Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:28](O)=[O:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(OC(C)C)(C)C>CN(C)C=O.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C@@H:10]([C:28](=[O:29])[NH:39][CH2:38][C:37]2[CH:40]=[CH:41][C:34]([O:33][C:32]([F:31])([F:42])[F:43])=[CH:35][CH:36]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)O)C1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)OC(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)NCc2ccc(OC(F)(F)F)cc2)C1
Yield: 66.4 %

Procedure:
To a solution of the compound (2.40 g) obtained in Step 2, 4-trifluoromethoxybenzylamine (1.21 g) and 1-hydroxybenzotriazole hydrate (1.21 g) in N,N-dimethylformamide (24 ml) was added, with stirring under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.21 g). After stirring overnight at room temperature, and the reaction mixture was partitioned by adding ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude crystals were suspended in a mixed solution of diisopropyl ether and n-hexane, collected by filtration and dried to give the title compound (2.20 g).
Reaction SMILES: C([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:16][CH2:15]2)[N:7]=1)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(OCC)(=O)C.Cl.C(OCC)(=O)C>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][C:8]2[NH:7][C:6](=[O:5])[CH:11]=[N:10][CH:9]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)Oc1cncc(CCN2CCC(COc3ccccc3F)CC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1cncc(CCN2CCC(COc3ccccc3F)CC2)[nH]1
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
After dissolving 167 mg of 2-tert-butoxy-6-[2-[4-(2-fluorophenoxymethyl)piperidino]ethyl]pyrazine in 3 ml of ethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate was added and the mixture was allowed to stand at room temperature for 30 minutes. Aqueous sodium carbonate solution was added to the reaction solution and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (113 mg, 79% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]#[N:21])[CH:14]=3)[N:11]=[C:10]([C:22]([O:24]CC)=[O:23])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]#[N:21])[CH:14]=3)[N:11]=[C:10]([C:22]([OH:24])=[O:23])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)n(-c2ccc(F)c(C#N)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: N#Cc1cc(-n2nc(C(=O)O)cc2-c2cccc(Cl)c2)ccc1F
Reaction time: 6 h

Procedure:
The preparation of the title compound takes place starting from the compound of Example 60A in analogy to the synthesis of the compound of Example 71A but with stiffing for 6 hours. 672 mg of the title compound with 61% purity are obtained.
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH3:19][N:20]([CH3:24])[C:21](=[O:23])C>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].[Cu]I>[C:13]([O:12][C:11]([NH:10][C:4]1[C:3]([Cl:18])=[C:2]([CH:2]2[CH2:3][CH2:24][N:20]([C:21]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:23])[CH2:19][CH2:7]2)[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(C2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (1.0 g, 3.02 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (0.206 g, 0.302 mmol), and copper(I) iodide (0.115 g, 0.603 mmol) in a dry microwave vial was flushed with nitrogen. N,N-dimethylacetamide (3 mL) was added followed by (1-(tert-butoxycarbonyl)piperidin-4-yl)zinc(II) iodide (9.52 mL, 9.05 mmol, approximately 1 M solution in N,N-dimethylacetamide prepared as described in the Journal of Organic Chemistry, 2004, 69, 5120). The vial was sealed and heated at 80° C. overnight. After cooling to RT, the reaction was partitioned between EtOAc and sat. aq. NH4Cl solution. This was left stirring for 30 min. The aqueous phase was washed with EtOAc and the combined organic phases were washed with brine and dried with sodium sulfate. Removal of the solvents followed by radial silica gel chromatography eluting with hexane containing 5 to 30% EtOAc afforded tert-butyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)piperidine-1-carboxylate (0.376 g) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[CH:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([O:22][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1F
Reactant: OC1CCCCC1
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1OC1CCCCC1

Procedure:
Then, N-(2-fluoro-5-nitrophenyl)methanesulfonamide and cyclohexanol are subjected to etherification in the presence of a base to give N-(2-cyclohexyloxy-5-nitrophenyl)methanesulfonamide.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([C:16](O)=[O:17])=[C:13]([C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=3)[C:12]=2[CH3:29])=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([C:16]([N:2]([CH3:3])[CH3:1])=[O:17])=[C:13]([C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=3)[C:12]=2[CH3:29])=[CH:7][CH:6]=1
Reactant: Cc1c(-c2ccc(Cl)cc2)sc(C(=O)O)c1-c1ccc(S(N)(=O)=O)cc1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccc(Cl)cc2)sc(C(=O)N(C)C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 10 °C
Yield: 22.6 %

