Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][CH:13]1[CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][NH:15][C:14]1=[O:22])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[CH2:1]([O:8][N:9]([CH2:12][CH:13]1[CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][N:15]([C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:40])[C:14]1=[O:22])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC1CNC(=O)C1CN(C=O)OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC1CN(C(=O)c2ccccc2)C(=O)C1CN(C=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
To a solution of (+/−)-(3RS,4SR)-N-benzyloxy-N-(4-butyl-2-oxopyrrolidin-3-yl-methyl)formamide (0.18 g, 0.59 mmol) in dry THF (3 mL) at −78° C. under argon was added dropwise lithium bis(trimethylsilyl)amide in THF (1 M, 0.71 mL). After 20 min, benzoyl chloride (0.077 mL, 0.89 mmol) was added dropwise and stirring continued for 2 h. The reaction was warmed up to 0° C., quenched with saturated aq. NH4Cl (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic solution was dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate/hexanes 1:1) to afford (+/−)-(3RS,4SR)-N-benzyloxy-N-[4-butyl-2-oxo-1-(1-phenylmethanoyl)pyrrolidin-3-yl-methyl)formamide as a white solid (0.12 g, 50%). MS(ES) m/e 409 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])=[C:9]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:8]=1)(=O)=O.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][SH:38])=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([S:38][CH2:37][C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)=[CH:8][C:9]=1[CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24]
Reactant: COc1ccc(CS)cc1
Reactant: COc1ccc(F)c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2CC(C)(C)C)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(CSc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)cc1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl trifluoromethanesulfonate (1.88 g) in toluene (22 mL) were added 4-methoxy-α-toluenethiol (748 μL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (78 mg), N-ethyldiisopropylamine (1.56 mL) and tris(dibenzylideneacetone)dipalladium(0) (123 mg) at room temperature, and the mixture was stirred at 120° C. for 20 hr. The mixture was poured into ice water at room temperature, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.68 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C:12]2[C:13]([C:27](O)=[O:28])=[N:14][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:16]=2[CH3:17])[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)[C:12]3[C:13](=[N:14][N:15]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[C:16]=3[CH3:17])[C:27]2=[O:28])[CH:3]=1
Reactant: COc1ccc(Cn2nc(C(=O)O)c(C(Nc3cc(Cl)c(=O)n(C)c3)c3ccc(Cl)cc3)c2C)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Cn2nc3c(c2C)C(c2ccc(Cl)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)(4-chlorophenyl)methyl)-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylic acid (Step 5.4). tR: 4.74 min (HPLC 1); tR; 1.04 min (LC-MS 2); ESI-MS: 509/511 [M+H]+ (LC-MS 2); Rf=0.64 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[C:10](=[CH:16][N:17]([CH3:19])[CH3:18])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].N1CC[CH2:23][CH2:22][CH2:21]1>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[C:10](=[CH:16][N:17]1[CH2:18][CH2:23][CH2:22][CH2:21][CH2:19]1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(=CN(C)C)C2=O
Product: CC(=O)Nc1ccc2c(c1)CCC(=CN1CCCCC1)C2=O

Procedure:
A mixture of 6-acetamido-2-(N,N-dimethylaminomethylidene)-1-tetralone (11 g) obtained in Example 41-1) and piperidine (100 ml) was refluxed with heating for 24 hours. After excess piperidine was distilled out under reduced pressure, the resulting residue was crystallized using tetrahydrofuran-isopropyl ether to give 6-acetamido-2-(1-piperidinylmethylidene)-1-tetralone (7 g) as a light yellow powder.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:15])[CH2:7][C:6]2[C:8]([CH3:14])=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C:16]1([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[CH3:15][C:3]1([CH2:2][N:27]2[CH2:28][CH2:29][CH:24]([NH:23][CH:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:25][CH2:26]2)[CH2:7][C:6]2[C:8]([CH3:14])=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: Cc1cc(C)c2c(c1C)OC(C)(CBr)C2
Reactant: c1ccc(C(NC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)c2c(c1C)OC(C)(CN1CCC(NC(c3ccccc3)c3ccccc3)CC1)C2
Temperature: 177 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
A suspension of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethylbenzofuran (1.0 g), N-(diphenylmethyl)-4-piperidinamine (1.5 g), and potassium carbonate (0.77 g) in N,N-dimethylacetamide (4 mL) was stirred under argon gas at 177° C. for 4 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to provide the title compound (1.5 g). Yield 97%.
Reaction SMILES: Br[CH2:2][C:3]([C@:5]1([OH:28])[CH2:22][C:21]2[C:20]([OH:23])=[C:19]3[C:10]([C:11](=[O:26])[C:12]4[C:13]([OH:25])=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:24])=[C:9]([OH:27])[C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:29]([O-:32])(=[O:31])[CH3:30].[K+].O>CC(C)=O>[C:29]([O:32][CH2:2][C:3]([C@:5]1([OH:28])[CH2:22][C:21]2[C:20]([OH:23])=[C:19]3[C:10]([C:11](=[O:26])[C:12]4[C:13]([OH:25])=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]3=[O:24])=[C:9]([OH:27])[C:8]=2[CH2:7][CH2:6]1)=[O:4])(=[O:31])[CH3:30]
Reactant: O=C1c2cccc(O)c2C(=O)c2c(O)c3c(c(O)c21)C[C@@](O)(C(=O)CBr)CC3
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCC(=O)[C@@]1(O)CCc2c(O)c3c(c(O)c2C1)C(=O)c1cccc(O)c1C3=O

