Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(#N)C.[BrH:15].N([O-])=O.[Na+]>O.[Cu]Br>[Br:15][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(F)cccc1C(=O)O
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cccc(F)c1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
In a 1 L, three necked flask fitted with a dropping funnel and thermometer, were charged 2-amino-3-fluorobenzoic acid (20.0 g, 0.13 mol) and acetonitrile (160 mL). After cooling to 0° C., HBr (47%, 160 mL) was added drop wise over 10 min. To the resulting solution a solution of NaNO2 (10.0 g, 0.14 mol) in water (20.0 mL) was added drop wise over 1 h. After addition, the reaction mixture was stirred at 0° C. for 5 min, and copper(I) bromide (22.0 g, 0.15 mol) was added portionwise over 30 min. Stirring was continued at 70° C. in a an oil bath for 1 h. After cooling to 0° C., 700 mL of water was added and the precipitate was filtered, washed with cold water and dried under vacuum to give 28.23 g (100%) of the title compound as a white solid. The crude product was used in the next step without purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([CH3:14])=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][C:3]1=[O:15].[C:16]1(=O)[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH2:17]1.C(N=C=NCCCN(C)C)C>C(#N)C>[CH3:1][N:2]1[C:6]2[C:7]([CH3:14])=[C:8]([C:11]([O:13][C:16]3[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH:17]=3)=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][C:3]1=[O:15]
Reactant: Cc1c(C(=O)O)ccc2sc(=O)n(C)c12
Reactant: O=C1CCCC(=O)C1
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: Cc1c(C(=O)OC2=CC(=O)CCC2)ccc2sc(=O)n(C)c12
Temperature: 50 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
1.1 g (5 mmol) of 3,4-dimethylbenzothiazol-2-one-5-carboxylic acid, 0.58 g of 1,3-cyclohexanedione and 1.25 g of ethyl(3′-dimethylaminopropyl)carbodiimide were dissolved in 40 ml of acetonitrile, and the solution was stirred at 50° C. for 4 hours. After the reaction had ended, the precipitate was filtered off and the solution was concentrated. The residue was taken up in water and extracted with methylene chloride. The organic phase was washed and dried and the solvent was then removed. Chromatography of the residue on silica gel (mobile phase: cyclohexane/ethyl acetate, gradient from 100:0 to 50:50) gave 0.77 g (2.4 mmol, 48% yield) of cyclohexenone-3-yl 3,4-dimethylbenzothiazol-2-one-5-carboxylate of m.p. 144° C.-146° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[C:9]2[CH3:15])=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[C:9]2[CH3:15])=[CH:6][CH:7]=1
Reactant: Cc1nc(CO)cn1-c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1nc(C=O)cn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
[1-(4-Fluoro-phenyl)-2-methyl-1H-imidazol-4-yl]-methanol (7.16 g, 34.7 mmol) was dissolved in 2.3 L methylene chloride. Manganese (IV) oxide (26.8 g, 278 mmol) was added and the reaction mixture was stirred at room temperature for 3 days. The suspension was filtered through a dicalite speed plus pad and washed with 1 L methylene chloride. The solvents were evaporated and the desired compound was obtained as a white solid (5.87 g, 83%), MS: m/e=205.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N:11][O:12][CH2:13][CH2:14][OH:15])[CH3:10])=[CH:5][N:4]=1.O[C:17]1[CH:49]=[CH:48][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[N:24]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]2=[O:47])=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N:11][O:12][CH2:13][CH2:14][O:15][C:17]2[CH:49]=[CH:48][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[N:24]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]3=[O:47])=[CH:19][CH:18]=2)[CH3:10])=[CH:5][N:4]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(C)=NOCCO)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(C(C)=NOCCOc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cn1
