Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:41]1[N:42]=[C:43]([NH2:47])[S:44][C:45]=1[Cl:46])[C:19]([NH:21][CH:22]1[C:39](=[O:40])[N:24]2[C:25]([C:36]([O-:38])=[O:37])=[C:26]([CH2:29][N+:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:27][S:28][C@H:23]12)=[O:20])=[O:14])(C)(C)C.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[C:13]([CH2:15][O:16][N:17]=[C:18]([C:41]1[N:42]=[C:43]([NH2:47])[S:44][C:45]=1[Cl:46])[C:19]([NH:21][CH:22]1[C:39](=[O:40])[N:24]2[C:25]([C:36]([O-:38])=[O:37])=[C:26]([CH2:29][N+:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:27][S:28][C@H:23]12)=[O:20])([OH:14])=[O:12]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nc(N)sc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: Nc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccccc4)CS[C@H]23)c(Cl)s1
Temperature: 25 °C
Yield: 38.2 %

Procedure:
Trifluoroacetic acid (11.2 ml) was added to a solution of 7-[2-t-butoxycarbonylmethoxyimino-2-(2-amino-5-chlorothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (2.8 g) in methylene chloride (6 ml) and anisole (2.8 ml) under ice-cooling, and the mixture was stirred for an hour at ambient temperature. The reaction mixture was added to diisopropyl ether (120 ml) and precipitates were filtered. The precipitates were added to water and adjusted to pH 4.0 with 10% aqueous sodium hydroxide. The resulting solution was subjected to column chromatography on macroporus non-ionic adsorption "Diaion HP-20" and eluted with 15% aqueous solution of isopropyl alcohol. The fractions containing the object compound were collected and concentrated and lyophilized to give 7-[2-carboxymethoxyimino-2-(2-amino-5-chlorothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (0.97 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH3:10])[N:3]=1.[C:11]([NH-:17])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].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([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:10][O:9][CH2:8][C:4]1[N:3]=[C:2]([NH:17][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH:6][CH:5]=1
Reactant: COCc1cccc(Br)n1
Reactant: CC(C)(C)C([NH-])=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COCc1cccc(NC(=O)C(C)(C)C)n1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-bromo-6-methoxymethylpyridine [1.00 g; J Heterocyclic Chem., 30, 563, (1993)], pivaloyl amide (0.756 g), palladium acetate (0.112 g), cesium carbonate (2.40 g), 4.5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.434 g) and 1,4-dioxan (5 ml) were sealed in a microwave vial and heated in a microwave oven with stirring for 30 minutes at 150° C. This process was repeated with a second batch of reagents and the products combined, the insoluble material filtered from solution and the filtrate evaporated under reduced pressure. The residue was purified by chromatography (silica; hexane/ethyl acetate) to afford the desired product as a yellow oil, 1.75 g. 1H NMR (CDCl3) δ: 9.84 (1H, s), 7.82 (1H, d), 6.87 (1H, d), 4.43 (2H, s), 3.48 (3H, s).
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[SH:18].[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>C1COCC1>[F:19][C:20]([F:27])([F:26])[C:21]([C:17]1[S:13][C:14]([SH:18])=[N:15][CH:16]=1)=[O:22]
Reactant: Sc1nccs1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(c1cnc(S)s1)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
iPr2NH (1.0 g, 9.4 mmol) was dissolved in THF (12 mL) and cooled to −10° C. n-Butyllithium (2.5M, 3.8 mL, 9.4 mmol) was added dropwise, and the reaction was cooled to −78° C. Thiazole-2-thiol (1.0 g, 8.5 mmol) in THF (2.5 mL) was added, followed by ethyl trifluoroacetate (1.3 mL, 11.1 mmol), and the reaction was stirred at −78° C. for 1 hours. The reaction was warmed to −10° C. and quenched with 5% aqueous NH4Cl (10 mL). The aqueous layer was acidified and extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (50% EtOAc in hexanes) to give the desired product, 10a.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:21])[CH:7]1[CH:12]([C:13]2=[O:18])[CH2:11][C:10]([CH3:19])=[C:9]([CH3:20])[CH2:8]1)([O-])=[O:2].O.C(=O)([O-])[O-].[K+].[K+]>COCCO>[OH:2][NH:1][C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:21])[C:7]1[CH:8]=[C:9]([CH3:20])[C:10]([CH3:19])=[CH:11][C:12]=1[C:13]2=[O:18]
Reactant: CC1=C(C)CC2C(=O)c3c(cccc3[N+](=O)[O-])C(=O)C2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCO
Solvent: O
Product: Cc1cc2c(cc1C)C(=O)c1c(NO)cccc1C2=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 5.0 parts of 5-nitro-2,3-dimethyl-1,4,4a,9a-tetrahydroanthraquinone with 50 parts of water, 50 parts of methylcellosolve and 0.05 parts of potassium carbonate was stirred at 60°C for 1 hour, then cooled to 20°C and filtered to recover crystals. The crystals were washed with water and dried under reduced pressure to obtain 4.5 parts of 5-hydroxylamino-2,3-dimethylanthraquinone.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:7]=[C:8]=[S:9])=[CH:4][S:5][CH:6]=1.[F:10][C:11]1[C:12]([NH2:21])=[C:13]([NH2:20])[C:14]([F:19])=[C:15]([F:18])[C:16]=1[F:17]>>[NH2:20][C:13]1[C:14]([F:19])=[C:15]([F:18])[C:16]([F:17])=[C:11]([F:10])[C:12]=1[NH:21][C:8]([NH:7][C:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)=[S:9]
Reactant: Nc1c(N)c(F)c(F)c(F)c1F
Reactant: Cc1cscc1N=C=S
Product: Cc1cscc1NC(=S)Nc1c(N)c(F)c(F)c(F)c1F

