Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:7][CH:6]=[CH:5]2.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[C:25]1[C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)=[C:28]([CH:47]([CH3:49])[CH3:48])[O:27][N:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.O1CCOCC1>[Cl:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[C:19]=1[C:25]1[C:29]([CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:7][CH:6]=[CH:5]4)=[CH:36][CH:37]=2)=[C:28]([CH:47]([CH3:49])[CH3:48])[O:27][N:26]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCOC(=O)c1nccc2cc(Br)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1nccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Temperature: 60 °C
Yield: 42.7 %

Procedure:
Palladium(II)acetate (2.5 mg, 11.2 μmol) was added to ethyl 6-bromo-1-isoquinolinecarboxylate (62.7 mg, 223.8 μmol), 3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-({[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxy}methyl)isoxazole (109.3 mg, 223.8 μmol), triphenylphosphine (5.9 mg, 22.4 μmol), and potassium phosphate (166.3 mg, 783.4 μmol). Then, dioxane (2.2 mL) was added to the mixture, followed by water (22.4 μL), and the reaction mixture was heated open to the atmosphere at 60° C. in an oil bath for 67 hours, then allowed to cool to room temperature. Water was added, followed by ethyl acetate, and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 2:3 ethyl acetate:hexanes to give 53.6 mg (43%) of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-isoquinolinecarboxylate as an oil. 1H NMR (400 MHz, d6-DMSO): δ 8.56 (d, J=5 Hz, 1H), 8.47 (d, J=9 Hz, 1H), 8.30 (s, 1H), 8.08-8.03 (m, 2H), 7.75 (d, J=9 Hz, 2H), 7.65-7.60 (m, 2H), 7.55 (dd, J=9, 7 Hz, 1H), 6.95 (d, J=9 Hz, 2H), 4.90 (s, 2H), 4.47 (q, J=7 Hz, 2H), 3.48 (septet, J=7 Hz, 1H), 1.38 (t, J=7 Hz, 3H), 1.34 (d, J=7 Hz, 6H). ESI-LCMS m/z 560 (M+H)+.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.[S:10]1[C:14]([CH:15]=[O:16])=[CH:13][N:12]=[CH:11]1>>[S:10]1[C:14]([C:15]([C:2]2[N:3]=[CH:4][N:5]3[CH:9]=[CH:8][S:7][C:6]=23)=[O:16])=[CH:13][N:12]=[CH:11]1
Reactant: Ic1ncn2ccsc12
Reactant: O=Cc1cncs1
Product: O=C(c1cncs1)c1ncn2ccsc12
Yield: 75.6 %

Procedure:
7-(Thiazol-5-yl)carbonylimidazo[5,1-b]thiazole (187 mg) was prepared in the same manner as in step a) of Synthesis Example 3, except that 265 mg of 7-iodoimidazo[5,1-b]thiazole and 119 mg of thiazole-5-aldehyde were used as the starting compounds.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][C:15]([NH:20]C(=O)OC(C)(C)C)=[CH:16][CH:17]=3)[C:12]=2[NH:28][C:29]([C@H:31]2[CH2:36][CH2:35][C@H:34]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:33][CH2:32]2)=[O:30])=[O:10])=[N:6][CH:7]=1.Cl.O1CCOCC1.CO>O1CCOCC1>[NH2:20][C:15]1[N:14]=[C:13]2[C:12]([NH:28][C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH2:33][CH2:32]3)=[O:30])=[C:11]([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])[O:19][C:18]2=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4)CC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl (2-{[(5-chloropyridin-2-yl)amino]carbonyl}-3-{[(trans-4-pyrrolidin-1-ylcyclohexyl)carbonyl]amino}furo[3,2-b]pyridin-5-yl)carbamate (280 mg) obtained in Example 96 is suspended in dioxane (3 ml). To the suspension is added 4 N hydrogen chloride-dioxane solution (3 ml). The reaction solution is warmed to room temperature, and thereto is added methanol (2 ml), followed by stirring for 8 hours. The reaction solution is concentrated under reduced pressure, and the resulting residue is suspended in diethyl ether. The precipitates are collected by filtration to give the title compound (266 mg) as hydrochloride. The resulting hydrochloride is suspended in chloroform and thereto is added saturated aqueous sodium hydrogen carbonate solution. The precipitated solid is collected by filtration to give the title compound (88 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1[C:19](OCC)=[O:20].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][C:26]=1[S:39]([NH2:42])(=[O:41])=[O:40]>C1(C)C=CC=CC=1>[NH2:42][S:39]([C:26]1[CH:27]=[C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:30][C:25]=1[NH:24][C:19]([C:3]1[C:4](=[O:18])[C:5]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[OH:1])=[O:20])(=[O:40])=[O:41]
Reactant: Nc1ccc(OCc2ccccc2)cc1S(N)(=O)=O
Reactant: CCCC1(CCC)C(=O)C(C(=O)OCC)=C(O)c2ccccc21
Solvent: Cc1ccccc1
Product: CCCC1(CCC)C(=O)C(C(=O)Nc2ccc(OCc3ccccc3)cc2S(N)(=O)=O)=C(O)c2ccccc21
Yield: 102.8 %

