Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@H:12]([CH3:23])[O:11][C@H:6]1[O:7][CH2:8][CH:9]=C)(=[O:3])[CH3:2].C[N+]1([O-])CC[O:28]CC1>CC(C)=O.O.O=[Os](=O)(=O)=O.C(O)(C)(C)C>[C:1]([O:4][C@H:5]1[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@H:12]([CH3:23])[O:11][C@H:6]1[O:7][CH2:8][CH:9]=[O:28])(=[O:3])[CH3:2]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCO[C@@H]1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](OCC=O)O[C@@H](C)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
To a solution of prop-2-en-1-yl 2,3,4-tri-O-acetyl-α-L-fucopyranoside (1.34 g, 4.06 mmol) in acetone (30 mL) and water (7.5 mL) was added 4-methylmorpholine 4-oxide (950 mg, 8.11 mmol) followed by the addition of 2.5% OsO4 in tert-butanol (2.04 mL, 0.162 mmol). The mixture was allowed to stir at rt for 16 hr. To the resulting mixture was then added a solution of NaIO4 (1.74 g, 8.11 mmol) in water (15 mL). After stirring for additional 4 hr, the precipitate was filtered and washed with acetone (50 mL). The volume of the filtrate was reduced to approximately ⅓ of the initial volume and then diluted with sat. NaHCO3 (100 mL). The mixture was extracted with EtOAc (3×50 mL). The organic phases were combined and washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (Teledyne Isco: 120 g), eluting with 0-80% EtOAc in hexanes to give the title compound (660 mg, 49%). 1H NMR (CDCl3) δ 9.72 (1H, s), 5.44 (1H, dd, J=10.9 and 3.3 Hz), 5.35 (1H, dd, J=3.4 and 1.8 Hz), 5.19 (1H, dd, J=10.9 and 3.8 Hz), 5.13 (1H, d, J=3.8 Hz), 4.26 (3H, m), 2.19 (3H, s), 2.15 (3H, s), 2.02 (3H, s), 1.17 (3H, d, J=6.6 Hz).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:17][C:16]3([CH3:19])[CH2:18][CH:12]2[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15]3)=[O:10])=[CH:5][CH:4]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:17][C:16]3([CH3:19])[CH2:18][CH:12]2[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15]3)=[O:10])=[CH:5][CH:4]=1)[S:23]([CH3:22])(=[O:25])=[O:24]
Reactant: CNc1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN(c1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1)S(C)(=O)=O
Reaction time: 4 h
Yield: 50.6 %

Procedure:
To a mixture of (4-methylamino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (0.7 g, 2.44 mmol), DCM (40 ml) and TEA (0.7 ml, 4.89 mmol) was added methansulfonyl chloride (285 μl, 3.67 mmol). The resulting mixture was stirred for 4 hrs. at room temperature followed by evaporation of the volatiles in vacuo. The residue was dissolved in diethyl ether (10 ml), washed with water (2×10 ml) evaporated and the residue purified by column chromatography (silica gel) using a mixture of EtOAc-Heptane (1:1) as eluent. Pure fractions were collected and evaporated to dryness. The residue was crystallized from diethyl ether (10 ml), filtered off and dried in vacuo at 50° C. affording 0.45 g (51%) of the title compound as a solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCCO4)c12
Reactant: c1c[nH]cn1
Product: Cc1csc2nc(-n3ccnc3)nc(NCc3ccc4c(c3)OCCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C@H:24]1[CH2:28][CH2:27][C@@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]1>ClCCl>[O:23]=[C:24]1[CH2:28][CH2:27][C@@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCC(=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
