Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[S:22](Cl)(=[O:24])=[O:23]>>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:23])=[O:24]
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(C)cc2OC)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-methoxy-4-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (2.3 mg) with purity >90%. LCMS (pos) m/z 371.2.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[CH3:11][C:12]([CH3:25])([CH3:24])[CH2:13][CH2:14][NH:15][C@H:16]([C:21](O)=[O:22])[CH2:17][C:18]([OH:20])=[O:19]>O1CCOCC1>[CH3:11][C:12]([CH3:25])([CH3:24])[CH2:13][CH2:14][N:15]1[C@@H:16]([CH2:17][C:18]([OH:20])=[O:19])[C:21](=[O:22])[O:4][C:3]1([C:5]([F:8])([F:7])[F:6])[C:2]([F:10])([F:9])[F:1]
Reactant: CC(C)(C)CCN[C@@H](CC(=O)O)C(=O)O
Reactant: O=C(C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: CC(C)(C)CCN1[C@@H](CC(=O)O)C(=O)OC1(C(F)(F)F)C(F)(F)F

Procedure:
A gas flow of hexafluoroacetone is blown at a moderate rate at room temperature onto an intensely stirred suspension of 10 mmol of N-(3,3-dimethylbutyl)-L-aspartic acid in 20 ml 1,4-dioxane. A clear solution is formed overnight. The solvent was removed in vacuo, and the oily residue was confirmed to be an almost quantitative amount of 2-[(4S)-3-(3,3-dimethylbutyl)-5-oxo-2,2-bis(trifluoromethyl)-1,3-oxazolan-4-yl]acetic acid by NMR.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11].S(Cl)([Cl:18])=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([Cl:18])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(-c2ccccn2)c1
Product: O=C(Cl)c1cccc(-c2ccccn2)c1

Procedure:
Thionyl chloride (10 mL) was added to 3-(pyridin-2-yl)benzoic acid (1.69 g, 8.5 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum to give 3-(pyridin-2-yl)benzoyl chloride. 1.66 g of crude product was obtained. To a solution of methyl 3-amino-2-hydroxybenzoate (0.84 g, 5 mmol) and pyridine (790 mg, 10 mmol) in toluene (50 mL) were added crude 3-(pyridin-2-yl)benzoyl chloride (1.6 g, 7.37 mmol) portion-wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain yellow solid of methyl 2-hydroxy-3-(3-(pyridin-2-yl)benzamido)benzoate (1.48 g, yield 85%). LC-MS (ESI) m/z: 349 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:10]([OH:12])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:33]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44]CC(C)C)[CH:39]=1)[CH:34]([CH3:36])[CH3:35]>C(Cl)Cl.C(Cl)(Cl)Cl.CN(C)C=O>[OH:44][C:40]1[CH:39]=[C:38]([O:37][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:43]=[CH:42][C:41]=1[C:10]([C:9]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH:8]=1)=[O:12]
Reactant: CCOC(=O)CCc1cc(C(=O)O)ccc1OCCC(C)C
Reactant: CC(C)COc1cccc(OCC(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1cc(C(=O)c2ccc(OCC(C)C)cc2O)ccc1OCCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
In 9 ml of methylene chloride is dissolved 0.90 g of 3-(3-ethoxy-3-oxopropyl)-4-isopentyloxybenzoic acid. At ambient temperature, 0.31 ml of oxalyl chloride and 20 μl of N,N-dimethylformamide are successively added and the mixture thus obtained is stirred at ambient temperature for one hour. Then, at 5-10° C., 0.78 g of aluminum chloride and 0.78 g of 1,3-diisobutoxybenzene are successively added. The mixture thus obtained is stirred first at the same temperature as above for 30 minutes and then at ambient temperature for 30 minutes. Further, 0.39 g of aluminum chloride is added at ambient temperature and stirred at the same temperature as above for 30 minutes. The reaction mixture is added to a mixture of chloroform and ice water and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=10:1) to obtain 0.67 g of ethyl 3-[5-(2-hydroxy-4-isobutoxybenzoyl)-2-isopentyloxyphenyl]propanoate as a light yellow oily product.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].O=[C:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]#[N:16].[Cl-].[Ca+2].[Cl-]>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10]1[CH2:14][CH2:13][CH2:12][C:11]=1[C:15]#[N:16]
Reactant: N#CC1CCCC1=O
Reactant: Nc1ccccc1F
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2ccccc2F)CCC1

Procedure:
2-Fluoro-aniline (Aldrich Chemicals) (2.3 g, 21 mmol), cyanoketone (Example 11) (2.2 g, 20 mmol), calcium chloride (2.5 g, 23 mmol) and T.H.F. (30 ml) were heated under reflux for 24 hours. After being allowed to cool, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (125° C. 0.05 mm Hg) have the product as an off-white power.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>CS(C)=O>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:22]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(Cl)ccc2[N+](=O)[O-])sc2ccccc12
Yield: 47 %

