Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([CH:13]=[S:14](=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]([CH2:12][Br:17])=[C:10]([CH:13]=[S:14](=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C=S(=O)=O)c(C)c1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C=S(=O)=O)c(CBr)c1Cl

Procedure:
80 g (0.3 mol) of methyl 2-chloro-3-methyl-4-sulfonylmethylbenzoate in 11 of carbon tetrachloride are heated at 76° C. together with 54 g (0.31 mol) of N-bromosuccinimide and 1.5 g of azoisobutyronitrile for 6 h. The reaction mixture is filtered and freed from the solvent under reduced pressure. Yield: 104 g; m.p. 83-85° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([OH:15])[CH3:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][N:18]=1>CN(C=O)C>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([CH:13]([O:15][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH3:14])=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(O)c1ccc(C(C)(C)C)cc1
Reactant: Clc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1ncnc2ccccc12)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
To a mixture of 0.5 g of sodium hydride in 100 ml of DMF was added 2.0 g of 1-[4-(t-butyl)phenyl]ethanol, and the resulting mixture was stirred at room temperature for one hour. Then 1.8 g of 4-chloroquinazoline in 30 ml of DMF were added. The mixture was stirred at room temperature for three hours, then poured into an ice/water mixture. The product was extracted into ether, the ether solution was concentrated and the residue was recrystallized from a pentane/ethyl acetate mixture to give 0.300 g of the title product. M.P. 85°-86° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][N:8]=[CH:7]2.[Br:12]Br>S([O-])([O-])(=O)=O.[Ag+2].OS(O)(=O)=O>[Br:12][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:11]2[C:6]=1[CH:7]=[N:8][CH:9]=[N:10]2
Reactant: BrBr
Reactant: Cc1cccc2cncnc12
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: Cc1ccc(Br)c2cncnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To a solution of 8-Methylquinazoline (10 g, 0.0694 mol) in conc.H2SO4 (100 mL), was added silver sulphate (34.64 g, 0.1111 mol) in portions at OCC. To this was added Bromine (4.4 mL, 0.0832 mol) in drops. The reaction mixture was stirred at RT for 16 h. Reaction was monitored by LCMS at regular intervals. At the end of 16 h, LCMS showed 42% starting material and 51% of product. The reaction mixture was quenched with ice and basified with NH4OH solution. The aqueous layer was extracted with EtOAc (4×500 mL), washed with water and brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude was purified by column chromatography using neutralized silica gel (60-120 mesh) and pet ether/ethyl acetate as an elutent to yield the titled compound as pale yellow liquid (51% yield). 1H NMR (DMSO-d6, 400 MHz) δ 9.60-9.58 (s, 1H), 9.40-9.38 (s, 1H), 7.93-7.91 (d, J=7.72 Hz, 1H), 7.77-7.75 (d, J=7.72 Hz, 1H), 2.62 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([N+:20]([O-])=O)=[C:14]([CH:19]=2)[C:15]([NH:17][CH3:18])=[O:16])[CH2:6][CH2:5]1>CO.CO.C(Cl)Cl>[NH2:20][C:13]1[CH:12]=[CH:11][C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)=[CH:19][C:14]=1[C:15]([NH:17][CH3:18])=[O:16]
Reactant: CNC(=O)c1cc(N2CCN(CCO)CC2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)c1cc(N2CCN(CCO)CC2)ccc1N

Procedure:
A solution of 5-[4-(2-hydroxyethyl)-1-piperazinyl]-N-methyl-2-nitrobenzamide 3 in 250 mL of MeOH in a 250 mL round bottom flask was stirred at room temperature under hydrogen balloon over night. The resulted mixture was filtered to get rid of the Pd catalyst. TLC in 10% MeOH/CH2Cl2 showed no more starting material and a major product. The solvent was rotavaped to dryness, and the residue was used without further purification. MS(ES) m/e 279 [M+H].
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[CH2:11][C:12]#[N:13].[OH-].[K+]>>[C:1]1(=[C:11]([C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[CH3:8])[C:12]#[N:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: Cc1ccccc1CC#N
Agent: [K+]
Agent: [OH-]
Product: Cc1ccccc1C(C#N)=C1CCCCC1
Temperature: 140 °C
Yield: 63 %

