Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:16][CH2:17][C:18]2[S:19][CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=2)=[CH:4][C:5]([NH:8]C(=O)OC(C)(C)C)=[N:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:3]([CH2:16][CH2:17][C:18]2[S:19][CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=2)=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: CC(C)c1csc(CCc2cc(NC(=O)OC(C)(C)C)ncc2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1csc(CCc2cc(N)ncc2F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
The tert-butyl N-{5-fluoro-4-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-pyridyl}-carbamate (393 mg, 1.08 mmol) obtained in (G) was dissolved in methylene chloride (10 ml), added with trifluoroacetic acid (10 ml) under ice cooling, and stirred overnight at room temperature. The reaction mixture was concentrated, and the resulting residue was dissolved in chloroform and washed with 1 N aqueous sodium hydroxide. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:2) to obtain the title compound (40.0 mg, 33%) as an oil.
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]3[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=3)[CH:10]=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C.Cl.[CH3:42][NH:43][C:44]([CH:46]1[CH2:51][CH2:50][CH2:49][NH:48][CH2:47]1)=[O:45]>O1CCCC1.CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:42][NH:43][C:44]([CH:46]1[CH2:51][CH2:50][CH2:49][N:48]([C:2]2[N:3]=[C:4]3[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]4[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=4)[CH:10]=[CH:9][N:5]3[C:6](=[O:8])[CH:7]=2)[CH2:47]1)=[O:45]
Reactant: CNC(=O)C1CCCNC1
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(O)nc3c2)n1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)C1CCCN(c2cc(=O)n3ccc(/C=C/c4nc(C(C)C)cs4)cc3n2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 79.4 %

Procedure:
2-Hydroxy-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4H-pyrido[1,2-a]-pyrimidin-4-one (157 mg, 0.501 mmol) was dissolved in anhydrous tetrahydrofuran (2.5 ml) and anhydrous dimethylformamide (2.5 ml), added with 4-dimethylamino-pyridine (80.0 mg, 0.651 mmol) and p-toluenesulfonyl chloride (105 mg, 0.551 mmol), and stirred at 0° C. for 1.5 hours. Subsequently, the reaction mixture was added with triethylamine (698 μl, 5.01 mmol) and N3-methyl-3-piperidinecarboxamide hydrochloride (448 mg, 2.50 mmol), and then the mixture was stirred at 60° C. for 5.5 hours. The reaction mixture was concentrated, added with saturated aqueous ammonium chloride, and then extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:2→100:3, v/v) to obtain the title compound (174 mg, 79%).
Reaction SMILES: [C:1]1([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13](=O)[CH3:14])[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]1([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[CH:13]([NH:19][CH:16]2[CH2:18][CH2:17]2)[CH3:14])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(=O)c1cc(F)ccc1C1=CCCC1
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(NC1CC1)c1cc(F)ccc1C1=CCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 132.6 %

Procedure:
To a solution of 510 mg (2.49 mmol) of 1-[2-(cyclopent-1-en-1-yl)-5-fluorophenyl]ethanone in 5 mL of methanol is added 0.5 g of 3 Å molecular sieves followed by addition of 285 mg (5 mmol) of cyclopropylamine and 375 mg (6.24 mmol) of acetic acid. The reaction mixture is stirred for 90 min at reflux. The reaction mixture is then cooled to 0° C. and 235 mg (3.74 mmol) of sodium cyanoborohydride are slowly added. The reaction mixture is further stirred for 2 hours at reflux. The cooled reaction mixture is filtered over a cake of diatomaceous earth and the cake is washed by ethyl acetate. The aqueous phase is extracted by ethyl acetate and the combined organic extracts are washed by a 1N aqueous solution of sodium hydroxide followed by a saturated aqueous solution of NaCl and dried over a ChemElut™ cartridge. Vacuum concentration yields 810 mg of crude N-{1-[2-(cyclopent-1-en-1-yl)-5-fluorophenyl]ethyl}cyclopropanamine as a brown oil used as such in the next step: (M+H)=246.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[CH:10]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([F:14])=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)=[O:27]>>[CH2:2]([N:3]1[C:9]2[C:8](=[CH:13][C:12]([F:14])=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH2:25][C:26]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)=[O:27])[CH2:17][CH2:16]3)[CH:10]=2)[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:1]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(Cl)cc4)CC3)cc21

