Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.S(Cl)(Cl)=O.[CH2:22](O)[CH3:23]>N#N>[CH2:22]([O:16][C:15](=[O:17])[C@H:13]([CH2:12][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)[NH2:14])[CH3:23]
Reactant: N[C@@H](Cc1ccc(O)c2ncccc12)C(=O)O
Reactant: CCO
Agent: N#N
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H](N)Cc1ccc(O)c2ncccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a stirred slurry of DL-3-(8-hydroxyquinolin-5-yl)alanine (HLM8) (2.19 g, 7.04 mmol) in absolute ethanol (26 ml) at 0° C., with protection from atmospheric moisture by CaCl2 tube in N2, thionyl chloride was added dropwise (1.1 ml, 14.1 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature for 30 minutes, and then refluxed overnight. The solution was evaporated to dryness in vacuum. The residue was dissolved in absolute ethanol and reevaporated to dryness. To ensure completeness of the esterification, the whole operation was repeated. The ester HLM9 (yellow solid, 1.67 g, 92% yield), which was shown by HPLC to contain about 1% of free amino acid, was further purified by FC(CH2Cl2:MeOH:AcOH 9:1.5:1.5). 1H NMR (250 MHz, D2O) 0.94 (dd, J=7.2, 7.2 Hz, 3H), 3.63 (m, 2H), 4.01 (m, 2H), 4.34 (dd, J=7.7, 7.5 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 8.01 (dd, J=8.7, 5.4 Hz, 1H), 8.93 (d, J=5.4 Hz, 1H), 9.08 (d, J=8.7 Hz, 1H).
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]([CH3:27])[C:6]1[CH:16]=[C:15]([CH:17](O)CS(C)(=O)=O)[CH:14]=[C:13]([N:24]([CH3:26])[CH3:25])[C:7]=1[N:8]([CH3:12])[C:9](=[O:11])[CH3:10].[NH:28]([CH2:35][CH2:36][C:37]#[N:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CS(C)=O>[NH:28]([CH:35]=[C:36]([C:37]#[N:38])[CH2:17][C:15]1[CH:14]=[C:13]([N:24]([CH3:26])[CH3:25])[C:7]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])=[C:6]([N:5]([CH3:27])[CH3:4])[CH:16]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)N(C)c1c(N(C)C)cc(C(O)CS(C)(=O)=O)cc1N(C)C
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)N(C)c1c(N(C)C)cc(CC(C#N)=CNc2ccccc2)cc1N(C)C

Procedure:
A mixture of 1.23 g. of sodium methylate, 5.31 g. of 2',6'-bis(dimethylamino)-4'-[1-hydroxy-2-(methylsulfonyl)ethyl]N-methylacetanilide and 3.3 g. of β-anilinopropionitrile in 40 ml. of dimethylsulfoxide was stirred at room temperature under nitrogen for 5 hours. The mixture was poured into 200 ml. of ice water, the separated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. After purification of the residue over aluminum oxide with benzene and recrystallization from ethyl acetate/petroleum ether, there was obtained 4'-(3-anilino-2-cyanoallyl)-2',6'-bis(dimethylamino)-N-methylacetanilide having a melting point of 190°-200° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([CH3:16])=[CH:9][N:10]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](N(OC)C)=[O:18])[N:3]=1.[CH3:23][Mg]Br>>[Cl:1][C:2]1[C:7]2[C:8]([CH3:16])=[CH:9][N:10]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=[O:18])[CH3:23])[N:3]=1
Reactant: COCCCn1cc(C)c2c(Cl)nc(C(=O)N(C)OC)cc21
Reactant: C[Mg]Br
Product: COCCCn1cc(C)c2c(Cl)nc(C(C)=O)cc21

