Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@H:15]([C:20]([NH:22][C@H:23]([CH2:31][OH:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])[C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:13])=[O:12].C(N(CC)CC)C.C(OCC)(=O)C>CS(C)=O.ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@H:15]([C:20]([NH:22][C@H:23]([CH:31]=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])[C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:13])=[O:12]
Reactant: CC(C)(C)[C@H](NS(=O)(=O)c1ccc2ccccc2c1)C(=O)N[C@H](CO)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)[C@H](NS(=O)(=O)c1ccc2ccccc2c1)C(=O)N[C@H](C=O)Cc1ccccc1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
N-(2-Naphthalenesulfonyl)-L-tert-leucyl-L-phenylalaninol (1.6 g) was dissolved in dimethyl sulfoxide (20 ml) and dichloromethane (10 ml), and triethylamine (2.1 g) was added. The solution was stirred at room temperature while adding a solution (15 ml) of sulfur trioxide-pyridine complex (2.2 g) in dimethyl sulfoxide, which was followed by stirring for 2 hr. After the completion of the reaction, ethyl acetate was added. The mixture was washed with dilute hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with a mixed solution of hexane-ethyl acetate to give 1.1 g of N-(2-naphthalenesulfonyl)-L-tert-leucyl-L-phenylalaninal (Compound 42) as white crystals.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH:4]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[C:12]([CH3:28])=[N:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[C:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[C:15]=2[CH3:16])=[O:10])[CH2:5]1)[CH3:2]>CCO.O.[Pt](=O)=O>[CH2:29]([N:3]([CH2:1][CH3:2])[CH:4]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[C:12]([CH3:28])=[N:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])[CH:18]=3)[C:15]=2[CH3:16])=[O:10])[CH2:5]1)[CH3:30]
Reactant: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(C#CC(C)C)c3)c2C)C1
Agent: O=[Pt]=O
Solvent: O
Solvent: CCO
Product: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(CCC(C)C)c3)c2C)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.5 %

Procedure:
A suspension of 0.041 g (0.10 mmol) of (3-diethylamino-pyrrolidin-1-yl)-{3,5-dimethyl-1-[3-(3-methyl-but-1-ynyl)-phenyl]-1H-pyrazol-4-yl}-methanone (Example 361) and 6 mg of platinum(IV) oxide hydrate in 0.2 ml of EtOH was stirred under hydrogen atmosphere 17 h at RT and 1 atm. The suspension was filtered and evaporated to give 0.038 g (93%) of the titled compound as colorless viscous oil. MS: 411.2 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([S:7](Cl)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[OH:11][C@:12]([CH3:48])([CH2:46][OH:47])[C:13](=[O:45])[C@@H:14]([NH:22][C:23](=[O:44])[C@@H:24]([NH:28][C:29](=[O:43])[C@@H:30]([NH:34][C:35]([C:37]1[S:41][C:40]([CH3:42])=[N:39][CH:38]=1)=[O:36])[CH2:31][O:32][CH3:33])[CH2:25][O:26][CH3:27])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:1]1[CH2:6][CH2:5][CH:4]([S:7]([O:47][CH2:46][C@:12]([OH:11])([CH3:48])[C:13](=[O:45])[C@@H:14]([NH:22][C:23](=[O:44])[C@@H:24]([NH:28][C:29](=[O:43])[C@@H:30]([NH:34][C:35]([C:37]2[S:41][C:40]([CH3:42])=[N:39][CH:38]=2)=[O:36])[CH2:31][O:32][CH3:33])[CH2:25][O:26][CH3:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Reactant: O=S(=O)(Cl)C1CCOCC1
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(=O)(=O)C1CCOCC1

Procedure:
Prepared according to procedures described above, by reacting tetrahydro-2H-pyran-4-sulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C30H42N4O11S2 m/z: 699 (M+H)+.
Reaction SMILES: C(OC([C:6]1([N+:27]([O-])=O)[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]([S:17]([OH:20])(=[O:19])=[O:18])=[N:8][CH:7]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)C.Cl>C(O)C>[NH2:27][C:6]1[C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:8][C:9]([S:17]([OH:20])(=[O:18])=[O:19])=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=CC(S(=O)(=O)O)=NC(c2ccccc2)C1(C(=O)OCC)[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(S(=O)(=O)O)nc(-c2ccccc2)c(N)c1C(=O)OCC
Temperature: 60 °C
Yield: 152.6 %

