Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=1.C(O)C.[OH-].[K+].Cl>O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCO)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCCCCCCCCCCO)cc1

Procedure:
A solution of 5 g. of ethyl 4-(11-hydroxyundecylamino)benzoate in 75 ml. 95% ethanol is saponified with 2.5 g. of 85% potassium hydroxide by refluxing for 5 hours. The warm solution is diluted with 150 ml. water and adjusted to pH 5 with 37% hydrochloric acid. The precipitate is filtered, washed with water, dried in vacuo and crystallized from acetic acid to yield 4-(11-hydroxyundecylamino)benzoic acid as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:17][O:18][CH2:19][C:20](O)=O.[OH-].[Na+]>O>[CH3:17][O:18][CH2:19][C:20]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Reactant: COCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCc1nc2cnc3ccccc3c2n1CC(C)C
Temperature: 200 °C
Reaction time: 0.12 h

Procedure:
3-Amino-4-(2-methylpropylamino)quinoline (5.0 g; 0.023 mol) and methoxyacetic acid (20 mL) were mixed and heated at about 200° C. until all bubbling had stopped. Heating was continued for 5-10 min longer and the dark solution was allowed to cool to room temperature. The solution was diluted with water, made strongly basic with 50% sodium hydroxide and extracted with ether. The combined extracts were dried over magnesium sulfate and evaporated to dryness to yield 5.2 g of crude product. The crude product was used as such for further reactions. A small sample was recrystallized from ether to yield nearly colorless crystals, m.p. 96°-99° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:29].CCOCC>O1CCOCC1>[ClH:29].[Br:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(Br)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Brc1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 20 mL vial which contained a solution the product from step 4 (130 mg, 0.3 mmol) in dioxane was added HCl (4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rt and stirred at rt for 16 h. The solvent was reduced to 1 mL and ether (15 mL) was added to this vial. the resulting solid was filtered out and dried in vacuo to yield the title product as a hydrogen chloride salt (80 mg, 80%); LCMS; 99%, ESI+, (Calcd: 346.3, Found m/z: 347.6, (M+1), 348.1, (M+2). 1H NMR (400 MHz, DMSO-d6); δ 1.68-1.76 (m, 1H), 1.86-2.02 (m, 2H), 2.07-2.14 (m, 1H), 3.15-3.24 (m, 2H), 3.86 (s, 2H), 3.83-3.92 (m, 1H), 4.02-4.07 (m, 1H), 4.21 (dd, J1=10.4 Hz, J2=3.6 Hz, 1H), 6.91 (d, J=8.8 Hz, 2H), 7.15-7.18 (m, 4H), 7.46 (d, J=8.4 Hz, 2H):
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH2:7])[CH2:2]1.[Cl-].[Na+].[CH3:10][NH:11][C:12](=[N:15][N+:16]([O-:18])=[O:17])OC.Cl>O.C(#N)C>[CH3:10][NH:11][C:12]([NH:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[N:15][N+:16]([O-:18])=[O:17]
Reactant: CNC(=N[N+](=O)[O-])OC
Reactant: NCC1CCOC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNC(=N[N+](=O)[O-])NCC1CCOC1
Reaction time: 4 h

