Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[C:16]([C:20]1[CH:25]=[CH:24][C:23](O)=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
Triflic anhydride (4.14 mL, 24.6 mmol) was added dropwise to a solution of 4-tert-butyl-2-nitrophenol (4.00 g, 20.5 mmol) and pyridine (2.16 mL, 26.7 mmol) in methylene chloride (50 mL) at 0° C. The yellow solution was stirred 0.25 h at 0° C., poured onto saturated aqueous NaHCO3 and extracted with methylene chloride. The combined extracts were washed with saturated aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by filtration through a plug of silica-gel (methylene chloride) to provide trifluoro-methanesulfonic acid 4-tert-butyl-2-nitro-phenyl ester (5.82 g, 87%) as a pale yellow oil which was utilized without further purification.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[N:12][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])=[CH:13][N:12]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)C(Cl)Cl)cn1
Reaction time: 1 h

Procedure:
Dichloroacetyl chloride, 97% (2.0 ml, 0.03 mol) was added over a period of 30 seconds to a mixture of 5-amino-2-methoxypyridine (3.7 g, 0.03 mol), pyridine (5.0 ml) and methylene chloride (100 ml). The reaction was exothermic and allowed to stand at room temperature for one hour. The reaction was then washed with 5% sodium carbonate solution (2×100 ml), dried over anhydrous magnesium carbonate, filtered, and evaporated in vacuo to give a solid that was triturated with hexane to yield 6.4 g of the title compound, m.p. 104°-107° C. The title product was identified by infrared (IR), nuclear magnetic resonance (NMR) and mass spectrocopy (MS) analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=1>>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([N:16]2[CH:17]=[C:13]([C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][O:10][C:11]=3[C:18]([F:21])([F:19])[F:20])[N:14]=[CH:15]2)=[N:24][CH:25]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: FC(F)(F)c1onc(-c2ccc(Cl)cc2)c1-c1c[nH]cn1
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)nc1
Yield: 75 %

Procedure:
As described for Example 4, 3-(4-chloro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (700 mg, 2.2 mmol) instead of 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole was converted, using methyl 6-chloronicotinate instead of 4-fluorobenzotrifluoride, to the title compound (750 mg, 75%) which was obtained as a white solid. MS: m/e=449.0 [M+H]+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:13][C:14]([NH2:16])=[S:15]>C(O)C>[BrH:12].[C:1]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][S:15][C:14](=[NH:13])[NH2:16])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCCCCBr
Reactant: NC(N)=S
Solvent: CCO
Product: Br
Product: CC(C)(C)C(=O)OCCCCSC(=N)N
Yield: 95 %

Procedure:
4-Bromobutyl pivalate (0.71 mol) and thiourea (0.78 mol) were dissolved in ethanol (330 ml) and the resulting mixture was refluxed for 1 h. The solvent was removed under vacuum. The resulting residue was used in the next step without further purification. Yield: 210 g (95% yield).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH:30]1([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCOCC1.CN(C=O)C>[CH:30]1([O:36][C:2]2[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]3[S:10][C:11]4[C:17]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=4[N:13]=3)=[O:7])=[CH:4][N:3]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(OC4CCCCC4)nc3)nc12

Procedure:
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with sodium hydride and cyclohexanol in dioxane and DMF. ES-MS m/e (%): 491 (M+Na+, 24), 469 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([OH:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].CCN(CC)CC.Cl[Si:37]([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([O:19][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](O[Si](C)(C)C)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 64.8 %

