Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(C)=O.C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: O=c1[nH]cnc2ccc(I)cc12
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Ic1ccc2ncnc(Nc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
In a 20 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 2.00 g (7.35 mmol) of 6-iodoquinazolin-4-one, 1.35 g (8.8 mmol) of phosphorus oxychloride, and 6 mL of toluene in a nitrogen atmosphere. While the mixture was stirred at room temperature, 0.89 g (8.8 mmol) of triethylamine was slowly added. The resulting mixture was heated to 75° C., and then reaction was carried out for 2 hours. Subsequently, the mixture was cooled to room temperature, and 3 mL of acetone and 821 mg (8.8 mmol) of aniline were added. The resulting mixture was again heated to 75° C., and then reaction was carried out under stirring for one hour. After the reaction was complete, the reaction mixture was cooled to room temperature, and thus precipitated crystalline product was collected by filtration. Subsequently, the crystalline product was placed in 30 mL of aqueous sodium hydroxide (1 mol/L), and the aqueous mixture was stirred for 30 minutes at room temperature. The crystalline product was collected by filtration, washed with 30 mL of water, and dried under reduced pressure, to give 1.91 g (isolated yield: 73%, purity 97% in terms of area percentage determined by high performance liquid chromatography) of 6-iodo-4-anilinoquinazoline as a yellowish crystalline product.
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)C.[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[CH:11]1[O:13]C1>>[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[CH:11]=[O:13]
Reactant: Clc1ccccc1C1CO1
Agent: C[S+](C)C
Agent: [H-]
Agent: [I-]
Product: O=Cc1ccccc1Cl

Procedure:
Following the procedure of Example 13 and employing 42.0 g. of 57% dispersion of sodium hydride in mineral oil, 200 g. (1.0 mol) of trimethylsulfonium iodide and 70.4 g. (0.50 mol) of o-chlorobenzaldehyde there is obtained o-chlorostyrene oxide.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:42]([O:49][C:50]([NH:52][C@H:53]1[CH2:59][CH2:58][C@@H:57]2[CH2:60][C@H:54]1[CH:55](O)[N:56]2[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[NH4+].[Cl-]>O1CCCC1>[CH2:42]([O:49][C:50]([NH:52][C@H:53]1[CH2:59][CH2:58][C@@H:57]([NH:56][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:60][C@H:54]1/[CH:55]=[CH:9]/[C:8]1[CH:7]=[C:6]([CH:31]=[CH:30][CH:29]=1)[C:4]([O:3][CH3:2])=[O:5])=[O:51])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1C(O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Reactant: COC(=O)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(/C=C/[C@@H]2C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]2NC(=O)OCc2ccccc2)c1
Yield: 58.7 %

Procedure:
A suspension of 3-(methoxycarbonyl)benzyltriphenylphosphonium bromide (1.8 g, see J. Chem. Soc. 1961, 5015) in tetrahydrofuran (5 mL) was stirred on an ice bath and treated dropwise over 10 min with a solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 7.3 mL). The resulting yellow suspension was stirred on ice for 15 min, then was treated with a solution of (1R,2S,5R)-tert-butyl 2-(benzyloxycarbonylamino)-7-hydroxy-6-aza-bicyclo[3.2.1]octane-6-carboxylate (460 mg) in tetrahydrofuran (3 mL). After allowing to stir on an ice bath for 75 min, the mixture was stirred at rt for 3 h. Saturated aqueous NH4Cl was added, the mixture was stirred rapidly until colorless, then was extracted three times with ethyl acetate. The combined organic phases were washed with 1.0 M aqueous HCl, then with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with 2:1 v/v hexane-ethyl acetate, to provide methyl 3-((E)-2-((1S,2S,5R)-2-benzyloxycarbonylamino-5-(tert-butoxycarbonylamino)cyclohexyl)vinyl)benzoate as a glassy foam (365 mg). MS found: (M+H)+=509.3.