Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][C@@H:15]2[O:20][C:19]3[C:21]([NH2:26])=[C:22]([NH2:25])[CH:23]=[CH:24][C:18]=3[O:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[F:27][C:28]([F:33])([F:32])[C:29](O)=O>C(Cl)Cl>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][CH:15]2[O:20][C:19]3[C:18](=[CH:24][CH:23]=[C:22]4[NH:25][C:29]([C:28]([F:33])([F:32])[F:27])=[N:26][C:21]4=3)[O:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1

Procedure:
A solution of 3.1 g (7.3 mmole) of [(2R)-7,8-diamino-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate dihydrochloride in 50 mL of trifluoroacetic acid was refluxed under nitrogen for 6 hours. The mixture was diluted to 400 mL with methylene chloride, washed with 400 mL of water and with 400 mL of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated to a crude foam in vacuum. The crude product was column chromatographed on silica gel with 1% methanol in chloroform and the product fractions combined and concentrated in vacuum to give 3.3 g of the (R)-enantiomer of the title compound as a white solid, m.p. 114-116° C., which retains one equivalent of chloroform.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.P(Br)(Br)([Br:16])=O.P(Br)(Br)Br>[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:16])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: CS(=O)(=O)c1cc(Br)ccc1CO
Agent: BrP(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1cc(Br)ccc1CBr
Temperature: 130 °C
Reaction time: 8 h
Yield: 160.5 %

Procedure:
To a solution of (4-bromo-2-methanesulfonyl-phenyl)-methanol (preparation 112) (100 mg, 0.38 mmol) in POBr3 (542 mg, 1.89 mmol) was added PBr3 (511 mg, 1.89 mmol). After the addition, the reaction mixture was stirred at 130° C. overnight. TLC (petroleum ether:EtOAc 1:1) showed the reaction was complete. The reaction was cooled to room temperature and then poured into brine (10 mL) and extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL×2), dried over sodium sulfate and concentrated in vacuo to give crude 4-bromo-1-bromomethyl-2-methanesulfonyl-benzene (200 mg, 80%) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:15]1[C:16](=[O:34])[N:17]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:18](=[O:26])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CC#N>[N:4]1([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:15]3[C:16](=[O:34])[N:17]([CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[C:18](=[O:26])[C:19]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CC#N
Solvent: O
Product: O=C1C(Nc2ccc(N3CCOCC3)cc2)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Temperature: 130 °C
Yield: 27 %

Procedure:
4-Morpholinoaniline (0.94 mmol, 178 mg) dissolved in dry CH3CN (2 mL) was added to crude 3-chloro-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione (0.47 mmol, 140 mg) and the reaction mixture was subjected to microwave heating single node 130° C. for 10 min. 0.3 mL water was added and the reaction mixture was purified using HPLC (57% 0.1M ammonium acetate buffer: 43% CH3CN→100% CH3CN, 20 mL/min) to give 56 mg (27%) of the title compound. 1H NMR (400 MHz, CD3CN) δ 8.63 (d, 1H), 8.51 (dd, 1H), 7.81-7.73 (m, 1H), 7.36-7.31 (m, 1H), 7.16-7.11 (m,1H), 7.10-7.04 (m, 2H), 6.99-6.93 (m, 2H), 6.69-6.64 (m, 2H), 6.59-6.53 (m, 2H), 4.75 (s, 2H), 3.74 (t, J=4.8 Hz, 4H), 2.97 (t, J=4.8 Hz, 4H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N-]=C=O.[CH2:22]([O:29][C:30]1[CH:35]=[C:34](/[CH:36]=[CH:37]/[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:33]=[CH:32][C:31]=1[N:45]1[S:49](=[O:51])(=[O:50])[N:48](CC[Si](C)(C)C)[C:47](=[O:58])[CH2:46]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([O:29][C:30]1[CH:35]=[C:34](/[CH:36]=[CH:37]/[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:33]=[CH:32][C:31]=1[N:45]1[S:49](=[O:51])(=[O:50])[NH:48][C:47](=[O:58])[CH2:46]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/Cc3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [N-]=C=O
Solvent: C1CCOC1
Product: O=C1CN(c2ccc(/C=C/Cc3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrabutylammonium fluoride (1.0M in THF, 2 mL) is added to a solution of PS-isocyanate resin (0.5 g) in THF (2 mL) and the mixture is stirred at RT for 2 h. The resin is filtered off and the filtrate is added to a solution of 5-[2-benzyloxy-4-((E)-3-phenylpropenyl)-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (89 mg, 0.163 mmol) in THF (1 mL). The reaction is stirred at 75° C. for 1 h then the mixture is cooled and concentrated. The residue is partitioned between EtOAc and water and the organic layer is washed with 2N HCl (3×) and brine. The organic layer is dried over sodium sulfate and the solvent removed under reduced pressure to afford the title compound as a light yellow foam: (M−1)−=433.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[C@@H:18]2[CH2:22][C@H:21]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[C@@H:20]([OH:28])[C@H:19]2[OH:29])=[C:11]([NH:30][CH2:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[N:10]=1.[CH:42]1[C:54]2C(CN)C3C(=CC=CC=3)C=2C=C[CH:43]=1>>[Cl:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[C@@H:18]2[CH2:22][C@H:21]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[C@@H:20]([OH:28])[C@H:19]2[OH:29])=[C:11]([NH:30][CH2:31][CH:32]2[C:54]3[CH:42]=[CH:43][CH:33]=[CH:34][C:35]=3[C:36]3[C:41]2=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:10]=1
Reactant: NCC1c2ccccc2-c2ccccc21
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC4c5ccccc5-c5ccccc54)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to N-((4S,2R,3S,4R)-4-{2-chloro-6-[(naphthalen-1-ylmethyl)-amino]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate (Example 50) by replacing 1-napthalenemethylamine with C-(9H-fluoren-9-yl)-methylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7](C(=O)C)[N:6]=[CH:5]2.Cl.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2
Reactant: CC(=O)n1ncc2cc(Br)c(F)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Fc1cc2[nH]ncc2cc1Br
Temperature: 90 °C

