Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:9]([O:22][CH3:23])[C:8]([Cl:24])=[C:7]([CH3:25])[C:6]=1[C:26](=[O:28])[CH3:27].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:24][C:8]1[C:7]([CH3:25])=[C:6]([C:26](=[O:28])[CH3:27])[C:5]([O:4][CH2:3][CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:9]=1[O:22][CH3:23]
Reactant: C1COCCN1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCCc1ccc(F)cc1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCOCC2)c1OCCCc1ccc(F)cc1
Yield: 26 %

Procedure:
Example 1e (83 mg, 0.18 mmol) was reacted with morpholine (3 mL) as described under General Procedure G and the crude mixture was purified by flash chromatography (silica-gel, DCM/EtOAc/MeOH 1:0:0, 9:8:2) to afford the title compound (23 mg, 26%) as light creamy oil. 1H NMR (300 MHz, CDCl3) δ 7.20-7.13 (m, 2H), 6.99-6.93 (m, 2H), 4.10-4.03 (m, 4H), 3.86 (s, 3H), 3.68 (t, J=4.4 Hz, 4H), 2.78 (t, J=7.6 Hz, 2H), 2.62 (t, J=5.5 Hz, 2H), 2.51 (s, 3H), 2.46 (t, J=4.45 Hz, 4H), 2.18 (s, 3H), 2.07-1.98 (m, 2H). MS (ES+) m/z 479.9 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Br)[CH3:2].[CH2:8]([NH2:11])[C:9]#[CH:10]>C(OCC)C>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][NH:11][CH2:8][C:9]#[CH:10])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: C#CCN
Solvent: CCOCC
Product: C#CCNCC(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a cooled solution of ethylbromoacetate (37.6 g) in diethyl ether (75 mL), was added propargylamine (25 g). The mixture was stirred for 3 hour at 0°-5° C. The reaction temperature was raised to ambient temperature, and the stirring continued for 18 hours. A solid formed. The solid was filtered and discarded. The filtrate was evaporated to dryness to give crude ethyl-N-propargylaminoacetate (30.1 g). The crude product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[N:21]1[NH:22][C:23](=[O:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]>[CH3:18][C@@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C@H:11]1[CH2:12][C@H:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([N:22]4[C:23](=[O:27])[CH:24]=[CH:25][CH:26]=[N:21]4)[CH:20]=[CH:19][C:5]=3[N:6]=2)[CH2:10]1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: O=c1cccn[nH]1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(-n4ncccc4=O)cc3s2)C1

Procedure:
The product of Example 1E (30 mg, 0.085 mmole), 3(2H)-pyridazinone (CAS # 504-30-3) (16 mg, 0.17 mmole), copper (11 mg, 0.17 mmole), and potassium carbonate (71 mg, 0.51 mmole) were mixed in degassed pyridine (1 ml) and the mixture was heated at reflux overnight. The reaction was quenched with water and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product which was purified by column chromatography (0.35% ammonium hydroxide and 3.5% methanol in dichloromethane) to give 23 mg (74% yield) of title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.15 (m, 1H) 8.05 (m, 1H) 7.92 (dd, J=3.74, 1.87 Hz, 1H) 7.69 (dd, J=8.73, 2.18 Hz, 1H) 7.20-7.32 (m, 1H) 7.08 (dd, J=9.51, 1.72 Hz, 1H) 3.86-3.99 (m, 1H) 3.58-3.70 (m, 1H) 3.15-3.27 (m, 1H) 3.01-3.13 (m, 1H) 2.74-2.87 (m, 1H) 2.28-2.71 (m, 4H) 1.90-2.03 (m, 1H) 1.79-1.90 (m, 1H) 1.66-1.78 (m, 1H) 1.44-1.65 (m, 1H) 1.16 (s, 3H) MS: (M+H)+=367.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:17]=O)=[CH:5][C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1.[Cl-].[OH:20][NH3+:21].Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH:17]=[N:21][OH:20])=[CH:5][C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1
Reactant: COc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Reactant: [NH3+]O
Agent: Cl
Agent: [Cl-]
Solvent: c1ccncc1
Product: COc1cc2c(cc1C=NO)C(C)(C)CCC2(C)C

