Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:39][O:40][CH2:41][CH2:42]Cl>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:30][CH2:31]6)=[O:28])[CH2:23]5)=[N:19][N:18]([CH2:42][CH2:41][O:40][CH3:39])[C:17]4=[O:32])=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (60 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (60 mg, 0.434 mmol, 3.1 eq) and 2-chloroethyl methyl ether (21 mg, 0.220 mmol, 1.5 eq). The vial was capped and purged with nitrogen gas, and the reaction mixture was stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction had progressed to 80% completion. The reaction mixture was cooled to room temperature and poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extracts were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 25-65% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (24 mg, 33%). MS(ES)+ m/e 487.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+]>O1CCOCC1.O.O>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:18][CH:19]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(CC(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(CC(=O)O)cc1

Procedure:
3.3 g (9.5 mmol) of methyl 2-[4-(2-butyl-4-chloro-5-formyl-imidazol-1-yl-methyl)-phenyl]-acetate are dissolved in 100 ml of dioxane/water (1:1) at 0° C. and a solution of 0.44 g (10.4 mmol) of lithium hydroxide monohydrate in 5 ml of water is added dropwise with stirring. After stirring at room temperature for 3 h, the mixture is concentrated to a half, diluted with water, washed with diethyl ether, and the aqueous phase is acidified with 1N hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulphate and concentrated.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:7]([NH2:8])=[C:6]([CH3:14])[CH:5]=1.[CH3:15]I.O>CN(C=O)C>[Br:3][C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:7]([NH:8][CH3:15])=[C:6]([CH3:14])[CH:5]=1
Reactant: CI
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1c(C)cc(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
3.80 g (86.6 mmol) sodium hydride (55%, suspension in mineral oil) were added batchwise to 20.0 g (86.6 mmol) 4-bromo-2-methyl-6-nitroaniline in 250 mL DMF with slight cooling and the mixture was stirred for 30 min. Then 5.40 mL (86.6 mmol) methyl iodide were slowly added dropwise, the cooling was stopped and the mixture was stirred overnight at RT. Then water was slowly added while the mixture was cooled and it was extracted several times with EtOAc. The organic phases were combined, dried on sodium sulphate, filtered and evaporated down i.vac. The residue was recrystallised from DIPE, cooled and the precipitate was suction filtered and dried.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:42]#[C:41][Si:38]([CH3:40])([CH3:39])[CH3:37])[C:9]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(COc2cnc(COC(C)=O)cc2OS(=O)(=O)C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(COc2cnc(COC(C)=O)cc2C#C[Si](C)(C)C)cc1
Temperature: 45 °C

Procedure:
(5-({[4-(Methyloxy)phenyl]methyl}oxy)-4-{[(trifluoromethyl)sulfonyl]oxy}-2-pyridinyl)methyl acetate (for a synthesis see WO2004058144 Example 60(d)) (10 g, 23 mmol) was dissolved in acetonitrile (400 ml) and triethylamine (65 ml) and copper (I) iodide (0.44 g, 2.3 mmol) were added. The mixture was degassed and placed under a blanket of argon. Trimethylsilylacetylene (10 ml, 69 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.645 g, 0.9 mmol) were added and the mixture heated to 45° C. for 18 h. The mixture was then allowed to cool and filtered. The filtrate was evaporated to dryness and the residue partitioned between ethyl acetate and water. The organic layer was separated and dried (sodium sulphate).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[CH3:21])[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]2[CH:13]=[C:9]([CH:7]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:10]([CH3:22])=[N:11]2)=[C:15]([CH3:21])[CH:16]=1
Reactant: Cc1cc(F)ccc1-n1cc(C(O)C2CCCCC2)c(C)n1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: Cc1cc(F)ccc1-n1cc(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)c(C)n1
Yield: 60.8 %

