Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].C(=O)([O-])[O-].[K+:14].[K+]>>[OH2:3].[C:1]([O-:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[K+:14]
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O
Product: O=C(O)C[C@H](O)C(=O)[O-]
Temperature: 10 °C
Reaction time: 6 h
Yield: 191.7 %

Procedure:
The filtrate obtained in paragraph (1) is mixed with 500 ml of an aqueous L-malic acid solution[L-malic acid content: 75.9 g (0.566 mole)/500 ml], and 39 g (0.282 mole) of potassium carbonate are added thereto. The solution (pH 4.3) is concentrated to about 130 ml and cooled to 10° C. Then, the mixture thus obtained (i.e., the mixture of the concentrated solution and crystals precipitated) is adjusted to a pH 5.4 with potassium hydroxide, and stirred at the same temperature for 6 hours. After stirring, the mixture had the pH of 5.6. The crystalline precipitates are collected by filtration. 102.8 g of monopotassium L-malate monohydrate are obtained. Total amount: 183.7 g Yield: 85.4% (calculated on the basis of L-malic acid used)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.I[CH2:15][C:16](=[O:38])[C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C:31](=[CH:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH:27]=[CH:28]2)[CH2:23][CH2:22]3)[CH2:19][C@H:18]1[CH3:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16](=[O:38])[C@@H:17]3[C@:34]4([CH3:35])[C@H:20]([C@H:21]5[C:31](=[CH:32][CH2:33]4)[C@:29]4([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH:27]=[CH:28]4)[CH2:23][CH2:22]5)[CH2:19][C@H:18]3[CH3:37])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CI
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cccc(Cl)c2)CC1

Procedure:
Following the general procedure of EXAMPLES 1-6A, 7, 8, 11-19, 83, 126 and 139 and making non-critical variations but starting with 4-(3-chlorophenyl)piperazine (PREPARATION A-57) and 21-iodo-16α-methylpregna-1,4,9(11)-triene-3,20-dione (PREPARATION S-22), the title compound is obtained.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:40][CH3:41])=[C:6]([C:8]2[C:9]([CH2:18][N:19]3[C@@H:23]([CH3:24])[C@@H:22]([C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=4)[O:21][C:20]3=[O:39])=[N:10][C:11]([N:14]3[CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:13]=2)[CH:7]=1.[I:42]CI.N(OCCC(C)C)=O>C1(C)C=CC=CC=1>[N:14]1([C:11]2[N:10]=[C:9]([CH2:18][N:19]3[C@@H:23]([CH3:24])[C@@H:22]([C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[C:27]([C:35]([F:37])([F:38])[F:36])[CH:26]=4)[O:21][C:20]3=[O:39])[C:8]([C:6]3[CH:7]=[C:2]([I:42])[CH:3]=[CH:4][C:5]=3[O:40][CH3:41])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: ICI
Reactant: COc1ccc(N)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: CC(C)CCON=O
Solvent: Cc1ccccc1
Product: COc1ccc(I)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of (4S,5R)-3-{[3-(5-amino-2-methoxyphenyl)-6-azetidin-1-ylpyridin-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (460 mg, 0.792 mmol) in toluene (7 mL) and diiodomethane (2 mL, 24.79 mmol) was added isoamyl nitrite (0.213 mL, 1.585 mmol) dropwise at room temperature. The mixture was stirred at 25° C. for 15 min. Then the mixture was heated at 80° C. for 45 min. The reaction mixture was loaded on a silica column directly and was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 270 mL, gradient to 35% EtOAc in hexanes over 972 mL) to afford (4S,5R)-3-{[6-azetidin-1-yl-3-(5-iodo-2-methoxyphenyl)pyridin-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=691.1. found=692.0 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.87 (s, 1H); 7.75 (s, 2H); 7.62 (dd, J=8.7, 2.2 Hz, 1H); 7.54-7.38 (m, 1H); 7.29 (d, J=8.3 Hz, 1H); 6.74 (d, J=8.7 Hz, 1H); 6.28 (d, J=8.3 Hz, 1H); 5.75-5.30 (m, 1H); 4.81 (d, J=16.3 Hz, 1H); 4.21-4.00 (m, 6H); 3.79 (s, 3H); 2.48-2.38 (m, 2H); 0.67 (s, br, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])=O.O.[NH2:19][NH2:20]>C(O)C>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:12])[NH:20][N:19]=1
