Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][NH2:16])=[O:14])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][NH2:16])=[O:14])[CH:8]=3)[CH2:2][CH2:3]2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: NNC(=O)c1cc(N2CCNCC2)ccn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NNC(=O)c1cc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)ccn1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of the product of (i) above (7.76 g), 4-fluoronitrobenzene (5.50 g) and sodium carbonate (4.50 g) in N,N-dimethylformamide (40 ml) was heated at 100° C. with stirring for 4 hours. The mixture was evaporated to about half volume and filtered. The residue was washed with ethanol followed by warm water and then dried to give the title compound (9.41 g), m.p. 230°-232° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:9]([O:11][C@H](C1C=CC=CC=1)C)=[O:10]>C(O)C.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:9]([OH:11])=[O:10]
Reactant: C[C@H](OC(=O)[C@@H](c1ccccc1F)N1CCCCC1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H](c1ccccc1F)N1CCCCC1
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A mixture of (R)—((S)-1-phenylethyl) 2-(2-fluorophenyl)-2-(piperidin-1-yl)acetate (0.737 g, 2.16 mmol) and 20% Pd(OH)2/C (0.070 g) in ethanol (30 mL) was hydrogenated at room temperature and atmospheric pressure (H2 balloon) for 2 hours. The solution was then purged with Ar, filtered through diatomaceous earth (CELITE®), and concentrated in vacuo. This provided the title compound as a colorless solid (0.503 g, 98%). 1H NMR (400 MHz, CD3OD) δ 7.65 (ddd, J=9.1, 7.6, 1.5 Hz, 1H), 7.47-7.53 (m, 1H), 7.21-7.30 (m, 2H), 3.07-3.13 (m, 4H), 1.84 (br s, 4H), 1.62 (br s, 2H). LC-MS: Anal. Calcd. for C13H16FNO2: 237; found: 238 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[S:8].[C:16]([C:18]1[S:19][C:20]([S:24][CH2:25][CH3:26])=[CH:21][C:22]=1[OH:23])#[N:17]>C(#N)C>[C:16]([C:18]1[S:19][C:20]([S:24][CH2:25][CH3:26])=[CH:21][C:22]=1[O:23][P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[S:8])#[N:17]
Reactant: CCSc1cc(O)c(C#N)s1
Reactant: CCOP(=S)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOP(=S)(OCC)Oc1cc(SCC)sc1C#N
Temperature: 20 °C
Reaction time: 24 h
Yield: 86.8 %

Procedure:
7 g of potassium carbonate and 9.4 g of O,O-diethyl chlorothiophosphate were added to a solution of 9.3 g of 2-cyano-3-hydroxy-5-ethylthio-thiophene in 150 ml of acetonitrile and the mixture was stirred for 24 hours at 20° C. and was filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with an 8-2 cyclohexane-ethyl acetate mixture yielded 14.6 g of 2-cyano-3-(diethoxythiophosphoryloxy)-5-ethylthio-thiophene with a refractive index of nD20 = 1.5635.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:13][C:11]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:3][CH2:1][CH3:2])[CH:12]=1
Reactant: CCOc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOc1cc(N)ccc1C(=O)O
Temperature: 80 °C
Yield: 88.1 %

Procedure:
2-Ethoxy-4-nitrobenzoic acid (20 g, 94 mmol, Aldrich) was suspended in ethanol (170 mL) and combined with a saturated aqueous solution of ammonium chloride (100 mL). As this was rapidly stirred, iron dust (13.3 g, 239 mmol) was added in portions. The temperature was raised to 80° C. for 1 h. The cooled suspension was filtered through Celite, and the cake washed with dichloromethane (150 mL). The filtrate was diluted with dichloromethane and washed with brine, dried over magnesium sulfate, filtered and evaporated. A brown solid was triturated with dichloromethane and filtered to give 15 g of 4-amino-2-ethoxybenzoic acid (88%).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1>C(O)(=O)C>[CH2:15]1[C:10]2[NH:7][C:1]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=2[CH2:12][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14]1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2[nH]c3ccccc3c2C1
Temperature: 0 °C
Yield: 93.8 %

