Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH2:27])=[N:29][CH:30]=3)[N:3]=[CH:4]2)[CH:12]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-n3cnc(I)c3)n2)cc1
Product: Nc1ccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.23) (0.525 g, 1.09 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.286 g, 1.3 mmol) according to the general procedure VI. Obtained as a yellow solid (0.148 g, 33%). MS (ISP) 450.2 [(M+H)+]; mp 245-247° C.
Reaction SMILES: I[N:2]1[C:7]([OH:8])=[C:6]2[CH:9]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:5]2[N:4]=[CH:3]1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.[Pd](Cl)Cl>[CH3:19][Si:20]([C:23]#[C:24][N:2]1[C:7]([OH:8])=[C:6]2[CH:9]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:5]2[N:4]=[CH:3]1)([CH3:22])[CH3:21]
Reactant: CC(C)(C)C(=O)Nc1cc2c(O)n(I)cnc-2n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cc2c(O)n(C#C[Si](C)(C)C)cnc-2n1

Procedure:
A mixture of 2.0 g of 3-iodo-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine, 1.2 g. of trimethylsilylacetylene, 0.1 g of palladium chloride, 0.23 g of triphenylphosphine, 0.06 g of cuprous iodide, and 2.6 g of triethylamine in 100 mL of acetonitrile is heated in a sealed tube for 1.5 hours at 50° C. and then at reflux for 3 hours. The solvent is removed under reduced pressure and the residue triturated with 1:1 ethyl acetate:hexanes and filtered. The solid thus collected is dissolved in methylene chloride and this solution is passed through a pad of silica gel eluting with 1% methanol on methylene chloride. The eluate is concentrated to yield 3-trimethylsilylethynyl-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=C(O)c1ccccc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccccc1Cl
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Into a 500 mL round bottom flask was placed a solution of 2-chlorobenzoic acid (20 g, 127.80 mmol) in toluene (150 mL). To the mixture was added SOCl2 (16 g, 134.45 mmol). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 75° C. in a bath of oil. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 22.3 g (100%) of 2-chlorobenzoyl chloride as yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.CN([CH:26]=[O:27])C>C1COCC1>[CH3:9][Si:8]([CH3:11])([CH3:10])[C:5]1[CH:6]=[CH:7][C:2]([CH:26]=[O:27])=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)c1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 103.2 %

Procedure:
Bromo-4-(trimethylsilyl)benzene (1.15 g, 5 mmol) was dissolved in THF (30 ml) and cooled to −78° C. Under argon a 1.6 M solution of n-butyl lithium in hexane (3.13 ml, 5 mmol) was added dropwise keeping the temperature below −70° C. The clear colorless solution was stirred at −78° C. for 15 min and DMF (1.156 ml, 15 mmol) was added quickly. The reaction temperature increased to −68° C. The reaction was stirred for additional 15 min at −78° C., quenched with 1N aqueous hydrogen chloride solution and extracted twice with diethyl ether. The combined organic layers were washed twice with water and once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated to leave the product as a colorless oil (920 mg, 100%). The product was pure enough to be used directly in the next step. MS (ISP) 179.2 (M+H+). 1H NMR (CDCl3, 300 MHz): δ 10.02 (s, 1H) 7.84 (d, 2H), 7.69 (d, 2H), 0.31 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.O.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.[ClH:21]>C(O)(C)C>[ClH:21].[ClH:21].[F:1][C:2]([F:12])([F:11])[C:3]1[C:4]2[NH:9][C:17]3[CH2:18][CH2:19][NH:14][CH2:15][C:16]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1ccccc1C(F)(F)F
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: FC(F)(F)c1cccc2c3c([nH]c12)CCNC3
Temperature: 95 °C
Yield: 63 %

Procedure:
To a solution of (2-trifluoromethyl-phenyl)-hydrazine (12.0 g, 68.13 mmol) and 4-piperidone monohydrate (10.46 g, 68.09 mmol), in iso-propyl alcohol was bubbled HCl (g) for 15 minutes at rt. The reaction was sealed in a pressure vessel and heated to 95° C. for 5 h, then cooled to rt. The reaction mixture was filtered and washed with iso-propyl alcohol and dried in vacuo to yield 6-trifluoromethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole bis-hydrochloride as a white solid (13.3 g, 63% yield). 1H NMR (CD3OD, 300 MHz) δ 3.203 (t, 2H, 12.4 Hz), 3.642 (t, 2H, 12.0 Hz), 4.472 (t, 2H, 2.6 Hz), 7.189 (t, 1H, 15.7 Hz), 7.435 (d, 1H, 7.7 Hz), 7.709 (d, 1H, 8.0 Hz) ppm.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:16])=[O:4].[CH2:19](I)[CH3:20].[H-].[Na+]>C1COCC1>[CH2:19]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([C:3](=[O:4])[C:2]([F:1])([F:17])[F:18])=[C:6]1[CH3:16])[CH3:20]
Reactant: COc1ccc2c(C(=O)C(F)(F)F)c(C)[nH]c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1c(C)c(C(=O)C(F)(F)F)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.3 %