Procedure:
4-Chloro-N-methoxy-1-(3-methoxypropyl)-N,3-dimethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxamide and methylmagnesium bromide were treated in the similar manner to Reference Example 6(5) to give 1-[4-chloro-1-(3-methoxypropyl)-3-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl]ethanone [REx(105-8)] as a colorless powder.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:49][C@@H:50]([CH2:64][C:65]1[CH:70]=[C:69]([F:71])[CH:68]=[C:67]([F:72])[CH:66]=1)[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1>CN(C=O)C>[F:71][C:69]1[CH:70]=[C:65]([CH:66]=[C:67]([F:72])[CH:68]=1)[CH2:64][C@H:50]([NH:49][C:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][CH2:3][C:2]2=[O:1])=[O:13])[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc3c(c2)C(=O)CC3)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-oxoindane-5-carboxylic acid (2.0 g, 11.5 mmol) in DMF (10 mL) is added diisopropylethylamine (8 mL, 46 mmol), HATU (5.5 g, 14.4 mmol), then (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method of Example SP-272 (5.6 g, 13.8 mmol). The reaction is stirred 1 h at room temperature. The reaction was partitioned between ethyl acetate and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/methylene chloride) gives the title compound. ESI MS m/z 493.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].F[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16](=[O:18])[CH3:17].O>O1CCCC1>[F:15][C:13]1[CH:12]=[CH:11][C:10]([C:16](=[O:18])[CH3:17])=[C:9]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:14]=1
Reactant: COCCO
Reactant: CC(=O)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1cc(F)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
A solution of 1.75 g 2-methoxy ethanol in tetrahydrofuran (23 mL) was added dropwise to a suspension of 0.84 g of 60% sodium hydride in tetrahydrofuran (21 mL), and subsequently a solution of 3.0 g 2′,4′-difluoroacetophenone in tetrahydrofuran (19 mL) was added dropwise thereto. The temperature of the mixture was increased to room temperature, then the mixture was stirred for 24 hours, water was carefully added thereto, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate, the solvent was removed, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 2.84 g of the title compound (yellow oil).
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:20]=[CH:19][CH:18]=[CH:17][C:7]=1[C:8]([N:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH3:11])=[O:9])=O.C[O-].[Na+].Cl.CC1C=CC(S(O)(=O)=O)=CC=1>CO.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:3]=1[C:4]1[C:6]2[C:7](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8](=[O:9])[N:10]([CH3:11])[C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CN(C)C(=O)c1ccccc1C(=O)c1ccc(C)cc1C
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
An ice cold mixture of methyl 2-(2-(2,4-dimethylbenzoyl)-N-methylbenzamido)acetate (60 g, 177 mmol) in methanol (400 mL) was treated with sodium methoxide (42.0 g, 194 mmol) and the resultant was allowed to stir at ambient temperature for 1 hour. The mixture was cooled to 0° C., treated with HCl (21.78 mL, 265 mmol) and then concentrated. The residue was dissolved in ethyl acetate, washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude intermediate was treated with Toluene (400 mL) and pTsOH (16.81 g, 88 mmol) and the mixture was heated at 120° C. for 1 hour. Additional pTsOH (16.81 g, 88 mmol) was added and the mixture was stirred at 120° C. overnight. LCMS indicated complete reaction. The mixture was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water, then brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-60% EA on hexane) to give the desired product as a white solid (24 g, 53%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.48-8.57 (m, 1 H) 7.50-7.58 (m, 2 H) 7.10-7.14 (m, 1 H) 7.04 (s, 3 H) 3.61 (s, 3 H) 3.54 (s, 3 H) 2.39 (s, 3 H) 2.04 (s, 3 H); LC/MS (m/z) ES+=322 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH2:11]([N:14]=[C:15]=[O:16])[CH:12]=[CH2:13]>>[CH2:11]([NH:14][C:15]([N:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1)=[O:16])[CH:12]=[CH2:13]
Reactant: O=c1[nH]sc2ccccc12
Reactant: C=CCN=C=O
Product: C=CCNC(=O)n1sc2ccccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6c (67% yield) was synthesized from benzo[d]isothiazol-3-one and allyl isocyanate as a white solid. mp 116-119° C.; IR(CHCl3) 3290, 1711, 1664, 1537 cm−1; 1H-NMR (CDCl3) δ 4.05-4.10 (m, 2H), 5.18-5.34 (m, 2H), 5.83-5.99 (m, 1H), 7.43 (t, J=7.2 Hz, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.70 (t, J=7.2 Hz, 1H), 8.02 (d, J=7.2 Hz, 1H), 8.99 (br s, 1H); ESIMS m/e 235 (M++1).
Reaction SMILES: [C:1]([O:20]C)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.O1CCC[CH2:24]1.CO.O.[OH-].[K+]>CCOCC.[Cu].[Zn]>[CH2:11]([C@H:10]1[CH2:24][C@H:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C1CCOC1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: [Cu]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CCCCCCCC[C@H]1C[C@H]1CCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 2.2 g of zinc-copper couple in 30 mL of dry ether is added 5.7 mL (16.9 mmol) of methyl oleate and 5.4 mL (70.7 mmol) of diiedomethane. The reaction mixture is refluxed overnight, cooled to room temperature, poured into 1.0N HCl, and extracted three times with ether. The organic layers are combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give an oil. The oil is subjected to the conditions described in Example 51 above to give an oil free of starting material. The oil is taken up in a combination of tetrahydrofuran :methanol:water (2:1:1), followed by the addition of 4.0 g of 85% KOH. After 4 hours stirring at room temperature, the solvents are evaporated, the residue taken up in 0.1N KOH, and extracted three times with ether. The aqueous phase is acidified using concentrated HCl and extracted three times with ether. The ether layers are combined, washed with brine, dried over, MgSO4, filtered, and concentrated in vacuo to give cis-8-(2-octylcyclopropyl) octanoic acid. Spectral data follows: 1H NMR (CDCl3, 400 MHz) δ 2.35 (t, 2H, J=7.0 Hz, CH2 C=O), 0.6-1.7 (m, 33H).
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([S:7][CH3:8])[C:5]#N.[NH:10]([CH2:12][CH2:13][OH:14])[NH2:11].Cl>C(O)C>[OH:14][CH2:13][CH2:12][N:10]1[C:3]([NH2:2])=[C:4]([S:7][CH3:8])[CH:5]=[N:11]1
Reactant: CSC(C#N)=CN(C)C
Reactant: NNCCO
Agent: Cl
Solvent: CCO
Product: CSc1cnn(CCO)c1N
Yield: 39.4 %

