Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5]CC)(=[O:4])[CH2:2][OH:3].[H-].[Na+].F[C:11]1[C:16]([CH:17]=O)=[C:15]([I:19])[CH:14]=[CH:13][CH:12]=1.[OH-].[Na+].Cl>CN(C)C=O.C(OCC)(=O)C.O>[C:1]([C:2]1[O:3][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([I:19])[C:16]=2[CH:17]=1)([OH:5])=[O:4]
Reactant: CCOC(=O)CO
Reactant: O=Cc1c(F)cccc1I
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1cc2c(I)cccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl glycolate (50.4 g) was added dropwise to a stirred suspension of sodium hydride (60% oil suspension, 38.7 g) in N,N-dimethylformamide (770 ml) for 8 minutes at 5-10° C. under nitrogen gas, and the mixture was stirred for 30 minutes at the same temperature. To the mixture was added dropwise over 10 minutes a solution of 6-fluoro-2-iodobenzaldehyde (110 g) in N,N-dimethylformamide (110 ml) at ambient temperature, and the mixture was stirred for 1.5 hours at 90-95° C. After cooling to 25° C., the reaction mixture was added 2N-sodium hydroxide (220 ml) and stirred for 1 hour at ambient temperature. The mixture was poured onto the mixture of water and ethyl acetate and the separated aqueous layer was adjusted to pH 2 with 6N-hydrochloric acid. The mixture was extracted with ethyl acetate and the extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 2-carboxy-4-iodobenzofuran. The mixture of the above residue and conc. sulfuric acid (20 ml) in methanol (200 ml) was heated under reflux for 16 hours. After evaporation of the solvent, the residue was added to water and the mixture was adjusted to pH 8 with potassium carbonate. The mixture was extracted with ethyl acetate and the extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give methyl 4-iodobenzofuran-2-carboxylate (16.13 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1.[CH3:31][C:32]([CH3:36])([CH3:35])[CH:33]=O>>[CH3:31][C:32]([CH3:36])([CH3:35])[CH2:33][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCNCC2)cn1
Reactant: CC(C)(C)C=O
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCN(CC(C)(C)C)CC2)cn1

Procedure:
Following the procedure for Example 81; 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (1-piperidin-4-yl-1H-imidazol-4-yl)-amide was reacted with trimethylacetaldehyde to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 18.8, 27.8, 30.5, 33.3, 33.8, 36.0, 43.1, 53.1, 53.3, 55.9, 69.6, 102.6, 102.9, 103.1, 105.8, 112.3, 112.6, 131.5, 137.6, 138.7, 162.0, 164.4, 169.2; MS 490.3 m/z (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.[CH3:40][N:41]1[C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][CH:43]=[N:42]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:25]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[S:22]([C:19]2[CH:20]=[CH:21][C:13]3[N:12]([C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:7][C:2]=4[C:45]4[N:41]([CH3:40])[N:42]=[CH:43][CH:44]=4)[CH2:17][CH2:16][O:15][C:14]=3[CH:18]=2)(=[O:24])=[O:23])=[CH:37][CH:36]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(C(F)(F)F)cc2Cl)cc1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(C(F)(F)F)cc2-c2ccnn2C)cc1
Temperature: 112 °C

