Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][CH2:14][CH:15]([OH:30])[CH2:16][NH:17][CH2:18][CH2:19][NH:20][C:21]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:22]=2[CH:23]=[N:24][NH:25]3)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(OC1C=CC(OCC2C=CC=CC=2)=CC=1)C1OC1.NCCNC1C=CC=C2C=1C=NN2>CN(C)C=O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH:15]([OH:30])[CH2:16][NH:17][CH2:18][CH2:19][NH:20][C:21]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:22]=2[CH:23]=[N:24][NH:25]3)=[CH:31][CH:32]=1
Reactant: OC(CNCCNc1cccc2[nH]ncc12)COc1ccc(OCc2ccccc2)cc1
Agent: NCCNc1cccc2[nH]ncc12
Agent: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Solvent: CN(C)C=O
Product: Oc1ccc(OCC(O)CNCCNc2cccc3[nH]ncc23)cc1
Reaction time: 48 h

Procedure:
The 1-(4-benzyloxyphenoxy)-3-[2-(indazol-4-ylamino)-ethylamino]-propan-2-ol used as starting material can be obtained in the following manner: 5.1 g. 4-benzyloxyphenyl glycidyl ether and 7.0 g. 4-(2-aminoethylamino)-indazole are dissolved in 10 ml. dimethylformamide and left to stand for 2 days at ambient temperature. The reaction mixture is then digested by the addition of 20 ml. methanol, filtered off with suction and then washed with methanol. There are obtained 5.0 g. (58% of theory) of the desired product in the form of colorless crystals; m.p. 151°-153° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[CH:22]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[BH3-]C#N.[Na+]>CC(O)=O>[Cl:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH2:23][CH2:22]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1ccc2c(c1)CCN2
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of 3-chloro-4-(2,4-difluorobenzyloxy)-1-(1H-indol-5-ylmethyl)-1H-pyridin-2-one (Step 5, synthesis of Example 86) (0.24 g, 0.60 mmol) in AcOH (5 mL) was added NaCNBH3 (0.06 g, 1.0 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was partitioned between water and EtOAc, and the precipitate was collected by filtration. Trituration with CH2Cl2 afforded 3-Chloro-4-(2,4-difluorobenzyl-oxy)-1-(2,3-dihydro-1H-indol-5-ylmethyl)-1H-pyridin-2-one as a white solid (0.2 g, 81%): mp 137-139° C.; 1H NMR (300 MHz, CDCl3) δ 7.51 (app q, J=9 Hz, 1H), 7.21 (d, J=6 Hz, 1H), 7.11 (s, 1H), 6.99-6.80 (m, 3H), 6.57 (d, J=9 Hz, 1H), 6.08 (d, J=9 Hz, 1H), 5.18 (s, 2H), 5.02 (s, 2H), 3.83 (br s, 1H), 3.55 (t, J=9 Hz, 2H), 2.99 (t, J=9 Hz, 2H). ESHRMS m/z 403.1022 (M+H C21H18ClF2N2O2 requires 403.1019).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[C:24]([CH3:34])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.[C:44]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=[O:47])[CH:45]=[CH2:46]>C(Cl)Cl.C(O)(C(F)(F)F)=O.CO>[C:49]([O:48][C:44](=[O:47])[CH2:45][CH2:46][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[C:24]([CH3:34])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)([CH3:52])([CH3:51])[CH3:50]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Cc1cc(OCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ccc1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(OCc2ccc(C3CCN(CCC(=O)OC(C)(C)C)CC3)cc2)ccc1-c1ccccc1
Temperature: 90 °C

