Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[F:3][C:4]([F:37])([F:36])[C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:35]=[CH:34][C:13]([O:14][CH:15]([C:19]3[CH:33]=[CH:32][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:9]=1.Cl>O1CCCC1>[F:37][C:4]([F:3])([F:36])[C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:35]=[CH:34][C:13]([O:14][CH:15]([C:19]3[CH:33]=[CH:32][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:9]=1
Reactant: CCCC(Oc1ccc(-n2cnc(C(F)(F)F)c2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC(Oc1ccc(-n2cnc(C(F)(F)F)c2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.2 %

Procedure:
Lithium hydroxide (1.0 mL, 1N in water, 1.0 mmol) was added to a room temperature solution of (+/−)-methyl 3-(4-(1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenoxy)butyl)benzamido)propanoate (89 mg, 0.18 mmol) in tetrahydrofuran (2 mL). The solution was stirred at room temperature 5 hours. The mixture was acidified to pH=2 with 1N HCl, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to give (+/−)-3-(4-(1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenoxy)butyl)benzamido)propanoic acid (84 mg, 98%). 1H NMR (400 MHz, CDCl3, δ): 7.74-7.68 (m, 3H), 7.45-7.41 (m, 1H), 7.39-7.34 (m, 2H), 7.18-7.12 (m, 2H), 6.91-6.85 (m, 2H), 6.84-6.77 (m, 1H), 5.17-5.11 (m, 1H), 3.73-3.65 (m, 2H), 2.71-2.64 (m, 2H), 2.03-1.94 (m, 1H), 1.86-1.74 (m, 1H), 1.60-1.35 (m, 2H), 0.99-0.91 (m, 3H). MS (M+1): 475.9.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[N:3]=1.[NH:22]1[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[C:24]([NH2:31])=[N:23]1.O.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[C:8]([C:6]1[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[N:3]=[C:2]([NH:31][C:24]2[C:25]3[C:26](=[N:27][CH:28]=[CH:29][CH:30]=3)[NH:22][N:23]=2)[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: Nc1n[nH]c2ncccc12
Reactant: CC(C)(C)c1cc(Cl)nc(-c2ccccc2C(F)(F)F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)c1cc(Nc2n[nH]c3ncccc23)nc(-c2ccccc2C(F)(F)F)n1
Temperature: 165 °C
Yield: 5.3 %

Procedure:
A mixture of 4-chloro-6-tert-butyl-2-(2-trifluoromethyl-phenyl)-pyrimidine (0.10 g, 0.32 mmol) and 1H-pyrazolo[3,4-b]pyridin-3-ylamine (0.064 g, 0.48 mmol) was heated neat at 160-170° C. for 16 hours. The resulting residue was cooled, dissolved in N-methyl-pyrrolidinone (2 mL), then poured into water (20 mL) and sodium bicarbonate (5 mL) and extracted twice with ethyl acetate. The combined organic layers were washed four times with water, once with brine, then dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC to provide the title compound (0.007 g, 4% yield) as a yellow solid. 1H-NMR (500 MHz, DMSO-d6) δ 13.2 (br s, 1H), 10.6 (br s, 1H), 8.49 (m, 2H), 7.84 (d, J=7.8 Hz, 2H), 7.76 (m, 2H), 7.68 (m, 1H), 7.12 (m, 1H), 1.32 (s, 9H) ppm; LC-MS 413.08 (M+H); Rt (Method A) 3.112 minutes.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=3[N:14]=2)[CH2:12][CH2:11][O:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[NH:17][C:13]([C:8]3([NH2:7])[CH2:12][CH2:11][O:10][CH2:9]3)=[N:14][C:15]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1(c2nc3cc(Cl)ccc3[nH]2)CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2nc3cc(Cl)ccc3[nH]2)CCOC1
Reaction time: 2 h

