Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)(O)[O-].[Na+]>>[CH3:17][O:16][C:14](=[O:15])[CH2:13][NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CNc1ccc(C(F)(F)F)cc1
Yield: 59.2 %

Procedure:
4-Trifluoromethylaniline (5.84 g), methyl chloroacetate (13.1 g) and sodium bicarbonate (3 g) were treated according to the method of Intermediate 5. The product was purified by FCC eluting with System B (1:3) to give the title compound (5.00 g), t.l.c. (System B, 1:3) Rf 0.32.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:33][CH2:32][CH2:31][CH2:30][N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1CCN(CCCN)CC1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Product: CN1CCN(CCCNc2cc3c(Nc4ccc(F)c(Cl)c4)c(C#N)cnc3cn2)CC1
Yield: 71 %

Procedure:
Following the procedure described above in Example 34, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile was reacted with 3-(4-methylpiperazin-1-yl)propan-1-amine. The crude product was purified by flash column chromatography (10% methanol in methylene chloride) to give a yellow solid (0.102 g, 71%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.8 (m, 2 H) 2.2 (s, 3 H) 2.4 (m, 8 H) 3.3 (m, 4 H) 6.9 (m, 2 H) 7.4 (s, 1 H) 7.5 (t, J=9.0 Hz, 1 H) 7.6 (d, J=7.1 Hz, 1 H) 8.3 (s, 1 H) 8.8 (s, 1 H) 9.7 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([O:25]CCCC)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1CC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C(=O)O)c(CC)o3)C[C@H]2OC)nc1Cl
Yield: 63.2 %

Procedure:
The same operation as in Example (91d) was performed using butyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (110d) (0.14 g, 0.29 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (5 mL) and THF (5 mL), to obtain 78 mg of the title compound as a colorless solid (63%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][N:14]3C(=O)C4=CC=CC=C4[C:15]3=O)=[CH:11][N:10]=[C:9]2[CH2:25][N:26]([CH3:28])[CH3:27])=[C:4](C(=O)C2C=CC=CC=2F)[CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:8]3[C:9]([CH2:25][N:26]([CH3:27])[CH3:28])=[N:10][CH:11]=[C:12]3[CH2:13][N:14]=[C:15]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:6]=2[CH:7]=1
Reactant: CN(C)Cc1ncc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(F)cc1C(=O)c1ccccc1F
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C)Cc1ncc2n1-c1ccc(F)cc1C(c1ccccc1F)=NC2

Procedure:
In the manner given in Example 4, N-[[1-[4-fluoro-2-(o-fluorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-imidazol-5-yl]methyl]phthalimide in ethanol is heated with hydrazine hydrate to give 8-fluoro-6-(o-fluorophenyl)-1-[(dimethylamino)methyl]-4H-imidazo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)[O:6][C:5](=[O:14])[CH:4]=1.[OH-:15].[Na+]>Cl>[CH3:13][C:10]1[CH:9]=[CH:8][C:7]2[O:6][CH:2]=[C:3]([CH2:4][C:5]([OH:14])=[O:15])[C:12]=2[CH:11]=1
Reactant: [OH-]
Reactant: Cc1ccc2oc(=O)cc(CCl)c2c1
Agent: Cl
Agent: [Na+]
Product: Cc1ccc2occ(CC(=O)O)c2c1
Yield: 94 %

Procedure:
4-chloromethyl-6-methyl-chromen-2-one (10.4 g, 50.0 mmol) is suspended in a 1.0 M aqueous NaOH solution (400 mL). The reaction mixture is heated under reflux for 30 min. until a clear solution is obtained. The reaction mixture is cooled in an ice bath and carefully neutralized with a 2 M aqueous HCl solution (200 mL). More of a 2 M aqueous HCl solution is added until a white precipitate formed (pH<5). The precipitate is collected by suction filtration, washed with a small amount of an 1 M aqueous HCl solution and dried in vacuo at 50° C. to afford the title compound as a white powder (9.94 g, 47 mmol, 94%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.63 (s, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.36 (s, 1H), 7.14 (d, J=8.3 Hz, 1H), 3.76 (s, 2H), 2.48 (s, 3H).
Reaction SMILES: [CH:1]([CH:3]([CH2:9][CH3:10])[CH2:4][C:5]([O:7]C)=O)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][NH2:19]>C(O)(=O)C>[CH2:9]([C:3]1[CH2:1][N:19]([CH2:18][CH2:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[C:5](=[O:7])[CH:4]=1)[CH3:10]
Reactant: NCCc1ccccn1
Reactant: CCC(C=O)CC(=O)OC
Solvent: CC(=O)O
Product: CCC1=CC(=O)N(CCc2ccccn2)C1

