Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](OB(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][NH:8][CH2:9]3)=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Reactant: Cc1ccc(OB(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2ccc3c(c2)CNCC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To 7-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (8.1 g), 4-methylphenylboric acid (3.9 g), a 2 M aqueous solution of potassium carbonate (40 ml) and ethanol (40 ml) was added toluene (100 ml), and the resulting mixture was stirred at room temperature under an argon atmosphere for 30 minutes. Thereto was added tetrakis(triphenylphosphine)palladium (1.26 g), and the resulting mixture was refluxed under an argon atmosphere for 4.5 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, methanol (200 ml) and a 2 M aqueous solution of potassium carbonate (50 ml) were added to the residue, and the resulting mixture was stirred overnight at room temperature. After concentration, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and was then back-extracted with 1 N hydrochloric acid. The aqueous layer was made alkaline with a 1 N aqueous solution of sodium hydroxide, was then saturated with sodium chloride and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinoline (4.2 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([C:9]#[N:10])[N:3]=1.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:11]([O:18][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([C:9]#[N:10])[N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: Cc1ccc(C#N)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C#N)nc1OCc1ccccc1
Temperature: 25 °C
Yield: 52 %

Procedure:
To a solution of 2-bromo-6-cyano-3-methylpyridine (272 mg) and benzyl alcohol (156 mg) in tetrahydrofuran (20 mL) was added sodium hydride (40 mg), and the mixture was heated under reflux for one hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. After removal of the sodium sulfate by filtration, the organic solvent was evaporated off in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=19:1) to give the title compound (161 mg) as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15]([NH:30][CH2:26][CH2:27][CH2:28][CH3:29])=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCCCN
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCCCNC(=O)C(C)(C)COc1cccc2nc(C)c(C(=O)OCC)c(N)c12

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and n-butylamine as a pale-yellow solid (91%). 1H NMR (400 MHz, DMSO-d6) δ 0.74 (t, J=8.0 Hz, 3H), 1.15-1.20 (m, 2H), 1.27 (s, 6H), 1.32-1.38 (m, 5H), 2.57 (s, 3H), 3.06-3.11 (q, J=8.0 Hz, 2H), 4.14 (s, 2H), 4.35 (q, J=8.0 Hz, 2H), 6.90 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.81 (t, J=8.0 Hz, 1H), 8.10 (s, 2H). MS 402 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[N:12]([CH2:21][CH2:22][NH:23][CH3:24])[C:13]3[C:18]([C:19]=2[OH:20])=[N:17][CH:16]=[CH:15][CH:14]=3)=[O:9])=[C:4]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:3]=1.[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35]>>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[N:12]([CH2:21][CH2:22][N:23]([C:34]([N:33]([CH3:37])[CH3:32])=[O:35])[CH3:24])[C:13]3[C:18]([C:19]=2[OH:20])=[N:17][CH:16]=[CH:15][CH:14]=3)=[O:9])=[C:4]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: CNCCn1c(=O)c(C(=O)NCc2ccc(F)cc2S(C)(=O)=O)c(O)c2ncccc21
Product: CN(C)C(=O)N(C)CCn1c(=O)c(C(=O)NCc2ccc(F)cc2S(C)(=O)=O)c(O)c2ncccc21

