Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH3:9].[Br:10]Br>C(Cl)(Cl)(Cl)Cl.[Fe].II>[Br:10][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:9])[C:4]=1[Cl:8]
Reactant: BrBr
Reactant: Cc1c(Cl)cccc1Cl
Agent: [Fe]
Agent: II
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c(Cl)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.2 %

Procedure:
Treat a mixture of 2,6-dichlorotoluene (50.0 g, 0.31 mol), iodine (0.10 g, 0.39 mmol), and 325 mesh iron powder (0.70 g, 12.5 mmol) in CCl4 (60 mL) dropwise with bromine (52.8 g, 0.33 mol) over 20 minutes and is stir for 3 hours at room temperature. Pour the mixture into ice water and extract with 1,2-dichloroethane. Wash the organic layer with saturated sodium bisulfite and dry using Na2SO4. Remove the solvent in vacuo to afford 76.01 g (100%) 1-bromo-2,4-dichloro-3-methyl-benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([C:15](OCCOCC)=[O:16])[CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: CCOCCOC(=O)c1ccnc(Nc2ccc(Cl)cc2)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1ccnc(Nc2ccc(Cl)cc2)n1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
A suspension of 2-ethoxyethyl 2-((4-chlorophenyl)amino)pyrimidine-4-carboxylate (0.4 g, 1.243 mmol) in THF (12 mL) was cooled to −78° C. and a 1M solution of DIBAL-H (4.97 mL, 4.97 mmol) in toluene was added. The mixture was stirred for 1.5 h at room temperature. The reaction mixture was diluted with THF (20 mL) and quenched with Na2SO4.10H2O followed by a few drops of water. The mixture was stirred at room temperature for 18 h, then filtered through a pad of Celite topped with silica gel. The pad was washed with ethyl acetate and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel using 75-100% ethyl acetate in hexanes. The desired fractions were concentrated to give (2-(4-chlorophenylamino)pyrimidin-4-yl)methanol as a pale yellow solid (0.224 g, 76%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.41 (1H, d, J=5.02 Hz), 7.55-7.86 (2H, m), 7.19-7.40 (2H, m), 6.95 (1H, d, J=5.02 Hz), 4.57 (2H, s). LCMS: R.T.=3.10; [M+H]+=236.12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:36][CH3:35])[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4)cc(-c4ccc(Cl)cc4)c3O2)cc1
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3ccc(Cl)cc3)c2O1

Procedure:
The title compound was prepared (0.056 g, 71%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(4-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.20 mmol) and methylamine (0.30 g, 9.8 mmol). mp >250° C.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][N:16]([CH:26]1[C:35]2[N:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:29][CH2:28][CH2:27]1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1.[BH4-].[Na+]>CO>[CH2:1]([NH:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:16]([CH2:15][C:7]2[NH:6][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)[CH:26]2[C:35]3[N:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH2:29][CH2:28][CH2:27]2)=[CH:19][CH:20]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: CC(C)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CNCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 24.8 %

Procedure:
Isobutyraldehyde (0.1 mL, 1.1 mmol) was condensed with N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (152 mg, 0.382 mmol) in dry CH3OH (5 mL) for 17 h and the resultant imine was reduced with NaBH4 (81 mg, 2.14 mmol) for 1 h (see General Procedures A and B). Purification of the crude product by radial chromatography (2 mm TLC plate, 50:1:1 CH2Cl2/CH3OH/NH4OH) gave the free amine (43 mg, 25%).
Reaction SMILES: CO[C:3]1[CH:13]=[C:12]([C@@H:14]2[CH2:16][C@H:15]2[C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][NH2:27])[CH:19]=2)[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8].F[C:30](F)(F)C(O)=O>>[NH2:27][CH2:26][CH2:25][O:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([C:15]1[CH:14]=[C:12]2[C:13](=[CH:30][CH:16]=1)[CH:3]=[C:4]([O:5][CH2:6][C:7]([OH:9])=[O:8])[CH:10]=[CH:11]2)=[O:28]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc([C@@H]2C[C@H]2C(=O)c2cccc(OCCN)c2)ccc1OCC(=O)O
Product: NCCOc1cccc(C(=O)c2ccc3cc(OCC(=O)O)ccc3c2)c1

