Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:18]3)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:31][C:32]#[C:33][CH2:34][CH2:35]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22]([CH2:35][C:34]#[C:33][CH2:32][Cl:31])[C@@:16]2([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:18]3)[CH:4]=[C:3]([C:2]([F:29])([F:1])[F:30])[CH:8]=1
Reactant: ClC#CCCCl
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3CC#CCCl)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of (1R*,2R*,5R*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 60; 400 mg, 0.93 mmol) in dimethylformamide (4 ml) was added to 1,4-dichlorobutyne (0.23 ml, 2.33 mmol) and potassium carbonate (386 mg, 2.79 mmol) in dimethylformamide (2 ml) at 60° C. The reaction mixture was stirred under N2 at 60° C. overnight. The mixture was diluted with water and extracted with ethyl acetate (×3), dried (MgSO4) and concentrated in vacuo to give a brown oil. This was purified by flash column chromatography [2.5%-7.5% methanol in dichloromethane] to give the title compound as a brown oil.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17](O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4]CC1.C(=O)CC(C)C.C(N)CCC.C([O:42][C:43](=[O:53])C(SC1SC(N)=NC=1)C)C>>[CH2:1]([N:7]([CH2:21][CH2:22][CH:23]([CH3:24])[CH3:28])[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][CH2:17][C:43]([OH:53])=[O:42])=[CH:13][N:14]=1)[CH2:6][CH2:5][CH3:4]
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: CCOC(=O)C(C)Sc1cnc(N)s1
Agent: CC(C)CC=O
Solvent: CCCCN
Product: CCCCN(CCC(C)C)C(=O)Nc1ncc(SCCC(=O)O)s1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid using isovaleraldehyde, butylamine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([O:8]C(C2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:4][N:3]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].[OH-].[Na+].O>C1COCC1.CO>[OH:8][C@H:5]1[CH2:4][N:3]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C@H:2]([CH3:1])[CH2:7][CH2:6]1
Reactant: C[C@@H]1CC[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CC[C@@H](O)CN1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of benzyl (2R,5R)-2-methyl-5-{[(4-nitrophenyl)carbonyl]oxy}piperidine-1-carboxylate (54.3 g, 136 mmol) in THF (850 mL) and MeOH (138 mL) was added 1 N NaOH (204 mL) and water (30 mL). The solution was stirred overnight, then concentrated in vacuo. The residue was diluted with minimal brine and water and extracted twice with EtOAc. The organics were washed with brine, dried over MgSO4, filtered, and concentrated to give the titled compound as a crude, orange-yellow oil which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.28-7.36 (m, 5H), 5.14 (d, J=3.5 Hz, 2H), 4.50 (t, J=6.8 Hz), 1H), 4.09 (d, J=8.8 Hz, 1H), 3.94 (s, 1H), 3.09 (dd, J=14.3, 1.9 Hz, 1H), 2.06-2.15 (m, 1H), 1.96 (br s, 1H), 1.75-1.83 (m, 1H), 1.66-1.72 (m, 1H), 1.24-1.32 (m, 2H), 1.16 (d, J=7.0 Hz, 2H) ppm. LRMS m/z (M+H) 250.1 found, 250.1 required.
Reaction SMILES: C[C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[C:8]([OH:10])=O.[NH2:11][CH:12]([CH3:16])[C:13]([O-:15])=[O:14].[CH3:17]N(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>C1COCC1>[Cl:7][C:5]1[S:4][C:3]([C:8]([NH:11][CH:12]([CH3:16])[C:13]([O:15][CH3:17])=[O:14])=[O:10])=[CH:2][CH:6]=1
Reactant: CC(N)C(=O)[O-]
Reactant: Cc1cc(Cl)sc1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)C(C)NC(=O)c1ccc(Cl)s1

