Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[F:11][C:12]1[CH:13]=[CH:14][C:15]2[N:19]=[C:18]([CH:20]([NH2:22])[CH3:21])[N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:16]=2[CH:30]=1.CCN(C(C)C)C(C)C>C(O)CCC>[F:11][C:12]1[CH:13]=[CH:14][C:15]2[N:19]=[C:18]([CH:20]([NH:22][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:21])[N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:16]=2[CH:30]=1
Reactant: CC(N)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a microwave vessel was added 6-chloropurine (0.113 g, 0.732 mmol), 1-(6-fluoro-1-(3-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethanamine (Prepared in Example 22, 0.200 g, 0.732 mmol), and DIEA (0.256 mL, 1.46 mmol) in n-butanol (3.66 mL). The solution was stirred at 120° C. for 3 h, filtered and the resulting precipitate was washed with EtOAc:hexane (1:4) to give an off-white solid. The solid was purified by column chromatography on a silica gel column using 10 to 90% gradient of DCM:MeOH:NH4OH (90:10:1) in DCM as eluent to give an off-white solid. This material was triturated in EtOAc:hexane (1:3) and the suspension was filtered to give N-(1-(6-fluoro-1-(3-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethyl)-9H-purin-6-amine as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60 (d, J=6.65 Hz, 3H) 5.57 (br. s., 1H) 6.94 (dd, J=8.90, 2.25 Hz, 1H) 7.11 (td, J=9.39, 2.35 Hz, 1H) 7.29 (t, J=7.04 Hz, 1H) 7.40-7.47 (m, 1H) 7.47-7.63 (m, 2H) 7.70 (dd, J=8.80, 4.89 Hz, 1H) 7.94 (s, 1H) 8.07 (s, 1H) 8.12 (s, 1H) 12.78 (br. s., 1H); LC-MS (ESI) m/z 392.1 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)[CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=2)[CH2:3][CH2:2]1.[Sn](Cl)Cl.Cl>C(O)C>[CH:1]1([C:4]2[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cn1nnnc1-c1cc(C2CC2)cc([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Cn1nnnc1-c1cc(N)cc(C2CC2)c1
Yield: 42.4 %

Procedure:
5-(3-Cyclopropyl-5-nitrophenyl)-1-methyl-1H-tetrazole (1.4 g, 5.7 mmol) was treated with tin (II) chloride (4.3 g, 22.8 mmol) and hydrochloric acid (0.5 mL) in ethanol (15 mL) at reflux for 1 hour. The solvent was removed under vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was washed with 1M aqueous potassium carbonate solution, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography, on silica gel, eluting with hexanes:ethyl acetate (70:30), to yield 3-cyclopropyl-5-(1-methyl-1H-tetrazol-5-yl)benzenamine (520 mg, 43% yield) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].C([O-])([O-])=O.[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([NH:7][NH:8][C:21](=[O:22])[CH2:20][Cl:19])=[O:6]
Reactant: NNC(=O)c1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CCl)NNC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
To a mixture of 3,5-dichlorobenzohydrazide 5 (0.5 g, 2.4 mmol) and K2CO3 (0.61 g, 4.4 mmol) in acetonitrile (30 mL) was added 2-chloroacetyl chloride (0.41 g, 3.66 mmol) dropwise at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 hours. The solid was collected, washed with H2O and ether, and dried to afford 3,5-dichloro-N′-(2-chloroacetyl)benzohydrazide 6 (0.63 g, 92%) which was used for the next step without further purification. A mixture of 3,5-dichloro-N′-(2-chloroacetyl)benzohydrazide 6 (0.63 g, 2.24 mmol) and phosphorous oxychloride (0.51 g, 3.36 mmol) in acetonitrile (20 mL) was stirred under reflux for 16 hours and concentrated. The residue was subjected to flush column chromatography eluting with 10-25% acetone/hexanes to give compound 7 (0.52 g). Yield: 88%.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH2:23]>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:21]=3[F:20])=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(O)C1c2ccccc2COc2ccc(Br)cc21
Reactant: Nc1ccc(F)cc1F
Product: O=C(Nc1ccc(F)cc1F)C1c2ccccc2COc2ccc(Br)cc21
Yield: 47.5 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.0 g of 2-bromo-6,11-dihydrodibenz[b,e]oxepin-11-carboxylic acid obtained in Example 46 (Compound H) in place of Compound A and 0.48 g of 2,4-difluoroaniline in place of aniline to obtain 0.64 g of Compound 40.
Reaction SMILES: C1CCC(N=C=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)CC1.[CH:16]1[CH:17]=CC2N(O)N=N[C:20]=2[CH:21]=1>CO>[CH3:17][CH2:16][CH2:21][CH2:20][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:10][NH2:9]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: On1nnc2ccccc21
Solvent: CO
Product: CCCCCCCCCCN

