Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19][CH3:20])[CH:17]=2)[CH:12]=[C:11]1[C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19][CH3:20])[CH:17]=2)[CH:12]=[C:11]1[C:21](=[O:25])[CH:22]([CH3:23])[CH3:24]
Reactant: CSc1ccc2cc(C(=O)C(C)C)n(CCNC(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccc2cc(C(=O)C(C)C)n(CCN)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 143.4 %

Procedure:
To a solution of tert-butyl(2-(2-isobutyryl-6-(methylthio)-1H-indol-1-yl)ethyl)carbamate (200 mg, 0.53 mmol) in CH2Cl2 (9 mL) at 0° C. was added TFA (1 mL). The reaction mixture was stirred at rt for 1 h. The mixture was concentrated (T<25° C.), treated with water (5 mL), adjusted to pH=11 with sat. NaHCO3 and extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated to afford 1-(1-(2-aminoethyl)-6-(methylthio)-1H-indol-2-yl)-2-methylpropan-1-one (210 mg, 100% yield) as a colorless oil. LC-MS MS (ESI) m/z 258.8 [M-18+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=2[F:19])[N:12]=[C:11]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:10]=1[CH3:27].I[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=2[F:19])[N:12]=[C:11]([N:21]2[CH2:26][CH2:25][N:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:23][CH2:22]2)[C:10]=1[CH3:27]
Reactant: Ic1ccccc1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(c3ccccc3)CC2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(piperazin-1-yl)quinoline 2,2,2-trifluoroacetate (75.0 mg, 0.18 mmol) and iodobenzene (1.0 eq of triethylamine added to account for TFA salt) in toluene to give 4-chloro-5,7-difluoro-3-methyl-2-(4-phenylpiperazin-1-yl)-quinoline. Mass Spectrum (ESI) m/e=374.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH2:21]([O:14][C:13]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[CH3:1])[NH:9][C:8](=[O:12])[CH2:7][CH2:6]2)=[O:15])[CH3:22]
Reactant: Cc1cc2c(cc1C(=O)O)CCC(=O)N2
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2c(cc1C)NC(=O)CC2
Temperature: 25 °C
Yield: 70 %

Procedure:
To the compound (40.0 g, 195 mmol) obtained in step A were added ethanol (600 ml) and concentrated sulfuric acid (60 ml), and the mixture was heated under reflux for 24 hr. After cooling to room temperature, the solution was concentrated under reduced pressure. The obtained oil was diluted with water, and extracted with chloroform. The organic layer was washed with diluted aqueous sodium hydroxide solution, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained solid was recrystallized from ethanol to give the title compound (32.0 g, yield 70%) as a colorless solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]([F:24])([F:23])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:19]3[N:20]=[CH:21][CH:22]=[C:18]3[N:17]=[CH:16][CH:15]=2)[CH:9]=1.[OH-].[Na+].CN(C)[CH:29]=[O:30]>>[F:24][C:7]([F:23])([F:6])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:19]3[N:20]=[CH:21][C:22]([CH:29]=[O:30])=[C:18]3[N:17]=[CH:16][CH:15]=2)[CH:9]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Temperature: 0 °C