Procedure:
A solution of 8a (0.08 g, 0.20 mmol), NEt3 (0.1 mL, 0.72 mmol) and chlorotrimethylsilane (0.1 mL, 0.79 mmol) in CH2Cl2 (30 mL) was stirred at room temperature overnight. The mixture was washed with saturated NaHCO3 (2×10 mL) and H20 (50 mL), dried (Na2SO4), and the solvent was removed under reduced pressure. The resulting crude solid was purified by column chromatography (eluent: ethyl acetate/nhexanes) to afford 16 (0.06 g, 68%) as a white solid, mp 197-200° C.; 1H NMR (CDCl3): δ 0.14 (9H, s, (CH3)3SiO; 1.11 (3H, s, H-19); 1.48 (3H, s, H-29); 1.50-1.73 (3H, m, H-7α,β and H-11β); 1.79 (1H, ddd, J=3.0, 3.0, 10.5 Hz, H-6α); 2.03 (1H, dd, obscured, H-8); 2.06 (1H, s, H-10); 2.10-2.38 (3H, m, H-3α,β and H-6β); 2.57 (1H, dd, J=5.1, 10.5 Hz, H-11α); 2.69 (1H, dd, J=3.9, 12.9 Hz, H-4); 3.72 (3H, s, CO2CH3); 4.12 (1H, dd, J=7.5, 11.7 Hz, H-2); 5.56 (1H, dd, J=5.1, 11.4 Hz, H-12); 6.38 (1H, dd, J=0.8, 1.7 Hz, H-14); 7.40 (1H, m, H-15); 7.42 (1H, m, H-16).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:54])([CH3:53])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[C:33]([O:45][CH3:46])[CH:32]=3)=[C:26]([CH2:47][CH2:48][CH3:49])[N:25]3[N:50]=[CH:51][CH:52]=[C:24]23)[CH2:19][CH2:18]1>C(OCC)(=O)C>[OH:13][C:14]([CH3:53])([CH3:54])[CH2:15][O:16][C@H:17]1[CH2:18][CH2:19][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[C:33]([O:45][CH3:46])[CH:32]=3)=[C:26]([CH2:47][CH2:48][CH3:49])[N:25]3[N:50]=[CH:51][CH:52]=[C:24]23)[CH2:21][CH2:22]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(OC)c2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)c(OC)c2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.16 g), sodium hydrogen carbonate (0.25 g) and dimethyl sulfoxide (1 mL) was stirred at 50° C. for 30 min, 4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)-2′-methoxybiphenyl-2-carbonitrile (0.085 g) was added, and the mixture was stirred at 90° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.030 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.027 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.058 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12](O)=[O:13])[CH:7]=[C:6]([CH3:15])[C:5]=1[N:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:17].[CH3:30][NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12](=[O:13])[N:31]([CH3:30])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:7]=[C:6]([CH3:15])[C:5]=1[N:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:17]
Reactant: CCCCCCCCNC
Reactant: COC(=O)c1cc(C=CC(=O)O)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Solvent: C1CCOC1
Product: CCCCCCCCN(C)C(=O)C=Cc1cc(C)c(N(C)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 182.6 mg (0.43 mmol) of the product of Example 204, 183 mg of molecular sieves and 105.8 mg (0.65 mmol) of 1,1'-dicyclohexylcarbodiimidazole in 4 ml THF was stirred for 1 h under nitrogen. A solution of N-methyloctylamine in 0.5 ml THF was then added to the reaction and the mixture was stirred for 18 hr at room temperature. The resulting mixture was filtered and the filtrate was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc/Hexane (1:1) to provide 200 mg (84%) of the desired product as a colorless oil. Electrospray Mass Spec 545(M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][N:11]2[C:15]3[C:16](=[O:20])[CH2:17][CH2:18][CH2:19][C:14]=3[N:13]=[C:12]2[CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:7][C:8]=1[Cl:9].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.CO>O1CCCC1>[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][N:11]2[C:15]3[C@H:16]([OH:20])[CH2:17][CH2:18][CH2:19][C:14]=3[N:13]=[C:12]2[CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(=O)CCC2
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)[C@H](O)CCC2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Intermediate 85 (900 g, 1.0 eq, 1.0 wt) was charged to a solution of (S)-(−)-2-methyl-CBS-oxazaborolidine (198 g, 0.3 eq, 0.22 wt) in tetrahydrofuran (3.6 L, 4 vol) at 20° C., followed by a line rinse with tetrahydrofuran (0.9 L, 1 vol). The suspension was cooled to 0° C. and chilled (0° C.) 1M borane in tetrahydrofuran solution (4.82 L, 2 eq 5.35 vol) was added over 1 hour 35 minutes at <3° C. The mixture was stirred at 0° C. for 1 hour 20 minutes when complete dissolution was observed and sampled for completion by HPLC. Reaction was complete. The mixture was added into chilled (0° C.) methanol (3.6 L, 4 vol) at <5° C. over 40 minutes, followed by a line rinse with methanol (0.9 L, 1 vol). The mixture was warmed to 20° C. and stirred at this temperature for 1 hour 15 minutes when effervescence had ceased. Water (2.7 L, 3 vol) was added, followed by the addition of 5M aqueous hydrochloric acid (0.9 L, 1 vol) at <10° C. over 10 minutes. The mixture was warmed to 20° C. and stirred at this temperature for 1 hour when effervescence had ceased. To the mixture was added 48% w/w aqueous sodium hydroxide (0.99 L, 1.1 vol) at <30° C. over 15 minutes and the mixture stirred vigorously for 10 minutes at 20° C. The basic aqueous layer was separated. The organic phase was diluted with isopropylacetate (3.6 L, 4 vol) and washed with water (2.7 L, 3 vol). The aqueous phase was separated and the organic phase was concentrated by vacuum (100-200 mbar) distillation to 3.6 L/4 vol at 25° C. To the mixture was added isopropylacetate (5.4 L, 6 vol), followed by water (6 L, 6.7 vol) and the mixture stirred vigorously for 10 minutes at 20° C. The aqueous phase was separated and the organic phase was concentrated by vacuum distillation on a rotary evaporator. The solids were slurried in heptane (9 L, 10 vol) on the rotary evaporator at 40 C for 1 hour and stirred at this temperature for 16 hours. The solids were collected by vacuum filtration, washed with heptane (2×0.9 L, 2×1 vol) and dried in vacuo at 40° C. for 23 hours 30 minutes. Yield of the title compound obtained was 739 g/90% theory yield/82% w/w yield.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][OH:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:15](#[N:19])[CH2:16][C:17]#[N:18].C(NCC)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[C:15]([NH2:19])[O:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: N#CCC#N
Reactant: CC(=O)Nc1ccc(C(=O)CO)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC(=O)Nc1ccc(-c2coc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a solution of 4′-acetamido-2-hydroxyacetophenone 4 (7.17 g, 39 mmol) in DMF (65 mL), malononitrile (2.84 g, 43 mmol) was added. With cooling in an ice-water bath, diethylamine (6.05 mL 59 mmol) was gradually added within 20 min. The mixture was stirred at room temperature for 2 h and then diluted with ethyl acetate (400 mL). The mixture was washed with brine (3×200 mL), dried over sodium sulfate, and then evaporated in vacuo. Residual material was treated with dichloromethane and n-hexane, concentrated in vacuo, and precipiated in the concentrated mixture. The precipitated material was filtrated and washed with n-hexane to give 5 (7.64 g) as a brown solid. MS(ES) m/e 242 [M+H].
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]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]=[N:42][C:43]([CH3:47])=[C:44]([CH3:46])[N:45]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[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]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]=[N:42][C:43]([CH3:47])=[C:44]([CH3:46])[N:45]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nnc(C)c(C)n4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nnc(C)c(C)n4)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(5,6-dimethyl-1,2,4-triazin-3-yl)methylthio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.25 g) was dissolved in dichloromethane (100 ml). The solution was cooled to −78° C., and to the solution, a solution of 3-chloroperbenzoic acid (0.14 g) in dichloromethane (3 ml) was added dropwise. The mixture was stirred for 1 hour at −78° C., and to the mixture was added sodium thiosulfate solution, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(5,6-dimethyl-1,2,4-triazin-3-yl)methylsulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 37) (0.20 g) as yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18]([N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[O:19])=[C:16]([OH:29])[CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[OH-:32].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18]([N:20]([CH:24]([CH3:25])[CH3:26])[CH:21]([CH3:23])[CH3:22])=[O:19])=[C:16]([CH:15]=2)[O:29][C:17]([CH3:27])([CH3:16])[C:18]([OH:19])=[O:32])=[CH:30][CH:31]=1)#[N:2]
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1O)C(C)C
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1OC(C)(C)C(=O)O)C(C)C