Procedure:
Dimethyl amine (0.055 g, 0.61 ml 2M solution in THF, 1.22 mmol) was added drop wise to a solution of 5-(4-chlorophenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid (compound 1c, 0.25 g, 0.61 mmol) in dry THF (15 ml) under a nitrogen atmosphere at 0° C. To the reaction mixture HATU (0.26 g, 0.67 mmol) and DIPEA (0.16 g, 0.21 ml, 1.24 mmol) were added at 0° C. with stirring. The mixture was then allowed to warm to 10° C. and stirred for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The concentrated mass so obtained was diluted with ethyl acetate (30 ml) and washed with saturated sodium bicarbonate solution (2×15 ml) and brine (1×15 ml). The organic layer obtained was then dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 25% ethyl acetate in hexanes as an eluent to obtain the title compound (0.06 g, 22.50%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+].O>C(OCC)C>[C:5]1([C:1]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:4])[CH2:2][CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCC(=O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CCC(O)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a well-stirred solution of propiophenone (20.1 g, 0.15 mol) in dry diethyl ether (125 ml) kept under nitrogen at room temperature was added a solution of phenylmagnesium bromide (55 ml, 3 M in diethyl ether) in dry diethyl ether (25 ml). The reaction mixture was stirred for 1 h and a mixture of a saturated ammonium chloride solution (100 ml) and water (50 ml) was added. The phases were separated and the aqueous phase was extracted with diethyl ether (100 ml). The combined organic phases was washed with a 0.5 N hydrochloric acid solution and dried (Na2SO4). The solvent was evaporated in vacuo to give a solid residue which was triturated with cyclohexane (100 ml). The solid was collected by filtration and dried to give 26.4 g (83%) of 1,1-diphenyl-1-propanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:20]([O:21][CH3:22])=[CH:19][C:12]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])=[C:11]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu][C:33]#[N:34]>[C-]#N.C([N+](CC)(CC)CC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[CH2:1]([O:8][C:9]1[C:20]([O:21][CH3:22])=[CH:19][C:12]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])=[C:11]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:33]#[N:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)OC(C)C)c(C(=O)c2ccccc2Br)cc1OCc1ccccc1
Reactant: N#C[Cu]
Agent: [Fe+2]
Agent: [Pd]
Agent: CC[N+](CC)(CC)CC
Solvent: C1COCCO1
Product: COc1cc(C(=O)OC(C)C)c(C(=O)c2ccccc2C#N)cc1OCc1ccccc1
Yield: 77.3 %

Procedure:
A mixture of isopropyl 4-benzyloxy-2-(2-bromobenzoyl)-5-methoxybenzoate (reference example 11-9) (600 mg), copper(I) cyanide (445 mg), tris(dibenzylideneacetone)dipalladium (114 mg), tetraethylammonium cyanide (194 mg), 1,1′bis(diphenylphosphino)ferrocene (206 mg) and 1,4-dioxane (73 mL) was stirred under reflux overnight. The mixture was passed through a layer of Celite (registered mark). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5%-30% ethyl acetate/hexane, gradient elution) to give the title compound (412 mg).
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])[CH2:6]1)C.[NH2:22][C:23]1[NH:27][N:26]=[C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:24]=1>CCO>[C:31]([O:30][C:29]([NH:28][C:25]1[CH:24]=[C:23]2[N:22]=[C:10]3[CH2:9][CH2:8][N:7]([C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[CH2:6][C:5]3=[CH:4][N:27]2[N:26]=1)=[O:35])([CH3:32])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)Nc1cc(N)[nH]n1
Reactant: COC(=O)c1cccc(N2CCC(=O)C(=CN(C)C)C2)c1
Solvent: CCO
Product: COC(=O)c1cccc(N2CCc3nc4cc(NC(=O)OC(C)(C)C)nn4cc3C2)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of methyl 3-(3-((dimethylamino)methylene)-4-oxopiperidin-1-yl)benzoate (0.145 g, 0.503 mmol) and tert-Butyl (5-amino-1H-pyrazol-3-yl)carbamate (0.150 g, 0.756 mmol) in EtOH (4.0 mL) was stirred at 80° C. for 20 h. The mixture was cooled and concentrated. The residue was washed with MTBE and hexanes. Dried under high vacuum. A mixture of the title compound and methyl 3-(2-((tert-butoxycarbonyl)amino)-5,6-dihydropyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-7(8H)-yl)benzoate was afforded, which was separated by prep HPLC to afford the title compound (0.011 g) and methyl 3-(2-((tert-butoxycarbonyl)amino)-5,6-dihydropyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-7(8H)-yl)benzoate (0.050 g). Prep HPLC Method: Phenomex Luna 100×21.2 mm, 10 μM, C(18) column; Gradient of 55% H2O and 45% CH3CN; Flow Rate 1 mL/min.; uv @215 nm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:18][C:3]1[C:4]([CH3:17])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)[C:6]([CH3:8])=[CH:7][C:2]=1[OH:1]
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(O)c(Cl)c(C)c1-c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 65 %

