Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8](O)=[O:9].P(Cl)(Cl)(Cl)(Cl)Cl.[C:31]([O:40][CH2:41][CH3:42])(=[O:39])[C:32]1[C:33](=[CH:35][CH:36]=[CH:37][CH:38]=1)[NH2:34]>ClCCl>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([NH:34][C:33]1[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=1[C:31]([O:40][CH2:41][CH3:42])=[O:39])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)c1ccccc1N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1NC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
Under an ice-cooled condition, 332 mg (1 mmol) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl) pyridine-3-carboxylic acid was suspended in dried dichloromethane. The mixture was stirred with addition of 229 mg (1.1 mmol) of phosphorus pentachloride little by little for one hour. At -30° C., 1650 mg (10 mmol) of ethyl anthranilate was added to the reaction mixture. The reaction mixture was further stirred at room temperature for one hour. After washing with water, the raction mixture was dried over anhydrous sodium sulfate. The thus obtained mixture was chromatographed on a silica gel column for purification, whereby 486 mg (100%) of the captioned compound was obtained as an oily material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:19])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH:5]=O.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1.N1CCCCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:19])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH:5]=[C:24]1[S:20][C:21](=[O:26])[NH:22][C:23]1=[O:25]
Reactant: COc1ccc(Oc2c(Cl)cc(C=O)cc2Cl)cc1
Reactant: O=C1CSC(=O)N1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1ccc(Oc2c(Cl)cc(C=C3SC(=O)NC3=O)cc2Cl)cc1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
To a solution of the title compound of Step B (284 mg, 0.96 mmol) in toluene (16 ml) was added 2,4-thiazolidinedione (140 mg, 1.2 mmol), a catalytic amount of piperidinium acetate which was generated from piperidine (five drops) and acetic acid (five drops) and 4 Å molecular sieves. The mixture was stirred under reflux for about four hours, cooled to room temperature, filtered and concentrated. The product was purified by preparative TLC (4% methanol in dichloromethane) to afford the title compound (153 mg). MS (APCI−) Calc: 395.0, Found: 394.0 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:12](Cl)(Cl)=[O:13])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH:16]([Mg]Br)=[CH2:17].[CH2:20]1COC[CH2:21]1>>[CH:20]([P:12](=[O:13])([CH:16]=[CH2:17])[C:5]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[CH2:21]
Reactant: C1CCOC1
Reactant: C=C[Mg]Br
Reactant: COc1cc(P(=O)(Cl)Cl)ccc1[N+](=O)[O-]
Product: C=CP(=O)(C=C)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: -78 °C
Yield: 75 %

Procedure:
To a solution of (3-methoxy-4-nitrophenyl)phosphonic dichloride (1.39 g, 5.15 mmol) in 15 mL THF at −78° C. under nitrogen was slowly added vinylmagnesium bromide (10.3 mL, 1.0 M in THF). After the addition was complete, the reaction stirred at −78° C. for an additional hour. The cold reaction mixture was quenched by the addition of saturated NH4Cl (20 mL) and the mixture was extracted with CH2Cl2. The combined organic layers were washed with 1 M NaOH, brine, and dried over MgSO4. The organic extracts were filtered and concentrated to provide Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.982 g, 75%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[CH2:4][N:5]([CH3:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1>C(O)(=O)C.CCOCC.O=[Pt]=O>[CH3:16][N:2]([CH3:1])[C:3](=[O:15])[CH2:4][N:5]([CH3:14])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CN(CCc1ccncc1)CC(=O)N(C)C
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CN(CCC1CCNCC1)CC(=O)N(C)C

