Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[I-].[K+].[Cl:16][C:17]1[N:22]=[C:21]([S:23][CH3:24])[N:20]2[CH:25]=[C:26]([CH2:28]Cl)[N:27]=[C:19]2[CH:18]=1>CN(C=O)C>[Cl:16][C:17]1[N:22]=[C:21]([S:23][CH3:24])[N:20]2[CH:25]=[C:26]([CH2:28][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:27]=[C:19]2[CH:18]=1
Reactant: C1COCCN1
Reactant: CSc1nc(Cl)cc2nc(CCl)cn12
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nc(Cl)cc2nc(CN3CCOCC3)cn12
Reaction time: 16 h

Procedure:
158 mg (1.81 mmol) of morpholine are introduced into 10 ml of DMF at 0° C., and 367 mg (3.63 mmol) of triethylamine and a catalytic amount of potassium iodide are added. A solution of 300 mg of 7-chloro-2-(chloromethyl)-5-(methylthio)imidazo[1,2-c]pyrimidine (Example 26A) in DMF is then slowly added dropwise. The mixture is allowed to reach RT and is stirred at this temperature for a further 16 h. Purification of the crude product by preparative HPLC and drying under high vacuum result in 221.8 mg (41% of theory) of product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][NH2:27])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][NH:27][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:12])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1c[nH]c2ccccc12
Product: O=C(NCC1CCN(Cc2ccccc2)CC1)c1c[nH]c2ccccc12
Yield: 60 %

Procedure:
Indole-3-carboxylic acid was converted to its acid chloride and then reacted with (1-benzyl-4-piperidyl)methylamine (D10) as in the method of Description 1b to afford N-[(1-benzyl-4-piperidyl)methyl] indole-3-carboxamide as a white solid (60%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:6]=[CH:5][N:4]=1.[Cl:18][C:19]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=S)=[CH:29][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1.C(Cl)CCl>CC#N>[Cl:18][C:19]1[CH:32]=[CH:31][C:30]([NH:33][C:34]2[NH:16][C:13]3[CH:14]=[CH:15][C:10]([O:9][C:7]4[CH:6]=[CH:5][N:4]=[C:3]([NH:2][CH3:1])[N:8]=4)=[CH:11][C:12]=3[N:17]=2)=[CH:29][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1
Reactant: CNc1nccc(Oc2ccc(N)c(N)c2)n1
Reactant: CN1CCN(Cc2cc(N=C=S)ccc2Cl)CC1
Solvent: ClCCCl
Solvent: CC#N
Product: CNc1nccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(CN5CCN(C)CC5)c4)nc3c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-methylamino-pyrimidin-4-yloxy)-benzene-1,2-diamine (Step C, 300 mg, 1.3 mmol, 1.0 eq) in anhydrous CH3CN (20 mL) was added drop-wise a solution of 1-(2-chloro-5-isothiocyanato-benzyl)-4-methyl-piperazine (405 mg [residual imidazole present], 1.3 mmol, 1.0 eq) in anhydrous CH3CN (10 mL). The solution was stirred for 16 h at RT. EDC (250 mg, 1.3 mmol, 1.0 eq) was added and the reaction was heated to 80° C. and stirred for 2 h. The solvent was removed under reduced pressure and residue was dissolved in CH2Cl2/MeOH (50 mL). The organic solution was washed with H2O (25 mL), NaHCO3 (aq, 25 mL) and brine (25 mL). The aqueous layers were back extracted with CH2Cl2 and the combined organic layers were dried over MgSO4, filtered and concentrated. The crude was further purified by column chromatography (0-10% MeOH/CH2Cl2 with 1% NH4OH) followed by preparative TLC and finally reverse phase HPLC (5-100% H2O/CH3CN with 0.1% TFA) to yield [4-chloro-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[5-(2-methylamino-pyrimidin-4-yloxy)-1H-benzimidazol-2-yl]-amine. MS m/z=479.2 (M+H)+; MW Calc'd for C24H27ClN8O: 478.20.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].CC[O:12][C:13]([CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)=O.OS(C(F)(F)F)(=O)=O>>[OH:2][C:1]1[C:9]2[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:13](=[O:12])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Product: O=c1cc(-c2ccccc2)c2c(O)cc(O)cc2o1
Reaction time: 16 h
Yield: 74.1 %

