Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[CH2:14][C@H:15]4[N:27]([CH3:28])[CH2:26][CH2:25][C@:21]56[C:22]=3[C:23]=2[O:24][C@H:20]5[C@@H:19]([OH:29])[CH:18]=[CH:17][C@@H:16]46)C(=O)C2=CC=CC=C12.CN.C(Cl)(Cl)Cl>O>[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][C@H:15]3[N:27]([CH3:28])[CH2:26][CH2:25][C@:21]45[C:22]=2[C:23]=1[O:24][C@H:20]4[C@@H:19]([OH:29])[CH:18]=[CH:17][C@@H:16]35
Reactant: CN1CC[C@]23c4c5ccc(OCCCN6C(=O)c7ccccc7C6=O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: CN
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN1CC[C@]23c4c5ccc(OCCCN)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87.8 %

Procedure:
To 14 g (29.6 mmol) of 3O-phthalimidopropyl morphine (13) was added 188 mL of 2M ethanolic methylamine, and the reaction mixture was allowed to stir for 3.5 h at room temperature under nitrogen. The reaction mixture was poured into 650 mL of chloroform and 425 mL of cold water. The organic layer was separated, and the aqueous layer was extracted with 3×90 mL of chloroform. The chloroform layers were combined and extracted with 2×140 mL of 1N HCl. The aqueous extract was basified with 140 mL of 2.5 N NaOH and extracted with 3×300 mL of chloroform. The organic layer was dried (Na2SO4) and concentrated. The residue was crystallized from diethyl ether to give 8.9 g (26 mmol, 88%) of 14 as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[NH:14][C:13](=[O:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=1)([O-])=O.[Cl-].[NH4+]>CN(C=O)C.[Fe]>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]2[NH:14][C:13](=[O:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c2ccccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
To a suspension of 2-nitro-6(5H)-phenanthridinone (3.8 g, 0.016 mol) in DMF (200 mL) was added an ammonium chloride solution (3%, 200 mL), followed by the addition of iron powder (22 g). The reaction mixture was stirred at 100° C. for 1 hr. The residue was removed by filtration, and the filtrate was made acidic by adding dilute HCl (25%, 20 mL). A solid separated from the solution and was filtered and washed thoroughly with cold water to remove acidic impurities. The solid was then dried under vacuum, to give hydrochloride salt of 2-amino-6(5H)-phenanthridinone (3.4 g, 89%).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH2:26].C(N(C(C)C)CC)(C)C>C(#N)C>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH:26][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NCc1cccs1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCc2cccs2)S/C1=C\c1ccc2ncccc2c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 67.7 %

Procedure:
The suspension of 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one (example 1a, 3.0 g, 10.5 mmol), thiophene methyl amine (2.4 g, 21.0 mmol) and diisopropylethylamine (DIEA) (3.66 mL, 21.0 mmol) in acetonitrile (30 mL) was stirred under at 80° C. for 12 h. After cooling to room temperature, the solid was collected by filtration, washed with a little bit of acetonitrile and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-10% methanol in methylene chloride in 30 min) afforded 2-[(thiophen-2-ylmethyl)-amino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one (2.5 g, 67%) as a light yellow solid: LC-MS m/e 352 (MH+).
