Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4].[Na+].[I-:18].[O-][Mn](=O)(=O)=O.[K+]>CC(C)=O>[I:18][CH2:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)CCl
Reactant: [I-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)CI
Temperature: 25 °C
Reaction time: 18 h
Yield: 116.5 %

Procedure:
To a solution of tert-butyl 2-(2-chloroacetyl)pyrrolidine-1-carboxylate (5 g, 20.24 mmol) in 200 mL of acetone was added 3 g (20.24 mmol) of NaI. The reaction was let to stir at room temperature for 18 h. The reaction was monitored by TLC (20% EtOAc/hexanes, the plate was developed by KMnO4 stain). The reaction mixture was filtered over celite, concentrated and dried to afford tert-butyl 2-(2-iodoacetyl)pyrrolidine-1-carboxylate (8 g, 99% yield). 1H NMR (CDCl3): δ 1.45 (d, 9H), 1.99 (s, 3H), 2.20 (m, 1H), 3.50 (m, 2H), 4.90 (m, 2H), 4.50 (m, 1H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:53])[C:7]([S:25][C@@H:26]1[CH2:30][CH2:29][O:28][C@@H:27]1[CH2:31][NH:32][C:33](=[O:52])[C@@H:34]([NH:38]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH:35]([CH3:37])[CH3:36])=[C:8]2[C:12]([O:14]CC1C=CC([N+]([O-])=O)=CC=1)=[O:13])[CH3:3].O>C(O)CCCCC.[Pd]>[NH2:38][C@@H:34]([CH:35]([CH3:37])[CH3:36])[C:33]([NH:32][CH2:31][C@@H:27]1[C@H:26]([S:25][C:7]2[C@H:6]([CH3:53])[C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([OH:14])=[O:13])[CH2:30][CH2:29][O:28]1)=[O:52]
Reactant: CC(C)[C@H](NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC[C@H]1OCC[C@H]1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Agent: [Pd]
Solvent: CCCCCCO
Solvent: O
Product: CC(C)[C@H](N)C(=O)NC[C@H]1OCC[C@H]1SC1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reaction time: 23 h
Yield: 81.6 %

Procedure:
To a mixture of 0.302 g of 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-{[(2R,3R)-2-({[(2S)-3-methyl-2-({[(4-nitrobenzyl)oxy]carbonyl}amino)-butanoyl]amino}methyl)tetrahydrofuran-3-yl]thio}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in 30 ml of 1-hexanol is added 30 ml of water followed by 0.15 g of 10% palladium-on-carbon. The reaction mixture is then hydrogenated in a Parr apparatus at 54 psi for 23 hours. To the mixture is added 30 ml of water and the mixture is filtered through a pad of diatomaceous earth. The pad is washed with an additional 20 ml of water. The filtrate is transferred to a separatory funnel, the aqueous layer separated and the 1-hexanol layer is washed with 10 ml of water. The combined aqueous layers are washed with 100 ml of ethyl acetate and lyophilized to afford 0.144 g(82%) of the desired product. MS (ES), m/z:442.3 (M+H)+, 99.5% area percent pure by analytical HPLC.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([C:23]2[N:19]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[N:20]=[CH:21][CH:22]=2)=[CH:9][C:6]=1[C:7]#[N:8])([O-:12])=[O:11]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(-c2ccnn2C2CCCCO2)ccc1[N+](=O)[O-]

Procedure:
5-Chloro-2-nitrobenzonitrile (1.5 g), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.74 g), PEPPSI ((1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) (3-chloropyridyl)palladium(ii) dichloride) (0.11 g), K2CO3 (2.27 g) in DMF (30 ml) and water (3 ml) was stirred under argon at 90° C. for 2.5 h. After pouring the mixture to water, it was extracted with EtOAc. Combined organic phases were washed with 5% NaHCO3, water and brine, dried with Na2SO4 and evaporated. The residue was triturated with ethanol. The precipitate was filtered and washed with water. Yield 1.96 g. 1H-NMR (400 MHz; d6-DMSO): δ 1.50-1.65 (m, 3H), 1.83-1.87 (m, 1H), 1.95-1.99 (m, 1H), 2.33-2.42 (m, 1H), 3.60-3.67 (m, 1H), 3.95-4.00 (m, 1H), 5.34 (d, 1H), 6.82 (d, 1H), 7.68 (d, 1H), 8.11 (dd, 1H), 8.32 (d, 1H), 8.54 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH2:22]O.CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33].CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH2:22][S:32]([CH3:31])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1ccc2c(Sc3ccccc3Cl)c(CO)[nH]c2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)Cc1[nH]c2cc(S(C)(=O)=O)ccc2c1Sc1ccccc1Cl