Procedure:
The mixture of cyclohexanone (44.7 g, 0.46 mol) and 2-methyl benzylcyanide (41.9 g, 0.32 mol) is treated with KOH (3.58 g, 0064 mol) and the resulting mixture is heated to 120° C. (oilbath temperature 140° C.) for 2 h with concomitant distillation of H2O as an azeotrope with cyclohexanone. The temperature is raised to 130° C. (oilbath temperature 150° C.) for 30 min, before cooling to 60° C. and dilution of the viscous mixture with toluene (50 ml). Standard aqueous workup is effected with toluene, H2O, sat. aq. Na2CO3-solution and brine. The organic layer is dried over MgSO4 and the volatiles removed in vacuo. The crude product (67 g), which crystallizes upon standing, is subjected to a short path distillation at 0.05 mbar/120-127° C. to yield 42.6 g of crystalline product which is recrystallized three times from hexane. From this, 33.6 g of white crystalline product is obtained (50% yield), m.p. 65.2-66.0° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[N:37]=[C:38]=[S:39])([CH3:29])[CH3:28].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[NH:37][C:38]([NH:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[S:39])([CH3:29])[CH3:28]
Reactant: NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Cc1ccc(C(C)C)c(N=C=S)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(C(C)C)c(NC(=S)NCCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (0.160 g, 0.442 mmol) in a 25 mL vial equipped with a stir bar was added 1-isopropyl-2-isothiocyanato-4-methylbenzene (65% in dichloromethane, 0.156 g, 0.530 mmol) in dichloromethane (6.31 ml) followed by triethylamine (0.062 ml, 0.442 mmol). The reaction was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and adsorbed onto Celite®. Purification by flash column chromatography using 2.5-40% ethyl acetate/B, where B=1:1 dichloromethane/hexanes as eluent provided a white solid. The solid was dried overnight at 50° C. at about 25 in. Hg providing the title compound as a white solid (0.172 g, 70%).
Reaction SMILES: [OH:1]O.[CH3:3][C:4]([C:7]1[CH:12]=[C:11]([C:13]2[S:14][C:15]([S:18][CH3:19])=[N:16][N:17]=2)[CH:10]=[C:9]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:8]=1[OH:24])([CH3:6])[CH3:5]>C(O)(=O)C>[CH3:21][C:20]([C:9]1[CH:10]=[C:11]([C:13]2[S:14][C:15]([S:18]([CH3:19])=[O:1])=[N:16][N:17]=2)[CH:12]=[C:7]([C:4]([CH3:3])([CH3:5])[CH3:6])[C:8]=1[OH:24])([CH3:23])[CH3:22]
Reactant: CSc1nnc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Reactant: OO
Solvent: CC(=O)O
Product: CS(=O)c1nnc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Temperature: 90 °C
Yield: 26.5 %

Procedure:
30% aqueous hydrogen peroxide (1.7 g, 0.015 mole) is added to a stirred solution of 2,6-bis(1,1-dimethylethyl)-4-[5-(methylthio)-1,3,4-thiadiazol-2-yl]-phenol (5.0 g, 0.015 mole) in glacial acetic acid (20 ml). The resulting mixture is heated to 90° C. for three hours. The mixture is cooled and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, 25% ethyl acetate/hexane eluent) to provide a solid which is recrystallized from ethyl acetate/hexane to give 1.4 g of 2,6-bis(1,1-dimethylethyl)-4-[5-(methylsulfinyl)-1,3,4-thiadiazol-2-yl]-phenol (5.3 g theor., 26%), mp 141.2° C.
Reaction SMILES: O[CH2:2][CH:3]([CH3:23])[O:4][C:5]1[C:6](=[O:22])[O:7][C:8]([CH3:21])([CH3:20])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.CCN(S(F)(F)[F:30])CC>C(Cl)Cl>[F:30][CH2:2][CH:3]([CH3:23])[O:4][C:5]1[C:6](=[O:22])[O:7][C:8]([CH3:21])([CH3:20])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CC(CO)OC1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(CF)OC1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Reaction time: 18 h

