Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([C@@H:13]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8](=[O:9])[C:7]2=[CH:26][CH:27]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([C@@H:13]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8](=[O:9])[C:7]2=[CH:26][CH:27]=1
Reactant: CCOC(=O)CC[C@@H](C(=O)OCC)N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC[C@@H](C(=O)OCC)N1C(=O)c2ccc(N)cc2C1=O
Reaction time: 26 h
Yield: 88.8 %

Procedure:
A suspension of diethyl (S)-2-(4-nitrophthalimido)glutarate (35.6 g, 94.1 mmol) and 10% palladium on carbon (0.5 g) (Aldrich) in ethanol (200 ml) was shaken under a hydrogen atmosphere (40-50 psi) for 26 hours. The solution was filtered through celite and concentrated in vacuo. The residue was purified by chromatography on silica gel (250 g) eluting with diethyl ether:hexane (4:1) to give diethyl (S)-2-(4-aminophthalimido)glutarate as a viscous yellow oil (29.1 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.10 (t, J=7 Hz, 3H, ester CH3), 1.12 (t, J=7 Hz, 3H, ester CH3), 2.17-2.39 (m, 4H, glu CH2CH2), 3.87-3.98 (m, 2H, ester CH2), 4.05-4.18 (m, 2H, ester CH2), 4.75-4.82 (m, 1H, glu CH), 6.57 (br s, 2H, NH2) 6.82 (dd, J=8,2 Hz 1H Ar) 6.93 (d, J=2 Hz, 1H, Ar), 7.51 (d, J=8 Hz, 1H, Ar). Mass spectrum (CI-CH4) 349 (M+1, 40.8%), 303 (60.1%), 275 (100%). Anal Calculated for C17H20N2O6 : C, 58.62; H, 5.79; N, 8.04. Found: C, 58.62; N, 5.80; N, 8.00.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[CH3:24][CH:25]([CH3:35])[CH2:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>>[CH3:24][CH:25]([CH3:35])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][O:2][C:1]([C:4]23[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:6][CH2:5]3)=[O:3])=[CH:33][CH:34]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CC(C)Cc1ccc(CBr)cc1
Product: CC(C)Cc1ccc(COC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 68.6 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 4-(2,2-dimethylethyl)benzyl bromide (23.2 mg) were used to obtain (2S,4S)-1-[[N-[4-[4-(2,2-dimethylethyl)benzyl]oxycarbonyl bicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (29.9 mg).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][NH:13][C:14]3=[O:17])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.O>CN(C)C=O>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[C:15]4[C:10]([CH2:11][CH2:12][NH:13][C:14]4=[O:17])=[CH:9][CH:8]=3)[CH2:2][CH2:3]2)=[CH:27][CH:26]=1
Reactant: O=C1NCCc2ccc(N3CCNCC3)cc21
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCc2ccc(N3CCN(Cc4ccc(Cl)cc4)CC3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
7-Piperazin-1-yl-3,4-dihydro-2H-isoquinolin-1-one (100 mg) synthesized according to the method described in J. Med. Chem., 39, 4583 (1996) was dissolved in N,N-dimethylformamide (5 ml). Potassium carbonate (71 mg) and 4-chloro benzyl bromide (106 mg) were added to the solution. The mixture was stirred at room temperature for 2 hr. Water was added to the reaction solution. The mixture was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=9:1) to give 7-[4-(4-chlorobenzyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one (75 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH2:22][CH3:23])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])[CH:8]=1.[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)#[N:25]>>[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH2:2][CH2:3][C:4]2[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH2:22][CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][CH3:15])[CH:8]=2)=[O:31])=[CH:28][CH:27]=1)#[N:25]
Reactant: CCC(CC)(NCCCn1cnc(CCN)c1)c1ccccc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: CCC(CC)(NCCCn1cnc(CCNC(=O)c2ccc(C#N)cc2)c1)c1ccccc1

