Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCCOC1C=CC(CCN)=CC=1)C.[C:16]([NH:26][CH2:27][CH2:28][C:29]1C=C[C:32]([OH:35])=[CH:31][CH:30]=1)(OCC1C=CC=CC=1)=O.[OH-].[K+].CS(OCCOCC)(=O)=O.C(OCCOC1C=CC(CCNC(=O)OCC2C=CC=CC=2)=CC=1)C>CS(C)=O.CO>[O:35]1[CH2:32][CH:31]1[C:30]1[CH:16]=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(NCCc1ccc(O)cc1)OCc1ccccc1
Agent: CCOCCOS(C)(=O)=O
Agent: CCOCCOc1ccc(CCN)cc1
Agent: CCOCCOc1ccc(CCNC(=O)OCc2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CO
Product: c1cncc(C2CO2)c1

Procedure:
from 1.3 g of p-(2-ethoxyethoxy)-phenethylamine (prepared by the reaction of N-carbobenzoxytyramine in DMSO in the presence of potassium hydroxide with ethoxyethyl methanesulfonate and catalytic hydrogenation of the benzyl [p-(2-ethoxyethoxy)]phenethylcarbamate obtained in methanol in the presence of pd/C) and 726 mg of 3-[(RS)-2-oxiranyl]pyridine there were obtained
Reaction SMILES: CC#N.O[Li].O.[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:18]([NH:20][C:21]2[S:22][C:23]([C:26]([O:28]CC)=[O:27])=[CH:24][N:25]=2)=[O:19])=[CH:13][CH:12]=1)(=[O:10])=[O:9]>C1COCC1.O>[CH3:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH2:31][CH:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[C:18]([NH:20][C:21]2[S:22][C:23]([C:26]([OH:28])=[O:27])=[CH:24][N:25]=2)=[O:19])=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: CCOC(=O)c1cnc(NC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2ncc(C(=O)O)s2)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Ethyl 2-aminothiazole-5-carboxylate (2.21 g, 12.8 mmol) was condensed with 2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionic acid (Preparation 41, 1.00 g, 3.2 mmol) using the procedure described for EXAMPLE 65, to give ethyl 2-[2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionylamino]thiazole-5-carboxylate: m/z (ES+)=508.3 [M+MeCN+H]+. LiOH.H2O (410 mg, 9.8 mmol) was added to a solution of this ester (1.44 g, 3.1 mmol) in THF-H2O (3:1, 30 mL). The mixture was stirred at 20° C. for 16 h and then at 55° C. for 24 h. The solvents were removed in vacuo, then the residue was dissolved in H2O (50 mL). The aqueous solution was washed with EtOAc (20 mL), before being acidified to pH 1 with 2M HCl and extracted with EtOAc (2×100 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to give a solid that was recrystallised (EtOAc-MeOH) to give the title compound: RTA=29.5 min; m/z (ES+)=480.2 [M+MeCH+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[CH:18])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[C:18][C:20]3[CH:21]=[N:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Brc1cnc2ccccc2c1
Reactant: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: O=[N+]([O-])c1cccnc1N1CCC(=CC#Cc2cnc3ccccc3c2)CC1
Yield: 655.7 %

Procedure:
A well homogenised mixture of the Compound 1c (50 mg, 0.21 mmol), 3-bromoquinoline (0.039 ml, 0.21 mmol), bis-(triphenylphosphine)palladium dichloride (5 mg, 0.007 mmol) and tetra-butylammonium fluoride (215 mg, 0.82 mmol) was stirred at 80° C. for 1 h in a sealed vessel. The reaction mixture was cooled, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether gradient from 2:8 to 4:6) affording the title product (0.51 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[C:14]([Si:18]([O:31][CH2:32][CH:33]([F:36])[CH2:34]I)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Si:18]([O:31][CH2:32][CH:33]([F:36])[CH2:34][N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[N:7]=[CH:8][C:9]1=[O:13])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)[Si](OCC(F)CI)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2ncc(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CC(F)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.9 %

