Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][CH:13](O)[CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][CH:13]=[C:12]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(O)C(c2ccccc2)C12CCN(Cc1ccccc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C1NC=C(c2ccccc2)C12CCN(Cc1ccccc1)CC2
Temperature: 0 °C

Procedure:
The intermediate 8-benzyl-3-hydroxy-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one (8.0 g, 23.8 mmol) was dissolved in glacial acetic acid (50 mL) and refluxed for 1.5 h. The reaction mixture was poured into ice water (500 mL) and adjusted to pH 8-9 by. addition of solid sodium hydroxide. The mixture was extracted three times with ethyl acetate (300 mL each). Organic phases were pooled, dried with magnesium sulfate and evaporated. The crude product was recrystallized from methylene chloride to give 8-benzyl-4-phenyl-2,8-diaza-spiro[4.5]dec-3-en-1-one as white crystalls (2.64 g, 35%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)(=O)=O.[C:28]([Si:30]([CH3:33])([CH3:32])[CH3:31])#[CH:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C(N(CC)CC)C.C(OCC)(=O)C.[Cu](I)I>[CH3:31][Si:30]([C:28]#[C:29][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)([CH3:33])[CH3:32]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1cccc(-c2nc(OS(=O)(=O)C(F)(F)F)cc3cccnc23)c1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cc2cccnc2c(-c2cccc([N+](=O)[O-])c2)n1
Reaction time: 2 h

Procedure:
To a solution of 6-trifluoromethylsulfonyloxy-8-(3-nitrophenyl)-1,7-naphthyridine (200 mg, 0.50 mmol; prepared according to example 13) in dimethylformamide (1 ml) and triethylamine (0.5 ml) is added ethynyltrimethylsilane (0.078 ml, 0.56 mmol), bis(dibensylideneacetone)palladium (5.8 mg, 0.020 mmol), triphenylphosphine (5.3 mg, 0.020 mmol) and copper iodide (3.8 mg, 0.020 mmol). The mixture is kept at 60° C. for 2 h. The solution is diluted with ethyl acetate and washed with water. The product is purified by flash column chromatography on silica gel (20:0.2 toluene/acetone) affording 6-trimethylsilylethynyl-8-(3-nitrophenyl)-1,7-naphthyridine. (Mass M+H 348; mp 160-163° C.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.[Mg].[CH3:13][C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=1)=O.[Cl-].[NH4+]>Cl.C(O)C.[Pd].CCOCC>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:14]([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:13])[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=1
Reactant: Fc1ccc(CCCBr)cc1
Reactant: COc1cc(OC)cc(C(C)=O)c1
Agent: [Pd]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Solvent: CCOCC
Product: COc1cc(OC)cc(C(C)CCCc2ccc(F)cc2)c1

Procedure:
A solution of 77 g. of 3-(4-fluorophenyl)propylbromide in 300 ml. of ether was added dropwise over a two hour period to a refluxing solution of 10 g. of magnesium in 100 ml. of ether. The reaction mixture was refluxed for an additional 30 minutes after the addition was completed. A solution of 68 g. of 3,5-dimethoxyacetophenone in 100 ml. of ether was then added dropwise to the reaction and the reaction mixture was refluxed for 11/2 hours. To the reaction was added 300 ml. of a saturated ammonium chloride solution dropwise with stirring. The layers were separated and the aqueous layer extracted with ether. The ether extract was dried over magnesium sulfate and the ether removed in vacuo to give an oil. An additional 111.7 g. of 3(4-fluorophenyl) propylbromide was reacted with 3.5-dimethoxyacetophenone in the above manner. The products from both runs were hydrogenated in ethanol-HCl using palladium as the catalyst. The solvents and catalyst were removed and the crude material distilled to yield 169.0 g. of 2-(3,5-dimethoxyphenyl)-5-(4-p-fluorophenyl)pentane, b.p. 145 - 155/0.05 mmHg.
Reaction SMILES: [C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]([C:47]([O:49][CH:50]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:48])[C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40](=[O:42])[CH3:41])=[C:35]([O:43][C:44](=[O:46])[CH3:45])[CH:34]=3)/[C:27](O)=[O:28])[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:63]1([CH:69]([O:76][C:77]([C:79]2[N:80]3[C@H:83]([S:84][CH2:85][C:86]=2[CH2:87][O:88][C:89](=[O:91])[CH3:90])[C@H:82]([NH2:92])[C:81]3=[O:93])=[O:78])[C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:63]1([CH:69]([O:76][C:77]([C:79]2[N:80]3[C@H:83]([S:84][CH2:85][C:86]=2[CH2:87][O:88][C:89](=[O:91])[CH3:90])[C@H:82]([NH:92][C:27](=[O:28])/[C:26](/[C:24]2[N:25]=[C:21]([NH:20][C:7]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[S:22][CH:23]=2)=[N:30]\[O:31][CH:32]([C:47]([O:49][CH:50]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])[C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40](=[O:42])[CH3:41])=[C:35]([O:43][C:44](=[O:46])[CH3:45])[CH:34]=2)[C:81]3=[O:93])=[O:78])[C:70]2[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=2)[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(=O)Oc1ccc(C(O/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(C(=O)OC(c3ccccc3)c3ccccc3)c3ccc(OC(C)=O)c(OC(C)=O)c3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.9 %