Procedure:
A solution of above 4-[4-(4-phenyl-3-methyl-phenoxymethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester in DCM/TFA (1:2 v/v, 3 mL) is stirred for 40 minutes. After concentration, the residue obtained is dissolved in methanol (2 mL). DIEA (5 eq) and t-butyl acrylate (2 eq) is added to this solution. The reaction mixture is heated at 90° C. for 30 minutes using microwave irradiation. After concentration, the residue is purified by silica gel chromatography (40% EtOAc in hexanes) to give 3-{4-[4-(4-phenyl-3-methyl-phenoxymethyl)-phenyl]-piperidin-1-yl}-propionic acid tert-butyl ester. This material is dissolved in DCM/TFA (1:1 v/v, 3 mL), and the solution is stirred at room temperature for 40 minutes. After concentration, the crude product is purified by preparative RP LC-MS to give 3-{4-[4-(4-phenyl-3-methyl-phenoxymethyl)-phenyl]-piperidin-1-yl}-propionic acid: MS (ES+): 430.6 (M+1)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][C:11]3[CH:21]=[C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH2:28][C:29]5[CH2:33][CH2:32][CH2:31][C:30]=5[C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=5)[CH2:24][CH2:23]4)[CH:19]=[CH:18][C:12]=3[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O[Li].O.Cl>O1CCCC1.CO.O.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][C:11]3[CH:21]=[C:20]([N:22]4[CH2:23][CH2:24][N:25]([CH2:28][C:29]5[CH2:33][CH2:32][CH2:31][C:30]=5[C:34]5[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=5)[CH2:26][CH2:27]4)[CH:19]=[CH:18][C:12]=3[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCOC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC3)CC2)cc1Oc1cccc2[nH]ccc12
Agent: Cl
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC3)CC2)cc1Oc1cccc2[nH]ccc12
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 143E (254 mg) in tetrahydrofuran (4 ml), methanol (2 ml) and water (2 ml) was added LiOH—H2O (126 mg). The mixture was stirred overnight. The mixture was then neutralized with 5% HCl and diluted with ethyl acetate (200 ml). After washing with brine, it was dried over Na2SO4. Evaporation of solvent gave the product.
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[CH3:16])([CH3:6])[C:3]([OH:5])=O>O>[CH3:6][C:2]1([CH3:1])[C:3](=[O:5])[C:13]2[C:12]([CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]([CH3:16])[C:8]=2[O:7]1
Reactant: Cc1cc(C)c(C)c(OC(C)(C)C(=O)O)c1
Solvent: O
Product: Cc1cc(C)c2c(c1C)OC(C)(C)C2=O
Temperature: 70 °C
Yield: 78.7 %

Procedure:
Polyphosphoric acid (1.5 kg) was added to 2-methyl-2-(2,3,5-trimethylphenoxy)propanoic acid (226 g, 1.02 mol) synthesized in Reference Example 34, and the mixture was stirred at 70° C. After reaction for 2 hours, the resulting mixture was poured into iced water and extracted using ethyl acetate. The extract was washed with 0.5 N sodium hydroxide aqueous solution and saturated saline, and dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure. Methanol was added to the residue, and the generated crystals were collected by filtration to give 164 g of the title compound (yield: 79%).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1.[H-].[Na+].[CH2:17](I)[CH2:18][CH2:19][CH3:20]>CN(C)C=O.ClCCl>[CH2:17]([O:1][C:2]1[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CC(C)c1ccc(CO)c(=O)c(O)c1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCOc1cc(C(C)C)ccc(CO)c1=O
Temperature: 80 °C
Yield: 37.7 %

Procedure:
A solution of 2-hydroxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (1.26 g, 6.49 mmol) in dimethylformamide (5 ml) was stirred, and 60% oily sodium hydride (285 mg, 7.13 mmol) was added in small portions to the solution. Subsequently, butyl iodide (1.1 ml, 9.6 mmol) was added and the reaction solution was heated at 80° C. for 4 hours. The solution was diluted with dichloromethane, washed with water and dried over sodium sulfate. Solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (1:1)] to give 612 mg of 2-butoxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one as a yellowish brown oil (yield, 38%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[C:17]([O:22]C)[CH:16]=[C:15]([O:24]C)[C:14]=2[C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]1[CH2:32][OH:33].Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[C:17]([OH:22])[CH:16]=[C:15]([OH:24])[C:14]=2[C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]1[CH2:32][OH:33]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc([N+](=O)[O-])c3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc([N+](=O)[O-])c4Cl)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 36 (0.900 g, 1.88 mmol) and pyridine hydrochloride (0.600 g, 5.1 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22]([OH:24])=O)=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([NH:35][C:22](=[O:24])[CH:21]([O:25][CH2:26][CH3:27])[CH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:1][CH2:2][CH2:3]2)=[CH:19][CH:18]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)O
Product: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)NCc1ccccc1
Yield: 71 %

