Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH2:19][C:20]2[N:21]([CH3:31])[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2F)[CH:6]=[CH:7][CH:8]=1)[CH3:2].C(C1C=CC([F:54])=C(C(C2N(C)N=C(C3C=CC=CC=3)N=2)O)C=1)C>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([F:54])=[C:5]([N:9]([CH2:19][C:20]2[N:21]([CH3:31])[N:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:24]=2)[C:10]2[CH:11]=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(F)c(C(O)c2nc(-c3ccccc3)nn2C)c1
Reactant: CCc1cccc(N(Cc2nc(-c3ccccc3)nn2C)c2ccc(C#N)cc2F)c1
Product: CCc1ccc(F)c(N(Cc2nc(-c3ccccc3)nn2C)c2ccc(C#N)cc2)c1

Procedure:
Following the procedure for Intermediate 382.1, Intermediate 385.1 (150 mg, 0.48 mmol) gave 155 mg of Intermediate 385.2 as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.95 (t, J=7.58 Hz, 3H) 2.35 (q, J=7.58 Hz, 2H) 3.59 (s, 3H) 5.87 (d, J=6.11 Hz, 1H) 6.35 (d, J=5.87 Hz, 1H) 6.48-6.57 (m, 2H) 6.86-6.94 (m, 1H) 6.95-7.02 (m, 1H) 7.11-7.19 (m, 1H) 7.22-7.32 (m, 5H).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:29])[CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[N:10][CH2:9][C:8]1=O)[CH2:2][CH3:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:31].N1C=CC=CC=1>C(Cl)Cl.O>[CH2:1]([O:4][C:5](=[O:29])[CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[N:10][CH2:9][C:8]1=[S:31])[CH2:2][CH3:3]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCOC(=O)CN1C(=O)CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCOC(=O)CN1C(=S)CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21

Procedure:
A mixture of 0.01 mole of 7-nitro-2,3-dihydro-5-(o-chlorophenyl)-2-oxo-1H-1,4-benzodiazepin-1-acetic acid propyl ester, 0.0105 mole of phosphorus pentasulfide and 100 ml. of pyridine is heated under reflux for about 24 hours. The mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue thus obtained is chromatographed on silica gel and eluted to give 7-nitro-2,3-dihydro-5-(o-chlorophenyl)-2-thioxo-1H-1,4-benzodiazepin-1-acetic acid propyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](N)=[C:6]([Br:11])[CH:5]=1.Cl.N([O-])=O.[Na+].[I-:18].[K+]>CC(C)=O.O>[Br:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[I:18])[C:3]([O:2][CH3:1])=[O:12]
Reactant: [I-]
Reactant: COC(=O)c1ccc(N)c(Br)c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(I)c(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
A solution of 4-amino-3-bromo-benzoic acid methyl ester (5.0 g, 22.0 mmol from Aldrich) in acetone (35 mL) was treated with 6M HCl (35 mL). The solution was cooled to 0° C. and treated dropwise with NaNO2 (1.84 g, 26.1 mmol) dissolved in 10 mL water. After stirring for 2 hours at 0° C., the reaction was slowly treated with potassium iodide (5.47 g, 32.6 mmol) dissolved in 20 mL water. The reaction mixture was allowed to warm to room temperature and stir for 1 hour. Reaction mixture was diluted with water and extracted with EtOAc (2×150 mL). The combined organic phase was dried (Na2SO4) and concentrated under vacuum. The residue was chromatographed (80 g Redi-Sep column) eluting from 100% heptane to 20:80 EtOAc:heptane to afford the intermediate (4.1 g, 55%) as a solid. 1HNMR (CDCl3) δ ppm: 8.27 (1H), 7.98 (1H), 7.64 (1H), 3.94 (3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]1([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:17](=[O:27])[C:16]([C:28](OCC)=[O:29])=[C:15]2[OH:33].C(N(C(C)C)C(C)C)C>O1CCOCC1.CCOC(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]1([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:17](=[O:27])[C:16]([C:28]([NH:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[O:29])=[C:15]2[OH:33]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCCC2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCCC2)C1=O
Temperature: 80 °C
Yield: 12.3 %

