Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1.[NH2:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19]>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: CC(C)(O)CN
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Solvent: ClCCl
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A mixture of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine (92.5 g, 321 mmol) and dichloromethane (1.5 L) was cooled to 10° C. 1-Amino-2-methylpropan-2-ol (63.01 g, 707 mmol) was added dropwise over a period of 30 minutes; during the addition, the reaction temperature did not rise above 13° C. The reaction mixture was allowed to warm to room temperature slowly and stirred overnight. The solvent was removed under reduced pressure, and the solid residue was mixed with deionized water (200 mL). The solid was isolated by filtration, washed with deionized water (2×200 mL), and dried in a vacuum oven overnight at 35° C. to provide 1-[(7-bromo-3-nitro[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]=[C:6]1[CH2:9][CH2:8][CH2:7]1)[CH3:2].[N+:11]([CH3:14])([O-:13])=[O:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]1([CH2:14][N+:11]([O-:13])=[O:12])[CH2:9][CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1CCC1
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.1 %

Procedure:
The unsaturated ester (2) (5.79 g, 41.4 mmol) was dissolved in tetrahydrofuran (20 mL) and stirred at 70° C. with nitromethane (4.67 mL, 86.4 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 55 mL, 55.0 mmol). After 18 hours, the mixture was cooled to room temperature, diluted with ethyl acetate (150 mL), and washed with 2N HCl (60 mL) followed by brine (100 mL). The organic phase was collected, dried (MgSO4), and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate:heptane 1:1) to give 4.34 g (52%) of a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11](=[O:27])[CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)(=[O:16])=[O:15].Cl[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:36])[F:37])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11](=[O:27])[CH2:12][N:13]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)(=[O:15])=[O:16]
Reactant: COc1ccc(S(=O)(=O)NCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(S(=O)(=O)N(CCN2CCOCC2)CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Temperature: 40 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,4-dimethoxyphenylsulfonamido)acetoxy)ethyl)pyridine 1-oxide (30 mg, 0.04 mmol) was dissolved in DMF (1 ml), then 4-(2 chloroethyl)morpholine free base (33 mg, 0.22 mmol), K2CO3 (12 mg, 0.088 mmol) and KI (7 mg, 0.0044 mmol) were added, and the mixture was stirred at 40° C. for 6 hours. The reaction was diluted with water, and the product was extracted with EtOAc. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude product was purified by Preparative reverse-phase HPLC to give 25 mg of the final product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=1[CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH2:19][CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1cc(C(=O)OC)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1cc(C(=O)O)ccc1OCc1ccccc1
Yield: 97.5 %

Procedure:
A solution of methyl 4-benzyloxy-3-propylbenzoate (6.84 g, 24.1 mmol) and a sodium hydroxide solution (2 mol/L, 30 ml) in ethanol (100 mL) was heated under reflux for two hours. The reaction solution was concentrated and then made acidic with dilute hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was recrystallized (hexane-ethyl acetate) to obtain 6.35 g of the title compound (yield: 98%) as a white powder.
Reaction SMILES: B(F)(F)F.CCOCC.[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:27])[C:16]([C:22](OCC)=[O:23])=[CH:17][N:18]2[CH3:21])=[CH:13][CH:12]=1.[CH3:28][NH2:29]>>[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:27])[C:16]([C:22]([NH:29][CH3:28])=[O:23])=[CH:17][N:18]2[CH3:21])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1cn(C)c2cc(Cl)ccc2c1=O
Reactant: CN
Agent: FB(F)F
Solvent: CCOCC
Product: CNC(=O)c1cn(C)c2cc(Cl)ccc2c1=O
Reaction time: 16 h

Procedure:
Boron trifluoride etherate (5 ml) was added cautiously to a mixture of ethyl 7-chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (5 g) and a solution of methylamine in IMS (32%; 35 ml) and the mixture was boiled under reflux for 8 hours. The same quantities of boron trifluoride etherate and methylamine in IMS were added and the mixture was boiled under reflux for 24 hours. The same quantities of boron trifluoride etherate and methylamine in IMS were added and the mixture was boiled under reflux for 8 hours. The mixture was kept at ambient temperature for 16 hours and then filtered. The residue was washed with IMS, dried and recrystallised from aqueous IMS to give the novel compound 7-chloro-1,N-dimethyl-4-oxo-1,4-dihydroquinoline-3-carboxamide, m.p. 260°-263°.
Reaction SMILES: [IH:1].[CH3:2][C:3]1([CH3:14])[CH2:9][CH2:8][C:7]([CH3:11])([CH3:10])[NH:6][C:5](SC)=[N:4]1.[NH2:15][NH2:16]>C(O)C.CCOCC>[IH:1].[NH:15]([C:5]1[NH:6][C:7]([CH3:11])([CH3:10])[CH2:8][CH2:9][C:3]([CH3:14])([CH3:2])[N:4]=1)[NH2:16]
Reactant: CSC1=NC(C)(C)CCC(C)(C)N1
Reactant: NN
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: CC1(C)CCC(C)(C)NC(NN)=N1