Procedure:
3-[4-(2-Aminoethyl)imidazol-1-yl]-N-(1-ethyl-1-phenylpropyl)propylamine (0.5 g) was reacted with 4-cyanobenzoyl chloride (0.27 g) in a similar manner to Example 55 to give 4-cyano-N-(2-{1-[3-(1-ethyl-1-phenylpropylamino)propyl]imidazol-4-yl}ethyl)benzamide, m.p. 107°-109° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Cl:10]N1C(=O)CCC1=O>ClCCl>[Cl:10][C:3]1[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1
Reactant: c1cc2[nH]ccc2cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Clc1c[nH]c2ccncc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.9 %

Procedure:
A solution of 1H-pyrrolo[3,2-c]pyridine (200 mg, 1.69 mmol) in dichloromethane (10 mL) was treated with N-chlorosuccinimide (332 mg, 2.5 mmol) and stirred at room temperature for about 5 hours. The reaction mixture was diluted with dichloromethane and washed with aq. sodium hydrogen carbonate solution, brine, dried over anhydrous sodium sulphate and concentrated. Purification by silica gel (100-200) column chromatography using methanol and dichloromethane gradient as eluent afforded 3-chloro-1H-pyrrolo[3,2-c]pyridine (103 mg, 40%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]2[N:27]([CH3:28])[C:26]3[CH:29]=[CH:30][C:31]([C@@:33]([NH:42][CH2:43][C:44]([O:46]CC)=[O:45])([C:35]([N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[O:36])[CH3:34])=[CH:32][C:25]=3[N:24]=2)=[CH:17][CH:16]=1)(=[NH:14])[NH2:13].[OH-].[K+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:12]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][CH2:22][C:23]2[N:27]([CH3:28])[C:26]3[CH:29]=[CH:30][C:31]([C@@:33]([NH:42][CH2:43][C:44]([OH:46])=[O:45])([C:35]([N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[O:36])[CH3:34])=[CH:32][C:25]=3[N:24]=2)=[CH:19][CH:20]=1)(=[NH:13])[NH2:14]
Reactant: CCOC(=O)CN[C@@](C)(C(=O)N1CCCC1)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc([C@@](C)(NCC(=O)O)C(=O)N3CCCC3)ccc21
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
3.7 kg (5.49 mol) of (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazol-p-toluenesulphonic acid salt are dissolved in 7.4 L of methanol at 40° C. To this solution is added a solution of 0.795 kg (12.8 mol) of potassium hydroxide powder in 5.6 L of methanol und this is then rinsed with 1.8 L of methanol. The mixture is stirred for 2.5 hours at 40° C. The potassium salt of the p-toluenesulphonic acid crystallises out. A solution of 1.37 kg (7.2 mol) of p-toluenesulphonic acid monohydrate in 2.8 L of methanol is added to the suspension, this is rinsed with 1.8 litres of methanol and cooled to 22° C. The precipitated potassium salt of p-toluenesulphonic acid is separated off using a pressure filter and the filter cake is washed with 7.4 litres of methanol. The filtrate is inoculated with the title compound and stirred overnight. The precipitated product is suction filtered under argon, washed with 3.7 L of methanol and recycled into the reactor while still damp. 18.5 L of methanol are added and the suspension is refluxed for one hour and cooled to 22° C. The product is suction filtered under argon, washed with 3.7 L of methanol and dried at 30° C. in a circulating air drier. 2.22 kg (85% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]([CH:8]=[CH:9][O:10][C:11](=[O:13])[CH3:12])=[CH:3][O:4]C(=O)C.ClC1C=CC=[C:17]([C:21]([O:23]O)=[O:22])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]([O:23][C:21](=[O:22])[CH3:17])([CH:8]=[CH:9][O:10][C:11](=[O:13])[CH3:12])[CH:3]=[O:4]
Reactant: CC(=O)OC=CC(C)=COC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC=CC(C)(C=O)OC(C)=O

