Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=[N:27][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NCCc1ccccc1
Reactant: O=Cc1ccccc1OCCCN1CCOCC1
Solvent: Cc1ccccc1
Product: C(=NCCc1ccccc1)c1ccccc1OCCCN1CCOCC1
Yield: 76.5 %

Procedure:
2-[3-(4-Morpholinyl)propoxy]benzaldehyde (31.7 g) is reacted with 15.8 g of phenethylamine in 130 ml of toluene following the procedure described in Example 1A to yield 34.3 g of product as an oil, boiling point 215°-219° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:35])=[C:16]([NH:26][C:27](=[O:34])OCC(Cl)(Cl)Cl)[C:17]([CH3:25])=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:36][CH2:37][CH2:38][CH2:39][OH:40]>CCCCCC.C(OCC)(=O)C>[OH:40][CH2:39][CH2:38][CH2:37][NH:36][C:27]([NH:26][C:16]1[C:17]([CH3:25])=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]=1[CH3:35])=[O:34]
Reactant: NCCCO
Reactant: Cc1c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)NCCCO)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Yield: 65 %

Procedure:
Using 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 142 and 3-amino-1-propanol, the title compound was synthesized in the same manner as in Example 143. Yield: 65%. Melting point: 145-146° C. (hexane-ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1[NH2:4].CC([O-])=O.[Na+].[I:17]Cl.O>C(O)(=O)C>[I:17][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1
Reactant: ClI
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(I)cc([N+](=O)[O-])c1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a mixture of 2-methyl-6-nitroaniline (106.5 g, 0.7 mol) and NaOAc (63.2 g, 0.77 mol) in acetic acid (525 mL) was added a solution of ICl (125 g, 0.77 mol) in acetic acid (350 mL). The mixture was heated at 80° C. for 50 min and poured into H2O (2100 mL). After stayed at the room temperature for 16 h, the mixture was filtered to furnish yellow solid that was washed with H2O (3×350 mL). Drying under reduced pressure at 40° C. for 48 h afforded the title compound (191 g, 98%). 1H NMR (CDCl3) δ 2.22 (s, 3H), 6.20 (br s, 2H NH), 7.53 (s, 1H), 8.34 (s, 1H). ESI-MS m/z 279 (MH+).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:12]1([O:18][CH2:17][CH2:16][O:15]1)[CH2:13][Br:14])[C:7]([O:9]CC)=[O:8].S(=O)(=O)(O)O>O.CO>[CH3:3][O:4][N:5]=[C:6]([C:12]1([O:15][CH2:16][CH2:17][O:18]1)[CH2:13][Br:14])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(=NOC)C1(CBr)OCCO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CON=C(C(=O)O)C1(CBr)OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
A solution of sodium hydroxide (8.64 g) in water (20 ml) was added to a solution of ethyl 2-methoxyimino-3,3-ethylenedioxy-4-bromobutyrate (syn isomer, 26.6 g) in methanol (60 ml) under ice-cooling, stirred at ambient temperature for 2 hours. Water (100 ml) was added to the resultant solution and adjusted to pH 7.0 with 20% sulfuric acid under ice-cooling. After removing methanol therefrom in vacuo, the solution was washed with diethyl ether (100 ml). Diethyl ether (100 ml) was added to the aqueous layer and adjusted to pH 2.0 with 20% sulfuric acid below 10° C. The organic layer was separated, and then the aqueous layer was extracted with diethyl ether (100 ml) twice. The organic layer was washed with water and a sodium chloride saturated aqueous solution in turn, and dried over magnesium sulfate. The solution was concentrated in vacuo and the residue was allowed to stand in refrigerator overnight to give 2-methoxyimino-3,3-ethylenedioxy-4-bromobutyric acid (syn isomer, 18.0 g). (Yield: 74.7%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.[CH3:10][S:11]([NH2:14])(=[O:13])=[O:12].N12CCCN=C1CCCCC2>O1CCCC1>[Br:1][C:2]1[N:3]=[C:4]([C:7]([NH:14][S:11]([CH3:10])(=[O:13])=[O:12])=[O:9])[S:5][CH:6]=1
Reactant: O=C(O)c1nc(Br)cs1
Reactant: CS(N)(=O)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC(=O)c1nc(Br)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Bromo-1,3-thiazole-2-carboxylic acid (1.0 g, 4.8 mmol) were initially charged in tetrahydrofuran (10 ml). N,N′-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added and the reaction mixture was heated under reflux for 1 h. Methanesulphonamide (0.69 g, 7.2 mmol) was added and, after 10 min, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.10 g, 7.2 mmol). The reaction mixture was stirred at room temperature for 16 h and then the solvent was removed under reduced pressure. The residue was taken up in water and acidified with hydrochloric acid. The precipitated product was filtered off with suction. This gave 1.18 g (84% of theory) of 4-bromo-N-(methylsulphonyl)-1,3-thiazole-2-carboxamide.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:25])=[O:4].C1(=O)[NH:30]C(=O)C2=CC=CC=C12.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:30][CH2:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:25])=[O:4]
Reactant: O=C(CCl)NCCCn1cc(-c2ccccc2)c2ccccc2c1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NCC(=O)NCCCn1cc(-c2ccccc2)c2ccccc2c1=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 34.3 %