Procedure:
A 5-mL glass microwave reaction vessel was charged with 4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE X, 0.150 g, 0.252 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.131 g, 0.629 mmol), 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (0.027 g, 0.038 mmol), and potassium phosphate (0.083 mL, 1.007 mmol). The vial was sealed and flushed with N2 and dioxane (1 mL) and water (0.32 mL) were added. The mixture was sparged with N2 for 5 min and heated microwave reactor at 112° C. for 3 h. The mixture was diluted with EtOAc and the organic layer was decanted, concentrate and absorbed onto a 5 g loading cartridge and passed through a silica gel column (12 g) using a gradient from 0% to 80% EtOAc in Heptanes to provide N-(4-methoxybenzyl)-4-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide. This product was dissolved in DCM (1 mL), cooled to 0° C., and trifluoroacetic acid was added (0.5 mL) dropwise. The solution was maintained at rt for 15 min, then concentrated to dryness. The residue was taken up in DCM and passed through an SCX column (10 g column), flushing with DCM. The product was released by treatment of the SCX column with ammonia (2.0 M) in methanol to afford EXAMPLE 42: 4-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.030 g, 0.058 mmol). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.66 (s, 2 H) 3.90 (s, 4 H) 4.11 (br. s., 1 H) 6.33 (d, J=1.82 Hz, 1 H) 6.49 (s, 1 H) 6.62-6.73 (m, 1 H) 7.05-7.15 (m, 2 H) 7.43 (d, J=1.82 Hz, 1 H) 7.67 (d, J=8.44 Hz, 1 H) 7.80 (s, 1 H) 7.85 (d, J=8.44 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[C:4]([F:32])[CH:3]=1.F[B-](F)(F)F.[N:38]1(OC(N(C)C)=[N+](C)C)[C:42]2[CH:43]=CC=C[C:41]=2N=N1.C(N(CC)C(C)C)(C)C.C(N)(C)C>C(#N)C.C(OCC)(=O)C.O>[CH:42]([NH:38][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=4[F:32])[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[CH:19]=1)=[O:22])([CH3:43])[CH3:41]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2c(F)cc(Cl)cc21
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)cc(F)c34)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
2-(6-Chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (59 mg, 0.124 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (60 mg, 0.186 mmol), N,N-diisopropylethylamine (0.11 ml, 0.62 mmol) and isopropylamine (11 ul, 0.124 mmol) were added together in acetonitrile (1.3 ml). The reaction was stirred at room temperature for 18 h then water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 46 mg (72%) of 2-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide. (M+H)+=517.
Reaction SMILES: I[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.O=O.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(N(CC)CC)C.CN(C=O)C.[Pd](Cl)Cl.[Cu]I>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1)([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: O=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1c[nH]c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 5-iodouracil (8g, 30mmol) in redistilled triethylamine (500 mL) and dry DMF (10mL) was deqassed with oxygen-free nitrogen for 15 minutes. Bis(triphenylophosphine palladium (II) chloride (0.5g), copper (I) iodide (0.5g) and trimethylsilylacetylene (10g, 102mmol ) were than added and the mixture was heated with stirring at 50° C for 24 hours. The cooled reaction mixture was filtered, the filtrate evaporated to dryness and the residue dissolved in dichloromethane (500mL). The organic solution was washed with a 2% aqueous solution of disodium EDTA (3×250mL), water (3×200mL), dried (Na2SO4) and evaporated to dryness. The residue was triturated with ethanol to give the first crop of the title compound. The solid filtered from the reaction mixture was also found to contain the required product but in a more impure form and so was worked up as above in a separate batch to give a second crop.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH:15]=[CH:14][C:13]=2[O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[N:4][N:3]=1.[NH2:32][C@@H:33]([C:40]([OH:45])([CH2:43][CH3:44])[CH2:41][CH3:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:41]([C:40]([OH:45])([CH2:43][CH3:44])[C@H:33]([NH:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH:15]=[CH:14][C:13]=2[O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[N:4][N:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:42]
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)c(-c3nnc(Cl)c4ccccc34)c2c1
Reactant: CCC(O)(CC)[C@H](N)c1ccccc1
Product: CCC(O)(CC)[C@H](Nc1nnc(-c2c(OS(=O)(=O)C(F)(F)F)ccc3ccc(OC)cc23)c2ccccc12)c1ccccc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To trifluoromethanesulfonic acid 1-(4-chlorophthalazin-1-yl)-7-methoxynaphthalen-2-yl ester (5.0 g, 11 mmol) was added 3-((R)-α-amino-benzyl)-pentan-3-ol (10 g, 52 mmol). The suspension was stirred for 18 hrs at 120° C. After cooling to 25° C., the mixture was filtered following addition of dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (toluene/EtOAc 10:1 to 5:1) to give the title compound as a brown solid, which was triturated from hexane/diethyl ether to give 4.8 g (7.7 mmol) of a pure product as a mixture of diastereomers.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11]O.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1.ClCCl>[Cl:15][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: OCc1ccc2ccccc2c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: ClCc1ccc2ccccc2c1