Procedure:
In the case of the reaction of 2-methyl-1,4-diacetoxy-buta-1,3-diene with m-chloroperbenzoic acid in chloroform, to give 2-methyl-2,4-diacetoxy-but-3-enal, the reaction can be represented by the following formulae: ##STR6##
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: COc1cccc(N)c1
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2cccc(OC)c2)[nH]c1=O
Reaction time: 17 h
Yield: 31.8 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (10 g) and 3-methoxyaniline (8.5 g) are added to ethanol (150 ml), and the mixture is refluxed with stirring for 17 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-(3-methoxyanilino)-6-oxo-5-pyrimidinecarboxylate (4.3 g). M.p. 233°-234° C.
Reaction SMILES: [H-].[C:2]([O:6][C:7]([NH:9][CH2:10][C:11](OC)=[O:12])=[O:8])([CH3:5])([CH3:4])[CH3:3].CO>C1(C)C=CC=CC=1>[C:2]([O:6][C:7](=[O:8])[NH:9][CH2:10][CH:11]=[O:12])([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC=O
Reaction time: 1 h
Yield: 53.2 %

Procedure:
A 1.02M solution of diisobutylalminium hydride in toluene (27 ml) was added dropwise to a solution of methyl tert-butoxycarbonylaminoacetate (2.00 g) in toluene (40 ml) at −70° C., and the mixture was stirred for 1 hour. The reaction solution, to which methanol (10 ml) was added at −70° C., was quenched and then left to room temperature. After the reaction solution was diluted with ethyl acetate, this solution was washed with a 1N aqueous hydrochloric acid solution. The organic layer was washed with a brine filtered through celite, dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:40→30:70) to yield tert-butyl(2-oxoethyl)carbamate (895 mg) as a colorless oil.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][CH:13]1[C:20](=[O:21])[N:19]2[CH:14]1[S:15][CH2:16][N:17]([S:32]([C:35]([F:38])([F:37])[F:36])(=[O:34])=[O:33])[CH:18]2[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44][C:45](Cl)=[O:46].Cl>C(Cl)Cl.N1C=CC=CC=1>[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44][C:45]([NH:12][CH:13]1[C:20](=[O:21])[N:19]2[CH:14]1[S:15][CH2:16][N:17]([S:32]([C:35]([F:37])([F:36])[F:38])(=[O:34])=[O:33])[CH:18]2[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:46]
Reactant: NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)OCc1ccccc1
Reactant: O=C(Cl)Cc1cccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1cccs1)NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)OCc1ccccc1
Temperature: -55 °C
Reaction time: 0.08 h
Yield: 67.2 %

Procedure:
To a suspension of p-toluenesulfonic acid salt of benzyl 7-amino-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate (800 mg.) in methylene chloride (8 ml.) was added pyridine (146 μl). After stirring at -55° C. for 5 minutes, 2-(2-thienyl)acetyl chloride (290 mg.) was added thereto, and then the mixture was gradually allowed to warm to 0° C. over a period of 1.5 hours. The mixture was poured into chilled dilute hydrochloric acid and extracted with ethyl acetate (50 ml.). The extract was washed with water (×2), a dilute aqueous solution of sodium bicarbonate, water and an aqueous solution of sodium chloride, successively. Drying over magnesium sulfate and removal of the solvent left an amorphous solid (800 mg.), which was chromatographed on silica gel (10 g.) with a mixed solvent of methylene chloride and ethyl acetate (95:5 to 90:10 by volume) to give benzyl 7-[2-(2-thienyl)acetamido] -8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate (667 mg.).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:8])[CH2:6][OH:7])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[N:25][C:26]([Cl:32])=[CH:27][CH:28]=2)[N:23]=1>O1CCCC1>[Cl:32][C:26]1[N:25]=[C:24]2[C:29]([CH:30]=[CH:31][C:22]([N:13]3[C:14](=[O:21])[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]3[O:7][CH2:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:8])=[N:23]2)=[CH:28][CH:27]=1
Reactant: CC(C)NC(=O)CO
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)NC(=O)COC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 32.1 %

