Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC([O-])(C)C.[K+].[CH3:12][O:13][C:14]([C:16]1[C:21]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])=[C:20]([F:30])[C:19](Cl)=[C:18]([C:32](=[O:34])[CH3:33])[N:17]=1)=[O:15]>C1COCC1>[CH3:12][O:13][C:14]([C:16]1[C:21]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])=[C:20]([F:30])[C:19]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])=[C:18]([C:32](=[O:34])[CH3:33])[N:17]=1)=[O:15]
Reactant: CC(C)=NO
Reactant: COC(=O)c1nc(C(C)=O)c(Cl)c(F)c1Nc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1nc(C(C)=O)c(ON=C(C)C)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of acetone oxime (2.20 equivalents) at room temperature is added t-BuOK (2.20 equivalents, 1.0 M solution in THF). After stirring for 30 minutes room temperature, the reaction mixture is cooled to 0° C. A solution 6-acetyl-5-chloro-4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (1.00 equivalent) in THF is added. After stirring for 1 hour at 0-5° C., the reaction mixture is quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4, concentrated in vacuo to give 6-acetyl-4-fluoro-3-(2-fluorophenylamino)-5-isopropylideneaminooxy-pyridine-2-carboxylic acid methyl ester that is used directly. A mixture of 6-acetyl-4-fluoro-3-(2-fluorophenylamino)-5-isopropylideneaminooxy-pyridine-2-carboxylic acid methyl ester in 5% aqueous MeOH is refluxed with stirring for 1 hour. The reaction mixture is diluted with EtOAc and washed with water. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by flash column chromatography to afford the desired product.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]#[N:18])(=[O:15])=[O:14])=[CH:9][CH:8]=1.Cl.C(N(CC)CC)C.[N-:27]=[N+:28]=[N-:29].[Na+]>C(OCC)(=O)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([CH2:16][C:17]2[NH:29][N:28]=[N:27][N:18]=2)(=[O:14])=[O:15])=[CH:11][CH:12]=1
Reactant: N#CCS(=O)(=O)c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(Cc1nnn[nH]1)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
To an N,N-dimethylformamide (100 ml) solution of 4-chlorophenylsulfonylacetonitrile (2.81 g, 13.0 mmol) and triethylamine hydrochloride (4.24 g, 65.2 mmol) was added sodium azide (10.8 g, 78.2 mmol) and the mixture was stirred at 80° C. for 16 hours. The reaction mixture was then cooled to room temperature. Ethyl acetate was added and the mixture was washed with a saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting solid was washed with diethyl ether and then, collected by filtration, whereby the title compound (2.53 g, 9.78 mmol, 75%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>CN(C)C=O.C(O)C>[CH2:29]([N:26]1[CH2:27][CH2:28][CH:23]([NH:22][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:14][CH:13]=2)[CH2:24][CH2:25]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](CNC1CCN(Cc2ccccc2)CC1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-amino-1-benzylpiperidine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=476.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:20])[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.[CH3:46][N:47]1CCCC1=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[C-]#N.[Zn+2].[C-]#N>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:46]#[N:47])=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:20])[N:3]=1
Reactant: Cc1cc2cc(OS(=O)(=O)C(F)(F)F)ccc2c(N)n1