Yield: 78.2 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 346 mg of 2-[1-(2-methoxy-5-pyridyl)ethylideneaminooxy]-ethanol (prepared as described in Preparation 31), 766 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 475 mg of triphenylphosphine and 301 mg of diethyl azodicarboxylate, 846 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O.ClCCl>[N:14]1([CH2:9][C:8]2[CH:7]=[C:6]([C:5]#[C:4][CH2:3][CH2:2][OH:1])[CH:13]=[CH:12][CH:11]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=Cc1cccc(C#CCCO)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OCCC#Cc1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1-L, 3-necked round-bottom flask was equipped with a mechanical stirrer, a rubber septum with a nitrogen inlet and a stopper. The flask was charged with the product of Example 5 (14.6 g) and dichloromethane (250 mL). Morpholine (8.85 mL) was added, and then to this well-stirred reaction mixture was added sodium triacetoxyborohydride (32 g) in 4 equal portions. After the addition, the reaction mixture was stirred at room temperature overnight. Aqueous NaOH (10% w/v, 75 mL) was added, and the reaction mixture was transferred to a 1-L separatory funnel, to which water(100 mL) was then added. After separation of the layers, the aqueous phase was extracted once with dichloromethane (100 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, and filtered. The solvents were removed from the filtrate under reduced pressure to yield the product as yellow oil. The crude product was purified by filtration through a pad of silica gel (ethyl acetate/hexanes; 7:3) to obtain the title compound as a pale yellow oil (13.7 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][C:6]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:10]2[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:9]=2[CH2:8][O:7]1.CO[C:26]1[CH2:27][CH2:28][CH2:29][CH2:30][N:31]=1>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:6]2([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[C:26]3[CH2:27][CH2:28][CH2:29][CH2:30][N:31]=3)[C:10]3[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:9]=3[CH2:8][O:7]2)=[CH:18][CH:19]=1
Reactant: COC1=NCCCC1
Reactant: CNCCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Product: CN(CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21)C1=NCCCC1
Temperature: 80 °C

Procedure:
A mixture of 0.200 g (0.64 mmol) of 1-[3-(methylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile (Preparation 1) and 6-methoxy-2,3,4,5-tetrahydropyridine (0.080 g, 0.71 mmol, 1.1 equiv.) was heated at 80° C. for 15 hr, cooled to rt and concentrated in vacuo to a gummy residue. The crude product was purified using column chromatography to give the title product as an off-white solid, 0.060 g (24%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4].[Br:22]C1CC(=O)NC1=O>C(#N)C.CCOC(C)=O>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:22])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4]
Reactant: O=C1CC(Br)C(=O)N1
Reactant: COc1ccc2c(c1)CC(C)N(C(=O)C(F)(F)F)CC2C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)C(C)C2
Reaction time: 8 h

Procedure:
A solution N-trifluoroacetyl-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.452 g, 1.50 mmol) in acetonitrile (20 mL) was treated with N bromosuccinimide (0.294 g, 1.65 mmol) and stirred overnight at 20 C. The product mixture was diluted with EtOAc (100 mL), washed with sodium bisulfite (50 mL) and brine (50 mL), dried with Na2SO4 and concentrated. Flash chromatography (20% EtOAc in hexane, silica) resulted in a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.32 (s, 1 H), 6.62 (m, 1 H), 4.37 (m, 1 H), 3.87 (s, 3 H), 3.81 (m, 1 H), 3.28-3.10 (m, 3 H), 2.73 (m, 1 H), 1.31 (m, 3 H), 1.25 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][CH2:5][C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].OCC[C:19]#[N:20]>>[F:1][C:2]([F:14])([F:15])[CH2:3][O:4][CH2:5][C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH2:12][C:19]#[N:20])=[O:9]
Reactant: N#CCCO
Reactant: CCOC(=O)CC(=O)COCC(F)(F)F
Product: N#CCCOC(=O)CC(=O)COCC(F)(F)F
Temperature: 142.5 °C
Yield: 95.1 %

Procedure:
