Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccccc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1OCc1ccccc1
Reaction time: 17 h
Yield: 60.4 %

Procedure:
To a solution of (2-benzyloxyphenyl)acetic acid (36 g) in dimethylformamide (360 ml) were added potassium carbonate (61.2 g) and methyl iodide (31.6 g) successively. After being stirred for 17 hours, the mixture was filtered and the filtrate was poured into aqueous 1N hydrochloric acid solution (1.8 l). The separated oil was extracted with diethyl ether and the organic layer was washed with brine, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel [eluting with ethyl acetate - n-hexane (1:1)] to afford methyl (2-benzyloxyphenyl)acetate (23 g).
Reaction SMILES: [NH2:1][C@@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH2:16][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.Cl.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C@@H:2]([C:13]([NH:16][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)=[O:14])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)[C@H](N)Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2.0 g (5.39 mmol) Chas-D-Phe(4-NO2)—OH and 1.42 g (5.39 mmol) H-Phe(4-NO2)—OMe.HCl were suspended in 30 ml of DMF and 2.82 g (5.39 mmol) of PyBOP and 2.81 ml (16.16 mmol) of DIPEA was added at 0° C. After 2 h of stirring at 0° C., the solvent was removed in vacuo and the brown residue resuspended in 5% KHSO4 soln./EtOAc. The organic phase was washed 3× with 5%-KHSO4 soln., 1× with sat. NaCl soln., 3× with sat. NaHCO3-soln., and 3× with sat. NaCl soln., subsequently dried with MgSO4, filtered, and the solvent was removed in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2.[H-].[Na+].[Cl:16][CH2:17][CH2:18][CH2:19]I>CN(C=O)C>[Cl:16][CH2:17][CH2:18][CH2:19][N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:13]
Reactant: ClCCCI
Reactant: O=C1CCc2cc(F)c(F)cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc(F)c(F)cc2N1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
A reaction flask was charged with 6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (97KK47) (0.181 g, 0.99 mmol) in dry DMF (5 mL) under an argon atmosphere. Washed NaH (0.026 g, 1.08 mmol) was added and the mixture was stirred at rt for 0.5 h. Then 3-chloro-1-iodopropane (0.205 g, 1.00 mmol) dissolved in DMF (1 mL) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into Et2O. The combined organic layers were washed with aqueous 4% MgSO4, dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; DCM) to give the title compound (112KK03) (0.122 g, 47%). 1H NMR (CD3OD) d 6.99-6.86 (m, 2H), 4.03-3.99 (m, 2H), 3.60 (t, J=6.1, CH2), 2.84-2.81 (m, 2H), 2.63-2.59 (m, 2H), 2.13-2.06 (m, 2H).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH:30]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31]1.C1CCN2C(=NCCC2)CC1>CS(C)=O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][N:30]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31]1
Reactant: O=C(O)C1CCNC1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCC(C(=O)O)C4)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) and pyrrolidine-3-carboxylic acid (22.81 mg, 0.198 mmol) in DMSO (2 mL) was added DBU (0.030 mL, 0.198 mmol). The reaction mixture was heated at 80° C. for 2 hours. The crude material was purified via preparative LC/MS with the following conditions: Column. Waters XBridge C18, 19×100 mm, 5-μm particles; Guard Column: none; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5, acetonitrile:water with 0.05% TFA; Gradient: 25-100% B over 10 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl) pyrrolidine-3-carboxylic acid was 16.3 mg, and its purity was 96%. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.21 (2H, d, J=8.35 Hz), 7.81 (2H, dd, J=8.02, 1.65 Hz), 7.69 (2H, d, J=8.35 Hz), 7.54-7.66 (3H, m), 5.10-5.22 (1H, m), 3.39-3.54 (4H, m), 3.24-3.27 (3H, m), 3.00-3.10 (2H, m), 2.23-2.57 (2H, m), 1.70-1.83 (2H, m), 1.05 (3H, t, J=7.36 Hz). MS (m+1)=489. HPLC Peak RT=2.08 minutes. (Analytical Method C). Purity=96%.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:15]#[N:16])=[N:6][CH:7]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-:3])=[O:2].O[CH2:18][C@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20]>>[NH2:21][C@H:19]([CH3:20])[CH2:18][N:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([C:15]#[N:16])=[N:6][CH:7]=2)=[N:14]1
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: N#Cc1ncc(-c2ccn[nH]2)cc1[N+](=O)[O-]
Product: C[C@@H](N)Cn1ccc(-c2cnc(C#N)c([N+](=O)[O-])c2)n1
Yield: 46.5 %

