Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl-].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH:26]=[C:25]([C:28]2[NH:44][C:31]3[N:32]=[CH:33][N:34]=[C:35]([N+]45CCN(CC4)CC5)[C:30]=3[CH:29]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(=O)(O)[O-].[Na+]>CS(C)=O.C(O)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH:24]=[C:25]([C:28]2[NH:44][C:31]3[N:32]=[CH:33][N:34]=[C:35]([O:3][C:4]4[CH:5]=[C:6]5[C:11](=[CH:12][CH:13]=4)[N:10]=[CH:9][CH:8]=[CH:7]5)[C:30]=3[CH:29]=2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Oc1ccc2ncccc2c1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c([N+]45CCN(CC4)CC5)ncnc3[nH]2)CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [H-]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Oc4ccc5ncccc5c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of sodium hydride (60% dispersion in mineral oil) (24 mg, 0.6 mmol) in anhydrous DMSO (4 mL) under argon, was added 6-hydroxyquinoline (239 mg, 1.65 mmol). The mixture was allowed to stir at rt for 1 h. To this mixture was added 1-[6-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-aza-1-azonia-bicyclo[2.2.2]octane chloride (100 mg, 0.3 mmol) in DMSO (0.3 mL), and the mixture stirred for a further 16 h. TLC analysis showed no starting material so the mixture was neutralised with glacial acetic acid and basified with saturated aqueous sodium bicarbonate solution. The product was extracted in to EtOAc (3×50 mL), the organics dried with MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified on silica gel by elution with iso-hexane:ethyl acetate to yield the title compound. 1H NMR (DMSO, 400 MHz) 1.4 (9H, s), 2.5 (2H, broad), 3.6 (2H, broad), 4.1 (2H, broad), 6.5 (1H, m), 6.7 (1H, s), 7.6 (1H, m), 7.7 (1H, d), 7.9 (1H, s), 8.1 (1H, d), 8.3 (1H, s), 8.4 (1H, d), 8.9 (1H, s), 12.4 (NH, s). MH+=444.24
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:12][CH2:11][N:10]([C@@:13]3([CH3:25])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[N:38][CH:39]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:40][C:37]1[N:38]=[CH:39][C:34]([C:2]2[C:3]3[CH2:12][CH2:11][N:10]([C@@:13]4([CH3:25])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]4)[C:4]=3[N:5]=[C:6]([S:8][CH3:9])[N:7]=2)=[CH:35][N:36]=1
Reactant: CSc1nc(Cl)c2c(n1)N([C@@]1(C)CCN(C(=O)OC(C)(C)C)C1)CC2
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CSc1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCN(C(=O)OC(C)(C)C)C1)CC2
Temperature: 120 °C
Yield: 58 %

Procedure:
To a suspension of tert-butyl(3S)-3-[4-chloro-2-(methylsulfanyl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidine-1-carboxylate (1.24 g, 3.22 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (1.0 g, 4.6 mmol) in dioxane (16 mL) was added 1 M Na2CO3 solution (13 mL, 12.9 mmol) at room temperature. The reaction mixture was purged with nitrogen for a few minutes before adding PdCl2(dppf)-DCM (395 mg, 0.484 mmol). The reaction mixture was heated at 120° C. for 40 h in a microwave reactor. The mixture was filtered through a pad of Celite® rinsing with EtOAc several times, concentrated and purified via ISCO normal phase silica gel chromatography (40 g column) with a 0-100% gradient of EtOAc/Heptane to give the title compound (828 mg, 58%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J=4.6 Hz, 2 H), 7.06 (s, 2 H), 3.79-3.64 (m, 3 H), 3.63-3.51 (m, 1 H), 3.39-3.34 (m, 2 H), 3.21-3.14 (m, 2 H), 2.45 (s, 3 H), 2.41-2.27 (m, 1 H), 2.10-1.99 (m, 1 H), 1.40 (s, 9 H), 1.28 (s, 3 H). m/z (APCI+) for C21H29N7O2S 444.2 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16](N5CCNCC5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:27]1([C:18]2[C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:8]=[C:9]4[C:14]=3[CH:15]=[CH:16][N:17]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Reactant: C1COCCN1
