Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]1=[O:17].[NH2:18][C:19]1[N:24]=[C:23]([SH:25])[C:22]([C:26]#[N:27])=[C:21]([S:28][CH3:29])[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:18][C:19]1[N:20]=[C:21]([S:28][CH3:29])[C:22]([C:26]#[N:27])=[C:23]([S:25][CH:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=3)[C:3]2=[O:17])[N:24]=1
Reactant: O=C1C(Br)CCN1c1cccc(C(F)(F)F)c1
Reactant: CSc1nc(N)nc(S)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nc(N)nc(SC2CCN(c3cccc(C(F)(F)F)c3)C2=O)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round-bottomed flask was added 3-bromo-1-[3-(trifluoromethyl)-phenyl]-pyrrolidin-2-one (21) (308 mg, 1.0 mmol, 1.0 eq.), DMF (3.0 mL), 2-amino-4-mercapto-6-methylsulfanyl-pyrimidine-5-carbonitrile (198 mg, 1.0 mmol, 1.0 eq.), and potassium carbonate (207 mg, 1.5 mmol, 1.5 eq.). The reaction was stirred at RT overnight before quenching with H2O (10 mL) and EtOAc (50 mL). The EtOAc layer washed with 10% LiCl (20 mL, 2×), washed with brine, dried with Na2SO4, and concentrated to give crude product. Pure 2-amino-4-methylsulfanyl-6-[2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylsulfanyl]-pyrimidine-5-carbonitrile was precipitated out with 20:80 EtOAc:Hexanes, filtered, and dried under high vacuum (193 mg, 45%). LC/MSD (HP Series 1100 MSD): Expected MW: 425, Observed M+H, 426.1, Retention time: 1.60 min. ANALYTICAL HPLC: >98%, Retention time: 5.56 min (8 minute run). 1H-NMR (d6-DMSO): 8.20 (s, 1 H), 7.85 (d, 1H), 7.69 (t, 1H), 7.50 (d, 1H), 4.75 (t, 1H), 4.00 (dt, 2H), 2.72 (m, 1H), 2.40 (s, 3H), 2.39 (m, 1H) ppm.
Reaction SMILES: [Mg].I[C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[O:13][CH3:14].[F:15][C:16]([F:21])([F:20])[C:17](O)=[O:18].S(=O)(=O)(O)O>C(OCC)C>[F:15][C:16]([F:21])([F:20])[C:17]([C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[O:13][CH3:14])=[O:18]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(C(C)(C)C)cc1I
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: COc1ccc(C(C)(C)C)cc1C(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
To 0.73 g of magnesium suspended in 5 ml of diethyl ether were added dropwise, under nitrogen, 8.70 g of 2-iodo-4-tert-butylanisole [described in Reference Example 1(a)] dissolved in 15 ml of diethyl ether and heated at reflux for one hour. To this solution were added dropwise 0.74 ml of trifluoroacetic acid dissolved in 3 ml of diethyl ether at room temperature, and heated at reflux for 1.5 hours. The reaction mixture was poured into ice-water, acidified with conc. sulfuric acid and extracted with diethyl ether. The extract was washed with water and saturated brine successively, dried over magnesium sulfate anhydride and concentrated at reduced pressure. The residue was chromatographed on silica gel column using a mixed solvent of methylene chloride and cyclohexane (1:2) as an eluting agent to give 1.83 g of the title compound having the following physical properties as pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].Cl.[CH3:13][NH:14][O:15][CH2:16][C:17]([OH:19])=[O:18].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([N:14]([CH3:13])[O:15][CH2:16][C:17]([OH:19])=[O:18])=[S:11]
Reactant: Cc1ccc(C)c(N=C=S)c1
Reactant: CNOCC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C)c(NC(=S)N(C)OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
A mixture of 2,5-dimethylphenyl-isothiocyanate (16.3 g), N-methyl aminooxy acetic acid hydrochloride (15.55 g), triethylamine (30 g) and chloroform (250 mL) was heated at reflux for one hour, stirred at ambient temperature for one hour, then evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with 2N HCl (2×200 mL) then with water (200 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness affording (25 g) of [[[[(2,5-dimethylphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid as an oil. 1H-NMR (DMSO-d6; 300 Mhz) δ13.25 (br s, 1H), 10.08 (s, 1H), 7.15-6.94 (m, 3H), 4.62 (s, 2H), 3.52 (s, 3H), 2.24 ppm (s, 3H and 2.10 ppm (s, 3H). The acid (24.1 g) was dissolved in benzene (250 mL). Phosphorus pentachloride (18.7 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (600 mL) and washed with sodium bicarbonate saturated solution (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residual oily substance crystallized upon standing. The solid mass was stirred in methanol (100 mL). The solid was collected by filtration and air dried to give the title compound (11.2 g), m.p. 104-106° C. Mass spectrum (El, M.+) m/z 250. 1H-NMR (CDCl3; 400 MHz) δ7.21-7.17 (m, 2H), 6.92 (s, 1H), 4.84 (ABq, 2H), 3.75 (s, 3H), 2.35 (s, 3H), and 2.12 ppm (s, 3H).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[BrH:13].BrBr.S([O-])(O)=O.[Na+]>ClCCl.C(O)(=O)C>[Br:13][CH2:11][C:10]([C:8]1[CH:7]=[N:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=1)=[O:12]
Reactant: Br
Reactant: CC(=O)c1cnn(C(C)(C)C)c1
Agent: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)n1cc(C(=O)CBr)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1.66 g (10.0 mmol) 1-(1-tert-butyl-1H-pyrazol-4-yl)-ethanone in 18 ml dichloromethane is added 5.86 μl (0.10 mmol) of a 32% solution of hydrobromic acid in acetic acid. Then a solution of 3.20 g (20 mmol) bromine in 5 ml dichloromethane is added dropwise. The reaction mixture is stirred for 3 days at room temperature. Then aqueous sodium hydrogen sulfite is added to reduce the excess bromine. The reaction mixture is reduced in volume under vacuum and it is then partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 2-bromo-1-(1-tert-butyl-1H-pyrazol-4-yl)-ethanone as yellow oil, which crystallizes on standing; HPLC/MS 2.28 min (B), [M+H] 245/247.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1.O.O.Cl[Sn]Cl>C(O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=3)[S:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3ccc(F)cc3s2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2nc3ccc(F)cc3s2)cc1
Temperature: 80 °C
Yield: 27.5 %