Procedure:
The entire amount of 9(R)-bromoacetyl-4,6,9,11-tetrahydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione was dissolved in acetone (110 ml). Potassium acetate (270 mg) was added to the above solution and the mixture was allowed to react at room temperature for 2 hours, followed by addition of water (100 ml). The precipitated crystals were collected by filtration to give reddish orange crystals of 9(R)-acetoxyacetyl-4,6,9,11-tetrahydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione. M.P. 215°-217° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[NH:19][CH:20]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].CC1C=C(C)[N:32]([C:36](=[N:38][N+:39]([O-:41])=[O:40])N)N=1>CO>[F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[N:17]=[C:18]([CH2:21][O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:19][CH:20]=3)=[CH:14][CH:15]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:36]([NH2:32])=[N:38][N+:39]([O-:41])=[O:40]
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1F
Reactant: Cc1cc(C)n(C(N)=N[N+](=O)[O-])n1
Solvent: CO
Product: NC(=N[N+](=O)[O-])Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1F

Procedure:
In a sealed glass tube suitable for microwave heating, 2-fluoro-4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (0.6 g, 1.6 mmol) and 3,5-dimethyl-N′-nitro-1H-pyrazole-1-carboximidamide (0.296 g, 1.6 mmol) in 5 ml of methanol are heated at 150° C. in a microwave oven (Biotage, Emrys Optimiser) for 2700 seconds. The reaction medium is evaporated to dryness. After passing the residue obtained through a silica column (eluent dichloromethane/ethanol 98/2), a solid is obtained in the form of white powder.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([CH:18]2[CH2:22][CH2:21][CH2:20][N:19]2C(OC(C)(C)C)=O)=[O:17])=[CH:11][CH:10]=1>O1CCOCC1>[ClH:1].[O:2]=[C:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([CH:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)=[O:17])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(N2CCOCC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)C1CCCN1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.2 40 ml of 4N hydrochloric acid in dioxane are added to a solution of 1.4 g (3.60 mmol) of tert-butyl 2-[4-(3-oxomorpholin-4-yl)phenyl-carbamoyl]pyrrolidine-1-carboxylate in 20 ml of dioxane, and the mixture is stirred at room temperature for 12 hours. The precipitate is subsequently filtered off with suction and washed successively with 10 ml of dioxane and 10 ml of diethyl ether and dried under reduced pressure, giving 1.1 g of N-[4-(3-oxomorpholin-4-yl)phenyl]pyrrolidine-2-carboxamide hydrochloride as a white powder; ESI 290.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27]>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2([OH:27])[C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1ccc(N2CCOCC2)cc1Br
Product: COc1ccc(N2CCOCC2)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 77.3 %

Procedure:
With 2.00 g of the compound obtained in Step 191-1 and 953 mg of 5-chloroisatin as starting materials, 1.52 g of the title compound (pale yellow amorphous) was obtained by a similar method to Step 21-1.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].CN([CH:11]=[C:12]([C:18](=O)[CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>C(O)C.CCOCC>[C:2]([N:6]1[C:18]([CH3:19])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=[N:7]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cnn(C(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
In ethanol (10 mL) was placed the tert-butylhydrazine hydrochloride (1.35 g, 10.8 mmol) and ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (2.00 g, 10.8 mmol). The mixture warmed to reflux and stirred for 2 hrs, then cooled to RT and stirred overnight. The mixture was evaporated at reduced pressure to give an oil which was dissolved in ether (25 mL) and washed successively with water (25 mL), saturated sodium bicarbonate (25 mL) and brine (25 mL), dried (Na2SO4), evaporated at reduced pressure and purified by chromatography (S1-25 column, ethyl acetate/hexanes) to give ethyl 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylate (1.48 g, 65% yield) as an oil. MS (ESI) m/z: 211.0 (M+H+).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([NH:9][C:10]([NH:21][CH3:22])=[N:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)#[N:8]>O>[C:7]([NH:9][C:10]([NH:21][CH3:22])=[N:11][CH2:12][CH2:13][S:14]([CH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)=[O:2])#[N:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CNC(=NCCSCc1nccs1)NC#N
Agent: [Na+]
Solvent: O
Product: CNC(=NCCS(=O)Cc1nccs1)NC#N
Reaction time: 1 h
Yield: 114.2 %

