Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:29]Br>C(#N)C.C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]2)=[CH:9][C:10]=1[Br:29])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(N2CCN(C)CC2)cc1
Reactant: BrBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(N2CCN(C)CC2)cc1Br
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 4-(4-methylpiperazin-1-yl)phenyl acetate 247 mg (1.05 mmol) and p-toluenesulfonic acid 209 mg (1.1 mmol) in acetonitrile was cooled in an ice bath and bromine 0.056 ml (1.1 mmol) was added dropwise. The reaction was stirred at room temperature until complete (3-4 hours), was diluted with ethyl acetate and extracted with water and saturated NaHCO3. The organic phase, dried over Na2SO4 and evaporated, was purified by flash chromatography (DCM/MeOH 85/15) to give the product as a dark brown oil. HPLC (254 nm) method 2 Rt 4.05 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H) 2.36 (s, 3H) 2.39 (m, 4H) 3.44 (m, 4H) 6.50 (dd. J=2.1, 8.3 Hz, 1H) 7.03 (d, J=8.3 Hz, 1H) 7.21 (d, J=2.1 Hz, 1H). Mass. Calc. 313.0546 Mass. Found: 313.0538
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=O)=[CH:13][CH:14]=3)[N:9]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[CH3:25][C:26]1[N:30]=[C:29]([C@H:31]([NH2:33])[CH3:32])[O:28][N:27]=1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:25][C:26]1[N:30]=[C:29]([C@H:31]([NH:33][C:16]([C:12]2[CH:11]=[C:10]3[C:15]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:8][N:9]3[C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)=[CH:14][CH:13]=2)=[O:18])[CH3:32])[O:28][N:27]=1
Reactant: O=C(O)c1ccc2c(N3CCOCC3)nn(-c3ccsc3)c2c1
Reactant: Cc1noc([C@@H](C)N)n1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1noc([C@@H](C)NC(=O)c2ccc3c(N4CCOCC4)nn(-c4ccsc4)c3c2)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(morpholin-4-yl)-1-(thiophen-3-yl)-1H-indazole-6-carboxylic acid (20.0 mg, 45.0 μmol), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine hydrochloride (18.1 mg, 90 μmol, and N-methylmorpholine (24.8 μL, 226 μmol) in N,N-dimethylformamide (226 μL) were added N-[2-(dimethylamino)ethyl]-N-ethylcarbodiimide hydrochloride (15.1 mg, 79.0 μmol), 1-hydroxy-7-azabenzotriazole (3.1 mg, 23 pawl). The mixture was stirred at 50° C. for 1 h. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.05% ammonium hydroxide) gave the title compound (19 mg). HRMS [M+1] found=439.1545. 1H NMR (400 MHz, DMSO-d6) δ: 9.37 (1H, d, J=7.33 Hz), 8.20 (1H, s), 8.05 (1H, d, 8.57 Hz), 7.77-7.74 (2H, m), 7.64 (1H, dd, J=8.56, 1.33 Hz), 7.56 (1H, 4.58, 2.12 Hz), 5.43-5.37 (1H, m), 3.83 (4H, t, J=4.39 Hz), 3.43 (4H, t, J=4.39 Hz), 2.33 (3H, s), 1.64 (3H, d, J=7.15 Hz).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11](=O)[CH2:12][CH2:13][CH3:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:20][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCCN
Reactant: CCCC(=O)Cc1ccc2c(c1)OCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: CCCCNC(CCC)Cc1ccc2c(c1)OCO2

