Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:16][C:17]1[CH:26]=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>CN(C=O)C>[Cl:16][C:17]1[CH:26]=[C:25]([N:27]([CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)[S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)cc1Cl
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(CCN2CCOCC2)S(C)(=O)=O)cc1Cl
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
1.2 g of 4-(2-chloroethyl)morpholine and 2.5 g of Cesium Carbonate were added to 334 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in 7 mL of DMF and stirred in the microwave at 150° C. for 30 minutes. The reaction mixture was extracted in Ethyl Acetate twice with water, dried over Magnesium Sulfate, filtered, concentrated to give crude methyl 2-chloro-4-(N-(2-morpholinoethyl)methylsulfonamido)benzoate. 476 mg of methyl 2-chloro-4-(N-(2-morpholinoethyl)methylsulfonamido)benzoate was hydrolyzed via Procedure M and purified by reverse phase HPLC to yield 460 mg of crude 2-chloro-4-(N-(2-morpholinoethyl)methylsulfonamido)benzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-(2-morpholinoethyl)methylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-morpholinoethyl)methylsulfonamido)benzamide. MS (Q1) 549 (M)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]1[CH2:24][CH3:25].S(Cl)([Cl:29])(=O)=O.O>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:3]1([CH2:24][CH3:25])[Cl:29]
Reactant: CCC1C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CCC1(Cl)C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1c1ccccc1
Temperature: 25 °C

Procedure:
(1-Oxo-2-ethyl-3-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (5.6 g., 0.0143 mole) is dissolved in warm acetic acid (70 ml.) and treated with sulfuryl chloride (1.3 ml., 0.016 mole). The solution is heated on a steam bath for two hours, cooled to room temperature and then added slowly to cold water (500 ml.) with stirring. The product precipitates and is collected by suction filtration, washed well with water and air-dried overnight to afford 5.9 g. of crude product. The crude product is recrystallized several times from ethanol (30 ml.) and water (20 ml.) and then from nitromethane to afford substantially pure (1-oxo-2-ethyl-3-phenyl-2,6,7-trichloro-5-indanyloxy)acetic acid, m.p. 190°-192° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=2[CH:17]=1.B([O-])([O-])O[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1.O.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>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=3[CH:17]=2)=[CH:21][CH:22]=1)[CH3:28]
Reactant: CCOC(=O)C1=Cc2cc(Br)ccc2OCC1
Reactant: CCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Product: CCOC(=O)C1=Cc2cc(-c3ccc(OCC)cc3)ccc2OCC1
Temperature: 25 °C
Yield: 81.5 %

Procedure:
Under argon atmosphere, to a solution of 4-bromo-phenetole (26.4 g) in tetrahydrofuran (200 ml) was dropwise added n-butyl-lithium (1.6M, hexane solution) (90.3 ml) at −78° C. for 50 minutes, and the mixture was stirred for 30 minutes. To the reaction mixture was dropwise added a solution of trimethyl borate (40.8 g) in tetrahydrofuran (40 ml) for 30 minutes, and the mixture was stirred for 30 minutes, warmed to room temperature, and further stirred for 1.5 hours. To the reaction mixture was added 10% sulfuric acid (182 ml) for 40 minutes or more, and the mixture was stirred 1.5 hours, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from diisopropylether-hexane to give 4-ethoxyphenyl borate (15.5 g) as colorless crystals. Under argon atmosphere, a solution of ethyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (504.5 mg), the above 4-ethoxyphenyl borate (310 mg) and potassium carbonate (0.47 g) in toluene-ethanol-water (20-2-2 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetrakistriphenylphosphinepalladium (0.06 g), and the mixture was refluxed for 20 hours and cooled to room temperature. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:9→1:5) to give ethyl 7-(4-ethoxyphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (468 mg) as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:25](=[O:42])[N:26]([C:33]2[O:41][C:37]3=[CH:38][CH:39]=[CH:40][C:36]3=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[OH-].[Li+]>C1COCC1.CO.O>[O:41]1[C:37]2=[CH:38][CH:39]=[CH:40][C:36]2=[CH:35][CH:34]=[C:33]1[N:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:25]([CH:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=2)=[CH:17][CH:18]=1)[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[CH:5][CH:6]=1)=[O:42]
Reactant: COC(=O)c1ccc(CC(Cc2ccc(C3=CCCCC3)cc2)C(=O)N(c2ccccc2)c2ccc3cccc-3o2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CC(Cc2ccc(C3=CCCCC3)cc2)C(=O)N(c2ccccc2)c2ccc3cccc-3o2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To the crude 4-[2-(4-Benzofuran-2-ylphenylcarbamoyl)-3-(4-cyclohex-1-enylphenyl)-propyl]-benzoic acid methyl ester from step e dissolved in 20 mL of THF/MeOH/H2O (3:1:1) was added lithium hydroxide (74 mg, 1.8 mmol) After stirring for 5 hrs at RT, the organic solvents were removed under vacuum and the reaction residue diluted further with water (25 mL). The aqueous mixture was made acidic with 1 N HCl and extracted with ethyl acetate. The ethyl acetate portion was then dried over Na2SO4 and concentrated under vacuum to afford 4-[2-(4-Benzofuran-2-ylphenylcarbamoyl)-3-(4-cyclohex-1-enylphenyl)-propyl]-benzoic acid which was carried on as is for the next step.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([C:9]2[N:10]=[C:11]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[C:12]3[CH2:17][N:16]([CH3:18])[CH2:15][C:13]=3[N:14]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>C1COCC1>[CH2:26]([NH:28][C:29]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([C:9]2[N:10]=[C:11]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[C:12]3[CH2:17][N:16]([CH3:18])[CH2:15][C:13]=3[N:14]=2)=[CH:8][C:2]=1[F:1])=[O:30])[CH3:27]
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)c(F)c2)nc2c1CN(C)C2
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C)C3)cc1F
Temperature: 40 °C
Reaction time: 48 h
Yield: 14.1 %