Procedure:
4-Ethyl-1-(2-(pyridin-2-yl)ethyl)-1H-pyrrol-2(5H)-one is synthesized by a cyclo-condensation between methyl 3-formylpentanoate and 2-(pyridin-2-yl)ethanamine in glacial acetic acid at 70° C. according to a procedure of R. Fisher (DE 4127111, 1992).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:18]([NH:19][CH:20]=O)=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C(Cl)(Cl)Cl>[CH2:1]([S:8][C:9]1[C:18]([NH:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(NC=O)c1SCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNc1cccc(C(=O)OC)c1SCc1ccccc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 93.1 %

Procedure:
20 ml of borane/dimethyl sulfide complex (BMS) are added dropwise to a solution of 61.5 g of methyl 2-benzylmercapto-3-formylaminobenzoate (cf. Example d)) in 100 ml of CHCl3 at 0° C. The mixture is subsequently heated at 60° C. for 2 h, a further 20 ml of BMS are added, and the mixture is stirred at this temperature for a further 2.5 h. Then 30 ml of MeOH are added dropwise at 0° C. The mixture is transferred to a separating funnel, washed with water and brine and then dried over MgSO4. Volatile components are removed by distillation to give 54.60 g of methyl 2-benzylmercapto-3-methylaminobenzoate in the form of a yellowish oil. 1H NMR (CDCl3, 80 MHz): δ:2.6 (d, 3H, NH-CH3), 3.8 (s, 3H, OCH3), 3.9 (s, 2H, SCH2Ph), 5.2 (s, broad, 1H, NH-Me), 6.5 (d, 1H, Harom.), 6.8 (d, 1H, Harom.), 7.0-7.4 (m, 6H, Harom.).
Reaction SMILES: C([Li])(C)(C)C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:29]1([CH2:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCCCC.O1CCCC1>[C:29]1([CH2:35][C:36]([O:6][CH:7]([C:20]2[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(OC(=O)Cc1ccccc1)c1coc([Si](C)(C)C)c1
Reaction time: 0.08 h

Procedure:
tert-Butyl lithium (a 1.7 M solution in pentane; 0.29 ml, 0.49 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (138.2 mg, 0.41 mmol) in tetrahydrofuran (7 ml) at -78 degrees under argon. After 5 minutes, a solution of phenylacetyl chloride (65 microliter, 0.49 mmol) in tetrahydrofuran (1/2ml) was added. Stirring was continued at room temperature for 16 hours and quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative TLC (20×20 cm, 500 micron silica plate; developed with 10% ethyl ether/hexane). The title ester was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][N:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1.N1C=CC=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:9][C:10]3[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:4]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Cc1ccc(N)cc1Nc1ncccc1-c1ccncn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cc1Nc1ncccc1-c1ccncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methyl-N3-(3-pyrimidin-4-yl-pyridin-2-yl)-benzene-1,3-diamine (40 mg, 0.14 mmol) in CH2Cl2 (2.5 mL) was added pyridine (0.012 mL, 0.14 mmol) and 4-chlorobenzenesulfonyl chloride (30 mg, 0.14 mmol). The mixture was stirred overnight at RT, concentrated and purified by flash chromatography (0→50% EtOAc/n-Hexanes) to yield 4-chloro-N-(4-methyl-3-((3-(4-pyrimidinyl)-2-pyridinyl)amino)phenyl)benzenesulfonamide. MS m/z=452 [M+1]+. Calc'd for C22H18ClN5O2S: 451.94.
Reaction SMILES: [ClH:1].Cl.[C:3]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([OH:5])=[O:4].[CH:28]1(O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[ClH:1].[ClH:1].[CH:28]1([O:4][C:3]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[O:5])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: OC1CCCCCC1
Reactant: O=C(O)COc1ccc(N2CCN(CCC3CCNCC3)CC2)cc1
Agent: Cl
Product: O=C(COc1ccc(N2CCN(CCC3CCNCC3)CC2)cc1)OC1CCCCCC1

