Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:11][C:12]1[C:20]([NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])=[CH:19][CH:18]=[C:17]([Cl:28])[C:13]=1[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Cl:11][C:12]1[C:20]([NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:23])=[O:24])=[CH:19][CH:18]=[C:17]([Cl:28])[C:13]=1[C:14]([NH:10][C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][NH:1][C:5]2=[N:6][CH:7]=1)=[O:15]
Reactant: Nc1cnc2[nH]ccc2c1
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]ccc3c2)c1Cl
Temperature: 60 °C
Reaction time: 24 h
Yield: 1.7 %

Procedure:
1H-Pyrrolo[2,3-b]pyridin-5-amine (192 mg, 1.44 mmol) in N,N-dimethylformamide (7.2 mL) was sequentially treated with 2,6-dichloro-3-(propylsulfonamido)benzoic acid (690.5 mg, 2.212 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (466.4 mg, 2.433 mmol), and 1-hydroxybenzotriazole (328.8 mg, 2.433 mmol) and heated to 60° C. After 24 hours, the reaction mixture was allowed to cool to ambient temperature. The mixture was diluted with ethyl acetate, washed with water (4×), sodium bicarbonate (2×), and brine (1×), dried over sodium sulfate, and concentrated. The crude product was applied directly to a silica gel column and eluted with a gradient (30% to 100%) of ethyl acetate-hexanes to provide 2,6-dichloro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (10.5 mg, 0.0246 mmol, 3.41% yield) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 11.70-11.59 (s, 1H), 10.77-10.68 (s, 1H), 9.88-9.75 (s, 1H), 8.39-8.30 (m, 2H), 7.56-7.47 (m, 3H), 6.49-6.45 (d, 1H), 3.21-3.04 (m, 2H), 1.82-1.70 (m, 2H), 1.03-0.95 (t, 3H); MS (APCI-neg) m/z=425.1 (M-H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]([CH3:17])[CH2:14][N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:11]=2[C:10]([CH:25]=O)=[C:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:34][OH:35].Cl>N1C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[CH:15]([CH3:17])[CH2:14][N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:11]=2[C:10]([CH:25]=[N:34][OH:35])=[C:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC1CN(Cc2ccccc2)Cc2c(C=O)c(-c3ccccc3)n(Cc3ccccc3)c21
Agent: Cl
Solvent: c1ccncc1
Product: CC1CN(Cc2ccccc2)Cc2c(C=NO)c(-c3ccccc3)n(Cc3ccccc3)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.9 %

Procedure:
A mixture of the compound from Example 13 (1.0 g) hydroxylamine hydrochloride (0.5 g) and anhydrous pyridine (50 ml) was stirred at room temperature for 18 hours and poured into 2N hydrochloric acid (500 ml). A gummy precipitate was formed, which was separated and crystallised by heating with methanol to give the oxime (0.9 g) M.pt 171°-2°C. (Found: C, 80.3; H, 6.9; N, 9.6. C29H29N3O requires: C, 80.0, H, 6.7; N, 9.6%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([N:21]3[CH2:26][CH2:25]S[CH2:23][CH2:22]3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.O[O:30][S:31]([O-:33])=O.[K+]>CO>[O:30]=[S:31]1(=[O:33])[CH2:25][CH2:26][N:21]([C:12]2[N:11]=[C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)=[O:9])[C:19]([OH:20])=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]3)[CH2:22][CH2:23]1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(N2CCSCC2)c2cccnc2c1O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1nc(N2CCS(=O)(=O)CC2)c2cccnc2c1O
Temperature: 25 °C
Reaction time: 28 h