Procedure:
A mixture of 0.34 g of 3,4-diethoxycarbonyl-3-nitro-2-phenyl-6-sulfopyridine, 0.41 g of reduced iron and 7 ml of ethanol was heated to 60° C., and then 0.5 ml of conc. hydrochloric acid was added. The mixture was heated under reflux for 20 minutes. After the reaction mixture was concentrated to dryness, the residue was subjected to silica gel column chromatography (eluent:chloroform/methanol 5:1), to give 0.24 g of the title compound as pale yellow crystals.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][C:7]1([CH3:24])[C:18]2[CH:17]=[CH:16][N:15]([CH2:19][C@H:20](O)[CH3:21])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([CH3:23])[CH:12]=2.C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+]>ClCCl.CN(C)C=O.O>[N:32]([C@@H:20]([CH3:21])[CH2:19][N:15]1[CH:16]=[CH:17][C:18]2[C:7]([CH3:24])([CH3:6])[C:8]3[C:13]([C:14]1=2)=[CH:12][C:11]([CH3:23])=[CH:10][CH:9]=3)=[N+:33]=[N-:34]
Reactant: Cc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2(C)C
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2c(c1)-c1c(ccn1C[C@H](C)N=[N+]=[N-])C2(C)C
Yield: 68.6 %

Procedure:
0.91 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.5 g of (R)-1-(4,4,7-trimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 3.27 ml of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The green solid obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 0.76 g of sodium azide and the reaction mixture was heated to 60° for 15 hours while stirring. After cooling the solution was poured into 100 ml of water and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (hexane/ethyl acetate 4:1). 1.13 g (68%) of (S)-1-(2-azido-propyl)-4,4,7-trimethyl-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a reddish oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([OH:25])[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].Cl.[CH2:27](O)[CH3:28]>O>[CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([OH:25])[C:22]([O:24][CH2:27][CH3:28])=[O:23])=[CH:18][CH:19]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: CCO
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc(CC(O)C(=O)O)cc1
Agent: Cl
Solvent: O
Product: CCOC(=O)C(O)Cc1ccc(OCCn2c(CC)nc(C)cc2=O)cc1
Temperature: 25 °C
Yield: 26 %

Procedure:
A solution of 3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl]-2-hydroxypropionic acid (346 mg, 1.0 mmol) (obtained from preparation 28) in ethanol (3 ml) containing concentrated hydrochloric acid (0.1 ml) was refluxed for 10 h. The solution was cooled to room temperature, diluted with water and extracted with EtOAc (2×10 ml). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated to yield the title compound (97 mg, 26%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[C:4]([CH:16]2[CH2:18][CH2:17]2)[N:3]=1.[NH2:19][CH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22].C([O-])(O)=O.[Na+].O1CCOCC1>O>[CH:16]1([C:4]2[N:3]=[C:2]([NH:19][CH2:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[OH:22])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=3)[N:5]=2)[CH2:18][CH2:17]1
Reactant: NC[C@H](O)c1ccccc1
Reactant: Clc1cc(-c2ccc(Cl)c(Cl)c2)nc(C2CC2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O[C@@H](CNc1cc(-c2ccc(Cl)c(Cl)c2)nc(C2CC2)n1)c1ccccc1
Yield: 81.9 %

Procedure:
A mixture of 4-chloro-2-cyclopropyl-6-(3,4-dichloro-phenyl)-pyrimidine (108 mg, 0.364 mmol), (R)-(−)-2-amino-1-phenylethanol (67.2 mg, 0.490 mmol), and NaHCO3 (190.1 mg, 2.26 mmol) and 1,4-dioxane was refluxed for 48 h. The mixture was poured into water and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound as a white solid (119.4 mg, 82%). MS (ESI): mass calcd. for C21H19Cl2N3O, 399.09; m/z found, 400.1 [M+H]+. 1H NMR (CD3OD): 8.13-8.05 (m, 1H), 7.85-7.79 (m, 1H), 7.64-7.58 (m, 1H), 7.45-7.31 (m, 4H), 7.30-7.23 (m, 1H), 6.68-6.59 (m, 1H), 4.93-4.85 (m, 1H), 3.81-3.65 (m, 1H), 3.56-3.48 (m, 1H), 2.16-2.01 (m, 1H), 1.16-1.09 (m, 2H), 1.02-0.94 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH:14]([OH:16])[CH3:15])=[N:10]2)=[C:5]2[NH:17][CH:18]=[CH:19][C:4]=12.C([Mg]Br)C.N1C=CC=CC=1.Cl[C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C1COCC1>[OH:16][CH:14]([C:11]1[N:12]=[CH:13][N:9]([C:6]2[N:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]3[C:19]([C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:18][NH:17][C:5]=23)[N:10]=1)[CH3:15]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1cnc(-n2cnc(C(C)O)n2)c2[nH]ccc12
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)c1c[nH]c2c(-n3cnc(C(C)O)n3)ncc(OC)c12
Temperature: -5 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 1-(1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)ethanol (100 mg, 0.386 mmol) in THF (8 mL) was added ethylmagnesium bromide (1.736 mL, 1.736 mmol) at −40° C. After stirring at −5° C. for 1 h, pyridine (0.016 mL, 0.193 mmol) was added quickly. The mixture was cooled to −40° C. and ethyl 2-chloro-2-oxoacetate (0.176 mL, 1.543 mmol) was added. After stirring at −40° C. for 30 min, the reaction was quenched by adding i-PrOH and water. The mixture was extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine (30 mL), dried over MgSO4 and concentrated under vacuum to give crude product ethyl 2-(7-(3-(1-hydroxyethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (100 mg, 0.278 mmol, 72.2% yield). LCMS: m/z 360.1 (M+H)+, 1.53 min (method 8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)=[CH:5][CH:4]=1
Reactant: Cc1cccc(N)n1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CCNc2cccc(C)n2)cc1

