Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:12](O)(=[O:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].B(F)(F)F.CCOCC>O>[C:12]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[OH:11])(=[O:27])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Oc1cccc2ccccc12
Reactant: CCCCCCCCCCCCCCC(=O)O
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCC(=O)c1ccc2ccccc2c1O

Procedure:
1-Naphthol (72.1 g, 500 mmol) and pentadecanoic acid (121.2 g, 500 mmol) were mixed with boron trifluoride etherate (400 ml) and heated on a steam bath for 4 hours. Then 400 ml water was carefully added and heating was continued to remove as much of the ether as possible. The precipitated solid was filtered off, washed well with water and air dried. The crude product was recrystallized from ethanol to give the pentadecanoylnaphthol as light yellow plates. Yield: 110 g (60 percent).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.Cl.Br[CH2:13][CH:14](OC)OC.[H][H]>C1COCC1.CO.[Pd].CCO>[N:1]1[CH:13]=[CH:14][N:3]2[CH:4]=[C:5]([NH2:8])[CH:6]=[CH:7][C:2]=12
Reactant: COC(CBr)OC
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc2nccn2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
2-Amino-5-nitro pyridine was suspended in a 40 mL solution of EtOH/conc. HCl (3:1). To this suspension was added 2-bromo-1,1-dimethoxy-ethane (6.37 mL, 53.91 mmol) and the resulting mixture was heated to reflux for 8 h, after which additional 2-bromo-1,1-dimethoxy-ethane (6.37 mL, 53.91 mmol) was added. The mixture was heated at reflux overnight, cooled to rt and placed in a refrigerator for 24 h. The precipitates were collected, washed with ice-cold EtOH, air-dried and converted to the free-based using standard procedures to afford a yellow solid. The resulting crude yellow solid, (404 mg) was dissolved in 150 mL THF/MeOH (1:1) and the resulting solution was hydrogenated for 4 h over Pd/C (250 mg, 10%) using a hydrogen balloon. The mixture was filtered though Celite eluting with THF/MeOH (1:1) and the filtrate was concentrated. Purification was achieved using silica gel flash chomatography with 20% MeOH in CH2Cl2 to give Compound 846A (241 mg, 75%) as a colorless oil which turns dark upon standing.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([N:1]3[C:5]4=[N:6][CH:7]=[CH:8][CH:9]=[C:4]4[CH:3]=[CH:2]3)=[CH:12][CH:13]=2)=[O:29])=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=C(Nc1ccc(-n2ccc3cccnc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound can be synthesized from pyrrolo[2,3-b]pyridine, 4-fluoronitrobenzene and 4-chloro-3-(trifluoromethyl)phenyl isocyanate by using the same techniques as in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[CH2:13][CH2:12][N:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=C(C2(C(F)(F)F)CCN(C3C=CC(C(Cl)=[O:45])=C([N+]([O-])=O)C=3)C2)C=C(Cl)C=1.FC(C1C=CC=CC=1C1(C(F)(F)F)CC(C2C=CC=CC=2C(F)(F)F)N(C2C([N+]([O-])=O)=C(C=CC=2)C(Cl)=O)C1)(F)F>>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:23]([F:25])([F:26])[F:24])[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:19])=[O:45])=[CH:21][CH:22]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(Cl)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Reactant: O=C(Cl)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Agent: O=C(Cl)c1cccc(N2CC(c3ccccc3C(F)(F)F)(C(F)(F)F)CC2c2ccccc2C(F)(F)F)c1[N+](=O)[O-]
Product: O=C(O)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1

Procedure:
Representative compounds of the formula (V) and formula (V-a), respectively, include: 4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl)benzoyl chloride; 4-(3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-nitrobenzoylchloride; 4-(3-[3,5-bis(trifluoromethylphenyl]-3-(trifluoromethyl)pyrrolidin-1-yl]-2-nitrobenzoyl chloride and the like.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]=[CH:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)[N:19]=2)=[CH:14][CH:13]=1)C(=O)OC(C)(C)C.[C:34](=O)([OH:36])[O-:35].[Na+]>>[CH3:1][NH:2][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:22]=[CH:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:31])[F:32])=[CH:25][CH:24]=3)[N:19]=2)=[CH:16][CH:17]=1.[F:33][C:30]([F:31])([F:32])[C:34]([OH:36])=[O:35]