Procedure:
[3-(5-Chloro-1H-benzoimidazol-2-yl)-tetrahydro-furan-3-yl]-carbamic acid tert-butyl ester (2.09 g, 6.19 mmol) is dissolved in DCM (100 mL) and treated with TFA (10 mL). Stirring is continued for 2 h. Volatiles are evaporated under reduced pressure and the resulting residue taken up twice with ethyl ether and evaporated under reduced pressure to give 3-(5-Chloro-1H-benzoimidazol-2-yl)-tetrahydro-furan-3-ylamine as trifluoroacetic salt crude (2.2 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1.S1C=CC(B(O)O)=C1.C(=O)([O-])[O-].[Na+].[Na+].[C:24]([O:27][CH2:28][CH3:29])(=O)[CH3:25]>COCCOC.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.O>[O:27]1[CH:28]=[CH:29][C:25]([C:2]2[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[N:4][CH:3]=2)=[CH:24]1
Reactant: CCOC(C)=O
Reactant: O=Cc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccsc1
Solvent: COCCOC
Solvent: O
Product: O=Cc1cncc(-c2ccoc2)c1
Temperature: 25 °C

Procedure:
A solution of 3-Bromo-5-pyridinecarboxaldehyde from Example 59 Step D (200 mg, 1.08 mmol) and tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol) in DME (5 mL) was stirred at room temperature for 5 minutes. Thiophene-3-boronic acid (141 mg, 1.08 mmol) was added and the stirring was continued for 10 more minutes. Then, sodium carbonate solution (2 M, 5 mL) was added and the reaction mixture was heated to refluxed for 12 hours. After it was cooled to room temperature, the reaction mixture was distributed between ethyl acetate (50 mL) and water (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified on preparative TLC (2000 microns, hexanes/ethyl acetate=1/1) to get 5-(3-furanyl)-3-pyridinecarboxaldehyde as a pale solid. 1H NMR (CDCl3, 300 MHz): δ10.18 (s, 1 H), 9.11 (d, J=2.1 Hz, 1 H), 8.98 (d, J=1.8 Hz, 1 H), 8.33 (t, J=2.1 Hz, 1 H), 7.44 (dd, J=1.2, 1.5 Hz, 1 H), 7.44-7.52 (m, 2 H).
Reaction SMILES: C([O:3][C:4](=[O:51])[CH:5]([NH:33][S:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[CH2:39][CH2:38]1)(=[O:36])=[O:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:20][CH:19]=3)[O:15][N:14]=2)=[C:9]([F:32])[CH:8]=1)C.CC1C=CC(CN2CCNCC2)=CC=1.C(N(CC)CC)C>C(#N)C>[C:28]([O:27][C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([NH:33][S:34]([N:37]4[CH2:38][CH2:39][N:40]([CH2:43][C:44]5[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=5)[CH2:41][CH2:42]4)(=[O:35])=[O:36])[C:4]([OH:51])=[O:3])=[CH:8][C:9]=3[F:32])[N:17]=2)=[CH:19][CH:20]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCOC(=O)C(Cc1ccc(-c2noc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)c(F)c1)NS(=O)(=O)N1CCN(Cc2ccc(C)cc2)CC1
Agent: Cc1ccc(CN2CCNCC2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(CN2CCN(S(=O)(=O)NC(Cc3ccc(-c4noc(-c5ccc(NC(=O)OC(C)(C)C)cc5)n4)c(F)c3)C(=O)O)CC2)cc1
Temperature: 85 °C
Yield: 69 %