Procedure:
Similarly prepared from 4-methoxyphenyl acetic acid and 2-amino-6-picoline.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].C([O:8][C:9](=O)[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:35])[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:14][CH:13]=1)C>CO.O>[OH:3][NH:2][C:9](=[O:8])/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:35])[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)C=Cc1ccc(CNC(=O)C(=Cc2ccccc2)c2ccccc2)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(/C=C/c1ccc(CNC(=O)C(=Cc2ccccc2)c2ccccc2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.2 %

Procedure:
Hydroxylamine hydrochloride (1.2 g, 17.5 mmol) in methanol (7.5 mL) was mixed with KOH (1.2 g, 17.5 mmol) in methanol (4 mL) at 0° C. and the reaction mixture was sonicated for 5 minutes. A white precipitate was formed which was filtered. The filtrate was immediately added to the ethyl-3-(4-((2,3-diphenylacrylamido)methyl)phenyl)acrylate (0.4 g, 0.9 mmol) followed by the addition of KOH. (0.14 g, 2.4 mmol) and the mixture was stirred at room temperature for 1 hour. Reaction mixture was diluted with water 20 mL and extracted with ethyl acetate, (100 mL). The organic layer was washed successively with water (3×50 mL) and brine solution (3×50 mL). The organic layer was dried over Na2SO4 and concentrated to give the crude compound, triturated with dichloromethane (20 mL), to afford the title compound as a pure colorless solid (0.040 g, 10% yield). 1H NMR (DMSO-d6) δ (ppm): 4.02-4.04 (2H, d, —CH2), 6.41-6.45 (1H, d, ═CH), 7.01-7.03 (2H, d, Ar—H), 7.17-7.22 (5H, m, Ar—H), 7.28-7.30 (2H, d, Ar—H), 7.41-7.46 (4H, m, Ar—H & ═CH), 7.46 (1H, s, ═CH), 7.50-7.52 (2H, d, Ar—H), 7.99-8.01 (1H, t, —NH), 9.03 (1H, s, —OH), 10.74 (1H, s, —NH). MS m/z: 399.1 (M++1). The following compounds were prepared according to the above procedure
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][C:17]([CH2:21][NH2:22])([CH3:20])[CH2:16]1)=[N:10][C:9]([O:23][CH3:24])=[CH:8][CH:7]=2.[O:25]=[C:26]1[CH2:31][S:30][C:29]2[CH:32]=[CH:33][C:34]([CH:36]=O)=[N:35][C:28]=2[NH:27]1>CO>[F:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][C:17]([CH2:21][NH:22][CH2:36][C:34]3[CH:33]=[CH:32][C:29]4[S:30][CH2:31][C:26](=[O:25])[NH:27][C:28]=4[N:35]=3)([CH3:20])[CH2:16]1)=[N:10][C:9]([O:23][CH3:24])=[CH:8][CH:7]=2
Reactant: COc1ccc2ncc(F)c(CCN3CCC(C)(CN)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: Cl
Solvent: CO
Product: COc1ccc2ncc(F)c(CCN3CCC(C)(CNCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 24 h
Yield: 23.5 %