Reactant: NN
Reactant: Cc1ccsc1C(=O)c1ccccc1C(=O)O
Solvent: O
Solvent: CCO
Product: Cc1ccsc1-c1n[nH]c(=O)c2ccccc12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(3-methylthiophene-2-carbonyl)benzoic acid (0.446 g, 1.81 mmol) and hydrazine hydrate (0.41 mL, 7.3 mmol) in ethanol (6 mL) was stirred at 80° C. overnight, concentrated, and azeotroped with toluene to provide the title compound, which was used without purification: 1H NMR (300 MHz, DMSO-d6) δ 8.41-8.23 (m, 1H), 8.01-7.80 (m, 2H), 7.68 (d, J=5.1, 1H), 7.62-7.42 (m, 1H), 7.10 (d, J=5.1, 1H), 2.08 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:5]([NH:7][C:8]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][C:9]=1[C:10]([O:12]CC)=[O:11])=[O:6].O.[Li+].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:5]([NH:7][C:8]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][C:9]=1[C:10]([OH:12])=[O:11])=[O:6]
Reactant: CCOC(=O)c1cc(Oc2ccccc2)ccc1NC(=O)c1ccc(OC)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc(Oc3ccccc3)cc2C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
A solution of 43C (60 mg, 0.14 mmol) in THF (2 mL):water (1 mL) at 0° C. was treated with a 1 M solution of LiOH (0.17 mmol). The reaction was warmed to room temperature and stirred for 30 minutes. The solution was neutralized with 1 N HCl and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to afford 43D (42 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[N:14]=[C:15]([C:25](OC)=[O:26])[C:16]([C:21](OC)=[O:22])=[N:17][C:18]=1[O:19][CH3:20])(=[O:11])=[O:10].C([BH-](CC)CC)C.[Li+]>O1CCCC1>[OH:22][CH2:21][C:16]1[N:17]=[C:18]([O:19][CH3:20])[C:13]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])(=[O:10])=[O:11])=[N:14][C:15]=1[CH2:25][OH:26]
Reactant: COC(=O)c1nc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OC)nc1C(=O)OC
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1nc(CO)c(CO)nc1NS(=O)(=O)c1cccc(Cl)c1Cl
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a solution of 5-{[(2,3-dichlorophenyl)sulphonyl]amino}-6-methoxypyrazine-2,3-dicarboxylic acid, dimethyl ester (Example 211b, 0.5 g) dissolved in anhydrous tetrahydrofuran (20 mL) at 0° C. was added a solution of lithium triethylborohydride (Super is hydride®) (5.55 mL of a 1M solution in tetrahydrofuran) and the resulting solution was stirred for 1 hour. The reaction was quenched by the addition of 1N hydrochloric acid (10 mL) and extracted into ethyl acetate (2×20 mL). The combined extracts were dried (MgSO4), filtered and concentrated to afford an oil that was purified by chromatography on silica gel eluting with ethyl acetate/dichloromethane mixtures to afford the titled compound (0.201 g) as a foam.
Reaction SMILES: [OH:1][CH2:2][N:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:17])=[C:12]([F:16])[C:13]=2[F:15])[C:8](=[O:18])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6]1)[CH3:4].[CH2:24](N(CC)CC)[CH3:25].C(Cl)(=O)C>C(Cl)Cl.O>[CH2:24]([O:1][CH2:2][N:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:17])=[C:12]([F:16])[C:13]=2[F:15])[C:8](=[O:18])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6]1)[CH3:4])[CH3:25]
Reactant: CCOC(=O)c1cn(N(C)CO)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CCOCN(C)n1cc(C(=O)OCC)c(=O)c2cc(F)c(F)c(F)c21
Yield: 23 %

Procedure:
A solution of ethyl 1-[N-(hydroxymethyl)-N-methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (8.4 g) and triethylamine (3.09 g) in methylene chloride (150 ml) was cooled to 0° C. and treated with acetyl chloride (2.18 g). After 3 hours the reaction was diluted with water and shaken in a separating funnel. The organic layer was dried over magnesium sulfate, evaporated, and the crude product purified by chromatography with silica gel (50% ethyl acetate-hexane elution) to yield ethyl 1-[N-(ethoxymethyl)-N-methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (2.1 g).
