Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:4]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C(Cl)Cl>[OH:33][C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(O)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: ClCCl
Product: Oc1nc(O)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reaction time: 2 h

Procedure:
To a 10 mL round bottom flask fitted with a magnetic stirrer bar was added 2-methylthio-4-hydroxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 11 (40 mg, 0.1 mmol) and 1.0 mL DCM. The reaction flask was cooled in an ice bath and mCPBA (70%, 50mg, 0.22 mmol) was added all at once. After 2 h, two new products were observed by LC. The product eluting at Rt=3.38 min was 2-methylsulfonyl-4-hydroxy-5-(4-chlorophenyl)-6-(2, 4-dichlorophenyl)pyrimidine, m/e=431 (M++1) and that at Rt=2.91 min is 2,4-dihydroxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine: m/e=367 (M+). The mixture was poured into 2 N NaOH and heated briefly. The precipitate that formed was filtered, washed with water and dried under reduced pressure. The title product was recovered. m/e=367 (M+). Rt=2.91 min; 1H-NMR 500 MHz (CDCl3): δ 6.98 (d, J=8 Hz, 2H), 7.08 (d, J=8 Hz, 1H), 7.17 (d, J=8 Hz, 3H), 7.38 (d, J=2 Hz, 1H), 9.8 (bs, 1H), 10.1 (bs 1H).
Reaction SMILES: O1C2C=CC=CC=2OB1.[Br:10][C:11]1[C:12]([N:27]2[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[Br:10][C:11]1[C:12]([N:27]2[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28]2)=[C:13]([C@H:19]([OH:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CC(C)(C)C2)c1Br
Agent: B1Oc2ccccc2O1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Product: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CC(C)(C)C2)c1Br
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 61.4 %

Procedure:
The 1.5 mL of benzo[d][1,3,2]dioxaborole (751 mg, 6.26 mmol) was added to a nitrogen purged solution of isopropyl 2-(5-bromo-4-(3,3-dimethylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (1.6 g, 4.17 mmol) and 1.25 mL of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (347 mg, 1.25 mmol) in toluene (40 mL) at −60° C. and allowed to warm to −15° C. before being placed in the freezer overnight. The reaction was quenched with 1M Na2CO3 (15 mL), diluted with EtOAc, and stirred for 20 min. The organic layer was washed with brine and dried (Na2SO4). The crude product was charged (DCM) to an 80 g ISCO silica gel cartridge and gradient elution (5-35% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-4-(3,3-dimethylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate 987 mg (61%). 1H NMR (500 MHz, DMSO-d6) δ 5.16 (s, 1H), 4.97-4.92 (m, 1H), 4.13 (d, J=7.7 Hz, 2H), 4.04 (d, J=7.7 Hz, 2H), 2.42 (s, 3H), 2.21 (s, 3H), 1.22 (s, 6H), 1.17 (d, J=6.2 Hz, 3H), 1.12 (d, J=6.2 Hz, 3H). UPLC (M+H)=387.2.
Reaction SMILES: C([Li])CCC.CN(C)CCNC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].[Cl:23]C(Cl)(Cl)C(Cl)(Cl)Cl.Cl>O1CCCC1.O>[Cl:23][C:16]1[C:15]([O:14][CH3:13])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]
Reactant: COc1cccc(C=O)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CNCCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C=O)c1Cl
Temperature: -70 °C
Reaction time: 2 h