Procedure:
Ex. 315. (+/-)-trans-[[2-methoxy-4-[2-((3-(2-aminoethoxy)benzoyl))cyclopropyl]phenoxy]]acetic acid.trifluoroacetic acid. MS(NH3): 404 (5%, M+NH4), 386 (base, M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1.[C:14]([CH2:16][C:17](O)=[O:18])#[N:15].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:14]([CH2:16][C:17]([NH:11][CH2:10][CH2:9][C:8]1[CH:12]=[CH:13][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=1)=[O:18])#[N:15]
Reactant: N#CCC(=O)O
Reactant: COCOc1ccc(CCN)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCOc1ccc(CCNC(=O)CC#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.9 %

Procedure:
4-Methoxymethoxyphenethylamine (1.58 g, 8.7 mmol) and cyanoacetic acid (0.82 g, 9.6 mmol) were dissolved in dimethylformamide (10 ml) and under ice-cooling and stirring diethylphosphoric cyanide (1.51 ml, 9.6 mmol) and triethylamine (1.34 ml, 9.6 mmol) were sequentially added. After stirring at room temperature for 24 hours, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was distilled out under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=19:1) to yield 2-cyano-N-(4-methoxymethoxyphenethyl)acetamide (0.97 g, 45%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:19][CH3:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:21][C:22]1[CH:23]=[C:24]([NH:32][C:33](OC2C=CC=CC=2)=[O:34])[C:25](=[CH:30][CH:31]=1)[C:26]([O:28][CH3:29])=[O:27]>>[C:15]([O:14][C:12]([CH:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([NH:1][C:33]([NH:32][C:24]2[CH:23]=[C:22]([Cl:21])[CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[O:34])(=[O:3])=[O:4])=[CH:10][CH:9]=1)[CH2:19][CH3:20])=[O:13])([CH3:16])([CH3:18])[CH3:17]
Reactant: CCC(C(=O)OC(C)(C)C)c1ccc(S(N)(=O)=O)cc1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: CCC(C(=O)OC(C)(C)C)c1ccc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OC)cc1
Yield: 83.8 %

Procedure:
1.02 g (3.41 mmol) of t-butyl (±)-2-(4-aminosulfonylphenyl)butyrate acid and 1.04 g (3.41 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as Example 1 to obtain 1.46 g (yield 84%) of methyl 2-[({4-[1-(t-butoxycarbonyl)propyl]benzenesulfonylamino}carbonyl)amino]-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, CDCl3):0.89 (3H, t), 1.38 (9H, s), 1.69–1.76 (1H, m), 2.03–2.10 (1H, m), 3.42 (1H, t), 3.94 (3H, s), 7.04 (1H, d), 7.47 (2H, d), 7.93 (1H, d), 8.01 (2H, d), 8.45 (1H, br), 11.04 (1H, br).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C(N(CC)CC)C.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>C(Cl)Cl>[CH:17]1([C:20]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[N:2]2)=[O:21])[CH2:19][CH2:18]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)n1nnc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a 0C solution of benzotriazole (5.05 g, 42.39 mmol) in CH2Cl2 (100 mL) was added dropwise triethylamine (9.0 ml, 64.57 mmol) followed by cyclopropyl carbonyl chloride (4.2 ml, 46.28 mmol). The mixture was stirred at rt for 1 h and then quenched with a solution of 2N aqueous HCl (75 ml). The organic phase was washed with 2 N HCl (2×75 mL) and water (100 ml), dried with MgSO4 and concentrated in vacuo. The solid residue was washed with hexenes, filtered and dried to yield 1-(cyclopropylcarbonyl)-1H-1,2,3-benzotriazole as a white solid (5.92 g, 75%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1([C:19]2[C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH3:38])[CH:20]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH2:1]([N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]=[C:9]1[C:28]1[C:19]([CH:16]2[CH2:18][CH2:17]2)=[CH:20][C:21]([CH3:38])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1nnc(Br)n1Cc1ccccc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C2CC2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2nnc(OC)n2Cc2ccccc2)c(C2CC2)cc1C
Temperature: 90 °C
Yield: 89.3 %

