Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH:5]=[CH:4][CH2:3]1.C([O-])(O)=O.[Na+].[I:16]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[I:16][C@@H:4]1[C@@H:5]2[CH2:6][C@@H:7]([C:8](=[O:10])[O:9]2)[C@H:2]([CH3:1])[CH2:3]1
Reactant: II
Reactant: C[C@@H]1CC=CC[C@H]1C(=O)O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1C[C@H](I)[C@@H]2C[C@H]1C(=O)O2
Reaction time: 24 h
Yield: 29022.6 %

Procedure:
To a solution of optically active 5 (16.8 g, 120 mmol), in methylene chloride (200 mL) and water (400 mL), was added NaHCO3 (20.1 g, 240 mmol), KI (120 g, 0.720 mmol) and iodine (91.0 g, 0.360 mmol). The resulting mixture was protected from light and stirred for 24 h. The solution was cooled (0° C.) and sodium thiosulfate was carefully added until the dark iodine color disappeared. This was extracted with diethyl ether (4×300 mL). The combined organics were dried (MgSO4) and the volatiles were removed in vacuo to give a yellowish solid (27.8 g, 87% yield). This was carried onto the next step without further purification. Rf 0.33 (ethyl acetate/hexane 1:9); m.p. 99-100° C.; 1H NMR (300 MHz, CDCl3) δ 4.86 (dd, J=3.6, 5.9, 1H), 4.35-4.38 (m, 1H), 2.90 (m, 1H), 2.63-2.73 (m, 1H), 2.49-2.52 (m, 1H), 2.20-2.36 (m, 2H), 1.95-2.00 (m, 1H). 1.38 (d, J=7.2, 3H); 13C NMR (75 MHz, CDCl3) δ 178.2, 81.6, 43.8, 34.3, 29.3, 27.8, 19.5, 19.1; MS (EI) m/z 266 (M+, 4), 139 ([M-I]+, 80), 95 (100), 79 (16), 67 (26), 55 (29); [α]D−3.60° (c=2.22, CHCl3).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[C@@H:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O>[CH:14]1([CH2:13][CH:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][N:6]=2)=[O:27])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: O=C(Nc1ccc(CO)cn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A solution of 6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid methyl ester (prepared as in Example 45, 398 mg, 0.95 mmol) in diethyl ether (30 mL) was cooled to 0° C. and then treated with lithium aluminum hydride (54 mg, 1.4 mmol) in one portion. There was immediate gas evolution. The reaction mixture was allowed to slowly warm to 25° C. and was stirred at 25° C. 16 h. After such time, the reaction mixture was diluted with water (10 mL) and then extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyridin-2-yl) propionamide (131 mg, 35%) as a white foam: FAB-HRMS m/e calcd for C20H22Cl2N2O2 (M+H)+ 392.1058, found 392.1062.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([Cl:15])[CH:9]=2)[C:3]=1[C:16]([NH2:18])=[O:17].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>CCO.N1CCCCC1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:4]2[C:3]([C:16]([NH2:18])=[O:17])=[C:2]([N:1]=[CH:24][C:23]3[CH:26]=[CH:27][C:20]([OH:19])=[CH:21][CH:22]=3)[NH:6][N:5]=2)=[CH:9][C:10]=1[Cl:15]
Reactant: NC(=O)c1c(Nc2ccc(Br)c(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccc(O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2ccc(Br)c(Cl)c2)n[nH]c1N=Cc1ccc(O)cc1

Procedure:
5-amino-3-((4-bromo-3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (194 mg, 1 eq.) and piperidine (4 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((4-bromo-3-chlorophenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: C(O[C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1)C.O.[NH2:17][NH2:18]>CO>[NH:17]([C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1)[NH2:18]
Reactant: CCOC1=NCc2c[nH]c3cccc1c23
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC1=NCc2c[nH]c3cccc1c23
Reaction time: 8 h

