Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:35][C:36](=[O:42])[C:37](OCC)=[O:38])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:20]([O:33][CH3:34])[CH:19]=3)[S:17][C:10]=12.[CH3:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][CH2:52][NH2:53]>>[F:1][C:2]1[CH:3]=[C:4]([NH:35][C:36](=[O:42])[C:37]([NH:53][CH2:52][CH2:51][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[O:44][CH3:43])=[O:38])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:20]([O:33][CH3:34])[CH:19]=3)[S:17][C:10]=12
Reactant: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)c(OC)c4)sc23)c(F)c1
Reactant: COc1ccccc1CCN
Product: COc1ccccc1CCNC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)c(OC)c4)sc23)c(F)c1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
Amino ester 140 (80 mg, 0.13 mmol) and 2-(2-methoxyphenyl)ethanamine (0.2 mL, 1.34 mmol) were mixed together and stirred at room temperature until completion of the reaction. The mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash chromatography (eluent: 3% MeOH/97% DCM to 5% MeOH/95% DCM). This solid product was then triturated with ethyl acetate to afford pure title compound 136 as a white solid (52 mg, 57% yield). 1H NMR (DMSO-d6) δ (ppm): 11.03 (s, 1H), 9.04 (t, J=5.9 Hz, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.05-8.01 (m, 2H), 7.82 (d, J=9.0 Hz, 1H), 7.53 (t, J=9.1 Hz, 1H), 7.47 (d, J=2.2 Hz, 1H), 7.38 (dd, J=2.2 and 8.2 Hz, 1H), 7.21 (td, J=1.8 and 7.8 Hz, 1H), 7.14 (dd, J=1.8 and 7.4 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.97 (d, J=7.4 Hz, 1H), 6.88 (td, J=1.0 and 7.3 Hz, 1H), 6.60 (d, J=5.5 Hz, 1H), 4.14 (t, J=6.0 Hz, 2H), 3.89 (s, 3H), 3.80 (s, 3H), 3.59-3.57 (m, 4H), 3.46-3.41 (m, 2H), 2.83 (t, J=7.0 Hz, 2H), 2.73-2.70 (m, 2H), one peak (4H) did not show, it was probably under H2O or DMSO. MS (m/z): 701.1 (M+H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([Cl:21])[C:12]3[C:22]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)(O)[O:23][C:24]4([CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([SiH](CC)CC)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([Cl:21])[C:12]3[C@H:22]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[O:23][C:24]4([CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:11]=3[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)OC3(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)O[C@H]3c1ccc(C(F)(F)F)cc1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
1.32 g (9S)-9-(tert-butyldimethylsilyloxy)-4-chloro-7,7-dimethyl-3-(4-(trifluoromethyl)phenyl)-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3-ol and 2.9 ml triethylsilane are dissolved in 40 ml dichloromethane, cooled to −50° C. and treated dropwise with 4.4 ml of a 1 m solution of titanium-(IV)-chloride in dichloromethane. Then the mixture is allowed to warm to room temperature and stirred for 30 minutes. The mixture is partitioned between saturated solution of sodium bicarbonate in water and dichloromethane. The aqueous phase is twice extracted with dichloromethane. The combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 90:10).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4C(O)=O)[NH:12][C:11]=3[N:10]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:9]2=[O:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(=O)C(Br)C(C1C=CC([C:48]2[NH:49][C:50]3N(CC4CCCCC4)C(=O)N(CC4CCCCC4)C(=O)[C:55]=3[N:56]=2)=CC=1)Br)C>CN(C)C=O.ClCCl>[CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:19]=[CH:23][CH:24]=[C:25](/[CH:11]=[CH:15]/[C:16]([N:49]5[CH:50]=[CH:55][N:56]=[CH:48]5)=[O:17])[CH:26]=4)[NH:12][C:11]=3[N:10]([CH2:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[C:9]2=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(Br)C(Br)c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Reactant: O=C(O)c1ccccc1-c1nc2c(=O)n(CC3CCCCC3)c(=O)n(CC3CCCCC3)c2[nH]1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1)n1ccnc1
