Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][C@@H:3]([OH:7])[CH2:2]1.CC(C)([O-])C.[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN1C(=O)CCC1>[CH2:15]([O:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][C@H:1]([OH:8])[CH2:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O[C@@H]1CCC[C@H](O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O[C@H]1CCC[C@@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
150.0 g (1.29 mol) of cis-1,3-cyclohexanediol were dissolved in 1.5 l of NMP, admixed with 111.6 g (0.99 mol) of potassium tert-butoxide (KOtBu) and stirred at 25–27° C. After about 30 minutes, the mixture was cooled to 0° C. and admixed dropwise with 78.1 g (0.46 mol) of benzyl bromide. The mixture was stirred at approx. 0° C. for 15 min and then 1.5 l of water were added. After washing three times with 700 ml of n-heptane and discarding the n-heptane solutions, the aqueous solution was extracted four times with 500 ml of MTBE. The combined MTBE phases were washed twice with in each case 1 l of water, dried (Na2SO4) and subsequently concentrated by evaporation under reduced pressure. 48.0 g of the desired compound were obtained as a clear, yellow oil; 1H NMR (CDCl3), δ =1.29 (m, 1H), 1.43–1.93 (m, 6H), 2.06 (m, 1H), 2.55 (s (br.), 1H), 3.56 (m, 1H), 3.74 (br, 1H), 4.55 (dd, 2H), 7.25–7.36 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.[Cu]>[CH2:26]([O:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[CH:8][N:7]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)Cc1cccnc1Oc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccnc1Oc1cccc(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
Methyl 2-(3-hydroxyphenoxy)-3-pyridinylacetate (0.8 g) and anhydrous potassium carbonate (0.21 g) were stirred together in DMF under nitrogen at 70° C. After 20 minutes benzyl bromide (1.06 g) was added together with copper bronze (cat.) and the reaction mixture heated to 100° C. for 3 hours. GC analysis indicated 50% reaction. A second equivalent of both potassium carbonate and benzyl bromide was added and heating continued at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered, diluted with water and extracted with ether (×3). The ether extracts were combined, dried, filtered and evaporated to give a brown oil. Chromatography on silica gel (eluent petroleum ether-ether, 50:50) afforded methyl 2-(3-benzyloxyphenoxy)-3-pyridinylacetate as a light yellow solid (0.5 g, 46%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:12]=[CH:11][C:10]([O:13]COC)=[C:9]2[C:4]=1[C:5](=[O:25])[C:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[CH:7][NH:8]2.O.[Na]>C(O)C>[F:2][C:3]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]2[C:4]=1[C:5](=[O:25])[C:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[CH:7][NH:8]2
Reactant: COCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c[nH]c12
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2c[nH]c3c(O)ccc(F)c3c2=O)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
2N Hydrochloric acid (6.0 ml) was added to an ethanol solution (18 ml) of 5-fluoro-8-methoxymethoxy-3-(4-methoxyphenyl)-1H-quinolin-4-one (350 mg, 1.06 mmol). The mixture was stirred at 55° C. for 1 hour. The stirred mixture was cooled to room temperature, and 1N sodium hydrate (11.6 ml) was added thereto to obtain a pH of 3 to 4. The mixture in which pH was adjusted was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (dichloromethane:methanol=50:1→20:1). The purified product was concentrated under reduced pressure, and the residue was crystallized from ethanol, collected by filtration, washed with ethanol, and dried to thereby obtain 165 mg of powdery pale dark brown 5-fluoro-8-hydroxy-3-(4-methoxyphenyl)-1H-quinolin-4-one (yield: 54%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12]O)[N:11]=1.P(Br)(Br)[Br:15]>CCOCC.C(OCC)(=O)C>[Br:15][CH2:12][C:10]1[N:11]=[C:7]([CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[S:8][CH:9]=1
Reactant: COCCOCc1nc(CO)cs1
Reactant: BrP(Br)Br
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCCOCc1nc(CBr)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.6 %

