Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][N:32]1[CH:36]=[CH:35][N:34]=[CH:33]1)=[O:6])[CH:2]=[CH2:3].[CH3:37][I:38]>CC(C)=O>[I-:38].[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][N+:32]1[CH:36]=[CH:35][N:34]([CH3:37])[CH:33]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cn3ccnc3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CC(C)=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C[n+]3ccn(C)c3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Temperature: 25 °C

Procedure:
A mixture of allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(imidazol-1-yl) methylpyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate (15.4 g), methyl iodide (18.6 ml) and acetone (80 ml) was stirred at ambient temperature for hours. The reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (75 g) eluting with a mixture of dichloromethane and methanol (9:1, V/V). The fractions containing the desired compound were collected and evaporated in vacu to give allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(3-methyl-1-imidazolio) methylpyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate iodide (17.72 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:10]=1.B(Cl)(Cl)Cl.CO.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[F:17][C:14]([F:15])([F:16])[C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])[O:13][N:12]=1
Reactant: COc1ccccc1-c1cc(C(F)(F)F)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Oc1ccccc1-c1cc(C(F)(F)F)no1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
To a mixture of 5-(2-methoxyphenyl)-3-(trifluoromethyl)-1,2-oxazole (C10) (502 mg, 2.06 mmol) and tetra-n-butylammonium iodide (915 mg, 2.48 mmol) in dichloromethane (20 mL) cooled to −78° C. was added boron trichloride (1 M in dichloromethane, 4.95 mL, 4.95 mmol). The reaction was allowed to stir at room temperature for 24 hours, and then cooled to −78° C., whereupon methanol (3 mL) was slowly added followed by water (30 mL). The mixture was extracted with dichloromethane (2×10 mL), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 20% tert-butyl methyl ether in heptanes) afforded the title compound as a white solid. Yield: 283 mg, 1.23 mmol, 60%. 1H NMR (400 MHz, CDCl3) δ 5.94 (s, 1H), 6.96 (br d, J=8.2 Hz, 1H), 7.02 (s, 1H), 7.09 (br dd, J=8, 8 Hz, 1H), 7.39 (ddd, J=8, 8, 1.6 Hz, 1H), 7.89 (dd, J=7.9, 1.7 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:15][C:16]([F:21])([F:20])C([O-])=O.[K+].C1(C)C=CC=CC=1>CN(C)C=O.[Cu]I>[CH3:14][C:3]1[C:2]([C:16]([F:21])([F:20])[F:15])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:12][CH3:13])[CH:4]=1
Reactant: COC(=O)c1cc(Br)c(C)cc1OC
Reactant: O=C([O-])C(F)(F)F
Agent: [Cu]I
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(F)(F)F)c(C)cc1OC
Temperature: 170 °C

Procedure:
To a mixture of methyl 5-bromo-4-methyl-2-(methyloxy)benzoate (may be prepared as described in Description 43; 2.5 g, 9.65 mmol) in N,N-dimethylformamide (40 ml) was added copper (I) iodide (4.04 g, 21.23 mmol) and potassium trifluoroacetate (2.94 g, 19.30 mmol). Toluene (10 ml) was added and the mixture heated in Dean Stark apparatus at 170° C. for 45 minutes. The toluene was removed via the Dean Stark trap and the resulting mixture was heated for 18 hours at 170° C. The mixture was diluted with water (10 ml) and ethyl acetate (20 ml) and the solid was removed using Celite. The filtrate was taken and the organic layer separated, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, 50% Cyclohexane/diethyl ether) to yield the title compound as a white solid. 1.76 g.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16](O)[CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:27].C(=O)([O-])O.[Na+]>C1C=CC=CC=1.CCOCC>[Br:27][CH:16]([CH2:17][CH3:18])[CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][N:8]([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][CH2:10]1
Reactant: BrP(Br)Br
Reactant: CCC(O)CCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCC(Br)CCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
1-(4-(diphenylmethyl)piperazinyl)pentane-3-ol (940 mg) was dissolved in benzene (10 ml) and ether (10 ml), and then phosphorus tribromide (0.2 ml) was added thereto, followed by stirring the mixture overnight at room temperature. To the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added and the resultant was extracted 3 times with ethyl acetate. Organic layers were combined and washed with brine. The resultant was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 340 mg of 1-(3-bromopentyl)-4-(diphenylmethyl)piperazine. Yield: 31%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:6][CH2:7][CH2:8][OH:9]>>[Br-:6].[OH:9][CH2:8][CH2:7][N+:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: OCCBr
Reactant: c1cscn1
Product: OCC[n+]1ccsc1
Product: [Br-]