A mixture of 4.04 g of ethyl 4-(2,2,2-trifluoroethyl)oxy-3-oxobutanoate (17.7 mmol) and 2.55 g of 3-hydroxypropionitrile (35.9 mmol) was heated at reflux temperature at a bath temperature of 135-150° C. at 10 torr for 6 hrs. The reflux condenser was replaced with a distillation head and the product was distilled under reduced pressure to give 4.26 g (96%) of the desired product as a viscous oil: bp 155-158° C. (1.5). The product was used in the next step after spectral characterization.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][N:14]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([CH2:23][NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:19]=[CH:20]2)=[N:15]1>>[Cl:8][C:7]1[C:2]([N:24]([CH2:23][C:18]2[CH:19]=[CH:20][C:21]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:13])[CH:22]=3)[S:25]([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3cn(C)nc3c2)cc1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3cn(C)nc3c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((2-methyl-2H-indazol-6-yl)methyl)sulfamoyl)benzoate (step-1 of Example 18).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[NH:15][N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[N:15]([S:34]([CH3:33])(=[O:36])=[O:35])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(-c2nc3c(-c4ccccc4)n[nH]c3c(=O)n2-c2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)c1ccc(-c2nc3c(-c4ccccc4)nn(S(C)(=O)=O)c3c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one (20.0 mg, 0.045 mmol) in DCM (0.5 mL) are added MsCl (7.05 μL, 0.091 mmol) and TEA (12.64 μL, 0.091 mmol). The reaction mixture is stirred at room temperature for overnight before removal of the solvent, The residue is purified by preparative LC/MS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 8.47 (dd, 2H), 7.48 (m, 3H), 7.34 (d, 2H), 7.28 (d, 2H), 7.14 (m, 4H), 3.77 (s, 3H), 2.87 (m, 1H), 1.22 (s, 3H), 1.21 (s, 3H); HPLC-MS calculated for C27H23ClN4O3S (M+H+) 519.1. Found: 519.1.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:28])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)C.[OH-].[Na+]>C(O)C>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:29])=[O:3])[N:7]=2)=[O:28])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A solution of {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (prepared as in Example 1(B)(c), 198.1 mg, 0.44 mmol) in absolute ethanol (2.2 mL) was treated with a 1N aqueous sodium hydroxide solution (910 μL, 0.91 mmol). The reaction mixture was heated under reflux for 2 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove absolute ethanol. The resulting residue was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and extracted with ethyl acetate (1×150 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting white residue was washed well with cold water and dried to afford {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-acetic acid (150 mg, 81%) as a white solid: mp 100-102° C.; FAB-HRMS m/e calcd for C19H20Cl2N2O3S (M+H)+ 427.0650, found 427.0633.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12](=[O:20])[NH:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[N:9][C:8]([C@@H:21]([NH:23]C(=O)OCC1C3C=CC=CC=3C3C1=CC=CC=3)[CH3:22])=[CH:7]2>N1CCOCC1>[NH2:23][C@H:21]([C:8]1[N:9]=[C:10]([C:12]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:20])[C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[CH3:22]
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(C(=O)NC2CCOCC2)n1
Solvent: C1COCCN1
Product: C[C@H](N)c1cc2cccc(Cl)c2c(C(=O)NC2CCOCC2)n1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
(S)-(9H-fluoren-9-yl)methy 1-(8-chloro-1-(tetrahydro-2H-pyran-4-ylcarbamoyl)isoquinolin-3-yl)ethylcarbamate (351) (20.0 g, 36.0 mmol, 1.0 eq) was suspended in morpholine (200 mL), and then stirred at 40-50° C. for 1 h. The reaction mixture was concentrated in vacuo and then 1,4-dioxane (200 mL) was added to the residue. The mixture was concentrated in vacuo. The operation was repeated for 3-4 times. The residue was purified by flash column chromatography on silica gel (2-10% MeOH-DCM) to afford (S)-3-(1-aminoethyl)-8-chloro-N-(tetrahydro-2H-pyran-4-yl)isoquinoline-1-carboxamide (352).