Reaction time: 18 h

Procedure:
A slurry of (E)-4-[(1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]benzoic acid (from part (a) of this example, 0.50 g) in anhydrous N,N-dimethylformamide (10 mL) was heated briefly to near reflux under nitrogen. N,N′-Carbonyldiimidazole (Aldrich, 0.211 g) was then added to the pale yellow slurry, which thinned and turned orange as a gas evolved. Within minutes the slurry turned a bright yellow and thickened as a yellow solid formed. The mixture was stirred for 18 h, diluted with dichloromethane (30 mL), and filtered. The bright yellow solid was washed with dichloromethane (30 mL), and dried at 40° C. to provide (E)-1,3-bis(cyclohexylmethyl)-8-[3-(2-(1H-imidazol-1-ylcarbonyl)vinyl)phenyl]-9H-purin-2,6(1H,3H)-dione as a yellow powder (0.32 g). A mixture of this sample (0.32 g), nonaethylene glycol monomethyl ether (from part (a) of example 10, 0.277 g) and anhydrous potassium carbonate (0.170 g) in acetonitrile (10 mL) was refluxed for 20 h. Chloroform (50 mL) was added and the solution was washed with 1N HCl, (20 mL). The organic layer was washed with brine, dried (magnesium sulfate), and eluted from a silica gel column with 10% methanol-chloroform. Evaporation of solvents left yellow waxy solid which was reprecipitated from ethyl acetate-hexanes. The yellow waxy solid precipitate was filtered and dried to (E)-4-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]benzoic acid nonaethylene glycol methyl ether ester (0.355 g, 65%); 1H-NMR (DMSO-d6) δ: 8.24 (d, J=8.4, 2,2 CH), 8.06 (d, I=8.6, 2, 2 CH), 4.40 (m, 2, CH2O), 3.90 (d, J=7.3, 2, CH2N), 3.75 (m, 4, CH2N and CH2O), 3.70-3.40 (m, 32, 16 CH2), 3.19 (s, 3, CH3), 2.1-1.6 and 1.4-1.0 (m, 22, cyclohexyl CH2 and CH).
Reaction SMILES: [BH4-].[Na+].[CH:3]([CH:6]1[CH2:14][C:13]2[C:8](=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[CH:10]=[CH:11][CH:12]=2)[C:7]1=O)([CH3:5])[CH3:4].C1(C)C=CC=CC=1.S(=O)(=O)(O)O>CO>[CH:3]([C:6]1[CH2:14][C:13]2[C:8]([CH:7]=1)=[C:9]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:17][CH:16]=1)[CH:10]=[CH:11][CH:12]=2)([CH3:5])[CH3:4]
Reactant: CC(C)C1Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)C1=Cc2c(cccc2-c2ccc(C(C)(C)C)cc2)C1
Temperature: 50 °C
Reaction time: 6 h
Yield: 96.3 %

Procedure:
4.83 g of sodium borohydride and 39.1 g of 2-isopropyl-7-(4′-tert-butylphenyl)-1-indanone together with 118 ml of toluene are placed in a reaction vessel. At 50° C., 22.5 ml of methanol are slowly added and the reaction mixture is stirred for 6 hours at 50° C. After cooling to room temperature, 50 ml of 2N sulfuric acid are added and the mixture is stirred vigorously for another 30 minutes. The mixture is subsequently transferred to a separating funnel, the phases are separated and the aqueous phase is shaken twice with a total of 60 ml of 2N sulfuric acid. The organic phases are combined and dried over magnesium sulfate. The solvent of the reaction mixture is removed virtually completely and 200 ml of toluene and 0.4 g of p-toluenesulfonic acid are subsequently added to the residue. Water is distilled from the reaction mixture by heating for 1.5 hours on a water separator until reaction is complete. The reaction mixture is subsequently washed once with 100 ml of saturated sodium hydrogen carbonate solution and dried over magnesium sulfate. After separating off the magnesium sulfate, the residue is dried in an oil pump vacuum. This gives 35.7 g of 2-isopropyl-4-(4′-tert-butylphenyl)indene (total yield: 96%).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH3:11][N:12]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Clc1noc2ccccc12
