Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[F:25][C:26]1([F:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[F:25][C:26]1([F:32])[CH2:31][CH2:30][N:29]([CH2:22][C:16]2([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:15][CH:14]=3)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:28][CH2:27]1
Reactant: FC1(F)CCNCC1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCO
Product: FC1(F)CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Yield: 7.5 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (260 mg, 0.82 mmol), 4,4-difluoropiperidine hydrochloride (323 mg, 2.05 mmol), absolute ethanol (11 mL), activated 4 Å molecular sieves, titanium (IV) isopropoxide (1.209 mL, 4.09 mmol) and STAB (1.475 g, 6.96 mmol) were reacted in accordance with the general procedure D. The isolated waxy solid was purified by reverse phase preparative HPLC on a Xterra column eluting with a gradient of MeCN:H2O:Et3N (from 29.9:70:0.1 to 94.9:5:0.1 in 13 min) to give the title compound (26 mg, 6%). 1H NMR (400 MHz, CDCl3) δ 7.21 (d, 2H), 6.88 (d, 2H), 4.02 (t, 2H), 3.77-3.73 (m, 2H), 3.53-3.47 (t, 2H), 2.64 (t, 2H), 2.54 (m, 4H), 2.39 (s, 2H), 2.30-2.24 (m, 6H), 2.13 (d, 2H), 2.02 (m, 2H), 1.90-1.71 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14]3[C:15](=[O:23])[O:16][C:17]([CH3:22])([C:19]([OH:21])=[O:20])[CH2:18][C:13]=3[N:12]=[CH:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:24][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[CH3:24][O:20][C:19]([C:17]1([CH3:22])[O:16][C:15](=[O:23])[C:14]2[N:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)[CH:11]=[N:12][C:13]=2[CH2:18]1)=[O:21]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC1(C(=O)O)Cc2ncn(-c3ccc(C#N)c(Cl)c3)c2C(=O)O1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1(C)Cc2ncn(-c3ccc(C#N)c(Cl)c3)c2C(=O)O1
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To 50 mg (0.15 mmol) of 44 in 2 mL of a 1:1 CH2Cl2/MeOH is added 0.07 mL (0.14 mmol) of 2 M trimethylsilyl diazomethane in hexanes. After stirring for 1 h another 0.07 mL (0.14 mmol) of 2M trimethylsilyl diazomethane is added. The mixture is stirred for 1 h, concentrated, dissolved in 50 mL of EtOAc, and washed with twice with 20 mL of H2O and once with 20 mL of brine. The organic phase is dried with MgSO4, filtered, and concentrated to give 21 mg (0.06 mmol) of 45.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:12]=[C:13]([C:14]([O:16]CC)=[O:15])[C:8]=2[C:7]([CH3:27])=[N:6]1)([CH3:4])[CH3:3].[OH-].[Na+]>CCO>[CH3:4][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:8]=2[C:7]([CH3:27])=[N:6]1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)nc2c1c(C)nn2C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2cc(C(=O)O)c3c(C)nn(C(C)(C)C)c3n2)cc1

Procedure:
The title compound was prepared in the same manner as described for intermediate 75 using ethyl 1-(1,1-dimethylethyl)-3-methyl-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (400 mg, 1.089 mmol), 3N sodium hydroxide (1.814 mL, 5.44 mmol), and EtOH (6 mL). The product was collected as 347 mg (94%). LCMS E-S (M+H)=340.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81 (s, 9 H), 2.55 (s, 3 H), 7.11 (d, J=8.84 Hz, 2 H), 7.89 (s, 1 H), 8.16 (d, J=8.84 Hz, 2 H).
