Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[SH:10].Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][CH:17]([NH:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=2)[CH2:18][CH2:19]1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCCl)CC3)nc3ccccc32)cc1
Reactant: Sc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(Cn2c(NC3CCN(CCSc4nc5ccccc5o4)CC3)nc3ccccc32)cc1
Yield: 50 %

Procedure:
A mixture of 1.5 parts of 2-benzoxazolethiol, 4.6 parts of N-[1-(2-chloroethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, 4.2 parts of potassium carbonate and 120 parts of 2-propanone was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 2.5 parts (50%) of N-[1-[2-[(2-benzoxazolyl)thio]ethyl]-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine; mp. 174.2° C. (compound 73).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@@H:12]1/[CH:17]=[CH:18]/[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([O:36][CH3:37])([O:34][CH3:35])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)=[O:20])[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@@H:12]1/[CH:17]=[CH:18]/[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([O:34][CH3:35])([O:36][CH3:37])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)[OH:20])[CH3:2]
Reactant: CCOC(=O)CCCCCCN1C(=O)CC[C@@H]1/C=C/C(=O)c1cccc(C(OC)(OC)c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCCCCCN1C(=O)CC[C@@H]1/C=C/C(O)c1cccc(C(OC)(OC)c2ccccc2)c1
Reaction time: 2.25 h

Procedure:
To an ethanol solution (5 mL) of 7-((R)-2-{(E)-3-[3-(dimethoxy-phenyl-methyl)-phenyl]-3-oxo-propenyl}-5-oxo-pyrrolidin-1-yl)-heptanoic acid ethyl ester (124 mg, 0.24 mmol)was added NaBH4 (36 mg, 0.96 mmol). The reaction mixture was stirred for 2.25 h and then concentrated to dryness. The residue was dissolved in ethyl acetate and washed with NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated to provide 7-((R)-2-{(E)-3-[3-(dimethoxy-phenyl-methyl)-phenyl]-3-hydroxy-propenyl}-5-oxo-pyrrolidin-1-yl)-heptanoic acid ethyl ester. To a methanol solution (5 mL) of 7-((R)-2-{(E)-3-[3-(dimethoxy-phenyl-methyl-phenyl]-3-hydroxy-propenyl}-5-oxo-pyrrolidin-1-yl)-heptanoic acid ethyl ester was added an aqueous solution (2.5 mL) of LiOH monohydrate (46 mg, 1.09 mmol). The reaction mixture was stirred for 6 h and then concentrated to remove the methanol. The aqueous concentrate was diluted with CH2Cl2 and 1 N HCl was added, extracted with CH2Cl2 and dried over MgSO4. This mixture was filtered and concentrated to yield 7-((R)-2-{(E)-3-[3-(dimethoxy-phenyl-methyl)-phenyl]-3-hydroxy-propenyl}-5-oxo-pyrrolidin-1-yl)-heptanoic acid (116 mg, 0.23 mmol) as an oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[CH2:16]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Yield: 100 %

Procedure:
Sodium hydride (60% in oil, 274.1 mg, 6.853 mmol) was suspended in DMF (8.0 ml). To the resulting suspension was added methyl indole-3-carboxylate (400.2 mg, 2.284 mmol) under stirring at 0° C., followed by stirring at the same temperature for 30 minutes. To the reaction mixture was added benzyl bromide (0.41 ml, 3.427 mmol) at 0° C. After stirring at room temperature for 1 hour, the reaction mixture was added with water to terminate the reaction. The reaction mixture was then extracted with ethyl acetate. The extract was washed with 1N HCl, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (6:1, v/v) eluate fractions, methyl 1-benzylindole-3-carboxylate (100%) was obtained as a gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6].[C:12]([OH:17])(=[O:16])[C:13]([CH3:15])=O.O>ClCCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:7][C:13]([C:12]([OH:17])=[O:16])=[CH2:15])=[O:6]
Reactant: CC(=O)C(=O)O
Reactant: COc1ccccc1C(N)=O
Solvent: O
Solvent: ClCCCl
Product: C=C(NC(=O)c1ccccc1OC)C(=O)O
Yield: 8.5 %