Reactant: CN1CCCC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: Cc1cc2cc(C#N)ccc2c(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Palladium acetate (0.28 g) was added to a heated mixture of trifluoro-methanesulfonic acid 1-amino-3-methylisoquinolin-6-yl ester (1.9 g), zinc cyanide (0.74 g) and triphenylphosphine (0.33 g) in 24 mL of N-methyl-pyrrolidone at 190° C. (exothermic!). Stirring was continued at 190° C. for 2 h After cooling to room temperature, ethyl acetate was added and the organic mixture washed with 2N aqueous ammonia, water and brine and dried (magnesium sulfate). Filtration and concentration afforded a brownish oil, which was purified by silica chromatography (dichloromethane/methanol=98/2) to give 0.68 g of the title compound. ESI-MS: 184 (MH+).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:11](O)=O)[CH3:10])=O)(C)(C)C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][C@@H:9]([NH2:8])[CH2:11][N:25]1[CH2:26][CH2:27][N:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH3:14])[CH2:23][CH2:24]1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccccc1N1CCNCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C[C@@H](C)N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a chilled solution of t-butoxycarbonyl D-alanine (9.45 g, 0.05 mol) and 1-(2-methoxyphenyl)piperazine (9.6 g, 0.05 mol) in 125 mL of CH2Cl2 was added diethyl cyanophosphonate (8.34 mL, 0.055 mol) in 50 mL of CH2Cl2 over 30 minutes followed by triethylamine (7.37 mL, 0.055 mol) in 50 mL of CH2Cl2 over 15 minutes. After 21/2 hours, the solution was washed with water (2×100 mL) and K2CO3 (2×100 mL of 10% aqueous), dried over anhydrous K2CO3 and evaporated to an oil. The crude 1-(t-butoxycarbonyl-D-alanyl)-4-(2-methoxyphenyl)piperazine was stirred in 200 mL of 4.5N HCl in ethyl acetate for 1 hour at room temperature, diluted with 400 mL of anhydrous diethyl ether, filtered, washed and dried in vacuo. The 1-(D-alanyl)-4-(2-methoxyphenyl)piperazine dihydrochloride was stirred in 200 mL of anhydrous tetrahydrofuran, treated with 225 mL of 1M BH3 in tetrahydrofuran, and refluxed 31/2 hours. After cooling in ice, the reaction was quenched with 140 mL of 2N aqueous HCl and refluxed 18 hours The tetrahydrofuran was removed on a Rotovapor, the aqueous solution was made basic with 6N sodium hydroxide and the amine was extracted into diethyl ether. The diethyl ether solution was dried over anhydrous K2CO3, filtered and acidified with 4.5N HCl in ethyl acetate. The salt was filtered, washed with diethyl ether, converted to free base in 2N NaOH and extracted into diethyl ether. After drying as above and evaporation, (R)-1-methyl-2-[4-(2-methoxyphenyl)-piperazinyl]ethylamine was obtained as an oil (11.8 g, 94.7% based on BOC-D-alanine). A sample was converted to the trihydrochloride sesquihydrate, mp. 219°-221° C.; [α]D25 =-26.4 c=0.99 MeOH. 1H NMR (DMSO-d6) δ: 1.32 (d, 3H), 3.8 (s, 3H), 6.9-7.0 (m, 4H). The IR curve was devoid of carbonyl peaks.
Reaction SMILES: C([C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:10](=[N:26][N:27]([CH2:30][CH3:31])[C:28]=3[CH3:29])[C:11]([N:19](C([O-])=O)C([O-])=O)=[N:12][C:13]=2[C:14]=1C(C)(C)C)(C)(C)C.C(C1C=CC2C3C(=NN(CCC)C=3C)C(N(C([O-])=O)C([O-])=O)=NC=2C=1C(C)(C)C)(C)(C)C.[O:64]=[C:65]1[CH2:70][CH2:69][S:68][CH2:67][CH2:66]1.C1(=O)CCC1>>[NH2:19][C:11]1[C:10]2=[N:26][N:27]([CH2:30][CH3:31])[C:28]([CH2:29][C:65]3([OH:64])[CH2:70][CH2:69][S:68][CH2:67][CH2:66]3)=[C:9]2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:14][C:13]=2[N:12]=1
Reactant: CCn1nc2c(N(C(=O)[O-])C(=O)[O-])nc3c(C(C)(C)C)c(C(C)(C)C)ccc3c2c1C
Reactant: O=C1CCSCC1
Agent: CCCn1nc2c(N(C(=O)[O-])C(=O)[O-])nc3c(C(C)(C)C)c(C(C)(C)C)ccc3c2c1C
Agent: O=C1CCC1
Product: CCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCSCC1

Procedure:
4-[(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]tetrahydro-2H-thiopyran-4-ol was prepared according to the method of Example 1 Part F using di(tert-butyl)2-ethyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate in lieu of di(tert-butyl)1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate and 4-oxothiane in lieu of cyclobutanone. The crude product was recrystallized from acetonitrile to provide 0.475 g of 4-[(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]tetrahydro-2H-thiopyran-4-ol as a white powder, mp 251.5-255° C.
