Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:33]([F:36])([F:35])[F:34])[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[C:19]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CO.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:33]([F:35])([F:34])[F:36])[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH2:28][C:29]([F:31])([F:32])[F:30])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1CC(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1CC(F)(F)F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Into a 50-mL pressure tank reactor (10 atm), was placed ethyl 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(2,2,2-trifluoroethyl)benzoate (300 mg, 0.55 mmol, 1.00 equiv), methanol (5 mL), sodium hydroxide (600 mg, 15.00 mmol, 13.69 equiv), water (5 mL). The resulting solution was stirred overnight at 70° C. The pH value of the solution was adjusted to 5 with hydrogen chloride (3 mol/L). The resulting solution was extracted with 3×10 ml of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. This resulted in 200 mg (crude) of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(2,2,2-trifluoroethyl)benzoic acid as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl-].[NH4+].[O-:13][C:14]#[N:15].[K+]>O>[NH:1]1[C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[NH:15][C:14]1=[O:13]
Reactant: Nc1ncccc1C(=O)O
Reactant: N#C[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Product: O=c1[nH]c(=O)c2cccnc2[nH]1
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
A slurry of 2-aminonicotinic acid (10 g, 72.5 mmol), ammonium chloride (39 g, 725 mmol) and potassium cyanate (30 g, 362 mmol) in water (80 ml) was heated to 80° C. and maintained at this temperature with stirring for 30 minutes before being heated to 200° C. The mixture was stirred for 2 hours at this elevated temperature and then left to cool. Water (200 ml) was then added and the resultant mixture filtered. The solid was washed with hot water (100 ml) and then with cold water (2×100 ml) to give a yellow solid which corresponded to the title compound (11.79 g, 99%) in suitably clean form to be used without any further purification. m/z (LC-MSW, ESP):164 [M+H]+, R/T=2.11 mins.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]1=[O:13].C([O-])([O-])=O.[K+].[K+].[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26]Br>CC(C)=O>[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26][O:12][C:9]1[CH:10]=[CH:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)[C:7](=[O:13])[CH:8]=1
Reactant: O=c1cc(O)ccn1Cc1cccc(F)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1cc(OCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
To a solution of 1-(3-fluorobenzyl)-4-hydroxy-1H-pyridin-2-one (from Step 2 EXAMPLE 107) (0.92 g, 4.2 mmol) and K2CO3 (1.2 g, 8.4 mmol) in acetone (62 mL) was added 2,4-difluorobenzyl bromide (1.3 g, 6.3 mmol), and the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled room temperature, concentrated under reduced pressure, and the residue was partitioned between water and EtOAc. The organic solution was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent methylene chloride to 95:5 methylene chloride/methanol) to provide 4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one as a white solid (1.21 g, 84%): 1H NMR (300 MHz, CDCl3) δ 7.45-7.20 (m, 2H), 7.14 (d, J=8 Hz, 1H), 7.05-6.75 (m, 5H), 6.05 (d, J=3 Hz, 1H), 5.95 (dd, J=5, 3 Hz, 1H), 5.08 (s, 2H), 5.00 (s, 2H).
Reaction SMILES: [OH:1][CH:2]([CH2:17][OH:18])[CH2:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=O.OC1C=C2C(=CC=1)C(=O)CCC2.Cl.[O:32]([NH2:34])[CH3:33].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O1CCCC1.CO>[CH3:33][O:32][N:34]=[C:9]1[C:10]2[C:5](=[C:4]([CH2:3][CH:2]([OH:1])[CH2:17][OH:18])[C:13]([O:14][CH3:15])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: CON
Reactant: COc1ccc2c(c1CC(O)CO)CCCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CON=C1CCCc2c1ccc(OC)c2CC(O)CO
Temperature: 25 °C
Yield: 82 %

