Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=1)[CH2:2][CH2:3][CH3:4].Cl>O.CO>[CH2:1]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cccc1Cc1cccc(NC(N)=O)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCCN1CCCC1Cc1cccc(NC(N)=O)c1
Reaction time: 1 h
Yield: 43.4 %

Procedure:
A suspension of 1.25 g (4.6 mmol) of 1-butyl-2-(3'-ureidobenzyl)pyrrole, prepared, for example, as described in Preparation 6D, in a mixture of 75 ml of water, 75 ml of methanol and 10 ml of a 1N solution of hydrochloric acid in methanol, was hydrogenated at 45 p.s.i. in the presence of 1 g of 5% rodium on activated alumina as catalyst, for 1 hour. The catalyst was then separated by filtration and the filtrate evaporated in vacuo. The aqueous residue was treated with concentrated ammonium hydroxide until an alkaline pH was obtained, and the product extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water (2×50 ml), dried and evaporated under reduced pressure. The residue was purified by column chromatography on 100 g of silica gel, using an (80:20) mixture of methylene chloride-[chloroform-methanol-ammonium hydroxide (60:10:1)] as the eluting system, thus obtaining 550 mg (44%) of the title compound, 1-butyl-2-(3'-ureidobenzyl)pyrrolidine, which was recrystallized from acetone-hexane. M.P. 80°-83° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=3)[CH:13]=2)[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[C:7]=1[CH2:33][C:34]([O:36]CC)=[O:35])=[O:5])C.[OH-].[Na+].Cl>CCO>[C:34]([CH2:33][C:7]1[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[C:9]2[C:14]([C:6]=1[C:4]([OH:5])=[O:3])=[CH:13][C:12]([O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][CH:21]=1)=[CH:11][CH:10]=2)([OH:36])=[O:35]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(OC(C)C)cc3)ccc2n1-c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(Oc2ccc3c(c2)c(C(=O)O)c(CC(=O)O)n3-c2cccc(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(3-chlorophenyl)-2-ethoxycarbonylmethyl-5-(4-isopropoxyphenoxy)indole-3-carboxylic acid ethyl ester (65 mg, 0.12 mmol, see step (a) above), NaOH (aq, 1 M, 15 mL), and EtOH (20 mL) was heated at 50° C. for 48 h and stirred at rt overnight and acidified to pH 4 with HCl (aq, 1 M) and extracted with CH2Cl2. The organic layer was washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography. Yield 45 mg (78%), mp 188-190° C.
Reaction SMILES: [CH3:1][NH:2][N:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>ClCCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:23])[N:2]([N:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4]2)[CH3:1])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CNn1cnc2ccccc2c1=O
Solvent: ClCCCl
Product: CN(C(=O)Nc1ccc(Cl)cc1)n1cnc2ccccc2c1=O