Procedure:
Seventy-five milliliters of dried dimethylformamide is cooled in an ice bath and 25 ml. of phosphorus oxychloride is added dropwise with swirling. To this ice cold mixture is added 19.5 g. of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine in one portion and the reaction mixture is then heated on a steam bath for 1.5 hours. The mixture is poured onto ice and made basic (pH 10) with 10 N NaOH. The precipitated solid is removed by filtration and recrystallized from methylene chloride-hexane to give the product, m.p. 196° 198° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18](C)[C:19](=O)C(F)(F)F)[C@H:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)C(F)(F)F)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
To a mixed solution of the compound (0.66 g) obtained in step 4 in methanol (6.5 mL) and water (1.3 mL) was added potassium carbonate (0.35 g) at room temperature, and the mixture was stirred at 50° C. for 24 hr. Furthermore, potassium carbonate (1.70 g) was added, and the mixture was stirred at 50° C. for 6 days. The organic solvent was evaporated under reduced pressure, and the residue was poured into saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 0→9% methanol/ethyl acetate) to give the title compound (0.30 g, 58%) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]2[C:13]([CH3:23])=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[N:15]=[C:6]12.Br[CH2:30][CH:31]1[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([F:1])[C:3]=1[CH2:4][N:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]2[C:13]([CH3:23])=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[CH:20][CH:21]=3)[N:15]=[C:6]12
Reactant: Cc1c(-c2ccc(O)cc2)nc2n(Cc3c(F)cccc3F)cc(Br)c(=O)n12
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(OCC3CC3)cc2)nc2n(Cc3c(F)cccc3F)cc(Br)c(=O)n12
Temperature: 60 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
To a solution of the compound obtained in Example 23 (0.25 g, 0.56 mmol) in DMF (30 ml) is added (bromomethyl)cyclopropane (0.114 g, 0.84 mmol), K2CO3 (0.116 g, 0.84 rmnol) and KI (0.047 g, 0.28 mmol). The residual reaction mixture is stirred at 60° C. for 4 hours. To this mixture is added (bromomethyl)cyclopropane (0.14 g, 1.0 mmol). It is stirred at this temperature for 21 hours and is evaporated under reduced pressure to afford the residue, which is partitioned between chloroform (100 ml) and aqueous saturated NaHCO3 solution (30 ml). The aqueous layer is extracted with chloroform (30 ml). The combined organic extract is dried over Na2SO4 and concentrated under reduced pressure to give the residue, which is chromatographed on silica gel to afford white crystals (0.23 g, 82%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[F:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][N:22]2[C:26]([CH3:27])=[CH:25][C:24]([NH2:28])=[N:23]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][N:22]2[C:26]([CH3:27])=[CH:25][C:24]([NH:28][C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]4)=[C:4]([O:14][CH3:15])[CH:3]=3)=[N:23]2)=[CH:19][CH:18]=1
Reactant: Cc1cc(N)nn1Cc1ccc(F)cc1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cc(C)n(Cc3ccc(F)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 43 starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole and 1-(4-fluoro-benzyl)-5-methyl-1H-pyrazol-3-ylamine. The title compound was obtained as a light yellow oil (Yield=41%). MS ISP (m/e): 392.2 (100) [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:24]C)[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:24])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1
Reactant: COCCOc1nc(N)c2nc(OC)n(Cc3ccc(F)cc3)c2n1
Agent: Cl
Product: COCCOc1nc(N)c2nc(O)n(Cc3ccc(F)cc3)c2n1
Yield: 77.1 %

Procedure:
6-Amino-9-(4-fluorobenzyl)-8-methoxy-2-(2-methoxyethoxy)purine (49 mg, 0.14 mmol) in concentrated hydrochloric acid (20 ml) was stirred for 12 hours. The reaction mixture was evaporated in vacuo to dryness and then 28% aqueous ammonia was added thereto. The resulting crystals were filtered to give the subject compound (36 mg, yield 77%).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)=[O:15])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:28][OH:29].C(N(CC)CC)C>C(O)C>[OH:29][NH:28][C:1](=[NH:2])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:20][CH2:21]3)=[O:15])[CH2:10][CH2:9]2)=[CH:25][CH:26]=1
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C#N)cc3)CC2)CC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=N)NO)cc3)CC2)CC1

Procedure:
A mixture of 0.15 g (0.42 mmol) of trans-[4-(4-cyano-phenoxy)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone, 0.118 g (1.69 mmol) of hydroxylamine hydrochloride, 0.24 ml (1.73 mmol) of triethylamine in 3 ml ethanol was refluxed for 1 hr. The mixture was evaporated to dryness to yield 0.34 g (84% yields, about 40% purity) of the titled compound. MS (m/e): 389.3 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=[O:3])[CH3:2].[O:9]1CCOCC1>O>[S:6]1[CH:7]=[CH:8][C:4]([C:1]([CH:2]=[O:9])=[O:3])=[CH:5]1
Reactant: CC(=O)c1ccsc1
Reactant: C1COCCO1
Solvent: O
Product: O=CC(=O)c1ccsc1

Procedure:
3-Acetylthiophene (20.0 g., 0.159 mol) and SeO2 (19.4 g., 0.175 mol) were dissolved 100 ml. dioxane and 8 ml. H2O by warming to 35°, then heated at reflux 16 hours. The reaction mixture was cooled, filtered and the filtrate stripped to a sludge (the hydrate of title product in crude form). The latter was distilled at reduced pressure to yield title product contaminated with about 10% starting material, 8.53 g.; tlc (5:3 hexane:ethyl acetate) Rf 0.27 (title product) and 0.59 (3-acetylthiophene). The latter was chromatographed on silica gel with 5:3 hexane:ethyl acetate as eluant. Clean product fractions were combined stripped to a solid, triturated with hexane, filtered and the solids (5.60 g.) sublimed to yield purified title product, 3.20 g.; tlc Rf 0.27 as above; sublimation point 70°/1 mm; ms: parent 141, base 111.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][OH:16].[OH-].[Na+].[I-].[Na+]>O>[OH:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: CC(=O)CCc1ccc(O)cc1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)CCc1ccc(OCCO)cc1

