Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]([NH2:17])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1.N1C=CC=CC=1>O1CCOCC1>[CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15](=[S:27])[NH2:17]
Reactant: NC(=O)c1ccc2c(c1)Nc1ccccc1S2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: NC(=S)c1ccc2c(c1)Nc1ccccc1S2
Temperature: 110 °C

Procedure:
A reaction mixture comprising 3.4 g (14 mmoles) of 10H-phenothiazine-2-carboxamide (J. Org. Chem. 1961, 26, 1138-1143) and 3.4 g (8.4 mmoles) of Lawesson reagent in solution in 40 ml of 1,4-dioxane to which 20 ml of pyridine has been added is heated at 110° C. for 1 h 30. The brown solution is then concentrated under vacuum and the residue is diluted in 200 ml of AcOEt and 100 ml of H2O. After stirring and decantation, the organic phase is washed successively with 100 ml of a 1N aqueous solution of HCl and 100 ml of salt water. After drying over sodium sulphate, filtration and evaporation of the solvent under vacuum, an orange powder is obtained. This powder is washed with Et2O, the filtrate is eliminated, and extracted with acetone. The acetone filtrate is then concentrated under vacuum and the evaporation residue is then purified using a silica column (eluent: Heptane/AcOEt:1/1 to 416). Orange powder. Melting point: 208-209° C.
Reaction SMILES: Cl.[CH2:2]([N:6]1[C:10](CC#N)=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=[C:7]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][CH3:5].O.[C:27]([O:30][CH2:31]C)(=[O:29])[CH3:28]>CO>[CH3:31][O:30][C:27](=[O:29])[CH2:28][C:10]1[N:6]([CH2:2][CH2:3][CH2:4][CH3:5])[C:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:8][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1CC#N
Reactant: CCOC(C)=O
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1CC(=O)OC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Hydrogen chloride gas is bubbled into solution of (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetonitrile (187) (640 mg, 2.03 mmol) in methanol (30 mL) at 0° C. for 10 minutes, followed by stirring for 30 minutes. Water (0.0365 ml, 2.03 mmol) is then added and the reaction refluxed at 80° C. for 2 hours. The methanol is then removed in vacuo, the reaction crude is dissolved in ethyl acetate (100 mL), and the organic layer is washed with saturated sodium bicarbonate (1×100 mL), brine (1×100 mL), and dried over magnesium sulfate. The sample is filtered, concentrated and purified by flash chromatography on SiO2 using an eluent of 2:3 ethyl acetate:hexane to afford (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetic acid methyl ester (188) as a colorless oil.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.Br[CH2:10][C:11]1[C:16]2[CH:17]=[CH:18][O:19][C:15]=2[CH:14]=[CH:13][C:12]=1[F:20].BrCC1C(F)=CC2C=COC=2C=1>C(#N)C>[F:20][C:12]1[C:11]([CH:10]=[O:5])=[C:16]2[CH:17]=[CH:18][O:19][C:15]2=[CH:14][CH:13]=1
Reactant: Fc1ccc2occc2c1CBr
Reactant: C[N+]1([O-])CCOCC1
Agent: Fc1cc2ccoc2cc1CBr
Solvent: CC#N
Product: O=Cc1c(F)ccc2occc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the N-methylmorpholine-N-oxide (13.6 g) in acetonitrile (135 ml) containing 3 Å molecular sieves (13.2 g) was stirred at room temperature overnight and cooled in ice. A solution of 4-bromomethyl-5-fluorobenzofuran and 6-bromomethyl-5-fluorobenzofuran (13.33 g) in acetonitrile (35 ml) was added and the mixture stirred at 5° for 4 h. The mixture was filtered and the filtrate evaporated to dryness. Water and ethyl acetate were added to the residue and the organic phase separated, dried and evaporated to give the mixture of aldehydes. The mixture was separated by chromatography on silica (600 g) using a mixture of ethyl acetate and hexane (1:9) as the eluant to give the title compound (A) (2.19 g);
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH:28]4[CH2:33][O:32][CH2:31][CH2:30][NH:29]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.C(O[C:41]1(O[Si](C)(C)C)[CH2:43][CH2:42]1)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH:28]4[CH2:33][O:32][CH2:31][CH2:30][N:29]4[CH:41]4[CH2:43][CH2:42]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Nc1ncnn2c(CC3COCCN3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ncnn2c(CC3COCCN3C3CC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 60 °C
Reaction time: 17 h
Yield: 43.5 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(morpholin-3-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.23 mmol) in MeOH (2.0 mL) containing 3 Å molecular sieves was added AcOH (130 μL, 2.28 mmol), [(1-ethoxycyclopropyl)oxy]trimethylsilane (238 mg, 1.37 mmol) and sodium cyanoborohydride (64 mg, 1.02 mmol). The reaction was stirred at 60° C. for 17 h. Aqueous NaOH (1N, 15 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 48 mg (44%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.91 (s, 1 H), 7.79 (d, 1 H), 7.59 (s, 1 H), 7.26-7.41 (m, 5 H), 7.14 (d, 1 H), 6.63 (s, 1 H), 5.65 (s, 2 H), 3.55-3.65 (m, 2 H), 3.44-3.52 (m, 1 H), 3.30-3.41 (m, 1 H), 3.19-3.28 (m, 1 H), 2.80-2.96 (m, 3 H), 2.34-2.44 (m, 1 H), 1.77-1.86 (m, 1 H), 0.23-0.64 (m, 4 H); ES-MS m/z 480.13 [M+H]+, HPLC RT (min) 2.19.
