Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH3:25])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:32]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:3]([C:1]([NH2:2])=[O:32])=[N:4][CH:5]=1)[CH3:25]
Reactant: CC(=O)O
Reactant: C[C@@H](Nc1cnc(C#N)c(Nc2cnc3ccccc3c2)n1)C(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: C[C@@H](Nc1cnc(C(N)=O)c(Nc2cnc3ccccc3c2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (R)-2-(5-cyano-6-(quinolin-3-ylamino)pyrazin-2-ylamino)propanamide (74 mg, 0.222 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (63 mg). MS 352.3 (M+H); UV 206.6, 223.0, 245.6, 295.3, 351.1 nm; t 0.360 min.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)=[O:3].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](OCC)=[O:21].[H-].[Na+].Cl>O.O1CCCC1>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](=[O:21])[CH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cccs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC(=O)c1cccs1)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
4-Trifluoromethoxyacetophenone (4.1 g, 20 mM) and ethyl 2-thiophenecarboxylate (3.1 g, 20 mM) were placed in a 300 ml eggplant type flask, and 100 ml of dehydrated tetrahydrofuran was added thereto. After this mixture was stirred at room temperature, a 60% oil suspension of sodium hydride (1.1 g, 26 mM) was slowly added thereto. Thereafter, the resulting mixture was heated under reflux for 6 hours and allowed to cool to room temperature. After 100 ml of water was added to the reaction mixture under cooling with ice, the reaction mixture was adjusted to pH 1.0 with a concentrated aqueous solution of hydrochloric acid and then extracted with 100 ml of ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain 6.2 g of 1-(2-thienyl)-3-(4-trifluoromethoxyphenyl)-1,3-propanedione in an almost quantitative yield.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1CCN>C(#N)C>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH2:11][CH2:12][NH:8][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NCCc1c(F)cccc1F
Solvent: CC#N
Product: Fc1cccc(F)c1CCNC(=S)n1ccnc1
Yield: 124.7 %

Procedure:
A solution of 1,1'-thiocarbonyldiimidazole (9.5 g, 48 mmol) and 2-(2,6-difluorophenyl)ethylamine (7.54 g, 48 mmol) in acetonitrile (100 mL) was stirred at room temperature for 20 h. The solution was concentrated under reduced pressure and the resulting precipitate was collected by filtration and triturated with hexane to provide 16 g of crude titled product as a brown solid:
Reaction SMILES: [ClH:1].C([S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH2:8]/[C:7]/1=[CH:25]\[C:26]1[N:30]([CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:29]=[N:28][N:27]=1)(=O)C>C(O)C>[ClH:1].[CH:15]1([C:13](=[O:14])[CH:12]([N:9]2[CH2:10][CH2:11][CH:6]([SH:5])/[C:7](=[CH:25]/[C:26]3[N:30]([CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:29]=[N:28][N:27]=3)/[CH2:8]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:16][CH2:17]1
Reactant: CCOC(=O)CCCn1nnnc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1SC(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCCn1nnnc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99 %

Procedure:
Hydrogen chloride was passed through a solution of (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({1-[3-(ethoxycarbonyl)propyl]-1H-tetrazol-5-yl}methylidene)piperidine (139 mg) in ethanol (4 ml) at 0° C. The mixture was stirred under tightly sealed condition at room temperature for 3.5 hours. The solvent and excess amount of hydrogen chloride were removed in vacuo, and the residue was purified by chromatography on silica gel using a mixture of ethanol and dichloromethane (2:98 to 12:88) as the eluent to afford the title compound as a pale yellow amorphous solid (136 mg, yield 99%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=O.[N:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+:12]=[N-:13].[O-]CC.[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:14]([N:11]=[N+:12]=[N-:13])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1cc(C)cc(C=O)c1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=Cc1cc(C)cc(C)c1)N=[N+]=[N-]
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A mixture of 5 g of 3,5-dimethylbenzaldehyde and 19.3 g of ethyl azidoacetate is added, at −10° C. under dry nitrogen, to a mixture of 25 ml of ethanol and 50 ml of a 21% solution of sodium ethoxide in ethanol. The mixture is left stirring for 1 hour at −10° C. and for fourteen and a half hours at +5° C. It is poured into 100 ml of water and the precipitate formed is filtered off and washed with water. The precipitate is dissolved in ether and this solution is dried over MgSO4 and then evaporated to give the product, which is used without further purification in the subsequent step.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:7][C@H:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:5]([N:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])NC(OC(C)(C)C)=O)[CH2:4][O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].BrCC(OC)=O>CC#N>[CH3:1][C:2]1([CH3:33])[O:7][C@H:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:5]([NH:17][C:26](=[O:27])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:4][O:3]1
Reactant: Cc1ccc(/C=C/[C@H]2OC(C)(C)OCC2N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Agent: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ccc(/C=C/[C@H]2OC(C)(C)OCC2NC(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Yield: 90 %