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:18][C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:24]OS(=O)(=O)OC>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClC1C=CC=CC=1>[Br:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([N:18]([CH3:24])[C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Reactant: COS(=O)(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CC(=O)N(C)c1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A mixture of 4-bromo-1-acetylaminoanthraquinone (purity 98%, 35.1 g), monochlorobenzene (420 g), tetra-n-butyl ammonium bromide (0.3 g) and 98.5% sodium hydroxide (8.1 g) was stirred for 1 hour, while being maintained at 30° C. Then, dimethylsulfuric acid (25.2 g) was dropped at 30° C. over 2 hours. The mixture was stirred at 30° C. for 30 minutes, 40° C. for 2 hours and 50° C. for 4 hours, successively. Then, the same after treatment as in Example 3 was conducted to obtain 4-bromo-N-acetyl-1-methylaminoanthraquinone (34.9 g, purity 93.7%, yield 91.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[NH:24][C:25]([NH:27][CH:28]1[CH2:30][CH2:29]1)=[O:26])[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[N:9]=[CH:8][CH:7]=1.[CH2:31]([O:33][CH2:34][CH2:35][NH2:36])[CH3:32].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O.C(OCC)(=O)C>[CH2:31]([O:33][CH2:34][CH2:35][NH:36][C:16]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:19][CH3:20])[N:9]=[CH:8][CH:7]=[C:6]2[O:5][C:4]1[CH:21]=[CH:22][C:23]([NH:24][C:25]([NH:27][CH:28]2[CH2:29][CH2:30]2)=[O:26])=[C:2]([Cl:1])[CH:3]=1)=[O:18])[CH3:32]
Reactant: CCOCCN
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1OC
Reaction time: 8 h
Yield: 88 %

Procedure:
After dissolving 4-(3-chloro-4-(((cyclopropylamino) carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (86 mg, 0.20 mmol) in dimethylformamide (2 ml) under a nitrogen atmosphere, 2-ethoxyethylamine (0.042 ml, 0.40 mmol), triethylamine (0.2 ml) and ((1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino)) phosphonium hexafluorophosphate) (133 mg, 0.20 mmol) were added in that order at room temperature, and the mixture was stirred overnight. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off and suspended in ethyl acetate, the suspension was diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (87.7 mg, 0.176 mmol, 87.9%) as white crystals.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1([CH2:15][CH2:16][CH2:17][N:18]([CH2:23][C:24](O)=O)[CH2:19][C:20](O)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)CO>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:20]1[CH2:19][N:18]([CH2:23][C:24]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1)[CH2:17][CH2:16][CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)CN(CCCc1ccccc1)CC(=O)O
Solvent: OCCO
Product: c1ccc(CCCN(Cc2nc3ccccc3[nH]2)Cc2nc3ccccc3[nH]2)cc1

Procedure:
2c was synthesised by an analogous procedure to that described for 2a using o-phenylenediamine (4.32 g, 40 mmol) and N-(3-phenyl)propyliminodiacetic acid (5 g, 20 mmol) in ethyleneglycol (10 ml) at 190° C. Yield 6.9 g (84%). 1H NMR (400.13 MHz, CD3OD, r.t.), δ 1.74 (quintet, 2H, CH2), 2.45 (m, 4H, CH2), 3.95 (s, 4H, NCH2), 6.88 (d, 2H, ArH), 6.94-6.95 (dd, 3H, ArH), 7.21 (m, 4H, ArH), 7.56 (m, 4H, ArH), 12.33 (broad s, 1.5H, NH). 13C NMR (100.6 MHz, MeOH-d4, r.t.), δ 29.49 (CH2), 34.04 (CH2), 53.95 (2 x NCH2) 55.13 (NCH2), 115.47 (broad, ArC), 123.59 (ArC), 126.58 (ArC), 129.09 (ArC), 129.24 (ArC), 142.95 (ArCq), 154.22 (ArCq from imidazole ring). Anal. Calc. for C25H25N5 (in %) C, 75.54; H, 6.85; N, 17.62. Found C, 75.88; H, 6.55; N, 17.65. +CI MS: (m/z): 396 ([MH+]), 280 ([M-CH2Ph]+).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([C:15](OCC)=[O:16])[C:11]2=[O:20])=[CH:6][CH:5]=1.[Cl-].[Ca+2].[Cl-]>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[C:11]2=[O:20])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1CCN(c2ccc(Cl)cc2)C1=O
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CO