Procedure:
To a mixture of 3-dimethylamino-2-methylthioacrylonitrile (5 g) and 2-hydrazinoethanol (2.68 g) in ethanol (50 ml) was added conc. hydrochloric acid (2.93 ml) under ice-cooling. The mixture was refluxed for 3 hours. The reaction mixture was evaporated to remove the solvent. The residue was adjusted to pH 7 with a saturated aqueous solution of sodium bicarbonate and extracted with a mixture of tetrahydrofuran and ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel using ethyl acetate as an eluent. Fractions containing the object compound were combined and evaporated to give 1-(2-hydroxyethyl)-4-methylthio-5-aminopyrazole (2.4 g).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:12][CH:11]([C:13]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][CH:16]=[CH:15][N:14]=2)[CH2:10]1)=O)(C)(C)C>CO>[ClH:1].[NH:9]1[CH2:12][CH:11]([C:13]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][CH:16]=[CH:15][N:14]=2)[CH2:10]1
Reactant: COc1ccc(-c2nccnc2C2CN(C(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2nccnc2C2CNC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4 N HCl in MeOH (10 mL) was added (21) (120 mg, 0.35 mmol) at 0° C. and the resulting mixture was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to give 2-azetidin-3-yl-3-(4-methoxy-phenyl)-pyrazine (22) (95 mg, yield 100%) which was used for the next step without further purification. ESI-MS (M+1): 242 calc. for C14H15N3O 241.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)[CH2:8][CH3:9])(=O)C.[Br-].[O:19]1CCO[CH:20]1[CH2:24][P+](CCCC)(CCCC)CCCC.CC(C)([O-])C.[K+].[Cl-].[Na+]>CN(C)C=O.Cl.O>[OH:4][CH2:5][CH2:6][N:7]([C:10]1[CH:11]=[CH:12][C:13]([CH:14]=[CH:24][CH:20]=[O:19])=[CH:16][CH:17]=1)[CH2:8][CH3:9]
Reactant: CCN(CCOC(C)=O)c1ccc(C=O)cc1
Reactant: CCCC[P+](CCCC)(CCCC)CC1OCCO1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CCO)c1ccc(C=CC=O)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of 235.3 g (1 mole) of 4-(N-2-acetoxyethyl-N-ethylamino)benzaldehyde in dimethylformamide is added 738.7 g (2.0 moles) of 1,3-dioxolan-2-ylmethyltributylphosphonium bromide in dimethylformamide, and the mixture is heated at 90° C. Potassium t-butoxide (224.4 g, 2.0 moles) is added, and heating is continued at 90° C. for 16 hours. After cooling to room temperature, the solution is poured into a seven-fold excess of water, the aqueous mixture is saturated with sodium chloride, and the solution is extracted with three portions of ether. The combined organics are dried over 4A sieves, filtered through cotton, and evaporated. The crude reaction product is dissolved in 3M HCl, and the reaction is stirred at room temperature for 16 hours. After neutralization with saturated sodium bicarbonate, the aqueous mixture is extracted with three portions of ether, and the combined organics are dried over 4A sieves, filtered through cotton, and evaporated to yield the cinnamaldehyde as an oil. The product is purified by flash chromatography (silica gel, 1:1 hexane:ethyl acetate).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])([O-])=O.C(O)C>[Fe].O>[NH2:2][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccccc1C=O
Yield: 96.7 %