Procedure:
The title compound (0.22 g, 74%) was prepared as a white solid from 3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.25 g, 0.65 mmol) obtained in example 29 and benzylamine (0.076 g, 0.71 mmol) by an analogous procedure to that described in example 32. mp: 92-93° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:17])=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1)(=[O:3])[CH3:2].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([O:17][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1c(-c2ccccc2)cc(OC(C)=O)cc1-c1ccccc1
Yield: 92.2 %

Procedure:
A mixture of 4-acetoxy-2,6-diphenylphenol (6.1 g, 20 mmol; prepared as described in Ber. 101, 2519 (1968) ), ethyl bromoacetate (4.0 g, 24 mmol), potassium carbonate (3.3 g, 24 mmol) and 2-butanone (150 ml) was refluxed for 24 h, then filtered and the solvent evaporated. The residue was purified by chromatography on silica gel (120 g, eluent benzene) to give 7.2 g (92%) of oily ethyl 4-acetoxy-2,6-diphenylphenoxyacetate .
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=O)[N:4]([CH3:6])[CH3:5].C(Cl)(=O)C(Cl)=O.[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>ClC(Cl)C>[CH3:1][N:2]([CH3:8])[C:3]([N:4]([CH3:6])[CH3:5])=[N:19][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CN(C)C(=O)N(C)C
Reactant: CCCCN
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Product: CCCCN=C(N(C)C)N(C)C
Temperature: 70 °C

Procedure:
N,N,N′,N′-tetramethyl-N″-butylguanidine was prepared as follows: 9.3 g tetramethyl urea was added to 80 mL dry dichloroethane in a two-neck 250 mL round-bottom-flask. 11.3 mL oxalyl chloride was added and the solution was heated at 70° C. for two hours. The solvent was evaporated in vacuo after the solution cooled to room temperature. Residual solid was then dissolved in dry acetonitrile and cooled to 0° C. 15 mL butyl amine (1.02 eq) was slowly added. The solution was slowly warmed and allowed to reflux for one hour. Finally, the mixture was cooled to room temperature and the solvent was removed in vacuo to yield 9 g of a clear oil. 1H (CDCl3): δ (ppm): 2.99 (t, 2H); 2.62 (s, 3H); 2.53 (s, 3H); 1.39 (quintet, 2H); 1.24 (quintet, 2H); 0.78 (t, 3H). The synthesis was performed several times and the yield ranged from 37%-70%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][N:3]=1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH2:17]([O:16][C:14]([C:13]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][N:3]2[CH:12]=1)=[O:15])[CH3:18].[CH:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:1]=2)[CH:4]=1)([CH3:10])[CH3:9]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)c1ccc(N)nc1
Product: CCOC(=O)c1cn2cc(C(C)C)ccc2n1

Procedure:
15.1 Ethyl 6-isopropylimidazo[1,2-a]pyridine-2-carboxylate Ethyl 6-isopropylimidazo[1,2-a]pyridine-2-carboxylate is prepared by condensing 2-amino-5-isopropylpyridine (PCT Int. Appl. WO 2005028444) with ethyl 3-bromopyruvate according to the method described by J. G. Lombardino in J. Org. Chem. (1965), 30(7), 2403.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[CH2:14]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1ccc2ccncc2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COc2ccc3ccncc3c2)cc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of 7-hydroxyisoquinoline (prepared by the method of R. B. Woodward and W. D. Doering, J. Am. Chem. Soc., 1945, 67, 860) (1.45 g, 10 mmol) in DMF (20 ml) was added sodium hydride (60% dispersion in oil, 0.4 g, 10 mmol) portionwise. After stirring for 30 minutes, benzyl bromide (1.2 ml, 10 mmol) was added and the reaction mixture stirred for 2 h. The reaction mixture was poured into water and extracted with diethyl ether (3×100ml). The ether extracts were combined, washed with 2N sodium hydroxide solution (2×50 ml), brine (50 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give the title compound (1.6 g, 68%); δH (CDCl3) 5.21 (2H, s, OCH2), 7.30-7.51 (7H, m, ArH), 7.59 (1H, d, J 8.3 Hz, ArH), 7.75 (1H, d, J 13 Hz, ArH), 8.42 (1H, d, J 8 Hz, ArH), and 9.14 (1H, s, ArH).
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[C:5]#[N:6].[C:13](O)(=O)C>O.[Fe]>[NH2:10][C:9]1[CH:2]=[CH:3][C:4]([C:5]#[N:6])=[C:7]([CH3:13])[CH:8]=1
Reactant: Cc1cc(C#N)ccc1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Fe]
Solvent: O
Product: Cc1cc(N)ccc1C#N
Temperature: 92.5 °C
Reaction time: 2 h