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[C:19]4[CH:26]=[C:25]([C:27]5[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=5)[NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C:13]=2[CH3:33])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[C:19]4[CH:26]=[C:25]([C:27]5[CH2:28][CH2:29][N:30]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:31][CH:32]=5)[NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C:13]=2[CH3:33])=[O:10])=[CH:34][CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]c(C3=CCNCC3)cc12
Solvent: ClCCl
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]c(C3=CCN(S(C)(=O)=O)CC3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Intermediate 39 (80 mg, 0.172 mmol) and TEA (0.048 ml, 0.344 mmol) in DCM was added methanesulfonyl chloride (0.021 ml, 0.258 mmol) dropwise. The resulting mixture was stirred at r.t. for 16 hrs, then quenched with water, and extracted with EtOAc. The organic layer was dried with Na2SO4 and filtered. The solvents were removed in vacuo, and the crude product was purified by flash chromatography (silica gel, EtOAc/MeOH/N H3 gradient) to yield Example 44.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.CN1CCOCC1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:32]Br.C(O)C(N)(CO)CO>CN(C)C=O>[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:32][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1
Reactant: Fc1ccc(CBr)cc1F
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1nc(N)c2c(OCC3CCN(Cc4ccc(F)c(F)c4)CC3)cccc2n1
Reaction time: 2 h
Yield: 41.7 %

Procedure:
5-(Piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was shaken for 60 hours at 60° C. in the presence of 3-(morpholino)propyl polystyrene sulfonamide (PS-NMM) (160 mg; 0.4 mmol) and 3,4-difluorobenzyl bromide (77 mg; 0.37 mmol) in 4 mL N,N-dimethylformamide. Tris-(2-aminoethyl)aminomethyl polystyrene (PS-Trisamine) (112 mg; 0.4 mmol) was then added to the mixture and continued to shake for an additional 2 hours. Resins were filtered off and rinsed with methanol. Filtrate was concentrated at reduced pressure, and residue was triturated with 2 mL 1 N NaOH and ethanol (1:1). Solids were collected by filtration to yield 5-[1-(3,4-difluorobenzyl)piperidin-4-ylmethoxy]quinazoline-2,4-diamine (30 mg; 42% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.61 (m, 2H), 7.34 (m, 2H), 7.14 (m, 2H), 6.76 (m, 1H), 6.52 (m, 1H), 5.94 (br s, 2H), 3.99 (d, J=6.0 Hz, 2H), 3.46 (s, 3H), 3.12 (m, 1H), 2.82 (br d, J=10.8 Hz, 1H), 2.11 (m, 2H), 1.95 (m, 2H), 1.73 (br d, J=11.2 Hz, 1H), 1.34 (m, 1H). MS m/z (ESI) 400 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:12]=1)=[O:6].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.O>CN1CCCC1=O>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[C:11]1[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:22]=[CH:23][N:24]=[C:2]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[CH:3]=2)[S:9][CH:10]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(Cl)c3)n2)c(C)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(N4CCN(C)CC4)c3)n2)c(C)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
A mixture of 2-chloro-N-(4-mesitylthiazol-2-yl)isonicotinamide (300.0 mg, 0.8 mmol, 1.0 equiv) and 1-methylpiperazine (1.12 mL, 10.1 mmol, 12 equiv) in methylpyrrolidone (9.0 mL) was stirred at 150° C. for 16 h. The mixture was poured into icy H2O (15.0 mL) and the resultant solids were filtered to provide N-(4-mesitylthiazol-2-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide (95.6 mg, 0.20 mmol) as yellow solids in 27% yield: 1H NMR (CDCl3, 500 MHz) δ 8.27 (d, J=5.1 Hz, 1H), 7.12 (s, 1H), 6.83-6.86 (m, 3H), 6.78 (s, 1H), 3.63-3.65 (m, 4H), 2.35 (s, 3H), 2.27 (s, 3H), 2.04 (s, 6H); ESI-MS: m/z 422.1 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][C:12]1[C:16]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][CH:13]=1)C>C1COCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]2[O:14][CH:13]=[C:12]([CH2:11][CH2:10][OH:9])[C:16]=2[CH:17]=1
Reactant: CCOC(=O)Cc1coc2ccc(F)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1coc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of LiAlH4 (200 mg, excess) in THF at 0° C., ethyl(5-fluoro-1-benzofuran-3-yl)acetate (1.11 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH4Cl solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO4, filtered and concentrated. The product, 2-(5-fluoro-1-benzofuran-3-yl)ethanol, was obtained as a white oil and was pure enough to be taken to the next step without purification. Yield: 820 mg (91%); (M+H): 181.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([NH:54][CH2:55][C:56](O)=[O:57])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>ClCCl>[C:44]([NH:54][CH2:55][C:56]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:57])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Solvent: ClCCl
