Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C:7]([C:10]([CH3:16])([CH:14]=[CH2:15])[C:11]([OH:13])=[O:12])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([C@H:30]([O:32][C:33](=[O:35])[CH3:34])[CH3:31])=[N:27]2)=[CH:22][CH:21]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:33]([O:32][C@@H:30]([C:26]1[CH:25]=[CH:24][C:23]2[C:28](=[CH:29][C:20](/[CH:15]=[CH:14]/[C:10]([C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:18])[CH3:17])([CH3:8])[CH3:9])([CH3:16])[C:11]([OH:13])=[O:12])=[CH:21][CH:22]=2)[N:27]=1)[CH3:31])(=[O:35])[CH3:34]
Reactant: C=CC(C)(C(=O)O)C(C)(C)O[Si](C)(C)C(C)(C)C
Reactant: CC(=O)O[C@H](C)c1ccc2ccc(Br)cc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)O[C@H](C)c1ccc2ccc(/C=C/C(C)(C(=O)O)C(C)(C)O[Si](C)(C)C(C)(C)C)cc2n1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
A solution of 2-[1-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-2-methyl-but-3-enoic acid (258 mg, 0.95 mmol), acetic acid (R)-1-(7-bromo-quinolin-2-yl)-ethyl ester (279 mg, 0.95 mmol), palladium(II) acetate (43 mg, 0.19 mmol), tris-(o-tolyl)phosphine (87 mg, 0.29 mmol) in anhydrous acetonitrile (3 mL) was treated with triethylamine (265 μL, 1.90 mmol). After stirring at 100° C. under microwave for 20 min, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The residue was partitioned between dichloromethane and a saturated potassium hydrogen sulfate solution. The organics were combined and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 25 g Biotage cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 0:1 to afford the title compound (300 mg, 65%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 0.20 (s, 3H), 0.22 (s, 3H), 0.94 (s, 9H), 1.44 (s, 3H), 1.45 (s, 3H), 1.50 (s, 3H), 1.68 (d, J=6.7 Hz, 3H), 2.17 (s, 3H), 6.06 (q, J=6.7 Hz, 1H), 6.76 (m, 2H), 7.43 (d, J=8.5 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 8.03 (s, 1H), 8.11 (d, J=8.5 Hz, 1H). LCMS (m/z) 486.3 [M+H], Tr=3.64 min.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:14]F>C(#N)C.ClC(Cl)(Cl)C(F)(F)F>[C:1]1([CH:7]([F:14])[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(=O)Cc1ccccc1
Reactant: FF
Solvent: FC(F)(F)C(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)C(=O)C(F)c1ccccc1

Procedure:
In the same manner as in Example 1, methyl 3-phenylpyruvate (35.62 g; 0.2 mol) is dissolved in a mixture of acetonitrile (240 g) and trichlorotrifluoroethane (1.6 L) and reacted with fluorine at -10° C. After the same work-up as in Example 1, the residue is rectified to give methyl 3-phenyl-3-fluoropyruvate (11.8 g). The silyl enol ether obtained by the treatment of the above product with bis-(trimethylsilyl)acetamide (BSA) in methylene chloride shows boiling point 93°-95° C./1 mmHg and 19F NMR (CDCl3), δ (int. C6F6)+31.5 (s).
Reaction SMILES: [F:1][CH:2]([F:34])[O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][C:14]=3[F:25])[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12.C(O)(=O)C.Cl>O>[F:34][CH:2]([F:1])[O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=3[F:25])[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12
Reactant: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OC(F)F)C2=O)c(F)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOc1c2c(c(OC(F)F)c3ccccc13)CN(c1ccc(CC(=O)O)cc1F)C2=O
Temperature: 25 °C
Yield: 85.8 %

