Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.C(=O)[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:8][N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]2)=[CH:35][CH:36]=1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N(CC1CCCN(Cc2ccc(OC)cc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (31 mg, 0.090 mmol) in 0.5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 4-anisaldehyde (16.7 μL, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 28.45 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×10 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(4-Methoxybenzyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 10 as a colorless oil (18.7 mg, 59%). LRMS 366.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1.[CH:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:22]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:16][CH:17]=3)[C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)C(NCCN1CCOCC1)c1ccc(Br)cc1
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1C(c2ccc(Br)cc2)N(CCN2CCOCC2)C(c2ccccc2)N1c1ccc(C(F)(F)F)cc1
Yield: 69.1 %

Procedure:
To a solution of 2-(4-bromo-phenyl)-2-(2-morpholin-4-yl-ethylamino)-N-(4-trifluoromethyl-phenyl)-acetamide (2.90 g, 6.00 mmol) in anhydrous MeOH (20 mL) was added benzaldehyde (633 mg, 6.00 mmol), followed by para-toluenesulfonic acid (229 mg, 1.20 mmol) and sodium sulfate (8.98 g, 63.2 mmol). The reaction was refluxed overnight, filtered, and directly purified by flash column chromatography eluting with ethyl acetate: petroleum ether gradient (10%-25%) to afford the product as a yellow solid (2.38 g, 69.2%).
Reaction SMILES: O[C:2]1([C:23]([F:26])([F:25])[F:24])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:23]([F:25])([F:26])[F:24])[N:3]=[C:4]2[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccncc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccncc2)cc1
Yield: 40.8 %

Procedure:
A mixture of the 4,5-dihydro-imidazole of step 2 (0.85 g, 2.2 mmol) and p-toluenesulfonic acid monohydrate (0.12 g) in toluene (150 ml) was heated to reflux for 24 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude mixture was purified by chromatography on silica gel using ethyl acetate/acetone (96/4) to give pure 4-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine (330 mg, 41%) as a white solid: mp (DSC) 197° C. Anal. Calc'd. for C16H12N3SO2F3: C, 52.30; H, 3.29; N, 11.44; S, 8.73. Found: C, 52.19; H, 3.26; N, 11.25; S, 8.99.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:31][C:32]([CH3:53])([CH3:52])[CH2:33][CH2:34][NH:35][C:36](=[O:51])[C@H:37]([CH3:50])[CH2:38][C@H:39]([OH:49])[C@@H:40]([NH2:48])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[CH2:41]([C@H:40]([NH:48][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=[C:2]([OH:1])[CH:3]=1)[C@@H:39]([OH:49])[CH2:38][C@H:37]([C:36](=[O:51])[NH:35][CH2:34][CH2:33][C:32]([CH3:31])([CH3:52])[CH3:53])[CH3:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NCCC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(O)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 3-hydroxy-5-(2-oxopyrrolidin-1-yl)benzoic acid (D6) (0.449 g, 2.03 mmol), EDC (0.389 g, 2.03 mmol) and HOBT (0.311 g, 2.03 mmol) in DMF (8 ml) was added (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (3,3-dimethylbutyl)amide (D2(0.50 g, 1.56 mmol). After stirring for 20 hrs at room temperature, the DMF was evaporated and ethyl acetate and water were added. The product was extracted into ethyl acetate and the combined extracts were washed with 2N HCl, saturated aqueous sodium bicarbonate solution and brine and then dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel (elution with 2–5% methanol in dichloromethane) gave the product, 0.588 g.
Reaction SMILES: [C:1]1(=[O:15])[C:9]2[CH:8]=[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]3=[CH:5][C:4]=2[C:3](=[O:14])[NH:2]1.[CH2:16]([O:18][C:19](=[O:22])[CH2:20]Br)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][N:2]1[C:3](=[O:14])[C:4]2[CH:5]=[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]3=[CH:8][C:9]=2[C:1]1=[O:15])[CH3:17]
Reactant: O=C1NC(=O)c2cc3ccccc3cc21
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CN1C(=O)c2cc3ccccc3cc2C1=O