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate (4.0 g), 2,4-dichloronitrobenzene (3.8 g) and dimethyl sulfoxide (55 ml), ethyl 2-(5-chloro-2-nitroanilino)benzo[b]thiophene-3-carboxylate (3.2 g) was obtained.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].N(OC(C)(C)C)=O.N[C:16]1[S:17][C:18]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([Cl:26])[C:19]=2[N:20]=1.Cl>[Cu](Cl)Cl.C(#N)C>[Cl:26][C:21]1[C:19]2[N:20]=[C:16]([CH:3]=[CH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[S:17][C:18]=2[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: Nc1nc2c(Cl)cc(F)cc2s1
Reactant: C=CC(=O)OCC
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)C=Cc1nc2c(Cl)cc(F)cc2s1
Reaction time: 72 h

Procedure:
150 g (1.48 mol) of ethyl acrylate, 11.4 g (85 mmol) of copper (II) chloride and 11.4 g (0.11 mol) of tert-butyl nitrite were added to a solution of 12 g (59 mmol) of 2-amino-4-chloro-6-fluorobenzothiazole in 0.4 1 of acetonitrile. Stirring was carried out for 3 days, after which the mixture was acidified with dilute hydrochloric acid. The product was extracted with methyl tert-butyl ether, after which the extracts were dried over magnesium sulfate and finally evaporated down. Purification of the crude product was effected by means of column chromatography over silica gel (eluent: 19:1 cyclohexane/methyl tert-butyl ether). Yield: 9,0 g.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](P(=O)(OC)OC)[O:3]1.[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[C:21]=12.CCN(CC)CC>C1COCC1>[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=[C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2](=[O:1])[O:3]3)[C:21]=12
Reactant: COP(=O)(OC)C1OC(=O)c2ccccc21
Reactant: O=Cc1cccn2ccnc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OC(=Cc2cccn3ccnc23)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.5 %

Procedure:
To a solution of dimethyl 3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate (610 mg, 2.4 mmol), imidazo[1,2-a]pyridine-8-carbaldehyde (350 mg, 2.4 mmol, 1 equiv.) in THF (5 mL) was added Et3N (0.33 mL 2.4 mmol). The mixture was stirred at rt for 48 h. The precipitation was filtered off and washed with EtOAc. The filtrate was concentrated to give 3-(imidazo[1,2-a]pyridin-8-ylmethylene)isobenzofuran-1(3H)-one (400 mg, 64%) as a yellow solid. Small crude sample (˜20 mg) was purified on RP-HPLC with CH3CN and water as eluent to separated the E/Z isomers (10 mg, 7 mg). 1H NMR (400 MHz, CD3OD) Z-form: δ=8.52 (d, 1H), 7.95-7.91 (m, 2H), 7.62-7.54 (m, 4H), 7.52-7.48 (m, 1H), 7.09 (s, 1H), 7.04 (t, 1H) E-form: δ=8.38 (d, 1H), 8.15 (d, H), 8.05 (d, 1H), 7.95 (d, 1H), 7.90-7.84 (m, 2H), 7.67 (t, 1H), 7.64 (s, 1H), 7.33 (s, 1H), δ 7.05 (t, 1H). LRMS (M+H+) m/z 263.1
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[F:17][CH:18]([F:21])[CH2:19][OH:20].O>CN(C)C=O>[F:17][CH:18]([F:21])[CH2:19][O:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: OCC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1OCC(F)F
Temperature: 120 °C
Yield: 85 %

Procedure:
In a microwave tube a mixture of 1-fluoro-2-nitrobenzene (100 mg, 0.7 mmol), potassium carbonate (193 mg, 1.4 mmol), and 2,2-difluoroethanol in N,N-dimethylformamide (2 ml) was heated in a microwave oven at 120° C. for 20 minutes. For the workup, the reactrion mixture was poured into water (5 ml). The precipitated product was filtered and the aqueous layer was extracted with ether. The combined organic layers were dried and evaporated to yield together with the precipitated material 130 mg (85%) of the 1-(2,2-difluoro-ethoxy)-2-nitro-benzene which was sufficiently pure to be engaged in the next step without further purification; (calculated) C8H7F2NO3 [203.15]; (found) [M+H]+=204.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH2:12][C:13]#[N:14])[N:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:2]2[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH2:12][C:13]#[N:14])[N:3]=2)=[CH:18][CH:17]=1
Reactant: CCCc1cc(Cl)nc(SCC#N)n1
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1cc(NCc2ccc(Cl)cc2)nc(SCC#N)n1