Procedure:
200 mg of 5-(2,3-dihydroxypropyl)-6-methoxy-1-tetralone synthesized from 6-hydroxy-1-tetralone according to the methods described in Example 7, (1)-(4), was dissolved in a mixed solution consisting of 5 ml of methanol and 3 ml of tetrahydrofuran. Thereafter, 401 mg of methoxylamine hydrochloride and 394 mg of sodium acetate were added to the reaction solution, and the obtained mixture was then stirred at room temperature. After completion of the reaction, a saturated sodium bicarbonate aqueous solution and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, so as to obtain 183 mg of 5-(2,3-dihydroxypropyl)-6-methoxy-3,4-dihydro-2H-naphthalen-1-one O-methyloxime. The subject compound was obtained from the thus obtained compound according to the method described in Example 1, (4).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](Cl)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:17]=1.N1C=CC=CC=1.O>ClCCl>[Cl:1][C:2]1[C:3]([C:12]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:17]=2)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1cc(N)ccn1
Reactant: O=C(Cl)c1nc2ccccc2nc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cc(NC(=O)c2nc3ccccc3nc2Cl)ccn1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
A solution of 3-chloroquinoxaline-2-carbonyl chloride (3.14 g, 13.83 mmol) in dichloromethane (30.19 mL) was added dropwise to a mixture of methyl 4-aminopyridine-2-carboxylate (2.10 g, 13.83 mmol), pyridine (3.36 mL, 41.49 mmol) and dichloromethane (43.49 mL) at 0° C. The mixture was stirred and allowed to warm up to room temperature for 2 hrs. To the reaction, water (100 mL) was added and a precipitate formed. The solid was isolated by filtration, washed with water (1×40 mL) and hexanes (2×50 mL), then with 10 ml EtOAc and 10 ml dichloromethane and dried to yield methyl 4-[(3-chloroquinoxaline-2-carbonyl)amino]pyridine-2-carboxylate (2.64 g, 55%) as a blue-colored solid (1.54 g). ESI-MS m/z calc. 342.05, found 343.2 (M+1)+; Retention time: 0.95 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.70 (d, J=5.4 Hz, 1H), 8.51 (d, J=2.1 Hz, 1H), 8.34-8.27 (m, 1H), 8.24-8.16 (m, 1H), 8.13-8.00 (m, 2H), 7.94 (dd, J=5.4, 2.2 Hz, 1H), 3.91 (s, 3H) ppm.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[C:7]1([N:13]=[C:14]=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCOCC1>[CH3:1][NH:2][C:3]([N:5]([CH3:6])[C:14]([NH:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15])=[O:4]
Reactant: CNC(=O)NC
Reactant: O=C=Nc1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)N(C)C(=O)Nc1ccccc1
Reaction time: 15 h
Yield: 60.3 %

Procedure:
In 50 ml of anhydrous dioxane, 3.5 g (0.04 mol) of 1,3-dimethyl urea was dissolved, and under stirring 4.8 g (0.04 mol) of phenylisocyanate was added thereinto. The reaction was carried out at a room temperature for 15 hours, then the reaction mixture was treated a procedure same as in Example 1. The residue thus obtained was recrystallized from ethanol-petroleum ether to obtain 5.0 g (yield 60%) of 1,3-dimethyl-5-phenylbiuret having a melting point of 93°-95° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:10]=[C:11](OB(O)O)[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:14]=[C:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccccn1
Reactant: OB(O)Oc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2ccccn2)c1

Procedure:
Under an inert gas atmosphere, 2-bromopyridine and 1.2 equivalents of 3-bromophenylboric acid were subjected to the Suzuki coupling (catalyst: tetrakis(triphenylphosphine)palladium(0), base: 2M sodium carbonate aqueous solution, solvent: ethanol, toluene), to obtain 2-(3′-bromophenyl)pyridine represented by the following formula:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=O)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].Cl.[NH2:28][OH:29].N1C=CC=CC=1>C(O)C.O>[C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[N:28][OH:29])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=O)=CC[C@@H]32)C1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=NO)=CC[C@@H]32)C1
Reaction time: 2 h
Yield: 83.4 %