Procedure:
A stirred solution of 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide (5.7 g, 13.4 mmol) in 50 mL of acetone is treated with sodium hydroxide (5.4 g, 134 mmol) and heated to reflux. The reaction is treated slowly with chloroform (1.4 mL, 17.4 mmol) in 150 mL of acetone and refluxed for 4 hours. The reaction is concentrated in vacuo and the residue is partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase is washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting material is purified by chromatography on silica gel (200 g) with 0-10% methanol/ethyl acetate as the eluent to afford 2-[5-[5-(4-cyanophenoxy)pentyloxy]-2-[N,N -bis(1-methylethyl)aminocarbonyl]phenoxy]-2-methylpropanoic acid as a colorless foam.
Reaction SMILES: Br[C:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[O:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[C:15]#[N:16].CC1(C)C(C)(C)OB([C:28]2[CH:45]=[CH:44][C:31]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:30][CH:29]=2)O1>C1(C)C=CC=CC=1.O.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]>[CH3:8][C:5]1([CH3:9])[O:4][C:3]([C:10]2[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=2)[C:15]#[N:16])=[C:2]([C:28]2[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:44][CH:45]=2)[C:6]1=[O:7]
Reactant: COc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1C#N
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)C(C)(C)O2)cc1C#N
Yield: 56.4 %

