Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC)(=O)[CH:2]=[CH:3][C:4]1C=CC=C[CH:5]=1.OOS([O-])=O.[K+].[O-]S([O-])=O.[Na+].[Na+].CC[O:27][C:28]([CH3:30])=[O:29]>CN(C=O)C.O=[Os](=O)(=O)=O>[C:28]([OH:27])(=[O:29])[C:30]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: COC(=O)C=Cc1ccccc1
Reactant: CCOC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])OO
Agent: O=S([O-])[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1
Reaction time: 0.08 h
Yield: 94 %

Procedure:
Methyl cinnamate (100 mg) was dissolved in DMF (5 mL), and OsO4 (0.076 mL, 2.5% in tBuOH) was added and stirred for 5 min. OXONE (1.52 g) was added in one portion and the reaction had a final volume (7 mL). The reaction was stirred at room temperature for 3 hours or until the solution becomes colorless. This usually marks the completion of the reaction which was verified by TLC or GC. Na2SO3 (600 mg) was added, to reduce the remaining Os(VIII), and stirred for an additional hour or until solution became dark brown/black. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (30 mL×3) and brine (30 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain the crude product. Benzoic acid was obtained in 94% yield without the need for further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([F:38])=[CH:31][C:30]=1[O:39][CH3:40]>>[F:38][C:32]1[C:33]([CH:35]([CH3:37])[CH3:36])=[CH:34][C:29]([C:20]2[CH:21]=[CH:22][C:23]([C:25]([F:27])([F:28])[F:26])=[CH:24][C:19]=2[CH2:18][N:8]2[C@@H:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:14][CH:13]=3)[CH2:11][O:10][C:9]2=[O:12])=[C:30]([O:39][CH3:40])[CH:31]=1
Reactant: Cc1ccc(C[C@H]2COC(=O)N2)cc1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Agent: [H-]
Agent: [Na+]
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)OC[C@@H]1Cc1ccc(C)cc1

Procedure:
(4S)-4-(4-methylbenzyl)-1,3-oxazolidin-2-one (Step B, 14 mg, 0.074 mmol) was treated with sodium hydride (60% in oil, 6.2 mg, 0.154 mmol) and 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl (Intermediate 10, 25 mg, 0.062 mmol) as described in Example 305 to afford (4S)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-(4-methylbenzyl)-1,3-oxazolidin-2-one as clear gum. LCMS=516.4 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.65-7.60 (m, 1H), 7.53 (s, 1H), 7.35-7.32 (m, 1H), 7.06-7.20 (m, 2H), 6.82-6.75 (m, 2H), 6.69 (d, J=11.7 Hz, 1H), 4.67 (d, J=15.8 Hz, 1H), 4.06 (d, J=15.8 Hz, 1H), 4.04-4.00 (m, 1H), 3.96-3.93 (m, 1H), 3.73 (s, 3H), 3.55-3.48 (m, 1H), 3.23-3.15 (m, 1H), 2.63 (dd, J=13.5, 3.6 Hz, 1H), 2.35 (d, J=13.5 Hz, 1H), 2.29 (s, 3H), 1.25-1.13 (m, 6H).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]2O[CH2:8]2)=[CH:5][CH:4]=1)=[CH2:2].NC(N)=S>CO>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C2CO2)cc1
Agent: NC(N)=S
Solvent: CO
Product: C=Cc1ccc(C=C)cc1
Reaction time: 72 h
Yield: 67.4 %

Procedure:
In a one-liter flask equipped with a stirrer and a thermometer was placed 300 ml of methanol. Thereto was added 100 g of 4-vinylstyrene oxide. With keeping the flask inside temperature at 5° to 10° C., 35 g of thiourea was added slowly. The mixture was stirred for 72 hours. After completion of the reaction, methanol was removed by distillation. The concentrate was water-washed to obtain 60 g of 4-vinylstyrene eipsulfide. In the proton NMR spectrum of the product, 4, 1, 1, 1, 1 and 2 protons were observed at δ values of 7.2 to 7.5, 6.65, 5.76, 5.20, 3.95 to 4.15 and 2.8 to 3.0, respectively.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[O:35][CH:36]([CH3:38])[CH3:37].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:3]1[N:4]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH:36]([CH3:37])[CH3:38])=[C:29]([F:28])[CH:30]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CC(C)Oc1ccc(B(O)O)cc1F
Reactant: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCc1nc(CC)n(-c2ccc(OC(C)C)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 60.3 %

