Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH:10]1([C:13](Cl)=O)[CH2:12][CH2:11]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:13]([CH:10]3[CH2:12][CH2:11]3)=[N:9][N:8]=2)[CH:7]=1
Reactant: NNc1ccc(Br)cn1
Reactant: O=C(Cl)C1CC1
Solvent: ClC(Cl)Cl
Product: Brc1ccc2nnc(C3CC3)n2c1
Temperature: 90 °C
Yield: 106.5 %

Procedure:
A mixture of 5-bromo-pyridin-2-yl-hydrazine (15.0 g, 79.8 mmol) and cyclopropane carbonyl chloride (65 mL, 71.8 mmol) was heated at 90° C. for 18 hours. The brown mixture was allowed to cool to room temperature, filtered, and washed with toluene to afford a light brown solid. This solid was taken up in CHCl3, and washed with saturated aqueous NaHCO3. The organic layer was isolated, and the aqueous layer extracted with CHCl3 (2×). The combined organics were washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give the title compound as a tan solid (18.2 g, 96%).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17](CC3C=CC=CC=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)O.[ClH:28]>[Pd].C(OCC)(=O)C.CO>[ClH:28].[ClH:28].[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: CN(C)CCCC(O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)CCCCc1ccc(N2CCNCC2)cc1

Procedure:
Prepared analogously to example A20b) from 4-[4-[4-(dimethyl-amino)-1-hydroxybutyl]phenyl]-1-(phenylmethyl)piperazine by catalytic hydrogenation in the presence of palladium/charcoal and hydrochloric acid in a quantitative yield. Colourless, amorphous substance of Rf 0.37 (eluant: ethyl acetate/methanol 50/50/0.5 v/v/v).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH3:1][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[N:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:6]=2)[NH:11]1
Reactant: Cc1ccc2cc(-c3ccccc3)c(-c3ccccc3)nc2n1
Agent: [Pd]
Solvent: CCO
Product: CC1CCc2cc(-c3ccccc3)c(-c3ccccc3)nc2N1
Reaction time: 8 h

Procedure:
A stirred solution of 7-methyl-2,3-diphenyl-1,8-naphthyridine (step 1) (352 mg, 1.188 mmol) in ethanol (10 ml) at room temperature under an atmosphere of argon was treated with 10% palladium on carbon (126 mg). The reaction mixture was purged three times with nitrogen and placed under an atmosphere of hydrogen overnight. The mixture was filtered through Celite® (filter material) and the catalyst was washed with EtOAc (200 ml). The solvent was removed in vacuo to afford the title compound as a yellow foam.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.O>CN(C)C=O>[CH3:10][C:11]([Si:14]([CH3:16])([CH3:15])[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:13])[CH3:12]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
To a stirred solution of 10.4 grams (0.085 mole) of 4-hydroxybenzaldehyde in 36.5 mL of dimethylformamide was added 15.4 grams (0.102 mole) of (1,1-dimethylethyl)dimethylsilyl chloride and then 14.8 grams (0.218 mole) of imidazole. Upon completion of addition the reaction mixture was stirred under a nitrogen atmosphere at ambient temperature for three hours. The reaction mixture was poured into a separatory funnel, and water was added. The mixture was extracted with diethyl ether. The ether layer was washed in turn with one portion of aqueous 10% sodium hydroxide, one portion of aqueous 10% hydrochloric acid, one portion of water, and one portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in diethyl ether and was stirred for 20 minutes with decolorizing carbon and neutral alumina. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to yield 19.4 grams of 4-[(1,1-dimethylethyl)dimethylsilyloxy]benzaldehyde. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][CH:11]=[C:12]([C:31]2[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(Br)cnc1F
Reactant: OB(O)c1ccncc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(-c2ccncc2)cnc1F