Procedure:
To an ice-cooled solution containing the product obtained in Step 5 of Example 8 (3.0 g) and (6R,7R)-7-amino-3-acetoxymethyl-8-oxo-5thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (1.58 g) in dichloromethane (90 ml) was added dicyclohexylcarbodiimide (0.74 g), and the mixture was stirred at room temperature for 4 hours. Insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The residue was redissolved in ethyl acetate and the insoluble matters were removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by slica gel column chromatography, giving 2.42 g of the objective compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@H:8](Br)[C@H:7]([OH:12])[CH2:6]1)=[O:4].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([N:13]=[N+:14]=[N-:15])[C@H:7]([OH:12])[CH2:6]1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1CC[C@H](Br)[C@H](O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CC[C@@H](N=[N+]=[N-])[C@H](O)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
A solution of bromide (a) (52.4 g, 221 mmol) in DMF (1.2 liters) was treated with sodium azide (21.5 g, 331 mmol) and heated at 60° C. for 8 hours. The mixture was stirred at room temperature overnight and then evaporated. The residue was extracted with warm iso-propanol (2×300 ml). Evaporation afforded an oil which was chromatographed on silica eluting with a gradient of ethyl acetate in petroleum ether affording an oil (31 g) which was a 2:1 mixture of desired (1R,3R,4R)-4-azido-3-hydroxy-cyclohexanecarboxylic acid methyl ester to (R)-3-oxo-cyclohexanecarboxylic acid methyl ester. Further chromatography on silica eluting with a methanol/dichloromethane gradient afforded the desired intermediate as an oil (18.4 g, 42%)
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]#[N:8].[F:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]#[N:8]
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: N#Cc1sccc1Br
Product: N#Cc1sccc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
3-Bromothiophene-2-carbonitrile was coupled with 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane using the conditions described in Example 1 to give 3-(2-fluoro-5-nitrophenyl)thiophene-2-carbonitrile as an off-white solid. This in turn was reduced using the conditions outlined in Example 1 to give 3-(5-amino-2-fluorophenyl)thiophene-2-carbonitrile: δH (400 MHz, CDCl3) 3.67 (2H, s), 6.68-6.72 (1H, m), 6.90 (1H, dd, J 6 and 3), 7.00 (1H, dd, J 9 and 1), 7.30 (1H), dd, J 5 and 2), 7.60 (1H, d, J 5).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[C:12]([C:15]3(O)[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][N:17]([CH3:25])[CH2:16]3)[CH:13]=[CH:14][C:7]1=2.C[Si]([C:31]#[N:32])(C)C.C(=O)([O-])[O-].[K+].[K+].O.[F-].[K+]>ClCCl.O>[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[C:12]([C:15]3([C:31]#[N:32])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][N:17]([CH3:25])[CH2:16]3)[CH:13]=[CH:14][C:7]1=2
Reactant: CN1Cc2ccccc2C(O)(c2ccc3sccc3c2)C1
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: CN1Cc2ccccc2C(C#N)(c2ccc3sccc3c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.5 %