Procedure:
To a suspension of 4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 3-fluoro-4-isopropoxyphenylboronic acid (0.55 g), triethylamine (0.97 mL), pyridine (0.57 mL) and molecular sieves 4 A (1 g) in dichloromethane (10 mL) was added copper(II) acetate (0.51 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.43 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][C@H:36]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[C:56]([Cl:58])[CH:55]=[CH:54][C:53]=2[F:59])=[CH:48][CH:47]=1)[CH2:37][C@:38]([CH2:43][OH:44])([CH3:42])[C:39]([OH:41])=[O:40].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:58][C:56]1[CH:55]=[CH:54][C:53]([F:59])=[C:52]([C:49]2[CH:48]=[CH:47][C:46]([CH2:45][C@@H:36]([NH:35][C:8]([C:6]3[O:5][N:4]=[C:3]([O:2][CH3:1])[CH:7]=3)=[O:10])[CH2:37][C@:38]([CH2:43][OH:44])([CH3:42])[C:39]([OH:41])=[O:40])=[CH:51][CH:50]=2)[CH:57]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)C(=O)O
Reactant: COc1cc(C(=O)O)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@](C)(CO)C(=O)O)on1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
3-Methoxyisoxazole-5-carboxylic acid (8 mg, 55 μmol) and HATU (20.8 mg, 55 μmol) were combined in DMF (0.2 mL) and allowed to stand at room temperature for 10 minutes. (2S,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (20 mg, 55 μmol) in DMF and DIPEA (28.6 μL, 164 μmol) were added, and the resulting mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure and the residue was dissolved in AcOH purified by preparative HPLC to yield the title compound (5.4 mg). MS m/z [M+H]+ calc'd for C24H24ClFN2O6, 491.13. found 491.2.
Reaction SMILES: [OH:1][CH:2]([CH:5]1[C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH:6]1[OH:22])[CH2:3][CH3:4].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[O:1]=[C:2]([CH:5]1[C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:8][CH2:7][C:6]1=[O:22])[CH2:3][CH3:4]
Reactant: CCC(O)C1C(O)CCC12CCN(C(=O)OC(C)(C)C)CC2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCC(=O)C1C(=O)CCC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
To a solution of tert-butyl 1-(1-hydroxyprop-1-yl)-2-hydroxy-8-azaspiro[4.5]decane-8-carboxylate (0.050 g, 0.16 mmol) from Step E in acetone (2 mL) at 0° C. was added 2.6M Jones reagent (0.122 mL, 0.32 mmol). The reaction was stirred at room temperature for 10 min and was then quenched with isopropanol. The mixture was diluted with water and extracted three times with methylene chloride. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to afford the title compound (0.033 g).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([C:34](=[O:36])[CH3:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][C:32]([C:34](=[O:36])[CH3:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(C(C)=O)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2cc(C(C)=O)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-acetyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:11][OH:12])=[C:4]([OH:10])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:16]Cl.[I-].[Na+].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[C:3]2[CH2:11][O:12][CH2:16][O:10][C:4]=2[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: ClCBr
Reactant: COc1ccc(F)c(CO)c1O
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(F)c2c1OCOC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the 6.1 g of 3-fluoro-2-hydroxymethyl-6-methoxyphenol in 90 ml of DMF there was added 3 g of sodium hydride (60% oily suspension) while cooling on ice, and the mixture was stirred at room temperature for 30 minutes. After adding 2.55 ml of bromochloromethane and 510 mg of sodium iodide to the reaction mixture, it was stirred at 80° C. for 6 hours under a hydrogen atmosphere. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (1.086 g).
Reaction SMILES: CS(C)=O.[H-].[Na+].[CH3:7][N:8]([CH3:21])[C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[C@H:11]([OH:20])[CH2:10]1.[F:22][C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1>Cl>[CH3:7][N:8]([CH3:21])[C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[C@H:11]([O:20][C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH2:10]1
Reactant: Fc1ccc(F)cc1
Reactant: CN(C)[C@@H]1CCc2ccccc2[C@H](O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)[C@@H]1CCc2ccccc2[C@H](Oc2ccc(F)cc2)C1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A mixture of 0.6 ml of dimethylsulfoxide and 60 mg of sodium hydride in the form of a 50% oil dispersion was heated at 60° C. for 25 minutes and was then cooled to 25° C. after which 205 mg of cis 7-dimethylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol were added thereto. After 15 minutes, 0.4 ml of p-difluorobenzene were added thereto and the mixture was heated at 90° C. for 63/4 hours and was then cooled to 20° C. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness to obtain 350 mg of raw product which was dissolved in 10 ml of N hydrochloric acid. The solution was washed with ether and made alkaline with sodium hydroxide solution. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness to obtain 270 mg of cis N,N-dimethyl-5-[4-fluorophenoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-amine in the form of an oil.
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:15][C:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[C:3]([O:8][CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=1
Reactant: Brc1cccnc1OC1CCOCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3cccnc3OC3CCOCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 3-bromo-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H19FN4O2, 366.15; m/z found, 367.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=1.5, 2H), 8.15 (dd, J=4.9, 1.9, 1H), 7.84 (dd, J=7.4, 1.9, 1H), 7.64-7.48 (m, 3H), 7.07 (dd, J=7.4, 4.9, 1H), 6.86 (s, 2H), 5.30 (m, 1H), 3.81-3.72 (m, 2H), 3.49 (m, 2H), 1.98 (m, 2H), 1.70-1.55 (m, 2H).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[O:10][CH:9]([CH3:26])[CH2:8]2)(=O)C>OS(O)(=O)=O.CO>[NH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]([C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)[O:10][CH:9]([CH3:26])[CH2:8]2
Reactant: COc1cc2c(cc1NC(C)=O)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COc1cc2c(cc1N)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Yield: 99.4 %