Procedure:
At 40° C. n-butyl lithium (6.25 mL, 1.6 M in hexane) was added to a solution of N,N,N′-trimethylethylenediamine (1.27 mL) in 10 mL tetrahydrofuran. After 15 min. the reaction mixture was cooled to −70° C. and a solution of 3-methoxybenzaldehyde (1.22 mL) in 5 mL of tetrahydrofuran was added. The reaction mixture was allowed to warm to 0° C. and was cooled again to −70° C. and n-butyl lithium (6.25 mL, 1.6 M in hexane) was added. The reaction mixture was allowed to warm to 10° C. and was cooled again to −30° C. before it was added to a solution of hexachloroethane (7.10 g) in 10 mL tetrahydrofuran. The reaction mixture was stirred for 2 h. at room temperature, poured into 20 mL 10% HCl in water and extracted several times with ethyl acetate. The combined organic phases were washed with saturated brine, dried on MgSO4 and concentrated. The title product was obtained after flash column chromatography (silica gel, heptane/ethyl acetate (75/25, v/v), Rf=0.38), followed by crystallisation from heptane.
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:7][CH2:6][CH:5]([CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([O:17]C)=[O:16])[CH2:12][CH2:11][N:10]2[C:19]([O:21][CH3:22])=[O:20])[CH2:4][CH2:3]1.[Br-].[Li+].CCN(CC)CC.CC(OC)(C)C>C(#N)C.O>[F:23][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][CH2:11][N:10]2[C:19]([O:21][CH3:22])=[O:20])[CH2:6][CH2:7]1
Reactant: COC(=O)C1CCN(C(=O)OC)C(CC2CCC(F)(F)CC2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: COC(C)(C)C
Product: COC(=O)N1CCC(C(=O)O)CC1CC1CCC(F)(F)CC1
Yield: 88.3 %

Procedure:
Dimethyl 2-((4,4-difluorocyclohexyl)methyl)piperidine-1,4-dicarboxylate (5.7 g, 17.10 mmol) was dissolved in acetonitrile (75 mL) and water (1.5 mL), then lithium bromide (11.88 g, 136.78 mmol) was added. Et3N (9.53 mL, 68.39 mmol) was added to the solution. The resulting yellow suspension was heated at reflux for 2 h. Water (100 mL) and MTBE (300 mL) were added. The phases were separated and the organic layer was extracted with water (2 times). The pooled water layers were acidified to pH 1 with 3.8 M HCl and extracted with MTBE (2 times). The combined organic layer was dried over Na2SO4, filtered and evaporated to yield 2-((4,4-difluorocyclohexyl)methyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.82 g, 88%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH:10]1[O:14][CH2:13][CH2:12][CH2:11]1>>[O:14]1[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: BrCC1CCCO1
Reactant: Oc1ccc(Br)cc1
Product: Brc1ccc(OCC2CCCO2)cc1

