Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([CH2:13]/[CH:14]=[CH:15]/[CH2:16][C:17](O)=[O:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[C:7]1([CH2:13]/[CH:14]=[CH:15]/[CH2:16][CH2:17][OH:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)C/C=C/Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC/C=C/Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To stirred solution of LAH(LiAlH4, 3.3 g, 86.73 mmol) in THF(66 mL) was added dropwise a solution (E)-5-phenylpent-3-enoic acid (Preparation example 235, 11.0 g, 57.82 mmol) in THF(44 mL) at 0° C. then stirred at room temperature for 1 h. The reaction mixture was quenched with H2O at 0° C., filtered through celite, washed with EtOAc, dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (7.2 g, 70˜90%)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([OH:35])=O)=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:36][C@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]4)=[O:35])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[C:16]=23)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COc1cc(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Product: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c7) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:48])[CH2:30][CH2:31][N:32]([C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1)[C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:28][N:29]([CH3:48])[CH2:30][CH2:31][N:32]([C:41]1[CH:42]=[CH:43][C:44]([NH:45]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:46][CH:47]=1)[C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CN(C)CCN(C(=O)c1ccccc1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)C(=O)c2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-benzoyl-amino)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C34H32N4O4
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCOCC.[Li+].[Cl-].[CH2:16]([O:18][C:19]([C:21]1([CH3:49])[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([C:33]3[CH:34]=[C:35](Br)[C:36]4[S:40][C:39]([NH:41][C:42]([NH:44][CH2:45][CH3:46])=[O:43])=[N:38][C:37]=4[CH:47]=3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17]>[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C1COCC1>[CH:1]1([C:35]2[C:36]3[S:40][C:39]([NH:41][C:42](=[O:43])[NH:44][CH2:45][CH3:46])=[N:38][C:37]=3[CH:47]=[C:33]([C:30]3[CH:29]=[N:28][C:27]([N:24]4[CH2:25][CH2:26][C:21]([CH3:49])([C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH2:22][CH2:23]4)=[N:32][CH:31]=3)[CH:34]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C3CCCCC3)c2s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Cyclohexylmagnesium chloride in Et2O (2.03 mL, 3.65 mmol) was added to a THF (2.5 mL) solution of LiCl (53 mg, 1.25 mmol) and 1M zinc chloride in Et2O (4.38 mL, 4.38 mmol) at rt, after which a grey precipitate immediately formed. After stirring at rt for 15 mins, a THF solution (3 mL) of 1-{5-[7-Bromo-2-(3-ethyl-ureido)-benzothiazol-5-yl]-pyrimidin-2-yl}-4-methyl-piperidine-4-carboxylic acid ethyl ester (100 mg, 182.66 mmol) and Pd(dppf)Cl2.DCM (10 mol %) and was allowed to stir at rt for 30 mins. Subsequent heating at reflux gave minimal formation of the desired product and an equimolar amount of the hydrodebrominated starting material. The reaction mixture was transferred to a microwave vessel and heated at 110° C. for 30 mins. The reaction mixture was quenched with 1M HCl (1×5 mL), extracted with EtOAc (10 mL), dried (MgSO4), concentrated in vacuo and subjected to reverse phase HPLC (60-80% water (0.1% FA):MeOH) to afford 2.7 mg (3% isolated yield) of a white solid.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][Cl:29])=[CH:23][CH:22]=2)[C:12]([NH2:19])=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16]>>[Cl:8][C:9]1[C:14]([C:15]([F:16])([F:17])[F:18])=[CH:13][C:12]2[N:19]=[C:3]([C:2]([OH:1])([CH3:7])[CH3:6])[N:20]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][Cl:29])=[CH:23][CH:22]=3)[C:11]=2[CH:10]=1
Reactant: CC(C)(O)C(=O)O
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1Nc1ccc(CCCl)cc1
Product: CC(C)(O)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCCl)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 339, step 3 & Example 1, step 5 from 2-hydroxyisobutyric acid and 4-chloro-N2-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1,2-benzenediamine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[O-]C1C=CC=CC=1.Cl[CH2:22][C:23]([OH:25])=[O:24].Cl>CN(C)C=O.C(OCC)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:22][C:23]([OH:25])=[O:24])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)c1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 10.0 g (66.7 mmoles) p-tertbutylphenol in 50 ml dry dimethyl formamide was added, dropwise, to a mechanically stirred slurry of 8.4 g sodium hydride (as 50% oil dispersion) in 500 ml dry dimethyl formamide. To the phenoxide solution was added, dropwise, a solution of 6.3 g (66.3 mmoles) chloroacetic acid in 50 ml dry dimethyl formamide. The reaction mixture was stirred at room temperature for two hours. The reaction mixture was diluted with 200 ml diethyl ether and acidified with 3 N hydrochloric acid. The aqueous layer was removed and washed with 200 ml diethyl ether. The organic layers were combined, dried (MgSO4) and evaporated to a white gummy residue which was dried in vacuo yielding p-t-butylphenoxyacetic acid, 9.0 g (65%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([C:7]([O:9][C:4]([CH3:7])([CH3:5])[CH3:3])=[O:8])[CH2:3]1
Reactant: O=C1CC[C@H](C(=O)O)C1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@H]1CCC(=O)C1