Procedure:
2 g (10.1 mmol) Benzo[f]isoindole-1,3-dione was reacted with bromoacetic acid ethyl ester analogously to Example D-21a. The crude product obtained was partitioned between ethyl acetate and water. Organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to give 2.68 g (9.5 mmol) of product. 1H NMR (200 MHz, CDCl3) δ 8.36 (s, 2H), 8.05 (m, 2H), 7.68 (m, 2H), 4.49 (s, 2H), 4.22 (q, J=7.0 Hz, 2H), 1.29 (t, 7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[NH:6][CH3:7].Cl[CH:12]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:13]#[N:14]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[N:6]([CH:12]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:13]#[N:14])[CH3:7]
Reactant: CCCCCC(=O)C(Cl)C#N
Reactant: CNc1cccc(OC)c1
Solvent: CCO
Product: CCCCCC(=O)C(C#N)N(C)c1cccc(OC)c1
Yield: 65.5 %

Procedure:
A solution of 3-methoxy-N-methylaniline (9.8 g) and 2-chloro-3-oxooctanenitrile (6.2 g) in ethanol (25 mL) was heated at reflux for 17 hours then the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (100 mL) and washed with 1N hydrochloric acid (3×50 mL). The aqueous layers were backwashed in turn with dichloromethane (50 mL) and the combined organic layers were dried (K2CO3) and evaporated. The residual oil was purified by HPLC (diethyl ether-hexane; 3:7) to yield 6.42 g of 2-(3-methoxy-N-methylanilino)-3-oxooctanenitrile as an oil. The above material was dissolved in trifluoroacetic acid (15 mL) and the solution was allowed to stand overnight at ambient temperature. The solvent was then evaporated and the residue was partitioned between dichloromethane (100 mL) and 1N sodium hydroxide solution (100 mL). The dried (K2CO3) organic layer was evaporated and the residue was purified by HPLC (diethyl ether-hexane; 1:1) to give 3.2 g of 6-methoxy-1-methyl-3-pentyl-2-indolecarbonitrile as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](O)=[O:4].C(Cl)(=O)C([Cl:19])=O>CN(C)C=O.ClCCl>[CH3:1][C:2]([CH3:15])([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([Cl:19])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(COCc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(COCc1ccccc1)C(=O)Cl
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Adapting procedures or variations thereof according to Lopez et al., Bioorg. & Med. Lett. 2003, 13(11), 1873-1878, a 500 mL round-bottomed flask equipped with a magnetic stirring bar was charged with 5.7 g (27.6 mmol) of 2,2-dimethyl-3-(phenylmethoxy)propanoic acid (26b), 20 mL of anhydrous dichloromethane (DCM), and 3 drops of N,N-dimethylformamide (DMF). Four-point-eight (4.8) mL (7.1 g, 55.2 mmol) of neat oxalyl chloride was slowly added to the solution. The reaction mixture was stirred at ca. 0° C. (ice-bath) for 5 hours. The solvents were removed under reduced pressure to provide the crude title compound (26c), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=1.34 (s, 6H), 3.54 (s, 2H), 4.56 (s, 2H), 7.29-7.37 (m, 5H) ppm. The analytical data was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.O.[NH2:16][NH2:17]>C(O)C>[Cl:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][NH2:17])[C:11]([O:12][CH3:13])=[N:10]2
Reactant: COc1nc2cc(Cl)ccc2nc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1nc2cc(Cl)ccc2nc1NN

Procedure:
A mixture of 4.9 g. (0.02 mole) of 2,6-dichloro-3-methoxyquinoxaline and 2.7 g. (0.053 mole) of hydrazine hydrate (2.6 ml.) in 75 ml. of ethanol was stirred at room temperature overnight (i.e., at ca. 20° C. for approximately 16 hours). Upon completion of this step, the resulting mixture was filtered and the recovered precipitate was washed with ethanol to ultimately afford 4.4 g. (98%) of pure 6-chloro-2-hydrazino-3-methoyquinoxaline, m.p. 175°-179° C. (decomp.). Mass Spectrum: m/e, 224 (P); m/e, 226 (P+2).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([CH2:15][CH2:16][CH:17]([OH:21])[CH:18]([CH3:20])[CH3:19])=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[F:22][C:23]1[CH:24]=C(N)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[F:22][C:23]1[CH:24]=[C:14]([N:12]2[C:3](=[O:4])[C:5]3[S:6][C:7]([CH2:15][CH2:16][CH:17]([OH:21])[CH:18]([CH3:19])[CH3:20])=[CH:8][C:9]=3[N:10]=[CH:11]2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][N:32]1[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: Nc1ccc(OCCN2CCCC2)c(F)c1
Reactant: COC(=O)c1sc(CCC(O)C(C)C)cc1N=CN(C)C
Product: CC(C)C(O)CCc1cc2ncn(-c3ccc(OCCN4CCCC4)c(F)c3)c(=O)c2s1