Procedure:
7.1 g of 2-(2-chloroacetamidopropyl)-4-phenyl-1(2H)-isoquinolone, 3.7 g of phthalimide and 3.7 g of potassium carbonate were added to 50 ml of dimethylformamide, and the mixture was stirred at 80° C. for 5 hours. The resulting reaction mixture was poured into water and the precipitated crystals were collected by filtration, washed with water and dried in air. The resulting crystals and 2 g of hydrazine hydrate were added to 100 ml of ethanol and the mixture was heated at reflux for 3 hours. After allowing the mixture to cool, 5 ml of concentrated hydrochloric acid was added to the resulting reaction mixture and the mixture was stirred for 5 hours. The solvent was then distilled off, and water was added to the residue, followed by thoroughly stirring. The mixture was filtered and the filtrate was rendered neutral with a 10% aqueous solution of sodium hydroxide. The precipitated was extracted with dichloromethane, and the extract was washed with water and dried. The solvent was distilled off and the resulting crystals were recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 2.3 g (34% yield) of 2-(2-aminoacetamidopropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 141° C. as colorless needles.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+].O>C1COCC1.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>[CH2:26]([O:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[CH:14][CH:15]=2)=[CH:24][CH:23]=1)[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCCCCOc1ccc(-c2ccc(Br)cc2)cc1
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: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCOc1ccc(-c2ccc(-c3ccc(C=O)cc3)cc2)cc1
Yield: 58 %

Procedure:
Under an argon atmosphere, (4-formylphenyl)boronic acid (0.54 g, 3.6 mmol), 4-Bromo-4′-pentyloxy-biphenyl (0.958 g, 3 mmol) 1) (A1), sodium hydrogen carbonate (0.76 g, 9 mmol), and tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (0.057 g, 0.030 mmol) were dissolved in THF (15 mL) and water (15 mL) and stirred under a reflux condition. After they reacted with each other, liquid separation and extraction were performed with water and chloroform. After an organic layer was dried with anhydrous sodium sulfate and filtered, the solvent was distilled off under a reduced pressure. After the obtained reaction mixture was separated and purified with a silica gel column chromatography using chloroform as a moving bed, the mixture was purified by a recrystallization method using chloroform and hexane. Thereby, a white solid of 4″-(pentyloxy)-[1,1′:4′,1″-terphenyl]-4-carbaldehyde (A2) was obtained (0.60 g, yield: 58%). The obtained product (A2) was identified by using a 1H-NMR method. 1H-NMR (CDCl3, 400 MHz) δ=10.06 (s, 1H, CHO), 7.95-7.97 (d, 2H, phenylene), 7.79-7.81 (d, 2H, phenylene), 7.71-7.66 (m, 4H, phenylene), 7.00-6.98 (s, 2H, phenylene), 4.03-3.99 (t, 2H, —O—CH2—), 1.84-1.81 (t, 2H, —CH2—), 1.47-1.40 (m, 4H, —CH2—), and 0.93-0.97 (t, 3H, —CH3). 13C NMR (CDCl3, 100 MHz) δ=191.7, 159.0, 146.7, 141.0, 137.8, 135.2, 132.4, 130.2, 128.0, 127.2, 114.9, 68.1, 29.0, 28.3, 22.7, and 14.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH2:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].CO[C:27]1[C:32]2[N:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[N:35]=[CH:36][C:31]=2[CH2:30][CH2:29][N:28]=1.CO>C(OCC)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10](=[O:11])[NH:12][NH:13][C:27]1[C:32]2[N:33]=[C:34]([C:37]([F:39])([F:40])[F:38])[N:35]=[CH:36][C:31]=2[CH2:30][CH2:29][N:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)c(F)cc1F
Reactant: COC1=NCCc2cnc(C(F)(F)F)nc21
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NNC1=NCCc2cnc(C(F)(F)F)nc21)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A mixture of 150 mg (0.433 mmol) of tert-butyl[(1R)-3-hydrazino-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (Intermediate 4), 100 mg (0.433 mmol) of 8-methoxy-2-(trifluoromethyl)-5,6-dihydropyrido[3,4-d]pyrimidine (Intermediate 5) and 4 mL of anhydrous methanol was stirred at room temperature for 5.5 h and then diluted with diethyl ether. The solid was collected on a filter and dried to give the title compound. LC-MS 547 (M+1).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][O:7][N:8]=[C:9]([C:15]([CH3:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].O>C(O)(=O)C>[CH3:6][O:7][N:8]=[C:9]([C:15]([CH2:17][Cl:4])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=NOC)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOC)C(=O)CCl