Procedure:
7-Methoxyquinoxalin-2(1H)-one (synthesized with Reference to WO2009/1126; 1.50 g, 8.50 mmol) and tert-butyl(2-fluoro-3-iodopropoxy)diphenylsilane (Reference Example 29; 5.64 mmol, 12.75 mmol) were dissolved in N,N-dimethylformamide (60 ml). Cesium carbonate (3.88 g, 11.90 mmol) was added to the solution, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 690 mg (17%) of the title compound in the form of a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:25]2[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=2)[CH2:28][NH:29]C(=O)OC(C)(C)C)[C:5]2[N:6]([N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1.[ClH:40]>C(Cl)Cl.CCOCC>[ClH:40].[ClH:40].[NH2:29][CH2:28][C:27]1[CH:26]=[C:25]([C:4]2[C:5]3[N:6]([N:8]=[C:9]([NH:11][CH:12]4[CH2:13][CH2:14][N:15]([C:18]5[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=5)[CH2:16][CH2:17]4)[N:10]=3)[CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: Cc1cc(-c2cccc(CNC(=O)OC(C)(C)C)c2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(-c2cccc(CN)c2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of tert-butyl 3-(6-methyl-2-(1-(6-methylpyrimidin-4-yl)piperidin-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzylcarbamate (46 mg, 87.0 μmol) in methylene chloride (1 mL) was added 2 M solution of HCl in Ether (500 μL). The suspension was stirred at room temperature over night. The solvent was decanted and the residue was digerated with diethyl ether three times. The title compound was dried under reduced pressure and was obtained as a yellow solid (39 mg, 89%). MS ISP (m/e): 429.3 (100) [(M+H)+], 412.4 (57).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([F:9])=[C:4](Cl)[N:3]=1.[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][C:14]2[CH:13]=[C:12]([CH3:11])[NH:16][N:15]=2)[C:5]([F:9])=[C:6]([Cl:8])[N:7]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Fc1c(Cl)nc(Cl)nc1Cl
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)nc(Cl)c2F)n[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.6 %

Procedure:
To a solution of 2,4,6-trichloro-5-fluoropyrimidine (4.03 g) in absolute ethanol (100 mL) was added DIEPA (5.3 mL) and 5-methyl-1H-pyrazol-3-amine (2.03 g). The resulting solution was stirred at room temperature for 6 hours. The precipitation was filtered and washed with cold ethanol. The compound was dried by vacuum oven give 2,6-dichloro-5-fluoro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine as solid (3.7 g). m/z 262. A mixture of morpholine (0.181 mL), 2,6-dichloro-5-fluoro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (500 mg) and DIPEA (0.505 ml) in absolute ethanol (10.0 ml) was heated at 80° C. for 5 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound as solid (236 mg). 1H NMR δ 12.05 (bs, 1H) 9.57 (s, 1H) 6.21 (s, 1H) 3.67 (t, 4H) 3.57 (t, 4H) 2.22 (s, 3H); m/z 313.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:32])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][C:5]2=O.Cl.[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CO.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH2:34]([O:41]/[N:42]=[C:5]1\[CH2:6][C:7]([CH2:15][O:16][C:17]2[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=2)([CH3:14])[O:8][C:9]2[C:4]\1=[C:3]([CH3:32])[C:2]([OH:1])=[C:11]([CH3:12])[C:10]=2[CH3:13])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)/C(=N/OCc1ccccc1)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reaction time: 168 h

Procedure:
A mixture of 1 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Example 22 of copending U.S. Ser. No. 644,996), 1.2 g of benzyloxylamine hydrochloride and 10 g of methanol was allowed to stand for 7 days at room temperature. At the end of this time, ethyl acetate and an aqueous solution of potassium carbonate were added. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography eluted with a 3:1 by volume mixture of hexane and ethyl acetate, to give the title compound, softening at 64°-69° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:15](=[O:29])[N:16]([CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)[N:17]=2)[CH:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:6]=[CH:5][N:4]3[C:15](=[O:29])[N:16]([CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)[N:17]=[C:3]3[C:2]=2[C:33]2[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccncc1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(Br)c(-c3ccc(Cl)cc3)ncn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ncn12
Temperature: 100 °C
Yield: 22 %

Procedure:
A suspension of 8-bromo-7-(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (24 mg, 0.05 mmol), pyridine-4-boronic acid (51 mg, 0.25 mmol), K3PO4 (53 mg, 0.25 mmol), and Pd(dppf)Cl2.CH2Cl2 (16 mg, 0.02 mmol) in THF (0.5 mL) at room temperature was degassed by bubbling with argon for 1 min. This was then stirred and heated at 100° C. in a sealed vessel for 3 h. Analysis by HPLC/MS indicated that starting material had been consumed. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The product was purified by silica gel column chromatography eluted with ethyl acetate-hexanes. This provided the title compound (5.3 mg) as a yellow solid. HPLC/MS (methanol-water with 10 mM NH4OAc): retention time=3.38 min, [M+H]30 =483.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C)C=O>[C:28]([O:27][C:25](=[O:26])[CH2:24][N:10]1[C:8]2[N:9]=[C:4]([NH2:3])[N:5]=[CH:6][C:7]=2[CH:13]=[C:12]([C:14]2[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:20])[C:11]1=[O:22])([CH3:31])([CH3:30])[CH3:29]
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Temperature: 50 °C
Yield: 30.1 %

