Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:23][O:24]CC2C=CC=CC=2)[C:8]([N:10]2[C@@H:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][O:12][C:11]2=[O:22])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.CN(C=O)C.[Pd]>[CH:1]1([CH2:6][C@H:7]([CH2:23][OH:24])[C:8]([N:10]2[C@@H:14]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:13][O:12][C:11]2=[O:22])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](COCc1ccccc1)CC1CCCC1
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](CO)CC1CCCC1
Reaction time: 60 h
Yield: 99.9 %

Procedure:
A solution of (4S)-3-((2R)-3-cyclopentyl-2-{[(phenylmethyl)oxy]methyl}propanoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one (42.7 g, 0.1 mol) in ethanol (800 mL) and DMF (180 mL) was subjected to catalytic hydrogenation using 10% Pd/C (4 g) and a balloon of hydrogen. The reaction was 50% complete by LCMS after 24 h. The reaction was purged with nitrogen and a fresh balloon of hydrogen was introduced. After an additional 60 h, the reaction was again purged with nitrogen, was filtered, and the filtrate solvents were removed to provide (4S)-3-[(2R)-3-cyclopentyl-2-(hydroxymethyl)propanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one (33.1 g, 100%). LCMS: (M+H)+: 332.3.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][CH2:7][OH:8])[CH2:4][OH:5].[CH3:9][C:10]1C=CC(S(O)(=O)=O)=C[CH:15]=1.C(N(CC)CC)C>CC(C)=O>[CH3:9][C:10]1([CH3:15])[O:5][CH2:4][CH:3]([CH2:6][CH2:7][OH:8])[CH2:2][O:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCC(CO)CO
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC1(C)OCC(CCO)CO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 989.3 %

Procedure:
A solution of compound 31 (160 g, 1.30 mol) and 2,2′-dimethoxypropane (207 g, 1.90 mol) in dry acetone (800 mL) was added p-TsOH (92 g, 0.053 mol) under N2 and stirred at RT for 12 h. To this was added triethylamine drop-wise to neutral pH and then concentrated under vacuum below 35° C. The crude residue was purified by column chromatography over neutral alumina (12% ethyl acetate in pet ether) to give the title compound (84 g, 39%). TLC: Pet ether/EtOAc, 1:1, Rf=0.2
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([CH2:15][C:5]2=[C:4]([NH2:17])[C:3]=1[C:18]#[N:19])=[CH:13][CH:12]=[C:11]([OH:16])[CH:10]=3.Br[CH2:21][C:22]([OH:24])=[O:23].BrCCOCC>>[NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([CH2:15][C:5]2=[C:4]([NH2:17])[C:3]=1[C:18]#[N:19])=[CH:13][CH:12]=[C:11]([O:16][CH2:21][C:22]([OH:24])=[O:23])[CH:10]=3
Reactant: N#Cc1c(N)nc2c(c1N)Cc1ccc(O)cc1O2
Reactant: O=C(O)CBr
Agent: CCOCCBr
Product: N#Cc1c(N)nc2c(c1N)Cc1ccc(OCC(=O)O)cc1O2

Procedure:
[(2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-8-yl)oxy]acetic acid was prepared from 2,4-diamino-8-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile in the same manner as described in Example 10 using bromoacetic acid in lieu of 2-bromoethyl-ethylether. The product was isolated as a tan solid (110.6 mg, 31% yield). 1H NMR (400 MHz, DMSO) δ 7.030 (d, 1H), 6.640 (d, 1H), 6.516 (d, 1H), 6.474 (bs, 2H), 6.278 (bs, 2H), 4.633 (s, 2H), 3.543 (s, 2H); m/z 427 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:24]2[CH:25]=[N:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:28]=2)O1.ClCCl>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:24]2[CH:25]=[N:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:28]=2)[CH:3]=1
Reactant: Oc1ccc(Cl)cc1I
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)n1cc(-c2cc(Cl)ccc2O)cn1
Temperature: 50 °C
Yield: 66 %

