Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]([NH2:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[CH3:10][O:9][C:7](=[O:8])[CH2:6][CH:5]([NH:11][C:13](=[O:15])[CH3:14])[CH2:4][C:3]([O:2][CH3:1])=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CC(N)CC(=O)OC
Solvent: c1ccncc1
Product: COC(=O)CC(CC(=O)OC)NC(C)=O

Procedure:
21.7 Parts of 3-aminoglutaric acid dimethyl ester is acetylated with 100 parts by volume acetic anhydride in 130 parts by volume pyridine to give N-acetyl-3-aminoglutaric acid dimethyl ester which has the following structural formula ##STR17##
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:18]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[NH:20]1[CH2:23][CH2:22][C:21]1=[O:24]>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:18][N:20]3[CH2:23][CH2:22][C:21]3=[O:24])=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1
Reactant: ClCc1c(-c2ccccc2)nc2ccc(Cl)cn12
Reactant: O=C1CCN1
Agent: Cl
Product: O=C1CCN1Cc1c(-c2ccccc2)nc2ccc(Cl)cn12

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 6-chloro-3-(chloromethyl)-2-phenylimidazo[1,2-a]pyridine hydrochloride and azetidin-2-one. m/e+ 312 for C17H15ClN3O [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 8.45 (d, J=1.4 Hz, 1H), 7.72 (d, J=1.4, 3.3 Hz, 2H), 7.62 (d, J=9.5 Hz, 1H), 7.49 (m, 2H), 7.25 (dd, J=2.5, 9.5 Hz, 2H), 4.81 (t, J=4.0 Hz, 2H), 3.20 (t, J=4.0 Hz, 2H), 3.00 (t, J=4.0 Hz, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([NH2:26])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:26][C:24]2[CH:23]=[CH:22][C:21]3[O:16][CH2:17][CH2:18][O:19][C:20]=3[CH:25]=2)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Clc1nc(Cl)nc(Nc2ccccc2)n1
Reactant: Nc1ccc2c(c1)OCCO2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1nc(Nc2ccccc2)nc(Nc2ccc3c(c2)OCCO3)n1
Reaction time: 24 h
Yield: 69 %

Procedure:
To a solution of 4,6-dichloro-N-phenyl-[1,3,5]triazine-2-amine (95 mg, 0.39 mmoles) in tetrahydrofuran (2 ml) was added a solution of 1,4-benzodioxan-6-amine (64 mg, 0.42 mmoles) and triethylamine (0.07 ml, 0.50 mmoles) in tetrahydrofuran (0.5 ml). After stirring for 24 hours, the mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate (10 ml). The solution was washed with a solution composed of saturated aqueous sodium chloride solution and 1 M hydrochloric acid (1:1, 2×10 ml), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 25% ethyl acetate-hexanes to provide CT-32028 (97 mg, 69% yield). 1H NMR (d6-DMSO) δ 9.88–10.28 (m, 2 H), 7.60–7.85 (m, 2 H), 7.20–7.40 (m, 3 H), 6.96–7.10 (m, 2 H), 6.77–6.81 (m, 1 H), 4.21 (s, 4 H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:5]=[C:6]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:7]=[CH:8][CH:9]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>>[F:1][C:2]([F:16])([F:17])[O:3][C:4]1[CH:5]=[C:6]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][O:15][S:19]([CH3:18])(=[O:21])=[O:20])[CH:7]=[CH:8][CH:9]=1
Reactant: OCCCC#Cc1cccc(OC(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCCC#Cc1cccc(OC(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 1G], 5-(3-trifluoromethoxy-phenyl)-pent-4-yn-1-ol and methanesulfonyl chloride gave the title compound as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[C:6]([N+:15]([O-:17])=[O:16])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].CO[C:25](OC)([CH3:27])[CH3:26]>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:26][C:25]1([CH3:27])[O:12][CH2:11][CH:10]([NH:9][C:7]2[C:6]([N+:15]([O-:17])=[O:16])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH2:13][O:14]1
Reactant: COc1ccc([N+](=O)[O-])c(NC(CO)CO)n1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(NC2COC(C)(C)OC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
2-{[6-(Methyloxy)-3-nitro-2-pyridinyl]amino}-1,3-propanediol (53.93 g, 228.7 mmol) was stirred in 2,2-dimethoxypropane (900 ml) under argon and p-toluenesulphonic acid monohydrate (1.00 g) was added. The mixture was stirred at room temperature overnight to give a clear yellow solution. This was with diluted with DCM (1 L) and the resulting solution was treated with saturated aqueous NaHCO3 (20 ml) and solid NaHCO3 (20 g) with vigorous stirring (effervescence). The mixture was vigorously stirred for 20 minutes, then the remaining water was absorbed by addition of anhydrous Na2SO4. The mixture was filtered with suction and the solids were washed with DCM (500 ml). The combined filtrate plus washings were evaporated under reduced pressure to give a yellow solid which was stirred with petroleum ether (40-60°) over the weekend. The solid was isolated by filtration with suction, washed with petroleum ether (40-60°) and air-dried to give the title compound as a bright yellow solid (57.83 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18](=O)[CH3:19]>CC(C)=O.ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:9][CH:17]=[C:18]([CH3:19])[C:7]=2[CH:8]=1
Reactant: COc1ccc(S)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Clc1ccccc1
Product: COc1ccc2scc(C)c2c1
Yield: 26.9 %

