Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:25][C:26]2[N:31]=[C:30]([C:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]([CH3:41])[CH:33]=3)[CH:29]=[CH:28][N:27]=2)=[CH:5][C:6]([N+:22]([O-])=O)=[C:7]([N:9]([CH3:21])[CH2:10][CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[NH2:22][C:6]1[CH:5]=[C:4]([NH:25][C:26]2[N:31]=[C:30]([C:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]([CH3:41])[CH:33]=3)[CH:29]=[CH:28][N:27]=2)[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:9]([CH3:21])[CH2:10][CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17]
Reactant: COc1cc(N(C)CCN(C)C(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N(C)CCN(C)C(=O)OC(C)(C)C)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 100 °C
Yield: 94 %

Procedure:
tert-Butyl N-[2-[[5-methoxy-4-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]-2-nitrophenyl]-methylamino]ethyl]-N-methylcarbamate (Intermediate 172, 428 mg, 0.76 mmol), iron (255 mg, 4.57 mmol) and NH4Cl (30.6 mg, 0.57 mmol) were heated in ethanol (16 mL) and water (5.33 mL) at reflux for 1.5 h (heating block at 100° C.) and then the mixture was cooled and concentrated in vacuo. The resulting residue was triturated in 10% CH3OH/CH2Cl2 (30 mL) and filtered. The residues were triturated again with 10% CH3OH/CH2Cl2 (30 mL) and filtered. The combined filtrates were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% CH3OH in CH2Cl2 gave the title compound (380 mg, 94%) as a light brown foam; 1H NMR: 1.41 (9H, s), 2.64 (3H, s), 2.80 (3H, s), 2.95 (2H, t), 3.34 (2H, t), 3.77 (3H, s), 3.89 (3H, s), 4.40 (2H, s), 6.78 (1H, s), 7.14-7.20 (2H, m), 7.23-7.27 (1H, m), 7.52 (1H, d), 7.55 (1H, s), 7.75 (1H, s), 8.28 (1H, d), 8.29 (1H, s), 8.42 (1H, d); m/z: ES+ MH+ 532.37.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.CO[CH:14](OC)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.[OH:25][CH2:26][CH2:27][C@H:28]([OH:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(OCC)(=O)C>CN(C)C=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:14]2[O:40][C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:27][CH2:26][O:25]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(C(OC)OC)cc1
Reactant: CCCCCCCCCCC[C@@H](O)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC[C@@H]1CCOC(c2ccc(OC)cc2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
p-Toluenesulfonic acid (152 mg, 0.80 mmol) and 4-methoxybenzaldehyde dimethylacetal (2.9 g, 16.0 mmol) was added to a solution of (R)-1,3-dihydroxytetradecane (1.85 g, 8.0 mnuol) in dimethylformamide (20 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate. The ethyl acetate layer was successively washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using cyclohexane:ethyl acetate=9:1 as the eluant to give the desired product (2.78 g, yield 99%).
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C([Li])CCC.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[C:32](=[O:37])N(OC)C)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[C:32]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)=[O:37])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Reactant: Brc1ccc2ccccc2n1
Agent: [H-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1ccc2ccccc2n1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
30% Potassium hydride dispersed in mineral oil (0.8 g, 6 mmol) was added to a stirred solution of 2-bromoquinoline (1.12 g, 5.29 mmol) (O. Sugimoto, Tet. Lett. 4, (1999), 7477-8) in anhydrous THF (20 ml) at −70° C. under argon. To this was added 2N n-butyllithium in hexanes (2.7 ml, 6.75 mmol) dropwise over 5 min. The resultant mixture was stirred for 10 min at −70° C. then a solution of (RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine, D1 (1.57 g, 5.77 mmol) in anhydrous THF (10 ml) was added over 2 min. The cooling bath was removed and the reaction mixture allowed to warm to −20° C. and held at −20° C. for 10 min. The mixture was poured into saturated ammonium chloride (300 ml) and extracted with ethyl actetate (2×100 ml). The combined organics were dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 0-10% ethyl acetate in pentane to yield the title compound as a pale yellow solid (1.2 g, 66%).
Reaction SMILES: [NH:1]([N:11]=[N+:12]=[N-:13])[C@H:2]([C:8](O)=[O:9])[CH2:3][C:4](=[O:7])[O:5][CH3:6].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH:1]([N:11]=[N+:12]=[N-:13])[C@H:2]([C:8]([NH:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9])[CH2:3][C:4](=[O:7])[O:5][CH3:6]
Reactant: NCc1ccccc1
Reactant: COC(=O)C[C@H](NN=[N+]=[N-])C(=O)O
Product: COC(=O)C[C@H](NN=[N+]=[N-])C(=O)NCc1ccccc1
Yield: 90 %

