Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:28]=1)[CH:7]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16](F)=[O:17])=[N:9]1.[F:29][C:30]([F:36])([F:35])[S:31]([NH2:34])(=[O:33])=[O:32]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:28]=1)[CH:7]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16]([NH:34][S:31]([C:30]([F:36])([F:35])[F:29])(=[O:33])=[O:32])=[O:17])=[N:9]1
Reactant: Cc1cc(CCC(=O)F)nn1C(OCc1ccc(Cl)cc1)c1cccc(Cl)c1
Reactant: NS(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(CCC(=O)NS(=O)(=O)C(F)(F)F)nn1C(OCc1ccc(Cl)cc1)c1cccc(Cl)c1
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of acid fluoride 9 (0.14 g, 0.33 mmol) and DMAP 0.161 g (1.3 mmol) in dry DCM, trifluoromethanesulfonamide 0.147 g (0.98 mmol) was added. The mixture was stirred under a nitrogen atmosphere for 16 hours before diluting with EtOAc. The organic phase was washed with 2M HCl, followed by brine, dried over MgSO4 and evaporated to dryness. The crude acyl sulphonamide 10 was purified on silica to yield 0.13 g as a white solid (72%).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 100 °C
Yield: 79.4 %

Procedure:
A pyridine suspension (40 ml) containing 2-amino-5-nitropyridine (4.0 g) and p-toluenesulfonyl chloride (5.7 g) was stirred for a day and night at 100° C. The reaction liquid was poured in water (200 ml), the precipitated solid was recovered by filtration, and successively washed with water and diethyl ether by the order stated. Drying the solid under reduced pressure, 4-methyl-N-(5-nitro-2-pyridinyl)benzenesulfonamide (6.7 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=O)[C:12](=O)[N:11]3[C@H:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[CH2:17][CH2:18][C@H:10]3[CH2:9]2)=[CH:4][C:3]=1[O:29][CH3:30].B.C1COCC1.CO>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[C@H:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[CH2:17][CH2:18][C@@H:10]3[CH2:9]2)=[CH:4][C:3]=1[O:29][CH3:30]
Reactant: COc1cc(N2C[C@@H]3CC[C@@H](c4ccc(OC)c(OC)c4)N3C(=O)C2=O)ccc1Cl
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N2CCN3[C@H](CC[C@H]3c3ccc(OC)c(OC)c3)C2)ccc1Cl
Temperature: 0 °C
Yield: 30.9 %

Procedure:
(±)-cis-2-(4-Chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazine-3,4-dione (49.7 mg, 0.115 mmol) was dissolved in dry THF (10 mL) and BH3.THF (1 mL, 1 mmol) was added dropwise to the mixture, which was then heated at reflux overnight. The solution was cooled to 0° C. and MeOH (2 mL) was added dropwise. The solvent was removed by evaporation and the crude product was dissolved in MeOH (10 mL) and 12N HCl (2 mL). The solution was refluxed for 4 hours. The reaction mixture was concentrated (˜2 mL) followed by basification with 1N NaOH. The aqueous solution was extracted with CH2Cl2 (3×25 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude products were purified by preparatory TLC eluting with CH2Cl2/MeOH (97:3) to yield the (±)-cis-(20.3 mg, 43.8%) and (±)-trans-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazine (14.3 mg, 30.9%) with (±)-cis-2-(4-chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazine eluting further up the plate. (±)-trans-2-(4-Chloro-3-methoxy-phenyl)-6-(3,4-dimethoxy-phenyl)-hexahydro-pyrrolo[1,2-a]pyrazine 1H NMR (CDCl3) δ 7.20 (d, J=8.7 Hz, 1H, ArH), 6.89–6.83 (m, 3H, ArH), 6.47–6.40 (m, 2H, ArH), 4.16 (m, 1H), 3.95–3.84 (m, 1H), 3.90 (s, 3H, OCH3), 3.88 (s, 6H, OCH3), 3.58–3.46 (m, 1H), 3.41–3.36 (m, 1H), 3.26–3.22 (m, 1H), 2.99–2.71 (m, 3H), 2.34–2.20 (m, 2H), 1.95–1.83 (m, 1H), 1.64–1.54 (m, 1H). LCMS m/z 403 (M++1, 100, 1.90 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.Cl.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1.CO>C(Cl)Cl>[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([C:10]3[C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[S:13][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:32])=[CH:34][CH:35]=2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COc1ccc(-c2cc3ccccc3s2)cc1
Reactant: O=C(O)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Yield: 59 %