Procedure:
To a solution of 2,2,2-trifluoro-1-(6-methoxy-2-methyl-1H-indol-3-yl)-ethanone 71a (1.3 g, 5.05 mmole) in 20 ml anhydrous THF was added ethyl iodide (2.36 g, 15.15 mmole) and sodium hydride (404 mg, 60% in mineral oil, 10.1 mmole) with ice bath cooling. The mixture was warmed slowly to room temperature and stirred for an additional four hours. The reaction was quenched with water and extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated under rot vap. The residue was purified by column chromatography (eluting with 20–30% EtOAc in hexanes) to give a brown oil (580 mg, 40% yield). 1H NMR (300 MHz, CDCl3) δ 7.91 (1H, d, J=8.9 Hz), 6.93 (1H, dd, J=2.3, 8.9 Hz), 6.82 (1H, d, J=2.3 Hz), 4.18 (2H, m), 3.88 (3H, s), 2.76 (3H, s), 1.40 (3H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](OC)=[C:16]([C:19]#[N:20])[C:17]#[N:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>CCO>[NH2:18][C:17]1[NH:25][N:24]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[C:16]=1[C:19]#[N:20]
Reactant: NN
Reactant: COC(=C(C#N)C#N)c1ccc(OCc2ccccc2)cc1
Solvent: O
Solvent: CCO
Product: N#Cc1c(-c2ccc(OCc3ccccc3)cc2)n[nH]c1N
Yield: 87.7 %

Procedure:
Compound 31C (3.1 g, 10.68 mmol) was dissolved in EtOH (20 mL). To this solution was added hydrazine hydrate (0.622 mL, 12.81 mmol). The reaction was heated under reflux for 2 hours. The solvent was removed, and the residue was taken up into EtOAc. It was then washed with water, brine, dried over MgSO4, and concentrated under reduced pressure to provide 2.72 g of the desired product: 1H NMR (DMSO-d6): δ 12.64 and 11.99 (s, 1H), 7.71-7.74 (m, 2H), 7.32-7.48 (m, 5H), 7.09-7.10 (br, 2H), 6.38 (s, 2H), 5.15 (s, 2H). MS (DCI(+)): m/z 291 (M+H).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=CC=1.C1C=CC2N(O)N=NC=2C=1.[NH:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1>ClCCl>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[C:16]3[CH2:29][CH2:28][N:27]([C:30]4[CH:38]=[CH:37][C:33]([C:34]([N:61]5[CH2:66][CH2:65][O:64][CH2:63][CH2:62]5)=[O:36])=[CH:32][C:31]=4[F:39])[C:17]=3[N:18]=[C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:20]=2)=[CH:13][N:14]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(C(=O)N3CCOCC3)cc2F)cn1
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (120 mg, 0.177 mmol) obtained in Step A in 1-D-21, WSCI (68 mg, 0.35 mmol), HOBt (24 mg, 0.15 mmol) and morpholine (31 μl, 0.35 mmol), dichloromethane (4 ml) was added, followed by stirring for 1 hour. The reaction mixture was washed with water, and subsequently dried over sodium sulfate. The drying agent was removed, followed by concentration and drying. To this, TFA (2 ml) was added, followed by stirring at 80° C. for 4 hours. After TFA was removed under reduced pressure, dichloromethane was added, followed by washing with aqueous sodium hydrogencarbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated, to obtain a crude product. Purification by silica gel column chromatography (dichloromethane/methanol=10/1) afforded {4-[4-(2-amino-pyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-fluoro-phenyl}-morpholin-4-yl-methanone as a colorless solid (86 mg, 96%).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH:5]2[C:9]3([CH2:18][C:19]4[C:24]([N:4]2[C:3]1=[O:33])=[CH:23][CH:22]=[C:21]([NH:25]C(=O)OC(C)(C)C)[CH:20]=4)[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]3=[O:17].[ClH:34].O1CCOCC1>C(Cl)Cl>[ClH:34].[NH2:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:4]1[C:3](=[O:33])[CH:2]([CH3:1])[O:7][CH:6]([CH3:8])[CH:5]1[C:9]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]1=[O:17])[CH2:18]2
Reactant: CC1OC(C)C2N(C1=O)c1ccc(NC(=O)OC(C)(C)C)cc1CC21C(=O)NC(=O)NC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1OC(C)C2N(C1=O)c1ccc(N)cc1CC21C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
A suspension of tert-butyl 1,1′,2,3′,4,4′,4a,6′-octahydro-2,4-dimethyl-2′,4′,6′-trioxospiro[[1,4]oxazino[4,3-a]quinolone-5(6H), 5′(2′H)-pyrimidin]-8-ylcarbamate (from Example 15) (7.4 g, 16.65 mmoles) in 250 mL of CH2Cl2 at room temperature is treated via pipette with a solution of 4.0 N HCl in dioxane (20 mL, 80 mmoles). The resulting slurry is stirred at room temperature for 2 days and then concentrated. The residue is dissolved in hot 1:1 EtOAc/methanol (˜300 mL) and recrystallized from heptane. After cooling to room temperature and then stirring at 0° C. for 30 minutes, the solid is isolated by filtration and dried (20 torr, 60° C., for 18 h) to give 6.31 g (99%) of the title compound as a beige solid. 1H NMR (DMSO-d6): δ 11.78, 11.47, 9.83, 7.06, 6.92, 6.87, 4.03, 3.67, 3.60, 3.50, 3.41, 2.90-2.82, 1.13, 0.91.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([C:10]3([F:13])[CH2:12][CH2:11]3)[CH2:9][O:8]2)=[CH:4][CH:3]=1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]([C:10]2([F:13])[CH2:12][CH2:11]2)([OH:8])[CH2:9][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: FC1(C2(Cc3ccc(Cl)cc3)CO2)CC1
Solvent: CN(C)C=O
Solvent: O
Product: OC(Cc1ccc(Cl)cc1)(Cn1cncn1)C1(F)CC1
Yield: 47.4 %