Procedure:
Ethyl {-4-[4-[(difluoromethyl)oxy]-9-(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-fluorophenyl}acetate (0.60 g, 1.27 mmol) was heated to 100° C. in a 1:1 mixture of acetic acid:2N aqueous hydrochloric acid (20 ml) for 50 minutes. The reaction was cooled to room temperature. On addition of water, the resulting white solid was collected by filtration, washed with water and dried under vacuum to give the title compound (0.516 g, 1.09 mmol).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[CH2:19]1[O:27][C:26]2[CH:25]=[CH:24][C:23]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:22][C:21]=2[O:20]1.[C:34]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>C1COCC1>[C:42]1([C:34]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([OH:41])[CH:29]([CH2:28][C:23]2[CH:24]=[CH:25][C:26]3[O:27][CH2:19][O:20][C:21]=3[CH:22]=2)[C:30]([O:32][CH3:33])=[O:31])[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCc1ccc2c(c1)OCO2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc2c(c1)OCO2)C(O)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 75.3 %

Procedure:
To a solution of di-isopropylamine (0.52 ml, 3.69 mmol) in dry THF (3 ml) at 0° C. under argon was added n-BuLi in hexane (1.36 ml, 2.5 M, 3.4 mmol). After stirring for 40 min the solution was cooled to -78° C. and a solution of methyl 3-(3,4-methylenedioxyphenyl)-propanoate (0.592 g, 2.84 mmol) in dry THF (2 ml) was added dropwise over 7 min. After a further 2 min a solution of benzophenone (0.517 g, 2.84 mmol) in dry THF (2 ml) was added dropwise. After a further 30 min at -78° C. the mixture was warmed to 0° C. over 30 min and poured into 1M aqueous HCl. The product was extracted with EtOAc (3X). The combined organic extract was washed with water (2X) then brine. After drying (Na2SO4 anhydrous), filtration and evaporation gave an off-white solid. Recrystallization from hot hexane gave the title compound (0.835 g, 76% yield) as a colorless solid.
Reaction SMILES: C(O[C:4](=[O:20])[CH2:5][N:6]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH2:9][C:10]([O-:12])=[O:11])C.[H-].[Na+].[C:23]1(C)C=CC=C[CH:24]=1>>[O:20]=[C:4]1[CH:9]([C:10]([O:12][CH2:23][CH3:24])=[O:11])[CH2:8][CH2:7][N:6]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:5]1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)CN(CCCC(=O)[O-])Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O

Procedure:
The anion of ethyl 3-oxo-1-phenylmethyl-4-piperidinecarboxylate is prepared according to Example 1(a) above, from 30.7 g (0.1 mole) of 4-[(2-ethoxy-2-oxoethyl)(phenylmethyl)amino]butanoate in 700 ml of toluene and 5 g (0.1 mole) of 50% strength sodium hydride.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[O:6][C:5]1=[O:24])[CH:2]=[CH2:3].Cl.[NH2:27][C@@H:28]([CH2:32][CH3:33])[C@@H:29]([OH:31])[CH3:30].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:16][C:12]1[CH:11]=[C:10]([C@H:8]([C@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[OH:6])[CH2:9][C@:4]([CH3:25])([CH2:1][CH:2]=[CH2:3])[C:5]([NH:27][C@@H:28]([CH2:32][CH3:33])[C@@H:29]([OH:31])[CH3:30])=[O:24])[CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@H](N)[C@H](C)O
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)cc2)OC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CC[C@@](C)(C[C@H](c1cccc(Cl)c1)[C@@H](O)c1ccc(Cl)cc1)C(=O)N[C@@H](CC)[C@H](C)O
Temperature: 25 °C

