Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH3:21])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:22][CH2:23][C:24]([OH:26])=O)=[CH:5][C:4]=2[N:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[S:48]1[CH2:52][CH2:51][NH:50][CH2:49]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH3:21])[N:14]([CH2:15][C:16]([CH3:17])([OH:19])[CH3:18])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:22][CH2:23][C:24](=[O:26])[N:50]3[CH2:51][CH2:52][S:48][CH2:49]3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCc1nc2c(N)nc3cc(CCC(=O)O)ccc3c2n1CC(C)(C)O
Reactant: C1CSCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: CCc1nc2c(N)nc3cc(CCC(=O)N4CCSC4)ccc3c2n1CC(C)(C)O
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
A round bottom flask, equipped with a stir bar, was charged with 3-[4-amino-2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoic acid (500 mg, 1.40 mmol), anhydrous pyridine (50 mL) and 1-hydroxybenzotriazole (379 mg, 2.80 mmol). After 30 minutes of stirring 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (537 mg, 2.80 mmol) was added to the reaction mixture in two portions. After 15 minutes, thiazolidine (250 mg, 2.80 mmol) was added in one portion. The pale yellow solution was stirred for 18 hours and then concentrated under reduced pressure. The resulting foam was dissolved in dichloromethane and washed with 1% aqueous sodium carbonate (2×15 mL). The combined aqueous fractions were extracted with chloroform (3×30 mL). The combined organic fractions were purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-25% gradient of CMA in chloroform) followed by recrystallization from acetonitrile to provide 516 mg of 1-{4-amino-2-ethyl-7-[3-oxo-3-(1,3-thiazolidin-3-yl)propyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as a white solid, mp 210-212° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:10]2)=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1.[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[N:10]2[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: CC(C)c1cc(I)ccc1N=C1NC2(CCCC2)CS1
Reactant: BrC1CCCC1
Product: CC(C)c1cc(I)ccc1N=C1SCC2(CCCC2)N1C1CCCC1

Procedure:
4-Iodo-2-isopropylaniline was converted to 4-iodo-2-isopropylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 4-iodo-2-isopropylphenyl isothiocyanate according to Method C2a to give 2-(4-iodo-2-isopropylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-iodo-2-isopropylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 2-(4-cyano-2-isopropylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: Br[C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]1(OB(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)C.Cl>O>[C:12]1([C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)Oc1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 89.2 %

Procedure:
In 400 ml of water, 21.7 g of 5-bromosalicylic acid, 13.41 g of phenylboric acid and 15.28 g of potassium carbonate were dissolved. The solution was stirred at room temperature for 40 minutes. After the completion of the reaction was confirmed with TLC, the reaction liquid was poured into a mixed medium of diluted hydrochloric acidethyl acetate. The mixture was extracted, and the organic phase was collected and washed with saturated sodium chloride aqueous solution. After dried with magnesium sulfate, the liquid was concentrated to form a crude product. The product was recrystallized from acetonitrile to obtain 18.58 g of 5-phenylsalicylic acid in the form of colorless crystallites. The yield was 87%. The product was confirmed with NMR and mass spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15](F)[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[C:17]([CH:18]=1)[O:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccccc1Oc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
Methyl 2-hydroxybenzoate (2.75 mL, 21.3 mmol) and 4-chloro-2-fluoro-1-nitrobenzene (1.85 g, 10.6 mmol) were dissolved in acetonitrile (25.0 mL). The cesium carbonate (6.94 g, 21.3 mmol) was added and the reaction mixture was stirred at 80° C. for 24 hours. The mixture was cooled down to room temperature then poor into ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography (10-30% ethyl acetate in hexanes) to afford title compound 419 (2.55 g, 78%). MS (m/z): 308.2 (M+H). 1H NMR (DMSO-d6) δ (ppm): 8.14 (d, J=8.8 Hz, 1H), 7.98 (dd, J=7.8, 1.6 Hz, 1H), 7.74 (ddd, J=8.1, 7.4, 1.8 Hz, 1H), 7.47 (td, J=7.6, 1.2 Hz, 1H), 7.39 (dd, J=8.8, 2.2 Hz, 1H), 7.36 (dd, J=8.3, 1.1 Hz, 1H), 6.88 (d, J=2.0 Hz, 1H), 3.69 (s, 3H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][CH:3]=1.[CH2:19]([C:21]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24])[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([C:21]1[C:22]([CH:23]=[O:24])=[CH:25][CH:26]=[CH:27][C:28]=1[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][CH:3]=1)[CH3:20]
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 120 °C
Yield: 85.9 %