Procedure:
A stirred suspension of 13.62 g. (0.06 mole) of (4-chloro-6-propyl-2-pyrimidinylthio)acetonitrile, 8.40 g. (0.06 mole) of p-chlorobenzylamine and 6.36 g. (0.06 mole) of sodium carbonate was heated under reflux in 150 ml of ethanol for five hours. The mixture was filtered and the filtrate was evaporated in a rotary evaportor. The residue was dissolved in ether (150 ml) and extracted with 150 ml of 10% concentrated hydrochloric acid solution. The ether layer was dried over magnesium sulfate, filtered and evaporated in a rotary evaporator. This residue was dissolved in benzene, diluted with a little heptane and was cooled in ice. The precipitate which formed was collected and recrystallized a second time from a benzene-heptane mixture to give 3.6 g. of product, m.p. 68°-70°.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([OH:10])=[C:5]([Cl:11])[CH:4]=1.[OH-].[K+].[Cl:14][C:15]([F:19])=[C:16]([F:18])[F:17].O>CN(C)C=O>[Cl:14][CH:15]([F:19])[C:16]([F:18])([F:17])[O:10][C:6]1[C:5]([Cl:11])=[CH:4][C:3]([NH2:2])=[C:8]([Cl:9])[CH:7]=1
Reactant: FC(F)=C(F)Cl
Reactant: Nc1cc(Cl)c(O)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Cl)c(OC(F)(F)C(F)Cl)cc1Cl
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
A solution of 25 g (0.12 mole) of 4-amino-2,5-dichlorophenol hydrochloride in 200 ml dimethylformamide was placed in a 500 ml 3-necked round bottom flask, fitted with a mechanical stirrer, thermometer, reflux condenser and sparger, and 13.4 g (0.24 mole) of potassium hydroxide pellets ground to powder were added. The mixture was heated to 90° C. with stirring under a nitrogen blanket. Then 21 g (0.18 mole) chlorotrifluoroethylene was bubbled in, while stirring and heating at 90° to 100° C., in about 1/2 hour. Stirring was continued for 5 minutes, the mixture cooled in an ice water bath, 500 ml of water were added and the resulting mixture extracted with 250 ml methylene dichloride and then 100 ml methylene dichloride. The extracts were combined, washed with 250 ml water and the methylene dichloride removed in a rotary evaporator. The residue was distilled through a 1"×10" Vigreaux. The cut from 110° to 120° C. at 2 mm pressure was a light tan liquid. Weight 21 grams. Yield was 59 percent. NMR analysis verified structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:40][C:35]3[C:36]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1
Reactant: Cc1ccccc1NN
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3cccc(F)c3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[C:12]([C:14](=[O:22])[CH2:15][C:16](=[O:21])[C:17]([O:19]C)=[O:18])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.C(Cl)(Cl)Cl>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[C:12]([C:14](=[O:22])[CH2:15][C:16](=[O:21])[C:17]([OH:19])=[O:18])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(=O)CC(=O)c1cc(Cc2ccccc2)ccc1Oc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(O)C(=O)CC(=O)c1cc(Cc2ccccc2)ccc1Oc1ccccn1

Procedure:
To a solution of methyl 4-[5-benzyl-2-(pyridin-2-yloxy)phenyl]-2,4-dioxo-butyrate (0.14 g) in THF (10 mL) at room temp., aq. NaOH (1 M, 0.44 mL) was added. The resultant mixture was stirred at room temp for 6 h. The product mixture was diluted with chloroform and partitioned with aq. HCl. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated with a mixture of diethyl ether and hexane. Filtration of the resultant solid provided the title acid. 1H NMR (CDCl3) δ8.25 (m, 1H), 7.8-6.8 (m, 12H), 4.05 (s, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]([CH2:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:18][C@@H:17]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[C:38]([C:43]([O:45]C(C)(C)C)=[O:44])[CH:37]=2)=[O:34])[C:16]1=[O:50])=[O:13])([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl>[CH3:42][C:39]1[CH:40]=[CH:41][C:36]([NH:35][C:33]([NH:32][C@H:17]2[C:16](=[O:50])[N:15]([CH2:14][C:12]([C:8]([CH3:11])([CH3:9])[CH3:10])=[O:13])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:18]2)=[O:34])=[CH:37][C:38]=1[C:43]([OH:45])=[O:44]
Reactant: Cc1ccc(NC(=O)N[C@@H]2CN(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)cc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)N[C@@H]2CN(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Trifluoroacetic acid (10 ml) was added to (R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonyl-4-methylphenyl)urea (1.9g) in methylene chloride (10 ml), the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, the mixed solvent (100 ml) of diisopropyl ether and ethanol (40:1) was added to the residue for crystallization, collected by filtrated, to thereby obtain 1.47 g of the title compound (Yield: 86%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([CH3:26])[O:19][C:18]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]3[CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.BrC[C:43]([NH:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=1)=[O:44].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O>[CH3:26][C:15]1([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([CH2:6][C:43]([NH:45][C:46]3[CH:47]=[CH:48][C:49]([C:52]([F:53])([F:54])[F:55])=[CH:50][CH:51]=3)=[O:44])[CH2:13][CH2:12]2)[O:19][C:18]2=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]2[CH2:16]1
Reactant: O=C(CBr)Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC1(CN2CCN(CC(=O)Nc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
A mixture of 2-(4-tert-butoxycarbonylpiperazin-1-yl)methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 306 (500 mg, 1.36 mmol) and trifluoroacetic acid (15 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (10 ml) and added triethylamine (2 ml, 14.35 mmol). The solution was concentrated under reduced pressure, and the residue was dissolved in DMF (10 ml). To the solution, 2-bromo-N-(4-trifluoromethylphenyl)acetamide (423 mg, 1.5 mmol), potassium carbonate (207 mg, 1.5 mmol), and sodium iodide (204 mg, 1.36 mmol) were added followed by stirring at room temperature for 5 hours. To the reaction mixture, water was added, and the solution was extracted with ethyl acetate twice. The organic phases were combined, washed with water three times and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford 2-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-N-(4-trifluoromethylphenyl)acetamide (389 mg, yield 61%) as a white powder.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:23])[C@H:11]([C@@H:20]([CH3:22])O)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([O:8][N:9]1[C@@H:20]([CH3:22])[C@H:11]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:10]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)NOCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCc1ccccc1
Yield: 114.4 %

