Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]([CH3:25])[CH3:24])=[C:16]([NH:26][C:27]2[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=2)[N:15]=1.O>CN(C=O)C>[CH:23]([N:20]1[CH:19]=[N:18][C:17]2[C:21]1=[N:22][C:14]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[N:15][C:16]=2[NH:26][C:27]1[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=1)([CH3:25])[CH3:24]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(Oc3cccc([N+](=O)[O-])c3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.4 %

Procedure:
To a solution of 3-nitro-phenol (143 mg, 1.03 mmol) in DMF (15 mL) was added sodium hydride (56 mg, 1.4 mmol) slowly and the mixture was stirred at rt for 30 min. 2-chloro-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (200 mg, 0.69 mmol), as prepared in step 1 of Example 2, was added slowly. After the addition, the mixture was stirred at 110° C. overnight. The cooled reaction mixture was poured into water (100 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried over Na2SO4, concentrated and the residue was purified by flash column chromatography (MeOH:EtOAc=1:10) to give the title compound (50 mg, 18% yield) as light yellow oil.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH2:16]([N:18]1[C:24]2[CH:25]=[C:26]([F:30])[C:27]([NH2:29])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20][CH2:19]1)[CH3:17].Cl[C:32]1[N:37]=[C:36]([NH:38][C:39]2[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:40]=2[C:41]([NH:43][CH3:44])=[O:42])[C:35]([Cl:50])=[CH:34][N:33]=1>C(O)(C)C>[Cl:50][C:35]1[C:36]([NH:38][C:39]2[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:40]=2[C:41]([NH:43][CH3:44])=[O:42])=[N:37][C:32]([NH:29][C:27]2[C:26]([F:30])=[CH:25][C:24]3[N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)=[N:33][CH:34]=1
Reactant: CCN1CCCOc2cc(N)c(F)cc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1CCCOc2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)c(F)cc21
Yield: 7.1 %

