Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[O:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:4](=[O:15])[C:3]1([CH3:17])[CH3:16].C(N(CC)CC)C.[O-:25][CH2:26][CH3:27].[Na+]>C(O)C>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][N:5]1[C:4](=[O:15])[C:3]([CH3:17])([CH3:16])[CH:2]([O:25][CH2:26][CH3:27])[O:6]1
Reactant: CC1(C)C(=O)N(Cc2ccccc2Cl)OC1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC1ON(Cc2ccccc2Cl)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
To a stirred solution of 3.0 grams (0.011 mole) of 5-chloro-2-[(2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone (Example 23 (A)) in 30 ml of absolute ethanol was added dropwise 1.2 grams (0.012 mole) of triethylamine. Upon completion of addition the reaction mixture was heated under reflux for 18 hours; thin layer chromatography of the reaction mixture indicated no reaction had taken place. The reaction mixture was cooled, 0.74 gram (1 equiv.) of sodium ethoxide was added, and the reaction mixture was stirred at ambient temperature for two hours; again thin layer chromatography on the reaction mixture indicated that no reaction had taken place. The reaction mixture was filtered and diluted with 150 ml of methylene chloride. The mixture was washed with two 100-ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give an oil residue. The oil was distilled at 80°/3.3 Pa. using a short-path distilling system. Nuclear magnetic resonance spectroscopy indicated 83% of the distillate to be the desired product. The distillate was subjected to column chromatography on silica gel, using 20% ethyl acetate in heptane for elution. The appropriate fractions were combined and concentrated under reduced pressure to give 1.3 grams of 2-[(2-chlorophenyl)methyl]-5-ethoxy-4,4-dimethyl-3-isoxazolidinone as an oil.
Reaction SMILES: [CH2:1]([N:3]([CH3:25])[C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([OH:23])=O)=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:2].[NH:26]1[CH2:29][CH2:28][CH2:27]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:1]([N:3]([CH3:25])[C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([N:26]3[CH2:29][CH2:28][CH2:27]3)=[O:23])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:2]
Reactant: CCN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Reactant: C1CNC1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Yield: 94.2 %

Procedure:
A mixture of 5-(2-(ethyl(methyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (144 mg, 419 μmol), azetidine (84.8 μl, 1.26 mmol), propylphosphonic anhydride (50% in ethyl acetate, 618 μl, 1.05 mmol) and N,N-diisopropylethylamine (214 μl, 1.26 mmol) in tetrahydrofuran (7 ml) was refluxed for 2.5 days (weekend). The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(ethyl-methylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (151 mg white solid, 94.1%) as a white solid. mp: 229-232° C., MS: m/z=383.1 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]([CH3:35])[C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:18][N:19]([CH3:35])[C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[O:26])[CH2:21]1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.1 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (60.9 mg, 53%).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:10]([CH2:22][C:23]([OH:25])=[O:24])[CH2:9][CH2:8][CH2:7]2.[CH2:26](O)[CH3:27]>>[CH2:26]([O:24][C:23](=[O:25])[CH2:22][CH:10]1[C:11]2[C:6](=[CH:5][C:4]([OH:3])=[C:13]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=2)[CH2:7][CH2:8][CH2:9]1)[CH3:27]
Reactant: O=C(O)CC1CCCc2cc(O)c(C(=O)c3ccccc3)cc21
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)CC1CCCc2cc(O)c(C(=O)c3ccccc3)cc21

Procedure:
Analogously to the description in Example 2, 5.5 g of 6-hydroxy-7-benzoyl-1,2,3,4-tetrahydro-naphthalene-acetic acid ethyl ester and 20 ml of 2 N sodium hydroxide solution in 250 ml of ethanol give 6-hydroxy-7-benzoyl-1,2,3,4-tetrahydro-1-naphthylacetic acid in the form of yellow crystals of melting point 118°-120° C (from ether-petroleum ether).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[S:17][C:16]([N:18]3[CH2:25][C:24]4[CH2:23][NH:22][CH2:21][C:20]=4[CH2:19]3)=[N:15][CH:14]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C([O-])=O.[Br:33][C:34]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:35]=1[C:36](O)=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[S:17][C:16]([N:18]3[CH2:25][C:24]4[CH2:23][N:22]([C:36](=[O:37])[C:35]5[CH:39]=[C:40]([O:43][CH3:44])[CH:41]=[CH:42][C:34]=5[Br:33])[CH2:21][C:20]=4[CH2:19]3)=[N:15][CH:14]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: O=C(NCCCc1ccccc1)c1cnc(N2CC3=C(CNC3)C2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Product: COc1ccc(Br)c(C(=O)N2CC3=C(C2)CN(c2ncc(C(=O)NCCCc4ccccc4)s2)C3)c1