Procedure:
Using cyclohexyl[1-(4-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]methanol (0.50 g) synthesized in Example 21(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.39 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.48 g, 60%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[N:10]([CH2:19][CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[CH:35]=[O:36].[CH3:37]Br.[Mg].[Cl-].[NH4+]>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[N:10]([CH2:19][CH2:20][CH:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:4][C:3]=1[CH:35]([OH:36])[CH3:37]
Reactant: O=Cc1cc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)ccc1Cl
Reactant: CBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)ccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
16 mg (0.033 mmol, 1 eq.) of 3-(4-chloro-3-formylphenyl)-1-(3,3-diphenylpropyl)-1-(2-morpholin-4-ylethyl)urea (obtained in Example 63) are dissolved in 0.7 mL of dry THF. Once the solution has been cooled to 0° C., 17 μL (0.049 mmol, 1.5 eq.) of magnesium methyl bromide in solution (3 M in diethyl ether) are added to the medium. After stirring for 20 min. at 0° C., the reaction is neutralised with a saturated ammonium chloride solution at 0° C. The aqueous phase is extracted with dichloromethane, the organic phases are washed with brine, dried over MgSO4, filtered and concentrated. The crude reaction product is subjected to chromatography over silica gel (eluent: 1/1 heptane/AcOEt). 11.4 mg of expected product are obtained (yield=67%).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=CC=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14]C(C3SC(C(OC)=O)=CN=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:31]O.O1CCOCC1.[OH-].[Na+]>O>[CH:3]1[C:2]2[C:1](=[CH:25][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]=1[S:7]([N:10]1[CH2:11][CH2:12][NH:31][CH2:14][CH2:15]1)(=[O:8])=[O:9]
Reactant: NO
Reactant: COC(=O)c1cnc(C2CCN(S(=O)(=O)c3ccc(-c4ccccc4)cc3)CC2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 2-[1-(1,1′-biphenyl-4-ylsulfonyl)piperidin-4-yl]-1,3-thiazole-5-carboxylate 25.3 (9 mg), 50% hydroxylamine in water (0.05 mL), and dioxane (1 mL) were cooled in ice-water. To the reaction was added 1N sodium hydroxide (0.053 mL) followed by removal of the cooling bath. After stirring overnight, the reaction was neutralized with 1 N hydrochloric acid (0.053 mL) and the solvent evaporated. The residue was purified by preparative hplc to give Example 25 as a floculant white solid (3.5 mg). 1H NMR (DMSO) δ: 2.75 (m, 2H), 2.15 (m, 2H), 2.5 (m, 2H), 3.1 (m, 1H), 3.75 (m, 2H), 7.45-7.55 (m, 3H), 7.72-7.96 (m, 6H), 8.08 (s, 1H), 11.3 (s, 1H); m/e=444 (M+H+).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(N(CC)CC)C>O1CCCC1>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@@H]2CN(CC(=O)OC(C)(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.5 g), tert-butyl bromoacetate (0.2 ml) and triethylamine (0.31 ml) in tetrahydrofuran (10 ml) was stirred at room temperature for 12 hours. After filtration, the filtrate was concentrated to a syrup, which was subjected to a chromatography on a silica gel with a mixture of toluene and ethyl acetate (20:1) to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(tert-butoxycarbonylmethyl)piperazine (0.52 g). This compound was treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-carboxymethyl-2-(3,4-dimethylbenzyl)piperazine hydrochloride (0.33 g) as a white powder.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16](/Cl)\[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[CH2:4][CH3:5].C([Li])(C)(C)C.[CH2:35]1[O:38][CH2:37][CH2:36]1.O>O1CCCC1>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16](\[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)/[CH2:35][CH2:36][CH2:37][OH:38])=[CH:13][CH:14]=1)[CH2:4][CH3:5]
Reactant: CCN(CC)CCOc1ccc(/C(=C(/Cl)c2ccccc2)c2ccccc2)cc1
Reactant: C1COC1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(/C(=C(/CCCO)c2ccccc2)c2ccccc2)cc1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
Clomiphene (3.8 g, 9.3 mmol) was dissolved in tetrahydrofuran (50 ml), cooled to -40° C. and then treated with t-butyl lithium (1M in pentane, 20 mmol). After 10 minutes, trimethylene oxide (6 ml, 93 mmol) was added, the mixture stirred for 16 hours at room temperature, and then poured into water. The product was extracted with ether and chromatographed on a silica gel column using 1:1:0.1 ether/petroleum ether/triethylamine as eluant to yield purified trans-product (1 g, 25%), m.p. 93°-95° C. and cis- product (N,N-diethylhydroxymethyl tamoxifen) (1.0 g, 25%), m.p. 85°-87° C. Anal. (C29H35NO2)C,H,N. Calc., C:81.08, H:8.21, N:3.26; Found, C:80.56, H:7.94, N:3.32. Values for aliphatic protons are presented in Table 3.
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[F:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH2:22].[N:28]1([C:34]2[N:35]=[C:36]([CH2:41][C:42]([O-])=[O:43])[NH:37][C:38](=[O:40])[CH:39]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[Na+]>CN(C)C=O>[F:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH:22][C:42](=[O:43])[CH2:41][C:36]1[NH:37][C:38](=[O:40])[CH:39]=[C:34]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:35]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
2.5 ml of pyridine, 233 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 400 mg of 2,4-difluoroaniline are added to a solution of 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 16 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 205 mg of N-(2,4-difluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]1([CH2:19][CH2:20][SH:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:1](=[O:12])([S:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: SCCc1ccccc1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)SCCc1ccccc1