Procedure:
is obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 3,4,5,6-tetrafluoro-1,2-diaminobenzene. Crystalline solid, m.p.: 286-290° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]([Cl:19])=[O:16])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1=CCN(c2ncccc2Cl)CC1
Solvent: c1ccccc1
Product: O=C(Cl)C1=CCN(c2ncccc2Cl)CC1

Procedure:
A solution of 1-(3-chloropyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (compound 24) (8 g, 34 mmol) and thionyl chloride (12 g, 100 mmol) in benzene was refluxed for two hours. The solvent was evaporated to give a crude product, which can be directly used for the next step.
Reaction SMILES: [CH3:1][C:2]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH:19]=[C:18]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1)[CH3:3].[OH-].[Na+]>O1CCCC1.CO>[CH3:3][C:2]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH:19]=[C:18]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:4]1[CH:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1)[CH3:1]
Reactant: COC(=O)c1ccc(C(C)(C)Oc2ccc3c(c2)C(c2ccccc2)=CC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(Oc1ccc2c(c1)C(c1ccccc1)=CC2)c1ccc(C(=O)O)cc1
Yield: 85.5 %

Procedure:
Methyl 4-(1,1-dimethyl-3-phenyl-1H-inden-5-yloxymethyl)benzoate (300 mg, 0.78 mmol) and 3.9 mL of 2N NaOH in 5 mL of tetrahydrofuran and 5 mL of methanol were stirred at room temperature for 16 hours. The mixture was concentrated and acidified with 1N HCl (10 mL), extracted with ethyl acetate (20 mL×3). The combined extracts were washed with water (10 mL), dried over magnesium sulfate, and evaporated. The residue was crystallized from ether-hexane to give 247 mg (85% yield) of the title compound as white crystals; 1H-NMR (DMSO-d6) δ1.31 (s, 6H), 5.20 (s, 2H), 6.57 (s, 1H), 6.89 (dd, J=1.1, 8.2 Hz, 1H), 7.02 (d, J=1.1 Hz, 1H), 7.36-7.57 (m, 8H), 7.95 (d, J=8.3 Hz, 2H), 12.94 (bs, 1H) ; MS m/e 371 (MH+).
Reaction SMILES: Cl[Si:2]([CH3:13])([CH3:12])[C:3]1([CH3:11])[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]1[CH3:10].[CH2:14]([NH-:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Li+]>CCOCC>[CH2:14]([NH:21][Si:2]([CH3:13])([CH3:12])[C:3]1([CH3:11])[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]1[CH3:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1=CC(C)([Si](C)(C)Cl)C(C)=C1C
Reactant: [NH-]Cc1ccccc1
Agent: [Li+]
Solvent: CCOCC
Product: CC1=CC(C)([Si](C)(C)NCc2ccccc2)C(C)=C1C
Reaction time: 8 h