Procedure:
To a suspension of 1,3-ketal-2-hydrazino (8B) (23 mg, 0.05 mmol) and Cs2CO3 (41 mg, 0.13 mmol) in 0.5 mL CH3CN, was added methyl bromoacetate (17 mg, 0.10 mmol) in 0.5 mL CH3CN. The reaction mixture was heated at 50° C. for 3 h. The reaction mixture was then refluxed until the intermediate was consumed as indicated by TLC. The reaction mixture was quenched with saturated NH4Cl (aq.), and extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and the solvent was removed in vacuo. Purification by flash chromatography on silica gel afforded the desired product as a white solid (90%) (Magnus et al., Org. Lett. 2009, 11, 5646).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH2:6]([C:8]([CH2:20][CH3:21])([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)[OH:9])[CH3:7].C(N(CC)CC)C.O1CCCC1>O>[C:1]([O:9][C:8]([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)([CH2:6][CH3:7])[CH2:20][CH3:21])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: CCC(O)(CC)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC(CC)(CC)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
A total of 15 mmole of acryloyl chloride was added dropwise to a mixture of 10 mmole of the above-prepared α, α-diethyl-1-adamantanemethanol, 20 mmole of triethylamine and 40 ml of tetrahydrofuran over about 30 minutes. After the completion of addition, the resulting mixture was stirred at room temperature for 6 hours. After the addition of water, the reaction mixture was concentrated, and the concentrate was subjected to column chromatography on a silica gel to thereby yield the title compound in a yield of 72%.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[CH:5][CH:4]=1.ClN1C(=[O:24])CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:10](=[O:24])[CH2:11][C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc2ccn(-c3ccccc3)c2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COc1ccc2c(n1)N(c1ccccc1)C(=O)C2
Temperature: 125 °C
Reaction time: 12 h
Yield: 46.5 %

Procedure:
To a stirred solution of 9.64 g (43 mmol) of the compound of step 1 in DCM (250 ml) was added N-chlorosuccinimide (6.02 g, 45 mmol) in one portion at room temperature. The reaction mixture was stirred for 12 h and the solvent was evaporated. The remaining residue was dissolved in a mixture of acetic acid (180 ml) and phosphoric acid (31 ml) and heated to 125° C. for 1 h. The solution was cooled to room temperature and concentrated in vacuo. The remaining residue was poured onto ice and the aqueous phase was extracted with EA. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The remaining oil was purified by column chromatography on silica gel (EA/HEP) to give 4.80 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].Cl[C:25](Cl)([O:27][C:28](=O)[O:29]C(Cl)(Cl)Cl)Cl>C1COCC1>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([C:2]2([NH:1][C:28](=[O:29])[O:27][CH3:25])[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:12])=[C:14]([O:22][CH3:23])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: COc1cc(C(C)C)ccc1C1(N)C(=O)c2ccccc2C1=O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)NC1(c2ccc(C(C)C)cc2OC)C(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.50 g, 1.62 mmol) in anhydrous THF (10 ml) was added triphosgene (0.21 g, 0.71 mmol) and stirred for 30 min. The reaction mixture was concentrated and was dissolved in methanol (6 mL) and was stirred for 2 hrs and was concentrated to afford the title compound (220 mg, 93%).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][O:11][C:12]([C:14]1[S:15][C:16]([CH2:19][CH2:20][CH2:21][C:22](=O)[CH2:23]Br)=[CH:17][CH:18]=1)=[O:13]>CN(C=O)C>[CH3:10][O:11][C:12]([C:14]1[S:15][C:16]([CH2:19][CH2:20][CH2:21][C:22]2[NH:9][C:4]3[N:3]=[C:2]([NH2:1])[NH:7][C:6](=[O:8])[C:5]=3[CH:23]=2)=[CH:17][CH:18]=1)=[O:13]
Reactant: COC(=O)c1ccc(CCCC(=O)CBr)s1
Reactant: Nc1cc(=O)[nH]c(N)n1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCc2cc3c(=O)[nH]c(N)nc3[nH]2)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.6 %