Reactant: O=C([O-])O
Reactant: CN(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)OC(C)(C)C
Agent: [Na+]
Product: CNCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: O=C(O)C(F)(F)F
Yield: 111 %

Procedure:
The title compound was prepared from tert-butyl methyl(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)carbamate (CB63), neutralized with aqueous sodium bicarbonate, and isolated as a yellow waxy solid with excess trifluoroacetic acid (5.73 g, 111%): 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.12 (d, J=8.2 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H), 7.37 (dd, J=9.0, 1.0 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H), 3.23-3.12 (m, 2H), 3.05 (dd, J=9.4, 6.3 Hz, 2H), 2.67 (s, 3H), 1.29-1.22 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −58.04, −75.71; ESIMS m/z 363 ([M+H]+).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:5]=1)(=[O:3])[CH3:2].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[CH3:25][N:26]([CH3:28])[CH:27]=[CH:2][C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=2)[N:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(C)=O)c1=O
Product: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)C=CN(C)C)c1=O
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 3-acetyl-5-methoxy-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (1.39 g, 4.45 mmol) in N,N-dimethylformamide dimethyl acetal (15 mL) was refluxed for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in AcOEt. The organic solution was washed with half-saturated brine, and the aqueous solution was extracted with AcOEt four times. The combined organic layers were dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (1.46 g, 89% yield) as orange crystals: mp 176-178° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.91 (3H, s), 3.14 (3H, s), 3.96 (3H, s), 5.80 (1H, d, J=13.2 Hz), 7.61-7.68 (2H, m), 7.80 (1H, br s), 7.84-7.90 (2H, m), 7.96 (1H, s). Anal. Calcd for C17H16F3N3O3: C, 55.59;
Reaction SMILES: N12CCCN=C1CCCCC2.[O:12]=[C:13]1[CH2:19][CH:18](S(C2C=CC=CC=2)(=O)=O)[C:17]2[CH:29]=[C:30]([C:33]([O:35][CH3:36])=[O:34])[CH:31]=[CH:32][C:16]=2[O:15][CH2:14]1.O.Cl>ClCCl>[O:12]=[C:13]1[CH:19]=[CH:18][C:17]2[CH:29]=[C:30]([C:33]([O:35][CH3:36])=[O:34])[CH:31]=[CH:32][C:16]=2[O:15][CH2:14]1
Reactant: COC(=O)c1ccc2c(c1)C(S(=O)(=O)c1ccccc1)CC(=O)CO2
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COC(=O)c1ccc2c(c1)C=CC(=O)CO2

Procedure:
0.084 ml (1.05 equivalents) of 1,8-diazabicyclo[5.4.0]undec-7-ene is added at ambient temperature to 217 mg (0.6 mmol) of methyl 3-oxo-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate, prepared according to example 2, in suspension in 20 ml of dichloromethane. From the addition of the base, the medium becomes translucent and slightly yellow. After addition of water and 1N hydrochloric acid, the phases are separated by settling and then the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with a saturated sodium hydrogencarbonate solution and then with brine. After drying and then concentrating under vacuum, 90 mg (68%) of methyl 3-oxo-2,3-dihydro-1-benzoxepin-7-carboxylate are obtained in the form of a white solid; M.p.