Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.ClCCl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[C:8]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc2c(O)c(-c3ccc(SC)cc3)ccc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)c(-c3ccc(SC)cc3)ccc2c1
Yield: 78.2 %

Procedure:
Stir a solution of 6-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalen-1-ol (1.98 g, 6.68 mmol), 4-fluoro-nitrobenzene (0.78 mL, 7.34 mmol) and phosphazene base P4-t-butyl (6.7 mL of 1M in hexane, 6.7 mmol) in N,N-dimethylformamide (30 mL) at ambient temperature for 4 hours. Dilute the reaction with dichloromethane, wash with 1N aqueous hydrochloric acid, water, dry with solid magnesium sulfate and chromatograph on silica gel with hexane/ethyl acetate mixtures to give 2.18 g of 6-methoxy-2-(4-methylsulfanyl-phenyl)-1-(4-nitro-phenoxy)-naphthalene (78%)
Reaction SMILES: [Cl:1][C:2]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]([CH2:16][CH2:17][OH:18])[CH:10]=[C:9]([C:19]([O:21]CC)=[O:20])[C:8]2=[O:24].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.C1COCC1>[Cl:1][C:2]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]([CH2:16][CH2:17][OH:18])[CH:10]=[C:9]([C:19]([OH:21])=[O:20])[C:8]2=[O:24]
Reactant: CCOC(=O)c1cn(CCO)c2c(F)cc(Cc3cccc(Cl)c3Cl)cc2c1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cn(CCO)c2c(F)cc(Cc3cccc(Cl)c3Cl)cc2c1=O
Temperature: 60 °C
Yield: 94.8 %

Procedure:
Ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylate (80 mg, 0.18 mmol) obtained in Step 6 was dissolved in a mixed solvent of ethanol (2 ml) and THF (1 ml), 1N aqueous sodium hydroxide solution (1 ml, 1.0 mmol) was added, and the mixture was stirred with heating at 60° C. for 1 hr. After allowing to cool, 10% aqueous citric acid solution was added to the reaction mixture. The precipitated solid was collected by filtration, washed with 30% aqueous ethanol and vacuum dried to give the object product (70 mg, yield 93%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:31]=1)[C:7](=[O:30])[C:8]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[C:9]([CH:11]([N:13]1C(=O)C3C(=CC=CC=3)C1=O)[CH3:12])[N:10]=2.O.NN>CCO>[NH2:13][CH:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:31][N:6]2[C:7](=[O:30])[C:8]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH3:12]
Reactant: CC(c1nc2ccc(F)cn2c(=O)c1-c1ccccn1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(N)c1nc2ccc(F)cn2c(=O)c1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-(1-(7-fluoro-4-oxo-3-(pyridin-2-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)isoindoline-1,3-dione (0.584 g, 1.409 mmol) in EtOH (28.2 mL) was added hydrazine, monohydrate (0.684 mL, 14.09 mmol), and the mixture was stirred under reflux. After 1 h, the mixture was cooled to rt and the precipitate was filtered and washed with EtOAc (50 mL×2). The filtrate was concd under reduced pressure and then it was redissolved in EtOAc (50 mL) and water (50 mL). The aq layer was extracted with EtOAc (50 mL×1). The combined organic layers were treated with 3N aq HCl (50 mL). The separated aq layer was washed with DCM (50 mL×2) to remove organic impurities, basified to ˜pH 13 with 10N NaOH (80 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were dried over MgSO4, filtered, and concd under reduced pressure to give 2-(1-aminoethyl)-7-fluoro-3-(pyridin-2-yl)-4H-pyrido[1,2-a]-pyrimidin-4-one as a yellow syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.93-8.98 (1 H, m), 8.65-8.71 (1 H, m), 8.13 (1 H, ddd, J=9.9, 7.1, 2.9 Hz), 7.81-7.93 (2 H, m), 7.59 (1 H, dt, J=7.9, 1.1 Hz), 7.39 (1 H, dd, J=6.3, 4.7 Hz), 3.85 (1 H, q, J=6.7 Hz), 1.23 (3 H, d, J=6.7 Hz); Mass Spectrum (ESI) m/e=285.1 (M+1).
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:5]=2[N:4]=[N:3]1.[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:12])[C:5]=2[N:4]=[N:3]1
Reactant: CCCCCCCCO
Reactant: O=C(O)c1cccc2[nH]nnc12
Agent: Cl
Product: CCCCCCCCOC(=O)c1cccc2[nH]nnc12
Temperature: 110 °C
Reaction time: 2 h