Procedure:
Prepared analogously to Example 1a from methyl 5-chloro-thiophene-2-carboxylic acid and 2-aminopropionate with TBTU and NMM in THF.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([C:24]2[N:25]=[C:26]([NH:29][C:30](=[O:32])[CH3:31])[S:27][CH:28]=2)=[O:23])=[CH:17][CH:16]=1)=[O:11])[NH:2]C(OC(C)(C)C)=O.O1CCOCC1.[ClH:39]>ClCCl>[ClH:39].[C:30]([NH:29][C:26]1[S:27][CH:28]=[C:24]([C:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][O:12][C:10]([NH:1][NH2:2])=[O:11])=[CH:20][CH:19]=2)=[O:23])[N:25]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Nc1nc(C(=O)Oc2ccc(CCOC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(C(=O)Oc2ccc(CCOC(=O)NN)cc2)cs1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.1 %

Procedure:
To a suspension of 2-[4-({[2-(acetylamino)-1,3-thiazol-4-yl]carbonyl}oxy)phenyl]ethyl tert-butyl hydrazine-1,2-dicarboxylate (371.6 mg, 0.800 mmol) in anhydrous dichloromethane (4 ml) was added 4M hydrogen chloride dioxane solution (4 ml). After stirring at room temperature for 2.5 hr, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. The operation was performed twice to remove hydrogen chloride gas azeotropically. The residue was suspended in a mixture of ethanol (5 ml) and ethyl acetate (30 ml), and the suspension was filtered. The filtered product was washed twice with ethyl acetate and dried under reduced pressure to give the title compound (317.7 mg, 0.793 mmol, yield 99.1%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][N:7]([C:14]1[C:15]([CH3:34])=[C:16]([CH3:33])[C:17]3[O:21][C:20]([CH3:23])([CH3:22])[CH:19]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)[C:18]=3[C:31]=1[CH3:32])[CH2:6]2.[CH:35](Cl)(Cl)[Cl:36]>>[ClH:36].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][N:7]([C:14]1[C:15]([CH3:34])=[C:16]([CH3:33])[C:17]3[O:21][C:20]([CH3:23])([CH3:22])[CH:19]([C:24]4[CH:25]=[CH:26][C:27]([CH2:30][CH3:35])=[CH:28][CH:29]=4)[C:18]=3[C:31]=1[CH3:32])[CH2:6]2
Reactant: ClC(Cl)Cl
Reactant: COc1cc2c(cc1OC)CN(c1c(C)c(C)c3c(c1C)C(c1ccc(C)cc1)C(C)(C)O3)C2
Product: CCc1ccc(C2c3c(C)c(N4Cc5cc(OC)c(OC)cc5C4)c(C)c(C)c3OC2(C)C)cc1
Product: Cl
Yield: 61 %

Procedure:
By using (−)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, the title compound was synthesized according to Example 19a. Yield: 61%. Melting point: 173-175° C. [α]D=−44.4° (c=0.501, chloroform)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:24]1[C:29]([C:30]2[N:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=3)[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[N:31]=2)=[CH:28][C:27]([CH2:56][N:57]2[CH2:62][CH2:61][N:60]([S:63]([CH3:66])(=[O:65])=[O:64])[CH2:59][CH2:58]2)=[CH:26][N:25]=1>C1COCC1>[CH3:55][O:54][C:51]1[CH:50]=[CH:49][C:48]([CH2:47][N:37]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[C:32]2[N:33]=[C:34]([CH3:36])[N:35]=[C:30]([C:29]3[C:24]([NH:1][C:2]4[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=4)=[N:25][CH:26]=[C:27]([CH2:56][N:57]4[CH2:62][CH2:61][N:60]([S:63]([CH3:66])(=[O:65])=[O:64])[CH2:59][CH2:58]4)[CH:28]=3)[N:31]=2)=[CH:53][CH:52]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Reactant: CC(=O)Nc1ccc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(NC(C)=O)c(F)c3)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.8 %