Procedure:
Of the crude N,N-dimethyl-2-[methyl-(2-pyridine-4-yl-ethyl)-amino]-acetamide, 44 g are dissolved in 500 ml of glacial acetic acid and hydrogenated with 4 g of PtO2 at ambient temperature under 3 bar H2. After the catalyst has been removed by suction filtering the filtrate is evaporated down. The residue is made alkaline with 50% potassium hydroxide solution while cooling with ice and the product obtained is taken up in ether. The ether solution is dried over sodium sulphate, filtered and the solution is evaporated down. The product is left as a yellow oil. Yield: 42 g
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8]C)=O.[CH2:10]([Mg]Br)[CH3:11].C(=O)(O)[O-].[Na+].[CH2:19](OCC)[CH3:20]>C1COCC1.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])([CH2:10][CH3:11])[CH2:19][CH3:20]
Reactant: CC[Mg]Br
Reactant: CCOCC
Reactant: COC(=O)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)(CC)c1ccco1
Temperature: -30 °C
Reaction time: 8 h

Procedure:
2-methyl furate (10.0 g, 79 mmol) is dissolved in THF (100 mL) under a nitrogen atmosphere. Ethyl magnesium bromide (3.0 M in Et2O, 55 ml, 166 mmol) is added initially at room temperature. The reaction is cooled to −30° C., and the remaining ethyl Grignard added. The mixture is stirred overnight at room temperature. Saturated sodium bicarbonate solution (10 mL) is added to the stirring solution followed by diethyl ether (100 mL) and water (50 mL). The organic layer is separated and washed with water. The ether layer is dried over magnesium sulfate, filtered, and evaporated under vacuum to give 10.7 g of a oil, which was used without further purification.
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.Br[C:19]1[CH:20]=[C:21]([CH3:26])[C:22]([Cl:25])=[N:23][CH:24]=1>>[Cl:25][C:22]1[N:23]=[CH:24][C:19]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]3)=[CH:20][C:21]=1[CH3:26]
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Reactant: Cc1cc(Br)cnc1Cl
Product: Cc1cc(N2C[C@H]3CN(C(=O)OCc4ccccc4)C[C@H]32)cnc1Cl
Yield: 11 %

Procedure:
The product of Example 52D (1.30 g, 5.60 mmol) and 5-bromo-2-chloro-3-methylpyridine (1.73 g, 8.39 mmol) were processed according to the procedure described in Example 1E. The crude product was purified by chromatography (SiO2, ethyl acetate:hexane, 1:1) to provide the title compound (0.22 g, 11% yield) which was used directly in the next step without further purification. MS (DCI/NH3) m/z 358, 360 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:15]I.O>CN(C)C=O>[CH3:15][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of known 6-nitro-1H-indole (5 g, 31 mm) in dimethylformamide (DMF) (50 mL) was cooled to 0° C. and treated with NaH (1 g, 37m). After stirring at 0° C. for two hours, CH3I (2.3 mL, 37 mm) was added, and the reaction was stirred overnight while allowing to warm to room temperature. After pouring into H2O (500 mL), the mixture was extracted with ethyl acetate (EtOAc) (200 mL×4). The combined organic fractions were dried over MgSO4, filtered and evaporated. Purification by flash column chromatography afforded the 1-methyl-6-nitro-1H-indole (5.34 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH2:20][CH3:21])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:24](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:19][CH2:20][CH3:21])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:24])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CCCC(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCCC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-hexanoyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a light yellow oil, MS (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([OH:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:23][N:24]([CH3:28])[C:25](Cl)=[S:26].O>CN(C)C=O>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[C:10]([O:13][C:25](=[S:26])[N:24]([CH3:28])[CH3:23])=[C:11]([F:12])[C:2]=1[F:1]
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)c1cc([N+](=O)[O-])c(O)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(OC(=S)N(C)C)c(F)c1F
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2,3-difluoro-4-hydroxy-5-nitrobenzoate in N,N-dimethylformamide is treated with one molar equivalent of cesium carbonate and warmed to 85° C. for 30 minutes. The stirring mixture is then treated dropwise rapidly with a solution comprised of a slight excess of N,N-dimethylthiocarbamoyl chloride in N,N-dimethylformamide. The reaction mixture is stirred at room temperature for one hour, or may be warmed over a steam bath for one hour. The mixture is then poured into water and extracted with ethyl acetate. The organic phase is washed with 5% aqueous sodium hydroxide, water, and brine, and is then dried with a drying agent like magnesium sulfate of sodium sulfate. The solvent is then removed in vacuo to give a crude product. The compound is purified by ordinary methods such as chromatography or crystallization from an appropriate solvent.
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Mg+2].C([O-])(=O)C.C(OCC)(=O)C>CO>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Temperature: 55 °C
Reaction time: 5 h