Procedure:
A suspension of phloroglucinol (2.10 g, 12.9 mmol) in ethyl benzoyl acetate (2.41 mL, 13.8 mmol) was added over 0.5 hours to triflic acid (4 mL). The reaction was mechanically stirred in an ice bath for 16 h. The reaction was quenched by carefully pouring into an ice bath. The solid was filtered and dried yielding a yellow solid (2.43 g, 74.8%): mp. 179-182° C.; 1H NMR (DMSO-D6) δ5.75 (s, 1H), 6.15 (s, 1H), 6.25 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:13])=[CH:5]2.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:42][C:43]([F:58])([F:57])[C:44]1[CH:49]=[CH:48][C:47]([N:50]2[CH2:55][CH2:54][CH:53](O)[CH2:52][CH2:51]2)=[CH:46][CH:45]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:58][C:43]([F:42])([F:57])[C:44]1[CH:45]=[CH:46][C:47]([N:50]2[CH2:55][CH2:54][CH:53]([O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[CH:7][C:6]([C:12]([NH:14][CH:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]3)=[O:13])=[CH:5]4)[CH2:52][CH2:51]2)=[CH:48][CH:49]=1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cnc3ccc(O)cc3c2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cnc3ccc(OC4CCN(c5ccc(C(F)(F)F)cc5)CC4)cc3c2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a stirred suspension of the product of step 2 above (0.7 g, 1.88 mmol) in toluene (15 mL) at room temperature was added diisopropyl azodicarboxylate (557 μl, 2.83 mmol), 1-(4-(trifluoromethyl)phenyl)piperidin-4-ol (0.693 g, 2.83 mmol), and triphenyl phosphine (0.742 g, 2.83 mmol). The mixture was stirred at 50° C. overnight and then concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 3% methanol in methylene chloride) to afford tert-butyl 4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)quinoline-3-carboxamido)piperidine-1-carboxylate as a white solid (0.306 g, 27%). LCMS (m/z): 599 (MH+)
Reaction SMILES: COC[N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl.C(O)C>C(OCC)(=O)C>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[S:14]([NH:13][C:11]1[CH:10]=[C:9]([O:22][C:23]([F:25])([F:26])[F:24])[CH:8]=[C:7]2[C:12]=1[NH:4][C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:6]2)(=[O:15])=[O:16]
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2n1COC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 50 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A mixed solution of ethyl 1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylate (105 mg), 6N hydrochloric acid (4 mL) and ethanol (4 mL) was stirred at 80° C. for 3 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained colorless crystals were suspended in dichloromethane (10 mL), and thionyl chloride (0.20 mL) and N,N-dimethylformamide (1 drop) were added. The mixture was stirred at 50° C. for 2 hr. Ethanol (2 mL) and triethylamine (1 mL) were added to the reaction solution, and the mixture was stirred at 50° C. for 2 hr. The reaction solution was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-2:8), and the obtained oil was crystallized from diethyl ether-hexane to give the title compound (41 mg, yield 43%) as colorless crystals. melting point 192-193° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].CS(O[CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])(=O)=O.C([O-])(O)=O.[Na+].O>C(#N)C>[CH2:18]([C:2]1([F:1])[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]1[CH3:9])[CH2:17][CH2:16][CH2:15][CH2:19][CH2:20][CH3:21]
Reactant: CCCC(CCC)OS(C)(=O)=O
Reactant: Cc1cc(N)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCCCCCC1(F)C=CC(N)=CC1C
Yield: 346.4 %