Procedure:
tert-Butyl 2-aminoacetate hydrochloride (901 mg, 5376 μmol) was added to a mixture of ethyl 6′-chloro-4′-hydroxy-2′-oxo-spiro[cyclohexane-1,1′-naphthalene]-3′-carboxylate (1.20 g, 3584 μmol) in 1,4-dioxane (3584 μL) and N-ethyl-N-isopropylpropan-2-amine (1873 μL, 10753 μmol). The resulting mixture was heated at 80° C. for 2 hours. The resulting mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (185 mg) as a light yellow solid after purification via preparatory HPLC. MS (m/z)=364(M+H-tBu)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=1[OH:22])[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([OH:25])[CH3:24].C(OC(=O)C)(=O)C>[Fe].C(O)(=O)C>[C:23]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH3:12])=[C:14]([OH:22])[CH:15]=1)(=[O:25])[CH3:24]
Reactant: CCO
Reactant: CN(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1O
Agent: [Fe]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(N(C)C(=O)OCc2ccccc2)c(O)c1
Temperature: 80 °C

Procedure:
3.3×10-2 mole (10 g) of 2-(N-benzyloxycarbonyl -N-methylamino)-5-nitrophenol is added to 40 g of iron powder in 60 ml of 96° strength ethanol mixed with 20 ml of acetic acid brought to 80° C., the temperature being maintained at 80° C. When the addition is complete, heating is maintained for 30 minutes. The inorganic salts present in the reaction medium are removed by filtration while hot. The filtrate is diluted with 800 ml of ice-cold water. 3.7×10-2 mole (3.5 ml) of acetic anhydride is then added. The expected product crystallizes after 3 hours. After filtration and drying, the product obtained is recrystallized from a water/ethanol mixture. It then melts at 174° C.
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:8]([CH3:27])[C@@H:9]([O:25][CH3:26])/[CH:10]=[CH:11]/[Sn:12]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])[C@@H:4]([CH3:7])[CH:5]=[O:6].CC(=CC)C.Cl([O-])=[O:34].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O.[Cl-].[Na+].O>[CH3:1][O:2][C@H:3]([C@@H:8]([CH3:27])[C@@H:9]([O:25][CH3:26])/[CH:10]=[CH:11]/[Sn:12]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])[C@@H:4]([CH3:7])[C:5]([OH:34])=[O:6]
Reactant: CCCC[Sn](/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)C=O)(CCCC)CCCC
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Cl-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCC[Sn](/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)C(=O)O)(CCCC)CCCC
Reaction time: 8 h
Yield: 90 %

Procedure:
To (E)-(2R,3R,4R,5R)-3,5-Dimethoxy-2,4-dimethyl-7-tributylstannanyl-hept-6-enal (98 mg, 0.2 mmol) in tert-butanol (2 ml) and 2-methyl-2-butene (0.22 ml, 2.03 mmol) at room temperature, was added a solution of sodium chlorite (92 mg, 1.02 mmol) and sodium dihydrogenphosphate (58 mg, 0.41 mmol) in water (0.5 ml). The reaction was stirred vigorously overnight, after which brine was added and then extracted with dichloromethane (2×). The organics were dried through a hydrophobic frit and concentrated in vacuo. The oily residue was left on a vacuum pump overnight to afford the product 5b as a solid (91 mg, 90%). 1H NMR (300 MHz, CDCl3) δ 6.05 (d, J=19.0 Hz, 1H), 5.58 (dd, J=19.0 Hz, 7.9 Hz, 1H), 3.72 (m, 1H), 3.38 (s, 3H), 3.23 (t, J=8.8 Hz, 1H), 3.16 (s, 3H), 2.52 (m, 1H), 1.61 (m, 1H), 1.43 (m, 6H), 1.24 (m, 6H), 1.01 (d, J=7.0 Hz, 3H), 0.82 (m, 15H), 0.71 (d, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH2:10])[CH3:9].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:10][C:40]([C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:29][CH:28]=1)[C:32]([CH3:44])=[C:33]2[CH3:43])=[O:41])[CH3:9]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1ccccc1F
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccccc3F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(2-fluorophenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 521 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.[H-].[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=[C:20]([Cl:23])[C:21]=1Cl.Cl>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=[C:20]([Cl:23])[C:21]=1[O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2
Reactant: Cc1ccc2ncc(O)cc2c1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2ncc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of 3-Hydroxy-6-methylquinoline (92) (348 mg, 2.19 mmol) in DMF (3.5 mL), was added NaH (60% oil suspension, 90 mg, 2.25 mmol) in one portion at room temperature. After 5 min 3,4,5-trichloronitrobenzene (509 mg, 2.25 mmol) in DMF (2 mL) was added and the reaction mixture was heated at 50° C. with stirring for 2 h. After cooling to room temperature. Ice/water was added to the reaction mixture, which was then acidified with 2N HCl and extracted twice with AcOEt. Organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated. Crude residue was purified by column chromatography (hexane/AcOEt4/1, 80 g of silica gel) to afford compound 93 (510 mg, 67%). 1H NMR (300 MHz, DMSO-d6) δ 7.52-7.57 (2H, m), 7.61 (1H, s), 7.94 (1H, d, J=8.6 Hz), 8.63 (2H, s), 8.86 (1H, d, J=2.9 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3]([CH3:6])(=[NH:5])=[O:4].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.CN(C)S(C)(=NS(C1C=CC(C)=CC=1)(=O)=O)=O>>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:5]=[S:3]([CH3:6])([N:2]([CH3:7])[CH3:1])=[O:4])=[CH:11][CH:10]=1
Reactant: CN(C)S(C)(=N)=O
Reactant: BrCc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)N=S(C)(=O)N(C)C)cc1
Product: CN(C)S(C)(=O)=NCc1ccc(Br)cc1

