Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][C:20]#[N:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[CH2:25](O)[CH3:26]>[Ni]>[CH2:25]([NH:21][CH2:20][CH2:19][CH2:18][CH2:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:9]=1)[CH3:26]
Reactant: N#CCCCc1nn(Cc2ccccc2)c2ccccc12
Reactant: CCO
Agent: [Ni]
Agent: NN
Solvent: O
Product: CCNCCCCc1nn(Cc2ccccc2)c2ccccc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A solution of 1-benzyl-3-(3-cyanopropyl)indazole (100 mg, 0.35 mM) in ethanol (10 ml) was stirred at room temperature and Raney nickel (approx. 100 mg, wet weight) was added. The resulting suspension was warned to 65° C. and hydrazine hydrate (0.1 ml, 87 mg) added carefully. The mixture was stirred at 70° C. for a further 2 hr then cooled and filtered through celite. Solvent was removed in vacuo and the residue purified by chromatography on silica (chloroform/methanol 9:1) to give the title product as a clear oil (25 mg, 26%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:5]([CH3:9])=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:26][CH3:27])=[CH:18][C:17]=3[Cl:16])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:5]=1[CH3:9]
Reactant: CCC(CC)n1c(C)c(Cl)nc(Cl)c1=O
Reactant: COc1cc(Cl)c2c(c1)CCN2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)n1c(C)c(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
Part C: A solution 3,5-dichloro-1-(1-ethylpropyl)-6-methyl-2(1H)-pyrazinone from Part B (80 mg, 0.321 mmol) and 7-chloro-5-methoxyindoline (61.9 mg, 0.337 mmol) in THF (1.6 mL) was cooled to 0° C. and was treated with sodium hexamethyldisilazide (353 μL, 0.353 mmol, 1 M in THF). The reaction mixture was allowed to warm up to room temperature and was stirred overnight. The mixture was transferred to a separatory funnel containing saturated NaHCO3 and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (10% EtOAc in hexanes→40% EtOAc in hexanes) to provide the target compound (22 mg, 17% yield) as a brown oil: 1H NMR (CDCl3) δ 6.72 (s, 2H), 4.27 (t, J=7.88 Hz, 2H), 4.00–3.95 (m, 1H), 3.77 (s, 3H), 3.09 (t, J=7.8 Hz, 2H), 2.48–2.38 (m, 2H), 2.42 (s, 3H), 1.95–1.81 (m, 2H), 0.87 (t, J=7.5 Hz, 6H); HRMS (ESI) m/z 396.1259 [(M+H)+, calcd for C19H24N3O2Cl2 396.1246].
Reaction SMILES: [I:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[C:3]([NH2:5])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[I:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[C:3]#[N:5]
Reactant: NC(=O)C(F)(I)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: N#CC(F)(I)C(F)(F)F
Temperature: 97.5 °C

Procedure:
2-Iodotetrafluoropropionamide prepared from Experiment 6 (16.3 g, 0.06 mol) was mixed well with P2O5 (16.3 g, 0.115 mol) in a flask under nitrogen atmosphere. The mixture was heated slowly to 95 to 100° C., a volatile product started to form and was collected in a cold trap (dry ice-acetone bath). The title product was obtained as a slightly pink liquid after purification by distillation, yield 12.5 g (82.5%), b.p. 68-70° C. 19F NMR (188.24 MHz, CDCl3): -78.7 (2 singlets, 3F), -137.9 (q, J =16 Hz, 1F); IR: 2288 cm-1 (C≡N); Mass. Calcd. for [M+ ]: 252.9382; Found: 252.9012.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccncc1C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccncc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4-(N-t-butoxycarbonylamino) nicotinic acid (2.72 g, 11.4 mmol), TFA (10 mL), and CH2Cl2 (20 mL) is stirred at room temperature for 12 h. The volatiles are removed under reduced pressure, and the resulting crude 4-amino nicotinic acid is used directly in the next reaction.
Reaction SMILES: N#N.[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][CH2:23][C@H:22]([NH:26]C(=O)[O-])[CH2:21]2)[C:17]2[C:12](=[CH:13][C:14]([CH3:30])=[CH:15][CH:16]=2)[N:11]=1.CO>CCOC(C)=O.[Pd]>[NH2:26][C@H:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:18]2[C:17]3[C:12](=[CH:13][C:14]([CH3:30])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[OH:3])[N:19]=2)[CH2:21]1
Reactant: Cc1ccc2c(N3CCC[C@H](NC(=O)[O-])C3)nc(-c3ccccc3O)nc2c1
Agent: [Pd]
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc2c(N3CCC[C@H](N)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 4 h
Yield: 49.6 %