Procedure:
Sulfuryl chloride (235 ml.) was dropwise added over 20 minutes with stirring and ice-cooling to a solution of ethyl 2-methoxyiminoacetoacetate (syn isomer) (500 g.) in acetic acid (500 ml.), and the mixture was stirred overnight under cooling with water. Nitrogen gas was introduced to the reaction mixture for 2 hours, and the resulting mixture was poured into water (2.5 l.) After extracting with methylene chloride (500 ml.) and twice with methylene chloride (200 ml.), the extracts were combined. The combined extract were washed with a saturated aqueous solution of sodium chloride, and adjusted to pH 6.5 by adding water (800 ml.) and sodium bicarbonate. Methylene chloride layer was separated, washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (559 g.).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][CH:8]([CH3:31])[CH:9]([NH:14][C:15]([C:17]1[S:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)[N:21]=1)=[O:16])[C:10]([O:12][CH3:13])=[O:11].[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[S:40]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:21]=[C:17]([C:15]([NH:14][CH:9]([CH:8]([CH3:31])[CH3:7])[C:10]([O:12][CH3:13])=[O:11])=[O:16])[S:18][CH:19]=2)=[CH:23][CH:24]=1)(=[O:42])=[O:41]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1nc(-c2ccc(NS(=O)(=O)c3ccc(Cl)cc3Cl)cc2)cs1)C(C)C
Reaction time: 0.08 h

Procedure:
Pyridine (1.5 ml) was added to a solution of methyl-2-(4-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 3, 160 mg) in DCM (4 ml), and reaction mixture was stirred for 5 minutes. 2,4 dichloro benzenesulfonyl chloride (130 mg) was added and reaction mixture was stirred for 16 hours at RT. Organic solvent was concentrated to obtain sticky solid, was purified by column chromatography (silica gel, EtOAc-petroleum ether) to obtain title compound as solid. Yield: 215 mg (82%); 1H NMR (CDCl3, 300 MHz): δ 7.97 (d, 1H), 7.81 (d, 2H), 7.75 (d, 1H), 7.63 (s, 1H), 7.51 (d, 1H), 7.33 (dd, 1H), 7.21 (d, 2H), 7.13 (bs, 1H), 4.73 (m, 1H), 3.78 (s, 3H), 2.32 (m, 1H), 1.04 (dd, 6H); MS (ESI) m/z 542.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Nc1ccc2cccnc2c1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(Br)cc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (720 mg, 5 mmol) and 4-bromobenzoic acid (1.51 g, 7.5 mmol) as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.91 (dd, 1H), 8.18 (d, 1H), 8.14 (dd, 1H), 8.06, (m, 2H), 7.85 (d, 1H), 7.81 (d, 2H), 7.67 (d, 2H), 7.37 (dd, 1H).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][S:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([C:14]2[C:15](O)=[N:16][CH:17]=[N:18][CH:19]=2)[CH:9]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(#N)C>[Cl:3][C:15]1[C:14]([C:10]2[CH:9]=[C:8]([S:7][CH3:6])[N:13]=[CH:12][N:11]=2)=[CH:19][N:18]=[CH:17][N:16]=1
Reactant: CSc1cc(-c2cncnc2O)ncn1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSc1cc(-c2cncnc2Cl)ncn1
Temperature: 85 °C