Procedure:
56 Parts of 3β-acetoxy-5β-pregn-16-en-20-one is mixed with 315 parts of ethanol and heated to reflux to effect solution. Then, 11.6 parts of hydroxylamine hydrochloride, 14.7 parts of pyridine, 11.2 parts of water and 395 parts of ethanol is added and the refluxing continued for 2 hours. Distillation is initiated and continued until the pot volume is about 200 parts. The pot residue is then chilled to afford a precipitate that is washed first with 150 parts by volume chilled distillate and then with 200 parts of water. Further cooling of the mother liquor affords a second crop. The first and second crops are combined to give 3β-acetoxy-5β-pregn-16-en-20-one oxime, in a yield of 83.4%. This compound melts at about 180°-183° C. and is represented by the following structural formula. ##STR3##
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([CH2:17][O:18][Si](C(C)(C)C)(C)C)[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][O:13]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[O:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[O:11][CH:10]([CH2:9][OH:8])[CH2:17][OH:18]
Reactant: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)OC1CCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCC(CO)OC1CCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of 4.25 g (11 mmol) 1,3-O-di-(t-butyldimethylsilyl)-2-O-tetrahydrofuranylglycerol in 30 ml tetrahydrofuran was added 30 ml of tetra-n-butylammonium fluoride (1 mol/l in THF) dropwise and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was then concentrated and the residue was subjected to column chromatography (silica gel/methylene chloride-methanol) to provide 1.70 g (96%) of 2-O-tetrahydrofuranylglycerol.
Reaction SMILES: [NH2:1][C:2]([NH:4][N:5]([CH2:19][C:20]([O:22]C)=O)[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:3].C[O-].[Na+]>CO>[O:12]([C:9]1[CH:10]=[CH:11][C:6]([N:5]2[CH2:19][C:20](=[O:22])[NH:1][C:2](=[O:3])[NH:4]2)=[CH:7][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CN(NC(N)=O)c1ccc(Oc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CN(c2ccc(Oc3ccccc3)cc2)NC(=O)N1
Reaction time: 2 h
Yield: 18.7 %

Procedure:
To a solution of methyl [2-(aminocarbonyl)-1-(4-phenoxyphenyl)hydrazino]acetate (Intermediate 77, 550 mg, 0.0017 mol) in methanol (20 ml) was added sodium methoxide (184 mg, 0.0014 mol) and the mixture was stirred for 2 hours then poured into pH6 buffer (70 ml). This was extracted with ethyl acetate (75 ml), dried (MgSO4) and evaporated to give an off-white solid. This was triturated with ethyl acetate-ether and filtered to give the title compound as an off-white solid (90 mg, 19%) m.p. 211°-213° (dec).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20]CC4C=CC(Cl)=C(Cl)C=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1>CO.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(O)cc1)O2)NC(=O)OC(C)(C)C
Yield: 106.1 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester (310 mg), was subjected to hydrogenation using 10% Pd on carbon (150 mg) in methanol (20 mL), ethyl acetate (10 mL) and TEA (1 mL) as described in General Procedure Q furnished (S)-2-tert-butoxycarbonylamino-3-[(S)-2-(4-hydroxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-propionic acid methyl ester (240 mg). LCMS (m/z): 431.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[C:13](=[O:21])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:11]=2[C:33](=[O:36])[CH2:34][CH3:35])=[CH:6][CH:5]=1.[CH2:38]1COCC1>ClCCl>[C:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[C:13](=[O:21])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:11]=2[C:33](=[O:36])[CH2:34][CH3:35])=[CH:8][CH:9]=1)(=[O:2])[CH3:38]
Reactant: C1CCOC1
Reactant: CCC(=O)c1c(-c2ccc(C(=O)OC)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Solvent: ClCCl
Product: CCC(=O)c1c(-c2ccc(C(C)=O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
To a solution (2.0 ml) of 4-[6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-3-propionyl-1,2-dihydroisoquinolin-4-yl]benzoic acid methyl ester (100 mg) in THF was added dropwise gently a methyl lithium diethyl ether solution (1.1 mol/l, 0.25 ml) at −50° C. with stirring, and the mixture was allowed to warm to room temperature and stirred for 18 hrs. The reaction mixture was diluted with dichloromethane, washed with 1N hydrochloric acid, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (9 mg) in beige crystals. 1H NMR (CDCl3) δ: 0.54 (3H, t, J=7.2 Hz), 1.78 (2H, q, J=7.2 Hz), 2.67 (3H, s), 3.02 (3H, s), 5.35 (2H, s), 7.19 (1H, d, J=2.1 Hz), 7.37-7.47 (4H, m), 7.54 (1H, dd, J=2.1 Hz), 7.89 (2H, d, J=8.7 Hz), 8.06 (2H, d, J=8.7 Hz), 8.47 (1H, d, J=8.7 Hz). HPLC analysis: purity 97.7% (retention time: 4.29 min). MS (ESI+): 522.0 (M+H), 524.0.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:16][C@H:15]([CH2:17]O)[O:14][C:13]3=[O:19])=[CH:8][C:7]=2[F:20])[CH:5]=[CH:4][N:3]=[CH:2]1.ClC(Cl)(Cl)COC([NH:27][C:28]1[CH:32]=[CH:31][O:30][N:29]=1)=O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[O:30]1[CH:31]=[CH:32][C:28]([NH:27][CH2:17][C@@H:15]2[O:14][C:13](=[O:19])[N:12]([C:9]3[CH:10]=[CH:11][C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)=[C:7]([F:20])[CH:8]=3)[CH2:16]2)=[N:29]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(-n2ccnc2)c(F)c1
Reactant: O=C(Nc1ccon1)OCC(Cl)(Cl)Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C1O[C@@H](CNc2ccon2)CN1c1ccc(-n2ccnc2)c(F)c1
Reaction time: 18 h
Yield: 158.5 %