Procedure:
A solution of N-(4-fluorobenzyl)-8-hydroxy-5-thiomorpholin-4-yl-1,6-naphthyridine-7-carboxamide (0.19 g, 0.49 mmol) in methanol (25 mL) was treated with an aqueous solution of Oxone (7.5 mL of a 1M solution, 0.75 mmol) and stirred at room temperature for 28 hr. The solvent was evaporated in vacuo and the residue partitioned between water and CH2Cl2. The organic extracts were purified by reverse phase HPLC. (Vydak C18, Gradient elution with Water:Acetonitrile 95:5 to 5:95 with 0.1% TFA at 30 mL/min over 15 mins). Lyophilization of the pure fractions afforded the title compound as an off white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>O1CCCC1>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:19][CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C#Cc1cccnc1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(COc2ccc(Cc3cc(-c4cccnc4)on3)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynylpyridine (50 mg, 0.485 mmol) and (4-benzyloxy-phenyl)-acetohydroximoyl chloride (214 mg, 0.776 mmol) described in Manufacturing Example 1-1-3 was added triethylamine (270 μL, 1.94 mmol), which was stirred for 2.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2) to obtain the title compound (80 mg, 48%).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=2)[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.O>C(Cl)Cl>[C:1]1([CH:7]=[CH:8][C:9]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc([C@H](C)NC(=O)C=Cc2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=O)C=Cc1ccccc1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-3-phenyl-N-[1-(3-methoxyphenyl)ethyl]acrylamide (100 mg) in CH2Cl2 (0.5 mL) at −78° C. was added boron tribromide (1.0 M solution in CH2Cl2, 2.14 mL). The resulting solution was warmed to room temperature and stirred at room temperature for 3 hours. Water was added, and the mixture was extracted with CH2Cl2 (three times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to provide the title compound.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CS(C)=O.N1(CC(O)CO[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])CCOCC1>>[N+:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:28]=1)([O-:36])=[O:35]
Reactant: O=[N+]([O-])c1ccccc1OCC(O)CN1CCOCC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
A five liter round bottom flask was charged with 63.8 ml (0.45 mole) of trifluoroacetic anhydride and 400 ml of MDC under nitrogen. The resulting solution was cooled to -65° C. with a dry ice bath, treated with 42.6 g (0.54 mole) of dimethylsulfoxide over a period of 15 minutes, stirred for 30 minutes, and then treated with a solution of 90 g (0.32 mole) of 2-[3-(4-morpholinyl)-2-hydroxy-1-propyloxy]nitrobenzene in 200 ml of MDC over a 35 minute period. The reaction mixture was stirred for 30 minutes, quenched with 261 ml of diisopropylethylamine, the reaction temperature allowed to rise to -10° C. and the mixture treated with one liter of diethyl ether. The pale yellow solid which separated was collected by filtration, slurried in 1.5 liters of diethyl ether and the product collected and dried to give 73.7 g of 2-3-(4-morpholinyl)-2-keto-1-propyloxy] nitrobenzene.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=1)[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:52]([NH2:59])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CCOC(C)=O.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16](=[O:18])[NH:59][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:14][N:13]=1)[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccc(C(=O)O)cn1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(O)c1ccc(C(=O)NCc2ccccc2)cn1
Reaction time: 8 h
Yield: 27.9 %

Procedure:
6-(2-tert-Butoxycarbonylamino-1-hydroxy-ethyl)-nicotinic acid (130 mg, 0.461 mmol), diisopropylethylamine (DIPEA) (0.426 mL, 2.44 mmol), [(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium tetrafluoroborate (319 mg, 1.00 mmol), and benzyl amine (0.246 mL, 2.30 mmol) were dissolved into 3 mL of dry DMF and stirred overnight. LC-MS indicated formation of the coupled product. The mixture was diluted with 30 mL of EtOAc, the organic phase washed with 2×20 mL H2O and 1×20 mL of brine, dried (MgSO4) filtered and concentrated. The residue was dissolved in CH2Cll2, applied to a SiO2 column and purified (10–30% EtOAc/hexanes) to give 47.8, 27.9% of [2-(5-benzylcarbamoyl-pyridin-2-yl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester.
Reaction SMILES: C([O:3][C:4]1[C:13]2[C:8](=[N:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.[CH2:20](Br)[CH3:21]>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:15]([C:5]1[C:4](=[O:3])[C:13]2[C:8](=[N:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[N:7]([CH2:20][CH3:21])[CH:6]=1)=[O:16])[CH3:19]
Reactant: CCBr
Reactant: CCOC(=O)c1cnc2nc(C)ccc2c1OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(CC)c2nc(C)ccc2c1=O
Temperature: 130 °C
Yield: 80 %

Procedure:
A mixture containing 1 g of ethyl 4-ethoxy-7-methyl-1,8-naphthyridine-3-carboxylate, 1.26 g of ethyl bromide and 20 ml of toluene was heated in a sealed tube at 130°C for 7 hours. The solvent was evaporated and the residue was worked up as above. There was obtained 0.8 g of ethyl-1-ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([S:12][CH3:13])[N:5]=1)[CH3:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1)[NH2:19]>C(O)(=O)C>[CH3:24][O:23][C:21]1[CH:20]=[C:18]([N:19]=[CH:10][C:9]2[C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]([S:12][CH3:13])=[N:7][CH:8]=2)[CH:17]=[C:16]([O:15][CH3:14])[CH:22]=1
Reactant: CCNc1nc(SC)ncc1C=O
Reactant: COc1cc(N)cc(OC)c1
Solvent: CC(=O)O
Product: CCNc1nc(SC)ncc1C=Nc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
To a stirred suspension of 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (5.0 g, 25.09 mmol, made by the method described in J. Med. Chem., 1998; 41(17):3276-3292) and 3,5-dimethoxyaniline (3.84 g, 25.09 mmol) water (190 mL) was added glacial acetic acid (5 mL). The reaction mixture was stirred at ambient temperature for 24 hours and the suspension filtered. The insoluble product was dried on the filter to afford 7.79 g (92%) of the titled compound: mp 100-105° C.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][C@@H:9]2[O:13][C@@H:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[Cl:24])[CH:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=[CH:3]1>C(O)C>[ClH:24].[N:2]1([CH2:7][CH2:8][C@@H:9]2[O:13][C@H:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[Cl:24])[CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: COc1ccc(OC[C@H]2C=C[C@H](CCn3ccnc3)O2)c(Cl)c1
Agent: Cl
Solvent: CCO
Product: COc1ccc(OC[C@@H]2CC[C@H](CCn3ccnc3)O2)c(Cl)c1
Reaction time: 8 h

