Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[C@H:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:19]([NH:29][C@H:30]([C:35](O)=[O:36])[CH2:31][CH2:32][S:33][CH3:34])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:35](=[O:36])[C@@H:30]([NH:29][C:19](=[O:20])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:31][CH2:32][S:33][CH3:34])[C@H:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1N
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 92.4 %

Procedure:
(1S,2S,4R)-4-(tert-Butyldimethylsilyloxy)-2-isopropylcyclohexanamine (2.9 g) was dissolved in DMF (36 mL) and cooled to 0° C. prior to the addition of N-Cbz methionine (5.5 g), 4-methyl morpholine (3.8 g), and BOP (8.7 g). The reaction was stirred for 12 h at rt and then partitioned between EtOAc and 1N HCl solution. The organic phases were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl (S)-1-((1S,2S,4R)-4-(tert-butyldimethylsilyloxy)-2-isopropylcyclohexylamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate (5.3 g). MS found: (M+H)+=537.3.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[Br:19][CH2:20][CH2:21][CH2:22]Br>C(C(C)=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:22][CH2:21][CH2:20][Br:19])=[CH:14][CH:13]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CC(C)=O
Product: Clc1ccc(OCCCBr)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
10 g of potassium carbonate was added to 30 ml of a methyl ketone solution containing 15.9 g of p-chlorophenol, and the solution was then heated with stirring at 60° C. for 1 hour. Afterward, 30 ml of a methyl ethyl ketone solution containing 50 g of 1,3-dibromopropane was added dropwise; After the addition, the solution was heated under reflux for 3 hours. The reaction solution was then cooled and a precipitate was removed therefrom, and the solution was evaporated to dryness under reduced pressure to obtain 23.2 g of 4-chlorophenoxypropyl bromide.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].COCCO[AlH2-]O[CH2:13][CH2:14][O:15]C.[Na+].[Cl-].[NH4+].[C:20]1([CH3:26])[CH:25]=CC=C[CH:21]=1>CCCCCC.O1CCCC1>[CH3:4][C:3]1[CH:13]([CH:14]=[O:15])[C:20]([CH3:26])([CH3:25])[CH2:21][CH2:1][CH:2]=1
Reactant: COCCO[AlH2-]OCCOC
Reactant: [Li]CCCC
Reactant: Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1=CCCC(C)(C)C1C=O
Yield: 65 %

Procedure:
9.3 Ml of a 1.42N slution of butyl-lithium in hexane (0.0132M) were added dropwise at -78° to a solution of 2.0 g (0.011M) of methyl alpha-cyclogeranate in 40 ml of anhydrous tetrahydrofuran (THF). Once the addition was over, the temperature of the mixture was increased to +15° and, at this temperature, 3.17 ml (0.011M) of a 70% solution of VITRIDE [sodium bis(2-methoxyethoxy)aluminum hydride] in toluene were added thereto. The reaction mixture was heated to 40° for 45 mn, then hydrolyzed by pouring it onto an icy saturated aqueous solution of ammonium chloride. The mixture was extracted with ether, the organic phase was separated and then subjected to the usual treatments of neutralization and washing to give a residue which, upon distillation, gave 1.27 g of alpha-cyclocitral having b.p. 60°-65°/66 Pa (purity: 80%; yield: 65%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].CCN(CC)CC.[CH3:18][O:19][CH2:20]Cl>C(Cl)Cl.CCOC(C)=O>[CH3:18][O:19][CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C=O)ccc1O
Reactant: COCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCOc1ccc(C=O)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
To a solution of 4-hydroxy-3-methylbenzaldehyde (900 mg, 6.61 mmol) in CH2Cl2 (19 mL) was added Et3N (5.90 mL, 42.3 mmol) and chloromethyl methyl ether (2.00 mL, 26.3 mmol). The reaction was stirred at 25° C. for 16 h. The reaction mixture was diluted with EtOAc and was successively washed with aqueous 1 N HCl solution, aqueous saturated NaHCO3 solution, water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Hexane:EtOAc, 4:1) to give the title compound (630 mg, 53% yield) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[NH:4][C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:7]=2[N:6]=1.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>CC(C)=O>[CH3:1][O:2][C:3]([NH:4][C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([O:14][S:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:27])=[O:26])=[CH:13][C:7]=2[N:6]=1)=[O:15]
Reactant: COC(=O)Nc1nc2cc(O)ccc2[nH]1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(OC(F)(F)F)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.2 %