Procedure:
To a suspension of NaH (60% in mineral oil, 67 mg) in 10 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (398 mg, 1.30 mmol). The mixture was heated at 45° C. to 55° C. for 40 minutes resulting in a clear solution. Tert-butyl bromoacetate (250 μL, 1.69 mmol) was added, and the solution was stirred at 50° C. for several minutes, then cooled to room temperature and poured onto 60 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The solid was purified by flash chromatography, eluting with a gradient of 1:2 hexane:ethyl acetate to all ethyl acetate to provide 165 mg (30%) of [2-amino-6-(2,6-dichlorophenyl)-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-yl]-acetic acid tert-butyl ester; mp 171°-173° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19]2[S:32][C:31]([CH2:33][OH:34])=[CH:30][C:20]=2[N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:41][CH2:42][CH2:43][CH2:44]Br>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:44][CH2:43][CH2:42][Br:41])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19]2[S:32][C:31]([CH2:33][OH:34])=[CH:30][C:20]=2[N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[N:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(O)cc3n2C(=O)OC(C)(C)C)c2sc(CO)cc21
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCBr)cc3n2C(=O)OC(C)(C)C)c2sc(CO)cc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a suspension of 2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-hydroxy-indole-1-carboxylic acid tert-butyl ester [1.45 g, 2.99 mmol, Intermediate (76)] in 1,3 dibromopropane (5 mL) was added cesium carbonate (2.43 g, 7.48 mmol). The suspension was stirred at 80° C. for 3 hours. It was allowed to cool down to room temperature. The insoluble was filtered off. The filtrate was loaded on silica gel for chromatography (n-heptane/ethyl acetate, 100/0 then gradually to 65/35 as eluant) to produce 6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [990 mg, 55%, Intermediate (77)]. LC/MS: 606.1 (M+H), RT=3.22 minutes.
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:32]=[CH:31][C:18]4[N:19]([CH2:28][CH2:29][OH:30])[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>N1C=CC=CC=1>[C:33]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:32]=[CH:31][C:18]4[N:19]([CH2:28][CH2:29][O:30][C:39](=[O:46])[C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCCn1c(-c2ccccc2)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Solvent: c1ccncc1
Product: O=C(OCCn1c(-c2ccccc2)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
To a stirred mixture of 5.03 parts of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-2-phenyl-1H-benzimidazole-1-ethanol and 50 parts of pyridine are added dropwise 3 parts of benzoyl chloride at room temperature. Upon completion, stirring at room temperature is continued for 2 hours. The reaction mixture is evaporated and water is added to the residue. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 20 parts of 2-propanol. The product is filtered off, washed with 2-propanol and with 2,2'-oxybispropane and dried, yielding 4 parts (66.5%) of [2-{5-[4-(diphenylmethyl)-1-piperazinylmethyl]-2-phenyl-1H-benzimidazol-1-yl}ethyl]benzoate; mp. 164.1° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH2:7][CH:8]([NH:23][C:24](=[O:43])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:9]([OH:22])[CH2:10][O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:44])[CH2:7][CH:8]([NH:23][C:24](=[O:43])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:9](=[O:22])[CH2:10][O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)CCCCCCCCCCNC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(NC(=O)CCCCCCCCCCNC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F
Yield: 40.9 %

Procedure:
Composition 15 (56 mg, 0.088 mmol) and Dess-Martin periodinane (48 mg, 0.114 mmol, 1.3 equiv) in DCM (2 mL) were added to a dry round bottom flask equipped with a magnetic stir bar. The cloudy white suspension was allowed to react for 20 minutes. Saturated NaHCO3 (20 ml) was added and the reaction was extracted with EtOAc (20 mL). The organic layer was dried over NaHCO3, concentrated in vacuo, and purified via column chromatography (silica gel, 1:1, hexanes/EtOAc) to give 16 (23 mg, 0.036 mmol, 64% yield) as a sticky white solid. ESMS: 635.4 (M+H+), 657.2 (M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([N:13]([CH3:34])[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[C:24]([N+:31]([O-])=O)[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:12]([N:13]([CH3:34])[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([NH2:28])[CH:25]=[C:24]([NH2:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1N(C)C(=O)N1CCN(c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCO
Product: COc1nc2ccccc2nc1N(C)C(=O)N1CCN(c2cc(N)cc(N)c2)CC1
Reaction time: 4 h
Yield: 44.5 %