Procedure:
1-Ethyl-6-fluoro-7-{4-[2-(4-chlorophenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was prepared from norfloxacin (0.5 g, 1.56 mmole) and 2-bromo-4′-chloroaceto-phenone(0.43 g, 1.86 mmole) by a method similar to that described for Example 4 (67% yield). Mp: 207° C. (dec). 1H NMR (DMSO-d6) δ 1.41 (7, 3H, J=7.2), 2.73 and 3.29 (two m, 8H), 3.95 (s, 2H), 4.58 (q, 2H, J=7.2 7.19 (d, 1H, J=7.2), 7.59 and 8.02 (m, 4H), 7.92 (d, 1H, J=13.2), 8.95 (s, 1H), 15.41 (br s, 1H). Anal. Calcd. for C24H23ClFN3O4•0.25H2O: C, 60.51; H, 4.97; N, 8.82. Found: C, 60.49; H, 4.96; N, 8.82.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].O>C(OCC)C>[C:19]([O:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=[O:21])[CH3:20]
Reactant: OCCn1ccc2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O
Product: CC(=O)OCCn1ccc2ccccc21
Temperature: 0 °C

Procedure:
An ice-cooled solution of 4.6 g of 1-(2-hydroxyethyl)indole in 10 ml of diethyl ether was treated with 1 ml of pyridine and 4 ml of acetic anhydride. After 2 hours 50 ml of water were added, the mixture was extracted with 100 ml of dichloromethane and the dichloromethane extract was dried. The solvent was evaporated to give 5.7 g of 1-(2-acetoxyethyl)indole.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.CN(C)C=[O:21]>>[O:17]1[CH2:16][CH:15]1[CH2:13][O:21][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: BrCC1CO1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C)C=O
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1OCC1CO1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3.70 g of potassium phthalimide was dissolved in 20 ml of N,N-dimethylformamide; 2.58 ml of epibromohydrin was added, followed by stirring at room temperature for 15 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure; ethyl ether was added to the residue; the crystal precipitated was collected to yield 3.7 g of N-(2-oxiranylmethoxy)phthalimide. 0.61 g of N-(2-oxiranylmethoxy)phthalimide and 0.802 g of 4-(diphenylmethoxy)piperidine were dissolved n 10 ml of ethanol, followed by thermal refluxing for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected to yield 1.30 g of N-[3-[4-(diphenylmethoxy)piperidino-2-hydroxypropyl]phthalimide as an oily substance. This oily substance was dissolved in 10 ml of ethanol; 0.14 ml of hydrazine monohydrate was added, followed by thermal refluxing for 3 hours. After cooling, the mixture was concentrated under reduced pressure; ethanol was added to the residue; the crystal precipitated was collected, dissolved in 3 ml of a 1 N aqueous solution of sodium hydroxide and 10 ml of water and extracted with ethyl acetate; the extract was washed with saline, dried over sodium sulfate and concentrated under reduced pressure; the crystal obtained was collected to yield 0.76 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([N:12]2[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:19])=O)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[CH3:19][C@H:13]1[CH2:14][CH2:15][CH2:16][C@@H:17]([CH3:18])[N:12]1[C:10]1[N:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:8][N:9]=1
Reactant: C[C@@H]1CCC[C@H](C)N1C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(F)cn12
Temperature: 55 °C
Yield: 79.9 %