Procedure:
A mixture of 3-methylamino-4(3H)quinazolinone (2.00 g, 11.4 mmol) and 4-chlorophenyl isocyanate 2.01 g, 13.1 mmol) in 1,2-dichloroethane is heated at reflux for 72 hours, concentrated in vacuo and diluted with ether. The organic mixture is heated to reflux and filtered. The filter cake is washed with ether and dried to give the title product as a white solid, 3.61 g (96%), mp 186°-188° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2>>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Yield: 64 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 1 with (R)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 1f obtained from step 5 of Example 1 and 5-chloro-1,3-dihydro-indol-2-one as starting materials to give (R,Z)-2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 2 (42 mg, yield 64%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@H:22]1[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([CH2:31][OH:32])[O:23]1)[CH:2]=[CH2:3].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[H-].[Na+].[NH4+].[Cl-]>C1COCC1.CN(C=O)C>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@H:22]1[C@H:27]([O:28][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:26]([O:29][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:25]([O:30][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:24]([CH2:31][O:32][CH2:22][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:5]=2)[O:23]1)[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
To a solution of the crude compound 25-1 and benzyl bromide (2.6 mL, 21.6 mmol) in THF/DMF (30 mL/10 mL) was added NaH (60% dispersion in mineral oil, 1.3 g, 32.4 mmol) portionwise at 0° C. The reaction mixture was gradually raised to room temperature and stirred at r.t. for 15 hour. The mixture was cooled to 0° C. and aqueous saturated NH4Cl solution (150 mL) was added to the mixture. The mixture was extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified using normal phase column chromatography to provide the desired product 26 (1.50 g, 85% (2-steps)).
Reaction SMILES: C([O:3][P:4]([CH2:16][C:17]([N:19]1[CH2:34][C@@H:33]([S:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:32][C@H:20]1[C:21]([O:23][CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:22])=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])C.Br[Si](C)(C)C.O.C(=O)(O)[O-].[Na+]>ClCCl>[OH:5][P:4]([CH2:16][C:17]([N:19]1[CH2:34][C@@H:33]([S:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:32][C@H:20]1[C:21]([O:23][CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:22])=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:3]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1C[C@@H](Sc2ccccc2)C[C@H]1C(=O)OCOC(=O)C(C)(C)C
Agent: C[Si](C)(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)C(=O)OCOC(=O)[C@@H]1C[C@H](Sc2ccccc2)CN1C(=O)CP(=O)(O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
To a solution of (cis)-1-[[ethoxy(4-phenylbutyl)phosphinyl]-acetyl]-4-(phenylthio)-L-proline, (2,2-dimethyl-1-oxopropoxy)methyl ester (3 g) in dichloromethane (30 ml) is added bromotrimethylsilane (1.2 g). The mixture is stirred at room temperature for 16 hours. After the addition of water (15 ml), saturated sodium bicarbonate (25 ml) is added, followed by water (500 ml) to effect solution. The aqueous alkaline solution is washed with ether and acidified to a pH of 3 with concentrated hydrochloric acid. The oil that separates from solution is extracted into ethyl acetate, washed with brine, and dried (MgSO4). The solvent is removed in vacuo to give a residue of 2.5 g which is chromatographed on silica gel (120 g) eluting with dichloromethane/methanol/acetic acid (19:1:1) to give the product (1.8 g) as a glass-like solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:13][C:14](O)=[O:15])[C:8](=[O:9])[C:7]2=[CH:17][CH:18]=1)([O-:3])=[O:2].S(Cl)([Cl:21])=O>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:13][C:14]([Cl:21])=[O:15])[C:8](=[O:9])[C:7]2=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: O=C(O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O

Procedure:
A mixture of (4-nitrophthalimido)acetic acid (2.17 g, 8.7 mmol) and thionyl chloride (5 mL) was refluxed for 80 minutes. The reaction mixture was cooled and, then, concentrated under reduced pressure to give a crude product of (4-nitrophthalimido)acetyl chloride. The crude product was dissolved, while heating, in 1,2-dichloroethane (10 mL). The solution was added (dropwise to a solution of (3aR*,10aS*)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]-diazepin-10(1H)-one (2.30 g, 7.9 mmol) in 1,2-dichloroethane (10 mL). The mixture was stirred for 5 minutes at room temperatures, to which was added a saturated aqueous solution of sodium hydrogen carbonate (25 mL). The aqueous layer was separated. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, which was dried over magnesium sulfate, and them subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was crystallized from chloroform-ethanol-hexane to give 1.91 g (yield 46%) of the titled compound, m.p. 196.5°-197.5° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=1.O.[OH-].[Na+]>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=1
Reactant: CCOC(=O)c1cc2c(nc1NCc1ccco1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2c(nc1NCc1ccco1)CCCC2
Temperature: 80 °C
Reaction time: 10 h
Yield: 96 %

Procedure:
To a solution of ethyl 2-[(furan-2-ylmethyl)amino]-5,6,7,8-tetrahydroquinoline-3-carboxylate (600 mg) in ethanol (4 ml)-water (4 ml) was added 8 M aqueous sodium hydroxide solution (1.25 ml), and the mixture was stirred at 80° C. for 10 hr. The reaction mixture was concentrated under reduced pressure to about 1/3 volume, and neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (522 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH:26]4[CH2:28][CH2:27]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NC1CC1)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 6-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.28 mmol) and cyclopropylamine (16.1 mg, 0.28 mmol) in THF (10 mL) were added at 0° C., 1-hydroxybenzotriazole hydrate (43.3 mg, 0.28 mmol), N-ethyldiisopropylamine (121 μL, 0.69 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (54.2 mg, 0.28 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by distillation. The remaining material was purified by chromatography (silica, dichloromethane:ethyl acetate=4:6 to 1:0) to afford the title compound (95.2 mg, 86%) as a white solid. MS: m/e=398.0 [M−H]+.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.COCOCCCCCCCCCCCC(O)=O.[CH:44]1([N:50]=[C:51]=[N:52][CH:53]2[CH2:58][CH2:57][CH2:56]CC2)CCCCC1>O1CCCC1>[CH3:1][N:50]([C:51]1[CH:56]=[CH:57][CH:58]=[CH:53][N:52]=1)[CH3:44]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COCOCCCCCCCCCCCC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 400 mg of radicicol, 716 mg of 12-(methoxymethoxy)dodecanoic acid, 7 ml of dry tetrahydrofuran, 567 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 756 mg of the title compound were obtained.
Reaction SMILES: [CH:1](N1CCCC1=O)=C.[CH:9]1[C:14]([C:15]([O:17][O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:1][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:14][C:15]([O:17][O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:16]
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Reactant: C=CN1CCCC1=O
Product: CCCCCCCC(=O)OOC(C)(C)C
Temperature: 130 °C

