Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]([CH3:21])([CH3:20])[C:16]([F:19])([F:18])[F:17])[CH:9]=1.CS(O[CH2:27][C@@H:28]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH3:29])(=O)=O.O>CN(C)C=O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:29][C@@H:28]([NH:30][C:31](=[O:32])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])[CH3:27])=[C:10]([C:15]([CH3:21])([CH3:20])[C:16]([F:17])([F:18])[F:19])[CH:9]=1
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: CC(C)(c1cc(Cl)ccc1O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](COc1ccc(Cl)cc1C(C)(C)C(F)(F)F)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Cesium carbonate (2.05 g, 6.28 mmol) was added to a solution of 4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenol (C48) (500 mg, 2.10 mmol) in N,N-dimethylformamide (5 mL). (2S)-2-[(tert-Butoxycarbonyl)amino]propyl methanesulfonate (P12) (0.53 g, 2.1 mmol) was added, and the reaction mixture was heated to 60° C. After 30 minutes, additional P12 (0.53 g, 2.1 mmol) was added, and heating was continued for 18 hours. Water (100 mL) was added, and the mixture was extracted with diethyl ether (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0% to 15% ethyl acetate in heptane) afforded the product as a colorless oil. Yield: 625 mg, 1.58 mmol, 75%.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.Br[CH:24]([CH:32]=O)[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C(=O)C>O>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][C:24]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][N:13]=1)=[CH:8]2
Reactant: CCOC(=O)CCC(Br)C=O
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCc1cnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (4.00 g), ethyl 4-bromo-5-oxopentanoate (3.80 g) and N,N-dimethylacetamide (25 mL) was stirred at 90° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (3.79 g, yield 70%) was obtained as yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:3, volume ratio). melting point 126-127° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][CH2:18][NH:19][C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21].Br[CH:26]1[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27]1>CC(C)=O>[CH:26]1[CH2:31][CH2:30][CH2:29][CH:28]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][CH2:18][NH:19][C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])[CH:27]=1
Reactant: BrC1C=CCCC1
Reactant: O=C(NCCc1c[nH]c2ccc(O)cc12)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(NCCc1c[nH]c2ccc(OC3C=CCCC3)cc12)C1CC1

Procedure:
1.98×10-2 mol of potassium carbonate, 1.33×10-2 mol of N-[2-(5-hydroxyindol-3-yl)ethyl]cyclopropylcarboxamide dissolved in 20 cm3 of anhydrous acetone, and 2.1×10-2 mol of 3-bromocyclohexene are introduced into a 50 cm3 flask with a ground neck. The mixture is heated under reflux for 22 hours. The reaction medium is filtered and the filtrate is evaporated under reduced pressure. Recrystallisation of the evaporation residue in ethyl acetate yields purified N-{2-[5-(cyclohexen-3-yloxy)indol-3-yl]ethyl}-cyclopropylcarboxamide.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]([CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:7]2=[O:20].CCN(C(C)C)C(C)C.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:9]1[N:8]([CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:7](=[O:20])[C:6]2[C:11](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)CCCn1c(=O)[nH]c2c(I)cccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCCn1c(Cl)nc2c(I)cccc2c1=O
Temperature: 120 °C