Procedure:
Benzyl-protected L-aspartate was used in the procedure of Lundquist and Pelletier17 to give N3(L)Asp(OMe)OH (46-L). Under these conditions, we observed transesterification to give the methyl ester product as opposed to the benzyl ester. N3(L)Asp(OMe)OH (46-L) was produced as a yellowish oil in 78% yield. N3(L)Asp(OMe)OH (46-L) was then coupled with benzylamine as above to give N3(L)Asp(OMe)NHBn (49-L) as a yellowish oil in 90% yield (70% overall, two steps). The procedure above was repeated with benzyl-protected D-aspartate to give N3(L)Asp(OMe)NHBn (49-D) as a yellowish oil in 67% overall yield. Spectral Data. The spectral data for both N3Asp(OMe)OH (D and L enantiomers) and both N3Asp(OMe)NHBn (D and L enantiomers) products are identical. N3(L)Asp(OMe)OH (46-L) 1H NMR (500 MHz, CDCl3) δ 10.24 (bs, 1 H), 4.47 (dd, J=7.4, 5.3 Hz, 1 H), 3.76 (s, 3 H), 2.91 (dd, J=16.9, 5.1 Hz, 1 H), 2.79 (dd, J=16.8, 7.6 Hz) ppm; 13C NMR (125 MHz, CDCl3) δ 174.68, 170.12, 50.09, 52.44, 35.84 ppm; MS (ESI) m/z 196.0340 (MNa+ [C5H7N3O4Na]=196.0334). N3(L)Asp(OMe)NHBn (49-L) 1H NMR (500 MHz, CDCl3) δ 7.38-7.27 (m, 5 H), 6.83 (bs, 1 H), 4.54 (m, 3 H), 3.75 (s, 3 H), 3.18 (dd, J=17.1, 3.7 Hz, 1 H), 2.75 (dd, J=17.3, 8.7 Hz, 1 H) ppm; 13C NMR (125 MHz, CDCl3) δ 170.77, 167.90, 137.35, 128.81, 127.80, 127.77, 60.32, 52.24, 43.71, 37.00 ppm; MS (ESI) m/z 285.0953 (MNa+ [C12H12N4O3Na]=285.0964).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28](F)[CH:27]=2)[N:3]=1.O.[NH2:36][NH2:37]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:27]=[C:28]3[C:29]([C:32]([NH2:33])=[N:36][NH:37]3)=[CH:30][CH:31]=2)[N:3]=1
Reactant: NN
Reactant: C[C@@H]1CO[C@H](CNS(=O)(=O)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CCO
Solvent: O
Product: C[C@@H]1CO[C@H](CNS(=O)(=O)c2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Reaction time: 17 h
Yield: 41.1 %

Procedure:
A mixture of crude N-({(2S,5R)-4-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methyl)benzenesulfonamide (0.29 mmol theoretical) and hydrazine monohydrate (0.28 mL, 5.78 mmol) in ethanol (3 mL) was stirred at 100° C. in a sealed tube for 17 hours. The mixture was concentrated in vacuo and the residue was purified on a Gilson reverse phase HPLC (CH3CN/water with 0.1% TFA). The product fractions were combined and concentrated in vacuo, taken up in EtOAc (15 mL) and a little CH3OH, washed with saturated aqueous NaHCO3 (2×10 mL) and brine (10 mL), then dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound (59 mg) as a pale yellow solid. LC-MS (ES) m/z=495 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.12 (d, J=6.3 Hz, 3H), 2.65-2.80 (m, 1H), 2.86-3.04 (m, 2H), 3.34-3.43 (m, 1H), 3.47-3.59 (m, 1H), 3.65-3.75 (m, 1H), 3.85-4.75 (bs, 2H), 5.39 (s, 2H), 6.13 (s, 2H), 6.52 (s, 1H), 7.56 (dd, J=8.6, 1.0 Hz, 1H), 7.58-7.68 (m, 3H), 7.69-7.74 (m, 1H), 7.85 (dd, J=7.6, 1.7 Hz, 2H), 7.88-7.97 (m, 2H), 11.53 (s, 1H).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([CH2:10][C:11]([NH2:13])=[O:12])#[N:9].C1(=O)CCCCC1.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[C:1]1(=[C:10]([C:8]#[N:9])[C:11]([NH2:13])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1
Reactant: N#CCC(N)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O=C1CCCCC1
Solvent: CC(=O)O
Product: N#CC(C(N)=O)=C1CCCCC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
600 ml of toluene, 200 g of cyanoacetamide, 193 g of cyclohexanone, 15 g of ammonium acetate and 24 g of acetic acid are placed in a 2 litre flask equipped with a mechanical stirrer, thermometer and Dean-Stark trap connected to a condenser, under nitrogen flow. The mixture is heated under reflux, simultaneously separating the water by distilling the water-toluene azeotrope. The separated water is collected in the Dean-Stark trap and removed at suitable time intervals. After 2 hours, on completion of the azeotropic distillation, it is cooled to 70° C., washed with 400 ml of a saturated sodium bicarbonate solution and cooled to 15° C. The precipitated solid is filtered off, washed with 70 ml of toluene, then 70 ml of water and dried in an oven at 40° C. under vacuum. 213 g of 2-cyclohexylidene-2-cyanoacetamide are obtained.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[C:26]([OH:31])(=[O:30])[CH:27]([CH3:29])[CH3:28]>>[C:26]([O:31][C:1]1([N:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:30])[CH:27]([CH3:29])[CH3:28]
Reactant: ON=C1CCCCC1
Reactant: CC(C)C(=O)O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CC(C)C(=O)OC1(N=O)CCCCC1