Procedure:
Pd/C (175 mg, 10% weight Pd on carbon) was added to a round bottom flask and the flask was flushed with N2. To this flask was then added MeOH (10 mL). After purging the flask again with N2, (S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate (1.75 g, 3.74 mmol) dissolved in EtOAc (60 mL) and MeOH (50 mL) was added. After flushing the flask 3 times with N2, and evacuating it under vacuum, H2 was passed through the vigorously stirring mixture for 4 h until hydrogenation was complete. The mixture was filtered through a pad of Celite. The filtrate was concentrated to afford 2-(4-((S)-3-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.62 g, 50%). LC/MS: m/z 335.5 (M+H)+ at 1.50 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][N:22]=3)[CH:19]=2)=[CH:10][CH:9]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:34]>C1COCC1>[CH3:34][N:7]([C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[O:6])[C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][N:22]=3)[CH:19]=2)=[CH:12][CH:13]=1
Reactant: CI
Reactant: COc1ccccc1-c1nnc2ccc(-c3ccc(NC(=O)C(C)(C)C)cc3)cn12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1nnc2ccc(-c3ccc(N(C)C(=O)C(C)(C)C)cc3)cn12
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
To a mixture of 6-(4-t-butylcarbonylaminophenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (120 mg, 0.29 mmol) in dry THF (20 mL) cooled at 0° C. was added NaH (12 mg, 0.32 mmol), and it was stirred for 2 h. To the mixture was added iodomethane (164 mg, 1.5 mmol) in THF (8 mL) dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated NH4Cl (20 mL) and extracted with ethyl acetate (100 mL×3). The combined organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by preparative TLC to give the title compound (38 mg, 31% yield) as yellow solids. MS: m/z 431.3 [M+H+].
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.[CH:19]1(O)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:16]=[CH2:17]
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Reactant: OC1CCCC1
Product: C=CCOC(=O)NC1CC(=O)OC1OC1CCCC1

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester as described for 40 using cyclopentanol to afford the title compound as a mixture of diastereomers. Flash column chromatography using hexanes/EtOAc (90/10 to 80/20) afforded the syn diastereomer of the title compound: syn diastereomer 1H NMR (500 MHz, CDCl3) δ 1.5-2.0 (m, 8H), 2.45 (dd, 1H), 2.81 (dd, 0.9H), 3.0 (dd, 0.1H), 4.31 (m, 1H), 4.59 (m, 4H), 5.23 (m, 1H), 5.32 (m, 1H), 5.45 (s, 0.1H), 5.51 (s, 0.9H), 5.92, (m, 1H) ppm; anti diastereomer 1H-NMR (500 MHz, CDCl3) δ 1.50 (m, 2H), 1.67 (m, 6H), 2.36 (d, 1H), 2.8 (dd, 0.08H), 2.96 (dd, 0.92H), 4.13 (m, 1H), 4.25 (m, 1H), 4.55 (br, 2H), 5.20 (d, 1H), 5.30 (m, 2H), 5.43 (s, 0.92H), 5.5 (d, 0.08H), 5.89 (s, 1H) ppm.
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH3+:5].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[S:17])=[CH:11][CH:10]=1)([O-:8])=[O:7]>>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([N:15]=[C:16]2[NH:5][CH2:4][CH2:3][S:17]2)=[CH:13][CH:14]=1)([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: [NH3+]CCCl
Agent: [Cl-]
Product: O=[N+]([O-])c1ccc(N=C2NCCS2)cc1

Procedure:
2-Chloroethylammonium chloride (Entry 1) was reacted with 4-nitrophenyl isothiocyanate according to Method C1a to give 2-(4-nitrophenylimino) -1,3-thiazolidine, which was reacted with isobutyl bromide according to Method D2a to give 2-(4-nitrophenylimino)-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(O[C:11]1(O[Si](C)(C)C)[CH2:13][CH2:12]1)C.C([BH3-])#N.[Na+]>CO>[CH:11]1([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[CH2:13][CH2:12]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: OC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: OC1CCN(C2CC2)CC1
Reaction time: 12 h