Reaction SMILES: [CH3:1][CH2:2][OH:3].[F:4][C:5]([F:12])([F:11])[C:6]([F:10])=[C:7]([F:9])[F:8]>>[F:8][C:7]([F:9])([CH:6]([F:10])[C:5]([F:12])([F:11])[F:4])[CH:2]([OH:3])[CH3:1]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: CCO
Product: CC(O)C(F)(F)C(F)C(F)(F)F
Temperature: 75 °C
Reaction time: 16 h
Yield: 95.6 %

Procedure:
A quantity of 3,3,4,5,5,5-hexafluoropentan-2-ol was prepared by combining absolute ethanol 200 proof (100 g, 2.17 moles, AAPER Alcohol and Chemical Co.) with t-amyl peroxy-2-ethylhexanoate (5 g, 0.021 moles) (available as Luperox 575 from Arkema, Oakville, Ontario, Canada) in a 600 mL Parr pressure reactor. The reactor was heated to 75° C. and hexafluoropropene (120 g, 0.8 moles) (MDA Manufacturing Inc., Decatur, Ala.) was added at a constant rate. The reactor was allowed to stir at this temperature for 16 h. The crude reaction material was distilled using a ten plate Oldershaw column to afford 150 g of 3,3,4,5,5,5-hexafluoropentan-2-ol (b.p.=121° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[C:4]([N:6]([C:15](=[O:24])[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][N:8]=1)=[O:5].C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[C:4]([N:6]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Br:31])=[CH:9][N:8]=1)[C:15](=[O:24])[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])=[O:5]
Reactant: O=C(c1c(Cl)cccc1Cl)N(C(=O)c1c(Cl)cccc1Cl)c1ccc(CO)cn1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(c1c(Cl)cccc1Cl)N(C(=O)c1c(Cl)cccc1Cl)c1ccc(CBr)cn1
Reaction time: 2.5 h
Yield: 65.8 %

Procedure:
In 40 ml of dichloromethane was dissolved 855 mg (1.8 mmol) of 2,6-dichloro-N-(2,6-dichlorobenzoyl)-N-(5-hydroxymethylpyrid-2-yl)benzamide (e), and 905 mg (2.7 mmol) of carbon tetrabromide and 573 mg (2.2 mmol) of triphenylphosphine were added. The mixture was stirred for 2.5 hours, and treated with a saturated sodium hydrogen carbonate aqueous solution. The mixture was subjected to extraction with chloroform, and the extract was washed with a saturated sodium chloride aqueous solution. The solvent was evaporated off under vacuum, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate (volume ratio)=3:1-2:1) to give 631 mg (yield 65%) of 2,6-dichloro-N-(5-bromomethylpyrid-2-yl)-N-(2,6-dichlorobenzoyl)benzamide (f).