Procedure:
A mixture of 2.0 g (9.7 mmol) of 1-(1,3-benzdioxol-5-yl)pentan-2-one, 0.71 g (9.7 mmol) of n-butylamine, 2.88 g (13.6 mmol) of sodium triacetoxyborohydride and 0.58 g (9.7 mmol) of acetic acid were stirred in 1,2-dichloroethane (34 ml) under argon gas for four days at room temperature. Thereafter, the mixture was alkalized with 1 N sodium hydroxide. Water (50 ml) was added to the mixture and was extracted three times with ether (70 ml). The obtained organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography. Chloroform was used for eluting solvent. 1-(1,3-Benzodioxol-5-yl)-2-butylaminopentane was obtained as light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]([C:25]([NH2:27])=[NH:26])[S:20][C:21]=2[S:22][CH2:23]C)[N:16]=1.Br.COC1C=CC(OC)=CC=1NC1SC=C(C2C=C(C(OC)=S)SC=2C)N=1.N>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]([C:25]([NH2:27])=[NH:26])[S:20][C:21]=2[S:22][CH3:23])[N:16]=1
Reactant: CCSc1sc(C(=N)N)cc1-c1csc(Nc2cc(OC)ccc2OC)n1
Agent: Br
Agent: COC(=S)c1cc(-c2csc(Nc3cc(OC)ccc3OC)n2)c(C)s1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(OC)c(Nc2nc(-c3cc(C(=N)N)sc3SC)cs2)c1
Yield: 27 %

Procedure:
4-{2-[(2,5-Dimethoxyphenyl)amino](1,3-thiazol-4-yl)}-5-ethylthiothiophene-2-carboxamidine: Methyl 4-{2-[(2,5-dimethoxyphenyl)amino]-(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide (45.5 mg, 0.09 mmol) was treated as described in Example 154, step (b), followed by preparative thin layer chromatography (500 μm silica gel plate, J. T. Baker, Phillipsburg, N.J., 10%-methanol-CH2Cl2-sat'd. NH3 eluent) to give 9.9 mg (27% yield of 4-{2-[(2,5-dimethoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine. 1H NMR (DMSO-d6, 300 MHz) δ 2.60 (s, 3H), 3.73 (s, 3H), 3.81 (s, 3H), 6.48 (dd, 1H, J=3.1, 8.8 Hz), 6.92 (d, 1H, J=7.9 Hz), 7.05 (s, 1H), 7.5 (bs, 2H), 8.04 (s, 1H), 8.34 (d, 1H, J=1.0 Hz), 9.6 (bs, 1H); Mass Spectrum (ESI) m/z calcd. for C17H18N4O2S3, 406.55 (M+H), found 407.1.
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:4]=1[Cl:13].[OH-].[Na+]>O>[Cl:13][C:4]1[CH:5]=[C:6]([F:12])[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[OH:2]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Yield: 97.9 %

Procedure:
A mixture of 2-chloro-4-fluoro-5-nitrophenyl methyl carbonate (120 g 0.48 mol) and sodium hydroxide (22.7 g, 0.57 mol) in water (300 mL) was refluxed for 4 h. The insoluble solids were removed by filtration and the filtrate was acidified with dilute HCl. The precipitated solid was collected by filtration and washed with water to give 2-chloro-4-fluoro-5-nitrophenol (90 g, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.10 (d, J=10.4 Hz, 1H), 7.62 (d, J=7.2 Hz, 1H); MS (ESI) m/z: 192.1 (M+H+)
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH:17]1([C:20]2[CH:21]=[C:22]([CH3:32])[C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][CH:25]=2)[CH2:19][CH2:18]1>>[CH:17]1([C:20]2[CH:21]=[C:22]([CH3:32])[C:23]([N:26]3[CH2:27][CH2:28][N:29]([C:12]([C:11]4[CH:10]=[CH:9][C:8]([CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][C:2]5=[O:1])=[CH:16][CH:15]=4)=[O:14])[CH2:30][CH2:31]3)=[N:24][CH:25]=2)[CH2:19][CH2:18]1
Reactant: O=C(O)c1ccc(CN2CCCC2=O)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(CN3CCCC3=O)cc2)CC1
Yield: 36.1 %

Procedure:
Using 4-(2-oxopyrrolidin-1-ylmethyl)benzoic acid (132 mg) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (156 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (91 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1.[NH3:22]>>[NH2:1][C:2]1[N:3]=[C:4]([NH2:22])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1
Reactant: N
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)nc(N)nc21

