Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[C:17]([F:23])[CH:16]=2)[O:3]1.ClC1C=C(C=CC=1)C(OO)=[O:30].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1([CH3:24])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:22])=[O:30])=[C:17]([F:23])[CH:16]=2)[O:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(C2=C(c3cccc(F)c3)C(=O)C(C)(C)O2)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc(C2=C(c3cccc(F)c3)C(=O)C(C)(C)O2)cc1F
Yield: 95.6 %

Procedure:
To a stirred solution of (2,2-dimethyl)-5-{3-fluoro-4-(methylthio)phenyl}-4-(3-fluorophenyl)-3(2H)-furanone (1.6 g) in 50 ml dichloromethane, which was prepared by a procedure similar to the procedure employed for Example 264, 1.25 g of m-chloroperoxybenzoic acid at 0° C. The reaction solution was stirred for one and half hours at the temperature, after which 30 ml 5% aqueous sodium bicarbonate was added and the solution was stirred for another 10 minutes. Then the reaction mixture was concentrated in vacuo, and the resulting residue was extracted with 50 ml water and dichloromethane (30 ml×3). The organic layer was concentrated in vacuo and was purified by column chromatography (hexane/ethylacetate=1:1) to give 1.6 g of 2,2-dimethyl-5-{3-fluoro-4-(methylsulfinyl)phenyl}-4-(3-fluorophenyl)-3(2H)-furanone as a solid. mp: 148-149° C. NMR: δ1.58 (s, 6H), 2.87 (s, 3H), 7.06 (m, 3H), 7.36(m, 1H), 7.42 (dd, J=10.5, 1.8 Hz, 1H), 7.66 (dd, J=8.4, 1.8 Hz, 1H), 7.87 (dd, J=8.1. 6.9 Hz, 1H). IR (cm−1): 1700, 1623, 1420, 1261, 1216, 1192, 1135, 1077.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C@H:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(C1CCCCC1=O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>[Cu]Cl.O.CN1CCCC1=O>[N:22]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([NH:12][C@H:13]2[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][CH2:14]2)[CH:6]=[CH:5]3)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: Brc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: c1c[nH]cn1
Agent: Cl[Cu]
Agent: CC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: c1ccc2c(c1)CC[C@H]2Nc1ccc2cc(-n3ccnc3)ccc2n1
Temperature: 130 °C
Yield: 57 %

Procedure:
A mixture of (6-bromo-quinolin-2-yl)-(R)-indan-1-yl-amine (see example 53, step A) (339 mg, 1.0 mmol), commercially available imidazole (136 mg, 2.0 mmol), copper(I)chloride (10 mg, 0.1 mmol), 2-acetyl-cyclohexanone (35 mg, 0.25 mmol), potassium carbonate (145 mg, 1.05 mmol) and 1-methyl-2-pyrrolidone (1 ml) was heated in a sealed tube at 130° C. for 18 h. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with saturated sodium bi-carbonate solution (2×20 ml) and brine (20 ml), dried (MgSO4) and evaporated. Further purification of the crude product by flash chromatography on silica gel (ethyl acetate/heptane) yielded the title compound (186 mg, 57%) as off-white foam.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:10]=[O:11].[CH:12](OC(=O)C)=[O:13]>C1COCC1>[CH:10]([N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)[CH:12]=[O:13])=[O:11]
Reactant: O=CNc1ccccn1
Reactant: CC(=O)OC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CN(C=O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (10.8 g, 60 wt %, 0.27 mol) in 50 mL of THF was added dropwise a solution of N-(pyridine-2-yl)formamide (22.4 g, 0.18 mol) in 250 mL of THF. When the addition was complete, the reaction was stirred at room temperature for 30 minutes and then cooled in an ice/salt bath. The acetic formic anhydride ethereal solution from the previous step was added in one portion. The resulting mixture was stirred in the ice bath for 30 minutes and then overnight at room temperature. The mixture was poured into 1 L of ice/water and extracted with 3×250 mL of CH2Cl2. The combined organic extracts were washed with 2×250 mL of H2O, dried and evaporated to give 33.2 g of solid. The crude product was column chromatographed (silica gel) eluting with 100% CH2Cl2 followed by 90:10 CH2Cl2:EtOAc. 14.2 g of product was isolated as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH2:19]([NH2:23])[CH:20]([CH3:22])[CH3:21]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CC(C)CN