Procedure:
To a solution of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (11.3 g, 50.0 mmol) in N,N-dimethylformamide (50 mL) was added N-chlorosuccinimide (6.68 g, 50.0 mmol) by small portions under ice-cooling, and the mixture was stirred at room temperature for 13 hr, and then at 50° C. for 3 hr. N-Chlorosuccinimide (1.34 g, 10.0 mmol) was added to the reaction mixture, and the mixture was stirred at the same temperature for 3 hr. N-Chlorosuccinimide (0.668 g, 5.00 mmol) was added again, and the mixture was further stirred at the same temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60), and the obtained crystals were recrystallized from ethyl acetate-heptane to give the title compound (8.47 g, yield 65%) as colorless crystals.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]([NH:12][C:13](=[O:24])[C:14]1[C:15](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:16](OC)=O)([CH3:11])[C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[NH2:4]>C1(C)C=CC=CC=1>[C:7]([C:6]1([CH3:11])[N:12]2[C:13](=[O:24])[C:14]3[C:15]([C:16]2=[N:4][C:3]1=[O:5])=[CH:20][CH:21]=[CH:22][CH:23]=3)([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)c1ccccc1C(=O)NC(C)(C(N)=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (from 1.92 g of a 50% suspension of sodium hydride in mineral oil) in 150 ml toluene is heated under reflux. During 20 minutes is then added portionwise 6.13 g (0.02 mole) methyl N-(1-carbamoyl-1,2,2-trimethylpropyl)phthalamate to the stirred, refluxing, mixture. Heating is continued for 30 minutes after the addition, the mixture filtered through diatomaceous earth, and the solvent removed in vacuo. The residue crystallizes and is recrystallized from a mixture of acetone-hexane to give 3-t-butyl-3-methyl-3H-imidazo[2,1-a]isoindole-2,5-dione, melting point 136.5°-137.5° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][CH:9]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:10]=[O:11].S(=O)(=O)(O)O>C1C=CC=CC=1.[Zn]>[CH3:8][CH:9]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:10]([OH:11])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: CC(C)=CCCC(C)=CCCC(C)C=O
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC(O)C(C)CCC=C(C)CCC=C(C)C
Yield: 52.1 %

Procedure:
A suspension of zinc (59 g) in benzene (400 ml) is heated up to the reflux temperature, and a mixture of ethyl bromoacetate (120 g) and 2,6,10-trimethyl-5,9-undecadienal (135 g) is added thereto. The resulting mixture is refluxed for 2 hours, cooled and poured into 5% aqueous solution of sulfuric acid. The benzene layer is washed with water, dried and evaporated. The residual material is distilled under reduced pressure to give ethyl 3,7,11-trimethyl-6,10-dodecadien-2-ol-1-carboxylate (100 g) as a pale yellow oil. B.P. 139° to 142°C/0.08 mm Hg. IR: 3480, 1030 cm-1 (OH); 1720, 1180cm-1 (COO). NMR (carbon tetrachloride): δ 1.25 (t), 1.58 (s), 1.65 (s), 1.95 (m), 2.38 (m), 4.10 (m), 5.05 (m).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].II.[CH3:16][O:17][C:18]1[C:26]2[O:25][C:24]([CH:27]=[O:28])=[CH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1>O1CCCC1>[Si:7]([O:6][CH2:5][CH2:4][CH2:3][CH:27]([C:24]1[O:25][C:26]2[C:18]([O:17][CH3:16])=[CH:19][CH:20]=[CH:21][C:22]=2[CH:23]=1)[OH:28])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: COc1cccc2cc(C=O)oc12
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cccc2cc(C(O)CCCO[Si](C)(C)C(C)(C)C)oc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A suspension of dried magnesium turnings (0.42 g) in anhydrous tetrahydrofuran (20 ml) was treated with 2 ml of (3-Bromopropoxy)-tert-butyldimethylsilane (4.4 g) in anhydrous tetrahydrofuran (10 ml) at room temperature under a dry nitrogen atmosphere. Initiation was achieved by the addition of catalytic iodine and warming to 80° C. The remaining solution (8 ml) was then added carefully. The reaction was cooled to −5° C. and a solution of 7-methoxybenzofuran-2-carbaldehyde (3 g) in anhydrous tetrahydrofuran (20 ml) was added carefully. After stirring at ambient temperature overnight the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (100 ml) and saturated aqueous ammonium chloride solution (100 ml). The organic extract was dried over magnesium sulphate, filtered and preadsorbed onto silica. Purification by column chromatography on silica eluting with 10% ethyl acetate in hexane afforded the title compound as a yellow oil (4.88 g).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][NH:6][N:5]=1.Br[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1>[C:17]1([CH2:16][CH2:15][N:6]2[CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([NH2:3])=[N:5]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(CCc2ccccc2)nc1N
Yield: 64.6 %