Procedure:
(R)-5-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-3-nitropicolinonitrile was prepared from 3-nitro-5-(1H-pyrazol-5-yl)picolinonitrile (0.88 g, 4.9 mmol) and (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate (0.86 g, 4.9 mmol) using the method of Example 34(d). Thus, 0.62 g (56%) of the title compound was obtained. m/z [273.3+1].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([F:27])[CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)CCC.[Cl-]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:19]1[CH:18]=[C:17]([N:9]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([C:33]3[N:34]=[CH:35][S:36][CH:37]=3)=[CH:3][CH:4]=2)[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(Br)cc2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(-c3cscn3)cc2)cc1F
Yield: 87.5 %

Procedure:
To a stirred solution of 2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole (0.361 g, 0.78 mmol) in 1,4-dioxane (12 mL) was added 4-(tributylstannyl)thiazole (0.35 g, 0.94 mmol), lithiun chloride (0.083 g, 1.95 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.090 g, 0.078 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 3 hours. After cooling, volatiles were removed by evaporation. The residue was redissolved in ethyl acetate (30 mL) and the whole washed with water and brine. After dried over MgSO4 and concentration in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (3/1). The resulting solid was recrystallized from ethyl acetate-hexane to give the title compound (0.319 g, 87.6% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]([CH3:8])([CH3:7])[CH3:6])=O.[N:9]#[C:10][NH2:11].[OH-].[Na+]>O.Cl>[CH3:6][C:5]([C:3]1[NH:9][C:10]([NH2:11])=[N:1][CH:2]=1)([CH3:8])[CH3:7]
Reactant: N#CN
Reactant: CC(C)(C)C(=O)CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cnc(N)[nH]1
Temperature: 90 °C
Yield: 6.1 %

Procedure:
To a stirred solution of 6.8 g of aminomethyl-(1,1-dimethylethyl)ketone, as the hydrochloride salt, in 30 ml of water were added portionwise 5.0 g of cyanamide. The pH of the reaction mixture was adjusted to 6.0 with 1N sodium hydroxide, and then the mixture was heated to 90° C. and stirred for fifty-five minutes. The reaction mixture was next cooled to room temperature, diluted with 100 ml. of water, and extracted several times with diethyl ether. The aqueous layer was made alkaline with ammonium hydroxide, and again extracted several times with diethylether. The extracts from the alkaline mixture were combined and concentrated to dryness to provide a solid residue. The residue thus obtained was dissolved in 20 ml of 6N hydrochloric acid and heated at reflux for sixteen hours. The reaction mixture was cooled, concentrated to an oil by evaporation of the solvent, and the oil was dissolved in water and made alkaline to pH 8.5. The alkaline mixture was extracted several times with diethyl ether. The etheral extracts were combined, washed with water, dried, and the solvent was removed by evaporation under reduced pressure to provide 0.5 g of 5-(1,1-dimethylethyl)-2-aminoimidazole.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH3:13])[C:10]2[CH:14]=[CH:15][S:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CC(O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH3:13])[C:10]2[CH:14]=[C:15]([Br:17])[S:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N1CCc2sccc2C(C)C1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)N1CCc2sc(Br)cc2C(C)C1
Reaction time: 0.25 h

