Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[C@@H:13]([OH:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:39]>>[ClH:39].[NH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:16])[C@@H:13]([OH:15])[CH3:14])[C:4]=23)[CH2:18]1
Reactant: C[C@H](O)C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](O)C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](N)C3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
tert-Butyl (R)-1-(5-bromo-3-((S)-2-hydroxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.120 g, 0.249 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added. The reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-50 CH3CN/water). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirred solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (S)—N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxypropanamide HCl (0.070 g, 62% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.20 (s, 1H), 7.48 (s, 1H), 4.37-4.32 (q, 1H), 3.61-3.55 (m, 2H), 3.31-3.24 (m, 2H), 3.16-3.13 (m, 1H), 2.09-2.05 (m, 1H), 1.77-1.71 (m, 2H), 1.54-1.51 (m, 1H), 1.35-1.33 (d, 3H). LCMS (APCI+) m/z 382, 384 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][P:5]([C:17]([C:19]1[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=1[CH3:27])=[O:18])[C:6]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=1[CH3:16])=[O:7].OO.C([O:32]CC)C>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][P:5]([C:6]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=1[CH3:16])=[O:7])([C:17]([C:19]1[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=1[CH3:25])=[O:18])=[O:32]
Reactant: Cc1cc(C)c(C(=O)P(CCCBr)C(=O)c2c(C)cc(C)cc2C)c(C)c1
Reactant: CCOCC
Agent: OO
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C(=O)P(=O)(CCCBr)C(=O)c2c(C)cc(C)cc2C)c(C)c1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
((3-bromopropyl)phosphinediyl)bis(mesitylmethanone) of example 4 (1.16 g, 2.59 mmol, 1 eq.) was dissolved in toluene (5 mL) and hydrogen peroxide (10%) (8.88 mL, 2.59 mmol, 1 eq.) was added. The reaction mixture was stirred at 40° C. for 12 hours. Afterwards diethylether (50 mL) were added and the solution was washed with twice sodium hydrogencarbonate (2%) solution, once with brine and finally dried with magnesium sulfate. After removing the solvent in vacuo at room temperature, the pure product was obtained as a yellow oil (Yield: 0.97 g, 2.10 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[N:7][C:6]=1[Cl:12])[CH3:2].[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]([F:14])([F:24])[F:25])=[CH:18][CH:19]=2)=[N:7][C:6]=1[Cl:12])[CH3:2]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(Cl)nc1Cl
Product: CCOC(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)nc1Cl
Yield: 829.4 %

Procedure:
2,6-dichloronicotinic acid ethyl ester (0.22 g, 0.1 mmol) and 4-trifluoromethoxy-phenol (0.178 g, 0.1 mmol) were coupled using the procedure of Example 17(a) to afford 0.3 g of the required produCt. Percentage purity (LCMS): 64.0%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:25])[C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[NH:17]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[ClH:26]>CO.O1CCOCC1>[ClH:26].[NH2:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:25]
Reactant: Cc1ccc(NC(=O)c2c(C)cccc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)c2c(C)cccc2N)cc1
Temperature: 18 °C
Reaction time: 3.5 h

Procedure:
A stirred solution of N-(4-methylphenyl)-2-{[(1,1-dimethylethoxy)carbonyl]amino}-6-methylbenzamide (1.67 g, 4.90 mmol) in methanol (4 mL) under an argon atmosphere, is treated with a saturated solution of hydrogen chloride in dioxane (30 mL) and stirred at 18° C. for 210 minutes. The solvent is evaporated off under reduced pressure to give the crude product which is purified by recrystallisation from methanol-di-isopropyl ether to give the title compound as a colourless crystalline solid, m.p. 217-220° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH2:36][CH:37]([C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([O:46][CH3:47])[CH:40]=1)[OH:38]>>[OH:38][CH:37]([C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([O:46][CH3:47])[CH:40]=1)[CH2:36][NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18]
Reactant: COc1cc(C(O)CN)ccc1O
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccc(O)c(OC)c2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 4-[(1RS)-2-amino-1-hydroxyethyl]-2-methoxyphenol, the title compound was obtained in 67% purity by HPLC. MS(ESI+): m/z=518.
Reaction SMILES: [O:1]=[C:2]1[C:7](C(O)=O)=[CH:6][NH:5][C:4]2[CH:11]=[N:12][NH:13][C:3]1=2>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:1]=[C:2]1[CH:7]=[CH:6][NH:5][C:4]2[CH:11]=[N:12][NH:13][C:3]1=2
Reactant: O=C(O)c1c[nH]c2cn[nH]c2c1=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=c1cc[nH]c2cn[nH]c12