=89–93° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[C:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)[N:6]=1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>N1C=CC=CC=1>[C:18]([O:17][C:16]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:35](=[O:36])[O:37][CH2:38][CH3:39])[S:3][C:4]=2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:14][CH:13]=1)=[O:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCc2nc(N)sc2Cc2ccc(S(C)(=O)=O)cc2)cc1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl [4-(2-{2-amino-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]carbamate (140 mg) was dissolved in pyridine (2 ml) under N2 atmosphere. Then, ethyl chloroformate (30.2 ml) was added to the solution at 0° C. The reaction mixture was stirred at r.t. for 2 hours, and concentrated in vacuo. The residue was dissolved in AcOEt, and washed with 1N-HCl, water and brine. The organic layer was dried over anhydrous MgSO4, and concentrated in vacuo to give ethyl {4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}carbamate (155.8 mg) as an off-white amorphous substance.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[N:12]([CH3:13])[C:11](=[O:14])[N:10]([CH3:15])[C:9](=[O:16])[CH:8]=1.[N+:17]([O-])([OH:19])=[O:18]>>[Cl:6][C:7]1[N:12]([CH3:13])[C:11](=[O:14])[N:10]([CH3:15])[C:9](=[O:16])[C:8]=1[N+:17]([O-:19])=[O:18]
Reactant: Cn1c(Cl)cc(=O)n(C)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(Cl)c([N+](=O)[O-])c(=O)n(C)c1=O
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To 25 ml of sulfuric acid was slowly added 8.5 g (0.049 mol) of 6-chloro-1,3-dimethyluracil as prepared in Synthesis Example 1 at 10° to 15° C. To this solution was gradually added 8.5 ml of fuming nitric acid at 0° to 5° C. After stirring for 5 minutes, the reaction mixture was poured onto ice and extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The resulting crystals were recrystallized from a mixed solvent of ethyl acetate and hexane to give 7.5 g (70%) of 6-chloro-1,3-dimethyl-5-nitrouracil having a melting point of 91° to 92° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25]2[C:29](OC)=[N:28][S:27](=[O:32])[N:26]=2)=[C:10]1[C:33]([O:35][CH2:36][CH3:37])=[O:34].[NH3:38]>>[OH2:16].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25]2[C:29]([NH2:38])=[N:28][S:27](=[O:32])[N:26]=2)=[C:10]1[C:33]([O:35][CH2:36][CH3:37])=[O:34].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25]2[C:29]([NH2:38])=[N:28][S:27](=[O:32])[N:26]=2)=[C:10]1[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: N
Reactant: CCOC(=O)C1=C(COCCNC2=NS(=O)N=C2OC)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Product: CCOC(=O)C1=C(COCCNC2=NS(=O)N=C2N)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Product: O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-{-2-[(4-{2,3-Dichlorophenyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl)methoxy]ethylamino}-4-methoxy-1,2,5-thiadiazole-1-oxide (0.3 g) was dissolved in ethanolic ammonia (10 ml) and stirred at room temperature for 1 hour. The solvent was evaporated and the residue chromatographed on silica "Kieselgel 60H" (Trade Mark), eluting with ethyl acetate. The product containing fractions were combined and evaporated to give an oil which was triturated with ethyl acetate to give the title compound as a solid, yield 0.15 g, m.p. 135°.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2[CH2:21][CH2:22][C:23]([OH:25])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N1C=CN=C1)([N:28]1C=CN=C1)=O.N.O>CN(C)C=O>[O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2[CH2:21][CH2:22][C:23]([NH2:28])=[O:25])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.3 %

Procedure:
3-[2-(2-Oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (10 g) was dissolved in 100 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. Ammonia (1 g) in 30 mL of dimethylformamide was added and the stirring continued overnight. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate that formed was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid was slurry-washed with 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 11 g (83% yield) of 3-[2-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionamide.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:24][N:23]=[C:22](SC)[N:21]=3)[C@H:14]2[CH3:47])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[S:50]([O-:55])(O[O-])(=O)=[O:51].[K+].[K+].[CH3:58]OC(C)(C)C>CC#N.O>[F:49][C:2]([F:1])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[C:41]([CH3:42])([CH3:43])[CH3:44])=[CH:24][N:23]=[C:22]([S:50]([CH3:58])(=[O:55])=[O:51])[N:21]=3)[C@H:14]2[CH3:47])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: COC(C)(C)C