Procedure:
A mixture of the product from Step B of Example 118 (24 mg) in aqueous ammonia (30%, 10 mL) was heated in a stainless steel autoclave at 100° C. overnight, then cooled and evaporated. The residue was purified on a silica gel column with CH2Cl2/MeOH (10/1 and 5/1) as the eluent to afford the title compound (15 mg).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[S:51]1[CH:55]=[CH:54][N:53]=[C:52]1[NH2:56]>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[C:8]([NH:56][C:52]2[S:51][CH:55]=[CH:54][N:53]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc2ccccc2c1=O
Reactant: Nc1nccs1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)C(CC1CCCC1)n1ncc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A solution of 3-cyclopentyl-2-(1-oxo-1H-phthalazin-2-yl)-propionic acid (0.31 g, 1.09 mmol) in methylene chloride (6.10 mL, 0.18M) at 25° C. was treated with N,N-diisopropylethylamine (0.57 mL, 3.29 mmol) and N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (0.39 g, 1.31 mmol). The resulting solution was stirred at 25° C. for 2 h. After this time, the reaction was treated with thiazol-2-ylamine (143 mg, 1.42 mmol). The resulting solution was stirred at 25° C. overnight. After this time, the reaction was partitioned between water (100 mL) and methylene chloride (3×75 mL). The combined organics were washed with water (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO, 40 g, 50% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(1-oxo-1H-phthalazin-2-yl)-N-thiazol-2-yl-propionamide as a white solid (247.7 mg, 61%); ES+-HRMS m/e calcd for C19H20N4O2S [M+H+] 369.1380 found 369.1378. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.99-1.17 (m, 1H), 1.20-1.80 (m, 8H), 2.04-2.18 (m, 1H), 2.23-2.36 (m, 1H), 5.73 (dd, J=10.4, 4.4 Hz, 1H), 7.22 (d, J=3.4 Hz, 1H), 7.47 (d, J=3.4 Hz, 1H), 7.83-7.93 (m, 1H), 7.94-8.02 (m, 2H), 8.26 (d, J=7.8 Hz, 1H), 8.52 (s, 1H), 12.46 (s, 1H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:53][C:18]2[N:19]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([C:45]4[C:46]([C:51]#[N:52])=[CH:47][CH:48]=[CH:49][CH:50]=4)=[CH:41][CH:40]=3)[C:20](=[O:37])[N:21]([CH2:24][C:25]([C:27]3[N:31]([CH3:32])[C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[N:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>O.C(OCC)(=O)C>[CH2:13]([C:15]1[S:53][C:18]2[N:19]([CH2:38][C:39]3[CH:40]=[CH:41][C:42]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=4[C:51]4[NH:3][C:4](=[O:7])[O:5][N:52]=4)=[CH:43][CH:44]=3)[C:20](=[O:37])[N:21]([CH2:24][C:25]([C:27]3[N:31]([CH3:32])[C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[N:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: CCc1cc2c(=O)n(CC(=O)c3nc4ccccc4n3C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3nc4ccccc4n3C)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 16.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.28 g), sodium hydrogencarbonate (0.42 g) and dimethyl sulfoxide (3 mL) was stirred at 50° C. for 30 min, 4′-{[6-ethyl-3-[2-(1-methyl-1H-benzoimidazol-2-yl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.28 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.097 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.090 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.051 g, 16%).
Reaction SMILES: BrBr.[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].P(Br)(Br)[Br:12]>>[Br:12][CH:7]([CH2:6][CH2:5][CH2:4][Br:3])[C:8]([OH:10])=[O:9]
Reactant: O=C(O)CCCCBr
Reactant: BrP(Br)Br
Agent: BrBr
Product: O=C(O)C(Br)CCCBr
Reaction time: 0.5 h

Procedure:
39 ml of bromine is added to a mixture of 106 g of 5-bromopentanoic acid and 1 ml of phosphorus tribromide. The reaction mixture is taken to 70-80° C. for 16 hours 30 minutes. The reaction medium is taken to 100° C. for 15 minutes and allowed to return to ambient temperature. 147 g of sought product is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:27](Br)=[CH:28][CH2:29][CH3:30].O>CC(=O)CC>[CH:27]([O:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[CH:28][CH2:29][CH3:30]
Reactant: CCC=CBr
Reactant: CCCCCCCCOc1ccc(C(=O)OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCC=COc1cc(OCCCCCCCC)ccc1C(=O)OC
Yield: 89.9 %