Procedure:
Iron powder (39 g; 700 mmol) and concentrated hydrochloric acid (0.583 mL; 7 mmol) were added to a solution of 2-nitrobenzaldehyde (10.58 g; 70 mmol) in a mixture ethanol (210 mL)-water (52 mL). The well-stirred reaction mixture was heated to reflux for 5 h. After cooling, the suspension was filtered on a plug of celite, washed with ethanol and the filtrate was concentrated under reduced pressure until the organics were removed. The remaining aqueous layer was extracted with ethyl acetate, the organics were combined, dried over sodium sulfate, concentrated under reduced pressure to furnish 8.2 g (96%) of 2-aminobenzaldehyde as a yellow oil, which crystallized slowly. ESI/APCI(+): 122 (M+H). NMR 1H (CDCl3) (ppm): δ 9.87 (s, 1H, CHO); 7.48 (dd, 1H, Harom.); 7.31 (td, 1H, Harom.); 6.75 (td, 1H, Harom.); 6.51 (dd, 1H, Harom.); 6.11 (bs, 2H, NH2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@H:7]([OH:9])[CH3:8])[CH:2]=1.C([Li])CCC.[C:15]12([C:25](Cl)=[O:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>C1COCC1.CCCCCC>[C:15]12([C:25]([O:9][C@@H:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH3:8])=[O:26])[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]3)[CH2:16]1)[CH2:24]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: C[C@@H](O)c1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@@H](OC(=O)C12CC3CC(CC(C3)C1)C2)c1cccnc1
Yield: 81.3 %

Procedure:
The method followed that described in Example 1, but using (+)-(R)-1-(3-pyridyl)ethanol [87% ee; prepared by asymmetric reduction of 3-acetylpyridine with (+)-B-chlorodiisopinocampheyl borane, J. Chandrasekharan, P. V. Ranachandran and H. C. Brown, J. Org. Chem., 50, 5446-5448 (1985)] (0.62 g, 5.0 mmol) in THF (20 ml), n-butyllithium (2.5 M; 2.0 ml, 5.0 mmol) in hexane, and 1-adamantanecarbonyl chloride (1.09 g, 5.5 mmol) in THF (5 ml). Chromatography, on elution with ether-petrol-triethylamine 100:50:1, gave the title compound (1.16 g, 81%) as an oil. [α]D +29.9° (c 2, MeOH), 87% ee. Recrystallisation of the (-)-(1R)-10-camphorsulfonate salt from ethyl acetate, and reliberation of the free-base, afforded the title compound with 98% ee, [α]D +33.7° (c 2, MeOH). IR νmax 1728 cm-1 ; 1H-NMR (CDCl3) δ1.54 (3H, d, J 6.5 Hz, CHCH3), 1.72 and 1.90 (12H, 2s, adamantyl CH2), 2.03 (3H, s, adamantyl CH), 5.88 (1H, q, J 6.5 Hz, CHCH3), 7.30 (1H, m, Py 5-H), 7.65 (1H, m, Py 4-H), 8.56 (1H, m, Py 6-H), 8.63 (1H, m, Py 2-H); MS m/z 285 (M+). Anal. Calcd: C, 75.76; H, 8.12; N, 4.91. Found: C, 75.30; H, 8.18; N, 4.46%.
Reaction SMILES: C([Li])CCC.[Cl-].[CH3:7][S:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O>O1CCCC1>[CH3:29][O:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=[CH:7][S:8][CH3:9]
Reactant: CSC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1C=CSC
Temperature: 25 °C
Reaction time: 1 h
Yield: 729.9 %

