Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[C:21]1([S:27]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[CH:15]=[CH:16]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2cc(F)ccc21
Reaction time: 0.17 h
Yield: 74 %

Procedure:
KHMDS (0.5 M in toluene, 23 mL, 11.65 mmol) was added at 0° C. to a solution of 5-fluoroindole (1.5 g, 11.09 mmol) in DMF (23 mL). After stirring for 10 minutes, benzenesulfonyl chloride (1.55 mL, 12.209 mmol) was added. The ice-bath was removed and the mixture was stirred at room temperature for 4 hours. A saturated solution of NH4Cl was added to the reaction, and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine; dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was recrystallized from toluene to afford 2.26 g (74% yield) of 1-benzenesulfonyl-5-fluoro-1H-indole as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28]>>[F:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=2)[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)c(F)c2)OC1(C)C
Reactant: COC(=O)c1cncc(Br)c1
Product: COC(=O)c1cncc(-c2ccc(C(F)(F)F)c(F)c2)c1

Procedure:
According to General Method 1A, 18.2 g (approx. 62.81 mmol) of the compound from Example 80A and 5.4 g (25.1 mmol) of methyl 5-bromonicotinate were reacted. Yield: 7.0 g (36% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[O:13][C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:15][C:16](=[O:17])[C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.[C:31](Cl)(=[O:38])C1C=CN=CC=1>ClCCl>[O:21]1[CH2:22][CH2:23][N:18]([C:14]2[O:13][C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:31](=[O:38])[C:26]5[CH:27]=[CH:28][CH:29]=[N:24][CH:25]=5)=[CH:3][CH:4]=4)=[CH:9][S:10][C:11]=3[C:16](=[O:17])[CH:15]=2)[CH2:19][CH2:20]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1ccc(-c2csc3c(=O)cc(N4CCOCC4)oc23)cc1
Reactant: c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2csc3c(=O)cc(N4CCOCC4)oc23)cc1)c1cccnc1
Temperature: 0 °C

Procedure:
A 40 mL vial was charged with a magnetic stirring bar, 3-(4-aminophenyl)-5-morpholino-7H-thieno[3,2-b]pyran-7-one (56) (200 mg, 609 μmol) and pyridine (5 mL). The mixture was magnetically stirred and cooled to 0° C. in an ice bath. Isonicotinoyl chloride hydrochloric acid (669 μmol) was added and the reaction was stirred at room temperature for 30 minutes. The reaction was diluted with dichloromethane (15 mL) and washed three times with saturated aqueous sodium bicarbonate solution (15 mL). The dichloromethane layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give N-(4-(5-morpholino-7-oxo-7H-thieno[3,2-b]pyran-3-yl)phenyl)nicotinamide (30) (94 mg, 217 μmol) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)[CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:10]1=[O:22].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.OC1C2N=NNC=2C=CC=1.Cl.[F:63][C:64]([F:72])([F:71])[CH:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>C(Cl)Cl>[Cl:23][C:6]1[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:68]3[CH2:69][CH2:70][CH:65]([C:64]([F:72])([F:71])[F:63])[CH2:66][CH2:67]3)=[O:31])=[CH:26][CH:25]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:10]1=[O:22]
Reactant: CO[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1
Reactant: FC(F)(F)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CO[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Mix 3′,5′-dichloro-4′-[(R)-trans-1-(4-methoxy-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (0.350 g, 0.74 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.216 g, 1.11 mmol), N-methylmorpholine (0.33 mL, 2.95 mmol), hydroxybenzotriazole (0.247 g, 0.74 mmol) and 4-trifluoromethyl-piperidine hydrochloride (0.226 g, 1.47 mmol) in CH2Cl2 (10 mL). Stir for 12 hours at room temperature. Quench with 1N HCl and extract with ethyl acetate. Wash the extract with saturated aqueous sodium bicarbonate brine. Dry over magnesium sulfate, filter, and concentrate under vacuum. Purify by flash column chromatography to recover 0.350 g (78%) of the title compound: MS (m/z): 611 (M+).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH2:23]([O:30][N:31]1[C:37](=[O:38])[N:36]2[CH2:39][C@H:32]1[CH2:33][CH2:34][C@H:35]2[C:40]([NH:42][NH:43][CH:44]=O)=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([O:30][N:31]1[C:37](=[O:38])[N:36]2[CH2:39][C@H:32]1[CH2:33][CH2:34][C@H:35]2[C:40]1[S:10][CH:44]=[N:43][N:42]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=CNNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: O=C1N2C[C@@H](CC[C@H]2c2nncs2)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
Lawesson's reagent (2.40 g, 6.0 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-N′-formyl-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbohydrazide (1.6 g, 6.0 mmol) in THF (30 mL) at rt. The mixture was stirred at rt for 8 hrs., then the solvent was concentrated and the residue was purified by silica gel column chromatography (1:6 to 1:1 EtOAc/hexanes) to give (2S,5R)-6-(benzyloxy)-2-(1,3,4-thiadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (568 mg, 30%) as a yellow solid. ESI-MS (EI+, m/z): 317.1 [M+H]+. 1H-NMR (400 MHz, CDCl3): δ 9.12 (s, 1H), 7.38-7.29 (m, 5H), 5.02 (d, J=8.8 Hz, 1H), 4.89-4.83 (m, 2H), 3.28 (m, 1H), 2.86-2.83 (m, 1H), 2.70-2.54 (m, J=2H), 2.29-2.24 (m, 1H), 2.17-2.13 (m, 1H), 2.07-1.79 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][NH:6][C:7]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)[NH:11][N:10]=1)=[O:8])C.CO.O.O[Li].O>C1COCC1>[CH2:21]([O:20][C:16]1[CH:15]=[C:14]([C:12]2[NH:11][N:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:28])=[O:3])=[O:8])[CH:13]=2)[CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)CNC(=O)c1cc(-c2cccc(OCc3ccccc3)c2)[nH]n1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CNC(=O)c1cc(-c2cccc(OCc3ccccc3)c2)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92080.2 %