Procedure:
A suspension of the product of Example 1F (617 mg, 1.95 mmol) and the product of Example 2D (542 mg, 1.95 mmol) in toluene (20 mL) was stirred at reflux for 18 hours and concentrated in vacuo to afford the title compound (1.1 g, 100%). 1H NMR (300 MHz, CDCl3): δ 17.85 (d, J=12.13 Hz, 1 H), 12.49 (s, 1 H), 12.35 (s, 1 H), 8.32 (d, J=6.62 Hz, 1 H), 8.18 (m, 1 H), 7.98 (d, J=9.19 Hz, 1 H), 7.66 (m, 2 H), 7.42 (m, 3 H), 7.27 (m, 4 H), 5.49 (s, 1 H), 5.37 (s, 1 H), 5.07 (d, J=30.89 Hz, 2 H), 2.31 (m, 2 H), 1.86 (m, 2 H), 0.94 (m, 2 H), 0.72 (m, 8 H).
Reaction SMILES: [OH-:1].[K+].[CH3:3][O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]1[C:16]2[O:15][C:14](=[O:17])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>CO>[OH:15][C:16]1[C:8]([O:7][C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH3:3])=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:13][C:14]([OH:1])=[O:17]
Reactant: [OH-]
Reactant: COc1ccccc1Oc1cccc2c1OC(=O)C2
Agent: [K+]
Solvent: CO
Product: COc1ccccc1Oc1cccc(CC(=O)O)c1O
Reaction time: 3 h
Yield: 71.9 %

Procedure:
A solution of potassium hydroxide (1.3 g) in methanol (30 ml) was added to a solution of 7-(2-methoxyphenoxy)-2,3-dihydrobenzofuran-2-one (1.3 g) in methanol (30 ml), and allowed to stand at room temperature for 3 hrs. Methanol was distilled off from the reaction mixture, and the residue was dissolved in water. The aqueous solution was acidified with conc. hydrochloric acid, and the precipitating crystals were collected by filtration, washed with water, dried and then recrystallized from a mixture of ethyl acetate and n-hexane to give 2-[2-hydroxy-3-(2-methoxyphenoxy)phenyl]acetic acid (1.0 g). mp 125°-126° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[Br:13]N1C(=O)CCC1=O>C(O)(=O)C>[Br:13][C:4]1[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[CH3:12]
Reactant: CC(=O)c1cc(Cl)c(C)cc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(5-chloro-2-hydroxy-4-methylphenyl)ethanone (10.0 g, 54.2 mmol) in acetic acid (100 mL) was added N-bromosuccinimide (11.6 g, 65.0 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, then neutralized with sat. sodium bicarbonate, insoluble succinimide filtered off and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and then concentrated to dryness under reduced pressure. The crude product was recrystalized from a mixture of ethyl acetate and hexane (11.42 g, 80%). 1H NMR (CDCl3, 300 MHz) δ 12.96 (1H, s), 7.72 (1H, s), 2.64 (3H, s), 2.59 (3H, s) ppm.
Reaction SMILES: C(O)(C(F)(F)F)=O.Br[C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[C:32]([CH:39]=[O:40])[CH:31]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=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.CO.CC#N>[CH:18]1([C:17]2[C:16]3[C:11](=[CH:12][C:13]([C:24]([O:26][CH3:27])=[O:25])=[CH:14][CH:15]=3)[N:10]3[CH:39]([OH:40])[C:32]4[C:33]([C:9]=23)=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=4)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
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: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C(O)c1cc(OC)ccc1-3
Temperature: 100 °C
Yield: 61.5 %