Reaction SMILES: [BH4-].[Na+].CO.[C:5]([C:9]1[S:13][C:12]([N:14]2[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([CH3:21])[C:15]2=[O:22])=[N:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]>C(O)(=O)C>[C:5]([C:9]1[S:13][C:12]([N:14]2[C:15](=[O:22])[C:16]([CH3:21])=[C:17]([CH3:20])[CH:18]2[OH:19])=[N:11][N:10]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC1=C(C)C(=O)N(c2nnc(C(C)(C)C)s2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1=C(C)C(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reaction time: 3 h
Yield: 77.3 %

Procedure:
Sodium borohydride (0.07 g) was added at room temperature to a methanol solution (100 ml) of N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-2,3-dimethylmaleinimide (0.95 g), and the mixture was stirred for 3 hours. After the reaction, glacial acetic acid (0.5 ml) was added and the solvent was evaporated under reduced pressure. Water (30 ml) was added to the residue, and potassium carbonate was added to make the mixture alkaline. It was extracted with dichloromethane (50 ml×2). The extractants were dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude crystals were washed with a small amount of diethyl ether to give the desired N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3,4-dimethyl-2-hydroxy-5-oxo-2,5-dihydropyrrole (0.74 g), mp. 179°-182° C.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[Cl:12][C:13]1[CH:14]=[C:15]([C@H:20]2[C@H:26]([CH:27]=O)[O:25][CH2:24][CH2:23][N:22]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:21]2)[CH:16]=[CH:17][C:18]=1[Cl:19].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([C@H:20]2[C@H:26]([CH:27]=[CH2:1])[O:25][CH2:24][CH2:23][N:22]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[CH2:21]2)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: C=C[C@@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (3.59 g) in THF (30 mL) was cooled under nitrogen purging to −78° C., and 1.6 M n-butyllithium/hexane solution (5.79 ml) was added. The mixture was warmed to 0° C., and stirred for 20 min, and a solution of tert-butyl (6R,7R)-6-(3,4-dichlorophenyl)-7-formyl-1,4-oxazepane-4-carboxylate (2.89 g) in THF (50 ml) was added. After stirring at 0° C. for 20 min, and at room temperature for 2 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-30%)) to give the title compound (1.10 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[Si]([N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)(C(C)(C)C)(C)C>>[F:1][C:2]1[C:3]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: CN1CCN([Si](C)(C)C(C)(C)C)CC1
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Product: CC1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
In a manner similar to that of Example 4, 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]-1,4-benzoxazin- 6-carboxylic acid (II, X: fluoro) is reacted with 4-(t-butyldimethylsilyl)-1-methylpiperazine (III, R2, R3 and R4 : methyl; R5 : t-butyl) to obtain a solid compound.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:8]=2[C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:3][CH2:2]1.Cl>CO.CCOCC>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[C:8]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=3)[CH2:21][CH2:20]2)=[O:18])[CH:9]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(C2=CCOCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(C2CCOCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
A suspension of [2-(3,6-Dihydro-2H-pyran-4-yl)-5-methanesulfonyl-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone, Example 60 (30 mg, 0.0607 mmol) in methanol (1.5 ml) was acidified to pH=1 with HCl solution in ether. The mixture was evaporated to dryness and the residue was taken up in Methanol (5 mL). Then Pd/C 10% (15 mg) was added and the mixture was hydrogenated at reflux temperature for 20 hours. The mixture was diluted with MeOH, filtered and the filtrate was concentrated in vacuo. The resulting mixture was purified on a SiO2: Eluent: Heptane/EtOAc 0% to 70% (20 minutes) then 70% (10 minutes) to provide the title compound (19 mg, white solid; Solid; M+H=497.2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[C:8]([CH3:43])=[N:7]1.Br[CH2:48][CH2:49][OH:50].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([N:27]5[CH2:28][CH2:29][N:30]([CH2:48][CH2:49][OH:50])[CH2:31][CH2:32]5)[CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=3)(=[O:34])=[O:35])[CH:13]=2)[C:8]([CH3:43])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4cccc(N5CCNCC5)c4)cnc32)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4cccc(N5CCN(CCO)CC5)c4)cnc32)cc1
Yield: 85 %

Procedure:
Using the same reaction conditions as described in step-ii of example-35, 3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(3-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (70 mg, 0.104 mmol) was alkylated with 2-bromoethanol (13 mg, 0.104 mmol) using potassium carbonate (73 mg, 0.522 mmol), DMF (2 ml) to yield 60 mg (84.5%) of the titled compound. MS: m/z=679.3 (M+1).