Procedure:
To a stirred solution of (S)-2-fluoro-4-(6-methyl-4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)aniline (intermediate 16) (139 mg, 0.40 mmol) in dry THF, was added ethyl isocyanate (70 μL, 0.89 mmol) dropwise. The reaction mixture was stirred at 40° C. for 48 hours, before removal of the solvent in vacuo. The crude material was then purified prep. HPLC (high pH), affording the title compound as a white solid (23.3 mg, 13.7%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25]([OH:27])=O)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(Cl)CCl.[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36][NH2:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36][NH:37][C:25]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:12]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:11]=1[CH:22]([CH3:23])[CH3:24])=[O:27]
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3cccnc3)c2c1
Reactant: NCc1ccc(F)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3cccnc3)c2c1

Procedure:
Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-3-carboxylic acid (Compound 41, 365 mg, 0.997 mmol) in CH2Cl2 (12 ml) was added EDC (288 mg, 2.00 mmol) and DMAP (146 mg, 1.50 mmol), followed by 3,4-difluorobenzyl amine (171 mg, 1.50 mmol). The crude material was purified by chromatography on silica gel (0→70% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[C:13]2[CH:14]=[CH:15][C:16]([N:18]3[CH2:22][CH2:21][NH:20][C:19]3=[O:23])=[CH:17][C:12]=2[CH2:11][CH2:10][O:9]1)(=O)=O.[C:24]([C:26]1[CH:41]=[CH:40][C:29]2[C:30]([N:33]3[CH2:38][CH2:37][NH:36][C@H:35]([CH3:39])[CH2:34]3)=[CH:31][S:32][C:28]=2[CH:27]=1)#[N:25]>>[C:24]([C:26]1[CH:41]=[CH:40][C:29]2[C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH2:6][CH2:7][C@H:8]4[C:13]5[CH:14]=[CH:15][C:16]([N:18]6[CH2:22][CH2:21][NH:20][C:19]6=[O:23])=[CH:17][C:12]=5[CH2:11][CH2:10][O:9]4)[C@H:35]([CH3:39])[CH2:34]3)=[CH:31][S:32][C:28]=2[CH:27]=1)#[N:25]
Reactant: C[C@@H]1CN(c2csc3cc(C#N)ccc23)CCN1
Reactant: CS(=O)(=O)OCC[C@@H]1OCCc2cc(N3CCNC3=O)ccc21
Product: C[C@@H]1CN(c2csc3cc(C#N)ccc23)CCN1CC[C@@H]1OCCc2cc(N3CCNC3=O)ccc21