Reaction SMILES: ClC1C=CC([C:8]2[C:9](=[O:26])[CH:10]=[C:11]([CH:24]=[O:25])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=CC=1.[BH4-].[Na+]>CO>[OH:25][CH2:24][C:11]1[O:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:8][C:9](=[O:26])[CH:10]=1
Reactant: CS(=O)(=O)c1ccc(-c2oc(C=O)cc(=O)c2-c2ccc(Cl)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2cc(=O)cc(CO)o2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a solution of 5-(4-chlorophenyl)-6-(4-methanesulfonylphenyl)-4-oxo-4H-pyran-2-carbaldehyde (1.8 g, 4.6 mmoles) in methanol (30 ml), sodium borohydride (0.26 g, 6.9 mmoles)was slowly added at 0° C. The resulting mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated and the residue was solved in ethyl acetate. The organic layer was washed with water, dried (Na2SO4), and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography with silica gel and ethyl acetate/n-hexane (1:1) as eluent. 3-4-chlorophenyl)-6-hydroxymethyl-2-(4-methanesulfonylphenyl)pyran-4-one (0.9 g) was obtained. m.p. 120° C. (Compound 60 in Table 4).
Reaction SMILES: [H][H].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.C(=O)C1C=CC=CC=1>CO>[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=Cc1ccc(O)cc1
Solvent: CO
Solvent: O=Cc1ccccc1
Product: OCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A 1.0 g quantity of the catalyst (CuO/ZnO/Aluminium oxide) in 50 ml methanol was placed in a 300 ml capacity Parr reactor. The contents were treated with hydrogen at 170° C., under pressure of 400-500 psig for 2-3 hrs. Cooled to room temperature, depressurized, followed by the addition of 10.0 g of 4-hydroxybenzaldehyde, in 50 ml of methanol. Hydrogenation was carried out at 170° C., under a pressure of 400-500 psig, for 2-3 hrs. The conversion of benzaldehyde was 100% providing 100% selectivity of 4-hydroxybenzyl alcohol, the desired alcohol product.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][CH:9]=1)[CH3:7])C.[OH-].[Na+].C(O)C>[Na].[Hg].O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([CH:6]([CH3:7])[CH2:5][C:4]([OH:22])=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C=C(C)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [Hg]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Reaction time: 5 h

Procedure:
3.02 g. of 3-(2',4'-difluoro-4-biphenylyl)-2-butenoic acid ethyl ester in 14 ml. of 1 N sodium hydroxide solution and 30 ml. of ethanol are heated under reflux for 3 hours. 40 ml. of water are added and 55 g. of 2.5% sodium amalgam are added in portions, at 25° with stirring, over the course of 5 hours. The mixture is stirred for 5 hours more and warmed on a water bath. The supernatant liquor is decanted from the mercury. Alcohol is distilled off and the reaction mixture is worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11](OCC)=[O:12])[CH:8]=2)[NH:3]1.CC(C[AlH]CC(C)C)C.[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O>[OH:12][CH2:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH2:10]2
Reactant: CCOC(=O)c1ccc2c(c1)CC(=O)N2
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: O
Product: O=C1Cc2cc(CO)ccc2N1
Reaction time: 0.5 h

Procedure:
To a solution/suspension of the compound obtained in Step B (66.8 mmol) in THF (850 ml) at −65° C. there is added, dropwise, 1M DIBAL-H solution (546 mmol) over one hour and under an inert atmosphere. The reaction mixture is brought to −30° C. over 1 hour 30 minutes. 22 ml of water are added dropwise and then 22 ml of 15% aqueous sodium hydroxide solution at 0° C. and then 55 ml of water. MgSO4 (300 g) is added to the reaction mixture and stirring is carried out for 30 minutes. The suspension is filtered over Celite and washed with THF. The filtrate is evaporated to dryness to yield a pasty solid that is brown in colour. The residue is triturated in methanol, and the powder obtained is filtered off and dried in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11]C(=O)OC(C)(C)C)[N:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][CH3:26])[CH:20]=2)[N:3]=1.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C:19]3[CH:20]=[C:21]([N:25]([CH3:26])[C:27](=[O:30])[CH:28]=[CH2:29])[CH:22]=[CH:23][CH:24]=3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: CNc1cccc(-n2nc(I)c3c(NC(=O)OC(C)(C)C)ncnc32)c1