Procedure:
To an ice cold solution of Intermediate 96a (1.38 g, 5.19 mmol) in THF (50.0 mL) was added sequentially triphenylphosphine (2.72 g, 10.4 mmol), Et3N (2.89 mL, 20.8 mmol) and hexachloroethane (2.46 g, 10.4 mmol). The cooling bath was removed and the reaction was heated to 55° C. overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted with 2M NH3 in MeOH. The residue was concentrated in vacuo then resubmitted to the reaction conditions overnight. After analogous workup the residue was concentrated in vacuo to give the title compound (1.03 g, 80%). 1H NMR (300 MHz, CDCl3): 0.68 (6H, d, J 6.2 Hz), 1.36-1.68 (3H m), 1.74-1.90 (3H, m), 3.35 (2H, m), 7.14 (1H, ddd, J 9.8, 7.5, 2.3 Hz), 7.65 (1H, ddd, J 9.9, 4.7, 0.8 Hz), 8.02 (1H, ddd, J 3.2, 2.3, 0.8 Hz).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](Cl)=[N:11][CH:10]=1.[CH3:34][S:35]([O-:37])=[O:36].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.ClCCl>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([S:35]([CH3:34])(=[O:37])=[O:36])=[N:11][CH:10]=1
Reactant: CS(=O)[O-]
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(S(C)(=O)=O)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A mixture of 369 mg (0.758 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide (Example 2) and 176 mg (1.67 mmol) sodium methanesulfinate in 4 ml N,N-dimethylformamide was heated at reflux over night. After cooling to room temperature the mixture was diluted with dichloromethane and treated with saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with three portions of dichloromethane. The combined organic layers were dried with sodium sulfate, concentrated and and dried in high vacuo. Flash column chromatography gave 118 mg (29%) of the title compound as a white solid.
Reaction SMILES: [NH:1]([N:18]=[N+:19]=[N-])[C@H:2]([C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:3][C:4](=[O:7])[O:5][CH3:6].N(N=[N+]=[N-])[C@H](C(O)=O)CC(=O)OC>>[CH3:6][O:5][C:4](=[O:7])[CH2:3][C@H:2]([N:1]=[N+:18]=[N-:19])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: COC(=O)C[C@H](NN=[N+]=[N-])C(=O)NCc1ccccc1
Agent: COC(=O)C[C@H](NN=[N+]=[N-])C(=O)O
Product: COC(=O)C[C@H](N=[N+]=[N-])C(=O)NCc1ccccc1

Procedure:
Benzyl-protected L-aspartate was used in the procedure of Lundquist and Pelletier17 to give N3(L)Asp(OMe)OH (46-L). Under these conditions, we observed transesterification to give the methyl ester product as opposed to the benzyl ester. N3(L)Asp(OMe)OH (46-L) was produced as a yellowish oil in 78% yield. N3(L)Asp(OMe)OH (46-L) was then coupled with benzylamine as above to give N3(L)Asp(OMe)NHBn (49-L) as a yellowish oil in 90% yield (70% overall, two steps). The procedure above was repeated with benzyl-protected D-aspartate to give N3(L)Asp(OMe)NHBn (49-D) as a yellowish oil in 67% overall yield. Spectral Data. The spectral data for both N3Asp(OMe)OH (D and L enantiomers) and both N3Asp(OMe)NHBn (D and L enantiomers) products are identical. N3(L)Asp(OMe)OH (46-L) 1H NMR (500 MHz, CDCl3) δ 10.24 (bs,1H), 4.47 (dd, J=7.4, 5.3 Hz, 1H), 3.76 (s, 3H), 2.91 (dd, J=16.9, 5.1 Hz, 1H), 2.79 (dd, J=16.8, 7.6 Hz) ppm; 13C NMR (125 MHz, CDCl3) δ 174.68, 170.12, 50.09, 52.44, 35.84 ppm; MS (ESI) m/z 196.0340 (MNa+[C5H7N3O4Na]=196.0334). N3(L)Asp(OMe)NHBn (49-L) 1H NMR (500 MHz, CDCl3) δ 7.38-7.27 (m, 5H), 6.83 (bs, 1H), 4.54 (m, 3H), 3.75 (s, 3H), 3.18 (dd, J=17.1, 3.7 Hz, 1H), 2.75 (dd, J=17.3, 8.7 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ 170.77, 167.90, 137.35, 128.81, 127.80, 127.77, 60.32, 52.24, 43.71, 37.00 ppm; MS (ESI) m/z 285.0953 (MNa+[C12H12N4O3Na]=285.0964).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][C:11](Cl)=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH:1]1[C:11](=[O:12])[CH2:10][O:8][C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]1=2
Reactant: Nc1cccnc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1COc2ncccc2N1
Yield: 27.7 %