Procedure:
1-Nitrosocyclohexyl isobutyrate was prepared from cyclohexanone oxime, lead tetraacetate and isobutyric acid using conditions of General Method 3. 1H NMR (400 MHz, chloroform-d) δ 2.68-2.79 (1H, sept, 7.0 Hz), 1.71-1.93 (8H, m), 1.48-1.62 (2H, m), 1.29 (3H, s), 1.27 (3H, s).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[N:15]=[CH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[C:19]([Br:24])[CH:18]=3)(=O)=O)=CC=1.[CH3:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:24][C:19]1[CH:18]=[C:17]2[C:22]([CH:23]=[C:14]([CH2:13][CH2:12][N:27]3[CH2:28][CH2:29][CH2:30][C@H:26]3[CH3:25])[N:15]=[CH:16]2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cc3ccc(Br)cc3cn2)cc1
Reactant: C[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1cc2ccc(Br)cc2cn1
Temperature: 52.5 °C

Procedure:
The product from Example 52F was dissolved in a solution of (2R)-2-methylpyrrolidine (0.26 g, 3.0 mmol) in acetonitrile (20 mL). The solution was treated with potassium carbonate (0.5 g, 3.6 mmol) and heated at 50-55° C. for 20 hours in a sealed flask. The mixture was allowed to cool to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was diluted with MTBE (20 mL) and water (20 mL) and the pH was adjusted to 3-3.5 with concentrated HCl. The aqueous layer was separated, extracted with MTBE (10 mL), adjusted to a pH of 8-8.5 with potassium carbonate, and extracted with isopropyl acetate (20 mL). The organic layer was separated and concentrated in vacuo. The residue was dissolved in heptane (20 mL), filtered, and the filtrate concentrated under vacuum to provide the title compound. 1H NMR (CDCl3) δ 1.10 (d, J=6.1 Hz, 3H); 1.35-1.49 (m, 1H); 1.62-1.85 (m, 2H); 1.85-1.98 (m, 1H); 2.23 (q, J=8.8. Hz, 1H); 2.28-2.42 (m, 1H); 2.46-2.57 (m, 1H), 3.04-3.19 (m, 2H); 3.19-3.30 (m, 2H); 7.47 (s, 1H); 7.60 (d, J=8.8 Hz, 1H), 7.647.70 (m, 1H), 8.05 (m, 1H); 9.09 (s, 1H); HRMS Calcd. for [C16H19BrN2+H+]: 319.0810. Found: 319.0795.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH:12]=C)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].I([O-])(=O)(=O)=[O:15].[Na+]>C(O)(C)C.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH:12]=[O:15])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: C=CCCC1(C(=O)OC)CCCC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COC(=O)C1(CCC=O)CCCC1
Reaction time: 24 h

Procedure:
To a solution of 1-but-3-enyl-cyclopentanecarboxylic acid methyl ester (4.0 g, 21.5 mmol) in isopropanol (35 mL) was added a solution of sodium periodate (10.1 g, 47.3 mmol) in H2O (35 mL) followed by the addition of osmium tetroxide (16 mg, 0.065 mmol). More isopropanol (30 mL) and H2O (35 mL) were added and the resulting suspension was stirred for 24 hours and then poured onto ice/H2O (200 mL) and extracted with EtOAc (2×200 mL). The organic layers were combined and dried over Na2SO4, filtered and concentrated to provide a crude oil which was purified by flash column chromatography (10 to 60% EtOAc/heptane) to provide 2.27 g (57 yield over two steps) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:13][CH:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(CN2CCC(O)CC2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(CN2CCC(OC(=O)c3ccccc3)CC2)cc1
Yield: 63.6 %

