Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:11]1[CH2:24][C:25]#[CH:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:27]([Li])CCC.IC>C1COCC1>[CH2:24]([C@H:11]1[C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:14][C:13]([CH3:15])([CH3:16])[N:12]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:25]#[C:26][CH3:27]
Reactant: [Li]CCCC
Reactant: C#CC[C@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N1C(=O)OC(C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CC#CC[C@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 72.8 %

Procedure:
A solution of (4S,5S)-tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(prop-2-ynyl)oxazolidine-3-carboxylate (0.60 g, 1.6 mmol) in THF (5 mL) was cooled to −78° C. and butyllithium (0.75 mL, 1.9 mmol) was added dropwise. After 5 min, the mixture was re-cooled to −78° C. and iodomethane (0.15 mL, 2.3 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 h and brought to RT and stirred for 15 h. The reaction mixture was quenched with sat NH4Cl, filtered, concentrated, and chromatographed on silica gel eluting with hexanes to afford a light yellow oil as (4S,5S)-tert-butyl 4-(but-2-ynyl)-5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.463 g, 74% yield). MS m/z: 298 (M+1).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][OH:15])=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:26][S:23]([O:15][CH2:14][C:12]1[S:13][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[CH:10][N:11]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cnc(CO)s2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2cnc(COS(C)(=O)=O)s2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-yl]-methanol (500 mg, 2.48 mmol) in dry CH2Cl2 (15 mL) was treated at 0° C. with Et3N (0.45 mL, 3.21 mmol) followed by DMAP (31 mg, 0.25 mmol) and Ms-Cl (0.25 mL, 3.14 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (5-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-yl)methyl methanesulfonate as a brown oil. This material was dissolved in dry DMF (10 mL) and treated with NaN3 (175 mg, 2.66 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 2-(azidomethyl)-5-(2-methyl-[1,3]dioxolan-2-yl)-thiazole as a yellow oil. LC-MS-conditions 02: tR=0.86 min; [M+H]+=227.47.
Reaction SMILES: P(=[S:5])([O-])([O-])[O-].[Na+].[Na+].[Na+].Cl.[OH:10][N:11]=[C:12]1[CH2:17][CH2:16][N:15]([C:18](=[NH:21])[CH2:19][Cl:20])[CH2:14][CH2:13]1.Cl>O>[ClH:20].[OH:10][N:11]=[C:12]1[CH2:17][CH2:16][N:15]([C:18](=[NH:21])[CH2:19][SH:5])[CH2:14][CH2:13]1
Reactant: [O-]P([O-])([O-])=S
Reactant: N=C(CCl)N1CCC(=NO)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=C(CS)N1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
1.77 g of trisodium phosphorothioate were added to an ice-cooled solution of 2.1 g of 2-(4-hydroxyiminopiperidin-1-yl)-2-iminoethylchloride hydrochloride in 12 ml of water, the mixture was stirred at room temperature for about one hour, 9.8 ml of 1N hydrochloric acid were then added, and the mixture was heated at 65° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, the concentrate was mixed with 9.8 ml of methanol, and insolubles were filtered off. The filtrate was concentrated under reduced pressure, ether was added to the concentrate, and the crystals which separated out were collected by filtration and washed with ether, giving 1.8 g of 2-(4-hydroxyiminopiperidin-1-yl)-2-iminoethylmercaptan hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]3[O:21][CH2:20][CH2:19][C:18]=3[CH:22]=1)[C:6]([C:23]([OH:25])=[O:24])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CO.[H][H]>[C].[Pd].C1COCC1>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([CH2:13][N:7]3[C:6]([C:23]([OH:25])=[O:24])=[C:5]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:4]4[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=4)[C:8]3=[O:12])=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: [H][H]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(-c2ccccc2)c2ccccc2c(=O)n1Cc1ccc2c(c1)CCO2
Yield: 65.1 %