Procedure:
Solution of 14 (0.114 g, 0.32 mmol) in 5 ml of 4N H2SO4 and 5 ml of methanol was heated to reflux. After refluxing for 15 hours, the methanol was removed under reduced pressure. The remaining aqueous solution was neutralized with NaHCO3 to pH 9, followed by extraction with ethyl acetate three times. The combined organic phase was dried over Na2SO4. Removal of the solvent afforded the desired product 15 (100 mg, 100%) which was used directly for next step.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:20]([CH:22]2[CH:25](OC(=O)C)[N:24]([NH2:30])[C:23]2=[O:31])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32]1([OH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>C1C=CC=CC=1.C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:20]([C@@H:22]2[C@H:25]([O:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:24]([NH2:30])[C:23]2=[O:31])=[O:21])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC1C(C(=O)[C@H](Cc2ccccc2)NC(=O)CCc2ccccc2)C(=O)N1N
Reactant: Oc1ccccc1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: NN1C(=O)[C@H](C(=O)[C@H](Cc2ccccc2)NC(=O)CCc2ccccc2)[C@@H]1Oc1ccccc1
Yield: 24.3 %

Procedure:
A mixture of (3S,4S)-3-{(N-(3-phenylpropionoyl)-L-phenylalanyl}-amino-4-acetoxy-azetidin-2-one (212 mg, 0.5 mmol) obtained in example 10, phenol (41 mg, 0.45 mmol), and zinc acetate dihydrate (110 mg, 0.5 mmol) in a mixture of benzene (8 ml) and toluene (8 ml) was refluxed for 5.5 hrs using Dean-Stark water separator. The reaction mixture was purified by silica gel column chromatography using hexane-ethyl acetate (2:1) as eluent and the title compound (50 mg) was obtained as a white solid.
Reaction SMILES: [CH2:1]([Zn]CC)C.[CH3:6][C:7]1[O:12][CH2:11][N:10]([C:13]([CH3:21])([CH:15]([OH:20])[CH2:16][C:17]([CH3:19])=[CH2:18])[CH3:14])[C:9](=[O:22])[C:8]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ICI.Cl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>CCCCCC.ClCCl.CCOCC>[CH3:6][C:7]1[O:12][CH2:11][N:10]([C:13]([CH3:14])([C:15](=[O:20])[CH2:16][C:17]2([CH3:1])[CH2:19][CH2:18]2)[CH3:21])[C:9](=[O:22])[C:8]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=C(C)CC(O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Reactant: CC[Zn]CC
Agent: O=[Cr](=O)([O-])Cl
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: ICI
Solvent: CCCCCC
Solvent: ClCCl
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)CC2(C)CC2)CO1
Reaction time: 3 h