Procedure:
Prepared by the method of Example 42 (b) using 4-bromophenol and tetrahydrofurfuryl bromide.
Reaction SMILES: [O:1]=[C:2]([NH:18][CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[C:20]([F:23])([F:22])[F:21])/[CH:3]=[CH:4]/[C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([C:14]([F:17])([F:16])[F:15])[CH:6]=1.ClC1C=C(O)C2N=NNC=2C=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)C(C)C)C.Cl.[F:67][CH2:68][CH:69]([NH2:71])[CH3:70]>ClCCl>[F:67][CH2:68][CH:69]([NH:71][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5](/[CH:4]=[CH:3]/[C:2](=[O:1])[NH:18][CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)[C:20]([F:22])([F:23])[F:21])=[CH:6][C:7]=1[C:14]([F:16])([F:17])[F:15])[CH3:70]
Reactant: O=C(/C=C/c1ccc(C(=O)O)c(C(F)(F)F)c1)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Reactant: CC(N)CF
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cc(Cl)cc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(CF)NC(=O)c1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
49 mg (1 eq, 0.1 mmol) of 4-[(1E)-3-oxo-3-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-amino)prop-1-en-1-yl]-2-(trifluoromethyl)benzoic acid from Example 2, Stage 2 were dissolved in 1 ml of dichloromethane. Then 17 mg (1.0 eq, 0.10 mmol) of 6-chlorohydroxybenzotriazole, 23 mg (1.2 eq, 0.12 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 26 mg (2 eq, 0.20 mmol) of N-ethyldiisopropylamine were added thereto, and the mixture was stirred at RT for 20 min. Subsequently, 11 mg (1.0 eq, 0.10 mmol) of 1-fluoropropan-2-amine hydrochloride were added and the reaction mixture was stirred at room temperature for 12 h. After this time, the reaction mixture was concentrated and the resulting crude product was purified by means of preparative HPLC (phenomenex Gemini C18 5 μm; 110A; AXIA 50×21.2 mm; gradient: 0-2 min 70% water, 30% MeOH, 2.5-6.0 min linear gradient to 5% water, 95% MeOH, 6.0-20.00 min 5% water, 95% MeOH; modifier: 20% HCOOH added at 2 ml/min). This gives 27 mg (37%) of N-(1-fluoropropan-2-yl)-4-[(1E)-3-oxo-3-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}amino)-prop-1-en-1-yl]-2-(trifluoromethyl)benzamide as a solid.
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[CH:9]=[C:10]3[NH:16][CH2:15][CH2:14][O:13][C:11]3=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.BrN1[C:29](=O)[CH2:28][CH2:27]C1=O.C1(OB(O)O)CC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:27]1([C:9]2[C:8]3[CH:2]([CH3:1])[CH2:3][N:4]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:5][CH2:6][C:7]=3[CH:12]=[C:11]3[O:13][CH2:14][CH2:15][NH:16][C:10]=23)[CH2:28][CH2:29]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1CN(C(=O)OC(C)(C)C)CCc2cc3c(cc21)NCCO3
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC1CN(C(=O)OC(C)(C)C)CCc2cc3c(c(C4CC4)c21)NCCO3
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
To a solution of 704 mg of t-butyl 6-methyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate in 15 ml of dichloromethane was added portionwise 438 mg of N-bromosuccinimide under ice-cooling, followed by stirring for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 446 mg of a pale yellow foamed substance. To a mixture of 445 mg of the resulting compound, 144 mg of cyclopropylboric acid, 724 mg of potassium phosphate, 65 mg of tricyclohexylphosphine, and 28 mg of palladium(II) acetate were added 10 ml of toluene and 0.5 ml of water, followed by stirring at 110° C. for 12 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 379 mg of t-butyl 5-cyclopropyl-6-methyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate as a pale brown foamed substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(F)c(F)c2)C1

Procedure:
The title compound was prepared from (3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine and 4-bromo-1,2-difluorobenzene using the procedure outlined for Description 11.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH2:22]OS(C)(=O)=O)=[CH:4][C:3]=1[F:28].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[N:29]([CH2:22][C@H:9]1[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:28])[CH:4]=2)[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[N+:30]=[N-:31]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](COS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN=[N+]=[N-])C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 192.3 %

Procedure:
To a solution of tert-butyl (6S,7R)-7-(4-chloro-3-fluorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (4.00 g) in DMF (46 mL) was added sodium azide (891 mg), and the mixture was stirred at 70° C. overnight. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel filtration to give the title compound (6.76 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:14])=[C:6]([C:8](=[O:13])[CH2:9][CH2:10][C:11]#[N:12])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:32][CH:31]([CH3:33])[N:30]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH2:29][CH:28]1[CH3:42])=[O:26]>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH2:24][C:25]([N:27]2[CH2:32][C@H:31]([CH3:33])[N:30]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[CH2:29][C@H:28]2[CH3:42])=[O:26])=[C:6]([C:8](=[O:13])[CH2:9][CH2:10][C:11]#[N:12])[CH:7]=1
Reactant: N#CCCC(=O)c1cc(Cl)ccc1O
Reactant: CC1CN(C(=O)CCl)C(C)CN1Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C(=O)CCC#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.8 %