Procedure:
4,7-Dihydro-7-oxo-1H-pyrazolo[4,3-b]pyridine-6-carboxylic acid (7.0 g, 39 mmol) was suspended in Dowtherm A (250 ml) and the mixture was heated under reflux under nitrogen for 2.5 h. After cooling, the mixture was diluted with 60°-80° petrol and filtered. The precipitate was washed well with petrol and dried to give the crude product as an off-white solid (3.9 g, 74%). Recrystallisation from aqueous ethanol/ether gave the title compound as very fine needles, m.p.>320° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:7]([O:14][CH:15]([CH3:17])[CH3:16])=[N:6][C:5]=1[NH2:18].[OH-].[Li+]>CO.O>[NH2:18][C:5]1[N:6]=[C:7]([O:14][CH:15]([CH3:16])[CH3:17])[CH:8]=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:4]=1[C:3]([OH:19])=[O:2]
Reactant: COC(=O)c1c(OC(C)C)cc(OC(C)C)nc1N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Oc1cc(OC(C)C)c(C(=O)O)c(N)n1
Temperature: 50 °C

Procedure:
To the solution of 2-amino-4,6-diisopropoxy-nicotinic acid methyl ester (1.6 g, 5.97 mmol) in methanol (9.0 mL) and water (1.0 mL), was added lithium hydroxide (750 mg, 17.91 mmol). The reaction mixture was heated to 50° C. for 8 hours. The solvent was removed; the residue was diluted with water and neutralized with 2 N HCl. The product was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with water, then brine, dried over Na2SO4, and evaporated, to give crude 2-amino-4,6-diisopropoxy-nicotinic acid as a light yellow solid. Yield: 1.48 g (98%, crude).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)[CH2:13]1)C1C=CC=CC=1.N1CCCC1>C(Cl)Cl>[CH3:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][CH:14]1[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1
Reactant: Cc1cccc(OC2CCN(Cc3ccccc3)C2)c1
Reactant: O=C(Cl)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: Cc1cccc(OC2CCN(C(=O)Cl)C2)c1
Reaction time: 8 h
Yield: 68.3 %

Procedure:
To a stirred solution of 9.5 g (0.097 mole) of phosgene in 100 ml of methylene chloride under nitrogen gas was added dropwise 23.84 g (0.088 mole) of 1-benzyl-3-(3-methylphenoxy)pyrrolidine in 50 ml of methylene chloride. When the addition was complete, thin-layer chromatography showed no starting pyrrolidine remained. The reaction mixture was stirred overnight and concentrated in vacuo to give an oil. The oil was triturated with 30/60 petroleum ether to remove benzyl chloride. A white solid, 14.4 g of crude product was obtained. A portion was recrystallized from hexane.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][C:14]=2[N:15]2[CH:19]=[CH:18][CH:17]=[CH:16]2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>>[N:20]1([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]3[S:11][CH:12]=[CH:13][C:14]=3[N:15]3[CH:19]=[CH:18][CH:17]=[CH:16]3)[N:3]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: C1CNCCN1
Reactant: Clc1cncc(OCc2sccc2-n2cccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccn(-c2ccsc2COc2cncc(N3CCNCC3)n2)c1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from the product obtained in step 1 above (1.78 g, 6.10 mmol), piperazine (1.58 g, 18.3 mmol) and K2CO3 (0.86 g, 6.2 mmol). The yield of the title compound was 1.43 g (69%) and was obtained as a beige solid. HRMS m/z calcd for C17H19N5OS (M)+ 341.1310, found 341.1301.
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:3]1(=[O:5])=[O:4].Cl[CH2:15][C:16]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[O:17].[H-].[Na+]>CS(C)=O>[OH:13][C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:3](=[O:5])(=[O:4])[N:2]([CH3:1])[C:15]=1[C:16]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[O:17]
Reactant: CN1C(=O)c2ccccc2S1(=O)=O
Reactant: COCCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCOC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reaction time: 2 h

Procedure:
To a solution of 3.0 g. (0.015 mole) of N-methylsaccharin and 2.3 g. (0.015 mole) of 2-methoxyethyl chloroacetate in 15 ml. of dimethylsulfoxide at 40° C. was added 810 mg. (0.033 mole) of sodium hydride over a 2 hour period. The resulting reaction mixture was stirred for 2 hours at 40°-50° C. and was then quenched in 5% hydrochloric acid solution. The resulting suspension was extracted with methylene chloride (2×100 ml.) and the organic layers separated, combined and washed with water (50 ml.) and a brine solution (50 ml). The organic layer was dried over magnesium sulfate and concentrated to an oil, 4.1 g. The product was purified by dissolution of the residue in 5 ml. of acetone and addition of the acetone slowly to 125 ml. of 0.25N hydrochloric acid. The suspension was allowed to stir for several hours, and was then filtered and dried 2.6 g. (55%). The product is indistinguishable from that reported in U.S. patent application Ser. No. 191,716, filed Sept. 29, 1980.
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21]>>[CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]2[C:20]([C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([CH3:16])[CH:18]=2)=[O:21])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Reactant: Cc1cccc(C(=O)Cl)c1
Product: Cc1cccc(C(=O)N2N(C3CCCCCCC3)C(=O)C2(C)C)c1

