Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:24]=[CH:23][C:22](C(=O)C)=[CH:21][C:20]=1[F:28])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=[C:32](C=CC=1)[C:33]([O:35]O)=[O:34]>C(Cl)(Cl)Cl.ClCCl>[C:33]([O:35][C:22]1[CH:23]=[CH:24][C:19]([O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:20]([F:28])[CH:21]=1)(=[O:34])[CH3:32]
Reactant: CC(=O)c1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(F)c1

Procedure:
1-(4-{[t-Butyl(diphenyl)silyl]oxy}-3-fluorophenyl)-1-ethanone (8.27 g, 21.07 mmol) was dissolved in chloroform (300 mL). 3-Chloroperoxybenzoic acid (4.0 g, 23.18 mmol) was added and the solution heated to reflux for 72 hours. The solution was diluted with dichloromethane, washed with saturated sodium hydrogen sulfate, saturated sodium hydrogen carbonate, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent evaporated to dryness in vacuo to yield the title compound which was used without further purification (5.28 g, 12.92 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]=[C:14]([O:16][C:17]4[C:23]([CH3:24])=[CH:22][C:20]([NH2:21])=[C:19]([CH3:25])[CH:18]=4)[S:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CO.CO[CH:30](OC)[N:31]([CH2:33][CH3:34])[CH3:32]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]=[C:14]([O:16][C:17]4[C:23]([CH3:24])=[CH:22][C:20]([N:21]=[CH:30][N:31]([CH2:33][CH3:34])[CH3:32])=[C:19]([CH3:25])[CH:18]=4)[S:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Oc2nc(C3(c4ccc(Cl)cc4)CC3)ns2)c(C)cc1N
Reactant: CCN(C)C(OC)OC
Solvent: CO
Solvent: Cc1ccccc1
Product: CCN(C)C=Nc1cc(C)c(Oc2nc(C3(c4ccc(Cl)cc4)CC3)ns2)cc1C
Yield: 61.6 %

Procedure:
0.30 g (0.81 mmol) of 4-({3-[1-(4-chlorophenyl)cyclopropyl]-1,2,4-thiadiazol-5-yl}oxy)-2,5-dimethylaniline is dissolved in 3 ml of toluene and 0.75 ml of methanol and treated with 0.32 g (2.42 mmol) of N-ethyl-N-methylformamide dimethylacetal. The reaction mixture is refluxed for 18 h, subsequently cooled, freed from the solvent under vacuum and purified by column chromatography. 0.22 g of product is obtained (99.3% purity, 61.7% yield; log P (pH2.3)=2.28).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].Br[C:14]1[S:18][N:17]=[CH:16][C:15]=1[N+:19]([O-:21])=[O:20].C([O-])(O)=O.[Na+].O>O1CCOCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N+:19]([C:15]1[CH:16]=[N:17][S:18][C:14]=1[C:7]1[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnsc1Br
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1ccc(-c2sncc2[N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 10000 %

Procedure:
To a solution of 4-carbamoylphenylboronic acid (3Q) (157 mg, 0.96 mmol) and 5-bromo-4-nitroisothiazole (P) (200 mg, 0.96 mmol) in dioxane was bubbled was nitrogen gas for 5 min Bis(tri-tert-butylphosphine)palladium (0) (49 mg, 0.096 mmol) and 1.2M NaHCO3 water solution (241 mg, 2.9 mmol) was added and stirred at 120° C. under nitrogen atmosphere for 15 min The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water, and concentrated in vacuo at room temperature (25° C.) to afford the product 4-(4-nitroisothiazol-5-yl)benzamide (3C4) (250 mg, 96 mmol)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[C:16]2[NH:21][C:20](=[O:22])[C:19](=[CH:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:26][N:25]=3)[NH:18][C:17]2=[O:38])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.O.[Zn]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]2[NH:21][C:20](=[O:22])[CH:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:26][N:25]=3)[NH:18][C:17]2=[O:38])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=Cc2ccc(OCc3ccccc3)cn2)c(=O)[nH]c1=Cc1ccc(OCc2ccccc2)cn1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(Cc2ccc(OCc3ccccc3)cn2)C(=O)NC1Cc1ccc(OCc2ccccc2)cn1
Yield: 39.7 %