Procedure:
A mixture of N-(4-amino-2-fluorophenyl)acetamide (0.110 g, 0.654 mmol) in THF (5 mL) was cooled to 0° C. under N2. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (Aldrich) (0.636 mL, 3.27 mmol) was added and the mixture was stirred at 0° C. for 30 min before 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.447 g, 0.720 mmol) was added. The resulting mixture was stirred at 0° C. for 10 min, and then the ice bath was removed and stirring was continued for 2 h. The reaction was quenched with sat. NH4Cl. The resulting mixture was partitioned between pH 7 buffer (1 M TRIS-HCl) and CHCl3. The aqueous layer was extracted with CHCl3 (2×15 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 3% MeOH and 12% EtOAc in DCM) to give the product as a yellow solid (0.125 g). m/z (ESI, +ve ion) 770.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 11.99 (br. s., 1H); 8.73 (s, 1H); 8.28 (s, 1H); 8.02-8.16 (m, 1H); 7.91 (s, 1H); 7.22 (d, J=7.45 Hz, 5H); 6.96 (d, J=8.33 Hz, 1H); 6.88 (d, J=8.18 Hz, 4H); 4.86 (br. s., 4H); 3.81 (d, J=2.92 Hz, 6H); 3.52 (s, 2H); 3.19 (br. s., 4H); 2.72 (s, 3H); 2.61 (s, 3H); 2.48-2.59 (m, 4H); 2.21 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][C:7]([CH3:21])=[N:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=3)[C:4]=2[CH:3]=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].C(N(CC)CC)C>C1CCCCC1>[C:28]1([O:27][C:25]([N:8]2[C:7]([CH3:21])=[CH:6][C:5]3[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][C:4]=3[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=3)=[N:9]2)=[O:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC1=NN=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)ccc2C1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCCCC1
Product: CC1=Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])c(C)c2)=NN1C(=O)Oc1ccccc1
Yield: 57.9 %

Procedure:
15 g (45.7 mmoles) of 8-chloro-4-methyl-1-(3-methyl-4-nitrophenyl)-5H-2,3-benzodiazepine are boiled in a mixture of 28.85 ml (228.5 mmoles) of phenyl chloroformate and 6.34 ml (45.7 mmoles) of triethylamine for 3.5 hours. The reaction mixture is diluted with 150 ml of cyclohexane, the solvent is decanted off the separated oily product, the residue is dissolved in dichloromethane, washed first with saturated sodium hydrogen carbonate solution, then with water and dried over anhydrous sodium sulfate. After evaporation the crude product is recrystallized from ethanol. Thus 11.86 g (58%) of the desired compound (yellow) melting at 188-190° C. are obtained.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@@H:24]([OH:26])[CH2:25][C@H:20]4[CH2:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5](OC)=[O:6].[CH3:29][O:30][CH2:31][CH2:32][O:33][CH2:34]Cl.C(N(C(C)C)CC)(C)C.CCOCC>C(Cl)Cl>[CH3:29][O:30][CH2:31][CH2:32][O:33][CH2:34][O:26][C@@H:24]1[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:20]([CH2:19][CH2:18][C@@H:17]3[C@@H:16]2[CH2:15][CH2:14][C@@:13]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH:5]=[O:6])[CH2:25]1
Reactant: COCCOCCl
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: COCCOCO[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC=O)CC[C@@H]32)C1
Reaction time: 4 h