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[C:13]1([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:28]([OH:30])=O)=[N:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>C1COCC1>[C:13]1([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:28]([NH2:3])=[O:30])=[N:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1nn(-c2ccccc2)c2ccccc12
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1nn(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a solution of 1,1′-carbonyldiimidazole (3.4 g, 21 mmol) in 60 mL of dry THF was added dropwise a solution of 1-phenyl-1H-indazole-3-carboxylic acid (5.0 g, 21 mmol) in 60 mL dry THF under nitrogen atmosphere. The resulting reaction mixture was stirred at ambient temperature for 30 minutes and refluxed for 30 minutes; then cooled to ambient temperature under nitrogen atmosphere. Ammonia, generated by warming concentrated aqueous ammonia solution, was bubbled through, and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated in vacuo to dryness, the solid was dissolved in 200 mL of ethyl acetate, the solution was successively washed with 1N aqueous HCl solution (2×50 mL), 1N aqueous NaOH solution (5×20 mL) and was dried over Na2SO4. Concentration and drying under vacuum gave 4.65 g (93%) of desired product as a white solid: mp 149° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[N:20]1([C:29](N2C=C[N+](C)=C2)=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>C(OCC)(=O)C.CCCCCCC>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:29]([N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[O:30])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: C[n+]1ccn(C(=O)N2CCc3ccccc32)c1
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCc2ccccc21

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(2,3-dihydro-indole-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to column chromatography(ethyl acetate/heptane, 1:5) (73%, crystals. HPLC-MS m/z=401.1) (M+1), Rt: 5.5 min.
Reaction SMILES: [I:1]Cl.[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][O:17]C(=O)C)[C:6]=2[N:7]=[CH:8][N:9]=1.CO.N>C(Cl)Cl>[Cl:3][C:4]1[C:5]2[C:12]([I:1])=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][OH:17])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: CC(=O)OCCOCn1ccc2c(Cl)ncnc21
Reactant: ClI
Agent: N
Solvent: CO
Solvent: ClCCl
Product: OCCOCn1cc(I)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Iodine monochloride (0.38 mL) was added dropwise with stirring under a nitrogen atmosphere to a solution of 4-chloro-7-(2-acetoxyethoxymethyl)pyrrolo[2,3-d]pyrimidine (3, 0.82 g) in dry CH2Cl2 (25 mL). The reaction mixture was stirred at room temperature for 20 hours. The solvent was evaporated at 40 degrees C. under high pressure and the dark purple syrup was placed on the top of a silica gel column. Elution of the column (15×2 cm) with CHCl3 yielded a dark colored syrup, after evaporation of the appropriate UV absorbing fractions, which on trituration with dry ether gave a crystalline product. (0.3 g) as colorless needles. These needles were covered with methanol saturated with ammonia (30 mL) at 0 degrees C., and the reaction mixture stirred at room temperature in a pressure bottle for 20 hours. The solvent was evaporated under high vacuum and the resulting solid was recrystallized from methanol to furnish colorless needles of 9b, 0.21 g (80.75%), mp 154- 155 degrees C. 1H-NMR (DMSO-d6): 8.69 (s, 1, C2-H), 8.14 (s, 1, C6-H), 5.66 (s, 2, N7-CH2), 4.57 (t, 1, J=3.0 Hz, 3.3 Hz, exchangeable with D2O, OH), 3.46-3.33 (m, 4, CH2): UVλmax nm (ε×104); (pH 7) 225 (1.8), 296 (0.9); (pH 1) 233 (2.1), 280 (0.95); (pH 11) 228 (0.8), 280 (0.85).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[Cl:13][C:14]([Cl:19])(Cl)[C:15](Cl)=[O:16].COCCOC>C(OCC)C.[Zn]>[Cl:13][C:14]1([Cl:19])[C:15](=[O:16])[CH2:1][C:2]21[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]2
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC2(CC(=O)C2(Cl)Cl)C1
Temperature: 10 °C
Reaction time: 14 h

Procedure:
Under an inert atmosphere, 7.728 g (118.19 mmoles) of zinc in nanopowder form are suspended in 100 ml of diethyl ether. 5.00 g (29.55 mmoles) of tert-butyl 3-methylene-azetidine-1-carboxylate (WO 2008124085) are added, then the medium is cooled to 10° C. A solution of 6.60 ml (59.09 mmoles) of trichloroacetyl chloride in ml of 1,2-dimethoxyethane is added drop by drop while maintaining the temperature of the reaction medium between 26 and 30° C. After stirring for 14 hrs at ambient temperature, the medium is filtered over celite, the celite is copiously rinsed with diethyl ether and the filtrate is partially concentrated under reduced pressure. The crude reaction product thus obtained is used as such in the following stage.