Procedure:
A solution of 1M diethyl zinc in n-hexane(1.4 ml) was added to a solution of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2,5-dimethyl-hex-5-en-3-ol (0.40 g) in dichloromethane at 20° C. Diiodomethane (0.13 ml) was then added and the mixture stirred and heated at reflux for 2 hours. Hydrochloric acid (1N) was added and the organic layer washed with brine, dried (magnesium sulphate), and evaporated to give crude 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-4-(1-methylcyclopropyl)-butan-3-ol. Powdered molecular sieve 4A (3 g) and pyridinium chlorochromate (0.6 g) were added to a stirred dichloromethane solution of the above compound at 20° C. After 3 hours, ether was added and the mixture filtered, evaporated and purified by silica gel column chromatography, eluting with n-hexane/ethyl acetate (3:1) to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-4-(1-methylcyclopropyl)butan-3-one (Compound 1066, 0.25 g), NMR: 1.33(4H), 1.08(s,3H), 1.42(s,6H), 1.92(s,3H), 2.47(s,2H), 5.26(s,2H), 7.20-7.40(5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:29]=[CH:28][C:11]([CH2:12][O:13][C:14]([C:24]([F:27])([F:26])[F:25])([C:20]([F:23])([F:22])[F:21])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]([C:20]([F:21])([F:22])[F:23])([C:24]([F:25])([F:26])[F:27])[C:15]([OH:17])=[O:16])=[CH:28][CH:29]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionate (3.3 g.), N aqueous sodium hydroxide (15 ml.) and ethanol (80 ml.) is stirred at ambient temperature for 18 hours, filtered, and the filtrate is evaporated in vacuo. An aqueous suspension of the residual solid is acidified with concentrated hydrochloric acid. The solid is filtered off, washed with water, dried and crystallised from cyclohexane to give 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionic acid, m.p. 130°-33° C. (2.5 g.)
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:34][C:33]2=[O:46])=[CH:28][C:27]=1[NH:47][CH3:48].[CH3:49][O:50][C:51]([CH:53]1[CH2:55][CH:54]1[C:56](O)=O)=[O:52].C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH2:39]([O:38][C:35]1[CH:36]=[CH:37][N:32]([C:29]2[CH:30]=[CH:31][C:26]3[N:25]=[C:56]([CH:54]4[CH2:55][CH:53]4[C:51]([O:50][CH3:49])=[O:52])[N:47]([CH3:48])[C:27]=3[CH:28]=2)[C:33](=[O:46])[CH:34]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COC(=O)C1CC1C(=O)O
Reactant: CNc1cc(-n2ccc(OCc3ccccc3)cc2=O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CC1c1nc2ccc(-n3ccc(OCc4ccccc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
HATU (4.97, g) was added to a solution of 1-(4-amino-3-(methylamino)phenyl)-4-(benzyloxy)pyridin-2(1H)-one (3.5 g), (1RS,2SR)-2-(methoxycarbonyl)cyclopropanecarboxylic acid (1.884 g) and N,N-diisopropylethylamine (3.80 ml) in DMF (70 ml) at room temperature. The mixture was stirred at room temperature for 1 h. To the resulting mixture was added water, and the resulting precipitate was collected by filtration and washed with water and IPA. The obtained solid was dissolved in AcOH (35 ml). The mixture was stirred at 80° C. for 1 h. After evaporation of the mixture, the residue was diluted with saturated NaHCO3 solution and EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was washed with IPE to give the title compound (2.9 g) as a pink solid.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[H][H]>C(O)C.[Pd]>[CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: [H][H]
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCN
Reaction time: 4 h