Procedure:
By carrying out the operation analogously to example 1, starting from 5-bromo-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VIII, and 4-pyridineboronic acid, the desired product is obtained in the form of a beige foam (yield=53%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH:15]([OH:18])([CH3:17])[CH3:16]>CN(C)C=O>[CH:15]([O:18][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1)([CH3:17])[CH3:16]
Reactant: CC(C)O
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1nc(OC(C)C)ccc1[N+](=O)[O-]

Procedure:
A procedure similar to that described in Preparation 88 was repeated, except that 6.00 g of 6-chloro-2-methylamino-3-nitropyridine (prepared as described in Preparation 66), 1.54 9 of sodium hydride (as a 55% by weight dispersion in mineral oil), 2.7 ml of isopropanol and 150 ml of dimethylformamide were used. After working up the product as described in preparation 88, the resulting crude product was crystallized by trituration with isopropanol, to give 6.10 g of the title compound, melting at 75°-76° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:44]=[CH:43][C:38]3[NH:39][C:40](=[O:42])[NH:41][C:37]=3[CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:35]2[CH:44]=[CH:43][C:38]3[NH:39][C:40](=[O:42])[NH:41][C:37]=3[CH:36]=2)[CH:3]=1)=[O:15]
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4[nH]c(=O)[nH]c4c3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzimidazol-2-one (63.3 mg, 0.243 mmol), DMSO (2 mL), sodium carbonate (0.281 mL, 0.562 mmol), and bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The final product was collected as 35 mg (40%). LCMS E-S (M+H)=472.4 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (d, J=6.4 Hz, 6H), 2.13 (s, 3H), 2.22 (s, 3H), 4.41 (d, J=4.8 Hz, 2H), 5.30 (quin, J=6.6 Hz, 1H), 5.91 (s, 1H), 7.07 (d, J=8.3 Hz, 1H), 7.86 (s, 1H), 7.92 (dd, J=8.3, 1.8 Hz, 1H), 8.10 (s, 1H), 8.30-8.41 (m, 1H), 8.98 (t, J=4.8 Hz, 1H), 10.82 (s, 1H), 10.89 (s, 1H). 11.58 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[NH2-].[Li+].[Li].N.Br[CH2:15][CH2:16][CH:17]1[O:21][CH2:20][CH2:19][O:18]1.[Cl-].[NH4+]>CS(C)=O>[CH2:20]1[O:21][CH:17]([CH2:16][CH2:15][C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[O:18][CH2:19]1
Reactant: BrCCC1OCCO1
Reactant: C#Cc1ccc(Br)cc1
Agent: N
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Product: Brc1ccc(C#CCCC2OCCO2)cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
4-bromophenylacetylene (10 g, 55 mmol), prepared according to Organic Reactions 5 (1), 50, (1949), in dry dimethyl sulphoxide (70 ml) was added to lithium amide (from 66 mmol) of lithium) in liquid ammonia (200 ml). The mixture was stirred for 1 hour at -30° C., 2-(2-bromoethyl)-1,3-dioxolane (10 g, 55 mmol) was added and the mixture was stirred for 2 hours at -30° C. Ammonium chloride (12 g) was added, the ammonia was allowed to evaporate and water (200 ml) was added to the residue. The emulsion was extracted with ether and the organic phase was washed with brine and dried. The solvents were removed and the product purified by dry column chromatography (silica, 5% ether in hexane 1:1 ether:hexane) to give 4.08 g (26% of theory) of 5-(4'bromophenyl)-4-pentyn-1-al ethylene acetal.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]=[CH2:19])=[C:8]2[CH3:20])=[CH:4][CH:3]=1.[N+](=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N-]>C1(C)C=CC=CC=1.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]3[CH2:19][CH:25]3[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:8]2[CH3:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: [Rh]
Solvent: CCCCCCCC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1c1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: 0 °C