Procedure:
[(3-tetrahydrofuryl)methyl]amine (38.0 g, 0.38 mole), 31.3 g of sodium chloride and 125.0 g of water were mixed, and the resulting mixture was cooled to −10 degree centigrade. N,O-dimethyl-N′-nitroisourea (49.2 g, 0.37 mole) was introduced into the above solution. Sodium chloride was dissolved in water with 76% of the saturated solubility at a water temperature of −10 degree centigrade. The suspension was stirred at −10 degree centigrade for 4 hours and then heated to 10 degree centigrade, and further stirred for 19 hours. 35% hydrochloric acid (6.7 g, 0.07 mole) was added to the suspension so that the pH became not more than 4. Water and acetonitrile were added to the above suspension for complete dissolution. The resulting solution was analyzed by HPLC and as a result, the reaction yield of the titled compound was 88%.
Reaction SMILES: [CH3:1][N:2]([S:42]([CH3:45])(=[O:44])=[O:43])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([NH:33][C@@H:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH3:35])=[O:32])[CH:30]=1)[C:6]([NH:8][C@@H:9]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:10]([O:14]C1CCCCO1)[C:11]([OH:13])=O)=[O:7].[NH2:46][C:47]1[NH:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1.C1C=CC2N(O)N=NC=2C=1.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:21]([C@H:9]([NH:8][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([N:2]([CH3:1])[S:42]([CH3:45])(=[O:44])=[O:43])[CH:30]=[C:29]([C:31]([NH:33][C@@H:34]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35])=[O:32])[CH:28]=1)[C@@H:10]([OH:14])[C:11]([NH:46][C:47]1[NH:51][C:50]2[CH:52]=[CH:53][CH:54]=[CH:55][C:49]=2[N:48]=1)=[O:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@@H](NC(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](OC2CCCCO2)C(=O)O)cc(N(C)S(C)(=O)=O)c1)c1ccccc1
Reactant: Nc1nc2ccccc2[nH]1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C(=O)Nc2nc3ccccc3[nH]2)cc(N(C)S(C)(=O)=O)c1)c1ccccc1
Reaction time: 8 h
Yield: 48 %

Procedure:
To a 2 mL solution of (2R,3S)-3-{[3-[methyl(methylsulfonyl)amino]-5-({[(1R)-1-phenylethyl]amino}carbonyl)benzoyl]amino}-4-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)butanoic acid obtained in Reference Example 27 64 mg (0.1 mmol), 2-aminobenzimidazole 27 mg (0.2 mmol), HOBt.H2O 31 mg (0.2 mmol) and 4-(dimethylamino)pyridine 2.4 mg (0.02 mmol) in N,N-dimethylformamide was added a polystyrene-supported carbodiimide (1.38 mmol/g) 181 mg (equivalent to carbodiimide 0.25 mmol) and the mixture was shaken overnight. After completion of the reaction, the mixture was filtered and the filtrate was extracted by adding ethyl acetate and 5% aqueous sodium carbonate solution. The organic layer was washed with an aqueous saturated sodium chloride solution and dried on the magnesium sulfate, filtered and concentrated. The concentrated residue was redissolved in chloroform 2 mL and thereto was added TFA 1 mL and the mixture was stirred at room temperature for 3 hours to remove the protecting group. After completion of the reaction, the mixture was concentrated and the concentrated residue was purified by HPLC fraction collector to give 32 mg (0.05 mmol) of the title compound (overall yields: 48%).
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[Cl:13][C:14]1[CH:15]=[C:16]([C@@H:21]2[C@:23]3([C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:32])[CH2:22]2)[CH:17]=[CH:18][C:19]=1[F:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([C@@H:21]2[C@:23]3([C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:2])=[O:12])[C:24]3=[O:32])[CH2:22]2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(F)c(Cl)c1
Product: O=C(O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(F)c(Cl)c3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 1 starting from 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-2-(3-chloro-4-fluorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C24H17ClFNO3: 421, observed (M+H)+: 422.2 1H NMR (400 MHz, DMSO-d6) δppm 2.04-2.15 (m, 1 H) 2.40-2.49 (m, 1 H) 3.21 (t, 1 H) 5.09 (s, 2 H) 6.18 (d, 1 H) 6.75 (t, 1 H) 6.96 (d, 1 H) 7.06-7.14 (m, 1 H) 7.29-7.39 (m, 2 H) 7.46-7.53 (m, 1 H) 7.56-7.65 (m, 2 H) 7.82-7.93 (m, 2 H) 13.03 (s, 1 H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:9][C:8]([F:34])([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:30]=[C:29]([Cl:31])[C:28]([Cl:32])=[C:27]([Cl:33])[CH:26]=4)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)[CH2:7]1)=[O:5])C.[OH-].[Li+]>CCO.O>[F:34][C:8]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:26]=[C:27]([Cl:33])[C:28]([Cl:32])=[C:29]([Cl:31])[CH:30]=4)([C:21]([F:22])([F:23])[F:24])[O:18][N:17]=3)=[CH:12][CH:11]=2)[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:9]1
Reactant: CCOC(=O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.2 %