Procedure:
To a solution of 1.000 g (4.651 mmol) (chloro)(dimethyl)(tetramethylcyclopentadienyl)silane in 70 mL ether was slowly added 0.526 g (4.651 mmol) lithium benzylamide. The reaction mixture was stirred overnight, then the solvent was removed, the residue was extracted with pentane and filtered. The pentane was removed under reduced pressure to give the product as a pale yellow oil. The yield was 1.234 g (93.3%). Mass spec. m/e 285 (18%). 1H NMR (C6D6) δ 7.0-7.24 (m, 5H), 3.71 (d, 2H), 2.73 (br s, 1H), 1.88 (s, 6H), 1.76 (s, 6H), 0.43 (br t, 1H), −0.07 (s, 6H). 13C NMR (C6D6) δ 144.5, 135.7, 132.0, 128.5, 127.3, 126.7, 56.7, 46.4, 14.6, 11.4, −2.3.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:24][C:25](=[O:34])[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH:21]([CH3:23])[CH3:22])[C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1.[OH-].[Li+].O>C1COCC1>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=1[C:25]([NH:24][C@@H:4]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH:21]([CH3:23])[CH3:22])[C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)=[CH:12][CH:13]=1)[C:3]([OH:35])=[O:2])=[O:34]
Reactant: COC(=O)[C@H](C/C=C/c1ccc(N(c2ncccn2)C(C)C)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(c1ccc(/C=C/C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1)c1ncccn1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 0.1 %

Procedure:
A solution of (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(isopropyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (526.2 g) in THF (15 ml) was cooled to 0° C. To the solution, 0.1N aqueous lithium hydroxide solution (15.4 ml) was added, and the resulting mixture was stirred at 0° C. for 40 minutes. Water (20 ml) was added to the reaction solution and the resulting mixture was washed with ether. Aqueous layer was acidified by adding 1N hydrochloric acid in small portions thereto, and extracted twice with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to dryness to obtain (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(isopropyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid (420.7 mg).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18][NH2:19])=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:22][C:23]([F:34])([F:33])[C:24]([F:32])([F:31])[C:25]([F:30])([F:29])[C:26](Cl)=[O:27]>N1C=CC=CC=1>[CH2:1]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18][NH:19][C:26](=[O:27])[C:25]([F:29])([F:30])[C:24]([F:31])([F:32])[C:23]([F:34])([F:33])[F:22])=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCCCOc1ccc(C(=O)NN)cc1
Solvent: c1ccncc1
Product: CCCCCCCCCCOc1ccc(C(=O)NNC(=O)C(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
46.8 g of 4-n-decyloxybenzoic acid hydrazide are dissolved in 320 ml of pyridine. 23.7 ml of heptafluorobutyric acid chloride are added dropwise at room temperature and the mixture is stirred for a further 11/2 hours. It is then poured on 1600 ml of ice/water, and the crystals are filtered off with suction and rinsed with water. Recrystallization from toluene gives 39.9 g of N-(4-n-decyloxybenzoyl)-N'-heptafluorobutyrylhydrazine of melting point 88° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[CH2:28][CH2:27][CH2:26]2.Br[CH2:35][C:36]([O:38][CH3:39])=[O:37]>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[CH:28]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:27][CH2:26]2
Reactant: COC(=O)CBr
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)CC1CCc2cc(OC)ccc2C1=O
Temperature: 25 °C