Procedure:
The title compound was prepared by condensation of 2-((1S)-6-(2-oxo-imidazolidin-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl)ethyl methanesulfonate and (3R)-1-(6-cyano-1-benzothien-3-yl)-3-methylpiperazine, as described for Example 1b). M+H=502.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=O)[CH:5]=[N:6][CH:7]=1.B.C([O-])(O)=O.[Na+]>C1COCC1.O.CCOC(C)=O.CC1(C)C(C2C=NC(C)=C([N+]([O-])=O)C=2)=CCNC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(Cc1cncc(Br)c1)N1CCOCC1
Agent: B
Agent: Cc1ncc(C2=CCNCC2(C)C)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1cncc(CCN2CCOCC2)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of 4-[(5-bromopyridin-3-yl)acetyl]morpholine (1.26 g, 4.40 mmol) in THF (15 mL) was added a 1M solution of borane in THF (23.2 mL, 23.2 mmol). The reaction mixture was allowed to stir at 55° C. overnight and then was allowed to cool to rt and then diluted with water (100 mL) and EtOAc (100 mL). The organic solution was separated and the aqueous solution was extracted with EtOAc (2×50 mL). The organic solutions were combined, dried over MgSO4, filtered and concentrated to give a yellow oil, which was dissolved in 1N HCl (100 mL). This solution was allowed to stir at 80° C. overnight. The reaction mixture was neutralized with sat. aq. NaHCO3 (100 mL) and then extracted with EtOAc (3×50 mL). The combined organic solutions were washed with brine, dried over MgSO4, filtered and concentrated to give 4-[2-(5-bromopyridin-3-yl)ethyl]morpholine (0.631 g, 2.33 mmol, 53%) as a light yellow oil. LCMS (FA): Rt=0.50 min, m/z=273.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:10]([CH2:24][CH2:25][C:26]2[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)[C:11]([C@@H:13]([O:20]C(=O)C)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9].O.[OH-].[Li+]>O1CCCC1.O>[OH:20][C@@H:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:11]([N:10]([C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:24][CH2:25][C:26]1[CH:27]=[N:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=1)=[O:12]
Reactant: COc1cc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](OC(C)=O)c2ccccc2)ccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](O)c2ccccc2)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.1 %

Procedure:
To a solution of acetic acid (S)-{(3-methoxy-4-methyl-phenyl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-carbamoyl}-phenyl-methyl ester (155 mg, 0.32 mmol) in tetrahydrofuran (2.0 mL) were added 1.0 mL water and 20.0 mg (0.84 mmol) lithium hydroxide monohydrate. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 13 mg (9%) of the title compound as a colourless oil. MS(m/e): 445.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([CH2:10][NH2:11])[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[NH2:12][C:13]1[C:21]([Cl:22])=[CH:20][C:16]([C:17](N)=[O:18])=[C:15]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([I:31])[CH:26]=2)[CH:14]=1>>[NH2:12][C:13]1[C:21]([Cl:22])=[CH:20][C:16]([C:17]([NH:11][CH2:10][C:2]2([OH:1])[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[O:18])=[C:15]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([I:31])[CH:26]=2)[CH:14]=1
Reactant: NCC1(O)CN2CCC1CC2
Reactant: NC(=O)c1cc(Cl)c(N)cc1OCc1cccc(I)c1
Product: Nc1cc(OCc2cccc(I)c2)c(C(=O)NCC2(O)CN3CCC2CC3)cc1Cl

Procedure:
Following the procedure of Example 2, the title compound is prepared from 3-hydroxy-1-azabicyclo[2.2.2]oct-3-ylmethanamine and 4-amino-5-chloro-2-[(3-iodophenyl)methoxy]benzamide.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:37][CH2:36][C:31]4([O:35][CH2:34][CH2:33][O:32]4)[CH2:30][CH2:29]3)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:37][CH2:36][C:31]4([O:35][CH2:34][CH2:33][O:32]4)[CH2:30][CH2:29]3)=[O:27])[CH2:23][NH:22][CH2:21]2)[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:18])=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCC3(CC2)OCCO3)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CCC3(CC2)OCCO3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.3 %