Procedure:
5 g (20 millimoles) of (5,6,7,8-tetrahydro-3-methoxy5,5,8,8-tetramethyl-2-naphthaldehyde and 2.1 g (30 millimoles) of hydroxylammonium chloride in 32.5 ml of dry pyridine were refluxed for 2 hours. The mixture was then allowed to cool, poured onto water and acidified with concentrated hydrochloric acid, and the precipitate which had separated out was filtered off under suction and dried to give 5.1 g of (5,6,7,8-tetrahydro-3-methoxy5,5,8,8-tetramethyl-2-naphthaldoxime of melting point 182°-183° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([Br:10])[C:3]=1[NH2:4].[C:11]1(C)[C:12]([S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1.O1CCC[CH2:25]1>>[Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([Br:10])[C:3]=1[NH:4][C:21]([NH:20][S:17]([C:12]1[CH:11]=[CH:16][C:15]([CH3:25])=[CH:14][CH:13]=1)(=[O:18])=[O:19])=[O:22]
Reactant: Cc1ccccc1S(=O)(=O)N=C=O
Reactant: Nc1c(Br)cc(Br)cc1Br
Reactant: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2c(Br)cc(Br)cc2Br)cc1
Reaction time: 3 h

Procedure:
50 mmol of 2,4,6-tribromoaniline were dissolved in 20 ml of tetrahydrofuran. A solution of 50 mmol of toluenesulfonyl isocyanate in 20 ml of tetrahydrofuran was added dropwise at room temperature, and the stirred reaction mixture was subsequently kept at 40° C. for 3 hours. The precipitated crystals were filtered off under suction. After recrystallization from toluene, the product had a melting point of 230° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CCOC(C)=O.[H][H]>[Pd].CO>[OH:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: [H][H]
Reactant: COc1ccc(C=CC(=O)O)cc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(CCC(=O)O)cc1O
Yield: 99 %

Procedure:
The mixture of 3-(3-Hydroxy-4-methoxy-phenyl)-acrylic acid (3 g), 10% Pd/C (0.5 g), EtOAc (50 ml) and MeOH (50 ml) was shaken in Parr apparatus for 5 hs under 30-40 psi of hydrogen. Then the solution was passed through a celite pad and was concentrated to give 3-(3-Hydroxy-4-methoxy-phenyl)-propionic acid (3 g). LC-MS: m/e 197 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:8](=[O:14])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C.O>C(O)C>[CH:15]1([NH:21][C:2]2[C:11]([C:12]#[N:13])=[CH:10][C:9]3[C:8](=[O:14])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: N#Cc1cc2c(nc1Cl)CCCC2=O
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#Cc1cc2c(nc1NC1CCCCC1)CCCC2=O
Yield: 59.4 %

Procedure:
A solution of 2-chloro-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (0.154 g, 0.75 mmol), cyclohexylamine (0.15 g, 1.5 mmol) and triethylamine (0.115 ml, 0.083 g, 0.82 mmol) in ethyl alcohol (3 ml) was heated at reflux for 3 h. Then water (10 ml) was added and the precipitated solid was filtered off and recrystallized from ethyl alcohol to give the title compound (0.12 g, 59%).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[C:12]2[O:14][CH2:15][O:16][C:11]2=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][OH:9])=[O:5].[CH3:17]OC(OC)OC.C(O)=O>C(Cl)(Cl)Cl.C(OCC)(=O)C>[O:16]1[C:11]2[C:12](=[CH:13][C:2]3[O:1][CH:17]4[O:9][CH:8]=[CH:7][N:6]4[C:4](=[O:5])[C:3]=3[CH:10]=2)[O:14][CH2:15]1
Reactant: O=C(NCCO)c1cc2c(cc1O)OCO2
Reactant: COC(OC)OC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=C1c2cc3c(cc2OC2OC=CN12)OCO3