Procedure:
N-(3-Phenylpropyl)-2-(3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)thiazole-5-carboxamide, trifluoroacetate (44.6 mg, 0.095 mmol) was reacted with 2-bromo-5-methoxybenzoic acid after activation with HATU analogously to example 3f. M+H+: 567.17.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:31](B1OC(C)(C)C(C)(C)O1)([CH3:33])=[CH2:32]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:31]([CH3:33])=[CH2:32])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=C(C)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12

Procedure:
In a manner similar to that described in Scheme 1 (Step 3), 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (3a) was coupled with isopropenylboronic acid pinacol ester to provide 6-chloro-3-(prop-1-en-2-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine. MS ESI calc'd. for C28H22ClIN3 [M+1]+ 436, found 436.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:36])([CH3:35])[C:23]([O:25]CC1C=CC(OC)=CC=1)=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:36])([CH3:35])[C:23]([OH:25])=[O:24])=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: COc1ccc(COC(=O)C(C)(C)CCCOC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(C)(C)C(=O)O
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate (8.24 g, 16.5 mmol) in CH2Cl2 (100 mL) at room temperature, was added trifluoroacetic acid (5 mL). After 1 h at room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 3→5% MeOH in CH2Cl2), to give 6.00 g of 5-(N-CBz-L-valyloxy)-2,2-dimethylvaleric acid. The compound can be activated and directly esterified to a drug or further modified as described below.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1([CH3:13])[CH3:12].C(N(CC)CC)C.[CH3:21][C:22]1[N:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[S:37][CH:38]=[C:39]([C:41](Cl)=[O:42])[N:40]=3)[CH2:32][CH2:31]2)=[O:29])[N:25]=[C:24]([C:44]([F:47])([F:46])[F:45])[CH:23]=1>ClCCl>[CH3:12][C:4]1([CH3:13])[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:3]1[N:2]([CH3:1])[C:41]([C:39]1[N:40]=[C:36]([CH:33]2[CH2:34][CH2:35][N:30]([C:28](=[O:29])[CH2:27][N:26]3[C:22]([CH3:21])=[CH:23][C:24]([C:44]([F:46])([F:47])[F:45])=[N:25]3)[CH2:31][CH2:32]2)[S:37][CH:38]=1)=[O:42]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Reactant: CNC1c2ccccc2CC1(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)C3c4ccccc4CC3(C)C)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.3 %

Procedure:
To a solution of 2,3-dihydro-N,2,2-trimethyl-1H-inden-1-amine (193 mg, 1.1 mmol) and triethylamine (0.19 mL, 1.38 mmol) in 5 mL of dichloromethane was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (386 mg, 0.92 mmol) (i.e. the product of Example 19, Step D) at 0° C. The reaction mixture was stirred at room temperature for 16 h, diluted with 4 mL of dichloromethane, and washed with water, 1 N aqueous hydrochloric acid, water, saturated solution of sodium bicarbonate and brine. The filtered reaction mixture was dried over magnesium sulfate and concentrated in vacuo to give 300 mg of the title compound, the product of present invention as a white foam.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[OH:15].Cl[C:17]1[S:21][C:20]([C:22](=[O:24])[CH3:23])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26].O>O1CCCC1>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][C:17]1[S:21][C:20]([C:22](=[O:24])[CH3:23])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Oc1ccc(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc([N+](=O)[O-])c(Oc2ccc(Cl)cc2Cl)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
Potassium t-butoxide (0.30 g, 2.67 mmol) was suspended in anhydrous tetrahydrofuran (25 mL), 2,4-dichlorophenol (0.40 g, 2.43 mmol) was added and the resulting mixture was stirred at ambient temperature under nitrogen for 30 minutes. After this time, 1-(5-chloro-4-nitro-2-thienyl)ethanone (0.5 g, 2.43 mmol) was added, the resulting mixture was stirred at ambient temperature for 45 minutes, then it was poured into water (100 mL) and stirred at ambient temperature overnight. The resulting solid was collected by filtration, washed with water (2×10 mL) and dried in air. The crude product was dissolved in acetonitrile (7 mL), the resulting solution was evaporated to near dryness and the residue was triturated with diethyl ether (2 mL). The resulting solid was collected by filtration and dried in vacuo at 40° C. overnight to afford the title product as a solid (0.45 g, 55% yield). 1H NMR (300 MHz, d6-acetone) δ: 8.15 (1H, s), 7.68 (1H, d), 7.51 (2H, m), 2.45 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:19][CH2:18][C:13]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:12][CH:11]=2)=[C:6]([F:20])[C:5]=1[F:21])[CH3:2].C([OH:24])C.[OH-].[Na+].OO>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:19][CH2:18][C:13]3([O:14][CH2:15][CH2:16][O:17]3)[CH2:12][CH:11]2[OH:24])=[C:6]([F:20])[C:5]=1[F:21])[CH3:2]
Reactant: CCO
Reactant: CCOc1ccc(C2=CCC3(CC2)OCCO3)c(F)c1F
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(C2CCC3(CC2O)OCCO3)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1400 ml (1.40 mol) of borane/THF complex (1 M solution) are added at −7° C. to a solution of 320.0 g (1.08 mol) of 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene in 3000 ml of THF, and the reaction mixture is stirred at room temperature for 3 h. 262 ml (4.50 mol) of ethanol, 650 ml (2.6 mol) of aqueous sodium hydroxide solution (4 M) and 360 ml (4.11 mol) of aqueous hydrogen peroxide soln. (35%) are added successively to the batch, during which the internal temperature does not exceed 47° C. (ice bath). When the addition is complete, the mixture is refluxed for 2 h, and the solution is cooled, added to water and stirred vigorously. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product (336 g of yellow oil) is purified by column chromatography (SiO2, dichloromethane: MTBE=8:2), giving 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decan-7-ol as pale-yellow oil.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][C:3]=1[CH:8]=[O:9].[CH3:10][C:11]1[CH:12]=[C:13]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:14]=[CH:15][C:16]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[Br:7][C:6]1[C:2]([C:16]2[CH:15]=[CH:14][C:13]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:12][C:11]=2[CH3:10])=[C:3]([CH:8]=[O:9])[S:4][CH:5]=1
Reactant: Cc1cc(NS(C)(=O)=O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=Cc1scc(Br)c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(NS(C)(=O)=O)ccc1-c1c(Br)csc1C=O
Temperature: 100 °C
Yield: 323.9 %

