Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=1.[OH-].[K+]>CO.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.3 %

Procedure:
To a stirred solution of ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (20 g, 0.05 mol) in MeOH (200 mL), a solution of KOH (12.6 g, 0.22 mol) in water (50 mL) was added dropwise and the reaction mixture was stirred for 1 h at RT. The methanol was then removed, and the reaction mixture was washed with EtOAc (2×100 mL) and acidified to pH ˜3 with 1 N HCl at 0° C. The precipitated solid was filtered and dried to afford 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (15 g, 92%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[O:10][C:11]([CH2:14]Br)=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:17]([N:19](CC)CC)C>C(#N)C>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[O:10][C:11]([CH2:14][C:17]#[N:19])=[CH:12][CH:13]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCc1ccc(CBr)o1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCc1ccc(CC#N)o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.5 %

Procedure:
The tert-butyl((5-(bromomethyl)furan-2-yl)methyl)carbamate (5.8 g, 20 mmol) obtained above and 50 mL of acetonitrile were added into a flask. Triethylamine (2.3 g, 22 mmol) was added thereto dropwise and the reaction mixture was stirred at room temperature for 6 h. After the completion of the reaction, the reaction mixture was washed successively with water and saturated brine. The organic layer was dried, concentrated, and crude product was purified by column chromatograph to give 3.9 g (83.3% yield) of 5-(tert-butoxycarbonylaminomethyl)-furan-2-acetonitrile.
Reaction SMILES: [C:1]1([S:7](NC2SC3CCCCC=3C=2C(OCC)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:25][CH:26]1[O:31][C:30]2[S:32][CH:33]=[C:34]([C:35]([O:37][CH3:38])=[O:36])[C:29]=2[CH2:28][CH2:27]1>>[C:1]1([S:7]([NH:25][CH:26]2[O:31][C:30]3[S:32][CH:33]=[C:34]([C:35]([O:37][CH3:38])=[O:36])[C:29]=3[CH2:28][CH2:27]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1csc2c1CCC(N)O2
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Product: COC(=O)c1csc2c1CCC(NS(=O)(=O)c1ccccc1)O2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1 starting from methyl 2-amino-3,4-dihydro-2H-thieno[2,3-b]pyran-5-carboxylate (Intermediate 17)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1.[CH2:36]([Sn](CCCC)(CCCC)C=C)[CH2:37]CC>O1CCOCC1.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([CH:36]=[CH2:37])[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OCCO)N1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 60 °C
Yield: 95.5 %

Procedure:
To a suspension of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.16 mmol) prepared in Example 190c in dioxane (10 mL) was added CuI (5 mg, 0.026 mmol) (Aldrich). The mixture was degassed under nitrogen for 5 min, then tris(dibenzylideneacetone)dipalladium(0) (11.7 mg, 0.013 mmol, Strem), tri-phenylphosphine (3.35 mg, 0.013 mmol), and tributyl(vinyl)tin (46 uL, 1.0 mmol, Aldrich) were added sequentially. The reaction mixture was heated at 60° C. under nitrogen for 2 h. After cooled to room temperature, the reaction mixture was partitioned between saturated water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-vinyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 80 mg, 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4](I)[CH:3]=1.[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[N:17][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Reactant: Nc1cncnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(F)cc(Nc2cncnc2)c1
Temperature: 100 °C
Yield: 93 %

Procedure:
1-fluoro-3-iodo-5-nitrobenzene (100 mg, 0.375 mmol, 1.00 eq), 5-aminopyrimidine (43 mg, 0.45 mmol, 1.2 eq, Cs2CO3 (171 mg, 0.525 mmol, 1.40 eq), Pd2(dba)3 (17 mg, 0.030 mmol, 0.080 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (26 mg, 0.045 mmol, 0.12 eq) and dioxane (0.8 mL) were added to a microwave vial. The vial was purged with argon, capped and heated at 100° C. for 18 h. After cooling the reaction was filtered over a plug of celite and the plug was washed with 5% MeOH/CH2Cl2. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 81 mg (93%) of the title compound as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.84 (s, 1H), 8.72 (s, 2H), 7.68 (s, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.36 (d, J=10.7 Hz, 1H); ES-MS [M+1]+: 235.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)cn1
Temperature: 37.5 °C
Yield: 91 %