Procedure:
10-Camphorsulfonic acid (77 mg, 0.33 mmol) was added to 9-Ethyl-2-fluoro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine (62 mg, 0.29 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (95 mg, 0.30 mmol) in Isopropyl alcohol (3 mL). The mixture was irradiated in a CEM microwave (130° C., 40 min), resulting in ˜20% conversion. The reaction was stopped, conc. in vacuo and purified by HPLC then free based with MP-carbonate resin in DCM/MeCN to afford 2-[5-Chloro-2-(9-ethyl-2-fluoro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide as a purple foam (10 mg, 7%). LCMS 489 (M+H), 1H-NMR (CDCl3): 8.78 (s, 1H), 8.05 (s, 1H), 7.65 (d, 1H, J=8.7 Hz), 7.35 (m, 1H), 7.29 (m, 1H), 7.23 (m, 1H), 6.84 (s, 1H), 6.55 (d, 1H, J=13.4 Hz), 6.21 (s, 1H), 3.97 (t, 2H, J=5.5 Hz), 3.12 (m, 4H), 2.91 (d, 3H, J=4.7 Hz), 1.96 (m, 2H), 1.17 (t, 3H, J=6.9 Hz); 19F-NMR: −111, −136.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[F:7][C:8]([F:23])([F:22])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])=O>>[F:7][C:8]([F:23])([F:22])[C:9]([Cl:2])=[N:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19]
Reactant: O=C(Nc1ccccc1C(F)(F)F)C(F)(F)F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: FC(F)(F)C(Cl)=Nc1ccccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
A mixture of 27.48 g of phosphorus pentachloride and 30.84 g of 2,2,2-trifluoro-N-(2-trifluoromethylphenyl)-acetamide was stirred at 80° C. for 4 hours and was then allowed to cool. The mixture was distilled under reduced pressure to obtain 15.2 g of 2,2,2-trifluoro-N-(2-trifluoromethylphenyl)ethanimidoyl chloride with a boiling point of 85° C. at 30 mm Hg and a refractive index of nD21 =1.4297.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[NH2:7][CH2:8][C@@H:9]([CH3:37])[O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:24]([CH3:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][C@H:9]([O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:24]([CH3:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2)[CH3:37])=[O:6]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(O[C@H](C)CN)c34)cc2C)cn1
Reactant: O=C=NCCCl
Solvent: ClCCl
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(O[C@H](C)CNC(=O)NCCCl)c34)cc2C)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Chloroethylisocyanate (116 μl, 1.36 mmol) was added drop wise to an ice-cooled solution of 5-[(1R)-2-amino-1-methylethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (516 mg, 1.24 mmol, obtained as described in Example 112, preparation of starting materials) in DCM (10 ml). The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 3% to 5% 7N ammonia-methanol in DCM) to give the title compound (584 mg, 74%); NMR Spectrum: (CDCl3) 1.46 (d, 3H), 2.28 (s, 3H), 2.52 (s, 3H), 3.46 (m, 1H), 3.57 (m, 4H), 4.00 (m, 1H), 4.76 (m, 1H), 6.40 (m, 1H), 6.62 (m, 1H), 6.67 (d, 1H), 6.91 (d, 1H), 7.08 (d, 1H), 7.12 (dd, 1H), 7.18 (d, 1H), 7.34 (t, 1H), 7.53 (dd, 1H), 7.67 (s, 1H), 8.27 (s, 1H), 8.34 (s, 1H), 9.82 (s, 1H); Mass spectrum: MH+ 521.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:31])[CH2:17][C:16]2[NH:15][C:14]3[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11][C:10](=[O:20])[C:9]=3[CH:8]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[C:7]=2[C:6](=[O:30])[CH2:5]1.Cl[C:33]([O:35][CH3:36])=[O:34]>O1CCCC1.CN(C)C=O>[CH3:19][C:12]1([CH3:18])[CH2:13][C:14]2[N:15]([C:33]([O:35][CH3:36])=[O:34])[C:16]3[CH2:17][C:4]([CH3:31])([CH3:3])[CH2:5][C:6](=[O:30])[C:7]=3[CH:8]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[C:9]=2[C:10](=[O:20])[CH2:11]1
Reactant: COC(=O)Cl
Reactant: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)N1C2=C(C(=O)CC(C)(C)C2)C(c2ccc([N+](=O)[O-])cc2)C2=C1CC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A slurry of 17 mg of sodium hydride (80% dispersion in mineral oil) in 10 ml of anhydrous tetrahydrofuran was stirred at room temperature under an atmosphere of dry nitrogen and treated dropwise with a solution of 200 mg of 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-(4-nitrophenyl)-1,8(2H,5H)-acridinedione in 5 ml of dimethylformamide. The mixture was then heated at reflux for 15 minutes, cooled to room temperature, treated with 44 ml of methyl chloroformate and stirred at room temperature under an atmosphere of dry nitrogen for 18 hours. The solvents were removed under reduced pressure and the resulting waxy residue was taken up in diethyl ether and the insoluble material was filtered off. The filtrate was then purified by column chromatography on silica gel using hexane/ethyl acetate (gradient: 80:20 to 50:50) as the eluent to give methyl 2,3,4,5,6,7,8,9-octahydro-3,3,6,6-tetramethyl-9-(4-nitrophenyl)-1,8-dioxo-1H-acridine-10-carboxylate as a white crystalline solid of melting point 189-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:33]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[O:40])[CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.7 %

Procedure:
72 mg of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.023 ml benzoylchloride (0.2 mmol). After 1.5 h of stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 84 mg residue which was purified by column chromatography (9 g silicagel, ethylacetate/heptane 2:1). 69 mg product as a light yellow solid (98%) was obtained. MS (ISP) 555.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23]C)[CH:19]=2)[C:14]=1[O:25][C:26]1[CH:40]=[CH:39][C:29]([O:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:28][CH:27]=1.Cl.B(Br)(Br)Br.CO>C(OCC)(=O)C.C(OCC)C>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9]([CH3:12])(=[O:10])=[O:11])[CH:5]=[CH:4][C:3]=1[C:13]1[C:14]([O:25][C:26]2[CH:40]=[CH:39][C:29]([O:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:28][CH:27]=2)=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16]2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)c(Cl)c3Cl)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)c(Cl)c1Cl
Temperature: 0 °C
Yield: 30 %