Procedure:
By essentially following the procedure detailed in Example 1, Part C, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3, Part A) and 4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride in 59% yield as an oil following radial chromatography (SiO2; gradient of 2-5% MeOH in CH2Cl2).
Reaction SMILES: [F:1][C:2]([F:8])([CH2:5][CH2:6][OH:7])[CH2:3][OH:4].N1C=CC=CC=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:4][CH2:3][C:2]([F:8])([F:1])[CH2:5][CH2:6][O:7][S:16]([CH3:15])(=[O:18])=[O:17])(=[O:18])=[O:17]
Reactant: OCCC(F)(F)CO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCC(F)(F)COS(C)(=O)=O
Reaction time: 8 h

Procedure:
To a stirred mixture of 2,2-difluoro-1,4-butanediol (12.97 g, 103 mM), dry pyridine (65 mL) and dichloromethane (200 mL) is slowly added a solution of methanesulfonylchloride (23.6 g) in dichloromethane (50 mL). Stirring is continued overnight. The reaction mixture is washed with 2N HCl (twice), followed by 10% aqueous NaHCO3 until neutral, and then with water. The organic layer is dried (MgSO4) and upon evaporation of the solvents, a slightly yellow oil is obtained. Crystallization is induced by scratching the oil with dry ether, to yield the compound 1,4-bis-methanesulfonyloxy-2,2-difluorobutane as white crystals: 22.3 g (77%).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[NH3:16]>C(Cl)(Cl)Cl>[C:10]1([C:1]2[CH:6]=[CH:5][C:4]([C:7]([NH2:16])=[O:8])=[CH:3][CH:2]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: N
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
A mixture of 27 g (0.12 mole) of 4-biphenylcarbonyl chloride and 300 ml of AR chloroform was saturated with anhydrous ammonia while maintaining a temperature of 20°. Following the 20 min. addition the white precipitate was collected, washed with cold water and oven-dried (60°) to give 23.5 g, m.p. shrinks 228°, melts 230°-233°.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].Cl[CH:17]1[O:21][CH:20]([CH2:22][O:23][C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[CH:19]([O:33][C:34](=[O:42])[C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[CH2:18]1>C(#N)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([CH:17]2[O:21][CH:20]([CH2:22][O:23][C:24](=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[CH:19]([O:33][C:34](=[O:42])[C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=3)[CH2:18]2)[CH:3]=1
Reactant: Cc1ccc(C(=O)OCC2OC(Cl)CC2OC(=O)c2ccc(C)cc2)cc1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(I)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(C(=O)OCC2OC(n3cc(I)c4cc([N+](=O)[O-])ccc43)CC2OC(=O)c2ccc(C)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a suspension of 1.0 g (3.5 mmol) 3-iodo-5-nitroindole in 15 ml acetonitrile were added 0.16 g (6.7 mmol) sodium hydride (Aldrich 223441-50G). The stirring was continued and the suspension turned red. After 15 min. 2.02 g (5.2 mmol) 5-chloro-2-(4-methyl-benzoyloxymethyl)-3-(4-methyl-benzoyloxy)-tetrahydro-furan were added in small portions and the stirring was continued for another 60 minutes at room temperature. The precipitate was removed by filtration and washed once with acetonitrile. The combined yellow filtrates were concentrated until a product precipitated. For complete precipitation of the product 50 ml ethanol were added. The yellow precipitate was removed by filtration und washed with ethanol. The residuum was dried over phosphorus pentoxide and potassium hydroxide in a vacuum (yield: 1.9 g).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[N:12]=2)=[CH:4][C:3]=1[N+:24]([O-])=O.CO.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=S)=[CH:33][CH:32]=1>[C].[Pd].[Fe](Cl)(Cl)Cl.C(OCC)(=O)C>[F:29][C:30]([F:40])([F:41])[C:31]1[CH:32]=[CH:33][C:34]([NH:37][C:38]2[NH:24][C:3]3[CH:4]=[C:5]([O:6][C:7]4[CH:8]=[CH:9][C:10]5[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]6[CH2:21][CH2:20]6)=[O:18])[N:15]=5)[N:12]=4)[CH:22]=[CH:23][C:2]=3[N:1]=2)=[CH:35][CH:36]=1
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Nc1cn2nc(Oc3ccc4nc(Nc5ccc(C(F)(F)F)cc5)[nH]c4c3)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.1 %