Procedure:
5 g of 4-hydroxypiperidine were dissolved in methanol. 23.8 mL of 1[(1-ethoxycyclopropyl)oxy]trimethylsilane and 5.8 g of sodium cyano borohydride were added and the mixture was reacted at 60° C. for 12 h. The same amounts of the two reagents were added again and stirring was continued at 60° C. for another 12 h. The mixture was diluted with methanol, filtered over celite and evaporated to dryness. The residue was taken up in ethyl acetate, extracted twice with 2N sodium hydroxide and once with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography to yield 2 g of product 20, MS: 141 (M+)
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:28])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:6][CH:5]=1.I[CH2:30][CH2:31][CH3:32].Cl.CN(C)C1C=CC([C@@H]2CCN(CC)C[C@H]2COC2C=CC(C(F)(F)F)=CC=2)=CC=1>C(O)C>[ClH:1].[CH3:2][N:3]([CH3:28])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH2:14][N:13]([CH2:30][CH2:31][CH3:32])[CH2:12][C@H:11]2[CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)=[CH:6][CH:5]=1
Reactant: CCCI
Reactant: CN(C)c1ccc([C@@H]2CCNC[C@H]2COc2ccc(C(F)(F)F)cc2)cc1
Agent: CCN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](COc2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Solvent: CCO
Product: CCCN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](COc2ccc(C(F)(F)F)cc2)C1
Yield: 37 %

Procedure:
Preparation from (41) (0.35 g) and 1-iodopropane (0.2 ml) by heating in ethanol of 70° C. for 8 h, as described for compound (42). Yield 37%, m.p. 224.2°-225.2° C.
Reaction SMILES: N1CCCCC1.[CH2:7]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[O:22][CH3:23])[CH2:8][CH2:9][CH2:10][C:11]#[CH:12].C([CH2:27][C:28]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34])=[O:29])(O)=O.Cl>C1(C)C=CC=CC=1>[CH2:7]([O:13][C:14]1[CH:21]=[CH:20][C:17](/[CH:18]=[CH:27]/[C:28]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[O:29])=[CH:16][C:15]=1[O:22][CH3:23])[CH2:8][CH2:9][CH2:10][C:11]#[CH:12]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: C#CCCCCOc1ccc(C=O)cc1OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: C#CCCCCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 73.4 %

Procedure:
Piperidine (0.30 mL, 3.0 mmol) was added to a suspension of 4-(hex-5-ynyloxy)-3-methoxybenzaldehyde (0.70 g, 3.0 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.61 g, 2.7 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(4-(Hex-5-ynyloxy)-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.78 g, 73%) as a yellow crystalline solid; mp 148-150° C.; δH (400 MHz, DMSO-d6) 1.59 (p, J=7.6 Hz, 2H, CH2), 1.81 (p, J=7.6 Hz, 2H, CH2), 2.24 (dt, J=7.6, 2.4 Hz, 2H, CH2CCH), 2.78 (t, J=2.4 Hz, 1H, CCH), 3.83 (s, 3H, OCH3), 4.01 (t, J=7.6 Hz, 2H, OCH2), 6.77 (d, J=15.6 Hz, 1H, CH═CHCO), 6.98 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.22 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.37 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 13.56 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 17.4, 24.6, 27.8, 55.7, 67.6, 71.4, 84.3, 110.7, 112.6, 116.6, 119.8, 120.3, 122.6, 122.7, 127.2, 131.1, 134.0, 141.1, 141.6, 149.1, 150.0, 164.2, 169.4; HRMS (ESI) calculated for C23H23NO5 [M+H]+ 394.1649. found 394.1649; vmax 755, 1237, 1508, 1609, 1669, 2944, 3424, 3567 cm−1.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]([CH3:33])=[N:31][N:32]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[S:29][C:30]([CH3:33])=[N:31][N:32]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)s2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)s4)cc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (70% EtOAc/hexanes) gave the product as a pale yellow solid (0.044 g, 15% yield). MS: m/z 529.3 [M+H]+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:13]([O:14]C(=O)C)[C@H:12]([O:18][C@@H:19]2[O:56][C@H:55]([CH2:57][O:58]C(=O)C)[C@H:30]([O:31][C@H:32]3[O:49][C@H:48]([CH2:50][O:51]C(=O)C)[C@H:43]([O:44]C(=O)C)[C@H:38]([O:39]C(=O)C)[C@H:33]3[O:34]C(=O)C)[C@H:25]([O:26]C(=O)C)[C@H:20]2[O:21]C(=O)C)[C@@H:11]([CH2:62][O:63]C(=O)C)[O:10][C@H:6]1[O:7][CH2:8][CH3:9])(=O)C>C[O-].[Na+]>[C@H:32]1([O:31][C@H:30]2[C@@H:55]([CH2:57][OH:58])[O:56][C@@H:19]([O:18][C@@H:12]3[C@@H:11]([CH2:62][OH:63])[O:10][C@@H:6]([O:7][CH2:8][CH3:9])[C@H:5]([OH:4])[C@H:13]3[OH:14])[C@H:20]([OH:21])[C@H:25]2[OH:26])[O:49][C@H:48]([CH2:50][OH:51])[C@H:43]([OH:44])[C@H:38]([OH:39])[C@H:33]1[OH:34]
Reactant: CCO[C@@H]1O[C@H](COC(C)=O)[C@@H](O[C@@H]2O[C@H](COC(C)=O)[C@H](O[C@H]3O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Product: CCO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Yield: 100 %