Procedure:
0.31 g (0.0015 mol) of 1-(4-methyl-benzyl)-piperidin-4-ol and 0.52 ml (0.00375 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.25 ml (0.00215 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:4). 0.295 g (64%) of 1-(4-methyl-benzyl)-piperidin-4-yl benzoate was obtained as a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH2:13]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([N:31]=[N+:32]=[N-:33])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:31]([CH2:13]/[CH:12]=[CH:11]/[CH:10]=[CH:9]/[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: OC/C=C/C=C/CCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC/C=C/C=C/CCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(2E,4E)-7-Phenylhepta-2,4-dien-1-ol (6.8 g) was dissolved in dry toluene (130 ml) and cooled in an ice-salt bath. Diphenyl phosphorazidate (7.83 ml) was added, followed by dropwise addition of DBU (6.53 ml) in dry toluene (15 ml). The mixture was stirred for 15 h while warming to room temperature. Solvents were evaporated and the residue was partitioned between diethyl ether and 1N NaOH. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography yielded a colorless liquid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([CH:29]([O:32][C:33]([O:35][CH2:36]I)=[O:34])[CH2:30][CH3:31])[CH3:28]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:36][O:35][C:33]([O:32][CH:29]([CH2:30][CH3:31])[CH2:27][CH3:28])=[O:34])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCC(CC)OC(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CCC(CC)OC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 79.4 %

Procedure:
In the same manner as in Example 81, 154 mg of the title compound was prepared from 149 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 120 mg of (1-ethylpropan-1-yl)oxycarbonyloxymethyl iodide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:4])([CH3:3])[CH3:2].[C-:25]#[N:26].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][C@H:10]([C:25]#[N:26])[CH2:9][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](C#N)CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of (4R)-1-(tert-butyloxycarbonyl)-4-(methane-sulfonyloxy)-L-proline tert-butyl ester (680 mg, 1.86 mmol) and sodium cyanide (912 mg, 18.6 mmol) in N,N-dimethylformamide (14 mL) was stirred for 16 hours at 80° C. under a nitrogen atmosphere. The cooled reaction mixture was diluted with ethyl acetate (100 mL), washed with water (2×), saturated brine solution, dried (Na2SO4), and evaporated. The crude product mixture was subjected to flash silica gel chromatography eluting with 20% ethyl acetate/hexane. Fractions containing the TLC less-mobile isomer were combined and evaporated to afford the desired title compound; yield 275 mg (50%). 400 MHz 1H NMR (CDCl3): δ1.42-1.48 (4s, 18H); 2.24 (m, 1H); 2.67 (m, 1H); 3.08 (m, 1H); 3.64 (m, 1H); 3.81-3.96 (m, 1H); 4.17-4.28 (m, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:25]([F:28])([F:27])[F:26])[CH:11]=2)=[CH:6][CH:5]=1.[O-:29][C:30]#[N:31].[Na+]>O.C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH:22][C:30]([NH2:31])=[O:29])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:11]=2)=[CH:8][CH:9]=1
Reactant: N#C[O-]
Reactant: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(OCCN)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(OCCNC(N)=O)cc2)cc1