Product: O=c1c2c[nH]c3c(N4CCOCC4)nccc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described in Step 4 for synthesis for 6a using 16 and morpholine. 1H-NMR (DMSO-d6) δ (ppm): 3.17 (4H, brm), 3.87 (4H, brm), 7.15 (1H, m), 7.43 (2H, m), 7.76 (1H, d, J=5.5 Hz), 8.17 (2H, d, J=8.8 Hz), 8.33 (1H, d, J=5.2 Hz), 8.44 (1H, s). m/z 348.1 (MH+).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:34])=[C:23]([CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:38][C:39]1[O:43][N:42]=[C:41]([CH2:44][NH2:45])[CH:40]=1.CS(C)=O.C(N(CC)CC)C>C(#N)C>[CH3:38][C:39]1[O:43][N:42]=[C:41]([CH2:44][NH:45][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([CH3:34])=[CH:29][CH:30]=[CH:31][C:32]=5[CH3:33])=[C:23]([CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])[CH:40]=1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1c(C)cccc1C
Reactant: Cc1cc(CN)no1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CS(C)=O
Product: Cc1cc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4c(C)cccc4C)c(C)c2)C3)no1

Procedure:
The title compound was prepared according to the procedure of Example 2 starting from 2,2,2-trichloro-1-{10-[(2,2′,6′-trimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 3 (1.8 g, 3.26 mmole), (5-methyl-3-isoxazolyl)methylamine (0.305 g, 2.7 mmole), dimethylsulfoxide (1.06 g, 13.6 mmole), and triethylamine (0.605 g, 6 mmole) in 20 mL of acetonitrile. The residue was flash chromatographed on silica Merck-60 using a gradient from 0 to 35% of ethyl acetate in dichloromethane, to provide an orange-yellow foam. Recrystallization from ethyl acetate/dichloromethane/hexane gave a white powder (0.334 g), m.p. 233-234° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[CH2:14]([O:16][CH:17]=[CH:18][C:19](Cl)=[O:20])[CH3:15]>N1C=CC=CC=1>[CH2:14]([O:16][CH:17]=[CH:18][C:19]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[CH:8][CH:9]=1)=[O:20])[CH3:15]
Reactant: CCOC=CC(=O)Cl
Reactant: Cc1nccn1-c1ccc(N)cc1
Solvent: c1ccncc1
Product: CCOC=CC(=O)Nc1ccc(-n2ccnc2C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
4-(2-methyl-1H-imidazol-1-yl)aniline (40.7 g, 232 mmol; RN: 74852-81-6, Maybridge, J. Med. Chem., 48(6), 1729-1744; 2005) was dissolved in dry pyridine (290 mL), 3-ethoxyacryloyl chloride (36.1 g, 268 mmol) was then added dropwise at 0°/−10° C. The resulting mixture was stirred at 0° C. for 2 hours and at r.t. overnight. The reaction mixture was quenched with 100 mL of water, and pyridine was distilled i.v., the residue was taken up with water and the pH was adjusted to pH=10, by adding K2CO3, the resulting suspension was extracted with AcOEt and concentrated. The resulting solid was stirred with hexane and filtered to afford the title product (58 g; 92%). C15H17N3O2, MW: 271.32.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[C:14]3[C:20]4([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH2:21][CH2:22][C:17]([CH2:32][O:33]S(C5C=CC(C)=CC=5)(=O)=O)([CH2:18][CH2:19]4)[CH2:16][N:15]3[C:44](=[O:47])[C:45]=2[OH:46])=[O:11])=[CH:4][C:3]=1[CH3:48].[C:49](C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.F[B-](F)(F)F.C[O+](C)C.CC1C=CC=CN=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[C:14]3[C:20]4([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:28])[CH3:29])=[O:26])[CH2:19][CH2:18][C:17]([CH2:32][O:33][CH3:49])([CH2:22][CH2:21]4)[CH2:16][N:15]3[C:44](=[O:47])[C:45]=2[OH:46])=[O:11])=[CH:4][C:3]=1[CH3:48]
Reactant: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(N(C)C(=O)C(=O)N(C)C)(CC2)c2nc(C(=O)NCc4ccc(F)c(C)c4)c(O)c(=O)n2C3)cc1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccn1
Product: COCC12CCC(N(C)C(=O)C(=O)N(C)C)(CC1)c1nc(C(=O)NCc3ccc(F)c(C)c3)c(O)c(=O)n1C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.79 %

Procedure:
To a solution of N-[2-[[[(4-fluoro-3-methylphenyl)methyl]amino]carbonyl]-6,7,8,9-tetrahydro-3-hydroxy-7-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-4-oxo-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl]-N,N′,N′-trimethyl-ethanediamide, Intermediate 28, (100 mg, 0.161 mmol) in CH2Cl2 (10 mL) was added 2,6-di-tert-butyl-4-methylpyridine (166 mg, 0.807 mmol) and trimethyloxonium tetrafluoroborate (48.5 mg, 0.807 mmol) and the mixture was stirred at room temp for 16 h. Another 5 equiv each of methylpyridine and trimethyloxonium tetrafluoroborate were added and the mixture was stirred at room temp for 5 h. The reaction was quenched by addition of 1N KHSO4 (30 mL) and stirred for 10 min and extracted with CH2Cl2 (25 mL×2). The combined extracts were dried, filtered and concentrated. The crude material was then dissolved in CH2Cl2 (1 mL) and treated with TFA (1 mL, 12.98 mmol) at room temp for 16 h. The mixture was concentrated in vacuuo and purified by preparative HPLC to afford the title compound (3.5 mg, 6.12 mmol, 3.79% yield) as a thick film. 1H NMR (500 MHz, CDCl3) δ: 12.15 (1H, br. s.), 9.59 (1H, br. s.), 7.24-7.27 (1H, m), 7.17-7.23 (1H, m), 6.90-6.97 (1H, m), 4.71 (1H, d, J=15.6 Hz), 4.58-4.65 (1H, m), 4.43-4.48 (1H, m), 3.51 (1H, d, J=15.6 Hz), 3.39-3.45 (1H, m), 3.20 (2H, d, J=5.8 Hz), 3.05 (3H, s), 3.02 (3H, s), 3.00 (3H, s), 2.27 (3H, d, J=1.8 Hz), 2.08-2.12 (3H, m), 1.76-1.83 (1H, m), 1.66-1.74 (2H, m), 1.38-1.49 (1H, m). LCMS (M+H)=544.5.