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)OCc1ccccc1
Yield: 47 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-glycine. Yield 47%. [α]D =+18.7° (c=0.95, dichloromethane). m.p. 108-109°.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:15])([CH3:14])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[H-].[Na+].[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([N+]([O-])=O)[C:22]=1[C:23]#[N:24])([O-:20])=[O:19]>C1COCC1>[C:23]([C:22]1[C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=[CH:26][C:25]=1[O:1][CH2:2][C:3]([CH3:15])([CH3:14])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])#[N:24]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(CO)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(COc1cccc([N+](=O)[O-])c1C#N)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of benzyl 3-hydroxy-2,2-dimethylpropanoate (Yang, D. et al. J. Am. Chem. Soc. 2002, 124, 9966. 6.68 g, 32.1 mmol) in dry THF (200 mL) was carefully added NaH (60% in mineral oil, 3.5 g, 87.5 mmol) in small portions at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. under nitrogen for 2 hrs. To this solution was added 2,6-dinitrobenzonitrile (6.19 g, 32.1 mmol), and the reaction solution was stirred at 0° C.—RT under nitrogen overnight. The reaction mixture was quenched with brine, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting (Elunet: 20% EtOAc in hexanes) to give the title compound as a brown solid (10.0 g, 87%). MS 355 (MH+).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([OH:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:19][C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:10]=2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Oc1cc(-c2ccccc2)nc(-c2ccncc2)n1
Product: Fc1ccc(COc2cc(-c3ccccc3)nc(-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared from 6-phenyl-2-pyridin-4-yl-pyrimidin-4-ol (which was obtained in Intermediate 3) and 4-fluorobenzyl bromide according to Method A; 1H NMR (DMSO-d6, 300 MHz) δ 5.72 (s, 2H), 7.50-7.70 (m, 6H), 7.93 (d, J=15.0 Hz, 2H), 8.30-8.37 (m, 2H), 8.37-8.41 (m, 2H), 8.80-8.90 (m, 2H); LC retention time 3.02 min; MS: m/z (ESI) 358 (M+H).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[NH2:8][C@H:9]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].C(OC(=O)C(=O)CCC1C=CC=CC=1)C.C(N(CC)CC)C.[H][H]>C(O)CCC.[Ni]>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH2:23]1[CH2:24][N:17]([C:15]([C@@H:9]([NH2:8])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:16])[C@@H:18]([C:19]([OH:21])=[O:20])[CH2:22]1
Reactant: [H][H]
Reactant: NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Ni]
Agent: CCOC(=O)C(=O)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: NCCCC[C@H](N)C(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 2 h

Procedure:
150 mmoles H-Nε -TFA-Lys-Pro-OH (50.9 g) were taken up in 120 ml n-butanol and approximately 50 ml n-butanol distilled off under vacuum. The solution was diluted with 500 ml ethanol. 22.5 g molecular sieve 3 A, 34 g 2-oxo-4-phenyl butyric acid ethyl ester and 30 mmoles triethylamine (4.2 ml) are added and the mixture agitated 2 hours under anhydrous conditions. Three teaspoons dehydrated Raney nickel were now added and the mixture was agitated for 4 hours at under an atmosphere of 4 bars of H2. After this time, the pressure was released, another 12.4 g 2-oxo-4-phenyl butyric acid ethyl ester was added and the mixture was reagitated for 2 hours. Then a pressure of 4 bars of hydrogen was applied and the mixture was hydrogenated a further 4 hours at this pressure. The catalyst was separated off (it can be directly reused) and the solution was evaporated to a small volume. Conversion (according to HPLC) relative to Nε -TFA-Lys-Pro: approximately 95%, product yield (according to HPLC): 90%, diastereomer ratio: SSS:RSS-isomer=95.5. The residue was suspended in 450 ml water and 450 ml 1,1,1-trichloroethane at 5° C., the pH was adjusted to 9.6 in the aqueous phase with 50% NaOH and the phases were thoroughly mixed. The organic phase was separated off and the aqueous product phase was post-extracted with 100 ml 1,1,1-trichloroethane. The pH of 4.6 was now adjusted to 5 in the aqueous phase and this phase was extracted twice with 400 ml 1,1,1-trichloroethane. The organic phase was evaporated to low volume and taken up in 250 ml methyl-tert.butyl ether. The solution was cooled down to 0° C. and seeded. Yield: 48 g (60% of theory), SSS diastereomer content: >99%, [α]D20 :-25.5° [(c=1 in MeOH/ ·1N HCl (1:1)].