Procedure:
To a room temperature solution of the indole from Step 1 (3.91 g, 11.0 mmol) in 20 mL toluene was added rhodium (II) octanoate dimer (109 mg, 0.14 mmol), and the solution was cooled to 0° C. A solution of ethyl diazoacetate (3.0 mL, 28.5 mmol) in 13 mL toluene was then added via syringe pump at 1.2 mL/hr. Fresh catalyst was then added along with an additional 1 mL ethyl diazoacetate in toluene over 2.5 h. The crude reaction mixture was applied directly to a silica gel column and eluted with 1% to 2.5% ethyl acetate/toluene. 1.1 g of the trans isomer of the title compound was thus obtained, followed by 1.2 g of the cis isomer of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:47]([O:49][C:50](=[O:54])[CH2:51][NH:52][CH3:53])[CH3:48]>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:47]([O:49][C:50](=[O:54])[CH2:51][N:52]([C:11](=[O:13])[CH2:10][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:9])[CH3:53])[CH3:48]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CN(C)C(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (tert-butoxycarbonyl-methyl-amino)-acetic acid (2.73 g, 14.4 mmol) in 70 mL of THF was added sequentially diisopropyl ethylamine (7.5 mL, 14.4 mmol) and HBTU (5.47 g, 14.4 mmol), and the reaction mixture was stirred at room temperature for one hour. To this reaction mixture was added methylamino-acetic acid ethyl ester (2.22 g, 14.4 mmol) in one portion, and the reaction mixture was heated at 65° C. for 12 h. The reaction mixture was cooled, diluted with a solution of saturated NaHCO3, and extracted with EtOAc. The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:18]=1)[C:5]([O:7]CC)=[O:6].[OH-].[Na+].Cl>C(O)C.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[N:18]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1ccc(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c(F)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To a solution (4 mL) of the compound (540 mg, 1.3 mmol) obtained in Example 189d in ethanol was added 2N aqueous sodium hydroxide solution (2.6 mL, 5.3 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N aqueous hydrochloric acid solution, saturated brine was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crude product was purified by recrystallization (ethyl acetate-hexane) to give the title compound (380 mg, 76%) as colorless crystals.
Reaction SMILES: [CH:1]([N:4]([CH:11]([CH3:13])[CH3:12])[C:5](=[O:10])[O:6][CH:7](Cl)[CH3:8])([CH3:3])[CH3:2].[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O-:36])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16].[Na+]>>[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O:36][CH:7]([O:6][C:5]([N:4]([CH:11]([CH3:13])[CH3:12])[CH:1]([CH3:3])[CH3:2])=[O:10])[CH3:8])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(Cl)OC(=O)N(C(C)C)C(C)C
Agent: [Na+]
Product: CC(OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12)OC(=O)N(C(C)C)C(C)C
Yield: 16.8 %

Procedure:
In the same manner as in step b) in Example 125, 92 mg of the title compound was prepared from 247 mg of 1-chloroethyl N,N-diisopropylcarbamate and 400 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[S:9]([NH:12][O:13][CH3:14])(=[O:11])=[O:10].[N+:15]([C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1Cl)([O-:17])=[O:16].[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[S:9]([N:12]([C:19]1[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=1[N+:15]([O-:17])=[O:16])[O:13][CH3:14])(=[O:10])=[O:11]
Reactant: CONS(=O)(=O)c1c(C)nn(C)c1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])S(=O)(=O)c1c(C)nn(C)c1Cl
Temperature: 25 °C
Yield: 80.1 %