Procedure:
In a 20 ml flask equipped with a reflux apparatus, 3-amino-pyridin-2-ol (300 mg, 2.72 mmol) was dissolved in acetonitrile (27 ml). To the reaction solution was added chloroacetyl chloride (0.24 ml, 3.0 mmol) dropwise at room temperature, followed by Potassium carbonate (940 mg, 6.80 mmol). The mixture was heated at 1000 for 15 hours. After completion of the reaction, acetonitrile was evaporated under the reduced pressure. To the residue was added water and then the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain white solid (113 mg, 28%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].COCCN(S(F)(F)[F:33])CCOC>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:33])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C#N)cc2)CC1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a stirred solution of compound 1.2 (5 g, 16.54 mmol, 1.00 equiv) in dichloromethane (250 mL) under nitrogen at −78° C. was added dropwise Deoxo-Fluor® (4.4 g, 19.89 mmol, 1.20 equiv). The resulting mixture was stirred for 1 h at −78° C. The reaction mixture was then carefully quenched by the addition of 50 mL of sodium bicarbonate (aq.sat.) and extracted with 3×100 mL of dichloromethane. The combined organic layers were washed with 150 mL of brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:30) as eluent to yield 2.5 g (35%) of the title compound as a white solid.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][SH:18])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[OH-].[Na+].O.[Cl:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1>C(O)C>[ClH:3].[ClH:24].[ClH:1].[ClH:3].[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][S:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][N:9]([CH2:8][C:7]4[CH:19]=[CH:20][C:4]([Cl:3])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:28][CH2:29]2)=[CH:35][CH:36]=1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: ClCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Clc1ccc(CN2CCN(CCCSCCN3CCN(Cc4ccc(Cl)cc4)CC3)CC2)cc1
Yield: 96.5 %

Procedure:
A mixture of 3-[4-(4-chlorobenzyl)piperazine-1-yl]propanethiol dihydrochloride (2 g), sodium hydroxide (0.3 g), water (10 ml), and ethanol (100 ml) is refluxed for 15 minutes, and then a solution of 1-(2-chloroethyl)-4-(4-chlorobenzyl)piperazine (1.9 g) in ethanol (20 ml) is added. The resulting mixture is refluxed for 2 hours and the ethanol is removed in vacuo. Water is added to the residue and the product is extracted with methylene chloride, dried (magnesium sulfate), and concentrated. The resulting oil is purified on a silica gel column (methylene chloride: methanol, 9:1), and then dissolved in ether. The product is precipitated with ethereal hydrochloric acid and recrystallized from aqueous ethanol to provide 1.2 g of {2-[4-(4-chlorobenzyl)piperazin-1-yl)ethyl}{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}sulfide tetrahydrochloride as colorless crystals, m.p. 292°-295° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[N:12]1([S:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)(=[O:10])=[O:9])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1cccc(F)n1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1cccc(F)n1)N1CCOCC1

Procedure:
To a solution of 6-fluoropyridine-2-sulphonyl chloride (1.96 g) in chloroform (40 cm3) at 0° C. was added a solution of morpholine (1.74 g) in chloroform (20 cm3). The reaction was quenched in water (100 cm3) and the product extracted into chloroform (3×50 cm3). The combined organic layers were washed with water, dried over anhydrous magnesium sulphate and the solvent evaporated under reduced pressure to give the title compound which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][N:8]1[C:12]([C:13](=[O:30])[NH:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([N:21]=[C:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:23]=3)[CH:20]=2)=[C:11]([C:31](O)=[O:32])[CH:10]=[N:9]1>>[N:24]1([C:22]2[N:23]=[C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:13]([C:12]4[N:8]([CH3:7])[N:9]=[CH:10][C:11]=4[C:31]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:32])=[O:30])=[CH:20][N:19]3[N:21]=2)[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: C1COCCN1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1