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9](Br)=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.C(=O)([O-])[O-].[K+].[K+].Cl.C1C(=O)N(Br)C(=O)C1>C1COCC1.[Pd].C(Cl)(Cl)Cl.C(O)(=O)C>[N:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][CH:2]=2)[N:7]=[CH:6][CH:5]=1
Reactant: Brc1ccc(Br)c2nccnc12
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: c1ccc2nccnc2c1
Yield: 72 %

Procedure:
In a reactor in a nitrogen atmosphere, while a solution (about 25 ml) of about 3.5 g (about 5.0 mmol) of 5,8-dibromoquinoxaline derivative synthesized in Preparative Example 1 (see: T. Yamamoto, et al. J. Am. Chem. Soc, 1996, Vol. 118, pp. 3930˜3937) and an excess of 2-thiophene borane derivative (about 15.0 mmol) in anhydrous THF was stirred, aqueous potassium carbonate (K2CO3, about 20 g, about 150 mmol) and about 10 mol % (about 578 mg, about 0.5 mmol) of a palladium catalyst (Pd(PPh3)4), based on the monomer, were added, and then the solution was allowed to react at about 80° C.˜about 85° C. for about 24 hours. The resultant reaction solution was treated with dilute aqueous hydrochloric acid and then extracted with chloroform. The obtained organic layer was distilled under reduced pressure, slightly washed with methanol, and dried, to thus prepare a thiophene-quinoxaline trimer, which was then reacted with NBS in a mixture of chloroform and acetic acid, thereby obtaining an orange solid thiophene-quinoxaline derivative (Yield: about 72%).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:3]=12.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:30]1([S:33]([N:11]2[C:4]3=[CH:5][C:6]4[S:10][CH:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: O=c1[nH]c2cc3scnc3c(F)c2n1-c1ccc(I)cc1F
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1n(-c2ccc(I)cc2F)c2c(F)c3ncsc3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (70 mg, 0.16 mmol) in CH2Cl2 (5 mL) was added triethylamine (48 mg, 0.49 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (35 mg, 0.25 mmol) and DMAP (10 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (10 mL×2). The combined organic phase was washed with water (10 mL) and brine (10 mL) successively, dried over
Reaction SMILES: [P:1]([O:19][C:20]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=1[F:40])([CH2:27][N:28]1[CH:32]=[N:31][CH:30]=[N:29]1)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].[OH-].[Na+].S(=O)(=O)(O)O>[Pd].O>[P:1]([OH:11])([OH:3])([O:19][C:20]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=1[F:40])([CH2:27][N:28]1[CH:32]=[N:31][CH:30]=[N:29]1)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)=[O:2]
Reactant: O=P(OCc1ccccc1)(OCc1ccccc1)OC(Cn1cncn1)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Pd]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=P(O)(O)OC(Cn1cncn1)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 20 h
Yield: 86.8 %

Procedure:
A slurry of the compound of step (a) (9.80 g, 17.3 mmol), 5% palladium on carbon catalyst (50% wet, 1.0 g) and sodium hydroxide (1.38 g, 34.6 mmol) in water (26 ml) was hydrogenated at room temperature and 414 kPa (60 p.s.i.) for 20 hours. The solution was filtered through a pad of celite (trade mark) and washed with water (5 ml). The toluene was separated and the aqueous phase cooled to 0° C. whereupon sulphuric acid (1.70 g, 17.3 mmol) was added. The resulting slurry was granulated at 0° C. for 1 hour and then filtered, washed with water (2×5 ml) and dried under vacuum at 50° C. to give the title compound (5.80 g, 87%). m.p. 223-224° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:21](=[O:23])[CH3:22])[CH:8]=[C:9]([O:11][CH2:12][CH2:13][O:14]C2CCCCO2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:24].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CC(=O)OCC>CO.C1COCC1>[Br:24][CH2:22][C:21]([C:7]1[CH:8]=[C:9]([O:11][CH2:12][CH2:13][OH:14])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)=[O:23]