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 2-phenylethanethiol as starting materials to give the aimed compound.
Reaction SMILES: [CH:1]1[C:6](C=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:17].[OH-].[K+]>C(Cl)Cl.CO>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([OH:17])=[CH:5][C:4]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
commercial piperonal (Aldrich) (60 g) was dissolved in CH2Cl2 (500 ml), m--chloroperoxybenzoic acid (MCPBA) (90 g) added in portions and left to stir at room temperature (18 hrs.). The precipitate was filtered off and washed with CH2Cl2. The combined filtrate was then washed with cold saturated Na2CO3 solution, followed by H2O, dried over anhy. MgSO4 and evaporated to dryness. The resulting formate ester, δ (CDCl3, 300 Hz): 5.99 (2H, s, OCH2O), 6.56 (1H, d, J=8 Hz, H-6), 6.65 (1H, d, J=2 Hz, H-2), 6.70 (1H, d, J=8 Hz, H-5), 8.25 (1H, s, formate), was dissolved in MeOH (250 ml) and mixed with a solution of 30 g KOH in 200 ml MeOH. The reaction mixture was left at room temp for 15 hrs., evaporated to dryness, the residue dissolved in water (300 ml), acidified to neutral by dilute HCl (6N) and extracted with ethyl acetate. The organic layer was washed with NaHCO3 followed by water, dried over anhy. MgSO4 and evaporated to dryness. The crude product (57 g) was recrystallized from hexane (48 g), to yield colourless crystals, mp. 54°-55° C.; IR νmaxKBr cm-1 : 3580, 1625; UV νmaxMeOH nm (ε): 300.1 (2436), 234.2 (2269), 215.3 (2697), with KOH in methanol 314.2 (2477), 242.6 (2781), 225.6 (2746); 1H-NMR δ (CDCl3): 5.90 2H, s, OCH2O), 6.15 (1H, dd, J=2.4, 8.0 Hz, H-6), 6.24 (1H, d, J=2.4 Hz, H-2), 6.34 (1H, d, J=8.0, Hz, H-5), 4.68 (1H, bs, exchanged with D2O, phenolic); HRMS m/z: 138.0316 (M+, 100, C7H6O3), 137.0238 (M+ -H, 88.42, C7H5O3).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Reactant: Fc1ccc(Br)cc1
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4ccc(F)cc4)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and 1-bromo-4-fluorobenzene
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][C:7]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:9]([OH:10])[C:8]=1O>>[CH3:6][C:7]1[CH:8]=[C:9]([OH:10])[CH:11]=[C:12]([CH3:14])[C:13]=1[OH:2]
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(C)c(O)c(O)c1
Product: Cc1cc(O)cc(C)c1O