Procedure:
To a solution of 5-(5-bromo-1,3-thiazol-2-yl)-2-[(1-methylethyl)oxy]benzonitrile (D65) (500 mg), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (443 mg) and tripotassium phosphate (657 mg) in N,N-dimethylformamide (DMF) (12 mL) and water (2 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (179 mg) in one charge. The reaction vessel was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (250 mL) and saturated brine (50 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 5-[5-(2-ethyl-3-formylphenyl)-1,3-thiazol-2-yl]-2-[(1-methylethyl)oxy]benzonitrile (D73) (500 mg) as a brown oil. MS (ES): C22H20N2O2S requires 376. found 377.1 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH:18]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:17][CH2:16]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[OH-:27].[Na+]>C(O)C>[NH2:2][C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][CH:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][CH2:20]2)(=[O:10])=[O:11])=[CH:5][CH:4]=1)=[O:27]
Reactant: CCOC(=O)CC1CCC(CCNS(=O)(=O)c2ccc(C#N)cc2)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc(S(=O)(=O)NCCC2CCC(CC(=O)O)CC2)cc1
Yield: 72 %

Procedure:
by saponification of the ethyl 4-[2-(4-cyanobenzenesulphonylamino)-ethyl]-cyclohexylacetate with 2N sodium hydroxide solution in ethanol analogously to Example 2c). Yield 72% of theory; m.p. 172°-174° C. after recrystallisation from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[N:36]1[C:41]2[NH:42][C:43]3[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=3[NH:45][CH2:46][C:40]=2[CH:39]=[CH:38][CH:37]=1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([N:45]1[C:44]2[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=2[NH:42][C:41]2[N:36]=[CH:37][CH:38]=[CH:39][C:40]=2[CH2:46]1)=[O:6]
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: Cn1ccc(-c2ccc(C(=O)O)c(Cl)c2)n1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ccc(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under anhydrous conditions a solution of 2-chloro-4-(1-methyl-1H-pyrazol-3-yl)-benzoic acid of Step E (2.1 g, 8.88 mmol) and triethylamine (1.3 mL, 9.2 mmol) in 75 mL of dichloromethane was treated in one portion with 2,4,6-trichlorobenzoyl chloride (1.48 mL, 9.2 mmol) and stirred at ambient temperature for 2 hours. To the solution was added the 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (1.74 g, 8.9 mmol) followed by 4-dimethylaminopyridine (1.1 g, 8.9 mmol) and stirring was continued for 18 hours. The reaction mixture was washed sequentially with saturated sodium bicarbonate and brine. After drying over sodium sulfate, the solution was concentrated to small volume and absorbed onto silica Merck-60. Elution with ethyl acetate-hexane (gradient from 4:3 to 2:1) gave the pure title compound as a syrup which crystallized from diethylether. The white solid (0.78 g) melted at 196-197° C.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[C:4]([CH3:16])[CH:3]=1.[I:17]I.N(OCCC(C)C)=O>C1(C)C=CC=CC=1>[I:17][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: II
Reactant: COc1cccc(-c2ccc(N)cc2C)c1
Agent: CC(C)CCON=O
Solvent: Cc1ccccc1
Product: COc1cccc(-c2ccc(I)cc2C)c1
Temperature: 90 °C
Yield: 74.2 %

Procedure:
A stirred solution of 4-amino-1-(3-methoxyphenyl)-2-methylbenzene (5.0 gm 23.4 mmol) and iodine (2.97 gm, 25.8 mmol) in toluene (120 mL) was heated to 50° C. and a solution of iso-amyl nitrite (3.46 mL, 25.8 mmol) in toluene (50 mL) was added. The mixture was heated at 90° C. for 2 h and cooled. The toluene was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with excess 5% aqueous sodium metabisulphite to remove iodine. The organic solution was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by repeated flash chromatography (first column gradient elution with hexane:ethyl acetate starting with neat hexane; second column eluted with hexane) to give 4-iodo-1-(3-methoxyphenyl)-2-methylbenzene as a pale orange oil (5.63 gm, 74%).
Reaction SMILES: CS[C:3](=[N:12][CH2:13][Si](C)(C)C)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([Cl:11])[CH:5]=1.[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27](F)(F)F)=[CH2:26])[CH:22]=[C:21]([Cl:31])[CH:20]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]2[CH2:27][C:25]([C:23]3[CH:22]=[C:21]([Cl:31])[CH:20]=[C:19]([Cl:18])[CH:24]=3)([CH3:26])[CH2:13][N:12]=2)=[CH:5][C:6]=1[Cl:11]
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(Br)c(Cl)c1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2cc(Cl)cc(Cl)c2)CN=C(c2ccc(Br)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 114.8 %

