Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[Cl:32])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[O:33]([C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46]O)[CH2:42][CH2:41]1)=[O:39])[C:34]([CH3:37])([CH3:36])[CH3:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:34]([O:33][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][O:13][C:14]2[CH:15]=[C:16]([O:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=3[Cl:32])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH2:42][CH2:41]1)=[O:39])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
Diethyl azodicarboxylate (349 mg, 2.0 mmol) was added to a solution of 2,3-dichlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (644 mg, 2.0 mmol), as prepared in the preceding step, N-tert-butoxylcarbonyl-4-piperidinemethanol (430 mg, 2.0 mmol), as prepared in step (b) of Example 1, and triphenylphosphine (525 mg, 2.0 mmol) in tetrahydrofuran (20 mL) at 0° C. The mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with saturated NaHCO3 (2×50 mL), brine (2×50 mL) and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (1:3 ethyl acetate/hexane) to give the title compound as a colorless syrup (930 mg, 88%). 1H-NMR (300 MHz, CDCl3) δ 1.26 (m, 2H), 1.47 (s, 9H), 1.75 (m, 2H), 1.90 (m, 1H), 2.25 (s, 3H), 2.73 (t, 2H, J=2.0 Hz), 3.68 (d, 2H, J=3.2 Hz), 4.13 (m, 2H), 6.47 (d, 1H, J=1.1 Hz), 6.53 (d, 1H, J=0.4 Hz), 6.59 (s, 1H), 7.34 (t, 1H, J=8.2 Hz), 7.75 (m, 1H), and 7.92 (m, 1H).
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[C:1]1([C:7](=[N:14][C:15]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)([CH3:29])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1cncnc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(N=C(c1ccccc1)c1ccccc1)c1cncnc1
Reaction time: 0.5 h

Procedure:
To a solution of 456 mg of ethyl [(diphenylmethylene)amino](pyrimidin-5-yl)acetate in 4.5 ml of DMF was added 69 mg of sodium hydride (55% mineral oil included) under ice-cooling, followed by stirring for 30 minutes. To the reaction mixture was added 0.1 ml of methyl iodide, followed by stirring at room temperature for 1.5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 224 mg of ethyl 2-[(diphenylmethylene)amino]-2-(pyrimidin-5-yl)propanoate.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:13]1([C:19]2[N:20]([CH2:30][C:31](O)=[O:32])[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:13]1([C:19]2[N:20]([CH2:30][C:31]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[N:8]=[CH:9][CH:10]=[CH:11][N:12]=4)[CH2:2][CH2:3]3)=[O:32])[CH:21]=[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:23]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(O)Cn1cc(-c2ccccc2)nc1-c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(Cn1cc(-c2ccccc2)nc1-c1ccccc1)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
40 mg 2-piperazin-1-yl-pyrimidine was added to 70 mg (2,4-diphenyl-imidazol-1-yl)-acetic acid, 80 mg TBTU, 50 μL TEA in 1 mL DMF. The reaction was stirred overnight at RT. The mixture was purified by HPLC to give 50 mg desired product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (3.0 g, 21 mmol) in DMSO (30 mL) was added ethyl piperidine-4-carboxylate (5.0 g, 32 mmol) and K2CO3 (5.9 g, 43 mmol). The resulting mixture was stirred at 100° C. for 8 h, and allowed to cool to rt. EtOAc (300 mL) was added. The organic layer was washed with water (3×100 mL) and brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:2 v/v)). Compound 54a was obtained as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C14H18N2O4: 279.1 (M+H). Found 279.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:17]>CCOC(C)=O>[CH2:16]([O:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:13]([C:11]2[O:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH:23]=1)[CH3:17]
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: CCOC(=O)CCc1cccc(N)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cccc(NC(=O)c2ccc(-c3ccc(Cl)cc3)o2)c1