Procedure:
n-Octyl alcohol (300 g) was saturated with hydrogen chloride gas passed in subsurface during about 2 hr. while the temperature rose to 55° C. Benzotriazolecarboxylic acid (16.3 g) prepared by the method of Example 1 was added and the reaction mixture was refluxed at 110° C. under reduced pressure for 1.25 hr. during which water was azeotropically distilled and collected in a Dean-Stark trap. Unreacted octyl alcohol was removed by reduced pressure distillation. The residue, which was solid when cooled, was recrystallized from benzene and washed with n-pentane to afford the ester, n-octyl benzotriazolecarboxylate, as a solid mp 64°-65° C. The infrared spectrum was similar to that of the ethyl ester, consistent with the ester structure, and the elemental analysis was as follows:
Reaction SMILES: C1(S([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:21][C:20]=4[CH:28]=3)[CH2:12][CH2:11]2)(=O)=O)C=CC=CC=1.S(=O)(=O)(O)O.[OH-].[NH4+]>>[N:13]1([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:21][C:20]=3[CH:28]=2)[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]1
Reactant: COC(=O)c1cc2cc(N3CCN(S(=O)(=O)c4ccccc4)CC3)ccc2o1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)c1cc2cc(N3CCNCC3)ccc2o1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Methyl 5-[4-(benzenesulfonyl)-1-piperazinyl]benzofuran-2-carboxylate (10 g) was added to sulfuric acid (25 g) at 25-30° C. and the mixture was heated to 98-102° C., followed by stirring for 15 minutes at the same temperature. The reaction mass was cooled to 25-30° C. and then poured into ice cold water (80 ml). The pH of the resulting aqueous layer was adjusted to 9-10 with ammonium hydroxide solution, followed by extracting with ethyl acetate (3×200 ml) and then distilling off the solvent under vacuum to produce 6.5 g of methyl 5-(1-piperazinyl)benzofuran-2-carboxylate (Yield: 96%).
Reaction SMILES: C1(C)C=CC(S([C:10]([C@H:13]2[C@H:17]([OH:18])[O:16][C:15](=[O:19])[CH2:14]2)([CH3:12])[CH3:11])(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH:17]([C:13](=[C:10]([CH3:12])[CH3:11])[CH2:14][C:15]([OH:19])=[O:16])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)C(C)(C)[C@@H]2CC(=O)O[C@H]2O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)=C(C=O)CC(=O)O
Temperature: -5 °C
Yield: 82.6 %

Procedure:
0.788 g of the product of Step C was added to a solution of 20 ml of water and 2.4 ml of methanol and 0.790 g of sodium carbonate were added with stirring at -5° C. to the resulting mixture. The mixture was stirred at 20° C. for 2 hours and was extracted with ether. The aqueous phase was acidified to a pH of 3.5 by addition of 1 N aqueous hydrochloric acid. The mixture was extracted with chloroform and the organic phase was evaporated to dryness under reduced pressure to obtain 0.310 g of 3-formyl-4-methyl-pent-3-ene-1-oic acid melting at 102° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].C(O[C:27](=N)[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])C.C(=O)([O-])O.[Na+]>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:27]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:15][C:14]=2[CH:16]=1
Reactant: CCOC(=N)CC(=O)OCC
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Yield: 95.1 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (200 mg, 0.646 mmol) in ethanol (5 mL) was added ethyl 3-ethoxy-3-iminopropionate (190 mg, 0.969 mmol), and this was heated to reflux for 2 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with ethyl acetate. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The crystals obtained were purified by silica gel column chromatography to yield the title compound (249 mg, 95% yield) as gray crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[CH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[CH2:12][C:13]([CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])([C:16]#[N:17])[C:14]#[N:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)CCBr
Reactant: N#CC(C#N)Cc1cccc(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cccc(OCc2ccccc2)c1
Yield: 40.7 %