Procedure:
To a solution of 4-(5-chloro-2-hydroxy-phenyl)-4-oxo-butyronitrile (0.15 g, 0.70 mmol) in acetonitrile (4 mL) was added potassium carbonate (0.16 g, 1.16 mmol), potassium iodide (0.040 g, 0.24 mmol) and (2-chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.21 g, 0.70 mmol). The reaction was stirred for 20 hours at ambient temperature. Tetrahydrofuran (8 mL) was added and solids were removed by filtration. The filtrate was concentrated and the crude product purified by flash chromatography to give the title compound (0.31 g).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[C:9]2[NH:8][C:7](=[O:13])[CH:6]3[CH2:14][O:15][CH2:16][CH2:17][N:5]3[C:4]=2[N:3]=1.IC.[CH3:20]C([O-])(C)C>CS(C)=O>[Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[C:9]2[N:8]([CH3:20])[C:7](=[O:13])[CH:6]3[CH2:14][O:15][CH2:16][CH2:17][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1Nc2c(Cl)nc(Cl)nc2N2CCOCC12
Reactant: CC(C)(C)[O-]
Solvent: CI
Solvent: CS(C)=O
Product: CN1C(=O)C2COCCN2c2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.8 %

Procedure:
2,4-Dichloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (500 mg, 1.818 mmol) and iodomethane (1.134 mL, 18.18 mmol) were mixed in DMSO (3 mL). 2-Methylpropan-2-olate (699 mg, 7.27 mmol) was added and the suspension was stirred overnight at room temperature. Ten more equivalents of iodomethane were added and the solution was heated at 50° C. for about 18 hours. The reaction was purified by mass-triggered preparative HPLC 20-60% of ACN (containing 0.035% TFA) in water (containing 0.05% TFA) on a Phenomenex Gemini 5 μm C18, 75×30 mm column)) to give 20 mg of 2,4-dichloro-5-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one as a tan solid. MS [M+H] Found 289.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:23][C:24]([C:26]3[CH:27]=[C:28]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=4)[CH:29]=[CH:30][C:31]=3[O:32]C)=[O:25])[C:17]3[O:21][N:20]=[C:19]([CH3:22])[N:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].B(Br)(Br)Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:23][C:24]([C:26]3[CH:27]=[C:28]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][CH:35]=4)[CH:29]=[CH:30][C:31]=3[OH:32])=[O:25])[C:17]3[O:21][N:20]=[C:19]([CH3:22])[N:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)c1nc(C)no1
Agent: BrB(Br)Br
Product: Cc1noc([C@@H](Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)NC(=O)c2cc(-c3ccc(C(F)(F)F)cc3)ccc2O)n1
Yield: 78.9 %

Procedure:
4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (94 mg) was prepared from 4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (122 mg, 0.20 mmol) and boron tribromide (0.5 mL, 0.5 mmol, 1.0 M solution in DCM) following the general procedure P.
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28]Cl.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccccn1
Reactant: c1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1ccc(Cc2ccc(OC[C@H]3CCCN3Cc3ccccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of Example 1 (0.20 g, 0.66 mmol) in DMF (5 mL) was added 2-picolyl chloride hydrochloride (0.10 g, 0.61 mmol) and triethylamine (0.24 mL, 1.72 mmol). The subsequent mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude residue was extracted into ethyl acetate (25 mL) and washed with water (25 mL) followed by brine (25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.07 g, 36%); 1H NMR (400 MHz, CDCl3); δ 1.73-1.80 (m, 3H), 2.05 (m, 1H), 2.40 (m, 1H), 3.02-3.08 (m, 2H), 3.71 (d, J=13.6 Hz, 1H), 3.83 (m, 1H), 3.91 (s, 2H), 3.95 (m, 1H), 4.25 (d, J=13.6 Hz, 1H), 6.79 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 7.15-7.20 (m, 4H), 7.25-7.27 (m, 2H), 7.41 (m, 1H), 7.61 (m, 1H), 8.53 (m, 1H); MS (m/z) 359.2 (M+1); LC (100.0%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([N:11]1[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16](F)[CH:17]=2)[C:12]1=[O:31])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.Cl>CO>[CH2:4]([N:11]1[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:2][CH3:1])[CH:17]=2)[C:12]1=[O:31])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(=O)n(Cc3ccccc3)c(C(=O)O)c(-c3ccccc3)c2c1