Procedure:
To a suspension of 2,6-diaminopyrimidin-4-one (315 mg, 2.5 mmol) in anhydrous DMF (15 mL) was added 7 (about 2.4 mmol). The resulting mixture was stirred under N2 at room temperature for 3 days. After evaporation of solvent under reduced pressure, MeOH (20 mL) was added followed by silica gel (1.5 g). The resulting plug was loaded on to a silica gel column (3.5×12 cm) and eluted with CHCl3 followed by 3% MeOH in CHCl3 and then 5% MeOH in CHCl3. Fractions with an Rf=0.56 (MeOH/CHCl3 1:5) were pooled and evaporated to afford 300 mg of 8 as white powder in 38% yield. 1H NMR (DMSO-d6): δ 1.89-1.97 (m, 2H), 2.49-2.54 (t, J=7.2 Hz, 2H), 2.82-2.85 (t, J=7.2 Hz, 2H), 3.78 (s, 3H), 5.89 (s, 1H), 5.96 (s, 2H), 6.97-6.98 (d, J=3.6 Hz, 1H), 7.64-7.65 (d, J=3.6 Hz, 1H), 10.13 (s, 1H), 10.82 (s, 1H).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[O:27]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:32]([CH:29]3[CH2:30][CH2:31][O:27][CH2:28]3)=[O:33])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)C1CCOC1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1CCOC1

Procedure:
The title compound, light yellow solid (79 mg, 75%), MS (ISP) m/z=425.2 [(M+H)+], mp 183° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and (RS)-tetrahydro-furan-3-carboxylic acid.
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:10]=[C:11]2[O:17][N:16]=[C:15]([OH:18])[C:12]2=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C.O>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2[C:15]([OH:18])=[N:16][O:17][C:11]=2[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Oc1noc2c[n+](Cc3ccccc3)ccc12
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Oc1noc2c1CCN(Cc1ccccc1)C2
Reaction time: 24 h
Yield: 69.7 %

Procedure:
To a stirred solution of 6-benzyl-3-hydroxy-isoxazolo[5,4-c]pyridin-6-ium bromide (93 g, 303 mmol) in ethanol/water (500 mL/500 mL) was added NaBH4 (18.66 g, 494 mmol) cautiously portionwise, keeping the temperature under 35° C. (caution! Foams on addition!). The mixture was stirred for 24 h. The mixture was filtered, and the residue was washed with water. The combined filtrates were evaporated under reduced pressure until all of the ethanol had evaporated. A solid began to precipitate, and so the mixture was cooled in an ice-water bath with stirring for 30 min. The solution was filtered, and the residue was washed with cold water. The residue was dried to give 6-benzyl-4,5,6,7-tetrahydro-isoxazolo[5,4-c]pyridin-3-ol (48.6 g, 70%; HPLC 94% pure) as a yellowish solid. After some further evaporation of the combined mother liquors, a second crop gave a further 10.3 g (HPLC: 97.7% pure).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:10]=1[CH2:11][NH:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:5])C.[OH-].[K+].C1COCC1>>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:10]([CH2:11][NH:12][CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2F)c1CNC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2F)c1CNC1CCCC1
Yield: 113.6 %

