Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH2:20][CH2:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][CH:28]3[S:32][C:31](=N)[NH:30][C:29]3=[O:34])=[CH:25][CH:24]=1)([CH3:19])[CH2:9][CH2:8]2)(=O)C.Cl.[OH2:38]>COCCO>[C:15]([C:14]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10]([CH2:20][CH2:21][O:22][C:23]3[CH:36]=[CH:35][C:26]([CH2:27][CH:28]4[S:32][C:31](=[O:38])[NH:30][C:29]4=[O:34])=[CH:25][CH:24]=3)([CH3:19])[O:11]2)=[CH:6][C:5]=1[OH:4])([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(CCOc1ccc(CC3SC(=N)NC3=O)cc1)CC2
Reactant: O
Agent: Cl
Solvent: COCCO
Product: CC1(CCOc2ccc(CC3SC(=O)NC3=O)cc2)CCc2cc(O)c(C(C)(C)C)cc2O1

Procedure:
75 mg of 5-{4-[2-(6-acetoxy-7-t-butyl-2-methylchroman-2-yl)ethoxy]benzyl}-2-iminothiazolidin-4-one (prepared as described in Example 6) were added to a mixture of 0.5 ml of concentrated hydrochloric acid, 2 ml of water and 2 ml of ethylene glycol monomethyl ether, and the mixture was heated under reflux for 4 hours. The mixture was then processed and purified by the procedures described in Example 1(a), except that the crude product, in the form of an oil, was purified by column chromatography through silica gel, eluted with a 5:1 by volume mixture of benzene and ethyl acetate, to give the title compound.
Reaction SMILES: [C:1]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)([C:3]1[S:7][CH:6]=[CH:5][CH:4]=1)=[O:2].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[S:7]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:1]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[OH:2]
Reactant: O=C(c1cccs1)c1cccs1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OC(c1cccs1)c1cccs1
Temperature: -40 °C
Reaction time: 2.5 h
Yield: 54 %

Procedure:
To a -35° to -40° C. solution of 2-(then-2-oyl)thiophene (Maybridge of Cornwall, UK) (500 mg, 2.60 mmol) in 10 mL of methylene chloride, is added dropwise a 1M solution of diisobutylaluminum hydride in methylene chloride (6.50 mL, 6.50 mmol) over 20 minutes. The reaction is stirred at -40° C. for 2.5 hours and then quenched by the slow addition of 10 mL of methanol. The mixture is warmed to room temperature and poured into 100 mL of saturated aqueous sodium tartrate. The aqueous solution is extracted with several portions of methylene chloride, the organic extracts combined, and dried over magnesium sulfate. Chromatography on silica gel, eluting with a 1:2 mixture of ethyl acetate to hexane, gives di-2-thienylmethanol as a light orange solid in 54% yield.
Reaction SMILES: C([BH3-])#N.[Na+].[ClH:5].[OH:6][CH2:7][CH:8]([NH:11][CH2:12][C:13]1[C:17]2[N:18]=[CH:19][NH:20][C:21](=[O:22])[C:16]=2[NH:15][CH:14]=1)[CH2:9][OH:10].[O:23]1CC(O)O[CH2:25][CH:24]1O>CO>[ClH:5].[OH:22][C:21]1[C:16]2[NH:15][CH:14]=[C:13]([CH2:12][N:11]([CH2:25][CH2:24][OH:23])[CH:8]([CH2:7][OH:6])[CH2:9][OH:10])[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: O=c1[nH]cnc2c(CNC(CO)CO)c[nH]c12
Reactant: OC1COC(O)CO1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: OCCN(Cc1c[nH]c2c(O)ncnc12)C(CO)CO
Reaction time: 16 h
Yield: 25.1 %