Procedure:
3-(Dimethylaminomethyleneamino)-5-(3-hydroxy-4-methylpentyl)thiophene-2-carboxylic acid methyl ester was reacted with 3-fluoro-4-(2-pyrrolidin-1-ylethoxy)phenylamine by method A. The product with the molecular weight of 459.58 (C24H30FN3O3S) was obtained in this way; MS (ESI): 460 (M+H+).
Reaction SMILES: C(NS(C1C=CC([N:14]2[C:22]3[C:21]4[CH:23]=[C:24]([NH:27][C:28](=[O:36])[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[Cl:35])[CH:25]=[CH:26][C:20]=4[CH2:19][CH2:18][C:17]=3[C:16]([C:37]([NH2:39])=[O:38])=[N:15]2)=CC=1)(=O)=O)(=O)C.C(Br)C=C>CN(C=O)C>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:20]2[CH2:19][CH2:18][C:17]3[C:16]([C:37]([NH2:39])=[O:38])=[N:15][NH:14][C:22]=3[C:21]=2[CH:23]=1)=[O:36]
Reactant: CC(=O)NS(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Solvent: CN(C)C=O
Solvent: C=CCBr
Product: NC(=O)c1n[nH]c2c1CCc1ccc(NC(=O)c3ccccc3Cl)cc1-2
Temperature: 25 °C
Yield: 106.7 %

Procedure:
To a stirring solution of the Cs+ salt of 1-{4-[(acetylamino)sulfonyl]phenyl}-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (637 mg, 0.92 mmol) in DMF (8 mL) was added a solution of allyl bromide (111 mg, 0.92 mmol). The solution was stirred at room temperature for over the weekend and concentrated. To the mixture was added MeOH—H2O (2:1). A precipitate was formed. It was filtered to give a yellow solid of 1-(4-[acetyl(allyl)amino]sulfonyl}phenyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (360 mg, 65%.)
Reaction SMILES: [Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][CH2:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:4][C:3]=1[CH3:15].CCN(C(C)C)C(C)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][CH2:7][CH:8]2[CH2:11][N:10]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:9]2)=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc(OCC2CNC2)cc(C)c1Br
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(OCC2CN(S(C)(=O)=O)C2)cc(C)c1Br
Temperature: 0 °C
Yield: 64 %

Procedure:
3-(4-Bromo-3,5-dimethyl-phenoxymethyl)-azetidine (400 mg, 1.48 mmol) and DIPEA (0.48 g, 3.7 mmol) are dissolved in 20 mL of dichloromethane and stirred at 0° C. Methanesulfonylchloride (0.12 mL, 1.48 mmol) is added and the reaction mixture is stirred at 0° C. for 2 h. The reaction mixture is washed with water, the organich phase is separated, dried over sodium sulfate and concentrated under vacuum. The crude product is purified by flash chromatography 0-50% ethyl acetate in cyclohexane) to give the title compound (Yield: 330 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]([O:28][CH3:29])=[O:27]>O1CCOCC1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:10]=2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[O:28][CH3:29]
Reactant: COC(=O)Cl
Reactant: Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl
Yield: 27.3 %

Procedure:
To a mixture of 5-(3-amino-4-chlorophenyl)-3-(2-furanyl)-1,2,4-oxadiazole (1.35 g) and 1.05 g of potassium carbonate in 30 ml of dioxane, 0.75 g of methyl chloroformate is added. The resulting mixture is heated at reflux for 16 hours, concentrated to dryness and the residue placed on an alumina column. The product is eluted with benzene to yield 0.45 g of the title compound, melting point 200°-201°C.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:13][C:12](=[O:14])[NH:11][CH:10]1[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])C1C=CC=CC=1.[H][H]>[Pd].O.CO>[ClH:1].[O:14]=[C:12]1[NH:11][CH:10]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[NH:9][CH2:13]1
Reactant: CC(C)COC(=O)CCC1NC(=O)CN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)COC(=O)CCC1NCC(=O)N1
Yield: 87.2 %