Procedure:
To a solution of 22.0 g (78.5 mmol) of the compound (29) and 65.0 g (471 retool) of potassium carbonate mixed in 300 ml of 2-butanone were added 32.0 g (236 mmol) of butenyl bromide and the whole was refluxed for 18 hours. Water was added to the solution and the whole was extracted with ethyl acetate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 23.6 g of methyl 2-butenyloxy-4-octyloxybenzoate as a colorless clear liquid (yield: 89.9%). Then, 20.0 g (59.8 mmol) of the resulting compound was dissolved in 100 ml of methanol. The solution was poured into a solution of 12.0 g (300 mmol) of sodium hydroxide dissolved in 40 ml of water and 400 ml of methanol. The whole was refluxed for another 2 hours. After removal of the solvent by distillation, the resulting white solid was dissolved in water and the solution was rendered acidic by adding hydrochloric acid, whereby white precipitate formed. The precipitate was extracted with methylene chloride. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 15.3 g of 2-butenyloxy-4-octyloxybenzoic acid (30) (yield: 80.0%).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:20]=[C:21]([C:26]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:27]=2)[CH:22]=[C:23](Br)[CH:24]=1.C([O-])([O-])=O.[K+].[K+].[N:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[C:56]1[CH:61]=[CH:60][C:59](B(O)O)=[CH:58][CH:57]=1>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.C(O)C.C1(C)C=CC=CC=1>[C:32]1([C:30]2[N:29]=[C:28]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:27]=[C:26]([C:21]3[CH:20]=[C:19]([C:59]4[CH:58]=[CH:57][C:56]([C:51]5[CH:52]=[CH:53][CH:54]=[CH:55][N:50]=5)=[CH:61][CH:60]=4)[CH:24]=[C:23]([C:13]4[C:14]5[C:5]([C:6]6[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=6[CH:12]=4)=[CH:4][CH:3]=[CH:2][CH:1]=5)[CH:22]=3)[N:31]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Brc1cc(Br)cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Reactant: OB(O)c1ccc(-c2ccccn2)cc1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
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: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3cc(-c4ccc(-c5ccccn5)cc4)cc(-c4cc5ccccc5c5ccccc45)c3)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
In a stream of argon, 1.91 g (8.56 mmol) of 9-phenanthreneboronic acid, 4.00 g (8.56 mmol) of 2-(3,5-dibromophenyl)-4,6-diphenyl-1,3,5-triazine and 98.9 mg (0.086 mmol) of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent composed of 320 mL of toluene and 40 mL of ethanol, and the resultant suspension was heated to 60° C. To the suspension, 25.7 mL (25.7 mmol) of an aqueous 1M K2CO3 solution was gradually added dropwise, and the mixture was stirred for 4 hours. Then the mixture was cooled to room temperature, and 2.56 g (12.8 mmol) of 4-(2-pyridyl)phenylboronic acid and 25.7 mL (25.7 mmol) of an aqueous 1M K2CO3 solution were added. Then the mixture was heated to 70° C. and maintained at that temperature for 12 hours while being stirred. Then the reaction mixture was cooled to room temperature, and was then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The obtained crude product was purified by silica gel chromatography using a hexane/chloroform (1:2) mixed solvent as an eluent to give 3.91 g of the target 4,6-diphenyl-2-[5-(9-phenanthryl)-4′-(2-pyridyl)biphenyl-3-yl]-1,3,5-triazine as a white solid (yield: 64%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([N:9]1[CH2:10][CH2:11][CH2:12][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:8]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulfonyl chloride (0.64 ml, 8.24 mmol) was added to a solution of tert-butyl 1,4-diazepane-1-carboxylate (1.5 g, 7.49 mmol) and triethylamine (1.6 ml, 11 mmol) in dichloromethane (20 ml), and the reaction stirred at room temperature for 18 hours. The solution was washed with sodium bicarbonate solution, then brine, dried (MgSO4) and evaporated under reduced pressure to give the title compound, 2.01 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15](F)=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([NH:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCCN1CCOCC1
Reactant: Fc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Brc1cccc(Nc2ncnc3cc(NCCCN4CCOCC4)ccc23)c1
Temperature: 110 °C
Yield: 77.7 %