Procedure:
2.17 parts of N-acetoacetyl-L-aspartic acid, 1.02 parts by volume of acetic anhydride, and 0.014 parts of magnesium acetate were mixed with 40 parts by volume of ethyl acetate and heated at 55±2° C. under nitrogen for 24 hours. 30 parts by volume of methanol was added and the mixture stirred at ambient temperatures for 5 hours. HPLC analysis of the resulting solution showed only 0.5% unreacted N-acetoacetyl-L-aspartic acid.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[NH2:12][C:13]([NH:15][C:16]1[NH:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[OH:30])=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22])=[O:14]>CN(C)C=O>[NH2:12][C:13]([NH:15][C:16]1[NH:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][C:8](=[O:10])[CH3:9])=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22])=[O:14]
Reactant: NC(=O)Nc1[nH]c(-c2ccccc2O)cc1C(N)=O
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1-c1cc(C(N)=O)c(NC(N)=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
Triethylamine (80 μL, 0.57 mmol) and acetyl chloride (33 μL, 0.46 mmol) were added to a solution of 2-aminocarbonylamino-5-(2-hydroxyphenyl)pyrrole-3-carboxamide (Compound No. 3-1, 100 mg, 0.39 mmol) in anhydrous N,N-dimethylformamide (2 mL), and the mixture was stirred overnight at room temperature. After the reaction solution was concentrated in vacuo, the residue was purified by silica gel column chromatography to give the target compound (41 mg) as a green-brown solid (Yield 35%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>ClCCl>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
(S)(+)-1-(2-Pyrrolidinylmethyl)pyrrolidine (1.07 g, 6.93 mmol) and triethylamine (763 mg, 7.56 mmol) are dissolved in dichloromethane (20 mL) and cooled to 0° C. 4-Fluorobenzoyl chloride (1.00 g, 6.3 mmol) in dichloromethane (2 mL) is added to the mixture at 0° C. and stirred at room temperature for 3 h. The reaction mixture is washed with brine, dried over Na2SO4, and evaporated. The residue is purified by silica-gel column chromatography (CH2Cl2:2M NH3 in MeOH=40:1) to give 1.45 g (83%) of the title compound. MS (APCI+) 277(M+1)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]([OH:16])=[O:15].[F:17][C:18]([F:28])([F:27])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>C1COCC1.O>[OH:20][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:18]([F:17])([F:27])[F:28])[CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: CC(=O)O
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)CC(O)(c1ccccc1)C(F)(F)F
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
To a cooled (0° C.) solution of n-butyl lithium (1.6M in hexanes, 40 mL) in dry THF (90 mL), was added dropwise diisopropylamine (9.45 mL) and the mixture was stirred for 5 min. Keeping the temperature at 0° C., AcOH (1.92 mL, 0.0336 mol) was added dropwise and the reaction mixture was stirred for 10 min and then heated at 50° C. for 30 min. The resulting solution was allowed to cool, a solution of 2,2,2-trifluoroacetophenone (4.76 mL (0.0336 mol) in dry THF (15 mL) was added at 0° C. and the resulting mixture was stirred at room temperature overnight. Finally, Et20 (150 mL) and H2O (50 mL) were added, the aqueous phase was separated, acidified with HCl and extracted with EtOAc (3×). The organic phase was dried and concentrated to afford the title compound as an orange solid (3.88 g, 49%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.CCOC(C)=O>C(O)(C)C>[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[N:3]=[CH:4][C:5]3[CH2:11][N:10]([C:12]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[O:13])[CH2:9][CH2:8][C:6]=3[N:7]=2)=[CH:24][CH:23]=1
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Reactant: COc1ccc(N)cc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncc3c(n2)CCN(C(=O)c2cccnc2)C3)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 4-methoxyaniline (0.018 g, 0.100 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 24.3% yield (0.008 g, 0.024 mmol).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.N1C(C)=CC=CC=1C.[Br:39][C:40]1[N:44]([C:45]2[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]([C:55]#[N:56])=[CH:47][CH:46]=2)[C:43]([S:57][CH2:58][C:59](O)=[O:60])=[N:42][CH:41]=1>ClCCl>[Br:39][C:40]1[N:44]([C:45]2[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]([C:55]#[N:56])=[CH:47][CH:46]=2)[C:43]([S:57][CH2:58][C:59]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])=[O:60])=[N:42][CH:41]=1
Reactant: CCOC(=O)CN
Reactant: N#Cc1ccc(-n2c(Br)cnc2SCC(=O)O)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CSc1ncc(Br)n1-c1ccc(C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Glycine ethyl ester hydrochloride (76 mg, 0.541 mmol, 1.2 equiv.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (130 mg, 0.676 mmol, 1.5 equiv.), 1-hydroxy-7-azabenzotriazole (92 mg, 0.676 mmol, 1.5 equiv.) and 2,6-lutidine (0.16 mL, 1.35 mmol, 3.0 equiv) were added to a solution of 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid (175 mg, 0.451 mmol) in dichloromethane (2.25 mL) and stirred at room temperature for 18 hours. The crude product was purified by SGC (0-100% ethyl acetate/hexanes) to afford the title compound containing some 1-hydroxy-7-azabenzotriazole. The impure product was dissolved in ethyl acetate (50 mL), washed with aqueous HCl solution (0.1M, 2×30 mL), saturated aqueous NaHCO3 solution (30 mL), and saturated sodium chloride solution (30 mL). The organics were dried over sodium sulfate, filtered, and concentrated to afford ethyl 2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)acetate as a yellow oil (199 mg, 93%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:16][CH:13]([O:14][CH3:15])[CH2:12][C@@H:11]1[OH:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C1(C)C=CC=CC=1.O.C(=O)([O-])[O-].[Ag+2]>[CH2:18]([O:17][C@@H:11]1[C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:16][CH:13]([O:14][CH3:15])[CH2:12]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COC1C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC1C[C@H](OCc2ccccc2)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Temperature: 65 °C