Procedure:
To a solution of sodium methoxide in methanol (28%, 4 ml) was added 2-benzyl-6-fluoro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (350 mg), and the mixture was heated under reflux for 6 hrs. To the reaction mixture were added water and 10% hydrochloric acid to acidify the aqueous layer of the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the title compound (260 mg).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][CH:2]=1.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>O1CCOCC1.C(O)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:17])=[CH:2][CH:3]=3)=[CH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:27]2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(C)cc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(C)cc2)n(-c2ccc(F)cc2)n1
Yield: 41.5 %

Procedure:
A mixture of ethyl 4-(4-tolyl)-2,4-dioxobutanoate (4.7 g) and 4-fluorophenylhydrazine hydrochloride (3.6 g) in dioxane (35 ml) and ethanol (35 ml) was refluxed for 5 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The oily residue (8 g) was purified.by column chromatography on silica gel (130 g) eluting with chloroform to give an oil of ethyl 1-(4-fluorophenyl)-5-(4-tolyl)pyrazole-3-carboxylate (2.7 g).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C@H:4]([C:7]([OH:9])=O)[O:3]1.[N+]([O-])(O)=O.[N+:14]([O:17][CH2:18][CH2:19][NH2:20])([O-:16])=[O:15].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>>[N+:14]([O:17][CH2:18][CH2:19][NH:20][C:7]([C@@H:4]1[O:3][C:2](=[O:1])[NH:6][CH2:5]1)=[O:9])([O-:16])=[O:15]
Reactant: O=C1NC[C@H](C(=O)O)O1
Reactant: NCCO[N+](=O)[O-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O=[N+]([O-])O
Product: O=C1NC[C@H](C(=O)NCCO[N+](=O)[O-])O1
Yield: 20.6 %

Procedure:
Following a procedure similar to that described in Example 1, but using 0.32 g of (5R)-2-oxooxazolidine-5-carboxylic acid, 0.50 g of N-(2-nitrooxyethyl)amine nitrate and 0.63 ml of diphenylphosphoryl azide, 0.11 g of the title compound was obtained as pale yellow plates, melting at 103°-105° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][N:6]1[C:14]([NH2:15])=[C:13]2[C:8]([N:9]=[C:10]([C:17]([CH3:20])([CH3:19])[CH3:18])[NH:11][C:12]2=[O:16])=[N:7]1>N1C=CC=CC=1>[CH3:5][N:6]1[C:14]([NH:15][C:1](=[O:3])[CH3:2])=[C:13]2[C:8]([N:9]=[C:10]([C:17]([CH3:20])([CH3:19])[CH3:18])[NH:11][C:12]2=[O:16])=[N:7]1
Reactant: Cn1nc2nc(C(C)(C)C)[nH]c(=O)c2c1N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1c2c(=O)[nH]c(C(C)(C)C)nc2nn1C

Procedure:
Acetyl chloride (3.8 g) was added slowly to a suspension of 2-methyl-3-amino-6-t-butyl-2,5-dihydropyrazolo[3,4-d]-pyrimidin-4-one (10.5 g) in pyridine (50 ml). The solution was left to cool overnight and then concentrated to an oil which was dissolved in 0.5 N hydrochloric acid (20 ml). Scratching induced crystallisation. The precipitate was recrystallised from 80:20 ethanol:water (1.5 g, 12%) m.p. 340°-42° decomposition.
Reaction SMILES: [CH2:1]([OH:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[C:11]1([CH2:17][C:18]([O:10][CH2:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCCCC/C=C/CO
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCOCC
Product: CCCCCC/C=C/COC(=O)Cc1ccccc1

Procedure:
To a flask equipped with a reflux condenser, mechanical stirrer and dropping funnel is added trans-2-nonenol (14.2 g, 0.1 mole), N1N-dimethylaniline (12 g, 0.1 mole) and 20 ml ether. To the stirred mixture is added dropwise phenylacetyl chloride (15.5 g, 0.1 mole) at a rate to maintain a vigorous reflux of ether. After the addition, the mixture is warmed on a water bath for 2 hours and then allowed to stand several hours. The ether layer is separated from the precipitate and extracted with 10% sulfuric acid. The ether layer is dried over anhydrous sodium sulfide and purified up to give trans-2-nonenyl phenylacetate.