Procedure:
3-(4-Imidazol-1-yl-3-fluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one (693 mg, 2.5 mM, see WO 96-23788) and 3-(2,2,2-trichloroethyloxycarbonylamino)isoxazole (649 mg, 2.5 mM) were suspended by stirring in dry tetrahydrofuran (25 ml) under nitrogen in an ice-bath. Tributylphosphine (808 mg, 4 mM) was added followed by 1,1′-(azodicarbonyl)dipiperidine (945 mg, 3.75 nM) dissolved in tetrahydrofuran (10 ml) over 10 minutes. The mixture was then stirred 18 hours, allowing the temperature to rise to ambient, then filtered, and the filter cake washed with tetrahydrofuran. The combined filtrates were evaporated and the residue purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 5% methanol in dichloromethane. Relevant fractions were combined, evaporated, and the residue triturated with diethyl ether to give the desired product (1.36 g), contaminated with tributylphosphine oxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]3[C:19]([N:20]=2)=[C:18]2[N:21]([C:25]4[C:26]([CH3:31])=[N:27][N:28]([CH3:30])[CH:29]=4)[C:22](=[O:24])[NH:23][C:17]2=[CH:16][N:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].I[CH2:35][CH3:36]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]3[C:19]([N:20]=2)=[C:18]2[N:21]([C:25]4[C:26]([CH3:31])=[N:27][N:28]([CH3:30])[CH:29]=4)[C:22](=[O:24])[N:23]([CH2:35][CH3:36])[C:17]2=[CH:16][N:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCI
Reactant: COc1ccc(-c2ccc3ncc4[nH]c(=O)n(-c5cn(C)nc5C)c4c3n2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2cn(C)nc2C)c2c3nc(-c4ccc(OC)c(OC)c4)ccc3ncc21
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A mixture of 8-(3,4-dimethoxy-phenyl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one (Example 249, 50 mg, 0.120 mmol) and NaH 55% (8 mg, 0.183 mmol) in DMF was stirred at rt for 25 min. Then iodoethane (0.015 ml, 0.186 mmol) was added and the RM was stirred at rt for 5.5 h. After that, the RM was quenched with saturated aqueous NaHCO3, the suspension was then filtered, the cake was washed with water and dried in the vacuum oven to give the title compound as a white solid. (HPLC: tR 2.74 min (Method A); M+H=445 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.03 (s, 1H), 8.40-8.32 (m, 1H), 8.25-8.19 (m, 1H), 7.95 (s, 1H), 7.60-7.52 (m, 1H), 7.41-7.36 (m, 1H), 7.04-6.97 (m, 1H), 4.11 (q, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 1.94 (s, 3H), 1.37 (t, 3H))
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][CH2:7][CH:6]1[N:9]1[CH:13]=[C:12]([N+:14]([O-])=O)[N:11]=[CH:10]1)=[O:4].[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][CH:29]([CH2:33][CH2:34][CH3:35])[C:30](O)=[O:31])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1>>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][CH2:7][CH:6]1[N:9]1[CH:13]=[C:12]([NH:14][C:30](=[O:31])[CH:29]([NH:28][C:26](=[O:27])[CH2:25][C:20]2[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([F:17])[CH:19]=2)[CH2:33][CH2:34][CH3:35])[N:11]=[CH:10]1)=[O:4]
Reactant: COC(=O)C1CCC1n1cnc([N+](=O)[O-])c1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCC2C(=O)OC)cn1