Procedure:
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added methyl 5-chloropyrazine-2-carboxylate (1.0 eq) and tetrahydrofuran (4.92 vols) under a nitrogen atmosphere. The reaction mixture was agitated until all the solid had dissolved, then filtered into a second flask. Water (8.65 vols) was added to the reaction mixture and the mixture agitated for approximately 15 minutes. Potassium carbonate (2.1 eq) was added to the reaction mixture and the mixture agitated for 16 hours at 20-25° C. Then 32% w/w hydrochloric acid (3.76 eq) was added over 3 hours in small portions, keeping the reaction temperature 20-25° C., to a pH end point of pH2.2. The resultant slurry was heated to approximately 35-40° C. and then distilled under vacuum at this temperature distilling approximately 5.3 vols, to a final volume of approximately 9.3 vols. The mixture was then cooled to 20-25° C. over at least 2 hours, agitated for 10 hours at this temperature and then filtered. The solid was washed with water (2.8 vols), and the wet product produced dried at 35° C. in a vacuum oven. The desired product was obtained as a solid (corrected yield 91%) 1H NMR δ (400 MHz CDCl3): 7.20 (1H, bs), 8.72 (1H, s), 9.21-9.21 (1H, m); m/z 157 (M−H)+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][CH2:20][CH3:21])[CH:18]=3)[S:13][C:6]=12.[BH4-].[Na+]>CO.C1COCC1.Cl[Ni]Cl>[F:1][C:2]1[CH:25]=[C:24]([CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][CH2:20][CH3:21])[CH:18]=3)[S:13][C:6]=12)[NH2:26]
Reactant: CCCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of the nitro compound 132 (4.13 g, 10.36 mmol) in MeOH/THF (100 ml/100 mL) was added NiCl2×6H2O (4.92 g, 20.73 mmol) and NaBH4 (1.54 mg, 41.44 mmol). The reaction mixture was allowed to stir for 1 hr, concentrated to dryness and the resultant solid was dissolved in 2 M HCl. The acidic solution was then made basic with aqueous ammonium hydroxide solution and extracted with EtOAc. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated The residue was purified by flash chromatography (eluents DCM-MeOH, 98:2, 95:5) to afford title compound 133 (3.31 g, 86% yield) as a pink solid. MS (m/z): 368.1 (M+H).
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:25]1(O)[CH2:29][CH2:28][CH2:27][CH2:26]1.C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[CH:25]1([O:16][C:15](=[O:17])[C@@H:2]([NH:1][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3][CH2:4][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: OC1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.7 %

Procedure:
To a solution of Boc-L-Glu(OBzl)-OH (15 g, 44.5 mmol) in dichloromethane (220 ml) in an ice-bath, was added cyclopentanol (4.8 ml, 53.3 mmol), EDC (9.4 g, 48.9 mmol) and DMAP (543 mg, 4.4 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 12 hours for complete reaction. The reaction mixture was diluted with DCM (200 ml) and washed with 1M HCl, 1M Na2CO3 and brine. The organic layer was then dried over magnesium sulphate and evaporated under reduced pressure. The product was purified by column chromatography using ethyl acetate/heptane (1:4) to give 12.4 g, 69% yield of title compound as a white solid. 1H NMR (300 MHz, CDCl3), δ: 7.38 (5H, m), 5.70 (1H, m), 5.10 (2H, s), 5.05 (1H, m), 4.25 (1H, m), 2.47 (2H, m), 2.15 (1H, m), 1.95-1.55 (9H, bm), 1.47 (9H, s).
Reaction SMILES: [C:1]1([NH:11][CH2:12][C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][C:21](=[N:35][NH:36][C:37]([NH2:39])=[O:38])[CH2:22][C@H:23]([NH:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH2:29])[CH:24]=[O:25])([CH3:19])([CH3:18])[CH3:17].O.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NC(N)CC(C)C)C>CN1CCCC1=O.C(Cl)Cl>[C:16]([O:20][C:21](=[N:35][NH:36][C:37]([NH2:39])=[O:38])[CH2:22][C@H:23]([NH:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:29][C:13](=[O:15])[CH2:12][NH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH:24]=[O:25])([CH3:18])([CH3:19])[CH3:17]
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Reactant: O=C(O)CNc1cccc2ccccc12
Agent: CCN=C=NC(N)CC(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCCC1=O
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)CNc1cccc2ccccc12)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 100.4 %