Procedure:
250 ml of toluene and 0.1 ml of aqueous 12.5M sodium hydroxide solution were added to a mixture of 15.69 g of ethyl 3-amino-4-pyrazolecarboxylate, 24.34 g of (2-bromoethyl)benzene, 2.54 g of Adogen 464 and 27.74 g of potassium carbonate, and heated under reflux for 2.5 hours. The reaction solution was washed with 200 ml of water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (n-hexane-ethyl acetate=2:1→1:1→1:2) to obtain 16.94 g of 1-(2-phenylethyl)-3-amino-4-ethoxycarbonylpyrazole as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.Cl.[O:25]([NH2:27])[CH3:26].C(=O)(O)[O-].[Na+].CO.O>CO.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Cl:1][CH:2]1[C:10](=[C:11]=[N:27][O:25][CH3:26])[C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]1[C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17]
Reactant: O=Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CO
Product: CON=C=C1c2cc(Cl)c(Cl)cc2N([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.7 %

Procedure:
To a solution of 2,5,6-trichloro-3-formyl-1-(β-D-ribofuranosyl)indole (4.3, 103 mg, 0.27 mmol) in MeOH (5 mL) was added a solution of methoxylamine hydrochloride (27 mg, 0.32 mmol) and sodium bicarbonate (22 mg, 0.26 mmol) in water (1.0 mL). The resulting mixture was stirred at room temperature for 16 h, then the solvent was evaporated to provide a pale yellow residue. The residue was suspended in 10 mL of 5% aqueous sodium thiosulfate and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered and evaporated to yield a yellow residue. The residue was subjected to column chromatography (40×350 mm) on C18 reverse-phase silica gel with 80% MeOH/H2O. The appropriate UV-active fractions were pooled and evaporated to yield a white powder. The powder was recrystallized from Et2O to yield 45 mg (41%) of 4.30 as a white crystalline solid: mp 197-198 C; Rf 0.4 (10% MeOH/CHCl3); 1H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 5.93 (d, 1H), 5.42 (d, 1H, D2O exch.), 5.40 (t, 1H, D2O exch.), 5.27 (d, 1H, D2O exch.), 4.42 (q, 1H), 4.14 (m, 1H), 4.00 (d, 1H), 3.96 (s, 3H), 3.71 (m, 2H). 13C NMR (125 MHz, DMSO-d6) δ 141.84, 133.04, 129.74, 126.09, 125.03, 123.82, 121.70, 115.46, 105.59, 88.85, 86.13, 71.43, 69.65, 61.84, 61.09. HRMS (EI) m/z calcd. for C15H15Cl3N2O5 408.0047. found 408.0047. Anal calcd for C15H15Cl3N2O5: C, 43.98; H, 3.69; N, 6.84. Found: C, 43.79; H, 3.68; N, 6.61.
Reaction SMILES: C([Li])CCC.C1([SiH3])C=CC=CC=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[C:21](=[CH:23]/C)/[CH3:22])=[CH:17][CH:16]=1.[H][H]>C1COCC1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1
Reactant: C/C=C(\C)c1ccc(OC)cc1
Reactant: [H][H]
Agent: [Li]CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
In a dry sealable Schlenk flask under an argon atmosphere 0.0364 g (0.061 mmol) (S,S)-ethylene-1,2-bisη5 -4,5,6,7-tetrahydro-1-indenyl)titanium (S)-1,1'-binaphth-2,2'-diolate was dissolved in THF (10 mL). The vessel was degassed by exposure to vacuum (2×~10 sec), put under an atmosphere of hydrogen and subsequently cooled to 0° C. in an ice water bath. After equilibration, a solution of n-butyllithium (0.075 mL, 1.58 M in hexanes, 0.118 mmol, 1.94 equiv) was added and the mixture was allowed to stir for 10 min. Phenylsilane (0.017 mL, 0.133 mmol, 2.4 equiv) and 0.189 g (1.17 mmol, 19.2 equiv) E-2-(4-methoxyphenyl)-2-butene were then added. The flask was sealed and the solution moved into a dry box and transferred to a Parr® high pressure reaction vessel containing a magnetic stir bar. The pressure vessel was sealed and moved to a fume hood where it was charged to 2100 psig with hydrogen and placed in an oil bath at 69° C. The reaction mixture was allowed to stir for 65 h. The vessel was cooled to room temperature, vented and opened to air. The reaction mixture was worked up by partitioning between diethyl ether/hexane (1/4) and water and separating the layers. The organic extract was distilled at reduced pressure to yield 0.133g (0.811 mmol, 69%) of 2-(4-methoxyphenyl)propane with an ee of 96.2%.