Procedure:
To the alcohol of Example 12 Step 2 (300 mg, 0.882 mmol) in CH2Cl2 (10 mL) at 0∞C. was added DAST (142 mL, 1.05 mmol). After a period of 18 h at room temperature and 2 days at reflux, the reaction mixture was partitioned between 25% aqueous NH4OAc and EtOAc. The organic phase was separated, dried over Na2SO4, filtered and evaporated under reduced pressure. The title compound (48 mg) was purified by flash chromatography.
Reaction SMILES: [F:1][C:2]([F:57])([F:56])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([C:38]4[CH:39]=[CH:40][C:41]([C:45]([O:47]CC5C=CC=CC=5)=[O:46])=[N:42][C:43]=4[CH3:44])[CH:31]=3)[C@H:14]2[CH3:55])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C(O)C.[Pd]>[F:57][C:2]([F:1])([F:56])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[C:30]3[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([C:38]4[CH:39]=[CH:40][C:41]([C:45]([OH:47])=[O:46])=[N:42][C:43]=4[CH3:44])[CH:31]=3)[C@H:14]2[CH3:55])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ccc(-c2ccc(C(=O)OCc3ccccc3)nc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-c2ccc(C(=O)O)nc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 3 h

Procedure:
Benzyl 5-[2′-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]-6-methylpyridine-2-carboxylate (52 mg, 0.065 mmol), palladium/active carbon (10%, w/w) (25 mg) were mixed in ethanol (10 mL). The resulting mixture was degassed and subject to H2 under 45 psi at room temperature on a Parr shaker for 3 hours to complete the reaction. The reaction mixture was filtered through a pad of Celite (521). The filtrate was concentrated in vacuo to afford a light brown glass. The residue was purified by preparative reverse-phase HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with a MeCN/H2O gradient mixture. The appropriate fractions were pooled and evaporated into an aqueous residue. The resulting residue was further lyophilized to afford 5-[2′-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]-6-methylpyridine-2-carboxylic acid. LCMS calc.=712.16; found=713.19 (M+1)+. 1H NMR signals are doubled because of atropisomerism 1H NMR (CDCl3, 500 MHz) δ 8.07 (s, 1H), 7.86 (s, 1H), 7.77 (s, 1H), 7.71-7.62 (m, 4H), 7.45-7.36 (m, 2H), 7.19-7.07 (m, 2H), 5.55 (d, J=7.0 Hz, 0.55H), 5.42 (d, J=7 Hz, 0.45H), 4.99 (d, J=13 Hz, 0.5H), 4.85 (d, J=12.5 Hz, 0.5H), 4.14 (d, J=13.5 Hz, 0.5H), 3.95 (d, J=13.5 Hz, 0.5H), 3.92-3.80 (m, 4H), 2.61, 2.58 (s, 3H), 0.58 (d, J=5.0 Hz, 1.35H), 0.49 (d, J=5.5 Hz, 1.65H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15].[Li]CCCC.Cl[P:22]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[CH:29]1([P:22]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: COc1ccccc1-c1ccccc1Br
Reactant: ClP(C1CCCCC1)C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.4 %