Procedure:
To a solution of 5-chloro-1,3-dimethyl-N-methoxy-4-pyrazolesulfonamide (0.48 g (2.00 mmol)) and 2,4-dinitrochlorobenzene (0.49 g (2.42 mmol)) in DMF (3.0 ml), sodium hydride (60%, 0.09 g (2.25 mmol)) was added dropwise under cooling with ice and with stirring and the mixture was stirred under cooling with ice for one hour and at room temperature for one hour. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with chloroform-hexane (10:1) as eluent to give 0.65 g (87%) of the title compound as pale yellow crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[OH:13][C:14]1[CH:15]=[C:16]([S:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25]C)=[O:24])[CH:17]=[CH:18][CH:19]=1>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:13][C:14]1[CH:15]=[C:16]([S:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([OH:25])=[O:24])[CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccccc1Sc1cccc(O)c1
Reactant: ClCc1ccc2ccccc2n1
Product: O=C(O)c1ccccc1Sc1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
Using the procedure described in Example 23 starting from 2-chloromethyiquinoline and methyl 2-(3-hydroxyphenylsulfanyl)benzoate, methyl ester of the title acid was obtained as red-brown crystals in nearly quantitative yield, m.p. 52-55° C. An analytical sample was further purified by crystallization from a mixture of ethanol and ether. For C24H19NO3S (401.5) calculated: 71.80% C, 4.77% H, 3.49% N, 7.99% S; found: 71.83% C, 4.76% H, 3.18% N, 7.75% S.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][Br:16])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: BrCCCCCCBr
Solvent: Cc1ccccc1
Product: BrCCCCCCOc1ccc(OCc2ccccc2)cc1
Reaction time: 96 h

Procedure:
4-Benzyloxyphenol and 1,6-dibromohexane were reacted using conditions reported in Example 15. The reaction time was 4 days and the extraction solvent used was toluene. The crude product was crystallized from hexane to give 1-benzyloxy-4-(6-bromohexyloxy)benzene, mp 72°-3°.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][C@H:8]1[O:12][C@@H:11]([N:13]2[CH:20]=[C:19]([CH2:21][CH3:22])[C:17](=[O:18])[NH:16][C:14]2=[O:15])[CH2:10][C@@H:9]1[O:23]C(=O)C)(=O)C.C[O-].[Na+]>CO>[CH2:21]([C:19]1[C:17](=[O:18])[NH:16][C:14](=[O:15])[N:13]([CH:20]=1)[C@@H:11]1[O:12][C@H:8]([CH2:7][CH2:6][CH2:5][OH:4])[C@@H:9]([OH:23])[CH2:10]1)[CH3:22]
Reactant: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](CCCOC(C)=O)O2)c(=O)[nH]c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CCCO)O2)c(=O)[nH]c1=O
Reaction time: 2 h
Yield: 58.3 %

Procedure:
0.10 g of 5'-(2-acetoxyethyl)-3'-O-acetyl-2',5'-dideoxy-5-ethyluridine was treated with 5 ml of a dilute solution of sodium methoxide in methanol. After standing at room temperature for 2 hours the solution was neutralized by the addition of a cross-linked polystyrene-divinylbenzene cation exchange resin containing sulfonic acid groups (H+ form) and then filtered. The filtrate was evaporated to dryness to give 0.045 g of 2',5'-dideoxy-5-ethyl-5'-(2-hydroxyethyl)uridine in the form of a white solid of melting point 113°-115° C.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([NH:14][C@H:15]([C:37]([N:39]3[CH2:44][CH2:43][N:42]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:41][CH2:40]3)=[O:38])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][S:24]([C:27]4[C:28]5[CH:29]=[CH:30][N:31]=[CH:32][C:33]=5[CH:34]=[CH:35][CH:36]=4)(=[O:26])=[O:25])=[CH:19][CH:18]=3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[H-].[Na+].[CH3:53]I.O>CN(C)C=O>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]([CH3:53])[C@H:15]([C:37]([N:39]3[CH2:40][CH2:41][N:42]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:43][CH2:44]3)=[O:38])[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][S:24]([C:27]4[C:28]5[CH:29]=[CH:30][N:31]=[CH:32][C:33]=5[CH:34]=[CH:35][CH:36]=4)(=[O:25])=[O:26])=[CH:21][CH:22]=3)(=[O:12])=[O:13])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: CI
Reactant: O=C([C@H](Cc1ccc(OS(=O)(=O)c2cccc3cnccc23)cc1)NS(=O)(=O)c1cccc2cnccc12)N1CCN(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN([C@@H](Cc1ccc(OS(=O)(=O)c2cccc3cnccc23)cc1)C(=O)N1CCN(c2ccccc2)CC1)S(=O)(=O)c1cccc2cnccc12
Reaction time: 1.5 h