Procedure:
The title compound is prepared from N,N-dimethyl-methanesulfonimidamide and 4-bromobenzyl bromide following a procedure analogous to that described for Intermediate 21 (Step 1). LC (method 1): tR=0.82 min; Mass spectrum (ESI+): m/z=291, 293 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][C:25]([CH3:30])=[CH:26][C:27](Cl)=[O:28].O>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:27](=[O:28])[CH:26]=[C:25]([CH3:30])[CH3:24])=[CH:4][CH:3]=1
Reactant: COc1cccc(Nc2ccc(C)cc2)c1
Reactant: CC(C)=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(N(C(=O)C=C(C)C)c2ccc(C)cc2)c1
Temperature: 25 °C

Procedure:
To a solution of 0.10 g (0.47 mmol) of N-(4-methylphenyl)-3-methoxyaniline (Compound 15) in 3.0 mL of tetrahydrofuran stirring at 0° C. under argon, were added 0.15 mL (0.11 g, 1.1 mmol) of triethylamine and then 0.19 g (1.6 mmol) of 3,3-dimethylacryloyl chloride. The reaction mixture was allowed to warm to room temperature over 30 minutes and then heated at 50° C. for 13 hours. The reaction mixture was cooled, water was added, and the mixture was extracted with diethyl ether (2x). The combined organic layers were then washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give an oil. The mixture was purified by flash chromatography (10% ethyl acetate in hexanes, 20% ethyl acetate in hexanes) to give the title compound as a yellow oil. PNMR (300 MHz, CDCl3) d 1.75 (3 H, s), 2.16 (3 H, s), 2.34 (3 H, s), 3.76 (3 H, s), 5.61 (1 H, s), 6.75-6.81 (2 H, m), 7.08 (2 H, d, J=8.5 Hz), 7.14 (2 H, d, J=8.5 Hz), 7.23 (1 H, t, J=7.8 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[CH3:15][C:16]1[CH:17]=[C:18]([CH:28]([NH2:30])[CH3:29])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:27])([F:26])[F:25]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:30]([CH:28]([C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[C:16]([CH3:15])[CH:17]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Yield: 62 %

Procedure:
The title compound is prepared in 62% yield (135 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (154 mg, 0.57 mmol, Amine-37, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C=O)C.O>[CH2:19]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(Cl)cc1C=O
Temperature: 50 °C

Procedure:
To a mixture of 5-chlorosalicylaldehyde (8.20 g, 52.37 mmol, 1.00 eq.) and potassium carbonate anhydrous (8.69 g, 62.85 mmol, 1.20 eq.) in DMF (100 mL), allyl bromide (4.7 mL, 54.99 mmol, 1.05 eq.) was added. The mixture was heated at 50° C. for 18 hours. The reaction mixture was allowed to cool to r.t. and poured in water (150 mL). The mixture was extracted with DCM (2×200 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo to give 2-allyloxy-5-chloro-benzaldehyde. The product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[OH:20])=[O:9])([CH3:6])[CH3:5].[C:22]1([CH:28]([CH3:32])[CH2:29][CH2:30]O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:6])([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:30][CH2:29][CH:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:32])=[O:9])[CH3:5]
Reactant: CC(CCO)c1ccccc1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCCC(C)c1ccccc1
Reaction time: 2 h