Procedure:
A mixture of 4-methoxythiophenol (2.8 g, 20 mmol), K2CO3 (5.5 g, 40 mmol) and chloroacetone (6.6 mL, 82 mmol) in acetone (50 mL) was heated at reflux over night. The reaction mixture was filtered and the solvent was evaporated giving 5.0 g crude product. The intermediate thioether was dissolved in chlorobenzene (50 mL) and polyphosphoric acid (PPA, 0.5 g) was added (Plé et al., (1988) J. Heterocyclic Chem. 25, 1271-1272). The reaction mixture was refluxed over night. The solvent was decanted and the PPA residue was treated with CH2Cl2. The combined organic extracts were washed with water and dried before the solvents were evaporated. The crude product was purified on silica using heptane as eluent to give the title compound (0.96 g, 27% over two steps). 1H NMR (400 MHz, CDCl3) δ ppm 2.44 (d, J=1.20 Hz, 3 H) 3.93 (s, 3 H) 7.03 (ddd, J=8.78, 2.51, 0.50 Hz, 1 H) 7.11 (dq, J=1.20, 0.50 Hz, 1 H) 7.17 (d, J=2.51 Hz, 1 H) 7.73 (dd, J=8.78, 0.50 Hz, 1 H).
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH:11](C(=O)C)[C:10]1=[O:19])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C(O)C>[CH2:1]([N:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][C:10]1=[O:19])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)C1C(=O)CCN(CCc2ccccc2)C1=O
Agent: Cl
Solvent: CCO
Product: O=C1CCN(CCc2ccccc2)C(=O)C1
Yield: 86.4 %

Procedure:
1-Phenethyl-3-acetyl-2,4-dioxopiperidine (5.0 g) and 10% hydrochloric acid (30 ml) are added to ethanol (50 ml), and the mixture is refluxed for 6 hours. After distilling off the solvent, the residue is dissolved in chloroform, and the solution is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent to give 1-phenethyl-2,4-dioxopiperidine (3.62 g, 86.4%) as an oily substance.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[C:6]([C:10]1[C:11](=[O:27])[CH2:12][CH:13]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([NH2:25])[C:18]=2[CH3:26])[CH2:14][C:15]=1[OH:16])(=[O:9])[CH2:7][CH3:8].C(Cl)Cl>C(O)C>[C:6]([C:10]1[C:11](=[O:27])[CH2:12][CH:13]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([NH:25][C:4]([NH:3][CH2:1][CH3:2])=[S:5])[C:18]=2[CH3:26])[CH2:14][C:15]=1[OH:16])(=[O:9])[CH2:7][CH3:8]
Reactant: CCN=C=S
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(N)c2C)CC1=O
Solvent: ClCCl
Solvent: CCO
Product: CCNC(=S)Nc1c(C)cc(C)c(C2CC(=O)C(C(=O)CC)=C(O)C2)c1C
Reaction time: 96 h
Yield: 31 %