Procedure:
Thiazole (4.3 g) and 2-bromoethanol (12.5 g) were mixed and heated under reflux for 5 hours. The reaction was left standing at room temperature to give white needles. The crystals were washed with acetone, collected by filtration and dried under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[C:9]([CH3:13])([CH3:12])[CH2:10][OH:11].N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[C:9]([CH3:12])([CH3:13])[CH:10]=[O:11]
Reactant: COC(=O)CCC/C=C\C(C)(C)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCC/C=C\C(C)(C)C=O
Reaction time: 5 h
Yield: 77.1 %

Procedure:
0.530 g (2.65 mmoles) of (Z)-8-Hydroxy-7,7-dimethyl-5-octenoic acid methyl ester in 5 ml of methylene chloride was added slowly to a mixture of CrO3 (2.1 g; 21 mmol) and pyridine (3.5 g; 42 mmol) suspended in 55 ml of methylene chloride at room temperature. The reaction mixture was stirred for 5 hrs. The dichloromethane phase was decanted, and the precipitate was washed three times with ether. The organic phases were combined, washed with chilled 1 N sodium hydroxide, 1 N sulfuric acid, saturated sodium bicarbonate solution and brine then dried (MgSO4) and concentrated to give 0.53 g of crude material. Purification by chromatography or a silica gel column afforded 0.405 g (77.1%) of pure (Z)-8-Oxo-7,7-dimethyl-5-octenoic acid methyl ester (100% pure, by GC-analysis).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13]/[CH:14]=[CH:15]/[CH2:16][N:17]([CH2:19][C:20]#[N:21])[CH3:18])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-:27].[K+].[K+].OO.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13]/[CH:14]=[CH:15]/[CH2:16][N:17]([CH3:18])[CH2:19][C:20]([NH2:21])=[O:27])=[CH:10][CH:9]=2)=[O:7])=[CH:24][CH:25]=1
Reactant: CN(CC#N)C/C=C/COc1ccc(C(=O)c2ccc(Br)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C/C=C/COc1ccc(C(=O)c2ccc(Br)cc2)cc1)CC(N)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 314.6 %

Procedure:
A suspension of 0.4 g of (E)-[[4-[4-(4-bromo-benzoyl)-phenoxy]-but-2-enyl]-methyl-amino]-acetonitrile (Ex. 2j) and 0.04 g of potassium carbonate in 3 ml of dimethyl sulphoxide is cooled to 0° C. and treated with 1 ml of 30% hydrogen peroxide solution. The reaction mixture is warmed to room temperature and stirred overnight. For the working up, the mixture is treated with 10 ml of water and the separated crystals are filtered off and washed with water. There is obtained 0.38 g of (E)-2-[[4-[4-(4-bromo-benzoyl)-phenoxy]-but-2-enyl]-methyl-amino]-acetamide, MS: m/e 372 (M+ -H2NCO, 1Br).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[Br:9][C:10]1[CH:11]=[C:12]([F:17])[C:13](F)=[N:14][CH:15]=1.[F:18]C1C=CC(S(N)(=O)=O)=CC=1[N+]([O-])=O>>[Br:9][C:10]1[CH:11]=[C:12]([F:17])[C:13]([O:8][CH2:7][C:4]2([F:18])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:14][CH:15]=1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Fc1cc(Br)cnc1F
Reactant: OCC1CCOCC1
Product: Fc1cc(Br)cnc1OCC1(F)CCOCC1