Procedure:
To a solution of LDA, prepared from diisopropylamine (0.84 ml) and n-butyl lithium (3.44 ml, 1.6M in hexane) in 10 ml of THF at -78° was added dropwise a solution of 6-methoxy-1-tetralone (0.88 g, 5.0 mmol) in 5 ml of THF in an atmosphere of nitrogen. To the stirred solution at -78° was then added methyl bromoacetate (0.5 ml, 6.0 mmole) and the mixture was allowed to warm to room temperature. Aqueous work-up and extraction with ether gave, after chromatography on silica gel, the title compound, m.p. 110`-112°.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=C)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:26].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=[O:26])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2c(c1)OCCc1sc(-c3ncnn3C(C)C)nc1-2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-vinyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.200 g, 0.591 mmol) in tetrahydrofuran (20 mL) and water (10 mL) was added osmium tetraoxide (0.0473 mmol, 4% wt in water, 0.3 ml) followed by sodium metaperiodate (0.253 g, 0.00118 mol) slowly. The mixture was stirred at room temperature for 6 hours. The reaction was quenched with saturated sodium thiosulfate, then diluted with ethyl acetate and extracted 3 times with ethyl acetate. The organic phases were combined, dried with Na2SO4 and concentrated to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde. MS(ESI+) 341.1
Reaction SMILES: Cl.[C:2]([C:6]1[CH:29]=[CH:28][C:9]2[NH:10][C:11]([C@@H:13]([NH:20]C(=O)OC(C)(C)C)[C@@H:14]([CH3:19])[C:15]([NH:17][CH3:18])=[O:16])=[N:12][C:8]=2[CH:7]=1)([CH3:5])([CH3:4])[CH3:3]>O1CCOCC1>[NH2:20][C@H:13]([C:11]1[NH:12][C:8]2[CH:7]=[C:6]([C:2]([CH3:3])([CH3:5])[CH3:4])[CH:29]=[CH:28][C:9]=2[N:10]=1)[C@@H:14]([CH3:19])[C:15]([NH:17][CH3:18])=[O:16]
Reactant: CNC(=O)[C@H](C)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)[C@H](C)[C@H](N)c1nc2ccc(C(C)(C)C)cc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
HCl in 1,4-dioxane (4M, 2 mL, 8.00 mmol) was added to a stirred solution of tert-butyl ((1S,2R)-1-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)-2-methyl-3-(methylamino)-3-oxopropyl)carbamate (50 mg, 0.13 mmol) in 1,4-dioxane (1 mL). The reaction mixture was stirred at room temperature for 4 hours before concentrating in vacuo. The residue was sonicated in diethyl ether (0.5 mL) for 30 minutes, the organic solvent was decanted and the fine precipitate dried under high vacuum to afford the title compound as the hydrochloride salt as a white solid (43.4 mg, quant).
Reaction SMILES: Br[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1(C(O)(C)C)C=CC=CC=1.[Br-].[Li+].C[Si](Cl)(C)C.C1O[C:31]2([CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]2)OC1>C(#N)C.O1CCCC1>[C:5]1([C:2]([C:31]2[CH2:32][CH2:33][C:34](=[O:37])[CH2:35][CH:36]=2)([CH3:4])[CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)(Br)c1ccccc1
Agent: CC(C)(O)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C1=CCC(=O)CC1)c1ccccc1