Reaction SMILES: [CH2:1]([O:9][CH:10]([CH3:13])[CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>N1C=CC=CC=1>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:12][CH2:11][CH:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:13])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCOC(C)CO
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCOC(C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
53 g of dry pyridine and 22.2 g of 2-octyloxypropanol were added into a four-necked flask and cooled with NaCl-ice. 35.4 g of p-toluenesulfonic acid chloride was added little by little, and after the reaction was carried out for 4 hours, the mixture was left standing at room temperature for 18 hours. The reaction product was added into 500 g of ice-cooled 6% HCl aq. and the mixture was extracted with 500 ml of benzene and dried over anhydrous Na2SO4, followed by evaporation of benzene, to give 40 g of (2'-octyloxypropyl) p-toluenesulfonate as an oily product.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:19]2[O:20][CH:21]=[C:22]([CH2:24][NH:25][C:26](=[O:34])[C:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=3)[N:23]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([F:18])[F:17])C1C=CC=CC=1>C(O)C.[C].[Pd]>[F:18][CH:16]([F:17])[O:15][C:14]1[CH:13]=[CH:12][C:11]([C:19]2[O:20][CH:21]=[C:22]([CH2:24][NH:25][C:26](=[O:34])[C:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=3)[N:23]=2)=[CH:10][C:9]=1[OH:8]
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(OCc3ccccc3)c2)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
0.16 g of N-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide obtained in Example 96 was dissolved in 5 ml of ethanol, 20 mg of 10% palladium carbon powder was added thereto, and the mixture was stirred at room temperature for 30 minutes under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated to obtain 0.12 g of white powdery N-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.[C:11]([NH:14][C:15]1[NH:16][C:17](=O)[C:18]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)[CH:22]=[CH:21][C:19]=2[N:20]=1)(=[O:13])[CH3:12].C(N(CC)CC)C>C(#N)C>[C:11]([NH:14][C:15]1[N:16]=[C:17]([C:5]2[N:4]=[CH:3][NH:2][N:1]=2)[C:18]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)[CH:22]=[CH:21][C:19]=2[N:20]=1)(=[O:13])[CH3:12]
Reactant: c1nc[nH]n1
Reactant: COc1ccc(-c2ccc3nc(NC(C)=O)[nH]c(=O)c3n2)cc1OC
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2ccc3nc(NC(C)=O)nc(-c4nc[nH]n4)c3n2)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.6 %

Procedure:
A suspension of 1,2,4-triazole (8.28 g, 120 mmol) and phosphorus oxychloride (3.2 ml, 36 mmol) in dry acetonitrile (150 ml) was added to a stirred suspension of 2-acetamido-6-(3,4-dimethoxyphenyl)pyrido[3,2-d]pyrimidin-4(3H)-one (4.08 g, 12 mmol) and triethylamine (5.2 ml, 36 mmol) in dry acetonitrile (150 ml). The mixture was stirred at room temperature under nitrogen for 3 days and the yellow precipitate was filtered off, then successively washed with ethanol and ether, and dried over P2O5 in a vacuum dessicator resulting in the pure title compound (4.3 g, yield 90%) which was characterized by its mass spectrum as follows: MS (m/z): 392 ([M+H]+, 100), 414 ([M+Na]+; 804 [2M+Na]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br>O1CCCC1>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:11]([S:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]#[N:13]
Reactant: COc1ccc(C(C#N)Sc2ccc(C)cc2)cc1OC
Reactant: BrCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)(CCCCCCCCCCCBr)Sc2ccc(C)cc2)cc1OC
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
To a solution of 2.50 g of 3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile in 50 mL of tetrahydrofuran, under an argon atmosphere with stirring, is added 0,367 g of 60% sodium hydride in oil. After 1.5 hours, 10.0 g of 1,11-dibromoundecane is added and stirring is continued for 43 hours. The reaction mixture is evaporated and the residue partitioned between diethyl ether and water. The organic phase is separated, washed with water, dried with magnesium sulfate, filtered and evaporated leaving an oil. The oil is purified via column chromatography, using hexane/ether (1:1) to afford 3.25 g of the desired product as a colorless oil.