Procedure:
To a stirred solution of 4-fluoro aniline (16a, 4g, 32.7 mmol) in pyridine as solvent and base to this 4-nitrobenzoyl chloride (17, 6.69 g, 36.0 mmol) is added slowly and reflux for 2h, after completion of the reaction, reaction mixture is poured in water, filter and washed with dil HCl to afford compound N-(4-fluorophenyl)-4-nitrobenzamide (18a). To a stirred solution of amide (18a, 8g, 30.7 mmol) taken in toluene lawessons reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide) (10.18 g, 25.2 mmol) is added and refluxed at 110° C. for 7h. After completion of the reaction toluene is evaporated under vacuum and water is added and extracted into chloroform finally purification by column chromatography to afford pure compound N-(4-fluorophenyl)-4-nitrobenzothioamide (19a). Treating the thioamide product (19a, 4g, 14.49 mmol) with potassium ferricyanide (4 eq) in aqueous sodium hydroxide (8 eq) solution at 90° C. for 3h cyclization takes place to obtain the 6-fluoro-2-(4-nitrophenyl)benzo[d]thiazole (20a) solid is precipitated from the reaction mixture filtered and washed with water to get 20a. Reduction of the nitro compound (20a, 1 g, 3.64 mmol) is proceeded with SnCl2.2H2O in ethanol and reflux at 80° C. for 2h. After completion of reaction ethanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered in celite bed and purified in silica column (60-120) to afforded pure compound (21a) The compound 4-(6-fluorobenzo[d]thiazol-2-yl)benzenamine (21a, 244 mg, 1 mmol) on reaction with 4-fluoro 3-methoxy benzaldehyde (22c, 152 mg, 1 mmol) in ethanol using catalytic amount of acetic acid and refluxed for 2h after completion reaction mixture is cooled to 0° C. solid is precipitated from the reaction mixture it is filtered and washed with ethanol to gave the enamine product, and immediately proceeded for the next reaction with using (p-tolylsulfonyl) methyl isocyanide (tosmic) (1.5 eq), and potassium carbonate (2 eq) as base, in 10 mL of methanol and 5 mL of DME was heated under reflux for 12 h after completion of reaction as monitored by TLC. It was cooled to room temperature (27° C.); the solution was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc and Hexane to gave compound 4c as a light yellow solid (68%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccccc1