Procedure:
2.6 ml of a 1.6 M butyllithium solution in tetrahydrofuran are slowly added dropwise at 0° C. to a solution of 1.5 g of methylmercaptomethyl-triphenyl-phosphonium chloride in anhydrous tetrahydrofuran. After 1 hour, 5.7 g of 2-methoxybenzaldehyde in 50 ml of tetrahydrofuran are added and the resulting mixture is stirred for a further 12 hours at ambient temperature. The solvent is distilled off in vacuo and the residue remaining is taken up in diethylether. After extraction with dilute, aqueous HCl solution, aqueous Na2CO3 solution (17%) and washing with water, the collected organic phases are dried and the solvent is distilled off in vacuo. Chromatography on silica gel (cyclohexane:ethyl acetate 90:10) yields 5.5 g of 1-methoxy-2-(2-methylsulphanyl-vinyl)-benzene.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:22])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:30]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([NH:22][C:34]([CH:30]2[CH2:33][CH2:32][CH2:31]2)=[O:35])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H](CC1CCCCC1)CN1CCN(c2ncccn2)CC1
Reactant: O=C(Cl)C1CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H](CC1CCCCC1)CN1CCN(c2ncccn2)CC1)C1CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 0.2 g (0.66 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(pyrimidin-2-yl)-piperazin-1-yl]-ethyl}-amine and 0.18 mL (1.32 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.082 g (0.69 mmol) of cyclobutanecarboxylic acid chloride in dichloromethane (2 mL). The reaction mixture was allowed to stir under nitrogen for two hours at 0° C. and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride salt of the title compound with ethereal HCl to yield 0.18 g (62%) as a white solid; mp=112–114° C.; MS (+) ESI m/z=386 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH2:7][OH:8])[CH:11]=1
Reactant: COC(=O)c1cc(Br)ccc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.3 %

Procedure:
A solution of methyl 5-bromo-2-chlorobenzoate (9.23 g) in THF (50 ml) was added dropwise under ice-cooling to a suspension of lithium aluminum hydride (1.42 g) in THF (100 ml). After the completion of addition, the reaction mixture was stirred at room temperature for 45 minutes. Water (1.4 ml), 5N sodium hydroxide solution (1.4 ml) and water (4.2 ml) were sequentially added under ice-cooling to the reaction mixture. The precipitate was removed through Celite and the filtrate was concentrated under reduced pressure to obtain a title compound (7.56 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[S:24][C:23]([NH2:25])=[N:22][N:21]=1>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[S:24][C:23]([NH2:25])=[N:22][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nnc(Br)s1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Product: Nc1nnc(NCCCOc2cccc(CN3CCCCC3)c2)s1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-(1-piperidinylmethyl)phenoxy]-1-propanamine and 5-bromo-1,3,4-thiadiazole-2-amine. The product obtained is identical to the substance described in Example 50.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH:17]([C:18]([OH:20])=[O:19])[CH2:16][CH:15]3[CH2:21][CH2:22][CH2:23][CH:14]23)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.C>CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH:17]([C:18]([OH:20])=[O:19])[CH2:16][CH:15]3[CH2:21][CH2:22][CH2:23][CH:14]23)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(O)C1CC2CCCC2N1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(S(=O)(=O)N2C(C(=O)O)CC3CCCC32)cc1
Reaction time: 2 h

Procedure:
1 g of 1-(4-nitrobenzenesulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid (14) was dissolved in 15 ml of DMF, after which 0.1 g of hydrogenation catalyst (10% Pd on active charcoal) was added and the starting compound was quantitatively hydrogenated within 2 h. After the solvent had been removed, the crude product was purified chromatographically.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Mg].[CH2:10]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=[CH:16]1)[CH2:11][CH2:12][CH2:13][CH3:14].Cl>C(OCC)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2([OH:21])[CH2:19][CH2:20][C:15]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:16][CH2:17]2)=[CH:3][CH:4]=1
Reactant: CCCCCC1C=CC(=O)CC1
Reactant: Brc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCC1=CCC(O)(c2ccc(Br)cc2)CC1

Procedure:
A solution of 8.5 g of p-dibromobenzene in 35 ml of anhydrous diethyl ether was added dropwise under stirring at 15°-20° C. to 1 g of magnesium metal powder, followed by reaction at room temperature for 1 hour so that a Grignard reagent was formed. After 5 g of 4-pentylcyclohexenone were added under stirring at -10° to 0° C. to the thus-formed Grignard reagent, they were reacted at room temperature for additional 1 hour. After the completion of the reaction, diluted hydrochloric acid was added dropwise to the reaction mixture, followed by the extraction of the reaction mixture with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The diethyl ether was distilled off under reduced pressure, whereby 4-(4-bromophenyl)-4-hydroxy-1-pentylcyclohexene was obtained as a crude reaction product.