Procedure:
To a solution of 2-{4-[5-(4-methoxyphenyl)-3-(tri-fluoromethyl)-1H-pyrazol-1-yl]phenoxy}ethanamine hydrochloride obtained by Example 96 (200 mg) in water (10 ml) and ethanol (5 ml) was added sodium cyanate (314 mg) at room temperature.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1.[CH3:7][N:8]([O:17][CH3:18])[C:9]([C:11](N(C)OC)=[O:12])=[O:10]>Cl>[CH3:7][N:8]([O:17][CH3:18])[C:9](=[O:10])[C:11](=[O:12])[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1
Reactant: CON(C)C(=O)C(=O)N(C)OC
Reactant: BrCC1CCC1
Agent: Cl
Product: CON(C)C(=O)C(=O)CC1CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
The finely divided Mg was treated with 22.5 mL (0.20 mol) of bromomethylcyclobutane maintaining the internal temperature at <5° C. The resulting mixture was stirred cold for 1 h, then was treated with 26.40 g (0.15 mol) of N,N′-dimethyl-N,N′-dimethoxy oxamide (from Step A) in portions as a solid. The resulting mixture was stirred at 0° C. for 16 h. The reaction was poured onto a mixture of 100 mL conc. HCl and 500 g of ice under N2 atmosphere. The quenched mixture was extracted with 1.5 L of EtOAc. The extract was washed with 500 mL of sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography on 500 g of silica gel using 3:1 v/v hexanes/EtOAc as the eluant afforded 22.3 g (80%) of the title compound: 1H NMR (500 MHz) δ 1.66-1.76 (m, 2H), 1.82-1.98 (m, 2H), 2.12-2.22 (m, 2H), 2.74-2.84 (3H), 3.20 (s, 3H), 3.66 (s, 3H).
Reaction SMILES: [C:1]([NH:6][C:7]1[N:8]=[C:9]([O:34][C:35](=[O:49])[N:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:10]2[N:11]=[CH:12][N:13]([C:32]=2[N:33]=1)[C@@H:14]1[O:31][C@H:21]([CH2:22][O:23][Si](C(C)(C)C)(C)C)[C@@H:16]([O:17][CH2:18]SC)[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C1CCCCC=1.[N-:56]=[N+:57]=[N-:58].[Na+].[NH4+].[F-]>C(Cl)Cl>[C:1]([NH:6][C:7]1[N:8]=[C:9]([O:34][C:35](=[O:49])[N:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:10]2[N:11]=[CH:12][N:13]([C:32]=2[N:33]=1)[C@@H:14]1[O:31][C@H:21]([CH2:22][OH:23])[C@@H:16]([O:17][CH2:18][N:56]=[N+:57]=[N-:58])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CSCO[C@H]1C[C@H](n2cnc3c(OC(=O)N(c4ccccc4)c4ccccc4)nc(NC(=O)C(C)C)nc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [F-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC(C)C(=O)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](OCN=[N+]=[N-])[C@@H](CO)O3)c2n1
Reaction time: 1.5 h
Yield: 36 %

Procedure:
To 786 mg 12 (1.1 mmol) dissolved in 8 mL dry CH2Cl2 was treated with 0.56 mL cyclohexene and 180 μL SO2Cl2 (2.2 mmol) at 0° C. and stirred for 1.5 h at the same temperature. The solvent was then removed by rotary evaporation, and further dried under high vacuum for 10 minutes. The crude product was then dissolved in 5 mL dry DMF and reacted with 600 mg NaN3 (10 mmol) at 0° C. and stirred at room temperature for 3 h. Reaction mixture was then partitioned H2O/CH2Cl2, the combined organic extract was then dried over Na2SO4, and concentrated by rotary evaporation. The crude was then dissolved in 5 mL dry MeOH, treated with 500 mg NH4F (13.5 mmol) at room temperature for more than 24 h. Then MeOH solvent was removed by rotary evaporation, and partitioned (H2O/CH2Cl2). The combined organic part was dried over Na2SO4 and concentrated by rotary evaporation and purified by silica gel column chromatography resulting pure product of 14 as white powder (230 mg, ˜36% yield in three steps; hex: EtOAc 1:1 to 1:5, (Rf=˜0.3, Hex:EtOAc/1:4). HR-MS: Obs. m/z 588.2343, calcd for C28H30O6N9 588.2319 [M+H]+. 1H-NMR (DFM-d6): δH 8.64 (brs, 1H), 7.48-7.34 (m, 10H), 6.36 (t, J=7.0 Hz), 4.93 (m, 2H), 4.76 (m, 1H), 4.04 (m, 1H), 3.57 (m, 1H), 3.34 (m, 2H), 2.97 (m, 1H), 2.81 (m, 1H), and 1.10 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=1[N+:18]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[NH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1cccc(OCc2ccccc2)c1N

Procedure:
A solution of O-benzyl-2,3-dinitrophenol (Description 12) (4.5 g) in ethanol (300 ml) was hydrogenated at atmospheric pressure over Raney nickel (2 g) until uptake of hydrogen ceased. The solution was filtered and evaporated to dryness in vacuo to afford unstable O-benzyl-2,3-diaminophenol which was immediately heated with phenylacetic acid (20 g) at 140°-150° C. for 3 h. The product was heated under reflux with 5N-hydrochloric acid (70 ml) for 3 h and neutralised with 10% sodium carbonate. The mixture was extracted with chloroform, and the organic layer washed with 10% sodium carbonate, water and dried (Na2SO4). The recovered product was chromatographed on Silica Gel 60 (250 g) eluting with ethylacetate-chloroform (1:19) to afford the title compound (1.6 g), m.p. 172°-174° C. (ethanol/ether).