of 2.0 g. of ethyl 5-hexadecylamino-2-furancarboxylate, 10 ml. of ethanol, and 2.0 ml. of 1 N sodium hydroxide is stirred under reflux for 3 hours and then allowed to cool. The mixture is concentrated in vacuo, diluted with water, and adjusted to pH 5 with the dropwise addition of dilute hydrochloric acid. The solid is collected by filtration, washed with water, and dried to yield the product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[CH:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: Cc1ncc(C(CN)C2CCOCC2)cn1
Product: Cc1ncc(C(CNC(=O)c2c(F)cccc2Cl)C2CCOCC2)cn1

Procedure:
From 2-chloro-6-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z=378.1, tR (minutes, Method F)=2.06
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C([Li])CCC.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].O>O1CCCC1>[CH:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][C:10]2[S:11][C:12]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)Oc1ccc(Oc2nccs2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(Oc2ccc(OC(C)C)cc2)s1
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of Example 1B (2.4 g, 0.01 mol) in dry tetrahydrofuran was added n-butyl lithium (4.4 mL, 2.5 M in hexane) at −78° C. drop wise. After stirring at this temperature for 1 h, tributyltin chloride (3.0 mL, 0.011 mol) was added slowly to the mixture. The brown solution was then stirred for 3 hours while warning up to room temperature. Water was added and the solution was extracted with ethyl acetate. The organic layer washed with saturated NH4Cl, brine, and then dried over magnesium sulfate. The solution was concentrated and the crude was purified on a silica gel flash column, eluting with 5-30% EtOAc in hexane, to give 4.85 g of the title compound (93% yield), 1H NMR (300 MHz, CDCl3) δ ppm 0.77-1.74 (m, 33 H) 4.40-4.63 (m, 1 H) 6.84-6.95 (m, 2 H) 7.12 (s, 1 H) 7.14-7.23 (m, 2 H). MS (ESI), m/z 526.2 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[N+:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(N2CCCCC2)c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A mixture of m-fluoronitrobenzene (9 g) and piperidine (40 ml) was heated with stirring at 100° C. for 15 hours and to the mixture were added ethyl acetate ester (100 ml) and aqueous saturated solution of potassium carbonate (100 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain N-(3-nitrophenyl)piperidine (13.5 g) as a yellow oily compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.[Br:17][CH2:18][CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Br:17][CH2:18][CH2:19][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Reactant: OCCBr
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C1CCc2ccc(OCCBr)cc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a 60 ml dichloromethane solution of ethyl 7-hydroxychromane-2-carboxylate (1.32 g, 5.9 mmol), 2-bromoethanol (0.84 ml, 11.9 mmol), and triphenylphosphine (3.12 g, 11.9 mmol) was added diisopropyl azodicarboxylate (2.34 ml, 11.9 mmol) dropwise upon cooling in an ice-water bath. After stirring at rt overnight, the solvent was removed under reduced pressure, and the residue was chromatographed on silica gel eluting with 10% AcOEt/hexanes to give the title compound 1.27 g (65%).
Reaction SMILES: [CH2:1]([N:4]([C:10]([O:12]C)=O)[CH2:5][C:6](OC)=[O:7])[C:2]#[CH:3].[NH3:14]>>[CH2:1]([N:4]1[CH2:5][C:6](=[O:7])[NH:14][C:10]1=[O:12])[C:2]#[CH:3]
Reactant: C#CCN(CC(=O)OC)C(=O)OC
Reactant: N
Product: C#CCN1CC(=O)NC1=O

Procedure:
3.0 g of methyl N-propargyl-N-methoxycarbonylglycinate were dissolved in 40 ml of 28% aqueous ammonia. Then the mixture was maintained under the pressure of 10-13 kg/cm2 at 100°-110° C. for an hour. Then the solvent was evaporated off from the reaction mixture. The resulting mixture was subjected to a column chromatography on silica gel (5:1 ethyl acetate:methanol as eluent) to obtain 0.65 g of 1-propargyl-2,4-dioxoimidazolidine.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]3[CH:15]=[CH:14][CH:13]=[CH:12][C:6]3=[CH:7][CH:8]=2)[N:3]=1.[Br:16][Si](C)(C)C.C(#N)CC.[OH-].[Na+]>>[Br:16][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]3[CH:15]=[CH:14][CH:13]=[CH:12][C:6]3=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[Si](C)(C)Br
Reactant: Clc1ccc2ccc3ccccc3c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCC#N
Product: Brc1ccc2ccc3ccccc3c2n1
Yield: 96 %

Procedure:
A mixture of 2-chlorobenzo[h]quinoline (2.43 g, 11.4 mmol), bromotrimethylsilane (3.00 ml, 22.7 mmol) and propionitrile (12 ml) was heated under reflux for 111 hours. The reaction mixture was then poured into a 10% NaOH solution containing ice. The organic phase was separated and the aqueous phase extracted with Et2O (3×15 ml). The organic phases were combined, dried over anhydrous Na2SO4 and the solvent evaporated under reduced pressure. The residue was purified by chromatography (SiO2, petroleum ether/acetate=9/1) to give 2-bromobenzo[h]quinoline in the form of a yellow solid: 2.82 g (96% yield); melting point: 113-114° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[C:28](B(O)O)=[CH:29][S:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:8][N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[C:27]([CH3:26])=[CH:31][S:30][CH:29]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: Cc1cscc1B(O)O
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cscc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Temperature: 105 °C
Reaction time: 18 h
Yield: 64.1 %

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-methyl-3-thienyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 200 mg, 64%). More specifically, a suspension of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-methyl-3-thienyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at 105° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:1) to give the title compound as a pale-yellow oil (yield 200 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+): m/z=423.1, tR (minutes, Method G)=2.58
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:13]2[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:35]=[CH:34][C:33](OS(C(F)(F)F)(=O)=O)=[C:32]2[C:27]=1[CH:28]1[CH2:44][CH:31]2[CH2:30][CH2:29]1.[H][H]>O1CCCC1.CO.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:13]2[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]1[CH2:44][CH:31]2[CH2:30][CH2:29]1
Reactant: [H][H]
Reactant: CCOC(=O)c1[nH]c2c(-c3ccccc3C)cccc2c1CCCOc1ccc(OS(=O)(=O)C(F)(F)F)c2c1C1CCC2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1[nH]c2c(-c3ccccc3C)cccc2c1CCCOc1cccc2c1C1CCC2C1

Procedure:
To a solution of EXAMPLE 546D (80 mg) in tetrahydrofuran and methanol (40 ml, 1:1) was added 10% palladium hydroxide (40 mg). The mixture was shaken under 30 psi of hydrogen for 4 hours. The catalyst was filtered off, the filtrate was concentrated and the residue was hydrolyzed with LiOH/tetrahydrofuran/methanol/H2O. The product was purified by reverse phase HPLC.