Procedure:
A stirred solution of (5-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid methyl ester (100 mg) and 4-trifluoromethoxy-benzenesulfonyl chloride (126 mg) in acetone (3 ml) was treated with triethylamine (130 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (1:1, v/v) to give 4-trifluoromethoxy-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester (65 mg) as an off-white solid Mass spectrum: 432 [M+H]+; retention time=15.04 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:41][CH2:40][CH2:39][CH:38]3[C:42]([O:44]C)=[O:43])=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([N:37]3[CH2:41][CH2:40][CH2:39][CH:38]3[C:42]([OH:44])=[O:43])=[CH:35][CH:36]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCCN1c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(N3CCCC3C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)pyrrolidine-2-carboxylate (61.2 mg, 0.091.4 mmol, example 11) in THF (4.00 ml) was added a solution of LITHIUM HYDROXIDE monohydrate (22.6 mg, 0.539 mmol) in Water (2.00 ml) dropwise. The reaction mixture was stirred at rt for 2 hrs before it was neutralized with 1N HCl. it was then diluted with EtOAc, washed with water (2×10 mL), brine (2×10 mL), dried and evaporated to give 1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)pyrrolidine-2-carboxylic acid as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 655. found: 655.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([CH3:25])[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:26][CH2:27][CH2:28][S:29][CH3:30])(=[O:5])[CH2:2][CH2:3][CH3:4].C([O-])(O)=[O:32].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([CH3:24])[CH3:25])=[CH:13][CH:12]=[CH:11][C:10]=2[O:26][CH2:27][CH2:28][S:29]([CH3:30])=[O:32])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])O
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1C(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1ccccc1C(C)C
Reaction time: 1 h
Yield: 57 %