Product: O=C1C(CO)CCN1c1ccc(Cl)cc1
Yield: 92.1 %

Procedure:
Under ice-cooling, 3.9 g of sodium borohydride was added portionwise to a solution of 30.0 g of 1-(4-chlorophenyl)-3-ethoxycarbonyl-2-pyrrolidinone and 15 g of anhydrous calcium chloride in 150 mL of methanol. After completion of the reaction, the mixture was concentrated, and water and ethyl acetate were added. The mixture was acidified with diluted hydrochloric acid. After separation, the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized with n-hexane-ethyl ether. The crystals were collected by filtration, washed with a mixture of n-hexane and diethyl ether and dried in vacuo to give 23.3 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH:10](=[O:14])[CH:11]([CH3:13])[CH3:12].Cl.C(Cl)Cl>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(C)C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)C(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1 M solution of p-chlorophenylmagnesium bromide in diethyl ether (100 mL) is added to a solution of isobutyraldehyde (9.08 mL, 0.1 mol) in diethyl ether at −5° C. After the addition is complete, the reaction mixture is stirred overnight at room temperature, diluted with an ice-water mixture, and acidified with 10% hydrochloric acid. The phases are separated and the aqueous phase is extracted with diethyl ether. The organic phase and extracts are combined, washed sequentially with saturated sodium hydrogen carbonate solution, water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an oil. Column chromatography of the oil using silica gel and a 33% methylene chloride in hexanes solution gives the title product as a colorless oil (14 g) which is identified by NMR spectral analyses.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[N:16]([CH2:28][C:29]4[C:34]([F:35])=[CH:33][C:32]([F:36])=[CH:31][C:30]=4[F:37])[N:17]=[C:18]4[C:23]=3[CH:22]=[CH:21][CH:20]=[C:19]4[C:24]([F:27])([F:26])[F:25])[CH:10]=2)C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO>CO>[F:35][C:34]1[CH:33]=[C:32]([F:36])[CH:31]=[C:30]([F:37])[C:29]=1[CH2:28][N:16]1[C:15]([C:11]2[CH:10]=[C:9]([NH2:8])[CH:14]=[CH:13][CH:12]=2)=[C:23]2[C:18]([C:19]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:21]=[CH:22]2)=[N:17]1
Reactant: Fc1cc(F)c(Cn2nc3c(C(F)(F)F)cccc3c2-c2cccc(N=C(c3ccccc3)c3ccccc3)c2)c(F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: Nc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2c(F)cc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
Then a solution of N-(diphenylmethylene)-N-{3-[2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl]phenyl}amine (0.77 g, 1.31 mmol) in methanol (10 mL) was treated with sodium acetate (0.25 g, 3 mmol) and hydroxylamine hydrochloride (0.15 g, 2.2 mmol), and stirred at room temperature for 2 hours. The methanol was evaporated and the residue slurried in ether, the inorganic solid filtered off, and the ether stripped to afford crude product, which was purified by flash chromatography (silica 60, 10% hexane/ethyl acetate) to afford the title compound (0.28 g, 50%).
Reaction SMILES: [Na].[Br-].[N+](C1C=CC(C[N+:11]2[CH:32]=[CH:31][C:14]3=[C:15]([C:27](OC)=[O:28])[C:16]4[NH:17][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=5[C:24]=4[C:25]([CH3:26])=[C:13]3[CH:12]=2)=CC=1)([O-])=O.N(C1C=CC(N(C)C)=CC=1)=O.N#N>CO.C(Cl)(Cl)Cl>[OH:28][CH2:27][C:15]1[C:16]2[NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]=2[C:25]([CH3:26])=[C:13]2[CH:12]=[N:11][CH:32]=[CH:31][C:14]=12
Reactant: COC(=O)c1c2cc[n+](Cc3ccc([N+](=O)[O-])cc3)cc2c(C)c2c1[nH]c1ccccc12
Agent: CN(C)c1ccc(N=O)cc1
Agent: N#N