Procedure:
To 1.26 mol of naphth-2-yl-methanol in 1.5 liters of toluene there are slowly added 3.8 mol of thionyl chloride. The mixture is then heated at reflux for two hours. After cooling, the solvent is evaporated off. The crude product is taken up in toluene twice and evaporated. The oil obtained is taken up in dichloromethane, washed and dried. After filtering and evaporating, the oil obtained is distilled to yield the expected product.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([NH:10][C:11]([C:13]2[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:8][CH:7]=[C:6]([O:20][CH3:21])[N:5]=1.[CH3:22]I>CS(C)=O>[Br:3][C:4]1[C:9]([N:10]([CH3:22])[C:11]([C:13]2[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:8][CH:7]=[C:6]([O:20][CH3:21])[N:5]=1
Reactant: CI
Reactant: COc1ccc(NC(=O)c2cccnc2Cl)c(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(N(C)C(=O)c2cccnc2Cl)c(Br)n1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.3 g of a 50% dispersion in mineral oil) was added to dimethylsulfoxide (10 ml) and warmed to 50° C. After cooling the mixture to room temperature, N-(2-bromo-6-methoxy-3-pyridinyl)-2-chloro-3-pyridinecarboxamide (2.0 g) was added and the resulting solution was stirred for 10 min. Methyl iodide (0.4 ml) was then added and the mixture was stirred for 30 min. The reaction mixture was quenched by the addition of water (10 ml) and ethyl acetate (100 ml) was then added. The organic phase was washed with water (4×100 ml), dried (anhydrous magnesium sulfate), concentrated, and purified on a silica gel column (methylene chloride followed by methylene chloride/ethanol, 98:2) to give 1.9 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:13]=[CH:12][C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)[NH2:4].[F:14]C1C2NC=NC=2C=C(C#N)C=1>>[F:14][C:12]1[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=[C:5]([C:3](=[N:2][OH:1])[NH2:4])[CH:13]=1
Reactant: N#Cc1cc(F)c2[nH]cnc2c1
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Product: NC(=NO)c1cc(F)c2[nH]cnc2c1

Procedure:
The title compound was prepared following the procedure described for Intermediate 1, step 2, but starting from 7-fluoro-1H-benzimidazole-5-carbonitrile obtained in step 2 (750 mg; 4.65 mmol) as a beige solid (814 mg, 90%). 1H NMR (DMSO-d6) δ 12.88 (bs, 1H), 9.67 (s, 1H), 9.30 (s, 1H), 7.68 (s, 1H), 7.33-7.29 (m, 1H), 5.89 (s, 2H). LC/MS (Method B): 195.1 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[CH3:8]>C(O)C>[CH2:7]([C:9]1[CH:10]=[CH:11][C:12]([S:15]([OH:18])(=[O:16])=[O:17])=[CH:13][CH:14]=1)[CH3:8].[CH2:7]([O:5][C:4](=[O:6])[C@H:2]([CH3:3])[NH2:1])[CH3:8]
Reactant: C[C@H](N)C(=O)O
Agent: CCc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)[C@H](C)N
Temperature: 25 °C

Procedure:
L-alanine (1.50 g, 16.84 mmol) and 4-ethylbenzenesulfonic acid (4-EBS) (3.76 g, 20.20 mmol) were added to ethanol (15 ml), and the mixture was heated overnight at 70 EC to perform esterification. To complete the esterification reaction, the mixture was heated to 90 EC, and ethanol (200 ml) was added over 3.5 hours, while distilling away almost the same amount of ethanol. Thereafter, the solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure. The obtained oily residue was cooled in a refrigerator to allow partial crystallization. Diethyl ether (5 ml) and ethyl acetate (5 ml) were added, the residue was completely dissolved at 40° C., and the mixture was stirred at room temperature. Since crystallization occurred when a vessel containing the reaction solution was immersed in ice water, ethyl acetate (15 ml) was further added, and the mixture was stirred at room temperature to give a slurry. This slurry was cooled overnight in a refrigerator, and the crystals were separated and dried to give 2.98 g of L-alanine ethyl ester 4-ethylbenzenesulfonate (L-Ala-OEt 4-EBS salt) dry crystals (L-Ala-OEt 4-EBS salt content 98.5%, 9.67 mmol, yield 57.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[C:14]2[S:15][CH:16]=[C:17]([CH2:19][C:20]([O:22]CC)=[O:21])[N:18]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[C:14]2[S:15][CH:16]=[C:17]([CH2:19][C:20]([OH:22])=[O:21])[N:18]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1csc(-c2cnn(C)c2-c2ccc(F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Yield: 104.4 %