Dess-Martin periodinane (961 mg, 2.27 mmol) was added portionwise to a solution of tert-butyl (1R,3S)-3-hydroxycyclopentylcarbamate (380 mg, 1.89 mmol) in dichloromethane (10 mL) at 0° C. After complete addition, the reaction mixture was stirred for 1 hour at 0° C., then, allowed to warm up to room temperature and stirred for 18 hours. The reaction mixture was quenched with a 50/50 of a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium thiosulfate. The aqueous layer was extracted 3 times with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to give the title compound (316 mg, 84% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([OH:14])[CH:13]=2)[N:6]=[C:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:4]=1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>>[C:16]([C:5]1[CH:4]=[C:3]([NH2:2])[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:13]=2)[N:6]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1O[Si](C)(C)C(C)(C)C
Yield: 86 %

Procedure:
The title compound was prepared from 5-[5-amino-3-(1,1-dimethylethyl)-1H-pyrazol-1-yl]-2-methyl-phenol hydrochloride (WO 03/005999, p 81-p 82) and tert-butyldimethylsilyl chloride, using the same method as that described for preparation 99, as a solid in 86% yield.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20]([O:22]CC)=O.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CC(N(C)C)=O>[CH:25]1([NH:28][C:20]([C:3]2[C:4](=[O:19])[NH:5][C:6]3[C:11]([C:2]=2[OH:1])=[N:10][CH:9]=[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=3)=[O:22])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Solvent: CC(=O)N(C)C
Product: O=C(NC1CC1)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclopropylamine employing methods similar to those described in Example 5 and using dimethylacetamide as the reaction solvent. The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.86 (1H, s), 10.87 (1H, s), 10.14 (1H, s), 8.20 (1H, s), 7.38-7.25 (6H, m), 4.01 (2H, br s), 2.79 (1H, m), 0.70 (2H, m), 0.45 (2H, m); HRMS calcd for C19H17N3O3+H+: 336.1348. Found: 336.1347.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:3]=1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>[Pd].C(O)(=O)C>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:4]2[C:3]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[CH:2][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=3)[N:5]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)c(Cl)c2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)cc2c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A suspension of ethyl 4-chloro-2,3-bis(4-methoxyphenyl)quinoline-6-carboxylate (150 mg, 0.33 mmol, 1.00 equiv), acetic acid (10 mL), NH4OAc (102 mg, 1.67 mmol, 5.00 equiv), and palladium on carbon (150 mg) were placed in a 25-mL round-bottom flask and stirred overnight at 40° C. in an oil bath under an atmosphere of H2(g). The resulting mixture was concentrated, then diluted with 30 ml of ethyl acetate and washed with 10 ml of NaHCO3 (aq.). The organic layer was concentrated in vacuo and purified via silica gel chromatography (PE:EA=30:1) affording 100 mg of ethyl 2,3-bis(4-methoxyphenyl)quinoline-6-carboxylate as yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH:9]=[CH:10][CH3:11].[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[CH:20]([CH3:22])[CH3:21]>CN(C)C=O>[CH2:8]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([Cl:12])=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:15]=1)[CH:9]=[CH:10][CH3:11]
Reactant: CC(C)c1cc(N)ccc1Cl
Reactant: CC=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=CCNc1ccc(Cl)c(C(C)C)c1
Reaction time: 1 h

Procedure:
2.8 g of anhydrous potassium carbonate and 2.0 g of -chloro-2-butene were added to 3.2 g of 4-chloro-3-isopropylaniline in 15 ml of N,N-dimethylformamide, followed by stirring at 70°-90° C. for 1 hour. After potassium carbonate was removed by filtration, 100 ml of water were added, and extraction was then carried out with toluene. After drying over anhydrous sodium sulfate, the reaction solution was concentrated by means of an evaporator, and silica gel chromatography was then done to obtain 1.5 g of the desired compound.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][CH:11]3[C:26](=[O:27])[N:14]4[CH2:15][CH2:16][N:17]([C:19](OC(C)(C)C)=[O:20])[CH2:18][CH:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)C(Cl)=O.C(N(CC)CC)C>O1CCOCC1.C(Cl)Cl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][CH:11]3[C:26](=[O:27])[N:14]4[CH2:15][CH2:16][N:17]([C:19](=[O:20])[C:38]5[CH:37]=[CH:33][CH:32]=[C:31]([C:30]([F:41])([F:40])[F:29])[CH:39]=5)[CH2:18][CH:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)C(Oc3cnc(C4CC4)cn3)CC2C1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(c1cccc(C(F)(F)F)c1)N1CCN2C(=O)C(Oc3cnc(C4CC4)cn3)CC2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.4 %

Procedure:
To a solution of the product from Example 205C (40 mg, 0.107 mmol) in 1,4-dioxane (0.5 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (0.5 mL, 2.0 mmol). The resulting mixture was stirred at room temperature for 90 minutes, and then it was concentrated in vacuo. To the residue was added CH2Cl2 (1 mL), 3-(trifluoromethyl)benzoyl chloride (0.020 mL, 0.130 mmol), and triethylamine (0.045 mL, 0.324 mmol), and the resulting mixture was stirred at ambient temperature for 90 minutes. The mixture was partitioned between water and CH2Cl2, and the organic layer was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-5% methanol in dichloromethane to give the title compound (36 mg, 75%). 1H NMR (300 MHz, CDCl3) δ ppm 0.88-1.02 (m, 4 H) 1.37-3.27 (m, 6 H) 3.55-3.93 (m, 2 H) 4.07-4.31 (m, 1 H) 4.64-5.14 (m, 1 H) 5.49-5.68 (m, 1 H) 7.56-7.67 (m, 2 H) 7.68-7.80 (m, 2 H) 7.94 (s, 1 H) 8.08-8.20 (m, 1 H); MS (ESI) m/z 447 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6]2.[H-].[Na+].Cl[CH2:21][C:22]1[O:23][CH:24]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[N:26]=1.[Cl-].[NH4+]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:21][C:22]1[O:23][CH:24]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[N:26]=1)[C:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[CH:6]2
Reactant: COc1ccc2[nH]c(-c3ccccc3)cc2c1
Reactant: COC(=O)c1coc(CCl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1coc(Cn2c(-c3ccccc3)cc3cc(OC)ccc32)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a solution of 5-methoxy-2-phenylindole (205 mg) in N,N-dimethylformamide (4.6 mL) was added sodium hydride (in oil, 50 to 72%, 55 mg) under cooling with ice and an argon atmosphere, and the mixture was stirred at room temperature for 2 hours. Then methyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate (193 mg) was added, and the mixture was stirred at 80° C. for 22 hours. The reaction mixture was allowed to cool to ambient temperature. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (229 mg).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]([C:18](=[O:36])[C@H:19]([CH3:35])[NH:20][C@H:21]([C:32]([OH:34])=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(C)(C)C.C(OCC)(=O)C.[ClH:44].C(OCC)C>C(O)(=O)C.C(OCC)(=O)C>[ClH:44].[ClH:44].[C:32]([C@@H:21]([NH:20][C@H:19]([C:18]([N:8]([CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)[CH2:7][C:6]([OH:37])=[O:5])=[O:36])[CH3:35])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([OH:34])=[O:33]
Reactant: C[C@H](N[C@@H](CCCCC1CCNCC1)C(=O)O)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[C@H](N[C@@H](CCCCC1CCNCC1)C(=O)O)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 1 h

