Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H][H].[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)C.Cl.[S:14](=O)(=[O:17])([OH:16])[OH:15]>[Ni].[Pd].C(O)=O>[C:3]1([CH3:9])[CH:8]=[CH:7][C:6]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: Cc1ccccc1
Reactant: O=S(=O)(O)O
Agent: [Ni]
Agent: [Pd]
Agent: Cl
Solvent: O=CO
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
That is to say, 2-(1,3-dioxane-2-yl)ethyltriphenylphosphonium halide 12 and an aldehyde derivative 11 are subjected to a Wittig reaction in the presence of a base such as sodium methylate, potassium-t-butoxide (t-BuOK) or butyl lithium in an ether solvent such as tetrahydrofuran (abbreviated to as “THF”) or diethyl ether to obtain a compound 13. Next, the hydrogen reduction of the compound 13 is carried out in the presence of a metal catalyst such as palladium/carbon or a Raney nickel in a mixed solvent of toluene/ethanol, and the thus reduced compound is then reacted with a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as formic acid or p-toluenesulfonic acid to obtain an aldehyde derivative 14. Furthermore, this aldehyde derivative 14 and a compound 15 are subjected to the Wittig reaction in the same manner as in the above preparation of the compound 13 from the aldehyde derivative 11 to obtain a compound 16, and this compound is then reacted with the same acid as mentioned above, thereby preparing an aldehyde derivative 17. Next, this aldehyde derivative 17 is reacted with a Grignard reagent 18 to carry out a Grignard reaction, and the same acid as mentioned above is added to the reaction system to accomplish dehydration. In succession, the hydrogen reduction is done by the use of the same metal catalyst as mentioned above, whereby a derivative 19 having a butylene group can be manufactured.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[C:21]3[CH:20]=[C:19]([NH2:22])[CH:18]=[CH:17][C:16]=3[CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[Cl:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:36]=1[C:37](Cl)=[O:38].CO>ClCCl>[Cl:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:36]=1[C:37]([NH:22][C:19]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:23])[F:24])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C:21]=2[CH:20]=1)=[O:38]
Reactant: Nc1ccc2c(c1)C(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCC2
Reactant: O=C(Cl)c1c(F)cccc1Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)C(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCC2)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8-(4-Trifluoromethylbenzenesulfonyl)-5,6,7,8-tetrahydronaphthalen-2-ylamine (25 mg, 0.070 mmol) and diisopropylethylamine (23 μL, 0.14 mmol) were combined in dichloromethane (500 μL) to form a reaction mixture. 2-Chloro-6-fluorobenzoyl chloride (21 mg, 0.11 mmol) was then added and the reaction mixture, and the reaction mixture was stirred for 12 hours at room temperature. Next, methanol (100 μL) was added and the solvent was removed under reduced pressure to provide a residue, which was purified by HPLC to provide the title compound. LCMS (ESI): calc. C24H18ClF4NO3S=511; obs. M+H=512.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([CH2:15][CH2:16]Br)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[N:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:24]=[N:25][C:21]=2[CH:20]=1.C(N(C(C)C)CC)(C)C.CO>C(O)C>[NH2:2][C:3]1[S:4][C:5]([CH2:15][CH2:16][N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:22]4[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=4[N:25]=[N:24]3)[CH2:31][CH2:30]2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1
Reactant: Nc1nc(-c2ccc(F)cc2)c(CCBr)s1
Reactant: Fc1ccc2c(c1)nnn2C1CCNCC1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CO
Product: Nc1nc(-c2ccc(F)cc2)c(CCN2CCC(n3nnc4cc(F)ccc43)CC2)s1
Temperature: 25 °C

Procedure:
A mixture of 0.917 g of 2-amino-5-(2-bromoethyl)-4-(4-fluorophenyl)thiazole hydrobromide, 0.441 g of 4-(5-fluoro-1H-benzotriazol-1-yl)piperidine, 1 ml of diisopropylethylamine and 4 ml of methanol was stirred with heating under reflux for 12 hours. After the reaction mixture was cooled to room temperature, ethanol was added thereto and the crystals were collected by filtration. The crystals were recrystallized from chloroform-ethanol to obtain 0.56 g of 2-amino-4-(4-fluorophenyl)-5-[2-[4-(5-fluoro-1H-benzotriazol-1-yl)piperidin-1-yl]ethyl]thizole.