Procedure:
Sodium cyanoborohydride (0.011 g, 0.18 mmol) was added to a solution of the product from Example 10.2 (0.041 g, 0.15 mmol) and 1,4-dioxane-2,5-diol (0.027 g, 0.22 mmol, Sigma-Aldrich) in MeOH (3 ml) and stirred at it for 16 h. The solvent was evaporated and the residue chromatographed on silica gel (iPrOH-28% aq. NH4OH-water, 98:1:1) to give the crude product as a yellow solid (˜21 mg). The solid was triturated with a little 7M NH3-EtOH solution to leave the free base form of the title compound as a colourless solid (˜12 mg). This solid was dissolved in excess 5% aq. HCl then the solvent evaporated to give 7-(((1,3-dihydroxypropan-2-yl)(2-hydroxyethyl)amino)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one hydrochloride as a solid (15 mg, 32%). 1H NMR (D2O, referenced to HOD at 4.72 ppm) δ 8.49 (s, 1H), 7.82 (s, 1H), 4.77 (s, 2H), 3.98-3.88 (m, 6H), 3.77 (sextet, J=6.1 Hz, 1H), 3.56 (br. s, 2H). 13C NMR (D2O), δ 154.4, 144.4, 139.5, 132.8, 118.6, 104.1, 64.3, 56.7, 55.7, 52.6, 47.1. +ESMS Found 283.1407 (M+H)+ C12H19N4O4 requires 283.1406.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][C:9]=1[Cl:20])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:20][C:9]1[CH:10]=[C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[CH:12]=[CH:13][C:8]=1[NH2:7]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCOCC2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(N2CCOCC2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.9 %

Procedure:
A solution of impure (2-chloro-4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (2.84 g) in dichloromethane (30 mL) was treated with trifluoroacetic acid (3.5 mL), stirred at room temperature for 24 h and evaporated. The residue was dissolved in ethyl acetate, was washed with 1N NaOH, water, and brine, was dried (sodium sulfate) and evaporated. Purification by flash chromatography (SiO2) eluted with 35:65 ethyl acetate:hexanes provided 2-chloro-4-morpholin-4-yl-phenylamine (0.77 g, 40% yield) as an off-white solid. 1H-NMR (CDCl3, 500 MHz) 6.92 (br, 1H), 6.77 (br, 2H), 3.89 (m, 6H), 3.05 (m, 4H) ppm; MS (FIA) 213.1 (M+H); HPLC (Method A) 1.975 min.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[H-].[Na+].Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1>O>[F:6][C:7]1[CH:14]=[C:13]([O:15][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: O=Cc1ccc(O)cc1F
Reactant: Fc1ccc(CCl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccc(F)cn2)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.2 %

Procedure:
To an N,N-dimethylformamide (20.0 mL) solution of 2-fluoro-4-hydroxy-benzaldehyde (1.48 g, 10.2 mmol) was added sodium hydride (411 mg, 10.3 mmol, 60% in oil) under nitrogen atmosphere at 0° C., which was stirred for 20 minutes at room temperature. 2-Chloromethyl-5-fluoro-pyridine (1.20 g, 8.56 mmol) described in Manufacturing Example 41-1-2 was then added at room temperature, and stirred for 30 minutes at 80° C. Water was added at room temperature to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:5-1:2) to obtain the title compound (901 mg, 42.2%).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[Cl:54][C:55]1[CH:70]=[CH:69][C:58]([C:59]([NH:61][CH2:62][CH:63]2[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]2)=[O:60])=[CH:57][C:56]=1[O:71][CH3:72]>ClCCl>[Cl:54][C:55]1[CH:70]=[CH:69][C:58]([C:59]([NH:61][CH2:62][CH:63]2[CH2:64][CH2:65][N:66]([C:12]([C:10]3[O:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:11]=3)=[O:14])[CH2:67][CH2:68]2)=[O:60])=[CH:57][C:56]=1[O:71][CH3:72]
Reactant: O=C(O)c1cc(-c2ccccc2)no1
Reactant: COc1cc(C(=O)NCC2CCNCC2)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCC2CCN(C(=O)c3cc(-c4ccccc4)no3)CC2)ccc1Cl
Reaction time: 0.08 h
Yield: 42.8 %

Procedure:
A solution of 3-phenylisoxazole-5-carboxylic acid (0.075 g) in dichloromethane (1.6 mL) was treated with 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.084 g), 1-hyroxybenzotriazole hydrate (0.067 g) and diisopropylethylamine (0.21 mL) and stirred for five minutes. The product prepared in Example 11 (0.17 g) was added and the mixture was stirred at room temperature overnight. The mixture was partitioned between 1 N hydrochloric acid and dichloromethane. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=9:1) to obtain the title compound (0.077 g) having the following physical data.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:10])[C:4]=2[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18]>CN(C=O)C>[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][NH:10][C:9]1[C:4]2[CH2:3][CH2:2][O:1][C:5]=2[CH:6]=[CH:7][CH:8]=1)[CH3:18]
Reactant: CCOC(CBr)OCC
Reactant: Nc1cccc2c1CCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(CNc1cccc2c1CCO2)OCC
Temperature: 100 °C