Procedure:
A suspension of 2-methoxybenzamide in 1,2-di-chloroethane (24.5 ml/g) is brought to reflux in the presence of 3 equivalents of freshly distilled pyruvic acid in a round-bottomed flask surmounted by a system which makes it possible to remove the water formed during the reaction. When the formation of water has finished 15 (approximately 7 hours), the reaction mixture is left at room temperature. After filtering off the insoluble materials, the filtrate is extracted with an aqueous sodium bicarbonate solution. The combined aqueous phases are extracted with dichloromethane and then acidified with hydrochloric acid. The precipitate formed is filtered off, dried and then taken up in ethyl acetate. After filtering off the insoluble material, the filtrate is concentrated under vacuum, dissolved in dichloromethane and then precipitated with heptane, thus providing pure N-(2-methoxybenzoyl)dehydroalanine. (Nonoptimized yield 8.5%).
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH3:9].[CH:10](=O)[C:11]1[O:15][CH:14]=[CH:13][CH:12]=1.C(O)C.[OH-].[K+]>O>[I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH:9]=[CH:10][C:11]1[O:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1N(C)C=C[NH+]1C
Reactant: O=Cc1ccco1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1C=C[NH+](C)C1C=Cc1ccco1

Procedure:
A mixture of 5.0 g of 1,2,3-trimethyl-1H-imidazolium iodide, 2.5 ml of furfural, 20 ml of ethanol and 1 g of potassium hydroxide is refluxed for 10 minutes. The mixture is cooled, water is added, and the resulting solid is filtered off and crystallized from ethanol to yield 5.0 g of the title compound, melting point 299°-300° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[SH:8].Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Sc1ccncc1Br
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Sc1ccncc1Br
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of 3-bromopyridine-4-thiol (step A, 4.75 g, 25 mmol), ethyl 2-bromoisobutyrate (9.75 g, 50 mmol), and sodium carbonate (7.95 g, 75 mmol) in DMF (50 mL) was stirred at 60° C. for 1 hour. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was washed with water (2×100 mL) and saturated sodium chloride (100 mL). The aqueous washes were back extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate, concentrated, and purified by normal phase chromatography (a gradient of 0-25% ethyl acetate in hexane) to yield ethyl 2-(3-bromopyridin-4-ylthio)-2-methylpropanoate as a pale yellow oil (6.6 g, 88%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>ClCCl.ClCCl.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([S:17]([CH3:18])=[O:27])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CSc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCCCCC
Solvent: ClCCl
Product: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reaction time: 0.03 h
Yield: 73.4 %

Procedure:
To a solution of 2-methylsulfanylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (2.00 g, 7.60 mmol) in dichloromethane (76 mL) was added m-CPBA (67%, 2.02 g, 7.84 mmol) in one portion. Solid precipitate appeared within 2 min, and after 10 min the solution was diluted with 2/1 dichloromethane/hexane (60 mL). The solids were collected by filtration and washed with 50% dichloromethane/hexane to afford, after drying, 1.558 g (73% yield) of the titled sulfoxide. A second crop was obtained by concentrating the filtrate and triturating the solids first with hot 2/1 dichloromethane/hexane, and then after filtration by a second trituration with acetone. An additional 0.22 g (10%) of titled product was obtained, and was shown by 1H NMR to be contaminated with 10% sulfone.
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].N1C=CC=CC=1.[CH:20]1([CH2:26][C@H:27]([OH:36])[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCOCC1>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:36][C@H:27]([C:28]([N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1)=[O:29])[CH2:26][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C([C@@H](O)CC1CCCCC1)N1CCOCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](CC1CCCCC1)C(=O)N1CCOCC1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 73.3 %