Procedure:
A suspension of N-[6-(4-amino-3-nitrophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (499 mg, 1.38 mmol), 10% palladium carbon (100 mg) and methanol (20.0 mL) was stirred under a hydrogen atmosphere (up to 1 atm) at room temperature overnight. The insoluble material was filtered through celite, and the filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (10 mL), 4-(trifluoromethyl)phenylisothiocyanate (120 mg, 0.59 mmol) was added to the mixture, and the mixture was stirred at room temperature for 1 hr. Iron (III) chloride (177 mg, 1.1 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1.5 hr. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, and filtrated. Dichloromethane (20 mL) was added to the residue, and the precipitate was collected by filtration to give the title compound (367 mg, 52%). The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate alone→ethyl acetate/methanol=9:1). Ethyl acetate was added to the obtained oily substance, and the precipitate was collected by filtration to give the title compound (116 mg, 32%) as a pale-yellow solid.
Reaction SMILES: [NH2:1][NH2:2].[C:3]([O:10]C)(=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CO>[C:3]([NH:1][NH2:2])(=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(=O)OC
Reactant: NN
Solvent: CO
Product: CCCCCC(=O)NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 271.5 %

Procedure:
Under nitroqen, a solution of 262 g (8 2 mol) of anhydrous hydrazine in 1300 mL of methanol was cooled to 0° C. and treated with 885 g (6.8 mol) of methyl caproate. The reaction was allowed to warm to ambient temperature and stir overnight prior to stirring at reflux for 7 h. The reaction was concentrated in vacuo; recrystallization from toluene gave 707 g (80%) of caproic acid hydrazide as a colorless solid: mp 72.5°-73.9° C.; NMR (CDCl3) δ 0.82 (t, J=7 Hz, 3H), 1.15-1.33 (m, 4H), 1.51-1.64 (m, 2H), 2.10 (t, J=7 Hz, 2H), 3.91 (br s, 2H), 7.56 (br s, 1H). A 5.0 g (39 mmol) sample of the hydrazide was dissolved in 40 mL of methanol and treated with 11.2 g (78 mmol) of ethyl iminocaproate [P. Reynaud and R. C. Moreau, Bull. Soc., Chim. France, 2997 (1964)-which. was only about 50% pure by NMR] under nitrogen. The reaction was stirred at reflux for 2 days and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (48:52) gave 7.56 g (92%) of 3,5-dipentyl-1H-1,2,4-triazole as a colorless solid: mp 66°-68° C.; NMR (CDCl3) δ 0.88 (t, J=7 Hz, 6H), 1.24-1.41 (m, 8H), 1.66- 1.81 (m, 4H), 2.72 (t, J=7 Hz, 4H); MS (FAB) m/e (rel intensity) 210 (100), 166 (14); HRMS. Calcd for M+H: 210.1970. Found: 210.1964.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]1=[O:23])=[O:5])[CH3:2].[OH:24]O>C(O)(=O)C>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=2)[NH:15][C:14](=[O:24])[C:13]1=[O:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCCCCn1c(=O)cnc2cc(Br)ccc21
Reactant: OO
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCCn1c(=O)c(=O)[nH]c2cc(Br)ccc21
Temperature: 0 °C