Procedure:
A solution of 5-ethoxy-1,3-dihydropyrrolo[4,3,2-de]isoquinoline (10.0 g), described in Example 5, in methanol (100 ml) is combined with a solution of hydrazine hydrate (3 g) in methanol (150 ml). After boiling overnight the mixture is concentrated to half of its original volume and diluted with ether. The resulting precipitate is collected to give the title compound, mp 188° - 189°C, νmaxnujol 3370, 3325, 3150, 1628, 1583, 1540 and 1510 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1([OH:25])[CH2:24][CH2:23][S:22][CH2:21]1)[C:10]([O:12]CC1C=CC=CC=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[K+].CO>O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1([OH:25])[CH2:24][CH2:23][S:22][CH2:21]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)C1(O)CCSC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C(=O)O)C1(O)CCSC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A slurry of N-(t-butoxycarbonyl)-α-(3-hydroxy-2,3,4,5-tetrahydro-3-thiofuranyl)glycine, benzyl ester (2.65 g, 7.22 mmole) in 20 ml of water was treated with potassium bicarbonate (1.0 g, 7.8 mmole) followed by 15 ml of methanol. Stirring at 25° C. for 14 hours gave a homogeneous solution which was diluted with water and extracted with ethyl acetate. The aqueous layer was acidified with 10% potassium bisulfate, saturated with sodium chloride, and extracted with ethyl acetate. Drying (sodium sulfate) and evaporation of the organic layer, and trituration of the residue with isopropyl ether gave the product as a white solid, 1.25 g, melting point 116°-118° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7].CN1CCOCC1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>CC(C)=O>[Cl:23][CH2:24][C:25]([NH:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:6]([NH:8][CH:9]1[CH2:10][CH2:11]1)=[O:7])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: Cl
Solvent: CC(C)=O
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)CCl
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
To a suspension of 3-amino-N-cyclopropyl-4-methyl-benzamide hydrochloride (Compound 1D, 22.7 g, 0.1 mol) in acetone (200 mL) was added 4-methyl morpholine (42.4 mL, 0.3 mol). The solution was cooled to −20° C. and chloroacetyl chloride (12 mL, 0.15 mol) was added dropwise. The reaction mixture was stirred at −10° C. for 10 min before being quenched with H2O (200 mL). The precipitate formed was collected by vacuum filtration and dried to provide 3-(2-chloro-acetylamino)-N-cyclopropyl-4-methyl-benzamide (38C) (25.3 g, 95% yield). mp: decomp 150° C.; 1H NMR(500 MHz, DMSO-D6) δ 9.83 (s, 1H), 8.39 (d, J=3.8 Hz, 1H), 7.82 (s, 1H), 7.58 (d, J=6.6 Hz, 1H), 7.28 (d, J=8.3, 1H), 4.32 (s, 2H), 2.82 (m, 1H), 2.22 (s, 3H), 0.66 (m, 2H), 0.56 (m, 2H); 13C NMR (100 MHz, DMSO-D6) δ: 167.2, 165.4, 136.0, 135.8, 132.8, 130.5, 124.8, 124.7, 43.4, 23.4, 18.1, 6.0;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[N:12][NH:13][N:14]=2)[N:7]=[C:6]([NH:15][C@H:16]([CH2:18][CH3:19])[CH3:17])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH3:29]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[N:14]([CH2:28][CH3:29])[N:13]=[N:12][N:11]=2)[N:7]=[C:6]([NH:15][C@H:16]([CH2:18][CH3:19])[CH3:17])[CH:5]=1
Reactant: CCI
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(-c2nn[nH]n2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(-c2nnnn2CC)n1

Procedure:
Treat a solution of (S)-2-sec-butylamino-6-(2H-tetrazol-5-yl)-isonicotinic acid methyl ester (720 mg, 2.61 mmol) in DMF (10 mL) with potassium carbonate (541 mg, 3.92 mmol) and iodoethane (0.364 mL, 3.92 mL) at room temperature. Dilute with ethyl acetate (100 mL), wash with water (twice), saturated aqueous sodium chloride, dry (sodium sulfate) and concentrate to give approximately a 1:1 mixture of the two title compounds which are used directly in the next step without further purification.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(#N)C.[CH2:25](Br)[CH:26]=[CH2:27]>C(N(CC)CC)C>[CH2:27]([N:12]1[CH2:11][CH2:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:15][CH2:14][CH2:13]1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: Oc1ccc(C2(c3ccccc3)CCNCCO2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCN1CCOC(c2ccccc2)(c2ccc(O)cc2)CC1