Procedure:
To a solution of the HCl salt of (±)-[(1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-methyl-3-pyrrolidinyl)methyl]amine (100 mg, 0.257 mmol) in MeOH (3 mL) were added NaHCO (215 mg, 2.57 mmol) followed by 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (51 mg, 0.317 mmol). After 24 h at 25° C., NaBH (15 mg, 0.398 mmol) was added. After 1 h, the reaction was concentrated and the residue was partitioned between DCM-H O. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over MgSO, concentrated and purified via column chromatography (silica, 4% MeOH in DCM (1% NH OH)) yielding the title compound (30 mg, 24%) as a brown oil: LC/MS (ES) m/e 497 (M+H)+; 1H NMR (CDCl3, 400 MHz) δ 8.8 (bs, 1H), 8.65 (s, 1H), 8.22 (d, J=9.0 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.19 (d, J=9.0 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.12 (s, 3H), 3.83 (s, 2H), 3.51 (s, 2H), 3.46-3.50 (m, 2H), 2.9 (m, 4H), 2.5 (m, 3H), 2.3 (m, 1H), 1.85 (m, 1H), 1.55 (m, 1H), 1.1 (s, 3H).
Reaction SMILES: [C:1]([O:11][CH2:12][CH:13]=[CH2:14])(=[O:10])/[CH:2]=[CH:3]\[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5].C(OO)(=[O:17])C>>[C:4]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O:11][CH2:12][CH:13]1[O:17][CH2:14]1)=[O:10]
Reactant: C=CCOC(=O)/C=C\C(=O)OCC=C
Reactant: CC(=O)OO
Product: C=CCOC(=O)/C=C\C(=O)OCC1CO1

Procedure:
The reaction of diallyl maleate with peracetic acid is reported in J. Am. Chem. Soc. 81, page 3354 (1959). In spite of a 4-fold excess of ester, the reaction time was 11.5 hours at 50° C. Allyl glycidyl maleate was obtained in a yield of only 71%. The preparation of diglycidyl maleate is not mentioned.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([O:23][CH3:24])=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:25]([C:28]2[CH:33]=[C:32]([F:34])[C:31](F)=[C:30]([F:36])[CH:29]=2)(=[O:27])=[O:26])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[CH3:37][O-:38].[Na+]>CS(C)=O>[F:34][C:32]1[CH:33]=[C:28]([S:25]([N:17]2[CH2:16][CH2:15][C:14]3[C@:19]([C:21]([O:23][CH3:24])=[O:22])([CH2:20][C:11]4[CH:10]=[N:9][N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[C:12]=4[CH:13]=3)[CH2:18]2)(=[O:27])=[O:26])[CH:29]=[C:30]([F:36])[C:31]=1[O:38][CH3:37]
Reactant: C[O-]
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cc(F)c(F)c(F)c1)C2
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cc(F)c(OC)c(F)c1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of (R)-methyl 1-(4-fluorophenyl)-6-((3,4,5-trifluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (150 mg, 0.288 mmol) in dimethyl sulphoxide (4 mL) was added sodium methoxide (25% in methanol) (65.8 μl, 0.288 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour, then allowed to stand at room temperature overnight. The crude product was purified by column chromatography on silica gel (gradient: 0-50% ethyl acetate in isohexane) to afford (R)-methyl 6-((3,5-difluoro-4-methoxyphenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (150 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.51 min, m+H=534.2.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([O:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:7]([NH:9]C(=O)C)[CH:8]=1.[OH-].[Na+]>C(O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([O:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:7]([CH:8]=1)[NH2:9]
Reactant: CC(=O)Nc1cc(Br)ccc1OC1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(Br)ccc1OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.7 %

Procedure:
Concentrated hydrochloric acid (5.8 ml) was added to an ethanol solution (100 ml) of N-(5-bromo-2-cyclopentyloxyphenyl)acetamide (3.4 g, 11.4 mmol), and the resulting mixture was stirred for 3 hours while heating under reflux. After the reaction mixture was cooled to room temperature, a 5N sodium hydroxide solution (14.2 ml) was added to obtain a pH of 11. The resulting mixture was then extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The purified product was concentrated under reduced pressure to thereby obtain 2.97 g of oily pale yellow 5-bromo-2-cyclopentyloxyaniline (yield: 100%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:23][CH3:24])=[CH:5][C:6]([O:21][CH3:22])=[C:7]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18](=[O:20])[CH3:19])[CH:8]=1)=[O:2].CN(C=O)C.O>[Pd](Cl)Cl.CCOC(C)=O>[C:18]([N:17]1[C:12]2[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[C:9]1[C:7]1[C:6]([O:21][CH3:22])=[CH:5][C:4]([O:23][CH3:24])=[C:3]([CH:8]=1)[CH:1]=[O:2])(=[O:20])[CH3:19]
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1NC(C)=O
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(-c2cc3ccccc3n2C(C)=O)cc1C=O
Temperature: 80 °C
Yield: 40.6 %