Procedure:
To a 10 mL round-bottom reaction flask was added (3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one (750 mg, 1.998 mmol), (2S,3S)-3-aminopentan-2-ol hydrochloride (837 mg, 6.00 mmol, reference: J. Org. Chem., 2003, 68 (26), 9948), and triethylamine (1966 μl, 13.99 mmol). The vessel was fitted with a reflux condensor and heated to 85 to 95° C. for 2d. The reaction was cooled to RT and diluted with ethyl acetate and washed with 1N HCl (2×20 mL) and brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography using 40 to 50% ethyl acetate in hexanes afforded (S)-2-((2R,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N-((2S,3S)-2-hydroxypentan-3-yl)-2-methylpent-4-enamide.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].C([Li])CCC.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>CCOCC>[CH3:16][Si:17]([CH3:19])([CH3:18])[NH:4][C:3]1[C:2]([Cl:1])=[CH:8][C:7]([Cl:9])=[CH:6][C:5]=1[Cl:10]
Reactant: C[Si](C)(C)Cl
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)Nc1c(Cl)cc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Et2O (50 mL) was added to a Schlenk flask under argon containing 2,4,6-trichloroaniline that had been recrystallized from hot hexane. The solution was chilled to −78° C. and n-butyllithium (2.0M in cyclohexane, 4.03 mL, 8.06 mmol) was added via syringe under an argon flow and the resulting white slurry was allowed to stir for 2 h; the slurry acquired a reddish tint over time. Trimethylsilylchloride (1.86 mL, 14.6 mmol) was added by syringe and the solution was allowed to warm to room temperature. Solvent was removed and the orange residue was charged with CH2Cl2. The mixture was filtered over Celite, the Celite washed with CH2Cl2 and the filtrate concentrated under reduced pressure to give an analytically pure orange oil in 90% yield (1.776 g, 6.61 mmol): 1H NMR (C6D6, 20° C.) δ 6.95 (s, 2H, Ar), 3.76 (s, 1H, NH), 0.16 (s, 9H, SiMe3); 13C NMR (C6D6, 20° C.) δ s179.50, 141.26, 124.83, 123.64, 1.783. Anal. Calcd for C9H12Cl3NSi: % C, 40.24; % H, 4.50; N, 5.21. Found: C, 40.01; H, 4.39; N, 5.22.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:19]=[C:18](Br)[O:17][C:16]=2[CH3:21])=[O:14])=[CH:8][CH:7]=1)[CH3:2].CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:19]=[C:18]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[O:17][C:16]=2[CH3:21])=[O:14])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2cc(Br)oc2C)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc(-c3ccc(O)cc3)oc2C)cc1
Yield: 61.1 %

Procedure:
A solution of {4-((5-bromo-2-methyl-furan-3-carbonyl)-amino]-phenyl}-acetic acid ethyl ester (3 g, 8.19 mmoles) (15), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (1.8 g, 8.19 mmoles), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (300 mg, 10%) and 2M aqueous cesium carbonate (15 ml, 15 mmoles) in N,N-dimethylformamide (35 ml) was heated in a microwave reactor at 100° C. for 15 minutes. The solvent was evaporated, and the residue was purified by flash chromatography (gradient elution with 100% cyclohexane to 100% ethyl acetate) to afford (4-{[5-(4-hydroxy-phenyl)-2-methyl-furan-3-carbonyl]-amino}-phenyl)-acetic acid ethyl ester (16) (1.9 g). LC/MS System A; Rt=3.54 mins, m/z (ES+)=380 (M+H for C22H21NO5).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].CCN(CC)CC.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[C:21]([Cl:38])[CH:20]=1>C(Cl)Cl>[Cl:38][C:21]1[CH:20]=[C:19]([NH:18][C:8](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:24]=[CH:23][C:22]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1
Reactant: O=C(Cl)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2Cl)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3ccccn3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
According to Scheme 5 Step 3: Picolinoyl chloride hydrochloride (3.68 mmol, 656 mg) and Et3N (7.37 mmol, 1.03 mL) were added to a solution of tert-butyl 4-(4-amino-2-chlorophenyl)piperazine-1-carboxylate (2.46 mmol, 766 mg) in DCM (40 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The organic phase was washed with a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The organic phase was washed with brine, was dried over Na2SO4, was filtered and was concentrated under reduced pressure to afford tert-butyl 4-(2-chloro-4-(picolinamido)phenyl)piperazine-1-carboxylate (2.46 mmol, 1.02 g, 100%).
Reaction SMILES: C1(CC([NH:10][C@@H:11]2[C:50](=[O:51])[N:13]3[C:14]([C:34]([O:36][CH:37]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:35])=[C:15]([C:18]4[CH:19]=[CH:20][C:21]5[C:22](=[O:33])[C:23]6[C:28]([C:29]=5[CH:30]=4)=[CH:27][CH:26]=[C:25]([CH2:31]O)[CH:24]=6)[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)[Cl:59].OP([O-])(O)=O.[K+]>C(Cl)Cl.CO>[NH2:10][C@@H:11]1[C:50](=[O:51])[N:13]2[C:14]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[C:22](=[O:33])[C:23]5[C:28]([C:29]=4[CH:30]=3)=[CH:27][CH:26]=[C:25]([CH2:31][Cl:59])[CH:24]=5)[CH2:16][S:17][C@H:12]12
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3ccc4c(c3)-c3ccc(CO)cc3C4=O)CS[C@H]12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3ccc4c(c3)-c3ccc(CCl)cc3C4=O)CS[C@H]12
Reaction time: 1.08 h