Procedure:
A solution of 2-(4-chloro-phenyl)-5-cyclopentylaminomethyl-1-(2-fluoro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester I-5f (1.2 g, 2.68 mmol) in 1:2 1M KOH/THF was stirred at 55° C. for 17 hours. The reaction mixture was concentrated under vacuum and acidified to pH˜1 with concentrated hydrochloric acid. The residue was slurried in EtOH and filtered to remove KCl. The filtrate was concentrated under vaccum to give I-5k as an off-white solid (1.26 g, 97%): +APCI MS (M+1) 414.0.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=1[CH:10]=[O:11].Cl[CH2:18][C:19]1[CH2:20][CH2:21][N:22]([C:31](=[O:33])[CH3:32])[CH2:23][C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.CCOC(C)=O>[C:31]([N:22]1[CH2:23][C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:19]([CH2:18][O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[CH:10]=[O:11])[CH2:20][CH2:21]1)(=[O:33])[CH3:32]
Reactant: CC(=O)N1CCC(CCl)=C(c2ccccc2)C1
Reactant: O=Cc1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(COc2cccc(O)c2C=O)=C(c2ccccc2)C1
Temperature: 50 °C
Yield: 34.6 %

Procedure:
To a suspension of K2CO3 (40 mg, 0.28 mmol) and 2,6-dihydroxybenzaldehyde (40 mg, 0.28 mmol) in DMF (1 mL) was added a solution of 1-(4-(chloromethyl)-5-phenyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (35 mg, 0.14 mmol) in DMF (1 mL), the mixture was heated at 50° C. for 3 h, cooled to room temperature, and was diluted with EtOAc, organic layer was separated and aqueous layer was extracted with EtOAc. EtOAc layers were combined, washed with Sat. NaHCO3, brine, dried over Na2SO4, and was concentrated to give crude oil, which was purified by column (DCM/MeOH=90:10) to give 2-((1-acetyl-5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-6-hydroxybenzaldehyde (17 mg). 1H NMR (400 MHz, CDCl3, NMR shows rotamer exist, only one set of signal was reported) □ (ppm) 11.93 (s, 1H), 10.36 (s, 1H), 7.34 (m, 5H), 7.22 (m, 1H), 6.49 (d, J=8.8 Hz, 1H), 6.10 (d, J=8.8 Hz, 1H), 4.47 (s, 2H), 4.32 (s, 2H), 3.68 (t, J=6.0 Hz, 2H), 2.47 (m, 2H), 2.18 (s, 3H); MS (ESI) m/z 352.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][C:10]=2[CH3:18])=[CH:5][C:4]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[CH2:29][N:30]1[C@@H:34]([CH3:35])[C@@H:33]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[O:32][C:31]1=[O:43].C(Cl)(=O)C(Cl)=O.[OH-].[NH4+].C([N:55](C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH2:55])=[O:17])=[CH:11][C:10]=2[CH3:18])=[CH:5][C:4]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][C:20]=1[CH2:29][N:30]1[C@@H:34]([CH3:35])[C@@H:33]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[O:32][C:31]1=[O:43]
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2ccnc(C)c2)[C@@H]1C
Reactant: CCN(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(C(N)=O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2ccnc(C)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid (15 mg, 0.025 mmol) in CH2Cl2 (2 mL), was added 2M oxalyl chloride in CH2Cl2 (0.038 mL, 0.076 mmol) and 2 drops of DMF. The mixture was stirred at room temperature under N2 for 30 min. The reaction mixture was concentrated in vacuo. The residue was re-dissolved in THF (2 mL), then ammonium hydroxide (0.035 mL, 0.254 mmol) and diisopropylethylamine (0.013 mL, 0.076 mmol) were added. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC reverse phase (C-18), eluting with MeCN/water. The fractions were collected and lyophilized to give 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxamide as a white powder. LCMS calc.