Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:37][CH2:38][CH3:39])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH:21]=2)=[O:19])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].Cl>C(O)C.O1CCOCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:37][CH2:38][CH3:39])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:21]=2)=[O:19])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)O)c2ccccc12)c1ccc(CC(C)C)cc1

Procedure:
A mixture of ethyl 4-[3-[8-(4-isobutylphenyl)undecanoyl]1-indolyl]butyrate obtained in Ex. 15 (44 mg) and 1N solution of sodium hydroxide (0.5 ml) in ethanol (1 ml) and 1,4-dioxane (2 ml) was stirred at room temperature for 3 hours. The mixture was then acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with water and brine, and dried over magnesium sulfate. Evaporation of the solvent afforded 4-[3-[8-(4-isobutylphenyl)-undecanoyl]1-indolyl]butyric acid as an oil (41 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]=[CH:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH:13]12[O:24][CH:14]1[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:12]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC2OC2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 103.5 %

Procedure:
To a solution of 1-benzyloxycarbonyl-3-pyrroline (5.0 g) in methylene chloride (125 mL) was added 3-chloroperbenzoic acid (12.17 g) and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added a saturated sodium thiosulfate solution (100 mL) and the mixture was stirred for 30 minutes. The reaction mixture was extracted with chloroform (×2) and the extract was washed successively with 2N sodium hydroxide solution (100 mL×2) and a saturated brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to give benzyl 6-oxa-3-azabicyclo[3,1,0]hexan-3-carboxylate (5.58 g, yield: 100%) as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: COCc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COCc1ccccc1-c1ccc(C(=O)OC)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-bromo-3-methylbenzoate (Aldrich 532878, 2 g; 8.73 mmol; 1 eq.), (2-methoxymethylphenyl)boronic acid (1.59 g; 9.60 mmol; 1.10 eq.), K2CO3 (6.03 g; 43.65 mmol; 5 eq.), tetrakis(triphenylphosphine)palladium (0) (1.01 g; 0.87 mmol; 0.10 eq.) were taken up in Toluene (10 mL) and water (10 mL) under N2 atmosphere. The reaction mixture was purged with vacuum, then degassed with N2 and then for 2 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with EtOAc (500 mL). The filtrate was concentrated to afford a yellow oil which was taken in EtOAc (100 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 solution (30 mL), water (30 mL) and brine (30 mL), dried over MgSO4 and concentrated affording the title compound as a brown oil used without further purification (3 g, quantitative). HPLC (Method A) Rt 5.20 min (Purity: 64.5%).
Reaction SMILES: [O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.[H][H]>CO.C(OCC)(=O)C.[Pd]>[O:49]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([CH:46]([CH3:47])[CH3:48])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 5.6 %