Reaction SMILES: [Na].[N+:2]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)([O-:4])=[O:3].Br[CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14]>C(#N)C>[CH3:14][C:13]([CH3:15])=[CH:12][CH2:11][N:6]1[CH:7]=[CH:8][N:9]=[C:5]1[N+:2]([O-:4])=[O:3]
Reactant: CC(C)=CCBr
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: [Na]
Solvent: CC#N
Product: CC(C)=CCn1ccnc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 80 %

Procedure:
To the sodium salt of 2-nitroimidazole prepared above was added acetonitrile (50 ml), 15-crown-5-ether (3.5 ml, 14.3 mmol) and 4-bromo-2-methyl-2-butene (2 ml; 17.4 mmol). The mixture was stirred at RT for ca 16 h. and then the solvent was removed to leave a crude semi-solid which was purified by column chromatography on silica. The intermediate product, 1-(3-methyl-2-butenyl)-2-nitroimidazole (80% yield) was eluted using a mixture of petroleum ether (40-60)/ethyl acetate (ratio 4:1 respectively).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([C:22]#[N:23])([CH3:21])[CH3:20])[CH:14]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[Br:25]Br.O>O1CCOCC1.C(Cl)Cl>[Br:25][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([C:22]#[N:23])([CH3:21])[CH3:20])[CH:14]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1cc(NC(=O)c2cccc(C(C)(C)C#N)c2)ccc1C
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a solution of N-(3-acetyl-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 112 (1.136 mmol, 364 mg) in dioxane (4 mL) and CH2Cl2 (1 mL) at 0° C. was added BROMINE (1.250 mmol, 0.064 mL). The reaction was stirred overnight at room temperature. Water was added and extracted with CH2Cl2. Organic layer was dried and evaporated to give N-(3-(2-bromoacetyl)-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 113 (450 mg, 99%). (m/z)=401 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20](SC)[N:19]=2)=[CH:4][CH:3]=1.O[O:27][S:28]([O-:30])=O.[K+].[CH3:32]O>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([S:28]([CH3:32])(=[O:30])=[O:27])[N:19]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3c(C)nccn23)n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1nccn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)nc12
Reaction time: 20 h
Yield: 38 %

Procedure:
To a solution of 2-(4-fluorophenyl)-8-methyl-3-(2-methylsulfanylpyrimidin-4-yl)-imidazo[1,2-a]pyrazine (Example #F.1A; 8.58 g, 24.4 mmol) in MeOH (200 mL) and DCM (200 mL) at ambient temperature was added Oxone® (30.0 g, 48.8 mmol) in water (100 mL) to form a suspension. After about 20 h of stirring the layers were separated. The aqueous layer was washed with DCM (3×30 mL). Combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to yield a yellow solid, which was purified via FCC using EtOAc as an eluent. The product-containing fractions were combined and concentrated under reduced pressure to give a white solid (6.5 g) that was recrystallized in IPA (700 mL) to yield the title compound (3.6 g) after filtration. Additional product was observed in the filtrate. (3.6 g, 38% yield): LC/MS (Table 1, Method b) Rt=1.7 min; MS m/z: 384.1 (M+H)+.