Procedure:
2.27 g of the amorphous compound obtained in Example 108 was dissolved in 30 ml of dimethylformamide, to the solution were sequentially added 160 mg of 60% sodium hydride and 0.3 ml of methyl iodide with ice cooling, and the mixture was stirred for 90 minutes with ice cooling. After adding 80 ml of water, the reaction mixture was extracted with 100 ml of ethyl acetate, and the extract was washed with 80 ml of saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with chloroform/methanol (60:1), to obtain 1.8 g of the title compound in a yellow amorphous form.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])=[O:8]>[Pd].CO>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: O=C1CC[C@@H](C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)N1
Agent: [Pd]
Solvent: CO
Product: O=C1CC[C@@H](C(=O)N2CCC[C@H]2C(=O)O)N1
Temperature: 23 °C
Reaction time: 4.5 h
Yield: 65.4 %

Procedure:
A solution of F2 (8.63 g, 31.34 mmol) and palladium on activated charcoal (10%, 86 mg, 10% w/w) in degassed MeOH (125 mL) was placed in a high pressure Parr reactor and purged with nitrogen gas (2×30 psi). The reaction mixture was sealed under hydrogen (30 psi) and stirred at 23° C. for 4.5 h. The mixture was filtered through a 0.45 μm teflon filter and concentrated at reduced pressure. The residue (6.29 g) was coated in SiO2 and loaded onto the top of a column (LC 5.5×10.0 cm) and eluted with hex:EtOAc 1:2 to yield F1 (4.64 g, 80%) as a white solid. Rf=0.22 (hex:EtOAc 1:1. [α]D20 −92.4 (c 0.12, CHCl3). M.p. 67-69° C.
Reaction SMILES: C([S:4][CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([NH2:14])=[O:13])=[C:8]([Cl:17])[CH:7]=1)(=O)C.[OH-].[Na+]>CO.O>[Cl:17][C:8]1[CH:7]=[C:6]([CH2:5][SH:4])[CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C:12]([NH2:14])=[O:13]
Reactant: CC(=O)SCc1ccc(OCC(N)=O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)COc1ccc(CS)cc1Cl
Reaction time: 48 h

Procedure:
To a solution of the product from example 15 step c) (1.0 g) in methanol (50 ml) was added sodium hydroxide pellets (0.15 g) and the mixture stirred for 2 days. The mixture was diluted with water and the subtitle compound collected by filtration. (0.7 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:22][C:21]3[C:16](=[N:17][C:18](Cl)=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:22][C:21]3[C:16](=[N:17][C:18]([C:31]4[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3nc(Cl)ccc3o2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3nc(-c4ccc(S(C)(=O)=O)cc4)ccc3o2)CC1
Temperature: 140 °C
Reaction time: 0.58 h

Procedure:
To a mixture of 4-(5-chloro-furo[3,2-b]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (50 mg) and 4-(methanesulfonyl)phenyl boronic acid (45 mg) in [1,4]dioxane (1.5 mL) in a microwave oven suited vessel charged with a stir bar a 2 M aqueous Na2CO3 solution (1904) is added. The mixture is sparged with argon for 10 min and Pd(PPh3)4 (21 mg) is added. The vessel is capped and the mixture is stirred under microwave irradiation at 140° C. for 35 min. After cooling the mixture to room temperature, dichloromethane and water are added. The organic phase is washed with brine, dried (MgSO4) and the solvent is evaporated. The crude product is purified by HPLC on reversed phase (MeOH/H2O/TFA). Yield: 25 mg (37% of theory); LC (method 2): tR=1.36 min; Mass spectrum (ESI+): m/z=457 [M+H]+.