Procedure:
Using 0.52 g of (3-benzyloxybenzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.34 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.28 g of 2-(3-(benzyloxy)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (88)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH3:34][O:35][CH2:36][CH2:37][C:38](Cl)=O.C>C(Cl)Cl.CCO.CO>[CH3:34][O:35][CH2:36][CH2:37][C:38]1[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[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: COCCC(=O)Cl
Reactant: CN(CCOCCNc1c(N)cnc2ccccc12)C(=O)OC(C)(C)C
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: COCCc1nc2cnc3ccccc3c2n1CCOCCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethyl(methyl)carbamate (6.05 g, 16.8 mmol) in 200 mL of anhydrous CH2Cl2 was cooled to 0° C. and treated with triethylamine (2.40 mL, 17.2 mmol). Methoxypropionyl chloride (1.72 mL, 17.2 mmol) was then added dropwise over 5 min. The reaction was then warmed to room temperature and stirring was continued for 3 h. The reaction mixture was then concentrated under reduced pressure to give an orange solid. This was dissolved in 200 mL of EtOH and 7.2 mL of triethylamine was added. The mixture was heated to reflux and stirred under N2 overnight. The reaction was then concentrated to dryness under reduced pressure and treated with 300 mL of Et2O. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give a brown solid. This was dissolved in 300 mL of CH2Cl2 and washed with H2O and brine. The organic portion was dried over Na2SO4 and concentrated under reduced pressure to give a brown oil. The oil was dissolved in 100 mL of hot MeOH and treated with activated charcoal. The hot solution was filtered and concentrated to give 7.20 g of tert-butyl 2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate as a yellow syrup.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:21][C:22]2[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:28]1([NH2:35])[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1>CN1C(=O)CCC1>[NH2:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([NH:35][C:2]2[CH:3]=[C:4]([NH:21][C:22]3[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[F:20])=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:29][CH2:30]1
Reactant: Cn1ccc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CN1CCCC1=O
Product: Cn1ccc(Nc2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Temperature: 110 °C

Procedure:
A mixture of 6-chloro-N-(3-fluoropyridin-4-yl)-8-(1-methyl-1H-pyrazol-3-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide 18A (19.9 mg, 0.044 mmol) and trans-cyclohexane-1,4-diamine (47.6 mg, 0.417 mmol) in NMP (0.7 mL) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature and purified by preparative HPLC. The desired fraction was concentrated and lyophilized to give 18B (14.9 mg, 40%) as a brown solid. [M+H]=465. HPLC Peak Rt=2.263 minutes. (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm.)
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][CH:8]1[C:12]2[N:13]=[CH:14][NH:15][C:16](=O)[C:11]=2[CH2:10][CH2:9]1.N>C(Cl)(Cl)Cl>[Cl:3][C:16]1[C:11]2[CH2:10][CH2:9][CH:8]([O:7][CH3:6])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC1CCc2c1nc[nH]c2=O
Agent: N
Solvent: ClC(Cl)Cl
Product: COC1CCc2c(Cl)ncnc21
Temperature: 25 °C