Procedure:
Equation 2 shows the synthetic steps involved in the construction of the required N-[p methyl-aminobenzoyl]-glutamyl-γ-4-fluoroglutamic acid (12). The free acid 7 was obtained by treatment with Dowex 50WX8 in 60% EtOH/H2O. Coupling of the α, γ carboxyl protected D,L-erythro, threo-4-fluoroglutamate ester to 8 was accomplished using DCC/HOBt giving the pipeptide 9 in 90% yield, hydrogenation of 9 in MeOH using 10% Pd on carbon catalyst gave the free amine 10 in quantitative yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[NH:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:30]4[CH:31]=[N:27][NH:28][CH:29]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3cn[nH]c3)cc1OCC2)c1ccccc1Cl

Procedure:
Following Examples 44 and 60, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and pyrazole-4-boronic acid pinacol ester were reacted to give 132. MS: (ESI+) 436.1
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[C:20]([C:27]([F:30])([F:29])[F:28])[CH:19]=1>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][C:20]=2[C:27]([F:29])([F:28])[F:30])=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: O=C=Nc1ccc(Cl)cc1C(F)(F)F
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2C(F)(F)F)cc1-c1c(Cl)cnn1C
Yield: 8 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-chloro-2-trifluoromethylphenyl isocyanate in a similar manner as described in Example 1.53, providing 4.4 mg (8%) of Compound 79 (Note: Compound 79 did not precipitate out. Therefore, the CH2Cl2 was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative HPLC): LCMS m/z (%)=461 (M+H37Cl, 60), 459 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.99 (s, 1H), 8.30 (s, 1H), 8.16 (dd, J1=8 Hz, J2=2 Hz, 1H), 8.01 (d, J=8 Hz, 1H), 7.66 (s, 1H), 7.64 (d, J=4 Hz, 1H), 7.45 (d, J=4 Hz, 1H), 7.43 (s, 1H), 7.12 (d, J=8 Hz, 1H), 3.79 (s, 3H), 3.63 (s, 3H).
Reaction SMILES: C(O[C:4](=O)[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][C:11]2[CH:26]=[CH:27][CH:28]=[N:29][C:10]1=2)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:20]1([CH:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:9]([CH2:8][CH2:7][CH2:6][NH:5][CH3:4])[C:10]3[N:29]=[CH:28][CH:27]=[CH:26][C:11]=3[NH:12]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)NCCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCCN1c2ccccc2C(c2ccccc2)Nc2cccnc21

