Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([CH:13]([CH2:19][CH2:20][CH3:21])[C:14](OCC)=[O:15])[CH2:8]1.O1CCCC1.[BH4-].[Li+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([CH:13]([CH2:19][CH2:20][CH3:21])[CH2:14][OH:15])[CH2:8]1
Reactant: CCCC(C(=O)OCC)N1CC(COc2cccc(Cl)c2)OC1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(CO)N1CC(COc2cccc(Cl)c2)OC1=O
Yield: 57.5 %

Procedure:
A procedure similar to that described in Preparation 5 was repeated, except that 4.38 g of ethyl 2-[5-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]pentanoate (less polar isomer), obtained as described in Preparation 96, 40 ml of anhydrous tetrahydrofuran, 0.39 g of lithium borohydride and 0.29 g of anhydrous methanol were used, to give 2.22 g of the title compound, melting at 79° C. to 81° C., from the less polar diastereomer.
Reaction SMILES: C1(C)C=CC(S([O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=O)=O)=CC=1.[CH3:22]CN(CC)CC.[N:29]12[C:35](=[O:36])[CH2:34][CH:33]1[CH2:32][C:31](=O)[CH:30]2[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>C(Cl)Cl>[C:19]1([CH3:22])[C:14]([S:11]([O:10][C:31]2[CH2:32][CH:33]3[N:29]([C:35](=[O:36])[CH2:34]3)[C:30]=2[C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])(=[O:12])=[O:13])=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-Toluenesulfonic anhydride (33 mg, 0.1 mmol) and Et3N (17 μl, 0.12 mmol) are added to a solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (26 mg., 0.1 mmol) in anhydrous CH2Cl2 (2 ml). The resulting solution is stirred at room temperature for 2 hours. The mixture is diluted with CH2Cl2 (10 ml), washed with H2O (2×5 ml), pH 3 phosphate buffer (5 ml) and 5% NaHCO3 (5 ml), dried with MgSO4, filtered and evaporated i.v. to provide benzyl 3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:20]1)=[O:17])C.[OH-].[Na+].Cl>C(O)C>[C:36]([O:35][C:33]([N:21]1[CH2:22][C@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:24][C@H:19]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:16]([C:8]2[N:7]([CH2:6][CH2:5][C:4]([OH:44])=[O:3])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)=[O:17])[CH2:20]1)=[O:34])([CH3:37])([CH3:39])[CH3:38]
Reactant: CCOC(=O)CCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCC(=O)O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.1 %

Procedure:
To a solution of tert-butyl(3S, 5R)-3-[{[1-(3-ethoxy-3-oxopropyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (225 mg) in ethanol (5 ml) was added 2M aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 3 days. The reaction mixture was adjusted to pH 7 with 1M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object product (215 mg).
Reaction SMILES: O.[OH-].[Li+].[F:4][CH:5]([F:29])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=1)[C:14]([O:16]C)=[O:15])[CH3:9]>O.C1COCC1>[F:4][CH:5]([F:29])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=1)[C:14]([OH:16])=[O:15])[CH3:9]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)COC(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](COC(F)F)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.6 %

Procedure:
Lithium hydroxide monohydrate (19 mg, 0.45 mmol) in water (2 mL) was added to methyl 3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-[(phenylmethyl)oxy]benzoate (0.11 g, 0.3 mmol) in THF (4 mL) and the mixture stirred at RT for 20 hours. The THF was removed in vacuo and the aqueous layer adjusted to pH3 with citric acid then extracted into ethyl acetate (2×30 mL). The organics were washed with water (30 mL), brine (30 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound (0.1 g).
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(N(CC)CC)C.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1COCC1>[CH3:1][N:2]([S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=1)(=[O:20])=[O:19])[NH2:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N(C)N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
Into a 100 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, and dropping funnel under an atmosphere of nitrogen was added THF (25 mL), methylhydrazine (2.53 g, 2.92 mL, 55 mmol), and triethylamine (4.35 g, 5.99 mL, 55 mmol). The temperature of the mixture was lowered to approximately 5° C. and 4-methylbenzenesulfonyl chloride (9.5 g, 50 mmol) dissolved in 25 mL of THF was added dropwise at a rate such that the temperature did not rise over 10° C. The cooling bath was removed and the mixture was allowed to stir overnight at RT. Ether (100 mL) was added to the reaction mixture and the resulting slurry was washed with water (50 mL), brine (50 mL), dried (Na2SO4), and the solvent was removed in vacuo to give 9.5 g (95% yield) of the title product. 1H NMR (CDCl3) δ 7.7 (d, 2H), 7.4 (d, 2H), 3.6 (s, b, 2H), 2.8 (s, 3H), 2.4 (s, 3H)
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[C:13]1([B:19]([OH:21])O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:22](O)(=O)CC.C=O>C1(C)C=CC=CC=1>[C:13]1([B:19]2[O:21][CH2:22][C:7]3[CH:8]=[CH:9][C:4]([S:3][C:2]([F:11])([F:1])[F:12])=[CH:5][C:6]=3[O:10]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(=O)O
Reactant: OB(O)c1ccccc1
Reactant: Oc1cccc(SC(F)(F)F)c1
Agent: C=O
Solvent: Cc1ccccc1
Product: FC(F)(F)Sc1ccc2c(c1)OB(c1ccccc1)OC2