Reaction time: 0.17 h

Procedure:
[3-(2-chloro-phenylsulfanyl)-6-methanesulfonyl-1H-indol-2-yl]-methanol (1 mmole) (as prepared in Example 5) was dissolved in 2 mL CH2Cl2 and treated with 0.3 mL NEt3 followed by 0.08 ml MsCl. After stirring 10 min. 3 mL DMF was added followed by 0.5 g NaSO2Me. The mixture was stirred overnight. The reaction mixture was evaporated to dryness and applied to a PTLC plate. Elution with 1:1 EtOAc/hexane gave 80 mg 3-(2-chloro-phenylsulfanyl)-6-methanesulfonyl-2-methanesulfonylmethyl-1H-indole 601, MS: 343 ([M+H]+).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH2:16][C:17](=O)[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C.O>C(Cl)Cl>[C:17]([CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])#[N:16]
Reactant: COC(=O)CC(C)(C)CC(N)=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC(C)(C)CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
Trifluoromethanesulfonic anhydride (5.4 mL; 31.8 mmoles) was added to an ice cooled solution of methyl 5-amino-3,3-dimethyl-5-oxopentanoate (5.00 g; 28.9 mmoles) in methylene chloride (250 mL) and triethylamine (8 mL; 57.8 mmoles), under nitrogen while keeping the temperature below 5° C. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. Water (125 mL) was added and the phases were separated. The aqueous phase was extracted with methylene chloride (100 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The solution was filtered and the solvent was removed under vacuum to give the product, methyl 4-cyano-3,3-dimethylbutanoate (3.1 g; 69%). 1H NMR (400 MHz) DMSO-d6 δ 3.60 (3H, s), 2.61 (2H, s), 2.35 (2H, s), 1.07 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH:18]([CH3:19])[CH2:17][NH:16][CH:15]([CH2:20][O:21][CH3:22])[C:14]3=[O:23])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Br[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:36])[CH:32]=2)[CH:27]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[C@@H:18]([CH3:19])[CH2:17][N:16]([CH2:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[C:31]([Cl:36])[CH:32]=5)[CH:27]=4)[C@@H:15]([CH2:20][O:21][CH3:22])[C:14]3=[O:23])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1ccc2cc(CBr)ccc2c1
Reactant: COCC1NCC(C)N(Cc2ccc3c(N)ncnc3c2)C1=O
Product: COC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)[C@@H](C)CN1Cc1ccc2cc(Cl)ccc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 268, using 1-(4-amino-quinazoline-7-ylmethyl)-3-methoxymethyl-6-methyl-piperazine-2-one, EXAMPLE 87, and 2-bromomethyl-6-chloronaphthalene, EXAMPLE 12. 1H NMR (CDCl3, 300 MHz) δ8.59 (s, 1H), 7.79 (d, 1H), 7.70-7.12 (m, 3H), 7.68-7.67 (m, 2H), 7.55 (d, 1H), 7.39 (d, 1H), 4.78 (d, 2H), 3.98 (d, 2H), 3.44 (s, 3H), 3.38 (t, 1H), 2.64 (m, 2H), 1.26 (d, 3H). MS (ISP) 490, 492, (M+H), Cl pattern.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:63]1([NH:69][CH2:70][C@@H:71]2[CH2:75][CH2:74][CH2:73][NH:72]2)[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:72]1[CH2:73][CH2:74][CH2:75][C@H:71]1[CH2:70][NH:69][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: c1ccc(NC[C@@H]2CCCN2)cc1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@H]3CNc3ccccc3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (S)-2-(phenylaminomethyl)-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]#[N:5].N.[OH:28]O>C(O)C>[OH:1][C@H:2]([CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:3][C:4]([NH2:5])=[O:28]
Reactant: OO
Reactant: N#CC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N
Solvent: CCO