Procedure:
To a solution of 1.4 g (0.0035 mole) of N-[3-[6-phenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-yl]propyl]carbamic acid ethyl ester (from Example 29) in tetrahydrofuran under nitrogen gas was added 0.4 g (0.0105 mole) of lithium aluminum hydride and slight exothermic reaction occurred. The mixture was cooled to prevent overheating. The mixture was stirred at reflux temperature for 6 hr. Thin layer chromatography indicated only partial conversion had occurred. An additional 0.4 g (0.0105 mole) of lithium aluminum hydride was added and the mixture refluxed overnight. Thin-layer chromatography indicated the product was predominantly the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[N:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]2[CH:18]=1)=[O:5])C.O.[OH-].[Li+]>O1CCCC1.O>[F:17][C:14]([F:15])([F:16])[C:11]1[N:12]=[CH:13][C:8]2[N:9]([CH:18]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH:10]=1
Reactant: CCOC(=O)c1cn2cc(C(F)(F)F)ncc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn2cc(C(F)(F)F)ncc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Step A was dissolved in tetrahydrofuran (10 mL) and a solution of lithium hydroxide monohydrate (97 mg, 8.3 mmol) in water (5 mL) was added. The reaction mixture was stirred at room temperature for one hour, after which time the tetrahydrofuran was removed on a rotary evaporator under reduced pressure, and water was added (5 mL), followed by the addition of 1 N HCl (5 mL). The resulting suspension was filtered through a glass-fritted filter funnel, and the isolated solid was washed with water and dried over nitrogen to afford 451 mg of the title compound as a solid. 1H NMR ((CD3)2SO) δ 9.33 (s, 1H), 9.30 (s, 1H), 8.69 (s, 1H).
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7](I)[CH:6]=1.[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15]>O1CCCC1>[Cl:15][C:14]1[N:13]=[C:20]([Cl:21])[N:19]=[C:17]([C:7]2[CH:6]=[C:5]([Cl:4])[CH:10]=[CH:9][C:8]=2[CH3:11])[N:16]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1ccc(Cl)cc1I
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Alternatively, to a mixture of magnesium (1.46 g, 60.0 mmol) and tetrahydrofuran (100 ml) was added a small crystal of iodine followed by 4-chloro-2-iodo-toluene (12.62 g, 50 mmol). The mixture was heated under gentle reflux in an argon atmosphere for 6 hours and then cooled to −78° C. A solution of cyanuric chloride (7.84 g, 42.5 mmol) in tetrahydrofuran (45 ml) was added over 25 minutes. After stirring at −78° C. for 1 hour, the mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture, cooled in an ice bath, was quenched by slow addition of hydrochloric acid (1 M, 15 ml). The mixture was diluted with water (150 ml) and extracted with dichloromethane (3×125 ml). The combined extracts was washed with water (150 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (7:93) to provide 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine (10.2 g, 87% yield) as a white powder.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([O:22][CH3:23])[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=2)=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([O:22][CH3:23])[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=2)=[CH:5][CH:6]=1
Reactant: COC(Cc1ccc(C#CCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CO[C@@H](Cc1ccc(CCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared as follows: (2S) 3-{4-[3-(Biphenyl-4-yloxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionic acid (0, Step C) (0.0325 g, 0.08 mmol) was dissolved in methanol (10 mL). Palladium 10% an activated carbon (0.004 g, 0.004 mmol) was added and the solution saturated with hydrogen (1 Atm) and stirred for 5 hours. The mixture was filtered through a pad of celite and concentrated under vacuum. The residue was purified by column chromatography (silica gel, hexanes/Ethyl acetate-Acetic acid 50:50:1, Rf0.23) (85%). 1H-NMR (CDCl3, 200.15 MHz): δ 7.56–7.24 (m, 11H), 6.94 (d, 2H, J=8.8), 4.02–3.95 (m, 3H), 3.38 (s, 3H), 3.11 (dd, 1H, J=14.3, 4.4), 2.98 (dd, 1H, J=14.3, 7.3), 2.79 (t, 2H, J=8.1), 2.16–2.03 (m, 3H). MS (ES) for C25H26O4 [M+NH4]+: 408.2, [M+Na]+: 413.2.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:8][Br:9])([CH2:6][OH:7])[CH2:4][OH:5].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)O>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([CH2:8][Br:9])[CH2:6][O:7][CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:5][CH2:4]1
Reactant: O=Cc1ccccc1
Reactant: OCC(CO)(CBr)CBr
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: BrCC1(CBr)COC(c2ccccc2)OC1
Reaction time: 6 h
Yield: 88.6 %

Procedure:
2,2-Bis(bromomethyl)propane-1,3-diol (250 g) and benzaldehyde (110 g) were added to benzene (500 cm3) containing concentrated sulphuric acid (2 cm3) and the mixture boiled. Water was removed using a Dean Stark apparatus. After about 6 hours the reaction was complete. The mixture was cooled and the sulphuric acid neutralised by the addition of excess sodium bicarbonate. The resulting solution was filtered and the benzene removed under reduced pressure to give an oil which solidified on standing. Recrystallisation from petroleum ether gave the 1,3-dioxane (296 g) as a white solid (m.p. 66° C.).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]#[N:13])[C:7]=1[O:14][CH3:15]>CN(C)C=O.O>[N:1]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]#[N:13])[C:7]=1[O:14][CH3:15])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1c(Br)ccnc1C#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(N=[N+]=[N-])ccnc1C#N
Temperature: 25 °C
Reaction time: 6 h
Yield: 35.2 %

Procedure:
To 1 g (0.0155 moles) of sodium azide in 25 ml of dimethylformamide at 0° C., there is added gently 3 g (0.0141 moles) of 4-bromo-2-cyano-3-methoxypyridine from Example b), dissolved in 40 ml of dimethylformamide. The mixture is stirred for 6 hours at ambient temperature. The reaction mixture is diluted in 200 ml of iced water and extracted with dichloromethane. The organic phase is washed twice with water, dried, concentrated and the residue chromatographed (ethyl acetate/heptane, 3:7). There is obtained 0.87 g (35% yield) of a white solid (MP=102° C.).
Reaction SMILES: CC1[C:11]2([O:19][C:18]3[C:13](=[C:14](O)[CH:15]=[C:16](C=O)[C:17]=3C(O)=O)C2)C2(C)C(C(C)(C)C(O)C(O)C2)CC1.[N:31]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[C:34]([NH:41][CH2:42]C2C=CC(OC)=CC=2)=[N:33][N:32]=1.C(=O)=O>CS(C)=O>[N:31]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[C:34]([N:41]([C:15]2[CH:14]=[CH:13][C:18]([O:19][CH3:11])=[CH:17][CH:16]=2)[CH3:42])=[N:33][N:32]=1
Reactant: COc1ccc(CNc2nnnc3ccccc23)cc1
Reactant: CC1CCC2C(C)(C)C(O)C(O)CC2(C)C12Cc1c(O)cc(C=O)c(C(=O)O)c1O2
Agent: O=C=O
Solvent: CS(C)=O
Product: COc1ccc(N(C)c2nnnc3ccccc23)cc1
Reaction time: 0.21 h