Procedure:
3-Butyryl-4-(2-isopropylphenylamino)-8-(2-methylthioethoxy)quinoline (0.22 g, 0.52 mmol) was dissolved in methylene chloride (15 ml) and added to a mixture of 0.093 g NaHCO3 in 15 ml H2O. A solution of 71% m-CPBA (0.12 g, 0.50 mmol) in 7 ml methylene chloride was added dropwise at 4° C. The solution was stirred for one hour at this temperature. The reaction mixture was washed with a saturated sodium bicarbonate solution. The organic layer was dried over Na2SO4 and evaporated. Chromatography with methylene chloride:methanol 10:1 as eluent gave 0.130 g (57%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:27])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].CO.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:27])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:20][CH:21]=2)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(CC(C)(C)C)cc1)C(O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)Cc1ccc(CC(C(=O)O)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-(4-neopentylbenzyl)propionate (3.756 g, 9.657 mmol), sodium hydroxide (0.77 g, 19.3 mmol), methanol (20 ml), water (10 ml) and tetrahydrofuran (20 ml) was stirred overnight at room temperature. The reaction solution was concentrated, diluted with water, acidified with hydrochloric acid, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give a crude product of (2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-(4-neopentylbenzyl)propionic acid as a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][OH:9])[N:6]=1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>O>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:9][CH2:8][CH2:7][C:5]1[N:6]=[C:2]([CH3:1])[S:3][CH:4]=1
Reactant: Cc1nc(CCO)cs1
Reactant: BrCCCCCCBr
Solvent: O
Product: Cc1nc(CCOCCCCCCBr)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-methyl-4-thiazoleethanol (2.22 g), 1,6-dibromohexane (7.1 ml) 12.5M aqueous sodium hydroxide (4 ml) and TAB (0.1 g) was stirred rapidly at room temperature for 16 h. The reaction mixture was diluted with water (30 ml), extracted with ether (3×30 ml) and the combined organic extracts were washed with water (30 ml) and brine (30 ml), dried and concentrated. The residual oil was purified by FCC eluting with diethyl eter-hexane (1:3) to give the title compound as an orange oil (2.21 g), t.l.c. (ether-hexane 1:3) Rf 0.17
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(NC(C)C)(C)C.[C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)#[N:14].C1(CBr)CC1>C1COCC1>[C:13]([C:15]1([CH2:1][CH:2]2[CH2:4][CH2:3]2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)#[N:14]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: BrCC1CC1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCC(C#N)(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium in hexanes (1.6M, 11.2 mL, 17.9 mmol) was added dropwise to diisopropylamine (2.5 mL, 17.8 mmol) in THF (20 mL) cooled in an ice bath. After stirring for 0.5 h, the solution was cooled in a dry-ice bath and a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (I-1) (2.50 g, 11.9 mmol) in THF (20 mL) was added dropwise. The solution was stirred in a dry-ice bath for 1 h then cyclopropylmethyl bromide (1.27 mL, 13.1 mmol) was added. The reaction mixture was allowed to warm to room temperature over 2 h then quenched with water. The mixture was extracted with DCM (3×). The combined organic phase was washed with brine, dried (MgSO4) and the solvent removed in vacuo. Biotage chromatography (5-10% ethyl acetate-hexanes) afforded tert-butyl 4-cyano-4-cyclopropylmethylpiperidine-1-carboxylate (I-2) as a colourless oil. 1H NMR (500 MHz, CDCl3): δ 4.12 (br s, 2H), 3.05 (br s, 2H), 2.02 (m, 2H), 1.52 (d, J=7.0, 2H), 1.46 (s, 9H), 0.89 (m, 1H), 0.58 (m, 2H), 0.19 (m, 2H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]([C:18]3([C:21]4[CH:29]=[CH:28][C:24]5[O:25][CH2:26][O:27][C:23]=5[CH:22]=4)[CH2:20][CH2:19]3)=[O:17])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:30]([CH3:33])([CH3:32])[CH3:31])=[N+]=[N-].CO.[CH3:36][C:37](O)=[O:38]>[Pd]>[C:37]([NH:1][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]([C:18]3([C:21]4[CH:29]=[CH:28][C:24]5[O:25][CH2:26][O:27][C:23]=5[CH:22]=4)[CH2:20][CH2:19]3)=[O:17])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:38])[CH3:36]
Reactant: CC(=O)O
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2n1CCN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCn1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc21

Procedure:
A solution of N-(1-(2-azidoethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (13 mg, 0.029 mmol) in MeOH-AcOH (0.2 mL, 99:1) in the presence of Pd—C (2 mg) was stirred at room temperature under 1 atm of H2 for 2 h, filtered through Celite, and concentrated under reduced pressure. The crude product was treated with AcCl (0.05 mL) and Et3N (0.05 mL) in anhydrous THF (0.2 mL) at 0° C. for 30 min and then 1 h at room temperature. The mixture was purified by preparative HPLC providing N-(1-(2-acetamidoethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]-dioxol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 462.0.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][SH:14])(=[O:10])[CH3:9].OO>O.CC(C)=O>[C:8]([NH:11][C@@H:12]([CH2:13][S:14][S:4][CH2:3][C@H:2]([NH2:1])[C:5]([OH:7])=[O:6])[C:15]([OH:17])=[O:16])(=[O:10])[CH3:9]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: OO
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)N[C@@H](CSSC[C@H](N)C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 10 %