Reactant: CC(=O)c1cc(OCCOC2CCCCO2)cc(C(C)(C)C)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1cc(OCCO)cc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.7 %

Procedure:
1-{3-tert-Butyl-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}ethanone (O2.061; 3.9 g) was dissolved in methanol/THF (60 ml/60 ml) and admixed while stirring with phenyltrimethylammonium tribromide (5.03 g). After stirring at RT for 3 h, the mixture was added to 20% citric acid and stirred for 1 h. After adding EA, the EA phase was removed, dried and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/EA gradient of 0-50% within 60 min). 2.56 g of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31](O)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:57][C:58]1[CH:63]=[CH:62][C:61]([CH:64]([C:66]2[C:71]([CH3:72])=[CH:70][CH:69]=[CH:68][N:67]=2)[OH:65])=[CH:60][CH:59]=1>CN(C=O)C.CN(C)C1C=CN=CC=1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:27])[F:28])[CH2:23][CH2:22][C:21]([C:31]([NH:57][C:58]4[CH:63]=[CH:62][C:61]([CH:64]([OH:65])[C:66]5[C:71]([CH3:72])=[CH:70][CH:69]=[CH:68][N:67]=5)=[CH:60][CH:59]=4)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cccnc1C(O)c1ccc(N)cc1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ncccc4C)cc2)CCN3C(=O)C(F)(F)F)cc1
Reaction time: 1 h
Yield: 45.2 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.5 g) and 1-hydroxybenzotriazole (0.28 g) in DMF (10 ml), was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.40 g) at room temperature, and the mixture was stirred for 1 hour. To the reaction solution were added a solution of (4-aminophenyl)(3-methylpyridin-2-yl)methanol (0.27 g) and triethylamine (0.60 ml) in DMF (5 ml) and 4-dimethylaminopyridine (1 flake), and the mixture was stirred for 3 days. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:3→1:2→1:1) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(3-methylpyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 99) (319.2 mg) as colorless amorphous.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[K+].C1(C)C=CC=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:18]1([O:24][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCOc1ccccc1
Temperature: 92 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
A 1-liter three necked round bottom flask was charged with 100 grams (0.33 moles) of 1-bromohexadecane, 92.5 grams (0.99 moles) of phenol, 55.2 grams (0.99 moles) of potassium hydroxide, 10 grams of tetra-n-butylammonium bromide, 167 ml of toluene, and 167 ml of water. The flask was fitted with a mechanical stirrer, nitrogen inlet, condenser, thermometer and heating mantle. The reaction mixture was heated to reflux at about 92° C., under a nitrogen purge for 16 hours with constant agitation. After 16 hours, the mixture was cooled and transferred to a separatory funnel where the aqueous layer was removed and the upper toluene layer was washed three times with 200 ml 0.5N NAOH and three times with 200 ml deionized water. The toluene was removed under reduced pressure leaving 102.6 grams (98% yield) of n-hexadecyl phenyl ether. Analysis by gas chromatography showed that the product was 98.3% pure.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([N:30]([C:34]1([C:40]#[CH:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:31][CH2:32][OH:33])[CH3:29]>>[CH2:28]([N:30]([C:34]1([C:40]#[C:41][C:16]2[CH:15]=[CH:14][C:13]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:26])([F:27])[F:1])=[CH:8][CH:7]=4)=[N:10][S:11][C:12]=3[CH:17]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:31][CH2:32][OH:33])[CH3:29]
Reactant: C#CC1(N(CC)CCO)CCCCC1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Product: CCN(CCO)C1(C#Cc2ccc3c(-c4ccc(C(F)(F)F)cc4)nsc3c2)CCCCC1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and 2-[Ethyl-(1-ethynyl-cyclohexyl)-amino]-ethanol were converted to yield 2-(Ethyl-{1-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-ylethynyl]-cydohexyl}-amino)-ethanol as brown oil, MS: 473.3 (MH+).