Procedure:
tert-Butyl (3S,5R)-3-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)piperidine-1-carboxylate (72 mg) was dissolved in acetonitrile (8 ml), TFA (2 ml) was added and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into 25% aqueous potassium carbonate solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC, and fractions eluted with water-acetonitrile (9:1) to acetonitrile were collected. The mixture was basified (pH 10) with saturated aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object compound (29 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].[H-].[Na+].C(Cl)OC.C1[CH2:34][O:33][CH2:32][CH2:31]1>>[CH2:32]([O:33][CH2:34][O:20][C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([C:10]#[C:9][C:6]3[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=3)[S:12][C:13]=2[CH:19]=1)[CH3:31]
Reactant: C1CCOC1
Reactant: CNc1ccc(C#Cc2nc3ccc(O)cc3s2)cc1[N+](=O)[O-]
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Product: CCOCOc1ccc2nc(C#Cc3ccc(NC)c([N+](=O)[O-])c3)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask under Ar containing 2-((4-(methylamino)-3-nitrophenyl)ethynyl)benzo[d]thiazol-6-ol (1 equiv) is added THF (5 vol). To this solution is added NaH (1.3 equiv). The solution is stirred at RT for 30 min. To this solution is added MOM-Cl (1.5 equiv). The reaction is stirred overnight at RT. The reaction is poured onto water (10 vol) and extracted into DCM (10 vol). The organic layer is washed with water (10 vol), dried (MgSO4), filtered and concentrated to dryness. The material is purified using EtOAc:Hexanes as the eluent over silica gel to afford the final product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:14].[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][C:18]=1[NH2:26]>>[NH2:26][C:18]1[CH:19]=[C:20]([C:21]2[O:14][C:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:7][C:2]=3[N:1]=2)[CH:24]=[CH:25][C:17]=1[O:16][CH3:15]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: Nc1cc(-c2ccccc2)ccc1O
Product: COc1ccc(-c2nc3cc(-c4ccccc4)ccc3o2)cc1N

Procedure:
Prepared by the method of Example 1a), from 2-amino-4-phenylphenol (554 mg, 2.9 mmol) and 4-methoxy-3-aminobenzoic acid (500 mg, 2.9 mmol) the subtitle compound was obtained, 111 mg (10%). 1H NMR (CDCl3) δ 7.84(s, 1H), 7.72–7.38(m, 9H), 6.93(d, J=8.3 Hz, 1H), 3.96(s, 3H). MS 316 m/z (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH:60]([CH3:62])[CH3:61].FC(F)(F)S(O)(=O)=O>C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:60]([CH3:62])[CH3:61])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CC(C)OC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Yield: 13.3 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (300 mg in 4.5 ml 33% methylene chloride in cyclohexane) isopropyl trichloroacetimidate (142 mg neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (13.4 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 5 days the reaction was diluted with ethyl acetate and quenched with saturated sodium bicarbonate. The layers were separated, and the organic layer was washed with brine then dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate : hexane (1:1)+1% methanol) gave the title compound (42 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:35])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][C@H:30]([CH3:34])[C:31](O)=[O:32])=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:69]([O:71][C:72]([N:74]1[CH2:79][CH2:78][NH:77][CH2:76][CH2:75]1)=[O:73])[CH3:70]>CN(C=O)C.ClCCl>[CH2:69]([O:71][C:72]([N:74]1[CH2:75][CH2:76][N:77]([C:31](=[O:32])[C@H:30]([NH:29][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:35])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:28])[CH3:34])[CH2:78][CH2:79]1)=[O:73])[CH3:70]
Reactant: CCOC(=O)N1CCNCC1
Reactant: C[C@@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@@H](C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 1 h

Procedure:
To a solution of 190 mg (R)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-propionic acid in 3 ml DMF were added 0.27 ml DIPEA, 150 mg HATU and 0.06 ml 1-ethoxycarbonylpiperazine. After stirring for 1 h it was diluted with dichlormethane and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[N:5]=1)([O-:3])=[O:2].CO[C:16](OC)([CH3:18])[CH3:17]>CC(C)=O.S(=O)(=O)(O)O>[CH3:17][C:16]1([CH3:18])[O:13][C@@H:10]([CH2:9][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH2:11][O:12]1
Reactant: COC(C)(C)OC
Reactant: O=[N+]([O-])c1ccn(C[C@H](O)CO)n1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC1(C)OC[C@H](Cn2ccc([N+](=O)[O-])n2)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
A solution of (S)-3-(3-nitro-pyrazol-1-yl)propane-1,2-diol (1.00 g, 5.35 mmol) in acetone (10 mL) was treated with concentrated sulfuric acid (5 drops) and 2,2-dimethoxypropane (3.34 g, 32.09 mmol). The reaction mixture was stirred for 5 h at room temperature. Upon completion of the reaction the mixture was concentrated at reduced pressure and then diluted with ethyl acetate, washed with a saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate The crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% to 80% ethyl acetate/hexanes) to afford 1-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-3-nitro-1H-pyrazole (0.70 g, 58%) as a yellow oil: LR-ES-MS m/z calculated for C9H13N3O4 [M]+ 227, observed 228 [M+H]+.