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]1S(C1C=CC=CC=1)(=O)=O)#[N:4].C>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[C:3]([C:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: COc1cccc2c1C=CN(S(=O)(=O)c1ccccc1)C2C#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: COc1cccc2c(C#N)nccc12
Temperature: 25 °C

Procedure:
Sodium hydride (1.2 g of 60% in mineral oil) is added to a stirred suspension of 1-cyano-2-benzenesulfonyl-1,2-dihydro-5-methoxyisoquinoline (10 g) in xylene (100 ml). The reaction mixture is refluxed under nitrogen for 3 hrs, cooled to RT, stirred for an additional hour, and filtered. The filtered solid is washed with xylenes. The filtrate is evaporated in vacuo. The filtered solid is stirred with methylene chloride and aqeuous 5% sodium hydroxide solution. The methylene chloride phase is combined with the residue from the evaporated filtrate and the combined extracts are washed with 5% sodium hydroxide solution, H2O and dried over sodium sulfate. The dried extract is filtered and the filtrate evaporated in vacuo, affording a moist solid which is triturated in hexanes. The triturated solid is filtered, washed with hexanes, and dried, affording a fluffy orange solid, M.P. 166°-175° C. The crude product is dissolved in ethyl acetate, treated with charcoal, filtered and recrystallized from ethyl acetate, affording the desired cyanoisoquinoline as a crystalline solid, M.P. 180°-182° C.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:26][N:27]1[C:31]([C:32]([C:34]2[CH:35]=[N:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=2)=[O:33])=[CH:30][N:29]=[CH:28]1.[Li]CCCC>C(=O)=O.CC(C)=O>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:32]([C:31]3[N:27]([CH3:26])[CH:28]=[N:29][CH:30]=3)([C:34]3[CH:35]=[N:36][C:37]([C:40]([F:42])([F:41])[F:43])=[CH:38][CH:39]=3)[OH:33])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (827 mg, 1.91 mmol, Intermediate 3: step c) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (536 mg, 2.10 mmol, Intermediate 2: step c). The flask was evacuated and back-filled with argon, then THF (27 mL) was added. The resulting yellow suspension was heated until nearly all solid dissolved, and the slightly cloudy yellow suspension was allowed to cool to room temperature, and then was cooled in a dry ice acetone bath for 7 minutes before addition of n-BuLi (1.6 M in hexane, 1.55 mL, 2.48 mmol) dropwise. The mixture was stirred for 5 minutes in dry ice/acetone bath, then was moved to an ice/water bath and stirred for 1 hour. The reaction was quenched by the addition of saturated aqueous NH4Cl, and was diluted with water. The aqueous was then extracted with EtOAc (3×). The organic layers were combined and washed once with water. The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, 0-2% MeOH-DCM) affording impure title compound which was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:7]2[C:8](=O)[CH2:9][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:11][C:6]=2[O:5][CH:4]=1.[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].[ClH:27].Cl.O>C(O)C>[ClH:27].[F:1][C:2]([F:21])([F:20])[C:3]1[C:7]2[C:8](=[N:26][NH:25][C:22]([NH2:24])=[NH:23])[CH2:9][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:11][C:6]=2[O:5][CH:4]=1
Reactant: N=C(N)NN
Reactant: Cc1ccccc1C1CC(=O)c2c(C(F)(F)F)coc2C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C(F)(F)F)coc2C1
Yield: 40.6 %

Procedure:
A mixture of 3-trifluoromethyl-6-(2-methylphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.15 g), aminoguanidine hydrochloride (0.06 g), concentrated hydrochloric acid (0.025 ml), water (0.025 ml) and ethanol (30 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol-ethyl acetate to give 3-trifluoromethyl-4-guanidinoimino-6-(2-methylphenyl)-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 52) (0.08 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.C1N2CN3CN(C2)CN1C3.[C:31](O)(C(F)(F)F)=[O:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:10]=1)[CH:31]=[O:32]
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1C=O
Temperature: 75 °C
Reaction time: 2 h

Procedure:
To a solution of 3,5-dichloro-4-(4-methoxy-phenoxy)-nitrobenzene (3.14 g, 10.0 mmol) in TFA (30 ml) was added hexamethylenetetramine (2.10 g, 15.0 mmol). The resulting mixture was stirred at 75° C. for 2 h then concentrated to a viscous oil. The residue was taken up in 30 ml H2O and stirred at RT. To this suspension was added sufficient sat'd aqueous NaHCO3 to neutralize the residual TFA and the mixture was then extracted with EtOAc (3×30 ml). The combined EtOAc extracts were washed with sat'd aqueous NaHCO3 (2×30 ml) and dried over Na2SO4. Dried extracts were filtered and concentrated to give the title compound of step A (3.67 g) as a yellow solid. The title product of Step A was used in the next step without further purification. MS (APCl−) Calc.: 341.0, Found: 340.1 (M−1).