Reaction SMILES: C(OC(=O)CCC[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](I)[CH:25]=[C:24]([C:29]3[CH:37]=[CH:36][C:32]4[O:33][CH2:34][O:35][C:31]=4[CH:30]=3)[CH:23]=2)[C:10]=1[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])C.[N:46]1[CH:51]=[C:50](B(O)O)[CH:49]=[N:48][CH:47]=1>>[CH2:43]([O:42][C:40](=[O:41])[CH:39]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:51]3[CH:50]=[CH:49][N:48]=[CH:47][N:46]=3)[CH:25]=[C:24]([C:29]3[CH:37]=[CH:36][C:32]4[O:33][CH2:34][O:35][C:31]=4[CH:30]=3)[CH:23]=2)[C:10]=1[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:38][CH3:10])[CH3:44]
Reactant: OB(O)c1cncnc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Product: CCOC(=O)CCc1c(CCCCCCOc2cc(-c3ccc4c(c3)OCO4)cc(-c3ccncn3)c2)cccc1OC(CC)C(=O)OCC
Yield: 151.3 %

Procedure:
A similar procedure as described in Example 12, step 8 was used, starting from 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-iodo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (47 mg, 0.06 mmol) and pyrimidin-5-ylboronic acid (32 mg, 0.26 mmol) to afford 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-pyrimidin-4-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy-butyric acid ethyl ester (31 mg, 71%) as a light yellow oil: ES(+)-HRMS m/e calculated for C40H46N2O8 (M+H)+ 683.3327, found 683.3327.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=2[N:5]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:4](=[O:21])[CH2:3]1.CC(C1C=C(C(C)C)C(S([N:37]=[N+:38]=[N-:39])(=O)=O)=C(C(C)C)C=1)C>C1COCC1>[N:37]([CH:3]1[C:4](=[O:21])[N:5]([CH2:17][CH:18]2[CH2:19][CH2:20]2)[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]([CH2:9][CH:10]2[CH2:11][CH2:12]2)[C:2]1=[O:1])=[N+:38]=[N-:39]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: O=C1CC(=O)N(CC2CC2)c2ccccc2N1CC1CC1
Solvent: C1CCOC1
Product: [N-]=[N+]=NC1C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Temperature: -30 °C

Procedure:
For this substrate General Procedure 4-K was modified in the following manner. Initially the product from Step A was suspended (not a solution) in THF at −78° C., and following addition of the KN(TMS)2 solution, this suspension was allowed to warm to −30° C., during which the suspension became a solution, and was re-cooled to −78° C. Upon re-cooling to −78° C. a precipitate began to form, therefore the reaction flask containing the mixture was partially raised above the cooling bath until the internal temperature rose to −50° C.; then the trisyl azide solution was added. The cooling bath was removed and the mixture allowed to warm to −20° C. whereupon the mixture had become a nearly homogenous solution, and the AcOH was added. Then the mixture was treated as described in the general procedure. 3-Azido-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was purified by trituration with hot to room temperature EtOAc, followed by recrystalization from hot to −23° C. CHCl3/EtOAc/EtOH (5:5:1) and isolated as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:18][CH:19]=[O:20])([CH2:15][CH2:16][CH3:17])[O:12][CH2:13][CH2:14][C:7]2=1.O.[O-:30]Cl=O.[Na+].Cl>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[O:22])=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:18][C:19]([OH:30])=[O:20])([CH2:15][CH2:16][CH3:17])[O:12][CH2:13][CH2:14][C:7]2=1
Reactant: CCCC1(CC=O)OCCc2c1[nH]c1c(F)ccc(C(=O)N3CCOCC3)c21
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCC1(CC(=O)O)OCCc2c1[nH]c1c(F)ccc(C(=O)N3CCOCC3)c21
Temperature: 25 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