Procedure:
Dissolve the product of Example 33 in ethyl acetate (10 mL) and diethyl ether (5 mL). Add 2M HCl in diethyl ether (0.5 mL, 1.0 mmol). Concentrate the slurry and dry in vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool the solution to 0° C. with external ice bath. Add BBr3 (0.1 mL, 1.1 mmol) and stir for 1 hour. Quench with water (1.0 mL) and dilute with dichloromethane (10 mL). Separate the layers, wash the organic layer with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). Dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting the 6-(2,3-dichloro-4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol with a step gradient of methanol/dichloromethane (0 to 5%). Dissolve the free base in diethyl ether (5.0 mL), ethyl acetate (6.0 mL) and methanol (1.0 mL) and add 2M HCl in diethyl ether (0.5 mL, 1.0 mmol). Collect the precipitate on filter paper, rinse with diethyl ether to give 38 mg of the title compound (30%): mass spectrum (ion spray): m/z=586.2.
Reaction SMILES: [Li+].[OH-:2].O.OO.C([C@@H]1COC(=O)N1[C:19](=[O:41])[C@@H:20]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[CH2:21][N:22]([CH2:30][CH:31]1[CH2:33][CH2:32]1)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])C1C=CC=CC=1>C1COCC1>[C:25]([O:24][C:23]([N:22]([CH2:30][CH:31]1[CH2:33][CH2:32]1)[CH2:21][C@H:20]([C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:19]([OH:41])=[O:2])=[O:29])([CH3:27])([CH3:26])[CH3:28]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)cc1
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)O)c1ccc(Cl)cc1

Procedure:
LiOH (1.41 g, 33.5 mmol) was added to a flask containing THF (360 mL) and H2O (120 mL), which was stirred until dissolved. At this point, the reaction was cooled to 0° C. with ice, and hydrogen peroxide (35 wt. %, 6.52 g) was added. This solution was stirred for 10 minutes, at which point tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl(cyclopropylmethyl)carbamate (8.6 g, 16.8 mmol) was added as a solution in THF (20 mL). The reaction was stirred overnight with warming. The reaction was quenched by the addition of 10% aqueous Na2SO3 (1 mL) and saturated aqueous NaHCO3 (1 mL) and stirred for 10 minutes. The reaction was concentrated to remove THF and the aqueous layer extracted with ether (3×). The aqueous layer was diluted with EtOAc and acidified with 1N HCl. The organic layer was removed, and the aqueous layer was extracted with EtOAc (2×). The combined organics were dried with MgSO4 and concentrated to give the crude product, (S)-3-( tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chlorophenyl)propanoic acid as a clear oil (LCMS (APCI+) [M-Boc+H]+ 254.1; Rt: 3.03 min).
Reaction SMILES: [CH:1]([C:4]([CH3:14])([N:7]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]1=[O:13])[C:5]#[N:6])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:16].[Cl-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[CH:1]([C:4]([CH3:14])([N:7]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]1=[O:13])[C:5]([NH2:6])=[O:16])([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C)C(C)(C#N)N1C(=O)C=CC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C(C)(C(N)=O)N1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
A solution of α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline-1-acetonitrile (2.0 g, 0.104 mol) in methylene chloride (30 ml) is added in a fine stream to concentrated sulfuric acid at room temperature. After stirring overnight at room temperature for 16 hours the mixture is poured onto ice, containing sodium chloride and ethyl acetate. The organic layer is washed with aqueous sodium bicarbonate, brine and dried. Evaporation after washing with ether-pentane gives a solid (72%), mp 138.5°-140° C. Anal. calcd. for C10H14N2O3 : C, 57.13; H, 6.71; N, 13.33. Found: C, 56.89; H, 6.64; N, 13.16.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[OH:10][C:11]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].[C:23](OCC)(=O)[CH3:24]>CC(=O)CC>[CH2:23]([O:10][C:11]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH2:8][CH3:9])=[O:14])[CH3:24]
Reactant: CCI
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1O
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1OCC
Temperature: 80 °C
Yield: 97 %