Procedure:
10.76 g of N-vinyl-2-pyrrolidone and the temperature is raised to 130° C. Then 0.9 g of tert-butyl perbenzoate is added. After 1 and 2 hours, respectively, a 0.4 g portion of tert-butyl perbenzoate is fed in. The charge is maintained at 130° C. for another 5 hours. A clouded viscous solution is obtained.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([C:11]#[N:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].O>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([C:11]#[N:12])[N:3]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CCCc1cc(I)nc(C#N)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1cc(-c2ccc(OC)c(OC)c2)nc(C#N)n1
Temperature: 105 °C
Yield: 54.9 %

Procedure:
Under nitrogen atmosphere, a solution (c=0.18 M) of 4-iodo-6-propyl-pyrimidine-2-carbonitrile (1 mL, 0.18 mmol) in degassed toluene, an aqueous solution (c=2 M) of potassium carbonate (0.225 mL, 0.45 mmol) and tetrakis-(triphenylphosphine) palladium (10 mg, 0.09 mmol) were successively added to a solution (c=0.216 M) of 3,4-dimethoxyphenyl boronic acid (1 ml, 0.216 mmol) in degassed toluene. The mixture was heated at 105° C. for 4 h, then was allowed to cool to room temperature and mixed with water (4 mL). The organic layer was evaporated under reduced pressure. The residue was chromatographed by preparative HPLC (H2O+0.05% TFA/CH3CN+0.05% TFA) to afford 4-(3,4-dimethoxy-phenyl)-6-propyl-pyrimidine-2-carbonitrile (28 mg).
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>>[OH:16][C@@H:7]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COP([O-])OC
Reactant: O=CC=Cc1ccccc1
Agent: Cl
Product: COP(=O)(OC)[C@H](O)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1 M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then, cinnamaldehyde (0.40 mmol) was added thereto. After reacting for 81 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S,E)-1-hydroxy-3-phenyl-2-propenylphosphonate as a final product in a yield of 85%. The chemical reaction in this Example is shown in chemical formula 34. ##STR28##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH:12]([C:16]([OH:18])=[O:17])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]([F:24])([F:23])[CH2:21]O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][CH:12]([C:16]([O:18][CH2:21][C:20]([F:24])([F:23])[F:19])=[O:17])[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC2CC(C(=O)O)CC2C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2CC(C(=O)OCC(F)(F)F)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
A mixture of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7-carboxylic acid (0.150 g, 0.588 mmol), 2,2,2-trifluoroethanol (0.118 g, 1.18 mmol), 4-N,N-dimethylaminopyridine (DMAP) (0.143 g, 1.18 mmol) and polymer supported dicyclohexylcarbodiimide (PS-DCC) (0.8 g, loading 3.2 mmol/g) in dichloromethane (20 mL) was stirred at ambient temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by HPLC, using acetonitrile and 0.05% aqueous TFA as mobile phase, to obtain 0.053 g (27% yield) of 2,2,2-trifluoroethyl 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7-carboxylate as an oil (1H NMR (CDCl3, 300 MHz): δ 4.48 (q, J=8.30 Hz, 2H), 3.58-3.46 (m, 2H), 3.26-2.92 (m, 4H), 2.82-2.63 (m, 1H), 2.28-2.07 (m, 2H, 1.84-1.65 (m, 2H), 1.45 (s, 9H); MS (m/z): 338 (M+1), 282 (M+1-56)). The 2,2,2-trifluoroethyl 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7-carboxylate was dissolved in dichloromethane (5.0 mL), treated with TFA (2.0 mL), and the reaction was stirred at ambient temperature for 1 h. The solvent was evaporated and the crude product was purified on HPLC, using acetonitrile and 0.05% TFA in water as mobile phase, to obtain 0.023 g of the trifluoroacetate salt of 2,2,2-trifluoroethyl 3-azabicyclo[3.3.0]octane-7-carboxylate (as a cis/trans mixture) as an oil (1H NMR (CD3OD, 300 MHz): δ 4.62 (q, J=8.79 Hz, 2H), 3.64-3.42 (m, 1H), 3.3.38-3.32 (m, 1H), 3.22-3.05 (m, 2H), 3.02-2.95 (m, 3H), 2.42-2.07 (m, 2H), 1.96-1.63 (m, 2H); MS (m/z): 238 (M+1)).
Reaction SMILES: [NH2:1][C@H:2]([C@H:8]([OH:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([BH3-])#N.[Na+].[CH2:19]([O:26][CH2:27][N:28]1[C:36]2[C:35]([O:37][CH3:38])=[N:34][CH:33]=[N:32][C:31]=2[C:30]([CH:39]=O)=[CH:29]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C>CO>[CH2:19]([O:26][CH2:27][N:28]1[C:36]2[C:35]([O:37][CH3:38])=[N:34][CH:33]=[N:32][C:31]=2[C:30]([CH2:39][NH:1][C@H:2]([C@H:8]([OH:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:29]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)[C@@H](O)[C@@H](N)C(=O)OCC
Reactant: COc1ncnc2c(C=O)cn(COCc3ccccc3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](O)[C@@H](NCc1cn(COCc2ccccc2)c2c(OC)ncnc12)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of (2R,3S)-diethyl 2-amino-3-hydroxysuccinate (prepared as described in A. Breuning, R. Vicik and T. Schirmeister, Tetrahedron Asymm., 2003, 14, 3301 and Z. Tang, Z.-H. Yang, X.-H. Chen, L.-F. Cun, A.-Q. Mi, Y.-Z. Jiang and L.-Z. Gong, J. Am. Chem. Soc., 2005, 127, 9285) (0.109 g, 0.53 mmol), sodium cyanoborohydride (0.055 g, 0.88 mmol) and 5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-7-carbaldehyde (0.131 g, 0.44 mmol) were evaporated from methanol (3×). The residue was dissolved in methanol (10 ml) and acetic acid added (5 drops). The reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was evaporated on to silica gel and chromatographed (ethyl acetate-petrol, 2:1 then ethyl acetate-triethylamine, 1:99) giving a colourless oil (0.166 g, 77%). 1H NMR (CDCl3) δ 8.55 (s, 1H), 7.34 (s, 1H), 7.33-7.23 (m, 5H); 5.70 (s, 2H), 4.62 (d, J=3.4 Hz, 1H), 4.48 (s, 2H), 4.23-4.15 (m, 5H), 4.10 (s, 3H), 3.99 (d, J=13.8 Hz, 1H), 3.85 (d, J=2.3 Hz, 1H), 2.25 (brs, 2H), 1.26 (t, J=7.1 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:30])/[CH:12]=[CH:13]/[CH:14]=[C:15](/[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)\[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1>O1CCCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22](/[C:15](/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: COc1ccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccnc2)cc1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: COc1ccc(/C(=C/C=C/C(=O)NCCCCc2cccnc2)c2cccnc2)cc1
Yield: 79.9 %