Procedure:
A mixture of 3-[(trifluoromethyl)thio]phenol (10.0 g, 51.5 mmol), phenylboronic acid (6.91 g, 56.7 mmol), propionic acid (1.92 ml, 25.8 mmol) and paraformaldehyde (1.46 g, 48.7 mmol), and toluene was heated at reflux using a Dean-Stark trap to separate water formed during the reaction. Additional paraformaldehyde was added (3×1 g+7×0.5 g, 0.22 mol) and additional propionic acid was added (2×0.5 ml, 13.4 mmol). The mixture was brought to ambient temperature, quenched with water and extracted with EtOAc. The combined organic layers were washed with Na2CO3 (10%), dried (Na2SO4), filtered and evaporated to dryness (14.0 g). MS m/z (rel. intensity, 70 eV) 310 (M+, 41), 309 (19), 242 (11), 241 (bp), 240 (28), 109 (14).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:23][CH3:24])=[CH:8][C:9]([CH3:22])=[C:10]([C:12](=[O:21])[C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[CH:11]=2)C[CH2:2]1.CCCBr.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:20])[C:13]=1[C:12]([C:10]1[CH:11]=[C:6]([O:5][CH2:4][CH2:1][CH3:2])[C:7]([O:23][CH3:24])=[CH:8][C:9]=1[CH3:22])=[O:21]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCCBr
Product: CCCOc1cc(C(=O)c2c(Cl)cccc2Cl)c(C)cc1OC
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 2,6-dichloro-5'-hydroxy-4'-methoxy-2'-methylbenzophenone (Compound 5; 1.0 g, 3.2 mmol), n-propyl bromide (0.5 g, 4 mmol), potassiumcarbonate (2.8 g, 20 mmol) and ethanol (10 ml) is stirred for 6 h at 80° C., filtered and the filtrate is evaporated in vacuo. The residue is applied onto a flash chromatography column (silica gel, 30 g). Elution with toluene (750 ml) yields Compound 6 as a brown oil, 800 mg, (70.7% y) which slowly crystallizes (mp 73°-75° C.)
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([CH:19]=O)[C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].O.[N+:27]([CH3:30])([O-:29])=[O:28]>>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([CH:19]=[CH:30][N+:27]([O-:29])=[O:28])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=[N+]([O-])C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Yield: 90 %

Procedure:
To a solution of 1- benzenesulphonyl-1H-indole-4-carboxaldehyde (1.9 g, 6.6 mmol) in nitromethane (12 ml) was added ammonium acetate (205 mg, 2.7 mmol) and the resulting mixture was refluxed for 2 hours. Water (50 ml) was added and products were extracted with ethyl acetate (2×100 ml). The combined organic phases were washed with brine (1×30 ml), dried (MgSO4) and concentrated. Flash chromatography (silica gel, dichloromethane-hexane, 75:25) of the residue gave 1.95 g (90%) of the title compound as a pale yellow solid; δH (250 MHz, CDCl3) 8.27 (1H, d, J=13.7 Hz), 8.14 (1H, d, J=8.2 Hz), 7.92-7.87 (2H, m), 7.75 (1H, d, J=3.7 Hz), 7.65 (1H, d, J=13.7 Hz), 7.62-7.34 (5H, m), 6.89 (1H, dd, J=3.7 and 0.9 Hz); m/z (CI) 299 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.S(=O)(=O)(O)O.[N-:17]=[N+]=[N-].[Na+].C(OCC)(=O)C>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:17][CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C1NCCc2cc(Br)ccc21

Procedure:
In benzene (71 ml), 5-bromoindanone (5.47 g) was suspended. The solution was added with concentrated sulfuric acid (14 ml) and the whole was vigorously stirred. Then, the solution was gradually added with sodium azide (2.52 g), followed by stirring at room temperature for 30 minutes. The resultant was added with ethyl acetate, washed with water and a saturated saline solution, and dried with magnesium sulfate. The solvent was distilled off.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8](C(N)=O)[CH:7]=1.C(#[N:27])C>>[NH2:27][C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:15]=[CH:16][C:17]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][N:9]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Oc2ccnc(C(N)=O)c2)cc1F
Reactant: CC#N
Product: CC(C)(C)C(=O)Nc1ccc(Oc2ccnc(N)c2)cc1F
Yield: 70 %