Procedure:
To a solution of (1-naphthylamino)acetic acid (0.076 g, 0.38 mmol) and (3S)-3-(leucinyl)amino-4-oxobutanoic acid tert-butyl ester semicarbazone (see Example 1, Part B, 0.180 g, ca 0.41 mmol) in N-methylpyrrolidone(1.0 mL)-CH2Cl2(1.0 mL) at 0° C. (ice bath) under nitrogen was added hydroxybenzotriazole hydrate (0.075 g) followed by 1-ethyl-3-(3′,3′-dimethyl-1′-aminopropyl)carbodiimide hydrochloride (0.100 g, 0.52 mmol). After stirring at 0° C. for 3 hrs and at room temperature for 16 hrs, the mixture was partitioned between EtOAc-water. The organic phase was washed with water, 5% KHSO4, saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography eluting with MeOH—CH2Cl2 (1:30 then 1:15) to give the title compound (0.201 g, 100%) as a pale yellow foam. TLC(MeOH—CH2Cl2; 5:95) Rf=0.29.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+].O>O1CCCC1>[NH2:1][C:2]1[C:10]([Br:11])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1Br)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc2c(c1Br)C(O)CC2
Reaction time: 2 h

Procedure:
A solution of 6-amino-7-bromoindanone (2.4 g, 10.6 mmol) in tetrahydrofuran (150 ml) is treated with sodium borohydride (360 mg, 10.6 mmol) in portions, stirred for two hours, and treated dropwise with water. Tetrahydrofuran is evaporated and the residue is dissolved in ethyl acetate and washed with water. The separated organic layer is dried over sodium sulfate, filtered, and evaporated to give 6-amino-7-bromoindan-1-ol; GC/MS: 228/230 (M+1)+.
Reaction SMILES: O[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.P(Cl)(Cl)([Cl:26])=O.CN(C)C1C=CC=CC=1>O1CCOCC1>[Cl:26][C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2
Reactant: COc1ccc(CSc2nc(O)c3nc[nH]c3n2)cc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(CSc2nc(Cl)c3nc[nH]c3n2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 35.2 %