Procedure:
To the solution of Intermediate 1 (4 g, 15 mmol) in a mixture of DME and H2O (150 mL/50 mL) were added N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (3.6 g, 1.65 mmol) and Na2CO3 (2.8 g, 3.1 mmol), the mixture was degassed with N2, and Pd(PPh3)4 (500 mg) was added, then the mixture was heated to 100° C. under N2 overnight. The reaction solution was concentrated to remove the organic solution, then the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure, the residue was purified by column chromatography to give N-(4-(4-bromo-2-formylthiophen-3-yl)-3-methylphenyl)methanesulfonamide (2.0 g, yield 35.7%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13]/[CH2:14][OH:15])=[CH:8][CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:35]([O:37][C:38](=[O:51])[C@@H:39]([O:48][CH2:49][CH3:50])[CH2:40][C:41]1[CH:46]=[CH:45][C:44](O)=[CH:43][CH:42]=1)[CH3:36]>C1C=CC=CC=1>[CH2:35]([O:37][C:38](=[O:51])[C@@H:39]([O:48][CH2:49][CH3:50])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:15][CH2:14]/[CH:13]=[C:12](/[C:9]2[CH:10]=[CH:11][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][CH:8]=2)\[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:43][CH:42]=1)[CH3:36]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: OC/C=C(\c1ccccc1)c1ccc(-c2ccco2)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\c2ccccc2)c2ccc(-c3ccco3)cc2)cc1)OCC
Yield: 52.7 %

Procedure:
Reaction of (E)-3-(4-furan-2-yl-phenyl)-3-phenyl-prop-2-en-1-ol (475 mg, 1.72 mmol), tributylphosphine (0.63 ml, 2.58 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (451 mg, 1.89 mmol) and azodicarboxylic dipiperidide (650 mg, 2.58 mmol) in benzene in an identical manner to example 3 gave the title compound (450 mg, 53%).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[C:29]1[N:30]=[CH:31][C:32](/[CH:35]=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N:33][CH:34]=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]12([C:11]3[CH:12]=[C:13]([C:29]4[CH:34]=[N:33][C:32](/[CH:35]=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31][N:30]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OB(O)c1ccc(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)c1
Reactant: CCOC(=O)/C=C/c1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCOC(=O)/C=C/c1cnc(-c2ccc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)c2)cn1
Temperature: 90 °C
Yield: 91.4 %