Procedure:
3-Methyl-4-nitrobenzonitrile (1.0 g, 6 mmol) was dissolved in acetic acid (15 ml). Water (3.75 ml) was added and the mixture was heated between 90-95° C. Iron powder (2.5 g) was added during 1.5 hours and the resulting mixture was heated for 1 hour. Other portion of water (3.75 ml) was added and the heating was continued for additional 2 hours. The solution was allowed to cool to room temperature and the mixture was diluted with water (100 ml) and extracted with ethyl acetate (4×40 ml). The organic phase was washed with 5% NaHCO3 (1×50 ml) and water (1×50 ml), dried over Na2SO4 and evaporated. The crude product was used without further purifications. 1H NMR (DMSO-d6): 2.28 (3H, s), 6.04 (2H, bs), 6.44 (1H, m), 6.48 (1H, m), 7.31 (1H, m).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(OC([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH:23]1[O:25][CH2:24]1)=O)(C)(C)C.[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][CH2:24][CH:23]([C@@H:19]1[CH2:20][CH2:21][CH2:22][NH:18]1)[OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: OC(COCc1ccccc1)[C@@H]1CCCN1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of benzylalcohol (2.0 ml) in DMF (10 ml) was added sodium hydride (60% dispersion in oil, 378 mg), and the mixture was stirred at room temperarture for 1 hour. A solution of (2S)-1-(tert-butoxycarbonyl)-2-(1,2-epoxyethyl)pyrrolidine (2.00 g) in DMF (10 ml) was dropwise added thereto, and the mixure was stirred for 4 hours. The reaction mixture was poured into saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluate: hexane-ethyl acetate). Thus-obtained purified compound (640 mg) was dissolved in a mixture of 1,4-dioxane-water (1:1, 30 ml), and barium hydroxide octahydrate (800 mg) was added thereto, and the mixture was refluxed at 120° C. for 4 hours. After the insoluble material was filtered off, the filtrate was adjusted to pH 5-6 with 1M phosphoric acid and washed with ether. The aqueous layer was then adjusted to pH 8 with 1N sodium hydroxide and extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and concentrated to give crude crystals of the title compound (297 mg).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][C@@H:6]([CH3:16])[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1.C(OCC)(=O)C>C(#N)C.CN(C)C1C=CN=CC=1.C(OCC)C>[CH3:16][C@@H:6]1[O:5][S:1](=[O:2])[N:8]([C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: C[C@H](O)CNC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)O1
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
A stirred solution of thionyl chloride (4.8 mL, 66.3 mmol) in acetonitrile (30 mL) is cooled down to −45° C. and a solution of tert-butyl [(2S)-2-hydroxypropyl]carbamate (5.1 g, 26.6 mmol) in acetonitrile (40 mL) is added by an addition funnel over about 20 min, keeping the internal temperature below −40° C. Then 4-dimethylaminopyridine (324 mg, 2.6 mmol) is added followed by the dropwise addition of pyridine (10.7 mL, 133.7 mmol), keeping the temperature below −40° C. The addition takes 1.5 h. Ethyl acetate (100 mL) is added to the suspension. The mixture is filtered at −35° C. to remove the solid and the solid is washed with EtOAc before it is discarded. Saturated Na2HPO4 solution (40 mL) is added to the filtrate and the mixture is stirred vigorously for 30 min. The organic layer is separated, washed with 1M NaHSO4 to remove residual pyridine, dried (Na2SO4) and concentrated to afford a clear oil. The residue was taken up in diethyl ether, a small amount of insoluble material was removed and the filtrate was concentrated to afford the title compound (5.7 g, crude) as an oil.