Procedure:
At 0° C. to a solution of 80 mg of 2-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester, 42 mg 3-phenyl-1-butanol and 73 mg triphenyl phosphine in 3 ml of dry THF 56 mg of diisopropylazodicarboxylate were added. After 2 h and again after 4 h at room temperature 36 mg of triphenylphosphine and 25 mg of diisopropylazodicarboxylate were added. After additional 12 h the reaction was concentrated in vacuo and after chromatography on silica (ethyl acetate/heptane) 110 mg of 2-methyl-2-{[1-(3-phenyl-butoxy)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester were obtained.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[N:6][NH:5][C:4](=S)[NH:3]1>CCO.[Ni]>[O:1]=[C:2]1[C:7]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[N:6][N:5]=[CH:4][NH:3]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1n[nH]c(=S)[nH]c1=O
Agent: [Ni]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1Cc1nnc[nH]c1=O

Procedure:
A slurry of 2-(5-oxo-3-thioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylmethyl)isoindole-1,3-dione (1.0 g, 3.47 mmol) in EtOH (40 mL) was charged with excess Raney Ni (3 spatula) and heated to reflux for 2 h. The reaction mixture was filtered hot through a small pad of celite and washed with a hot mixture of EtOH/THF (1:1) (100 mL) and the filtrate was concentrated in vacuo resulting in the title compound as an off-white solid; 1H NMR (DMSO-d6, 400 MHz) δ 4.75 (s, 2H), 7.84-7.98 (m, 4H), 8.66 (s, 1H); MS (ES+): m/z 257.22 (100) [MH+].
Reaction SMILES: [O:1]=[C:2]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4][CH:3]1[NH:25]C(=O)OCC1C=CC=CC=1.Br.CC(O)=O>CCOCC>[NH2:25][C@@H:3]1[C:2](=[O:1])[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4]1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(c2ccccn2)C1=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: N[C@H]1N=C(c2ccccc2)c2ccccc2N(c2ccccn2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
Intermediate 1A (5.24 g, 11.33 mmol) and 33% HBr/HOAc (50 mL, 11.33 mmol) were combined and stirred at room temperature for 2 h. The reaction mixture was diluted with 300 mL of ether. The resulting precipitate was collected by filtration, rinsed with ether (2×50 mL), then dried under vacuum. The solid was dissolved in 100 mL of water and made basic by the addition of solid NaHCO3. The mixture was extracted with EtOAc (2×200 mL), and the combined organic extracts were washed with water (1×40 mL) and brine (1×50 mL), then dried (MgSO4), filtered and concentrated in vacuo to give the crude racemic amine. This solid was purified by preparative SFC chromatography (Berger SFC MGII, AD-H 250×30 mm ID, 5 μm, 78/22 CO2/MeOH with 0.1% DEA, 85 mL/min). After the fractions containing product were concentrated and dried overnight under vacuum, Intermediate 1B (1.576 g, 42.4%) was obtained as a colorless solid: 1H NMR (400 MHz, DMSO-d6) δ 8.47 (1 H, dd, J=4.73, 1.65 Hz), 7.98 (1 H, td, J=7.70, 1.98 Hz), 7.62 (3 H, dd, J=14.75, 7.48 Hz), 7.45-7.57 (5 H, m), 7.26-7.43 (3 H, m), 6.92 (1 H, d, J=8.14 Hz), 4.57 (1 H, br. s.), 2.67 (1 H, br. s.); Chiral HPLC: RT=5.160 min (Berger SFC, AD-H 250×4.6 mm ID, 5 μm, 75/25 CO2/MeOH with 0.1% DEA, 2.0 mL/min); HPLC: RT=1.290 min (CHROMOLITH® ODS 4.6×50 mm (4 min grad) eluting with 10-90% aqueous MeOH over 4 minutes containing 0.% TFA, 4 mL/min, monitoring at 220 nm); MS(ES): m/z=329.0 [M+H]+.
Reaction SMILES: [ClH:1].[CH2:2]1[O:27][C:26]2[CH:25]=[CH:24][C:6]([O:7][CH2:8][C@H:9]3[C@H:14]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=4)[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:5][C:4]=2[O:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C(O)C>[ClH:1].[CH2:2]1[O:27][C:26]2[CH:25]=[CH:24][C:6]([O:7][CH2:8][C@H:9]3[C@H:14]([C:15]4[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=4)[CH2:13][CH2:12][N:11]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:10]3)=[CH:5][C:4]=2[O:3]1
Reactant: CCCCCBr
Reactant: O=[N+]([O-])c1ccc([C@@H]2CCNC[C@H]2COc2ccc3c(c2)OCO3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCN1CC[C@@H](c2ccc([N+](=O)[O-])cc2)[C@H](COc2ccc3c(c2)OCO3)C1