Procedure:
When n is the bridging group --C(CH3)2 --, an appropriately substituted or unsubstituted phenyl methyl ketone, for example, methyl (3-chlorophenyl) ketone, is prepared by the reaction of methylmagnesium bromide and an appropriate benzonitrile in tetrahydrofuran. The ketone is in turn treated with methylmagnesiun bromide in tetrahydrofuran, yielding the corresponding 2-phenylpropan-2-ol, which is then converted to the 2-bromo-2-phenylpropane by the treatment of the alcohol with lithium bromide and trimethylsilyl chloride in acetonitrile. The Grignard reagent of the 2-bromo-2-phenylpropane is then prepared and reacted with 1,4-cyclohexanedione mono-ethylene ketal in tetrahydrofuran, yielding the corresponding 1-(2-phenylpropan-2-yl)-1-cyclohexen-4-one. The so-prepared cyclohexenone is reduced with hydrogen gas in the presence of 10% palladium on charcoal, yielding the 4-(2-phenylpropan-2-yl)cyclohexanone, which is in turn reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-(2-phenylpropan-2-yl)-5,6,7,8-tetrahydroquinazoline. Example 7 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[C:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][C:3]=1[NH:16][CH2:17][CH3:18].[CH:19](O)=O>>[CH2:17]([N:16]1[C:3]2[CH:4]=[C:5]([CH:6]=[C:7]3[S:11][C:10](=[O:12])[NH:9][C:8]3=[O:13])[CH:14]=[CH:15][C:2]=2[N:1]=[CH:19]1)[CH3:18]
Reactant: CCNc1cc(C=C2SC(=O)NC2=O)ccc1N
Reactant: O=CO
Product: CCn1cnc2ccc(C=C3SC(=O)NC3=O)cc21
Temperature: 100 °C
Yield: 63 %

Procedure:
5(4-Amino-3-ethylamino-benzylidene)-thiazolidine-2,4-dione (50 mg, 0.19 mmol) (intermediate 36) was dissolved in formic acid (5 mL) and the solution stirred at 100° C. over night. Formic acid was then removed in vacuo. The crude residue was then purified by silica gel column to give the title compound (35 mg, 63%).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[NH2:9][C:10]1N(C2C=CC=C(I)C=2)[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[N:11]=1>>[NH2:9][C:10]1[N:6]([C:5]2[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=2)[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[N:11]=1
Reactant: Nc1nc2ccccc2n1-c1cccc(I)c1
Reactant: Nc1ccc(I)cc1
Product: Nc1nc2ccccc2n1-c1ccc(I)cc1

Procedure:
1-(2-Amino-1-benzimidazolyl)-4-iodobenzene (mp 212°-214° C. ) was prepared from 4-iodoaniline via 4-iodo-2'-nitrodiphenylamine (mp 174°-175° C.) and 4-iodo-2'-aminodiphenylamine (mp 127°-128° C.), in analogy with the sequence used in the preparation of 1-(2-amino-1-benzimidazolyl)-3-iodobenzene.
Reaction SMILES: [F:1][C:2]1[C:3]([N:17]=[CH:18][N:19]([CH3:21])[CH3:20])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.N1CC[CH2:24][CH2:23]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([N:17]=[CH:18][N:19]2[CH2:21][CH2:24][CH2:23][CH2:20]2)=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: CN(C)C=Nc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: C1CCNC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: Fc1ccc(COc2ncc(F)c(N=CN3CCCC3)n2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 52.4 %