Procedure:
A mixture of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (100 mg, 0.145 mmol) and 10% Pd/C (90 mg, 0.087 mmol) in methanol (5 mL) and ethyl acetate (5 mL) was loaded onto a PARR shaker reactor and treated with hydrogen for 25 hours under 40 psi at room temperature. The reaction mixture was filtered through a celite pad to remove the catalyst. The filtrate was purified by HPLC to provide the title compound as a white solid (5.6 mg, 28%). LCMS: m/e 693.46 (M+H)+, 2.46 min (method 10). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H), 5.39 (d, J=4.6 Hz, 1H), 3.50-3.36 (m, 1H), 3.36-3.21 (m, 6H), 3.21-2.98 (m, 5H), 2.31-1.29 (m, 24H), 1.29 (s, 3H), 1.13 (s, 6H), 1.03 (s, 3H), 1.01 (s, 3H), 0.94 (d, J=6.7 Hz, 3H), 0.86 (d, J=6.7 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH:12]([C:16]([OH:18])=[O:17])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]([F:24])([F:23])[CH2:21]O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][CH:12]([C:16]([O:18][CH2:21][C:20]([F:24])([F:23])[F:19])=[O:17])[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC(C(=O)O)CC2C1
Reactant: OCC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2CC(C(=O)OCC(F)(F)F)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
A mixture of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7-carboxylic acid (0.150 g, 0.588 mmol), 2,2,2-trifluoroethanol (0.118 g, 1.18 mmol), 4-N,N-dimethylaminopyridine (DMAP) (0.143 g, 1.18 mmol) and polymer supported dicyclohexylcarbodiimide (PS-DCC) (0.8 g, loading 3.2 mmol/g) in dichloromethane (20 mL) was stirred at ambient temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by HPLC, using acetonitrile and 0.05% aqueous TFA as mobile phase, to obtain 0.053 g (27% yield) of 2,2,2-trifluoroethyl 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7-carboxylate as an oil (1H NMR (CDCl3, 300 MHz): δ 4.48 (q, J=8.30 Hz, 2H), 3.58-3.46 (m, 2H), 3.26-2.92 (m, 4H), 2.82-2.63 (m, 1H), 2.28-2.07 (m, 2H, 1.84-1.65 (m, 2H), 1.45 (s, 9H); MS (m/z): 338 (M+1), 282 (M+1-56)). The 2,2,2-trifluoroethyl 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7-carboxylate was dissolved in dichloromethane (5.0 mL), treated with TFA (2.0 mL), and the reaction was stirred at ambient temperature for 1 h. The solvent was evaporated and the crude product was purified on HPLC, using acetonitrile and 0.05% TFA in water as mobile phase, to obtain 0.023 g of the trifluoroacetate salt of 2,2,2-trifluoroethyl 3-azabicyclo[3.3.0]octane-7-carboxylate (as a cis/trans mixture) as an oil (1H NMR (CD3OD, 300 MHz): δ 4.62 (q, J=8.79 Hz, 2H), 3.64-3.42 (m, 1H), 3.3.38-3.32 (m, 1H), 3.22-3.05 (m, 2H), 3.02-2.95 (m, 3H), 2.42-2.07 (m, 2H), 1.96-1.63 (m, 2H); MS (m/z): 238 (M+1)).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[N:27][CH:26]=[CH:25]2)=[CH:20][CH:19]=1)=[O:17].[F:29][C:30]([F:37])([F:36])[C:31](OCC)=[O:32]>C1COCC1>[F:29][C:30]([F:37])([F:36])[C:31](=[O:32])[CH2:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH:25]=[CH:26][N:27]=[CH:28]2)=[CH:22][CH:23]=1)=[O:17]
Reactant: CC(=O)c1ccc(-n2ccnc2)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-n2ccnc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a THF (5 mL) solution of 1,1,1,3,3,3-hexamethyldisilazane (0.178 g, 1.1 mmol) was added n-butyl lithum (1.6 M solution in hexane, 0.72 mL, 1.2 mmol) at 0° C. under nitrogen, and the mixture was stirred for 30 minutes, and cooled to −78° C. 4-(1-Imidazolyl)acetophenone (prepared according the method of M. A. Khan et. al., J. Chem. Soc. C., 1970, 85., 0.186 g, 1.0 mmol) was added to the mixture, and residue was stirred for 1 hour. Ethyl trifluoroacetate (0.17 g, 1.2 mmol) was added to the reaction mixture, the residure was warm to room temperature. The reaction mixture was poured into ice water and the whole was extracted with ethyl acetate (30 mL×2). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting solid was washed with small amount of ethyl acetate to give the title compound (0.163 g).
Reaction SMILES: CS[C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:17]2[NH:21][C:20]([C:22]3[N:27]=[CH:26][C:25]([CH:28]([OH:30])[CH3:29])=[CH:24][CH:23]=3)=[CH:19][CH:18]=2)[CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:7][CH:8]=1.O1CCC[CH2:32]1.O.O[O:38][S:39]([O-:41])=O.[K+]>C(OCC)(=O)C.CO>[CH3:32][S:39]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:17]2[NH:21][C:20]([C:22]3[N:27]=[CH:26][C:25]([CH:28]([OH:30])[CH3:29])=[CH:24][CH:23]=3)=[CH:19][CH:18]=2)[CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:7][CH:8]=1)(=[O:41])=[O:38]
Reactant: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(C(C)O)cn3)[nH]2)nc1
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cn3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
To a mixture of 1-[6-(5-{1-[5-(methylsulfanyl)pyridin-2-yl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]ethanol (76.1 mg), tetrahydrofuran (1 mL), water (1 mL) and methanol (1 mL) was added Oxone (registered trademark) (133 mg), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (40.3 mg, yield 49%) was obtained as a white amorphous solid from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio). MS: 456 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:6]1.[H][H]>[Pd].C(O)C>[CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:6]1
Reactant: CCOC(=O)C=Cc1cn(CC(=O)N(C)CCc2ccccc2)c2ccc(OCc3ccccc3)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cn(CC(=O)N(C)CCc2ccccc2)c2ccc(OCc3ccccc3)cc12