Reaction SMILES: [P:1](Cl)(=[O:18])([O:10]CC1C=CC=CC=1)[O:2]CC1C=CC=CC=1.C([O:27][C:28]1[CH:33]=[C:32]([O:34]COCC)[C:31]([CH:39]([CH3:41])[CH3:40])=[CH:30][C:29]=1[C:42]1[N:46]([C:47]2[CH:48]=[C:49]3[C:53](=[CH:54][CH:55]=2)[N:52]([CH3:56])[CH:51]=[CH:50]3)[C:45](=[O:57])[N:44](C(OCC2C=CC=CC=2)=O)[N:43]=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[P:1]([OH:18])([OH:10])([O:34][C:32]1[CH:33]=[C:28]([OH:27])[C:29]([C:42]2[N:46]([C:47]3[CH:48]=[C:49]4[C:53](=[CH:54][CH:55]=3)[N:52]([CH3:56])[CH:51]=[CH:50]4)[C:45](=[O:57])[NH:44][N:43]=2)=[CH:30][C:31]=1[CH:39]([CH3:41])[CH3:40])=[O:2]
Reactant: CCOCOc1cc(OCc2ccccc2)c(-c2nn(C(=O)OCc3ccccc3)c(=O)n2-c2ccc3c(ccn3C)c2)cc1C(C)C
Reactant: O=P(Cl)(OCc1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)c1cc(-c2n[nH]c(=O)n2-c2ccc3c(ccn3C)c2)c(O)cc1OP(=O)(O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dibenzyl phosphorochloridate was added to the solution of benzyl 3-(2-(benzyloxy)-4-(ethoxymethoxy)-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-carboxylate and potassium carbonate in acetone. The reaction mixture was stirred at room temperature overnight. After removal of solvent, the reaction mixture was purified by column chromatography to produce pale yellow oil, which was hydrogenated to give the desired.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].[CH:26]([N:29]=[C:30]=[S:31])([CH3:28])[CH3:27].Br[CH2:33][C:34](=O)[C:35]([O:37][CH2:38][CH3:39])=[O:36].O>C1COCC1>[CH:26]([NH:29][C:30]1[S:31][CH:33]=[C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])([CH3:28])[CH3:27]
Reactant: CC(C)N=C=S
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1csc(NC(C)C)c1C(=O)OCC
Temperature: -78 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
Ethoxycarbonylmethylene triphenyl phosphorane (33.8 g) in dry THF (200 ml) was treated with isopropyl isothiocyanate (10.1 g) at 65° C. for 16 h under nitrogen. The mixture was cooled to −78° C. and ethyl bromo-pyruvate (19.5 g) was added. The reaction was allowed to warm slowly to room temperature. After 24 h at room temperature more ethyl bromo-pyruvate (3.17 g) was added and the mixture was stirred at room temperature for 16 h. The reaction was poured into water (1.5 L) and extracted into ether. Drying and evaporation gave an oil which was chromatographed (SiO2/5:1 isohexane-ethyl acetate) to afford the subtitle compound (21.2 g). δ 1HCDCl3 1.23-1.43 (12H, m), 3.46 (1H, m), 4.2-4.35 (4H, m), 6.50 (1H, s), 7.52 (1H, br.d)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:15](=[O:16])[CH2:14][C:13](=[O:17])[N:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[C:11]1=[O:27].C(N(C(C)C)CC)(C)C.[N:37]([CH2:40][C:41]([O:43]CC)=[O:42])=[C:38]=[O:39]>ClCCl>[OH:17][C:13]1[N:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[C:11](=[O:27])[N:10]([CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:15](=[O:16])[C:14]=1[C:38]([NH:37][CH2:40][C:41]([OH:43])=[O:42])=[O:39]
Reactant: CCOC(=O)CN=C=O
Reactant: COc1ccccc1CN1C(=O)CC(=O)N(Cc2ccccc2OC)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1Cn1c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc2ccccc2OC)c1=O
Reaction time: 5 h

Procedure:
N-[(6-hydroxy-1,3-bis{[2-(methyloxy)phenyl]methyl}-2,4-dioxo-1,2,34-tetrahydro-5-pyrimidinyl)carbonyl]glycine. A mixture of 1,3-bis{[2-(methyloxy)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione (1.64 g, 4.45 mmoles) and diisopropylethylamine (1.56 mL, 8.94 mmoles) was stirred in dichloromethane (30 mL) and treated with ethyl isocyanatoacetate (500 uL, 4.45 mmoles). The mixture was stirred for 5 hours, washed with 1 molar hydrochloric acid (×2), evaporated, taken up in ethanol-6 molar sodium hydroxide and stirred overnight. The mixture was acidified and extracted into ethyl acetate (×2). The extracts were washed with 1 molar hydrochloric acid evaporated, dried and evaporated. The title compound was recrystallized from acetic acid (1.0 g, 48%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (br. s., 1 H), 10.11 (t, J=4.93 Hz, 1 H), 7.20-7.28 (m, 2 H), 7.00 (d, J=7.83 Hz, 2 H), 6.86-6.96 (m, 4 H), 5.00 (s, 4 H), 4.10-4.18 (m, 2 H), 3.82 (s, 6 H).
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1.[C:33]([NH:37][C:38](=[O:52])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:40]=1)([CH3:36])([CH3:35])[CH3:34].C(N(CC)CC)C>ClCCl>[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24]([N:49]2[CH2:48][CH2:47][N:46]([CH2:45][C:41]3[CH:40]=[C:39]([CH:44]=[CH:43][CH:42]=3)[C:38]([NH:37][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:52])[CH2:51][CH2:50]2)=[O:26])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(N)c(Cl)cc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (5.90 g, 9.2 mmol, 5.52 mL) was added dropwise to a solution of 4-ammo-5-chloro-2-ethoxy benzoic acid (1 g, 4.6 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (1.40 g, 5.1 mmol) and triethylamine (1.401 g, 13.8 mmol, 1.93 mL) in dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure and the residue was taken up in ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic phase was concentrated under vacuum to afford the title compound (2.08 g).
Reaction SMILES: [H-].[Na+].C1C=CC([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=CC=1.[Br-].[CH:30]12[CH2:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][CH2:32][C:31]2=O>CS(C)=O>[CH:30]12[CH2:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][CH2:32][C:31]2=[CH:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC2CCC1C2
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)CCCC=C1CCC2CCC1C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
A mixture of 3.92 g (93 mmol) of sodium hydride (57% oil dispersion) and 30 ml of dry dimethylsulfoxide was heated at 70-80° under nitrogen until gas evolution ceased (2.5 hr). The mixture was cooled, and 19.7 g (44.3 mmol) of 4-(carboxybutyl)triphenylphosphonium bromide (Aldrich # 15,794-5) was added, followed by 20 ml of dimethylsulfoxide. The resulting deep red mixture was stirred for 45 min at room temperature under nitrogen before a solution of 5.0 g (40.2 mmol) of bicyclo[3.2.1]octan-2-one (Aldrich #11,903-2) in 20 ml of dimethylsulfoxide was added dropwise over 1.75 hr. The resulting mixture was stirred for 16 hr at room temperature before it was quenched by the additon of 125 ml of water. The resulting solution was extracted with three 250 ml portions of ether/ethyl acetate-1:1 (V/V) to remove neutral by products. The remaining aqueous phase was acidified by the addition of 15 ml of concentrated hydrochloric acid and extracted with three 250 ml portions of ether-hexane-1:1 (V/V). These combined acidic ether-hexane extracts were dried (MgSO4), and evaporated in vacuo to yield 6.0 g of crude 5-(bicyclo[3.2.1]oct-2-ylidene)pentanoic acid as an oil. This oil was purified by chromato graphy on silica gel 60 (elution with CHCl3 containing 0.5% formic acid) to yield 4.1 g (49%) of pure material as a colorless oil.