Procedure:
In a mixture of 2 ml of acetic acid and 2 ml of ethyl acetate is dissolved 0.28 g of N-[N-[(S)-5-(4-piperidyl)-1-carboxypentyl]-L-alanyl]-N-(indan-2-yl)glycine tert-butyl ester, and 5 ml of 5N hydrogen choride-ethyl acetate solution is added to the solution, followed by standing at room temperature for 1 hour. 100 ml of ethyl ether is added to the reaction solution, and the precipitate which separates out is colleted by filtration to give 0.22 g of N-[N-[(S)-1-carboxy-5-(4-piperidyl)pentyl]-L-alanyl]-N-(indan-2yl)glycine.dihydrochloride as a colorless powder.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][C:10](=[O:69])[NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26](=[O:68])[NH:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:67]=[CH:66][C:35]([C:36]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][CH2:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][CH2:57][NH:58]C(=O)OC(C)(C)C)=[CH:40][CH:39]=2)=[O:37])=[CH:34][CH:33]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:58][CH2:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][CH2:45][NH:44][C:41]1[CH:40]=[CH:39][C:38]([C:36]([C:35]2[CH:66]=[CH:67][C:32]([O:31][CH2:30][CH2:29][CH2:28][NH:27][C:26](=[O:68])[CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][NH:11][C:10](=[O:69])[CH2:9][CH2:8][N:3]3[C:4](=[O:7])[CH:5]=[CH:6][C:2]3=[O:1])=[CH:33][CH:34]=2)=[O:37])=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NCCCOCCOCCOCCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCN3C(=O)C=CC3=O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCOCCOCCOCCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCN3C(=O)C=CC3=O)cc2)cc1
Reaction time: 1 h
Yield: 108.5 %

Procedure:
tert-butyl (3-(2-(2-(3-((4-(4-((1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,19-dioxo-7,10,13,16-tetraoxa-4,20-diazatricosan-23-yl)oxy)benzoyl)phenyl)amino)propoxy)ethoxy)ethoxy)propyl)carbamate (6.31 g, 6.50 mmol) was dissolved in a solution of DCM:TFA (2:1, 60 ml) and stirred ca. 1 h. Upon completion, reaction was then concentrated under reduced pressure, co-evaporated with toluene, and dried on oil pump for 2 hs to yield 6.15 g of crude N-(3-(4-(4-((3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)-amino)benzoyl)phenoxy)propyl)-1-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3,6,9,12-tetraoxapentadecan-15-amide as yellow oil. The crude product was used without any further purification.
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]3=[O:31])[C@H:26]([O:37][C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:39])[C@@H:25]2[O:48][C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:50])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>ClCCl>[CH2:41]([O:40][C:38]([O:37][C@@H:26]1[C@H:25]([O:48][C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:50])[C@@H:24]([CH2:23][OH:22])[O:28][C@H:27]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OC(=O)OCc3ccccc3)[C@@H]2OC(=O)OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)O[C@@H]1[C@H](OC(=O)OCc2ccccc2)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
To a solution of the compound 4u (370 mg, 460 μmol) in dichloromethane (50 mL) was added DCA (1.5 mL). The mixture was stirred for 10 minutes, and washed with 5% aqueous NaHCO3 (3×50 mL). The aqueous layer was back-extracted with dichloromethane (10 mL), and the combined organic layer was dried over Na2SO4, filtered to separate Na2SO4, and dried under reduced pressure. The residue was purified by silica gel chromatography (eluent: 0 to 4% methanol in dichloromethane) to give the objective compound 5u (200 mg, 87%) as white foam.