Procedure:
A solution of 3.3 g (15.7 mmol) of 2-(4-chlorobenzyl)-2-(1-fluorocyclopropyl)-oxirane in 10 ml of dimethylformamide is added dropwise to a mixture of 3.3 g (47.1 mmol) of 1,2,4-triazole and 0.35 g (3.14 mmol) of potassium tert.-butylate in 20 ml of dimethylformamide at a temperature of 80° C., while stirring. When the addition has ended, the reaction mixture is stirred for 13 hours at 80° C. The solvent is then stripped off under reduced pressure, and the remaining residue is taken up with water. The aqueous phase is extracted four times with methylene chloride. The combined organic phases are dried over sodium sulphate and then concentrated under reduced pressure. The remaining residue is chromatographed over silica gel using cyclohexane:ethylacetate=2:1 as the mobile phase. Evaporation of the eluate gives 2.2 g (47% of theory) of 1-(4-chlorophenyl)-2-(1-fluorocyclopropyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol in form of a solid substance. 1H-NMR (200 MHz, CDCl3): δ0.0-0.8 (m, 4H); 3.0 (AB-system, 2H); 4.01 (s,lH, OH); 4.3 (AB-system, 2H); 7.28 7.98 (s, 1H); 8, 13 (s, 1H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1
Reactant: COC(=O)c1cc(Br)oc1C
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccccc2OC)oc1C
Reaction time: 8 h
Yield: 93 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 2-methoxyphenylboronic acid (1.8 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.3 g, 92%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]([O:22]C)=[O:21])[CH:13]=2)[O:9][N:8]=1.[OH-].[Na+]>CO.O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]([OH:22])=[O:21])[CH:13]=2)[O:9][N:8]=1
Reactant: COC(=O)c1cc(OC)cc(-c2nc(-c3ccccn3)no2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A stirred suspension of 3-(2-pyridyl)-5-(3-methoxycarbonyl-5-methoxyphenyl)-1,2,4-oxadiazole (191.3 mg, 0.62 mmol) in methanol-tetrahydrofuran (1:1, 10 mL) was treated with 1M sodium hydroxide (1.5 mL, 1.5 mmol). The reaction was stirred at 50° C. for 5 hours and the solvent then removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH 4-5) by the addition of 2 N hydrogen chloride. The precipitate was collected and dried to afford 131.8 (72%) of 3-(2-pyridyl)-5-(3-carboxy-5-methoxyphenyl)-1,2,4-oxadiazole: 1H NMR (DMSO): δ-8.81 (d, 1H), 8.28 (s, 1H), 8.21 (d, 1H), 8.06 (t, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.65 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(O)(=[O:39])CCCCCCC/C=C\C/C=C\C/C=C\CC>>[OH:39][CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH:7]=[CH:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Product: CCCCCC(O)CCC=CCC=CCCCCC(=O)O