Procedure:
A pressure vessel was charged with 8-iodo-3-(3-(methylsulfonyl)propyl)-quinazoline-2,4(1H,3H)-dione (1.09 g, 2.67 mmol), DIEA (1.858 mL, 10.68 mmol) and phosphorus oxychloride (1.222 mL, 13.35 mmol). The tube was sealed and heated in an oil bath at 120° C. for 3 h, then cooled to RT. The solvent was removed in vacuo and the residue was poured into ice/water (50 mL) and 1 M NaOH was added until pH 10. The suspension was filtered and the solid was dried to give the crude product. MS (ESI, pos. ion) m/z: 426.8 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[Cl:15][C:16]1[CH:17]=[C:18]([S:23]([CH2:25][CH2:26][CH2:27][CH2:28]Br)=[O:24])[CH:19]=[CH:20][C:21]=1[Cl:22].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:15][C:16]1[CH:17]=[C:18]([S:23]([CH2:25][CH2:26][CH2:27][CH2:28][O:1][C:2]2[CH:3]=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=3[CH:14]=2)=[O:24])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: O=S(CCCCBr)c1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)Nc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 1.9 gm (0.01 mol) of 6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4.1 gm (0.0125 mol) of 4-(3,4-dichlorophenyl-sulfinyl)-butylbromide (m.p.: 63°-64° C.) in 40 ml of dimethylsulfoxide is mixed with 3.5 gm (0.025 mol) of potassium carbonate, and the mixture is stirred for three hours at 40° C. After cooling, copious amounts of ice water are added, and the mixture is extracted with chloroform. The extract is washed with water and dried with sodium sulfate, and the chloroform is distilled off. The residue is recrystallized from isopropanol/diisopropylether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:12][CH2:13][C:14]#[CH:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH:4]([N:12]([C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:25]=1[Cl:24])[CH2:13][C:14]#[CH:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: C#CCNC(Cc1ccccc1)C(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN(C(=O)c1ccc(Cl)cc1Cl)C(Cc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-Phenyl-2-prop-2-ynylamino-propionic acid methyl ester (75 mg, 0.346 mmol) in anhydrous CH2Cl2 (2 mL) was cooled to 0° C. in an ice bath, then triethylamine (0.1 mL) and 2,4-dichlorobenzoyl chloride (0.06 mL, 0.45 mmol) were added. The mixture was stirred at room temperature for 3 h. Excess of benzoyl chloride was quenched by adding ice-cold water and then the reaction mixture was partitioned between water and CH2Cl2. The organic layer was separated, dried (Na2SO4), and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 2-[(2,4-Dichloro-benzoyl)-prop-2-ynyl-amino]-3-phenyl-propionic acid methyl ester as a syrup, 125 mg (93%).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:27]3[O:26][CH2:25][O:24][CH2:23][C:22]=3[CH:21]=[C:20]([F:28])[CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[F:28][C:20]1[CH:19]=[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])[C:27]2[O:26][CH2:25][O:24][CH2:23][C:22]=2[CH:21]=1
Reactant: CCOC(=O)C1(NC(=O)c2cc(F)cc3c2OCOC3)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cc(F)cc2c1OCOC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
The mixture of 2-[(6-fluoro-4H-benzo[1,3]dioxine-8-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (61) (560 mg, 1.45 mmol) and KOH (1 g, 17.9 mmol) is dissolved in EtOH (10 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more precipitate came out of the water. After the filtration, the solid is purified by HPLC to give a pure product (62) as white solid (520 mg, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([C:22]([F:25])([F:24])[F:23])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:21][C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[C:17]([C:22]([F:25])([F:23])[F:24])=[CH:18][CH:19]=1
Reactant: C#CCCc1nc2c(C(F)(F)F)ccc(F)c2o1
Reactant: Brc1ccccn1
Product: Fc1ccc(C(F)(F)F)c2nc(CCC#Cc3ccccn3)oc12
Yield: 14.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (49 mg, 0.31 mmol) and 2-(but-3-ynyl)-7-fluoro-4-(trifluoromethyl)-benzo[d]oxazole (80 mg, 0.31 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5) to yield 15 mg (44 μmol, 14%) of 7-fluoro-4-(trifluoromethyl)-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH:14]=1.C(NCC)C.CCCCCC.C([OH:35])C>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:10][CH2:11][NH:12][CH2:13][C@@H:14]1[OH:35]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2Cl)CC1
Solvent: CCCCCC
Solvent: CCNCC
Product: O[C@H]1CNCC[C@@H]1c1ccc(F)cc1Cl