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([C@@:7]1([NH:12][C:13](N2C=C[N+](C)=C2)=[O:14])[CH2:9][C@H:8]1[CH:10]=[CH2:11])=[O:6])[CH3:3].[CH2:21]([N:28]([CH3:37])[C:29]([C@@H:31]1[CH2:35][C@@H:34]([OH:36])[CH2:33][NH:32]1)=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].C(OC([C@@]1(NC(N2C[C@H](O)C[C@H]2C(=O)N(CCCCC=C)C)=O)C[C@@H]1C=C)=O)C>>[CH2:2]([O:4][C:5]([C@@:7]1([NH:12][C:13]([N:32]2[CH2:33][C@H:34]([OH:36])[CH2:35][C@H:31]2[C:29](=[O:30])[N:28]([CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH3:27])[CH3:37])=[O:14])[CH2:9][C@@H:8]1[CH:10]=[CH2:11])=[O:6])[CH3:3]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)n1cc[n+](C)c1)C(=O)OCC
Reactant: C=CCCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Agent: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)N[C@]1(C(=O)OCC)C[C@@H]1C=C
Agent: [I-]
Product: C=C[C@H]1C[C@]1(NC(=O)N1C[C@H](O)C[C@H]1C(=O)N(C)CCCCC=CC)C(=O)OCC
Yield: 38 %

Procedure:
Compound 72a was synthesized from compounds 34 and 71a as a beige solid in 38% yield, following the procedure as described for compound 50.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[Si:39]([O:46][CH2:47][CH2:48][CH2:49][N:50]1[CH:54]=[C:53](B2OC(C)(C)C(C)(C)O2)[CH:52]=[N:51]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Si:39]([O:46][CH2:47][CH2:48][CH2:49][N:50]1[CH:54]=[C:53]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:52]=[N:51]1)([C:42]([CH3:45])([CH3:43])[CH3:44])([CH3:40])[CH3:41]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cnn(CCCO[Si](C)(C)C(C)(C)C)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cnn(CCCO[Si](C)(C)C(C)(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, 0.2 mmol) was treated with 1-(3-(tert-butyldimethylsilyloxy)propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (180 mg, 0.49 mmol), tetrakistriphenylphosphine palladium (72 mg, 0.06 mmol) and aqueous solution of sodium carbonate (2M, 250 μl, 0.5 mmol) in DMF (3 ml). The reaction mixture was submitted at vacuum-argon cycles and stirred at 100° C. for 3 h. The reaction mixture was cooled down to room temperature and poured over ice, basified with potassium carbonate and extracted with ethyl acetate (×3). The organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified by normal phase using SP1® Purification System (0% to 50%, hexane-diethyl ether) to obtain 124 mg (69% yield) of the title compound. Purity: 85%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([CH3:10])=[N:3]1.[CH3:11][CH2:12][CH2:13][CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17]>>[CH3:11][CH2:12][CH2:13][CH:14]([NH:18][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=1)=[O:9])[CH2:15][CH2:16][CH3:17]
Reactant: Cc1cc(C(=O)O)n(C)n1
Reactant: CCCC(N)CCC
Product: CCCC(CCC)NC(=O)c1cc(C)nn1C

Procedure:
Prepared in a similar manner to example 4 using 1,3-dimethyl-1H-pyrazole-5-carboxylic acid and 4-heptylamine. 1H NMR (500 MHz, CDCl3): δ 0.90 (t, 6H, J=7.2 Hz), 1.41 (m, 4H), 1.50 (m, 4H), 2.27 (s, 3H), 3.77 (s, 3H), 4.09 (m, 1H), 6.49 (d, 1H), 6.53 (s, 1H). MS (M+H, 238).