Procedure:
The mixture of 11.2 g of 7-(4-hydroxyphenyl)-7-phenylhexahydro-1,4-oxazepine hydrochloride, 110 ml of dry acetonitrile. 14.0 g of triethylamine and 5.05 g of allyl bromide is stirred at room temperature for 48 hours. It is evaporated and the residue partitioned between benzene and 2N aqueous sodium hydroxide. The aqueous layer is separated, combined with a further basic extraction of the benzene solution, and the combined aqueous solutions are adjusted to 9 pH of 4-6.3 with acetic acid. The solid which separates is collected, dried and converted to the hydrochloride in acetone (mp. 150°-153°). The free base is liberated again and crystalized from ethanol, to yield the 4-allyl-7-(4-hydroxyphenyl)-7-phenyl-hexahydro-1,4-oxazepine melting at 205°-207°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[N:18][C:13]2=[N:12][C:11]=1[C:19]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:20]=1[C:21]([OH:23])=O.[C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])[NH:33][NH2:34].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[N:18][C:13]2=[N:12][C:11]=1[C:19]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:20]=1[C:21]([NH:34][NH:33][C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:23]
Reactant: COc1cc(OC)c(-c2nc3ncccn3c2Nc2c(Cl)cccc2Cl)c(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)NN
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(-c2nc3ncccn3c2Nc2c(Cl)cccc2Cl)c(C(=O)NNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
3.1 500 mg of 2-[3-(2,6-dichlorophenylamino)imidazo[1,2-a]pyrimidin-2-yl]-3,5-dimethoxybenzoic acid, 144 mg of tert-butyl carbazate and 250 mg of DAPECl are dissolved in 1 ml of DMF and stirred at RT for 16 h. The reaction mixture is poured into water, the precipitate formed is filtered off and dried. Purification by column chromatography (ethyl acetate/methanol) gives 120 mg (19%) of tert-butyl N′-{2-[3-(2,6-dichlorophenylamino)-imidazo[1,2-a]pyrimidin-2-yl]-3,5-dimethoxybenzoyl}hydrazinecarboxylate as solid; MS-FAB (M+H+)=574.2; Rf (polar method): 1.80 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][CH2:17][O:18][C:19]([CH3:21])=[O:20]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]=[CH:21][C:19]([O:18][CH2:17][CH3:16])=[O:20])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: CCOC(=O)C=CC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 15.5 mL of 1 M sodium bis(triemthylislyl)amide in 20 ml of THF was added 2.8 g triethyl phosphonoacetate at 0° C., and stirred at 0° C. for 15 min. After the addition of 1-benzyl-piperidine-4-carbaldehyde (from Example 162, step A) in 10 mL of 1BF, the reaction was stirred at 0° C. for 15 min. The reaction was warmed up to rt and stirred for 14 hr. The mixture was diluted with 35 ml of EtOAc and washed with H2O. Aqueous phase was extracted with 2×30 mL EtOAc. The combined organic phases were washed with brine and dried over MgSO4. Concentration gave a 2.43 g of title compound as a viscous oil.
Reaction SMILES: O[CH:2]([CH2:10][CH2:11][CH2:12][CH2:13]C)[CH2:3][CH2:4][CH2:5][C:6](=[O:9])C=C.CC1C(=[O:21])CCC1=O.C1(C)C(C)=CC=CC=1>C(O)(=O)C>[O:9]1[C:13]2[CH2:12][C:11](=[O:21])[CH:10]=[CH:2][C:3]=2[CH:4]=[CH:5][CH2:6]1
Reactant: C=CC(=O)CCCC(O)CCCCC
Reactant: CC1C(=O)CCC1=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: O=C1C=CC2=C(C1)OCC=C2

Procedure:
A mixture of the optically active 7-hydroxy-1-dodecen-3-one, obtained as described in Example 4, 2.25 grams of 2-methylcyclopentane-1,3-dione, 50 milliliters of xylene, and 25 milliliters of acetic acid was refluxed for 11/2 hours under a nitrogen atmosphere. After evaporation under vacuum, the residue was extracted with cold benzene leaving 400 milliliters of unreacted methylcyclopentanedione as an insoluble residue. The benzene solution was then evaporated to yield 5.56 grams of optically active 3-pentyl-6aβ-methyl-1,2,3,5,6,6a-hexahydrocyclopenta]f][1]benzopyran-7(8H)-one. After chromatographing the crude product on alumina, followed by crystallization from methanol-water, the product melted at 60°-61°C., [α]D25 -166°.
Reaction SMILES: C(N1CCC(C#N)CC1)(=O)C.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1.FC(F)(F)C1C=C(C=CC=1)[C:29]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30]>>[F:12][C:13]([F:23])([F:22])[C:14]1[CH:19]=[CH:18][C:17]([C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Reactant: O=C(c1cccc(C(F)(F)F)c1)C1CCNCC1
Agent: CC(=O)N1CCC(C#N)CC1
Product: O=C(c1ccc(C(F)(F)F)cc1)C1CCNCC1