Procedure:
3.62 g of the entitled compound was obtained as a pale orange solid from the latter fraction (retention time: 14.8 min) in the same method as in Production Example 25-3, for which, however, tert-butyl 4-(2-chloro-4-fluorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate was used in place of tert-butyl 4-(2-chlorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate used in Production Example 25-3, and an optically-active column (Daicel's CHRALPAK AD column, 2 cm×25 cm; 0.1% diethylamine, hexane/ethanol=9/1; flow rate, 20 mL/min) was sued for the optical resolution.
Reaction SMILES: [O:1]=[C:2]1[C:9]2[C:8]([C:10]([OH:12])=O)=[CH:7][O:6][C:5]=2[CH2:4][CH2:3]1.[CH2:13]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH3:14]>>[CH2:13]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:10]([C:8]2[C:9]3[C:2](=[O:1])[CH2:3][CH2:4][C:5]=3[O:6][CH:7]=2)=[O:12])=[CH:18][CH:17]=1)[CH3:14]
Reactant: CCOc1ccc(N)cc1
Reactant: O=C(O)c1coc2c1C(=O)CC2
Product: CCOc1ccc(NC(=O)c2coc3c2C(=O)CC3)cc1

Procedure:
Starting from 4-oxo-5,6-dihydro-4H cylopenta[b]furan-3-carboxylic acid and 4-ethoxyaniline, General Procedure B provided the title compound:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:14]1[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=1.CS(O)(=O)=O>O1CCOCC1.C(OCC)(=O)C>[I:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([NH:1][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: COC(=O)c1cc(N)cc(I)c1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cc(I)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 100 °C
Yield: 70.2 %

Procedure:
To a flask containing methyl 3-amino-5-iodobenzoate (500 mg, 1.81 mmol) was added a solution of 2-chloro-4-(trifluoromethyl)pyrimidine (379 mg, 2.08 mmol) in dioxane (5.6 mL). Methanesulfonic acid (199 mg, 2.08 mmol) was added and the reaction was heated at 100° C. overnight. The reaction was cooled, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield methyl 3-iodo-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}benzoate (538 mg, 1.27 mmol, 71% yield). MS ESI: [M+H]+ m/z 424.0.
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])C.[CH2:11]([SH:15])[CH2:12][CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:11]([S:15][CH:4]=[C:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])[CH2:12][CH2:13][CH3:14]
Reactant: CN(C)C=C1CCOC1=O
Reactant: CCCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCSC=C1CCOC1=O

Procedure:
A mixture of γ-butyrolactone (1 mol) and tris(dimethylamino)methane (1.5 mol) is stirred under dry nitrogen at 75° C. for 2 days to give 3-[(dimethylamino)methylene]dihydro-2(3H)-furanone. A solution containing 3-[(dimethylamino)methylene]dihydro-2(3H)-furanone (1 mol), n-butanethiol (1.1 mol) and para-toluenesulfonic acid (1 mol) in benzene is heated at reflux overnight to give upon aqueous work-up 3-[(butylthio)methylene]dihydro-2(3H)-furanone. After a solution of 3-[(butylthio)methylene]dihydro-2(3H)-furanone (1 mol) in anhydrous diethyl ether is added to a solution of lithium di-n-butylcuprate (1.1 mol) in diethyl ether at -78° C., the resulting mixture is stirred at -78° C. for an additional 0.5 hours and then quenched with methanol. Work-up affords 3-ethylidenedihydro-2(3H)-furanone. Freshly prepared W-2 Raney nickel (about 3 parts) is deactivated by refluxing in benzene for 1 hour, whereupon 3-ethylidenedihydro-2(3H)-furanone is added and the mixture is heated at reflux under nitrogen for 24-48 hours; the reaction is monitored by thin layer chromatography. After complete washing of the Raney nickel with hot benzene, the title compound is obtained.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([N:6]1[CH2:17][CH2:16][CH2:15][C@H:7]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5])[CH3:3].[H][H].C(Cl)(Cl)Cl.CO>CO.[Pd]>[NH2:1][C@H:2]([C:4]([N:6]1[CH2:17][CH2:16][CH2:15][C@H:7]1[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[O:5])[CH3:3]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
9.36 g of Z-Ala-Pro-OtBu are hydrogenated in 100 ml of methanol in the presence of 500 mg of Pd on charcoal (10%) at room temperature. The hydrogen uptake has ended after 90 minutes. The solution is freed of catalyst by filtration and evaporated in a waterpump vacuum at 30° C. to give an oil. This proves to be homogeneous in a thin layer chromatogram on silica gel. Rf = 0.35 in the system chloroform-methanol (1:1).
Reaction SMILES: [CH3:1][CH:2]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:3][CH2:4][C:5]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH2:14][C:13](=[O:15])[C:12]2[C:7](=[C:8]([CH3:19])[C:9]([CH3:18])=[C:10]([OH:17])[C:11]=2[CH3:16])[O:6]1.[C:37](OC(=O)C)(=[O:39])[CH3:38].N1C=CC=CC=1>C1C=CC=CC=1>[C:37]([O:17][C:10]1[C:11]([CH3:16])=[C:12]2[C:7](=[C:8]([CH3:19])[C:9]=1[CH3:18])[O:6][C:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)[CH2:14][C:13]2=[O:15])(=[O:39])[CH3:38]
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(CCC(C)CCCC(C)C)(COc1ccc([N+](=O)[O-])cc1)O2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(CCC(C)CCCC(C)C)(COc1ccc([N+](=O)[O-])cc1)O2