Procedure:
POCl3 (1.51 mL, 16.2 mmol, 3.0 eq.) is added slowly to a suspension of 6-methylsulfanyl-[4,5′]bipyrimidinyl-4′-ol 6 (1.20 g, 5.44 mmol) and triethyl amine (0.76 mL, 5.44 mmol, 1.0 eq.) in acetonitrile (30 ml). After heating at 85° C. for 2 hours, the reaction mixture is cooled to room temperature, poured into ice-water, neutralized by saturated NaHCO3 solution, and then extracted with ethyl acetate. The organic layer is washed with brine and dried over Na2SO4, filtered and concentrated. The crude product is purified by silica gel flash chromatography eluting with ethyl acetate in hexanes from 0% to 40% to give 4′-chloro-6-methylsulfanyl-[4,5′]bipyrimidinyl as a white solid. 1H NMR 400 MHz (DMSO-d6) δ 9.19 (s, 1H), 9.12 (d, 1H, J=1.2 Hz), 9.07 (s, 1H), 7.91 (d, 1H, J=1.6 Hz), 2.62 (s, 3H).
Reaction SMILES: C(O[C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][C:30]=1[SH:39].B(F)(F)F.CCOCC>C(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@H:5]1[S:39][C:30]1[CH:31]=[C:32]([C:35]([CH3:37])([CH3:36])[CH3:38])[CH:33]=[CH:34][C:29]=1[CH3:28])(=[O:10])[CH3:9]
Reactant: Cc1ccc(C(C)(C)C)cc1S
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Sc2cc(C(C)(C)C)ccc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 84.9 %