Procedure:
The general methods below were used with the following experimental procedures until indicated otherwise: LCMS data: Stop time: Gradient time+1 minute; Starting conc: 0% B unless otherwise noted; Eluent A: 5% CH3CN/95% H2O with 10 mM NH4OAc (for columns A and D); 10% MeOH/90% H2O with 0.1% TFA (for columns B and C); Eluent B: 95% CH3CN/5% H2O with 10 mM NH4OAc (for columns A and D); 90% MeOH/10% H2O with 0.1% TFA (for columns B and C); Column A: Phenomenex 10 4.6×50 mm C18; Column B: Phenomenex C18 10 3.0×50 mm; Column C: Phenomenex 4.6×50 mm C18 10μ; Column D: Phenomenex Lina C18 5μ 3.0×50 mm; Column E: Phenomenex 5μ 4.6×5.0 mm C18. To a slurried solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (4.3 g, 13 mmol), 4-methoxy-2-formylphenylboronic acid (3.0 g, 17 mmol) and LiCl (2.2 g, 51 mmol) in EtOH/toluene (1:1, 100 mL) was added Pd(PPh3)4 (1.4 g, 1.3 mmol) and then 1M Na2CO3 (aq.) (32 mL, 32 mmol). The reaction solution was flushed with nitrogen and heated at 100° C. for 3 h and cooled to rt. The reaction was concentrated to remove EtOH, diluted with H2O (200 mL) and extracted with EtOAc (2×150 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated to dryness. The residue was triturated with CH2Cl2 and the solids were collected by filtrated and washed with Et2O and CH2Cl2 to yield methyl 11-cyclohexyl-6-hydroxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxylate (3.0 g, 8.0 mmol, 63%) as a yellow solid which was used without further purification. LCMS: m/e 374 (M+H)+, ret time 3.09 min, column B, 3 minute gradient.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[K+].[NH2:19]OS(O)(=O)=O>CN(C=O)C>[NH2:19][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([Cl:1])=[CH:3]1
Reactant: NOS(=O)(=O)O
Reactant: Clc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nn1cc(Cl)c2ccccc21
Temperature: 0 °C
Yield: 40.4 %