Procedure:
A suspension of 3,6-di[(5-benzyloxypyridin-2-yl)methylidene]piperazine-2,5-dione (Compound 10; 0.2 g) and excess of zinc powder in a mixture of 10 mL of acetic acid and 10 mL of water was stirred and refluxed for 5-10 minutes and filtered while hot. Water was added to dissolve zinc acetate. The filtrate was concentrated and filtered. The solid thus obtained was collected and washed with water to give 80 mg (40%) of the desired 3,6-di[(5-benzyloxypyridin-2-yl)methyl]piperazine-2,5-dione (Compound 13).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:12][CH2:13][OH:14])[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:15](=O)(O)[O-].[Na+].[C:20]([C:22]1[CH:23]=[C:24]([C:32](Cl)=[O:33])[C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)#[N:21]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:12][CH2:13][OH:14])[CH2:10][N:11]([CH3:15])[C:32]([C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:31]=[C:22]([C:20]#[N:21])[CH:23]=2)=[O:33])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])O
Reactant: NC[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cc(C(=O)Cl)c2ccccc2c1
Agent: [Na+]
Solvent: ClCCl
Product: CN(C[C@@H](CCO)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12
Temperature: 0 °C
Reaction time: 20 h
Yield: 78 %

Procedure:
(S)-2-(3,4-Dichlorophenyl)-4-hydroxybutylamine (20.8 g, 83.8 mmol) was dissolved in DCM (700 mL). To the stirred solution was added 10% aqueous sodium bicarbonate (300 mL), and the mixture cooled to 0° C. A solution of 3-cyano-1-naphthoyl chloride (17.4 g, 80.6 mmol) in DCM (300 mL) was added dropwise over 30 minutes. The mixture was then allowed to warm to ambient temperature and stir for 20 h. The layers were separated, and the aqueous phase washed with DCM (300 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated in vacuo to give a white foam. Purification by chromatography (silica gel; 0-25% acetonitrile in DCM) provided the desired product as a white foam (27.0 g, 78%). 1H-NMR (DMSO-d6) δ1.46-1.60 (m, 1H, CH); 1.77-1.91 (m, 3H, CH); 4.38-4.41 (t, 1H, CH); 4.54-4.57 (t, 2H, CH); 6.43 (broad, 1H, OH); 6.84-7.26 (m, 2H, aromatic); 7.44-7.54 (m, 3H, aromatic); 7.57-7.80 (m, 7H, aromatic); 8.04-8.33 (m, 2H, aromatic); 8.61 (s, 1H, aromatic).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C(O)(=O)[C:10](O)=[O:11].[C:15]1(C=O)[C:16]([CH3:22])=[CH:17][CH:18]=[CH:19][C:20]=1[OH:21]>O>[CH:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22].[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:10]=[O:11]
Reactant: O=C(O)C(=O)O
Reactant: Cc1cccc(O)c1C=O
Agent: Oc1cccc(O)c1
Solvent: O
Product: C=O
Product: Cc1cccc(O)c1
Temperature: 60 °C

Procedure:
Into another reactor having the same equipments as described above were charged 220 parts (2 mol) of resorcin, 110 parts of water and 2.5 parts of oxalic acid, and the resulting mixture was heated at 60° C. to form a solution. Then, the above obtained m-cresol-formaldehyde reaction liquid was added dropwise to the solution in 2 hours while agitating the resulting mixture at 60° C. After completion of the addition, the resulting mixture was further agitated at 60° C. for 3 hours, and then water in the reaction liquid was removed. The residue was poured into a distillation vessel, and unreacted m-cresol and resorcin were removed by a distillation under reduced pressure to obtain a m-cresol/resorcin/formaldehyde cocondensate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(OC)cc2)cc1
Yield: 87 %

Procedure:
From 4-methoxy-bromobenzene and 4-methoxyphenyl boronic acid, yield 87%; mp 178-180° C. (lit.,1 179-180° C.); IR: 1599, 1493, 1466 and 1290; 1H NMR (400 MHz; CDCl3): 7.47 (4H, d, J 8.7), 6.96 (4H, d, J 8) and 3.84 (6H, s); 13C NMR (CDCl3): 159.1, 133.9, 128.1, 114.5 and 55.7; m/z (EI) 214 (100%, M+), 171 (70), 128 (50) and 69 (40)(Found: M+, 214.099. C14H14O2 requires M, 214.099).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[N:3]=1.C(=O)([O-])[O-:13].[K+].[K+].[CH3:18][CH2:19][O:20][CH2:21][CH3:22]>CC(C)=O.BrCC(OCC)=O>[Br:1][C:2]1[N:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([O:8][CH2:18][C:19]([O:20][CH2:21][CH3:22])=[O:13])=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1nc(Br)ccc1O
Agent: CCOC(=O)CBr
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 89 %