Procedure:
To a solution of 4-[(3-bromophenyl)amino]-7-fluoroquinazoline (0.60 g, 1.89 mmol) in Dimethylsulfoxide (DMSO) (10 mL) was added 4-(3-aminopropyl)morpholine (7.54 mmol, 1.10 mL). The reaction mixture was heated at 110° C. for 26 hours and then diluted with water, basified by the addition of saturated NaHCO3 and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Column chromatography on Grade III alumina with gradient elution from EtOAc to EtOAc/MeOH (98:2) followed by recrystallization from EtOAc/hexane gave 4-[(3-bromophenyl)amino]-7-[(3-morpholinopropyl)amino]-quinazoline (0.65 g, 78%) as cream crystals, mp 162-162.5° C.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16].C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:13]([NH:17][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN
Reactant: Clc1nnnn1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCNc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
5-Chloro-1-phenyl-1H-tetrazole (1.00 g, 5.54 mmol), butylamine (0.547 mL, 5.54 mmol), and diisopropylethylamine (1.48 mL, 8.31 mmol) were dissolved in DMF (5 mL), and stirred overnight at room temperature. Reaction diluted with EtOAc and washed with water and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo. Residue purified by flash chromatography on silica gel eluting with 35% EtOAc/Hexanes to afford the desired product as a white solid (625 mg, 52%). m/e (DCI) 218 (MH+)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:20].[C:21]1([Se:27]Cl)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([Se:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]1=[O:20]
Reactant: Cl[Se]c1ccccc1
Reactant: CN1CCCCC1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CN1CCCC([Se]c2ccccc2)C1=O
Reaction time: 0.08 h

Procedure:
A solution of diisopropylamine (3.02 mL, 21.21 mmol) in tetrahydrofuran (44.2 mL) under argon was cooled to −78° C. and added butyllithium solution, 2.5M in hexanes (8.48 mL, 21.21 mmol). After 5 min, a solution of 1-methylpiperidin-2-one (2 g, 17.67 mmol) in tetrahydrofuran (2 mL) was added dropwise. After stirring for 10 min, a solution of phenylselenenyl chloride (4.06 g, 21.21 mmol) in 16 mL of tetrahydrofuran was added, and the reaction was stirred at −78° C. for 2 h. The reaction was quenched with aqueous saturated NH4Cl solution and diluted with CH2Cl2; the aqueous layer was back-extracted with CH2Cl2 (1×). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to afford a crude crop of 1-methyl-3-(phenylselanyl)piperidin-2-one in dichloromethane. To the crude 1-methyl-3-(phenylselanyl)piperidin-2-one in dichloromethane (50 mL) at 0° C. under argon was added 3-chlorobenzoperoxoic acid (7.92 g, 35.3 mmol). The resulting mixture was allowed to gradually warm to room temperature overnight. The orange suspension was filtered, and the filtrate was concentrated in vacuo and partitioned between CH2Cl2 and aqueous saturated NaHCO3 solution; the aqueous layer was back-extracted with CH2Cl2 (5×). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% EtOAc/Hexanes to 100% EtOAc) afforded 1-methyl-5,6-dihydropyridin-2(1H)-one (1.33 g, 67.7% yield) as a brown oil. [M+1]=112.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:26])=[C:23]([CH:25]=1)[NH2:24]>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:26])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Nc1cc(Cl)ccc1O
Product: Oc1ccc(Cl)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-chloro-2-hydroxyaniline (42 mg, 0.290 mmol) similar to Example 117 and isolated as a tan solid (38 mg, 54%). 1H NMR (DMSO-d6): 10.44 (s, 1H), 9.74 (s, 1H), 9.42 (s, 1H), 8.75–8.74 (m, 1H), 8.58–8.54 (m, 1H), 8.29 (s, 1H), 7.48 (s, 1H), 7.61–7.57 (m, 1H), 7.08 (dd, J=2.1, 8.7 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H).