Procedure:
To a stirred solution of 12.6 g of 3-chloroindole in 125 ml of dry DMF at 0° C. was added 0.5 g of milled K2CO3 in 20 ml of dry DMF, followed by 30 g of KOH in 20 ml of dry DMF. The mixture was cooled to about 0° C. after which was added 13.3 g of NH2OSO3H such that the temperature did not rise above 0° C. When addition was complete, a second charge of 2.22 g of NH2OSO3H was added. When addition was complete a third 2.22 g charge of NH2OSO3H was added. The mixture was poured into ice/water/toluene, extracted into toluene, washed with water and concentrated to provide 5.6 g of an oil which crystallized on standing overnight.
Reaction SMILES: [OH:1][C:2]1[CH2:3][C:4]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][C:6](=[O:8])[CH:7]=1.C[N:23]1CCOCC1.ClC(OC)=O>C(Cl)Cl>[OH:1][C:2]1[CH2:3][C:4]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH2:23])=[O:21])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][C:6](=[O:8])[CH:7]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)CCCCC1(c2ccccc2)CC(O)=CC(=O)O1
Agent: COC(=O)Cl
Solvent: ClCCl
Product: NC(=O)CCCCC1(c2ccccc2)CC(O)=CC(=O)O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 50 mL reaction flask was added 1.2 mmol of 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)pentanoic acid (±), 2.4 mmol of 4-methylmorpholine, and 10 mL of CH2Cl2. The reaction was cooled to 0° C. and 2.4 mmol of methyl chloroformate in 3 mL of CH2Cl2 was added. The reaction was stirred at 0° C. for 2 hours. Ammonia was bubbled into the vessel for 10-15 minutes and the reaction allowed to stir for 30 minutes at 0° C. The reaction was poured into ethyl acetate and 1N HCl, the aqueous layer extracted with ethyl acetate, dried over MgSO4, and concentrated. The crude solid was triturated using CH2Cl2 to afford 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)pentanoic acid amide (±) as a solid (m.p. 173°-174° C.). 1H NMR (DMSO-d6) δ0.8-1.0 (m, 1H), 1.1-1.3 (m, 1H), 1.3-1.5 (m, 2H), 1.8-2.0 (m, 4H), 2.9 (ABq, 2H), 4.8 (s, 1H), 6.6 (s, 1H), 7.2 (s, 1H), 7.2-7.5 (m, 5H), 11.4 (s, 1H).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[C:19]([Cl:26])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:26][C:19]1[C:20]([C:22]([F:23])([F:25])[F:24])=[CH:21][C:7]2[N:6]3[C:2]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1cc2c(cc1Cl)C(c1ccccn1)=NCc1nnc(Br)n1-2
Product: FC(F)(F)c1cc2c(cc1Cl)C(c1ccccn1)=NCc1nnc(N3CCNCC3)n1-2

Procedure:
In the manner given in Example 1, 1-bromo-8-chloro-9-(trifluoromethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess of piperazine to give 8-chloro-9-(trifluoromethyl)-1-piperazino-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:33]([O:35][C:36]([O:38][CH2:39][O:40][C:41](=[O:62])[C@@:42]([CH2:60][OH:61])([CH3:59])[CH2:43][C@H:44]([NH2:58])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:48][CH:47]=1)=[O:37])[CH3:34]>CN(C=O)C.CCN(C(C)C)C(C)C>[CH2:33]([O:35][C:36]([O:38][CH2:39][O:40][C:41](=[O:62])[C@@:42]([CH2:60][OH:61])([CH3:59])[CH2:43][C@H:44]([NH:58][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:45][C:46]1[CH:47]=[CH:48][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:50][CH:51]=1)=[O:37])[CH3:34]
Reactant: O=C(O)c1c[nH]nn1
Reactant: CCOC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)OCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8161.3 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 nmol), DIPEA (86.3 mL, 496 nmol) and HATU (47.1 mg, 124 nmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid ethoxycarbonyloxymethyl ester (51 mg, 120 nmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (5 mg; purity 90%). MS m/z [M+H]+ calc'd for C26H30N4O2, 511.21. found 511.6.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][O:5][CH:6]=1.[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:7]([O:1][C:2]1[CH:3]=[N:4][O:5][CH:6]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Oc1cnoc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(COc2cnoc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture containing 200 mg of 4-hydroxyisoxazole in 10 ml of acetone together with 1.5 equivalents of benzyl bromide and 1.5 equivalents of potassium carbonate is stirred at about 25° C. for five hours. The solid is filtered and the filtrate concentrated to an oil. The crude material is purified by chromatography on silica gel.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8]2)([O-:4])=[O:3].[C:22](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[ClH:1].[N+:2]([C:5]1[CH:13]=[C:12]2[C:8](=[CH:7][CH:6]=1)[CH:9]([NH:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:10]([CH3:22])[CH2:11]2)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(NCc1ccccc1)C2
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CC1Cc2cc([N+](=O)[O-])ccc2C1NCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 5-nitro-2-(phenylmethyl)aminoindane hydrochloride (2.29 g, 7.52 mmol) in DMF (100 ml) was added potassium carbonate (2.60 g, 18.80 mmol) followed by methyl iodide (0.47 ml, 7.52 mmol). The mixture was warmed to room temperature, stirred for 16 hr, dumped into water (400 ml), and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered through a small plug of silica gel and reduced to a syrup. The titled compound was isolated as the hydrochloride salt: (1.08 g, 45%); m.p. dec 280° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:7].[BH4-].[Na+]>C(O)C.C1COCC1>[CH3:1][N:2]([CH3:3])[CH2:5][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])[OH:7]
Reactant: CNC
Reactant: COC(=O)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(O)CN(C)C)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dimethylamine (33% in ethanol, 156 ml) was added to a stirred suspension of methyl 5-(bromoacetyl)-2-(phenylmethoxy)benzoate (105.8 g) in absolute ethanol (1l) and THF (1l). The resulting solution was stirred at RT for 2 h, treated with NaBH4 (25 g) and stirred at RT overnight. The solvent was removed in vacuo and H2O (500 ml) was added to the residue. The mixture was extracted with EA (2×500 ml), the combined extracts were washed with H2O and BR, dried (Na2SO4) and concentrated in vacuo. The product was purified twice by [FCS] eluted with EA-methanol-triethylamine (80:20:1) to give the title compound as a fawn solid (59.8 g) m.p. 79-81°.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])[CH3:8])[CH3:3].CN(C)C=O.[C:27](Cl)(=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C1(C)C=CC=CC=1>[CH2:20]([O:21][C:27](=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])/[CH:19]=[C:17](/[CH2:16][CH2:15][CH2:14][C@@H:12]([CH2:11][CH2:10][CH2:9][C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:8])[CH3:13])\[CH3:18]
Reactant: CCCCCCCC(=O)Cl
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C