Procedure:
A 10.0 g portion of 4,5,6,7-tetrahydro-4,4,7,7-tetramethyl-2-methylthio-1H-1,3-diazepine, hydroiodide was dissolved in 150 ml of ethanol and 2.5 g of hydrazine was added. The mixture was refluxed 6 hours, diluted with 300 ml of ether and stored at -10° C. The solid was removed by filtration. The filtrate was concentrated to about 25 ml in vacuo, diluted with 50 ml of 2-propanol, then 200 ml of ether and stored at -10° C. The solid was collected, washed with ether and dried in vacuo at 60° C., giving 3.5 g of the desired intermediate, mp 154°-155° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH2:14][OH:15])=[N:10]2)=[C:5]2[NH:16][CH:17]=[CH:18][C:4]=12.C([Mg]Br)C.N1C=CC=CC=1.Cl[C:30](=[O:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1COCC1>[OH:15][CH2:14][C:11]1[N:12]=[CH:13][N:9]([C:6]2[N:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]3[C:18]([C:30](=[O:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:17][NH:16][C:5]=23)[N:10]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1cnc(-n2cnc(CO)n2)c2[nH]ccc12
Agent: CC[Mg]Br
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c[nH]c2c(-n3cnc(CO)n3)ncc(OC)c12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution of (1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)methanol (70 mg, 0.285 mmol) in THF (5 mL) was added ethylmagnesium bromide (1.284 mL, 1.284 mmol) at −40° C. After stirring at −5° C. for 1H, pyridine (0.012 mL, 0.143 mmol) was added quickly. The mixture was cooled to −40° C. and ethyl 2-chloro-2-oxoacetate (0.130 mL, 1.142 mmol) was added. After stirring at −40° C. for 30 min, the reaction mixture was quenched by adding i-PrOH and water. The mixture was extracted with EtOAc (2×40 mL). The organic layers were combined, washed with brine (30 mL), dried over MgSO4 and concentrated under vacuum to give crude product ethyl 2-(7-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (70 mg, 0.203 mmol, 71.0% yield). LCMS: m/z 346.1 (M+H)+, 1.42 min (method 8).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([Cl:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([Cl:23])[CH:29]=[C:28]([Cl:30])[CH:27]=3)[CH2:36][CH2:35]2)=[S:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Product: COc1nc2ccccc2cc1NC(=S)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 62 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 109 to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[O:12][C:11]([CH3:13])=[N:10][CH:9]=2)=[CH:6][CH:5]=[C:4]([Cl:14])[N:3]=1.[CH3:15][O-:16].[Na+]>CO>[Cl:14][C:4]1[N:3]=[C:2]([O:16][CH3:15])[C:7]([C:8]2[O:12][C:11]([CH3:13])=[N:10][CH:9]=2)=[CH:6][CH:5]=1
Reactant: C[O-]
Reactant: Cc1ncc(-c2ccc(Cl)nc2Cl)o1
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)ccc1-c1cnc(C)o1

Procedure:
To a mixture of 2,6-dichloro-3-(2-methyl-1,3-oxazol-5-yl)pyridine (2.22 g) in methanol (25 mL) was added sodium methoxide (5M methanol solution, 1.9 mL) at room temperature, and the mixture was stirred under a nitrogen atmosphere over the weekend. The reaction mixture was concentrated and diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was separated, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and separated by HPLC (column: Chiralpak AD, mobile phase: hexane/2-propanol) to give the title compound (867 mg).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:25]([CH2:26][NH:27][CH2:28][CH3:29])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH:9]=1)[CH3:4].C(N(C(C)C)CC)(C)C.[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:25]([CH2:26][N:27]([C:43]([CH:40]3[CH2:42][CH2:41]3)=[O:44])[CH2:28][CH3:29])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH:9]=1)[CH3:4]
Reactant: CCNCc1cc2ccccc2nc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(-c2nc3ccccc3cc2CN(CC)C(=O)C2CC2)c1
Reaction time: 0.08 h