Procedure:
The compound was prepared in a manner similar to that described for Example 22, using N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-1-[2-(methylamino)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and N,N-dimethylcarbamoyl chloride.
Reaction SMILES: FC(F)(F)[S:3]([O-:6])(=[O:5])=[O:4].[C:9]([O:13][C:14](=[O:55])[C:15]([O:18]/[N:19]=[C:20](/[C:42]1[N:43]=[C:44]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[S:45][CH:46]=1)\[C:21]([NH:23][C@@H:24]1[C:27](=[O:28])[NH:26][C@@H:25]1[CH2:29][N:30]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][N+:38]([CH3:41])=[CH:37][CH:36]=2)[N:32]=[N:31]1)=[O:22])([CH3:17])[CH3:16])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14](=[O:55])[C:15]([O:18]/[N:19]=[C:20](/[C:42]1[N:43]=[C:44]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[S:45][CH:46]=1)\[C:21]([NH:23][C@@H:24]1[C:27](=[O:28])[N:26]([S:3]([O-:6])(=[O:5])=[O:4])[C@@H:25]1[CH2:29][N:30]1[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][N+:38]([CH3:41])=[CH:39][CH:40]=2)[N:32]=[N:31]1)=[O:22])([CH3:16])[CH3:17])([CH3:10])([CH3:11])[CH3:12]
Reactant: C[n+]1ccc(-c2cn(C[C@H]3NC(=O)[C@H]3NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)nn2)cc1
Reactant: O=S(=O)([O-])C(F)(F)F
Solvent: CN(C)C=O
Product: C[n+]1ccc(-c2cn(C[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N3S(=O)(=O)[O-])nn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
4-(1-(((2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-1-methylpyridin-1-ium trifluoromethanesulfonate (70 mg, 0.10 mmol) in DMF (1 mL) was treated with SO3.DMF (80 mg, 0.52 mmol). The reaction mixture was stirred at rt for 16 h then concentrated in vacuo and purified by HP21 resin (ACN-water, 10-100%), affording the title compound (24 mg, 31%) as a beige solid. LCMS: m/z=748.1 (M−1).
Reaction SMILES: [N:1]([CH2:4][C:5]([N:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[N:9]1)([CH3:7])[CH3:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[CH3:7][C:5]([N:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[N:9]1)([CH3:6])[CH2:4][NH2:1]
Reactant: CC(C)(CN=[N+]=[N-])n1cc([N+](=O)[O-])cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CN)n1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of 1-(1-azido-2-methylpropan-2-yl)-4-nitro-1H-pyrazole (10 g) obtained in Step C of Example 115 in a mixed solvent of tetrahydrofuran/water (v/v=10/1, 88 mL) was added triphenylphosphine (15 g), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (8.7 g) as a mixture with triphenylphosphine oxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]5=[O:30])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]([OH:34])=O)=[N:10]2)=[CH:5][CH:4]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:57][S:58]([NH2:61])(=[O:60])=[O:59]>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]5=[O:30])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]([NH:61][S:58]([CH3:57])(=[O:60])=[O:59])=[O:34])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc(C(=O)O)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(=O)NS(C)(=O)=O)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Reaction time: 0.25 h

Procedure:
To 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (0.2 g, 0.43 mmol) in CH2Cl2 (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.1 g, 0.5 mmol) and TEA (0.18 mL, 1.3 mmol) and the reaction was stirred for 15 min. 1-Hydroxybenzotriazole (71 mg, 0.5 mmol) was added and the reaction was stirred for 15 min. Methane sulfonamide (0.125 g, 1.3 mmol) and DMF (1 mL) were added and the reaction was stirred for 72 h. The solvents were removed and after purification by HPLC and freeze-drying 75 mg (33%) white solid was obtained; High Resolution Mass Spec (M+H)+ for C26H24N5O6S 534.1468.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:23](O)=[O:24])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:15]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].C(Cl)Cl.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:51]([CH2:53][NH2:54])[OH:52]>>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:23]([NH:54][CH2:53][CH2:51][OH:52])=[O:24])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:15]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: NCCO
Reactant: CC(=O)Nc1cc(-c2nc(-c3ccccc3Cl)c(C(=O)O)s2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2nc(-c3ccccc3Cl)c(C(=O)NCCO)s2)ccn1
Reaction time: 1 h
Yield: 55.4 %