Procedure:
A mixture of 6-bromo-2-(2,3-dihydrobenzofuran-5-ylmethyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (350 mg), 10% palladium carbon (150 mg), methanol (5 ml) and THF (5 ml) was stirred at room temperature under 1 atm hydrogen pressure for 12 hrs. Palladium carbon was filtered off, and the filtrate was concentrated. The obtained crystals were washed with diethyl ether to give the title compound (190 mg).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18](F)=[O:19].[O:23]=[CH:24][C@@H:25]([C@H:27]([C@@H:29]([C@@H:31]([C:33]([OH:35])=[O:34])[OH:32])[OH:30])[OH:28])[OH:26].O.C(=O)(O)[O-].[Na+]>CC(C)=O.O>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([O:23][C@@H:24]1[O:32][C@H:31]([C:33]([OH:35])=[O:34])[C@@H:29]([OH:30])[C@H:27]([OH:28])[C@H:25]1[OH:26])=[O:19]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)F)C(C)(C)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O[C@@H]2O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]2O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Retinoyl fluoride can be mixed with commercially available glucuronic acid. The reaction is carried out in acetone/water to facilitate the solubility of the water-insoluble retinoyl fluoride and the water-soluble glucuronic acid. The reaction takes place in slightly alkaline pH and hence sodium bicarbonate is used in the reaction mixture. Stirring the mixture at room temperature for 20-24 hours followed by acidification of the solution and extraction with ethyl acetate yields retinoyl glucuronide as the major product. Pure all-trans retinoyl β-glucuronide can be obtained by a combination of column and high-performance liquid chromatography (HPLC).
Reaction SMILES: O=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:5]=2[N:4]=[CH:3]1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:5]2=[N:4][CH:3]=1
Reactant: COC(=O)c1cc2[nH]c(=O)cnc2s1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc2nc(Cl)cnc2s1
Yield: 78.5 %

Procedure:
A solution of methyl 2-oxo-1,2-dihydrothieno[3,2-b]pyrazine-6-carboxylate 21 (0.35 g, 1.665 mmol) in phosphorus oxychloride (10 mL, 107 mmol) was stirred at 105° C. for 5 h. Evaporated to dryness. Dissolved in EtOAc and washed with NaHCO3 solution, brine, dried and evaporated to give crude methyl 2-chlorothieno[3,2-b]pyrazine-6-carboxylate 22 (299 mg, 79%). NMR (400 MHz, CDCl3) 4.02 (s, 3H), 8.11 (s, 1H), 8.61 (s, 1H). (m/z)=229 and 231 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:15](N)(=O)C1C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([O:11][CH3:12])=[C:6]([C:7](=[O:9])[CH3:15])[CH:10]=1
Reactant: NC(=O)c1ccccc1
Reactant: COc1cc(Br)cc(C(=O)O)c1OC
Product: COc1cc(Br)cc(C(C)=O)c1OC