Procedure:
[3-(3-Ethylaminomethyl-quinolin-2-yl)-4-methoxy-phenyl]-acetic acid ethyl ester, dihydrochloride (0.40 g, 0.89 mmol) and diisopropylethylamine (1.0 mL, 5.74 mmol) were combined in CH2Cl2 (5 mL) and stirred for 5 minutes. Cyclopropanecarbonyl chloride (0.09 mL, 0.99 mmol) was added, and the reaction was stirred at room temperature until no starting material was seen by analytical LCMS. The mixture was partitioned between CH2Cl2 and saturated aqueous NaHCO3, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-75% EtOAc in hexanes) to give the title compound.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]2=[O:18])=[CH:5][CH:4]=1>O1CCCC1>[OH:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH2:13][C:12]([CH3:16])([CH3:17])[CH2:11][C:10]2=[O:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2C(=O)CC(C)(C)CC2=O)cn1
Solvent: C1CCOC1
Product: CC1(C)CC(=O)N(c2ccc(O)nc2)C(=O)C1
Temperature: 190 °C
Yield: 89 %

Procedure:
6′-Methoxy-4,4-dimethyl-4,5-dihydro-3H-[1,3′]bipyridinyl-2,6-dione (2.56 g, 10.3 m dissolved in a mixture of tetrahydrofuran and diethyl ether. HCl-gas was bubbled into the solution for 5 minutes. More diethyl ether was added and the white precipitate was collected by suction, washed twice with diethyl ether and heated in a kugelrohr apparatus at 190° C. for 15 minutes yielding the title compound (2.16 g, 89% yield) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][C:28]([NH2:30])=[O:29])[C:16]([C:31]([F:34])([F:33])[F:32])=[CH:15][N:14]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[CH2:35]=O>CO>[CH3:35][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][C:28]([NH2:30])=[O:29])[C:16]([C:31]([F:33])([F:32])[F:34])=[CH:15][N:14]=3)[CH:9]=[N:8]2)[CH2:5][CH2:6]1
Reactant: C=O
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2cnn(C3CCNCC3)c2)ncc1C(F)(F)F
Solvent: CO
Product: CN1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cn2)CC1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
NaHB(OAc)3 (147 mg, 0.693 mmol) was added cautiously to a stirred solution of 2-(2-(2-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (35) (82 mg, 0.17 mmol) in 37% aqueous formaldehyde solution (39 μL, 0.52 mmol) and MeOH (5.0 mL). The reaction mixture was stirred for 1 hr and then quenched with water (50 mL). The resultant precipitate was removed by filtration, washed with cyclohexane and dried under high vacuum to yield the title compound as a white solid (82 mg, 97%). LCMS-A: rt 4.751 min; m/z 488.3 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:14][C:15]1[C:16](=[O:34])[N:17]([C:21]2[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])[CH:18]=[CH:19][N:20]=1)([CH3:13])[CH3:12].[CH3:35][NH2:36]>O1CCOCC1.C(OCC)(=O)C>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]([CH3:13])([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:36][CH3:35])[CH3:12])[C:16]3=[O:34])[CH:22]=2)[CH2:29][CH2:28]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O
Reactant: CN
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNCCOc1ccccc1C(C)(C)Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide (Example 198e, 17.5 g) in dioxane (50 mL) was treated with 40% Methylamine solution (50 ml) under nitrogen. The resulting suspension was heated in a sealed system at 100° C. for 4 h. After cooling to room temperature, the solution was evaporated to dryness. The crude product was purified by flash chromatography (SiO2, eluent 10% methanol in dichloromethane and 1% triethylamine). Evaporation of the relevant fractions to dryness and trituration of the residue in diethyl ether gave a solid which was filtered off. The filtrate was collected and evaporated. This residue was purified by preparative HPLC (Waters X-Terra column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent). The fractions containing the desired compound were evaporated to dryness. Further purification by preparative HPLC (phenomenex column, aqueous 0.2% ammonia in acetonitrile as eluent) and freeze-drying of the relevant fractions gave a solid. This freeze dried material readily dissolved in ethyl acetate (30 mL) at room temperature and after stirring for 1 h some solid precipitated. The mixture was then heated to at 85° C. for 1 h to effect dissolution and then cooled and stirred at room temperature for 1 week. The solid was filtered off and dried in vacuo at 40° C. to afford the title compound (2.20 g).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH:21]=[CH2:22])[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[IH:27].C(O)C>C(OCC)C>[IH:27].[CH2:20]([N:19]1[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[N:16]=[C:15]1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1)[CH:21]=[CH2:22]
Reactant: C=CCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: C=CCn1c(N2CCCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-allyl-1H-benzimidazol-2-yl)[1,4]diazepane (0.89 g, 2.5 mmol), aqueous hydriodic acid (10 mL, 57%), and ethanol (10 mL). Heat to reflux. After 1 hour, cool to ambient temperature, pour the reaction mixture into diethyl ether (250 mL), and stir to give a solid. After 1 hour, collect the solid by filtration, rinse with diethyl ether, and dry in vacuo to give the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:11][C:12]([F:23])([F:24])[O:13][C:14]1[CH:15]=[C:16]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH:17]=[CH:18][CH:19]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)Oc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 75 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
To a mixture of 4-bromoindole (4.50 g, 22.95 mmol), and 4-trifluoromethoxyphenylboronic acid (4.73 g, 22.95 mmol) in THF (78 mL)) were added Palladium catalyst Pd(PPh3)4 (795.6 mg, 0.69 mmol) and the freshly prepared sodium hydroxide solution (2.75 g, 68.9 mmol in 32 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 16 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 5.56 g (78%) of the product 4-(4-trifluoromethoxy-phenyl)-1H-indole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[N+:58]([O-])([O:60]C(C)C)=[O:59].S(=O)(=O)(O)O>ClCCl>[OH:1][C:2]1[C:3]([N+:58]([O-:60])=[O:59])=[C:4]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)O[N+](=O)[O-]
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: COc1ccc(C(=O)Cc2ccccc2)c([N+](=O)[O-])c1O