Procedure:
A mixture of 0.93 g of N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxyvinyl)indol-1-yl]acetamide, 0.5 g of 10% palladium on activated carbon and 150 ml of ethanol is shaken under 40 psi of hydrogen on a Parr Apparatus for 40 minutes. The mixture is filtered to remove the catalysts and the filtrate is concentrated in vacuo. The residue is purified by dry column chromatography over silica gel eluting with a solvent system of ethyl acetate/hexane (2:1, v/v) to give N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxyethyl)indol-1-yl]acetamide as white powder (m.p. 81°-83° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH2:17][CH2:18][CH2:19]Cl)[CH:3]=1.[C-:21]#[N:22].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH2:17][CH2:18][CH2:19][C:21]#[N:22])[CH:3]=1
Reactant: [C-]#N
Reactant: ClCCCc1cc(Cl)ccc1OCCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: N#CCCCc1cc(Cl)ccc1OCCc1ccccc1
Yield: 98.7 %

Procedure:
To a solution of 1.62 g of crude 4-chloro-2-(3-chloropropyl)-1-(2-phenylethoxy)benzene in 20 ml of acetonitrile, were added 681 mg of potassium cyanide and 138 mg of 18-crown-6 and heated under reflux for 11 hours. After cooling, the solvent was evaporated under reduced pressure and ethyl acetate and water were added to the residue thus obtained. Then the ethyl acetate layer was collected, washed thrice with water and a saturated aqueous solution of sodium hydrogencarbonate and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, 1.55 g of crude 4-[5-chloro-2-(2-phenylethoxy)phenyl]butyronitrile was obtained. This compound was not purified any more but used in the subsequent reaction.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH:5]([OH:6])[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[CH2:24](Cl)Cl>[Ag]=O>[CH3:1][C:2]1([CH3:23])[CH:5]([O:6][CH3:24])[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:3]1[C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: CC1(C)C(c2ccc(S(C)(=O)=O)cc2)=C(c2ccccc2)C1O
Reactant: ClCCl
Agent: O=[Ag]
Product: COC1C(c2ccccc2)=C(c2ccc(S(C)(=O)=O)cc2)C1(C)C
Temperature: 25 °C

Procedure:
To a solution of Example 62 (70 mg) in CH2Cl2 (1 mL) at r.t., was added silver oxide (100 mg) and Mel (1 mL). The mixture was stirred reflux for 18 hr, cooled to r.t., filtered through celite® and the solvents evaporated. The residue was purified by flash chromatography (silica gel; hexane/EtOAc (85:15)) to give the title product as a white solid, m.p. 130°-132° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O1CCOCC1.[CH2:18]([N:24]=[C:25]=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:25](=[O:26])[NH:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCN=C=O
Reactant: Oc1ccc2ncccc2c1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCCCCCNC(=O)Oc1ccc2ncccc2c1
Temperature: 32 °C
Reaction time: 48 h