Procedure:
A mixture of 2,3-dihydro-benzofuran-4-ylamine (preparation. J. Hetereocyclic Chem., 18, 1333 (1980)) (4.34 g), potassium carbonate (8.87 g) and bromo acetaldehyde diethyl acetal (9.7 ml) in dry DMF (60 ml) was heated to 100° C. for 2 days under. The mixture was cooled and was partitioned between water and ethyl acetate. The dried extracts were evaporated and the residue chromatographed on silica gel (250 g). Elution with ethyl acetate:cyclohexane 1:4 gave the title compound as a pale yellow oil (4.95 g).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][OH:7])[C:2]#[CH:3].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(OCC)C.O>[CH3:15][S:16]([O:7][CH2:6][CH2:5][O:4][CH2:1][C:2]#[CH:3])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCOCCO
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: C#CCOCCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
A solution of 1.7 g of 11b and 3 ml of triethyl amine in 20 ml of diethyl ether was treated at 0° C. with 1.5 ml of methanesulfonyl chloride. The mixture was stirred for an additional 30 min and then diluted with 35 ml of water and extracted with ethyl acetate. The combined organic layers were washed with 1M aq. K2CO3 solution and water, dried and concentrated, to provide 2.45 of 11c as a colorless oil; Rf 0.45 (heptane/ethyl acetate 1/1).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20](=O)[C:19]3[C:18]([C:22](OCC)=[O:23])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][CH:12]2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:7][CH:6]=1)=[O:4].O.[NH2:36][NH2:37]>CO>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH:12]2[NH:13][C:14]3[C:19]4[C:20](=[N:36][NH:37][C:22](=[O:23])[C:18]=4[CH:17]=[CH:16][CH:15]=3)[CH:11]2[C:8]2[CH:9]=[CH:10][C:5]([C:3]([N:2]([CH3:1])[CH3:34])=[O:4])=[CH:6][CH:7]=2)=[CH:28][CH:29]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(=O)N(C)C)cc1)C(c1ccc(F)cc1)N2
Solvent: O
Solvent: CO
Product: CN(C)C(=O)c1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(F)cc2)cc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A mixture of ethyl 3-(4-(dimethylcarbamoyl)phenyl)-2-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (400 mg, 0.87 mmol) and hydrazine monohydrate (85%, 10 mL) were dissolved in MeOH (20 mL), and stirred at 35° C. for 2 h. The mixture was concentrated under reduced pressure. The resulting mixture was filtered, the solid was washed with water and methanol to obtain a white solid, and the solid was dried in vacuum at 40° C. to obtain the title compound (100 mg, yield 54%). 1H-NMR (400 MHz, DMSO-d) δ (ppm): 2.85 (s, 3H), 2.94 (s, 3H), 4.37-4.40 (d, 1H), 4.80-4.82 (d, 1H), 7.17-7.25 (m, 5H), 7.33-7.36 (m, 2H), 7.39-7.41 (d, 1H), 7.45 (s, 1H), 7.57-7.61 (t, 1H), 12.19 (s, 1H); LC-MS (ESI) m/z: 429 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1([CH3:20])[CH2:10][CH2:9][C:8]2[C:11]([CH3:19])=[C:12]([O:17][CH3:18])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.Cl>N1C=CC=CC=1>[CH3:18][O:17][C:12]1[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]2[O:6][C:5]([CH2:4][CH2:3][CH2:2][O:1][S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=3)(=[O:29])=[O:28])([CH3:20])[CH2:10][CH2:9][C:8]=2[C:11]=1[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CCCO)O2
Agent: Cl
Solvent: c1ccncc1
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(CCCOS(=O)(=O)c1ccc(C)cc1)O2
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
The crude 3,4-dihydro-2-(3-hydroxypropyl)-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran (5.0 g) obtained in the above manner was dissolved in 50 ml of pyridine and the solution was cooled to 0° C. To the solution was added slowly 3.9 g of p-toluenesulfonyl chloride with vigorous stirring. After stirring at 0° C. for 1 hour, the reaction mixture was poured into 100 ml of dilute hydrochloric acid and extracted with diethyl ether. The ether layer was washed with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. Low-boiling substances were distilled off from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography to give 3.8 g of 3,4-dihydro-6-methoxy-2-[3-(p-toluenesulfonyloxy)propyl]-2,5,7,8-tetramethyl-2H-benzopyran.
Reaction SMILES: [OH:1][CH:2]([CH:11]=[CH2:12])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(C(C(C)C)=C[CH2:18][B:19]([O-])[O-:20])(C)C>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[OH:20][B:19]1[CH2:18][CH:12]=[CH:11][CH:2]([CH2:3][C:4]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:5])[O:1]1
Reactant: C=CC(O)CC(=O)OC(C)(C)C
Reactant: CC(C)C(=CCB([O-])[O-])C(C)C
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC1C=CCB(O)O1
Temperature: 65 °C
Yield: 92.7 %