Procedure:
To a solution of 4.10 g (3.28 mmol) of 4-fluoro-3-methylaniline in 30 mL of acetonitrile was added 7.64 g (3.93 mmol) of 4-methanesulfonyloxyheptane, and 3.4 g (4.1 mmol) of NaHCO3 (s). The mixture was stirred at reflux for 24 hours, then poured into 150 mL of H2O and extracted with diethyl ether (2×30 mL). The combined ether layers were back extracted with brine (1×30 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 97.5:2.5 hexanes: ethyl acetate, to give 2.56 g (35%) of a pale yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:16]1(I)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O.[Cu]I>[C:16]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Ic1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1ccc(-n2ccc3ccccc32)cc1
Yield: 86.2 %

Procedure:
A mixture of indole (500 mg, 4.27 mmol), copper(I) iodide (122 mg, 0.64 mmol), cesium carbonate (1.9 g, 6 mmol) and phenyliodide (470 μL, 4.2 mmol) in anhydrous N,N-dimethylformamide (10 mL) was refluxed for 24 hours under a nitrogen atmosphere. The reaction mixture was then filtered and concentrated in vacuo. The residue was partitioned between dichloromethane (30 mL) and water (10 mL). The organic layer was washed with water (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to afford the desired product (5a) as a yellow oil (700 mg, 3.62 mmol, 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH2:20])=[CH:15][C:14]([N+:21]([O-:23])=[O:22])=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:15][C:14]([N+:21]([O-:23])=[O:22])=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCN)c1
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCNC(=O)c2ccccc2)c1
Reaction time: 0.33 h

Procedure:
To a solution of 2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]ethylamine (3.0 g in 80 mL dry methylene chloride) at 0° C. was added 4.0 mL triethylamine followed by 1.4 mL benzoyl chloride and the mixture stirred at low temperature. After 20 minutes, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with water and concentrated in vacuo to give the crude title compound (1.43 g).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][C:16](C#N)=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH4+].[OH-]>CO.C1COCC1.[Ni]>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 111.1 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzooxazole-5-carbonitrile (500 mg, 1.85 mmol) in MeOH-THF (12 mL, 5:3) was added NH4OH (1.5 mL) and Raney Ni (100 mg). The mixture was stirred for 12 h at rt under a H2 atmosphere. After filtration, the mixture was concentrated to give 5-aminomethyl-[2-(4-cyclopropylpiperazin-1-yl)benzooxazole (500 mg, 99%), which was used in the next step without further purification.
Reaction SMILES: [OH:1][C@H:2]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:3]([N:5]1[CH2:30][CH2:29][CH2:28][C@H:6]1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH:18]([NH:20]C(OC(C)(C)C)=O)[CH3:19])=[O:8])=[O:4]>CCOC(C)=O>[OH:1][C@H:2]([CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[C:3]([N:5]1[CH2:30][CH2:29][CH2:28][C@H:6]1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH:18]([NH2:20])[CH3:19])=[O:8])=[O:4]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H](O)C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(N)c1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H](O)C1CCCCC1
Temperature: 0 °C

Procedure:
1-((2R)-2-Hydroxy-2-cyclohexylethanoyl)-N-(2-(1-(tert-butyloxycarbonylamino)ethyl)-5-chlorobenzyl)-L-prolinamide from the previous step (0.40 g, 0.077 mmol) was dissolved in EtOAc (10 mL) and cooled with stirring to 0° C. Into this solution was bubbled in HCl gas for 5 min. The resulting solution was stirred at 0° C. for 30 min, then concentrated in vacuo. The solid which had formed was triturated with Et2O and collected by filtration and washed with several portions of ether. The hydrochloride of the title compound was obtained as a white solid after drying under high vacuum (HPLC RT=2.72 min, method A; LC-MS m/z=422.1; 1H NMR, 400 MHz, CD3OD, 7.65 ppm (d, 1H), 7.35 ppm (s, 1H), 7.25 ppm (d, 1H), 4.81 ppm (dd, 2H), 4.24 ppm (q, 1H), 4.1 ppm (m, 2H), 3.74 ppm (m, 1H), 3.64 ppm (m, 1H), 2.2 ppm (m, 2H), 2.08 ppm (m, 2H), 1.94 ppm (m, 4H), 1.16 ppm (d, 3H), 1.2 ppm (m, 7H)).
Reaction SMILES: O=C(COC1C=NC=CC=1)[CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6].[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]CC)=O)=[CH:20][CH:19]=1>CC(C)=O>[O:28]=[C:26]([CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][N:18]=[CH:23][CH:22]=1)[CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6]
Reactant: COP(=O)(CC(=O)COc1cccnc1)OC
Reactant: CCOC(=O)CCc1ccncc1
Solvent: CC(C)=O
Product: COP(=O)(CC(=O)CCc1ccncc1)OC