Reaction SMILES: [C:1]([CH2:7][C@@H:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([OH:11])=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.Cl.[CH3:21][O:22][C:23](=[O:32])[C@H:24]([CH2:26][C:27]1[N:31]=[CH:30][NH:29][CH:28]=1)[NH2:25].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:21][O:22][C:23](=[O:32])[C@H:24]([CH2:26][C:27]1[N:31]=[CH:30][NH:29][CH:28]=1)[NH:25][C:9](=[O:11])[C@@H:8]([CH2:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.9 %

Procedure:
A suspension of 3.0 g (12 mmol) of (R)-α-(pivaloylmethyl)hydrocinnamic acid (see EPA 0.184.550) and 2.66 g (11 mmol) of L-histidine methyl ester dihydrochloride in 340 ml of dimethylformamide is treated at room temperature under a nitrogen atmosphere with 3.45 g (34 mmol) of triethylamine and 4.58 g (12 mmol) of HBTU. The reaction mixture is stirred at room temperature for 5 hours and subsequently evaporated in a high vacuum. The residue is dissolved in 500 ml of ethyl acetate and washed in succession with 100 ml of water, three times with 100 ml of saturated sodium bicarbonate solution each time and 100 ml of saturated sodioum chloride solution. The organic phase is dried over sodium sulphate, evaporated under reduced pressure and the yellowish crude product obtained is chromatographed on silica gel with a 95:5 mixture of methylene chloride and methanol which contains 0.1% ammonia. In this manner there are obtained 3.6 g of N-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamoyl]-L-histidine methyl ester as a colourless foam, MS: 399 (M)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:21]1=[O:29].CC([O-])(C)C.[K+].CO>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>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[N:3]=[C:2]2[N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:21]1=[O:29]
Reactant: COc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Reactant: O=c1[nH]c2ccccc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2nc(-c3cccnc3)nc(-n3c(=O)[nH]c4ccccc43)c2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To a 50-mL two-neck round bottom flask equipped with a reflux condenser was added a mixture of 4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline (50 mg, 0.18 mmol, 1 eq.) and 1H-benzo[d]imidazol-2(3H)-one (27 mg, 0.21 mmol, 1.1 eq.) in 5 mL of dry 1,4-dioxane. Pd(PPh3)4 (10.6 mg, 0.009 mmol, 0.05 eq) and t-BuOK (41 mg, 0.36 mmol, 2 eq.) were added. The resulting mixture was stirred at 100° C. under N2 atmosphere overnight. After cooling, 20 mL of methanol was added. The mixture was filtered, the filtrate was concentrated in vacuo and then was purified with chromatography on silica gel (ethyl acetate/petroleum ether from 1:4 to 1:2) to give the crude product, which was further purified with reverse phase HPLC to afford 4.8 mg of vi-e as a pale yellow solid (7%). MS m/z=370.1 (M+1) (Method B) (retention time=1.680 min). 1H NMR (400 MHz, DMSO-d6): δ 11.51 (s, 1H), 8.78 (d, J=8.0 Hz, 2H), 8.17 (d, J=9.2 Hz, 1H), 7.80 (dd, J=9.2, 2.8 Hz, 1H), 7.70-7.64 (m, 1H), 7.46 (d, J=2.8 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.20 (d, J=4.0 Hz, 2H), 7.16-7.08 (m, 1H), 3.89 (s, 3H).