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 3-methylbenzoyl chloride were used for a similar reaction and treatment as Example 96, and the title compound was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:38])[CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](C3N(C)C=CN=3)[S:17][C:10]=12.[CH2:39]([N:41]1[CH:45]=[C:44](C2SC3C(=NC=CC=3OC3C=CC(N)=CC=3F)C=2)[N:43]=[CH:42]1)[CH3:40]>>[CH2:39]([N:41]1[CH:45]=[C:44]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:24][C:25](=[O:38])[CH2:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])=[O:28])=[CH:3][C:2]=3[F:1])[CH:15]=2)[N:43]=[CH:42]1)[CH3:40]
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5OC)cc4F)c3s2)c1
Yield: 69 %

Procedure:
Following the procedure described above for the compound 28a (example 8, step 2) but replacing amine 9 for amine 15, title compound 28b was obtained in 69% yield. 1H NMR (DMSO-d6) δ (ppm): 10.78 (s, 1H), 9.62 (s, 1H), 8.66 (d, 1H), 8.37 (broad, s, 1H), 8.33 (s, 1H), 8.05 (dd, 1H), 7.94 (s, 1H), 7.92 (dd, 1H), 7.55 (t, 1H), 7.47 (dd, 1H), 7.07 (m, 2H), 6.96 (d, 1H), 6.89 (m, 1H), 4.13 (q, 2H), 3.84 (s, 2H), 1.42 (t, 3H). MS (m/z): 546.0 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:20](I)[CH:21]=[CH2:22]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:22][CH:21]=[CH2:20])[C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN1CCN(C(=O)OCc2ccccc2)CC1=O
Yield: 69.7 %

Procedure:
Add to a solution of 4-benzyloxycarbonylpiperazin-2-one (1.6 g, 6.8 mmol) in dry THF (10 mL/mmol) under nitrogen, sodium hydride (188 mg, 7.4 mmol, 60% dispersion in mineral oil) in one portion and stir at room temperature for 30 min. Add allyl iodide (0.9 mL, 10 mmol) and stir at room temperature overnight. Concentrate, add ethyl acetate and wash with water, saturated aqueous sodium chloride solution, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 1:1 hexanes/ethyl acetate) to give the title compound as an oil (1.3 g, 72%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([O-])=[O:5].[CH3:12][NH2:13].C1COCC1>>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([NH:13][CH3:12])=[O:5]
Reactant: CN
Reactant: O=C([O-])c1c(O)cccc1O
Solvent: C1CCOC1
Product: CNC(=O)c1c(O)cccc1O
Temperature: 100 °C

Procedure:
The mixture of 2,6-dihydroxybenzoate (168 mg, 1.0 mmol) and 2 M methylamine in THF (3 mL, 6.0 mmol) in a sealed tube was heated to 100° C. overnight. The reaction mixture was then concentrated under reduced pressure and purified on silica gel eluting with hexane/ethyl acetate (1:1) to provide titled compound (67 mg). MS (ESI(+)) m/e 168 (M+H)+; 1H NMR (300 MHz, DMSO-d6) 12.57(bs, 2H), 8.82 (bs, 1H), 7.14 (t, 1H), 6.35 (d, 2H), 2.85(d, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:31])[C@@H:17]3[C@H:21]([O:23][Si](C(C)(C)C)(C)C)[CH3:22])[C:14]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:9][C@H:8]1[CH2:38][O:39][CH2:40][CH2:41][Cl:42])=[O:6])[CH:2]=[CH2:3].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:31])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:9][C@H:8]1[CH2:38][O:39][CH2:40][CH2:41][Cl:42])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCCl)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCCl)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 50.7 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-chloroethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.72 g) in tetrahydrofuran (7.2 ml) were added glacial acetic acid (0.65 ml) and a 1M solution (5.6 ml) of tetrabutylammonium fluoride in tetrahydrofuran in a stream of nitrogen, and the mixture was stirred at room temperature for 10 hours. To the mixture was added ethyl acetate (50 ml). The solution was washed with water (50 ml×3), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was chromatographed on silica gel (10 g) and eluted with a mixture of hexane and ethyl acetate (80:20 V/V) to give allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-chloroethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.30 g).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[N:7][N:6]([C@@H:9]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[N:5]=1)([O-])=O.O.NN>CO.[Pd]>[NH2:1][C:4]1[CH:8]=[N:7][N:6]([C@@H:9]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[N:5]=1
Reactant: O=[N+]([O-])c1cnn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1cnn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Yield: 106.4 %