Procedure:
A solution of 2-bromo-2′methoxy-1,1′-biphenyl (535 mg, 2.03 mmol) in THF (20 mL) was cooled to −78° C. under argon, then n-BuLi (1.6 M in hexane, 1.35 mL, 2.16 mmol) was added dropwise. After 2.5 h at −78° C., a solution of chlorodicyclohexylphosphine (570 mg, 2.45 mmol) in THF (3 mL) was added over 10 min. The reaction mixture was then allowed to warm to room temperature overnight, then quenched with saturated aqueous NaHCO3 and concentrated in vacuo. The resulting aqueous suspension was extracted with ether (2×50 mL), and the combined ethereal layers were dried (Na2SO4), filtered and concentrated in vacuo. The resulting crude solid was recrystallized from ethanol to afford 420 mg (54 %) of a white solid.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1.[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:11])=[CH:8][N:7]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OCc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(OCc1ccccc1)c1ccc(Cl)nc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Sulfurous dichloride (6.8 g, 57 mmol) was added to a solution of 6-chloronicotinic acid (4.5 g, 28.5 mmol) in toluene (40 mL) at 0° C. The mixture was stirred at 110° C. for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. Benzyl alcohol (4.65 g, 43.1 mmol), pyridine (6.9 mL) and toluene (50 mL) were added to the residue. The mixture was stirred at 25° C. for 3 hours. HCl (20 mL, 4 N) was added and the mixture was extracted with toluene. The toluene layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford benzyl 6-chloronicotinate. MS ESI calc'd. for C13H11ClNO2 [M+H]+ 248. found 248. 1HNMR (400 MHz, DMSO-d6) δ 8.94 (d, J=2.0 Hz, 1H), 8.34-8.31 (m, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.50-7.17 (m, 5H), 5.38 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[C@H:11]([CH3:22])[O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]1([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[NH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:32]=[C:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:17][CH:16]=2)[C@H:11]([CH3:22])[O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CCc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CCc1ccc(N=C(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 81.7 %

Procedure:
To a solution of (4S,5S)-4-[2-(4-bromo-phenyl)-ethyl]-2,2,5-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.13 g) in toluene (30 ml) were added diphenylmethanimine (1.71 g) and sodium tert-butoxide (1.06 g). The reaction mixture was degassed by bubbling argon through the mixture for several minutes. BINAP (489 mg) and Pd2(dba)3 (216 mg) were then added and the reaction mixture was stirred at 100° C. for 20 h. The reaction mixture was then cooled to room temperature, poured into EtOAc, and extracted with water. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, gradient: 0% to 30% EtOAc in hexane) to afford (4S,5S)-4-{2-[4-(benzhydrylidene-amino)-phenyl]-ethyl}-2,2,5-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester as a yellow oil (3.2 g, 82%). MS (ISP): 499.3 ([M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:14][CH2:13][C@@H:12]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:11][NH:10][C:9]1=[O:23])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.O>C1COCC1>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:14][CH2:13][C@@H:12]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:11][N:10]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:9]1=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1cccnc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CNC1=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CN(Cc2cccnc2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.2 %

Procedure:
To a stirred solution of [(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester (4.0 g, 11.1 mmol) in THF (30 mL) at −78° C. is added KN(Si(CH3)3)2 (45.0 mL 1M THF, 45.0 mmol) slowly. The mixture is stirred at room temperature for 20 min, cooled to −78° C., and 3-chloromethyl-pyridine hydrochloride (2.75 g, 16.7 mmol) is added in portions. The reaction is warmed to room temperature and stirred for 16 h, H2O (20 mL) is added and the mixture is partitioned with H2O/ether, the organic layer is separated, dried with Na2SO4 and evaporated to give a white solid, 5.0 g (quantitative) of [(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl]-carbamic acid tert-butyl ester. MS (ESI) 899.3 (2M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([N+:11]([O-])=O)=[CH:9][CH:10]=1)=[O:5])[CH3:2].Cl.[Sn].[OH-].[Na+]>C(Cl)Cl>[NH2:11][C:8]1[S:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N)s1
Reaction time: 6 h

Procedure:
A mixture of 60.4 g. of ethyl-5-nitro-2-thiophenecarboxylate and 480 ml. of concentrated hydrochloric acid is cooled in an ice-bath to below -5°. To this mixture is added 72 g. of granular tin in small amounts, keeping the temperature near -5°. After stirring for 6 hours, 575 ml. of 10 N sodium hydroxide is added to neutralize the mixture. Methylene chloride and Celite are added and the mixture is filtered. The methylene chloride layer of the filtrate is separated, dried over sodium sulfate, and filtered through Magnesol. Evaporation affords an oil which is distilled to yield the product.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].Cl.[C:21]1([C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([CH3:30])[CH2:28][NH2:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[C:31]1([C:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([CH3:30])[CH2:28][NH:29][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: CC(CN)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 456 h