Procedure:
T-47D, HT29, H1299, MX-1 and MDAMB435 cells were grown and harvested as in Example 29. An aliquot of 90 μL of cells (4.4×104 cells/mL) was added to a well of a 96-well microtiter plate containing 5 μL of a 10% DMSO in RPMI-1640 media solution containing 10 nM to 100 μM of benzo[d][1,2,3]triazin-4-yl-(4-methoxy-phenyl)methyl-amine (1 nM to 10 μM final). An aliquot of 45 μL of cells was added to a well of a 96-well microtiter plate containing 5 μL of a 10% DMSO in RPMI-1640 media solution without compound as the control sample for maximal cell proliferation (LMax). The samples were mixed by agitation and then incubated at 37° C. for 48 h in a 5% CO2-95% humidity incubator. After incubation, the samples were removed from the incubator and 25 μL of CellTiter-Glo™ reagent (Promega) was added. The samples were mixed by agitation and incubated at room temperature for 10-15 min. Plates were then read using a luminescent plate reader (Model SPECTRAfluor Plus, Tecan) to give Ltest values.
Reaction SMILES: CS[C:3]1[C:12]2[C:7]([CH:8]=[N:9][CH2:10][N:11]=2)=[CH:6][C:5]2=[N:13][CH:14]=[N:15][C:4]=12.[C:16]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])#[CH:17].[ClH:25].N1C=CC=CC=1>C(O)(C)(C)C>[ClH:25].[C:16]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH:21][CH:6]1[C:7]2[N:8]=[CH:9][N:10]=[CH:11][C:12]=2[CH:3]=[C:4]2[N:15]=[CH:14][N:13]=[C:5]12)#[CH:17]
Reactant: CSc1c2c(cc3c1=NCN=C3)=NC=N2
Reactant: C#Cc1cccc(N)c1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: c1ccncc1
Product: C#Cc1cccc(NC2C3=NC=NC3=Cc3cncnc32)c1
Temperature: 25 °C

Procedure:
A mixture of 4-methylthio-6H-imidazo[4,5-g]quinazoline (0.0455 g, 0.210 mmol), prepared as described in Leonard, N. J.; Morrice, A. G.; Sprecker, M. A., J. Org. Chem., 1975, 40 (3), 356-363, 3-ethynylaniline (0.0672 g, 0.574 mmol) and pyridine hydrochloride (0.0274 g, 0.237 mmol) in t-butanol (5 mL) was heated to reflux for 6 hours then cooled to room temperature. Precipitate was collected and washed with t-butanol to give 4-(3-ethynylanilino)-imidazo[4,5-g]-quinazoline hydrochloride as a yellow solid: 0.0349 g (58%); 1H NMR (DMSO-d6) δ4.34 (1H, s), 7.48 (1H, m), 7.53 (1H, m), 7.82 (1H, m), 7.98 (1H, s), 8.13 (1H, s), 8.81 (1H, s), 8.99 (1H, s), 9.24 (1H, s), 11.49 (1H, br s ); m/e 286 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH3:28][N:29]([CH3:44])[C:30]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:31]=1[CH:32]=[CH:33][CH:34]=[C:35]2[S:40](Cl)(=[O:42])=[O:41].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:40]([C:35]3[C:36]4[C:31](=[C:30]([N:29]([CH3:44])[CH3:28])[CH:39]=[CH:38][CH:37]=4)[CH:32]=[CH:33][CH:34]=3)(=[O:42])=[O:41])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(Sc2ccc(OS(=O)(=O)c3cccc4c(N(C)C)cccc34)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 19 (167 mg, 0.94 mmol) was reacted with 5-Dimethylamino-naphthalene-1-sulfonyl chloride (245 mg, 0.94 mmol) in 10 mL of CH2Cl2 with N,N-diisopropylethylamine (0.530 mL, 410 mmol) for 22 h. Washed with water and dried over Na2SO4, filtered and concentrated under vacuum giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (35 mg, 40%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.75 (s, 3 H) 2.86 (s, 6 H) 6.65 (d, J=6.99 Hz, 1 H) 6.76 (d, J=9.19 Hz, 2 H) 6.87 (d, 2 H) 7.16 (d, J=8.82 Hz, 1 H) 7.34 (d, J=7.72 Hz, 1 H) 7.53-7.62 (m, 2 H) 7.69-7.79 (m, 3 H) 7.97 (d, J=7.35 Hz, 1 H) 8.22 (d, J=8.82 Hz, 1 H) 8.50 (d, J=6.99 Hz, 1 H) 8.60 (d, J=8.46 Hz, 1 H) 8.82 (d, J=8.82 Hz, 1 H); MS 1 H) 8.50 (d, J=6.99 Hz, 1 H) 8.60 (d, J=8.46 Hz, 1 H) 8.82 (d, J=8.82 Hz, 1 H); MS (DCI NH3+) m/z 611 (M+H)+.
Reaction SMILES: C([O-])C.[Na+].[O:5]=[C:6]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[N:14][C:15]#[N:16]>C(O)C>[NH2:16][C:15]1[N:14]=[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:7]=1[C:6]([C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)=[O:5]
Reactant: Cc1ccc(C(=O)CN2CCCCC2=NC#N)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C(=O)c2c(N)nc3n2CCCC3)cc1
Yield: 68.5 %