Procedure:
Prepared from 1-(4-carboxymethyloxyphenyl)-4-[2-(piperidin-4-yl)ethyl]piperazine dihydrochloride and cycloheptanol.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:14][C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:15]([CH2:14][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1)#[N:16]
Reactant: Oc1ccc(-c2cccs2)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1ccc(-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.3 %

Procedure:
A mixture of 4-(2-thienyl)phenol (1.30 g), chloroacetonitrile (668 mg) and potassium carbonate (1.53 g) in DMF (7 ml) was stirred for 5 hours at ambient temperature. The mixture was diluted with H2O and the separated solid was recovered to give 1.45 g of 2-(4-cyanomethoxyphenyl)thiophene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH:5]=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[CH:16][C:15]=1[F:21].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>O>[F:21][C:15]1[CH:16]=[N+:17]([O-:20])[CH:18]=[CH:19][C:14]=1[C:3]1[N:4]=[CH:5][C:6]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])=[N:7][C:2]=1[C:24]1[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Nc1cnc(-c2cc[n+]([O-])cc2F)c(Cl)n1)C1CC1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1cnc(-c2cc[n+]([O-])cc2F)c(-c2cccnc2)n1)C1CC1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 55.6 %

Procedure:
In a sealed tube three cycles of vacuum and argon were applied to a mixture of the N-[6-chloro-5-(3-fluoro-1-oxidopyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide (2.23 g, 7.22 mmol), pyridin-3-ylboronic acid (1.15 g, 9.39 mmol) and Cs2CO3 (7.06 g, 21.66 mmol). A solution of 1,4-dioxane:H2O (64 mL, 9:1) was added and argon was bubbled for 5 min, after which, PdCl2dppfCH2Cl2 (0.59 g, 0.72 mmol) was added and argon was again bubbled other 5 min. The reaction mixture was heated at 90° C. for 1 h. Upon the reaction completion the 1,4-dioxane was concentrated in vaccuo, and the obtained residue was adsorbed onto silica gel with 10% MeOH/THF (150 mL) and purified by column chromatography on silica gel eluting with a MeOH/EtOAc gradient (0→20%). The green solid obtained was precipitated with 1% MeOH/CH2Cl2 (5 mL), and washed with 1% MeOH/CH2Cl2 (3×3 mL), CH2Cl2 (3×5 mL), 1% MeOH/Et2O (3×5 mL) and Et2O (4×5 mL) to yield the title compound as a white powder (1.41 g, 56%).
Reaction SMILES: [N:1]([C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[N+]=[N-]>CC1C=CC(C)=CC=1>[CH2:16]([C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[NH:1]2)=[CH:11][CH:12]=1)[CH3:17]
Reactant: CCc1ccc(C=C(N=[N+]=[N-])C(=O)OC)cc1
Solvent: Cc1ccc(C)cc1
Product: CCc1ccc2cc(C(=O)OC)[nH]c2c1
Yield: 59.1 %

Procedure:
Methyl 2-azido-3-(4-ethylphenyl)acrylate (36) (1.0 g, 4.33 mmol) was dissolved in p-xylene and heated at reflux for 3 h. After evaporation of the solvent, the residue was purified by flash column chromatography eluting with a linear gradient ranging from 0 to 20% EtOAc-hexanes to provide 0.52 g (59%) of product 37 as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 1.28 (t, J=7 Hz, 3H), 2.79 (q, J=7 Hz, 2H), 3.94 (s, 3H), 7.03 (dd, J=2, 8 Hz, 1H), 7.17-7.18 (m, 1H), 7.21-7.23 (m, 1H), 7.60 (d, J=8 Hz, 1H), 8.78 (s, 1H). LC-MS (CI): m/z 202.0 [(M−H)− C12H13NO2 requires 203.09].
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.Cl[C:22]([O:24][CH:25]1[CH:32]2[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:34][CH:26]1[CH2:27]3)[CH2:31]2)=[O:23].Cl>C(Cl)Cl>[C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:22]([O:24][CH:25]2[CH:26]3[CH2:34][CH:30]4[CH2:29][CH:28]([CH2:33][CH:32]2[CH2:31]4)[CH2:27]3)=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OC1C2CC3CC(C2)CC1C3)N1CCCC1c1ccccc1
Yield: 61.5 %