Procedure:
A solution of 1-(5-bromo-6-fluoro-1H-indazol-1-yl)ethanone (2C, 5.0 g, 19.5 mmol) was treated with aq HCl (3M soln., 100 mL) and methanol (20 mL) and heated at 90° C. for 3 h, when the reaction turns homogenous. The reaction mixture was cooled to room temperature and basified with aq. NaOH. A colorless solid precipitated out which was filtered and dried to yield 5-bromo-6-fluoro-1H-indazole (22D)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[C:5]([NH2:8])=[N:6][N:7]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.C(OCC)(=O)C>CN(C=O)C>[NH2:8][C:5]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[C:3]([CH2:2][NH:1][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=2)=[N:7][N:6]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NCC1=NN=C(N)C1=NNc1ccc(F)c(F)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: NC1=NN=C(CNC(=O)c2cccnc2)C1=NNc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
To a solution of 5-aminomethyl-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (245 mg, 0.97 mmole) and triethylamine (202 mg, 2 mmole) in 10 mL of anhydrous DMF was added nicotinoyl chloride (178 mg, 1.0 mmol) in 7 mL of anhydrous DMF. The reaction was stirred at ambient temperature for 1 hour, and then mixed with saline and ethyl acetate. The title compound was purified by column chromatography (CH2Cl2:CH3OH=13:1) to yield 119 mg of the title compound as a yellow powder. MS (m/z, ES−): 356 (M−1, 20%); 1H NMR (ppm, 400 MHz, DMSO-d6) □δ 11.86 (br s, 1H), 9.04 (brs, 1H), 9.01 (s, 1H), 8.67 (d, 1H), 8.19 (d, 1H), 7.71 (dd, 1H), 7.57 (m, 1H), 7.47 (m, 2H), 7.11 (br s, 2H), 4.69 (s, 2H).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH3:16])[CH2:15][CH2:14][CH2:13]2)=[CH:8][C:7]=1[N+:17]([O-:19])=[O:18])=O.CO.C(=O)([O-])[O-].[K+].[K+].O>>[CH3:16][C:12]1([C:9]2[CH:10]=[CH:11][C:6]([NH2:5])=[C:7]([N+:17]([O-:19])=[O:18])[CH:8]=2)[CH2:13][CH2:14][CH2:15]1
Reactant: CC1(c2ccc(NC(=O)C(F)(F)F)c([N+](=O)[O-])c2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1(c2ccc(N)c([N+](=O)[O-])c2)CCC1
Temperature: 45 °C
Yield: 102.1 %