Procedure:
Sodium metaperiodate (220 mg, 1.03 m.mol) was added to a stirred solution of N-cyano-N'-methyl-N"-[2-((2-thiazolyl)methylthio)ethyl] guanidine (225 mg, 1.0 m.mol) in water (90 ml). After 1 hour at 25° then 17 hours at 5° t.l.c. indicated the reaction was essentially complete. The solution was evaporated under reduced pressure at 60° to dryness, with azeotroping with n-propanol (2x). The residue was boiled with isopropanol (20 ml) for 3 minutes, filtered hot from 205 mg of inorganic salts, (100%), and evaporated under reduced pressure to a clear glass which was stirred continuously for 4 days under ether to give crude product (273 mg, 100%) m.p. 110° (softens only). Purification was effected by dissolution in acetonitrite (15 ml) and dilution of the filtered warm solution with ether to 220 ml. After 17 hours standing the precipitate had crystallized yielding, after filtration and washing with ether, N-cyano-N' -methyl-N"-[2-((2-thiazolyl)methylsulphinyl)ethyl]guanidine, (335 mg), m.p. 112°-113°C. Found: C, 39.62; H, 5.03; N, 25.64%. C9H13N5OS2 requires: C, 39.83; H, 4.83; N, 25.81%.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26](=[O:29])[CH2:27][CH3:28].C(N(C(C)C)CC)(C)C>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH:10]=1
Reactant: CCC(=O)Nc1ccc(Cl)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCC(=O)Nc1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 6.2 %

Procedure:
(Step 3) A solution of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.88 g), N-[2-(aminomethyl)-4-chlorophenyl]propanamide hydrochloride obtained in Step 2 (1.99 g) and diisopropylethylamine (4.1 ml) in ethanol (15 ml) was stirred overnight at 70° C. The reaction solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate and 1N sodium hydroxide, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was further purified by HPLC. The obtained residue was extracted with ethyl acetate and saturated sodium hydrogen carbonate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was dissolved in ethanol, and 4N hydrogen chloride-ethyl acetate solution was added. The precipitated crystals were collected by filtration, and recrystallized from ethanol and ethyl acetate to give the title compound (100 mg).
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH:12]2[CH2:17][CH2:16][CH2:15][S:14][CH2:13]2)[CH2:7][C:6]1=[O:18])(=O)[CH2:2][CH3:3].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][CH2:28][O:29][NH2:30])=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]=[CH:27][CH2:28][O:29][N:30]=[C:1]([C:5]2[C:10](=[O:11])[CH2:9][CH:8]([CH:12]3[CH2:17][CH2:16][CH2:15][S:14][CH2:13]3)[CH2:7][C:6]=2[OH:18])[CH2:2][CH3:3])=[CH:24][CH:25]=1
Reactant: CCC(=O)C1C(=O)CC(C2CCCSC2)CC1=O
Reactant: NOCC=Cc1ccc(Br)cc1
Product: CCC(=NOCC=Cc1ccc(Br)cc1)C1=C(O)CC(C2CCCSC2)CC1=O
Yield: 68.4 %

Procedure:
3.0 g (0.011 mol) of 2-propionyl-5-(3-tetrahydrothiopyranyl)-cyclohexane-1,3-dione and 3.0 g (0.013 mol) of 3-(4-bromophenyl)-prop-2-enyloxyamine in 100 ml of methanolwere stirred at 20° C. for 16 hours. The precipitated reaction product was separated off at 0° C., washed with ice-cold methanol and petroleum ether and dried. Yield: 68.4% mp.: 97°-99° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[Cl:19].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:9]2[CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[NH:10][C:8]=2[CH:7]=[CH:6][C:5]=1[Cl:19])=[O:20]
Reactant: COC(=O)c1cc(N=Cc2cccc(Br)c2)ccc1Cl
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(Cl)ccc2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred mixture solution of 5-[(3-bromo-benzylidene)-amino]-2-chloro-benzoic acid methyl ester (39.8 g, 113.2 mmol) and ytterbium(III) triflate hydrate (10.5 g, 16.9 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (10.4 mL, 113.2 mmol) and water (2.1 mL, 113.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-6-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (48 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrClNO3 (M+H)+: 425.73, observed: 405.9 & 407.9.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:17])(=[O:3])[CH3:2].[C:18](OC)(OC)([O:21][CH3:22])[CH2:19][CH3:20]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:10][CH:11]=2)[C:6](=[C:18]([O:21][CH3:22])[CH2:19][CH3:20])[C:5]1=[O:17])(=[O:3])[CH3:2]
Reactant: CCC(OC)(OC)OC
Reactant: CCC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CCC(=O)c1ccc2c(c1)C(=C(CC)OC)C(=O)N2C(C)=O