Procedure:
A mixture of 4-[4-hydroxyphenyl]butan-2-one (16.4 g], 2-bromoethanol (16.9 g), sodium hydroxide (7.5 g), sodium iodide (7.5 g) and water (200 ml) was heated under reflux for 4 hours, cooled and extracted with dichloromethane. The extract was washed with brine, dried (MgSO4) and evaporated to dryness. The residual oil was distilled to give the title compound as a colourless liquid, bp 170°-1°/0.8 mm. P τ(CDCl3) 7.85 (3H, s), 7.15-7.35 (4H, complex), 7.4-7.6 (1H, t), 5.85-6.25 (4H, complex), 2.8-3.4 (4H, dd).
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13](OCC)[CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH2:28]([CH2:30][NH2:31])[OH:29]>O.C(OCC)(=O)C>[ClH:1].[CH2:2]([N:4]([C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:31][CH2:30][CH2:28][OH:29])[CH:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:3]
Reactant: CCOc1cc(N(CC)c2ccccc2)cc(C)n1
Reactant: NCCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(c1ccccc1)c1cc(C)nc(NCCO)c1
Yield: 24 %

Procedure:
4-(N-ethylanilino)-2-ethoxy-6-methylpyridine hydrochloride (0.584 g, 2 mM) in ethanolamine (5 ml) was heated under argon at 180° C. for 24 hours. The solution was cooled, diluted with water (50 ml), basified with aqueous sodium carbonate solution and extracted with methylene chloride (4×10 ml). The organic extracts were combined, dried (MgSO4) and evaporated to give a gum. This gum was triturated with ether to give, 4-(N-ethylanilino)-2-hydroxy-6-methylpyridine as a white solid (0.05 g) which was collected by filtration. The filtrate was evaporated and the residue was purified by flash column chromatography, eluting successively with methanol/methylene chloride (1:19 v/v), methanol/methylene chloride, (1:9 v/v/) and methanol/methylene chloride/0.88d aqueous NH4OH (20:80:1 v/v) to give a gum. This gum was dissolved in ethyl acetate and treated with etheral hydrogen chloride to give a gum which solidified on standing. The solid was washed with ether to give 4-(N-ethylanilino)-2-(2-hydroxyethylamino)-6-methylpyridine hydrochloride (0.15 g, 24% yield); m.p. 190° C.; microanalysis, found C, 62.2; H, 7.5; N, 13.7%; C16H22N3OCl requires: C, 62.4; H, 7.15; N, 13.6%; NMR: 1.1-1.2 (3H, t, CH3), 2.23(3H, s, CH3), 3.2-3.32(2H, q, CH2), 3.5-3.6(2H, t, CH2), 3.7-3.85(2H, q, CH2), 5.7(1H, s, CH), 5.9(1H, s, CH), 7.2-7.6(5H, complex, aromatic), 4.7-5.1(1H, broad, OH), 12.4(1H, NH).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH2:20][CH:21]=[CH2:22])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1)=O)(C)(C)C.Cl.[CH3:24]O>C(OCC)C>[CH3:24][O:19][C:17](=[O:18])[CH:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH2:8])=[CH:11][CH:12]=1)[CH2:20][CH:21]=[CH2:22]
Reactant: C=CCC(C(=O)O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: C=CCC(C(=O)OC)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
To a stirred solution of commercially available (Astatech) 2-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-pent-4-enoic acid (2.00 g, 6.55 mmol) in methanol (30 cm3) under an atmosphere of dry nitrogen at ambient temperature was added 2M HCl in diethyl ether. The solution was stirred at ambient temperature for 20 hours and the filtrate volatile fractions removed in vacuo to afford the title compound as a white solid (1.67 g, 99.9%) with a positive ion ESI (M+H)+219.2.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@@H:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1.[CH2:21]([CH:29]1[CH2:31][O:30]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:30][C@@H:29]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][N:8]1[CH2:12][CH2:11][C@@H:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1
Reactant: c1ccc(CCC2CO2)cc1
Reactant: Oc1ccc(S[C@@H]2CCNC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(S[C@@H]2CCN(C[C@@H](O)CCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=344.4 (M+H+) was prepared from (R)-4-(pyrrolidin-3-yl-sulfanyl)-phenol trifluoro-acetic acid and (RS)-2-phenethyl-oxirane.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][CH:19]([C:21](O)=[O:22])[CH3:20])[CH:14]=[CH:15][C:16]=1[Cl:17]>>[CH3:1][NH:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:5][C:21](=[O:22])[CH:19]([CH3:20])[NH:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: CNC(=O)[C@@H](N)C(C)C
Product: CNC(=O)[C@@H](NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1)C(C)C