Procedure:
To a stirred solution of 2-[2-(acetylamino)pyridin-4-yl]-4-(2-chlorophenyl)-1,3-thiazole-5-carboxylic acid (0.050 g, 0.130 mmol) in methylene chloride (3.00 mL, 46.80 mmol) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.056 g, 0.294 mmol) followed by 1-hydroxybenzotriazole (0.040 g, 0.294 mmol) and the resulting solution was stirred for 1 h. Ethanolamine (0.081 mL, 1.340 mmol) was added and the reaction mixture was continued to stir for 18 h. The mixture was quenched by the addition of water (5.0 mL) and extracted with EtOAc (10.0 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, elution with 0-75% EtOAc in hexanes) to provide 0.0300 g of product as a clear colorless oil (54% 2 steps). LC/MS (AA) ES+ 417, 419. 1H NMR (400 MHz, d1 CDCl3) δ: 8.06-7.98 (m, 1H), 7.72-7.54 (m, 3H), 7.49-7.44 (m, 2H), 7.02-6.96 (m, 1H), 6.28 (br s, 1H), 4.72 (br t, J=5.6 Hz, 1H), 4.66 (br t, J=5.4 Hz, 1H), 3.37 (q, J=6.0 Hz, 2H), 3.18 (q, J=6.4 Hz, 2H), 2.12 (s, 3H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:14]2=[O:20])[CH:10]=[CH:11][CH:12]=1>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:14]2=[O:20])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(C2CCCCNC2=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1NCCCCC1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A 1M solution of BBr3 (1.0 mL, 1.00 mmol) in CH2Cl2 was added to 3-(3-methoxy-phenyl)-azepan-2-one (as described in Step B above) (0.200 g, 0.912 mmol) dissolved in anhydrous CH2Cl2 (5 mL) at −78° C. After 30 hr of stirring at RT, the reaction was quenched with H2O, extracted with CH2Cl2 (3×), dried (MgSO4), concentrated and purified using reverse phase chromatography (95/5-5/95 H2O/CH3CN with 0.1% TFA, flow=65 mL/min) to give the title compound.
Reaction SMILES: N.C12C(=CC=CC=1)[NH:7]C(=O)OC2=O.[N+:14]([C:17]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[C:19]2[C:20](OC(=O)[NH:24][C:18]=12)=[O:21])([O-:16])=[O:15]>>[NH2:24][C:18]1[C:17]([N+:14]([O-:16])=[O:15])=[CH:28][C:27]([N+:29]([O-:31])=[O:30])=[CH:26][C:19]=1[C:20]([NH2:7])=[O:21]
Reactant: O=c1[nH]c2c([N+](=O)[O-])cc([N+](=O)[O-])cc2c(=O)o1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: N
Product: NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N

Procedure:
A process for the manufacture of 2-amino-3,5-dinitrobenzamide which comprises nitrating at -20° C. to 80° C. isatoic anhydride dissolved in an inert organic solvent with an acid mixture consisting of 85-100% strength nitric acid and oleum, said acid mixture containing 0.5 to 20 moles of sulfur trioxide per mole of nitric acid, to produce 3,5-dinitroisatoic anhydride, allowing the reaction mixture to separate into an organic phase and an acid phase containing the 3,5-dinitroisatoic anhydride, adding 20-30% strength aqueous ammonia to the resultant acid phase in an amount of 9 to 25 moles of ammonia per mol of isatoic anhydride, and reacting the ammonia and the acid phase to produce a high yield of 2-amino-3,5-dinitrobenzamide.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>N1C=CC=CC=1.N1CCCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(C=O)ccc1F
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1cc(/C=C/C(=O)O)ccc1F
Yield: 96.7 %

Procedure:
To a solution of 4-fluoro-3-methoxybenzaldehyde (30 g, 195 mmol) in pyridine (134 ml) and piperidine (4.12 ml) was added malonic acid (30.4 g, 292 mmol) at room temperature. The reaction mass was refluxed for 18 h. The solvent was evaporated under reduced pressure and the residue was acidified with 1.5N HCl solution. The precipitated solid was filtered washed with pet ether to get crude compound (37 g, 97%) as white solid. The crude compound was taken to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ ppm 12.37 (s, 1H), 7.59-7.55 (d, J=16 Hz, 1H), 7.53 (s, 1H), 7.26-7.22 (m, 2H), 6.59-6.55 (d, J=16 Hz, 1H), 3.89 (s, 3H); MS: MS m/z 195.0 (M+−1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[CH3:28])[C:24](=[O:29])[N:23]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH:22]=[CH:21]2.O>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[CH3:28])[C:24](=[O:29])[N:23]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH:22]=[CH:21]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cn2ccc3cc(F)c(C)cc3c2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ccc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)c(C)cc3c2=O)cc1
Temperature: 80 °C
Yield: 88.6 %