Procedure:
To 1-[(2-methoxyquinoxalin-3-yl)N-methylaminocarbonyl]-4-(3,5-dinitrophenyl)piperazine dissolved in ethanol (30 ml), 10% palladium/carbon (10 mg) was added. The mixture was hydrogenated for 4 hours, and then filtered to remove the 10% palladium/carbon. The filtrate was concentrated and purified by column chromatography to obtain the titled compound.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]4[O:24][CH2:23][CH2:22][NH:21][CH2:20][C:19]=4[CH:25]=3)=[CH:14][C:8]=2[N:7]=1)[CH3:4].Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=2)[N:30]=[C:29]([CH3:39])[N:28]=1.C(N(C(C)C)CC)(C)C.O>CN1C(=O)CCC1>[CH2:3]([NH:5][C:6]1[NH:7][C:8]2[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]4[O:24][CH2:23][CH2:22][N:21]([C:27]5[C:36]6[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=6)[N:30]=[C:29]([CH3:39])[N:28]=5)[CH2:20][C:19]=4[CH:25]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:4]
Reactant: CCNc1nc2cc(-c3ccc4c(c3)CNCCO4)ccc2[nH]1
Reactant: COc1ccc2c(Cl)nc(C)nc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CCNc1nc2ccc(-c3ccc4c(c3)CN(c3nc(C)nc5cc(OC)ccc35)CCO4)cc2[nH]1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a mixture of N-ethyl-5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-amine dihydrochloride (50 mg, 0.13 mmol) and 4-chloro-7-methoxy-2-methylquinazoline (27 mg, 0.13 mmol) in NMP (1 mL) was added diisopropylethylamine (91 uL, 0.52 mmol). The mixture was heated to 90° C. and stirred for 1 h. After cooling to rt, water was added, and the resulting aqueous mixture was extracted twice with 10% methanol in ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered, and then concentrated. The residue was purified by reverse-phase preparative HPLC to provide N-ethyl-6-{4-[2-methyl-7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1H-benzimidazol-2-amine as an acetate salt (34.2 mg, 0.063 mmol, 49% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.91 (br s, 1H), 10.83 (br s, 1H), 7.92 (d, 1H), 7.58 (d, 1H), 7.43 (dd, 1H), 7.35 (s, 1H), 7.20-7.10 (m, 3H), 7.05-6.97 (m, 2H), 6.61 (br s, 1H), 4.99 (s, 2H), 4.44-4.38 (m, 2H), 4.18-4.11 (m, 2H), 3.33-3.25 (m, 2H), 2.44 (s, 3H), 1.91 (s, 4H), 1.19 (t, 3H); MS (EI) for C28H28N6O2: 481 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.Cl.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([OH:27])[C:21]=1[OH:28].CCN(CC)CC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([OH:27])[C:21]=1[OH:28]
Reactant: NCc1ccc(O)c(O)c1O
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNCc1ccc(O)c(O)c1O
Yield: 28.9 %

Procedure:
To a mixture of 6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (200 mg, 0.71 mmol) and 4-aminomethyl-benzene-1,2,3-triol hydrochloride salt (139.6 mg, 1 mmol) in N,N-dimethylformamide (DMF) (10 mL) is added Et3N (0.25 mL, 1.83 mmol). The resulting precipitate is filtered to give 83 mg (28.9%) of the title compound as a dark brown solid. (ESI) m/z 403.0 (M−H)−1. 1H NMR (DMSO-d6) δ 4.53 (d, 2H, J=6 Hz), 6.29 (d, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 7.28 (d, 1H, J=8 Hz), 7.85 (d, 1H, J=8 Hz), 8.05 (s, 1H), 8.39 (s, 1H), 8.67 (d, 1H, J=12 Hz), 8.80 (s, 1H), 9.18 (s, 1H), 10.63-10.68 (m, 1H), 11.05 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:16]=2[C:17]([O:19]C(C)(C)C)=[O:18])[CH:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:16]=2[C:17]([OH:19])=[O:18])[CH:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(Nc2cnc(-c3ccccc3)c(F)c2)c(C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Nc2cnc(-c3ccccc3)c(F)c2)c(C(=O)O)c1

Procedure:
A solution of tert-butyl 2-(5-fluoro-6-phenylpyridin-3-ylamino)-5-methylbenzoate (0.83 mmol, 0.313 g) in TFA (5 ml) was stirred at room temperature for 30 minutes. The solvent was reduced under reduced pressure and the crude mixture was purified by reverse phase chromatography using a 30% to 100% (Water-ACN) gradient and affording 0.119 g (40% of yield) of the expected product.