Procedure:
Carboxylic acid (145)(58 mg, 0.26 mmol) was coupled to aniline (124)(50 mg, 0.26 mmol) using Method C. During this reaction, partial hydrolysis occurred. The acid was re-dissolved in EtOAc (2 ml) and the organic layer was washed with 1M HCl (2×1 ml), dried (Na2SO4), filtered and the solvent removed in vacuo to give a mixture of acid and ester, which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:46])[C@H:10]([CH3:45])[NH:11][C:12](=[O:44])[C@H:13]([CH2:40][CH:41]([CH3:43])[CH3:42])[N:14]([C:16](=[O:39])[C@H:17]([CH:35]([CH2:37][F:38])[CH3:36])[NH:18][C:19](=[O:34])[C@H:20]([CH2:30][CH:31]([CH3:33])[CH3:32])[N:21](C(OC(C)(C)C)=O)[CH3:22])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:46])[C@H:10]([CH3:45])[NH:11][C:12](=[O:44])[C@H:13]([CH2:40][CH:41]([CH3:43])[CH3:42])[N:14]([C:16](=[O:39])[C@H:17]([CH:35]([CH2:37][F:38])[CH3:36])[NH:18][C:19](=[O:34])[C@H:20]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:21][CH3:22])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](C(=O)N[C@H](C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)CF)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)CF
Temperature: -15 °C
Reaction time: 16 h
Yield: 989 %

Procedure:
To a stirred solution of 650 mg (0.001 mole) of Boc-N-methyl-L-leucyl-4-fluoro-L-valyl-N-methyl-L-leucyl-L-alanine benzyl ester in 10 ml of dry methylene chloride and cooled at 10° C. was added 6.5 ml of trifluoroacetic acid, which was previously cooled at -15° C. The reaction was stirred for 16 hours, then carefully poured into a mixture of 7.7 g. of sodium bicarbonate, ice, and 75 ml of methylene chloride with stirring. The organic layer was extracted with 3×20 ml of saturated sodium bicarbonate solution, then dried over magnesium sulfate. The solvent was removed in vacuo leaving the product as a stiff oil, which weighed 540 mg. The yield is 989% of theory and the FAB m.s. showed a molecular ion peak at 551.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5](=[O:7])[CH3:6])=[O:2].O[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16].N1CCCC1>C1(C)C=CC=CC=1>[CH3:6][C:5]1([CH2:4][NH:3][CH:1]=[O:2])[CH2:16][C:15](=[O:17])[C:10]2[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7]1
Reactant: CC(=O)c1ccccc1O
Reactant: CC(=O)CNC=O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CC1(CNC=O)CC(=O)c2ccccc2O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
20.2 g (0.2 mol) of formylaminoacetone [A. Treibs u.a., Chem. Ber. 84 96 (1951)] and 27.2 g (0.2 mol) of o-hydroxyacetophenone are dissolved in 100 ml of toluene, and 10 ml of pyrrolidine are added. The mixture is stirred at 25° C. for 20 hours and then at 115° C. for 2 hours. After cooling, the mixture is extracted by shaking successively with 2N HCl, 2N NaOH and water, the organic phase is concentrated and the 2-methyl-2-formylaminomethylchroman-4-one formed is isolated by chromatography. Melting point: 96°-8° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14]Br)[CH2:7][OH:8])[CH3:2].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>CC(C)=O>[CH2:16]([NH:23][CH2:14][CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[O:3][CH2:1][CH3:2])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: CCOc1cc(CO)ccc1OCCBr
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOc1cc(CO)ccc1OCCNCc1ccccc1
Yield: 74.7 %

Procedure:
A mixture of 27.5 g of 3-ethoxy-4-(2-bromoethoxy)benzyl alcohol and 53.5 g of benzylamine was heated to 130°-135° C. for 1.5 hours with stirring. After cooling the reaction mixture, 300 ml of ethyl acetate was added therein and the mixture was washed twice each time with 50 ml of water, dried with anhydrous sodium sulfate and distilled under reduced pressure to provide an orange oily product. To the product was added 50 ml of acetone to form crystals, which were recovered by filtration under suction to provide 22.5 g of N-benzyl-2-(2-ethoxy-4-hydroxymethylphenoxy)ethylamine having a melting point of 164°-167° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].CO>C(OCC)C>[CH2:3]([O:6][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]#[CH:5]
Reactant: C#CCO
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: C#CCOCC(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.4 %