Procedure:
A suspension of 4-chloro-2-iodophenol (200 mg, 0.78 mmol) and potassium carbonate (434 mg, 3.14 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was degassed and heated for 1 hour at 50° C. tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (347 mg, 1.18 mmol) and palladium (0) tetrakis(triphenylphoshine) (91 mg, 0.08 mmol) were added and the mixture heated at 50° C. for 5 hours. Dichloromethane (20 ml) and water (10 ml) were added and the organics separated and evaporated in vacuo. The residue was purified by column chromatography (silica gel) eluting with ethyl acetate:heptane (2:8 to 1:0, by volume) to afford the title product as a white solid, 155 mg, 66% yield.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:12]([OH:14])(=[O:13])[CH3:11]
Reactant: CCOC(=O)/C=C/c1ccc2c(c1)CCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc2c(c1)CCO2

Procedure:
Ethyl (E)-3-(2,3-dihydrobenzofuran-5-yl)propenoate (50.0 g, 227 mmol) was dissolved in acetic acid (312 g), and the reaction system was replaced with nitrogen. Then, 5% Pd/C (4.96 g, as dry weight) was added to the solution and pressurized with hydrogen to 196 to 294 kPa. The mixture was reacted at 50° C. for 1 hr under a pressure of 196 to 294 kPa. The catalyst was filtered, and washed with acetic acid (208 g) to give a solution of the title compound in acetic acid (amount 569 g, apparent yield 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH:4]([OH:28])[C@H:5]([NH:8]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][CH3:7])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@H:5]([CH2:6][CH3:7])[CH:4]([OH:28])[C:2]([CH3:29])([CH3:3])[CH3:1]
Reactant: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](N)C(O)C(C)(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of (3RS,4R)-2,2-dimethyl-4-(trityl-amino)-hexan-3-ol (0.57 g, 1 eq, 1.47 mmol) in DCM (10 mL) under an argon atmosphere at room temperature, was added CF3COOH (5 mL) dropwise, and the solution was stirred at this temperature for 1 h. The solvent was evaporated in vacuo, the residue was precipitated from Et2O (3 mL) with hexane (20 mL) with stirring to give a yellow oil. The solvent was decanted from the oil, and the oil was washed with hexane (20 mL) and dried in vacuo to afford the title compound as a light yellow oil. Yield: 0.21 g (100%). (55% de 3S,4R: 45% de 3R,4R). 1H-NMR (d6-DMSO, 250 MHz): δ 0.84-0.99 (m, 3H, NH2CH(CH2CH3)CH(C(CH3)3)OH), 1.25-1.29 (m, 9H, NH2CH(CH2CH3)CH(C(CH3)3)OH), 1.20-1.72 (m, 2H, NH2CH(CH2CH3)CH(C(CH3)3)OH), 3.14 (m, 1H, NH2CH(CH2CH3)CH(C(CH3)3)OH), 3.39 (m, 1H, NH2CH(CH2CH3)CH(C(CH3)3)OH), 3.65 (m, 1H, NH2CH(CH2CH3)CH(C(CH3)3)OH), 7.43, 7.77 & 8.54 (3×bs, 2H, NH2CH(CH2CH3)CH(CH(CH3)2)OH).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: NC(Cc1cccc(Oc2ccccc2)c1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(Oc2ccccc2)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(phenyloxy)phenyl)-1-propanol (300 mg, 0.89 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (169 mg, 0.89 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (256 mg, 1.33 mmol) and 1-hydroxy-1H-benzotriazole (136 mg, 0.89 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1). Recrystallization from ethyl acetate-hexane gave the title compound (148 mg, 33%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:19][O:20][C:21]([C:23]1[O:24][C:25]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:26]=2[CH:27]=1)=[O:22].C([O-])(O)=O.[Na+]>ClCCl>[CH3:19][O:20][C:21]([C:23]1[O:24][C:25]2[CH:31]=[CH:30][C:29]([NH:32][S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[CH3:12])(=[O:10])=[O:9])=[CH:28][C:26]=2[CH:27]=1)=[O:22]
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc2cc(NS(=O)(=O)c3cccc(Cl)c3C)ccc2o1
Reaction time: 0.08 h
Yield: 76.5 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (99 mg, 0.44 mmol) in dichloromethane (3 mL) was added pyridine (85 μL, 1.05 mmol) and the mixture was stirred under N2 for 5 min, after which time 5-amino-benzofuran-2-carboxylic acid methyl ester (80 mg, 0.42 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford an off-white solid (122 mg, 77%), single spot at Rf 0.47 (2:1 hexane:ethyl acetate). mp 139.4-140.1° C., HPLC purity 99+% (tR 1.90 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.83 (1H, d, J=7.9 Hz), 7.55 (1H, d, J=7.9 Hz), 7.44 (1H, d, J=9.0 Hz), 7.42 (1H, s), 7.39 (1H, d, J=2.2 Hz), 7.17 (1H, t, J=8.0 Hz), 7.05 (1H, dd, J8.7, 2.2 Hz), 6.65 (1H, s, N—H), 3.95 (3H, s), 2.72 (3H, s). LCMS: 378.16. FAB-MS (MH+, C17H14ClNO5S): calcd 379.0281, found 379.0281.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH:14]([N:18]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][C:20]([OH:22])=[O:21])[C:15]([OH:17])=[O:16])=O)C1C=CC=CC=1>[OH-].[Na+].[Pd]>[NH2:11][CH2:12][CH2:13][CH:14]([N:18]([CH2:19][C:20]([OH:22])=[O:21])[CH2:23][C:24]([OH:26])=[O:25])[C:15]([OH:17])=[O:16]
Reactant: O=C(O)CN(CC(=O)O)C(CCNC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: NCCC(C(=O)O)N(CC(=O)O)CC(=O)O
Yield: 119.3 %