Procedure:
As before in Example 134, a solution of (2E,4Z)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid 4-nitrophenyl ester (2.01 g) and 3-pyridinebutanamine (0.75 g) in tetrahydrofuran (25 mL) was stirred for 17 hours at room temperature. After the usual workup. the crude product was crystallized from ethyl acetate to yield 1.65 g of (2E,4Z)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 108°-110° C. Recrystallization of a portion from the same solvent provided the analytical sample, mp 109°-110° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19]2)=[O:17])=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:19]2)=[O:17])=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(C(=O)N2CCOC(c3ccccc3)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(NCc2ccccc2)cc1)N1CCOC(c2ccccc2)C1
Temperature: 45 °C
Reaction time: 48 h
Yield: 70.3 %

Procedure:
Benzaldehyde (0.1 ml, 1 mmol) was added to a stirred solution of (4-amino-phenyl)-(2-phenyl-morpholin-4-yl)-methanone (240 mg, 0.84 mmol) in dichloromethane (20 ml) and the resulting mixture was heated to 45° C. for 2 hours. The reaction mixture was cooled to room temperature then sodium triacetoxyborohydride (250 mg, 1.2 mmol) was added and the reaction was stirred at room temperature for 48 hours. The reaction was diluted with dichloromethane (10 ml) and quenched by the addition of water (10 ml). The aqueous was washed with dichloromethane (2×10 ml), the organics combined and dried over magnesium sulfate. The solvent was concentrated in vacuo and the residue purified by flash chromatography to afford the title compound as a colourless oil (0.22 g, 70% yield). HPLC retention time 6.18 min. Mass spectrum (ES+) m/z 373 (M+H).