Procedure:
2-(2-Hydroxy-4,5-methylenedioxybenzamido)ethanol (8.9 g; 40 mmol) was suspended in 320 mL dry chloroform, to which trimethylorthoformate (32 mL, 290 mmol) and formic acid (7.8 mL, 170 mmol) were added. The suspension was heated to reflux for 2.5 hours and diluted with ethyl acetate. The diluted solution was washed with a sodium bicarbonate buffer (pH 10), followed by a saturated sodium chloride solution and finally, dried over anhydrous sodium sulfate. The solution was evaporated onto silica gel and purified by multiple flash chromatographic steps on silica gel (ethyl acetate/hexane=1:1 or diethyl ether/hexane=9:1). Subsequent isolation of intermediate byproducts and treatment with formic acid yielded a total of 4.78 g (51%; after recrystallization from methylene chloride/diethyl ether) of (R,S)-7,8-dihydro-5aH, 10H-1,3-dioxolo[4,5-g]oxazolo[2,3-b][1,3]benzoxazin-10-one with mp=152-153° C. IR (thin film): 2899, 1667, 1460, 1420, 1260, 1117, 1034, and 926 cm-1. 1HNMR (500 MHz; CDCl3): δ 7.27 (1H, s), 6.53 (1H, s), 6.18 (1H, s), 6.015 (2H, AB quartet), 4.30 (1H, td, J=7 & 1.2 Hz), 4.22-4.28 (1H, m), 4.20 (1H, ddd, J=10, 7 & 1.4 Hz), and 3.55-3.60 ppm (1H, m.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[Cl:16][C:17]1[CH:22]=[C:21]([NH:23]N)[N:20]=[CH:19][N:18]=1.C(O)(C(F)(F)F)=O.Cl.C[O-].[Na+]>O1CCOCC1.C(O)C>[ClH:16].[Cl:16][C:17]1[N:18]=[CH:19][N:20]=[C:21]([N:23]2[C:4](=[O:15])[C:5]([N:10]3[CH:14]=[CH:13][N:12]=[N:11]3)=[CH:6][NH:7]2)[CH:22]=1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Reactant: NNc1cc(Cl)ncn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1

Procedure:
10.0 g (47.7 mmol) of the compound from Example 3A and 8.3 g (57.1 mmol) of the compound from Example 7A are initially introduced into 100 ml ethanol and 1.5 ml (2.2 g, 19.0 mmol) TFA are added. The mixture is stirred under reflux for 12 h. A 4 M solution of hydrogen chloride in dioxane is then added in excess to the cooled reaction mixture, the mixture is extracted by stirring for approx. 1 h, the crystals which have precipitated out are filtered off and the residue on the filter is washed with dioxane and ethanol. The intermediate product obtained in this way is dissolved in 150 ml ethanol, 50 ml of a 25% strength methanolic sodium methylate solution are added and the mixture is stirred at RT for 2 h. The reaction mixture is then adjusted to pH 5 with 1 N hydrochloric acid and extracted by stirring at RT for a further 2 h, the solid is filtered off, the residue on the filter is washed with ethanol and the product is dried in vacuo.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>C(O)CCC>[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH:27][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]c(-c3ccc(-c4ccccc4)cc3)cc12
Reactant: Nc1cccc(Cl)c1
Solvent: CCCCO
Product: Clc1cccc(Nc2ncnc3[nH]c(-c4ccc(-c5ccccc5)cc4)cc23)c1
Reaction time: 8 h

Procedure:
A suspension of 220 mg (0.72 mmol) of 4-chloro-6-(biphen-4-yl)-7H-pyrrolo[2,3-d]-pyrimidine and 151 μl (1.44 mmol) of 3-chloro-aniline in 5 ml of butanol is heated at boiling overnight. Cooling, filtering and washing with a large amount of ethanol and, finally, hexane yield the title compound; 1H-NMR (200 MHz, DMSO-d6): 12.46 (sb, 1H), 9.6 (s, 1H), 8.40 (s, 1H), 8.28 (m, 1H), 7.98 (d, J=8, 2H), 7.8 (m, 5H), 7.52 and 7.38 (2t, J=8, each 2H), 7.30 (s, 1H), 7.08 (db, J=8, 1H); MS: (M)+ =397.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:12])[CH:6]=[C:5]2[CH:13]([CH3:17])[C:14](O)=[O:15].C[N:21](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH4+].[Cl-].CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:12])[CH:6]=[C:5]2[CH:13]([CH3:17])[C:14]([NH2:21])=[O:15]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1c(Br)cc(F)c2c1c(C(C)C(=O)O)cn2C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Br)cc(F)c2c1c(C(C)C(N)=O)cn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To the solution of 9-3 (150 mg, 0.45 mmol), HATU (260 mg, 0.68 mmol) and NH4Cl (26 mg, 0.49 mmol) in THF (10 mL) was added DIPEA (147 mg, 0.57 mmol) at 0° C. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (30 mL) and washed with brine twice. The combined organic layers were dried over anhydrous sodium sulfate. After filtration and concentration, the obtained residue was purified by flash chromatography (Silica gel, DCM:MeOH) to afford 9-4 (90 mg, 84%) as yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[CH:4][N:3]=1.[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][NH2:18]>C(O)C.C(OCC)(=O)C>[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][NH:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Reactant: CC(C)(C)CCN
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(F)cnc1NCCC(C)(C)C
Temperature: 150 °C