Procedure:
To an anhydrous solution containing 5.1 g of 55% oily sodium hydride in 120 ml of diethyl ether were added 24 ml of an anhydrous diethyl ether solution containing 5.6 g of propargyl alcohol. The mixture was stirred at room temperature for 1.5 hours, after which 20.9 g of ethyl bromoacetate were added dropwise. The mixture was allowed to stand overnight, after which the excess sodium hydride was decomposed with methanol. After separating off the precipitate produced, the filtrate was distilled to give 10 g of ethyl α-propargyloxyacetate, boiling at 52°-60° C./4-7 mmHg.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(OC(=O)[NH:16][CH:17]([CH3:31])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([OH:30])[C:26]=2[CH:28]=O)[CH:21]=[N:20]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:6][O:5][C:3]([C:2]1[O:30][C:25]2=[CH:24][CH:23]=[C:22]3[C:27]([N:19]([CH2:18][C@@H:17]([NH2:16])[CH3:31])[N:20]=[CH:21]3)=[C:26]2[CH:28]=1)=[O:4]
Reactant: COC(=O)CBr
Reactant: CC(Cn1ncc2ccc(O)c(C=O)c21)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc2c(ccc3cnn(C[C@H](C)N)c32)o1
Temperature: 90 °C

Procedure:
To a 50 mL round bottom flask containing NMP (20 mL), methyl bromoacetate (0.35 g 2.3 mmol), and [2-(7-formyl-6-hydroxy-indazol-1-yl)-1-methyl-ethyl]-carbamic acid benzyl ester (0.751 g, 2.1 mmol) was added K2CO3 (1.4 g, 10 mmol). This mixture was heated to 90° C. for 16 h, then allowed to cool to 23° C., decanted into a saturated aqueous NaHCO3 solution (50 mL), and extracted with ethyl acetate (2×20 mL). The combined extracts were dried (Na2SO4), filtered and concentrated. The crude product was purified by chromatography (silica gel, hexanes: ethyl acetate gradient, 3:1 to 1:1) to provide an oil: LC/MS m/z 408 [M+H]+; 1H NMR (D2O): δ 8.19 (s, 1H), 8.06 (s, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.43 (d, J=9.0 Hz, 1H), 7.30 (bm, 4H), 5.15 (d, 1H), 5.08 (dd, 2H), 4.8 (m, 1H), 4.6 (m, 1H), 4.29 (m, 1H), 4.01 (s, 3H), 1.19 (d, J=6.6 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15](O)[CH3:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:25])CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([F:25])[CH3:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(F)CN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.1 %

Procedure:
To a cold solution of [1-(2-hydroxy-propyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.70 g, 2.7 mmol) in DCM (30 mL) was added DAST (1.1 mL, 8.1 mmol) and the mixture was stirred at 25° C. for 20 h. The reaction mixture was washed with saturated sodium bicarbonate solution, water, brine, dried over Na2SO4 and concentrated under reduced pressure to afford [1-(2-fluoro-propyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.5 g, 70%). LCMS (Method G; ESI): RT=0.53 min; m+1=261.3. This was used without further purification below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][NH:6][C:7]([C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][NH:6][C:7]([C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[S:27]
Reactant: CCOC(=O)CNc1ccccc1C(=O)NCc1ccc(Cl)c(Cl)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Product: CCOC(=O)CNc1ccccc1C(=S)NCc1ccc(Cl)c(Cl)c1
Yield: 80.8 %