=590.2; found=590.0 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture o atropisomers) δ 8.49 (t, J=4.3 Hz, 1 H); 7.77 (br s, 1 H); 7.72 (s, 0.5 H); 7.66 (br s, 1.5 H); 7.46-7.38 (m, 3 H); 7.33-7.29 (m, 1 H); 7.14 (dd, J=2.2, 7.7 Hz, 1 H); 7.09 (dd, J=6.2, 8.5 Hz, 1 H); 7.06 (s, 0.5 H); 7.01 (s, 0.5 H); 6.95 (d, J=4.3 Hz, 0.5 H); 6.90 (d, J=4.4 Hz, 0.5 H); 6.17 (br s, 1 H); 5.79 (br s, 1 H); 5.43 (d, J=8.1 Hz, 0.5 H); 5.20 (d, J=8.0 Hz, 0.5 H); 4.92 (d, J=15.9 Hz, 0.5 H); 4.86 (d, J=15.8 Hz, 0.5 H); 4.22 (d, J=15.8 Hz, 0.5 H); 4.00 (d, J=15.8 Hz, 0.5 H); 3.88 (s, 1.5 H); 3.87 (s, 1.5 H); 3.80-3.75 (m, 1 H); 2.57 (s, 1.5 H); 2.56 (s, 1.5 H); 2.39 (s, 1.5 H); 2.35 (s, 1.5 H); 0.58 (d, J=6.5 Hz, 1.5 H); 0.47 (d, J=6.5 Hz, 1.5 H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:30])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:16]=1)[C:11]([CH3:29])([CH3:28])[CH2:10]2)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:30][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:16]=1)[C:11]([CH3:29])([CH3:28])[CH2:10]2
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(N3CCN(C)CC3)c1)C(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
To a stirred mixture solution of 6-chloro-3,3-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (1.0 g, 2.4 mmol) in methanol (5.0 mL) and tetrahydrofuran (6.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 6-chloro-3,3-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (892 mg, 90%) as a white solid: LC/MS m/e calcd for C23H28ClN3O2 (M+H)+: 414.95, observed: 414.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]#[N:15])[CH:10]([NH:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=1)[CH2:9][CH2:8]2)(=O)[CH3:2].C([OH:32])C.OO.[OH-].[Na+]>O>[CH3:2][C:1]1[NH:15][C:14](=[O:32])[C:13]2[C:5](=[CH:6][C:7]3[CH2:8][CH2:9][CH:10]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:28][CH:29]=4)[C:11]=3[CH:12]=2)[N:4]=1
Reactant: CCO
Reactant: CC(=O)Nc1cc2c(cc1C#N)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2cc3c(cc2c(=O)[nH]1)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC3
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 8 (1.33 g, 3.40 mmol), ethanol (15 ml), and water (3.1 ml) was cooled in an ice-bath, then 30% aqueous H2O2 solution (2.8 ml) was added followed by granulated sodium hydroxide pellets (0.230 g, 5.78 mmol). The reaction mixture was stirred at ˜0° C. for 10 min, then it was placed in an oil bath preheated to 55° C. and stirred at this temperature for 40 min. The reaction mixture was allowed to cool to room temperature, then the solvents were removed in vacuo and the residue was suspended in water (˜40 ml). The pH of this mixture was adjusted to ˜5 with 1N hydrochloric acid. The white precipitate was collected by filtration, washed with water, dried in vacuo over P2O5, then it was triturated with ether, collected by filtration and dried in vacuo. The title compound 9 was obtained as a white solid 1.11 g (83%), m.p. 277-281° C. (it melts with decomposition), (Found: C, 70.22; H, 6.43; N, 10.65; C23H25N3O3 requires C, 70.57; H, 6.44; N, 10.73%); δH ((CD3)2SO) 1.50 (9H, s, C(CH3)3), 2.31 (3H, s, Me), 1.87, 2.55 (each 1H, m, 7-H), 2.97 (2H, m, 8-H), 5.15 (1H, q, J 7.50, 6-H), 6.77 (2H, d, J 8.6, 3′,5′-H), 6.91 (1H, d, J 8.70, N10—H), 7.44, 7.87 (each 1H, s, 5-H, 9-H), 7.66 (2H, d, J 8.75, 2′,6′-H); m/z ESI) 783 {(2M+H)+, 100%}, 392 {(N+H)+, 30%}, 199 (90).