Procedure:
The above ester (3.43 g, 9.0 mmol) was reacted with 30% H2O2 (14.9 ml) in glacial acetic acid (40 ml) at 55° C. for 20h. The mixture was poured onto crushed ice (250 ml) and extracted with ethyl acetate (2×400 ml). The combined organic extract was washed with half saturated sodium hydrogen carbonate solution and water, dried (Na2SO4), evaporated to dryness and stripped with ether. The product was triturated with heptane (20 ml) overnight, the precipitate filtered off, washed with heptane and dried to afford 2.86 g of the title compound. M.p. 187°-190° C. 1H-NMR(DMSO-d6):δ0.80(m, 3H), 1.1(t, 3H), 1.12-1.4(m, 6H) 1.9-2.25(m, 2H), 4.0-4.17(m, 2H), 5.2-5.7(m, 3H), 12.28(s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5](O)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)([Cl:14])=O>>[Cl:14][C:5]1[N:4]=[CH:3][CH:2]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)cnc1O
Product: O=C(O)c1cccnc1Cl

Procedure:
Substituted pyridines 12 can be prepared by the procedure described in Scheme 4. A solution of sodium hypobromite is freshly prepared and added to a 2-hydroxynicotinic acid 7 and heated, such as at a temperature of about 50° C. Additional sodium hypobromide may be added to form the bromo compound 8 as needed. The 5-bromo-2-hydroxynicotinic acid 8 is reacted with thionyl chloride, at suitable temperature, such as at a temperature >RT, and preferably at about 80° C., to form the 2-chloro-nicotinic acid analog 9. The acid is coupled with an amine, preferably in the presence of a suitable coupling agent(s), such as EDC, HOBT, and DIEA, to form the corresponding substituted amide 10. Suzuki coupling with the bromo nicotinamide 10 and suitable boronic acids, provides the substituted nicotinamide 11. 2-Amino-nicotinamides 12 are prepared from the corresponding chloro compounds 11 such as by reacting with substituted amines at a suitable temperature, such as about 80° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:20]([O:22]CC)=[O:21])=[CH:6][N:7]2[CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>OS(O)(=O)=O.O.CC(O)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:20]([OH:22])=[O:21])=[CH:6][N:7]2[CH:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cn(C2CCOCC2)c2cc(F)c(F)c(N)c2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CCOCC1
Temperature: 0 °C
Yield: 80.3 %

Procedure:
A suspension of ethyl 5-amino-6,7-difluoro-1,4-dihydro-4-oxo-1-(tetrahydropyran-4-yl)-3-quinolinecarboxylate (70.0 mg, 0.199 mmol) in a mixture of H2SO4/H2O/AcOH (1:5:6, 3 mL) was heated under reflux for 1 h. The reaction mixture was poured into ice-water and the resulting precipitates were collected by filtration. The filtered precipitates were washed with water, and dried in vacuo to give 5-amino-6,7-difluoro-1,4-dihydro-4-oxo-1-(tetrahydropyran-4-yl)-3-quinolinecarboxylic acid (51.8 mg, 80%) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH: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]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[CH3:36][N:37]([CH3:46])[C:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39]>>[CH3:36][N:37]([CH3:46])[C:38]([N:40]1[CH2:41][CH2:42][N:43]([C:20]([N:11]2[C@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C@@:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH3:35])[N:9]=[C:10]2[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH:32]([CH3:33])[CH3:34])=[O:21])[CH2:44][CH2:45]1)=[O:39]
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: CN(C)C(=O)N1CCNCC1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(C(=O)N(C)C)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazine-1-carboxylic acid dimethylamide (Aldrich) to give the title compound. LC-MS: 652.2 [(M+H)+]
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#N)=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:33]>C1(C)C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:33])=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(=O)(O)O
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(C#N)cc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A solution of 7.08 g of p-[2-(trans-4-pentylcyclohexyl)ethyl]benzonitrile in 50 ml of absolute toluene was placed at 0° C. in a sulphonation flask under argon gasification and treated within 15 minutes with 29 ml of a 1.21N solution of diisobutylaluminium hydride in toluene in such a manner that the internal temperature did not exceed 5° C. After completion of the addition, the mixture was stirred at room temperature for a further 2 hours, then treated cautiously with 50 ml of 0.5N sulphuric acid and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 50 ml of semi-saturated sodium chloride solution each time, dried over magnesium sulphate and concentrated. There were obtained 6.20 g (87%) of p-[2-(trans-4-pentylcyclohexyl)ethyl]benzaldehyde as a colourless viscous oil (purity 97%) which was used without additional purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][C:6]([C:13]2[NH:14][C:15](=[O:22])[C:16]([CH:19]([CH3:21])[CH3:20])([CH3:18])[N:17]=2)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].[OH:23][CH:24]([CH3:29])[CH2:25][C:26](O)=[O:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH:19]([C:16]1([CH3:18])[C:15](=[O:22])[NH:14][C:13]([C:6]2[N:5]=[CH:4][C:3]([CH:1]3[O:23][CH:24]([CH3:29])[CH2:25][C:26](=[O:27])[O:2]3)=[CH:12][C:7]=2[C:8]([O:10][CH3:11])=[O:9])=[N:17]1)([CH3:20])[CH3:21]
Reactant: COC(=O)c1cc(C=O)cnc1C1=NC(C)(C(C)C)C(=O)N1
Reactant: CC(O)CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C2OC(=O)CC(C)O2)cnc1C1=NC(C)(C(C)C)C(=O)N1
Yield: 20 %