Procedure:
2.5 ml of phosphorus oxychloride were added to 1.0 g of 6,7-dihydro-7-methoxy-3H,5H-cyclopenta[d]pyrimidin-4-one [prepared as described in step (d) above], and the mixture was heated under reflux for 5 minutes. The mixture was then cooled to room temperature, 20 ml of chloroform were added, and the mixture was then poured into ice-water. The cold mixture was made alkaline by the addition of concentrated aqueous ammonia, and then the chloroform layer was separated. This chloroform layer was washed with water, dried over anhydrous sodium sulfate and treated with active carbon. The chloroform was then evaporated off under reduced pressure, to give 1.01 g of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][CH2:9][C:10](=O)[CH2:11]Cl>C(O)C>[Cl:8][CH2:9][C:10]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:11]=1
Reactant: O=C(CCl)CCl
Reactant: Nc1ccccn1
Solvent: CCO
Product: ClCc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
A mixture of 4.7 g (0.05 mole) of 2-aminopyridine and 6.4 g (0.05 mole) of 1,3-dichloropropan-2-one in 50 ml of ethanol was stirred overnight at room temperature. The mixture was concentrated in vacuo and the residue was triturated with acetonitrile. The solid that formed was recrystallized from acetonitrile-methanol to yield ca. 1 g of 2-chloromethylimidazo[1,2-a]pyridine as the hydrated hydrochloride salt. [Calcd. for C8H7N2Cl.HCl.H2O: C, 43.42; H, 4.52; N, 12.67; Cl, 32.12. Found: C, 42.94; H, 4.62; N, 12.68; Cl, 32.12.] A mixture of 790 mg (3.89 mmole) of the chloromethyl compound and 585 mg (3.90 mmole) of 2-mercaptobenzimidazole in 200 ml of isopropyl alcohol was stirred for two days. The mixture was concentrated in vacuo and the residue was dissolved in boiling isopropyl alcohol. The precipitate that formed upon cooling was collected and partitioned between saturated aqueous sodium bicarbonate and chloroform. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to a solid. Recrystallization from isopropyl alcohol yielded (in two crops) 500 mg of the title compound as an analytically pure solid, m.p. 220°-222°. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[NH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=1)=[O:23].[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([C:48](O)=[O:49])[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[O:23]=[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:32])([F:33])[F:34])[CH:25]=1)[CH2:21][NH:20][C:48]([CH:45]1[CH2:46][CH2:47][N:42]([C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])[CH2:43][CH2:44]1)=[O:49]
Reactant: NCC(=O)c1cccc(OC(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2cccc(OC(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
Add triethylamine (1.1 mL, 7.89 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.51 g, 7.87 mmol) to a solution of 2-amino-1-(3-(trifluoromethoxy)phenyl)ethanone (1.56 g, 6.10 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.66 g, 7.24 mmol) in CH2Cl2 (15 mL) at 0° C. Stir at 0° C. for 3 h, then at room temperature overnight. Concentrate the mixture in vacuo. Purify the residue by silica gel chromatography (80 g SiO2 eluting with 50% ethyl acetate/hexanes, 1 L) to provide tert-butyl 4-(2-oxo-2-(3-(trifluoromethoxy)phenyl)ethylcarbamoyl)piperidine-1-carboxylate (1.50 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32](=[O:38])[N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:39][CH2:40][CH3:41])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:44][S:45]([CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)(=[O:47])=[O:46]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:53]3[CH2:52][CH2:51][N:50]([CH2:49][CH2:48][S:45]([CH3:44])(=[O:46])=[O:47])[CH2:55][CH2:54]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:31])([CH3:30])[C:32]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:38])=[CH:25][C:24]=3[O:39][CH2:40][CH3:41])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C(=O)N(CC)CC)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C(=O)N(CC)CC)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1
Yield: 87.2 %