Procedure:
A mixture of 4-benzyl-3-bromo-5-methoxy-4H-1,2,4-triazole (compound 91.3, 1.2 g, 4.48 mmol), methyl 4-cyclopropyl-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 91.1, 1.56 g, 4.93 mmol), PdCl2(dppf)CH2Cl2 (0.37 g, 0.45 mmol) and potassium carbonate (3.10 g, 22.5 mmol) in dioxane (50 mL) and water (20 mL) was degassed with argon. The mixture was heated at 90° C. for 18 hours under argon, then cooled to room temperature. The mixture was diluted with ethyl acetate (300 mL) and washed with water then brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc 10:1 to 4:1) to yield 1.51 g (89%) of the title compound as thick oil. m/z (ES+) 378 (M+H)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.Cl.[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH:20][C:9](=[O:11])[CH2:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)COC(=O)C(C)N
Reactant: O=C(O)Cc1cccnc1
Agent: Cl
Product: CC(C)COC(=O)C(C)NC(=O)Cc1cccnc1

Procedure:
Following General Procedure BF and using 3-pyridylacetic acid hydrochloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 62°-64° C. The reaction was monitored by tlc on silica gel (Rf=0.48 10% methanol/dichloromethane) and purification was by silica gel chromatography.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH3:18][C:19]1[N:20]=[C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[S:22][CH:23]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:27]1[CH2:28][CH2:29][N:24]([C:21]2[S:22][CH:23]=[C:19]([CH3:18])[N:20]=2)[CH2:25][CH2:26]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Cc1csc(N2CCNCC2)n1
Product: Cc1csc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)n1
Yield: 87 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(4-methyl-thiazol-2-yl)-piperazine. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as an amorphous yellow solid (yield 87%). MS (m/e): 424.1 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13](Cl)=[O:14].[CH2:22]([NH2:24])[CH3:23]>O1CCCC1.O>[CH2:22]([NH:24][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:10]([S:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:11]=1)[CH3:23]
Reactant: CCN
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(2,4-difluorophenylthio)-4nitrobenzoyl chloride (1 g) in tetrahydrofuran (3 ml) was added to a stirred solution of 70% ethylamine (0.5 ml) in water (5 ml) at 5° to 10° C. The mixture was stirred at the same temperature for 1 hour and at room temperature for 1 hour. Water (30 ml) was added to the reaction mixture. The precipitates were filtered, washed with water, and dried under reduced pressure to give a yellow powder of N-ethyl-3-(2,4-difluorophenylthio)-4-nitrobenzamide (0.94 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(NC3C=CC(CC)=CC=3)=O)=[CH:11][CH:10]=2)[CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][C:29]=1[C:37]([F:40])([F:39])[F:38]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([Cl:27])=[C:29]([C:37]([F:38])([F:39])[F:40])[CH:30]=3)=[O:36])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCc1ccc(NC(=O)Nc2ccc(Cc3cc(N)ncn3)cc2)cc1
Solvent: CN(C)C=O
Product: Nc1cc(Cc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ncn1
Reaction time: 2 h