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCC(C)C

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (300 mg, 1.13 mmol) was treated with isobutylamine following general procedure B to afford 4-isobutylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (280 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (180 mg) following general procedure E. The above ethylamide (0.6 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-1-isobutyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (22 mg). LCMS: m/z 328 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[C:4]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C@H:24]3[C:33]4[C:28](=[C:29]([F:34])[CH:30]=[CH:31][CH:32]=4)[O:27][CH2:26][CH2:25]3)[C:20]([N+:35]([O-:37])=[O:36])=[CH:19][N:18]=2)[CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][C@H:24]2[C:33]3[C:28](=[C:29]([F:34])[CH:30]=[CH:31][CH:32]=3)[O:27][CH2:26][CH2:25]2)[C:20]([N+:35]([O-:37])=[O:36])=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@@H]2CCOc3c(F)cccc32)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@@H]2CCOc3c(F)cccc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A freshly prepared solution of 30% TFA/DCM (100 mL) was added to (R)-tert-butyl 4-fluoro-2-(4-(8-fluorochroman-4-ylamino)-5-nitropyrimidin-2-ylamino)phenylcarbamate and the solution was stirred at room temperature for 60 min. The solvents were removed in vacuo to yield (R)—N2-(2-amino-5-fluorophenyl)-N4-(8-fluorochroman-4-yl)-5-nitropyrimidine-2,4-diamine that was carried on without further purification. MH+=415.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:4][N:3]=1.ON1C2C=CC=CC=2N=N1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:11])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)Cc1ccnc(Cl)c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccnc(Cl)c1)N1CCOCC1

Procedure:
A solution of (2-chloropyridin-4-yl)acetic acid (300 mg), 1-hydroxybenzotriazole (284 mg), triethylamine (0.487 mL), morpholine (0.183 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (469 mg) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 18 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (239 mg).
Reaction SMILES: [CH2:1]([CH:5]([C:8](=O)[CH3:9])[CH:6]=O)[CH2:2][CH2:3][CH3:4].[Na].[C:12]([CH2:14][C:15]([NH2:17])=[O:16])#[N:13].C([O-])(=O)C.C(O)(=O)C>O>[C:12]([C:14]1[C:15](=[O:16])[NH:17][C:8]([CH3:9])=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=1)#[N:13]
Reactant: CCCCC(C=O)C(C)=O
Reactant: N#CCC(N)=O
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.6 %

Procedure:
According to the method described in J. Heterocyclic Chem., 24, 351 (1987), a mixture of crude sodium 2-butyl-3-oxobutanal (7.39 g), cyanoacetamide (4.15 g, 39 mmol), aqueous piperidinum acetate (3.5 mL) [prepared from glacial acetic acid (0.85 ml), water (2.0 mL) and piperidine (1.45 ml)] in water (32 mL) was refluxed for 3 hours. Acetic acid (2.5 mL) was cautiously added. After cooling to room temperature and stirring overnight, the precipitated solids were collected by filtration. These residues (2.87 g) was chromatographed on silica gel by gradient elution with 1-3% methanol/ethyl acetate. The appropriate fractions were combined and evaporated. Crystallization from methanol gave 1.01 g of pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)([CH2:12][CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(C(C)=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)([CH2:12][CH3:13])[C:9]([O:11][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCC(Cn1cncn1)(C(=O)O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC(Cn1cncn1)(C(=O)OCc1ccccc1)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a 300 mL flask stirring under nitrogen was charged 4.19 g (0.015 mole) of 2-(4-chlorophenyl)-2-[(1,2,4-triazol-1-yl)methyl]-butanoic acid in 75 mL of methyl ethyl ketone. To the slurry was added 2.83 g (0.0157 mole) of potassium carbonate and the mixture was heated to reflux. After 30 minutes, 2.56 g (0.01575 mole) of benzyl bromide was added and the mixture was stirred at reflux for 2 hours then at 50° C. for 12 hours. After monitoring by GLC showed the consumption of starting material, the reaction was quenched by adding 20 mL of saturated sodium bicarbonate and 100 mL of ether. The phases were separated and the ether phase was washed with saturated sodium bicarbonate (2×50 mL) then with 50 mL of brine, dried and concentrated, giving 4.26 g (77% yield) of a thick oil, Example 177 of Table 1.