Procedure:
A mixture of ethyl 2-[2-{N-(3,4-dichlorobenzyl)-carbamoyl}anilino]acetate (16.3 g), phosphorus pentasulfide (19.0 g) and 1,4-dioxane (320 ml) was refluxed for 1 hour. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel (300 g) eluting with chloroform to give ethyl 2-[2-{N-(3,4-dichlorobenzyl)thiocarbamoyl}anilino]-acetate (13.72 g).
Reaction SMILES: C([O:5][C@@H:6]1[C@:14]2([CH2:15][CH3:16])[C@H:9]([C@@H:10]3[CH2:24][CH2:23][C:22]4[CH:21]=[C:20]([O:25][CH3:26])[CH:19]=[CH:18][C:17]=4[C@H:11]3[CH2:12][CH2:13]2)[CH2:8][CH2:7]1)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[OH:5][C@@H:6]1[C@:14]2([CH2:15][CH3:16])[C@H:9]([C@@H:10]3[CH2:24][CH2:23][C:22]4[CH:21]=[C:20]([O:25][CH3:26])[CH:19]=[CH:18][C:17]=4[C@H:11]3[CH2:12][CH2:13]2)[CH2:8][CH2:7]1
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Yield: 103.4 %

Procedure:
A solution of 0.4 g (1.12 mmoles) of (+)-17β-tert.butoxy- 13β-ethyl-3-methoxygona-1,3,5(10)-triene and 0.1 g of p-toluenesulfonic acid monohydrate in 10 ml of toluene was stirred and heated at reflux for 1 hr. The resulting solution was cooled and treated with saturated aqueous sodium bicarbonate solution then extracted twice with ether. The combined organic extracts were dried, filtered and concentrated in vacuo giving 0.348 g of (+)-17β-hydroxy-13β-ethyl-3-methoxygona-1,3,5(10)-triene as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[O:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:22][CH:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[O:10][C:9]([CH2:11][N:19]3[CH2:22][CH:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:20]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CN(C2CNC2)CCO1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Clc1nc(N2CCOCC2)c2oc(CN3CC(N4CCOCC4)C3)cc2n1
Reaction time: 6 h
Yield: 80.9 %

Procedure:
A solution of 2-chloro-4-morpholin-4-ylfuro[3,2-d]pyrimidine-6-carbaldehyde (300 mg, 1.12 mmol) and 4-azetidin-3-yl-morpholine (191 mg, 1.34 mmol) in DCE (12 mL) was stirred at ambient temperature for 1 h. Sodium triacetoxyborohydride (358 mg, 1.69 mmol) was added and the mixture stirred for 6 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; gradient from 100:0 to 90:10) to afford the title compound as a tan solid (357 mg, 81%). LCMS (Method H): RT=2.26 min, M+H+=394
Reaction SMILES: O1CCCC1.[F:6][C:7]([F:17])=[C:8]([CH3:16])[CH2:9][CH2:10][CH2:11][C:12](OC)=[O:13].[BH4-].[Na+].CO>O>[F:6][C:7]([F:17])=[C:8]([CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: COC(=O)CCCC(C)=C(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(CCCCO)=C(F)F
Temperature: 25 °C
Yield: 81 %