Procedure:
A solution of (2-((2-methoxyethoxy)methyl)thiazol-4-yl)methanol (0.35 g, 1.72 mmol) in ether (15 mL) was treated with PBr3 (0.1 mL, 1.06 mmol) at RT. There is formation of a precipitate. The reaction was stirred at RT for 18 hours, then diluted with ethyl acetate and washed with sat. NaHCO3 (1×) and brine (1×), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (3×10 cm, 20% ethyl acetate/CH2Cl2) to give the title material (0.233 g, 51%) as a clear oil. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.27 (s, 1H), 4.83 (s, 2H), 4.55 (s, 2H), 3.73-3.76 (m, 2H), 3.57-3.60 (m, 2H), 3.39 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:13][O:14][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: OCC1(c2ccc(Cl)cc2)CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(c2ccc(Cl)cc2)CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
To a stirred solution of 1-(4-chlorophenyl)-cyclopentyl]-methanol (319) (12 g, 56.95 mmol) in dichloromethane (110 mL) was added triethyl amine (16 mL, 113.90 mmol) followed by mesyl chloride (5.3 mL, 68.34 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 h, diluted with dichloromethane (50 mL) and washed with water (100 mL), saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL). The organic part was dried, concentrated and purified by CombiFlash column (eluted at 10-20% ethyl acetate in hexane) to get methanesulfonic acid 1-(4-chlorophenyl)-cyclopentylmethyl ester (320) (14 g, 85%) as a light yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C([Cl:16])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:16])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Product: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Yield: 100 %

Procedure:
A solution of (3,4-dichloro-phenyl) acetic acid (3.51 g, 0.0179 mol) and oxalyl chloride (17.5 g, 12.08 mL, 0.089 mol) in 150 mL of benzene was refluxed for 6 h. The solution was evaporated with benzene 3 times and dried in vacuum. Yield 100%.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:41]=[CH:40][C:30]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:29][CH:28]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:5]1[CH:4]=[CH:3][C:2]([CH2:1][NH:8][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:27]3[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[CH:40][CH:41]=3)=[CH:13][N:12]=2)=[O:18])=[CH:7][CH:6]=1
Reactant: CC1(C)OB(c2ccc(OCCN3CCOCC3)cc2)OC1(C)C
Reactant: O=C(Cc1ccc(Br)cn1)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Temperature: 150 °C
Yield: 78.8 %

Procedure:
A 10 mL reaction tube with a septum closure and stir bar was charged with N-benzyl-2-(5-bromopyridin-2-yl)acetamide (123 mg, 0.403 mmol), 4-(2-(4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenoxy)ethyl)morpholine (171 mg, 0.513 mmol), and FibreCat 1007 (30 mg, 0.015 mmol). Ethanol (3 mL) was added, followed by aqueous potassium carbonate solution (0.60 mL, 1.0 M, 0.60 mmol). The tube was sealed and heated under microwave conditions at 150° C. for 10 minutes. The reaction was cooled and concentrated to remove the majority of the ethanol, and then taken up in 10 mL of ethyl acetate and washed successively with water and saturated sodium chloride solution. The organic layer was dried with MgSO4, filtered and concentrated to a white solid. This white solid was triturated with ethyl ether to give KX2-391 as a white solid (137 mg, 79%): mp 135-137° C.; 1H NMR (300 MHz, CDCl3) δ 8.70 (d, 1H, J=2.0 Hz), 7.81 (dd, 1H, J=2.4 Hz, J=8.0 Hz), 7.65 (br s, 1H), 7.49 (d, 2H, J=8.8 Hz), 7.37-7.20 (m, 6H), 7.01 (d, 2H, J=8.8 Hz), 4.49 (d, 2H, J=5.8 Hz), 4.16 (t, 2H, J=5.7 Hz, 3.82 (s, 2H), 3.78-3.72 (m, 4H), 2.84 (t, 2H, J=5.7 Hz), 2.62-2.58 (m, 4H); HPLC (Method B) 98.0% (AUC), tR=1.834 min.; APCI MS m/z 432 [M+H]+.
Reaction SMILES: Cl.[C:2]([NH:6][C:7](=[O:14])[C@@H:8]1[CH2:12][C@H:11]([Cl:13])[CH2:10][NH:9]1)([CH3:5])([CH3:4])[CH3:3].[CH2:15]([O:22][C:23]([NH:25][C@H:26]([C:31]([NH:33][C@@H:34]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:35]([OH:39])[C:36](O)=[O:37])=[O:32])[CH2:27][C:28](=[O:30])[NH2:29])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O>[CH2:15]([O:22][C:23]([NH:25][C@H:26]([C:31]([NH:33][C@@H:34]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C@H:35]([OH:39])[C:36]([N:9]1[CH2:10][C@@H:11]([Cl:13])[CH2:12][C@H:8]1[C:7]([NH:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:14])=[O:37])=[O:32])[CH2:27][C:28](=[O:30])[NH2:29])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
680 mg (2.23 mmol) of (4S)-1-t-butoxycarbonyl-N-t-butyl-4-chloro-L-prolinamide (prepared as described in Preparation 2) were treated with 10 ml of a 4N solution of hydrogen chloride in dioxane, in order to eliminate the t-butoxycarbonyl group and give (4S)-N-t-butyl-4-chloro-L-prolinamide hydrochloride. The whole of the hydrochloride thus obtained and 880 mg (1.99 mmol) of (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 1) were dissolved in 5 ml of dimethylformamide, and the solution was cooled with ice. 420 mg (2.58 mmol) of diethyl cyanophosphate, followed by 640 mg (6.40 mmol) of triethylamine, were then added to the ice-cooled mixture, and the mixture was stirred for 3 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was mixed with a 10% w/v aqueous solution of citric acid and then extracted with ethyl acetate. The organic extract was washed with a 10% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by preparative thin layer chromatography using a 10:1 by volume mixture of methylene chloride and methanol as the developing solvent, to give 850 mg of the title compound as a colorless powder, melting at 107°-109° C.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[CH2:14]([C:24]1[N:25]=[N:26][N:27]([CH2:29][C:30](O)=[O:31])[N:28]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH3:12][CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:30](=[O:31])[CH2:29][N:27]1[N:26]=[N:25][C:24]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N:28]1)[CH3:13]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CCCCCCCCCCc1nnn(CC(=O)O)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCc1nnn(CC(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.7 %