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]2[C@@H:18]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=3)[C:19](=[O:34])[N:20]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C@@H:21]([CH3:22])[CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[C:48](Cl)(=[O:54])[CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].C(N(CC)CC)C>C(OCC)(=O)C>[C:48]([O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C@@H:18]2[N:13]3[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:12]3[C@H:21]([CH3:22])[N:20]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:19]2=[O:34])=[CH:37][CH:38]=1)(=[O:54])[CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: C[C@H]1C2N(C(=O)NCc3ccccc3)CCC(=O)N2[C@@H](Cc2ccc(O)cc2)C(=O)N1Cc1cccc2ccccc12
Reactant: CCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCC(=O)Oc1ccc(C[C@H]2C(=O)N(Cc3cccc4ccccc34)[C@@H](C)C3N(C(=O)NCc4ccccc4)CCC(=O)N32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a solution of (6S,9S)—N-benzyl-6-(4-hydroxybenzyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxamide 60 mg (0.106 mmol) in dry-THF (2 ml), hexanoyl chloride 44 μl (0.319 mmol) and then triethylamine 45 μl (0.319 mmol) were added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml), saturated sodium bicarbonate (10 ml), water (10 ml), and brine (10 ml). The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by Büchi silica gel column chromatography (chloroform:methanol=99:1 to 98:2) to obtain title compound 46.6 mg (66%).
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@@H:32]([CH2:37][CH3:38])[C:33]([CH3:36])([OH:35])[CH3:34]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@@H:32]([CH2:37][CH3:38])[C:33]([CH3:36])([OH:35])[CH3:34])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CC[C@H](N)C(C)(C)O
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@H](Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)C(C)(C)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (1.25 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.25 mL, 14.4 eq, 1.44 mmol) followed by (3S)-3-amino-2-methyl-pentan-2-ol (40 mg, 3.2 eq, 34 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 6.5 mg (16%). 1H-NMR (d-CDCl3, 250 MHz): 1.00 (t, 3H, J=7.42 Hz, —NHCH(CH2CH3)C(CH3)2OH), 1.22 & 1.31 (2×s, 6H, —NHCH(CH2CH3)C(CH3)2OH), 1.57 (d, 6H, J=6.79 Hz, —CH(CH3)2), 1.70-1.90 (m, 2H, —NHCH(CH2CH3)C(CH3)2OH), 3.66-3.81 (m, 1H, —NHCH(CH2CH3)C(CH3)2OH), 4.56-4.73 (m, 1H, —CH(CH3)2), 4.78-5.01 (m, 2H, —HNCH2-Pyr), 7.20-7.45 (m, 3H, 2×Pyr-H & —N═CH—N—), 7.48-7.69 (m, 1H, Pyr-H), 7.77 (d, 1H, J=7.74 Hz, Pyr-H). FABMS m/z (relative intensity): 384 ([M+H]+, 100), 366 (30), 324 (85), 286 (40), 242 (65), 192 (63), 176 (70). Accurate Mass (M+H): Actual: 384.2512, Measured: 384.2494.
Reaction SMILES: [Na].[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=O)/[CH:8]=[C:9](/[O:12][CH:13]([CH3:15])[CH3:14])\SC.[C:17]([CH2:19][C:20]([NH2:22])=[O:21])#[N:18]>C(O)(C)C>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[NH:22][C:20](=[O:21])[C:19]([C:17]#[N:18])=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:8]=1
Reactant: CS/C(=C\C(=O)c1ccco1)OC(C)C
Reactant: N#CCC(N)=O
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)Oc1cc(-c2ccco2)[nH]c(=O)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
Sodium (309 mg, 13.4 mmol) was dissolved in isopropanol (46 mL). Then, (Z)-1-(2-furyl)-3-isopropoxy-3-(methylsulfanyl)-2-propen-1-one (3.03 g, 13.4 mmol) and 2-cyanoacetamide (1.13 g, 13.4 mmol) were added thereto, followed by stirring overnight at room temperature. Ice-water was added to the reaction solution, and then the solid was collected by filtration, and washed with water and diethyl ether, to give the title compound (2.3 g, 70%).