Procedure:
2.9 g of the butyric acid derivative obtained were dissolved in 16 ml of 1N sodium hydroxide solution and, after the addition of a spatula tip of 5% Pd/C, hydrogenated at room temperature and normal pressure. The catalyst was filtered off and the filtrate was evaporated. There resulted 2.2 g of N-[3-amino-1-carboxypropyl]-iminodiacetic acid whose structure, NH2 --(CH2)2 --CH(COOH)--N(CH2COOH)2, was confirmed by the NMR spectrum.
Reaction SMILES: OS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:20][C:21]([F:48])([F:47])[C:22]1[CH:23]=[C:24]([C:28]2([C:34]([CH:36]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:37](OCC)=[O:38])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[F:20][C:21]([F:47])([F:48])[C:22]1[CH:23]=[C:24]2[C:25]([C:37]([OH:38])=[C:36]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:34](=[O:35])[C:28]32[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2cccc(C(F)(F)F)c2)CCOCC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2ccc(C(F)(F)F)cc2C2(CCOCC2)C1=O
Reaction time: 1.5 h
Yield: 35.6 %

Procedure:
H2SO4 (25 mL, 296 mmol) was cooled to 0° C. and treated with P2O5 (10 g, 70 mmol). The mixture was brought to room temperature and added to diethyl 2-(4-(3-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-carbonyl)malonate (4.27 g, 10 mmol). The reaction mixture was then stirred for 1.5 hours. Ice (H2O) was added, and the aqueous mixture was extracted with EtOAc (2×). The combined organic layers were washed with water (2×) and brine, dried (MgSO4), and concentrated in vacuo to give the crude compound as a brown oil. The crude oil was purified by silica flash chromatography (0-100% DCM/hexane) to give the desired compound as a white solid (1.32 g). MS (m/e)=371.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13](OC)=[O:14])[C:5](=[CH:10][C:11]=1[Cl:12])[C:6](OC)=[O:7].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([CH2:6][OH:7])=[C:4]([CH2:13][OH:14])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(Cl)c(Cl)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of dimethyl 4,5-dichlorophthalate A5 (98.86 g, 375.78 mmol) in tetrahydrofuran (150 mL) is added dropwise over 1 h to a mechanically stirred suspension of LAH (20.8 g, 548.1 mmol) in tetrahydrofuran (1.5 L). During the addition, the reaction is cooled in an ice-water bath. When the addition is completed, the reaction is stirred overnight at RT. The excess LAH is decomposed by cautious addition of water (20 mL), 10% aqueous NaOH (40 mL) and water (20 mL). The solids are removed by filtration through a celite pad and washed with tetrahydrofuran. The combined filtrate and wash is concentrated in vacuo on a rotary evaporator to afford crude 251 as white solid that is purified by crystallization from acetone (150 mL)-heptane (150 mL). The crystals are collected by filtration, washed with heptane and dried to give 4,5-dichloro-1,2-bis(hydroxymethyl)benzene (37.2 g). The combined filtrate and wash afforded a second crop of 251 (18.8 g, 24.1%). [L. A. Levy, Synth. Commun., 13, 639-648 (1983); O. Farooq, Synthesis, 1035-1036 (1994)]
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16]>CO.C1COCC1.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])=[C:2]([F:1])[CH:7]=1
Reactant: O=C1CCCN1c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(N2CCCC2=O)c(F)c1