Procedure:
A vial equipped with a flea stir bar was charged with 2-phenylpyrrolidine (17 mg, 0.12 mmol), i-Pr2NEt (0.031 mL, 0.17 mmol). A solution of 2-adamantyl chloroformate (25 mg, 0.12 mmol) in CH2Cl2 (1.5 mL) was added. The mixture was stirred over the weekend and applied to a 10-mL ChemElut cartridge prewetted with 5% aq HCl (5 mL). The cartridge was eluted with ether (20 mL). The eluate was concentrated and the residue was purified by prep HPLC to afford the title compound (24 mg, 63%). LC-MS Method 2 tR=11.81 min, m/z=326, 1H NMR (CDCl3) 0.92 (m, 1H), 1.03 (m, 1H), 1.30-2.20 (14H), 2.32 (m, 1H), 2.50 (br s, 1H), 3.64 (m, 2H), 4.70-5.10 (2H), 7.18 (m, 3H), 7.28 (m, 2H).
Reaction SMILES: C[Si]([O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9](I)=[CH:8][C:7]=1[Cl:14])(C)C.[O:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1>>[Cl:14][C:7]1[CH:8]=[C:9]([C:16]2[O:15][CH:19]=[CH:18][CH:17]=2)[CH:10]=[C:11]([Cl:12])[C:6]=1[OH:5]
Reactant: c1ccoc1
Reactant: C[Si](C)(C)Oc1c(Cl)cc(I)cc1Cl
Product: Oc1c(Cl)cc(-c2ccco2)cc1Cl
Yield: 52 %

Procedure:
2,6-Dichloro-4-(2-furanyl)phenol [IV; R1 =2-Cl, R2 =6-Cl, Het=2-furanyl] was prepared from 2,6-dichloro-4-iodophenyl trimethylsilyl ether and furan according to the procedure of Example 1(b), and was obtained in 52% yield as a light brown solid, m.p. 68-70° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)C.[CH:16](OCC)(OCC)[O:17][CH2:18][CH3:19]>O>[CH2:18]([O:17][C:16]1[NH:11][C:10]2[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=2[N:1]=1)[CH3:19]
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: CCOC(OCC)OCC
Solvent: O
Solvent: CC(=O)O
Product: CCOc1nc2c(C(=O)O)cccc2[nH]1
Reaction time: 2 h
Yield: 89 %

Procedure:
1.0 g of 2,3-diaminobenzoic acid is dissolved into 20 ml of glacial acetic acid. Triethyl orthoformate (2.1 eq.) is added into the above mixture at temperature of 0° C.; and to stir it for 2 hours at temperature of 0˜5° C.; and 150 ml of water is added into it, and then to isolate and filter to produce 2-ethoxy-1H-benzimidazole-4-formic acid. The yield is about 89%. 2-ethoxy-1H-benzimidzzole-4-formic acid is added into 15 ml of thionyl chloride, and to react for 60 minutes, and after end of the reaction completely, and (L)-2-amino-1-p-nitrophenyl-1,3-propylene glycol (1.1 eq) is added into the reaction mixture under stirring for 2 hours at the room temperature, and then to filter the inorganic salt, and evaporate the solvent to dry, to obtain the final product of (L)-2-ethoxy-1H-benzimidazole-4-[N-(1-hydroxymethyl-2-p-nitrophenylhydroxyethyl)amide. The yield is about 91%. Using the same process to prepare the compounds in Table 3.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29]>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COc1ccccc1Br
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(N)nn23)c1
Product: COc1ccccc1Nc1nc2cccc(-c3cccc(S(C)(=O)=O)c3)n2n1
Yield: 37.7 %