Procedure:
2 g of oleylamine in 120 ml of ethanol are hydrogenated at 30° C. under 8 bar of hydrogen in the presence of palladium-on-charcoal. After reacting for 4 h and evaporating the solvent, 1.6 g of product are obtained in the form of a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22](O)=[O:23])[C:17](=[O:25])[CH:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:15]=1)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.Cl.[NH2:44][C@H:45]([C:49]([NH:51][C@H:52]([C:56]([O:58][CH3:59])=[O:57])[CH:53]([CH3:55])[CH3:54])=[O:50])[CH:46]([CH3:48])[CH3:47].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(N(CC)CC)C>[CH3:59][O:58][C:56](=[O:57])[C@H:52]([CH:53]([CH3:54])[CH3:55])[NH:51][C:49](=[O:50])[C@H:45]([CH:46]([CH3:48])[CH3:47])[NH:44][C:22](=[O:23])[CH2:21][CH:18]1[CH2:19][CH2:20][C:14]([C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH3:13])=[CH:15][CH:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17]1=[O:25]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C
Reactant: C[C@H](NC(=O)OCc1ccccc1)C1=CC(Cc2ccccc2)C(=O)C(CC(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CC1CCC([C@H](C)NC(=O)OCc2ccccc2)=CC(Cc2ccccc2)C1=O)C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.9 %

Procedure:
To a stirred solution of the above acid (37) (1.0 g) in dimethylformamide (20 mL) was added hydroxybenzotriazole (0.62 g), HCl.Val-Val-OMe (0.67 g), triethylamine (1.93 mL) followed by Bop reagent (1.93 g). After stirring at room temperature for 16 h the reaction was evaporated to dryness and flash chromatographed on silica gel eluted with 60% ethyl acetate in n-hexane to give the titled product (38) (0.95 g, 57%). TLC Rf 0.48, 0.41 (60% ethyl acetate, n-hexane) Rf 0.40, 0.37 (97:3 CHCl3 :MeOH); MS DCI/NH3 (M+H)+ =648.5; 1H NMR (CDCl3) δ0.8-1.0(12H, m) Val γ(CH3)2 's, 1.12(3H, d, J=7 Hz) Ala CH3, 3.7(3H, s) CO2CH3, 5.1(2H, s) Cbz CH2, 5.4(1H, d) vinyl CH, 7.22(5H, s) phenyl, 7.46(5H, s) Cbz phenyl.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1)[C:2]([CH3:4])=O.C(=O)(O)O.[OH:23][CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[CH2:25][NH2:26].O>C1C=CC=CC=1>[Cl:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH:24]([OH:23])[CH2:25][NH:26][CH:2]([CH3:4])[CH2:1][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)COc1ccc(C2=NNC(=O)CC2)cc1
Agent: O=C(O)O
Solvent: c1ccccc1
Solvent: O
Product: CC(COc1ccc(C2=NNC(=O)CC2)cc1)NCC(O)c1cccc(Cl)c1
Reaction time: 18 h

Procedure:
A mixture of 4,5-dihydro-6-(4-acetonyloxyphenyl)3(2H)-pyridazinone (0.3 g) and 2-hydroxy-2-(3-chlorophenyl) ethanamine carbonate (0.26 g) in dry benzene (80 ml) was heated under reflux, with azeotropic removal of water, for 3 hr. The solvent was evaporated and the residue dissolved in methanol (80 ml) and treated with sodium cyanoborohydride (0.5 g). After 18 hr. the methanol was evaporated and the residue partitioned between ethylacetate and brine. The organic phase was washed with water, dried (MgSO4) and evaporated to a gum which was chromatographed on silica gel. Elution with methanol-chloroform (4:96) gave 6-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyloxy]-phenyl]-4,5-dihydro-3(2H)-pyridazinone as a white crystalline solid, m.p.t. 140°-158° C., as a 1:1 mixture of diastereoisomers.