Procedure:
To a stirred solution of 5-(3-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid (1 g, 0.00340 mol) in DMF (5 mL) was added DIPEA (1.976 g, 0.01529 mol), HOBt (0.574 g, 0.00425 mol) and EDCI.HCl (0.814 g, 0.00425 mol) at ambient temperature. After 5 minutes glycine ethyl ester hydrochloride (0.498 g, 0.00357 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried. The crude product was recrystallized from ethyl acetate to afford 0.54 g (36%) of {[5-(3-benzyloxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid ethyl ester. LCMS: 380.15 (M+1)+, 92.05%. To a stirred solution of {[5-(3-benzyloxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid ethyl ester (0.54 g, 0.00136 mmol) in a mixture of THF (50 mL), methanol (25 mL) and H2O (25 mL) was added LiOH.H2O (0.18 g, 0.0042 mol) at ambient temperature. The resulting mixture was stirred at ambient temperature overnight. Volatiles were removed by evaporation and the resulting residue was diluted with water, acidified with concentrated HCl solution. The resulting precipitate was isolated by filtration and dried afford 0.44 g (92%) of {[5-(3-benzyloxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid. LCMS: 352.12 (M+1)+, 97.85%,
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[C:11]([C:12](=O)[CH3:13])=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C([O:22][C:23]([C:25]1[CH:48]=[CH:47][C:28]2[N:29]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[C:30]([C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([CH:39]=O)[CH:33]=3)=[N:31][C:27]=2[CH:26]=1)=[O:24])C.[OH-].[K+].Cl>C(O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[C:11]([C:12]3[CH:13]=[CH:39][C:34]4[C:35](=[CH:36][CH:37]=[C:32]([C:30]5[N:29]([CH:41]6[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]6)[C:28]6[CH:47]=[CH:48][C:25]([C:23]([OH:24])=[O:22])=[CH:26][C:27]=6[N:31]=5)[CH:33]=4)[N:38]=3)=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1-c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)c(C=O)c1)n2C1CCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc([N+](=O)[O-])ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
1-(4′-Chloro-4-nitro-biphen-2-yl)-ethanone (69 mg, 0.25 mmol) and 2-(4-amino-3-formyl-phenyl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester (98 mg, 0.25 mmol) were dissolved in 500 μL ethanol and 500 μL 10% ethanolic KOH were added. The reaction was stirred at 75° C. overnight. The reaction was acidified with 4N hydrochloric acid, extracted three times with ethyl acetate, the organic extracts were dried with sodium sulfate and then evaporated. Purification via reverse-phase HPLC gave 34 mg product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1.[CH2:20]([NH2:24])[CH2:21][CH2:22]C.O.[OH-].[Na+].[C:28](#N)C>>[CH3:22][CH2:21][CH:20]([NH:24][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1)[CH3:28]
Reactant: O=C(c1ccccc1)c1ccc(OCCCCl)cc1
Reactant: CC#N
Reactant: CCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)NCCCOc1ccc(C(=O)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
10 g (36 mmol) 4-(3-chloropropoxy)benzophenone was dissolved in 100 mL acetonitrile. 26.3 g (0.36 mol) n.-butyl amine was added and the mixture was heated to 70° C. for 30 hours. The solvent was evaporated under reduced pressure and the residue was treated with 500 mL water. The pH was adjusted to pH=1. The mixture was stirred for one hour at 40° C. The mixture was cooled to 10° C. and the precipitated compounds were isolated by filtration. The precipitate was treated with 200 mL water and the pH was adjusted to 12, using a 1 N NaOH-solution. The mixture was extracted with 200 mL methylene chloride. The organic fraction was dried over MgSO4 and evaporated under reduced pressure. The crude 4-[(3-butylamino)propoxy]benzophenone was purified by preparative column chromatography on a SVP D40 Merck-Np column, using a gradient elution from methylene chloride to methanol at a flow rate of 40 mL per minute. 4.4 g of 4-[(3-butylamino)propoxy]benzophenone was isolated.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:13]1)=[O:4].[OH-].[Na+]>>[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:13]1)([OH:4])=[O:2]
Reactant: COC(=O)CCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)n1
Yield: 78.9 %