Procedure:
By following in the same manner as in Example 53, except that 1.10 g. of strong acidic sulfonic type ion exchange resin Amberlist 15 (manufactured by Rohm & Haas Co.) was used instead of sulfuric acid, 2.88 g. (20.9 m. moles) of 3,5-dimethylcatechol and 1.74 g. (12.6 m. moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 65.9 percent.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[C:19](O)=[O:20].C1([C@H](CC)C(O)=O)C=CC=CC=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:19](=[O:20])[C:18]([CH3:17])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CC(C)(C(=O)O)c1ccccc1
Agent: CC[C@H](C(=O)O)c1ccccc1
Product: CC(C)(C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and 2-methyl-2-phenylpropanoic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.49-7.38 (m, 4H), 7.31 (ddd, J=7.3, 14.4, 22.5, 5H), 7.08 (d, J=7.3, 1H), 4.46-4.35 (m, 1H), 3.58 (d, J=13.2, 1H), 3.43 (d, J=13.2, 1H), 2.84 (d, J=6.7, 1H), 2.36 (d, J=4.8, 3H), 2.31 (d, J=9.6, 1H), 2.21-2.13 (m, 1H), 2.04 (td, J=5.9, 11.7, 1H), 1.70 (dd, J=6.7, 12.3, 1H), 1.67 (s, 6H), 1.53-1.41 (m, 1H), 1.38-1.26 (m, 1H); MS (ESI+) m/z 363 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]([O:13][CH2:14][Cl:15])=[O:12].[CH3:16][C:17]1[C@@H:34]([O:35][C:36]([C@H:38]([OH:55])[C@@H:39]([NH:46][C:47]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[O:48])[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[CH2:33][C@:29]2([OH:56])[C:30]([CH3:32])([CH3:31])[C:18]=1[C@@H:19]([O:74][C:75]([CH3:77])=[O:76])[C:20]([C@@:22]1([CH3:73])[C@H:27]([C@@H:28]2[O:57][C:58]([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)=[O:59])[C@:26]2([O:68][C:69]([CH3:71])=[O:70])[CH2:66][O:67][C@@H:25]2[CH2:24][C@@H:23]1[OH:72])=[O:21]>ClCCl>[C:75]([O:74][C@@H:19]1[C:18]2[C:30]([CH3:31])([CH3:32])[C@@:29]([OH:56])([CH2:33][C@H:34]([O:35][C:36](=[O:37])[C@H:38]([O:55][C:11]([O:13][CH2:14][Cl:15])=[O:12])[C@@H:39]([NH:46][C:47](=[O:48])[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:17]=2[CH3:16])[C@@H:28]([O:57][C:58](=[O:59])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:27]2[C@:26]3([O:68][C:69](=[O:70])[CH3:71])[CH2:66][O:67][C@@H:25]3[CH2:24][C@H:23]([OH:72])[C@@:22]2([CH3:73])[C:20]1=[O:21])(=[O:76])[CH3:77]
Reactant: O=C(Cl)OCCl
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](OC(=O)OCCl)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.7 %

Procedure:
DIPEA (0.026 g, 46.0 mmol, 4.0 eq) was added to a solution of chloromethyl chloroformate (CMCF) [8] (0.04 g, 23.0 mmol, 4.0 eq) in dry dichloromethane under an argon atmosphere at 0° C. To the above reaction mixture at 0° C., a solution of paclitaxel 14114 (0.10 g, 11.7 mmol, 1.0 eq) in dry dichloromethane (y ml) was added. The reaction mixture was stirred at room temperature for 16 h. reaction progress was monitored by TLC. After 16 h the reaction mixture was diluted with dichloromethane (25 ml), washed with a 10% solution of NaHCO3 (15 ml), brine (10 ml), and then dried over anhydrous Na2SO4. Evaporation of the solvents under vacuum gave a white solid, (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2-(((chloromethoxy)carbonyl)oxy)-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxete-6,12b-diyl diacetate [315], (0.08 g, 70%)
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]([C:10]([OH:12])=O)=[C:7]([CH3:9])[N:8]=1)[CH2:2][CH3:3].CN(C)C=O.C(Cl)([Cl:20])=O>C1(C)C(C)=CC=CC=1>[CH2:1]([C:4]1[S:5][C:6]([C:10]([Cl:20])=[O:12])=[C:7]([CH3:9])[N:8]=1)[CH2:2][CH3:3]
Reactant: O=C(Cl)Cl
Reactant: CCCc1nc(C)c(C(=O)O)s1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: CCCc1nc(C)c(C(=O)Cl)s1

Procedure:
In a 200-ml three-neck flask, 15.0 g (0.08 mole) of 2-propyl-4-methylthiazole-5-carboxylic acid were suspended in 100 ml of xylene, followed by the addition of 0.05 g of N,N-dimethylformamide. Under heating and reflux, phosgene was blown at a flow rate of 1.5 l/hr for 3 hours (0.20 mole). After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 16.2 g of 2-propyl-4 -methylthiazole-5-carboxylic acid chloride. Its purity and yield were 97.3% and 98.2%, respectively.