Procedure:
A solution of 1.08 g of phenylhydrazine and 1.84 g of ethyl 4-oxocyclohexanecarboxylate in 25 ml of acetic acid was refluxed for 30 minutes and then poured into ice water. The aqueous layer was extracted with ethyl acetate. The organic extract was washed thoroughly with a saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 50 g of silica gel with a 4:1 v/v mixture of hexane and ethyl acetate as the eluent and then recrystallized from ethyl acetate and hexane, to yield 2.28 g of the title compound, melting at 95°-96° C.
Reaction SMILES: O1CCOCC1.[NH2:7][CH:8]([CH3:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][N:11]=1.[CH:21]1[C:33]2[CH:32]([CH2:34][O:35][C:36](Cl)=[O:37])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+]>O>[CH:21]1[C:33]2[CH:32]([CH2:34][O:35][C:36]([NH:7][CH:8]([CH3:20])[CH2:9][C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=4)[NH:12][N:11]=3)=[O:37])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(N)Cc1n[nH]c2ccc(O)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(Cc1n[nH]c2ccc(O)cc12)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
To a mixture of dioxane and water (4:1, 10 mL) was added 3-(2-aminopropyl)-1H-indazol-5-ol (0.10 g, 0.36 mmol), 9-fluorenylmethoxycarbonyl chloride (0.13 g, 0.54 mmol) and sodium bicarbonate (0.9 g, 0.54 mmol). The reaction mixture poured into dilute sodium bicarbonate and the resulting mixture extracted with ether. The combined organic extracts were dried (MgSO4) and concentrated to a residue that was purified by chromatography.
Reaction SMILES: [I:1][CH2:2][CH2:3][OH:4].Cl[C:6]([O:8][CH2:9][CH3:10])=[O:7].N1C=CC=CC=1>C1C=CC=CC=1>[C:6](=[O:7])([O:8][CH2:9][CH3:10])[O:4][CH2:3][CH2:2][I:1]
Reactant: CCOC(=O)Cl
Reactant: OCCI
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)OCCI
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a well-stirred solution consisting of 34.40 g. (0.20 mole) of 2-iodoethanol dissolved in 25 ml. of benzene precooled to 0° C. with the aid of an ice/water bath, there is added in a dropwise manner a solution consisting of 19.1 ml. (0.20 mole) of ethyl chloroformate dissolved in 25 ml. of benzene. Upon completion of this step, the reaction mixture is treated with 19.1 ml. (0.20 mole) of pyridine which is also added in a dropwise manner. The resulting suspension is then stirred for a period of one hour at 0° C. (while under a nitrogen atmosphere) and for six hours at room temperature (~20° C.). At the end of this time, the pyridine hydriodide is removed by filtration and the organic filtrate is washed twice with 50 ml. of 3N hydrochloric acid and once with 50 ml. of brine, followed by drying over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there is obtained 2-iodoethyl ethyl carbonate as the residual material.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][CH:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11].C(N1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])(OCC)=O>O.C(#N)C>[C:29]1(=[O:38])[N:7]([CH:8]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:17][CH:18]=2)[CH2:9][C:10]([OH:12])=[O:11])[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCCOc1ccc(C(N)CC(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCOc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 35 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a stirred solution of sodium