Procedure:
To a mixture of 10% palladium on charcoal (1 g) and 99% formic acid (1 ml) in methanol (25 ml), under nitrogen, was added a solution of isobutyl 3-benzyl-5-oxo-2-imidazolidinepropanoate hydrochloride (1 g, 2.93 mmol) and 99% formic acid (1.25 ml) in methanol (25 ml). The mixture was stirred under nitrogen for 6 hours. After addition of water (15 ml) and removal of the catalyst, the solvent was evaporated and the residue was triturated with ethanol to give 0.3 g (41%) of the title compound, m.p. 136°-140° C. The same compound was obtained also by the following procedure: into a mixture of isobutyl 3-benzyl-5-oxo-2-imidazolidinepropanoate hydrochloride (2.2 g, 6.4 mmol), and 10% palladium on charcoal (1.1 g) in water-methanol 2:1 (150 ml) hydrogen was bubbled at room temperature and at atmospheric pressure for 2 hours. Removal of the catalyst and evaporation of the solvent under reduced pressure gave a residue which was triturated with ethanol to afford 1.4 g (90%) of the title compound, m.p.136°-140° C. NMR (DMSO-d6): deltaH =11.1-9.50 (b.s., 2H, NH2+); 9.20 (b.s., 1H, CONH); 4.95 (t, J=6.2 Hz, 1H, NHCHNH); 3.84 (d, J=6.7 Hz, 2H, COOCH2); 3.65 (s, 2H, NCH2CO); 2.70-2.30 (c.a., 2H, CH2CH2COO); 2.25-1.60 (c.a., 3H, CH2CH2COO, CH(CH3)2); 0.87 (d, J=6.7 Hz, 6H, CH(CH3)2. MS (E.I., 70 eV, 1.5 mA) m/z=214 (M+), 141 (M-OC4H9)+, 85 (C3H5N2O)+.
Reaction SMILES: [CH2:1]([CH2:4][SH:5])[CH2:2][NH2:3].Cl.Cl.O[CH2:9][C:10]1[N:11]=[CH:12][NH:13][C:14]=1[CH3:15].[BrH:16]>>[BrH:16].[BrH:16].[CH3:15][C:14]1[N:13]=[CH:12][NH:11][C:10]=1[CH2:9][S:5][CH2:4][CH2:1][CH2:2][NH2:3]
Reactant: NCCCS
Reactant: Cc1[nH]cnc1CO
Agent: Br
Agent: Cl
Product: Cc1nc[nH]c1CSCCCN

Procedure:
A solution of homocysteamine hydrochloride (22.0 g.) and 4-hydroxymethyl-5-methylimidazole hydrochloride (25.6 g.) in aqueous hydrobromic acid (500 ml.) was heated under reflux for 1 hour. Concentration under reduced pressure, followed by recrystallisation from methanol-isopropyl alcohol afforded 4-methyl-5-[(3-aminopropyl)thiomethyl]imidazole dihydrobromide (24.5 g.), m.p. 200.5°-202.5°.
Reaction SMILES: [CH:1]1([CH2:5][CH:6]([NH2:19])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:4][CH2:3][CH2:2]1.[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH2:34][C:35](O)=[O:36])[CH:26]=[CH:27][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:21]>>[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH2:34][C:35]([NH:19][CH:6]([CH2:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:36])[CH:26]=[CH:27][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:21]
Reactant: NC(CC1CCC1)c1ccccc1N1CCCCC1
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Product: CCOC(=O)c1ccc(CC(=O)NC(CC2CCC2)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
Prepared analogously to Example 47 from α-cyclobutylmethyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenyl acetic acid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:15][NH:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].C1COCC1.[CH:36]1[CH:41]=[CH:40][C:39]([CH2:42][O:43][C:44](Cl)=[O:45])=[CH:38][CH:37]=1>O>[CH2:42]([O:43][C:44]([N:14]1[CH2:15][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:11][C@H:12]([C:22]([O:24][CH3:25])=[O:23])[C@@H:13]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:45])[C:39]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)CN[C@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Yield: 102.3 %

