Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[H-].[H-].[H-].[H-].[Li+].[Al+3].[F:11][C:12]([F:30])([F:29])[C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[N:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1>CCOCC.C1COCC1>[F:29][C:12]([F:11])([F:30])[C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[N:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1
Reactant: N#CCc1ccc(Oc2ccc(C(F)(F)F)cc2)nc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCc1ccc(Oc2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.4 %

Procedure:
To a solution of AlCl3 (268 mg, 1.8 mmol) in Et2O cooled to 0° C. in an ice bath was added LiAlH4 (66 mg, 1.8 mmol) in one portion, under N2. After stirring 15 min, a solution of [6-(4-trifluoromethylphenoxy)-pyridin-3-yl]-acetonitrile (500 mg, 1.8 mmol) in Et2O (2 mL) and THF (1 mL) was added dropwise resulting in an exotherm. The reaction was allowed to cool to room temperature, and after 2 h, the reaction was quenched by careful addition of 5 mL of saturated aqueous ammonium chloride. The resulting mixture was made alkaline by addition of 2M NaOH solution. The precipitate which formed was removed by filtration through Celite. The filtrate phases were separated, and the aqueous phase was extracted 3 times with Et2O. The pooled organic fractions were dried with Na2SO4 and suction filtered. The solvent was removed in vacuo to yield 2-[6-(4-trifluoromethylphenoxy)-pyridin-3-yl]-ethylamine (200 mg), as a brown oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6]([O:9][C:10]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]3[N:22]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:23]4[C:28]([CH:29]=3)=[CH:27][C:26]([CH:30]=O)=[CH:25][CH:24]=4)=[C:15]3[C:11]=2[CH2:12][NH:13][C:14]3=[O:39])(=[O:8])=[O:7])=[CH:2]1.Cl.[CH3:41][NH:42][CH3:43].C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[S:1]1[CH:5]=[CH:4][C:3]([S:6]([O:9][C:10]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]3[N:22]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[C:23]4[C:28]([CH:29]=3)=[CH:27][C:26]([CH2:30][N:42]([CH3:43])[CH3:41])=[CH:25][CH:24]=4)=[C:15]3[C:11]=2[CH2:12][NH:13][C:14]3=[O:39])(=[O:7])=[O:8])=[CH:2]1
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccsc1)CNC2=O
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc(-c2cc3cc(CN(C)C)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccsc1)CNC2=O
Yield: 45.2 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-(3-thiophenesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.219 g, 0.385 mmol) was dissolved in acetonitrile (6.0 mL), and the solution was treated with dimethylamine hydrochloride (0.630 g, 7.70 mmol), triethylamine (1.10 mL, 7.70 mmol), acetic acid (0.441 mL, 7.70 mmol) and sodium triacetoxyborohydride (0.245 g, 1.16 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=85/15) to obtain 4-(3-thiophenesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(dimethylaminomethyl)indol-2-yl]isoindolinone (0.104 g, 45%).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[S:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[K].S(OC)(O[CH3:18])(=O)=O>CC(C)=O>[CH3:7][C:6]1[C:2]([O:1][CH3:18])=[C:3]([C:9]([O:11][CH3:12])=[O:10])[S:4][C:5]=1[CH3:8]
Reactant: COC(=O)c1sc(C)c(C)c1O
Reactant: COS(=O)(=O)OC
Agent: [K]
Solvent: CC(C)=O