Procedure:
The same procedure as in Example 2 was repeated, except that linoleic acid was replaced by α-linolenic acid, whereby 13-hydroxy-6,9-octadecadienoic acid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.CC1O[N:29]=[C:28]([C:31]2C=CC=CC=2)[C:27]=1COC1C=CC(C(O)=O)=CN=1.C(N)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH:28]([CH3:31])[CH3:27])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Solvent: CC(C)N
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 76 %

Procedure:
As described for example 8b, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (103 mg, 0.3 mmol), instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid, was converted, using isopropylamine instead of methylamine, to the title compound (88 mg, 76%) which was obtained as an off white solid. MS: m/e=368.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[OH:22])=[CH:5][CH:4]=1)#[N:2].Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH:10]2[O:22][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In analogy to the procedure described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-(4-cyano-phenyl)-3-hydroxy-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-cyano-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a light yellow resin; MS: 443 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]1([C:21]2[O:25][N:24]=[C:23]([CH2:26][NH2:27])[CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:27][CH2:26][C:23]1[CH:22]=[C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:25][N:24]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCc1cc(-c2ccccc2)on1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCc1cc(-c2ccccc2)on1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A suspension of 4-chloro-3-nitroquinoline (2.29 g, 11.0 mmol) and (5-phenylisoxazol-3-yl)methylamine (1.92 g, 11.0 mmol) in dichloromethane (200 mL) was cooled to 0° C., and triethylamine (2.30 mL, 16.5 mmol) was added. The resultant solution was allowed to warm to room temperature slowly and stirred overnight. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluting with 3% to 8% methanol in dichloromethane) to provide 2.90 g of 3-nitro-N-[(5-phenylisoxazol-3-yl)methyl]quinolin-4-amine.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38](O)=[O:39])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:38](=[O:39])[CH2:37][N:34]3[CH2:33][CH2:32][N:31]([C:29]([O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:30])[CH2:36][CH2:35]3)([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-carboxymethyl-piperazine-1-carboxylic acid tert-butyl ester to yield (3aR,4S,7aR)-4-[2-(4-tert-butoxycarbonyl-piperazin-1-yl)-acetoxy]-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. This NBoc-protected product was then stirred in hydrochloric acid dioxane solution (4M, 10 equiv.) at room temperature for 6 hrs. Subsequently the solvent was removed the residue dissolved in dichloromethane and washed with saturated sodium hydrogencarbonate solution. The organic layer was tried with sodium sulfate, filtrated and evaporated. The crude product was subjected to silica gel flash chromatography (ISCO CombiFlash; dichloromethane/methanol; 100/0 to 95/5) to yield (3aR,4S,7aR)-methyl 4-(2-(piperazin-1-yl)acetoxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H] 440; RT=4.882 min; LCMS Method III
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6](OS(C(F)(F)F)(=O)=O)[CH:7]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(F)cc1-c1ccccc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of trifluoromethanesulfonic acid 5-fluoro-2-nitrophenyl ester (4.0 mmol) in DME (10 mL) are added phenylboronic acid (4.8 mmol), Pd(PPh3)4 (0.4 mmol), and K3PO4 (3.2 mmol) at room temperature. After stirring at 80° C. for 6 h, the reaction mixture is filtered through celite, and the filter cake is washed with AcOEt. The filtrate is diluted with water and extracted with ether (×2). The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=6:1) to give the title compound; 1H NMR (CDCl3), δ 7.12-7.19 (2H, m), 7.29-7.32 (2H, m), 7.42-7.45 (3H, t), 7.94 (1H, dd).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:19])([CH:16]([CH3:18])[CH3:17])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:5][CH:4]=1)#[CH:2].CO.[I:22]I.[OH-].[Na+]>O>[I:22][C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:19])([CH:16]([CH3:17])[CH3:18])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:5][CH:4]=1
Reactant: II
Reactant: C#Cc1ccc(C(O)(Cn2cncn2)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C(O)(Cn1cncn1)c1ccc(C#CI)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5.1 g 2-(4-ethynylphenyl)-3-methyl-1-(1H-1,2,4-triazole-1-yl)butan-2-ol in 100 ml abs. CH3OH are simultaneously added, with stirring at 20°-25°, 2.6 g iodine and 10 ml 30% NaOH solution. The reaction mixture is maintained at room temperature for 24 hours, with stirring, then poured into 500 ml H2O and extracted with CH2Cl2. The organic phase is washed, dried and evaporated. The residue is stirred in hexane fraction and kept over 16 hours at rest. The precipitate is sucked off and dried to give the title compound m.p. 122° as colourless crystals.