Procedure:
Prepared in a manner similar to that which is described in Step A of Example 91. 4-(3-Fluoro-4-pivalamidophenoxy)picolinamide (110 mg, 0.33 mmol) in acetonitrile (4 mL) was converted to N-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)pivalamide (70 mg, 70% yield). MS(ESI+): m/z 304.21 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([CH2:17][CH2:18][CH2:19][C:20]([N:8]2[CH2:9][CH2:10][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: c1ccc(C2CCN2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCc1ccccc1)N1CCC1c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
A solution of 2-phenylazetidine (266 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 4-phenylbutyryl chloride (456.6 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:5). The fractions containing 4-phenyl-1-(2-phenylazetidin-1-yl)butan-1-one are collected and the solvent is removed in vacuo to give 488 mg of colorless oil.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH2:16][C@@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[C:20]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[CH:21]=[CH:22][CH:23]=2)[CH2:18]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:33][N:30]1[CH2:31][CH2:32][N:27]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:19]=2[CH2:18][C@H:17]([NH:16][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([N:4]4[CH2:3][CH2:2][S:1][CH2:6][CH2:5]4)=[CH:15][CH:14]=2)[CH2:26][CH2:25]3)[CH2:28][CH2:29]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)c1ccc(N2CCSCC2)cc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCSCC4)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Thiomorpholinobenzoic acid (0.25 g, 1.1 mmol) was dissolved in thionyl chloride (25 mL). The excess of thionyl chloride was immediately evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (107 mg, 0.44 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (104 mg, 0.42 mmol) and triethylamine (68 μL, 0.87 mmol) in methylene chloride (35 mL) . After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with diluted aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) as the eluent. Yield: 58 mg (31%) of the title compound as white crystals: mp 190-191° C.; [α]21D −86° (c 0.25, chloroform); EIMS (70 eV) m/z (relative intensity) 450 (2, M+).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:23]CCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]1O.C1CCC(NC2CCCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[NH2:76][C@H:77]([C:90]([NH:92][C@H:93]([C:101]([NH:103][C@H:104]([C:110]([NH:112][C@H:113]([C:122]([NH:124][C@H:125]([C:133]([OH:135])=[O:134])[CH2:126][C:127]1[CH:132]=[CH:131][CH:130]=[CH:129][CH:128]=1)=[O:123])[CH2:114][C:115](=[O:121])[O:116][C:117]([CH3:120])([CH3:119])[CH3:118])=[O:111])[CH2:105][CH2:106][C:107](=[O:109])[NH2:108])=[O:102])[C@@H:94]([CH3:100])[O:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[O:91])[CH2:78][C:79]1[CH:84]=[CH:83][C:82]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[CH:81][CH:80]=1>C(OCC)(=O)C.C(#N)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:76][C@H:77]([C:90]([NH:92][C@H:93]([C:101]([NH:103][C@H:104]([C:110]([NH:112][C@H:113]([C:122]([NH:124][C@H:125]([C:133]([O:135][CH3:23])=[O:134])[CH2:126][C:127]1[CH:132]=[CH:131][CH:130]=[CH:129][CH:128]=1)=[O:123])[CH2:114][C:115](=[O:121])[O:116][C:117]([CH3:118])([CH3:119])[CH3:120])=[O:111])[CH2:105][CH2:106][C:107](=[O:109])[NH2:108])=[O:102])[C@@H:94]([CH3:100])[O:95][C:96]([CH3:97])([CH3:98])[CH3:99])=[O:91])[CH2:78][C:79]1[CH:80]=[CH:81][C:82]([O:85][C:86]([CH3:87])([CH3:88])[CH3:89])=[CH:83][CH:84]=1)=[O:12])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCC(F)(F)C(O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C)[C@@H](C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
The acid is liberated from 2.85 g of Z-Thr(tBu)-OH.dicyclohexylammonium salt in ethyl acetate by means of citric acid as described under 23 and the resulting oil consisting of Z-Thr(tBu)-OH is stirred with 3.33 g of H-Tyr(tBu)-Thr(tBu)-Gln-Asp(OtBu)-Phe-OCH 3 in 80 ml of acetonitrile at room temperature. 1.20 g of dicyclohexylcarbodiimde are added thereto in the solid form and the mixture is stirred for 23 hours at room temperature. After filtering off the precipitated dicyclohexylurea, which is washed with three portions of acetonitrile each of 7 ml, the solution is evaporated in vacuo and the residue is three times precipitated from ethyl acetate/alcohol solution by means of petroleum ether.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[Br:15])(=O)C.O.[OH-].[Li+].N1C=CN=C1.[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25]>C1COCC1.O.C(O)C>[Br:15][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[CH2:5][O:4][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30]
Reactant: CC(=O)OCc1c(Br)cccc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li+]
Agent: [OH-]
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1c(Br)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A 150-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with a solution of 114b (11.6 g, 42.3 mmol) in a mixture of THF (20 mL), ethanol (20 mL) and water (20 mL). Lithium hydroxide monohydrate (7.00 g, 167.0 mmol) was added and the reaction was stirred at room temperature for 1 h. After this time, the reaction mixture was partitioned between water (200 mL) and ethyl acetate (400 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2×200 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was dissolved in anhydrous methylene chloride (50 mL). Imidazole (14.4 g, 68.0 mmol) was added, followed by dropwise addition of tert-butyldimethylchlorosilane (16.0 g, 106 mmol). The mixture was stirred at room temperature for 14 h. After this time, water (200 mL) was added and the layers separated. The aqueous layer was extracted with methylene chloride (2×200 mL) and the combined organic layers were washed with brine, and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford an 89% yield (13.1 g) of 114c as a white semi-solid: 1H NMR (500 MHz, CDCl3) δ 7.67 (d, 1H, J=8.5 Hz), 7.54 (d, 1H, J=8.5 Hz), 7.18 (t, 1H, J=8.0 Hz), 4.96 (s, 2H), 0.80 (s, 9H), 0.007 (s, 6H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[C:3]([O:14][CH2:15][CH2:16][NH2:17])[CH:2]=1.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:24]([NH:36][S:37](=[O:42])(=[O:41])[N:38]([CH3:40])[CH3:39])[CH:23]=1)=[O:21].CO.C(Cl)(Cl)[Cl:46].Cl.C(O)C>C(#N)C>[ClH:46].[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[C:3]([O:14][CH2:15][CH2:16][NH:17][CH2:19][CH:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:24]([NH:36][S:37]([N:38]([CH3:39])[CH3:40])(=[O:42])=[O:41])[CH:23]=2)[OH:21])[CH:2]=1
Reactant: CN(C)S(=O)(=O)Nc1cc(C(=O)CBr)ccc1OCc1ccccc1
Reactant: ClC(Cl)Cl
Reactant: NCCOc1ccc2c(c1)sc1ccccc12
Agent: Cl
Solvent: CCO
Solvent: CC#N
Solvent: CO
Product: CN(C)S(=O)(=O)Nc1cc(C(O)CNCCOc2ccc3c(c2)sc2ccccc23)ccc1OCc1ccccc1
Reaction time: 1.83 h