Procedure:
Compound (6) (1 g) was dissolved in abs. ethanol (50 ml). K2CO3 (0.7 g) and 1-bromopentane (0.63 ml) were added. Reflux for 6 h, filtering and evaporation to dryness gave a crystalline mass which was extracted with NaOH(4N)ether. The etheral layer was dried, evaporated and purified on a silica gel column using CH2Cl2 /CH3OH 9/1 as eluent. Precipitated as the hydrochloride from acetone/ether. Yield 0.5 g. M.p. 57° C.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[CH3:15][CH2:16][C@H:17]([OH:49])[C@H:18]([C@H:20]1[O:22][C@@H:21]1[CH2:23][C@@H:24](/[CH:26]=[CH:27]/[CH:28]=[C:29](/[C@H:31]1[O:43][C:41](=[O:42])[CH2:40][C@H:39]([OH:44])[CH2:38][CH2:37][C@:36]([OH:46])([CH3:45])[C@@H:35]([OH:47])[CH2:34][CH2:33][C@@H:32]1[CH3:48])\[CH3:30])[CH3:25])[CH3:19].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:15][CH2:16][C@H:17]([OH:49])[C@H:18]([C@H:20]1[O:22][C@@H:21]1[CH2:23][C@@H:24](/[CH:26]=[CH:27]/[CH:28]=[C:29](/[C@H:31]1[O:43][C:41](=[O:42])[CH2:40][C@H:39]([OH:44])[CH2:38][CH2:37][C@:36]([OH:46])([CH3:45])[C@@H:35]([O:47][C:8]([CH3:9])=[O:10])[CH2:34][CH2:33][C@@H:32]1[CH3:48])\[CH3:30])[CH3:25])[CH3:19]
Reactant: CC[C@H](O)[C@@H](C)[C@H]1O[C@@H]1C[C@H](C)/C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O)CC[C@@](C)(O)[C@@H](O)CC[C@@H]1C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](O)[C@@H](C)[C@H]1O[C@@H]1C[C@H](C)/C=C/C=C(\C)[C@H]1OC(=O)C[C@H](O)CC[C@@](C)(O)[C@@H](OC(C)=O)CC[C@@H]1C
Temperature: 0 °C
Yield: 82 %

Procedure:
Triethylamine (17.2 μl, 123 μmol), acetic anhydride (5.83 μl, 616 μmol) and 4-dimethylaminopyridine (1.50 mg, 12.3 μmol) were added to anhydrous dichloromethane (2.00 ml) solution of pladienolide A (30.5 mg, 61.6 μmol) under stirring at 0° C. After the reaction solution was stirred at 0° C. for one hour, it was poured into a saturated sodium hydrogen carbonate aqueous solution, which was then extracted with ethyl acetate. After the organic layer was washed with brine, it was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:acetone=3:1→2:1) to obtain the title compound (27.2 mg) as a colorless oil. This was obtained as a white amorphous by purifying by HPLC (Shiseido, commercial name CAPCELL PAK C18SG120; acetonitrile:water=45:55) followed by performing lyophilization.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:5][C:6]=1[CH:7]([CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH3:1][C:2]1[O:3][C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:5][C:6]=1[CH:7]([CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)[O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(OC(c2cc(-c3ccccc3)oc2C)C2CCOCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCOCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of (2-methyl-5-phenylfuran-3-yl)(tetrahydro-2H-pyran-4-yl)methanol (545 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (365 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (1.0 mL) and 1,1′-(azodicarbonyl)dipiperidine (1.0 g), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 30% ethyl acetate/hexane) to give methyl 4-[(2-methyl-5-phenylfuran-3-yl)(tetrahydro-2H-pyran-4-yl)methoxy]benzoate as an oil. The obtained methyl 4-[(2-methyl-5-phenylfuran-3-yl)(tetrahydro-2H-pyran-4-yl)methoxy]benzoate was dissolved in methanol (4 mL) and tetrahydrofuran (4 mL). 2N Lithium hydroxide (2.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (361 mg, 47%) as an amorphous compound.