Procedure:
Ethylisothiocyanate (0.35 g, 3.98 mmol) was added to a solution of 2-propionyl-3-hydroxy-5-(3-amino-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (1.0 g, 3.32 mmol) in ethanol (5 ml). Stirring was continued at 20° for 4 days. Dilute acid and methylene chloride were added. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (elution with an increasing gradient of methanol in methylene chloride) to yield 2-propionyl-3-hydroxy-5-(3-ethylthioureido-2,4,6-trimethylphenyl)cyclohex-2-en-1-one as an oil (0.4 g, 33%). The compound was characterized by proton magnetic resonance spectroscopy (CDCl3, δ in ppm): 1.12 (6H,t); 2.18 (3H,s); 2.28 (3H,s); 2.39 (3H,s); 2.4-4.2 (9H,m); 5.4 (1H,brs); 6.29 (1H,s); 8.34 (1H,brs).
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:71])[C:29](=[N:55][O:56][CH2:57][C:58]3[CH:63]=[CH:62][C:61]([O:64]COCCOC)=[CH:60][CH:59]=3)[C:30]3[N:31]=[C:32]([NH:35]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:33][CH:34]=3)[C:25](=[O:72])[N:7]2[C:8]=1[C:9]([O:11]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:10].[SH:73][C:74]1[O:75][C:76]([C:79]2[CH:84]=[CH:83][C:82]([O:85]COCCOC)=[C:81]([O:92]COCCOC)[CH:80]=2)=[N:77][N:78]=1>>[NH2:35][C:32]1[S:33][CH:34]=[C:30]([C:29](=[N:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([OH:64])=[CH:60][CH:59]=2)[C:28]([NH:27][C@@H:26]2[C:25](=[O:72])[N:7]3[C:8]([C:9]([OH:11])=[O:10])=[C:3]([CH2:2][S:73][C:74]4[O:75][C:76]([C:79]5[CH:84]=[CH:83][C:82]([OH:85])=[C:81]([OH:92])[CH:80]=5)=[N:77][N:78]=4)[CH2:4][S:5][C@H:6]23)=[O:71])[N:31]=1
Reactant: COCCOCOc1ccc(-c2nnc(S)o2)cc1OCOCCOC
Reactant: COCCOCOc1ccc(CON=C(C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Product: Nc1nc(C(=NOCc2ccc(O)cc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nnc(-c5ccc(O)c(O)c5)o4)CS[C@H]23)cs1
Yield: 38 %

Procedure:
The same operation as in EXAMPLE 1 was conducted by using 2.04 g (2 mmol) of benzhydryl 3-chloromethyl-7β-{2-[4-(2-methoxyethoxymethoxy)benzyloxyimino]-2-(2-tritylaminothiazol-4-yl) acetamido}-3-cephem-4-carboxylate (syn-isomer) and 773 mg (2 mmol) of 2-mercapto-5-[3,4-di(2-methoxyethoxymethoxy) phenyl]-1,3,4-oxadiazole, whereby 530 g (yield: 38.0%) of the above identified compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([NH:14]C(OCC2C=CC=CC=2)=O)=[C:11]([OH:13])[CH:12]=1)=[O:5])[CH3:2].C1CCCCC=1.C>C(O)C>[NH2:14][C:10]1[CH:9]=[CH:8][C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][C:11]=1[OH:13]
Reactant: CCOC(=O)Nc1ccc(NC(=O)OCc2ccccc2)c(O)c1
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOC(=O)Nc1ccc(N)c(O)c1

Procedure:
0.06 mole (20 g) of 5-(ethoxycarbonylamino) -2-(benzyloxycarbonylamino)phenol in 60 ml of 96° strength ethanol to which 40 ml of cyclohexene and 4 g of palladinized charcoal (10% palladium) are added is heated to reflux for 30 minutes. After removal of the catalyst by filtration while hot, the expected product is precipitated by adding 17.5 ml of ethanolic hydrochloric acid (7M) to the cooled filtrate. After drying, analysis of the product obtained gives the following results:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[CH:6][CH:5]=1.C(I)[I:19].[N+]([O-])([O-])=O>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([I:19])[CH:5]=1
Reactant: COC(=O)c1cccc(-c2ccc(C)cn2)c1
Reactant: ICI
Agent: O=[N+]([O-])[O-]
Product: COC(=O)c1cc(I)cc(-c2ccc(C)cn2)c1

Procedure:
5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester was treated with methylene iodide and isoamy nitrate using the procedure of step 5 of preparation 6, to afford 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, MS (M+H)=353.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].Br[CH2:6][C:7]([NH:9][C:10]1[S:11][C:12]([C:20]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[C:13]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)=[O:8]>C(O)C>[CH2:2]([O:1][CH2:6][C:7]([NH:9][C:10]1[S:11][C:12]([C:20]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[C:13]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)=[O:8])[CH3:3]
Reactant: CC[O-]
Reactant: O=C(CBr)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Agent: [Na+]
Solvent: CCO
Product: CCOCC(=O)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Temperature: 60 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
Sodium ethoxide (62.0 mg, 0.900 mmol) was dissolved in ethanol (2 mL), and Compound 531 (120 mg, 0.300 mmol) was added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform:methanol=99:1) and crystallized from 2-propanol to afford the entitled Compound 532 (53.4 mg, 49%).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=1>>[C:8]1([C:6]2[N:7]=[C:3]([CH2:2][O:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:26]=3)[O:4][C:5]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: COC(=O)CCc1ccc(O)cc1
Product: COC(=O)CCc1ccc(OCc2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1