Procedure:
2-(7-Methoxycarbonylheptyl)4,5-diphenyltriazole (1 g) was reacted with 2N sodium hydroxide in a method similar to Example 58. Recrystallisation from ethanol and water gave 2-(7-carboxyheptyl)-4,5-diphenyltriazole (0.76 g, 79%) as a white solid, m.p. 86°-88° C.
Reaction SMILES: [CH2:1](O)[C:2](N)(CO)CO.Cl.[C@@H:10]1([N:19]2[C:28]3[N:27]=[CH:26][N:25]=[C:23](N)[C:22]=3[N:21]=[CH:20]2)[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:11]1O.[OH2:29]>>[C:1]([C@:15]1([CH2:16][OH:17])[O:18][C@@H:10]([N:19]2[C:28]3[N:27]=[CH:26][N:25]=[C:23]([OH:29])[C:22]=3[N:21]=[CH:20]2)[CH2:11][C@@H:13]1[OH:14])#[CH:2]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NC(CO)(CO)CO
Reactant: O
Agent: Cl
Product: C#C[C@]1(CO)O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
To a Tris-HCl buffer solution (6 ml, pH 7.5) of Compound 23 (0.022 g, 0.08 mmol), adenosine deaminase (0.044 ml, 20 unit) was added, and the mixture was stirred for 2.5 hours at 40° C., followed by cooling to room temperature. The reaction mixture was applied to a reverse-phase ODS silica gel column (50 g), desalted by water (500 ml) flow, and through use of a 2.5% aqueous ethanol, Compound 29 was eluted. Subsequently, the Compound 29 was pulverized with isopropanol, to thereby yield 0.016 g of Compound 29 (72%).
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[OH:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:26][CH2:25][C:20]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C1COCC1.O1CCOCC1>O>[O:21]1[C:20]2([CH2:19][CH2:18][N:17]([C:14]3[CH:15]=[CH:16][C:11]([CH2:10][N:9]([OH:8])[C:6]([NH2:5])=[O:7])=[CH:12][CH:13]=3)[CH2:26][CH2:25]2)[O:24][CH2:23][CH2:22]1
Reactant: ONCc1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC(=O)N(O)Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.3 %