Product: NC(=O)C[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 27.5 °C

Procedure:
To a stirring solution of (S)-3-hydroxy-4-trityloxybutanenitrile (5.15 g, 15.01 mmol) in 15 mL of ethanol at room temperature was added aqueous NH3 (50 mL) and H2O2 (100 vol.) (34 mL, 300.00 mmol) was added in portions while maintaining the temperature of the reaction mixture below 25° C. After complete addition, the resultant reaction mixture was stirred vigorously at 25-30° C. and the reaction progress was monitored by TLC. On completion of the reaction (overnight) as indicated by the TLC, the reaction volume was concentrated to about 50% of the original volume under reduced pressure and the resultant mixture was extracted with dichloromethane (3×75 mL). The combined organic layers were dried over anhydrous Na2SO4 and the solvent was evaporated to leave a residue, which was purified by column chromatography employing EtOAc-hexane (80:20) as eluent to afford (S)-3-hydroxy-4-trityloxy butanamide in almost quantitative yield. m.p. 96-100° C.; [α]27D=−18.08 (c 1.0, MeOH); IR (KBr) 3467, 3349, 3012, 2980, 2918, 2839, 1671, 1098, 1076 cm−1; 1HNMR (300 MHz, CDCl3) δ 2.36 (d, 2H, J=6.5 Hz), 3.13-3.16 (m, 2H), 3.28 (6S, 1H), 4.11-4.15 (m, 1H), 5.44 (br, s, 1H), 7.18-7.38 (m, 9H), 7.39-7.42 (m, 6H); Mass (EI) 361, 259, 243, 165, 77.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([O:16][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:10]=1[F:34])[O:6][CH2:7][CH3:8])C.O.O[Li].O>C1COCC1.CO>[F:34][C:10]1[C:11]([OH:16])=[CH:12][CH:13]=[C:14]([F:15])[C:9]=1[CH:5]([O:6][CH2:7][CH3:8])[C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)C(OCC)c1c(F)ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1F
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C(=O)O)c1c(F)ccc(O)c1F
Temperature: 65 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of (RS)-[3-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-ethoxy-acetic acid ethyl ester (62.5 g) in THF (250 ml) and MeOH (250 ml) was added H2O (200 ml) and LiOH.H2O (10.5 g) and it was stirred 2 h at 65° C. MeOH and THF were evaporated and the aqueous residue was washed with Hept/Et2O 9:1 (2×150 ml). The organic layers were extracted with two portions of H2O (200 ml). The combined aqueous layers were cooled in an ice bath and acidified with 35 ml 25% aq. HCl. Extraction with AcOEt (3×200 ml) followed by washing with brine, drying (Na2SO4) and evaporation of the solvent afforded 28.7 g (99%) of (RS)-(2,6-difluoro-3-hydroxy-phenyl)-ethoxy-acetic acid. Yellow viscous oil. MS 231.2 ([M−H]−).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:27][C:28]([O:30][CH3:31])=[O:29])[O:5][CH2:4]1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:58][Cr](O[Cr]([O-])(=O)=O)(=O)=O>CN(C=O)C>[C:12]([O:11][C:9]([N:8]1[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:27][C:28]([O:30][CH3:31])=[O:29])[O:5][CH2:4][C@H:3]1[C:2]([OH:58])=[O:1])=[O:10])([CH3:14])([CH3:15])[CH3:13]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)CO1)C(c1ccccc1)c1ccccc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To tert-butyl (2R,5R)-5-(hydroxymethyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (1 eq) in DMF (0.1M) at rt were added PDC (10 eq) and 4A molecular sieve (1 g/mmol of substrate). The reaction mixture was stirred at rt for 16 hrs. The reaction mixture was then filtered on a celite and the celite pad was washed with EtOAc and water. The filtrate was extracted with EtOAc. The combined organic layers were washed with brine, 1N aqueous HCl and brine, dried over Na2SO4, filtered and concentrated. The crude product was used as such for next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][CH3:10].[C:11](=[O:13])=[O:12].Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([OH:13])=[O:12])=[C:4]([F:8])[C:3]=1[O:9][CH3:10]
Reactant: O=C=O
Reactant: COc1c(F)cccc1Br