Procedure:
The procedure is as in Example 22, but starting with N-isopropylglycolamide (5.3 g) in tetrahydrofuran (250 cc), an oily suspension (50% by weight; 2.2 g) of sodium hydride and 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (10 g). After purification by recrystallization in acetonitrile, [2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]-N-isopropylacetamide (4 g), m.p. 188° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19].O>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5 g, 32.6 mmol) in THF (50 mL) was added NaH (30%, 4 g, 50.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour before the addition of (2-(chloromethoxy)ethyl)-trimethylsilane (15 g, 90.0 mmol). The reaction was stirred at ambient temperature for 3 hours. It was then treated with water (5 mL) and extracted with EtOAc. The organic layer was concentrated under reduced pressure, and the residue was purified by chromatography to give the title compound. MS (m/z): 284 (M+H)+ (35Cl), 286 (M+H)+ (37Cl).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:18]=3[NH2:24])[CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].C(O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]4[NH:24][C:27](=[O:28])[NH:23][C:19]=4[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[O:7])=[CH:25][CH:26]=1
Reactant: Nc1cccc(N2CCN(CCNC(=O)c3ccc(F)cc3)CC2)c1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NCCN1CCN(c2cccc3[nH]c(=O)[nH]c23)CC1)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
10 Mmol (3.57 g) of 4-fluoro-N-[2-{4-(2,3-diaminophenyl)-1-piperazinyl}ethyl]benzamide were dissolved in 35 ml of tetrahydrofuran (which had been distilled over LiAlH4), and the solution was cooled in an ice-bath to 0° C. under an atmosphere of nitrogen. 21 Mmol (3.4 g) of 1,1'-carbonyldiimidazole in 20 ml of tetrahydrofuran was added in one portion to this solution while vigorously stirring. The temperature raised to 10° C. Thereafter the mixture was stirred for 3 hours at room temperature. The reaction mixture was evaporated to dryness under reduced pressure, the residue was taken up into chloroform, and the solution was washed with water. The organic layer was evaporated to dryness, and the residue was chromatographed over silicagel with a mixture of methylene chloride, methanol and 25% of ammonia (92:7.5:0.5) as the eluent. The so obtained base was cyrstallized from ethanol, and the title compound was obtained having a melting-point of 240°-243.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH2:10][CH2:11][C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25][OH:26].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:22])[CH2:10][CH2:11][C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([N:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25][OH:26])=[O:18])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.3 %

Procedure:
N-(benzyloxysuccinyl)-L-proline (152.5 g, 0.5 mol), L-prolinol (50.5 g, 0.5 mol) and triethylamine (200 ml) are dissolved in methylene chloride (2 l), and a solution of DMC (127 g, 0.75 mol) in methylene chloride (500 ml) is added dropwise thereto over a period of 40 minutes under water-cooling. The mixture is stirred for a further three hours at room temperature. The reaction liquid is washed successively with water (1 l), a saturated aqueous solution of sodium hydrogen carbonate (1 l), 1N hydrochloric acid (1 l) and water (1 l), and the organic layer is dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated to dryness under reduced pressure and the residue is purified by column chromatography on silica gel (chloroform:methanol) to give N-(benzyloxysuccinyl)-L-prolyl-prolinol (90 g, 46.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:19]([S:21][C:22]1[C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=1)[CH3:20]>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][N:9]2[C:28]([C:27]2[C:22]([S:21][CH2:19][CH3:20])=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:29])=[CH:4][CH:3]=1
Reactant: O=C1CCNc2cc(Cl)ccc21
Reactant: CCSc1ncccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCSc1ncccc1C(=O)N1CCC(=O)c2ccc(Cl)cc21
Temperature: 5 °C