Reaction SMILES: NC1C(Br)=C[C:5]([O:9]C)=C(Br)N=1.BrC1C(O)=CC=CN=1.[Br:20][C:21]1[C:26](OC)=[CH:25][CH:24]=[C:23]([N+:29]([O-:31])=[O:30])[N:22]=1>C(O)C>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([O:9][CH3:5])=[C:23]([N+:29]([O-:31])=[O:30])[N:22]=1
Reactant: COc1cc(Br)c(N)nc1Br
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Agent: Oc1cccnc1Br
Solvent: CCO
Product: COc1ccc(Br)nc1[N+](=O)[O-]

Procedure:
Starting material -2-amino-6-bromo-5-methoxybromo-pyridine, was prepared in following manner: 2-bromopyridin-3-ol (Aldrich) was converted to 2-bromo-3-methoxy-6-nitropyridine as described in J. Med. Chem. 1981, 24, 39-42. Hydrogenation of 2-bromo-6-nitro-5-methoxypyridine in ethanol (Pt on C, 1 atm) gave the starting material as a reddish oil. This product was then condensed with cis/trans mixture of 2-(2-chloro-3-ethoxy-6-fluorophenyl)cyclopropyliso-cyanates, described in Example 53, in a manner analogous to the method n Example 7 to provide cis/trans (50:50) mixture of N-2-(2-Chloro-3-ethoxy-6-fluorophenyl)-cyclopropyl-N′-(6-bromo-5-hydroxypyrid-2-yl)-ureas. 1H NMR (250 MHz, CDCl3) δ 7.62-7.43 (m, 1H), 7.29-7.12 (m, 1H), 6.91-6.67 (m, 2H), 4.10-3.94 (m, 2H), 3.90 and 3.84 (2 s, 3H),3.38-3.02 (m, 1H) 2.18-2.00 (m, 1H), 1.55-1.30 H (m, 5H), 1.43 (t, 3H), 0.92-0.80 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:18]=[C:17]([F:19])[C:16]2[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=2)[N:10]=1)=[O:8])[CH3:2].C(N(CC)CCN[C:29]([C:31]1[CH:32]=[C:33]([Sn:42](CCCC)([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:43][CH2:44][CH2:45][CH3:46])C=C2C=1N=CC=C2F)=O)C>>[CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:18]=[C:17]([F:19])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Sn:42]([CH2:43][CH2:44][CH2:45][CH3:46])([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:33][CH2:32][CH2:31][CH3:29])[CH:15]=2)[N:10]=1)=[O:8])[CH3:2]
Reactant: CCN(CC)CCNC(=O)c1cc(F)c2cc(I)ccc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)NCCN(CC)CC)c2nccc(F)c2c1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc2nc(C(=O)NCCN(CC)CC)cc(F)c2c1
Yield: 57 %

Procedure:
This compound was prepared, starting from compound 106 (206 mg, 0.50 mmol), according to the procedure developed for compound 112. The purification was performed using column chromatography (Al2O3, cyclohexane/AcOEt, 5/5, v/v) to give compound 113 (165 mg, 0.29 mmol) as an orange oil. Yield 57%; Rf (Al2O3, cyclohexane/AcOEt, 5/5, v/v) 0.73; IR (CCl4) ν 1521, 1684, 2929, 2962 cm−1; 1H NMR (200 MHz, CDCl3) δ 0.88 (t, 9H, J=7.0 Hz), 1.10 (t, 6H, J=7.1 Hz), 1.17 (m, 6H), 1.33 (m, 6H), 1.55 (m, 6H), 2.64 (q, 4H, J=7.1 Hz), 2.74 (t, 2H, J=6.3 Hz), 3.59 (q, 2H, J=6.3 Hz), 7.88 (d, 1H, J=8.3 Hz), 7.94 (d, 1H, 3JH-F=10.4 Hz), 8.04 (dd, 1H, J=1.4, 8.3 Hz), 8.20 (d, 1H, 3J119Sn/117Sn-H=40.8 Hz), 8.61 (m, 1H); ESI-MS m/z 580.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[F:15][C:16]([F:27])([F:28])[O:17][C:18]1[CH:23]=[C:22]([C:2]2[C:6]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=3[O:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: COC(=O)c1ccc2occ(Br)c2c1
Product: COC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1
Yield: 80 %

Procedure:
In the same manner as in Reference Example 19 and using methyl 3-bromo-1-benzofuran-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and [3-(trifluoromethoxy)phenyl]boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 80%) was obtained as colorless crystals.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=O)C=CC=CC=1.[N+:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([O-])=[O:20].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:23]([C:22]1[CH:9]=[C:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:20][N:19]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCC[N+](=O)[O-]