Procedure:
Following General Procedure D and using L-valine N-methyl amide (from Example E above) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a solid (mp=145-160° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].[C:34]([O:37][CH2:38]CBr)(=[O:36])[CH3:35].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[NH:22][C:23]([N:24]([CH3:26])[CH3:25])=[O:27])[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:35][C:34]([O:37][CH3:38])=[O:36])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1O
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc2ncnc(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A starting compound (N′-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-dimethylurea, 50 mg), potassium carbonate (138 mg), and bromoethyl acetate (49 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 37 mg (yield 60%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH3:29][NH:30][CH3:31]>>[CH3:29][N:30]([CH3:31])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: CNC
Product: CN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Cl)c(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI): predicted mass calcd. for C19H21ClN6O2, 400.9
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:15]=[CH:16][C:17]=1[CH3:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=[CH:16][C:17]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1ccc(NC(=O)CCC2CCCCC2)cc1N
Product: Cc1ccc(NC(=O)CCC2CCCCC2)cc1NC(=O)c1ccc(Cl)nc1

Procedure:
Using an analogous procedure to that described in Example 3, 6-chloropyrid-3-ylcarbonyl chloride was reacted with N-(3-amino-4-methylphenyl)-3-cyclohexylpropionamide (J. Med. Chem. 1996, 39, 3343-3356) to give the title compound; Mass Spectrum: M+H+ 400.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([C:33]([F:36])([F:35])[F:34])[N:32]=[N:31]2)=[CH:26][CH:25]=1)=[N+]=[N-]>C1COCC1>[F:36][C:33]([F:34])([F:35])[C:30]1([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][NH2:20])=[CH:29][CH:28]=2)[N:31]=[N:32]1
Reactant: [N-]=[N+]=NCc1ccc(C2(C(F)(F)F)N=N2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NCc1ccc(C2(C(F)(F)F)N=N2)cc1
Yield: 77.5 %

Procedure:
Triphenylphosphine polymer bound (Fluka, cat #93094) (1.6 g/mol, 6.3 mmol) was added to an aqueous (378 μL, 21.0 mmol)/THF (10 mL) solution of 3-[4-(azidomethyl)phenyl]-3-(trifluoromethyl)-3H-diazirine (506 mg, 2.1 mmol). The mixture was shaken until the starting material was no longer evident by TLC analysis (18 h). The triphenylphosphine-based support was filtered, washed with CH2Cl2, and the filtrate was concentrated in vacuum to obtain 350 mg (80%) of a yellow oil corresponding to the free amine: 1H NMR (CDCl3) δ 1.35-1.50 (br s, NH2), 3.89 (s, CH2), 7.17 (d, J=8.2 Hz, 2 C6H4), 7.35 (d, J=8.2 Hz, 2 C6H4); 13C NMR (CDCl3): δ 28.4 (q, J=39.9 Hz, C diazirine), 45.9 (CH2NH2), 122.2 (q, J=273.2 Hz, CF3), 126.7 (C6H2), 127.5 (C6H2), 145.0 (C6H2) (one peak is overlapped with an other one).
Reaction SMILES: [C:1]1([CH2:7][C:8](O)=[O:9])[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1.Cl.[C:12]1([C:18]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[C:21](=[O:27])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:1]1([CH2:7][C:8]([CH:25]2[CH:26]3[CH:22]([C:21](=[O:27])[CH2:20][CH2:19][C:18]3([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][NH:24]2)=[O:9])[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)CC1=CCC=CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2C1CNC2C(=O)CC1=CCC=CC1
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
N,N'-Carbonyldiimidazole (3.6 g) is added to a solution of (cyclohexa-1,4-dien-1-yl)acetic acid (2.35 g) in dry dichloromethane (50 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of 7,7-diphenyl-4-perhydroisoindolone hydrochloride (6.55 g) and triethylamine (5.6 cc) in dichloromethane (30 cc) is then added. The reaction mixture is stirred for 1 hour at +5° C. and then for 16 hours at 20° C. and is washed with normal hydrochloric acid (150 cc) and an aqueous saturated sodium chloride solution (150 cc). The organic phase is dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter 6 cm, height 30 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture (3 liters) of cyclohexane and ethyl acetate (50/50) and then with ethyl acetate (2 liters) and collecting 100 cc fractions. Fractions 10 to 48 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from acetonitrile (15 cc). The crystals are drained, washed with acetonitrile (5 cc) and isopropyl ether (25 cc) and dried. (3aRS,7aRS)-2-(cyclohexa-1,4-dien-1-yl)-acetyl-7,7-diphenyl-4-perhydroisoindolone (5.7 g) is obtained. m.p.=186° C.