Procedure:
2-Bromo-5-hydroxy-6-nitropyridine (30 g, 0.14 mole) was suspended in acetone (200 ml), and potassium carbonate (39 g, 0.28 mole) was added, followed by ethyl bromoacetate (15.7 ml, 0.14 mmole). The reaction was heated at reflux for 10 hr, then was cooled to room temperature and diluted with Et2O. The precipitate was removed by suction filtration, and the filtrate was concentrated in vacuo to afford material (38 g, 89%), which was used without further purification; MS (ES) m/z 305.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.Br[CH:13]([CH3:15])[CH3:14].[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]([CH3:15])[CH3:14])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Reactant: CC(C)Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(C)Oc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 61.1 %

Procedure:
A mixture of 4-bromo-2-nitrophenol (2.17 g, 10 mmol), 2-bromopropane (2.44 g, 20 mmol), KOH (2.24 g, 40 mmol) and 18-crown-6 (224 mg, 1.0 mmol) in benzene (100 mL) was heated at reflux for 4 h. Cooling to room temperature, concentration and purification by chromatography afforded the sub-title compound (1.59 g, 61%).
Reaction SMILES: ClC1C=CC(C([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH3:18])=O)=CC=1.[Na].ClC1C=CC(C(C2N(C)C(CC#N)=CC=2C)=O)=CC=1.C([SH:43])C.Cl>>[CH3:13][N:12]1[CH:8]=[C:9]([CH3:18])[CH:10]=[CH:11]1.[S:43]1[CH:8]=[CH:9][CH:10]=[C:11]1[CH2:14][C:15]([O-:17])=[O:16]
Reactant: Cc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Reactant: CCS
Agent: Cc1cc(CC#N)n(C)c1C(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na]
Product: Cc1ccn(C)c1
Product: O=C([O-])Cc1cccs1

Procedure:
A process of preparing sodium 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid which comprises reacting 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetonitrile with ethyl mercaptan in the presence of hydrogen chloride in an anhydrous aprotic organic solvent under an inert atmosphere at or below 10° C. to yield ethyl 5-(p-chlorobenozyl)- 1,4-dimethylpyrrole-2-thiolacetate and then hydrolyzing said thiolacetate by treatment with aqueous sodium hydroxide.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:33])[NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[C:25]3[C:31]#[N:32])=[CH:14][CH:13]=1)([CH3:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[NH2:7][CH2:8][C:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[C:25]3[C:31]#[N:32])=[O:33])=[CH:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1ccc(C(=O)NCCc2ccc3[nH]cc(C#N)c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(CN)c1ccc(C(=O)NCCc2ccc3[nH]cc(C#N)c3c2)cc1
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of (2-[4-[2-(3-cyano-1H-indol-5-yl)-ethylcarbamoyl]-phenyl]-2-methyl-propyl)-carbamic acid tert-butyl ester (1.16 g, 2.5 mmol) (prepared using the procedure of reference example 1w) in CH2Cl2 (8 ml) was added TFA (1.6 ml) and the reaction stirred 2 hrs. Water (50 μL) was add-ed and the reaction concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 10% 7M NH3 in CH3OH/CH2Cl2) to give 808 mg of product. MS (ion spray) m/z 361 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:15]([NH:17][C:18]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=[C:20]([F:30])[CH:19]=1)=[O:16].N1C=CC=CC=1.O>C(OCC)C>[Cl:34][C:33]1[CH:32]=[CH:31][C:14]([C:15]([NH:17][C:18]2[CH:23]=[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:21]=[C:20]([F:30])[CH:19]=2)=[O:16])=[CH:13][C:12]=1[NH:11][C:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: Nc1cc(C(=O)Nc2cc(F)cc(N3CCOCC3)c2)ccc1Cl
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc(F)cc(N2CCOCC2)c1)c1ccc(Cl)c(NC(=O)c2ccc(Cl)nc2)c1
Temperature: 100 °C
Yield: 90.5 %