Procedure:
To 110 ml of tetrahydrofuran, 53 g (0.30 mol) of methyl 6,6-difluoro-5-methyl-5-hexenoate was dissolved, followed by adding 23 g (0.61 mmol) of sodium borohydride, heating the mixture under refluxing and slowly drop-wisely adding 50 ml of methanol. After the end of the drop-wise addition, the reaction liquid was stirred under refluxing for 1 hour, followed by cooling to room temperature, adding water and extracting with diethyl ether. The organic layer was washed with water, dilute hydrochloric acid and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate, and concentrating under reduced pressure to obtain 36.5 g (yield: 82%) of 6,6-difluoro-5-methyl-5-hexenol.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([C:11]2[CH:16]=CC=C[CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([C:21]1[CH:26]=[C:25](C)[CH:24]=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:22]=1O)(C)(C)C.[N+]([CH3:36])([O-])=O>>[C:11]([C:5]1[CH:6]=[CH:7][C:8]([C:26]2[CH:21]=[CH:22][C:23]([C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:24][CH:25]=2)=[CH:9][CH:10]=1)([CH3:12])([CH3:16])[CH3:36]
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: C[N+](=O)[O-]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Into a 250 ml 3-neck round bottom flask equipped with a mechanical stirrer, thermometer, and inlet was charged, with agitation, 40 mL of nitromethane to which was added portionwise 20.7 grams (156 mmol, 1.69 eq) of aluminum chloride with agitation and cooling so as not to exceed 40° C. This solution was added to a mixture of 14.2 grams (92.1 mmol, 1.0 eq) of biphenyl and 26.5 grams (120 mmol, 1.3 eq) of 2,6-di-t-butyl-4-methylphenol in 40 mL of nitromethane at 15° C. over a period of 5 to 10 minutes. The mixture turned a dark opaque color and near the end of the addition, the mixture became very thick. The reaction mixture was allowed to stir for 30 minutes and then poured into ice-water. The mixture was extracted with ether twice and the ether layer was concentrated in vacuo. Additional ether was added to the solid and the mixture was concentrated in vacuo. Toluene was added to the solid and the mixture was concentrated in vacuo. This treatment was to insure removal of nitromethane before washing with base. The brown solid residue was dissolved in ether and washed with approximately 300 mL of 1M sodium hydroxide until the aqueous layer was no longer deeply colored. The organic layer was washed with water and concentrated in vacuo. The brown residue was recrystallized from approximately 150 mL of ethanol to give 10 grams (41% yield). Melting point=129°-130° C.
Reaction SMILES: [CH3:1][N:2]([S:23]([CH3:26])(=[O:25])=[O:24])[C:3]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[CH:9][C:4]=1[C:5]([O:7]C)=O.[H-].[Na+].CO>CN(C=O)C>[CH3:1][N:2]1[C:3]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:9][C:4]=2[C:5](=[O:7])[CH2:26][S:23]1(=[O:25])=[O:24]
Reactant: COC(=O)c1cc(C#CCOC2CCCCO2)ccc1N(C)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN1c2ccc(C#CCOC3CCCCO3)cc2C(=O)CS1(=O)=O
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a solution of methyl 2-(methyl(methylsulfonyl)amino)-5-(3-(tetrahydro-2H-pyran -2-yloxy)-1-propynyl)benzoate (Preparation 51, 0.93 g) in DMF (15 mL) at 0° C. is added NaH (0.20 g; 60% dispersion in mineral oil) portionwise. The reaction mixture is warmed to ambient temperature stirring for 1 h upon which methanol (4 mL) is added and the organic portion is washed with a saturated solution of citric acid (50 mL). The aqueous layer is extracted with Et2O (2×50 mL). The organic layer is separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude orange liquid is purified by silica gel column chromatography (2/1, hexanes/EtOAc) to afford 0.59g (69%) of the title compound as a white solid. Physical characteristics: m.p. 107-108° C.; 1H NMR (300 MHz, CDCl3) δ 8.21, 7.71, 7.10, 4.87, 4.48, 4.33, 3.88, 3.55, 3.44, 1.79, 1.62; IR (diffuse reflectance) 2962, 2908, 1684, 1493, 1339, 1211, 1204, 1156, 1135, 1130, 1123, 1030, 899, 886, 838 cm−1; MS (ESI−) 348 (M−H−). Anal. Found: C, 58.37; H, 5.58; N, 3.96.
Reaction SMILES: C1(OC)C=CC=CC=1.C1(C([O:22][C:23]([C:25]2[N:30]3[C:31](=[O:44])[C@@H:32]([NH:33][C:34](=[O:43])[CH2:35][O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@H:29]3[S:28][CH2:27][C:26]=2[O:45][CH3:46])=[O:24])C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[O:36]([CH2:35][C:34]([NH:33][C@@H:32]1[C:31](=[O:44])[N:30]2[C:25]([C:23]([OH:24])=[O:22])=[C:26]([O:45][CH3:46])[CH2:27][S:28][C@H:29]12)=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.87 ml of anisole is added to a solution of 2.0 g (3.78mmols) of 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester in 5 ml of methylene chloride and the mixture is cooled to 0° C. and, after adding 1.2 ml of trifluoroacetic acid, left to stand for 1 hour. The reaction mixture is concentrated in vacuo and the residue is crystallised from acetone/ether. 7β-Phenoxyacetamido-3-methoxy-ceph-3em-4-carboxylic acid of melting point 170° C. (decomposition) is obtained.