Procedure:
6-hydroxy-2-(4-methoxy-3-nitrobenzylsulfanyl)-9H-purine (14.67 g, 44 mmol) was suspended in dioxane (30 ml), phosphorus oxychloride (12.3 ml, 132 mmol) and dimethylaniline (8.3 ml, 66 mmol) were added and heated and stirred at 100° C. for 2 hours. The reaction solution was poured into ice water and extracted twice with ethyl acetate. After combining the ethyl acetate layers and washing with a saturated saline solution, it was dried with MgSO4 and the solvent was distilled away under reduced pressure. Separation and purification were performed by silica gel column chromatography (dichloromethane: methanol=20:1) to obtain 5.45 g (35% yield) of 6-chloro-2-(4-methoxy-3-nitrobenzylsulfanyl)-9H-purine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[O:45]1[C:49]2[CH:50]=[CH:51][C:52]([S:54]([N:57]([CH2:82][CH:83]([CH3:85])[CH3:84])[CH2:58][C@@H:59]([OH:81])[C@@H:60]([NH:69][C:70](=[O:80])[O:71][C@@H:72]3[C@H:79]4[C@H:75]([O:76][CH2:77][CH2:78]4)[O:74][CH2:73]3)[CH2:61][C:62]3[CH:67]=[CH:66][C:65](O)=[CH:64][CH:63]=3)(=[O:56])=[O:55])=[CH:53][C:48]=2[O:47][CH2:46]1>C(Cl)Cl>[O:45]1[C:49]2[CH:50]=[CH:51][C:52]([S:54]([N:57]([CH2:82][CH:83]([CH3:85])[CH3:84])[CH2:58][C@@H:59]([OH:81])[C@@H:60]([NH:69][C:70](=[O:80])[O:71][C@@H:72]3[C@H:79]4[C@H:75]([O:76][CH2:77][CH2:78]4)[O:74][CH2:73]3)[CH2:61][C:62]3[CH:63]=[CH:64][C:65]([O:28][CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:66][CH:67]=3)(=[O:55])=[O:56])=[CH:53][C:48]=2[O:47][CH2:46]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: OCCc1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCc2ccccc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To a solution of 66 mg (0.25 mmol) of triphenylphosphine and 30 μL (0.25 mmol) of phenethyl alcohol in 3 mL of anhydrous CH2Cl2 was added 58 mg (0.25 mmol) of di-tert-butyl azodicarboxylate. The resulting solution was stirred at RT for 5 minutes and was then treated with a solution of 50 mg (0.084 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate in 2 mL of CH2Cl2. After stirring at RT for 1.5 hours the solution was concentrated to dryness and the residue purified by flash chromatography (SiO2, 4:6 hexane/EtOAc) to give the desired product as a white foam in 72% yield. 1H NMR (CDCl3): 7.34-7.17 (m, 6H), 7.15 (s, 1H), 7.07 (d, 2H), 6.86 (d, 1H), 6.78 (d, 2H), 6.03 (s, 2H), 5.61 (d, 1H), 4.98 (m, 1H), 4.86 (d, 1H), 4.09 (t, 2H), 3.92 (m, 1H), 3.84-3.56 (m, 6H), 3.17-3.01 (m, 3H), 3.00-2.81 (m, 4H), 2.80-2.64 (m, 2H), 1.78 (m, 1H), 1.56 (m, 1H), 1.47 (m, 1H), 0.91 (d, 3H), 0.85 (d, 3H). MS(ESI): 697(M+H).
Reaction SMILES: [Mg].BrCCBr.C(Br)(C)C.[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([CH2:18][CH2:19][C:20]#[CH:21])=[O:17].C1(S([CH:31]2[CH2:37][CH2:36][CH2:35][CH2:34][C@@H:33]([CH2:38][O:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)[O:32]2)(=O)=O)C=CC=CC=1>C1COCC1.[Zn+2].[Br-].[Br-]>[F:46][C:43]1[CH:42]=[CH:41][C:40]([O:39][CH2:38][C@H:33]2[O:32][C@H:31]([C:21]#[C:20][CH2:19][CH2:18][C:16]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][O:10]3)=[O:17])[CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:45][CH:44]=1
Reactant: C#CCCC(=O)C1CCCCO1
Reactant: O=S(=O)(c1ccccc1)C1CCCC[C@@H](COc2ccc(F)cc2)O1
Agent: [Br-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CC(C)Br
Solvent: BrCCBr
Product: O=C(CCC#C[C@@H]1CCCC[C@@H](COc2ccc(F)cc2)O1)C1CCCCO1
Reaction time: 1 h

Procedure:
To a suspension of magnesium (0.58 g, 24.2 mmol) in dry THF (10 ml) was added catalytic 1,2-dibromoethane followed by dropwise addition of a soluton of isopropyl bromide (1.85 g, 15.1 mmol) in THF (5 ml). The reaction mixture was stirred for 1 hour and isoprpylmagnesiumbromide was cannulated into a 50 ml two-necked flask. A solution of 4-tetrahydropyranoyl-1-butyne (1.86 g, 12.0 mmol) in THF (5 ml) was added and the mixture was stirred for 30 minutes followed by addition of freshly prepared ZnBr2 solution (1 M, 7.25 ml, 7.2 mmol) in THF at 0° . After 45 minutes (2RS,7S)-2-(benzenesulfonyl)-7-(4-fluorophenoxymethyl)oxepane (2.2 g, 6.0 mmol) in THF (10 ml) was added and the mixture stirred for 30 hours. The reaction was quenched with saturated aqueous NH4Cl solution at 0° C. THF was removed under reduced preesure and the residue was portioned between EtOAc and water. The organic layer was washed with a brine, dried over Na2SO4 and concentrated to give (2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-tetrahydropyranoyl-1-butynyl)oxepane. The crude product was dissolved in MeOH (25 ml) and 1% HCl in MeOH (5ml) was added. The hydrolysis of the THF group was completed in 2 hours and neutralized with saturated Na2CO3 solution and concentrated. The crude product was purified by silica gel chromatography using EtOAc-hexane (1:8) to give (2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-hydroxybutynyl)oxepane (1.32 g, 75%); [α]D−74 (c 3.63, CHCl3), 1H-NMR (CDCl3, 200 Hz): δ 1.4-2.0 (m, 7H), 2.12 (m, 1H), 2.3 (s, 1H), 2.46 (dt, 2H), 3.65 (t, J=3.6 Hz, 2H), 3.74-3.97 (m, 2H), 4.51 (q, 1H), 6.8-7.0 (m, 4H); HRMS (EI): calcd. for C17H21O3F (M+) 292.147756 found 292.147473. Also, (2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-hydroxybutynyl)oxepane by similar procedure: [α]D+26.9 (c 2.2, CHCl3), 1H-NMR (CDCl3, 200 Hz): δ 1.48-2.03 (m, 8H), 2.2 (s, 1H), 2.47 (dt, 2H), 3.69 (t, J=6.9 Hz, 2H), 3.74-4.02 (m, 3H), 4.34 (dt, 2H), 6.78-7.0 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Cl[CH2:11][C:12]1[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1.ClCC1C=CC(OC)=CC=1>>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([CH2:11][S:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:13]=[C:14]([O:22][CH3:23])[C:15]=1[O:20][CH3:21]
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: COc1ccc(S)cc1
Agent: COc1ccc(CCl)cc1
Product: COc1ccc(SCc2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
The desired product was prepared by substituting 4-methoxybenzenethiol and 5-(chloromethyl)-1,2,3-trimethoxybenzene for Example 85A and 1-(chloromethyl)-4-methoxybenzene, respectively, in Example 85B.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1.[C:24]1(B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27][CH2:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.O>[C:12]([O:11][C:10]([N:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:24]2[CH2:28][CH2:27][CH2:26][CH:25]=2)[CH:3]=1)[C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N(Cc1cccc(C2=CCCC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 94.2 %