Procedure:
Methyl lithocholate is dissolved in methylene chloride, and β-methoxyethoxymethyl chloride and diisopropylethylamine are added. The mixture is stirred for four hours, ether added and washed with water. After drying the solvents are evaporated, the residue dissolved in toluene and the 24-ester group reduced to the 24-alcohol group with Vitride. The 24-alcohol then is oxidized with chromium trioxide-pyridine and the 3α-(β-methoxyethoxymethoxy)-5β-cholane-24-aldehyde obtained.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:10]1[C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:17])=[O:16]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccccc2)c1Br
Yield: 71 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-biphenylsulfonamide was prepared in the same manner as described in Example 200b from 5-amino-4-bromo-3-methylisoxazole and 2-biphenylsulfonyl chloride in 71% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 145-147° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[C:20](O)=[O:21])=[O:6])[CH:2]=[CH2:3].[CH:23]1(N=C=NC2CCCCC2)CCCCC1.CC1(C)OC(=O)CC(=O)O1.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[C:20]([C@@H:8]1[CH2:9][C@@H:10]([O:12][Si:13]([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:15])[CH3:14])[CH2:11][N:7]1[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])(=[O:21])[CH3:23]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)O
Agent: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-carboxypyrrolidine (15 g) in dichloromethane (150 ml) were added dicyclohexylcarbodiimide (11.5 g), Meldrum's acid (8.0 g) and 4-dimethylaminopyridine (6.8 g) at 0° C. After stirring for 24 hours at ambient temperature, the resulting precipitate was removed by filtration. The filtrate was washed with 1N hydrochloric acid solution, and evaporated in vacuo. The residue was dissolved in a mixture of acetic acid (80 ml) and water (60 ml), and refluxed for 1 hour. Evaporation of the solvent gave a residue, which was taken up into ethyl acetate. The solution was washed in turn with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated. The residue was dissolved in dimethylformamide (60 ml) and then imidazole (8.7 g) and t-butyldimethylsilyl chloride (8.7 g) were added thereto at ambient temperature. After stirring for 10 hour, the mixture was poured into water (200 ml), extracted with ethyl acetate (100 ml×2), dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1, V/V) to give (2S,4R)-2-acetyl-1-allyloxycarbonyl-4-t-butyldimethylsilyloxypyrrolidine (10.6 g).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N2CCN(C(C3C=C4C(=CC=3)NC(C(N3CCS(=O)(=O)CC3)=O)=C4)=O)CC2)CCCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:80][C:81]1[CH:87]=[CH:86][CH:85]=[CH:84][C:82]=1[NH2:83].C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:80][C:81]1[CH:87]=[CH:86][CH:85]=[CH:84][C:82]=1[NH:83][C:23]([C:18]1[NH:19][C:20]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:12]([N:9]1[CH2:8][CH2:7][N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:11][CH2:10]1)=[O:13])=[CH:22][CH:21]=2)=[O:24]
Reactant: Nc1ccccc1F
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1F)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Yield: 6 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride (example 34, intermediate b), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2-fluoroaniline (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow solid (6%).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[H][H].F[C:17]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>CN(C)C=O.O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([O:13][C:17]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:18]=2[C:19]([NH:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:20])=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=C(Nc1ccccc1)c1cc([N+](=O)[O-])ccc1F
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cc2C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 47 %

Procedure:
To 0.18 g (6 mmole) of 80% sodium hydride in 7.5 ml of dry dimethylformamide was slowly added 0.9 g (6 mmole) of 4-t-butylphenol in 2.5 ml of dimethylformamide. After cessation of hydrogen evolution, 1.3 g (5 mmole) of solid 2-fluoro-5-nitrobenzanilide was added and the deep red solution was stirred at room temperature for 5 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with IN hydrochloric acid, saturated aqueous sodium bicarbonate solution, dried with magnesium sulphate and the solvent removed to yield the crude product. Recrystallisation from methylene chloride and hexare yielded 0.92 g product (47%) m.p. 138°-140° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=[O:16])[CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.N[CH:19](C(=O)C1CCOC1)[C:20](OCC)=O.O1CCC(C(Cl)=O)CC1.C(OCC)(OCC)(OCC)C>CO>[CH3:19][C:20]1[O:16][C:9]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=1
Reactant: CCOC(=O)C(N)C(=O)C1CCOC1
Reactant: CCOC(=O)C(N)C(=O)C1CCOCC1
Agent: CCOC(C)(OCC)OCC
Agent: Cl
Agent: O=C(Cl)C1CCOCC1
Solvent: CO
Product: CCOC(=O)c1nc(C)oc1C1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl 2-amino-3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate, hydrochloride salt [C61, which may be prepared according to the general procedure for synthesis of ethyl 2-amino-3-oxo-3-(tetrahydrofuran-3-yl)propanoate, hydrochloride salt (C11) in Example 3, through the use of tetrahydro-2H-pyran-4-carbonyl chloride in place of tetrahydrofuran-3-carbonyl chloride] (200 g, ≦0.56 mol) was combined with triethyl orthoacetate (200 mL, 1.1 mol) in methanol (200 mL), and the reaction was stirred at room temperature for 2 days. Concentration in vacuo afforded the crude intermediate, ethyl 2-methyl-5-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole-4-carboxylate (C62). This was mixed with acetic acid (500 mL), treated with ammonium acetate (600 g, 7.8 mol) and heated to 99° C. for 2 days. At this point, additional ammonium acetate (100 g, 1.3 mol) was added, and heating was continued for 24 hours. The reaction mixture was then diluted with ethyl acetate (4 L) and water (2 L), and the pH was adjusted to ˜9 with aqueous ammonium hydroxide solution. The aqueous layer was extracted with ethyl acetate (1 L), and the combined organic layers were diluted with cyclohexane (1 L), washed with saturated aqueous potassium bicarbonate solution (1 L), washed with saturated aqueous sodium chloride solution (1 L), and concentrated under reduced pressure. The residue was dissolved in diethyl ether (1 L) and seeded; the resulting crystals were isolated by filtration, affording the product as a solid. Yield: 75 g, 0.31 mol, 55% from tetrahydro-2H-pyran-4-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:23][CH2:22][C@@H:21]3[CH2:24][C@H:18]2[C:19](=[O:32])[N:20]3[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:13]1=[O:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[BH4-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:23][CH2:22][C@@H:21]([NH:20][C:25](=[O:26])[O:27][C:28]([CH3:30])([CH3:31])[CH3:29])[CH2:24][C@H:18]2[CH2:19][OH:32])[C:13]1=[O:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CO)C1
Reaction time: 5 h
Yield: 104.1 %