To a solution of [8-fluoro-5-(morpholine-4-carbonyl)-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl]-acetaldehyde (8) (99 mg, 0.255 mmol) in DMSO (3.5 mL) was added a solution of NaH2PO4 in H2O (0.36 mL of 0.7 M in H2O, 0.255 mmol) at room temperature. To the mixture was added a solution of NaClO2 in H2O (1.52 mL of 0.5 M in H2O, 0.765 mmol). After stirring for 20 hours at room temperature, the mixture was acidified with HCl. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to give 77 mg (75%) of title compound as a white solid. Mp=98–100° C.; HRMS (ESI) [M+H]+ calculated for C21H26FN2O5 405.1820, found 405.1821; 1H NMR (DMSO-d6): 300 MHz δ 12.30 (bs, 1H), 11.45 (s, 1H), 6.95–6.85 (m, 2H), 3.92 (m, 2H), 3.66 (m, 2H), 3.45 (m, 1H), 3.15 (m, 1H), 2.94 (d, J=10.2 Hz, 2H), 2.70 (d, J=10.2 Hz, 2H), 2.59 (m, 1H), 2.57 (s, 1H), 2.51 (m, 2H), 1.99 (t, J=5.10 Hz, 2H), 1.31 (m, 1H), 0.86 (m, 1H), 0.08 (t, J=5.10 Hz, 3H). LCMS retention time: 2.073 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1)=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH:22]([CH2:26][NH2:27])[CH2:21]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH:22]([CH2:26][NH:27][C:12](=[O:14])[CH2:11][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[O:4])[CH2:21]1
Reactant: COC(=O)c1cccc(CC(=O)O)c1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
A mixture of [3-(methoxycarbonyl)phenyl]acetic acid (0.200 g), Intermediate 1 (0.284 g), 1-hydroxybenzotriazole (0.182 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.316 g) was stirred in dichloromethane (10 ml), and N,N-diisopropylethylamine (0.352 ml) was added to the solution. Stirring at 20° C. under nitrogen was continued for 8 h. The mixture was purified by solid phase extraction (2×10 g Varian Bondelut silica gel cartridges), eluting successively with one column volume of dichloromethane, chloroform, ether, ethyl acetate, acetone, acetonitrile and methanol, to give the title compound as a colourless gum, (0.266 g).
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([O-:12])=O)=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Na+].[CH3:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][C:25]([F:30])=[CH:26][CH:27]=2)[NH:22]1>>[F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[C:25]([F:30])[CH:24]=3)[CH2:29][CH:21]2[CH3:20])=[O:12])=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Reactant: CC1Cc2ccc(F)cc2N1
Agent: [Na+]
Product: CC1Cc2ccc(F)cc2N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Yield: 52.5 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 123 mg of sodium (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate obtained in step 2a of example 6a and 62 mg of (+)-2-methyl-6-fluoro-2,3-dihydro-1H-indole (reference example 6a). After silica column purification: eluent 98/02 dichloromethane/methanol, 84 mg of 5-fluoro-2-[2-((−)-6-fluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>C(#N)C>[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([CH2:2][C:3]([C:5]3[CH:18]=[CH:17][C:8]([O:9][CH2:10][C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: CC(C)OC(=O)COc1ccc(C(=O)CBr)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Product: CC(C)OC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 1 h

Procedure:
iso-Propyl 4-bromoacetylphenoxyacetate (6.3 g) was added to a stirred, cooled (4° C.) solution of 1-(4-pyridyl)piperazine (6.5 g) in acetonitrile (225 ml). Stirring was continued for 1 hour at 4° C., then overnight at ambient temperature when the precipitated solid was removed. The filtrate was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica, eluting firstly with 0 to 10% v/v methanol/dichloromethane and then toluene/ethyl acetate/.880 ammonium hydroxide/ethanol (60:20:10:35 v/v/v/v), gave a cream solid. Recrystallisation from iso-propanol gave the title compound, 2.1 g: m.p. 121°-122° C.; NMR (d6DMSO) δ 8.14 (2H, d), 7.98 (2H, d), 7.02 (2H, d), 6.80 (2H, d), 4.99 (1H, m), 4.85 (2H, s), 3.84 (2H, s), 3.33 (4H, t), 2.62 (4H, t), 1.22 (6H, d); m/e 398 (M+H)+ ; calculated for C22H27N3O4 : C, 66.5; H, 6.9; N, 10.6. found: C, 65.8; H, 6.8; N, 10.4%.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([CH3:17])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:20]N1C(=O)CCC1=O>ClC(Cl)Cl>[Br:20][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH:4]([CH:3]([CH3:17])[C:2]([F:18])([F:19])[F:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(c1ccc(C)cc1)C(C)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(c1ccc(CBr)cc1)C(C)C(F)(F)F

Procedure:
2.25 g (8.2 mmol) of ethyl 4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)butanoate, 1.53 g (8.6 mmol) of N-bromosuccinimide and 67 mg (0.41 mmol) of 2,2′-azobis-2-methylpropanenitrile in 36 ml of trichloromethane were stirred under reflux overnight. After the reaction had gone to completion, the succinimide was filtered off, the filter residue was washed with dichloromethane and the filtrate was concentrated under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 40:1). This gave 2.667 g (7.5 mmol, 92% of theory) of a yellowish oil.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[N+:13]([CH2:16][CH2:17][CH3:18])([O-:15])=[O:14]>>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:16]([N+:13]([O-:15])=[O:14])[CH2:17][CH3:18])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: CCC[N+](=O)[O-]
Reactant: COC(=O)c1ccc(C=O)cc1
Product: CCC(=Cc1ccc(C(=O)OC)cc1)[N+](=O)[O-]

Procedure:
The title compound was prepared in an identical manner to that described in Description 27 using 4-carbomethoxybenzaldehyde and 1-nitropropane. τ(d6DMSO) 8.8 (3H, t, J=7 Hz), 8.08 (3H, s), 7.19 (2H, q, J=7 Hz), 6.12 (3H, s), 2.38 (2H, d, J=8 Hz), 1.97 (2H, d, J=8 Hz), 1.97 (1H, s).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:23])[C:4]=1[CH2:24][CH2:25][C:26]([OH:28])=O)[CH3:2].C[CH2:30][N:31](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN>CN(C=O)C.C1COCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:23])[C:4]=1[CH2:24][CH2:25][C:26]([NH:31][CH3:30])=[O:28])[CH3:2]
Reactant: CCc1cc(-c2nc(-c3cc(C)c(CCC(=O)O)c(CC)c3)no2)cc(C)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1cc(-c2nc(-c3cc(C)c(CCC(=O)NC)c(CC)c3)no2)cc(C)n1
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 3-{2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid (26 mg, 69 μmol) and DIPEA (27 mg, 207 μmol) in DMF (3 mL) is added PyBOP (40 mg, 76 μmol) at 0° C. The mixture is stirred for 15 min at 0° C. before methylamine (2.4 mg, 76 μmol, 38 μL of a 2 M solution in THF) is added. Stirring is continued for 1 h at 0° C. The reaction is quenched with water (2 mL), and the mixture is diluted with sat. aq. NaHCO3 solution. The mixture is extracted twice with ether. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 1:4 to give 3-{2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-N-methyl-propionamide (21 mg) as a white solid; LC-MS: tR=0.90 min; [M+1]+=393.45; 1H NMR δ 1.32 (t, J=7.5 Hz, 3 H), 1.40 (t, J=7.8 Hz, 3 H), 2.34-2.41 (m, 2 H), 2.45 (s, 3 H), 2.69 (s, 3 H), 2.77 (q, J=7.5 Hz, 2 H), 2.85 (d, J=4.8 Hz, 3 H), 2.95 (q, J=7.8 Hz, 2 H), 3.07-3.13 (m, 2H), 5.41 (s br, 1 H), 7.76 (s, 2 H), 7.84 (s, 1 H), 7.86 (s, 1 H).