Agent: [Br-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c2cnccc2c(CO)c2[nH]c3ccccc3c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 170 mg (0.74 mmol) of metallic sodium in 150 mL of MeOH, 1.78 g (3.5 mmol) of the quaternary salt 22, 581 mg (3.5 mmol) of p-nitrosodimethylaniline, and 75 mL of dry CHCl3 was stirred for 5 hours at room temperature in an atmosphere of N2. The suspension was evaporated to dryness and the dried residue was dissolved in 100 mL of dry THF. To the resulting solution there was added 300 mg of LAH. After the mixture was stirred for 1 hour at room temperature, 600 mg of LAH was added. After 20 min the reaction was judged to be complete (TLC). The mixture was worked up in the usual way, and the solid that was collected was washed thoroughly with five portions of hot CH2Cl2 -MeOH (1:1). The aqueous filtrate was extracted with 3×200 mL portions of CH2Cl2. The combined organic layers were concentrated to dryness, and the residue was suspended in 30 mL of CH2Cl2 and 5 mL of MeOH. The suspension was flash chromatographed on silica gel, first with EtOAc as the eluant and then with EtOAc-MeOH (5:1). The purest fractions were combined, concentrated to a small volume, and cooled, whereupon the desired carbinol crystallized to give 518 mg (56% for the two steps) of 25, which melted at 257°-258° C. dec after one crystallization from EtOAc-MeOH (5:1): NMR (Me2SO-d6) δ11.46 (s, 1 H), 9.71 (s, 1 H), 8.43 (d, 1 H), 8.39 (d 1 H), 8.08 (d, 1 H), 7.62-7.48 (m, 2 H), 7.30-7.22 (m, 1 H), 5.25 (s, 3 H), 3:32 (s, 3 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:15]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:36]1[CH:37]=[CH:38][C:39]([C:41]([F:44])([F:43])[F:42])=[CH:40][C:35]=1[O:34][CH3:33])=[N:3][CH:4]=[C:5]2[F:32])(=[O:14])=[O:13]
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
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: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)ncc(F)c3c2)c(OC)c1
Temperature: 100 °C

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate PPP; 0.041 g, 0.083 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (0.027 g, 0.125 mmol), Pd(PPh3)4 (9.59 mg, 8.30 μmol), and potassium carbonate (0.057 g, 0.415 mmol). Dioxane (0.415 mL) and water (0.138 mL) were added, the vial was flushed with argon and sealed, and heated in a microwave reactor at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel chromatography (12 g, gradient elution 0 to 100% EtOAc:Heptane) to afford N-(2,4-dimethoxybenzyl)-4-fluoro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide. The material was dissolved in DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature after which time the reaction was concentrated and triturated with diethyl ether. The solids were filtered, washed with diethyl ether, and vacuum dried to afford 4-fluoro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.008 g, 0.017 mmol, 19.94% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=13.00 (s, 1H), 8.74 (d, J=1.6 Hz, 1H), 8.51 (d, J=1.4 Hz, 1H), 7.99 (dd, J=1.7, 8.9 Hz, 1H), 7.79 (dd, J=1.8, 9.0 Hz, 1H), 7.61-7.55 (m, 1H), 7.55-7.46 (m, 2H), 7.31 (d, J=4.6 Hz, 1H), 6.90 (d, J=4.6 Hz, 1H), 3.75 (s, 3H). m/z (ESI) 484.2 (M+H)+.
Reaction SMILES: ClCCl.B(F)(F)F.C(Cl)(Cl)Cl.C[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]3=[N:30][N:31]=[C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:22]3[N:21]=2)=[CH:16][CH:15]=1>O>[C:33]1([C:32]2[N:22]3[N:21]=[C:20]([C:17]4[CH:16]=[CH:15][C:14]([OH:13])=[CH:19][CH:18]=4)[C:29]4[C:24]([C:23]3=[N:30][N:31]=2)=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccc(-c2nn3c(-c4ccccc4)nnc3c3ccccc23)cc1
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(-c2nn3c(-c4ccccc4)nnc3c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 136.6 %

Procedure:
1.5 ml (1.5 mmol) of a dichloromethane solution of 1 M boron trifluoride was added to a chloroform solution (4 ml) of 305 mg of the obtained 6-(4-methoxyphenyl)-3-phenyl-[1,2,4]triazolo[3,4-a]phthalazine, and stirred overnight at room temperature. Water was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 400 mg of a crude product of 4-(3-phenyl-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)-phenol.