Procedure:
A solution of ethyl {2-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}acetate (245 mg, 0.709 mmol) and 6N aqueous sodium hydroxide solution (0.355 mL, 2.13 mmol) in ethanol (2.8 mL) was heated under reflux for 2 hr. Ethanol was evaporated, and 2N hydrochloric acid was added until the mixture became pH2. The precipitate was collected by filtration to give {2-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}acetic acid (235 mg, 100%) as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:22])=[C:4]([C:17]([CH3:21])=[CH:18][C:19]=1[CH3:20])[NH:5][CH2:6][C:7]([N:9]([CH3:16])[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([CH3:22])=[C:4]([C:17]([CH3:21])=[CH:18][C:19]=1[CH3:20])[NH:5][CH2:6][C:7]([N:9]([CH:10]1[CH2:15][CH2:14][N:13]([C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:12][CH2:11]1)[CH3:16])=[O:8]
Reactant: Cc1cc(C)c(NCC(=O)N(C)C2CCNCC2)c(C)c1N
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(NCC(=O)N(C)C2CCN(C(=O)c3ccccc3)CC2)c(C)c1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A mixture solution of 300 mg of the compound (23) obtained in the Example 23, 114 μl of benzoyl chloride and 206 μl of triethylamine in 5 ml of methylene chloride were stirred for 2 hours at 0° C. After the reaction, the solvent was removed and the obtained residue was purified by amine-coated silica gel (Fuji Silysia Chemical Ltd.; NH-DM1020) column chromatography (methylene chloride:ether=1:1) to give the above-mentioned compound (128) in 66% yield.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])=[N:2]1.[H-].[Na+].[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1.C(OCC)(=O)C>CN(C=O)C>[CH:20]1([CH2:23][N:1]2[CH:5]=[CH:4][C:3]([CH2:6][N:7]3[C:15](=[O:16])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8]3=[O:17])=[N:2]2)[CH2:22][CH2:21]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc[nH]n1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccn(CC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a colorless solution of 2-(1H-pyrazol-3-ylmethyl)-1H-Isoindole-1,3(2H)-dione (CAN 95533-75-8; 3.66 g, 16.1 mmol) in DMF (80 mL) at 0° C. was added in 4 portions sodium hydride (1.29 g, 32.2 mmol) within 15 min. After warming to room temperature the mixture was stirred for 30 min and cyclopropylmethyl bromide (21.7 g, 15.6 mL, 161 mmol) in DMF (20 mL) was added within 30 min. The mixture was stirred for 22 h at room temperature, poured into ethyl acetate (200 mL) and extracted with water (3×100 mL). Water phases were washed with ethyl acetate (200 mL), organic phases were combined, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 100% EtOAc in heptane) and finally by preparative HPLC to give 1.63 g (36%) of the title compound as a white solid; MS (EI): 282.2 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[NH:5][CH:6]=1.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[CH:17])[CH:11]=1.C(N(CC)CC)C.CCCCCC>CN(C=O)C.O.[Cu](I)I.C(OCC)(=O)C>[Br:9][C:10]1[CH:11]=[C:12]([C:16]#[C:17][C:2]2[CH:3]=[C:4]([CH:7]=[O:8])[NH:5][CH:6]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1cc(I)c[nH]1
Reactant: C#Cc1cccc(Br)c1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(C#Cc2cccc(Br)c2)c[nH]1
Yield: 93.5 %

Procedure:
A solution of 4-iodo-1H-pyrrole-2-carbaldehyde (0.50 g; 2.262 mmol) and bis(triphenylphosphine)palladium-(II)chloride (0.079 g; 0.113 mmol)) in DMF (15 mL; degassed with nitrogen for 30 minutes) was stirred at ambient temperature for 15 minutes. Then the following were added: 1-bromo-3-ethynylbenzene (0.61 g; 3.394 mmol), copper iodide (43 mg; 0.226), and triethylamine (1.58 mL, 11.3 mmol). The course of the reaction was followed with TLC (4:1, hexane:ethyl acetate). After 2 hours the reaction mixture was diluted with water and the organic material was extracted into dichloromethane. The organic extracts were washed with water and brine, dried over MgSO4, filtered, and evaporated. The residue was chromatographed on silica gel using 3:1 hexane:ethyl acetate to yield 0.58 g (93%) of the title compound as a yellow crystalline solid, mp 152-156° C.; MS (ES) m/z 272.0, [M−H]−.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH2:6][CH3:7])[CH:3]=[O:4].[CH:8]1([Mg]Cl)[CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH3:1][C:2]([CH:3]([CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[OH:4])=[CH:5][CH2:6][CH3:7]
Reactant: CCC=C(C)C=O
Reactant: Cl[Mg]C1CCCC1
Product: CCC=C(C)C(O)C1CCCC1
Reaction time: 1.5 h