Reaction SMILES: [C:1]([N:9]1[C:14](=[O:15])[C:13]([CH3:16])=[CH:12][N:11]([C@H:17]2[CH2:21][CH2:20][C@H:19]([O:22][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[C@H:18]2[CH2:40][O:41]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:10]1=[O:61])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.O>[C:1]([N:9]1[C:14](=[O:15])[C:13]([CH3:16])=[CH:12][N:11]([C@H:17]2[CH2:21][CH2:20][C@H:19]([OH:22])[C@H:18]2[CH2:40][OH:41])[C:10]1=[O:61])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn([C@H]2CC[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)n(C(=O)c2ccccc2)c1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cn([C@H]2CC[C@H](O)[C@H]2CO)c(=O)n(C(=O)c2ccccc2)c1=O
Reaction time: 1 h
Yield: 73.9 %

Procedure:
Compound 56 (0.45 g, 0.55 mmol) was dissolved in mixture of TFA (15 ml) and water (5 ml). The solution was stirred under argon for 1 h, then concentrated, co-evaporated 2 times with water to remove residual TFA and chromatographed on silica eluting with a gradient (5-7%) of MeOH in dichloromethane to yield nucleoside 57 (0.140 g, 75% yield) as a white solid. 1H NMR (DMSO-d6): δ7.95-7.92 (m, 2H), 7.80-7.74 (m, 2H), 7.57 (t, J=7.7 Hz, 2H), 4.96-4.86 (m, 1H), 4.81 (d, J=5.1 Hz, 1H), 4.62 (t, J=4.0, 1H), 3.95-3.88 (m, 1H), 3.50-3.45 (m, 1H), 3.35-3.25 (m, 1H), 2.12-1.98 (m, 4H), 1.86 (s, 3H), 1.48-1.38 (m, 1H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3]([CH:9]=O)=[CH:2]2.[ClH:11].[NH2:12][OH:13]>CO.C(O)(C)C>[ClH:11].[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3]([CH:9]=[N:12][OH:13])=[CH:2]2
Reactant: O=CC1=CN2CCC1CC2
Reactant: NO
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: ON=CC1=CN2CCC1CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
1-Azabicyclo[2.2.2]oct-2-ene-3-carboxaldehyde (1 g, 7.29 mmol) was dissolved in 50 ml of methanol. Hydroxylamine hydrochloride was added to the solution and the reaction was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo to afford a white crystalline residue. The crystalline residue was suspended in 50 ml of isopropanol and refluxed for 15 minutes A crystalline material separated to afford the desired oxime (1.08 g, 75%), mp 227°-229° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][C@@H:4]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20](C(OC(C)(C)C)=O)[CH:21]=[C:22]([C:23]([O:25]C)=[O:24])[C:15]=12)[C:5](=[O:11])[N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>CO>[CH3:1][CH:2]([CH3:34])[CH2:3][C@@H:4]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[NH:20][CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:15]=12)[C:5](=[O:11])[N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@H](CC(C)C)C(=O)N3CCCC3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@@H](NCc1ccnc2[nH]cc(C(=O)O)c12)C(=O)N1CCCC1

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-1-tert-butyl 3-methyl 4-((4-methyl-1-oxo-1-(pyrrolidin-1-yl)pentan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (160 mg, 0.339 mmol) under nitrogen. Aqueous NaOH (12N, 2 mL) and MeOH (1 mL) were added and the solution was stirred at 53° C. for 48 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-90%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:24][C:25]([F:28])([F:27])[F:26])=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)[CH2:35][CH2:34]1)(=[O:32])=[O:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:22])[NH:46][C:43]3[CH:44]=[CH:45][C:40]([CH2:39][N:36]4[CH2:35][CH2:34][N:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:38][CH2:37]4)=[CH:41][CH:42]=3)=[CH:17][CH:16]=2)[C:12]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)O)cc2)c1
Reactant: CS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(S(C)(=O)=O)CC4)cc3)cc2)c1
Reaction time: 16 h

Procedure:
A mixture of 5′-tert-butoxycarbonylamino-2′-trifluoromethoxy-biphenyl-4-carboxylic acid (50 mg), 4-(4-methanesulfonyl-piperazin-1-ylmethyl)-phenylamine (35.2 mg), HBTU (49.6 mg) and N-Methylmorpholine (30 ul) in dry DMF (3 ml) was stirred for 16 hrs.