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:47]1[CH:46]=[C:45]3[C:48]([CH2:51][C:52]4[CH:57]=[CH:56][C:55]([CH2:58][CH3:59])=[CH:54][CH:53]=4)=[CH:49][S:50][C:44]3=[CH:43][C:42]=1[CH2:41][O:40]2)C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1.B(Cl)(Cl)Cl.CO>ClCCl>[CH2:58]([C:55]1[CH:54]=[CH:53][C:52]([CH2:51][C:48]2[C:45]3[C:44](=[CH:43][C:42]4[CH2:41][O:40][C@:10]5([C:47]=4[CH:46]=3)[C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]5)[S:50][CH:49]=2)=[CH:57][CH:56]=1)[CH3:59]
Reactant: CCc1ccc(Cc2csc3cc4c(cc23)[C@]2(OC4)O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: Cc1cc(C)c(C)c(C)c1C
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc(Cc2csc3cc4c(cc23)[C@]2(OC4)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
(3′R,4′S,5S,5′S,6′R)-3′,4′,5′-tris-benzyloxy-6′-benzyloxymethyl-3-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydro-spiro[thieno[2,3,f]isobenzofuran-5(7H),2′-[2H]pyran] (34.1 mg, 0.042 mmol) was dissolved in dichloromethane (1.4 mL). To the resultant solution was added pentamethylbenzene (94.3 mg, 0.636 mmol), and then the solution was cooled to −78° C. Boron trichloride (1.0 M dichloromethane solution, 0.212 mL) was added dropwise, and the solution was stirred for 3 hours. To the solution was then added methanol (1.5 mL) to stop the reaction. The temperature of the solution was raised to room temperature. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (developing solution=ethyl acetate:n-hexane (2:25)), and the resultant product was then further isolated and purified by reverse phase HPLC (developing solution=acetonitrile:water (35:65 to 100:0)), to thereby obtain the titled compound (13.3 mg, 70%).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].[C:25]([C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[C:25]([C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[S:40]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:42])=[O:41])(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1S(=O)(=O)Cl
Reactant: CCOC(=O)CCCCCCCCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7 ml of anhydrous triethylamine are added to 5.3 g of ethyl 11-aminoundecanoate hydrochloride in 30 ml of anhydrous methylene chloride and, after stirring for one hour at ambient temperature, 6.3 g of 2-benzoyl-4-chlorobenzenesulphonyl chloride are added dropwise. After stirring for 12 hours, the reaction medium is evaporated to dryness under vacuum, taken up with water and extracted with ethyl acetate. The organic phase which is washed with water until the washings are free of Cl- ions is dried over sodium sulphate and evaporated to dryness under vacuum.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[NH:4][N:3]=1.[CH3:15]OS(OC)(=O)=O>[OH-].[Na+].O>[CH3:15][N:3]1[C:2]([CH3:1])=[C:10]2[C:5]([N:6]([CH3:14])[C:7](=[O:13])[N:8]([CH3:12])[C:9]2=[O:11])=[N:4]1
Reactant: Cc1n[nH]c2c1c(=O)n(C)c(=O)n2C
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Step 4 intermediate (5.2 g, 26.77 mmol) in 1 N sodium hydroxide (52 ml) was added dimetylsulphate (5.2 ml) and stirred at room temperature for 1 h. The reaction mixture was diluted with water and the solid precipitated out was filtered, washed with water and dried to give 3.85 g of the product as off white solid; 1H NMR (300 MHz, CDCl3): δ 2.59 (s, 3H), 3.36 (s, 3H), 3.48 (s, 3H), 3.79 (s, 3H).