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=O.Cl.[OH:13][NH2:14].C([O-])(=O)C.[Na+].C(O)C>O>[CH3:1]/[C:2](/[NH:14][OH:13])=[C:4]1/[CH:5]=[CH:6][C:7]([CH:8]=[C:9]/1[OH:10])=[O:11]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C/C(NO)=C1/C=CC(=O)C=C1O
Yield: 93.4 %

Procedure:
A mixture of 306 g of 2,4-dihydroxyacetophenone, 164 g of hydroxyamine hydrochloride, 328 g of sodium acetate, 1,000 ml of ethanol and 500 ml of water was refluxed by heating for 4 hours. The reaction solution was poured into 10 l of water to precipitate crystals and these crystals were collected by filtration. 314 g of 2,4-dihydroxyacetophenoneoxime was obtained.
Reaction SMILES: C(C([N:7]1[CH2:12][CH2:11][N:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)=O)(C)(C)C.[OH-].[Na+]>Cl>[N:10]1([C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]1
Reactant: CC(C)(C)C(=O)N1CCN([C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](N2CCNCC2)CC1

Procedure:
A stirred solution of 0.52 g of 1,3-dihydro-1-{trans-4-[4-(tert--butylcarbonyl)piperazin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one in 15 mL of 1N HCl was heated to reflux for 1 h, cooled and basified with 6N NaOH. The basic mixture was extracted with 2×50 mL portions of chloroform. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. After drying overnight under vacuum, there was obtained 0.28 g of 1,3-dihydro-1-{trans-4-[1-piperazinyl]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: 1H NMR (400 MHz, CDCl3) 7.16-7.03 (m, 4H), 4.27 (m, 1H), 2.94 (m, 4H), 2.61 (m, 4H), 2.25 (m, 2H), 2.1 (d, 2H), 1.97 (d, 2H), 1.54 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17].[OH-].[Na+]>C(O)C>[CH3:13][S:10]([C:8]1[CH:7]=[CH:6][C:5]([O:14][C@@H:15]([CH3:20])[C:16]([F:17])([F:18])[F:19])=[C:4]([CH:9]=1)[C:3]([OH:21])=[O:2])(=[O:12])=[O:11]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1O[C@@H](C)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To 0.604 mmol 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl ester in 1.97 ml ethanol was added 1.21 mmol 2 N aq NaOH solution and the reaction mixture was stirred at 80° C. for 0.5 hour. After such time the solvent was removed in vacuo, the residue was taken in water and acidified by addition of 2N HCl to yield after filtration the title compound as a white solid (88%). MS (m/e): 311.0 ([M−H]−, 100%)
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][C@@H:16]3[CH2:18][C@H:13]2[C:14](=[O:19])[S:15]3)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)Cl>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][C@@H:16]([SH:15])[CH2:18][C@H:13]2[C:14]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[O:19])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN1CCNCC1
Reactant: O=C1S[C@H]2C[C@@H]1N(C(=O)OCc1ccc([N+](=O)[O-])cc1)C2
Solvent: ClCCl
Product: CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 7 h

Procedure:
To a solution of (1S,4S)-5-p-nitrobenzyloxycarbonyl -2-thia-5-azabicyclo[2.2.1]heptan-3-one (308 mg) in methylene chloride (2.0 g) was added N-methylpiperazine (105 mg). The mixture was stirred for 7 hours at room temperatures. After the reaction was over, the solvent was distilled to give solid 1-[(2S,4S)-1-p-nitrobenzyloxycarbonyl-4-mercapto-2-pyrrolidinecarbonyl]-4-methylpiperazine.