Procedure:
2-(4-Nitro-imidazol-1-yl)-cyclobutanecarboxylic acid methyl ester was reduced and coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford the title compound; MS 463.1 m/z (M+1).
Reaction SMILES: O=[C:2]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17])[C:3]([OH:5])=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:29](=[O:33])([O:31][CH3:32])[NH2:30]>C1(C)C=CC=CC=1>[CH3:32][O:31][C:29]([NH:30][C:2]1[C:3](=[O:5])[O:4][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])[CH:6]=1)=[O:33]
Reactant: COC(N)=O
Reactant: COc1cccc(C=CC(=O)C(=O)O)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)NC1=CC(c2cccc(OC)c2OC)OC1=O
Temperature: 105 °C
Yield: 94 %

Procedure:
300 g of 2-keto-4-(2,3-dimethoxyphenyl)-3-butenoic acid, 2680 ml of toluene, 13.4 g of p-toluenesulfonic acid and 133.8 g of methyl carbamate are placed into a 6 l 4-necked round-bottomed flask in an oil-bath, the mixture is heated to 105° C. for 4 hours with stirring, and the present water is removed azeotropically, the mixture is filtered and the solution is evaporated to dryness under vacuum, then the residue is triturated for about 2 hours with 1260 ml of Et2O, filtered washing with petroleum ether (40-70° C.) and dried under vacuum at 60° C. 313.00 g are obtained. (Yield 94%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([NH:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[S:22][CH:23]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11].Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.CCCCCC>C(Cl)Cl.C(OCC)(=O)C>[CH3:28][C:25]1([CH3:29])[CH2:26][O:27][C:31](=[O:33])[N:24]1[C:21]1[S:22][CH:23]=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=2)[N:20]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(CO)Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: CC1(C)COC(=O)N1c1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 117.4 %

Procedure:
N,N-diisopropylethylamine (1.0 mL, 5.7 mmol) was added dropwise to a solution of 2-{[4-(4-nitrophenyl)-1,3-thiazol-2-yl]amino}-2-methylpropan-1-ol (0.7 g, 2.4 mmol), prepared in the previous step, in 20 mL of dry methylene chloride at 0° C., followed by triphosgene (0.8 g, 2.8 mmol) in 20 mL of dry dichloromethane. The orange solution was stirred at 0° C. for 3 h, and then allowed to warm to room temperature. TLC (3:1 hexane:ethyl acetate) indicated the reaction was complete. The reaction was washed with 2N HCl and the aqueous layer was extracted with methylene chloride. The combined organic layer was dried (anhydrous MgSO4), filtered and concentrated under reduced pressure to give 900 mg of a yellow solid. Purification of the solid on silica gel using a stepwise gradient of 6:1 to 5:1 hexane:ethyl acetate gave the title compound (268 mg, 35%), mp 176-179° C.