Procedure:
To a solution of N′-[5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]-N,N-dimethylformamidine (0.10 g, 0.36 mmol) in toluene (2 mL) was added pyrrolidine (0.051 g, 0.72 mmol) and a catalytic amount of camphorsulfonic acid. The vented vial was placed on an orbital shaker, agitated at 90° C. for 16 h, cooled, and evaporated to dryness. Purification by reverse phase chromatography afforded the title compound (0.060 g, 53% yield) as a white solid: mp 102-103° C.; 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 8.06 (d, J=2.7 Hz, 1H), 7.49-7.42 (m, 2H), 7.09-7.01 (m, 2H), 5.32 (s, 2H), 3.73-3.62 (m, 4H), 2.07-1.96 (m, 4H); HPLC-MS (ESI) m/z 319 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]1[C:19]([Cl:20])=[C:18]([Cl:21])[C:10]2[N:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[NH:13][C:9]=2[C:8]=1[S:22](Cl)(=[O:24])=[O:23].Cl>CC(C)=O>[Cl:6][C:7]1[C:19]([Cl:20])=[C:18]([Cl:21])[C:10]2[N:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[NH:13][C:9]=2[C:8]=1[S:22]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1c(Cl)c(Cl)c(Cl)c2nc(C(F)(F)F)[nH]c12
Reactant: CCNCC
Agent: Cl
Solvent: CC(C)=O
Product: CCN(CC)S(=O)(=O)c1c(Cl)c(Cl)c(Cl)c2nc(C(F)(F)F)[nH]c12
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
Diethylamine (102 parts) was added dropwise to a suspension of the 5,6,7-trichloro-2-trifluoromethylbenzimidazole-4-sulphonyl chloride (136 parts) in acetone (400 parts) cooled in an ice bath to maintain a temperature of about 30°C. After the addition of all the diethylamine, the mixture was stirred for 15 minutes and then poured into excess ice/water. The resulting solution was acidified with concentrated hydrochloric acid to precipitate a cream solid which was filtered off, washed with water and dried to give 5,6,7-trichloro-N,N-diethyl-2-trifluoromethylbenzimidazole-4-sulphonamide (144 parts, 97% yield), melting point 155°-157°C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]2[O:9][C:10]3[C:15]([C:16]([O:18][CH2:19][C:4]=2[CH:3]=1)=[O:17])=[C:14]([O:20][CH3:21])[C:13]([C@@H:22](O)[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:12][CH:11]=3.S(Cl)([Cl:30])=O>O1CCOCC1>[Cl:30][CH:22]([C:13]1[CH:12]=[CH:11][C:10]2[O:9][C:5]3[C:6]([OH:8])=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=3[CH2:19][O:18][C:16](=[O:17])[C:15]=2[C:14]=1[O:20][CH3:21])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: COc1c([C@@H](O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(O)c1O2
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: COc1c(C(Cl)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(O)c1O2

Procedure:
200 mg (0.54 mmol) of penicillide (Ib) are heated under reflux for 5 h (exclusion of moisture) in 1 ml of dioxane and 0.38 ml (5.2 mmol) of thionyl chloride. After evaporating in vacuo, the residue is taken up in methylene chloride, and the solution is washed with aqueous bicarbonate, then with water, dried and evaporated. Chromatography on silica gel Si60 in ether/petroleum ether=2:1 yields 187 mg (93% of theory) of colorless solid.
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:40][O:41][CH2:42][C:43]1[S:44][CH:45]=[C:46]([CH2:48][N:49]2[N:53]=[C:52]([NH2:54])[CH:51]=[N:50]2)[N:47]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:41][CH2:42][C:43]1[S:44][CH:45]=[C:46]([CH2:48][N:49]2[N:53]=[C:52]([NH:54][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[CH:51]=[N:50]2)[N:47]=1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: COCc1nc(Cn2ncc(N)n2)cs1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: COCc1nc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)cs1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 5-phenyloxazole-4-carboxylic acid (42 mg, 0.21 mmol) in CH2Cl2 (3.0 mL) was treated at rt with DMAP (6.6 mg, 0.05 mmol), HOBt (36 mg, 0.26 mmol), EDC (102 mg, 0.53 mmol) and DIPEA (0.16 mL, 0.96 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((2-(methoxymethyl)thiazol-4-yl)methyl)-2H-1,2,3-triazol-4-amine (48 mg, 0.21 mmol) in CH2Cl2 (3.0 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (15.0 mL), the layers were separated and the org. phase was washed with 1N HCl (10.0 mL), water (5.0 mL), followed by brine (10.0 mL) and dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (60:40 hept-EA) gave the title compound as a white solid. TLC: rf (7:3 hept-EA)=0.15. LC-MS-conditions 07: tR=0.83 min, [M+H]+=397.23.