Procedure:
The product of step d) (80 mg, 0.35 mmol) was dissolved in 2 mL of 1:1 CHCl3 /HOAc. N-Bromo-succinimide (62 mg, 0.35 mmol) was added and the reaction was stirred for 15 minutes. Concentration and purification by silica gel chromatography gave the subtitle compound as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH2:15])=[N:10][CH:11]=2.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:16]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH2:15])=[N:10][CH:11]=2)(=[O:18])[CH3:17]
Reactant: Nc1ncc2ncn(COCCO)c2n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OCCOCn1cnc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 0.82 g (3.92 mM) of 9-(2-hydroxyethoxymethyl)-2-amino-9H-purine, 48 mg (0.392 mM) of a 4-dimethylaminopyridine and 0.75 ml (7.84 mM) of acetic anhydride in 18 ml of dry dimethylformamide was stirred at room temperature for two days. The reaction mixture was evaporated in vacuo and the residue dissolved in ethyl acetate and absorbed on silica gel. The solvent was removed by flash evaporation and the residual powder added to a column prepared for flash chromatography. Elution with 5% methanol in dichloromethane gave 1.0 g of a semicrystalline oil which on recrystallization from benzene-hexane gave analytically pure 9-(2-acetoxyethoxymethyl)-2-amino-9H-purine, mpt. 115°-118° C. An additional crop was obtained from the mother liquor.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=O)C)C=O)(=[O:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[C:25]([O:24][C@H:23]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:9][C@@H:10]1[S:35][C:32]1[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C=O)OC(C)=O
Reactant: Cc1ccc(S)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OC[C@H]1O[C@H](Sc2ccc(C)cc2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a mixture of D-mannose pentaacetate (16.0 g, 0.041 mol) and p-thiocresol (7.6 g, 0.0615 mol) in CH2Cl2 (200 mL), boron trifluoride diethyl etherate (6.8 mL, 0.0533 mol) was added. The mixture was stirred overnight. The reaction mixture was then diluted with CH2Cl2 (200 mL), washed with sat. NaHCO3 (2×120 mL) and water (100 mL). The organic layer was dried over Na2SO4. The solvent was removed, and the residue was purified by column chromotography on silia gel (hexanes/EtOAc 3:1) to give product (16.2 g, 87%) as a syrup: 1HNMR (500 MHz, CDCl3), δ 7.38 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 5.49 (dd, 1H, J=2.5, 1.5 Hz), 5.42 (d, 1H, J=1.0 Hz), 5.30–5.35 (m, 2H), 4.54–4.58 (m, 1H), 4.30 (dd, 1H, J=12.5, 6.0 Hz), 4.11 (dd, 1H, J=12.0, 2.5 Hz), 2.33 (s, 3H), 2.15 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H); HRMS (M+Cs) calcd for C21H26O9SCs 587.0352. found 587.0331.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[O:20][CH3:21])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].[N+:23]([O-])([OH:25])=[O:24]>O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]([C:12]1[CH:17]=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[O:20][CH3:21])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCCCCC(CC(=O)OCC)c1cccc(OC)c1OC
Reactant: O=[N+]([O-])O
Solvent: O
Product: CCCCCC(CC(=O)OCC)c1cc([N+](=O)[O-])cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.13 g (3.66 mmol) of 3-(2, 3-dimethoxyphenyl) octanoic acid ethyl ester and 3 ml of 60% nitric acid was stirred at room temperature for 2 hours. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane (1/5) to give 1.15 g of 3-(2, 3-dimethoxy-5-nitropheyl) octanoic acid ethyl ester as a yellow oil. Yield, 89%. This compound showed a coupling constant of J=2.6 Hz in 1H NMR (CDCl3) spectra, suggesting meta-coupling. Further, 0.10 g of 3-(2, 3-dimethoxy-6-nitrophenyl) octanoic acid etheyl ester (yield, 7.7%) was obtained, showing a coupling constant of J=9.1 Hz in 1H NMR (CDCl3) spectra.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18]CC)=[O:17])(=[O:12])=[O:11].C(O)C.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([OH:18])=[O:17])(=[O:12])=[O:11]
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Nc2c(F)cccc2F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(S(=O)(=O)Nc2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To the product of Step A was added ethanol (8 mL) followed by a solution of 50% NaOH (0.96 g, 12.1 mmol) in water (8 mL). The reaction was stirred at ambient temperature for 1.5 hours. To the mixture was added dropwise 1 N HCl (28 mL), and the mixture was stirred at ambient temperature overnight. The solids were collected by filtration, washed with water (2×5 mL), and dried in a vacuum oven at 50° C. overnights to give 3-{[(2,6-difluorophenyl)amino]sulfonyl}benzoic acid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.11 (t, J=8.1 Hz, 2H), 7.33-7.41 (m, 1H), 7.71 (t, J=7.7 Hz, 1H), 7.92 (dt, J=8.4, 1.1 Hz, 1H), 8.19 (dt, J=7.8, 1.1 Hz, 1H), 8.27 (t, J=1.51 Hz, 1H), 10.20 (s, 1H), 13.48 (s, 1H); MS (ESI) m/z 312 (M−H)−.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[C:34]([C:33]([F:32])([F:43])[F:44])[CH:35]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccc(C(F)(F)F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (80 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 3-trifluoromethylbenzoyl chloride (0.42 mL, 2.8 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was filtered, and the solid was rinsed with CH2Cl2 (15 mL) and acetone (15 mL). The solid was then recrystallized with MeOH to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-trifluoromethyl-benzamide as a white solid (0.5 g, 54%): mp, 241-243° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.4 min. (99%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.53-2.65 (m, 2H), 2.85-2.93 (m, 1H), 4.96 (d, J=5.8 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.46-7.84 (m, 6H), 9.33 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.96, 30.92, 38.49, 48.86, 106.93, 110.58, 110.69, 110.82, 110.93, 121.99, 127.21, 131.54, 133.20, 134.83, 137.42, 138.62, 160.51, 160.67, 163.78, 163.95, 164.10, 166.92, 167.48, 169.81, 172.73. Anal Calcd for C21H15FN3O5: C, 59.02; H, 3.54; N, 9.83; F, 8.89. Found: C, 58.90; H, 3.15; N, 9.73; F, 9.08.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[OH:13].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30](=[O:37])[CH:31]=[C:32]([CH2:35][OH:36])[O:33][CH:34]=1.O>CN(C=O)C>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30](=[O:37])[CH:31]=[C:32]([CH2:35][OH:36])[O:33][CH:34]=1
Reactant: O=c1cc(CO)occ1OCCCCCBr
Reactant: Oc1ccnc2c(C(F)(F)F)cccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(CO)occ1OCCCCCOc1ccnc2c(C(F)(F)F)cccc12
Reaction time: 0.17 h
Yield: 35 %