Procedure:
The title compound tert-Butyl (1S)-3-Oxocyclopentane carboxylate was prepared starting from (1S)-3-Oxocyclopentane carboxylic acid (Sung, S-Y., Frahm, A. W. Arch. Pharm. Pharm. Med. Chem. 1996 329, 291-300) according to Procedure A. [α]D20=25.5° (c=7.93, chloroform).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:12]1)=[O:10].O>CS(C)=O>[O:10]1[CH2:2][CH:9]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: C[S+](C)(C)=O
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(C2CO2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
Trimethylsulfoxonium iodide (1.65 g, 7.5 mmol) was added in two portions to a solution of NaH (300 mg, 7.5 mmol) in anhydrous DMSO (10 mL) at room temperature. The resulting mixture was stirred for 1 hour, whereupon a solution of phenylmethyl 4-formyl-1-piperidinecarboxylate (1.24 g, 5.0 mmol) in anhydrous DMSO (10 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, then poured into cold water (100 mL), and extracted with Et2O (2×100 mL). The extracts were combined, washed with water, brine, and dried (Na2SO4). The solvent was removed in vacuo to give the title compound (0.95 g, 73%) as a colorless oil. MS (ES) m/e 262 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1.[N+:16]([O-])([O-:18])=[O:17].[K+].Cl>CCO>[N+:16]([C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][NH:7][CH2:6]2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sulfuric acid (9.90 mL, 0.186 mol) was cooled to 0° C. To the cooled solution was added 1,2,3,4-Tetrahydroisoquinoline (2.5 mL, 020.0 mmol) dropwise via syringe. Potassium nitrate (2.16 g, 0.0214 mol) was then added in small portions over 4 min. The cooling bath was removed and the mixture was allowed to stir at rt for 12 h. Ice was added to the slurry and the mixture basified with NH4OH (precipitate formed). The solution was extracted with chloroform, dried over Na2SO4, filtered, and concentrated to give a brown oil. The oil was dissolved in ethanol (14.8 mL, 0.254 mol) and to this solution was added HCl (2.47 mL, 0.0808 mol). Additional EtOH was added to transfer the precipitated solid for filtration. The white solid was dried under vacuum to yield the desired product without further purification (2.19 g, 51%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7](Br)[N:6]=1)=[O:4].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([CH3:27])[CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][C:20]=2[CH3:27])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Reactant: Cc1cc(Cl)ccc1B(O)O
Product: COC(=O)c1nc(-c2ccc(Cl)cc2C)c(C(F)(F)F)cc1N

Procedure:
This compound was prepared from 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) and 4-chloro-2-methylphenylboronic acid analogously to Intermediate H; LC-MS Rt=1.53 mins, [M+H]+ 331 (Method 2 min LC_v002).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[O:29]1[C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=[N:30]1>C(Cl)Cl.C1COCC1>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][C:34]([C:33]4[O:29][N:30]=[CH:31][CH:32]=4)=[O:35])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reactant: O=C(O)c1ccno1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNC(=O)c1ccno1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 4 %

Procedure:
To a solution of (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3, 0.08 g, 0.21 mmol) in DCM-THF mixture (1:1, 4 ml) at 0° C. was added 1.0 eq. of isoxazole-5-carboxylic acid loaded TFP resin. The resulting mixture was stirred vigorously for 1 hour at 0° C., and then filtered. The remaining resin was then washed with DCM-THF (1:1, 2×10 ml portions) for 30 min, and then filtered. The combined filtrates were concentrated, and the resulting oil was purified by column chromatography to give the title compound (3.4 mg, 4%). MS: Calcd.: 479. Found: [M+H]+ 480.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH:18]([C@H:31]1[O:36][CH2:35][C@@H:34]([NH2:37])[CH2:33][CH2:32]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH:18]([C@H:31]1[O:36][CH2:35][C@@H:34]([NH:37][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:33][CH2:32]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(F)cc1)N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Reaction time: 2 h
Yield: 80 %