Procedure:
In a vial, add ethanol (1 ml) to the product of Example 100 (0.050 g) and add PtO (0.025 g). Place a balloon filled with H2 gas over the mouth of the vial and stir overnight. Purify the resultant product on a silica column, eluting with CH2Cl2 →5% methanol/CH2Cl2. Add 0.1 N HCl (2 ml) to the resulting product and lyophilize to obtain the title compound, MS: m/z 339 (M+ +1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[NH:15][N:16]=2)[CH:13]=1.Cl[CH2:26][C:27]1[C:28]([CH3:37])=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=1.BrC1C2N(C(=O)N(CC3C(C)=NC(C(F)(F)F)=CC=3)N=2)C(C)=CC=1C1C=CC(Cl)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[N:15]([CH2:26][C:27]3[C:28]([CH3:37])=[N:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)[N:16]=2)[CH:13]=1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cn12
Reactant: Cc1nc(C(F)(F)F)ccc1CCl
Agent: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(Cl)cc3)cc(C)n2c1=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cn2c1=O
Yield: 47.2 %

Procedure:
The title compound (25 mg, 47% yield) as an off-white solid was prepared from 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (36 mg, 0.1 mmol) and 3-(chloromethyl)-2-methyl-6-(trifluoromethyl)pyridine (31 mg, 0.15 mmol) in a manner analogous to that in which 8-bromo-7-(4-chlorophenyl)-5-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was prepared. HPLC/MS: retention time=4.30 min, [M+H]+=529.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:14]([F:17])([F:16])[F:15])=[N:8][N:9]([CH:11]2[CH2:13][CH2:12]2)[CH:10]=1)=O)C.CC(C[AlH]CC(C)C)C.Cl>C1(C)C=CC=CC=1>[CH:11]1([N:9]2[CH:10]=[C:6]([CH2:4][OH:3])[C:7]([C:14]([F:17])([F:16])[F:15])=[N:8]2)[CH2:13][CH2:12]1
Reactant: CCOC(=O)c1cn(C2CC2)nc1C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: OCc1cn(C2CC2)nc1C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 1-Cyclopropyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (Preparation 145, 3.5 g, 14.11 mmol) in dry toluene (70 mL) was cooled to −78° C. and DIBAL-H (29.4 mL of a 1.2 M solution in toluene, 35.3 mmol) was added dropwise to it. The reaction mixture was stirred at −78° C. for 2 hours and then poured into 2N HCl (25 mL) followed by further stirring for 2 hours at room temperature. The mixture was extracted with EtOAc (2×50 mL) and the combined organic layers were washed with water (2×15 mL), brine (15 mL) and dried (Na2SO4) and evaporated in vacuo to afford the title compound as off white solid in 100% yield, 3 g.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].F[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1>>[N+:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: O=[N+]([O-])c1cccc2nc[nH]c12
Product: O=[N+]([O-])c1cccc(-n2cnc3c([N+](=O)[O-])cccc32)c1

Procedure:
4-Nitro-1-(3-nitrophenyl)benzimidazole was prepared analogueously to 3 g from 4-nitrobenzimidazole and 1-fluoro-3-nitrobenzene. Mp 260°-262° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])O.[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=1
Reactant: COc1cccc(O)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cccc(Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 160 °C
Reaction time: 9 h
Yield: 20.2 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (103 mg) and commercially available 3-methoxyphenol (158 mg) were mixed and stirred at 160° C. for 9 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate to obtain 29 mg of the title compound (yield: 52%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2].C(O)(=O)C.[S:25]1[CH2:29][CH2:28][C:27](=O)[CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH:27]2[CH2:28][CH2:29][S:25][CH2:26]2)[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2]
Reactant: O=C1CCSC1
Reactant: CCc1nc2cnc3ccccc3c2n1CCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1nc2cnc3ccccc3c2n1CCCCNC1CCSC1
Reaction time: 0.17 h