carbonate (1.45 g, 13.7 mmol) in 500 mL of water-acetonitrile (1:1, v/v) was added 3-amino-3-(4-propoxyphenyl)propionic acid (3.05 g, 13.7 mmol) as a solid. The mixture was warmed to 30-40° C. to dissolve the solids. The reaction mixture was allowed to cool to room temperature and N-carboethoxyphthalimide (3.00 g, 13.7 mmol) was added and the reaction mixture was stirred for one hour at room temperature. The reaction mixture was then partially concentrated to remove the acetonitrile and the pH of the resulting solution was adjusted to approximately 3 with 4N hydrochloric acid. The resulting slurry was stirred overnight and then filtered and the solid was washed with copious amounts of water. The solid was dried in vacuo (60° C.,<1 mm) to afford 3.64 g (75%) of 3-phthalimido-3-(4-propoxyphenyl)propionic acid as a white powder: mp 142.5-143.6° C., 1H NMR(DMSO-d6, 250 MHz)δ 12.43 (br s, 1H), 7.80-7.95 (m, 4H), 7.34 (d, 2H, J=9 Hz), 6.89 (d, 2H, J=9 Hz), 5.63 (overlapping dd, 1H), 3.88 (t, 2H, J=7 Hz), 3.45 (dd, 1H, J1=9 Hz, J2=16.5 Hz), 3.30 (dd, 1H, J1=7 Hz, J2=16.5 Hz), 1.60-1.85 (m, 2H), 0.95 (t, 3H, J=7 Hz); 13C (DMSO-d6)δ 171.8, 167.6, 158.6, 134.7, 131.1, 130.8, 128.3, 123.2, 114.4, 68.9, 49.7, 36.0, 22.0, 10.3; Anal. Calcd. for C20H19NO5. Theoretical: C, 67.98; H, 5.42; N, 3.96. Found: C, 67.90; H, 5.40; N, 4.00.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]([CH3:14])[CH2:12][O:11][CH2:10][CH:9]2[CH3:15])[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[CH:18][CH:17]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)O1>>[NH2:39][C:38]1[CH:40]=[CH:41][C:35]([C:2]2[N:7]=[C:6]([N:8]3[CH:13]([CH3:14])[CH2:12][O:11][CH2:10][CH:9]3[CH3:15])[N:5]=[C:4]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[CH:18][CH:17]=3)[N:3]=2)=[CH:36][CH:37]=1
Reactant: CNC(=O)Nc1ccc(-c2nc(Cl)nc(N3C(C)COCC3C)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3C(C)COCC3C)n2)cc1
Yield: 86 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 4 using 1-(4-(4-chloro-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Yield 2 g, 86% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:11]Br>[Fe].O>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccccc1C(=O)O
Reactant: BrBr
Agent: [Fe]
Solvent: O
Product: Cc1ccc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
2-Methylbenzoic acid (40.0 g, 0.290 mol) was added to a suspension of Br2 (160 mL) and iron powder (3.20 g, 0.057 mol) under N2 atmosphere in an ice bath. The mixture was allowed to warm to room temperature and was stirred for 2 hours. The reaction mixture was poured into water and the reddish solid was collected by filtration. The solid was dried under vacuum at 50° C. The solid was dissolved in 400 mL of methanol before 640 mL of 0.1N aqueous HCl was added at room temperature. The mixture was stirred and a white solid was produced. This solid was recrystallized from ethanol to afford 5-bromo-2-methyl-benzoic acid (12.0 g, 19%). 1H NMR (300M Hz, CDCl3) δ 8.17 (d, J=2.1, 1H), 7.56 (dd, J=8.1, 2.1, 1H), 7.15 (d, J=8.1, 1H), 2.59 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[NH2:11][C:12]1[NH:16][N:15]=[N:14][N:13]=1>>[NH:13]1[C:12]([NH:11][C:8]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=2)=[O:10])=[N:16][N:15]=[N:14]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cc(Br)ccn1
Product: O=C(Nc1nnn[nH]1)c1cc(Br)ccn1
Yield: 60.1 %