Procedure:
A solution of 2,2,2-trifluoro-N-[4-(1-methylcyclobutyl)-2-nitrophenyl]acetamide (580 mg. 1.9 mmol) in Methanol (18 ml, 440 mmol) was treated with a solution of Potassium carbonate (788 mg, 5.70 mmol) in Water (4.5 ml, 250 mmol) and the mixture was heated at 45° C. for 50 minutes The reaction mixture was cooled to RT and the methanol was removed in vacuo. The remaining aqueous phase was diluted with 10 ml H2O and extracted with three 20 ml portions of EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated to yield an oil. The material was placed on high vacuum where upon it solidified giving the desired compound (400 mg). The material was used directly in the next step 1H NMR (400 MHz. CDCl3) d ppm 7.90 (d, J=2.07 Hz, 1 H), 7.23 (dd, J=8.50, 2.28 Hz, 1 H), 6.77 (d, J=8.71 Hz, 1 H), 5.96 (br. s., 2 H), 2.33 (m, 2 H), 2.13 (m, 1 H), 2.04 (m, 2 H), 1.84 (m, 1 H), 1.43 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:8])=[O:7].[N:16]1([CH:21]2[CH:30]3[CH:25]([CH2:26][CH2:27][CH2:28][NH:29]3)[CH2:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>CCOCC>[ClH:8].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([N:29]1[CH:30]2[CH:25]([CH2:24][CH2:23][CH2:22][CH:21]2[N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:26][CH2:27][CH2:28]1)=[O:7]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: C1CNC2C(C1)CCCC2N1CCCC1
Agent: Cl
Solvent: CCOCC
Product: COc1cc(C(=O)N2CCCC3CCCC(N4CCCC4)C32)cc(OC)c1OC
Yield: 36.3 %

Procedure:
510 mg of 3,4,5-trimethoxybenzoyl chloride and 417 mg of the product of Step C of Example 1 were reacted in ether for 40 hours at ambient temperature and the crude product obtained in the form of the base was converted into the hydrochloride as in Example 1 to obtain 319 mg of the expected product melting at ≈260° C.
Reaction SMILES: Cl.NO.[OH-].[Na+].[F:6][C:7]1[CH:47]=[CH:46][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[CH2:30][CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]5)[CH:27]=4)[CH:22]3[C:42]([O:44]C)=[O:43])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.Cl>O.O1CCOCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[CH2:30][CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]5)[CH:27]=4)[CH:22]3[C:42]([OH:44])=[O:43])(=[O:19])=[O:20])=[CH:14][CH:13]=2)=[CH:46][CH:47]=1
Reactant: COC(=O)C1c2ccc(OCCCN3CCN(C)CC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(CCCOc2ccc3c(c2)CCN(S(=O)(=O)c2ccc(Oc4ccc(F)cc4)cc2)C3C(=O)O)CC1
Reaction time: 0.17 h

Procedure:
A solution of 61 mg (0.88 mmol) of hydroxylamine hydrochloride in 1 ml of H2O is mixed with a solution of 56 mg (1.4 mmol) of NaOH in 0.5 ml of H2O and stirred for 10 minutes. At 0° C., a solution of 240 mg (0.4 mmol) of methyl 2-[4-(4-fluorophenoxy)-benzenesulfonyl]-6-[3-(4-methylpiperazin-1-yl)propoxy]-1,2,3,4-tetrahydroisoquinoline-1-carboxylate in 0.5 ml of dioxane is added, and the mixture is stirred at 0° C. To achieve complete conversion, 61 mg (0.88 mmol) of hydroxylamine hydrochloride and 56 mg (1.4 mmol) of NaOH are added twice more. For work up, the mixture is neutralized with 1 N HCl and extracted with ethyl acetate. The organic phase is separated off, dried with MgSO4 and concentrated. Chromatography of the residue on silica gel affords the hydroxamic acid (exemplary compound 3) as colorless solid in 46% yield, and the carboxylic acid (exemplary compound 4), likewise as colorless solid in a yield of 15%.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].C1C=CC2N(O)N=[N:38]C=2C=1.N.C(Cl)CCl.C(N1CCOCC1)C.CCN=C=NCCCN(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH2:38])=[O:19])=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Reactant: On1nnc2ccccc21
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)N1c2ccc(-c3ccc(C(N)=O)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
A flask was charged with 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzoic acid (for a preparation see example 6) (109 mg, 0.251 mmol), HOBT.NH3 (85 mg, 0.501 mmol) and EDC (57.7 mg, 0.301 mmol) then filled with dichloromethane (DCM) (5 mL) and the resulting mixture was treated with N-ethylmorpholine (NEM) (0.095 mL, 0.752 mmol) then stirred a room temperature. After 4 h, 50% of the previous quantities of EDAC, HOBT and NEM were added and the resulting mixture was stirred at room temperature for 16 h. Most of the DCM was removed in vacuo and the residue was partitioned between AcOEt and water. The layers were separated and the aqueous phase was extracted with AcOEt. The combined organic phases were washed twice with a saturated NaHCO3 aqueous solution then brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated with Et2O then filtered off and dried under house vacuum to give 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzamide (75 mg, 0.173 mmol, 69.0% yield) as a very pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OCCCCCl
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(SCCCCO)cc1

