Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15]>CN(C)C=O.C(OCC)(=O)C>[CH3:15][C:14]([CH3:16])=[CH:13][CH2:12][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: CC(C)=CCBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)=CCn1ccc([N+](=O)[O-])n1
Yield: 80.4 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 1.00 g, 8.85 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL) and a 60% dispersion of sodium hydride in mineral oil (390 mg, 9.74 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min, the 1-bromo-3-methyl-but-2-ene (1.33 g, 9.00 mmol) was added. The reaction continued to stir under nitrogen for 20 min. The solution was diluted with ethyl acetate (200 mL), washed with water (2×75 mL), saturated aqueous brine solution (75 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 5% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) afforded 1-(3-methyl-but-2-enyl)-3-nitro-1H-pyrazole (1.29 g, 81%) as a yellow oil: H1-NMR (400 MHz, CDCl3) δ 1.79 (3H, s), 1.83 (3H, s), 4.80 (2H, d, J=7.2 Hz), 5.45 (1H, t, J=7.2 Hz), 6.88 (1H, s), 7.43 (1H, s).
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12](Cl)(Cl)=[O:13].Cl.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[C:28]([C:30]3[CH:39]=[C:38]4[C:33]([CH2:34][CH2:35][NH:36][CH2:37]4)=[CH:32][CH:31]=3)[N:27]=[C:26]([NH2:40])[N:25]=2)[CH2:20][CH2:19]1>>[NH2:40][C:26]1[N:27]=[C:28]([C:30]2[CH:39]=[C:38]3[C:33]([CH2:34][CH2:35][N:36]([C:12]([NH:11][CH:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH2:4][CH2:3][CH2:2]4)=[O:13])[CH2:37]3)=[CH:32][CH:31]=2)[CH:29]=[C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]2)[N:25]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: NC1CCCc2ccccc21
Reactant: O=C(Cl)Cl
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)NC3CCCc5ccccc53)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from 1,2,3,4-tetrahydronaphthalen-1-amine (Aldrich, Cat. #247820), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=498.3.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1.[Cl:12][C:13]([Cl:18])([Cl:17])[C:14](Cl)=O.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[N:26]1C=CC=CC=1.N>O.C1C=CC=CC=1>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([CH2:2][NH:1][C:14](=[NH:26])[C:13]([Cl:18])([Cl:17])[Cl:12])=[CH:4]1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: NCc1c[nH]c2ccccc12
Reactant: c1ccncc1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: N
Solvent: O
Solvent: c1ccccc1
Product: N=C(NCc1c[nH]c2ccccc12)C(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
To a stirred solution of 14.6 g. (0.1 mole) of 3-(aminomethyl) indole in 30 ml. of benzene is added dropwise 18.2 g. (0.1 mole) of trichloroacetyl chloride over a period of approximately 5 minutes. The reaction mixture is heated at reflux for 30 minutes, cooled and concentrated to dryness in vacuo. The resultant solid is broken up and ground in a mortar to give a powder which is mixed well with 20.8 g. (0.1 mole) of phosphorus pentachloride. The mixture is heated in an oil bath at 110° C. until the evolution of hydrogen chloride ceases (approximately 3 hours). The reaction mixture containing the imidoyl chloride is cooled to room temperature and dry pyridine (7.9 g., 0.1 mole) is added followed by 6.5 ml. of concentrated aqueous ammonia. The reaction mixture is then stirred and warmed to 90° C. for 30 minutes, after which 100 ml. of water is added dropwise to precipitate the product. Overnight storage in the cold affords a solid which is crystallized from benzene-hexane to provide N-(3-indolylmethyl) trichloroacetamidine m.p. 135.5° to 138.5° C.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=2[O:2]1.[CH2:13]([NH2:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21].[OH-:23].[K+]>C(Cl)CCl>[CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([C:6]([NH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:22][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:11]4[O:23][CH2:1][O:2][C:3]=4[CH:4]=3)=[O:7])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: [OH-]
Reactant: NCCCCCCCCN
Agent: [K+]
Solvent: ClCCCl
Product: O=C(NCCCCCCCCNC(=O)c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2

Procedure:
m.p. 179°-180° C., 21.6 g., was prepared as in Example 1 using 3,4-methylenedioxybenzoyl chloride (from 30 g. of 3,4-methylenedioxybenzoic acid as in Example 6) in 100 ml. of ethylene dichloride, 11.5 g. of 1,8-octanediamine, 200 ml. of 10% aqueous potassium hydroxide solution, 500 ml. of ethylene dichloride and recrystallization from ethanol.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:7]1[CH:18]=[CH:17][C:10]2[O:11][C:12]([CH3:16])([CH3:15])[O:13][CH2:14][C:9]=2[CH:8]=1)[OH:6])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][C@@H:5]([C:7]1[CH:18]=[CH:17][C:10]2[O:11][C:12]([CH3:15])([CH3:16])[O:13][CH2:14][C:9]=2[CH:8]=1)[OH:6]