Procedure:
0.3 g of 4-bromo-2-pyridinecarboxylic acid, 0.25 g of N,N'-carbonyldiimidazole and 0.14 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.24 g of N-(5-tetrazolyl)-4-bromo-2-pyridinecarboxamide is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:17]([F:20])([F:19])[F:18])=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1)#[N:2]>[Ni].C1COCC1>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:17]([F:18])([F:19])[F:20])=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14])[CH:8]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)ccc1C(F)(F)F
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(CN)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 5-cyano-2-trifluoromethyl-phenylcarbamate (8.5 g; 29.7 mmol), Ra—Ni (174 mg; 2.97 mmol) and THF (60 mL) was stirred under H2-atmosphere (5 atm) overnight at rt. The mixture was filtered through celite and the celite pad was washed with THF and EtOAc. Concentration gave the sub-title compound which was used in the next step without further purification. Yield: 8 g (93%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[NH2:22]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:22][C:21]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:19]([O:18][CH3:17])[CH:20]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1cc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc(OC)c1OC

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3,4,5-trimethoxyaniline were reacted to produce 5-fluoro-N4-(3-hydroxyphenyl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.33 (s, 1H), 9.17 (s, 1H), 8.99 (s, 1H), 8.06 (d, 1H, J=3.3 Hz), 7.27 (d, 1H, J=7.5 Hz), 7.08-7.02 (m, 4H), 6.46 (dd, 1H, J=1.8 and 7.8 Hz), 3.60 (s, 6H), 3.57 (s, 3H); LCMS: purity: 99%; MS (m/e): 387 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[O:11])[CH:3]=[CH:2]1.[CH3:12][N+:13]([CH3:15])=[CH2:14].[I-]>C(#N)C>[CH3:12][N:13]([CH2:15][C:3]1[C:4]2[C:9](=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:14]
Reactant: C=[N+](C)C
Reactant: O=Cc1cccc2cc[nH]c12
Agent: [I-]
Solvent: CC#N
Product: CN(C)Cc1c[nH]c2c(C=O)cccc12
Yield: 72.7 %

Procedure:
A mixture of 7-indolcarboxaldehyde (0.25 g, 1.7 mmol) and Eschenmoser's salt (0.35 g, 1.9 mmol) in dry acetonitrile (10 ml) was heated under reflux for 2½h. After cooling, solvent was removed under reduced pressure and water was added to the residue. The cooled mixture (ice bath) was made alkaline with 10% sodium hydroxide and then extracted with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated to afford 0.25 g (74%) of the entitled product.
Reaction SMILES: [NH2:1][CH:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH3:3].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]([C:29](=O)[CH3:30])[C:25]([O:27][CH3:28])=[O:26].CC(O)=O>CCO>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:29]([NH:1][CH:2]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:8][CH2:9]1)[CH3:3])[CH3:30]
Reactant: COC(=O)C(C(C)=O)c1ccccc1Br
Reactant: CC(N)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C(=C(C)NC(C)C1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1Br
Temperature: 85 °C
Yield: 49.1 %

Procedure:
To a round bottomed flask was added (R or S)-tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (9.35 g, 40.9 mmol), EtOH (75 mL), and methyl 2-(2-bromophenyl)-3-oxobutanoate (7.40 g, 27.3 mmol) (from Step 4). To this solution was added AcOH (1.563 ml, 27.3 mmol) and the reaction was heated overnight at 85° C. before cooling to room temperature and concentrating. The crude residue was purified via silica gel chromatography (330 g, 100% hexanes to 25% EA in hexanes) to afford the title compound (6.45 g, 13.40 mmol, 49.1% yield).
Reaction SMILES: [O:1]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:16]12([C:26](Cl)=[O:27])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>>[C:16]12([C:26]([N:13]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8][N:7]([C:26]([C:16]45[CH2:25][CH:20]6[CH2:19][CH:18]([CH2:24][CH:22]([CH2:21]6)[CH2:23]4)[CH2:17]5)=[O:27])[CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:1][CH2:15][CH2:14]3)=[O:27])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2
Reactant: C1COCCNCCOCCOCCN1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Product: O=C(N1CCOCCOCCN(C(=O)C23CC4CC(CC(C4)C2)C3)CCOCC1)C12CC3CC(CC(C3)C1)C2

Procedure:
Analogously to Example 2 from 1,4,10-trioxa-7,13-diazacyclopentadecane and 1-adamantylcarbonyl chloride.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH:33]([O:48][Si](C(C)(C)C)(C)C)[CH2:34][NH:35][C:36]([C:38]2[CH:47]=[CH:46][C:41]3[NH:42][C:43](=[O:45])[O:44][C:40]=3[CH:39]=2)=[S:37])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.CCOC(C)=O>[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH:33]([OH:48])[CH2:34][NH:35][C:36]([C:38]2[CH:47]=[CH:46][C:41]3[NH:42][C:43](=[O:45])[O:44][C:40]=3[CH:39]=2)=[S:37])[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CNC(=S)c1ccc2[nH]c(=O)oc2c1)CN1CCC(Cc2ccccc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(C(=S)NCC(O)CN3CCC(Cc4ccccc4)CC3)cc2o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 105.6 %