Procedure:
Mixture of quinolin-6-ol (0.58 g., 4 mmol), dry dioxane (20 ml), hexyl isocyanate (0.698 ml, 4.8 mmol) and dry pyridine (0.2 ml) was stirred at room temperature (32° C.) for 48 hours. Reaction mixture was concentrated under vaccum, titurated with water (1 ml) and crystallised with ether, to give 1a; yield: 0.80 g. (73.5%), m.p. 89° C., C16H20N2O2; 1H NMR δ ppm (CDCl3): 0.91 (bs, 3H), 1.33-1.34 (bs, 6H), 1.56-1.62 (m, 2H), 3.24-3.34 (m, 2H), 5.21 (bs, 1H), 7.35-7.42 (m, 1H), 7.48-7.52 (m, 1H), 7.60-7.61 (m, 1H), 8.07-8.12 (m, 2H), 8.86-8.89 (m, 1H); IR vmax (KBr) (cm−1): 478, 530, 674, 730, 788, 839, 909, 970, 1002, 1040, 1158, 1215, 1258, 1300, 1356, 1462, 1495, 1543, 1709, 1919, 2373, 2861, 2961, 3032, 3286, 3346, 3777, MS: m/z: 273 (M+).
Reaction SMILES: C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:22]([N:39]([CH2:47]COCCO)[CH2:40][C:41]1C=CC=[CH:43][CH:42]=1)([O:24][CH2:25][CH:26]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23].N1C=CC=CC=1.CO>C1COCC1>[C:22]([N:39]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:47]1)([O:24][CH2:25][CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:23]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N(CCOCCO)Cc1ccccc1
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CO
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCCCC1
Temperature: 65 °C
Reaction time: 0.42 h

Procedure:
THF (15 ml) was added to 2-Chlorotrityl chloride resin (4.0 g, 1.2 mmol/g) and the mixture was agitated for 25 min. FmocN(Bn)CH2CH2OCH2CH2OH (6.1 g, 14.7 mmol) in THF (25 ml) was added followed by pyridine (850 μl, 10.5 mmol) and the mixture was heated to 65° C. for 15 h. MeOH (5 ml) was added and heating was continued for 35 min. The resin was filtered, washed with DMF (3×), CH2Cl2 (3×). MeOH (3×) and Et2O (3×) to give 5.0 g. A small sample was dried carefully and deprotected with DCM/piperidine (1:1) for 30 min. Photometric determination of the resulting Fmoc-piperidine adduct (absorption at 301 nm) gave a resin loading of 0.45 mmol/g.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[O:14][CH2:15][C@H:16]([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:18]#[N:19])=[CH:6]3.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][NH2:30])[CH:22]=1>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:30][CH2:29][CH2:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)[C:9]2[O:14][CH2:15][C@H:16]([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:18]#[N:19])=[CH:6]3
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Reactant: NCCCc1cccnc1
Solvent: CS(C)=O
Product: C[C@H]1COc2c(NCCCc3cccnc3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 120 °C
Yield: 15.1 %