Procedure:
Trimethylsilyl isocyanate (2.1 mL, 14.85 mmol) was added dropwise into a mixture of 8-{4-[(hydroxyamino)methyl]phenyl}-1,4-dioxa-8-azaspiro[4.5]decane (2.61 g, 9.9 mmol) (which was obtained in Example 52), THF(20 mL) and dioxane (20 mL). The mixture was stirred at room temperature for 24 hours, poured into water and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/ethyl acetate/methyl alcohol 10/5/1) gave a white solid (2.2 g, 73% yield); mp 153–154° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.70 (m, 4H), 3.21 (m, 4H), 3.89 (s, 4H), 4.37 (s, 2H), 6.23 (brs, 2H), 6.86 (m, 2H), 7.10 (m, 2H), 9.19 (s, 1H); MS (ES) m/z: 308 (MH+); Anal. Calcd. for C15H21N3O4: C, 58.62; H, 6.89; N, 13.67. Found: C, 58.37; H, 6.78; N, 13.47
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.CS(C)=O.[CH2:17]([N:19]1[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[C:23](=[O:29])[N:22]([CH3:30])[C:21]2[CH:31]=[C:32]([CH2:35][N:36]([CH2:50][C:51]3[C:52]([CH2:57][OH:58])=[N:53][CH:54]=[CH:55][CH:56]=3)[CH2:37][CH2:38][N:39]3[CH:44]=[CH:43][C:42]4[O:45][C:46]([CH3:48])=[CH:47][C:41]=4[C:40]3=[O:49])[CH:33]=[CH:34][C:20]1=2)[CH3:18]>O>[CH2:17]([N:19]1[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[C:23](=[O:29])[N:22]([CH3:30])[C:21]2[CH:31]=[C:32]([CH2:35][N:36]([CH2:50][C:51]3[C:52]([CH:57]=[O:58])=[N:53][CH:54]=[CH:55][CH:56]=3)[CH2:37][CH2:38][N:39]3[CH:44]=[CH:43][C:42]4[O:45][C:46]([CH3:48])=[CH:47][C:41]=4[C:40]3=[O:49])[CH:33]=[CH:34][C:20]1=2)[CH3:18]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3cccnc3CO)ccc21
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3cccnc3C=O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
2-iodoxybenzoic acid (IBX, 0.235 g) was added to the dimethyl sulfoxide suspension (10 mL) of 1-ethyl-7-((N-((2-(hydroxymethyl)pyridin-3-yl)methyl)-N-(2-(2-methyl-4-oxofuro[3,2-c]pyridin-5(4H)-yl)ethyl)amino)methyl)-3,3,5-trimethyl-1H-benzo[b][1,4]diazepine-2,4(3H, 5H)-dione (0.48 g) and the mixture was stirred overnight at room temperature. Water was added to the resulting mixture and then the mixture was extracted with ethyl acetate twice. The combined organic layer was concentrated under reduced pressure, and then the residue was purified by column-chromatography (ethyl acetate:hexanes=50:50→100:0). The purified product was recrystallized from ether to afford the titled compound as ivory powder (0.29 g).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([N:14]3[CH2:18][C@@H:17]([CH2:19]CO)[O:16][C:15]3=[O:22])=[CH:9][C:8]=2[F:23])[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:43][C:44]1[NH:48][N:47]=[N:46][N:45]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl.C(OCC)(=O)C.CO>[S:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][N:46]4[N:47]=[N:48][C:44]([CH3:43])=[N:45]4)[O:16][C:15]3=[O:22])=[CH:9][C:8]=2[F:23])[CH2:3][CH2:2]1
Reactant: Cc1nnn[nH]1
Reactant: O=C1O[C@H](CCO)CN1c1cc(F)c(C2CCSCC2)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nnn(C[C@H]2CN(c3cc(F)c(C4CCSCC4)c(F)c3)C(=O)O2)n1
Yield: 52.1 %