Procedure:
3-{4-[5-(4-tert-Butoxycarbonylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-3-fluoro-phenyl}-2-[4-(4-methyl-benzyl)-piperazine-1-sulfonylamino]-propionic acid ethyl ester. A mixture of oxazolidione from Step A (40 mg, 0.065 mmol), 1-(4-methylbenzyl)piperazine (24.7 mg, 0.13 mmol), and triethylamine (20 mg, 0.2 mmol) in acetonitrile (3 mL) was heated at 85° C. for 2.5 hrs. TLC showed the reaction was completed. The solution was concentrated. Ethyl acetate (20 mL) and 1N aq. HCl solution (10 mL) were added to the solution. The layers were separated, and the aqueous portion was extracted with ethyl acetate (20 mL). The combined organic layer was washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (32 mg, 69% yield) as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:4])=[O:3].B.B(F)(F)F.CCOCC>C1COCC1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[CH2:8][OH:9])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Agent: B
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CS(=O)(=O)c1cccc(CO)c1
Temperature: 25 °C

Procedure:
To a solution of 3-(methylsulfonyl)benzoic acid (1.2 g, 6.0 mmol) in THF (30 mL) at 0° C., is added equimolar amounts of borane (6.0 mL of a 1.0 M solution in THF) and boron trifluoride diethyl etherate (0.8 mL, 6.0 mmol). The reaction is allowed to warm to ambient temperature overnight, and then quenched by pouring into a mixture of ice and solid NaHCO3. Following extraction with EtOAc, the organic layer is washed with brine and dried over Na2SO4. Removal of solvent affords the product as a colorless oil: MS (M+NH4)+=204.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH2:5][C:6]1(O)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.N.[Li]>CCOCC.O>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[C:12]2[CH2:13][CH:14]=[CH:15][CH2:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2
Reactant: CN(C)CCCC1(O)c2ccccc2CCc2ccccc21
Agent: N
Agent: [Li]
Solvent: O
Solvent: CCOCC
Product: CN(C)CCCC1C2=C(CC=CC2)CCc2ccccc21
Reaction time: 0.33 h
Yield: 98.3 %

Procedure:
5-[3-(Dimethylamino)propyl]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol (50.2 g) is partially dissolved in 350 ml of ether and added to 2 liters of liquid ammonia. Lithium ribbon (4.73 g) is then added portionwise over a period of 15 minutes. After stirring for 20 minutes, absolute alcohol is added dropwise until the color is discharged (about 90 ml added over a period of 1 hour). More ether is added and the ammonia is boiled off. While cooling in an ice bath the mixture is diluted slowly with 1 liter of water. The layers are separated and the aqueous layer is reextracted with ether. The combined organic layers are dried over potassium carbonate, filtered, and the solvent is removed in vacuo, leaving 47.0 g of an oil. NMR indicates this is about 50% of the desired diene (the bulk of remaining material being unreduced starting material).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([CH:20]2[C@H:25]([O:26]CC3C=CC=CC=3)[C@@H:24]([O:34]CC3C=CC=CC=3)[C@H:23]([O:42]CC3C=CC=CC=3)[C@@H:22]([CH2:50][O:51]CC3C=CC=CC=3)[O:21]2)=[CH:16][C:3]=1[CH2:4][C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:8][N:9]=1.I[Si](C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([CH:20]2[C@H:25]([OH:26])[C@@H:24]([OH:34])[C@H:23]([OH:42])[C@@H:22]([CH2:50][OH:51])[O:21]2)=[CH:16][C:3]=1[CH2:4][C:5]1[S:6][C:7]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)=[N:8][N:9]=1
Reactant: Clc1ccc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1nnc(-c2ccncc2)s1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: OC[C@H]1OC(c2ccc(Cl)c(Cc3nnc(-c4ccncc4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 50 °C
Yield: 11 %