Procedure:
650 mg (2.9 mmol) of 1-(2-fluoro-4-nitro-phenyl)-pyrrolidin-2-one (Example 14b) and 65 mg of Pd/C 10% are shacked in 15 ml of MeOH/THF (1:1) under 1.1 bar of H2 for 2 h at rt. After completion of the reaction, the catalyst is filtered-off and the filtrate is evaporated in vacuo to give the title compound as an off-white solid. ES-MS: 195 (M+H)+; analytical HPLC: tret=1.91 minutes (Grad 1).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([CH2:16][CH2:17][O:18]C(=O)C)[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)(=O)C.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31]C(O)=O)=[CH:27][CH:26]=1)([O-:24])=[O:23].N1CCCCC1>CN(C)C=O>[OH:18][CH2:17][CH2:16][N:7]([CH2:6][CH2:5][OH:4])[C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:31][C:28]2[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[CH:14][CH:15]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OCCN(CCOC(C)=O)c1ccc(C=O)cc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(N(CCO)CCO)cc2)cc1
Temperature: 0 °C

Procedure:
A mixture of the crude reaction product of the previous step, viz. 4-di(2-acetyloxyethyl)aminobenzaldehyde, 270 g of 4-nitrophenyl acetic acid, 2 l of dimethyl formamide, and 100 ml of piperdine was stirred for 4 days at 20°-25° C. Next, the reaction mixture was concentrated by evaporation at 70° C. to a thick red oil, which was titrated three times, each time with 1 l of n-hexane. The residue was dissolved in 2.5 l of dimethyl formamide. Then there was added a solution of 320 g of sodium hydroxide in 800 ml of water. The resulting reaction mixture was then heated for 16 hours to 100° C. and subsequently poured into 10 l of ice water. The precipitated product was filtered off and thoroughly after-washed three times, each time with 1 l of water. After drying the crude reaction product was crystallized from 250 ml of dimethyl formamide and 500 ml of dichloromethane. The resulting yield of 4-di(2-hydroxy-ethyl) amino-4'-nitrostilbene was 190 g with a melting point of 184°-185° C. Calculated on N,N-di(2-hydroxyethyl)aniline this is 58% of theory.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][C@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>C(O)(C)C>[CH2:1]([C@H:8]([CH2:12][C@@H:13]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C(O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.33 h