Procedure:
Reaction of 2-bromomethyl-4,5-diphenyloxazole and methyl 3-(4-hydroxyphenyl)propanoate according to the procedure of Example 17 provided the title compound, m.p. 92°-95° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2].[CH3:10][C:11]([CH3:13])=O.C(O)(=O)C.C([O-])(=O)C.[NH4+]>C(O)(C)C.[C].[Pd]>[C:1]([CH:3]([CH:11]([CH3:13])[CH3:10])[C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2]
Reactant: N#CCC(=O)NC(N)=O
Reactant: CC(C)=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(C)C(C#N)C(=O)NC(N)=O
Temperature: 80 °C

Procedure:
Cyanoacetylurea (38.7 g) was suspended in isopropanol (77.4 ml), and acetone (24.6 ml), acetic acid (3.43 ml) and ammonium acetate (2.31 g) were added. This suspension was subjected to catalytic hydrogenation in the presence of 10% palladium carbon (0.78 g, 50% wet product) under normal pressure at 30° C. for 8 hours. The reaction mixture was heated to 80° C. for 1 hour, and the catalyst was filtered off. Water (150 ml) was added to the filtrate to allow precipitation of crystals. The crystals were collected by filtration to give crystals of N-(2-cyano-3-methylbutanoyl)urea (yield 21.7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[N:13][C:14]([O:17]C)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1.I[Si](C)(C)C>C(#N)C.O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[N:13][C:14]([OH:17])=[CH:15][CH:16]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(Oc2ccc(OC)nc2)cc1
Agent: C[Si](C)(C)I
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2ccc(O)nc2)cc1
Yield: 96.8 %

Procedure:
To a solution of 4-(6-methoxy-pyridin-3-yloxy)-benzoic acid methyl ester (0.2 g, 0.8 mmol) in acetonitrile (6 ml) was added iodotrimethylsilane (0.346 g, 1.73 mmol) and the mixture was allowed to reflux for 1 h. The reaction mixture was diluted with water (8 ml) and extracted with chloroform. The extract was washed with 10% aqueous Na2S2O3 and water and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford 0.19 g (87%) of 4-(6-hydroxy-pyridin-3-yloxy)-benzoic acid methyl ester as yellowish crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([Cl:17])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:20]([OH:19])[CH:21]=3)[N:7]=2)[CH:14]=[C:13]([CH3:15])[C:12]=1[OH:16]
Reactant: Cc1cc(Nc2nc(Cl)ncc2F)cc(Cl)c1O
Reactant: Nc1cccc(O)c1
Product: Cc1cc(Nc2nc(Nc3cccc(O)c3)ncc2F)cc(Cl)c1O