Product: COC(=O)c1sc(C)c(C)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-hydroxy-4,5-dimethylthiophene-2-carboxylate (Preparation 1) (29.7 g, 160 mmol) in anhydrous acetone (500 ml) was added anhydrous potassium carbonte (24.5 g, 178 mmol) and the mixture stirred for 1 hour at room temperature. Dimethyl sulphate (22.4 g, 178 mmol) was added and the mixture stirred under reflux for 2.5 hours. The solvent was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was washed with brine, dried with sodium sulphate and evaporated to give crude product which was used in the following preparation.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:18])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:24](N(C)C)[N:25]([CH3:27])[CH3:26])(C)(C)C>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:24][N:25]([CH3:27])[CH3:26])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Product: CN(C)C=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 95.3 %

Procedure:
16.0 g of 3-benzyloxy-4-nitrotoluene and 23.0 g of tert-butoxybis(dimethylamino)methane are heated for 8 hours to 100° C. After allowing the mixture to stand for 8 hours at room temperature, the pure reaction product is crystallized. This product is filtered off and washed with a mixture of ethyl acetate and cyclohexane 1:4, thus obtaining 18.7 g of 1-(3-benzyloxy-4-nitrophenyl)-2-dimethylaminoethene, mp 111°-114° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](O)=[O:11]>C1COCC1>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:13]
Reactant: COC(=O)CCCCCCC(=O)O
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Cis-9,10-octadecenoamide, cis-11,12-octadecenoamide, and trans-9,10-octadecenoamide were prepared from their respective acids as follows: cis-9,10-octadecenoic acid (oleic acid) in CH2Cl2 (0.2M) at 0° C. was treated with oxalyl chloride (3 eq) and stirred at 25° for 4 hour. Removal of solvent followed by treatment with saturated aqueous NH4OH at 0° C. gave cis-9,10-octadecenoamide, which was purified by silica gel column chromatography (40-75% ethyl acetate-hexanes gradient elution). Cis-8,9-octadecenoamide was synthesized as follows: 1) Suberic acid monomethyl ester in THF at -20° C. was treated with BH3 -THF (1.05 eq) and stirred for 12 hour at 25° C. to afford methyl 8-hydroxyoctanoate (18); 2) Methyl 8-hydroxyoctanoate in CH2Cl2 at 0° C. was treated sequentially with CBr4 (1.3 eq) and Ph3P (1.4 eq) and stirred for 10 hour at 4° C. to give methyl 8-bromooctanoate; 3) Methyl 8-bromooctanoate was dissolved in CH3CN (0.8M) and warmed at reflux. Ph3P (1.1 eq) was added to the solution and stirring was continued for 20 hour to afford the corresponding phosphonium salt; 4) The phosphonium salt of methyl 8-bromooctanoate was dissolved in THF at 25° C. and treated with KHMDS (1.1 eq). After stirring at reflux for 1 hour, the solution was cooled to -78° C. and decanal (1.5 eq) was added. The mixture was allowed to warm to 25° C. and stirred for 30 minute to afford methyl cis-8,9-octadecenoate; 5) Methyl cis-8,9-octadecenoate was hydrolyzed to afford cis-8,9-octadecenoic acid with LiOH (3 eq) in THF-CH3OH--H2O (3:1:1); 6) Conversion of cis-8,9-octadecenoic acid to cis-8,9-octadecenoamide was conducted as described above.
Reaction SMILES: CC([O-])(C)C.[K+].[NH2:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[O:13])=[CH:10][CH:9]=1.[Br:29][C:30]1[CH:31]=[CH:32][C:33](F)=[C:34]([CH:37]=1)[C:35]#[N:36].[NH4+].[Cl-]>CS(C)=O.ClCCl>[Br:29][C:30]1[CH:31]=[CH:32][C:33]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]3)=[O:13])=[CH:27][CH:28]=2)=[C:34]([C:35]#[N:36])[CH:37]=1
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Nc3ccc(Br)cc3C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