Procedure:
A solution of 15 (2.46 g, 0.01 mol) in methanol (50 ml) and 5% palladium-on-carbon catalyst (500 mg) was stirred at room temperature while a solution of 99% hydrazine hydrate in methanol (1:3, v/v) was added dropwise until evolution of nitrogen ceased. The catalyst was removed by filtration through Celite and the solvent was removed by evaporation in vacuo to give 2.30 g of syrup. The syrup was dissolved in methanol and absorbed on 5 g of silica gel. The methanol was removed and the mixture was added to a dry packed silica gel column (2.5 × 28 cm). The column was eluted with chloroform (0.2 liter), chloroform-ethyl acetate (1:1, 0.2 liter), ethyl acetate (0.2 liter), and ethyl acetate-methanol (9:1, 0.5 liter); 20 ml fractions were collected. Fractions 30-35 provided 2.0 g (93%) of 17 as a syrup: nmr (DMSO-d6) δ 5.62 (d, 1, J1',2' 4.0 Hz, 1'--H), 7.03 (s, 1, 5--H).
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:53]([OH:55])[CH3:54])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH:53]([OH:55])[CH3:54])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:51])([F:50])[F:52])=[CH:43][CH:42]=1
Reactant: CC(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: CC(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)(F)F)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Temperature: 25 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(2,2,2-trifluoroethoxyl) phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol 17n (350.0 mg, 0.45 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 15 mL) were added o-dichlorobenzene (0.25 mL, 2.25 mmol) and 10% Pd/C (50.0 mg, 0.04 mmol) at room temperature. The mixture was stirred at room temperature under H2 for 3 hours and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=3/1 to give a few white solid. Then the solid was further purified by prep-HPLC to give the title compound 17 as a white solid (70.5 mg, 30.7%, HPLC: 90.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 505.20 [M+H]+; and 1H NMR (600 MHz, DMSO-d6) δ(ppm): 7.41 (m, 2H), 7.31 (d, 1H), 7.15 (d, 2H), 6.97 (d, 2H), 5.31 (m, 1H), 4.85 (m, 2H), 4.68 (m, 2H), 4.64 (d, 1H), 4.02 (m, 1H), 3.98 (d, 2H), 3.83 (q, 1H), 3.76 (d, 1H), 3.54 (m, 1H), 3.43 (m, 2H), 1.16 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[ClH:9].OO.C([O-])([O-])=O.[K+].[K+]>>[Cl:9][C:4]1[C:3]([NH2:8])=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1ccncc1N
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Product: Cc1ccnc(Cl)c1N
Reaction time: 1 h

Procedure:
A mixture of 4-methylpyridin-3-amine (0.62 g), 12N hydrogen chloride (3.8 mL) and 30% hydrogen peroxide (0.75 mL) was stirred at 0° C. to room temperature for 1 h. The mixture was neutralized with K2CO3, and the mixture was extracted with AcOEt. The organic layer was dried over MgSO4, and concentrated in vacuo to give 2-chloro-4-methylpyridin-3-amine (0.75 g) as an orange solid.
Reaction SMILES: C(O)(=O)C.[CH3:5][N:6]([CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[CH:15]=2)[CH2:10]1)[CH3:7]>[Zn].C1COCC1>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH:9]([CH2:8][N:6]([CH3:5])[CH3:7])[CH2:18][CH2:17]3)=[CH:22][CH:23]=1
Reactant: CN(C)CC1CCc2cc(OCc3ccc([N+](=O)[O-])cc3)ccc2C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)CC1CCc2cc(OCc3ccc(N)cc3)ccc2C1
Reaction time: 6 h
Yield: 60.3 %

Procedure:
After acetic acid (6 ml) was added to THF solution (12 ml) of 2-[(N,N-dimethylamino)methyl]-6-(4-nitrobenzyloxy)tetralin (1.91 g) under ice-cooling, zinc powder (3.67 g) was further added, which was stirred for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated. 10% aqueous potassium carbonate solution and ethyl acetate were added to the residue, the precipitate was removed by celite filtration, and the filtrate was extracted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using aluminum column chromatography (development solvent; hexane˜hexane:ethyl acetate=4:1) to give the titled compound (1.05 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[S:44]1[CH:48]=[CH:47][N:46]=[C:45]1[C@@H:49]([NH2:51])[CH3:50]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:36]([NH:51][C@H:49]([C:45]2[S:44][CH:48]=[CH:47][N:46]=2)[CH3:50])=[O:42])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: C[C@H](N)c1nccs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)N[C@@H](C)c4nccs4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (30 mg, yield 68%).