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH3:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][O:50][C:51]1[CH:52]=[C:53]([CH:57]=[C:58]([N:60]2[CH2:64][CH2:63][CH2:62][C:61]2=[O:65])[CH:59]=1)[C:54]([OH:56])=O.[CH:66]12[CH2:72][CH:69]([CH2:70][CH2:71]1)[CH2:68][CH:67]2[NH:73][C:74](=[O:89])[C@H:75]([CH3:88])[CH2:76][C@H:77]([OH:87])[C@@H:78]([NH2:86])[CH2:79][C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1>>[CH2:79]([C@H:78]([NH:86][C:54](=[O:56])[C:53]1[CH:57]=[C:58]([N:60]2[CH2:64][CH2:63][CH2:62][C:61]2=[O:65])[CH:59]=[C:51]([O:50][CH2:49][CH2:48][CH2:47][CH2:46][O:45][CH3:44])[CH:52]=1)[C@@H:77]([OH:87])[CH2:76][C@H:75]([C:74](=[O:89])[NH:73][CH:67]1[CH2:68][CH:69]2[CH2:72][CH:66]1[CH2:71][CH2:70]2)[CH3:88])[C:80]1[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Reactant: COCCCCOc1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: COCCCCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CC3CCC2C3)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to E6 from 3-(4-methoxybutoxy)-5-(2-oxopyrrolidin-1-yl)benzoic acid (D59) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[C:15]([C:16]3[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][C:10]([C:11](O)=[O:12])=[C:9]([F:24])[CH:8]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:60][S:61]([NH2:64])(=[O:63])=[O:62]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[C:15]([C:16]3[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][C:10]([C:11]([NH:64][S:61]([CH3:60])(=[O:63])=[O:62])=[O:12])=[C:9]([F:24])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: COc1ncccc1-c1cc(C(=O)O)c(F)cc1Oc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ncccc1-c1cc(C(=O)NS(C)(=O)=O)c(F)cc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 117.9 %

Procedure:
To a mixture of 4-(4-chlorophenoxy)-2-fluoro-5-(2-methoxypyridin-3-yl)benzoic acid (Preparation 30, 236 mg, 0.63 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (462 mg, 1.21 mmol), N,N-diisopropylethylamine (838 μL, 4.81 mmol) in dichloromethane (40 mL) and dimethylformamide (5.4 mL) which had been stirred at room temperature for 10 minutes was added methyl sulfonamide (151 mg, 1.59 mmol). The reaction was heated at 45° C. for 18 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated in vacuo to afford a brown residue. The brown residue was partitioned between aqueous hydrochloric acid (0.5 M, 40 mL) and dichloromethane (100 mL). The organic extract was washed with aqueous hydrochloric acid (0.5 M, 2×40 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil (335 mg). The product was purified by flash column chromatography eluting with dichloromethane/methanol (100% to 97%) to afford a yellow gum (91.0 mg). A portion of this material (50 mg) was purified by A-HPLC to afford the title compound as an off-white solid (35.8 mg, 13%):
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)[CH:19]=1)[C:10]([O:12]C(C)(C)C)=[O:11])[C:3]([F:6])([F:5])[F:4].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([O-:31])=[O:30].[NH2:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)[CH:19]=1)[C:10]([OH:12])=[O:11])[C:3]([F:4])([F:5])[F:6]
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C(N)C(F)(F)F)c2)nc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(N)C(F)(F)F)c2)nc1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl 3-(1-amino-2,2,2-trifluoroethyl)-5-(5-methylpyridin-2-yl)benzoate (30.0 mg, 0.08 mmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.3 mL). The mixture was stirred at ambient temperature. After 5 h, the mixture was concentrated to dryness to give the trifluoracetate salt of the title compound (35 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[CH2:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12])[C:5]([N+:21]([O-])=O)=[CH:4][N:3]=1>CC(O)=O.Cl.O.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:21][C:11](=[O:12])[C:10]([F:17])([F:16])[CH2:9][N:8]([CH:18]([CH3:20])[CH3:19])[C:6]=2[N:7]=1
Reactant: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)N1CC(F)(F)C(=O)Nc2cnc(Cl)nc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
Ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(isopropyl)amino)-2,2-difluoropropanoate (1.90 g, 5.39 mmol) was dissolved in HOAc (10 mL) and HCl (conc, 3.1 mL). Iron (0.610 g, 10.9 mmol) was added and the rm was stirred at rt for 3 h and at 60° C. overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated in vacuo. The residue was purified using flash column chromatography on silica gel (40 g SiO2, hexanes:ethyl acetate 2:1-1:1) to afford the title compounds as a light yellow solid (0.809 g, 54%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (d, J=6.82 Hz, 6 H) 3.42 (s, 3 H) 3.89 (t, J=12.38 Hz, 2 H) 4.97-5.10 (m, 1 H) 8.06 (s, 1 H).