Procedure:
1,2,3,4,6-Penta-O-acetyl-β-D-glucopyranose 8 (30 g, 77 mmol) was dissolved in anhydrous DCM (34 mL). 2-Methyl-5-tert-butyl thiophenol (17 mL, 92 mmol, 1.2 eq) were added under stirring. BF3.OEt2 (13.6 mL, 108 mmol, 1.4 eq) was added dropwise and the resulting yellow solution was stirred over night. After completion the solution was diluted with DCM and extracted with saturated aqueous NaHCO3 and H2O, and the organic layer was dried over MgSO4. The solvent was evaporated in vacuo and the residue was dried in high vacuum. The resulting yellow solid was purified by column chromatography on silica gel (cyclohexane/ethyl acetate) to afford 9 (33.4 g, 65.4 mmol, 85%). [α]D20=−8.0° (c=1.0, CHCl3); IR (CHCl3): 2961, 1747, 1366, 1211, 1034, 912 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.52 (1H, d, J 2.0, Ar—H), 7.25-7.10 (2H, m, Ar—H), 5.19 (1H, dd, J1J2 9.4, 1-H), 5.10-4.98 (2H, m, 4-H, 2-H), 4.64 (1H, d, J 10.6, 1-H), 4.23 (1H, dd, J1 12.2, J2 5.0, 6-Ha), 4.10 (1H, dd, J112.2, J2 1.9, 6-Hb), 3.71-3.63 (1H, m, 5-H), 2.34 (3H, s, CH3), 2.07-2.03 (6H, m, OAc), 2.00-1.96 (6H, m, OAc), 1.29 (9H, s, tBu); 13C-NMR (100 MHz, CDCl3) δ 170.8, 170.3, 169.5, 169.4 (C═O OAc), 149.8, 137.51, 131.47, 130.53, 130.2, 125.8, 87.0 (C-1), 75.9 (C-5), 74.2 (C-3), 70.3 (C-3), 68.3 (C-4), 62.4 (C-6), 31.4 (tBu), 20.89, 20.88, 20.74, 20.70 (OAc), 20.5 (CH3); HRMS (ESI): Calcd for C25H34O9S [M+Na]+ 533.1816. found 533.1832.
Reaction SMILES: [C:1]([C@@:3]1([N:34]2[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[O:33][C@H:7]([CH:8]([C:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[OH:9])[C@@H:5]([OH:6])[CH2:4]1)#[N:2].[C:43]([Si:47]([CH3:50])([CH3:49])Cl)([CH3:46])([CH3:45])[CH3:44].N1C=CN=C1>N1C=CC=CC=1>[C:1]([C@@:3]1([N:34]2[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[O:33][C@H:7]([CH:8]([C:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[OH:9])[C@@:5]([Si:47]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:50])[CH3:49])([OH:6])[CH2:4]1)#[N:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C(c2ccccc2)(c2ccc(OC)cc2)C(O)[C@H]2O[C@@](C#N)(n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)cc1
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: COc1ccc(C(c2ccccc2)(c2ccc(OC)cc2)C(O)[C@H]2O[C@@](C#N)(n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1′-Cyano-5′-(4,4′-dimethoxytrityl)thymidine in anhydrous pyridine is added to a stirred solution of t-butyldimethylchlorosilane (1.5 equivalents) and imidazole (3.0 equivalents) in anhydrous pyridine at 0° C. The resulting reaction mixture is stirred at room temperature overnight. Pyridine is evaporated and the residue dissolved in ethyl acetate, washed with brine. The crude is directly used for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.P(Br)(Br)[Br:17]>CCOCC.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][Br:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(-c2ccc(F)cc2)cc1
Solvent: CCOCC
Solvent: O
Product: Fc1ccc(-c2ccc(CBr)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4'-fluoro-4-biphenylylmethanol (7.38 g, 36.93 mmol) in Et2O (250 ml) is added phosphorous tribromide (7 ml, 73.06 mmol). The reaction is allowed to warm slowly to room temperature and is then refluxed for 12 hours. After the reaction is cooled to room temperature ice chips are added until gas no longer evolves. The reaction mixture is then diluted with H2O (200 ml) and extracted with 1N NaOH (300 ml) and saturated NaCl solution (300 ml), dried over MgSO4, and concentrated in vacuo to give 4'-fluoro-4-biphenylylmethyl bromide as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:18])=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]#[N:17])[CH:11]=2)[CH:9]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:18])=[C:8]([C:10]2[CH:15]=[CH:14][N+:13]([O-:27])=[C:12]([C:16]#[N:17])[CH:11]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(-c2ccnc(C#N)c2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1ccc(F)c(-c2cc[n+]([O-])c(C#N)c2)c1
Reaction time: 72 h
Yield: 77.3 %

Procedure:
A solution of 4-(5-ethoxy-2-fluoro-phenyl)pyridine-2-carbonitrile (which may be prepared as described in Description 111) (6.19 g, 25.55 mmol) in DCM (200 mL) was treated with mCPBA (7.56 g, 30.66 mmol) and then was reluxed under nitrogen for 3 days. The mixture was diluted with 5% sodium metabisulfite (100 ml) and DCM (200 ml) and shaken vigourously. The organic layer was then washed with sat NaHCO3 solution (200 ml) and then dried (Na2SO4) and concentrated. Purification by flash chromatography gave 4-(5-ethoxy-2-fluoro-phenyl)-1-oxido-pyridin-1-ium-2-carbonitrile (D112) (5.102 g);
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([O-:11])=[O:10].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:18][C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Nc1cc(Cl)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Temperature: 150 °C
Reaction time: 72 h
Yield: 21.2 %

Procedure:
2-Amino-4-chloropyridine (2.00 g) was dissolved in N-methylpyrrolidone (31.8 ml) under a nitrogen atmosphere, and 4-nitrophenol (6.51 g) and N,N-diisopropylethylamine (15.9 ml) were added, followed by stirring at 150° C. for 3 days. The reaction mixture was allowed to cool down to room temperature, and partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide (32 ml). The organic layer was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2 to 1:5). Fractions containing the target compound were concentrated under reduced pressure, and the residue was dried under reduced pressure to provide the titled compound as a brown solid (764 mg, 21.2%).