Procedure:
A mixture of 9.0 g. (0.034 mole) of methyl 5-O-(t-butyldimethylsilyl)-2-deoxyribofuranoside, 15 g (0.19 mole) of benzyl bromide, and 21 g (0.076 mole) silver carbonate in 50 ml dry dimethylformamide or other aprotic solvent is heated at 60° C. under a dry nitrogen atmosphere for five days. The mixture is cooled and the solids filtered. The filtrate is then concentrated at reduced pressure to 30 ml volume. To this are added 20 ml pyridine and the mixture heated at 65° C. for three hours. The solvents are again removed under reduced pressure affording a dark gummy residue which is taken up in a mixture of 150 ml toluene and 100 ml DI water. The organic phase is separated, washed with water (2×100 ml), dried (Na2SO4) and filtered. The solvent is removed at reduced pressure affording the methyl 3-O-benzyl-5-O-(t-butyldimethylsilyl)-2-deoxyribofuranoside compound as a red oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][C@H:15]([CH2:17]N3C=C(C)N=N3)[O:14][C:13]2=[O:24])[CH:5]=[CH:6][C:7]=1[Sn:8]([CH3:11])([CH3:10])[CH3:9].[Si:25]([O:32]C[C@@H]1OC(=O)N(C2C=CC(I)=CC=2)C1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>>[Si:25]([O:32][CH2:17][C@@H:15]1[O:14][C:13](=[O:24])[N:12]([C:4]2[CH:3]=[CH:2][C:7]([Sn:8]([CH3:9])([CH3:10])[CH3:11])=[CH:6][CH:5]=2)[CH2:16]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Reactant: Cc1cn(C[C@H]2CN(c3ccc([Sn](C)(C)C)c(F)c3)C(=O)O2)nn1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc([Sn](C)(C)C)cc2)C(=O)O1