Procedure:
The title compound is prepared as described in Example 102 but using 6-(4-aminobenzyl)-pyrimidin-4-ylamine (see Example 157), 4-chloro-3-(trifluoromethyl)-phenyl isocyanate, and DMF as the solvent. The reaction mixture is stirred for 2 h. The title compound is obtained as a white solid: ES-MS: 422.8 [M+H]+; single peak at tR=7.58 min (System 2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[CH3:38]>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:28][C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[NH:34][CH:33]=[C:32]4[CH3:38])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Cc1c[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCc1ccccc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline (7.859 g, 26.1 mmol), (prepared as described for the starting material in Example 1), potassium carbonate (18.03 g, 130 mmol) and 5-hydroxy-3-methylindole (5.00 g, 34.0 mmol), (Journal of Organic Chemistry 1993, 58, 3757), in DMA (600 ml) was stirred at 75° C. for 2 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated in vacuo. The crude solid was purified by silica column chromatography, eluting with 2.5% methanol/97.5% dichloromethane to give 7-benzyloxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (7.791 g, 73%).
Reaction SMILES: C1(C[O:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[C:27](O)([CH3:29])[CH3:28])=[O:10])C=CC=CC=1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:21]1([CH2:20][O:19][C:17]([N:14]2[CH2:15][CH2:16][N:11]3[C:9](=[O:8])[O:10][C:27]([CH3:29])([CH3:28])[CH:12]3[CH2:13]2)=[O:18])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)N2CCN(C(=O)OCc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
Bis(phenylmethyl)2-(1-hydroxy-1-methylethyl)-1,4-piperazinedicarboxylate (1.7 g, 4.2 mmol) was dissolved in N,N-dimethylformamide (20 mL). 60% Sodium hydride (0.25 g, 6.3 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate (200 ml), and then washed with an aqueous sodium hydrogen carbonate solution. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1 to 1:1) and recrystallized from ethyl acetate-hexane to obtain the title compound (0.97 g, yield 76%).
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH3:18])=[CH:12][CH:11]=2.CN([CH:22]=[O:23])C.C(O)CC>C1COCC1>[F:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[CH:22]=[O:23])=[CH:14][C:13]([O:17][CH3:18])=[CH:12][CH:11]=2
Reactant: COc1ccc2ncc(F)cc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCO
Solvent: C1CCOC1
Product: COc1ccc2ncc(F)c(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a solution of DIPA (15.5 mL) in THF (300 mL), cooled to −78° C., was added n-BuLi (2.35N in hexanes, 44 mL). The reaction mixture was stirred 5 min at this temperature before warming to 0° C. The reaction mixture was stirred 15 min before cooling to −78° C. 3-fluoro-6-methoxy-quinoline (prepared as described in FR 2004/01105, 15 g) in THF (50 mL+10 mL rinse) was added and the mixture was stirred 3 h at −78° C. DMF (3 mL) was added quickly. After 45 min., 1-propanol (8 mL) was added and the mixture was warmed to rt. The mixture was partitioned between water (100 mL) and EA (200 mL). The aq. layer was extracted with EA (200 mL). The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue triturated in Hept to give an orange solid (9.0 g, 51% yield).
Reaction SMILES: [CH3:1][C:2]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:11])[CH:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([O:35][CH3:36])[C:26]=1[C:27](Cl)=[O:28].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([O:35][CH3:36])[C:26]=1[C:27]([NH:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:2]([CH3:1])([N:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1)[CH3:11])=[O:28]
Reactant: COc1cc(Cl)cc(Cl)c1C(=O)Cl
Reactant: CC(C)(C(N)c1ccccc1)N1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Cl)cc(Cl)c1C(=O)NC(c1ccccc1)C(C)(C)N1CCCC1
Reaction time: 0.03 h
Yield: 72.4 %

Procedure:
To a solution of (+)-[2-methyl-1-phenyl-2-(1-pyrrolidinyl)propyl]amine D6 (0.10 g; 0.459 mmol) and triethylamine (0.15 ml; 1 mmol) in DCM (3 ml) was added a solution of 2,4-dichloro-6-methyloxybenzoyl chloride (0.13 g; 0.540 mmol) in DCM (2 ml). After 1 h. saturated aqueous sodium hydrogen carbonate (8 ml) was added and the mixture shaken for 2 minutes. The organic layer was passed through a phase separation cartridge and the solvent removed under reduced pressure. The residue was dissolved in the minimum of DCM and applied to a 10 g silica gel column. Elution with 0-100% ethyl acetate in pentane gradient and removal of solvent under reduced pressure afforded the title compound as a colourless gum (0.14 g: 72%). 1H NMR (CDCl3) δ: 0.91 (3H, s), 0.96 (3H, s), 1.60-1.80 (4H, m), 2.55-2.75 (4H, m), 3.82 (3H, s), 4.76 (1H, d, J=2.4 Hz), 6.81 (1H, d, J=1.6 Hz), 7.02 (1H, d, J=1.6 Hz), 7.20-7.50 (6H, m). Mass spectrum (Electrospray LC/MS). Found 421 (MH+). C22H2635Cl2N2O2 requires 420. Ret. Time: 1.97 min.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:7])[CH:4]=[CH:5][CH:6]=1.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10]>C(O)C>[CH2:13]([O:12][C:8](=[O:11])[CH2:9][CH2:10][N:2]1[C:3](=[O:7])[CH:4]=[CH:5][CH:6]=[N:1]1)[CH3:14]
Reactant: O=c1cccn[nH]1
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCn1ncccc1=O
Temperature: 0 °C
Yield: 82.4 %