Procedure:
A mixture of 4-nitrothiophenol (0.11 mol), 4-chloro-1-butanol (0.09 mol), and potassium carbonate (0.1 mol) in dimethoxyethane (100 mL) is heated at reflux temperature for 18 hrs. The mixture is filtered and the filtrate is concentrated to dryness. The residue is dissolved in methylene chloride and washed with 10% sodium hydroxide. The chloroform solution is dried and concentrated to obtain the title compound.
Reaction SMILES: [O:1]([C:8]([C:10]1[CH:19]=[C:18]([OH:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[OH:21])=[O:9])[C:2]1C=CC=C[CH:3]=1.CC[O-].[Na+].C(O)(=O)C>C(O)C>[CH2:2]([O:1][C:8]([C:10]1[CH:19]=[C:18]([OH:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[OH:21])=[O:9])[CH3:3]
Reactant: O=C(Oc1ccccc1)c1cc(O)c2ccccc2c1O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(O)c2ccccc2c1O

Procedure:
28 g of 2-phenoxycarbonyl-1,4-dihydroxynaphthalene was dissolved in ethanol under a nitrogen stream, and 20.4 g of sodium ethylate was added thereto, followed by refluxing for 5 hours under heating. After being cooled, the solution was made weakly acidic with acetic acid, then ethanol was distilled off. Ethyl acetate and water were added thereto to separate and extract the product. The product was purified through silica gel column chromatography with an element having the same composition as that used in the Synthesis Example 1 to obtain compound (6) as crytals. Yield: 13 g (56%).
Reaction SMILES: OC1C=C2C(CCC2=O)=CC=1OC.Cl.[N+](C1C=CC(CNO)=CC=1)([O-])=O.N1C=CC=CC=1.[N+:33]([C:36]1[CH:58]=[CH:57][C:39]([CH2:40][O:41]/[N:42]=[C:43]2\[CH2:44]C[CH2:46][C:47]3[C:52]\2=[CH:51][C:50]([O:53]C)=[C:49]([O:55][CH3:56])[CH:48]=3)=[CH:38][CH:37]=1)([O-:35])=[O:34]>C(O)C>[N+:33]([C:36]1[CH:58]=[CH:57][C:39]([CH2:40][O:41]/[N:42]=[C:43]2\[CH2:44][CH2:46][C:47]3[C:52]\2=[CH:51][C:50]([OH:53])=[C:49]([O:55][CH3:56])[CH:48]=3)=[CH:38][CH:37]=1)([O-:35])=[O:34]
Reactant: COc1cc2c(cc1OC)/C(=N/OCc1ccc([N+](=O)[O-])cc1)CCC2
Agent: COc1cc2c(cc1O)C(=O)CC2
Agent: Cl
Agent: O=[N+]([O-])c1ccc(CNO)cc1
Solvent: CCO
Solvent: c1ccncc1
Product: COc1cc2c(cc1O)/C(=N/OCc1ccc([N+](=O)[O-])cc1)CC2
Yield: 48 %