Procedure:
The title compound was prepared by substituting EXAMPLE 306C for (tetrahydro-2H-pyran-4-yl)methanol and 5-bromo-2,3-difluoropyridine for 4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 279A.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:36](O)(=O)[CH3:37].[C:40](=O)([O-])O.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([NH:34][CH2:40][CH2:36][CH3:37])=[CH:32][CH:33]=2)[N:15]=1)([CH3:8])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])O
Reactant: CC(=O)O
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(N)cc2)nc1
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCNc1ccc(CN(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)c2ncc(CC)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[(4-{2-[(4-Aminobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (175 mg) synthesized in Example 439-2 was dissolved in dichloroethane (2.0 mL), propionylaldehyde (24 mg), acetic acid (20 μL) and triacetoxysodium tetrahydroborate (100 mg) were successively added thereto, and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1) to give the title compound (68 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:19][C:20]([O:22]C)=[O:21].[OH-].[Li+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: COC(=O)Cc1ccc(OC2CCN(C(C)=O)CC2)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(OC2CCN(C(C)=O)CC2)ccc1CC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl 2-methoxy-4-(1-acetyl-4-piperidyloxy)phenylacetate (0.18 g, 0.56 mmol) was dissolved in THF (5 ml) and treated with lithium hydroxide (0..67 ml of a 1M aqueous solution, 0.67 mmol). The mixture was stirred at ambient temperature for 4 hours, then treated with an additional 0.2 ml of 1M lithium hydroxide. The mixture was heated at 60° for 6 hours, then cooled and concentrated in vacuo. The residue was acidified with 1M HCl, and extracted with ethyl acetate. The combined ethyl acetate layers were extracted with saturated aqueous sodium carbonate. The combined sodium carbonate layers were acidified with concentrated HCl and extracted with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give 2-methoxy-4-(1-acetyl-4-piperidyloxy)phenyl-acetic acid.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.COCCO>[OH-].[OH-].[Pd+2].CC(O)=O>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:9]2[CH:4]([CH2:5][NH:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)n1ccc2cnccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: COCCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2CNCCC21
Temperature: 70 °C
Yield: 99.8 %

Procedure:
To a solution of tert-butyl 1H-pyrrolo[3,2-c]pyridine-1-carboxylate (2.55 g) in the mixture solvent of glycol monomethyl ether (40 mL) and AcOH (1 mL) was added a catalytic amount of Pd(OH)2/C. The suspension was heated at 70° C. for 24 h under H2 (2.0 MPa) and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 10:1 (v/v) CH2Cl2/MeOH) to give the product as viscous liquid (2.64 g, 100.00%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:17])[N:6]([CH3:18])[CH2:5]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:18][N:6]1[CH2:5][CH:4]([CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][N:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)[CH2:26][CH2:27]2)[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7]1=[O:17]
Reactant: CN1CC(CCCl)c2nc3ccccc3n2C1=O
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1CC(CCN2CCN(c3ccccn3)CC2)c2nc3ccccc3n2C1=O

Procedure:
To 50 mL of toluene was added 5.0 g (0.019 mol) of 4-(2-chloroethyl)-3,4-dihydro-2-methylpyrimido[1,6-a]benzimidazol-1(2H)-one, 6.19 g (0.038 mol) of 1-(2-pyridyl)piperazine, and 3.8 g (0.038 mol) of triethylamine. The reaction mixture was heated to reflux for 24 hours. The reaction mixture was washed with 2×50 mL of NaOH, dried over Na2SO4, filtered and concentrated by rotary evaporation. The residue was crystallized from isopropyl alcohol to afford 5.5 g (75%) of analytically pure crystals, mp 158°-59° C.
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1.[CH2:10]([NH:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH:32]([CH3:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]([CH3:41])([CH3:40])[CH2:24]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C.Cl.C(N(CC)CC)C>O1CCCC1>[CH3:8][C:5]1([CH3:9])[CH2:6][O:7][P:2]([N:22]([CH:23]2[CH2:28][C:27]([CH3:29])([CH3:30])[N:26]([O:31][CH:32]([CH3:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:25]([CH3:40])([CH3:41])[CH2:24]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[O:3][CH2:4]1
Reactant: CCCCCCCCCCCCNC1CC(C)(C)N(OC(C)c2ccccc2)C(C)(C)C1
Reactant: CC1(C)COP(Cl)OC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCN(C1CC(C)(C)N(OC(C)c2ccccc2)C(C)(C)C1)P1OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A solution of 3.03 grams (18.0 mmol) of 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane in 10 ml of tetrahydrofuran is added over ten minutes to a solution of 8.00 grams (18.0 mmol ) of 4-dodecylamino-1-alpha-methylbenzyloxy2,2,6,6-tetramethylpiperidine, 1.91 grams (18.9 mmol) of triethylamine, and 25 ml of tetrahydrofuran. The reaction temperature increases from 20° C. to 30° C. during the addition, and triethylamine hydrochloride precipitates from solution. The reaction mixture is stirred at ambient temperature for two hours. The precipitate is removed by filtration, and the filtrate is concentrated at reduced pressure. Residual volatiles are removed by Kugelrohr distillation (at 100° C./0.2 mm) to afford 10.1 grams (97% yield) of the title compound as a viscous oil.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:3].[C:23](=O)([O-])[O-].[K+].[K+].C(O[CH2:33][CH3:34])(=O)C>>[CH2:20]([N:16]([CH2:17][CH2:18][CH3:19])[C:14]([C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([C:2]2[O:3][CH:23]=[C:33]([CH3:34])[N:1]=2)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:15])[CH2:21][CH3:22]
Reactant: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)OC)c1
Reactant: CCOC(C)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2nc(C)co2)c1
Temperature: 25 °C