Procedure:
Sodium ethanolate (2.44 mL; 6.55 mmol) was added to a solution of N-(1-(2-oxo-2-p-tolylethyl)piperidin-2-ylidene)cyanamide (1.52 g; 5.95 mmol) in dry ethanol (36 mL) under a nitrogen atmosphere and the reaction mixture was heated at reflux for 30 min. After cooling, the volatiles were removed under reduced pressure and the crude residue was purified by flash-chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane to afford 1.04 g (68%) of (2-amino-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)(p-tolyl)methanone as a brownish solid. ESI/APCI(+): 256 (M+H). 1H NMR (DMSO-d6): δ 7.35 (m, 4H, Harom.); 5.63 (bs, 2H, NH2); 3.64 (m, 2H, CH2); 2.66 (m, 2H, CH2); 2.36 (s, 3H, CH3); 1.74 (m, 4H, 2×CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:35])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21]Cl)=[N:19][N:18]=[C:17]1[CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].[I-].[K+].[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:35])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:40]([CH2:41][CH3:42])[CH2:38][CH3:39])=[N:19][N:18]=[C:17]1[CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]
Reactant: O=C(NCc1nnc(CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl)OCc1ccccc1
Reactant: CCNCC
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN(CC)Cc1nnc(CNC(=O)OCc2ccccc2)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
To a solution of 2',5-dichloro-2-(3-carbobenzoxyaminomethyl-5-chloromethyl-4H-1,2,4-triazol-4yl)-benzophenone (1.32 g) in methanol (20 ml) and chloroform (20 ml), potassium iodide (0.4 g) and diethylamine (3 ml) are added, and the resultant mixture is refluxed for 5 hours. The reaction mixture is evaporated under reduced pressure to remove the solvent, and the residue is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried, and evaporated under reduced pressure to remove the ethyl acetate. The residue is treated with ether to give 2',5-dichloro-2-(3-carbobenzoxyaminomethyl-5-diethylaminomethyl-4H-1,2,4-triazol-4-yl)-benzophenone (1.1 g). The product is recrystallized from ether-ethyl acetate to give crystals melting at 89° to 94° C.
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH:12]=[C:11]([S:36][CH3:37])[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C1C=C(Cl)C=C(C(OO)=[O:46])C=1>C(Cl)Cl>[NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:31][CH2:32][CH:33]2[CH2:34][CH2:35]2)[CH:12]=[C:11]([S:36]([CH3:37])=[O:46])[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(SC)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Solvent: ClCCl
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(S(C)=O)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.6 %

Procedure:
To a cold (0° C.) solution of tert-butyl 2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-4-(methylsulfanyl)nicotinate (1.72 g, 3.30 mmol) in CH2Cl2 (20 mL) was added m-CPBA (69%, 0.82 g, 3.30 mmol). The reaction mixture was stirred at 0° C. for 15 min, quenched with saturated aqueous NaHCO3 solution (20 mL) containing Na2S2O3 (1 g). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography on silica gel (hexane/ethyl acetate=3:2 to 1:1) gave solid, which was triturated with ethyl acetate and diisoproyl ether to give tert-butyl 2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-4-(methylsul-finyl)nicotinate as a white powder (1.112 g, yield; 63%).