Procedure:
To a stirred solution of 3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid ethyl ester (non-polar compound from Preparation 5, 2 g, 3.72 mmol) in EtOH:H2O (1:1, 140 mL) was added lithium hydroxide (0.782 g, 18.62 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 16 hours. After consumption of starting material, reaction mixture was concentrated in vacuo; suspension was diluted with water (100 mL) and Acidified with 1M HCl up to pH=2 at 0° C. Solid was precipitated out, which was filtered on Whatmann filter paper. Solid was dissolved in EtOAc (100 mL), dried over sodium sulphate, filtered and evaporated to afford solid. Solid was washed with n-pentane (3×5 mL), dried to afford white solid (1.6 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ: 2.75 (d, J=8.72 Hz, 2H), 2.81 (d, J=8.68 Hz, 2H), 3.37-3.39 (m, 1H), 4.29-4.41 (m, 2H), 7.55 (d, J=8.12 Hz, 2H), 7.77 (d, J=8.12 Hz, 2H), 7.84 (s, 2H), 12.50 (bs, 1H); LC-MS (m/z): 507.80 (M−H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][CH:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14](OC)=[CH:13][CH:12]=2)[C:5](=[O:19])[CH:4]=1.[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23]N.C(Cl)(Cl)Cl.CO>CO>[C:11]1([CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:9][C:6]2[C:5](=[O:19])[CH:4]=[C:3]([CH2:2][OH:1])[N:8]([CH2:23][CH:22]([O:25][CH3:26])[O:21][CH3:20])[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(CN)OC
Reactant: COc1ccc(COC2C=NC(CO)=CC2=O)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(Cn1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1CO)OC
Reaction time: 72 h

Procedure:
To a suspension of 3.33 g of 6-hydroxymethyl-3-(p-methoxybenzyl)oxy-4-pyridone in 20 ml of methanol is added 11.35 g of 2,2-dimethoxyethylamine at room temperature, and the mixture is stirred for 3 days. The reaction mixture is condensed under reduced pressure, and subjected to flash column chromatography on 100 g of Wako-Gel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) with an eluent of chloroform-methanol (20:1) to perform separation and purification. The title compound is obtained as colorless foam in a yield of 2.062 g.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH3:27][NH:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:27][N:28]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13]
Reactant: CNCCc1ccccc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Product: CN(CCc1ccccc1)S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and methyl-phenethyl-amine. The reaction was subjected to work-up and purification after stirring for 2 h at room temperature. MS (ESI): 512.5 (MH+).
Reaction SMILES: [CH3:1][N:2]([C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:24]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:25]=2[CH3:35])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=1)=[O:11])[CH2:3][CH2:4][C:5]([O:7]CC)=[O:6]>C(O)C.CCCCCC>[CH3:1][N:2]([C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH:19]([C:24]2[CH:28]=[C:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:26][C:25]=2[CH3:35])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:17]=1)=[O:11])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccccc3)oc2C)cc1
Solvent: CCO
Solvent: CCCCCC
Product: Cc1oc(-c2ccccc2)cc1C(CC(C)C)Nc1ccc(C(=O)N(C)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Ethyl 3-{methyl[(4-{[3-methyl-1-(2-methyl-5-phenylfuran-3-yl)butyl]amino}phenyl)carbonyl]amino}propanoate (2.54 g) which is a synthetic intermediate in Example 125 was dissolved in ethanol-hexane (1:1, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with ethanol-hexane (1:1, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 12 min was collected, and concentrated. The obtained amorphous compound (1.24 g) was dissolved in ethanol (5 mL) and tetrahydrofuran (5 mL), 1N lithium hydroxide (5.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (20 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (1.1 g, 97%).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([OH:14])[CH2:11][CH2:12][CH3:13].S([O-])([O-])(=O)=O.[Mg+2]>>[CH2:6]([O:9][CH:8]([O:14][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:1][CH2:2][CH3:3]
Reactant: CCCCO
Reactant: O=CCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CCCCOC(Cc1ccccc1)OCCCC
Temperature: 100 °C
Reaction time: 6 h
Yield: 172.1 %