Reaction SMILES: [N:1]([C@@H:4]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[O:6][C@@H:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N+]=[N-].Cl>C(O)C.[Pd]>[NH2:1][C@@H:4]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[O:6][C@@H:5]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: [N-]=[N+]=N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of (2R,3S)-3-azido-2-phenyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (64d) (1.128 g, 4.024 mmol)) in ethanol (80 mL) was added 1N hydrochloric acid (4.43 mL) and 5% palladium on carbon (60 mg). The reaction was purged with hydrogen and stirred for 2 h under a balloon of hydrogen. The reaction was purged with nitrogen then filtered through diatomaceous earth. The solvent was evaporated to afford a white solid that was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate while stirring. The organic phase was separated and the aqueous phase extracted an additional two times with ethyl acetate. The combined organic extracts were dried, filtered and evaporated to afford the title compound (973 mg, 95%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ1.36 (br, 2H), 3.93 (d, 1H, J=6.2 Hz), 5.45 (d, 1H, J=6.2 Hz), 7.06-7.22 (m, 4H), 7.32-7.46 (m, 5H), 9.96 (br, 1H). MS APCI, m/z=255 (M+1). LC/MS: 1.29 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(C(C)C)CC)(C)C.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([C:4]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:5])=[CH:7][C:8]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:9]([CH:10]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(C(=O)OCc2ccccc2)cc1Cl
Reactant: C1COCCN1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-5-[(phenylmethyl)oxy]-4-{[(phenylmethyl)oxy]carbonyl}benzoic acid (may be prepared as described in Description 63; 480 mg, 1.21 mmol) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (0.63 ml, 3.63 mmol), morpholine (0.13 ml, 1.45 mmol), 1-hydroxy-7-azabenzotriazole (198 mg, 1.45 mmol) and EDC (417 mg, 2.18 mmol). The solution was stirred for 18 hours. Water (10 ml) and ethyl acetate (15 ml) were added and the organic layer was separated. The organic layer was washed further with water (2×10 ml), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (SiO2, 1:1 cyclohexane/ethyl acetate) gave the title compound as an orange solid. 381 mg.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[OH:18][C:19]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][C:20]=1[NH2:21]>>[OH:18][C:19]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: CC(C)c1ccc(O)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: CC(C)c1ccc(O)c(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyridinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol) and 2-hydroxy-5-isopropylaniline (35 mg, 0.231 mmol) similar to Example 185 and was isolated as a solid (32 mg, 55%). 1H NMR (DMSO-d6): 8.74 (s, 1H), 8.73 (d, J=0.9 Hz, 1H), 8.35 (d, J=7.8 Hz, 2H), 7.95 (t, J=8.1 Hz, 2H), 7.54 (m, 2H), 6.60 (m, 2H), 2.78 (sep, J=6.9 Hz, 1H), 1.20 (d, J=6.9 Hz, 6H).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[O:21]1CCOCC1>>[C:14]1([P:7](=[O:21])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C1COCCO1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate 2 (25.72 g, 40 mmol) was suspended in a solution of triphenylphosphine (10.94 g, 41.7 mmol) and 5% aqueous hydrochloric acid (2 mL) in 1,4-dioxane (200 mL). Stirring at room temperature in a stoppered flask for 2 h produced a solution of the product 3 and triphenylphosphine oxide. The reaction was worked up with ether and brine giving a solid from which 3 was extracted with hexanes at room temperature. The yield of 3 was 26.58 g (82.4 mmol, 103%).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH:13]1[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]1
Reactant: Nc1ccccc1I
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCC(Nc2ccccc2I)CC1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 2-iodoaniline (1.0 g, 4.57 mmol) in 15 mL 1,2-dichloroethane was treated with 1-methylpiperidin-4-one (530 μL, 4.57 mmol) followed by sodium triacetoxyborohydride (1.55 g, 7.31 mmol) then acetic acid (259 μL). The suspension was stirred at room temperature for 21 hours. After this time, the mixture was cooled to 0° C., quenched with 20 mL 1N NaOH and extracted with 2×100 mL CH2Cl2. The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2. A light yellow oil was obtained (579 mg, 40.2%). 1H-NMR (CDCl3) δ 7.64 (dd, J=1.2, 8.1 Hz, 1H), 7.21-7.15 (m, 1H), 6.57 (d, J=8.1 Hz, 1H), 6.44-6.39 (m, 1H), 4.12-4.10 (m, 1H), 3.37-3.35 (m, 1H), 3.79-2.75 (m, 2H), 2.31 (s, 3H), 2.22-2.03 (m, 4H), 1.65-1.53 (m, 2H). MS (ESI): 317.1 (M+1, 100%).