Reaction SMILES: [C:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)[CH2:4]O)#[N:2].N1C=CC=CC=1.P(Br)(Br)[Br:20]>C(Cl)Cl>[C:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)[CH2:4][Br:20])#[N:2]
Reactant: N#CC(CO)c1ccc(Br)cc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CC(CBr)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 24 g (0.11 mol) 2-cyano-2-(4-bromophenyl)-ethanol and 4.5 g (0.055 mol) pyridine in 100 ml CH2Cl2 are slowly added, at -5° to 0°, 12 g (0.044 mol) PBr3. The mixture is stirred for 3 hours at room temperature, thereafter for 2 hours at 40°, allowed to cool off, then poured into 500 ml ice water and extracted with CH2Cl2. The extract is washed with water, dried and evaporated. The resulting residue is chromatographed over a silica gel column with hexane/diethylether 6:4. The glassy residue obtained after evaporation is worked up in toluene and thereafter ether to give the title compound in the form of a yellow powder, m.p. 171° (decomposing).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH3:32])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16]([CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:25][OH:26])[CH:15]=[CH:14][C:13]1=2.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1([CH3:32])[CH2:21][CH2:20][C:19]([CH3:22])([CH3:23])[C:18]2[CH:17]=[C:16]([CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:25]=[O:26])[CH:15]=[CH:14][C:13]1=2
Reactant: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCCC(C=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
A solution of 0.35 ml of oxalyl chloride in 20 ml of methylene chloride was treated, at −78° C., with 0.4 ml of DMSO absolute. The mixture was stirred at −78° C. for 5 minutes then 554 mg of (RS)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptanol dissolved in 4 ml of methylene chloride were added dropwise. The reaction mixture was stirred at −78° C. for 15 minutes. 1.3 ml of triethylamine were added and the mixture was stirred 15 minutes at −78° C. then 2.5 hours at room temperature. The mixture was quenched with 20 ml water and extracted with 3 portions of 20 ml of methylene chloride. The combined extracts were washed with 2 portions of 5 ml of water and 1 portion of 50 ml of a saturated aqueous solution of NaCl. The organic phase was dried over MgSO4 and the solvent evaporated to yield a yellow oil. The product was purified with flash chromatography (SiO2, 5% ethyl acetate/hexanes), to yield 483 mg of a colorless oil, 1H NMR (CDCl3): 9.64 (d, J=2.0 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.08 (d, J=3.0 Hz, 1H), 6.95 (dd, J=8.4, 3.0 Hz, 1H), 3.43 (td, J=7.2, 2.0 Hz, 1H), 2.05 (m, 1H), 1.70 (m, 1H), 1.68 (s, 4H), 1.22-1.40 (m, 6H), 1.27 (s, 12H), 0.86 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH:17]=[CH2:18])=[CH:8]2.B.[OH-:20].[Na+].OO>C1COCC1.O>[OH:20][CH2:18][CH2:17][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:3]=2[O:2][CH3:1])[CH:8]=1
Reactant: C=Cc1ccc2c(OC)c(OC)c(OC)cc2c1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2cc(CCO)ccc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5,6,7-Trimethoxy-2-vinylnaphthalene (1.215 g) was dissolved in dry THF (10 mL) under an argon atmosphere, a 1 M THF solution (4.7 mL) of borane was added dropwise to the solution at 0° C., and the mixture was stirred at room temperature for 2 hours. Water (4 mL) was added to the reaction mixture at 0° C., and a 4 M aqueous solution (1.2 mL) of sodium hydroxide was then added. 31% Aqueous hydrogen peroxide (0.5 mL) was added to the reaction mixture at 0° C., and the mixture was stirred at 50° C. for 50 minutes. The solvent was distilled off, and water was added to the residue to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:8) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:10])=[CH:6][C:7]=1[C:8]#[N:9].[F:11][C:12]([S:15]Cl)([Cl:14])[Cl:13]>C(Cl)Cl>[CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:10])=[C:6]([S:15][C:12]([Cl:14])([Cl:13])[F:11])[C:7]=1[C:8]#[N:9]
Reactant: FC(Cl)(Cl)SCl
Reactant: COc1[nH]c(C)cc1C#N
Solvent: ClCCl
Product: COc1[nH]c(C)c(SC(F)(Cl)Cl)c1C#N
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A suspension of 2-methoxy-3-cyano-5-methylpyrrole (0.5 g) in 5 ml of CH2Cl2 was treated with Cl2FCSCl (0.45 ml) and stirred at room temperature for 14 h. The resulting precipitate was filtered, washed with CH2Cl2, and dried under high vacuum to afford an off-white solid (0.59 g), m.p. 175° C.