Procedure:
Into a solution of 4-fluorophenylacetic acid (0.23 g, 1.46 mmol) in dichloromethane (25 ml) was added oxalyl chloride (0.22 g, 1.76 mmol) dissolved in dichloromethane (5 ml) at 0° C. which was followed by addition of one drop of DMF. The reaction mixture was allowed to reach at room temperature over a period of 2 hours. The solvent was removed in vacuo, and the residue was dissolved in dichloromethane (5 ml) and was added into a solution of cis-N-(6-benzhydryl-tetrahydropyran-3-yl)-amine (0.26 g, 0.96 mmol) and triethylamine (0.31 g, 1.46 mmol) in dichloromethane (25 ml) at 0° C. After 20 minutes the reaction mixture was allowed to come to room temperature. After 3 hours, more dichloromethane was added and the mixture was washed in turn with 1N NaHCO3, H2O and brine, then dried over anhydrous Na2SO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography (hexane/ethyl acetate 7:3) to give cis-N-(6-benzhydryl-tetrahydropyran-3-yl)-2-(4-fluorophenyl)-acetamide 17 (0.31 g, yield 80%) as an oil.
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:7][CH2:6][N:5]2[C:20]=1[CH3:21].C([Mg]Br)C.[C:26]([OH:29])(=[O:28])C>C1COCC1>[CH2:13]([O:12][C:10]([N:8]1[CH2:7][CH2:6][N:5]2[C:20]([CH3:21])=[C:2]([C:26]([OH:29])=[O:28])[N:3]=[C:4]2[CH2:9]1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)O
Reactant: Cc1c(I)nc2n1CCN(C(=O)OCc1ccccc1)C2
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)nc2n1CCN(C(=O)OCc1ccccc1)C2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
A solution of benzyl 2-iodo-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (900mg, 2.266 mmol) in dry THF (25 ml) was cooled to 0 ° C. and ethyl magnesiumbromide (1.888 ml, 5.66 mmol) was added at such a rate as to maintain the reaction temperature below 2.5° C. The reaction was stirred under Nitrogen at 0 ° C. for 15 minutes, then the reaction was quenched with a stream of carbon dioxide. The reaction was concentrated to solids and acetic acid (0.60 ml, 10.48 mmol) ethyl acetate (50 ml) were added and the suspension was stirred vigorously at room temperature for 15 minutes. The resulting solid was filtered and washed with an additional 15 ml ethyl acetate. The residue was dissolved in 10 ml water plus 2N HCl to pH 4, then washed 2 times 10 ml ether then extract with 4×20 ml CH2Cl2. Dry the combined organic extracts over sodium sulfate, filtered and dried under reduced pressure to yield 3-Methy-5,6-dihydro -8H-imidazo[1,2-a] pyrazine-2,7-dicarboxylic acid 7-benzyl ester (374 mg, 52%) as a foam. LCMS (Table 1, Method a) Rt=2.28 min, m/z 316.10 (M+H)+; 1H NMR (400 MHz, DMSO-d6)δ 7.35 (m, 5H), 5.11 (s, 2H), 4.56 (s,broad, 2H), 3.88 (m, 2H), 3.83 (s, broad, 2H), 2.36 (s, 3H).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([F:18])=[C:13]([F:17])[CH:14]=2)[C:9]1=[O:19])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([F:18])=[C:13]([F:17])[CH:14]=2)[C:9]1=[O:19]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2cc(F)c(F)cc2C1=O
Solvent: ClCCl
Solvent: CO
Product: O=CCC1Cc2cc(F)c(F)cc2C1=O
Reaction time: 0.67 h
Yield: 76 %

Procedure:
An ozone stream (2 g ozone/hour) was conducted for 40 minutes while stirring through a solution, cooled to -70°, of 5.3 g of (RS)-2-(2-buten-1-yl)-5,6-difluoro-1-indanone in 125 ml of anhydrous dichloromethane and 25 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 2.64 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 60 ml of dichoromethane and, after the addition of 10 ml of water and 10 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 80 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 40 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. There was obtained a yellow oil which was crystallized from diethyl ether/hexane. 3.82 g (76%) of (RS)-2-(2-oxoethyl)-5,6-difluoro-1-indanone were obtained as a white solid with m.p. 78°-81°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([NH2:9])[C:6](=[NH:8])[NH2:7])[CH3:2].[F:11][C:12]([F:22])([F:21])[C:13](=O)[C:14](=O)[C:15]([F:18])([F:17])[F:16]>>[NH2:8][C:6]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:10])=[N:9][C:14]([C:15]([F:18])([F:17])[F:16])=[C:13]([C:12]([F:22])([F:21])[F:11])[N:7]=1
Reactant: CCOC(=O)C(N)C(=N)N
Reactant: O=C(C(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)nc1N