Procedure:
A solution of 5-(3-bromo-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile (0.15 g, 0.465 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (0.17 g, 0.465 mmol), and Cs2CO, (0.75 g, 2.32 mmol) in toluene (6 mL) and water (3 mL) was degassed. Then, Pd(dppf)Cl2 (0.76 g, 0.090 mmol) was added under an inert atmosphere and the solution was again degassed. The reaction was then refluxed for 2 h, filtered through a pad of Celitc® and the filtrate was diluted with EtOAc (40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile (125 mg, 58%) as a pale yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.43 (d, J=8.5 Hz, 1H), 8.02 (t, J=7.9 Hz, 2H), 7.90 (s, 1H), 7.81-7.77 (m, 2H), 7.70 (d, J=8.2 Hz, 1H), 7.62 (t, J=8.2 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.19 (d, J=7.4 Hz, 2H), 7.12 (d, J=7.5 Hz, 2H), 5.40 (s, 2H), 3.95 (s, 3H), 1.46 (s, 6H). MS: [M+Na]: m/z=499.3, [M+H]: m/z=477.2. HPLC: 98%, Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][N:6]=1.[O:13]1CCOC[CH2:14]1>CO.CCOC(C)=O.O>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[NH:12])[O:13][CH3:14])=[CH:7][N:6]=1
Reactant: C1COCCO1
Reactant: N#Cc1ccc(Cl)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=N)c1ccc(Cl)nc1

Procedure:
Sodium methoxide (725 mg, 13.42 mmol) was added to a solution of 2-Chloro pyridine-5-carbonitrile (1.8 g, 13.04 mmol) in MeOH:dioxane (40 ml, 1:1) at 0° C., then stirred for 30 minutes at 0° C., and 1 hour at room temperature. The reaction was diluted with EtOAc (200 ml) and H2O (100 ml), organic layer separated, dried over Na2SO4, filtered and solvent evaporated to yield title compound 1BX as a white solid (2.6 g, 100%) MS (MH 171)
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=O)[NH:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[CH2:2]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:28]2)=CC=1>C1(C)C=CC=CC=1>[CH2:1]1[N:12]2[C:13]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[S:28])[NH:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2ccccc2N2CCc3cccc1c32
Solvent: Cc1ccccc1
Product: S=C1Nc2ccccc2N2CCc3cccc1c32
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To 1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one (67 g) in 1 l of toluene, under nitrogen, was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (45 g). The mixture was refluxed for 1 hr and allowed to stand overnight. The precipitate was collected and recrystallized from chloroform to afford 43 g, (60.2%) of product, mp 185°-186° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]([OH:15])=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:37]1[C:46]2[C:41](=[C:42]([NH2:48])[C:43]([NH2:47])=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[NH2:48][C:42]1[C:43]([NH:47][C:13](=[O:15])[CH2:12][CH2:11][C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:44][CH:45]=[C:46]2[C:41]=1[CH:40]=[CH:39][CH:38]=[N:37]2.[NH2:47][C:43]1[C:42]([NH:48][C:13](=[O:14])[CH2:12][CH2:11][C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[C:41]2[C:46](=[CH:45][CH:44]=1)[N:37]=[CH:38][CH:39]=[CH:40]2
Reactant: O=C(O)CCc1cnc2ccccc2n1
Reactant: Nc1ccc2ncccc2c1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Nc1c(NC(=O)CCc2cnc3ccccc3n2)ccc2ncccc12
Product: Nc1ccc2ncccc2c1NC(=O)CCc1cnc2ccccc2n1
Reaction time: 0.5 h

Procedure:
To a solution of 3-(quinoxalin-2-yl)propanoic acid (550 mg, 2.7 mmol) in DCM (30 mL) was added HOBt (550 mg, 4 mmol) and EDCI (780 mg, 4 mmol). After stirring for 30 minutes, quinoline-5,6-diamine (430 mg, 2.7 mmol) was added and the reaction was stirred for 3 hours. The mixture was washed with water (10 mL) and extracted with DCM (30 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford a yellow mixture which was purified by reverse phase chromatography. N-(5-Aminoquinolin-6-yl)-3-(quinoxalin-2-yl)propanamide (180 mg) and N-(6-aminoquinolin-5-yl)-3-(quinoxalin-2-yl)propanamide (80 mg) were isolated. MS (ESI) m/z 343 (M+H+).