Procedure:
Using the general method of Example 1, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.8 mmol) was reacted with benzoyl chloride (0.26 g, 1.8 mmol) to provide N1-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide as a solid, m.p. 164-170° C. 1H NMR (500 MHz, DMSO-d6) δ 8.47 (t, J=6.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.59 (dd, J=8.0, 1.2 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.38 (dt, J=8.0, 1.2 Hz, 1H), 7.17 (dt, J=8.0, 1.2 Hz, 1H), 6.48 (broad s, 2H), 4.53 (t, J=7.0 Hz, 2H), 3.31 (q, J=6.0 Hz, 2H), 2.60 (s, 3H), 1.88 (quintet, J=7.0 Hz, 2H), 1.68 (quintet, J=7.0 Hz, 2H); MS (EI) m/e 373.1903 (373.1903 calcd for C22H23N5O).
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C>C1COCC1>[CH2:11]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[C:8]=[O:9])[CH3:12]
Reactant: CCC(C(=O)Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=C=O)c1ccccc1
Reaction time: 1 h
Yield: 70 %

Procedure:
A THF solution of 2-phenyl butyryl chloride (55 g, 0.3 mol) was added dropwise to a mixture of triethyl amine (91 g, 0.9 mol) in THF under nitrogen atmosphere. After one hour, precipitated triethyl amine hydrochloride was filtered. Filtrate was distilled under reduced pressure and EPK was obtained (60–70° C./4 mmHg). Amount obtained was 30 g (yield was 70%).
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:32])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][O:28][C:29]([NH2:31])=[O:30])[O:24][CH2:23]2)[CH:17]([CH:33]([OH:35])[CH3:34])[C:16]3=[O:36])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:41].O.[H][H]>[Pd].O1CCOCC1>[Na+:41].[NH2:31][C:29]([O:28][CH2:27][CH:25]1[O:24][CH2:23][CH:22]([S:21][C:20]2[CH:19]([CH3:32])[CH:18]3[N:15]([C:16](=[O:36])[CH:17]3[CH:33]([OH:35])[CH3:34])[C:14]=2[C:12]([O-:13])=[O:11])[CH2:26]1)=[O:30]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COC(N)=O)C3)C(C)C12
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(COC(N)=O)C3)C(C)C12
Yield: 67 %

Procedure:
A mixture of 0.181 g of product from Example 17, 0.032 g of sodium bicarbonate, 2 ml of water, 11 ml of dioxane and 0.100 g of 10% palladium/carbon is reduced in a Parr apparatus at 42 psi of hydrogen for 3 hours. The reaction mixture is filtered through a pad of diatomaceous earth, washed with water and concentrated to 1/2 volume. The solution is extracted with ethyl acetate and the aqueous layer is freeze-dried. The product is purified using C18 reverse phase chromatography (95/5 water/ethyl alcohol) to give 0.095 g of the desired product as a yellow solid.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11](=[O:49])[C@@H:12]([C@H:39]([CH3:48])[O:40]CC1C=CC=CC=1)[NH:13][C:14](=[O:38])[C@H:15]([CH:27](CC1C=CC=CC=1)[C:28](=[O:30])[OH:29])[NH:16]C(OCC1C=CC=CC=1)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C(O)(=O)C>CO.[Pd].[C]>[CH2:1]([C@H:3]([NH:10][C:11](=[O:49])[C@@H:12]([C@H:39]([CH3:48])[OH:40])[NH:13][C:14](=[O:38])[C@H:15]([CH2:27][C:28](=[O:29])[OH:30])[NH2:16])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC[C@H](NC(=O)[C@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)[C@H](C)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@H](NC(=O)[C@H](NC(=O)[C@@H](N)CC(=O)O)[C@H](C)O)c1ccccc1
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a solution of 5.30 g (8.0 mmols) of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-O-benzyl-D-threonine (S)-α-ethylbenzylamide in 150 ml of methanol were added 1.0 ml of acetic acid and 3.0 g of 5% Pd-carbon (water content 50%), and the mixture was reduced under hydrogen overnight at room temperature and then at 50° C. for 3 hours. The catalyst was removed by filtration, the resulting filtrate was concentrated under reduced pressure, and the residue was crystallized from water to obtain 1.60 g (4.6 mmols) of α-L-aspartyl-D-threonine (S)-α-ethylbenzylamide.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[N+:17]([O-])([OH:19])=[O:18]>C(OC(=O)C)(=O)C.C(O)(=O)C>[F:1][C:2]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:5]2[N:6]([CH2:11][CH:12]([CH3:13])[CH3:14])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)CN1C(=O)COc2cc(F)ccc21
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(C)CN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To 2.50 g (11.2 mmol) of 7-fluoro-4-isobutyl-2H-1,4-benzoxazin-3(4H)-one in 25 ml of acetic anhydride was added dropwise over 10 min. a solution of 2.5 g (26.9 mmol) of 70% nitric acid in 5 ml of glacial acetic acid. After the addition was complete, the reaction was stirred for 1 hour at room temperature then it was quenched by pouring into 50 ml of ice/water. The resulting white precipitate was collected by vacuum filtration and dried in a vacuum oven at 60° C. overnight to yield 2.71 g (90% yield) of the desired nitrated product, m.p. 108°-110° C.
Reaction SMILES: O.I([O-])(=O)(=O)=O.[Na+].[CH2:8]([O:15][CH2:16][CH:17]([OH:20])CO)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OCC)(=O)C>[CH2:8]([O:15][CH2:16][CH:17]=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCC(O)COCc1ccccc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=CCOCc1ccccc1
Reaction time: 2 h
Yield: 86.2 %