Procedure:
To a solution of 3 g phytol (3,7,11,15-Tetramethyl-2-hexadecen-1-ol), 1,5 g dimethyl formamide in 50 ml toluene is being added dropwise during one half hour a solution consisting of 2 g caprylic acid chloride (excess) in 25 ml toluene at 20° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6]1)[OH:4].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>C1COCC1>[CH3:10][C:7]1([CH3:11])[O:6][C@@H:5]([C@@H:3]([OH:4])[CH2:2][NH:1][C:13](=[O:12])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][O:8]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC1(C)OC[C@H]([C@@H](O)CN)O1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H](O)[C@H]1COC(C)(C)O1

Procedure:
Aminoalcohol 23 was dissolved in THF and BOC2O was added and stirred for several hrs. The solvent was removed and the product purified using silica gel chromatography.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]3[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])[CH2:9][CH2:8]1)=[O:6].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.[I-].[K+]>CC(N(C)C)=O>[Cl:33][C:29]1[C:28]([F:34])=[C:27]([CH:32]=[CH:31][CH:30]=1)[NH:26][C:17]1[C:16]2[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH:10]3[CH2:9][CH2:8][N:7]([C:5](=[O:6])[NH:4][CH2:3][CH2:2][N:35]4[CH2:39][CH2:38][CH:37]=[CH:36]4)[CH2:12][CH2:11]3)[CH:15]=2)[N:20]=[CH:19][N:18]=1
Reactant: C1CCNC1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)NCCCl)CC1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)NCCN2C=CCC2)CC1
Temperature: 80 °C
Yield: 35.6 %

Procedure:
A mixture of 6-{[1-(N-(2-chloroethyl)carbamoyl)piperidin-4-yl]oxy}-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline (204 mg, 0.4 mmol), pyrrolidine (0.14 ml, 1.6 mmol) and potassium iodide (134 mg, 0.8 mmol) in dimethylacetamide (3 ml) was heated at 80° C. for 4 hours. After cooling and evaporation of the solvents under vacuum, the residue was partitioned in water, dichloromethane and extracted with dichloromethane. The organic layer was washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvents under vacuum, the residue was purified by chromatography on silica gel (eluant: 3% to 4% 7N methanolic ammonia in dichloromethane) to give the title compound as a white solid (77 mg, 36%).