Procedure:
The title compound was prepared from amino-carbamimidoyl-acetic acid ethyl ester (Intermediate B2) and 1,1,1,4,4,4-hexafluorobutane-2,3-dione analogously to Intermediate B; 10 LCMS Rt=4.72 minutes, [M+H]+ 304.2/326.1 Method 10minLC_v002.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH2:13][CH2:12][CH:11]=1)[CH3:2]>CCO.O=[Pt]=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:21][CH:22]=2)[C:14](=[O:28])[CH2:13][CH2:12][CH2:11]1)[CH3:2]
Reactant: CCOc1ccccc1C1=CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: CCOc1ccccc1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 50 °C

Procedure:
A mixture of 6-(2-ethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)-3,4-dihydropyridin-2(1H)-one (11 mg; 0.028 mmol) and PtO2 (10 mg) in anh. EtOH (1 ml), under hydrogen (60 bars), was heated to 50° C. for 17 h. After cooling to rt, the mixture was filtered over celite, and the filtrate was concentrated to dryness under reduced pressure affording 6-(2-ethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)piperidin-2-one. LC-MS (conditions E): tR=0.82 min.; [M+H]+: 394.22 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](P2(=O)CCCC2)[CH:5]=[CH:6][CH:7]=1.[PH3]=O.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1([SiH3])C=CC=CC=1.C(O)C1C=CC=CC=1>>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: Cc1cccc(P2(=O)CCCC2)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=[PH3]
Agent: [SiH3]c1ccccc1
Solvent: OCc1ccccc1
Product: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 792.7 %

Procedure:
The reaction is illustrated in FIG. 9. In air, a 1-dram vial equipped with a stir-bar was charged with phosphine oxide 1 (9.7 mg, 10 mol %), 4-nitrobenzoic acid (51.7 μL, 0.5 mmol), and diisopropyl azodicarboxylate (DIAD, 147.5 μL, 0.75 mmol). The vial was then sealed with a septum, and purged with argon. Distilled Toluene (1.5 mL) was added. Reaction was allowed to stir. Phenylsilane (67.8 μL, 0.55 mmol), and benzyl alcohol (51.7 μL, 0.5 mmol) was added. The septum was replaced with a PTFE-lined screw cap under an inert atmosphere, and the reaction was heated at 80° C. for 24 hours. The crude reaction mixture was filtered through a plug of celite, concentrated in vacuo, and purified via flash chromatography yielding the title compound 63%, 81.0 mg. To the best of our knowledge this is the first example of a Mitsunobu reaction catalytic in phosphine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=2[CH:17]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=3[CH:17]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(S)cc1
Reactant: O=C1Nc2ccc(OCCCCCl)cc2CO1
Product: Cc1ccc(SCCCCOc2ccc3c(c2)COC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4H-3,1-benzoxazin-2-one and 4-methyl-thiophenol.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([Si:28]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)Cl)([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:11][CH2:12][CH2:13][O:14][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCO)C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 12 h

Procedure:
(S)-2-tert-Butoxycarbonylamino-5-hydroxy-pentanoic acid benzyl ester (2.5 g) was dissolved in 50 ml DMF and treated with 2.0 ml tert-butyldiphenylchlorosilane, 1.2 ml triethylamine and 95 mg DMAP. After stirring for 12 h equivalent portions of the reagents were added and the mixture stirred for additional 12 h. The mixture was concentrated, the residue was dissolved in ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 2.0 g.
Reaction SMILES: CN[C:3]([O:5][CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:4].[CH3:20]COCC>C(O)(=O)C>[C:3]([O:5][CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)(=[O:4])[CH3:20]
Reactant: CCOCC
Reactant: CNC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: CC(=O)O
Product: CC(=O)OC1c2ccccc2Oc2ccccc21
Reaction time: 1 h

Procedure:
To 15 g. of 9-(N-methylcarbamoyloxy)xanthene, suspended in 200 ml. of dry ether, was added 18 ml. of glacial acetic acid with stirring. After one hour, the lower acid layer was removed. The ether phase was then cooled, neutralized with cold aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was recrystallized from benzene-hexane to give 9-acetoxyxanthene, m.p. 109°-112°C.