Reaction SMILES: C([O:4][CH2:5][CH:6]1[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][C:9]2[C:19]3[CH:25]=[C:24]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH:23]=[C:22]([Cl:35])[C:20]=3[O:21][C:8]=2[CH2:7]1)(=O)C.O.[OH-].[Li+]>CO.O>[Cl:35][C:22]1[C:20]2[O:21][C:8]3[CH2:7][CH:6]([CH2:5][OH:4])[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][C:9]=3[C:19]=2[CH:25]=[C:24]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:23]=1
Reactant: CC(=O)OCC1Cc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2c(oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc23)CC1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To the crude product of step K (110 mg, 0.22 mmol) in methanol (5 mL) and water (5 mL) at 0° C. was added lithium hydroxide monohydrate (92 mg, 2.2 mmol). The solution was stirred at ambient temperature for 2 h then concentrated in vacuo. Water (10 mL) was added and the mixture extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. Purification by flash column chromatography (SiO2, 9:1 to 7:3, hexanes/ethyl acetate) afforded tert-butyl 6-chloro-3-(hydroxymethyl)-8-(phenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (85 mg, 80%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.98-7.95 (m, 3H), 7.84 (d, J=1.5 Hz, 1H), 7.56-7.51 (m, 3H), 4.93 (br s, 2H), 4.13-4.10 (m, 1H), 3.64-3.61 (m, 2H), 3.17-3.08 (m, 1H), 2.88 (d, J=17.4 Hz, 1H), 1.85 (br s, 1H), 1.53 (s, 9H).
Reaction SMILES: OC1C=CC(NC(C)(C)C)=CC=1.C1(NC(C)(C)C)C=CC=CC=1.NC(N)=O.[CH3:28][C:29]([NH:39][CH2:40][C:41]([C:43]1[CH:44]=[CH:45][C:46]([OH:52])=[C:47]([CH2:49][C:50]#[N:51])[CH:48]=1)=[O:42])([CH3:38])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[OH:52][C:46]1[CH:45]=[CH:44][C:43]([CH:41]([OH:42])[CH2:40][NH:39][C:29]([CH3:38])([CH3:28])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[CH:48][C:47]=1[CH2:49][C:50]#[N:51]
Reactant: CC(C)(Cc1ccc(O)cc1)NCC(=O)c1ccc(O)c(CC#N)c1
Agent: CC(C)(C)Nc1ccc(O)cc1
Agent: CC(C)(C)Nc1ccccc1
Agent: NC(N)=O
Product: CC(C)(Cc1ccc(O)cc1)NCC(O)c1ccc(O)c(CC#N)c1

Procedure:
The procedure of Example 1(c) is repeated with substitution of an equimolar amount of p-hydroxyphenyl-t-butylamine for phenyl-t-butylamine in that example. The resulting aminoketone, 5-[N-(1,1-dimethyl-2-p-hydroxyphenylethyl)glycyl]-2-hydroxyphenylacetonitrile, is reduced according to the procedure of Example 1(d) to yield 2-hydroxy-5-[1-hydroxy-2-[(1,1-dimethyl-2-p-hydroxyphenylethyl)amino]-ethyl]benzeneacetonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]2[O:9][CH:8]=[C:7](C(O)=O)[C:6]=2[CH:13]=1>N1C2C(=CC=CC=2)C=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1coc2c([N+](=O)[O-])cc(Br)cc12
Solvent: c1ccc2ncccc2c1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Br)cc2ccoc12
Temperature: 190 °C

Procedure:
5-Bromo-7-nitro-1-benzofuran-3-carboxylic acid (4.65 g, 16 mmol; obtained in Step 2) was suspended in quinoline (25 mL), 0.1 g CuO was added and the mixture heated to 190° C. for 30 minutes. The warm reaction mixture was diluted with hot toluene (100 mL), filtered and the filter cake washed with hot toluene (total 400 mL). The combined toluene extracts were washed with 1 M HCl (2×100 mL) and brine, evaporated and the solid product washed with hexane, collected by filtration and dried. Yield: 1.9 g (48%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.13 (d, J=2.3 Hz, 1H) 8.20 (d, J=2.0 Hz, 1H) 8.28 (d, J=2.3 Hz, 1H) 8.32 (d, J=2.0 Hz, 1H).