Procedure:
A solution of 3.2 g (15.9 mmol) 1-tert-butoxycarbonyl-4-hydroxypiperidine in 110 mL dimethylacetamide was stirred with 1.36 g (45.4 mmol) of 80-% sodium hydride for 1 h at room temperature. Then a suspension of 4.5 g (15.1 mmol) of 6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one in dimethylacetamide was added. The reaction mixture was heated to 80° C. for 2 h during which time a clear solution was obtained. The reaction mixture was slowly added to 160 mL water and after 1 h of stirring the product was isolated by filtration and dried over night in vacuum. 6.4 g of 4-[2-(4-Methoxy-benzyl)-7-methyl-1-oxo-1,2-dihydro-isoquinolin-6-yloxy]-piperidine-1-carboxylic acid tert-butyl ester were obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[S:37][C:36]([CH3:38])=[N:35][C:34]=2[C:39](O)=[O:40])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[S:37][C:36]([CH3:38])=[N:35][C:34]=2[C:39]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@@H:3]2[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:40])=[CH:31][CH:32]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: C[C@@H]1CCCN[C@H]1CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@@H]2CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of rac-trans-tert-butyl ((3-methylpiperidin-2-yl)methyl)carbamate (1 eq) from the previous step in DMF was added DIPEA (2 eq) followed by 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (1.5 eq) and HATU (2 eq). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with 1M HCl, sat aq. NaHCO3, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give tert-butyl (((2R,3R)-1-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-3-methylpiperidin-2-yl)methyl)carbamate as a light yellow oil. To a solution of this carbamate in CH2Cl2 was added TFA (1:1 v/v). The reaction was aged at rt and monitored for disappearance of starting material by analytical reverse-phase HPLC. When starting material was consumed, the reaction was concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with sat aqueous NaHCO3, brine, dried (MgSO4), and concentrated to afford the title compound as a pale yellow oil which crystallized. MS (ESI) 348.2 (M+H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:28]2[C:33]([CH3:34])=[CH:32][C:31]([CH2:35][CH2:36][C:37]([OH:40])([CH3:39])[CH3:38])=[CH:30][C:29]=2[CH3:41])=[C:8]2[C:12]=1[C@H:11]([O:13][C:14]1[CH:27]=[CH:26][C:17]3[C@H:18]([CH2:21][C:22]([O:24]C)=[O:23])[CH2:19][O:20][C:16]=3[CH:15]=1)[CH2:10][CH2:9]2>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:28]2[C:33]([CH3:34])=[CH:32][C:31]([CH2:35][CH2:36][C:37]([OH:40])([CH3:38])[CH3:39])=[CH:30][C:29]=2[CH3:41])=[C:8]2[C:12]=1[C@H:11]([O:13][C:14]1[CH:27]=[CH:26][C:17]3[C@H:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][O:20][C:16]=3[CH:15]=1)[CH2:10][CH2:9]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(CCC(C)(C)O)cc5C)ccc(F)c43)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(CCC(C)(C)O)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 50 °C
Reaction time: 48 h