Procedure:
Potassium carbonate (60.4 g, 437 mmol) and iodoethane (17.6 mL, 218.4 mmol) were added to a mechanically stirred solution of 2-hydroxy-4-nitro-benzoic acid (10.0 g, 54.6 mmol) in 2-butanone (165 mL). The resulting mixture was heated in an 80° C. oil bath for 16 h and then allowed to cool. TLC (20% ethyl acetate in hexanes) showed consumption of starting material. The reaction mixture was concentrated to dryness, and the residue was taken up in ethyl acetate and washed three times with a saturated solution of sodium thiosulfate, dried over magnesium sulfate and concentrated to give ethyl 2-ethoxy-4-nitro-benzoate as a yellow solid (12.7 g, 97%). LC-MS: 240.1 [(M+H)+].
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([CH2:12][O:13][N:14]=[C:15]([C:43]2[N:44]=[C:45]([NH:48][C:49](=[O:54])[C:50]([F:53])([F:52])[F:51])[S:46][CH:47]=2)[C:16]([NH:18][CH:19]2[C:41](=[O:42])[N:21]3[C:22]([C:28]([O:30]CC4C=CC([N+]([O-])=O)=CC=4)=[S:29])=[C:23]([CH:26]=[CH2:27])[CH2:24][S:25][C@H:20]23)=[O:17])=[O:11])=CC=1)([O-])=O.C(O)C.P([O-])([O-])([O-])=O.[H][H]>[Pd].O1CCCC1>[C:10]([CH2:12][O:13][N:14]=[C:15]([C:43]1[N:44]=[C:45]([NH:48][C:49](=[O:54])[C:50]([F:51])([F:52])[F:53])[S:46][CH:47]=1)[C:16]([NH:18][CH:19]1[C:41](=[O:42])[N:21]2[C:22]([C:28]([OH:30])=[S:29])=[C:23]([CH:26]=[CH2:27])[CH2:24][S:25][C@H:20]12)=[O:17])([OH:11])=[O:9]
Reactant: [H][H]
Reactant: C=CC1=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCc3ccc([N+](=O)[O-])cc3)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CC1=C(C(O)=S)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Yield: 67.5 %

Procedure:
p-Nitrobenzyl 7-[2-(p-nitrobenzyloxycarbonylmethoxyimino)-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-vinylthio-3-cephem-4-carboxylate (syn isomer) (2.3 g) was hydrogenated in the presence of 5% palladium on carbon in a mixture of tetrahydrofuran (100 ml), ethanol (11.5 ml) and 0.025M phosphate buffer solution (pH 6.85) (125 ml) at ambient temperature for 5 hours under 1 atmospheric pressure of hydrogen. The catalyst was filtered off and washed with ethyl acetate and a saturated aqueous solution of sodium bicarbonate successively. The filtrate and washings were combined and adjusted to pH 8 with dilute hydrochloric acid. The aqueous layer was separated, adjusted to pH 6 with dilute hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated in vacuo and triturated with diisopropyl ether to give 7-[2-carboxymethoxyimino-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-vinylthio-3-cephem-4-carboxylic acid (syn isomer) (1.05 g).
Reaction SMILES: [Cl:1][C:2]([Cl:14])([Cl:13])[CH2:3][CH:4](Cl)[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6].N12CCCN=C1CCCCC2.O>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:13])([Cl:14])[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6]
Reactant: CCCCOC(=O)C(Cl)CC(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(=O)C=CC(Cl)(Cl)Cl
Reaction time: 3 h
Yield: 76 %

Procedure:
6 g of butyl 4,4,4,2-tetrachloro-butanoate (22.4 mmoles) in 20 ml of anhydrous toluene are charged under inert gas into a 250 ml flask and 5 ml of 1,8-diazabicyclo[5.4.0]undecan-7-ene (DBU) are added with exothermy. The mixture is brought to 60° C. for 3 hours. Upon GC control, it is observed that the reaction is complete; the mixture is cooled, water is added, the mixture is extracted with ethyl ether and anhydrified on Na2SO4. The residue obtained after evaporation of the solvent and purification by silica gel chromatography (eluant: hexane/ethyl acetate=9/1) weighs 4 g (76% yield).
Reaction SMILES: [C:1]([CH2:3][C@@H:4]1[CH2:9][C@H:8]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])[CH2:7][CH2:6][C@@H:5]1[NH:15]C(=O)[O-])#[N:2].[BrH:19]>C(O)(=O)C>[NH2:15][C@H:5]1[CH2:6][CH2:7][C@@H:8]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])[CH2:9][C@H:4]1[CH2:3][C:1]#[N:2].[BrH:19]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)[O-])[C@H](CC#N)C1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)N(C)[C@@H]1CC[C@H](N)[C@H](CC#N)C1
Reaction time: 2.5 h