Procedure:
A solution of methyl 5-formyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate (0.55 g, 0.0018 mol), 3-hydroxybutyric acid (0.28 g, 0.0027 mol) and a catalytic amount of para-toluenesulfonic acid in chloroform (25 mL) is heated at reflux temperature for 113 hours. During this time, water is removed by placement of an addition funnel containing 3 angstrom molecular sieves between the reaction flask and the reflux condensor. The reaction mixture is poured into aqueous saturated sodium bicarbonate and the layers are separated. The aqueous portion is extracted with additional methylene chloride and the combined organic extracts are dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. The residue is purified by chromatography using silica gel and ethyl acetate in hexanes as eluant to yield the title compound (0.14 g, 20%) as a white solid, mp 65°-75° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7](Cl)(=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[O:19]=[C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH2:2]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C1CNCCN1
Reactant: CCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCC(=O)N1CCN(C(=O)CCCCCCCCCCC)CC1

Procedure:
Example 1 was repeated using piperazine and two equivalents of dodecanoyl chloride to obtain 1,4-bis(1-oxododecyl)-piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:39]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[O:40])[CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N1CCOCC1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.20 mmol) (from Example 25a supra) in tetrahydrofuran (3 mL) was added triethylamine (32 mg, 0.3 mmol), followed by the addition of morpholine-4-carbonyl chloride (38 mg, 0.24 mmol) (Aldrich). The mixture was stirred at 45° C. for 3 hours, then cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with another two portions of ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue were triturated with dichloromethane-hexanes to give rac-6-chloro-3-(3-chloro-benzyl)-3-[1-(morpholine-4-carbonyl)-piperidin-3-yl]-1,3-dihydro-indol-2-one as a white solid. (Yield 60 mg, 60%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][CH:9]=[CH:8][CH:7]=2.[C:14](OC(=O)CC)(=O)[CH2:15][CH3:16].[OH-].[Na+]>O>[CH2:15]([C:16]1[O:13][C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:2]=1)[CH3:14]
Reactant: Nc1cnc2ccccc2c1O
Reactant: CCC(=O)OC(=O)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1nc2cnc3ccccc3c2o1

Procedure:
3-Aminoquinolin-4-ol hydrochloride (6 g) was refluxed with propanoic anhydride (8 eq.) until analysis by thin layer chromatography indicated that the reaction was complete. The reaction mixture was cooled, diluted with ice and water, made basic with 10% sodium hydroxide and then extracted with dichloromethane. The extract was washed with water and brine, dried over magnesium sulfate and then concentrated under vacuum. The residue was purified by column chromatography (silica gel eluting with methanol/ethyl acetate) to provide 4.0 g of 2-ethyloxazolo[4,5-c]quinoline.