Procedure:
To a solution of 2-(2-chloro-5-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)benzyl)-5-(pyridin-4-yl)-1,3,4-thiadiazole (2.83 mmol) from Step 1 in acetonitrile (5 mL) was added Iodotrimethylsilane (5 mL). The resulting reaction mixture was heated to 50° C. overnight. After cooling to 0° C., the reaction quenched with methanol and concentrated in vacuo. Purification by reverse phase preparative HPLC (Gilson®, SunFire™ Prep, 5 to 50% acetonitrile in water gradient) provided the title compound (139 mg, 0.31 mmol, 11%, mixture of α,β-anomer) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][N:28]=[N+]=[N-])[O:24][C:23]2=[O:31])[CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39].CO.C(Cl)(Cl)Cl>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][NH:28][C:38](=[O:40])[CH3:39])[O:24][C:23]2=[O:31])[CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)cc(N3CC(CN=[N+]=[N-])OC3=O)cc2F)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)NCC1CN(c2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
The [[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]azide (22.4 g, 51 mmol) was dissolved in 1 L of EtOAc and then degassed three times with N2. Next, 10% Pd-C (4.48 g, 20% by weight) was added and the solution was degassed again three times (with N2) before replacing the atmosphere with H2 (balloon). After 3 hours, the reaction was determined to be complete by TLC (20% MeOH/CHCl3, UV short wave). At this point, pyridine (8.26 mL, 102 mmol) was added, followed by treatment with acetic anhydride (9.64 mL, 102 mmol). The reaction mixture was allowed to stir overnight at room temperature. The reaction was found to be complete by TLC (20% MeOH/CHCl3, UV short wave). The reaction mixture was filtered through celite (the filter cake was washed with 500 mL EtOAc), the filtrate concentrated down to approximately 600 mL, and washed with H2O (2×500 mL) and brine (500 mL). The aqueous portions were back-extracted with more EtOAc (2×500 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid. Recrystallization of the crude product from hot CHCl3 and hexane afforded 19.167 g (83%) of the title compound as a white solid with mp 177°-179° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:16]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:4][CH:3]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(S(=O)(=O)O)c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(S(=O)(=O)O)c2ccccc12)c1ccccc1
Reaction time: 8 h
Yield: 61.1 %

Procedure:
To a solution of 4-amino-naphthalene-1-sulfonic acid (2.3 g, 10.0 mmol) in pyridine (15 mL), was added benzoyl chloride (1.4 mL, 12.0 mmol) and the resultant solution was heated at 100° C. and stirred overnight. The solvent was removed in vacuo and the crude material was recrystallized from MeOH (2×) to give the pyridinium salt of 4-benzoylamino-naphthalene-1-sulfonic acid (2.0 g) as a gray colored solid. 1H NMR (300 MHz, DMSO) δ 8.92 (m, 3H), 8.60 (t, 1H), 8.00 (m, 6H), 7.55 (m, 6H); LC/MS m/z 327 (M−H)−.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4]/[C:5](/[CH3:21])=[CH:6]/[CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[C:11]([CH3:17])=[C:10]([CH3:18])[C:9]=1[O:19][CH3:20].[Na+].[I-:23].CC(C)=O>O>[I:23][CH2:2][CH2:3][CH2:4]/[C:5](/[CH3:21])=[CH:6]/[CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[C:11]([CH3:17])=[C:10]([CH3:18])[C:9]=1[O:19][CH3:20]
Reactant: [I-]
Reactant: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCCl)c1C
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCI)c1C
Temperature: 25 °C
Yield: 99 %