Procedure:
L-cysteine (2.42 g, 20 mmol) and N-acetyl-L-cysteine (3.26 g, 20 mmol) were dissolved in 25 mL of water. The pH of this solution was 2.6 according to lithmus paper. Aqueous hydrogen peroxide (30%, 2.3 mL, 21 mmol) was added, and the reaction mixture was allowed to stand at room temperature overnight. A white precipitate stand at room temperature overnight. A white precipitate was filtered off (1.26 g). This material was shown to be L-cystine by comparison of spectral data with an authentic sample. The yellowish filtrate, containing the desired compound and the two symmetrical compounds (R,R)-N,N'-diacetylcystine and (minor amounts of) cystine was separated on a preparative HPLC using a Dynamax C1 8-column (8 μm, 60 Å, 21.4×250 mm) with a Dynamax C1 8-guard column (8 μm, 21.4×50 mm) and with Gilson dual solvent delivery system (305 pump, pumphead 100 SC acting as a solvent delivery pump, pumphead 5 SC acting as a sample injector, 806 manometric module, 811B dynamic mixer, 115 UV detector, 201 fraction collector, 201-202 fraction controller). The solvents used were A=10 mM HOAc/H2O and B=MeOH, with a 95:5 ratio of A:B. The solvent flow was 10 mL/min and the separation was recorded at 230 nm. After detection of each fraction on TLC (Merck 16483, plastic sheets silica gel 60 WF 254s, eluent nBuOH/HOAc/H2O 1:1:1, I2 as visualization agent), the fractions with acceptable purity were pooled and evaporated to give an oily residue. This residue was dissolved in acetone (pa) and the solution was evaporated to give the title product as white crystals.
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1C=CC(C(C)C)=CC=1)(C)C.[CH3:22][C:23](C)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[OH:24].[OH2:32]>>[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])[CH3:22].[O-:32][OH:24].[C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(O)c1ccccc1
Reactant: O
Agent: CC(C)c1ccc(C(C)C)cc1
Solvent: CC(C)c1ccccc1
Product: CC(=O)c1ccccc1
Product: [O-]O

Procedure:
Using 79.9 g (0.665 mole) of cumene in lieu of p-diisopropylbenzene, oxidation was carried out in the same apparatus and under the same conditions as those employed in Example 1. The reaction product obtained subsequent to its water washing and drying was an oily matter whose weight was 79.6 g. According to results of a high-performance liquid chromatographic analysis, the oily matter was found to contain 3.1 g (0.026 mole; conversion: 96.1%) of cumene and 75.3 g (0.553 mole; yield: 83.2 mole %) of dimethylphenylcarbinol. Acetophenone or cumene hydroperoxide was not formed practically.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[ClH:18]>P(Cl)(Cl)(Cl)=O>[Cl:18][C:6]1[N:1]=[C:2]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:5]=1
Reactant: Cl
Reactant: CCOC(=O)c1ccc[n+]([O-])c1C(=O)OCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(Cl)nc1C(=O)OCC

Procedure:
A mixture of 75.6 g of diethyl pyridine-2,3-dicarboxylate-N-oxide and 150 mL of phosphorous oxychloride is warmed slowly in a large reaction vessel equipped with a reflux condenser and gas scrubber. Caution: exothermic reaction! At about 70°, an exothermic reaction ensues with vigorous liberation of hydrogen chloride gas. The reaction is heated at reflux after the exotherm subsides for an additional hour. The reaction is cooled and concentrated in vacuo to a syrup. This material is dissolved in methylene chloride, washed cautiously with saturated sodium bicarbonate, dried and concentrated in vacuo to give the desired product as an oil. An analytical sample is obtained by chromatography on silica gel using 2:1 petroleum ether-ether as eluant to give the product as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.[NH2:22][C:23]1[C:24]([C:30]([OH:32])=O)=[N:25][C:26](Br)=[CH:27][CH:28]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>>[NH2:22][C:23]1[C:24]([C:30]([NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:21])[C:6]=2[O:7][CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[O:32])=[N:25][C:26]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[F:33])=[CH:27][CH:28]=1
Reactant: Cn1ncc(N)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: OB(O)c1ccccc1F
Reactant: Nc1ccc(Br)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)ccc2N)c1OC1CCNCC1
Yield: 14 %