Procedure:
A solution of 2,6-diisopropyl aniline (0.97 g, 0.006 mol) and 5-decyl-2H-tetrazole-2-acetic acid (1.47 g, 0.006 mol) in 100 mL dichloromethane was cooled to 0° C. under an atmosphere of nitrogen. Solid DCC (1.19 g, 0.006 mol) was added in one portion and the resulting suspension was warmed to room temperature and stirred for 16 hours. Concentrated in vacuo and triturated the residue with diethyl ester. Filtered to remove the dicyclohexyl urea by-product. Concentrated the filtrate and triturated with hexanes to give the title compound (2.02 g, 86%) as an off-white solid, mp 108°-110° C.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:16])[NH:8][C@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[NH:11][CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[C:20]([NH2:25])[N:19]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[CH:1]1([O:6][C:7](=[O:16])[NH:8][C@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[N:11]([C:22]3[CH:23]=[C:18]([Cl:17])[N:19]=[C:20]([NH2:25])[N:21]=3)[CH2:10]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@@H]1CC[C@H](NC(=O)OC2CCCC2)CN1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@@H]1CC[C@H](NC(=O)OC2CCCC2)CN1c1cc(Cl)nc(N)n1
Temperature: 100 °C
Yield: 80.7 %

Procedure:
To a solution of cis-cyclopentyl[6-methyl-3-piperidinyl]carbamate (107 mg, 0.473 mmol) in ethanol (3 mL) were added 4,6-dichloro-2-pyrimidinamine (116 mg, 0.709 mmol) and K2CO3 (98 mg, 0.709 mmol) in a 5 mL sealable vial. The solution was capped and heated at 100° C. overnight. The reaction was then check with LCMS and was not complete. Additional 4,6-dichloro-2-pyrimidinamine (30 mg) and K2CO3 (50 mg) were added and the resulting mixture was heated overnight. The reaction was concentrated, then 5 mL of DMF were added. Some solids were not soluble. Water (10 mL) was added, and the resulting mixture was extracted 3× with EtOAc. The organics were combined, washed with brine, dried over MgSO4, filtered and concentrated. The clear oil was then purified on Biotage SNAP 10 g column with gradient of 0 to 50% EtOAc in hexane over 30 minutes to afford the title compound (135 mg) as a clear oil. LC-MS (ES) m/z=354 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>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>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:14]2[C:19]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)=[CH:18][C:17]3[C:5]([CH3:10])([CH3:6])[C:17]4[C:16](=[CH:15][C:14]([C:8]5[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=5)=[C:19]([C:8]5[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=5)[CH:18]=4)[C:1]([CH3:3])([CH3:2])[C:16]=3[CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: c1ccccc1
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
Product: CC(C)(C)c1ccc(-c2cc3c(cc2-c2ccc(C(C)(C)C)cc2)C(C)(C)c2cc(-c4ccc(C(C)(C)C)cc4)c(-c4ccc(C(C)(C)C)cc4)cc2C3(C)C)cc1
Temperature: 80 °C