Reactant: C=CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)N(C)c1cccc(-n2nc(I)c3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a stirred solution of tert-butyl 3-iodo-1-(3-(methylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (46) (440 mg, 0.99 mmol) in DCM (8 mL) at 0° C. was added acryloyl chloride (103 mg, 1.13 mmol) dropwise. The resulting mixture was stirred at RT overnight before introducing TFA (8 mL). Stirring was continued for an additional 2 h. Solvents were removed and the residue was dissolved in sat. aquous NaHCO3. The product was extracted with 85% DCM/IPA (50 mL×3). The combined organic extracts were dried over Na2SO4, filtered and concentrated to provide N-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-N-methylacrylamide (50) (375 mg, 95%) as a white solid. LC-MS (ESI): m/z (M+1) 421.0.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH3:31])[C:12]=1[C:13](=[O:30])[NH:14][C:15]1[CH:20]=[CH:19][N:18]2[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=[C:17]2[N:16]=1)=[O:7])C.O.Cl>C1COCC1.C(O)C>[CH3:31][N:11]1[C:12]([C:13](=[O:30])[NH:14][C:15]2[CH:20]=[CH:19][N:18]3[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:23]=[C:17]3[N:16]=2)=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaOH (3N, 6.9 ml) was added to a solution of 1-methyl-5-(2-phenyl-imidazo[1,2-a]pyrimidin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester (2.70 g, 6.9 mmol) in THF/ethanol=1:1 (40 ml), an the mixture was stirred at RT overnight. Water (10 ml) and HCl (conc., approx. 3 ml) were added to the cooled (0° C.) mixture, until the mixture had a pH of 3. The suspension was stirred for 15 min, and filtered. The precipitate was washed with a small amount of water, and dried under vacuum. The thus obtained product (910 mg, 36%) was used in the next step without further purification. MS (m/e)=361.3 [M−H+].
Reaction SMILES: CS([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]2[N:6]=1)(=O)=O.[Cl:16][C:17]1[CH:26]=[CH:25][C:20]([O:21][CH2:22][CH2:23][NH2:24])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:26]=[CH:25][C:20]([O:21][CH2:22][CH2:23][NH:24][C:5]2[N:15]=[C:8]3[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]3[N:6]=2)=[CH:19][CH:18]=1
Reactant: NCCOc1ccc(Cl)cc1
Reactant: Cc1cc(C)n2nc(S(C)(=O)=O)nc2n1
Product: Cc1cc(C)n2nc(NCCOc3ccc(Cl)cc3)nc2n1
Yield: 26 %

Procedure:
The title compound was prepared according to the experimentals described for Example 18 above from 2-methanesulfonyl-5,7-dimethyl-[1,2,4]-triazolo[1,5-a]pyrimidine and 2-(4-chlorophenoxy)ethylamine in 26% yield; EM (calc.): 317.1; MS (ESI) m/e: 318.2 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.31 (dt, 2H), 7.03 (d, 1H), 6.98 (dt, 2H), 6.85 (s, 1H), 4.13 (t, 2H), 3.60 (q, 2H), 2.57 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH2:21]([N:23]([C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1)[CH2:24][CH2:25][NH2:26])[CH3:22].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([N:23]([C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1)[CH2:24][CH2:25][NH:26][C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17])[CH3:22]