Procedure:
(E)-1-(6-chloro-3-methylhex-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene (725.8 mg, 2.334 mmol) and NaI (3.09 g, 20.61 mmol) were dissolved into acetone (10 mL) and heated to reflux for 18 h. The reaction mixture was cooled to room temperature and the cloudy solution added to H2O (50 mL) and of a 50% EtOAc/hexanes solution (50 mL), the layers separated and the aqueous phase extracted with hexanes (3×25 mL), then MTBE (2×25 mL). The organics were combined and washed with saturated NaCl solution (2×25 mL) and dried over anhydrous Na2SO4. Concentration yielded 930.0 mg (99.0%) of 1-((E)-6-iodo-3-methylhex-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene as a pale yellow oil. 1H NMR (400 MHz, CDCl3) d 5.12 (t, J=6.4 Hz, 1H), 3.65 (s, 6H), 3.36 (d, J=6.0 Hz, 2H), 3.12 (t, J=7.2 Hz, 2H), 2.18 (S 9H), 2.07 (t, J=7.2 Hz, 2H), 1.91 (t, J=7.2 HZ, 2H), 1.77 (s, 3H), 13C NMR (100 MHz, CDCl3) d 153.1, 152.6, 133.0, 131.3, 128.4, 127.9, 127.6, 124.7, 60.9, 60.1, 40.1, 31.7, 26.1, 16.1, 12.8, 12.7, 12.2.
Reaction SMILES: [ClH:1].[C:2]([CH2:6][CH2:7][C:8]([NH2:10])=[NH:9])([O:4]C)=[O:3].Cl>>[ClH:1].[C:8]([CH2:7][CH2:6][C:2]([OH:4])=[O:3])(=[NH:9])[NH2:10]
Reactant: COC(=O)CCC(=N)N
Agent: Cl
Product: N=C(N)CCC(=O)O
Yield: 99 %

Procedure:
A solution of 7.8 g. (0.047 mole) of β-carbomethoxypropionamidine hydrochloride in 217 ml. of 12N hydrochloric acid is heated at steam bath temperatures for 1 hour. The solution is cooled. evaporated in vacuo to dryness, and the residual product triturated several times with ethylene dichloride and filtered, 7.1 g. (99% yield), m.p. 138°-140° C. (McElvain, et al., J. Am. Chem. Soc., 71, 40 (1949) reports a melting point for crude product of 131°-137° C.).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Cl:9][C:10]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:21]([O-:23])=[O:22])=[C:17]([CH:20]=1)[CH:18]=O>O.C(O)C>[Cl:9][C:10]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:21]([O-:23])=[O:22])=[C:17]([CH:20]=1)[CH:18]=[N:2][OH:3]
Reactant: O=Cc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1C=NO

Procedure:
To a solution of hydroxylamine hydrochloride (0.33 g., 0.0048 mole) and sodium acetate (0.394 g., 0.0048 mole) in 2-3 ml of water was added a hot solution of 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzaldehyde (1.5 g., 0.00434 mole) in ethanol (10-12 ml). The clear yellow solution was heated for 1.5 hours and then the solvent was stripped on a rotary evaporator to give a yellow waxy solid which solidified giving 1.5 g., mp. 111°-115° C. Recrystallization from ethanol/water gave a solid mp. 114°-118° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]#[N:14].[N:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)=[N+:16]=[N-:17].C[O-].[Na+]>CO>[NH2:14][C:13]1[N:15]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:22][CH:23]=2)[N:16]=[N:17][C:12]=1[C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=1[F:1]
Reactant: [N-]=[N+]=Nc1ccc(S(N)(=O)=O)cc1
Reactant: N#CCc1ccc(C(F)(F)F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1c(-c2ccc(C(F)(F)F)cc2F)nnn1-c1ccc(S(N)(=O)=O)cc1
Yield: 99 %