Procedure:
Tin(IV) chloride in dichloromethane (0.51 mL, 1.0 M) was added dropwise to a suspension of 4-benzo[b]thiophen-5-yl-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-ol (300 mg, 1.02 mmol) from Example 92, and trimethylsilylcyanide (0.68 mL, 5.1 mmol) in dichloromethane (4.5 mL) at 0° C. The resulting solution was allowed to stir at room temperature overnight, then additional tin(IV) chloride in dichloromethane (1.02 mL, 1.0 M) was added and the solution stirred at room temperature for an additional 24 hours. Potassium carbonate (636 mg, 4.60 mmol), potassium fluoride hydrate (435 mg, 7.49 mmol) and then water (0.135 mL, 7.50 mmol) were added and the mixture stirred overnight. Silica gel (2.5 g) and enough water to make the mixture stirrable were added and the mixture filtered. The filter pad was washed with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum. The crude material was filtered through a plug of silica (1:1 hexane/ethyl acetate). The filtrate was concentrated under vacuum. The residue was purified by column chromatography (95:5, then 90:10 hexane/ethyl acetate) to give 4-benzo[b]thiophen-5-yl-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-carbonitrile (17 mg, 6%). Recrystallization from ethanol gave 10 mg white solid. The carbonitrile (10 mg, 0.033 mmol) was converted to the fumarate salt by dissolving in a minimum amount of methanol and treated with a solution of fumaric acid (3.0 mg, 0.026 mmol) in methanol. The solution was concentrated to dryness and the residue dissolved in 1:1 acetonitrile/water and lyophilized to give 4-benzo[b]thiophen-5-yl-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-carbonitrile, fumarate salt (13 mg, 94%, >99.0% AUC HPLC): mp 170-172° C.; 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J=1.8 Hz, 1H), 7.89 (d, J=11.5 Hz, 1H), 7.63 (d, J=5.5 Hz, 1H), 7.38 (d, J=5.5 Hz, 1H), 7.35-7.32 (m, 1H), 7.28-7.20 (m, 3H), 7.04 (d, J=8.00 Hz, 1H), 6.75 (s, 1.4H), 3.90 (d, J=15.2 Hz, 1H), 3.70 (d, J=15.2 Hz, 1H), 3.34 (d, J=12.0 Hz, 1H), 2.95 (d, J=12.0 Hz, 1H), 2.48 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[C:10]2[N:11]=[C:12]([NH2:20])[N:13]=[C:14]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[C:9]=2[N:8]=[N:7]1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[CH2:5][N:6]2[C:10]3[N:11]=[C:12]([NH2:20])[N:13]=[C:14]([C:15]4[O:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[N:8]=[N:7]2)=[CH:27][CH:26]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1cccc(Cn2nnc3c(-c4ccco4)nc(N)nc32)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1nc(-c2ccco2)c2nnn(Cc3cccc(NCc4ccc(F)cc4)c3)c2n1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
A suspension of 3-(3-aminobenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (200 mg, 0.65 mmol) and 4A molecular sieves in THF (10 mL) was treated with 4-fluorobenzaldehyde (0.04 mL, 0.37 mmol), heated to 40° C. for 3 h, cooled to room temperature, treated sodium triacetoxyborohydride (400 mg, 1.89 mmol) and acetic acid (0.1 mL) and stirred for 15 minutes. The reaction was quenched by addition of sat. NaHCO3 (5 mL), extracted with EtOAc (2×5 mL) and the combined organic phase dried (MgSO4), concentrated in vacuo and purified by chromatography [(SiO2; EtOAc:Heptane (1:2)] to give the title compound (60 mg, 44%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=[C:9]1[CH:17]([NH:21][CH2:22][C:23](=[O:37])[CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])[CH:18]([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:45]1([CH3:54])[CH:50]=[CH:49][C:48]([C:51](Cl)=[O:52])=[CH:47][CH:46]=1>C(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[N:10]=[C:9]1[CH:17]([N:21]([CH2:22][C:23](=[O:37])[CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])[C:51](=[O:52])[C:48]1[CH:49]=[CH:50][C:45]([CH3:54])=[CH:46][CH:47]=1)[CH:18]([CH3:20])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C(NCC(=O)CCN2C(=O)c3ccccc3C2=O)C(C)C)n(Cc2ccccc2)c(=O)c1C
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(CC(=O)CCN2C(=O)c3ccccc3C2=O)C(c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
To 2-{4-[1-(1-Benzyl-4,5-dimethyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-2-methyl-propylamino]-3-oxo-butyl}-isoindole-1,3-dione (1.024 g, 2.046 mmol) in CH2Cl2 (14 mL) was added triethylamine (0.31 g, 3.069 mmol) and p-toluoyl chloride (0.474 g, 3.069 mmol). The reaction was stirred for 16 h at room temperature, washed with water, dried (Na2SO4), and evaporated to dryness. The residue was purified by flash chromatography on silica gel (1:1 hexanes:EtOAc) to give the title compound as a white foam (0.885 g, 70%). MS(ES+) m/e 619 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].C(Cl)CCl.O[N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25].C([O-])(O)=O.[Na+]>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([O:13][N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25])=[O:12]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: O=C1CCC(=O)N1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(ON1C(=O)CCC1=O)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-quinoline carboxylic acid (1.2 eq.) in DMF at 0° C. was treated with EDC (1.4 eq.). The mixture was stirred at 0° C. for 1 to 2 h and then N-hydroxysuccinimide (1.0 eq.) was added. After stirring at RT for more than 3 h, the reaction mixture was poured into 60% sat. NaHCO3 and the product filtered: 1H NMR (CDCl3, 300 MHz, ppm) 8.35 (d, 1H), 8.27 (d, 1H), 8.19 (d, 1H), 7.87 (d, 1H), 7.80 (m, 1H), 7.68 (m, 1H), 2.91 (s, 4H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH3:15])[C:4]([NH:6][O:7]CC1C=CC=CC=1)=[O:5].[F:16][C:17]1[CH:22]=[C:21]([CH:23]([CH3:27])[C:24]([OH:26])=O)[CH:20]=[CH:19][C:18]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[F:16][C:17]1[CH:22]=[C:21]([CH:23]([CH3:27])[C:24]([NH:2][C@H:3]([CH3:15])[C:4]([NH:6][OH:7])=[O:5])=[O:26])[CH:20]=[CH:19][C:18]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[C@@H](N)C(=O)NOCc1ccccc1
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Product: CC(C(=O)N[C@H](C)C(=O)NO)c1ccc(-c2ccccc2)c(F)c1