Procedure:
In a 100-ml three-necked flask, 24 g (0.2 mole) of phenylacetaldehyde, 18 g (0.24 mole) of n-butanol, 10 g of anhydrous magnesium sulfate and 0.1 mg of stannous chloride dihydrate were charged. The resulting mixture was stirred at 100° C. under atmospheric pressure for 6 hours in a nitrogen atmosphere. After the removal of magnesium sulfate, the residue was purified by chromatography on a silica gel column to give 43.1 g of phenylacetaldehyde dibutyl acetal [R1 =a benzyl group, R2 =a hydrogen atom and R3 =an n-butyl group] (yield: 86.3%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:39])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]([CH3:38])[CH:32]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][C:35]1[CH:36]=[C:31]([C:27]2[CH:26]=[C:25]([C:23]3[CH2:22][C:21](=[O:39])[NH:20][C:9]4[CH:10]=[C:11]([C:16]([F:18])([F:19])[F:17])[C:12]([CH2:14][CH3:15])=[CH:13][C:8]=4[N:7]=3)[CH:30]=[CH:29][CH:28]=2)[CH:32]=[C:33]([CH3:38])[N:34]=1
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M208) (155 mg, 0.28 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (72 mg, 59%).
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].[Cl:19][C:20]([F:28])([F:27])[C:21]([Cl:26])([F:25])[CH2:22][CH2:23]I.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Cl:26][C:21]([F:25])([C:20]([Cl:19])([F:28])[F:27])[CH2:22][CH2:23][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: FC(F)(Cl)C(F)(Cl)CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCC(F)(Cl)C(F)(F)Cl)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 9 h
Yield: 2.2 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.5 g of 1,2-dichloro-4-iodo-1,1,2-trifluorobutane were dissolved in 5 ml of dimethyl sulfoxide, 0.83 g of potassium carbonate was added, and the mixture was stirred at room temperature for 9 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.05 g of 2-(3,4-dichloro-3,4,4-trifluorobutyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (67)).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([C:24]([N:26]2[C:34]3[C:29](=[C:30]([F:36])[C:31]([F:35])=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH:21]=[C:20]([O:37][CH3:38])[N:19]=1>CN1C(=O)CCC1>[F:36][C:30]1[C:31]([F:35])=[CH:32][CH:33]=[C:34]2[C:29]=1[CH2:28][CH2:27][N:26]2[C:24]([C:22]1[CH:21]=[C:20]([O:37][CH3:38])[N:19]=[C:18]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:23]=1)=[O:25]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: COc1cc(C(=O)N2CCc3c2ccc(F)c3F)cc(Cl)n1
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)N2CCc3c2ccc(F)c3F)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1

Procedure:
0.98 g (4.5 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 0.50 g (1.5 mmol) (2-chloro-6-methoxy-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone were stirred in 3 mL NMP for 12 h at 130° C. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: C[Al](C)C.[C:5]([N:9]1[C:13]([NH2:14])=[CH:12][C:11]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[N:10]1)([CH3:8])([CH3:7])[CH3:6].[N:25]1([C:31]2[CH:41]=[CH:40][C:34]([C:35](OCC)=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[C:5]([N:9]1[C:13]([NH:14][C:35](=[O:36])[C:34]2[CH:33]=[CH:32][C:31]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:41][CH:40]=2)=[CH:12][C:11]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[N:10]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: COc1cccc(CCc2cc(N)n(C(C)(C)C)n2)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cccc(CCc2cc(NC(=O)c3ccc(N4CCNCC4)cc3)n(C(C)(C)C)n2)c1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 22.5 %