Procedure:
A solution of 4-nitrophenyl chloroformate (20.55 g, 102 mmol) in dioxane (150 mL) is treated with pyridine (50 mL) resulting in a suspension. This material is heated to 70° C. and a solution of 3 (12.30 g, 51.0 mmol) in dioxane (50 mL) is added via pressure equalizing dropping funnel over 5 minutes. After stirring for an additional 5 minutes, the reaction is allowed to cool to room temperature and the solvent is removed by rotary evaporation. The resulting mass is partitioned between ethyl acetate and water. The organic layer is collected and the aqueous phase is extracted once more with ethyl acetate and discarded. The combined organics are dried over MgSO4 and the solvent is removed. The resulting solid is dissolved in a minimal amount of hot dichloroethane and treated with dichloromethane. The mixture is then kept in a −4° C. refrigerator overnight and filtered. The mother liquor is concentrated and purified over 330 g of silica gel using a gradient of 0-100% ethyl acetate in hexane to afford 15.2 g (73% yield) of (S)-2-cyclohexyl-1-(morpholine-4-carbonyl)ethyl 4-nitro-phenyl carbonate (4) as a slightly yellow oil; 1H NMR (CDCl3, 400 MHz) δ 0.97-1.08 (m, 2H), 1.09-1.36 (m, 3H), 1.48-4.62 (m, 2H), 1.65-1.68 (m, 4H), 1.82-1.97 (m, 2H), 3.41-3.60 (m, 3H), 3.64-3.80 (m, 5H), 5.29-5.36 (m, 1H), 7.38-7.44 (m, 2H), 8.24-8.30 (m, 2H); HPLC-MS calculated for C20H26N2O7 (M+H+) 407.2, found 407.4.
Reaction SMILES: [C:1]([C:3]1[N:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=[O:6])#[N:2].[OH-].[K+:15]>O>[C:1]([C:3]1[N:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O-:7])=[O:6])#[N:2].[K+:15]
Reactant: CCOC(=O)c1cccnc1C#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#Cc1ncccc1C(=O)[O-]
Reaction time: 10 h
Yield: 603.4 %