Reactant: CNCCN1CCOCC1
Product: CN(CCN1CCOCC1)c1noc2ccccc12
Temperature: 140 °C
Yield: 23.5 %

Procedure:
To a sealed tube was added 3-chloro-1,2-benzisoxazole (3.0 g) and N-methyl-N-[2-(4-morpholinyl)ethyl]-amine (12.7 g). The reaction was heated to 140° C. over 72 hours and then cooled to room temperature. The residue was partitioned between EtOAc and water, extracted again with EtOAc, and the organic phase was dried over MgSO4 and concentrated in vacuo. Flash column chromatography (silica gel) eluting with 1-3% MeOH/DCM provided the product (1.2 g), as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([N:26]=[C:27]=[O:28])[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:26][C:27](=[O:28])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2cc(OC)c(OC)c(OC)c2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 4.3 g of ethyl 2-aminothiazol-4-ylglyoxylate, 5 g of 3,4,5-trimethoxyphenyl isocyanate and 30 ml of dimethylformamide. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: P(Br)(Br)([Br:3])=O.CN(C)C=O.[NH:11]1[C:20](=O)[C:19]2[NH:18][CH:17]=[N:16][C:15]=2[N:14]=[C:12]1[NH2:13]>O>[NH2:13][C:12]1[N:14]=[C:15]2[C:19]([NH:18][CH:17]=[N:16]2)=[C:20]([Br:3])[N:11]=1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: O=P(Br)(Br)Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Br)c2[nH]cnc2n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
86.0 g (0.3 mol) of phosphorus oxybromide was added to 73.1 g (1.0 mol) of N,N-dimethylformamide, and 15.1 g (0.1 mol) of guanine (manufactured by Sumika Fine Chemicals Co., Ltd.) was then added, followed by stirring at 100° C. for 4 hours. After cooling, 200 ml of water was carefully added at 20° C. After stirring at room temperature for 24 hours, the precipitating crystal was collected by filtration and dissolved in 200 ml of 25% aqueous ammonia with heating, and the insoluble substances were filtered out. The mother liquor was concentrated under reduced pressure, and the precipitating crystal was collected by filtration to yield 11.1 g (0.052 mol) of a pale yellow crystal of 2-amino-6-bromopurine (yield 52%). Its properties are as follows:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].[C:20]([O:24][C:25]([NH:27][C:28](=[N:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])SC)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C1COCC1.CO.C1COCC1>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28]([NH:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])=[N:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]
Reactant: NCCCCCCCCNCCCCCCCCN
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NCCCCCCCCNCCCCCCCCN)NC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
To a stirred solution of 1,17-diamino-9-azaheptadecane 3 (4.9 g, 15.06 mmol) in THF/CH3OH 5/3 (80 mL) at 50° C., a solution of N,N′-bis(tert-butoxycarbonyl)-S-methylisothiourea (1.456 g, 5.02 mmol) in THF (25 mL) was added dropwise over 1 h. After 16 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (6% methanol, 4% triethylamine, 90% ethyl acetate), affording 12 as a pale yellow oil, 3.51 g (70%).