Procedure:
Benzhydryl 7β-phenylacetamido-3-(7-hydroxymethyl-9-fluorenon-3-yl)-ceph-3-em-4-carboxylate (150 mg) was dissolved in methylene chloride (6 ml), cooled to -15° under nitrogen. Pyridine (0.240 ml was added followed by PCl5 (2.4 ml, 8% solution in CH2Cl2). The reaction mixture was stirred at -15° to -10° for 65 min. The temperature was then lowered to -30° and MeOH (1.5 ml) was added drop wise and the reaction was stirred at -10° to -5° for 1.5 hrs, then at 0° for 1 hr. and then at room temperature for 1 hr. KH2PO4 (6.0 ml, 0.5M solution) was added. The reaction mixture was stirred vigorously for 0.5 hr. The organic solvents were removed under reduced pressure and the residual suspension was filtered, the residue was washed well with water and then with ether and the residue dried to give the desired product as a yellow solid(108.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].P(Cl)(Cl)([Cl:27])=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]2[Cl:27])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Solvent: c1ccncc1
Product: COC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using methyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate with phosphorus oxychloride and pyridine within 7 hours at room temperature there is obtained methyl 2-chloro-5-[2-chloro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate, m.p. 89°-91° C.;
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])[CH3:2].Br[CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:21]([CH2:20][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:17][CH:16]=1)#[N:22]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(O)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(OCC#N)cc1
Yield: 84.3 %

Procedure:
To 150 ml of acetone were added 14.58 g of ethyl 2-ethoxycarbonyl-2-(4-hydroxyphenyl)acetate, 8.8 g of bromoacetonitrile and 9.6 g of anhydrous potassium carbonate. After refluxing under heating for 5 hours, insoluble materials were removed by filtration, and the resulting filtrate was concentrated to dryness. The residue thus obtained was purified by silica gel column chromatography using toluene as an elution solvent, thereby obtaining 14.2 g of ethyl 2-[4-(cyanomethoxy)phenyl]-2-ethoxycarbonylacetate in the form of colorless oil.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[CH3:18])[CH:9]2[CH:7]([CH2:8]2)[O:6][C:5]([NH2:10])=[N:4]1.[N+:20]([O-])([O-:22])=[O:21].[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.O.ClCCl>[F:19][CH:2]([F:1])[C:3]1([C:11]2[CH:16]=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=[C:13]([F:17])[C:12]=2[CH3:18])[CH:9]2[CH:7]([CH2:8]2)[O:6][C:5]([NH2:10])=[N:4]1
Reactant: Cc1c(F)cccc1C1(C(F)F)N=C(N)OC2CC21
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: Cc1c(F)cc([N+](=O)[O-])cc1C1(C(F)F)N=C(N)OC2CC21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40.1 %

Procedure:
5-(Difluoromethyl)-5-(3-fluoro-2-methylphenyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (0.470 g, 1.739 mmol) was dissolved in sulfuric acid, 95% (5 mL) and cooled in an ice bath. Sodium nitrate (0.177 g, 2.087 mmol) was added in one portion and the reaction stirred for 5 minutes. The reaction was warmed to rt and stirred for 1 hr and poured into a mixture of dichloromethane (50 mL), iced water (90 mL), and potassium phosphate tribasic (20.02 g, 87 mmol). The mixture was stirred for 5 minutes then saturated sodium bicarbonate was added slowly until pH 8. The phases were separated and the aqueous extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. The crude residue was purified via silica gel flash chromatography eluting with 0-30% hexane to ethyl acetate to afford the title compound 5-(difluoromethyl)-5-(3-fluoro-2-methyl-5-nitrophenyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (0.22 g, 0.698 mmol, 40.1% yield). LC/MS (ESI+) m/z=316.1 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])C.[OH-].[Na+]>C1COCC1.C(O)C>[CH2:24]([C:7]1([OH:23])[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:6]1[C:4]([OH:5])=[O:3])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1(O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(c1)C(O)(Cc1ccccc1)C(C(=O)O)=C2c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 108 %