Procedure:
Ethyl 2-cyanonicotinate (compound 2) (20 g; 0.113 mol) is added to a solution of potassium hydroxide (6 g; 0.017 mol) in distilled water (150 cc). The mixture is then allowed to stand for 10 hours at 25° C., and then washed with ether (2×50 cc). The aqueous solution is then evaporated to dryness to give compound 3 (19.1 g; m.p. 300° C.).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:40]1[CH2:44][CH2:43][C@@H:42]([C:45]2[O:49][N:48]=[C:47]([C:50]3[S:51][CH:52]=[CH:53][N:54]=3)[N:46]=2)[CH2:41]1>CN(C=O)C>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([N:40]1[CH2:44][CH2:43][C@@H:42]([C:45]2[O:49][N:48]=[C:47]([C:50]3[S:51][CH:52]=[CH:53][N:54]=3)[N:46]=2)[CH2:41]1)=[O:6]
Reactant: c1csc(-c2noc([C@@H]3CCNC3)n2)n1
Reactant: O=C(O)CCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCC(F)(F)F)N1CC[C@@H](c2nc(-c3nccs3)no2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)—N—Boc-pyrrolidine-3-carboxylic acid (700 mg, 3.25 mmol, 1.1 equiv), HBTU (1.23 g, 1.1 equiv) and DIEA (1.53 mL, 3 equiv) were dissolved in DMF (15 mL). The solution was stirred 5 min and then 1,3-thiazole-2-amidoxime (5a) (422 mg, 2.95 mmol, 1 equiv) was added. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure. The residue was dissolved in AcOEt, washed twice with saturated aqueous NaHCO3, once with brine, then dried over MgSO4 and evaporated under reduced pressure. The residue was dissolved in 15 mL of DMF and then heated at 110° C. for 7 h. The solvent was removed under vacuum and the residue was dissolved in AcOEt. The organic layer was washed once with HCl 1N, once with saturated aqueous NaHCO3 and once with brine, then dried over MgSO4 and evaporated under reduced pressure. The obtained product was used in the next step without further purification. Boc intermediate was dissolved in dioxane (10 mL) and HCl 4N solution in dioxane (6 mL) was added. The reaction mixture was stirred overnight at room temperature and then the product was recovered by filtration and washed with petroleum ether to give 5-[(3R)-pyrrolidin-3-yl]-3-(1,3-thiazol-2-yl)-1,2,4-oxadiazole (yield 66% over two steps). 4,4,4-trifluorobutyric acid (1.3 equiv), EDCI (1.3 equiv), HOBt (0.4 equiv) and DIEA (4 equiv) were mixed in DMF (2 mL) for 5 minutes. 5-[(3R)-pyrrolidin-3-yl]-3-(1,3-thiazol-2-yl)-1,2,4-oxadiazole (0.62 mmol, 1 equiv) was added with 3 mL of DMF. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure and purified by preparative HPLC. Beige powder; Yield 33%; 1H NMR (CDCl3) δ 8.02-8.00 (m, 1H), 7.57-7.60 (m, 1H), 3.89-4.03 (m, 2H), 3.69-3.87 (m, 2H), 3.53-3.65 (m, 1H), 2.38-2.55 (m, 6H); 13C NMR (CDCl3) cis/trans isomer mixture (60 isomer A/40 isomer B); isomer A δ 180.31, 168.50, 163.98, 153.53, 144.99, 126.94 (q, J=276 Hz), 122.87, 49.24, 45.52, 35.03, 29.05 (q, J=29 Hz), 28.86, 27.07 (q, J=3 Hz); isomer B δ 179.84, 168.31, 163.98, 153.38, 144.94, 126.92 (q, J=276 Hz), 122.81, 49.43, 45.25, 36.82, 30.28, 29.05 (q, J=29 Hz), 27.24 (q, J=3 Hz). tR LCMS 4.6 min. Purity >99%; MS [M+H]+ m/z 347.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.6 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (93 mg, 72%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15][C@H:16]2[O:33][C@H:32]([CH2:34][O:35]C(=O)C)[C@@H:27]([O:28]C(=O)C)[C@H:22]([O:23]C(=O)C)[C@H:17]2[O:18]C(=O)C)[C@@H:8]([CH2:39][O:40]C(=O)C)[O:7][C@H:6]1[O:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:52](=[O:108])[CH2:53][CH2:54][C:55]([NH:57][C:58]2[CH:63]=[CH:62][C:61]([O:64][C@@H:65]3[O:102][C@H:101]([CH2:103][O:104]C(=O)C)[C@@H:76]([O:77][C@H:78]4[O:95][C@H:94]([CH2:96][O:97]C(=O)C)[C@@H:89]([O:90]C(=O)C)[C@H:84]([O:85]C(=O)C)[C@H:79]4[O:80]C(=O)C)[C@H:71]([O:72]C(=O)C)[C@H:66]3[O:67]C(=O)C)=[CH:60][CH:59]=2)=[O:56])=[CH:47][CH:46]=1)(=O)C>CO.N>[C@H:78]1([O:77][C@@H:76]2[C@@H:101]([CH2:103][OH:104])[O:102][C@@H:65]([O:64][C:61]3[CH:62]=[CH:63][C:58]([NH:57][C:55](=[O:56])[CH2:54][CH2:53][C:52]([NH:51][C:48]4[CH:47]=[CH:46][C:45]([O:44][C@@H:6]5[O:7][C@H:8]([CH2:39][OH:40])[C@@H:9]([O:15][C@H:16]6[O:33][C@H:32]([CH2:34][OH:35])[C@@H:27]([OH:28])[C@H:22]([OH:23])[C@H:17]6[OH:18])[C@H:10]([OH:11])[C@H:5]5[OH:4])=[CH:50][CH:49]=4)=[O:108])=[CH:59][CH:60]=3)[C@H:66]([OH:67])[C@H:71]2[OH:72])[O:95][C@H:94]([CH2:96][OH:97])[C@@H:89]([OH:90])[C@H:84]([OH:85])[C@H:79]1[OH:80]
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](Oc3ccc(NC(=O)CCC(=O)Nc4ccc(O[C@@H]5O[C@H](COC(C)=O)[C@@H](O[C@H]6O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]6OC(C)=O)[C@H](OC(C)=O)[C@H]5OC(C)=O)cc4)cc3)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: O=C(CCC(=O)Nc1ccc(O[C@@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1)Nc1ccc(O[C@@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1
Reaction time: 18 h

Procedure:
A 3.0 g portion of N,N'-bis[4-[2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-β-D-glucopyranosyloxy]phenyl]butanediamide was dissolved in a 0° C. solution of 50 ml of methanol saturated with ammonia. The solution was allowed to stand at room temperature, under an inert atmosphere, for 18 hours, then was evaporated. The residue was crystallized from methanol/water to yield 1.35 g of the title compound as a dihydrate, m.p. 190°-200° C.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][O:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1>CCCCO>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][O:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCOC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCOC4)c23)C1
Temperature: 160 °C
Reaction time: 18 h
Yield: 20.5 %