Procedure:
(1R,2S,5R)-tert-Butyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (2.0 g) was dissolved in THF (50 mL) and water (15 mL) prior to the addition of NaBH4 (827 mg). After 5 h, the reaction was quenched with saturated NaHCO3 solution and extracted with EtOAc (2×). The organic extracts were combined, dried (MgSO4), filtered, and concentrated in vacuo to afford tert-butyl (1R,3R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-(hydroxymethyl)cyclohexylcarbamate (2.1 g). MS (ES+)=462.5 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[CH2:12]([S:15](Cl)(=[O:17])=[O:16])[CH2:13][CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:15]([CH2:12][CH2:13][CH3:14])(=[O:17])=[O:16])[CH2:7][CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCCN2
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)N1CCCc2cc(Br)ccc21
Yield: 43.2 %

Procedure:
This compound was prepared according to the general procedure for sulfonylation of indolines and tetrahydroquinolines described in Example 4 using 6-bromo-1,2,3,4-tetrahydroquinoline (0.40 g, 1.89 mmol) and propanesulfonyl chloride (0.31 mL, 2.8 mmol) to provide 6-bromo-1-(propylsulfonyl)-1,2,3,4-tetrahydroquinoline (0.26 g). MS (ES) m/z 317.6; HPLC purity 100.0% at 210-370 nm, 10.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [OH:1][CH:2]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:3]1[NH:12][C:13]([CH3:15])=[O:14].CC(O[C:20]([CH3:22])=[O:21])=O.[CH2:23]([OH:26])[CH:24]=C>N1C=CC=CC=1.C[N+]([O-])=O>[C:13]([NH:12][C@H:3]1[C@@H:4]([O:5][C:23](=[O:26])[CH3:24])[C@H:6]([O:7][C:2](=[O:1])[CH3:3])[C@@H:8]([CH2:10][O:11][C:20](=[O:21])[CH3:22])[O:9][C@@H:2]1[O:1][CH2:8][CH:6]=[CH2:4])(=[O:14])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCO
Reactant: CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: c1ccncc1
Solvent: C[N+](=O)[O-]
Product: C=CCO[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1NC(C)=O

Procedure:
A solution of ManNAc (5.0 g, 2.6 mmol), and Ac2O (10 mL) in pyridine (20 mL) was stirred for 10 hours at room temperature, and the mixture was concentrated, followed by coevaporation with toluene. A solution of the residue, allyl alcohol (2.63 g, 45.2 mmol; 3.1 mL), BF3 ·OEt2 (1.60 g, 11.3 mmol; 1.39 mL) in CH3NO2 (150 mL) was gently refluxed for 2.5 hours. After cooling, the mixture was concentrated. The residue was chromatographed on silica gel, with toluene-EtOAc (1:2) to give allyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-mannopyranoside in 6.47 g (74 percent);