Procedure:
A solution of 67 (440 mg, 0.46 mmol) in methanolic sodium methoxide (0.005M, 40 ml) was left at room temperature for 18 h, then neutralized with Duolite C26 (H+) resin and the solvent was removed. The residue was dissolved in water and lyophilized to give 68 (245 mg, 100%) with [α]D21 +71° (c 0.5, water) 1H-NMR (DMSO-d6, 50°, D2O added, Me4Si) δ 4.81 (d, 1H, J=3.5 Hz, H1"), 4.28, 4.20 (d, each 1H, J=7 and 8 Hz, H1 and H1'), 1.14 (t, 3H, J=7 Hz, CH3 --CH2). 13C-NMR (D2O, TSP) δ 106.1, 104.5, 103.2 (Cl, l', l"), 81.5, 80.2, 78.3, 77.7, 77.3, 75.8, 75.0, 73.7, 73.6, 72.0, 71.8, 71.4, 69.1 (CH2), 63.3 (CH2), 63.2 (CH2), 62.9 (CH2), 17.1. Sugar49 and methylation50 analysis was in agreement with the proposed structure.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:3].CN(C)C=O.C[Si]([N:33]=[N+:34]=[N-:35])(C)C>[Cu]I.CO>[CH3:3][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:33]=[N:34][NH:35][CH:18]=3)[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:1]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)N1c2ccc(-c3c[nH]nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 58) (80 mg, 0.254 mmol) and copper(I) iodide (2.423 mg, 0.013 mmol) then filled with N,N-dimethylformamide (DMF) (1.8 mL) and Methanol (0.200 mL). Trimethylsilyl azide (0.059 mL, 0.509 mmol) was added and the resulting mixture was stirred under microwave irradiation at 100° C. for 5 h then cooled to room temperature. The solution was partitioned between AcOEt and water/brine (1/1) and the layers were separated. The aqueous phase was extracted three times with AcOEt and the combined organic phases were washed with water then brine, dried over MgSO4 and concentrated in vacuo. The residue was purified using MDAP (modifier: ammonium bicarbonate). The appropriate fractions were concentrated in vacuo and the residue dissolved in DCM. The organic phase was dried using a phase separator then concentrated in vacuo to give 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (30 mg, 0.084 mmol, 33.0% yield) as a white foam.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[CH2:15]([N:6]1[CH:7]=[C:2]([I:1])[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5]1=[O:8])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Cc1c(I)c[nH]c(=O)c1[N+](=O)[O-]
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCn1cc(I)c(C)c([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-iodo-4-methyl-3-nitro-2-pyridone (8.0 g. 28.6 mmol) and sodium hydride (1.03 g, 43 mmol) in DMF (150 mL) was stirred at rt for 1 hour. n-Hexyl bromide (8.03 mL, 57.2 mmol) was added, and the mixture was stirred for 24 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed, dried, filtered and evaporated. Chromatography of a portion of the residue over silica gel (20% petroleum ether/methylene chloride) gave 1-hexyl-5-iodo-4-methyl-3-nitro-2-pyridone.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[O:24])[CH2:19][CH2:18]1>>[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[CH2:18][CH2:19][N:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([N:4]3[CH2:3][C@@H:2]([CH3:1])[CH2:6][S:5]3(=[O:8])=[O:7])=[CH:27][CH:26]=2)=[O:24])[CH2:21][CH2:22]1
Reactant: C[C@@H]1CNS(=O)(=O)C1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C[C@@H](C)CS4(=O)=O)cc3)CC2)c(C)c1
Yield: 9.1 %