Procedure:
Into a suspension of water (1055 g) and sodium periodate (406 g) was dropped 3-benzyloxy-1,2-propanediol (366 g, 2.0 mol) at 20 to 25° C. over a period of 21 hours, and the mixture was stirred for 2 hours. Ethyl acetate (495 ml) was added, and the mixture was filtrated and washed. The aqueous layer was extracted with ethyl acetate (825 ml) again, and the organic layers were combined, and washed with a 10% sodium thiosulfate aqueous solution (363 g). The organic layer was treated with phosphoric acid to regulate pH to around 7, then, washed twice with 5% saline (660 g) and dehydrated over anhydrous magnesium sulfate (100 g). Magnesium sulfate was filtrated off, and hydroquinone (1.3 g) was added, the solvent was distilled off, to obtain a title compound (259 g, yield 85.9%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][O:15][CH3:16])[C:8](=[O:17])[C:7](=[O:18])[NH:6]2.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:21]([O-:23])=[O:22])[N:9]([CH2:13][CH2:14][O:15][CH3:16])[C:8](=[O:17])[C:7](=[O:18])[NH:6]2
Reactant: COCCn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)ccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COCCn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c([N+](=O)[O-])cc21
Yield: 50 %

Procedure:
100 mg of 6-trifluoromethyl-1-(1-methoxyeth-2-yl)-1,2,3,4-tetrahydro-2,3-dioxoquinoxaline is suspended in 1 ml of concentrated sulfuric acid, mixed at 4° C. with 0.1 ml of a mixture of concentrated sulfuric acid:concentrated nitric acid=1:1 and stirred for 1 hour at 4° C. Then, everything is dissolved. Then, it is poured on ice and the settled precipitate is suctioned off. 59 mg (50% of theory) of 6-trifluoromethyl-7-nitro-1-(1-methoxyeth-2-yl)-1,2,3,4-tetrahydro-2,3-dioxoquinoxaline is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[C:6]([Br:17])[CH:5]=1)(=[O:3])[CH3:2].[Br-:18].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(O)C>[Br:17][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH2:2][Br:18])[CH:9]=[CH:8][C:7]=1[NH:10][C:11](=[O:16])[C:12]([F:13])([F:14])[F:15]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(NC(=O)C(F)(F)F)c(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCO
Product: O=C(CBr)c1ccc(NC(=O)C(F)(F)F)c(Br)c1
Yield: 46.1 %