Reaction SMILES: [F:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[NH2:21][OH:22].Cl.O>C(O)C>[F:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[N:21][OH:22])=[CH:15][CH:14]=2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=O)cc2)C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=NO)cc2)C1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-fluoro-3-(4-formylphenyl)azetidine-1-carboxylate (Preparation 6, 460 mg, 1.65 mmol) in ethanol (30 mL) was added NH2OH.HCl (127 mg, 1.8 mmol) and water (2.5 mL). The solution was heated to 50° C. for 1 hour and then allowed to stir at room temperature for 2 hours. The reactants were concentrated under vacuum to remove the ethanol. Water (5 mL) was added to the remaining residue and extracted with EtOAc (2×10 mL). Combined organic phases were dried (Na2SO4) and concentrated under vacuum to afford the intermediate as a solid. Yield 485 mg. 1H NMR (CDCl3) δ 8.17 (s, 1H), 7.65 (d, 2H), 7.50 (d, 2H), 5.32 (s, 1H), 4.37-4.50 (m, 2H), 4.28 (m, 2H), 1.45-1.55 (m, 9H). LC/MS retention time=2.926 minutes; MS calculated for (C15H19FN2O3), 294.13; found 195.0 M-Boc.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:49][CH2:50][N:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:49][CH2:50][N:51]3[CH2:55][CH2:54][CH2:53][CH2:52]3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: OCCN1CCCC1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCN2CCCC2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 11 %

Procedure:
1,4-Diethylazodicarboxylate (205 μL) is added to a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41, triphenylphospine (341 mg), and 1-(2-hydroxyethyl)pyrrolidine (292 μL) in THF (10 mL). The reaction mixture is stirred at room temperature for 20 h and then poured into 0.5 N aqueous NaOH solution (25 mL). The mixture is extracted with EtOAc (3×25 mL). The organic layer is dried (Na2SO4) and concentrated. The crude product is purified by column chromatography (CH2Cl2/methanol, 100/1; 50/1; 20/1; 10/1) followed by recrystallization from ethanol to afford 54 mg (11%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH2:5]2.C([Li])CCC.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([C:30]2([OH:69])[C@H:35]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@@H:34]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@H:33]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C@@H:32]([CH2:60][O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[O:31]2)=[CH:26][C:23]=1[CH:24]=[O:25]>C1COCC1.C1(C)C=CC=CC=1>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([C:30]2([OH:69])[C@H:35]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C@@H:34]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@H:33]([O:52][CH2:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C@@H:32]([CH2:60][O:61][CH2:62][C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)[O:31]2)=[CH:26][C:23]=1[C:24]([C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH2:5]2)=[O:25]
Reactant: COc1ccc(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C=O
Reactant: Brc1ccc2c(c1)CCC1(CCC1)O2
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C(=O)c1ccc2c(c1)CCC1(CCC1)O2
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a stirred solution of 6-bromospiro[chromane-2,1′-cyclobutane] (0.563 g, 2.23 mmol) in THF (3 mL) at −78° C. was added n-butyl lithium (1.45 mL, 2.23 mmol) and stirred for 1 h. Compound obtained in step III (0.3 g, 0.45 mmol) in toluene (3 mL) was cooled to −78° C. and Ithium salt prepared above was added to this at −78° C. This reaction mixture was stirred for 1 h, quenched with sat. NH4Cl (10 mL) and extracted with ethyl acetate (2×20 mL). The ethyl acetate layer was washed with water, brine, dried over sodium sulphate, concentrated and purified by silica gel column chromatography to furnish [2-methoxy-5-[(3R,4S,5R,6R)-3,4,5-tribenzyloxy-6-(benzyloxymethyl)-2-hydroxytetrahydropyran-2-yl]phenyl]-spiro[chromane-2,1′-cyclobutane]-6-yl-methanone (0.250 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH2:7][CH2:6][S:5][C:4]2[CH:9]=[CH:10][S:11][C:3]1=2.C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>C(Cl)Cl>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][O:1][CH:2]1[CH2:8][CH2:7][CH2:6][S:5][C:4]2[CH:9]=[CH:10][S:11][C:3]1=2