Procedure:
Tetrabutylammonium fluoride (TBAF) (1.24 μmol, 1.24 mL, 1 M in THF) was added to a mixture of 2-oxo-2,3-dihydrobenzoxazole-6-carbothioic acid [3-(4-benzylpiperidin-1-yl)-2-(tert-butyldimethylsilanyloxy)propyl]amide (336 mg, 623 μmol) and 4 Å molecular sieves (1 g) in THF (2 mL). After stirring at room temperature for 1.5 hours, the mixture was diluted with EtOAc, washed with saturated NaHCO3, brine and dried (MgSO4) to yield 2-oxo-2,3-dihydrobenzoxazole-6-carbothioic acid [3-(4-benzylpiperidin-1-yl)-2-hydroxypropyl]amide (280 mg, quantitative) as a solid yellow foam:
Reaction SMILES: C(OC(=O)CCN[C:13](=[O:41])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:40])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:15]=1)C1C=CC=CC=1.NC1C=C(C=CC=1)C(O)=[O:48]>>[CH2:33]([O:32][C:30]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([OH:41])=[O:48])=[O:40])=[O:31])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C(CCCCCCCNC(=O)OCc1ccccc1)Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1
Product: O=C(CCCCCCCNC(=O)OCc1ccccc1)Nc1cccc(C(=O)O)c1

Procedure:
The ester starting material (m.p. 123°-124° C.) is obtained by coupling 8-[1-(benzyloxy)formamidooctanoic acid and 3-aminobenzoic acid to give m-[8-[1-(benzyloxy)formamido]octanamido]benzoic acid, m.p. 167°-168° C., and reacting the latter with β-alanine benzyl ester p-toluenesulphonate.
Reaction SMILES: C[N:2]([CH:21]1[CH:28]2[CH2:29][C:24]3([C:31](O)=[O:32])[CH2:25][CH:26]([CH2:30][CH:22]1[CH2:23]3)[CH2:27]2)[C:3](=[O:20])[C:4]([N:7]([CH2:18][CH3:19])[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])(=[O:10])=[O:9])([CH3:6])[CH3:5].C[CH2:35][N:36]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[OH-]>C(Cl)Cl.O>[CH3:35][NH:36][C:31]([C:24]12[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:30][CH:22]([CH:21]3[NH:2][C:3](=[O:20])[C:4]([N:7]([CH2:18][CH3:19])[S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])(=[O:9])=[O:10])([CH3:6])[CH3:5])[CH2:23]1)[CH2:25]2)=[O:32]
Reactant: CCN(C(C)(C)C(=O)N(C)C1C2CC3CC1CC(C(=O)O)(C3)C2)S(=O)(=O)c1ccccc1C
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCN(C(C)(C)C(=O)NC1C2CC3CC1CC(C(=O)NC)(C3)C2)S(=O)(=O)c1ccccc1C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
N-methyl-4-(2-(N-ethyl-2-methylphenylsulfonamido)-2-methylpropanamido)adamantane-1-carboxylic acid (380 mg, 0.82 mmol) was dissolved in CH2Cl2 (10 ml), and added with EDCI (314 mg, 1.64 mmol) and HOBT (222 mg, 1.64 mmol), followed by stirring for 30 minutes. 30% NH4OH aqueous solution (5 ml) was added thereto, followed by stirring at room temperature for 12 hours. The resultant solution was added with H2O, extracted with CH2Cl2 (×3), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain N-methyl-4-(2-(N-ethyl-2-methylphenylsulfonamido)-2-methylpropanamido)adamantane-1-carboxamide (296 mg, 0.64 mmol, 78%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[S:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=3)[CH:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[S:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[NH:35][C:36](=O)[O:37]C1C=CC([N+]([O-])=O)=CC=1>C(#N)C.CCOC(C)=O>[S:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[NH:35][C:36]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[S:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=3)[CH:8]=2)[CH2:3][CH2:2]1)=[O:37]
Reactant: CCOC(=O)c1csc(-c2ccc3c(c2)NCC3)n1
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CC3)n1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A mixture of ethyl 2-(indolin-6-yl)thiazole-4-carboxylate (28D) (56 mg, 0.14 mmol), K2CO3 (22 mg, 0.16 mmol), and 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) (48 mg, 0.15 mmol) was heated to reflux in acetonitrile (3 mL) for 5.5 hours. The reaction mixture was cooled to rt and diluted in EtOAc (5 mL), washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE/EtOAc (1:1), to provide 22 mg (34%) of the desired product ethyl 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)indolin-6-yl)thiazole-4-carboxylate (28E): 1H NMR (300 MHz, CDCl3) δ 8.67 (1H, s), 8.12 (1H, s), 7.68 (2H, m), 7.52 (1H, m), 7.38 (1H, m), 7.25 (2H, m), 4.43 (2H, q), 4.22 (2H, m), 3.18 (2H, m) 1.45 (3H, t). LC/MS (APCI): m/z 451.1 (M+H).