Procedure:
1 M aqueous NaOH solution (310 μL) is added to a solution of methyl 2-((S)-6-((R)-7-fluoro-4-(4-(3-hydroxy-3-methylbutyl)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (110 mg) in methanol (4 mL). The mixture is stirred at room temperature for 12 hours and at 50° C. for 2 days. 1 M aqueous NaOH solution (100 μL) is added and the mixture is stirred at 50° C. for 1 hour. Methanol is evaporated in vacuo, the residue is diluted with water and neutralized with 1 M aqueous HCl. The resulting mixture is extracted with ethyl acetate, and the combined organic phases are washed with brine and dried (MgSO4). The solvent is evaporated to give the title compound. Yield: 80 mg; LC (method 8): tR=0.59 min; Mass spectrum (ESI+): m/z=519 [M+H]+.
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:15][CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[I:17]I.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([C:5]2[C:14]([I:17])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:15][CH3:16])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: II
Reactant: CCc1cc(C2CCC2)ccc1C(=O)OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCc1cc(C2CCC2)c(I)cc1C(=O)OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a solution of methyl 4-cyclobutyl-2-ethylbenzoate (compound 181.3, 7.70 g, 35.3 mmol, 1.00 equiv) in acetic acid (80 mL) was added iodine (8.98 g, 35.4 mmol, 1.00 equiv), NaIO4 (3.78 g, 17.7 mmol, 0.50 equiv), and sulfuric acid (0.870 g, 8.87 mmol, 0.25 equiv). The reaction mixture was stirred at 60° C. overnight. After cooling to room temperature, the reaction was slowly quenched with Na2S2O3 (aq., sat.). The mixture was extracted with 200 mL of ethyl acetate and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:50) to furnish 10.5 g (86%) of the desired product as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:28]1[CH:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][C:34]([C:31]3[CH:32]=[CH:33][C:28]([C:22]4[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=4[Cl:20])=[CH:29][CH:30]=3)=[O:35])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Reactant: CN1CCC(CN(C)c2nc3cc(N)ccc3o2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)c4ccc(-c5ccc(Cl)cc5Cl)cc4)ccc3o2)C1
Yield: 45.9 %

Procedure:
Combine rac-N2-methyl-N2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.040 g, 0.154 mmol), 2′,4′-dichloro-biphenyl-4-carboxylic acid (0.062 g, 0.230 mmol), HATU (0.058 g, 0.154 mmol), polystyrene-bound diisopropylamine (0.385 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (10 mL). Shake the mixture overnight at room temperature. Filter the mixture and wash the polystyrene resin with 1:1 CH2Cl2/MeOH. Subject the mixture to flash column chromatography on an ISCO Companion (12 g column, eluting with 10% 2M NH3 in MeOH/CH2Cl2) to yield a colorless oil (0.036 g). Dissolve the oil in CH2Cl2, wash with 1.0M NaOH (3×25 mL), dry over Na2SO4, filter, concentrate in vacuo, and pump overnight on high vacuum to yield the desired product (0.031 g, 40%). mass spectrum (m/e): 509.0 (M+1), 507.0 (M−1). 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.03 (d, J=8.8 Hz, 2H), 7.80-7.78 (m, 1H), 7.73-7.71 (m, 1H), 7.61-7.48 (m, 4H), 7.40-7.33 (m, 2H), 3.50 (d, J=8.0 Hz, 1H), 3.13 (s, 3H), 2.65-2.55 (m, 1H), 2.44-2.34 (m, 2H), 2.28-2.21 (m, 1H), 2.23 (s, 3H), 1.93-1.83 (m, 2H), 1.49-1.39 (m, 2H).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:21])[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[CH2:18]([O:17][C:15]1[C:14]([Cl:21])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1)[CH:19]=[CH2:20]
Reactant: C=CCOc1cc2c(cc1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOc1cc2c(cc1Cl)C(C)CNCC2
Reaction time: 8 h
Yield: 114.4 %

Procedure:
A solution of N-trifluoroacetyl-7-allyloxy-8-chloro-1-methyl-2,3,4,5tetrahydro-1H-3-benzazepine (23 mg, 0.066 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred overnight at 20 C. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated to give 19 mg of a white solid. 1H NMR (400 MHz, CD3OD) d 7.12 (s, 1 H), 6.81 (s, 1 H), 6.03 (m, 1 H), 5.43 (d, J=17 Hz, 1 H), 5.24 (d, J=10 Hz, 1 H), 4.57 (d, J=5 Hz, 2 H), 3.1-2.9 (m, 5 H),