Procedure:
10 mmol of product in Example 2, 40 mmol of 4-tert-butylphenylboronic acid, and 0.2 mmol of Pd(PPh3)4 were charged in a reaction vessel under nitrogen. The mixture was added deoxygen benzene (50 mL), ethanol (4 mL), and 2M potassium carbonate solution (10 mL) to be dissolved, and then heated to 80° C. and reacted for 24 hours. The reaction result was extracted by 50 mL of ethyl acetate to obtain an organic layer. The organic layer was filtered through diatomite and dried by anhydrous magnesium sulphate. Most of the solvent of the dried organic layer was removed to obtain a solid. The solid was subsequently washed by distillation water, methanol, ethyl ether to obtain 2,3,6,7-Tetrakis-(4-tert-butyl-phenyl)-9,9,10,10-tetramethyl-9,10-dihydro-anthracene (hereinafter TTA-tBu). The Suzuki coupling was shown in Formula 7, and the product had spectra as below. 1H NMR (400 M Hz, CDCl3): δ 1.31 (s, 36 H), 1.79 (s, 12 H), 7.12 (d, 8 H, J=8.4 Hz), 7.24 (d, 8 H, J=8.4 Hz), 7.55 (s, 4 H). 13C NMR (100 M Hz, CDCl3): δ 31.4 (CH3), 34.4(C), 35.1 (CH3), 37.1 (C), 124.6 (CH), 128.9 (CH), 129.5 (CH), 138.3 (C), 138.8 (C), 141.0 (C), 149.1 (C). HRMS (FAB, m/z): calcd for C58H68 764.5321, found 765.5397 (M+H+). Anal. Calcd. for C58H68: C, 91.04; H, 8.96%. Found: C, 91.07; H, 8.90%. FIG. 4 shows UV-VIS absorption and photo luminescent spectra of the TTA-tBu in a dichloromethane solution and thin film type, and solid phosphorescence emission spectra at 77K of the TTA-tBu.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:11]([NH:14][C:15]([NH2:17])=[NH:16])(=[O:13])[CH3:12]>CN(C=O)C.CCOC(C)=O>[C:5]1([C:3]2[N:16]=[C:15]([NH:14][C:11](=[O:13])[CH3:12])[NH:17][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)NC(=N)N
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2.0 g (10 mmol) of 2-bromoacetophenone in DMF (30 mL) was added 3.0 g (29 mmol) 1-acetylguanidine in one portion, the reaction mixture was stirred at rt for 2 days. The reaction mixture was diluted with EtOAc (250 mL) and washed with saturated NH4Cl aq. solution (50 mL). The organic phase was dried over MgSO4 and concentrated under vacuum. The residue was purified by a flash column chromatography eluting with EtOAc to give N-(4-phenyl-1H-imidazol-2-yl)-acetamide. (0.5 g, 24%). LCMS: 203 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([CH2:12][CH3:13])[C:6](=[O:14])[C:5]2([CH3:16])[CH3:15].[N+:17]([C:20]1[C:21]([C:25](O)=O)=[N:22][NH:23][CH:24]=1)([O-:19])=[O:18].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH2:12]([N:7]1[C:8]2[CH:9]=[C:10]3[N:11]=[C:25]([C:21]4[C:20]([N+:17]([O-:19])=[O:18])=[CH:24][NH:23][N:22]=4)[NH:1][C:2]3=[CH:3][C:4]=2[C:5]([CH3:15])([CH3:16])[C:6]1=[O:14])[CH3:13]
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: CCN1C(=O)C(C)(C)c2cc(N)c(N)cc21
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4[N+](=O)[O-])nc3cc21
Temperature: 150 °C
Reaction time: 6 h