Reactant: CC1(C)OCc2cc([C@@H](O)CN=[N+]=[N-])ccc2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OCc2cc([C@@H](O)CN)ccc2O1
Yield: 38.5 %

Procedure:
(1R)-2-Azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (16.99 g) was hydrogenated over 10% Pd—C (1 g) in ethanol (300 ml). The catalyst was collected by filtration, and washed with ethanol. The combined washings were evaporated under reduced pressure and the residue was triturated in diethyl ether to give the title compound (5.86 g). The mother liquors were chromatographed on a Biotage column eluting with toluene:ethanol:aqueous ammonia (85:14:1) to give a further batch of the title compound (5.99 g). LCMS RT=1.68 min, ES+ve 206 (MH-H2O)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)=[O:18])=[C:15]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(-c3cccnc3)c2)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3ccc(OC)cc3)c(-c3cccnc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
4-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridyl)benzoic acid (44 mg, 0.1119 mmol) was dissolved in methylene chloride (10 ml), then p-anisidine (28 mg, 0.2276 mmol), triethylamine (23 mg, 0.2277 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (38 mg, 0.1982 mmol) were added thereto at room temperature and the mixture was stirred for 16 hours. 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 preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (33 mg, 0.0662 mmol, 59%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2[S:18][C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=3)=[CH:20][N:21]=2)=[O:15])[CH2:10][CH2:9]1.CCN=C=NCCCN(C)C.[CH3:42][S:43]([NH2:46])(=[O:45])=[O:44].O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:42][S:43]([NH:46][C:26]([C:25]1[CH:29]=[CH:30][C:22]([C:19]2[S:18][C:17]([NH:16][C:14]([N:11]3[CH2:12][CH2:13][C:8](=[CH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:9][CH2:10]3)=[O:15])=[N:21][CH:20]=2)=[CH:23][CH:24]=1)=[O:28])(=[O:45])=[O:44]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(-c2cnc(NC(=O)N3CCC(=Cc4ccccn4)CC3)s2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)NC(=O)c1ccc(-c2cnc(NC(=O)N3CCC(=Cc4ccccn4)CC3)s2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.7 %

Procedure:
The compound (100 mg, 238 μmol) obtained in Example 20 was dissolved in DMF (4 mL), and N,N-dimethyl-4-aminopyridine (hereinafter referred to as DMAP) (6.0 mg, 48 μmol) and WSC (50 mg, 262 μmol) were added thereto, followed by stirring at room temperature for 10 minutes. Methanesulfonamide (34 mg, 357 μmol) was added to the resulting mixture, followed by stirring at room temperature for 16 hours. Water was added to the resulting mixture, and after extraction with methanol:chloroform (1:10), the extract was dried over anhydrous sodium sulfate. The desiccant was filtered off, and the residue obtained by evaporation under reduced pressure was purified using medium pressure flash column chromatography (silica gel; methanol:chloroform=1:15), thereby giving the title compound (15 mg, 13%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+]([O-])=O)[CH:9]=1)(=[O:4])=[O:3].[Br:17]C1C=C(CCO)C=CC=1>>[CH3:1][S:2]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:17])[CH:9]=1)(=[O:4])=[O:3]
Reactant: OCCc1cccc(Br)c1
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Product: CS(=O)(=O)OCCc1cccc(Br)c1
Yield: 77 %

Procedure:
The title compound was prepared in 77% yield using a similar procedure to description D4 starting from 2-(3-bromophenyl)ethanol.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:39]=[CH:38][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])=[CH:28][CH:27]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:39]=[CH:38][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:4]3[C:5](=[O:16])[C:6](=[O:15])[C:7]=3[NH:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:28][CH:27]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Reactant: NCCCCCCOc1ccc(OCCN2CCOCC2)cc1
Product: O=c1c(NCCCCCCOc2ccc(OCCN3CCOCC3)cc2)c(Nc2cccnc2)c1=O
Yield: 76 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-3-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 1A and 6-[4-(2-morpholin-4-yl-ethoxy)-phenoxy]-hexylamine.