Procedure:
A solution of 12.67 g of N-benzyloxy-t-butoxycarbonyl-threonine amide, 11.5 g of triphenylphosphine, and 6.23 ml of diethylazodicarboxylate in 380 ml of tetrahydrofuran was stirred under nitrogen for about 16 hours. The solution was evaporated and chromatographed on a 900 g silica gel column. Elution with chloroform-ethyl acetate (3:1) gave 13.69 g of compound that crystallized from ether-hexane to yield 9.18 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]([N+:25]([O-])=O)[C:14]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][C:16]=32)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]([NH2:25])[C:14]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][C:16]=32)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCNc1cc2c(cc1[N+](=O)[O-])C1CC2CN(C(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCCNc1cc2c(cc1N)C1CC2CN(C(=O)OC(C)(C)C)C1
Yield: 100.3 %

Procedure:
4-Butylamino-5-nitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (460 mg, 1.27 mmol) was treated with ammonium formate (850 mg, 12.7 mmol) and 10% Pd(OH)2/C (50 mg) in methanol (20 mL) and brought to reflux for 1 hour then filtered through a Celite pad and concentrated. The solids were treated with saturated aqueous Na2CO3 solution, extracted with CH2Cl2 (3×30 mL) and dried by filtration through a cotton plug to give an oil (440 mg, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH2:36][O:37][CH3:38])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:24][CH:25]=1.COCC(=O)CC(OC)=O.Cl.FC(F)(F)C1N=CC(C2C(C(N)=N)=CC=CC=2)=CC=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH2:36][O:37][CH3:38])=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)=[N:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Agent: COCC(=O)CC(=O)OC
Agent: Cl
Agent: N=C(N)c1ccccc1-c1ccc(C(F)(F)F)nc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2COC)cc1C

Procedure:
In analogy to the procedures described in example 101A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (prepared from methyl 4-methoxyacetoacetate and 6-(trifluoromethyl)pyridine-3-benzamidine hydrochloride, in analogy to the procedures described in examples 101C] to 101F]) to give 2-{4-[4-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 101B] to yield the title compound as off-white crystalls of mp. 120–121° C.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([CH3:14])[N:3]=1.[CH2:15]([NH2:20])[C:16]([CH3:19])([CH3:18])[CH3:17]>CN1C(=O)CCC1.CCOC(C)=O.O>[CH3:14][C:4]1[N:3]=[C:2]([NH:20][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=1
Reactant: CSc1ncc2cc(C)nc(Cl)c2n1
Reactant: CC(C)(C)CN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CSc1ncc2cc(C)nc(NCC(C)(C)C)c2n1
Temperature: 80 °C
Yield: 24.2 %

Procedure:
To a solution of 8-chloro-6-methyl-2-(methythio)pyrido[3,4-d]pyrimidine (Preparation 52, 128 mg, 0.567 mmol) in NMP (6 mL) was added neopentylamine (0.66 mL, 5.67 mmol). The reaction mixture was heated to 80° C. for 3 hours. The reaction mixture was diluted with EtOAc (30 mL) and water (30 mL), the organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-50% EtOAc in cyclohexane to give the title compound (38 mg, 24%).