Procedure:
To a solution of 462 mg of Intermediate 39 in 20 ml of anhydrous acetonitrile, a solution of 470 mg of Intermediate 40 in 10 ml of anhydrous acetonitrile was added under argon atmosphere at 0° C. whereupon the reaction mixture was removed from the ice bath and was agitated for 110 minutes. Thereto was then added a solution of 215 mg of sodium borohydride in 20 ml of absolute ethanol at room temperature. After agitation for 70 minutes, the reaction was terminated using 1 N hydrochloric acid (pH 4) and the thereto was added 0.54 g of ethanolamine. After agitation for 10 minutes, the mixture was diluted with ethyl acetate, organic layer was rinsed with saturated aqueous sodium chloride solution and dried, whereupon it was evaporated under a reduced pressure, whereby a crude product was obtained. This was purified by a column chromatography (methanol/chloroform of 3/100), whereby 200.2 mg of free amine product of the above-identified compound were obtained. Rf=0.37 (methanol/chloroform of 1/10). The procedures of adding thereto 1.1 equivalent amount of 0.1 N hydrogen chloride/ethanol to convert it into hydrochloride salt (the above-identified compound), distilling off of the solvent under a reduced pressure, adding to the resulting residue diethyl ether and filtering off the thereby deposited precipitate were repeated twice, followed by drying under a reduced pressure, whereby 210.8 mg of the above-identified compound were obtained.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[CH2:12][C:13](=[O:19])C(OCC)=O)=O.[OH-:22].[K+].[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)[CH3:25]>C(O)C.O>[C:27]1([C:24]2[N:5]=[C:6]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]3=[C:12]([C:13]([OH:19])=[O:22])[CH:25]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(=O)Cc1cnccc1NC(=O)C(C)(C)C
Reactant: CC(=O)c1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)nc2ccncc12
Reaction time: 6 h

Procedure:
A mixture of 3.59 g of ethyl 4-trimethylacetamido-3-pyridylpyruvate, 2.89 g of potassium hydroxide in 10 mL of ethanol and 40 mL of water is heated at reflux for 2 hours. At this time 3.1 g of acetophenone is added and refluxing is continued for 6 hours. The ethanol is removed in vacuo, the resulting aqueous solution is washed with ether and the aqueous layer is acidified to pH5. The product is collected washed with water and dried to afford (2-phenylpyridino[4,3-b]pyridin-4-yl) carboxylic acid as a white solid.