Procedure:
This compound was synthesized by coupling 2-amino-N-benzyloxy-(R)-propionamide HCl salt 42b with (R/S)-2-fluoro-α-methyl-4-biphenylacetic acid (flurbiprofen, Sigma) followed by hydrogenation using the procedures as described in Example 42. MS (ESI): (M−H)−=329.0.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].S([O-])([O-])(=O)=O.[Mg+2].[F:15][C:16]([F:49])([F:48])[C:17]1[CH:18]=[C:19]([C@@H:27]([N:29]([CH3:47])[C:30]([N:32]2[CH2:37][CH2:36][C:35](=O)[CH2:34][C@@H:33]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:31])[CH3:28])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1>CO>[F:49][C:16]([F:15])([F:48])[C:17]1[CH:18]=[C:19]([C@@H:27]([N:29]([CH3:47])[C:30]([N:32]2[CH2:37][CH2:36]/[C:35](=[N:2]/[OH:3])/[CH2:34][C@@H:33]2[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[CH3:46])=[O:31])[CH3:28])[CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=1
Reactant: Cc1cc(F)ccc1[C@H]1CC(=O)CCN1C(=O)N(C)[C@@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1C/C(=N\O)CCN1C(=O)N(C)[C@@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Hydroxylamine hydrochloride (695 mg), sodium acetate (820 mg) and dry magnesium sulphate (500 mg) were added to a solution of intermediate 5b (500 mg) in dry MeOH (50 mL) under a Nitrogen atmosphere.
Reaction SMILES: C([O:4][C:5]([CH3:26])([CH3:25])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[C:16]=2[CH3:23])=[C:11]([CH3:24])[CH:10]=1)(=O)C.[NH2:27][C:28]1[CH:41]=[CH:40][C:31]([CH2:32][N:33]2[C:37](=[O:38])[NH:36][C:35](=[O:39])[O:34]2)=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+:55]>C(O)(=O)C>[OH:4][C:5]([CH3:26])([CH3:25])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:27][C:28]3[CH:41]=[CH:40][C:31]([CH2:32][N:33]4[C:37](=[O:38])[N-:36][C:35](=[O:39])[O:34]4)=[CH:30][CH:29]=3)[C:16]=2[CH3:23])=[C:11]([CH3:24])[CH:10]=1.[Na+:55]
Reactant: CC(=O)OC(C)(C)CCOc1ccc(-c2cccc(C=O)c2C)c(C)c1
Reactant: Nc1ccc(Cn2oc(=O)[nH]c2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(OCCC(C)(C)O)ccc1-c1cccc(CNc2ccc(Cn3oc(=O)[n-]c3=O)cc2)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 56 %