Procedure:
5,6-Diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one (5.00 g, 22.80 mmol), and 4-nitro-pyrazole carboxylic acid (3.58 g, 22.80 mmol) were mixed with polyphosphoric acid (22.34 g, 228.0 mmol) and phosphorus pentoxide (1.63 g, 11.4 mmol) and stirred under nitrogen at 150° C. for 6 h. It was quenched with ice water (250 ml) and the resulting suspension was adjusted to pH 5 by adding aqueous ammonia. The crude microcrystalline solid was dissolved in ethyl acetate (400 mL). The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (4×400 mL). After evaporation of the solvent, the crude product was purified by HPLC (High Performance Liquid Chromatography). 5-Ethyl-7,7-dimethyl-2-(4-nitro-1H-pyrazol-3-yl)-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one was obtained as an orange solid (2.47 g, 32%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15][CH2:16][C:17]([NH2:19])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22](=O)[CH2:23][CH3:24].C(=O)([O-])O.[Na+].CCCCCC>CC(CC)=O>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:21]=[C:22]([CH2:23][CH3:24])[C:15]=2[CH2:16][C:17]([NH2:19])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)CCc1ncccc1OCc1ccccc1
Reactant: CCC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCC(C)=O
Product: CCc1cn2cccc(OCc3ccccc3)c2c1CC(N)=O
Yield: 48.2 %

Procedure:
A mixture of the pyridine derivative (16, 4.00 g, 15.6 m mol), 1-bromo-2-butanone (3.53 g, 23.4 m mol) and sodium hydrogencarbonate (6.55 g, 78 m mol) in methylethylketone (30 ml) was heated under reflux for 60 hours. The solid was filtered off. The volatile materials were removed by distillation under reduced pressure. The residue was chromatographed on silica gel eluting with hexane:ethyl acetate (1:2) and with ethyl acetate. The first fraction was crystallized from benzene:hexane to give 2.32 g (48.2% yield) of the titled compound 17b and, mp, 117-119° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=O)[C:8]([OH:19])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1([NH2:27])[CH2:26][CH2:25][CH2:24]1>>[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:19])=[C:7]([CH2:20][NH:27][C:23]2([CH3:22])[CH2:26][CH2:25][CH2:24]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(N)CCC1
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(Cl)c(Cl)c2)c1
Product: CC1(NCc2cc(C(C)(C)C)cc(-c3ccc(Cl)c(Cl)c3)c2O)CCC1

Procedure:
5-(tert-Butyl)-3′,4′-dichloro-3-(((1-methylcyclobutyl)amino)methyl)-[1,1′-biphenyl]-2-ol was prepared as a white solid using the procedure described in Example 5 from 5-(tert-butyl)-3′,4′-dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde (from Example 19, Step 1) and 1-methylcyclobutylamine.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:7](O)(=[O:11])/[CH:8]=[CH:9]/[CH3:10]>O>[CH3:10][CH:9]1[C:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C:1]=2[C:7](=[O:11])[CH2:8]1
Reactant: C/C=C/C(=O)O
Reactant: C1=CCCCC1
Solvent: O
Product: CC1CC(=O)C2=C1CCCC2
Yield: 65.8 %

Procedure:
Cyclohexene (27.3 g, 0.33 mol), crotonic acid (28.7 g, 0.33 mol) and polyphosphoric acid (300 mL) were mechanically stirred under a nitrogen atmosphere at 60° C. for 30 minutes. The slurry was poured into water and the aqueous solution extracted with diethyl ether. The diethyl ether extract was washed successively with a 10 percent NaHCO3 solution and a saturated NaCl solution. The organic extract was dried over anhydrous MgSO4. The solution was filtered and the solvent removed under reduced pressure. The crude product was purified via vacuum distillation (bp 87°-92° C. at 5 mm) to give 32.6 g (66 percent) of purified material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.[S:52](Cl)(=[O:55])(=[O:54])[NH2:53]>O1CCCC1>[F:8][C:6]1[CH:7]=[C:2]([NH:1][S:52]([NH2:53])(=[O:55])=[O:54])[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[CH:10]=2)[CH:5]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(F)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: NS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(F)cc(NS(N)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
(S)-2-(1-((5-(3-Amino-5-fluorophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (40 mg, 0.06 mmol) was treated with pyridine (20 μL, 0.25 mmol) and sulfamoyl chloride (24 mg, 0.21 mmol) in tetrahydrofuran (0.5 ml) according to the method described in Preparation 175 but stirring at room temperature overnight. The title compound was obtained (46 mg, 93% yield) without further purification.