Procedure:
The chiral (S,S)-2,4-dibenzylglutaric acid is prepared as follows: To 5.0 g of (R*,R*)-2,4-dibenzylglutaric acid in 20 ml of isopropanol is added 0.81 g of triethylamine and the mixture is stirred for 20 minutes. To this mixture is added 0.97 g of d(+)-alpha-methylbenzylamine in 20 ml of isopropanol and the solution is stirred overnight. The solid is collected and recrystallized twice from isopropanol to yield (S,S)-2,4-dibenzylglutaric acid as the d(+)-alpha-methylbenzylamine salt melting at 201°-203°; [alpha]D =-20.4° (c=1 in methanol). To a warm solution of the above salt in 70 ml of water and 30 ml of ethanol is added 1 ml of concentrated hydrochloric acid. After standing 24 hours the solid is collected, washed with water and dried to yield (S,S)-2,4-dibenzylglutaric acid melting at 150°-152°; [alpha]D =+8.9° (c=2.0 in methanol).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[CH3:13].CC1C=CC(S(O[CH2:25][C:26]2([C:29]#[N:30])[CH2:28][CH2:27]2)(=O)=O)=CC=1.[Cl-].[NH4+]>CN(C)C=O>[Br:3][C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[C:7]([CH3:13])[N:8]([CH2:25][C:26]3([C:29]#[N:30])[CH2:28][CH2:27]3)[N:9]=2)[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C#N)CC2)cc1
Reactant: Cc1n[nH]c2ccc(Br)cc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1c2cc(Br)ccc2nn1CC1(C#N)CC1
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
To a suspension of 60% sodium hydride (143 mg) in N,N-dimethylformamide (3 ml) was added a solution of 5-bromo-3-methyl-1H-indazole (500 mg) in N,N-dimethylformamide (1 ml) at 0° C., and the mixture was stirred at the same temperature for 30 min. To the obtained reaction mixture was added (1-cyanocyclopropyl)methyl 4-methylbenzenesulfonate (420 mg), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (60 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1.[Si:35]([O:42][C@H:43]1[CH2:52][C@H:51](O)[C@H:50]2[C:45]([CH:46]=[CH:47][C@H:48]([CH3:71])[C@@H:49]2[CH2:54][CH2:55][C@H:56]2[O:61][C:60](=[O:62])[CH2:59][C@H:58]([O:63][Si:64]([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65])[CH2:57]2)=[CH:44]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>C(Cl)Cl>[Si:35]([O:42][C@H:43]1[CH2:52][C@H:51]([O:5][C:4](=[O:6])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])[C@H:50]2[C:45]([CH:46]=[CH:47][C@H:48]([CH3:71])[C@@H:49]2[CH2:54][CH2:55][C@H:56]2[O:61][C:60](=[O:62])[CH2:59][C@H:58]([O:63][Si:64]([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:65])[CH3:66])[CH2:57]2)=[CH:44]1)([C:38]([CH3:39])([CH3:40])[CH3:41])([CH3:37])[CH3:36]
Reactant: CC(C)(C)CC(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)CC(C)(C)C)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
0.46 ml (3.6 mmol) of 3,3-dimethylbutyric acid, 741 mg (3.6 mmol) of dicyclohexyl carbodiimide and 13 mg (0.09 mmol) of 4-(1-pyrrolidinyl)pyridine were added to a solution of 1.00 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] in 15 ml of methylene chloride, whilst ice-cooling. The resulting mixture was stirred at the same temperature for 30 minutes and then stirred at room temperature for a further 19 hours. At the end of this time, the solvent was removed by distillation under reduced pressure and the resulting residue was mixed with 20 ml of diethyl ether. Any insoluble material was removed by filtration and then washed twice with diethyl ether, using 5 ml for each washing. The filtrate and the washings were then combined and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by flash column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 555 mg (47% yield) of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)[CH:15]=[C:14]2[CH:29]=[C:30]1[S:34][C:33](=[O:35])[NH:32][C:31]1=[O:36]>>[C:1]([NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)[CH:15]=[C:14]2[CH:29]=[C:30]1[S:34][C:33](=[O:35])[NH:32][C:31]1=[O:36])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2c(c1)c(C=C1SC(=O)NC1=O)cn2Cc1ccc(Cl)c(Cl)c1
Product: O=C1NC(=O)C(=Cc2cn(Cc3ccc(Cl)c(Cl)c3)c3ccc(NC(=O)c4ccccc4)cc23)S1

Procedure:
The title compound was prepared by General Procedure 7 with benzoyl chloride and the amino compound from Example 47 as reactants. Nmr and ms data were consistent; ms m/e 523 (M+1). HPLC (System 1): purity greater than 80%.