Procedure:
To a solution of 4-bromo-3-chloro-N-trimethylsilanylmethyl-thiobenzimidic acid methyl ester (Example I14) (1.83 g) and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (see WO 2007125984) (1.38 g) in THF (25 ml) was added at −5° C. tetrabutylammonium fluoride trihydrate (TBAF) (0.41 g) dissolved in THF (15 ml). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture concentrated and the residue was purified by chromatography on silica gel (eluent: ethyl acetate/heptanes 1:6) to give 5-(4-bromo-3-chloro-phenyl)-3-(3,5-dichloro-phenyl)-3-methyl-3,4-dihydro-2H-pyrrole (2.50 g). 1H-NMR (400 MHz, CDCl3): 7.95-7.25 (m, 6H), 4.88 (d, 1H), 4.42 (d, 1H), 3.75 (d, 1H), 3.40 (d, 1H) ppm.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1.ClN1C(=O)CCC1=O.[Cl:30][C:31]1[C:32]([CH:38]=[CH2:39])=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])O.[K+]>C(OCC)(=O)C.O>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[C:32]=1[CH:38]1[O:1][N:2]=[C:3]([C:4]2[N:5]=[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[S:7][CH:8]=2)[CH2:39]1
Reactant: C=Cc1c(O)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4c(O)cccc4Cl)C3)cs2)CC1

Procedure:
To a solution of tert-butyl 4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (400 mg) in ethyl acetate (10 ml) was added N-chlorosuccinimide (206 mg). The reaction mixture is stirred at reflux for 30 min. To the reaction mixture were added 3-chloro-2-vinylphenol (397 mg) and potassium hydrogencarbonate (257 mg) at room temperature, and then one drop of water. After stirring at room temperature overnight, the reaction mixture was admixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave tert-butyl 4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (345 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH2:26][CH2:27][N:28]=4)=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[O-2].[Ca+2].[H][H]>[Pd].CO>[O:25]1[CH2:26][CH2:27][N:28]=[C:24]1[C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:5]3[N:4]=[N:3][CH:2]=[CH:7][CH:6]=3)[CH2:13][CH2:12]2)=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: Clc1ccc(N2CCN(CCCOc3ccc(C4=NCCO4)cc3)CC2)nn1
Agent: [Pd]
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Product: c1cnnc(N2CCN(CCCOc3ccc(C4=NCCO4)cc3)CC2)c1
Yield: 17.2 %

Procedure:
A mixture of 3.8 parts of 3-chloro-6-[4-[3-[4-(4,5-dihydro-2-oxazolyl)phenoxy]propyl]-1-piperazinyl]pyridazine, 200 parts of methanol and 2 parts of calcium oxide was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off, washed with 2-propanol and 2,2'-oxybispropane and dried over weekend at 60° C., yielding 0.7 parts (17.2%) of 3-[4-[3-[4-(4,5-dihydro-2 -oxazolyl)phenoxy]propyl]-1-piperazinyl]pyridazine; mp. 144.7° C. (comp. 169).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=1[N+:23]([O-])=O)([O-])=O.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:23][C:15]1[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:14]=1[O:13][C:5]1[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc(N)cc2N)c(N)c1
Yield: 24 %

Procedure:
The dinitro compound obtained from Example 7 (22.1 g, 0.035 mole) was mixed with 10% Pd/C (2.2 g) in ethyl acetate/ethanol (6/4 by volume, 88 g) solvent. Hydrogenation was carried out with 50-60 psi of hydrogen pressure at ambient temperature for about 6 hrs. After reaction, the solution was filtered to remove the metal residue and the solvent was removed in vacuo. The final diamino product was purified by distillation, 4.75 g of (24% yield) clear, viscous liquid was obtained. Bp. 120° C./0.02 mm. H1NMR (CDCl3): δ7.61 (d, J=8.0 Hz, 1H), 6.08 (d, J=2.0 Hz, 1H), 6.02 (dd, J=2 Hz, 8 Hz, 1H), 4.11 (t, J=13.5 Hz, 2H), 3.55 (s, br, 4H, --NH2); F19NMR (CDCl3): -71.3 (m, 2F), - 77.5 (m, 1F), -80.2 (m, 3F), -82.3 to -86.0 (m, 4F), -124.0 (m, 2F), -146.2 (m, 1F).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=1.Cl.[NH2:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[NH:33][C:32]2=[O:37])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[N:21][O:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:30][CH:31]3[S:35][C:34](=[O:36])[NH:33][C:32]3=[O:37])=[CH:38][CH:39]=2)[CH3:18])=[CH:13][CH:12]=1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2)c(OC)c1
Agent: Cl
Product: COc1ccc(-c2ccc(C(C)=NOCCOc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c(OC)c1
Yield: 89.8 %