Procedure:
To a solution of 5 (30 mg, 0.108 mmol) in 5 ml of DMSO, 29.5 mg (0.216 mmol) of 3-(pyridine-3-yl)propan-1-amine were added. The reaction mixture was heated to 120° C. for 3 h. The DMSO was removed under vacuo and the remaining solid was purified by preparative HPLC to give the title compound as a yellow solid (6.4 mg, 15% yield).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH3:53])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:62]1([CH2:67][C:68]2[CH:75]=[CH:74][C:71]([CH:72]=O)=[CH:70][CH:69]=2)[CH:66]=[CH:65][CH:64]=[N:63]1>C(O)C.CN(C=O)C>[N:62]1([CH2:67][C:68]2[CH:75]=[CH:74][C:71]([C:72]3[NH:42][C:39]4=[N:40][CH:41]=[C:36]([Cl:35])[C:37]([N:46]5[CH2:51][CH2:50][N:49]([CH2:52][CH3:53])[CH2:48][CH2:47]5)=[C:38]4[N:43]=3)=[CH:70][CH:69]=2)[CH:66]=[CH:65][CH:64]=[N:63]1
Reactant: CCN1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc(Cn5cccn5)cc4)nc23)CC1
Reaction time: 6 h
Yield: 24.5 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-chloro-4-(4-ethylpiperazin-1-yl)-3-nitropyridin-2-amine (25 mg, 0.087 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.26 mmol, 0.26 mL) and 4-(1H-pyrazol-1-ylmethyl)benzaldehyde (1.1 eq, 0.096 mmol, 18 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (9 mg, 24%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.06 (t, J=7.2 Hz, 3H, NCH2CH3), 2.40 (q, J=7.1 Hz, 2H, NCH2CH3), 2.58 (t, br, J=3.8 Hz, 4H, piperazine N(CH2)2), 3.70 (t, J=3.9 Hz, 4H, piperazine N(CH2)2), 5.42 (s, br, 2H, PhCH2), 6.30 (t, J=2.1 Hz, 1H, pyrazole H-4), 7.35 (d, J=8.3 Hz, 2H, phenyl H-2 & H-6), 7.49 (d, J=1.5 Hz, 1H, pyrazole H-3 or H-5), 7.86 (d, J=2.2 Hz, 1H, pyrazole H-3 or H-5), 8.10 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.13 (d, J=8.2 Hz, 2H, phenyl H-3 & H-5);
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].[C:13]1([CH:19]([Mg]Cl)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:7])[CH:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:20])[CH3:12]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: CC([Mg]Cl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(OCC)C(=O)C(C)c1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere, to a solution of ethyl diethoxyacetate (1.80 mL, 10.1 mmol) in THF (20 mL) was added slowly a THF solution of (92) prepared above at −78° C. After stirring at −78° C. for 3 hours, to this was added 20% aqueous solution of ammonium chloride (10 mL) and the product was extracted with ethyl acetate (×3). The organic layer was sequentially washed with water (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=19/1) to give 1,1-diethoxy-3-phenylbutan-2-one (93) as a colorless oily substance (330 mg, 1.37 mmol, 13.7%).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)C)=[CH:7][C:6]=1[CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N+:19]([CH3:22])=[CH:18]1)(=O)C.[ClH:23]>>[ClH:23].[ClH:23].[Cl-:23].[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N+:19]([CH3:22])=[CH:18]1
Reactant: CC(=O)Nc1ccc(NC(C)=O)c(CCn2cc[n+](C)c2)c1
Agent: Cl
Product: C[n+]1ccn(CCc2cc(N)ccc2N)c1
Product: [Cl-]

Procedure:
The 3-[2-(2,5-bis(acetylamino)phenyl)ethyl]-1-methyl-3H-imidazol-1-ium gum obtained was then refluxed for 6 hours in 100 ml of aqueous 36% hydrochloric acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]=[C:26]=[O:27].CCN(CC)CC.Cl>C1COCC1>[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:27])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1ccccc1I
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1I
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methoxyphenylacetate (1.94 g, 8.16 mmol) in THF (20 ml) was added 2-iodophenylisocyanate (2.0 g, 8.16 mmol) and Et3N (114 ul, 0.816 mmol). After stirring overnight, the mixture was poured into 1 N HCl (200 ml). The resulting precipitate was collected by filtration and dissolved in CHCl3 (200 ml). The solution was dried over MgSO4 and evaporated to give tert-butyl 4-[N′-(2-iodophenyl)ureido]-3-methoxyphenylacetate (3.93 g, quant) as a pale yellow amorphous solid 1H-NMR (CDCl3) δ1.44 (s, 9 H), 3.49 (s, 2 H), 3.85 (s, 3 H), 6.78-6.88 (m, 4 H), 7.07 (s, 1 H), 7.31-7.35 (m, 1 H), 7.76 (dd, J=7.8, 1.5 Hz, 1 H), 7.95 (d, J=8.3 Hz, 1 H), 7.99 (dd, J=8.3, 1.5 Hz, 1 H). MS (ESI), m/z 483 (M++1).