Procedure:
To a stirred solution of 5.76 g (0.06 mole) of 3(2H)-pyridazinone and 8 g (0.08 mole) of ethyl acrylate in 100 ml of ethanol, 2 ml of Triton-B was added dropwise while maintaining the temperature at 0° C. The mixture was refluxed for 4 hours, then distilled to give an orange oil residue. The crude oil was extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and distilled. The residual oil was distilled in a vacuum to give 9.7 g (83% yield) of ethyl-3-(3-oxo-2-pyridazinyl)propionate as a colorless liquid boiling at 120°/121° C./1 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](=[NH:7])[NH2:6].[CH3:11][O-:12].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:6][C:11](=[O:12])[C:10]3[CH2:9][CH2:8][CH2:4][CH2:3][C:2]=3[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: N=C(N)c1cccc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(-c2cccc(Cl)c2)nc2c1CCCC2
Temperature: 85 °C
Yield: 52.2 %

Procedure:
A solution of 3-chlorobenzimidamide (5 g, 32.34 mmol) in ethanol (90 mL) was treated with ethyl-2-cyclohexaneonecarboxylate (6.3 g, 40.43 mmol) and sodium methoxide (2.1 g, 38.81 mmol). The reaction mixture was heated at 85° C. for 18 h. After this time, the reaction mixture was cooled and concentrated to a volume of approximately 50 mL. Then, 2.0 M HCl (68 mL) was added slowly. The resulting precipitate was filtered, washed with water and ether, and the residue was dried on a high vacuum overnight to afford the title compound (2.2 g, crude) as a light yellow solid. MW=260.72. 1H NMR (DMSO-d6, 300 MHz) δ 12.64 (s, 1H), 8.16-8.10 (m, 1H), 8.08-7.99 (m, 1H), 7.66-7.57 (m, 1H), 7.54 (t, J=7.9 Hz, 1H), 2.66-2.55 (m, 2H), 2.44-2.33 (m, 2H), 1.84-1.61 (m, 4H); APCI MS m/z 261 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>C(#N)C>[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:28][CH2:29][N:30]([CH2:2][C:3]([C:5]3[CH:20]=[CH:19][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:31][CH2:32]2)=[CH:23][CH:22]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COC(=O)CNC(=O)COc1ccc(C(=O)CBr)cc1
Solvent: CC#N
Product: COC(=O)CNC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of methyl N-[4-(bromoacetyl)phenoxyacetyl]glycinate (0.85 g) in acetonitrile (10 ml) was added to a stirred solution of 1-(4-pyridyl)piperazine (0.81 g) in acetonitrile (30 ml). After stirring overnight the solvent was removed in vacuo and the residue partitioned between water/ethyl acetate. The organic phase was washed with water, then dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica, eluting with 0 to 7.5% v/v methanol/dichloromethane. Evaporation of the fractions gave the title compound, 130 mg, as a foam: NMR (d6DMSO) δ8.58(1H,t) 8.16(2H,d), 8.01(2H,d), 7.08(2H,d), 6.83(2H,d), 5.75(1H,s), 4.68(2H,s), 3.92(2H,d), 3.84(2H,s), 3.65(3H,s), 3.34(4H,t+H2O), 2.65(4H,t); m/e 427 (M+H)+ ; calculated for C22H26N4O5. 0.5CH2Cl2 : C, 57.6; H, 5.8; N, 11.9. found: C, 57.8; H, 5.7; N, 12.0%.