Procedure:
To a solution of tert-butyl 3-hydroxypent-4-enoate, XLVI (674 mg, 3.92 mmol) in DCM (15 mL) was added diisopropylallylboronate XLV (2 g, 11.76 mmol) via syringe. To the mixture was then added Grubbs' first generation catalyst (260 mg, 0.31 mmol, 7.5 mol %) and the vessel was purged with argon. The reaction was heated at 65° C. under nitrogen for 18 h. The mixture was concentrated under vacuum and the residue was purified by flash column chromatography (100% hexane→30% EtOAc/hexane) to afford tert-butyl 2-(2-hydroxy-3,6-dihydro-2H-1,2-oxaborinin-6-yl)acetate XLVII (770 mg, 3.63 mmol, 92.7% yield).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4].C([Li])(CC)C.B(OC)(OC)[O:27]C.OO.Cl>C1COCC1.C1(C)C=CC=CC=1.CCCCCC.C1CCCCC1>[CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:27])=[C:15]([F:19])[C:14]=2[F:20])[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4]
Reactant: COB(OC)OC
Reactant: C=CCC[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Agent: Cl
Agent: OO
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCC[C@H]1CC[C@H](COc2ccc(O)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3 g of 1-((trans-4-(3-butenyl)cyclohexyl)methoxy)-2,3-difluorobenzene was dissolved in 30 mL of THF, and 11.7 mL of sec-butyllithium (1.01 M cyclohexane, a hexane solution) was added dropwise thereto at an internal temperature of −40 to −60° C. Then, the solution was stirred for 30 min. To this solution, 1.3 g of trimethyl borate was added, and the solution was heated to room temperature. Then, 1.8 mL of 30% hydrogen peroxide solution was added thereto, and the solution was stirred at 40° C. for 1 hours. To the solution, 5% hydrochloric acid was added, and the solution was stirred for 1 hour. Toluene was added thereto, and the organic layer was fractioned, washed with saturated saline, and then dried over anhydrous magnesium sulfate, to thereby obtain 4-((trans-4-(3-butenyl)cyclohexyl)methoxy)-2,3-difluorophenol.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][C:9]([C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])=[CH:8]2.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][C:9]([C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])=[CH:8]2
Reactant: COc1cccc2c1OCC(C(=O)N1CCOCC1)=C2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(C1=Cc2cccc(O)c2OC1)N1CCOCC1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution (70 ml) of 4-(8-methoxy-2H-chromen-3-ylcarbonyl)morpholine (3.5 g) in methylene chloride was added dropwise boron tribromide (9.5 g) at −78° C. The reaction temperature was set to room temperature and the mixture was stirred for 2 hr. The reaction mixture was poured into water and stirred for 1 hr. The organic layer was separated and washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (3.3 g) as brown crystals.
Reaction SMILES: C(OC([N:8]1[CH2:29][CH2:28][C:11]2([N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12]2=[O:27])[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.[ClH:36]>C(OCC)C>[ClH:36].[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:13]2[C:12](=[O:27])[C:11]3([CH2:10][CH2:9][NH:8][CH2:29][CH2:28]3)[N:15]([CH3:16])[C:14]2=[O:17])=[CH:24][CH:23]=1
Reactant: COc1ccc(CN2C(=O)N(C)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc(CN2C(=O)N(C)C3(CCNCC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
403 mg (1 mmol) of 3-(4-methoxy-benzyl)-1-methyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester were dissolved in a minimum of diethyl ether before adding 3 mL of a solution of dioxane/HCl 4N. The reaction mixture was agitated 10 minutes at room temperature and then evaporated. The yellow crude was triturated with diethyl ether and filtered to yield 115.3 mg (34%) of 3-(4-methoxy-benzyl)-1-methyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride as a pale yellow solid.