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-4-pyrimidineamine with 3-hydroxyaniline gave N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: retn, time: 18.20 min.; purity: 94%; MS (m/e): 360 (M+); 1□□□ (DMSO-d6): δ 9.26 (1H, s), 9.23 (1H, s), 9.16 (1H, s), 8.89 (1H, s), 8.14 (1H, d, J=4.5 Hz), 7.66 (1H, d, J=2.1 Hz), 7.60 (1H, d, J=2.1 Hz), 7.29 (1H, d, J=8.4 Hz), 7.11 (1H, s), 7.06 (1H, t, J=8.4 Hz), 6.41 (1H, d, J=8.4 Hz), 2.30 (3H, s).
Reaction SMILES: Cl[C:2]1[N:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.[NH:25]([CH2:27][CH2:28][OH:29])[NH2:26]>N1C=CC=CC=1>[C:12]([C:10]1[CH:11]=[C:6]([C:4]2[C:3]3[C:2](=[N:24][CH:23]=[CH:22][CH:21]=3)[N:25]([CH2:27][CH2:28][OH:29])[N:26]=2)[CH:7]=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: NNCCO
Reactant: CC(C)(C)c1cc(C(=O)c2cccnc2Cl)cc(C(C)(C)C)c1O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(-c2nn(CCO)c3ncccc23)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
A solution of 45.2 g of 4-(2-chloronicotinoyl)2,6-di-tertiary butylphenol and 21 g of 2-hydrazinoethanol in 230 ml of pyridine is refluxed under stirring for 18 hours. After completion of the reaction, the pyridine is concentrated and 140 ml of ethanol and 70 ml of water are added to the residue. The mixture is warmed to dissolve and then cooled to 0° C. The precipitated crystals are collected by filtration, recrystallized from 70% dioxane and then dried to give 40 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridine, melting at 135°-137° C.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[N:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[O:9][N:10]=[C:11]([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:21]([N:14]([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:8](=[N:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[O:9][N:10]=[C:11]([CH3:13])[CH3:12])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=NOC(=NC1CCCCC1)NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N(C(=NC1CCCCC1)ON=C(C)C)C1CCCCC1
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of 1,3-dicyclohexyl-O—(N-isopropylideneamino)-isourea (Cmpd. 3) (16.7 g, 60 mmol) and 4-dimethylaminopyridine (180 mg) in pyridine (40 ml) is added acetic anhydride (8.9 ml, 90 mmol). The mixture is stirred 2 h and then evaporated under reduced pressure. The residue is diluted with hexane (150 ml), washed with water (5×20 ml), dried over MgSO4 and evaporated. The solid residue is recrystallized from hexane to afford 13.3 g of the title compound as white crystals, mp 74-78° C.
Reaction SMILES: C([N:3](CC)CC)C.ClC(OC)=O.[CH2:13]([N:20]1[C:28](=[O:29])[CH:27]2[CH:22]([C:23]3([C:31](O)=[O:32])[CH2:30][CH:26]2[CH:25]=[CH:24]3)[C:21]1=[O:34])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N>O1CCCC1>[CH2:13]([N:20]1[C:28](=[O:29])[CH:27]2[CH:22]([C:23]3([C:31]([NH2:3])=[O:32])[CH2:30][CH:26]2[CH:25]=[CH:24]3)[C:21]1=[O:34])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C2C3C=CC(C(=O)O)(C3)C2C(=O)N1Cc1ccccc1
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)C12C=CC(C1)C1C(=O)N(Cc3ccccc3)C(=O)C12
Temperature: 0 °C

Procedure:
1.1 g (11 mmol) of triethylamine and then 1.15 g (12 mmol) of methyl chloroformate are added dropwise to 3 g (10 mmol) of 4-benzyl-3,5-dioxo-4-azatricyclo[5.2.1.02,6 ]dec-8-ene-1-carboxylic acid in 20 ml of absolute tetrahydrofuran at 0° C. The mixture is stirred at 0° C. for a further hour and the solution is poured onto 20 ml of ammonia solution. The mixture is stirred at room temperature for 1 hour and extracted several times with chloroform, and the extracts are dried over MgSO4 and concentrated, whereupon the product crystallizes.
Reaction SMILES: C([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.COC(=O)[CH2:26][NH2:27]>CO.[Pd]>[CH2:13]([C@@H:12]1[NH:11][C:9](=[O:8])[CH2:26][NH:27][C:20]1=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CN
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C1CNC(=O)[C@H](Cc2ccccc2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
A solution of 23.30 g (62.91 mmol) N-Benzyloxycarbonyl-phenylalanine-glycine-methylester (obtained above) in 650 ml dry methanol was hydrogenated by adding Pd/C-catalyst and stirring the resulting mixture under H2 at r.t. for 3 h. After that, the mixture was filtered through celite and then half of the solvent was evaporated. The remaining solution was refluxed for 17 h. Filtration of the white precipitate and washing it twice with methanol yielded 10.71 g (52.45 mmol, 83.37%) 6-(S)-Benzyl-piperazine-2,5-dione as a white solid.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)CCC.C1(C)C=CC=CC=1>CCOCC.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>[C:13]([C:11]1[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=[C:2]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(Br)cc2c1OCC2(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)c1cc(-c2cccs2)cc2c1OCC2(C)C
Temperature: 25 °C
Yield: 281 %

Procedure:
A mixture of 5-bromo-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]furan (2.26 g, 8.0 mmol), 2-(tributylstannyl)thiophene (3.05 mL, 9.6 mmol), tetrakis(triphenylphosphine)palladium (0.92 g, 0.8 mmol), and 40 mL of toluene is heated under argon at reflux of 2 h. The reaction mixture is cooled to room temperature, diluted with ether, washed with 10% aqueous ammonium hydroxide solution and with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 6.44 g of a dark oil. Purification by flash column chromatography on silica gel (0.5% ethyl acetate-hexane) yields about 0.98 g (45%) of the title compound initially as a colorless oil, which solidifies upon standing; mp 61-63° C.