Procedure:
A solution of ethyl 2-chloro-5-fluoro-3-pyridinecarboxylate (0.300 g, 1.47 mmol) in ethanol (3.0 mL) was treated with (3,3-dimethylbutyl)amine (0.210 mL, 1.58 mmol). The mixture was heated to 150° C. for 0.5 h in a Biotage Initiator microwave synthesizer. The solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic portion was dried over magnesium sulfate, filtered, and concentrated in vacuo. The title compound was obtained as an amber oil (0.347 g, 88%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 6.61 (d, J=3.0 Hz, 1H), 6.30 (dd, J=8.8, 3.0 Hz, 1H), 6.24 (br. s., 1H), 2.80 (q, J=7.1 Hz, 2H), 1.88-1.99 (m, 2H), −0.02-0.09 (m, 2H), −0.14 (t, J=7.2 Hz, 3H), −0.53 (s, 9H). MS(ES+) m/e 269 [M+H]+.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C[O-].[Na+]>CO>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]2[O:18][C:2]32[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]3=[O:11])=[CH:15][CH:14]=1
Reactant: O=C1c2ccccc2CC1Br
Reactant: O=Cc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1c2ccccc2CC12OC2c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
To a stirred solution of 2-bromo indanone and 5 g. of p-chloro-benzaldehyde in 20 ml of methanol under nitrogen is added at 5° to 10°C a solution of sodium methoxide in methanol (prepared by dissolving 1.15 g. of sodium in 50 ml of methanol). After 2 hours, 3'-(p-chlorophenyl)-spiro[indan-2,2'-oxirane]-1-one precipitates and is filtered off and recrystallized from methanol.
Reaction SMILES: C([O:9][C@H:10]1[CH2:14][O:13][C@@H:12]2[C@@H:15]([O:18]C(=O)C3C=CC=CC=3)[CH2:16][O:17][C@H:11]12)(=O)C1C=CC=CC=1.[OH-].[Na+].CO>O1CCCC1>[O:13]1[CH2:14][C@H:10]([OH:9])[C@H:11]2[O:17][CH2:16][C@H:15]([OH:18])[C@@H:12]12
Reactant: O=C(O[C@H]1CO[C@H]2[C@@H]1OC[C@@H]2OC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O[C@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To (3S,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diyl dibenzoate (6.30 g, 17.8 mmol), a mix of NaOH 10%:MeOH=1:1 (60 ml) was added. After stirring at room temperature for 24 hrs, the solvent was evaporated under reduced pressure. Water (30 ml) was added and extraction with EtOAc (30 ml) was carried out. The aqueous layer (pH adjusted to 6 with H3PO4 5%) was evaporated under reduced pressure to leave a white residue. Tetrahydrofuran was added in a large amount, then the suspension was filtered and the filtrate was concentrated to give the title product as a white solid.
Reaction SMILES: B(Br)(Br)[Br:2].S(O[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[C:23]2[C:18](=[CH:19][C:20]([O:24]C)=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1([C:27]1[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=1)[CH3:26])(C)(=O)=O.O>C(Cl)Cl>[Br:2][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[C:23]2[C:18](=[CH:19][C:20]([OH:24])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH3:26]
Reactant: COc1ccc(C2(C)CCc3cc(OC)ccc3C2CCCCOS(C)(=O)=O)cc1
Reactant: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC1(c2ccc(O)cc2)CCc2cc(O)ccc2C1CCCCBr
Temperature: -60 °C