Reaction SMILES: CCCCCC.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][C:9]=1[CH3:17].[CH2:18]([O:25][C@@H:26]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[S:29][C:27]1([C:58]1[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([CH:65]=[O:66])[CH:59]=1)[OH:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:18]([O:25][C@@H:26]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[S:29][C:27]1([C:58]1[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([CH:65]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][C:9]=2[CH3:17])[OH:66])[CH:59]=1)[OH:28])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1cc(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Reactant: CCOc1ccc(Br)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(C(O)c2cc(C3(O)S[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
Then, 2.6 M n-butylithium hexane solution (1.6 mL) was added to a mixture of 1-bromo-4-ethoxy-2-methylbenzene (0.94 g, 4.37 mmol) and tetrahydrofuran (12 mL) at −78° C. After stirred for one hour, the mixture was added with a tetrahydrofuran (10 mL) solution of 2,3,4,6-tetra-O-benzyl-1-C-(4-chloro-3-formylphenyl)-5-thio-D-glucopyranose (1.52 g, 2.18 mmol), and, further stirred for 20 minutes, and the reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 2,3,4,6-tetra-O-benzyl-1-C-{4-chloro-3-[(4-ethoxy-2-methylphenyl)(hydroxy)methyl]phenyl}-5-thio-D-glucopyranose (1.72 g, 95%) as a yellow amorphous diastereomer mixture.
Reaction SMILES: BrC1C=CC(O)=C([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.C([CH:40]1[CH2:43][CH:42]([CH2:44][C:45]([OH:47])=[O:46])[C:41]1([CH3:49])[CH3:48])(=O)C.[OH-].[K+]>C(O)C>[C:45]([CH2:44][CH:42]1[CH2:43][CH:40]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[C:41]1([CH3:49])[CH3:48])([OH:47])=[O:46]
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)C1CC(CC(=O)O)C1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)C(CC(=O)O)CC1c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 16 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e 100 mg, 0.256 mmol) was reacted with (3-acetyl-2,2-dimethyl-cyclobutyl)-acetic acid (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (21 mg, 16% yield). MS: 512.31 (M+H+); HPLC Procedure A, retention time=9.07 min.
Reaction SMILES: CC(C(Cl)=O)=C.OCC[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26]CCO)=[CH:22][CH:21]=2)([CH3:19])[CH3:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>CC(C)=O>[OH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)([CH3:19])[CH3:18])=[CH:15][CH:16]=1
Reactant: CC(C)(c1ccc(OCCO)cc1)c1ccc(OCCO)cc1
Agent: C=C(C)C(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
45 g. of methacryl chloride is slowly added to a mixture of 66.2 g. of 2,2-bis[4-(2-hydroxyethoxy)phenyl]-propane, 41 g. of triethylamine and 300 ml. of dry acetone. The temperature is maintained below 32° C with cooling. The resulting amine hydrochloride is filtered off and washed with acetone. The acetone solution is added to 500 ml. of ice and water, the oily layer recovered and washed with sodium bicarbonate, followed by water, and dried at 40° C. in a vacuum with a stream of air passing through the liquid. The infrared spectrum of the product contains only a very small band indicating hydroxyl hydrogens, a large ester carbonyl band, and a carbon double bond band.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH2:10][C:11]([NH2:13])=[O:12]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:10][C:11]([NH2:13])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: NC(=O)CBr
Solvent: CCO
Product: NC(=O)CNc1cccc(F)c1
Temperature: 25 °C

Procedure:
An ethanol solution (50 ml) of 1.45 ml of 3-fluoroaniline and 1.37 g of 2-bromoacetamide was heated under reflux for 24 hours. The reaction liquid was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in chloroform and washed with 1N aqueous sodium hydroxide solution. The aqueous solution used for the washing was extracted with chloroform and combined with the earlier obtained chloroform extract, dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was separated and purified on silica gel column chromatography (chloroform/methanol=100/3) to provide 1.03 g of the title compound as a pale yellow solid.