Procedure:
The process described in Example 1 for the preparation of dimethyl [2-oxo-3-(pyrid-3-yloxy)propyl]-phosphonate was repeated, using ethyl 3-(pyrid-4-yl)propionate in place of ethyl 3-pyridyloxyacetate, to give dimethyl [2-oxo-4-(pyrid-4-yl)butyl]phosphonate, RF = 0.63 (acetone). The n.m.r. spectrum in deuteriochloroform showed the following characteristic absorptions (δ values):
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([F:35])[CH:34]=4)=[N:25][CH:26]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:19][C:17]1[CH:18]=[C:13]2[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([F:35])[CH:34]=4)=[N:25][CH:26]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Cc2ccc(NCc3cncc(F)c3)nc2)c2cc(Cl)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cncc(CNc2ccc(Cc3c[nH]c4ncc(Cl)cc34)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine (601, 0.060 g, 0.12 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.11 g, 0.35 mmol). The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (P-0324, 13.5mg, 31%). MS (ESI) [M+H+]+=368.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C=O)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:21][CH:20]=1
Reactant: Sc1ccc(Br)cc1
Reactant: O=C(O)c1ccccc1CCCCCCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccccc1CCCCCCCSc1ccc(Br)cc1

Procedure:
The compound of Example 14(a), 2-(7-bromoheptyl)benzoic acid (0.6 g., 2.01 mm), was reacted with 4-bromothiophenol (0.60 g., 3 mm), and triethylamine (1.12 ml, 8.05 mm) in DMF (35 ml) as in Example 14(b) to afford the desired product. This was further purified by flash chromatography over silica gel with ethyl acetate in hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][C:6]=2[CH:13]=O.[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][C:6]=2[CH:13]=[N:18][C:17]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=1[Cl:15]
Reactant: O=Cc1ccc(Cl)c2cc(Cl)cnc12
Reactant: Nc1ccc(Cl)cc1Cl
Product: Clc1ccc(N=Cc2ccc(Cl)c3cc(Cl)cnc23)c(Cl)c1