Procedure:
Using the procedure described for (5R)-3-[3-fluoro-4-(trimethylstannyl)phenyl]-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (above), but starting from (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(4-iodophenyl)-1,3-oxazolidin-2-one (2.45 g, 5.66 mM) gave the title compound as a white solid after chromatography, using hexanes then 20% ethyl acetate/hexanes (1.59 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>>[CH3:22][C:20]1[CH:19]=[CH:18][C:17]([S:23][C:24]2[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: Cc1ccc(Sc2cccc(O)c2)c(N)c1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3cccc(O)c3)ccnc2n1

Procedure:
The product from Example 2g (275 mg, 1.33 mmol) was reacted with the product from Example 52b (307 mg, 1.33 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (305 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3 H) 1.75-1.94 (m, 2 H) 2.38 (s, 3 H) 2.98 (t, J=7.35 Hz, 2 H) 6.30 (d, J=6.99 Hz, 1 H) 6.49-6.66 (m, 3H) 6.91-7.04 (m, 1 H) 7.29-7.44 (m, 3 H) 7.79 (d, J=8.82 Hz, 1 H) 8.39 (d, J=7.35 Hz, 1 H) 8.96 (d, J=8.46 Hz, 1 H) 9.57 (s, 1 H) 10.95 (s, 1 H) 14.34 (s, 1 H); MS (ESI+) m/z 402 (M+H−TFA)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[O:11]=[C:12](C(OCC)=O)[C:13]([O:15]CC)=[O:14].Cl[Sn](Cl)(Cl)Cl.[OH-].[K+]>O.C(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:12]([OH:11])[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CC(C)Cc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1ccc(C(O)C(=O)O)cc1
Temperature: 0 °C
Yield: 73.8 %

Procedure:
To a dry 3-necked round-bottom flask under argon atmosphere equipped with a dropping funnel, septum and magnetic stir bar was added 12.6 mL (80 mmol) of isobutylbenzene, 12.3 mL (80 mmol) of diethyl ketomalonate (DEOM) and 40 mL of CH2Cl2. The flask was cooled with stirring to 0° C. followed by the dropwise addition of 11.7 mL (100 mmol) of SnCl4. The yellow reaction mixture was allowed to warm slowly to room temperature and after 3 hours the reaction was quenched by pouring the suspension into a mixture of 50 g of ice and 50 mL of 5% aqueous HCl and extracted with ether (3×100 mL). The ether layers were combined and washed with water (2×50 mL), 25 mL of brine, dried over MgSO4 and concentrated. The crude diester was diluted with 120 mL of H2O and 18 g (320 mmol) of KOH was added. The orange reaction mixture was stirred at 90° C. for 1.5 h, and washed with 2×30 mL of ether. Decarboxylation was effected by adjusting the pH to 1 with concentrated HCl and warming to 90° C. for 45 minutes. The pH of the solution was monitored and additional HCl was added as needed to maintain the pH of the solution below 2. The two phase system was extracted with 3×75 mL of ether and the combined ether layers were washed with 25 mL of H2O, 25 mL of brine, dried over MgSO4 and concentrated leaving 12.3 g (73.8%) of a white solid which was not purified, but directly resolved into individual enantiomers.