Reaction SMILES: C[C@@H]1N([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)[C@@H](C)COC1.Cl.Cl.C[N:24]1C2CCC1CC(N)C2>>[O:9]1[C:10]2=[CH:16][CH:15]=[CH:14][C:13]([C:17]([NH2:24])=[O:19])=[C:11]2[N:12]=[CH:8]1
Reactant: C[C@H]1COC[C@H](C)N1c1nc2c(C(=O)O)cccc2o1
Reactant: CN1C2CCC1CC(N)C2
Agent: Cl
Product: NC(=O)c1cccc2ocnc12

Procedure:
Following general procedure GP-C1, a mixture of 2-((3S,5S)-3,5-dimethylmorpholino)benzoxazole-4-carboxylic acid and 8-methyl-8-azabicyclo[3.2.1]octan-3-amine dihydrochloride were coupled to provide N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2-(3 S,5S)-3,5-dimethylmorpholino)benzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O.C([O-])(O)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][N:31]3[CH2:32][CH2:33][CH:28]([C:24]4[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=4)[CH2:29][CH2:30]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(Cl)cc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
4-(4-chlorophenoxy)benzaldehyde (0.119 g, 0.510 mmol) and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (0.126 g, 0.510 mmol) were mixed in 1,2-dichloroethane (5 mL) and then treated with sodium triacetoxyborohydride (0.424 g, 2.00 mmol) and HOAc (0.03 mL, 0.5 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was neutralized with saturated NaHCO3 aqueous solution and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, concentrated in vacuo, and purified by preparative TLC using 5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product (53 mg, 23%). 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.34-7.19 (m, 7H), 6.98-6.87 (m, 5H), 3.50 (s, 2H), 2.98 (d, 2H, J=11.8 Hz), 2.58-2.44 (m, 2H), 2.10-1.98 (m, 2H), 1.83-1.76 (m, 4H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 463.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13](OC)=[O:14])=[O:8])=[CH:5][CH:4]=1)#[N:2].O.[NH2:23][NH2:24]>CCO>[C:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:12]([C:13]([NH:23][NH2:24])=[O:14])[CH:11]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: COC(=O)c1cccc(NC(=O)c2ccc(C#N)cc2)c1
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C(=O)Nc2cccc(C(=O)NN)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
To a suspension of methyl 3-[(4-cyanobenzoyl)amino]benzoate (762 mg, 2.72 mmol) in EtOH (8 mL) was added hydrazine hydrate (1.79 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (3 mL) and water (3×3 mL) and drying under vacuo at 60° C. for 2 hrs gave 518 mg of the title compound (68%) as a white solid in 98.8% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8]1([P:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)(Cl)Cl.CCOCC>[Br-:1].[C:5]([CH2:4][CH2:3][CH2:2][P+:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([OH:7])=[O:6]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)CCCBr
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
A mixture of 100 g of 4-bromobutyric acid and 156.9 g of triphenylphosphine was heated under argon at 130° C. for 2 hours. The cooled reaction mixture was suspended in 250 mL of chloroform and heated to reflux, then diluted with 200 mL of ether. This was stirred for 30 minutes at room temperature, chilled to 0° C, and filtered. The solid was dried in vacuo to afford 240 g title salt.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.O.[K].CN(C)C=O.[F:18][C:19]([F:26])([F:25])[C:20]([F:24])=[C:21]([F:23])[F:22]>O.C(OCC)(=O)C>[F:22][C:21]([F:23])([O:10][C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)[CH:20]([F:24])[C:19]([F:26])([F:25])[F:18]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OC(F)(F)C(F)C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 4.63 g of p-nitrophenol and 0.56 g of potassium hydrate added to 100 ml of N,N-dimethylformamide blowed hexafluoropropene at room temperature, and then the solution was stirred at 50° C. for 1 hour. Next, ethyl acetate and water were introduced in the reaction solution for separating the organic phase. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under a reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:EtOAc=20:1) to obtain 3.81 g of the desired product (Yield: 42%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=O)[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].Cl.