Procedure:
8-Trifluoromethyl-quinolin-4-ol (0.84 g, 2.88 mmol) was dissolved in DMF (5 mL). Cs2CO3 (0.98 g, 3.02 mmol) was added at room temperature and the mixture was stirred for 10 min. A solution of 5-(5-bromo-pentyloxy)-2-hydroxymethyl-pyran-4-one 10 (0.86 g, 3.02 mmol) in DMF (5 mL) was added via syringe. This mixture was stirred at 50° C. for 18 h. Water (10 mL) was added and the mixture extracted with EtOAc (2×50 mL), washed with water (3×50 mL), brine (3×50 mL) dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent (CH2Cl2:MeOH)=90:10. 5-(5-(8-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 14 was obtained (0.53 g, 35% yield) as a pale yellow foam.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:9]>C(O)C.[B-](F)(F)(F)F.[Ag+]>[C:1]([NH2:8])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: N#Cc1ccccc1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: NC(=O)c1ccccc1
Temperature: 90 °C
Yield: 87407.4 %

Procedure:
(0.0045 g, 0.0097 mmol) of the catalyst of Example 4, was dissolved in a vigorously stirred mixture of benzonitrile (3.5 g, 0.034 mmol), ethanol (7 cm3) and water (2 ml, 0.06 mmol). To this was added an excess of AgBF4 (0.0045 g, 0.019 mmol) and the reaction mixture refluxed at 90° C. for five hours. After cooling, it was filtered to remove the precipitated AgCl. The solvent was then removed under reduced pressure to give benzamide (3.60 g, 87%), which was dried in vacuo.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:15])[CH:4]=[C:5]([CH:9]([OH:14])[C:10]([F:13])([F:12])[F:11])[N:6]([CH3:8])[CH:7]=1.[CH2:16]=[O:17].[OH-].[Na+].Cl>CO>[OH:1][C:2]1[C:3](=[O:15])[CH:4]=[C:5]([CH:9]([OH:14])[C:10]([F:11])([F:12])[F:13])[N:6]([CH3:8])[C:7]=1[CH2:16][OH:17]
Reactant: Cn1cc(O)c(=O)cc1C(O)C(F)(F)F
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(C(O)C(F)(F)F)cc(=O)c(O)c1CO
Temperature: 40 °C
Reaction time: 1 h
Yield: 146.4 %

Procedure:
In each of three parallel synthesis tubes equipped with a magnetic stir bar was placed 5-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (0.50 g, 2.24 mmol), a 36.5% by wt formaldehyde solution (6 mL, 80.4 mmol), and a 6.00 N sodium hydroxide solution (0.45 mL, 2.7 mmol). The resulting solution was heated to about 40° C. for overnight. Analysis by HPLC Method 1 (Example 24) indicated consumption of the starting material. The contents of the three tubes were combined, and the resulting solution was cooled in an ice-water bath. A 6.00 N hydrochloric acid solution (1.1 mL, 6.6 mmol) was added to adjust the pH of the solution to about 6. The mixture was concentrated in vacuo to remove most of the solvent to give a solid/liquid mixture. To the mixture was added methanol (100 mL), and the mixture was stirred for 1 h. The first crop of the solid was collected by suction filtration and washed with de-ionized water thoroughly to give 3-hydroxy-2-hydroxymethyl-1-methyl-6-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (0.83 g, 48% yield, HPLC Method 1 (Example 24), RT=7.7 min, HPLC purity (peak percent area): 99.2% at λ=280 nm). 1H NMR (DMSO-d6+D2O) δ ppm: 6.53 (s, 1H), 5.54 (q, J=6.5 Hz, 1H), 4.67 (s, 2H), 3.76 (s, 3H); MS-ESI (m/z) 254.1 [M+1]+, 236.1, 208.1 (100%), 139.2.
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH:29](=O)[CH2:30]C>>[CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[C:21]=4[CH2:29][CH3:30])[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2]
Reactant: CCC=O
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Product: CCc1c2c(nc3cc(F)ccc13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 84 is treated with propionaldehyde according to a procedure similar to Stage 95e in order to produce the expected solid.