Procedure:
A mixture of 6-chloro-9-β-D-ribofuranosylpurine (2.32 g, 8.09 mmol), 2,2-diphenylpropylamine hydrochloride (2.01 g, 100 mol %), and triethylamine (2.3 mL, 204 mol %) in N,N-dimethylformamide (30 mL) is stirred under nitrogen at room temperature for 19 days, filtered, the solid is washed with ether, and the filtrate is evaporated to an oil. The oil is purified by column chromatography over silica gel, eluting with 5/1 chloroform/methanol, and the appropriate fractions are evaporated to afford N6 -(2,2-diphenylpropyl)adenosine as a foam which retains one-half mole of N,N-dimethylformamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH3:17])=[O:15])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19]>>[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[C:4]([C:14]([NH:16][CH3:17])=[O:15])[CH:3]=2)=[CH:22][CH:21]=1)=[O:19]
Reactant: CNC(=O)c1cc(Br)cc(-c2ccccc2)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: CNC(=O)c1cc(-c2ccccc2)cc(-c2ccc(C=O)cc2)c1

Procedure:
In a manner similar to that of Example 1(e), by reacting 2 g (7 mmol) of 5-bromo-N-methyl-3-biphenylcarboxamide and 1.4 g (9.3 mmol) of 4-formylbenzene boronic acid, and after purification by recrystallization from acetonitrile, 1.4 g (63%) of the expected product are obtained in the form of a beige-colored solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[C:17]([O:24][CH3:25])[C:16]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.Cl.[O:34]=[C:35]1[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:50]3[CH:51]=[C:52]([C:56]([OH:58])=[O:57])[CH:53]=[N:54][CH:55]=3)[CH:48]=2)[O:43][C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36]1.Cl>O.C(N(CC)CC)C.CN(C=O)C>[CH3:25][O:24][C:17]1[CH:18]=[C:19]([C:21]([N:40]2[CH2:41][CH2:42][C:37]3([CH2:36][C:35](=[O:34])[C:49]4[C:44](=[CH:45][CH:46]=[C:47]([C:50]5[CH:51]=[C:52]([C:56]([OH:58])=[O:57])[CH:53]=[N:54][CH:55]=5)[CH:48]=4)[O:43]3)[CH2:38][CH2:39]2)=[O:23])[CH:20]=[C:15]([O:14][CH3:13])[C:16]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Reactant: COc1cc(C(=O)O)cc(OC)c1-c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)cc(OC)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
Carbonyldiimidazole (81 mg) was added to a DMF solution (2 mL) of 2,6-dimethoxybiphenyl-4-carboxylic acid (129 mg), and stirred at 60° C. for 2.5 hours. To the reaction liquid, added were 5-(4-oxospiro[chroman-2,4′-piperidin]-6-yl)pyridine-3-carboxylic acid dihydrochloride (246 mg) and triethylamine (209 ml), and stirred at that temperature for 17 hours. 1 N hydrochloric acid and water were added to the reaction liquid, and the resulting solid was purified through high-performance preparative liquid chromatography (0.1% TFA, water/acetonitrile). Then, this was further purified through silica gel thin-layer chromatography (chloroform/methanol) to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 9.06 (1.0H, d, J=2.4 Hz), 9.02 (1.0H, d, J=2.0 Hz), 8.41 (1.0H, dd, J=2.4, 2.0 Hz), 8.12-8.01 (2.0H, m), 7.38-7.32 (2.0H, m), 7.29-7.24 (2.0H, m), 7.23-7.19 (2.0H, m), 6.75 (2.0H, s), 4.36-4.22 (1.0H, br m), 3.69-3.12 (3.0H, m), 3.68 (6.0H, s), 2.95 (2.0H, s), 2.15-1.93 (2.0H, m), 1.91-1.75 (2.0H, m). MS [M+H]+=579.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24]Br)[CH:7]=1)[CH3:2].[C:27]1([SH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][S:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:7]=1)[CH3:2]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CSc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 10, Step 4, using the following starting materials: [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and thiophenol.