Procedure:
Using morpholine and 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. White solid (130 mg, 65%). MS: m/z=441 (M+H+).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:17](=[N:19][OH:20])[CH3:18])[CH2:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[CH3:21][C:22]([CH3:24])=[O:23].O>CCCCCC.O1CCCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2([C:17](=[N:19][OH:20])[CH2:18][C:22]([OH:23])([CH3:24])[CH3:21])[CH2:14][CH2:15][CH2:16]2)=[CH:11][CH:12]=1
Reactant: CC(=NO)C1(c2ccc(Cl)cc2)CCC1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)CC(=NO)C1(c2ccc(Cl)cc2)CCC1
Temperature: -5 °C
Reaction time: 16 h

Procedure:
A 1.6M solution of butyllithium in hexane (55 ml) was added to a stirred solution of the 1-[1-(4-chlorophenyl)cyclobutyl]ethanone oxime (8.94 g) in dry tetrahydrofuran (120 ml) the temperature being maintained below 0° C. for 40 minutes. The mixture was cooled to -5° C. and acetone (2.67 ml) was added dropwise. The temperature of the reaction mixture was allowed to rise to ambient temperature over a period of 16 hours. The mixture was cooled to 10° C. and water (100 ml) was added and the resulting aqueous mixture was washed with ether. The aqueous layer was acidified with 5N sulphuric acid and an oil separated. The oil was dissolved in ether and the ether solution was washed with water, dried and evaporated to yield 1-[1-(4-chlorophenyl)cyclobutyl]-3-hydroxy-3-methylbutan-1-one oxime.
Reaction SMILES: [N:1]#[C:2][NH2:3].[N:4]([C:7]1[CH:21]=[CH:20][C:10]([O:11][CH2:12][C@H:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH3:14])=[CH:9][CH:8]=1)=[C:5]=[S:6].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)=[O:25]>>[C:10]([OH:25])(=[O:11])[CH3:20].[NH2:1][C:2]1[N:3]=[C:5]([NH:4][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][C@H:13]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)[CH3:14])=[CH:20][CH:21]=2)[S:6][C:23]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)=[O:25]
Reactant: C[C@H](COc1ccc(N=C=S)cc1)N1CCCC1
Reactant: N#CN
Reactant: COc1cccc(C(=O)CBr)c1
Product: CC(=O)O
Product: COc1cccc(C(=O)c2sc(Nc3ccc(OC[C@@H](C)N4CCCC4)cc3)nc2N)c1

Procedure:
This compound was prepared from cyanamide, [R]-1-[2-(4-isothiocyanato-phenoxy)-1-methyl-ethyl)-pyrrolidine (of Example 11) and 2-bromo-1-(3-methoxyphenyl)ethanone (Aldrich) following the procedure used in Example 118. Mass spectrum (ES) MH+=453.
Reaction SMILES: BrC1C=CC(Br)=CC=1C1[O:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=2)=[N:12][N:13]=1.[Br:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Br:39])[CH:38]=1)[C:33](Cl)=[O:34].C(OC1C=CC(C(NN)=O)=CC=1)CCCCCCC>>[Br:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Br:39])[CH:38]=1)[C:33]([NH:13][NH:12][C:11](=[O:10])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=1)=[O:34]
Reactant: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Br)ccc3Br)o2)cc1
Reactant: O=C(Cl)c1cc(Br)cc(Br)c1
Agent: CCCCCCCCOc1ccc(C(=O)NN)cc1
Product: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Br)cc(Br)c2)cc1
Yield: 36 %

Procedure:
By the general method for the synthesis of 2-(2,5-dibromophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole in Example 1, the reaction of 3,5-dibromobenzoyl chloride (20.13 g, 0.06747 mole) with 4-octyloxybenzoic acid hydrazide (17 g, 0.06747 mole) gave the intermediate 3,5-dibromo-N′-[4-(octyloxy)benzoyl]benzohydrazide (12.87 g, 36% yield). Cyclocondensation of the intermediate 3,5-dibromo-N′-[4-(octyloxy)benzoyl]-benzohydrazide (12.17 g) with POCl3 (63 mL) gave the required 2-(3,5-dibromophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole (6.12 g, 52% yield).