Procedure:
Following the procedures for Example 141, tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yloxy)piperidine-1-carboxylate and 3-amino-6-bromopicolinic acid were coupled and the intermediate amide was reacted with 2-fluorophenylboronic acid under palladium catalyzed Suzuki conditions to give 116 as a white solid (10 mg, 14%) over three steps. 1H NMR (400 MHz, DMSO) δ 9.67 (s, 1H), 8.05 (t, J=7.5, 1H), 7.73 (dd, J=8.8, 1.9, 1H), 7.66-7.38 (m, 3H), 7.38-7.25 (m, 3H), 7.03 (s, 2H), 4.43-4.20 (m, 1H), 3.63 (s, 3H), 2.96-2.79 (m, 2H), 2.39 (dd, J=26.9, 16.6, 2H), 1.92 (d, J=12.0, 2H), 1.55 (td, J=13.2, 3.9, 2H). ESIMS m/z=411.1 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([CH:12]=[C:13](Cl)Cl)=[O:11].[Na].S(=O)(=O)(O)[OH:18].[CH2:22]([OH:24])[CH3:23]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([CH2:12][C:13]([O:24][CH2:22][CH3:23])=[O:18])=[O:11]
Reactant: O=S(=O)(O)O
Reactant: O=C(C=C(Cl)Cl)c1cc(F)c(F)cc1F
Reactant: CCO
Agent: [Na]
Solvent: ClCCl
Product: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F
Yield: 82.2 %

Procedure:
21.2 g of 2,2-dichlorovinyl 2,4,5-trifluorophenyl ketone are added dropwise to a solution of 3.85 g of sodium in 65 ml of absolute ethanol at 5°-10° C., while cooling (ice/methanol) and stirring. When the exothermic reaction has subsided, the mixture is stirred at room temperature for a further 30 minutes, the solvent is stripped off in vacuo and the residue is taken up in 100 ml of methylene chloride. The mixture is shaken thoroughly with 50 ml of 2N sulphuric acid, the methylene chloride phase is separated off in a separating funnel and the aqueous phase is subsequently extracted another three times with 50 ml of methylene chloride each time. The combined CH2Cl2 solutions are washed with 100 ml of saturated sodium chloride solution and dried over sodium sulphate. The solvent is then distilled off in vacuo and the oily residue is fractionated under a fine vacuum. 16.8 g (82.2%) of ethyl 2,4,5-trifluoro-benzoylacetate of boiling point 98°-100° C./0.15 mbar are obtained. The melting point is 63°-64° C.
Reaction SMILES: [Li][CH:2](CC)[CH3:3].Cl[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:15]1[CH2:19][O:18][CH2:17][CH2:16]1>>[CH2:7]([CH:15]1[CH2:16][CH2:17][CH2:3][CH2:2][C:19]1=[O:18])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCCc1ccccc1
Reactant: C1CCOC1
Reactant: [Li]C(C)CC
Product: O=C1CCCCC1CCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
s-BuLi (28.0 mL, 1.3 M) was added slowly to a solution of Compound 20b (7.0 g) in THF (50 mL) at −78° C. The mixture stirred for 1 hr at −78° C. and then (2-chloro-ethyl)-benzene Compound 20c (5.11 g, 36.4 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred for 24 hrs while warming to r.t. The reaction was quenched with 1N HCl (5 mL), then diluted with water (100 mL) and EtOAc (500 mL). The organic layer was washed with brine, separated and dried with anhydrous sodium sulfate, then filtered and concentrated in vacuo to yield a crude product. Purification by flash chromatography (eluted with 10% EtOAc in Hexane) afforded 2-phenethyl-cyclohexanone Compound 20d (4.05 g, 20.0 mMol, 58%) as a yellow oil.