Procedure:
Prepared from 1-acetyl-5-propionyl-2-indolinone and trimethyl orthopropionate
Reaction SMILES: [CH2:1]([C:8]1O[C:10]([O:20]CC)=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH2:27][CH:26]=[CH:25][CH2:24]1>>[CH2:1]([C:8]1[C:25]2[CH2:24][O:23][CH2:27][C:26]=2[C:10]([OH:20])=[C:11]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1oc(Cc2ccccc2)nc1Cc1ccccc1
Reactant: C1=CCOC1
Product: Oc1c(Cc2ccccc2)nc(Cc2ccccc2)c2c1COC2
Yield: 37 %

Procedure:
44 g (150 millimoles) of 2,4-dibenzyl-5-ethoxyoxazole and 210 g (3 moles) of 2,5-dihydrofuran are heated for 8 hours at 180° C. Excess 2,5-dihydrofuran is distilled off and the residue is digested in ether. The undissolved constituent is recrystallized from ethanol. 17.6 g of 4,6-dibenzyl-1,3-dihydro-furo[3,4-c]pyridin-7-ol are obtained; melting point 204°-205° C.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8](=[O:24])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH:21](O)[OH:22])[O:19][CH:20]=2)[CH:14]=1.[CH3:29][Al](C)C.[NH4+].[Cl-]>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8](=[O:24])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH:21]([OH:22])[CH3:29])[O:19][CH:20]=2)[CH:14]=1
Reactant: O=C(Nc1cnn(Cc2coc(C(O)O)n2)c1)OCc1ccccc1Cl
Reactant: C[Al](C)C
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(O)c1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)co1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [1-(2-dihydroxymethyl-oxazol-4-ylmethyl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester (212 mg, 0.56 mmol) in CH2Cl2 (4.0 mL) was treated at 0° C. with trimethylaluminum (1.40 mL of a 2M solution in toluene, 2.80 mmol). The reaction mixture was then stirred at 0° C. for 1 h and at rt for 16 h. Sat. aq. NH4Cl was then added and the aq. layer was extracted with CH2Cl2 (3×10 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a pale yellow oil. TLC: rf (1:1 hept-EA)=0.28. LC-MS-conditions 02: tR=0.86 min, [M+H]+=377.17.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15]Cl)=[C:8]([O:17][CH3:18])[CH:7]=1)[CH3:2].[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])=[C:8]([O:17][CH3:18])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OCCCCl)c(OC)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(OCCCN2C(=O)c3ccccc3C2=O)c(OC)c1
Yield: 93.3 %

Procedure:
A mixture of 40.5 g (0.141 mole) of 4-(3-chloropropoxy)-3-methoxybenzeneacetic acid ethyl ester and 27.2 g (0.144 mole) of potassium phthalimide (98%, Aldrich) in 300 mL of dimethylformamide was stirred and heated at reflux for 5 h, then was stirred at ambient temperature overnight. The solvent was evaporated under reduced pressure to give 52.3 g (93%) of a gummy residue which solidified upon standing. An analytical sample, mp 70°-72° C., was prepared from ethyl ether-petroleum ether (30°-60° C.) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]4[CH2:35][O:34][CH2:33]4)[CH2:28][CH2:27]3)=[CH:22][N:21]=2)[C:5]2[N:9]=[CH:8][N:7](COCC[Si](C)(C)C)[C:6]=2[CH:18]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]4[CH2:35][O:34][CH2:33]4)[CH2:28][CH2:27]3)=[CH:22][N:21]=2)[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:18]=1
Reactant: C[Si](C)(C)CCOCn1cnc2c(Nc3ccc(N4CCN(C5COC5)CC4)cn3)cc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c2nc[nH]c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.8 %

Procedure:
A mixture of 116b (720 mg, 1.4 mmol) in TFA (10 mL) was stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure and the diluted with water (10 mL). The pH of the mixture was adjusted to 7 by adding aqueous ammonia. It was then extracted with dichloromethane (3×20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 116c as a brown solid (500 mg, 93%). MS-ESI: [M+H]+ 385.1