KOtBu (2.81 g, 25.08 mmol) was dissolved into 20 ml DMSO in a round bottom flask. tert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate (7 g, 22.92 mmol) in 30 ml DMSO was added and the resulting mixture was stirred for 15 minutes at room temperature, then cooled in an iced bath for 5 minutes. 5-bromo-2-fluorobenzonitrile (4.6 g, 23.00 mmol) in 20 ml DMSO was added. The ice bath was removed and the mixture stirred for 5 hours while warming to room temperature. LCMS showed product and unreacted starting materials. Additional KOtBu (2 g, 17.82 mmol) was added and the reaction stirred at room temperature overnight. The mixture was transferred into a separating funnel that was loaded with dichloromethane and dilute aq. NH4Cl solution. The layers were separated, the organic layer washed one more time with water, then brine, dried over Mg504, filtered and concentrated in vacuum. The crude was dissolved in dichloromethane, and refluxed while adding ethyl acetate until the solution becomes cloudy, then allowed to stand and cool to room temperature. The product precipitated and was collected by filtration. 6.40 g tert-butyl 4-(4-(4-bromo-2-cyanophenylamino)-benzoyl)piperazine-1-carboxylate were isolated as a white solid. The mother liquor was concentrated in vacuum and purified by column chromatography on silica, gradient from 100% dichloromethane to 50% ethyl acetate in dichloromethane. Product containing fractions were combined and evaporate to give additional 0.90 g product as a pale yellow solid. MS (ESI) m/z 485/487 (1 Br isotope pattern) (M+H), 429/431 (1 Br isotope pattern) (M+H—C4H8). 1H NMR (CDCl3) δ ppm 7.64 (s, 1H), 7.50 (d, 1H, J=9.2), 7.42 (d, 2H, J=8.3), 7.19-7.15 (m, 3H), 6.39 (s, 1H), 3.80-3.40 (b, 8H), 1.47 (s, 9H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[CH2:9](OC(OCC)OCC)C>>[N:1]1[N:2]=[CH:9][N:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=12
Reactant: CCOC(OCC)OCC
Reactant: NNc1ccccn1
Product: c1ccn2cnnc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Hydrazinylpyridine (5.06 g, 46.4 mmol) was treated with triethoxymethane (50.2 mL, 302 mmol) and the mixture was heated to reflux for 4 hours with nitrogen flowing over the top of the air condenser. The air condenser was replaced with a small distillation head and the low boiling solvents (75-80° C.) were removed from the system. Heating continued for 16 hours. The reaction was cooled to ambient temperature and concentrated in vacuo to a dark residue. The residue was chromatographed on SiO2 eluting with a gradient of 6% NH4OH in MeOH/ethyl acetate. The desired product was isolated as a light orange solid (4.2 g). MS APCI (+) m/z 120.0 (M+1) detected.
Reaction SMILES: Cl[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:9]2[C:8](=[O:19])[N:7]([CH3:20])[C:6](=[O:21])[N:5]([CH3:22])[C:4]=2[N:3]=1.[NH:23]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]([NH2:30])[CH2:24]1.C(N(CC)CC)C.O>CS(C)=O.ClCCl>[NH2:30][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][N:23]([C:2]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:9]3[C:8](=[O:19])[N:7]([CH3:20])[C:6](=[O:21])[N:5]([CH3:22])[C:4]=3[N:3]=2)[CH2:24]1
Reactant: Cc1ccccc1Cn1c(Cl)nc2c1c(=O)n(C)c(=O)n2C
Reactant: NC1CCCCNC1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccccc1Cn1c(N2CCCCC(N)C2)nc2c1c(=O)n(C)c(=O)n2C
Reaction time: 0.17 h

Procedure:
8-Chloro-1,3-dimethyl-7-(2-methylbenzyl)-3,7-dihydropurine-2,6-dione (85A) (300 mg, 0.9 mmol) and azepan-3-ylamine (322 mg, 2.8 mmol), and triethylamine (0.7 ml, 4.7 mmol) were dissolved in 3 ml of DMSO and the mixture was subjected to microwaves (method F, 200° C., 300 W) for 10 minutes. To the reaction mixture was added 100 ml of water and 100 ml of dichloromethane, and the organic layer was washed with 1N NaOH, and dried over sodium sulfate. The solvents were evaporated and the crude product was purified by preparative HPLC (method A1, Rt=7.5 min.). Evaporation of the solvent afforded the title compound as a brown oil.