Procedure:
N-[2-(5-Formyl-2,4-dimethoxy-phenyl ethynyl)phenyl]acetamide (Ex-57E, 535 mg, 1.6 mmol) was added to 150 mL of DMF (nitrogen purged) at room temperature and the resulting solution was heated to 80° C. Palladium(II) chloride (22 mg) was added in one portion. After 6 h the reaction mixture was poured into water (50 mL) and EtOAc (50 mL), and the layers were cut. The organic layer was filtered through Celite, washed with brine, and concentrated to an orange solid. The crude was purified by silica gel chromatography (25% ethyl acetate/hexane) to yield 210 mg (39%) of 5-(1-acetyl-1H-indol-2-yl)-2,4-dimethoxybenzaldehyde as a white solid. 1H-NMR (300 MHz, DMSO-d6) 10.22 (s, 1H), 8.13 (d, 1H, J=8.1 Hz), 7.71 (s, 1H), 7.55 (d, 1H, J=6.3 Hz), 7.25 (m, 2H, J=6.9 Hz), 6.84 (s, 1H), 6.64 (s, 1H), 4.01 (s, 3H), 3.87 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:43]=[CH:44][C:45]=1[OH:46])[O:7][CH2:8][CH2:9][N:10](CC1C=CC=CC=1)[CH2:11][CH:12]([C:14]1[CH:19]=[C:18]([O:20]CC2C=CC=CC=2)[CH:17]=[C:16]([O:28]CC2C=CC=CC=2)[CH:15]=1)[OH:13])(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([CH:43]=[CH:44][C:45]=1[OH:46])[O:7][CH2:8][CH2:9][NH:10][CH2:11][CH:12]([OH:13])[C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([OH:28])[CH:15]=1)(=[O:3])[NH2:2]
Reactant: [H][H]
Reactant: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)ccc1O
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cc(OCCNCC(O)c2cc(O)cc(O)c2)ccc1O

Procedure:
A solution of 31 g of crude N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-N-[2-(3,5-dibenzyloxyphenyl)-2-hydroxy-ethyl]-benzylamine in 300 ml of methanol is hydrogenated under normal conditions over 6 g of palladium-on-charcoal catalyst (5%) until 3 mol equivalents of hydrogen have been taken up. The catalyst is filtered off, the filtrate is evaporated and the residue is dissolved in 200 ml of isopropanol. Filtering through silica gel and evaporating the filtrate yields α-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]aminomethyl]-3,5-dihydroxy-benzyl alcohol in the form of a brownish foam. After recrystallisation from ethylacetate/methanol the compound is obtained in pure state with a melting point of 203°-205°, and contains 1/4 mol of crystal-water. The compound is characterised by the following signals in the proton nuclear magnetic resonance spectrum in hexadeuterodimethylsulfoxide as the solvent:
Reaction SMILES: C([O:4][C:5](=[O:40])[C:6]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:16][CH:15]=2)=[CH:10][C:9]([O:35][CH2:36][CH2:37][CH3:38])=[CH:8][C:7]=1[CH3:39])C=C.C1([SiH3])C=CC=CC=1>C(Cl)Cl>[CH3:39][C:7]1[CH:8]=[C:9]([O:35][CH2:36][CH2:37][CH3:38])[CH:10]=[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:16][CH:15]=2)[C:6]=1[C:5]([OH:40])=[O:4]
Reactant: C=CCOC(=O)c1c(C)cc(OCCC)cc1OCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: CCCOc1cc(C)c(C(=O)O)c(OCc2ccc(OCCc3nc(-c4ccccc4)oc3C)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of the title D compound, 2-methyl-6-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-4-propoxy-benzoic acid allyl ester (620 mg, 1.16 mmol), tetrakis-(triphenyl-phosphine)palladium(0) (27 mg, 0.02 equivalents), and phenyl silane (252 mg, 2.33 mmol) in DCM (15 mL) is stirred at RT for 4 h. The mixture is concentrated under vacuum, and the residue is chromatographed on silica gel using a solvent mixture consisting of 0.5% formic acid and 20% ethyl acetate in hexane as the eluent to afford 2-methyl-6-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-4-propoxy-benzoic acid as a white foam: m.p. 50-52° C.