Procedure:
A mixture of 6-chloropyrid-3-ylcarbonyl chloride (1.96 g), 3-amino-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide (3 g) and pyridine (20 ml) was stirred and heated to 100° C. for 4 hours. The mixture was cooled to ambient temperature. Water and diethyl ether were added. The resultant precipitate was washed with a saturated aqueous sodium bicarbonate solution and with methanol. There was thus obtained the title compound (3.8 g); NMR Spectrum: (DMSOd6) 3.1 (t, 4H), 3.75 (t, 4H), 6.52 (d, 1H), 7.1 (s, 1H), 7.2 (d, 1H), 7.6-7.7 (m, 2H), 7.7-7.8 (m, 1H), 8.2 (d, 1H), 8.35-8.4 (m, 1H), 8.97 (d, 1H), 10.2-10. 32 (br S, 1H); Mass Spectrum: M+H+ 489.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C@H:11]2[C:23](OC)=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[BH4-]>>[C:1]1([C@H:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[CH2:23][OH:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Product: C[C@@H](N[C@@H]1CCNC[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 261B (270 mg, 0.75 mmol) was added LiBH4 (15.5 mg, 0.71 mmol). The mixture was heated to reflux for 1.0 hr. HPLC showed still some starting material remaining. More LiBH4 (15.5 mg, 0.71 mmol) was added, and the mixture was heated for another 2.0 hrs. After cooling to room temperature, ice water was added, and the mixture was concentrated in vacuo to remove the THF. The aqueous residue was extracted with EtOAc (×3) and the combined extracts were dried (Na2SO4), and concentrated in vacuo. The residue was taken into 2 mL of CH2Cl2 and 2 mL of TFA was added. The mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo, followed by drying under high vacuum overnight to afford 261C as an oil. It had an analytical HPLC retention time=0.590 min. (Chromolith SpeedROD column 4.5×50 mm, 10–90% aqueous methanol containing 0.1% TFA over 4 min, 4 mL/min, monitoring at 220 nm) and a LC/MS M++1=235. This material was used directly in the next reaction step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])[CH:8]=2)[N:3]=1.[BH4-].[Na+].C(=O)(O)[O-]>C(Cl)Cl.CO>[NH2:1][C:2]1[C:11]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[CH:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=1
Reactant: Cc1cccc(C(=O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc(C(O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C

Procedure:
(2-(2-Amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanone (0.152 g, 0.359 mmol) was dissolved in a mixture of DCM (4.0 mL) and MeOH (5.0 mL). Sodium borohydride (0.041 g, 1.077 mmol) was added to the mixture in three portions (each portion added at 3 h intervals) and the mixture was stirred at ambient temperature. The mixture was treated with DCM (10 mL) and saturated aqueous bicarbonate (10 mL) and stirred for 20 min. The phases were separated and the organic layer was concentrated to afford a yellow solid (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanol which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:28])[CH2:11][C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)CCC([O-])=O.C([O-])(O)=O.[Na+].[CH3:42][C:43]1[CH:53]=[CH:52][CH:51]=[C:50]([CH3:54])[C:44]=1[O:45][CH2:46][C:47](Cl)=[O:48]>CCOC(C)=O.O>[CH3:42][C:43]1[CH:53]=[CH:52][CH:51]=[C:50]([CH3:54])[C:44]=1[O:45][CH2:46][C:47]([NH:1][C@H:2]([C@@H:10]([OH:28])[CH2:11][C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:48]
Reactant: Cc1cccc(C)c1OCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: O=C([O-])CCC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Oxallyl chloride (36.3 ml, 0.42 mol) was added to a slurry of 2-6 dimethylphenoxyacetic acid (50 g, 0.28 mol) in 500 ml toluene followed by addition of 5 drops of DMF and stirred at room temperature for 30 min, then at 55° C. for 1.5 hours. The toluene was removed on a rotary evaporator and remaining volatiles were removed in vacuo to afford 2,6-dimethyl-phenoxyacetyl chloride as an amber oil, 55 grams, 100%. [2S,3S,5S]-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane×0.5 succinate (111.9 g, 0.25 mol) was charged to a 2 L, 3-necked round-bottomed flask with mechanical stirring. NaHCO3 (106 9, 1.26 mol), 600 ml H2O and 600 ml EtOAc were added and stirred vigorously until all solids were dissolved (15 minutes). Stirring was slowed and a solution of the 2,6-dimethyl-phenoxyacetyl chloride and EtOAc (100 ml) was added in a narrow stream via addition funnel. After 30 min of stirring, starting materials were consumed (HPLC analysis) and the layers were separated. The aqueous layer was extracted with EtOAc, the organic layers were combined and washed with 200 ml of 1 M NaOH, 200 ml of 10% HCl, 200 ml of brine, dried over MgSO4, filtered and concentrated to provide the desired product as a white solid.
Reaction SMILES: [C:1]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)C(=O)[O:4]1)#N.C[C:14]([CH3:17])([O-:16])[CH3:15].[Li+]>O1CCCC1>[C:7]1([O-:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:3]1([CH:12]=[CH:17][C:14]([OH:16])=[CH:15][CH:1]=1)[OH:4].[C:3]1([CH:12]=[CH:17][C:14]([OH:16])=[CH:15][CH:1]=1)[OH:4]
Reactant: N#CC1OC(=O)c2ccccc21
Reactant: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1ccc(O)cc1
Product: [O-]c1ccccc1
Temperature: -40 °C