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[C@H:10]([NH:13][C:14]([CH2:16][C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:24]([O-:26])=[O:25])=O.[Na+].[SH:28][C:29]1[O:33][C:32]([CH2:34][C:35]([NH2:37])=[O:36])=[N:31][N:30]=1.C(=O)(O)[O-].[Na+].C(O)CCC>P([O-])([O-])([O-])=O.C(O)C.O.C(O)(=O)C>[S:21]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:16][C:14]([NH:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:24]([OH:26])=[O:25])=[C:6]([CH2:5][S:28][C:29]3[O:33][C:32]([CH2:34][C:35](=[O:36])[NH2:37])=[N:31][N:30]=3)[CH2:23][S:22][C@H:9]12)=[O:15]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: NC(=O)Cc1nnc(S)o1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCO
Solvent: CC(=O)O
Product: NC(=O)Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)o1
Temperature: 0 °C

Procedure:
Sodium cephalothin (2.09 g, 5.0 mmole), 5-mercapto-1,3,4-oxadiazol-2-ylacetamide (0.84 g., 5.5 mmole) and sodium bicarbonate (0.42 g., 5.0 mmole) in pH 6.5 phosphate buffer (25 ml) were heated at 60° C. for 6.5 hours, then poured onto crushed ice (~25 g), washed with ethyl acetate (2×20 ml), acidified to pH 2.0 with N hydrochloric acid and extracted with ethyl acetate (3×50 ml). The extracts were washed with water (2×20 ml) and saturated brine (20 ml), dried and evaporated to dryness in vacuo to give a gummy solid. This was extracted with hot ethyl acetate (10 ml) to leave the product as an off white solid, 1.23 g., 49.8%; t.l.c. (SiO2 ; n-butanol, acetic acid, water; 12:3:5) Rf=0.41; λmax (95% ethanol), 272 nm (εm=9,650); δ[(CD3)2SO], 3.5-4.0 (2H,m, C2 methylene), 3.85 and 3.90 (4H, 2×s, 2×--CH2CO--), 4.33 and 4.49 (2H, AB quartet, J=14 Hz, --CH2S--), 5.22 (1H,d, J=5 Hz, C6 proton), 5.81 (1H,dd, J=5,8 Hz, C7 proton), 7.0-7.6 (3 H,m, thienyl protons), 7.65 (2H, d, J=26 Hz, --CONH2 ), 9.33 (1H,d, J=8 Hz, --CONH--).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)#[CH:14].O1CCCC1>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.[Cu]I.C(N(CC)CC)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:14]#[C:13][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(Cl)c(I)c1
Reactant: C#Cc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c(C#Cc2ccc(F)cc2)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Under an inert atmosphere of nitrogen, a mixture of methyl 4-chloro-3-iodobenzoate (200 mg, 0.68 mmol, 1.00 equiv), 1-ethynyl-4-fluorobenzene (243 mg, 2.02 mmol, 3.00 equiv), Pd(PPh3)2Cl2 (94.6 mg, 0.14 mmol, 0.20 equiv), CuI (13 mg, 0.07 mmol, 0.10 equiv), tetrahydrofuran (12 mL), and triethylamine (4 mL) was stirred overnight at 70° C. in an oil bath. The solids were filtered out, and the filtrate was concentrated in vacuo. The residue was purified via silica gel column chromatography (ethyl acetate/petroleum ether (1:100)) resulting in 130 mg (67%) of methyl 4-chloro-3-(2-(4-fluorophenyl)ethynyl)benzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.Br[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)OCC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 108.1 %

Procedure:
In a 50 mL pressure tube, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 1 g, 1.62 mmol), tert-butyl 2-bromoacetate (316 mg, 240 μL, 1.62 mmol) and cesium carbonate (634 mg, 1.95 mmol) were combined with dry dimethyl formamide (10 mL) to give a white suspension. The tube was capped and heated at 50° C. After 10 min, the reaction mixture was cooled down to room temperature, poured into water and extracted with ethyl acetate (2×). The combined ethyl acetate layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated to give 2-tert-butoxy-2-oxoethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as light yellow solid (1280 mg), which was used without further purification.