Procedure:
A stirred solution of methyl 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate (200 mg, 0.65 mmol) chloroacetone (10 mL, 93 mmol) and potassium carbonate (90 mg, 0.65 mmol) was refluxed for 18 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 2 N sodium hydroxide (2×50 mL), and saturated sodium chloride, dried (magnesium sulfate), and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:1 ethyl acetate/hexanes) provided methyl 3-[(dipropylamino)carbonyl]-5-(4-methyl-1,3-oxazol-2-yl)benzoate (119 mg): 1H NMR (300 MHz, CDCl3) δ 8.70 (d, J=1 Hz, 1H), 8.20 (d, J=1 Hz, 1H), 8.09 (d, J=1 Hz, 1H), 7.48 (s, 1H), 3.96 (s, 3H), 3.46 (d, J=7 Hz, 2H), 3.16 (t, J=7 Hz, 2H), 2.26 (s, 3H), 1.71 (d, J=7 Hz, 2H), 1.54 (d, J=7 Hz, 2H), 1.00 (t, J=7 Hz, 3H), 0.74 (t, J=7 Hz, 3H); ESI MS m/z 345 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:17][CH:18]1[NH:22][C:21](=O)[CH2:20][CH2:19]1.P(Cl)(Cl)(Cl)=O>>[CH3:1][C:2]1([CH3:16])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]([C:21]2[CH2:20][CH2:19][CH:18]([CH3:17])[N:22]=2)[C:10]2[C:15]1=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CC1(C)c2ccccc2Nc2ccccc21
Reactant: CC1CCC(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCC(N2c3ccccc3C(C)(C)c3ccccc32)=N1
Yield: 11 %

Procedure:
Reaction of 9,9-dimethylacridan, 5-methyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 9,9-DIMETHYL-10-(5-METHYL-1-PYRROLIN-2-YL)ACRIDAN as a distillable oil, b.p. 160-180° C. at 0.15 mm Hg. in 11% yield. Conversion of the free base to the hydrochloride salt affords 9,9-DIMETHYL-10-(5-METHYL-1-PYRROLIN-2-YL)ACRIDAN HYDROCHLORIDE, m.p. 232.5-234.5° C. (dec.) (corr.), by trituration with hot benzene.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[Cl-].[Cl-].[Al+3].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH3:22]>C(Cl)Cl>[Cl:13][C:14]1[C:15]([O:21][CH3:22])=[CH:16][C:17]([CH3:20])=[C:18]([C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:19]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1cc(C)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1cc(Cl)c(OC)cc1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.1 %