[NH2:52][OH:53]>CO.N1C=CC=CC=1.C(OCC)(=O)C>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15]/[C:16](=[N:52]\[OH:53])/[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)/C(=N/O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (100 mg, 0.143 mmol) in methanol (1 mL) and pyridine (1 mL) was added hydroxylamine hydrochloride (100 mg, 1.43 mmol) at room temperature, and the mixture was stirred under nitrogen overnight. The mixture was diluted with ethyl acetate, washed with 1N HCl and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative TLC (silica gel, 95:5 chloroform/methanol) to afford (6R,6aS,14aR,E)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-(hydroxyimino)-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (17 mg, 16%) as an orange solid: 1H NMR (500 MHz, CDCl3) δ 12.02 (s, 1H), 8.45 (s, 1H), 6.93 (s, 1H), 6.54 (s, 1H), 6.52 (d, J=9.0 Hz, 1H), 5.33 (br s, 1H), 5.00 (br s, 1H), 4.84-4.82 (m, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 3.78-3.68 (m, 3H), 3.62 (s, 3H), 3.54 (dd, J=19.5, 6.5 Hz, 1H), 3.45-3.42 (m, 1H), 3.43 (s, 3H), 3.36 (d, J=19.5 Hz, 1H), 3.13 (t, J=9.5 Hz, 1H), 2.46 (d, J=5.0 Hz, 1H), 2.39 (s, 3H), 1.38 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 713 (M+H); HPLC 95.0% (AUC), tR 12.31 min.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CC(C)=O>[C:23]([O:22][C:20](=[O:21])[CH2:19][O:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:4]=1[C:2](=[O:3])[CH3:1])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(=O)c1c(O)cccc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1c(O)cccc1OCC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 2,6-dihydroxyacetophenone (35.37 g, 0.23 moles), potassium carbonate (51.4 g, 0.37 moles), and t-butyl bromoacetate (28.4 mL, 0.23 moles) in 440 mL of acetone was heated at reflux for 1.5 hours. It was then cooled to room temperature and filtered. The filter cake was washed with acetone and the combined mother liquors were concentrated in vacuo. (2-Acetyl-3-hydroxy-phenoxy)-acetic acid tert-butyl ester was isolated as thick yellow oil, which was used directly used for the next step.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:19][C@@H:20]1[CH2:54][N:23]2[C:24](=[O:53])[C@@H:25]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C@H:31]([OH:44])[CH2:32][C@@H:33]3[CH2:38][C@@:34]3([C:39]([O:41][CH2:42][CH3:43])=[O:40])[NH:35][C:36](=[O:37])[C@@H:22]2[CH2:21]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:11]([O:19][C@@H:20]1[CH2:54][N:23]2[C:24](=[O:53])[C@@H:25]([NH:45][C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:44])[CH2:32][C@@H:33]3[CH2:38][C@@:34]3([C:39]([O:41][CH2:42][CH3:43])=[O:40])[NH:35][C:36](=[O:37])[C@@H:22]2[CH2:21]1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)[C@@]12C[C@H]1C[C@@H](O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](OC(=O)c3ccccc3)C[C@H]1C(=O)N2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)[C@@]12C[C@H]1CC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](OC(=O)c3ccccc3)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
To a solution of oxalyl chloride (0.092 ml, 1.05 mmol) in dichloromethane (1.75 ml) at −78° C. was added dropwise DMSO (0.149 ml, 2.10 mmol). The reaction mixture was stirred for 10 min and then a solution of (2S,6S,12S,13aS,14aR,16aS)-ethyl 2-(benzoyloxy)-6-(tert-butoxycarbonylamino)-12-hydroxy-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 1b, 0.43 g, 0.698 mmol) in dichloromethane (4 ml) was added dropwise. The reaction mixture was stirred at −78° C. for 30 min and triethylamine (0.730 ml, 5.24 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min and warmed to room temperature and stirred for 1.5 hr. The reaction mixture was quenched with water, stirred for 30 min and extracted with dichloromethane and the organic layer dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/methanol=40/1) to provide the title compound (2S,6S,13aS,14aR,16aS)-ethyl 2-(benzoyloxy)-6-(tert-butoxycarbonylamino)-5,12,16-trioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (0.36 g, 0.59 mmol, 84% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: CCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCOc1ccc(Br)c(F)c1

Procedure:
This was prepared using a similar method to that described for compound 3. Quantities: compound 1 (2.31 g, 12.1 mmol), 1-bromopentadecane (3.97 g, 13.6 mmol), potassium carbonate (2.97 g, 21.5 mmol) and butanone (80 ml).