Procedure:
A 2M solution of trimethylaluminium in toluene (6.25 mL, 12.50 mmol) was added dropwise to a stirred solution of and 1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-amine (1.367 g, 5.00 mmol) and ethyl 4-(piperazin-1-yl)benzoate (1.171 g, 5 mmol) in toluene (20 mL) at 4° C., over a period of 5 mins under nitrogen. The resulting solution was stirred at 20° C. for 18 h. The reaction mixture was quenched with methanol (20 mL), filtered and evaporated to afford tan solid. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in DCM and 0.1% ammonia. Pure fractions were evaporated to dryness to afford N-(1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-yl)-4-(piperazin-1-yl)benzamide (0.520 g, 22.53%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([CH2:13][N:14]([C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=2)[C:15]([C@@H:17]2[CH2:19][C@H:18]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].C[CH2:42][O:43][C:44]([CH3:46])=O>CC#N.O.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>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([CH2:13][N:14]([C:15]([C@@H:17]2[CH2:19][C@H:18]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=2)=[O:16])[C:27]2[CH:32]=[CH:31][C:30]([C:8]3[CH:12]=[CH:11][C:46]([CH2:44][O:43][CH3:42])=[CH:10][CH:9]=3)=[CH:29][CH:28]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)NC1(CN(C(=O)[C@@H]2C[C@H]2c2cccc(F)n2)c2ccc(Br)cc2)CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCc1ccc(-c2ccc(N(CC3(NC(=O)OC(C)(C)C)CCCC3)C(=O)[C@@H]3C[C@H]3c3cccc(F)n3)cc2)cc1
Reaction time: 0.33 h

Procedure:
A mixture of [1-({(4-bromo-phenyl)-[trans-2-(6-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-amino}-methyl)-cyclopentyl]-carbamic acid t-butyl ester (95 mg, 0.18 mmol), arylboronic acid (0.22 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and K2CO3 (47 mg, 0.34 mmol) in CH3CN/H2O (3.5/0.5 mL) was macrowaved at 140° C. for 20 min. The reaction mixture was passed through a short silica pad (EtOAc) and concentrated. The residue was subjected to ISCO (12 g column, 0-50% EtOAc in hexane over 25 min) to give the desired products. MS (MH+ 574).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[CH:21]=[C:20]([O:22]CC)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>Cl>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[CH2:21][C:20](=[O:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: CCOc1cc(NCCSCc2[nH]cnc2C)nc2ccccc12
Agent: Cl
Product: Cc1nc[nH]c1CSCCNC1=Nc2ccccc2C(=O)C1

Procedure:
2-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-4-ethoxyquinoline (1.69 gms) and concentrated HCl (30 mls) were refluxed together for 17 hours. The solution was evaporated to dryness, the residue dissolved in water and basified with potassium carbonate. The precipitated oil was separated by decantation, washed with water and crystallised from isopropanol-water to give 2[-2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-quinolone m.p.=121°-124° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[S:28][C:29]([CH2:32][N:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=2)=[CH:21][N:20]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[S:28][C:29]([CH2:32][N:33]([CH3:34])[CH3:35])=[CH:30][CH:31]=3)=[CH:21][N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)s1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNc2ncc(Cc3ccc(CN(C)C)s3)c(=O)[nH]2)o1

Procedure:
A mixture of 2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamine (1.64 g) and 2-nitroamino-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone (2.01 g) in ethanol (10 ml) was heated under reflux for 30 hr. The ethanol was evaporated in vacuo to yield 2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone as a brown oil which was washed with hot water by decantation. The residue was dissolved in isopropanol and an excess of ethanolic hydrochloric acid was added to the solution.