Agent: Cl
Solvent: C1CCOC1
Product: COc1c(Br)ccc(C(=O)O)c1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (LDA) is formed by dropwise addition of n-butyllithium (1.6 M in hexanes, 56.0 mL, 89.6 mmol) to a stirred solution of diisopropylamine (13.7 mL, 96.9 mmol) in tetrahydrofuran (150 mL) at −78° C. The resulting solution is stirred at −78° C. for 5 min, 0° C. for 15 min, and then cooled again to −78° C. A solution of 1-bromo-3-fluoro-2-methoxybenzene (15.28 g, 74.5 mmol) in tetrahydrofuran (40 mL) is added dropwise to the previous solution over a period of 30 min. to give an amber solution. After stirring this solution at −78° C. for 1.5 h, dry ice (˜125 g) is added, and the resulting mixture is allowed to warm slowly (˜1 h) to room temperature with stirring as it degasses. The reaction mixture is acidified to pH ˜1 by addition of a 5% aqueous solution of hydrochloric acid (˜500 mL), and the product is extracted with diethyl ether (6×100 mL). The combined organic extracts are washed with brine (100 mL), and the product extracted with a saturated solution of aqueous sodium bicarbonate (3×100 mL). The combined aqueous extracts (pH ˜9) are washed with diethyl ether (3×100 mL) and acidified slowly to pH ˜1 by addition of a 37% aqueous solution of hydrochloric acid (˜50 mL). The product is extracted with diethyl ether (3×200 mL), and the combined organic extracts are washed with brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 12 as an off-white solid. This product is of sufficient purity (≧95% by NMR spectroscopy) to use directly in the next synthetic step. mp 168-170° C. 1H NMR (CD3OD): δ 3.92 (d, JH-F=1.0 Hz, 3H, OCH3), 7.44 (dd, JH-H=8.5 Hz, JH-F=1.5 Hz, 1H, H-5), 7.55 (dd, JH-H=8.5 Hz, JH-F=7.0 Hz, 1H, H-6). 19F{1H} NMR (CD3OD): δ −127.0 (s). 13C{1H} NMR (CD3OD): 662.1 (d, JC-F=4.5 Hz, OCH3), 121.5 (d, JC-F=8.5 Hz, C-1), 123.6 (d, JC-F=2.0 Hz, C-4), 128.0 (s, C-6), 129.0 (d, JC-F=4.5 Hz, C-5), 147.7 (d, JC-F=13.5 Hz, C-3), 157.1 (d, JC-F=263.5 Hz, C-2), 166.3 (d, JC-F=3.0 Hz, CO2H). HRMS m/z calcd for C8H679BrFNaO3 270.9382 ([M+Na]+). Found 270.9377.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.[OH-].[K+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:8]2[C:9]3[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=3)[CH:5]=[CH:6][C:7]2=[O:12])=[CH:17][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1ccc2cc(Br)ccc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2c(=O)ccc3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
6-Bromoquinolin-2(1H)-one (4.0 g, 18 mmol), 4-methoxybenzyl chloride (3.6 g, 23 mmol), and tetrabutylammonium bromide (1.2 g, 3.6 mmol) were dissolved in PhMe (200 mL) and then KOH (powder, 1.8 g, 32 mmol) was added into the reaction mixture. The reaction mixture was stirred at RT for 4 h, then poured into H2O and extracted with EtOAc (3×50 mL). The organic layer was washed with H2O, dried (Na2SO4), and concentrated. Trituration with hexane, followed by collection of the solids yielded 1-(4-methoxybenzyl)-6-bromoquinolin-2(1H)-one (5.4 g, 87% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J=2.4 Hz, 1H), 7.66 (d, J=9.6 Hz, 1H), 7.52 (dd, J=2.0, and 8.8 Hz, 1H), 7.19 (d, J=9.2 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 6.83 (d, J=9.4 Hz, 1H), 5.48 (brs, 2H), 3.78 (s, 3H), 1.36 (s, 12H); LC-MS (EI) m/z: 344.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9](NC(OCC2C=CC=CC=2)=O)[CH2:8][CH2:7]1)=[O:5]>CO.[Pd]>[CH3:1][N:2]([CH3:23])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CN(C)CC(=O)N1CCN(NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)CC(=O)N1CCNCC1
Reaction time: 8 h
Yield: 95.2 %

Procedure:
Benzyl 4-(2-dimethyaminoacetyl)piperazine-1-carbamate (954 mg, 3.12 mmol) synthesized in Production example 51-1 was dissolved in methanol (50 ml) under nitrogen atmosphere; 10% palladium on carbon (50% wet, 665 mg) was added thereto; the reaction system was purged with hydrogen at atmospheric pressure; and the reaction mixture was stirred overnight. After the reaction system was purged with nitrogen, the catalyst was filtered out, and washed with methanol. The solvent, together with the filtrate and washing solution, was distilled off, and the residue was dried under reduced pressure to yield the title compound (508 mg, 2.97 mmol, 95.0%) as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)[C:4]#[N:5].[N-:21]=[N+:22]=[N-:23].[Na+]>O>[N:21]([CH2:2][C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)[C:4]#[N:5])=[N+:22]=[N-:23]
Reactant: N#CC(CCl)(CCOC1CCCCO1)c1ccccn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: N#CC(CCOC1CCCCO1)(CN=[N+]=[N-])c1ccccn1
Temperature: 140 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
To a solution of 8.01 g of the compound obtained in Step 2 in 200 ml of dimethylformamide(DMF) was added 8.84 g of sodium azide. The resulting mixture was stirred for 18 hours at 140° C. After the reaction was completed, water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue thus obtained was purified by a silica gel column chromatography using a mixture of ethyl acetate and n-hexane of 1:6 to obtain 6.2 g of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12]C(OCC2C=CC=CC=2)=O)[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CC(NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CC(N)C1
Reaction time: 5 h

Procedure:
To a solution of 1.4 g 3-Benzyloxycarbonylamino-azetidine-1-carboxylic acid butyl ester in 50 ml ethyl acetate were added 150 mg Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (1 bar) for 5 h. The reaction mixture was filtrated over a plug of Celite®, washed with ethyl acetate and concentrated. Yield: 740 mg colorless solid
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.Cl.O1CCOCC1.[CH3:26][CH:27](O)[CH3:28]>>[F:1][C:2]1[CH:3]=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH:27]([CH3:28])[CH3:26])=[O:17])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCNc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)OC(=O)CCCCNc1cc(F)ccc1[N+](=O)[O-]

Procedure:
A mixture of 2.19 g (8.55 mmol) of 5-(3-fluoro-6-nitrophenyl)aminovaleric acid, 100 ml of 2-propanol and 5 ml of 4N hydrochloric acid-dioxane was subjected to heating under reflux for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (developing solvent: hexane:ethyl acetate=9:1 to 6:1) to give 2.55 g (stoichiometric) of isopropyl 5-(3-fluoro-6-nitrophenyl)aminovalerate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@@H:9]([CH:17]=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([Mg]Br)[CH:21]=[CH2:22].[Cl-].[NH4+]>CCOCC.O>[C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:17]([OH:18])[CH2:22][CH:21]=[CH2:20])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=CC[Mg]Br
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](C=O)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: C=CCC(O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
N-((1R)-1-Formyl-2-phenylethyl)-N-methylcarbamic acid tert-butylester (6.0 g, 20.0 mmol) was dissolved in ether (150 mL). The solution was cooled to −78° C. and allylmagnesium bromide (22 mL of a 1.0 M solution in ether, 22 mmol) was added dropwise. After addition, the solution was warmed to room temp. It was given onto 10% ammonium chloride solution in water (200 mL). The phases were separated. The aqueous phase was extracted with ethyl acetate (3×50 mL). The organic layers were combined and washed with satd. sodium hydrogencarbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (260 g) with ethyl acetate/heptane 1:1 to give 4.00 g of N-((1R)-1-benzyl-2-hydroxypent-4-enyl)-N-methylcarbamic acid tert-butylester.