Procedure:
cis-4,5-Bis-(4-chloro-phenyl)-2-[4-(1-diethylcarbamoyl-1-methyl-ethyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (27 mg, 0.0439 mmol) was reacted with 1-(2-methanesulfonyl-ethyl)piperazine dihydrochloride (17.5 mg, 0.0659 mmol, example 17) using the procedure described in example 25 to give cis-2-(4-{4,5-bis-(4-chloro-phenyl)-1-[4-(2-methanesulfonyl-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-N,N-diethyl-isobutyramide (29.5 mg, 87% yield) as white solids. HR-MS (ES, m/z): observed 770.2909, calculated for C39H50Cl2N5O5S [(M+H)+] 770.2904.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][CH2:4][C@:5]1([CH3:30])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[S:22][CH:23]=[C:24]([CH2:25]O)[C:19]=3[S:18](=[O:28])(=[O:27])[N:17]=2)[C:6]1=[O:29].N12CCCN=C1CCCCC2.C1(P([N:58]=[N+:59]=[N-:60])(C2C=CC=CC=2)=O)C=CC=CC=1>ClCCl>[N:58]([CH2:25][C:24]1[C:19]2[S:18](=[O:28])(=[O:27])[N:17]=[C:16]([C:7]3[C:6](=[O:29])[C@@:5]([CH2:4][CH2:3][C:2]([CH3:32])([CH3:31])[CH3:1])([CH3:30])[C:14]4[C:9]([C:8]=3[OH:15])=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:21][C:20]=2[S:22][CH:23]=1)=[N+:59]=[N-:60]
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CO)csc3N2)=C(O)c2ccccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CN=[N+]=[N-])csc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
A solution of Example 185 (1 g, 2.11 mmol) in 25 mL of dichloromethane was cooled to 0° C., treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.7 mL, 11.2 mmol) and diphenylphosphoryl azide (2.3 mL, 10.9 mmol), allowed to warm to room temp, stirred for 16 h, and concentrated onto silica gel. The crude material was chromatographed on silica gel with hexane, hexane/dichloromethane (1:1), followed by dichloromethane, and methanol/dichloromethane (1:99) to afford the title compound (610 mg, 59% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.39 (td, J=12.7, 3.3 Hz, 1H), 0.72 (s, 9H), 0.81 (td, J=13.1, 4.6 Hz, 1H), 1.57 (s, 3H), 2.05 (m, 1H), 2.22 (td, J=12.6, 4.6 Hz, 1H), 4.56 (s, 2H), 7.29 (m, J=8.6, 8.6 Hz, 1H), 7.54 (s, 1H), 7.74 (m, J=4.0 Hz, 2H), 8.13 (d, J=7.7 Hz, 1H), 14.09 (s, 1H); MS (APCI+) m/z 498 (M+H)+.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[O:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([O-])(=O)C.[NH4+].[N+:29]([CH3:32])([O-:31])=[O:30]>CO>[N+:29]([CH:32]=[CH:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:15]([O:22][CH3:23])[CH:16]=1)([O-:31])=[O:30]
Reactant: C[N+](=O)[O-]
Reactant: CCCCCCCCCCCCOc1ccc(C=O)cc1OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCCCCCCCCCCOc1ccc(C=C[N+](=O)[O-])cc1OC

Procedure:
4-Dodecyloxy-3-methoxybenzaldehyde (166 g; 0.519 mol) is heated for 2 hours at 100° C. with ammonium acetate (20 g; 0.388 mol) and nitromethane (49 ml; 0.914 mol). The resulting melt is then added dropwise with vigorous stirring to methanol, yellow crystals precipitating. After filtration, the residue is washed several times with methanol and then dried.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH2:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)[C:2]([NH2:4])=[O:3].[CH:15](OCC)=[O:16]>>[NH:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH:14][CH:15]=[O:16])[CH3:13])[CH:8]=[CH:9][CH:10]=1)[C:2]([NH2:4])=[O:3]
Reactant: CCOC=O
Reactant: CC(N)Cc1cccc(NC(N)=O)c1
Product: CC(Cc1cccc(NC(N)=O)c1)NC=O

Procedure:
A mixture consisting of 4.8 gm of 1-(3'-ureido-phenyl)-2-amino-propane and 5 ml of ethyl formate was refluxed for 5 hours. Thereafter, the reaction solution was evaporated, and the residue was purified by chromatography on a silicagel column, using methanol/chloroform (2:8) as the flow agent. The eluate was evaporated, and the residue was recrystallized from ethanol and ether, yielding the compound of the formula ##STR25## which had a melting point of 133-136° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:29])([CH3:28])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[NH:10][C:11]=2[CH:12]=[CH:13][C:14]=1[F:15])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[F:15][C:14]1[CH:13]=[CH:12][C:11]2[NH:10][CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[C:8]([CH3:29])([CH3:28])[CH2:7][C:6]=2[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(F)ccc2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)Cc2c(ccc(F)c2C(=O)O)NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a stirred mixture solution of 6-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (400 mg, 1.0 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 6-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (345 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25FN2O3 (M+H)+: 385.45, observed: 385.1.