Procedure:
1-Benzyl-1-hydroxy-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (35 mg, 0.087 mmol) prepared in Example 5 was dissolved in THF, and an excess amount of sodium hydroxide dissolved in aqueous ethanol was added thereto in such a way not to cause layer separation. The mixture was stirred for 24 hrs at RT, and the pH was adjusted to 3˜4 using 2N hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure, to obtain 35 mg of the titled compound (yield: 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19]([C@H:21]([NH:24]C(=O)OC(C)(C)C)[CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=3)[CH:9]=2)[CH2:4][O:3]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:24][C@H:21]([CH2:22][CH3:23])[C:19]([NH:18][C:15]1[CH:16]=[N:17][C:12]([O:11][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH2:4][O:3][C:2]3([CH3:1])[CH3:32])=[CH:13][CH:14]=1)=[O:20]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc3c(c2)C(C)(C)OC3)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc3c(c2)C(C)(C)OC3)nc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To a solution of tert-butyl N-[(1R)-1-[[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]carbamoyl]propyl]carbamate (Intermediate 53, 25 mg, 0.0566 mmol) in DCM (2 mL) 2,2,2-trifluoroacetic acid (0.5 ml, 6.53 mmol) was added and the reaction mixture was stirred for 3 hours at 0° C. The reaction was diluted with DCM (10 ml) and an aqueous saturated solution of NaHCO3 was added while the pH was allowed to reach ˜8. Two phases were separated and the organic layer was dried (Na2SO4), filtered and evaporated to afford the title compound (18 mg) as white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[BH4-].[Na+].Cl>C(OCC)C.Cl[Ni]Cl>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][NH2:12])=[CH:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(C2CCOCC2)cc1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCOCC
Product: NCc1ccc(C2CCOCC2)cc1

Procedure:
340 mg (1.82 mmol) 4-(tetrahydro-2H-pyran-4-yl)benzonitrile was reduced according to the general procedure with NiCl2 and NaBH4. The intermediate Boc-protected amine was treated with 2M HCl in diethyl ether to remove the Boc group. The crude was treated with aqueous NaHCO3 and extracted with CH2Cl2 to afford after drying and evaporation 234 mg (67%) of the title compound as an oil.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][CH:10]([CH3:13])[C:11]#[CH:12]>CCN(CC)CC.CCOCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][CH:10]([CH3:13])[C:11]#[C:12][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: C#CC(C)C
Reactant: Nc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)C#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-iodoaniline (Aldrich, 5.0 g, 22.8 mmol) in Et3N (50 ml) in a re-sealable pressure tube was added copper (I) iodide (22 mg, 0.114 mmol), Pd(PPh3)2Cl2 (80 mg, 0.114 mmol), and 3-methylbut-1-yne (Alfa Aesar, 3.1 g, 45.7 mmol). The mixture was stirred at room temperature for 20 h and was diluted with Et2O, filtered through Celite, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 30% Et2O-hexanes to yield 2-(3-methylbut-1-ynyl)aniline (Compound 37) as orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3Cl)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:27].[Na+]>CO.O>[CH:18]1[CH:19]=[CH:20][C:21]2[C:22]([C:23]([OH:27])=[C:14]([C@@H:11]3[CH2:10][CH2:9][C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)[C:15](=[O:26])[C:16]=2[CH:17]=1)=[O:25]
Reactant: [OH-]
Reactant: O=C1C(Cl)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1C(O)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Temperature: 2.5 °C

Procedure:
6.0 g of trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-1,4-naphthoquinone (trans-isomer of Formula IV) as obtained in Example 3 was suspended in 120 ml methanol. 6.0 g sodium hydroxide dissolved in 60 ml water was added drop-wise to the suspension under heating over a period of 20 minutes. Further, it was refluxed for 45 minutes and cooled to 0-5° C. and filtered. The filtrate was acidified with 50% aqueous hydrochloric acid to precipitate the product. The precipitated product was filtered, and recrystallized from acetonitrile to obtain 4 g (70% yield) atovaquone.