Procedure:
To a stirred and ice-cooled solution of 2-fluoro-4-(trifluoromethyl)phenyl acetonitrile (1.066 g, 5.2471 mmol) and 4-azido-benzenesulfonamide (0.800 g, 4.0362 mmol) in methanol (50 ml), sodium methoxide (0.3271 g, 6.0543 mmol) is added portion wise and the mixture is allowed to attain room temperature spontaneously and stirred for additional 24 hours at this temperature. The reaction mixture is concentrated, water (10 ml) is added and extracted with ethyl acetate (3×80 ml). The combined organic layers are washed with brine (15 ml), dried over MgSO4, filtered and concentrated to afford an off-white solid (1.61 g, ˜99% yield, 97.7% pure at HPLC). M.p. 183.8-185.2° C. LC-ESI-HRMS of [M+H]+ shows 402.0638 Da. Calc. 402.064783 Da, dev. −2.4 ppm.
Reaction SMILES: [C@@H:1]1([O:11][CH2:12][CH2:13][N:14]([CH2:27][CH2:28][O:29][C@@H:30]2[O:38][C@@H:37]([CH3:39])[C@@H:35]([OH:36])[C@@H:33]([OH:34])[C@@H:31]2[OH:32])[CH2:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:17])[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[B-](F)(F)(F)F.CN(C(O[N:53]1[C:58](=[O:59])[CH2:57][CH2:56][C:54]1=[O:55])=[N+](C)C)C.CCOC(C)=O.CO.C(#N)C.O>CN(C=O)C>[C@@H:30]1([O:29][CH2:28][CH2:27][N:14]([CH2:13][CH2:12][O:11][C@@H:1]2[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]2[OH:3])[CH2:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][N:53]2[C:58](=[O:59])[CH2:57][CH2:56][C:54]2=[O:55])=[O:25])=[O:17])[O:38][C@@H:37]([CH3:39])[C@@H:35]([OH:36])[C@@H:33]([OH:34])[C@@H:31]1[OH:32]
Reactant: C[C@@H]1O[C@@H](OCCN(CCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)CC(=O)NCCCCCC(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1O[C@@H](OCCN(CCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)CC(=O)NCCCCCC(=O)ON2C(=O)CCC2=O)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(2-(bis(2-[(α-L-fucopyranosyl)oxy)ethyl)amino)acetamido)hexanoic acid (20 mg, 0.037 mmol, 1.0 eq) in DMF (1 mL) was added TSTU (16.68 mg, 0.055 mmol, 1.5 eq) followed by Hunig'sBase (7.74 μl , 0.044 mmol, 1.2 eq). The reaction was stirred at rt for 1 h. TLC (4/1/1/1 EtOAc/MeOH/ACN/water) indicated no starting material left. UPLC indicated formation of pdt. Remove DMF under reduced pressure. The crude product was used without purification. UPLC Method B: m/e=666.3351 [M+1]; Rt=2.28 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH:17](O)[CH3:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)Cl.CCOC(C)=O>[N:34]([CH:17]([CH:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)[CH3:18])=[N+:35]=[N-:36]
Reactant: CC(O)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(N=[N+]=[N-])C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)-3-(1-hydroxyethyl)piperidine (510 mg, 1.94 mmol) in methylene chloride (5 mL) at 0° C. was added diisopropylethylamine (507 μL, 2.91 mmol) followed by methanesulfonyl chloride (180 μL, 2.33 mmol). After stirring 10 min at 0° C., the ice bath was removed and the mixture stirred at room temperature for 30 min The reaction mixture was diluted with EtOAc then was washed with saturated aqueous NaHCO3, 1N HCl, saturated aqueous NaHCO3 and brine, respectively. The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was dissolved in DMF (5 mL), and to this was added sodium azide (190 mg, 2.91 mmol). The mixture was heated at 100° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with H2O (3×20 mL) followed by brine. The organic layer was dried over Na2SO4. The crude material was purified by flash chromatography using 1:15 EtOAc:hexane system to obtain 442 mg of the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 7.34 (m, 5H); 5.12 (br s, 2H); 3.38 (m, 1H); 1.3 (br s, 3H). Mass spectrum 289.4 (ESI, M+1).
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Br.[C:26]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH2:33])[CH:27]=1>>[C:26]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH:33][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)[CH:18]=2)[CH:27]=1
Reactant: NCc1cccc(-c2ccccc2)c1
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Agent: Br
Product: CCCCCCCCCCCc1noc(-c2cccc(CNCc3cccc(-c4ccccc4)c3)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1,1′-biphenyl-3-ylmethylamine hydrobromide gave the title compound as an oil. M+(LC/MS(ESI)): 496.5. HPLC (Condition A), Rt: 4.99 min (HPLC purity: 87.7%).