Procedure:
A molar solution of boron tribromide in methylene chloride (27.6 ml.) was added to a stirred solution of (1RS,2RS)-1,2,3,4-tetrahydro-1-(4-mesyloxybutyl)-6-methoxy-2-p-methoxyphenyl-2-methylnaphthalene (Example 1; 2.3 g.) in methylene chloride (30 ml.) which was cooled to -60° C. under an atmosphere of argon, and the mixture was allowed to warm up to laboratory temperature and then poured into iced water. The mixture was extracted with ethyl acetate and the extract was dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 9:1 v/v mixture of toluene and ethyl acetate as eluent. There were thus separately obtained the (1RS, 2RS)- and (1RS,2SR)-isomers of 1-(4-bromobutyl)-2-p-hydroxyphenyl- 2-methyl-1,2,3,4-tetrahydronaphth-6-ol.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([C:10]2[NH:14][CH:13]=[N:12][C:11]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:24][Si:25]([CH2:28][CH2:29][O:30][CH2:31]Cl)([CH3:27])[CH3:26].O>CN(C=O)C>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([S:7]([C:10]2[N:14]([CH2:31][O:30][CH2:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:13]=[N:12][C:11]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1ccc(S(=O)(=O)c2[nH]cnc2-c2ccccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)c2c(-c3ccccn3)ncn2COCC[Si](C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-[5-(toluene-4-sulfonyl)-1H-imidazol-4-yl]-pyridine (Tetrahedron Lett. 1976, 285) (1.65 g, 5.51 mmol) in dry DMF (15 mL) was added NaH (60% in mineral oil, 0.36 g, 9.0 mmol) at room temperature under N2. After 30 minutes stirring, SEM-Cl (1.21 mL, 6.83 mmol) was added through a syringe. The slurry was further stirred at room temperature for 6 hours, and then poured into cold H2O (100 mL), extracted with dichloromethane (3×50 mL). Combined dichloromethane solution was washed with H2O (2×50 mL) and brine (50 mL). Flash silica gel chromatography (hexane to 2:1 hexane/ethyl acetate) afforded the 2-[5-(Toluene-4-sulfonyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-pyridin as a syrup intermediate in the forms of 1:1 regioisomers (1.89 g, 80%). 1H NMR δ −0.09 (s, 9H), 0.75 (t, 2H, J=7), 2.38 (s, 3H), 3.30 (t, 2H, J=7), 5.40 (s, 2H), 7.22 (d, 2H, J=8), 7.4 (t, 1H, J=6), 7.65–7.95 (m, 5 H), 8.70 (d, 1H, J=4) ppm; the other regio-isomer shows chemical shift at δ −0.02 (s, 9H), 0.8 (t, 2H, J=7), 2.41 (s, 3H), 3.41(t, 2H, J=7), 5.65 (s, 2H), 7.2–7.35 (m, 7.70–7.90 (m, 5H), 8.1 (d, 1H, J=8), 8.68 (d, 1H, J=4)ppm; (ESMS calcd for (C21H27N3O3SSI): 429.2; found: 430.4 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1[O:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:6]=1[CH2:15][O:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)\[CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:19][CH:18]=1.O.Cl>O1CCCC1.CO>[CH3:4][C:5]1[O:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:6]=1[CH2:15][O:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)\[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:19][CH:18]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3cccs3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2cccs2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
Lithium hydroxide monohydrate (73.6 mg) was added to a solution of methyl E-4-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-4-phenylbutyrate (430 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (1.8 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-[5-methyl-2(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-4-phenylbutyric acid (366 mg, yield 88%) as colorless crystals. m.p. 142-143° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[O:9][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1)=[O:4].[CH2:26]([Li])CCC.CI.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][NH:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[O:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:11][C:7]=2[C:6]=1[CH3:26])=[O:4]
Reactant: [Li]CCCC
Reactant: CNC(=O)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: CNC(=O)c1ccc2c(c1C)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of 3.30 g of N-methyl-2,2-diphenyl-1,3-benzodioxole-5-carboxamide in 20 ml of tetrahydrofuran, cooled to -78° C., were added 12.5 ml of a 1.6M solution of n-butyllithium in hexane. The solution was stirred for 1 hour, the temperature being allowed to warm up to 20° C. Then, 1.37 g of methyl iodide were added, and stirring was continued for 1 hour. After the addition of 20 ml saturated ammonium chloride solution, the mixture was extracted with ethyl acetate. The organic layer was washed successively with 2N potassium hydrogensulfate solution, saturated potassium bicarbonate solution and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the solid residue was crystallized from ethanol to give 15.6 g of N, 4-dimethyl-2,2-diphenyl-1,3-benzodioxole-5-carboxamide, m.p. 178°-180° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:40])[CH2:22][N:23]([C:25]([CH:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)=[O:26])[CH3:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:14]1([CH2:13][CH2:12][CH2:11][CH:10]([NH:20][C:21](=[O:40])[CH2:22][N:23]([C:25]([CH:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]2)=[O:26])[CH3:24])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(CC(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 138 %

Procedure:
N-(N-tert-Butoxycarbonyl-piperidine-4-carbonyl)-(N-methyl)-2-aminoacetic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (67) (1.46 g; 2.66 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (15 mL) is added in a slow stream, and the solution is stirred for 2 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.65 g) as a clear oil. ESMS: MH+ 450.2