Reaction SMILES: [Na:1].[S:2]([O:6][N:7]1[C:13](=[O:14])[N:12]2[CH2:15][C@H:8]1[CH2:9][CH2:10][C@H:11]2[CH2:16][NH:17]C(OC(C)(C)C)=O)([OH:5])(=[O:4])=[O:3].FC(F)(F)C(O)=O>ClCCl>[Na:1].[S:2]([O:6][N:7]1[C:13](=[O:14])[N:12]2[CH2:15][C@H:8]1[CH2:9][CH2:10][C@H:11]2[CH2:16][NH2:17])([OH:5])(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Agent: [Na]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
The sodium salt of (2S, 5R)-6-sulfooxy-2-(tert-butoxycarbonylaminomethyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane (2.4 g, 0.006 moles) was suspended in dichloromethane (6 ml) and to the reaction mixture was slowly added trifluoroacetic acid (6 ml) at about 0-5° C. The reaction mixture was stirred between about 0-5° C. for additional 2 hours. The solvent and excess trifluoroacetic acid was evaporated under vacuum below 40° C. to approximately ⅓ of its original volume to provide pale yellow oily residue. This oily residue was triturated with diethyl ether and ether was decanted (40 ml×2). The crude solid was again triturated with dichloromethane (40 ml×2) and solvents were decanted. The final solid was dried under vacuum below 40° C. to furnish 2.2 g of sodium and trifluoroacetic acid salt of (2S, 5R)-6-sulfooxy-2-(aminomethyl)-7-oxo-1,6-diaza-bicyclo [3.2.1]octane (X) (90% yield).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17](=[O:31])[N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]=1[CH3:32])(C)(C)C.[OH-].[Li+]>O.CO.O1CCCC1>[C:25]1([N:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:17]([O:16][CH2:15][C:11]2[C:10]([CH3:32])=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][C:6]([OH:33])=[O:5])=[O:31])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1c(COC(=O)N(c2ccccc2)c2ccccc2)cccc1OCC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(COC(=O)N(c2ccccc2)c2ccccc2)cccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
{3-[(Diphenylcarbamoyloxy)methyl]-2-methylphenoxy}acetic acid tert-butyl ester (104.1 g, 233 mmol) and lithium hydroxide (10.3 g, 245 mmol) were dissolved in a mixture of water (100 mL), methanol (300 mL), and tetrahydrofuran (300 mL). The mixture became solid, but reliquefied upon heating at reflux temperature. The clear solution was stirred at room temperature for about 16 hours, and evaporated in vacuo. The residue was poured into dilute hydrochloric acid and extracted with dichloromethane. Evaporation of the solvent and recrystallization of the residue from hexane/acetone gave {3-[(diphenylcarbamoyloxy)methyl]-2-methylphenoxy}acetic acid as off-white granules (87.0 g, 95%); m.p. 180.1-180.7° C. Analysis for C23H21NO5: Calcd.: C, 70.58; H, 5.41; N, 3.58. Found: C, 70.51; H, 5.37; N, 3.76.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][C@@H:5]1[CH3:10])(=[O:3])[CH3:2].Cl.[N:12]([O-])=[O:13].[Na+].[OH-].[Na+]>O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([N:12]=[O:13])[CH2:6][C@@H:5]1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNC[C@@H]1C
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N1CCN(N=O)C[C@@H]1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
To a slurry of (S)-1-acetyl-2-methylpiperazine (424 mg) in water (2.5 ml) was added concentrated hydrochloric acid (0.9 ml) dropwise below 25° C. A solution of sodium nitrite (227 mg) in water (2 ml) was added dropwise at 0° C. The mixture was stirred at 0° C. for 2 hours. A solution of sodium hydroxide (409 mg) in water (6 ml) was added dropwise at 0° C. The mixture was extracted with chloroform, washed with water, dried and evaporated to give (S)-1-acetyl-2-methyl-4-nitrosopiperazine (350 mg). This product was used for next step without purification.