Reactant: CCN(CCN)c1cccc(C)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCN(CCNC(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1)c1cccc(C)c1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and N1-ethyl-N1-m-tolyl-ethane-1,2-diamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H30N2O5 [M+H]+: 414.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[SH:11].Cl[CH:13]([C:18]([O:20][CH3:21])=[O:19])[C:14]([O:16][CH3:17])=[O:15]>C(O)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH:13]([C:18]([O:20][CH3:21])=[O:19])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C(Cl)C(=O)OC
Reactant: COc1ccccc1S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C(Sc1ccccc1OC)C(=O)OC
Reaction time: 1 h

Procedure:
1 g of KOH was added to a solution of 2.2 ml of 2-methoxythiophenol in 30 ml of ethanol. The reaction mixture was treated at room temperature with a solution of dimethyl chloromalonate in 5 ml of ethanol, stirred for 1 hour and evaporated. The residue was partitioned between ether and water. The organic phase was dried, concentrated and the residue was purified over silica gel with methylene chloride. 3.6 g of dimethyl (2-methoxy-phenylsulphanyl)malonate, MS: M=270, were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].C(OCC)(=O)C.Cl.Br[C:20]([F:27])([F:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1.C[Si](Cl)(C)C.[Zn]>[F:26][C:20]([F:27])([CH:7]([OH:8])[C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C(F)(F)Br
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)C(O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of zinc (962 mg) in tetrahydrofuran (25 mL), trimethylsilyl chloride (1 drop) and ethyl bromodifluoroacetate (2.2 mL) were added at room temperature, and the mixture was stirred for 5 minutes under reflux by heating. To the reaction mixture, 3-nitrobenzaldehyde (695 mg) was added, and the mixture was stirred for 30 minutes under reflux by heating. The reaction mixture was cooled to room temperature, and then ethyl acetate and 1.0 mol/L aqueous hydrochloric acid were added to the mixture. The organic layer was separated, washed successively with 1.0 mol/L aqueous hydrochloric acid and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 60% hexane in ethyl acetate) to obtain ethyl 2,2-difluoro-3-hydroxy-3-(3-nitrophenyl)propanoate (C29, 1.02 g).
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:24]=[O:25].Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[Si:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]1[S:11][C:12]([CH:24]=[O:25])=[CH:13][CH:14]=1)([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCCCc1cccs1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc(C=O)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyldimethyl(3-(thiophen-2-yl)propoxy)silane (787 mg, 3.07 mmol) in 15 mL 9:1 tetrahydrofuran/hexamethylphosphoramide under argon at −78° C. was added n-butyllithium (1.35 mL, 2.5 M in hexanes) dropwise over 5 minutes. The resulting solution was stirred at −78° C. for 1 h. Dimethylformamide (1.18 mL, 15.35 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature before being poured into 100 mL of 1 N hydrochloric acid. Organics were extracted with ether (2×75 m), dried over magnesium sulfate, filtered and concentrated to give crude 5-(3-((t-butyldimethylsilyl)oxy)propyl)thiophene-2-carbaldehyde. Used without further purification.
Reaction SMILES: [C:1]1([CH2:7][C:8](C(OCC)=O)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>>[C:1]1([CH2:7][CH:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(Cc1ccccc1)(C(=O)OCC)C(=O)OCC
Agent: Cl
Product: CCOC(=O)CC(Cc1ccccc1)C(=O)OCC
Yield: 84.7 %

Procedure:
A solution of the product from step (a) (23.6 g) in c.HCl (326 ml) was stirred under reflux for 46 hours, then cooled. The resulting precipitate was extracted with chloroform (×3) and the extracts combined, washed with 2M aqu. KOH (×2), acidified to pH 4.0 (2M aqu. HCl) and cooled. The resulting precipitate was filtered off, washed with water and dried in vacuo to give the desired product (15.7 g). The 200 MHz 1H NMR was consistent with the proposed structure.