Procedure:
To a stirred solution of 1-(3-hydroxy4-methoxyphenyl-2-phenyl-ethanone (8.57 g, 35.4 mmol) in dichloromethane (90 mL) at room temperature was added tetrabutylammonium sulphate (0.6 g, 5 mol %) followed by isopropyl nitrate (7.44 g, 70.8 mmol). Sulphuric acid (96%, 8.5 mL) was then added dropwise causing a gently exothermic reaction, and after stirring for forty minutes, the reaction mixture was poured onto water (250 mL). The phases were separated and the aqueous phase was extracted by dichloromethane (30 mL). The combined organic phases were washed with brine and dried over anhydrous sodium sulphate. Filtration and evaporation of the solvent (40° C., water aspirator pressure) afforded a solid residue which was triturated with a small volume of diethylether (20 mL) to afford orange crystals, (6.9 g, 68%) of m.p. 176–177° C., identified by NMR as the ortho-nitrated title product. Concentration of the mother liquors and subsequent trituration with diethyl ether (15 mL) allowed the isolation of a small amount of a minor product, which was recrystallised from a dichloromethane/heptane mixture to give yellowish crystals of m.p. 142–143° C., corresponding (TLC) to a standard of the para-nitrated product, 1-(3-hydroxy-4-methoxy-6-nitrophenyl)-2-phenyl-ethanone (1.22 g, 12%). (80% combined yield, Ortho:Para selectivity, 5.7:1)
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:28]1[N:32]([C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)[N:31]=[CH:30][CH:29]=1)CCC>C1COCC1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:11][C:9]1[N:10]=[C:5]2[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[C:3]([CH3:22])[C:2]([C:28]3[N:32]([C:33]4[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=4)[N:31]=[CH:30][CH:29]=3)=[CH:7][N:6]2[N:8]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Reactant: Cc1c(Br)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Yield: 44.4 %

Procedure:
6-Bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (Int. 2, 100 mg, 0.27 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 115 mg, 0.25 mmol) were dissolved in THF (5 mL) and degassed then bis(triphenylphosphine)palladium (II) dichloride (18 mg, 0.025 mmol) was added. The reaction mixture was stirred at reflux temperature for 21 hrs then allowed to cool before washing with cesium fluoride (saturated aqueous solution) and extracting with EtOAc (2×30 mL). The combined organic extracts were filtered and the filtrate was concentrated in vacuo. The resultant residue was subjected to preparative C18 HPLC, eluting with a gradient 40-90% MeCN in water (+0.1% formic acid) to afford 51 mg of an impure title compound (containing 25% starting material) which was dissolved in THF (3 mL) with 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 4.72 g, 0.103 mmol) and degassed before addition of bis(triphenylphosphine)palladium (II) dichloride (10 mg, 0.014 mmol). The reaction mixture was heated at 75° C. for 6.5 h then purified using an SCX-2 cartridge (loading in MeOH/eluting with 2 N NH3 in MeOH). The resultant residue was taken up in MeOH (5 mL) and treated with 3-mercaptopropylethyl sulfide silica (PhosphonicS SPM 32, 0.5 eq by weight) and stirred at 50° C. for 1 hr then filtered and evaporated. The resultant residue was dissolved in DCM then filtered and evaporated in vacuo before further purification by preparative C18 HPLC, eluting with a gradient 40-90% MeCN in water (+0.1% formic acid) to give the title compound as a white solid (25 mg).