Procedure:
(5R)-3-[4-(Tetrahydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-[(hydroxymethyl)methyl]oxazolidin-2-one (Intermediate 47) (0.66 g, 2 mmol), triphenylphosphine (0.786 g, 3 mmol), 5-methyl tetrazole (0.303 g, 3.6 mmol) and diisopropylazodicarboxylate (0.59 ml, 3 mmol) were reacted as described for Example 28. Chromatography on silica gel with 0.2-0.5% methanol in dichloromethane followed by 40% ethyl acetate in hexanes gave the title product (0.412 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([C:14]([OH:16])=[O:15])[CH2:3]1.[CH3:17][Si](C=[N+]=[N-])(C)C>CCCCCC>[CH3:17][O:15][C:14](=[O:16])[C@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][N:5]1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Solvent: CCCCCC
Product: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2 M (triimethylsilyl)diazomethane in hexane (4 mL) was added to a solution of cis-4-hydroxy-N-tert-butoxycarbonyl-D-proline (916 mg) at 0° C. After stirring at room temperature for 1 hr, a solution of 2 M (trimethylsilyl)diazomethane in hexane (6 mL) was added additionally and stirred at room temperature for 30 min. The solvents were evaporated in vacuo to afford the title compound (971 mg) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[C:11]#[CH:12]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:13][CH2:10][C:11]#[CH:12])=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCN
Reactant: O=C(O)c1ccc(Cl)s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C#CCNC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
2-Fluoro-4-iodoaniline (1.1, 6.50 g, 27.4 mmol) was dissolved in 25 mL TFA and stirred in ice bath. Solid NaNO2 (2.07 g, 30.1 mmol) was added in small portions. The resulting mixture was stirred for 30 min in ice bath. Sodium azide (1.87 g, 28.8 mmol) was dissolved in 10 mL water and chilled in ice bath. This cold solution was then added to the TFA solution in three portions. The mixture was stirred in ice bath for 1 hr and concentrated in vacuo to remove TFA. The residue was taken into 600 mL DCM and washed with water three times. The organic phase was dried using MgSO4 and concentrated in vacuo to afford 1-azido-2-fluoro-4-iodobenzene 1.2 as a brownish waxy solid in >99% yield. In the mean time, 5-chlorothiophene-2-carboxylic acid (1.3, 9.13 g, 56 mmol) was dissolved in 200 mL dry DCM along with 0.5 mL dry DMF. To the vigorously stirred solution was carefully added oxalyl chlororide (14.7 mL, 169 mmol) dropwise. The resulting solution was stirred for 3 hrs at RT and concentrated in vacuo. The residue was pumped to dryness and then dissolved in 300 mL dry DCM. To this solution was added propargylamine (5.8 mL, 84 mmol) dropwise. The mixture was stirred at RT overnight during which time solid precipitated out. 600 mL hexane was added and the mixture was vigorously stirred for a few hours. The solid was collected by filtration and washed with hexane to give 5-chloro-N-(prop-2-ynyl)thiophene-2-carboxamide 1.4 (9.47 g, 85%) which was used directly without further purification. MS found for C8H6ClNOS as (M+H)+ 200.0, 202.0 (chlorine pattern).
Reaction SMILES: [Fe:1](Cl)Cl.[C:4]([O-:23])(=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Na+].C(O)C.O>CCCCCC>[Fe:1].[C:4]([O-:23])(=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Cl[Fe]Cl
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Solvent: O
Product: [Fe]
Temperature: 70 °C
Reaction time: 4 h

Procedure:
As the first exemplary example for demonstrating the method of synthesizing monodisperse nanoparticles according to the present invention, 10.8 g of iron chloride [FeCl3.6H2O, 40 mmol] and 36.5 g of sodium oleate (120 mmol) were dissolved in a mixture of solvents containing 80 mL of ethanol, 60 mL of distilled water, and 140 mL of hexane, and thereafter the resulting mixture was heated to 70° C. and kept at the same temperature for 4 hours to obtain an iron-oleate complex. During this process, the initial scarlet color in aqueous phase became clear, and the initial transparent organic phase turned to scarlet, indicating that iron-oleate complex was successfully synthesized. When the reaction was completed, the upper organic layer containing the metal-oleate complex was separated and thereafter the hexane was evaporated off, resulting in a waxy solid form. In FIG. 1, the FT-IR spectrum of the resulting iron-oleate complex shows a C═O stretching peak at 1700 cm−1, which is a unique characteristics for a metal-oleate complex.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][CH2:14][NH:15]3)=[CH:11][C:10]=2[O:18][CH3:19])[CH2:3]1.C[Al](C)C.[C:24]([NH:27][C:28]1[N:33]=[C:32]([CH3:34])[C:31]([C:35]2[CH:44]=[CH:43][C:38]([C:39](OC)=[O:40])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>C1(C)C=CC=CC=1>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][CH2:14][N:15]3[C:39]([C:38]3[CH:37]=[CH:36][C:35]([C:31]4[CH:30]=[CH:29][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[N:33][C:32]=4[CH3:34])=[CH:44][CH:43]=3)=[O:40])=[CH:11][C:10]=2[O:18][CH3:19])[CH2:3]1
Reactant: COc1cc2c(cc1N1C[C@@H](C)N[C@@H](C)C1)NCC2
Reactant: COC(=O)c1ccc(-c2ccc(NC(C)=O)nc2C)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1C[C@@H](C)N[C@@H](C)C1)N(C(=O)c1ccc(-c3ccc(NC(C)=O)nc3C)cc1)CC2
Temperature: 90 °C
Yield: 45.4 %

Procedure:
A stirred solution of D3 (40 mg, 150 umole) in toluene (2 ml) at room temperature under argon was treated with 2M trimethylaluminium in toluene (0.15 ml, 300 umole) and maintained for 15 min, then a solution of D7 (57 mg, 200 umole) in toluene (3 ml) was added and the mixture heated at 90° C. for 1 h. The solution was allowed to cool, then added directly to a silica gel column (5 g) and eluted initially with 2% MeOH/DCM to remove high Rf impurities, then with 10% MeOH/DCM to afford the product. This was triturated with Et2O/DCM to afford the title compound as a beige solid (35 mg, 82%).