Reactant: C#CCc1ccccc1
Solvent: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCc1cc(Cc2ccccc2)on1
Reaction time: 1 h

Procedure:
To a room temperature, stirred solution of 3-phenyl-1-propyne (54.86 g, 0.4723 mol) and phenyl isocyanate (104 mL, 0.957 mol) in benzene (800 mL) under nitrogen was added dropwise over 30 minutes a solution of 1-nitrotridecane (109.14 g, 0.47583 mol) and triethylamine (6.7 mL, 0.048 mol) in benzene (400 mL), and the mixture was stirred for 1 hour. The mixture was refluxed for 6 hours, allowed to cool, and chilled. The solids were filtered off and the filtrate rotoevaporated to an oil. The oil was chromatographed on silica gel (1.4 kg, 230-400 mesh) using petroleum ether-ether (25:1, 15×1 L), and product fractions rotoevaporated to give an off-white solid; yield 96.1 g (62%), mp 45°-47° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:50])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C@H:19]([C:47](O)=[O:48])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:46])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH:32][CH2:33][CH2:34][O:35][C@@H:36]1[O:44][C@@H:43]([CH3:45])[C@@H:41]([OH:42])[C@@H:39]([OH:40])[C@@H:37]1[OH:38])=[O:31])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][C:71]([NH:73][CH2:74][CH2:75][O:76][C@@H:77]1[O:85][C@@H:84]([CH3:86])[C@@H:82]([OH:83])[C@@H:80]([OH:81])[C@@H:78]1[OH:79])=[O:72]>CN(C=O)C>[C@@H:77]1([O:76][CH2:75][CH2:74][NH:73][C:71](=[O:72])[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][NH:65][C:47](=[O:48])[C@@H:19]([NH:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:50])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:46])[CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:31])[NH:32][CH2:33][CH2:34][O:35][C@@H:36]2[O:44][C@@H:43]([CH3:45])[C@@H:41]([OH:42])[C@@H:39]([OH:40])[C@@H:37]2[OH:38])[O:85][C@@H:84]([CH3:86])[C@@H:82]([OH:83])[C@@H:80]([OH:81])[C@@H:78]1[OH:79]
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCCC(=O)NCCCC[C@H](NC(=O)CCCCCCC(=O)OCc2ccccc2)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCCCN)[C@@H](O)[C@H](O)[C@@H]1O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@@H]1O[C@@H](OCCNC(=O)CCCCCNC(=O)[C@H](CCCCNC(=O)CCCCC(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)NC(=O)CCCCCCC(=O)OCc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 40 mL vial was added N2-{8-(benzyloxy)-8-oxooctanoyl}-N6-[6-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-6-oxohexanoyl]-L-lysine (100 mg, 0.141 mmol) and DMF (5 mL). To the above solution at 0° C. was added EDC (40.5 mg, 0.211 mmol) and HOBt (23.7 mg, 0.155 mmol). The reaction was warmed to rt and stirred at rt for 20 min. To the above mixture was added 6-amino-N-{2-[(α-L-fucopyranosyl)oxy]ethyl}hexanamide (45.1 mg, 0.141 mmol). After stirring at rt for 18 hr, the mixture was concentrated. The residue was purified by flash chromatography eluting with 0-40% AcCN in water to give the title compound. UPLC Method B: m/e=1012.6348 [M+1]; Rt=3.28 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH2:7][S:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH2:7][S:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[NH2:17])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCSCc2cccc([N+](=O)[O-])c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(CCSCc2cccc([N+](=O)[O-])c2)c1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (3-{2-[(3-nitrobenzyl)thio]ethyl}phenyl)carbamate (0.38 g, 0.97 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid and stirred for 30 min. The reaction mixture was concentrated and poured into 10% potassium carbonate (30 mL) and ethyl acetate (100 mL). The organic layer was separated, washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude orange oil. This material was purified by flash column chromatography to give the desired product (0.19 g, 67%) as an orange oil. LCMS for C15H17N2O2S (M+H)+: m/z=289.0.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([CH3:33])[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]([C:31]#[N:32])[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([NH:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH:14]=2)=[O:9])C.[OH-].[Na+]>CO>[C:31]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([NH:21][C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH:14]=2)[C:19]([OH:20])=[C:10]([C:8]([NH:7][CH2:6][C:5]([CH3:34])([CH3:33])[C:4]([OH:35])=[O:3])=[O:9])[N:11]=1)#[N:32]
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(NC(=O)c3ccc(F)cc3)ccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(NC(=O)c3ccc(F)cc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
3-{[1-Cyano-7-(4-fluoro-benzoylamino)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid ethyl ester (60 mg, 0.125 mmol) was methanol (7 mL) and aqueous sodium hydroxide (7 mL, 2M) was added via syringe. The reaction was permitted to stir overnight at room temperature. Upon completion, the reaction was concentrated, diluted with water and acidified to pH 3 with 1M hydrochloric acid. The resulting precipitate was isolated by filtration and dried to provide the title compound as a white solid in 50% yield. MS ESI(−) m/e: 449.1046 (M−1), MS ESI(+) m/e: 451.0812 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)=[C:10]2[CH2:16][CH:15]3[N:17](CC=C(C)C)[CH:12]([CH2:13][CH2:14]3)[CH2:11]2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+].C(O)C>ClCCl>[CH:12]12[NH:17][CH:15]([CH2:14][CH2:13]1)[CH2:16][C:10](=[C:9]([C:23]1[CH:27]=[CH:26][S:25][CH:24]=1)[C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1)[CH2:11]2
Reactant: COc1cccc(C(=C2CC3CCC(C2)N3CC=C(C)C)c2ccsc2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Oc1cccc(C(=C2CC3CCC(C2)N3)c2ccsc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.3 %

Procedure:
To 400 mg (1.05 mmol) of 3-[(3-methoxy-phenyl)-thiophen-3-yl-methylene]-8-(3-methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]octane in 12 mL of dichloromethane at −78° C. was added 8.43 mL ([1M] in DCM) of boron tribromide drop wise. The reaction solution was slowly warmed to room temperature over 1 hr and allowed to stir 3 hr at room temperature. After 3 hr, to the reaction solution was added 20 mL of a saturated solution of NaHCO3, and 20 mL of 20% ethanol in DCM. The aqueous phase was removed. The organic phase was washed with 20 mL of brine, dried over MgSO4, and concentrated. The concentrated sample was purified by reverse phase chromatography (20×100 mm J'sphere H-80 YMC column using a gradient of 0.1% TFA/water to 5% water/0.1% TFA/acetonitrile). The eluent corresponding to 3-[(8-Aza-bicyclo[3.2.1]oct-3-ylidene)-thiophen-3-yl-methyl]-phenol (earlier eluent) was evaporated to yield 76 mg of the title compound as a white solid; MS m/z (MH+) 298; 1H NMR 300 MHz (MeOD-d4) δ 7.34-7.36 (dd,1H), 7.13-7.18 (m, 2H), 6.86-6.88 (dd, 1H), 6.58-6.70 (m, 3H), 3.99-4.04 (m, 2H), 2.48-2.80 (m, 4H), 1.90-2.06 (m, 4H).