Procedure:
To a solution of (1S,2S,4R)-2-(cyanomethyl)-4-(isopropyl(methyl)amino)cyclohexylcarbamate (479 mg) in 4 ml of acetic acid was added 4 ml of 30% HBr in acetic acid, and the mixture was stirred for 2.5 hours. The acid was evaporated off under reduced pressure and residue was dried by azeotroping with benzene several times. The residue was further dried under vacuum to give 2-((1S,2S,5R)-2-amino-5-(isopropyl(methyl)amino)cyclohexyl)acetonitrile as a bis-HBr salt as a solid (673 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].N#N.[CH2:23]1[CH2:27]OCC1>>[CH3:9][N:1]1[CH2:23][CH2:27][C:3]2([C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: O=C1Cc2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N#N
Agent: [Na+]
Product: CN1CCC2(CC1)C(=O)Nc1ccccc12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 57 %

Procedure:
A solution of oxindole 9 (6.25 g, 47 mmol) in THF (500 ml) was cooled to −78° C. and to it a solution of sodium hexamethyldisilazide (43 g, 235 mmol) in THF (300 ml) was added drop wise under N2 atmosphere. After stirring at −78° C. for 45 min, N-methylbis(2-chloromethyl)amine hydrochloride (9 g, 47 mmol) was added, as a solid. The reaction mixture was stirred at −78° C. for 1 h and at room temperature for 24 h. After quenching with H2O (90 ml), the mixture was extracted with ethyl acetate (3×100 ml). The organic extracts were washed with brine (25 ml), dried and the solvent removed in vacuo. Silica gel chromatography (5-50% MeOH/CH2Cl2, gradient) gave 6 g (57%) of 10 as a solid. 1HNMR (CD3OD, 400 MHz) δ 1.84 (m, 2H); 2.51 (m, 2H); 2.62 (s, 3H); 3.02 (m, 2H); 3.37 (m, 2H); 6.82 (d, 1H, J=7.68 Hz); 6.94 (t, 1H, J=7.58 Hz); 7.12 (t, 1H, J=7.7 Hz); 7.26 (d, 1H, J=9 Hz); 9.27 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:12])[CH:10]=[O:11])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[C:9]([CH3:12])[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CC(C=O)=Cc1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=Cc1ccc(F)cc1)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution of 113 g (0.69 mole) of 3-(4-fluorophenyl)-2-methyl-2-propen-1-al in 800 ml ethanol at 10° C. was added in portions 13.1 g (0.345 mole) of sodium borohydride. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The mixture was cooled in an ice bath while 350 ml of 1 N hydrochloric acid was added dropwise to give a final pH of ~7. The mixture was diluted with 500 ml water and extracted three times with methylene chloride. The organic extracts were dried and concentrated and the residue distilled to give 56.1 g (49%) of colorless liquid, b.p. 68°-70° C. (15 mm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[F:27][C:28]1([F:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:27][C:28]1([F:34])[CH2:33][CH2:32][N:31]([C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:9][O:10][C:11]=3[CH2:24][OH:25])=[CH:20][N:19]=2)=[O:23])[CH2:30][CH2:29]1
Reactant: FC1(F)CCNCC1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Agent: Cl
Product: O=C(c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1)N1CCC(F)(F)CC1
Yield: 31 %

Procedure:
As described for example 34b, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (75 mg, 0.22 mmol) was converted, using 4,4-difluoropiperidine hydrochloride instead of S-(+)-1-amino-2-propanol, to the title compound (45 mg, 31%), which was obtained as a colourless gum. MS: m/e=448.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].IC.[C:31](OCC)(=O)[CH3:32]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:31][CH3:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nc3ccc([N+](=O)[O-])cc3s2)C1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCN(CC1CCN(C(=O)OC(C)(C)C)C1)c1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 34 %

Procedure:
Dissolve 3-[(6-nitro-benzothiazol-2-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (5.55 g, 14.7 mmol) in DMF (30 mL) and cool to 5° C. Add 60% NaH in mineral oil (1.12 g, 16.13 mmol) and stir for 5 min. Add iodomethane (6.0 mL, 74 mmol) and stir at 5° C. for 30 min. Quench the reaction with water and dilute with ethyl acetate. Wash the organic layer with water (5×20 mL), then wash with brine. Collect the organic layer, dry over Na2SO4, filter, and concentrate in vacuo. Chromatograph (silica gel, eluting with 20-60% Ethyl acetate:Hexane) to yield 1.96 g (34%) of the title compound. mass spectrum (ion-spray): (m/z)=393.3 (M+1).