Procedure:
To a mixture of 7-chloro-2,3-dihydro-4(lH)-quinolinone (25 g), pyridine (32 g) and dioxane (200 ml) was added dropwise 2-ethylthio-3-pyridylcarbonyl chloride (37 under cooling at 0 C. to 5° C. with stirring. The mixture was allowed to react at room temperature for additional 3 hours. The reaction mixture was subjected to the procedure described in example 1, and 43 g of 7-chloro-l-(2-ethylthio-3-pyridylcarbonyl)-2,3-dihydro-4(lH)-quinolinone was obtained as white crystal.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[N:13][CH:14]=1.[H-].[Na+].O>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[N:13][CH:14]=1
Reactant: COCCOCCl
Reactant: O=Cc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(C=O)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
##STR94## A. Methoxyethoxymethyl chloride (MEM) (19 g, 153 mmol) was added to a solution of 5-hydroxy-2-pyridinecarboxaldehyde (18.4 g, 149 mmol)in 300 ml DMF. NaH (6.3 g of 60% oil dispersion, 158 mmol) were added in portions while cooling the mixture to maintain 20°-30° C. The mixture was stirred an additional 1 hour at 25° C. 5 ml water were added, most of the solvent was evaporated, and water was added to the residue. The mixture was extracted with EtOAc. The extracts were dried over Na2SO4, filtered, and evaporated to a residue. The residue was chromatographed on silica gel eluting with EtOAc-hexanes (35:65) to obtain 5-[(2-methoxyethoxy)methoxy]-2-pyridinecarboxaldehyde: C10H13NO4 (211.22); 1H-NMR (CDCl3) δ 10.01 (s,1), 8.52 (d,1), 7.93 (d,1), 7.49 (m,1), 5.39 (s,2), 3.80 (m,2), 3.53 (m,2), 3.32 (s,3).
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=O.[CH3:14][N:15]1[CH:19](P(OCC)(=O)OCC)[C:18](=[O:28])[NH:17][C:16]1=[O:29]>>[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=[C:19]1[N:15]([CH3:14])[C:16](=[O:29])[NH:17][C:18]1=[O:28]
Reactant: Cc1ccc([N+](=O)[O-])c(C=O)c1C
Reactant: CCOP(=O)(OCC)C1C(=O)NC(=O)N1C
Product: Cc1ccc([N+](=O)[O-])c(C=C2C(=O)NC(=O)N2C)c1C
Yield: 88 %

Procedure:
Reaction of 2,3-dimethyl-6nitrobenzaldehyde with diethyl 1-methyl-2,4-dioxoimidazolidine-5-phosphonate according to the procedure of Method D provided the title compound (partial hydrate) as a mixture of geometrical isomers, m.p. 195°-198° C. in 88% yield.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH3:17])=[O:15]>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CCCCC1CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCC[C@H]1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
MsCl (0.543 mL, 6.97 mmol) was added to a solution of methyl 2-(hydroxymethyl)cyclohexanecarboxylate (1.0 g, 5.8 mmol, Rieke) in DCM (4 mL) at about 0° C. TEA (0.971 mL, 6.97 mmol) was then added. The mixture was stirred at rt for about 4 h. The mixture was washed with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give (trans)-methyl 2-((methylsulfonyloxy)methyl)cyclohexanecarboxylate (1.4 g, 100%). LC/MS (Table 2, Method c) Rt=1.35 min; MS m/z 251 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30]>O1CCCC1>[CH2:22]([N:19]1[CH2:18][CH2:17][CH:16]([N:15]2[CH:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[NH:1][C:29]2=[O:30])[CH2:21][CH2:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(Cc2ccccc2)CC1
Yield: 81 %

Procedure:
To a solution of 27.6 g (74.4 mmol) of α-(2-aminophenyl)-N-(1-benzylpiperidin-4-yl)benzylamine in 300 mL of tetrahydrofuran was added 12.1 g (74.5 mmol) of 1,1'-carbonyldiimidazole, and the mixture was heated under reflux for 8 hours. After allowing to cool, the reaction mixture was concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform). The resulting crude crystals were recrystallized from ethanol to give 24.0 g (60.3 mmol) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Brc1cncnc1
Reactant: Cc1cc(NC(=O)c2nc(C)ccc2N)ccn1
Product: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cncnc2)ccn1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide in accordance with the general method of example 20 using 5-bromopyrimidine instead of 3-Bromopyridine to yield the final compound as a beige solid, MS (ISP): m/e=321.0 (M+H+).