Procedure:
[5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2-methoxyphenyl)-amine was prepared from 5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100 mg, 0.35 mmol) and 1-bromo-2-methoxy benzene (52 μL, 0.42 mmol) in a manner analogous to Example 77 to yield [5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2-methoxyphenyl)-amine (52 mg, 38%) as a yellow powder following purification on a 12 g Isco silica gel column using 0-5% methanol in dichloromethane as an eluent. MP=88° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.78 (br s, 1H), 8.79 (m. 1H), 8.36 (d, J=7.1 Hz, 1H), 8.20 (d, J=7.1 Hz, 1H), 8.12 (d, J=7.1 Hz, 1H), 8.00 (s, 1H), 7.89 (t, J=12.9, 8.2, 1H), 7.72 (m, 1H), 7.65 (d, J=9.4 Hz, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.05 (d, J=5.9 Hz, 1H), 6.92 (m, 2H), 3.87 (s, 3H), 3.32 (s, 3H). MS=395 (MH)+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:64][N:65]1[CH2:70][CH2:69][N:68]([CH:71]2[CH2:76][CH2:75][CH:74]([NH2:77])[CH2:73][CH2:72]2)[CH2:67][CH2:66]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:77][C@H:74]5[CH2:73][CH2:72][C@H:71]([N:68]6[CH2:67][CH2:66][N:65]([CH3:64])[CH2:70][CH2:69]6)[CH2:76][CH2:75]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(C2CCC(N)CC2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(C)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (66 mg, 0.15 mmol, 1 eq), DIPEA (52 μl, 0.3 mmol, 2 eq) and TBTU (54 mg, 0.17 mmol, 1.1 eq) were added to 1 mL DMF and the resulting solution was stirred at rt for min before the addition of 4-(4-methylpiperazin-1-yl)cyclohexanamine (Intermediate 17) (35 mg, 0.18 mmol, 1.2 eq) dissolved in DMF (0.5 mL). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—2 and Preparative—3) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-N-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-3-methoxybenzamide (white solid, 17 mg, 18%).
Reaction SMILES: S(Cl)(Cl)=O.C([NH:8][C:9]1[C:17]([Cl:18])=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([O:19][CH3:20])[CH:10]=1)(=O)C.[NH2:21][CH:22]1[CH2:26][N:25]([CH2:27][CH3:28])[N:24]([CH2:29][CH3:30])[CH2:23]1>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:17]([Cl:18])=[CH:16][C:12]([C:13]([NH:21][CH:22]2[CH2:26][N:25]([CH2:27][CH3:28])[N:24]([CH2:29][CH3:30])[CH2:23]2)=[O:15])=[C:11]([O:19][CH3:20])[CH:10]=1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Reactant: CCN1CC(N)CN1CC
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCN1CC(NC(=O)c2cc(Cl)c(N)cc2OC)CN1CC
Reaction time: 0.17 h

Procedure:
To 75 ml. of thionyl chloride was added 12 g. (0.05 mole) of 4-acetamido-5-chloro 2-methoxy-benzoic acid and the stirred suspension refluxed one hour. The resulting solution was concentrated and 100 ml. of chloroform added to the residue which was concentrated to remove traces of thionyl chloride. The residue was dissolved in 100 ml. of chloroform and the solution added at a rapid drop to 7 g. (0.05 mole) of 4-amino-1,2-diethylpyrazolidine in 100 ml. of chloroform while stirring and cooling to 20°-25° C. with an ice bath. After 30 minutes the chloroform solution was extracted two times with 100 ml. of 3 N hydrochloric acid and the chloroform solution retained. The acid extract was boiled 10 minutes, cooled with ice, made basic with concentrated sodium hydroxide while cooling and extracted with chloroform. The chloroform was dried (sodium sulfate), concentrated and the residue crystallized from isopropyl ether-isooctane to give 3 g. of material which melted at 116°-118° C. The retained chloroform solution was extracted with dilute sodium hydroxide and concentrated. The residue was dissolved in 3 N hydrochloric acid and extracted with isopropyl ether. The acid solution was refluxed for 10 minutes, cooled with ice bath, made basic with sodium hydroxide while cooling and extracted with chloroform. The chloroform was dried (sodium sulfate) and concentrated. The residue was crystallized three times from isopropyl ether to give 0.7 g. of material which melted at 117°-119° C. A mixture melting point of both materials gave no depression of the melting point. The combined yield was 3.7 g. (23%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14].O>CN(C)C=O>[N:1]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2cccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the mixture of pyrrole (2.3 ml) and 60% sodium hydride (1.3 g) in N,N-dimethylformamide (50 ml) was added methyl 3-(bromomethyl)benzoate (5.0 g) under ice-cooling and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with water, dried over magnesium sulfate and evaporated to give methyl 3-(pyrrol-1-yl)methylbenzoate (4.14 g) as an oil.