Procedure:
Tert-butyl N-[(3-bromophenyl)methyl]-N-tert-butoxycarbonylcarbamate (5.40 g) was dissolved in a mixed solvent of toluene (150 mL), ethanol (100 mL), and water (100 mL). To the solution, 2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.26 g), tetrakis(triphenylphosphine) palladium complex (1.62 g), and sodium carbonate (4.45 g) were added at room temperature, and the mixture was then heated to reflux for 19 hours. The reaction solution was cooled to room temperature, and ethyl acetate was then added thereto for separation into organic and aqueous layers. The organic layer was washed with water and concentrated under reduced pressure, and the obtained residue was then purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate) to obtain the title compound (4.92 g).
Reaction SMILES: CCN(CC)CC.C(O[C:16](=[O:32])[CH2:17][C:18](=O)[CH2:19][O:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2)C1C=CC=CC=1.Cl.[CH:34]1([NH:40][NH2:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CCO>[C:21]12([O:20][CH2:19][C:18]3[CH:17]=[C:16]([OH:32])[N:40]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[N:41]=3)[CH2:28][CH:27]3[CH2:29][CH:23]([CH2:24][CH:25]([CH2:26]3)[CH2:30]1)[CH2:22]2
Reactant: O=C(COC12CC3CC(CC(C3)C1)C2)CC(=O)OCc1ccccc1
Reactant: NNC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1cc(COC23CC4CC(CC(C4)C2)C3)nn1C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
NEt3 (800 μl, 5.7 mmol) was added to a solution of 4-(adamantan-1-yloxy)-3-oxo-butyric acid benzyl ester (1.91 g, 5.6 mmol), and cyclohexyl hydrazine hydrochloride (877 mg, 5.82 mmol) in EtOH (30 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 4 h. The precipitated white solid was filtered and dried to afford the product as a white solid, (1.23 g, 66%.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:34]([O:35][CH3:36])=[CH:33][C:6]2[CH2:7][C:8](=[O:32])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:31])[CH2:16][CH2:17][CH2:18][S:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)=[O:20])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Se](=O)=[O:38]>>[CH3:1][O:2][C:3]1[C:34]([O:35][CH3:36])=[CH:33][C:6]2[C:7](=[O:38])[C:8](=[O:32])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:31])[CH2:16][CH2:17][CH2:18][S:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)=[O:20])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(S(=O)CCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Reactant: O=[Se]=O
Product: COc1ccc(S(=O)CCCN(C)CCCN2CCc3cc(OC)c(OC)cc3C(=O)C2=O)cc1OC

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-N-[3-(3,4-dimethoxy-phenylsulfinyl)-propyl]-methylamine and selenium dioxide analogously to Example 55.