Reactant: CSc1ncc(-c2sc(-c3ccc(C(=O)O)cc3C)nc2C(C)(C)C)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(-c2cnc(S(C)(=O)=O)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4-{5-[4-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfanyl)pyrimidin-5-yl]-4-tert-butyl-1,3-thiazol-2-yl}-3-methylbenzoic acid (INTERMEDIATE 51, 225 mg, 0.31 mmol) was dissolved in 10 mL CH3CN and 10 mL of water. Potassium peroxymonosulfate (5.1 g, 8.31 mmol) was added, and it was stirred at 60° C. for 2 hours. Then, it was worked up with water (100 mL) and t-butyl methyl ether (200 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated. The crude isolate was purified by silica gel chromatography, eluting with 60% ethyl acetate in hexanes to give the title compound as a slightly yellow solid (226 mg, 96% yield). LCMS (M+H)+: 757.1 1H NMR (DMSO, 500 MHz): δ 9.24 (s, 1H), 8.15 (s, 1H), 8.03 (s, 2H), 7.96 (s, 1H), 7.90 (s, 2H), 6.06 (m, 1H), 4.48 (m, 1H), 3.52 (s, 3H), 2.69 (s, 3H), 1.26 (s, 9H), 0.72 (d, J=6.0 Hz, 3H).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:9][C:10]1[C:11]([Cl:32])=[CH:12][C:13](F)=[C:14]([S:16]([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH3:30])([CH3:29])[CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:15]=1.Cl>CN(C=O)C>[Br:9][C:10]1[C:11]([Cl:32])=[CH:12][C:13]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])=[C:14]([S:16]([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH3:30])([CH3:29])[CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:15]=1
Reactant: CC1(C)CCN(S(=O)(=O)c2cc(Br)c(Cl)cc2F)c2ccccc21
Reactant: OCCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CCN(S(=O)(=O)c2cc(Br)c(Cl)cc2OCCCCO)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 171 %

Procedure:
To a solution of 1,4-butanediol (0.44 mL, 5 mmole) in DMF (5 mL) at 0° C. was added sodium hydride (60%, 48 mg, 1.2 mmole) and the mixture stirred for 10 minutes. A solution of 1-(5-bromo-4-chloro-2-fluoro-benzenesulfonyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (0.41 g, 1 mmole) in DMF (5 mL) was added. The mixture warmed to rt and was stirred for 1 hour. 1N hydrochloric acid solution (1 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and was dried over anhydrous MgSO4. Concentration of the filtrate provided a residue that was purified by silica gel chromatography [eluent: 40% ethyl acetate in hexane] to afford 4-[4-bromo-5-chloro-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-butan-1-ol as a light yellow foam (0.86 g). MS: 503.9 (M+H)+; tR=2.66 min (method 1).
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])([CH3:11])([CH3:10])[CH3:9].C1(C)C=CC(S([Cl:28])(=O)=O)=CC=1>O1CCCC1>[C:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([Cl:28])[C:13]1=[O:18])([CH3:11])([CH3:9])[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)C1CCCCC1=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C1CCCC(Cl)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
N-butyl lithium is added dropwise to a solution, cooled to 0° C., of diisopropylamine (5.5 mmol) in dry tetrahydrofuran. After the addition is complete the mixture is cooled to −78° C., and a solution of 2-tert-butylcyclohexanone (5 mmol) in dry tetrahydrofuran (50 ml) is introduced, followed by the addition of p-toluenesulphonyl chloride (5 mmol), also dissolved in dry tetrahydrofuran (50 ml). The reaction mixture is heated to room temperature and after stirring for 30 mins over silica gel filtered with ether as eluant. After concentration by evaporation in a vacuum 2-tert-butyl-6-chlorcyclohexanone (760 mg) is obtained in a yield of 81% (Tet. Lett. 1999, 40(12), 2231-2234).