Procedure:
A mixture of 3-[(3′-formyl-2,2′-dimethylbiphenyl-4-yl)oxy]-1,1-dimethylpropyl acetate (479 mg), 2-(4-aminobenzyl)-1,2,4-oxadiazolidine-3,5-dione (340 mg) and acetic acid (6 ml) was stirred at room temperature for 20 hours. Sodium triacetoxyborohydride (573 mg) was added to the reaction solution, followed by stirring at room temperature for 2 hours. After evaporation of the solvent under a reduced pressure, water was added to the residue, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate), and a mixture of the resulting pale yellow foamy substance (719 mg), THF (5 ml), methanol (5 ml) and a 1 M sodium hydroxide aqueous solution (4 ml) was stirred at 50° C. for 4 hours. The pH was made to 4 to 5 by adding 1 M hydrochloric acid, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate), and a 1 M sodium hydroxide aqueous solution (0.89 ml) was added to a mixture of the resulting pale yellow oil (448 mg), THF (3 ml) and methanol (3 ml), followed by stirring for 10 minutes. After evaporation of the solvent under a reduced pressure, the resulting residue was washed with diethyl ether to obtain sodium 2-[4-({[4′-(3-hydroxy-3-methylbutoxy)-2,2′-dimethylbiphenyl-3-yl]methyl}amino)benzyl]-3,5-dioxo-1,2,4-oxadiazolidin-4-ide (398 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][CH2:12][CH:11]1/[CH:22]=[CH:23]/[C:24](=[O:32])[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[BH4-].[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][CH2:12][CH:11]1/[CH:22]=[CH:23]/[CH:24]([OH:32])[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)CCCCCCC1C(/C=C/C(=O)CC2CCCCC2)CCC1OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CCCCCCC1C(/C=C/C(O)CC2CCCCC2)CCC1OC1CCCCO1
Temperature: 0 °C

Procedure:
To an ice cold solution of trans-2-(4-cyclohexyl-3-oxo-1-butenyl)-5-[(tetrahydropyran-2-yl)oxy]cyclopentaneheptanoic acid methyl ester (43 g), prepared in Example 7, in 200 ml of methanol, sodium borohydride (3.8 g) is added portionwise. After stirring for 30 min. acetic acid (4.2 ml) is added. The mixture is concentrated under reduced pressure. The residue is taken up in ether. The ether solution is washed to neutral with water and saturated NaCl solution, dried and evaporated to yield trans-2-(4-cyclohexyl-3-hydroxy-1-butenyl)-5-[(tetrahydropyran-2-yl)oxy]cyclopentaneheptanoic acid methyl ester, νmaxCHCl3 3,450, 1,735, 1,030 cm- 1.
Reaction SMILES: FC(F)(F)S([CH:6](S(C(F)(F)F)(=O)=O)[CH2:7][CH:8]([S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(=O)=O.[C:32]1([OH:40])[C:33](C)=[CH:34][CH:35]=[CH:36][C:37]=1[CH3:38]>C(#N)C>[F:13][C:12]([F:15])([F:14])[S:9]([CH:8]([S:16]([C:19]([F:21])([F:20])[F:22])(=[O:17])=[O:18])[CH2:7][C:6]1[C:33]([CH3:34])=[C:32]([OH:40])[C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:10])=[O:11]
Reactant: Cc1cccc(C)c1O
Reactant: O=S(=O)(C(CC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: Cc1ccc(CC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)c(C)c1O
Reaction time: 3 h
Yield: 94 %

Procedure:
1,1,3,3-Tetrakis(trifluoromethylsulfonyl)propane [4] (143.2 mg, 0.25 mmol) was added to an acetonitrile (0.25 ml) solution of 2,6-xylenol (34.1 mg, 0.28 mmol) at room temperature. After 3 hours of stirring, the reaction solution was concentrated under a reduced pressure. An obtained residue was purified by Kugelrohr distillation (180-200° C./3 mmHg) thereby obtaining 4-(2,2-bis(trifluoromethylsulfonyl)ethyl-2,6-dimethylphenol [1d] with a yield of 94% (96.9 mg, 0.234 mmol). Further, recrystallization was performed thereby obtaining a colorless crystal from hexane.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]([CH3:23])[NH:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][CH:11]=1.C(O)(=O)C.CO>O>[NH:5]([CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]([CH3:23])[NH:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:14][CH:15]=1)[C:2]([NH2:3])=[O:1]
Reactant: CC1NC(=O)NN=C1c1ccc(NCCCN)cc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC1NC(=O)NN=C1c1ccc(NCCCNC(N)=O)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 32.1 %

Procedure:
Potassium cyanate (0.516 g) was added to a solution of 6-[4-(3-aminopropylamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.66 g), acetic acid (0.382 g) and methanol (10 ml) in water (20 ml), and the mixture was stirred for 60 hours at room temperature. The resulting precipitates were collected by filtration, washed with water and recrystallized from 80% aqueous ethanol to give 6-[4-(3-ureidopropylamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.62 g).