Procedure:
To a suspension of 4-(2-Ethyl-imidazo[4,5-c]quinolin-1-yl)-butylamine obtained in step VI in tetrahydrofuran was added acetic acid (1 eq.) and dihydrothiophen-3-one (1.1 eq.). Resulting reaction mixture was stirred for 10 min. Sodium triacetoxyborohydride (2.2 eq.) was added to reaction mixture over a period of 1 hrs and resulting suspension was then stirred for 4-5 hrs. Reaction was then quenched with methanol and concentrated to dryness. Reaction mixture was basified using aq.sodium hydroxide solution and extracted with chloroform. Organic layer was dried over sodium sulphate and concentrated under reduced pressure to yield sticky solid. Product was then purified by silica gel column chromatography to afford [4-(2-Ethyl-imidazo[4,5-c]quinolin-1-yl)-butyl]-(tetrahydro-thiophen-3-yl)-amine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.Cl.[N:24]1([C:29]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[N:24]1([C:29]([C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:9](=[O:11])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:14])=[CH:35][CH:36]=2)=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Nc1ccc(C(=O)N2CCCC2)cc1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(C(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
To a solution of 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (50 mg, 0.16 mmol) and 4-(pyrrolidinylcarbonyl)phenylamine hydrochloride (43 mg, 0.19 mmol) in pyridine (3 mL) cooled in ice-bath, POCl3 (0.028 mL, 0.31 mmol) was added. The mixture was stirred at room temperature overnight. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (15 mg). MS 491.4 and 493.4 (M+H, Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:14])[CH2:9][CH2:10][N:11]([CH2:26][CH2:27][CH:28]=[C:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[N:39][C:34]=3[CH2:33][O:32][C:31]3[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]2=3)[CH2:12][CH2:13]1
Reactant: OC1(c2ccccc2Cl)CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(O)(c3ccccc3Cl)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 14 h
Yield: 51.4 %

Procedure:
To a solution of the 4-(2-chloro-phenyl)-piperidin-4-ol (0.210 g, 1.0 mmol) in isopropanol was added 2,6-lutidine (0.31 mL, 2.7 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.287 g, 0.77 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.200 g, 52%). 1H-NMR (CDCl3): δ 1.55 (s, 6H), 1.70 (d, 2H), 2.10–2.30 (m, 2H), 2.36–2.54 (m, 2H), 2.57–2.92 (m, 6H), 5.30 (bs, 2H), 6.16 (t, 1H), 6.77 (d, 1H), 7.16–7.36 (m, 5H), 7.48 (s, 2H), 7.58 (d, 1H), 8.37 (dd, 1H). ESI-MS m/z: 505 (M+1), retention time 1.48.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][Si](C)(C)C)=[CH:9][CH:10]=2)[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CCN(c2ccccc2)c2cc(C#C[Si](C)(C)C)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2c(c1)N(c1ccccc1)CCC2(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 0.050 g (0.15 mmol) of 4,4-dimethyl-1,2,3,4-tetrahydro-N-phenyl-7-[2-(trimethylsilyl)ethynyl]quinoline (Compound 7) in 4.0 mL of methanol was added 0.032 g (0.23 mmol) of potassium carbonate, and the resulting mixture was stirred at room temperature for 20 hours. The mixture was then concentrated in vacuo, water was added, and the mixture was extracted with diethyl ether (2x). The organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as an oil. PNMR (300 MHz, CDCl3) d 1.34 (6 H, s), 1.84 (2 H, t, J=6.0 Hz), 2.88 (1 H, s), 3.62 (2 H, t, J=6.0 Hz), 6.82 (1 H, d, J=1.6 Hz), 6.85 (1 H, rid, J=7.9, 1.6 Hz), 7.13-7.39 (6 H, m).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:8])=[CH:5][N:4]=[CH:3]1.N#C[Br:20].[Al]>C(#N)C>[Br:20][C:3]1[N:2]([CH3:1])[C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:8])=[CH:5][N:4]=1
Reactant: Cn1cncc1C(=O)NCCN1CCOCC1
Reactant: N#CBr
Agent: [Al]
Solvent: CC#N
Product: Cn1c(C(=O)NCCN2CCOCC2)cnc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 115 (550 mg, 2.31 mmol) in acetonitrile (5 mL) was added cyanogen bromide (489 mg, 4.6 mmol). The reaction flask was covered with aluminum foil and the mixture was allowed to stir at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (eluents 100% EtOAc to 30% MeOH/EtOAc), to afford title compound 116 as a beige solid (230 mg (31%). MS (m/z) 317.1/319.1 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.[CH:31](O)=[O:32]>>[CH:31]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1)=[O:32]
Reactant: O=C(NC1CCNCC1)c1cc2ccccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Reactant: O=CO
Product: O=CN1CCC(NC(=O)c2cc3ccccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1

Procedure:
A solution of 50 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid piperidin-4-ylamide in 2 ml formic acid was heated to 100° C. for 5 h. After removal of the solvent under reduced pressure the residue directly purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a white solid. Yield: 14 mg MS (ES+): m/e=469, chloro pattern.