Procedure:
5-Bromo-2,3-dimethoxybenzoic acid (2 g) was converted to the benzamide derivative analogously to O3.043, and the latter to the title compound analogously to O2.059. 1.1 g of the title compound were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:3])[NH2:2].O1CCOCC1.C(=O)(O)[O-].[Na+].[C:27](=O)([O:33]C(C)(C)C)[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>O>[C:29]([O:28][C:27]([N:13]1[CH2:14][CH2:15][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:1](=[O:3])[NH2:2])[CH2:11][CH2:12]1)=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NC(=O)c1ccccc1N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
1-(2-Carbamoylphenyl)piperazine (300 mg, 1.5 mmol) was dissolved in water (2 ml) and 1,4-dioxane (2 ml) The resulting solution was mixed with sodium bicarbonate (250 mg, 2.9 mmol) and di-t-butyl carbonate (480 mg, 2.2 mmol), and then stirred at a room temperature for 4 hours. The reaction solution was mixed with water (20 ml), and the reaction product was extracted with chloroform (80 ml) and washed with water and saturated brine. Then the solvent was evaporated under a reduced pressure to obtain colorless crystals. Thereafter, the crystals were washed with hexane and then dried to obtain 430 mg of the title compound (1.4 mmol, 96% in yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2].Cl.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:36]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)=[O:43])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(CN)ccc1C(C)(C)C)c1cc(OC)c(OC)cc1OC
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: CCCCCC(CC(=O)Nc1cc(CNC(=O)c2ccncc2)ccc1C(C)(C)C)c1cc(OC)c(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 144, but using N-(2-t-butyl-5-aminomethylphenyl)-3-(2,4,5-trimethoxyphenyl)octanamide (prepared as described in Preparation 72B) and isonicotinoyl chloride hydrochloride, the title compound was obtained as a colorless foam-like substance.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[C:4]([CH:9]=[C:10]([O:12][CH2:13][CH:14]=[C:15]([Cl:17])[Cl:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30]O)=[N:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[C:3]([O:18][CH2:30][CH2:29][CH2:28][O:27][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:33])([F:19])[F:32])=[CH:26][N:25]=2)=[C:4]([CH:9]=[C:10]([O:12][CH2:13][CH:14]=[C:15]([Cl:16])[Cl:17])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1O
Reactant: OCCCOc1ccc(C(F)(F)F)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an atmosphere of protective gas, 1.85 g of methyl 3-chloro-5-(3,3-dichloroprop-2-enyloxy)-2-hydroxybenzoate, 1.3 g of 3-(5-trifluoromethylpyrid-2-yloxy)-propan-1-ol and 1.64 g of triphenylphosphine were dissolved in 50 ml of dry tetrahydrofuran (THF). With ice-bath cooling, 1.09 g of diethyl azodicarboxylate were added dropwise. After about 30 minutes, the ice-bath was removed, and the mixture was stirred at room temperature for 15 hours. The mixture was then concentrated under reduced pressure and the residue was taken up in a mixture of ethyl acetate and water. After shaking, the organic phase was isolated, dried and concentrated under reduced pressure. The crude product was purified chromatographically. Yield: 1.79 g (59%)
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][NH:6][C:5](=O)[C:4]=2[CH:3]=[CH:2]1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:5]1[C:4]2[CH:3]=[CH:2][S:1][C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2sccc12
Product: Clc1nccc2sccc12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
5H-Thieno[3,2-c]pyridin-4-one (1.0 g, 6.62 mmol) is dissolved in 30 mL of phosphorous oxy chloride. The solution is heated to 100° C. After 4 hours, the solution is concentrated. The residue is dissolved in CH2Cl2. The resulting solution is washed with water and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 40% CH2Cl2 /hexanes to 60% CH2Cl2 /hexanes. The title compound (1.0 g, 5.8 mmol) is obtained as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][CH2:5][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:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:36])[CH:26]=[CH:27][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:21]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: CCCCCC(N)c1ccccc1N1CCCCC1
Product: CCCCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared from 1-(2-piperidino-phenyl)-1-n-hexylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid analogous to Example 1.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)=O.Cl.[CH2:22]([O:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C.[Na+]>CO.O>[CH2:22]([O:29]/[N:30]=[CH:1]/[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NOCc1ccccc1
Reactant: O=Cc1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc(/C=N/OCc2ccccc2)cc1)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 8 mL sealed vial was mixed N-(4-formylphenyl)isoindoline-2-carboxamide (50 mg, 0.188 mmol) in methanol (1 ml). A solution of O-benzylhydroxylamine hydrochloride (45.0 mg, 0.282 mmol) and sodium acetate (46.0 mg, 0.338 mmol) in water (1.000 ml) was then added and the reaction was stirred overnight at room temperature. The reaction was diluted with water and the product was extracted with dichloromethane. The organic layer was washed with brine, dried with sodium sulfate, decanted, and concentrated. Purification by chromatography provided the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (s, 1H), 8.21 (s, 1H), 7.65 (m, 2H), 7.50 (m, 2H), 7.44-7.28 (m, 9H), 5.14 (s, 2H), 4.78 (bs, 4H); MS (ESI(+)) m/e 372 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH2:28]>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH:28][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCCc1ccccn1
Product: CCc1cc(-c2cncc(C(=O)NCCc3ccccn3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (2-pyridin-2-yl-ethyl)-amine to afford the title compound. MS: m/e=363 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=[N:3]1.O[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.O1CCCC1>[CH3:1][N:2]1[C:6]([CH2:7][CH2:8][O:9][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: Cn1nccc1CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1nccc1CCOc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.6 %

Procedure:
A mixture of 2-(1-methyl-1H-pyrazol-5-yl)ethanol (1.00 g), 4-hydroxybenzotrifluoride (2.57 g), 1.9 M diisopropyl azodicarboxylate (6.26 mL, toluene solution), triphenylphosphine (3.12 g) and tetrahydrofuran (50 mL) was stirred at a room temperature for 2 days. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with water, and was then dried over anhydrous sodium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=90:10 to 55:45), so as to obtain the title compound (1.17 g) in the form of a light yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].Cl[C:14]1[CH:24]=[C:18]2[N:19]([CH3:23])[CH2:20][CH2:21][CH2:22][N:17]2[C:16](=[O:25])[N:15]=1>>[CH3:23][N:19]1[CH2:20][CH2:21][CH2:22][N:17]2[C:16](=[O:25])[N:15]=[C:14]([O:12][CH2:11][CH2:10][C:4]3[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=3)[CH:24]=[C:18]12
Reactant: OCCc1cc(F)c(F)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCCc1cc(F)c(F)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from 2-(3,4,5-trifluorophenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([OH:16])=O)[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][CH:18]([P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([NH:17][CH:18]([P:19](=[O:26])([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])[P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:16])[N:10]=[CH:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1cnc(CC(=O)O)c1
Reactant: CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(NC(=O)Cc1cn(C(=O)OC(C)(C)C)cn1)P(=O)(OCC)OCC
Yield: 65.9 %