Procedure:
A solution of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-3-carboxamide (205 mg, 0.625 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butyl piperidin-3-ylcarbamate (626 mg, 3.12 mmol) and stirred at 160° C. for 18 hours in a sealed tube. The solvent was then removed in vacuo, and the residue was dissolved in EtOAc (50 mL) and washed with water (1×10 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by C-18 flash chromatography (25M+) on Biotage SP4 unit eluting with a gradient of 7-80% CH3CN/water (25 CV) to provide tert-butyl (3R)-1-(5-bromo-3-(tetrahydrofuran-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (65 mg, 20% yield). 1H NMR (400 MHz, CDCl3) δ 9.65 (s, 1H), 8.78 (br s, 1H), 8.26 (s, 1H), 8.02 (s, 1H), 4.54-4.47 (m, 1H), 4.05-3.98 (m, 2H), 3.96-3.90 (m, 1H), 3.83-3.72 (m, 1H), 3.70-3.60 (m, 1H), 3.47-3.39 (m, 2H), 3.18-3.09 (m, 2H), 3.07-3.00 (m, 1H), 2.41-2.33 (m, 1H), 2.28-2.16 (m, 1H), 2.03-1.95 (m, 1H), 1.85-1.74 (m, 2H), 1.42 (s, 9H); LCMS (APCI+) m/z 508.1, 510 (M+H)+, Retention time=3.42 minutes (Method 2).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C[O:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]([C:32]([NH2:34])=[NH:33])[S:28][C:29]=3[S:30][CH3:31])(=[O:24])=[O:23])[CH:17]=2)[CH:13]=[CH:14][CH:15]=1.B(Br)(Br)Br>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]([C:32]([NH2:34])=[NH:33])[S:28][C:29]=3[S:30][CH3:31])(=[O:24])=[O:23])[CH:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(-c2cccc(S(=O)(=O)c3cc(C(=N)N)sc3SC)c2)c1
Agent: BrB(Br)Br
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2cccc(O)c2)c1
Yield: 58.4 %

Procedure:
4-(3′-Methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (1.4 mg, 3.3 μmol, as prepared in Example 44) was treated with BBr3 (1 M in DCM) for 18 hr at rt. The reaction was quenched with MeOH at 0° C. and then concentrated in vacuo to a solid. Purification of this solid using C18-HPLC (10–80% CH3CN in H2O (0.1% TFA) over 25 min) afforded 1.0 mg (77%) of the title compound as a white solid. 1H-NMR (CD3OD): δ 8.33 (s, 1H), 8.23 (t, 1H, J=1.6 Hz), 7.98–8.01 (m, 1H), 7.92–7.95 (m, 1H), 7.68 (t, 1H, J=7.8 Hz), 7.31 (t, 1H, J=7.8 Hz), 7.05–7.12 (m, 2H), 6.84–6.87 (m, 1H), 2.74 (s, 3H). ESI-MS (m/z): Calcd. for C18H16N2O3S3: 405.5 (M+H); found: 405.2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7]/[CH:8]=[CH:9]/[C:10]([O:12]C(C)(C)C)=[O:11])[CH2:3][CH2:2]1.Cl>C1(C)C=CC=CC=1>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7]/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)/C=C/CN1CCOCC1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(O)/C=C/CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.4 %

Procedure:
To (E)-tert-butyl 4-morpholino-2-butenoate (B14, 179 mg), 1.0 mol/L aqueous hydrochloric acid (4 mL) was added at room temperature, and the mixture was stirred for 1 hour and 40 minutes under reflux by heating. The reaction mixture was cooled to room temperature, and then toluene was added to the mixture, and the solvent was evaporated under reduced pressure. To the obtained residue, ethyl acetate was added. The solid matter was taken by filtration, washed with chloroform, and then dried under reduced pressure to obtain (E)-4-morpholino-2-butenoic acid (B15) hydrochloride (134 mg).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20]C)=[O:19])[CH2:4][CH2:5][C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CO>[CH2:3]([O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([OH:20])=[O:19])[CH2:4][CH2:5][C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCC#CCCCOc1cccc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCC#CCCCOc1cccc(C(=O)O)c1
Yield: 99.4 %

Procedure:
300 μL of 1 N sodium hydroxide solution (300 μmol) are added portionwise to 48 mg of 25 (157 μmol) in methanol (2 mL). The solution is refluxed for 1 hour 30 minutes. After evaporating off the solvent, the reaction medium is acidified with 0.5 N HCl and extracted with DCM. 45 mg of a pale yellow oil are obtained, i.e. a yield of 99%.