Procedure:
Following the same procedure as described in Preparation 16, 1.8 g of 2-(3,7-dimethyloctyl)-6-hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one (prepared as described in Preparation 30), 0.5 g of acetic anhydride, 5 ml of pyridine and 10 ml of benzene were reacted, to give the title compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:12])[CH2:10][Cl:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13](O)[CH2:14][OH:15]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[OH:1][N:2]=[C:3]([C:9]1([O:15][CH2:14][CH2:13][O:12]1)[CH2:10][Cl:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: OCCO
Reactant: CCOC(=O)C(=NO)C(=O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C(=NO)C1(CCl)OCCO1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
A mixture of ethyl 2-hydroxyimino-3-oxo-4-chlorobutyrate (syn isomer, 10 g), ethylene glycol (16 g), p-toluenesulfonic acid (0.3 g) and dried benzene (100 ml) was heated for 19 hours under reflux while removing water azeotropically. After the reaction mixture was cooled to ambient temperature, water (30 ml) and benzene (20 ml) were added thereto. The mixture was saturated with sodium chloride and the benzene layer was separated, and the remaining aqueous layer was further extracted with benzene (20 ml). The benzene layer and extract were combined together, washed with a saturated aqueous solution of sodium chloride (30 ml×2), dried over magnesium sulfate and then filtered. The filtrate was evaporated to give an oil of ethyl 2-hydroxyimino-3,3-ethylenedioxy-4-chlorobutyrate (syn isomer, 7.23 g). (Yield: 58.9%).
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:7](=[O:21])[C:6]([C:22]([OH:24])=O)=[CH:5]1)([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[CH3:54][C:55]1[O:59][C:58]([CH2:60][NH2:61])=[N:57][N:56]=1>CN(C=O)C>[CH3:54][C:55]1[O:59][C:58]([CH2:60][NH:61][C:22]([C:6]2[C:7](=[O:21])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[C:9]([CH3:10])[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:24])=[N:57][N:56]=1
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1C(C)C
Reactant: Cc1nnc(CN)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nnc(CNC(=O)c2cn(C(C)C)c(C)c(-c3cccc(C(F)(F)F)c3)c2=O)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid (preparation 3, 65 mg, 0.192 mmol), TBTU (75 mg, 0.232 mmol), N-methylmorpholine (42 μL, 0.383 mmol) in DMF (1 mL) is stirred for 15 min at room temperature. C-(5-Methyl-[1,3,4]oxadiazol-2-yl)-methylamine (24 mg, 0.211 mmol) is added and the reaction mixture is stirred for 18 h at room temperature. The reaction mixture is purified by preparative reversed-phase HPLC (Sunfire, gradient of acetonitrile in water, 0.1% TFA, 60° C.). Yield: 6 mg (7% of theory); ESI mass spectrum: [M+H]+=435; Retention time HPLC: 0.86 min (Z018_S04).
Reaction SMILES: [H-].[Na+].[CH2:3]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])P(=O)(OCC)OCC.[CH:20]([C@@:22]1([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:26][CH2:25][C@H:24]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:29][CH:28]=2)[CH2:23]1)=O>C1COCC1>[CH2:17]([O:16][P:12](/[CH:3]=[CH:20]/[C@@:22]1([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:26][CH2:25][C@H:24]([C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:31][CH:32]=2)[CH2:23]1)([O:13][CH2:14][CH3:15])=[O:19])[CH3:18]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CCCCCCCCc1ccc([C@H]2CC[C@@](C=O)(NC(=O)OC(C)(C)C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc([C@H]2CC[C@@](/C=C/P(=O)(OCC)OCC)(NC(=O)OC(C)(C)C)C2)cc1
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
Sodium hydride (0.020 g, 0.498 mmol) (Aldrich) was stirred in THF (3.32 ml) under nitrogen to give a colorless suspension. Tetraethyl methylenediphosphonate (0.124 ml, 0.498 mmol) (ALDRICH) was added and the reaction stirred for about 30 min. Tert-butyl (1R,3S)-1-formyl-3-(4-octylphenyl)cyclopentylcarbamate (0.2 g, 0.498 mmol) was added in small portions and the reaction stirred for about 16 h. Solvents were removed under reduced pressure. Ethyl acetate (50 mL) and water (10 mL) were added and the layers separated and extracted with ethyl acetate (2×10 mL). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated to a yellow oil. The residue was purified by flash column chromatography (40 g Redi-Sep) eluting with ethyl acetate/heptane and the product fractions combined. The solvent was removed under reduced pressure to provide tert-butyl (1R,3S)-1-((E)-2-(diethoxyphosphoryl)vinyl)-3-(4-octylphenyl)cyclopentylcarbamate (0.237 g, 0.442 mmol, 89% yield) as an orange oil: LC/MS (method f) Rt=3.12 min.; MS m/z: 553.42 (M+H2O)+.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([S:10][CH3:11])=[N:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCOC(C)=O>[CH3:15][O:14][C:12]([C:3]1[N:4]=[C:5]([S:10][CH3:11])[N:6]([CH3:9])[C:7](=[O:8])[C:2]=1[O:1][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:13]
Reactant: COC(=O)c1nc(SC)n(C)c(=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(SC)n(C)c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 84 h
Yield: 18.7 %