Procedure:
Following a procedure similar to that described in Example 40(f), but using 256 mg of 4'-(2,4-dimethoxyphenyl)acetophenone and 382 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)], 467 mg of the title compound, melting at 186°-188° C., were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].N1C=CN=C1.[C:19]1(=[O:24])[CH2:23][CH2:22][CH:21]=[CH:20]1>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]([OH:13])[C:20]1[C:19](=[O:24])[CH2:23][CH2:22][CH:21]=1
Reactant: O=C1C=CCC1
Reactant: COC(=O)c1ccc(C=O)c(Cl)n1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C(O)C2=CCCC2=O)c(Cl)n1
Yield: 90 %

Procedure:
The clear solution of Methyl 6-chloro-5-formyl-2-pyridincarboxylate (10 mmol, 1.99 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 90% yield (2.53 g).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[O:8][CH:7]=[N:6][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(C)C=O.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[Cl:22][CH2:2][CH2:3][C:4]1[O:8][CH:7]=[N:6][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCCc1ocnc1-c1ccccc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: ClCCc1ocnc1-c1ccccc1

Procedure:
5-(2-Hydroxyethyl)-4-phenyloxazole (10.0 g) was dissolved in chloroform (100 ml) and N,N-dimethylformamide (4.4 ml) was added. Under ice-cooling and stirring, 12.6 ml of thionyl chloride was added dropwise and the mixture was refluxed for an hour. The solvent was distilled off, followed by addition of saturated aqueous sodium hydrogen carbonate and extraction with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off to give an oil (11.0 g) of 5-(2-chloroethyl)-4-phenyloxazole. This product was dissolved in methyl ethyl ketone (150 ml), followed by addition of sodium iodide (13.0 g). The mixture was refluxed under stirring for 24 hours. The resulting precipitate was filtered off and the filtrate was concentrated, followed by addition of water and extraction with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off to give an oil of 5-(2-iodoethyl)-4-phenyloxazole, yield 14.4 g (83.2%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:14]2[C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]([CH3:18])([CH3:17])[C:9]=2[CH:8]=[CH:7][C:6]=1B(O)O.Br[C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[CH:26]=[CH:27][C:28]([OH:30])=[O:29]>CCCCCCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:14]2[C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]([CH3:18])([CH3:17])[C:9]=2[CH:8]=[CH:7][C:6]=1[C:32]1[CH:31]=[C:25]([CH:26]=[CH:27][C:28]([OH:30])=[O:29])[CH:24]=[CH:23][CH:33]=1
Reactant: COCOc1c(B(O)O)ccc2c1C(C)(C)CCC2(C)C
Reactant: O=C(O)C=Cc1cccc(Br)c1
Solvent: CCCCCCC
Product: COCOc1c(-c2cccc(C=CC(=O)O)c2)ccc2c1C(C)(C)CCC2(C)C
Yield: 61.2 %

Procedure:
In a manner similar to that of Example 1(c), by reaction of 3.4 g (11.6 mmol) of 1-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalene-boronic acid with 1.32 g (5.8 mmol) of 3-bromocinnamic acid, trituration in heptane gave 1.4 g (62%) of 3-[3-(1-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)phenyl]acrylic acid in the form of a white powder having a melting point of 188°-9° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]([NH:25][C:26](=[N:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])SC)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>C(Cl)Cl>[CH2:15]([O:22][C:23]([N:25]=[C:26]([NH:29][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[NH:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][CH:3]=1)=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(NC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a solution of t-butyl 4-aminobenzoate (2.0 g, 10.3 mmol) in CH2Cl2 (20 mL) was added 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea (5.6 g, 15.5 mmol), Et3N (5.0 mL, 36 mmol), and mercuric chloride (3.37 g, 12.4 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite®, and the filtrates were concentrated in vacuo and purified by column chromatography (1:1 CH2Cl2/hexanes to 100% CH2Cl2, and then 10% EtOAc/CH2Cl2) to provide tert-butyl 4-(2,3-bis(benzyloxycarbonyl)guanidino)benzoate (3.9 g, 75%). To a pressure bottle was charged 20% palladium hydroxide on carbon (2 g) followed by a solution of t-butyl 4-(2,3bis(benzyloxycarbonyl)guanidine)benzoate (3.9 g, 7.7 mmol) in EtOAc (80 mL). The mixture was stirred under hydrogen at 50 psi at room temperature overnight. The solution was filtered through Celite® and the filtrate evaporated in vacuo to provide t-butyl guanidinobenzoate (1.8 g, 100%). To the guanidine (855 mg, 3.6 mmol) in EtOAc (50 mL) was add 2M HCl in Et2O (1.9 mL, 3.8 mM). The solution was concentrated and the precipitate was collected by filtration, washed with Et2O and dried in vacuo to yield (840 mg, 85%) of the HCl salt.