Procedure:
The title compound is prepared from 1-acetyl-4-cyanopiperidine and 4-trifluoromethylphenylmagnesium bromide according to the procedure given for 4-(3-trifluoromethylbenzoyl)piperidine in J. Med. Chem. 13, 1-6 (1970).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[C:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[C:25]([N:28]1[CH2:33][CH2:32][N:31]([C:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][CH2:8][C:9]3[NH:13][C:12]4[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=4[N:10]=3)=[O:6])=[CH:3][C:2]=2[Cl:1])=[O:24])[CH2:30][CH2:29]1)(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)N1CCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)CC1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, N-acetylpiperazine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.13 minutes; C22H21Cl2N5O3 (474.35); mass spectrum: (M+H)+=474.2.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:7]([C@@H:8]2[CH2:12][C@H:11]([SH:13])[CH2:10][N:9]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[CH2:6][N:5]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[O:28])[CH2:4]1.O(P(O[C:57]1[C@H:58]([CH3:81])[C@H:59]2[C@@H:76]([C@H:77]([OH:79])[CH3:78])[C:75](=[O:80])[N:60]2[C:61]=1[C:62]([O:64][CH2:65][C:66]1[CH:71]=[CH:70][C:69]([N+:72]([O-:74])=[O:73])=[CH:68][CH:67]=1)=[O:63])(OC1C=CC=CC=1)=O)C1C=CC=CC=1>>[OH:79][C@@H:77]([C@H:76]1[C:75](=[O:80])[N:60]2[C:61]([C:62]([O:64][CH2:65][C:66]3[CH:67]=[CH:68][C:69]([N+:72]([O-:74])=[O:73])=[CH:70][CH:71]=3)=[O:63])=[C:57]([S:13][C@@H:11]3[CH2:10][N:9]([C:14]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=4)=[O:15])[C@H:8]([CH:7]4[CH2:6][N:5]([C:27]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=5)=[O:28])[CH2:4][CH:3]4[CH2:2][OH:1])[CH2:12]3)[C@H:58]([CH3:81])[C@H:59]12)[CH3:78]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC(CO)C([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4CO)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 57.3 %

Procedure:
The same procedure as in Example 1-1) was carried out by using (2S, 4S)-2-[3-hydroxymethyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer A (3.34 g, 5.42 mmol, compound of Reference Example 5) and p-nitrobenzyl (1R, 5S, 6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (3.22 g, 5.42 mmol) to obtain p-nitrobenzyl (1R, 5S, 6S)- 6-[(R)-1-hydroxyethyl]-2-[(2S,4S)-2-[3-hydroxymethyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer A (2.81 g, yield: 57.3%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[C:15]([Cl:21])[CH:14]=1)([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:6]>>[C:5]([NH:12][C:13]1[CH:14]=[C:15]([Cl:21])[C:16]([Cl:20])=[C:17]([Cl:19])[C:18]=1[N+:1]([O-:4])=[O:2])([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)c(Cl)c(Cl)c1
Product: CCOC(=O)C(=O)Nc1cc(Cl)c(Cl)c(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
20 ml 100% nitric acid was cooled to 0° C. and 2.0 g (6.8 mmol) N-ethoxalyl-3,4,5-trichloroaniline was added. The reaction mixture was stirred at 0° C. for 10 min. and 200 ml ice-water was added. The precipitate was filtered off, washed with water and ethanol to give 1.2 g (52%) of N-ethoxalyl-2-nitro-3,4,5-trichloroaniline. M.p. 84° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12](=[O:23])(=[O:22])[NH:13][C:14]3([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:15]=2[CH3:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:16][C:15]1[C:14]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13][S:12](=[O:23])(=[O:22])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=1
Reactant: CC1=C(c2ccc(S(C)(=O)=O)cc2)S(=O)(=O)NC12CCCCC2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(C2=C(CBr)C3(CCCCC3)NS2(=O)=O)cc1
Yield: 67.6 %

Procedure:
3-(4-methanesulfonyl-phenyl)-4-methyl-2-thia-1-azaspiro[4.5]dec-3-ene 2,2-dioxide (4.5 g, 12.6 mmol) and N-bromo succinimide (2.5 g, 14 mmol) were stirred in 200 ml CCl4 with a catalytic amount of benzoyl peroxide for 4 hours at 85° C. Then the solvent was evaporated and the residue disolved in dichloromethane, washed with water and NaHCO3 solution, dried (Na2SO4) and evaporated. The solid product was recrystallized from ethanol to yield 4-bromomethyl-3-(4-methanesulfonyl-phenyl)-2-thia-1-aza-spiro[4.5]dec-3-ene 2,2-dioxide (3.7 g, 68%). This product was dissolved in ethanol (20 ml), ethylamine (70% solution in water, 20 ml) was added, the mixture was left at room temperature for 3 hours and evaporated. The residue was dissolved in CH2Cl2, washed with water and extracted with 2 M HCl. After addition of NaOH and extraction with CH2Cl2 the organic layer was dried (Na2SO4) and evaporated. Chromatography on silica (eluent CH2Cl2/EtOH 95:5) yielded 1.50 g (66%) N-ethyl-N-[3-(4-methanesulfonyl-phenyl)-2,2-dioxo-2-thia-1-aza-spiro[4.5]dec-3-en-4-ylmethyl]-amine, shown below. 1H-NMR (CDCl3) δ 8.01 (d, 2H), 7.83 (d, 2 H), 4.81 (s, 1 H), 3.45 (s, 2 H), 3.09 (s, 3 H), 2.54 (q, 2 H), 2.02-1.15 (m, 10 H), 0.96 (t, 3 H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=O.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=[N:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1
Reactant: CN1CCC(N)CC1
Reactant: O=Cc1nc2ccccc2[nH]1
Solvent: CCO
Product: CN1CCC(N=Cc2nc3ccccc3[nH]2)CC1