Procedure:
In a round-bottomed flask, methyl 5-hydroxy-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (55.0 g, 239 mmol) and potassium carbonate (33.0 g, 239 mmol) were combined with DMF (200 ml) to give a black suspension. Benzyl bromide (40.9 g, 239 mmol) was added and the resulting mixture was stirred at room temperature for 3.5 days. The reaction was quenched by the addition of cold water. The mixture was filtered to provide a brown solid. Chromatography (SiO2; 10% to 50% EtOAc in hexanes) provided the desired product as an off-white solid (14.3 g; 18%). LCMS: m/z=321 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([CH:8]1[CH2:10][CH2:9]1)=[O:7])[CH3:2].[N:12]1[CH:17]=[C:16]([C:18](Cl)=[O:19])[CH:15]=[N:14][CH:13]=1>>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([C:6]([CH:8]1[CH2:10][CH2:9]1)=[O:7])[C:18](=[O:19])[C:16]1[CH:17]=[N:12][CH:13]=[N:14][CH:15]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)C1CC1
Reactant: O=C(Cl)c1cncnc1
Product: CCOC(=O)C(C(=O)c1cncnc1)C(=O)C1CC1
Yield: 40 %

Procedure:
In analogy to the procedure described in Example 162A], 3-cyclopropyl-3-oxo-propionic acid ethyl ester and pyrimidine-5-carbonyl chloride gave the title compound as a yellow oil (40%). MS: 261.3 (M−H−).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-n2cnc3ccccc32)c1
Agent: [Ni]
Product: Nc1cccc(-n2cnc3ccccc32)c1
Yield: 71 %

Procedure:
Reduction of 1-(3-nitrophenyl)benzimidazole (prepared by the method of M. A. Khan and J. B. Polya, J. Chem. Soc. (C), 1970: 85-91) with Raney nickel as for Example 8, followed by chromatography on silica gel, eluting with EtOAc, gave Example 3 (71%) mp (EtOAc/hexane) 93-95° C.