Procedure:
To a solution of 3-(1-adamantyl)-4-benzyloxyphenylboronic acid (474 mg, 1.31 mmol) and ethyl(E)-3-(5-bromo-2-pyrazinyl)-2-propenoate (278 mg, 1.08 mmol) in DME (11 mL, degassed) was added tetrakis(triphenylphosphine)palladium (151 mg, 0.13 mmol) and degassed 2 M Na2CO3 (2.3 mL). The reaction mixture was heated at reflux (90° C. oil-bath) for 19.5 h, cooled to room temperature, and then diluted with EtOAc (155 mL). The organic layer was washed (H2O and brine) and dried. After solvent removal at reduced pressure, the residue was purified on silica gel (10% to 25% EtOAc/hexane) to give 488 mg (91%) of ethyl(E)-3-{2-[3-(1-adamantyl)-4-benzyloxyphenyl]-5-pyrazinyl}-2-propenoate as a yellow solid, mp 145-148° C. IR 2899, 1710, 1238 cm−1; 1H NMR δ (CDCl3) 1.35 (t, J=7.3 Hz, 3H, OCH2CH3), 1.73 (bs, 6H, AdCH2), 2.06 (bs, 3H, AdCH), 2.20 (bs, 6H, AdCH2), 4.29 (q, J=7.3 Hz, 2H, OCH2CH3), 5.19 (s, 2H, CH2), 6.98 (d, J=15.9 Hz, 1H, CH═CHCO), 7.04 (d, J=8.5 Hz, 1H, 5-ArH), 7.28-7.52 (m, 5H, C6H5), 7.72 (d, J=15.9 Hz, 1H, CH═CHCO), 7.84 (dd, J=8.5 Hz, 2.4 Hz, 1H, 6-ArH), 8.02 (d, J=2.4 Hz, 1H, 2-ArH), 8.63 (d, J=1.24 Hz, 1H, 3-PyrH), 8.99 ppm (d, J=1.24 Hz, 1H, 6-PyrH). HRMS calcd C32H34N2O3 [M+H]+ 495.2642. found 495.2659.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:35]([NH2:39])([CH3:38])([CH3:37])[CH3:36]>C1COCC1.CC#N>[C:35]([NH:39][C:9]([C:6]1[CH:5]=[C:4]([CH2:3][C:2]([CH3:1])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:11])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)Cc1cc(C(=O)O)no1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)Cc1cc(C(=O)NC(C)(C)C)no1
Reaction time: 0.5 h

Procedure:
To a solution of 5-(2,2-dimethyl-propyl)-isoxazole-3-carboxylic acid (125.4 g, 0.685 mol) in THF (1500 ml) and MeCN (1500 ml) is added HOBT (101.75 g, 0.753 mol) and EDCI (144.3 g, 0.753 mol). After stirred 30 min, tert-butyl amine (86.7 ml, 0.821 mol) is added dropwise under nitrogen atmosphere and then the reaction is stirred at rt for 1.5 h. The solvents are evaporated under reduced pressure and the residue is taken into DCM (2000 ml). The mixture is washed with saturated aq sodium bicarbonate (500 ml×2), the organic layer is dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica (DCM) to give the product as white solid.
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4].[H-].[Na+].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[O:24]([CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccccc1
Reactant: CCCCCCCCCCC(Br)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCC(Oc1ccccc1)C(=O)O
Reaction time: 17 h
Yield: 92 %

Procedure:
To 2-bromododecanoic acid (500 mg) dissolved in N,N-dimethylformamide (DMF, 10 ml) at 0° C. were added 60% sodium hydride (163 mg) followed by phenol (154 mg), and the mixture was stirred for 17 hours. Then, the solvent (DMF) was evaporated, and the residue was distributed into water and ethyl acetate. The ethyl acetate layer was dried and concentrated to give 2-phenoxydodecanoic acid (440 mg). To 2-phenoxydodecanoic acid (440 mg) dissolved in DMF were added para-nitrophenol (190 mg) and N,N'-dicyclohexylcarbodiimide (283 mg), and the mixture was stirred for 15 hours. Then, precipitates produced were removed by filtration, and 6-(4'-N-glycylspicaminyl-amino)purine hydrochloride (529 mg) and triethylamine (2.0 ml) were added to the filtrate. The mixture was further stirred for 15 hours. The DMF was evaporated from the reaction mixture, and the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK242 in the yield of 118 mg.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:15][C:16](=[O:27])[C:17]2[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=2[N:19]=1)[CH3:6].O>S(=O)(=O)(O)O>[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]=1[C:14]1[NH:15][C:16](=[O:27])[C:17]2[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=2[N:19]=1)[CH3:6]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3OCC)nc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc([N+](=O)[O-])ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
Concentrated nitric acid (0.5 ml) was added dropwise to a stirred solution of 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1.6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2.0 g, 0.0064 mol) in concentrated sulphuric acid (10 ml) at 0° C., and the resulting orange solution was stirred at room temperature for 18 hours. The reaction solution was then added dropwise to stirred ice and water (200 g) and the solid precipitate collected by filtration. This solid was then dissolved in dichloromethane (50 ml) and the solution washed successively with brine (2×30 ml) and water (30 ml), dried (Na2SO4) and evaporated under vacuum to give a yellow solid. Crystallisation from acetonitrile gave the title compound as yellow needles (1.40 g, 61%), m.p. 214-216° C. Found: C,57.35; H,5.21; N,19.49. C17H19N5O4 requires C,57.13; H,5.36; N,19.60%.