Procedure:
N-(4-acetyl-2-bromophenyl)-2,2,2-trifluoroacetamide (12.1 g; 39.0 mmol) and tetrabutylammonium tribromide (18.8 g; 39.0 mmol) were dissolved separately in ethanol. After combination, and refluxing for 4 hrs, there was precipitate formation. The solvent was removed. NaHCO3 solution was added to neutralize any residue acid. The solid was filtered, and washed with CH2Cl2, to afford 7.0 g (yield 46%) of product as pale green solid. 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H, N—H), 8.51 (d, 3JHH=8.6 Hz, 1H, Ar—H), 8.25 (d, 4JHH=2.0 Hz, 1H, Ar—H), 7.98 (dd, 3JHH=8.6 Hz, 4JHH=2.0 Hz, 1H, Ar—H), 4.38 (s, 2H, —CH2—Br).
Reaction SMILES: N[C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=[O:6].N([O-])=[O:14].[Na+]>CC(O)=O.OS(O)(=O)=O.O>[OH:14][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: O=N[O-]
Reactant: COC(=O)c1cccc(N)c1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(O)cccc1C(=O)O
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
A solution of 20.6 g (0.125 mol) of methyl 3-amino-2-methylbenzoate in 150 mL of HOAc and 25 mL of conc. H2SO4 was cooled in ice and diazotized by the dropwise addition of a solution of 8.7 g (0.125 mol) of NaNO2 in 50 mL of H2O. After stirring for 15 minutes, the diazonium solution was added dropwise to a boiling solution of 200 mL of 50% H2SO4, and the refluxing continued for 15 minutes after the addition was complete. The mixture was diluted with H2O and extracted twice with Et2O. The Et2O was washed 5 times with H2O, then with saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left 17.98 g (94.4% yield) of the product as a tan solid, mp 137-140° C. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][Si:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>C1C=CC=CC=1>[C:31]([O:1][CH2:2][CH2:3][CH2:4][Si:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:34])[CH:32]=[CH2:33]
Reactant: C=CC(=O)Cl
Reactant: OCCC[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCC[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
32.9 g (91.4 mmol) of compound (C) was added to a 1 N solution of sodium carbonate in ethanol and the mixture was heated at 70° to 80° C. for 3 h to conduct the hydrolysis. 27.7 g (87.1 mmol) of 3-hydroxypropyltriphenylsilane (D) was thus obtained (yield: 95.4%). 250 ml of dry benzene was placed in a flask after replacing air in the flask with a dry inert gas (argon). 5.0 g (15.7 mmol) of compound (D) and 1.9 g of triethylamine were dissolved therein. 50 ml of a solution of 1.6 g (17.7 mmol) of acryloyl chloride in benzene was added slowly thereto. After the completion of the addition, the mixture was stirred at room temperature for 6 h. The reaction solution was washed with a 0.5 N hydrochloric acid, water, a 1 N sodium carbonate solution and water successively and then dried over magnesium sulfate. Benzene was distilled off and the residue was purified according to column chromatography (silica gel/benzene) to obtain 5.1 g (13.7 mmol) of 3-acryloyloxypropyltriphenylsilane in the form of white crystals (yield: 87.3%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][CH2:8][CH2:7][C:6]2([CH3:18])[C:14]([O:16][CH3:17])=[O:15])#[N:2].C([O-])([O-])=O.[K+].[K+].[Cl:25][C:26]1[CH:43]=[CH:42][C:29]([CH2:30][CH2:31][NH:32][C:33](=[O:41])[C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1>CN1CCCC1=O>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][CH2:31][NH:32][C:33]([C:34]2[CH:39]=[CH:38][C:37]([O:40][C:12]3[CH:11]=[C:10]4[C:5]([C:6]([CH3:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:36][CH:35]=2)=[O:41])=[CH:42][CH:43]=1
Reactant: COC(=O)C1(C)CCOc2cc(F)c(C#N)cc21
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1(C)CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3)c(C#N)cc21
Temperature: 110 °C
Reaction time: 5 h
Yield: 59.4 %

Procedure:
Methyl 6-cyano-7-fluoro-4-methylchroman-4-carboxylate (10 mg, 0.040 mmol) was diluted with N-methylpyrrolidone (2 mL) followed by the addition of K2CO3 (28 mg, 0.20 mmol) and N-(4-chlorophenethyl)-4-hydroxybenzamide (11 mg, 0.040 mmol). The reaction was bubbled with argon for 10 minutes and then heated at 110° C. and stirred for 5 hours. The reaction was allowed to cool, loaded directly onto a 25 samplet and eluted on the horizon with 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes to yield the title compound (12 mg, 59% yield). MS (ESI)=504.9 (M+1).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1)(=O)=O.[F-:19].C([N+](CCCC)(CCCC)CCCC)CCC>>[F:19][CH2:6][C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](COS(C)(=O)=O)C1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC(C)(C)OC(=O)N1CC[C@@H](CF)C1

Procedure:
Tetrabutylammonium fluoride (1M solution in THF, 530 mL) was added to (R)-tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (30 g from previous step) and the resulting mixture was refluxed overnight. After cooling, the solvent was removed and the residue was partitioned between 10% aqueous citric acid and dichloromethane. The organic layer was washed with water, dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. The residue was purified by flash chromatography on a silica gel column (0 to 50% ethyl acetate/hexanes) to afford 14.3 g of (R)-tert-butyl 3-(fluoromethyl)pyrrolidine-1-carboxylate as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 4.49-4.41 (m, 1H), 4.37-4.29 (m, 1H), 3.40-3.28 (m, 2H), 3.24-3.18 (m, 1H), 3.02-2.98 (m, 1H), 2.58-2.52 (m, 1H), 1.95-1.88 (m, 1H), 1.67-1.54 (m, 1H), 1.38 (s, 9H).