Procedure:
Using (R)-4-methylisothiazolidine 1,1-dioxide (203 mg) described in Preparation Example 7 and [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (420 mg) described in Preparation Example 108 and by the reaction and treatment in the same manner as in Example 1, the title compound (39 mg) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20]O)=[CH:15][CH:14]=2)[C:6]2=[N:7][C:8]([CH3:11])=[CH:9][CH:10]=[C:5]2[N:4]=1)[CH3:2].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:67]=[N+:68]=[N-:69])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:67]=[N+:68]=[N-:69])=[CH:15][CH:14]=2)[C:6]2=[N:7][C:8]([CH3:11])=[CH:9][CH:10]=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(C)nc2n1-c1ccc(CCO)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nc2ccc(C)nc2n1-c1ccc(CCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 29.7 %

Procedure:
A mixture of 2-[4-(2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol (step 4, 217 mg, 0.77 mmol) in THF (20 mL) was added diethyl azodicarboxylate (DEAD) (0.3 mL, 1.5 mmol), triphenylphosphine (380 mg, 1.5 mmol) and diphenylphosphoryl azide (DPPA) (0.4 mL, 1.5 mmol). The mixture was stirred at room temperature for 4.5 h. After removal of solvent, the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 1:1 to 1:2) to afford 70 mg (30%) of the title compound as a brown oil:
Reaction SMILES: [CH2:1]([C@@:3]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:9]([F:11])([F:10])[CH2:8][O:7][CH2:6][C:5]([NH2:12])=[N:4]1)[CH3:2].[N+:20]([O-])([OH:22])=[O:21].[OH-].[Na+]>S(=O)(=O)(O)O>[CH2:1]([C@@:3]1([C:13]2[CH:18]=[C:17]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:15][C:14]=2[F:19])[C:9]([F:10])([F:11])[CH2:8][O:7][CH2:6][C:5]([NH2:12])=[N:4]1)[CH3:2]
Reactant: CC[C@]1(c2ccccc2F)N=C(N)COCC1(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC[C@]1(c2cc([N+](=O)[O-])ccc2F)N=C(N)COCC1(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-5-ethyl-6,6-difluoro-5-(2-fluoro-phenyl)-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine (1.2 mmol) in sulfuric acid (5.0 ml) was added at 0° C. red fuming nitric acid (1.9 mmol) over a period of 20 min and stirring was continued for 30 min. The solution was dropped slowly into ice/water (60 ml), the pH was adjusted to 9 by addition of aqueous 4 N NaOH and extracted with ethyl acetate. The organic layer was dried, evaporated and the residue purified by chromatography on silca-NH2 using n-heptane/ethyl acetate to give (R)-5-ethyl-6,6-difluoro-5-(2-fluoro-5-nitro-phenyl)-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine as a pale yellow solid. MS: m/z=318.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C:12]([CH3:14])=[CH2:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>>[Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C:12]2([CH3:14])[CH2:13][O:23]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CCn1cc([N+](=O)[O-])nc1Cl
Product: CC1(CCn2cc([N+](=O)[O-])nc2Cl)CO1
Yield: 88 %

Procedure:
Epoxidation of alkene 139 with 3-chloroperbenzoic acid as in Example 2G for 4 h, followed by chromatography of the product on silica gel, eluting with CH2Cl2 (foreruns) and then with 0-5% EtOAc/CH2Cl2, gave 2-chloro-1-[2-(2-methyl-2-oxiranyl)ethyl]-4-nitro-1H-imidazole (140) (88%) as a cream solid: mp (CH2Cl2/pentane) 82-85° C.; 1H NMR (CDCl3) δ 7.78 (s, 1H), 4.12 (t, J=7.6 Hz, 1H), 2.66 (d, J=4.4 Hz, 1H), 2.62 (d, J=4.4 Hz, 1H), 2.19 (dt, J=14.3, 7.7 Hz, 1H), 2.04 (dt, J=14.3, 7.4 Hz, 1H), 1.39 (s, 3H); HRFABMS calcd for C8H11ClN3O3 m/z [M+H]+ 234.0459, 232.0489. found 234.0466, 232.0488.