Reaction SMILES: BrC1C=CC([C:8]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]=3[CH:9]=2)=CC=1.[Br:22][C:23]1[CH:24]=[C:25](I)[CH:26]=[CH:27][CH:28]=1>>[Br:22][C:23]1[CH:28]=[C:27]([C:8]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]=3[CH:9]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Brc1ccc(-c2ccc3c(ccc4ccccc43)c2)cc1
Reactant: Brc1cccc(I)c1
Product: Brc1cccc(-c2ccc3c(ccc4ccccc43)c2)c1

Procedure:
Synthesis was performed in the same manner as in the synthesis of 2-(4-bromophenyl)phenanthrene except that 3-bromoiodobenzene was used instead of 4-bromoiodobenzene.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C(N(CC)CC)C.O1CCOCC1.[CH3:19][C@@H:20]([C@@H:27]1[C@@:31]2([CH3:49])[CH2:32][CH2:33][CH:34]3[C@@:39]4([CH3:48])[CH2:40][CH2:41][CH:42]([O:44][C:45](Cl)=[O:46])[CH2:43][C:38]4=[CH:37][CH2:36][CH:35]3[CH:30]2[CH2:29][CH2:28]1)[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25]>O>[CH3:26][CH:24]([CH2:23][CH2:22][CH2:21][C@H:20]([C@@H:27]1[C@:31]2([CH3:49])[C@H:30]([C@H:35]3[C@H:34]([CH2:33][CH2:32]2)[C@:39]2([CH3:48])[C:38]([CH2:43][C@@H:42]([O:44][C:45]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:46])[CH2:41][CH2:40]2)=[CH:37][CH2:36]3)[CH2:29][CH2:28]1)[CH3:19])[CH3:25]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: NCC(=O)O
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
To a suspension of glycine (1.50 g) in water (100 ml) was added triethylamine (4.04 g). After dioxan (200 ml) and cholesteryl chloroformate (8.98 g) were added to the resulting clear solution at 0° C., the mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure and, 1 N hydrochloric acid (23 ml) and chloroform (100 ml) were added to the residue. The organic phase was separated and washed with water and then dried over magnesium sulfate. The solvent was distilled off to give crude crystals. After washing with ethanol, the crystals were filtered to give N-(cholest-5-ene-3β-oxycarbonyl)glycine (6.64 g) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].Cl.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:31]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[O:38])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccncc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 100, Step 1, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and isonicotinoyl chloride hydrochloride.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][CH:15]1[CH:19]([CH3:20])[N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:17](=[O:30])[CH2:16]1.O>C(Cl)Cl>[CH3:8][S:9]([O:13][CH2:14][C@H:15]1[CH2:16][C:17](=[O:30])[N:18]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C@@H:19]1[CH3:20])(=[O:11])=[O:10]
Reactant: COc1ccc(CN2C(=O)CC(CO)C2C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(=O)C[C@H](COS(C)(=O)=O)[C@H]2C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (1.47 g, 14.57 mmol) and methanesulfonyl chloride (1.25 g, 10.93 mmol) were added to a solution of rac-(4R,5S)-4-(hydroxymethyl)-1-(4-methoxybenzyl)-5-methylpyrrolidin-2-one (1.8 g, 7.29 mmol) in DCM (36 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour, and then water (70 mL) was added and the mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to afford [(2R,3S)-1-(4-methoxybenzyl)-2-methyl-5-oxopyrrolidin-3-yl]methyl rac-methanesulfonate. MS ESI calc'd. for C15H22NO5S [M+H]+ 328. found 328. 1H NMR (400 MHz, CDCl3): δ 7.17 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.96-4.91 (m, 1H), 4.10-4.05 (m, 2H), 3.91-3.86 (m, 1H), 3.81 (s, 3H), 3.36-3.30 (m, 1H), 2.92 (s, 3H), 2.76-2.68 (m, 1H), 2.39-2.29 (m, 1H), 2.27-2.20 (m, 1H), 1.24 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:18]([OH:20])=[O:19])[CH:11]=[CH:10][CH:9]=1.C(O)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CO>[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:18]([O:20][CH3:1])=[O:19])[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of (trimethylsilyl)diazomethane (8.0 mL of a 2.0 M solution in hexanes, 16.0 mmol) was added slowly to a suspension of quinoline-8-carboxylic acid (2.0 g, 11.5 mmol) in toluene (80 mL) and MeOH (12 mL) at 0° C. After 30 min at 0° C., the reaction mixture was warmed to room temperature and stirred for 64 h. Aqueous acetic acid was added and then enough saturated aqueous Na2CO3 was added to bring the pH to 7.5. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried (MgSO4SO4), filtered and concentrated in vacuo. The resulting brown oil was purified on 40 g silica gel (2:1 CH2Cl2/EtOAc) to afford 1.72 g (80%) of methyl quinoline-8-carboxylate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([OH:13])[CH2:11][NH2:12].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](=O)[CH3:30])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CO>ClCCl>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH:29]([NH:12][CH2:11][CH:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[OH:13])[CH3:30])=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NCC(O)c1cc2ccccc2o1
Reactant: CC(=O)Cc1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(Cc1ccc(OCc2ccccc2)cc1)NCC(O)c1cc2ccccc2o1

Procedure:
This was prepared in an identical manner to the compound described in Example 2 using 2-(2-benzofuranyl)-2-hydroxyethanamine (3.51 g) and 1-(4-benzyloxyphenyl)propan-2-one (4.75 g). Chromatography of the residual oily solid on Kieselgel 60 (4% methanol in dichloromethane) gave the title compound, m.p. 111°-122°, as a 20:80 mixture of diastereoisomers.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29]C)=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:26][O:25][C:24]1[C:3](=[O:2])[C:4]([CH3:31])=[C:5]([CH2:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:8]=2)[C:22](=[O:29])[C:23]=1[O:27][CH3:28]
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(-c3ccccc3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(-c3ccccc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.7 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-phenylbenzoic acid (76 mg, 1.1800 mmol) was dissolved in a mixed solvent of acetonitrile (3 ml) and water (1 ml), then CAN (247 mg, 0.4507 mmol) was added thereto at room temperature and the mixture was stirred for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (5% methanol-methylene chloride) to give the title compound (54 mg, 0.1377 mmol, 77%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]([CH3:35])[C@@H:19]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:17])=[CH:11][CH:10]=1)=O)CCC.[ClH:36].[OH-].[Na+]>C1(OC)C=CC=CC=1.CC(O)=O>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]([CH3:35])[C@@H:19]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:17])=[CH:11][CH:10]=1.[ClH:36]
Reactant: CCCCOC(=O)Nc1ccc(CC(=O)N(C)[C@H](CN2CCCC2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COc1ccccc1
Solvent: CC(=O)O
Product: CN(C(=O)Cc1ccc(N)cc1)[C@H](CN1CCCC1)c1cccc([N+](=O)[O-])c1

Procedure:
The product from Example 59 (2.9211 g, 6.053 mmol) and anisole (2 drops) were mixed in AcOH (10 mL) and 4N HCl (10 mL) and stirred at 25° C. overnight, fitted with a drying tube. The mixture was adjusted to pH 13 with 1N NaOH with stirring in ice-H2O and then extracted with CH2Cl2 (2×70 mL). The combined organic fraction was dried (Na2SO4), filtered through celite, and evaporated. The product was gravity column chromatographed eluting with CHCl3:2% NH3 before it was converted to the HCl salt with Et2O—HCl to yield 15 HCl.(0.5531 g, 22%, unoptimized): m.p. (HCl salt) 200° C. (dec); 1H NMR (HCl salt, DMSO-d6) δ1.98 (br s, 4H, —CH2CH2—), 2.86 (s, 3H, —NCH3), 3.2-4.3 (complex, 8H, 4 —CH2—), 7.16 (d, J=7.4 Hz, 2H, aromatic), 7.33 (d, J=7.5 Hz, 2H, aromatic), 7.7 (m, 2H, aromatic), 8.08 (s, 1H, aromatic), 8.23 (m, 1H, aromatic). MS(FAB) m/z 383. Anal. (C, H, N) C21H26N4O30.2HCl.0.75H2O.