Procedure:
In the first of two late-stage ring-forming (bond-pair) coupling reactions, components 7 and 8 were combined in a Kraus-Sugimoto cyanophthalide annulation reaction (Kraus, G. A.; Sugimoto, H. Tetrahedron Lett. 1978, 19, 2266-2266) (FIG. 2C). Thus, addition of solution of enone 8 (1 equiv) to the cyanophthalide anion derived from deprotonation of 7 (3.0 equiv) with lithium tert-butoxide (3.0 equiv) in tetrahydrofuran at −78° C. led to rapid formation of Michael addition product(s) (based on tic analysis, not characterized); upon warming to −40° C. these underwent cyclization to form a single dihydroquinone phenolate, which was trapped in situ by monomethylation with dimethylsulfate (9.0 equiv, −26→23° C.). The anthrone methyl ether 22 was obtained in 57% yield (3-g scale, yellow foam) after chromatographic purification, a process facilitated by the characteristic long-wavelength (365 nM) UV absorption of the product, with blue-green fluorescence, a characteristic of trioxacarcins. Oxidative cleavage of the alkenyl side-chain at 0° C. (4.0 equiv of NalO4; 0.1 equiv of K2OsO4.2H2O; 2.0 equiv of 2,6-lutidine) then provided the corresponding aldehyde as an orange foam (69% yield) (Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217-3219). The methoxymethyl (MOM) protective group was cleanly and selectively removed by treatment of the latter product with B-bromocatecholborane (2.0 equiv), affording the bisphenol intermediate (89% yield) (Boeckman, R. K.; Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411-1414) as a yellow foam. Protection of this moderately air-sensitive product (t-Bu2SiCl2, HOBt, DIPEA, 55° C.) provided the much more stable, di-tert-butylsiloxane derivative (5, 50% yield) for final coupling. Unprotected aldehyde was found to be unstable to silica gel chromatography and was incompatible with the subsequent cycloaddition reaction.
Reaction SMILES: [OH:1][C@H:2]([CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1([CH3:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[CH2:25]([O:1][C@H:2]([CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1([CH3:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H](O)CCCCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](CCCCOC1(C)CCN(C(=O)OC(C)(C)C)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of (R)-tert-butyl 4-((5-hydroxyhexyl)oxy)-4-methylpiperidine-1-carboxylate (4.5 g, 14.27 mmol) in DMF (50 mL) at 0° C. was added 60% NaH (0.685 g, 17.12 mmol) and the resulting mixture was stirred at room temp for 1 h. Benzyl bromide (2.55 mL, 21.40 mmol) was then added and the mixture was stirred for 16 h. Water (20 mL) was then added and the mixture was extracted with ether (100 mL), washed with brine (25 ml), dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (0-20% EtOAc/hexane) to afford (R)-tert-butyl 4-((5-(benzyloxy)hexyl)oxy)-4-methylpiperidine-1-carboxylate (3.5 g, 8.63 mmol, 60.5% yield) as light yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.38-7.35 (m, 4H), 7.31-7.25 (m, 1H), 4.60 (d, J=11.8 Hz, 1H), 4.48 (d, J=11.8 Hz, 1H), 3.86-3.62 (m, 3H), 3.58-3.50 (m, 1H), 3.31 (t, J=6.3 Hz, 2H), 3.14 (br. s., 2H), 1.74 (d, J=12.9 Hz, 2H), 1.59-1.51 (m, 3H), 1.47 (s, 9H), 1.46-1.37 (m, 4H), 1.22 (d, J=6.1 Hz, 3H), 1.17 (s, 3H). LCMS (M+H)=406.3.