Procedure:
20 parts of 3,5-dichloroquinoline-8-carbaldehyde (prepared by a method similar to that in Example 4) and 14.6 parts of 2,4-dichloroaniline in 300 parts of alcohol were refluxed for 3 hours. The solution was cooled and the precipitated product was filtered off with suction and recrystallized from methylglycol. 30 g of 3,5-dichloro-8-(2,4-dichlorophenyliminomethyl)-quinoline of melting point 156° C. were obtained. The yield corresponds to 90% of theory.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:21])[CH2:4][C:5]([O:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[N:22]([O-])=[O:23].[Na+].[Cl-].[Na+]>C(O)(=O)C.O>[Br:1][CH2:2][C:3](=[O:21])[C:4](=[N:22][OH:23])[C:5]([O:7][CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:6]
Reactant: O=N[O-]
Reactant: O=C(CBr)CC(=O)OC(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(CBr)C(=NO)C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
In 30 ml of acetic acid there were dissolved 6.94 g of benzhydryl 4-bromo-3-oxobutyrate and, under ice-cooling and stirring, a solution of 1.588 g of sodium nitrite in 6 ml of water was added dropwise. The mixture was further stirred at that temperature for 20 minutes and, following addition of 60 ml of a saturated aqueous solution of sodium chloride, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was removed under reduced pressure to recover 7.56 g of the captioned compound.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[CH2:12]([N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][C:27]([Br:32])=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:21]=[C:20]1[NH2:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:46]>>[CH2:12]([N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][C:27]([Br:32])=[CH:26][C:25]=3[N:24]=[C:23]([NH2:46])[C:22]=2[N:21]=[C:20]1[NH2:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc2cnc3cc(Br)ccc3c2n1Cc1ccccc1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: Nc1nc2cc(Br)ccc2c2c1nc(N)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Chloroperoxybenzoic acid (3.7 g of approximately 77% pure material) was added to a solution of 1-benzyl-7-bromo-1H-imidazo[4,5-c]quinolin-2-amine (2.91 g, 8.24 mmol), and the reaction was stirred for two hours at room temperature. Concentrated aqueous ammonium hydroxide (50 mL) and p-toluenesulfonyl chloride (3.1 g, 16 mmol) were added, and the mixture was stirred overnight at room temperature. The organic layer was separated and washed with water (3×200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product (1.88 g) was purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.55:10.45:89) to provide 123 g of 1-benzyl-7-bromo-1H-imidazo[4,5-c]quinolin-2,4-diamine as a reddish-brown solid.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:13]C)=[CH:12][C:7]=2[O:6][CH:5]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=2[O:6][CH:5]=1
Reactant: COc1ccc2c(CC(C)(C)C)coc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C)Cc1coc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a -10° C. solution of the product of Step D (2.379 grams) in dry methylene chloride (35 mL) was added 1M boron tribromide solution (CH2Cl2 ; 3.70 mL). Warming to ambient temperature was followed by stirring for 1 hour. The reaction was partitioned between isopropyl acetate and aqueous sodium bicarbonate. The organic was washed twice with water and dried over magnesium sulfate. Filtration and removal of volatiles provided a residue which was chromatographed over silica gel (5:1 hex/ethyl acetate), giving the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][CH:7]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=3)[NH:8][CH:7]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: N#Cc1ccc2[nH]cc(CCCCO)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCc2c[nH]c3ccc(C#N)cc23)cc1

Procedure:
3-[4-(p-Toluenesulfonyloxy)butyl]-1H-indole-5-carbonitrile was prepared by reacting 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile with p-toluenesulfonyl chloride in the presence of base in dichloromethane as per the process exemplified in example 2 of Chinese Patent Application Publication No. CN 102267932 A.
Reaction SMILES: [C:1]([N:8]1[CH:13]([C:14](=[O:22])[C:15](=[O:21])[C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])[CH2:12][CH2:11][CH2:10][NH:9]1)(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].I[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>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.[Cu]I>[CH3:20][C:16]([CH3:19])([CH2:17][CH3:18])[C:15](=[O:21])[C:14]([CH:13]1[CH2:12][CH2:11][CH2:10][NH:9][N:8]1[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:22]
Reactant: C#CCCCC(=O)N1NCCCC1C(=O)C(=O)C(C)(C)CC
Reactant: Ic1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCC(C)(C)C(=O)C(=O)C1CCCNN1C(=O)CCCC#Cc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of 1-(2-hex-5-ynoylperhydropyridazinyl)-3,3-dimethylpentane-1,2-dione (0.384 g, 1.25 mmol) in 10 ml CH2Cl2under nitrogen was added 3-iodopyridine (0.283 g, 1.38 mmol), (Ph3P)2PdCl2 (0.044 g, 0.06 mmol), CuI (0.0024 g, 0.013 mmol) and triethylamine (0.3 ml, 2 mmol). The reaction mixture was stirred 30 minutes at room temperature and then refluxed overnight. The mixture was concentrated and purified by silica gel column, eluting with 30% ethyl acetate in hexane, to yield product as light yellow oil (0.31 g, 65%). 1H NMR (CDCl3, 400 MHz) δ 0.84 (t, 3H, J=7.4); 1.21 (s, 6H); 1.70 (m, 6H); 1.96(m, 2H), 2.52 (m, 3H); 2.90 (m, 2H); 3.60 (m, 1H); 4.42 (m, 2H); 7.20 (m, 1H); 7.66 (m, H); 8.49 (m, 1H); 8.62 (m, 1H).