Reaction SMILES: C(N(CC)CC)C.C1C(=O)OCC1=[O:10].[CH:15]([N:18]=[C:19]=[N:20][CH:21]([CH3:23])[CH3:22])([CH3:17])[CH3:16]>ClCCl>[CH:15]([NH:18][C:19]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:10])([CH3:17])[CH3:16]
Reactant: CC(C)N=C=NC(C)C
Reactant: O=C1COC(=O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NC(=O)NC(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (0.75 mL, 5.5 mmol) was added to a suspension of tetronic acid (500 mg, 5.00 mmol) in dichloromethane (25 mL) to obtain a homogeneous solution. The solution was cooled to 0° C., mixed with 4-N,N-dimethylaminopyridine (200 mg, 1.7 mmol), 3-cyclohexne-1-carboxylic acid (0.65 mL, 5.6 mmol), and then, diisopropylcarbodiimide (1.0 mL, 6.3 mmol), followed by stirring for 30 min. The resulting mixture was removed from the ice bath, stirred for 14 hours at room temperature, and filtered to remove thus-produced insoluble diisopropyl urea; the reaction solution was washed twice with 5% hydrochloric acid (20 mL) and the water layer was extracted twice with dichloromethane (10 mL). The organic layers were combined, dried over sodium sulfate anhydride, and concentrated; the thus-obtained residue was purified by silica gel column chromatography (silica gel, ethyl acetate:methanol=15:1). The resultant was arranged to be a sodium salt by adding an excess amount of sodium hydrogencarbonate and distilled water (100 mL), and then washed with dichloromethane; the water layer was acidified by adding 5% hydrochloric acid and extracted four times with dichloromethane (20 mL). The resultant was dried over sodium sulfate anhydride and concentrated to give pale yellow crystals (394 mg, 38%).
Reaction SMILES: [C:1]([C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16][C:17]#[N:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:19].CCOC(C)=O>[Pt]=O.CCO>[ClH:19].[CH:2]1([C:1]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[CH3:15])[CH2:16][CH2:17][N:18]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cccc(CC#N)c1C(=O)c1ccccc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cccc2c1C(C1CCCCC1)=NCC2
Reaction time: 72 h

Procedure:
To (2-benzoyl-3-methylphenyl)acetonitrile (4.6 g) were added EtOH (70 mL), 4 M HCl/EtOAc (15 mL), and platinum oxide (IV) (0.40 g), followed by stirring under a hydrogen atmosphere for 3 days. The reaction liquid was filtered through celite and then concentrated. Toluene was added to the concentrate, followed by extraction with an aqueous 1 M HCl solution. A 28% aqueous ammonia solution was added to the aqueous layer, which was then extracted with toluene and dried over magnesium sulfate. The solvent was evaporated and the residue was dissolved in toluene. 4 M HCl/EtOAc (7 mL) was added to the mixture, followed by concentration under reduced pressure. iPrOH and diisopropyl ether were added to the resulting residue, and the precipitated solid was collected to obtain 1-cyclohexyl-8-methyl-3,4-dihydroisoquinoline hydrochloride (2.2 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([C:27]([CH3:32])([CH3:31])[CH:28]([CH3:30])[CH3:29])[O:23][SiH:24]([CH3:26])[CH3:25])=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CN(C)[CH:41]=[O:42]>C1(C)C=CC=CC=1.CCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([C:27]([CH3:32])([CH3:31])[CH:28]([CH3:30])[CH3:29])[O:23][SiH:24]([CH3:26])[CH3:25])=[C:14]([CH:41]=[O:42])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(C)(C)C(O[SiH](C)C)c1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: CC(C)C(C)(C)C(O[SiH](C)C)c1nc2c(cc1C=O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of 26.5 g (0.049 mol) (4R,9aR)-7-bromo-6-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 800 ml toluene was added at −78° C. during 10 minutes 50 ml of a 1.5 M solution of tert. butyllithium in pentane. The reaction mixture was stirred at −78° C. for 30 minutes. To the resulting orange solution was added 30 ml dimethylformamide during 3 minutes. The reaction mixture was stirred at −78° C. for 30 minutes and the cooling bath was then removed and the mixture was stirred for 30 min at ambient temperature. The reaction was quenched by addition of 300 ml of a 10% aqueous solution of citric acid and extracted with ethyl acetate. The organic phase was washed with a 10% aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate, evaporated under aspirator vacuum and purified by chromatography on silica gel with heptane:ethyl acetate=4:1 to 3:1. to yield 22.70 g (94.6%) of the title compound as yellow foam (MS: 490 (M+H+)).