Procedure:
To a stirred and ice-cooled mixture of (2R*,3S*,5R*)-5-(tert-butyldimethylsilyloxy)methyl-3-methoxycarbonyl-2-phenylpiperidine (4.86 g, 13.4 mmol), NaHCO3 (1.68 g, 20.1 mmol), THF (5.0 ml), and H2O (30.0 ml) was added Cbz-Cl (2.51 g, 14.7 mmol), and the mixture was stirred with ice-cooling for 30 minutes. The mixture was extracted with AcOEt (40.0 ml×3). The combined AcOEt extracts were washed with sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give a viscous pale yellow oil (6.82 g). This was flash chromatographed over SiO2 (Merck Kieselgel 60, 80.0 g). Elution with n-hexane-AcOEt (30:1/20: 1) gave title compound (6.51 g, 97.9%) as a viscous colorless oil. IRmax (film): 1735(s), 1700(s), 1605(w), 1585(w), 1495(m), 1250(s), 1115(s), 775(s), 740(m), 700(s) cm-1 ; 1H-NMR δ: 7.45-7.31(m, 4H), 7.31-7.15(m, 6H), 6.05(d, J=5.5 Hz, 0.6H), 5.87(d, J=5.5 Hz, 0.4H), 5.32-5.10(5.30, 5.25, 5.21, 5.18, and 5.13; m, 2H), 4.20-4.05(m, 1H), 3.65-3.45(m, 2.4H), 3.60(br.s, 3H), 3.40(dd, J=9.9, 6.6 Hz, 0.6H), 3.08-2.91(m, 1H), 2.63(dd, J=11.7, 11.7 Hz, 0.4H), 2.52(dd, J=13.6, 11.7 Hz, 0.6H), 2.11-1.98(m, 1H), 1.98-1.70(m, 2H), 0.86(s, 3.6H), 0.83(s, 5.4H), 0.026, 0.018, and 0.008(each s, total 6H) ppm.
Reaction SMILES: CS[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=2[N:7]=1.[CH3:15][N:16]([CH3:22])[C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1>C1(C)C=CC=CC=1>[CH3:15][N:16]([CH3:22])[CH:17]1[CH2:21][CH2:20][N:19]([C:3]2[O:4][C:5]3[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=3[N:7]=2)[CH2:18]1
Reactant: CSc1nc2cc([N+](=O)[O-])ccc2o1
Reactant: CN(C)[C@@H]1CCNC1
Solvent: Cc1ccccc1
Product: CN(C)C1CCN(c2nc3cc([N+](=O)[O-])ccc3o2)C1
Yield: 45 %

Procedure:
Suspend 2-methylsulfanyl-5-nitro-benzooxazole (1.68 g, 7.99 mmol) in toluene (8 mL). Add (3R)-(+)-3-(dimethylamino)pyrrolidine (1.8 mL) and heat to 70° C. overnight. Cool the reaction to room temperature, dilute with toluene (10 mL) and filter. Wash the product with toluene (5 mL) and hexane (10 mL). Dry on the filter flask for 30 min to afford the title compound (1.00 g, 45%). 1H NMR (400 MHz, DMSO-d6): δ 8.03 (d, 1H, J=2.2 Hz), 7.94 (dd, 1H, J=8.6, 2.4 Hz), 7.62 (d, 1H, J=8.8 Hz), 3.81 (dd, 1H, J=10.1, 7.0 Hz), 3.75 (m, 1H), 3.57 (dt, 1H, J=10.0, 7.2 Hz), 3.34 (m, 1H), 2.86 (m, 1H), 2.21-2.13 (m, 7H), 1.87 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:8][C:9](=O)[C:10]3[CH2:15][CH2:14][CH2:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:19].C([O-])(O)=O.[Na+]>>[Cl:19][C:9]1[C:10]2[CH2:15][CH2:14][CH2:13][C:11]=2[N:12]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]=1
Reactant: O=c1[nH]c(-c2ccc(Cl)s2)nc2c1CCC2
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ccc(-c2nc(Cl)c3c(n2)CCC3)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
An 18-mL vial was charged with 2-(5-chloro-2-thienyl)-3,5,6,7-tetrahydrocyclopenta[d]pyrimidin-4-one (180 mg, 0.71 mmol). POCl3 (1 ml) was added. The resulting mixture was stirred at 90 C for 4 hr. After cooling to room temperature, the mixture was added dropwise slowly to cold NaHCO3 aq. Dichloromethane was added. The organic layer was separated and passed through a plug of silica gel, using dichloromethane as eluent to give 4-chloro-2-(5-chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (178 mg, 92% yield).