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])(=O)=O.[CH2:22]([C:24]([C:49]1[CH:54]=[CH:53][C:52](O)=[C:51]([CH3:56])[CH:50]=1)([C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:44][CH2:45][O:46][CH3:47])([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[C:29]([CH3:48])[CH:28]=1)[CH2:25][CH3:26])[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:22]([C:24]([C:49]1[CH:54]=[CH:53][C:52]([O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15])=[C:51]([CH3:56])[CH:50]=1)([C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:44][CH2:45][O:46][CH3:47])([C:40]([F:42])([F:43])[F:41])[C:36]([F:38])([F:39])[F:37])=[C:29]([CH3:48])[CH:28]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(/C=C/C(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(CC)(c1ccc(/C=C/C(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
Pyridine (0.513 mL, 6.36 mmol) and trifluoromethanesulfonic anhydride (0.835 mL, 5.09 mmol) were added to a solution of 4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenol (Example 26-(2); 2.14 g, 4.24 mmol) in dichloromethane (20 mL) in a nitrogen atmosphere at 0° C., and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 70:30) to give the target product as a colorless oil (2.41 g, 89%).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[O-]S([O-])(=O)=O.[Mg+2].P([O-])([O-])([O-])=O>>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To one liter of an aqueous solution containing glucose, MgSO4 ·7H2O and phosphate buffer at a concentration of 0.1 M, 0.005 M and 0.05 M, respectively, is added a given amount of an insolubilized glucose isomerase. The mixture thus obtained is slowly stirred at a temperature of 70° C for 60 minutes to effect the isomerization. Then, the insolubilized isomerase is separated from the reacted solution and the amount of fructose so produced is determined according to the cystein carbazol method. The activity is calculated as in 1 above.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH:14]1([C@H:17]([NH2:39])[C:18]([N:20]2[CH2:24][C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])=[CH:22][C@H:21]2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:19])[CH2:16][CH2:15]1.C(N(CC)CC)C>ClCCl>[CH:14]1([C@H:17]([NH:39][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[C:18]([N:20]2[CH2:24][C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])=[CH:22][C@H:21]2[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:19])[CH2:16][CH2:15]1
Reactant: N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
A solution of 4-nitrophenyl chloroformate (188 mg, 0.931 mmol, 1.10 equiv) in dichloromethane (5 mL) was added dropewise to a solution of (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethanamine (16-7, 300 mg, 0.847 mmol, 1 equiv) and triethylamine (0.354 mL, 2.54 mmol, 3.00 equiv) in dichloromethane (10 mL) at 0° C. The reaction mixture was warmed to 23° C. and stirred for 20 hours. The reaction mixture was then partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (75 mL). The organic layer was washed with brine, then dried over magnesium sulfate and concentrated to provide 4-nitrophenyl(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethylcarbamate (31-1) as a pale yellow solid. LRMS m/z (M+H) 520.5 found, 520.2 required.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)=[C:4]([N:21]=[N+]=[N-])[N:3]=1.C(O)=O.N>[Pd].CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:14][O:15][C:16]([CH3:19])([CH3:20])[O:17][CH2:18]2)=[C:4]([NH2:21])[N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(N=[N+]=[N-])nc(N)nc32)CO1
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: O=CO
Product: CC1(C)OCC(CCn2cnc3c(N)nc(N)nc32)CO1
Yield: 65 %

Procedure:
A mixture of 2-amino-6-azido-9-[2-(2,2-dimethl-1,3-dioxan-5-yl)ethyl]purine (318 mg, 1.0 mmol), formic acid (0.15 ml, 4.0 mmol), concentrated ammonia (0.22 ml, 4.0 mmol), 10% palladium-on-charcoal (30 mg) and methanol (10 ml) was heated under reflux for 1 hour. The solution was allowed to cool, filtered and the solvent removed. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol mixtures (20:1 and 15:1) to give 2,6-diamino-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (190 mg, 65%), m.p. 202-204° C.); νmax (KBr) 1670, 1640, 1595, and 1410 cm−1; δH (CDCl3—CD3OD) 1.42 (6H, s, C(CH3)2), 1.6-2.0 (3H, m, CHCH2CH2), 3.5-4.2 (6H, m, 2×CH2O and CH2N), and 7.68 (1H, s, 8-H) (Found: C, 52.88; H, 6.78; N, 28.36%; M+ 292.1652. C13H20N6O2 requires C, 53.41; H, 6.90; N, 28.75%; M+ 292.1648).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:10]([O:8][C:7]([CH:4]1[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]1)=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: O=C1CCC(C(=O)OCc2ccccc2)C1

Procedure:
The mixture of 3-oxo-cyclopentanecarboxylic acid (750 mg), of benzyl alcohol (633 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 1 (680 mg), and of 1-hydroxybenzotriazole (350 mg) in 50 ml tetrahydrofuran was stirred overnight. After addition of aq. Sodium bicarbonate (sat. 25 mL), the reaction mixture was extracted with of ethyl acetate (50 ml×2). The organic layer was washed with brine, dried with anhydrous sodium sulfate and concentrated to yield 3-oxo-cyclopentanecarboxylic acid benzyl ester as oil.