Procedure:
To a solution of 2-[1-(tert-butoxycarbonyl)imidazol-4-yl]acetic acid (45 mg) and tetraethyl (aminomethylene)bis(phosphonate) (91 mg) in N,N-dimethylformamide (1 ml) was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (42 mg) with stirring on ice-sodium chloride bath under nitrogen atmosphere. After stirring for 36 hours at 5° C., the mixture was diluted with chloroform (10 ml) and washed with cold 1N aqueous solution of citric acid (10 ml). The aqueous layer was extracted with chloroform (10 ml) twice and the combined organic layers were dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in ethyl acetate (10 ml) and the solution was washed with water (10 ml), dried over sodium sulfate and evaporated in vacuo to give a colorless syrup of tetraethyl [[2-{1-(tert-butoxycarbonyl)imidazol-4-yl}acetamido]methylene]bis(phosphonate) (67 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:10])[CH3:9].[Br-:20].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)(=O)C>[Br:20][CH2:9][C:8]([C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:3][C:2]=1[CH3:1])=[O:10]
Reactant: CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: Cc1cc(-c2ccc([N+](=O)[O-])cc2)ccc1C(=O)CBr
Temperature: 110 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
A mixture of 1-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone (5.66 g, 22 mmol), pyridinium tribromide (10.63 g, 33.0 mmol), and glacial acetic acid (60 mL) was stirred at 110° C. for 3 h. The reaction mixture was cooled to 0–5° C., and the precipitated product was collected by filtration and washed with small amounts of water, ethanol, and diethyl ether. The crude material was purified by flash chromatography (5:95 ethyl acetate/hexane) to give 2-bromo-1-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone as a light yellow solid (4.33 g, 59% yield). HPLC ret. time 3.63 min; 1H NMR (CDCl3) δ: 2.63 (s, 3H), 2.25 (s, 2H), 7.52–7.58 (m, 2H), 7.72–7.83 (m, 3H), 8.32 (d, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[C:11](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[C:11]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cn[nH]c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 115.1 %

Procedure:
0.78 g of ethyl pyrazole-4-carboxylate was dissolved in 15 ml of methylene chloride and 1.56 g of trityl chloride and 0.86 ml of triethylamine were added thereto and then the resulting mixture was stirred for 1.5 hours at room temperature. The reaction mixture was washed with 10% aqueous solution of citric acid and SSC and then dried with sodium sulfate. The solvent was distilled off to give 2.45 g of ethyl 1-tritylpyrazole-4-carboxylate as an oil.
Reaction SMILES: C[Mg]Br.[CH:4]([C:6]1[N:7]=[C:8]([CH2:53][CH2:54][CH3:55])[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:5].[C:56](OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[OH:5][CH:4]([C:6]1[N:7]=[C:8]([CH2:53][CH2:54][CH3:55])[N:9]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:32]=[N:31][N:30]=3)=[CH:21][CH:22]=2)[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:56]
Reactant: CCCc1nc(C=O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(C)=O
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1nc(C(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 3 h

Procedure:
4.0 ml of a 1M solution of methylmagnesium bromide in tetrahydrofuran were added dropwise at -10° C. to a solution of 1.2 g of ethyl 4-formyl-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] in 5 ml of tetrahydrofuran, and the resulting mixture was stirred at a temperature between -10° C. and 0° C. for 3 hours. At the end of this time, the reaction mixture was mixed with ethyl acetate and with an aqueous solution of ammonium chloride, and the mixture was stirred at room temperature for 20 minutes. The ethyl acetate layer was then separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using 1:4 and 1:2 by volume mixtures of ethyl acetate and methylene chloride as the eluent, to give 1.23 g of the title compound as a viscous oil.