Procedure:
Ethyl 2-chloro-2-oxoacetate (6.43 mL, 57.47 mmol) was added dropwise to a stirred suspension of aluminum trichloride (7.66 g, 57.47 mmol) in DCM (60 mL) at 0° C., over a period of 5 minutes under nitrogen. The resulting suspension was stirred at 0° C. for 15 minutes. A solution of 1-chloro-2-methoxy-4-methylbenzene (5 g, 31.93 mmol) in DCM (50 mL) was added dropwise over a period of 5 minutes and the resulting mixture was stirred at 0° C. for 90 minutes. The reaction mixture was cautiously quenched with water (300 mL) at 0° C., extracted with EtOAc (2×200 mL), the organic layers were combined, dried over MgSO4, filtered and evaporated to afford cream solid. The crude solid was triturated with DCM to give a solid which was collected by filtration and dried under vacuum to give ethyl 2-(5-chloro-4-methoxy-2-methylphenyl)-2-oxoacetate (4.27 g) as a white solid. The residue was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford ethyl 2-(5-chloro-4-methoxy-2-methylphenyl)-2-oxoacetate (1.85 g,) as a white solid. Total yield of ethyl 2-(5-chloro-4-methoxy-2-methylphenyl)-2-oxoacetate (6.12 g, 74.7%).
Reaction SMILES: ClC(Cl)C.[OH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH:16]=[O:17].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:22]([N:24]([CH2:29][CH3:30])[S:25](Cl)(=[O:27])=[O:26])[CH3:23]>C(Cl)Cl>[OH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:25](=[O:27])(=[O:26])[N:24]([CH2:29][CH3:30])[CH2:22][CH3:23])[CH:12]=2)[C:7]=1[CH:16]=[O:17]
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: CCN(CC)S(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCN(CC)S(=O)(=O)c1ccc2c(C=O)c(O)ccc2c1
Temperature: 50 °C
Yield: 85.1 %

Procedure:
600 ml of a dichloroethane solution containing 150 g (0.87 mole) of 2-hydroxy-1-naphthaldehyde and 250 g (1.87 moles) of anhydrous aluminum chloride was stirred with heating at 50° C. To the solution was added dropwise 172.2 g (1 mole) of N,N-diethylsulfamoyl chloride. After the completion of the dropwise addition, the mixture was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was poured into 1 liter of ice water. Methylene chloride was added to the mixture and it was extracted and separated. The organic layer was concentrated to about 500 ml. To the concentrate was added methanol to precipitate crystals. The precipitated crystals were collected by filtration, and washed with methanol to obtain 228 g (0.74 mole) of 2-hydroxy-6-(N,N-diethylsulfamoyl)-1-naphthaldehyde.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=2[O:18][CH3:19])=[C:4]([CH2:20][N:21]2[C@@H:25]([CH3:26])[C@@H:24]([C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)[O:23][C:22]2=[O:41])[CH:3]=1.N(OC(C)(C)C)=O.[CH3:49][S:50]SC>>[F:34][C:33]([F:35])([F:36])[C:31]1[CH:32]=[C:27]([C@H:24]2[O:23][C:22](=[O:41])[N:21]([CH2:20][C:4]3[CH:3]=[C:2]([S:50][CH3:49])[CH:7]=[CH:6][C:5]=3[C:8]3[CH:13]=[C:12]([CH:14]([CH3:15])[CH3:16])[C:11]([F:17])=[CH:10][C:9]=3[O:18][CH3:19])[C@H:25]2[CH3:26])[CH:28]=[C:29]([C:37]([F:39])([F:38])[F:40])[CH:30]=1
Reactant: CSSC
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(N)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: CC(C)(C)ON=O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(SC)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution (4S,5R)-3-[(4-amino-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (200 mg, 0.34 mmol) in methyl disulfide (2 mL) was added tert-butyl nitrite (70 mg, 0.68 mmol). The resulting mixture was stirred at 80° C. for 30 min. An aliquot indicated completion of the reaction. The titled compound was obtained as a glassy material after two preparative TLC plates using respectively 20% EtOAc in hexanes and 10% EtOAc in dichloromethane as the eluent. LC-MS: 616.21 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 1:1 mixture of rotamers δ 7.84 (s, 1H), 7.67 (s, 2H), 7.35 (s, 0.5H), 7.22-7.28 (m, 1.5H), 7.12-7.19 (m, 1H), 6.94-7.02 (m, 1H), 6.61-6.68 (m, 1H), 5.55 (d, J=8.0 Hz, 0.5H), 5.31 (d, J=9.5 Hz, 0.5H), 4.85 (d, J=16.0 Hz, 0.5H), 4.83 (d, J=15.5 Hz, 0.5H), 3.99 (d, J=15.5 Hz, 0.5H), 3.69-3.81 (m, 4.5H), 3.12-3.24 (m, 1H), 2.54, (s, 1.5H), 2.53 (s, 1.5H), 1.11-1.27 (m, 6H), 0.50 (d, J=6.5 Hz, 1.5H), 0.31 (d, J=7.0 Hz, 1.5H).