Procedure:
To a dry 2 liter multi-neck round bottom flask fitted with an air stirrer, nitrogen inlet condenser and an addition funnel 800 ml of 2 M of cyclopentyl magnesium chloride was added and stirred. 139 g of 2-methyl-2-pentenal was added over the next 90 minutes. The reaction mixture was aged for another 90 minutes and the first sample was taken. 25 minutes later the reaction mixture was quenched with water, aged for 30 minutes and the organic layer was separated and washed with 2 one liter portions of water. The NMR spectrum of the Alpha-[1-Methyl-1-Butenyl]-Cyclopentanemetanol is as follows: 1.00 ppm (s, 3H); 1.1-1.2 ppm (s, 1H); 1.4-1.5 ppm (s, 2H); 1.5-1.7 ppm (m, 4H); 1.8 ppm (s, 1H); 2.1 ppm (m, 3H); 3.7 ppm (d, 1H); 5.4 ppm (t, 1H)
Reaction SMILES: C1(N)CCCCC1.[C:8]([O:12][C:13](=[O:28])[CH2:14][C@@H:15]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]([OH:18])=[O:17])([CH3:11])([CH3:10])[CH3:9].C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[OH-].[Na+:49]>O>[Na+:49].[C:8]([O:12][C:13](=[O:28])[CH2:14][C@@H:15]([CH2:19][CH2:20][CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[C:16]([O-:18])=[O:17])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: NC1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.8 %

Procedure:
(R)-2-[2-(tert-Butoxy)-2-oxoethyl]-5-phenylpentanoic acid cyclohexylamine salt (Preparation 166, 6.8 g, 17 mmol) and ethyl acetate (100 ml) were added to an aqueous solution of citric acid (10%, 100 ml) and the organic phase was separated and washed with water (100 ml). Iso-propyl alcohol (20 ml) and 5% rhodium on alumina (51.6 g) were added and the mixture was stirred at room temperature, under hydrogen (10 atmospheres, 150 p.s.i.) for 48 hours and then filtered through celite. To the filtrate was added a solution of sodium hydroxide (0.67 g, 17 mmol) in water and the mixture was stripped and replaced with acetonitrile by distillation at atmospheric pressure to a volume of 30 ml. The mixture was allowed to cool to room temperature where it was stirred for 24 hours. The mixture was cooled to 0° C. and then filtered. The residue was washed with acetonitrile (2×10 ml) and then dried in vacuo at 45° C. for 2 hours to leave the title compound as a colourless solid (3.8 g, 69% yield, 95% pure by NMR).
Reaction SMILES: [OH:1][C:2]1[C:25]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=[C:24]([O:31][CH2:32][O:33][CH3:34])[CH:23]=[C:22]([O:35][CH2:36][O:37][CH3:38])[C:3]=1[C:4](=[O:21])[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH2:16][O:17][CH3:18])=[C:9]([O:19][CH3:20])[CH:8]=1>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[C:25]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[C:24]([O:31][CH2:32][O:33][CH3:34])[CH:23]=[C:22]([O:35][CH2:36][O:37][CH3:38])[C:3]=1[C:4](=[O:21])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH2:16][O:17][CH3:18])=[C:9]([O:19][CH3:20])[CH:8]=1
Reactant: COCOc1cc(OCOC)c(C(=O)C=Cc2cc(OC)c(OCOC)c(OC)c2)c(O)c1CC=C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1cc(OCOC)c(C(=O)CCc2cc(OC)c(OCOC)c(OC)c2)c(O)c1CCC(C)C
Yield: 98.5 %

Procedure:
Then, 26.9 g of 2'-hydroxy-3,5-dimethoxy-4,4',6'-tris(methoxymethoxy)-3'-(3-methyl-2-butenyl)chalcone was dissolved in 400 ml of ethyl acetate, and catalytic reduction was carried out by using 5% palladium/carbon. The reaction liquid was filtered through Celite to obtain 26.7 g (yield=98.5%) of 1-[2-hydroxy-4,6-bis(methoxymethoxy)-3-isopentylphenyl]-3-(3,5-dimethoxy-4-methoxymethoxyphenyl)-1-propanone.