Reactant: OC1CCCSc2ccsc21
Reactant: COCCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOC1CCCSc2ccsc21
Reaction time: 117 h
Yield: 81.8 %

Procedure:
To a solution of 8-hydroxy-5,6,7,8-tetrahydrothieno[3,2-b]thiepin (16.6 g, 0.089 mole) and diisopropylethylamine (18.1 g, 0.14 mole) in methylene chloride (185 ml) was added β-methoxyethoxymethyl chloride (17.5 g, 0.14 mole) over 10 minutes under nitrogen at ambient temperature. The solution was stirred for 117 hours and then washed with cold 0.5N HCl (2×100 ml), saturated sodium bicarbonate solution, twice with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel (2.5 kg), eluting with 20% ethyl acetate-hexane (v/v), to yield 19.97 g (82%) of oily product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:14][C:15]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:16]=1[NH2:17].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][CH2:9][C:10]([NH:17][C:16]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=1[Cl:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COc1ccc(Cl)c(N)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)c(NC(=O)COCc2ccccc2)c1
Temperature: 25 °C
Yield: 103 %

Procedure:
Benzyloxy acetyl chloride (1) (11.0 g, 60.0 mmol) and 2-chloro-5-methoxyaniline hydrochloride (11.7 g, 60.2 mmol) in dichloromethane (100 mL) at 0° C., was stirred and triethylamine (13.0 g 126.0 mmol, 18.0 mL) added slowly over 15 min. The stirred reaction was allowed to warm to RT over 18 h. There was a heavy precipitation of triethylamine hydrochloride. The dichloromethane solution was washed with 10% aqueous potassium carbonate (50 mL), dried over magnesium sulfate and concentrated in vacuo to afford 18.9 g (quantitative) of 2-Benzyloxy-N-(2-chloro-5-methoxy-phenyl) acetamide (2) as a gum. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 55.6, 69.6, 73.6, 106.2, 111.1, 114.1, 127.7, 128.3, 128.6, 129.2, 134.6, 136.5, 158.9, and 167.7.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][CH3:29])[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=1)[CH3:11].[OH-].[Na+].CO>O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][CH3:29])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: CCOC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino)ethoxy]-phenyl]-2-methoxypropanoate (1.5 g), 10% aqueous sodium hydroxide solution (7.5 mL) and methanol (23 mL) was stirred for 1.5 hrs at room temperature and then diluted with water (600 mL), washed with dichloromethane (300 mL) and acidified to pH2 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (3×300 mL) and the combined ethyl acetate solutions washed with water (2×200 mL) and brine (200 mL), dried (MgSO4) and evaporated. The residue was crystallised from ethyl acetate-dichloromethane-hexane to afford the title compound, mp 150°-153° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:19])[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].O[Li].O>C1COCC1.O>[C:15]([O:14][C:12]([N:6]1[C:5]([CH3:19])([C:3]([OH:4])=[O:2])[CH2:9][O:8][C:7]1([CH3:11])[CH3:10])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)C1(C)COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C(C)(C)OCC1(C)C(=O)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a stirring solution of 4 (9.392 g, 34 mmol) in THF (65 mL) and H2O (35 mL) under an inert atmosphere was added solid LiOH—H2O (1.426 g, 34 mmol) in one portion. The reaction mixture was heated to 90° C. and stirred 8 h at which point the reaction mixture was cooled to rt. The crude reaction mixture was washed with Et2O (3×50 mL) and the Et2O extracts were discarded. The aqueous solution was then acidified with 2M KHSO4 until a white precipitate began to form on addition, pH=5. The acid was added dropwise until the precipitate persisted and the aqueous solution was extracted with Et2O (50 mL). After extraction, two addition drops of acid were added to the aqueous layer and it was again extracted with Et2O (25 mL). The Et2O extracts were combined and quickly back extracted with 1M NaOH (15 mL). The organic phase was then dried over sodium sulfate and concentrated in vacuo to give 5 (7.458 g, 85%) as a white solid which was used without further purification. Compound was observed as an uneven mixture of rotomers.