Procedure:
6-Hydroxy-5-methoxy-1-indanone (114 mg, 0.64 mmol) was subjected to reaction with (4-nitrobenzyl)hydroxylamine hydrochloride (149 mg, 0.73 mmol) in ethanol (5 mL) and pyridine (0.6 mL, 7.74 mmol) under the same conditions as described for (E)-6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one O-4-nitrobenzyl oxime. The solid obtained on work up was recrystallized (isopropanol) to yield the title compound (101 mg, 48%) as off-white crystals, m.p. 146-149° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@@H:10]([NH:49][C:50](OCC1C=CC=CC=1)=[O:51])[C:11]([N:13]([CH:23]([C:41]1[C:42]([CH3:48])=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=1)[C:24](=[O:40])[NH:25][C:26]1C=C[CH:29]=[CH:28][C:27]=1OCC1C=CC=CC=1)[C@@H:14](C(OC)=O)[C@H:15]([CH2:17][CH3:18])[CH3:16])=[O:12].[C:60]([OH:63])(=O)[CH3:61]>C(O)C.[Pd]>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C@H:10]1[NH:49][C:50](=[O:51])[C@@H:14]([C@@H:15]([CH3:16])[CH2:17][CH3:18])[N:13]([CH:23]([C:41]2[C:42]([CH3:48])=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[C:24]([NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:61][C:60]=2[OH:63])=[O:40])[C:11]1=[O:12]
Reactant: CC(=O)O
Reactant: CC[C@H](C)[C@H](C(=O)OC)N(C(=O)[C@H](NC(=O)OCc1ccccc1)C1Cc2ccccc2C1)C(C(=O)Nc1ccccc1OCc1ccccc1)c1ccc(C)nc1C
Agent: [Pd]
Solvent: CCO
Product: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1ccc(C)nc1C

Procedure:
The crude methyl N-[(2R)-2-(2,3-dihydro-1H-inden-2-yl)-2-({[(phenylmethyl) oxy]carbonyl}amino)acetyl]-N-[1-(2,6-dimethyl-3-pyridinyl)-2-oxo-2-({2-[(phenylmethyl)oxy]phenyl}amino)ethyl]-D-alloisoleucinate (intermediate 1) (7.46 g) was dissolved in ethanol (150 mL) and acetic acid (10 mL) and the mixture was hydrogenated at 1 atmosphere of H2 over 10% palladium on carbon (Degussa type) (1.8 g wetted with water 1:1 w:w) for 18 h. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water with saturated aqueous sodium hydrogen carbonate added until the aqueous phase was basic (pH 8). The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate:water 3:1 (100 mL) then with saturated brine before being dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The crude product was purified on a Redisep silica column (120 g) eluted with 0-10% methanol in ethyl acetate to give the title compound as a pair of diastereomers (2.94 g).
Reaction SMILES: [Na+].[I-].C[Si](Cl)(C)C.C([O:15][CH2:16][CH2:17][C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)(O)[CH3:28])C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(#N)C.CCOC(C)=O>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:27]([C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:18]=1[CH2:17][CH2:16][OH:15])[CH3:28]
Reactant: CC(O)(c1ccccn1)c1c(CCOCc2ccccc2)sc2ccccc12
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(c1ccccn1)c1c(CCO)sc2ccccc12
Reaction time: 0.08 h
Yield: 20 %

Procedure:
To a solution of NaI (2.29 g, 15.4 mmol) in acetonitrile (45 mL) at room temperature, trimethylsilyl chloride (1.96 mL, 15.4 mmol) was added and the mixture was stirred for 5 min. 1-[2-(2-benzyloxy-ethyl)-benzo[b]thiophen-3-yl]-1-pyridin-2-yl-ethanol (2 g, 5.14 mmol) was added and the mixture was refluxed for 4 hours. An additional aliquot of trimethylsilyl chloride (2.6 mL, 20.5 mmol) and NaI (3.06 g, 20.6 mmol) was added and refluxing was continued for another 6 hours. Sat. NaHCO3 and EtOAc were added and the organic layer was separated. After extraction of the aqueous layers with EtOAc, the combined organic layers were dried (Na2SO4) and concentrated. Silica gel column chromatography (eluent: hexanes up to EtOAc/hexanes=1/1) afforded 2-[3-(1-pyridin-2-yl-ethyl)-benzo[b]thiophen-2-yl]-ethanol in 20% yield.
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](=O)([O-])[O-:13].[K+].[K+]>O>[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH:12]=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=CN[C@@H]1C[C@H]1c1ccccc1
Reaction time: 8 h
Yield: 91 %

Procedure:
trans-2-Phenylcyclopropylamine hydrochloride (2.74 g, 16.15 mmol) was dissolved in water (50 ml), and the solution was alkalified with potassium carbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. To the residue was added formic acid (18.5 ml), and the mixture was ice-cooled, and acetic anhydride (7 ml) was added dropwise with stirring. The reaction mixture was stood at room temperature overnight, ice-cooled again. Water (7 ml) was added, and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with 5% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (2.36 g, yield 91%) as a pale-bistered solid.