Procedure:
1H-Benzimidazole-2-carboxaldehyde (781 mg, can be prepared according to Fegy, K. Angewandte Chemie Int Ed, 1998, vol. 37, 1270-1273), 4-amino-1-methylpiperidine (781 mg) and 4 Å molecular sieves (15 g) in ethanol (100 mL) are heated under reflux for 4 h. The mixture is then filtered and the filtrate concentrated under reduced pressure to yield (1H-benzimidazol-2-ylmethylene)(1-methylpiperidin-4-yl)amine as a beige solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9]C)[CH:8]=1.[Br:12][CH2:13][C:14]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=O>>[Br:12][C:13]1[O:2][C:3]2[C:8](=[C:7]([OH:9])[CH:6]=[C:5]([OH:11])[CH:4]=2)[C:14]=1[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Reactant: COc1cc(O)cc(OC)c1
Product: Oc1cc(O)c2c(-c3cc(F)cc(F)c3)c(Br)oc2c1
Yield: 14 %

Procedure:
This compound was prepared using Method B from 3,5-dimethoxyphenol and 2-bromo-1-(3,5-difluorophenyl)ethanone: Yield 14% following procedures B.2, B.3 and B.5; m.p. 121-122° C.; IR 3379, 1620, 1591, 1429, 1121, 1069 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 9.25 (s, 1H), 9.24 (s, 1H), 7.02 (t, J=8.8 Hz, 1H), 6.72 (d, J=6.4 Hz, 2H), 6.28 (s, 1H), 6.06 (s, 1H); 13C NMR (126 MHz, δ ppm, CDCl3) 163.4 (dd, J=246.0 Hz, 13.4 Hz), 157.5, 156.7, 154.7, 153.2, 139.3 (t, J=10.6 Hz), 115.8, 114.9 (dd, J=7.5 Hz, 17.0 Hz), 112.0, 102.8 (t, J=25.6 Hz), 98.9, 90.4.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([Li])[CH2:23][CH2:24]C.C(I)CC>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:14][C:15]=1[CH2:22][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]CCCC
Reactant: c1ccc(COCCc2coc(-c3ccccc3)n2)cc1
Solvent: C1CCOC1
Solvent: CCCI
Product: CCCc1oc(-c2ccccc2)nc1CCOCc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 44 %

Procedure:
4-(2-Benzyloxyethyl)-2-phenyloxazole (670 mg, 239 mmol) was dissolved in THF (10 mL) and cooled to −78° C. before adding n-butyllithium (1.15 mL of a 2.5 M solution in hexanes). The resulting orange solution was warmed to −65° C., stirred 45 min, and then propyl iodide (1.22 g, 7.17 mmol, 0.70 mL) was added via syringe. The solution was warmed to ambient temperature and stirred 90 min. The mixture was concentrated and the product purified by flash chromatography (100 mL SiO2, hexanes to 20% EtOAc/hexanes) and obtained as a colorless oil (340 mg, 44%): Rf=0.49 in 20% EtOAc/hexanes; 1H NMR (500 MHz, CDCl3) δ 8.00-7.96 (m, 2H), 7.42-7.26 (m, 8H), 4.54 (s, 2H), 3.76 (t, J=7.0 Hz, 2H), 2.83 (t, J=7.0 Hz, 2H), 2.64 (t, J=7.0 Hz, 2H) 1.68 (sextet, J=7.0 Hz, 2H), 0.96 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH3:27]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)(N)c1ccccn1
Product: CC(C)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1ccccn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α,α-dimethyl-2-pyridinemethanamine (CAN 52568-28-2) as starting materials, LC-MS (UV peak area/ESI) 100%, 352.2021 (M+H)+.