Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH:26]=4)[C:21]4([CH2:38][O:37]C(C)(C)[O:35][CH2:34]4)[CH2:20]3)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl>C1COCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH:26]=4)[C:21]([CH2:38][OH:37])([CH2:34][OH:35])[CH2:20]3)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(COC(C)(C)OC2)c2ccc(N3CCOCC3)cc21
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(CO)(CO)c2ccc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1′-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-2,2-dimethyl-6′-morpholinospiro[[1,3]dioxane-5,3′-indoline] (0.057 g, 0.105 mmol) in THF (1 mL) was added 1.0 N HCl (1.05 mL, 1.05 mmol). After stirring at rt for 1 h, the solution was purified by column chromatography (eluting with a gradient of 0-10% MeOH in DCM) to give (1-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-6-morpholinoindoline-3,3-diyl)dimethanol as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.72 (1H, d, J=4.89 Hz), 8.03 (1H, td, J=7.70, 1.71 Hz), 7.97 (1H, dd, J=9.29, 6.11 Hz) 7.92 (1H, d, J=7.83 Hz), 7.84 (1H, dd, J=10.15, 2.57 Hz), 7.47-7.57 (2H, m), 7.06 (1H, d, J=8.07 Hz), 6.21 (1H, dd, J=8.19, 2.08 Hz), 5.45 (1H, d, J=1.96 Hz), 4.91 (1H, t, J=5.26 Hz), 4.84 (1H, t, J=5.26 Hz), 3.79-3.91 (2H, m), 3.72 (2H, d, J=5.38 Hz), 3.65 (2H, dd, J=5.38, 1.22 Hz), 3.58 (4H, t, J=4.89 Hz), 2.76-2.89 (4H, m), 2.29 (s, 3H). Mass Spectrum (ESI) m/e=501.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O.ClCCl>[N:14]1([CH2:9][C:8]2[CH:7]=[C:6]([C:5]#[C:4][CH2:3][CH2:2][OH:1])[CH:13]=[CH:12][CH:11]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(C#CCCO)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OCCC#Cc1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1-L, 3-necked round-bottom flask was equipped with a mechanical stirrer, a rubber septum with a nitrogen inlet and a stopper. The flask was charged with the product of Example 5 (14.6 g) and dichloromethane (250 mL). Morpholine (8.85 mL) was added, and then to this well-stirred reaction mixture was added sodium triacetoxyborohydride (32 g) in 4 equal portions. After the addition, the reaction mixture was stirred at room temperature overnight. Aqueous NaOH (10% w/v, 75 mL) was added, and the reaction mixture was transferred to a 1-L separatory funnel, to which water(100 mL) was then added. After separation of the layers, the aqueous phase was extracted once with dichloromethane (100 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, and filtered. The solvents were removed from the filtrate under reduced pressure to yield the product as yellow oil. The crude product was purified by filtration through a pad of silica gel (ethyl acetate/hexanes; 7:3) to obtain the title compound as a pale yellow oil (13.7 g).
Reaction SMILES: [C:1]([C:9]1[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].NN>C(O)COCCOCCO>[CH2:1]([C:9]1[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cccc(CO)n1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Product: OCc1cccc(Cc2ccccc2)n1
Reaction time: 4 h

Procedure:
A mixture of (6-benzoyl-2-pyridyl)methanol (1.5 g, 7 mmol), potassium hydroxide (1.3 g, 23 mmol) and hydrazine 85% (1 ml, 25 mmol) in triethylene glycol (10 ml) is refluxed for 1.5 hours, and then the water and excess hydrazine are removed by a takeoff condenser until the temperature rises to 195°-200°. After 4 hours at 195°-200°, the solution is cooled, poured into ice and water (50 ml) and extracted with ether (3×20 ml). The combined ether layers are washed with water (3×20 ml), brine (10 ml) and dried over calcium sulfate. Removal of solvents gives (6-benzyl-2-pyridyl)methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][CH:17]=[C:16]2[CH:20]=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:20]([C:16]3[C:15]4[C:19](=[C:11]([CH3:10])[CH:12]=[CH:13][CH:14]=4)[NH:18][CH:17]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: Cc1cccc2c(C=O)c[nH]c12
Product: Cc1cccc2c(-c3nc4cc(Br)cnc4[nH]3)c[nH]c12

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 7-methylindole-3-carboxaldehyde.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH2:22][CH2:21][CH2:20][C:19]3([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][C:6](O)=[O:7])[CH3:2].C(Cl)(=O)C(C)(C)C.[CH2:35]([C@@H:42]1[CH2:46][O:45][C:44](=[O:47])[NH:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Br-].[Li+]>O1CCCC1.C(N(CC)CC)C>[CH2:35]([C@@H:42]1[CH2:46][O:45][C:44](=[O:47])[N:43]1[C:6](=[O:7])[CH2:5][CH:4]([O:3][CH2:1][CH3:2])[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]2[CH2:22][CH2:21][CH2:20][C:19]3([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:18]=2)=[CH:13][CH:14]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: CCOC(CC(=O)O)c1ccc(OCC2=CC3(CCCCC3)CCC2)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(OCC2=CC3(CCCCC3)CCC2)cc1
Temperature: -32.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-pr opionic acid (2.95 g) obtained in Example 41 and triethylamine (3.3 mL) in tetrahydrofuran (60 mL) was added dropwise a solution of pivaloyl chloride (1.265 mL) in tetrahydrofuran (5 mL) at −35° C., followed by stirring the reaction mixture at −35 to −30° C. for 30 minutes. Then, to the reaction mixture was added dropwise a solution of (R)-4-benzyl-2-oxazolidinone (1.82 g) and lithium bromide (892 mg) in tetrahydrofuran (10 mL), followed by raising the temperature up to 0° C. over 2 hours while stirring the reaction mixture. The reaction mixture was poured into ice-cold water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by mid-pressure preparative chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:5) to give (R)-4-benzyl-3-(3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionyl)oxazolidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[C:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][CH:36]1[CH2:38][CH2:37]1>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:35][CH:36]2[CH2:38][CH2:37]2)[C:13](=[O:18])[CH:12]=[C:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[O:7])=[CH:26][CH:27]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.7 %

Procedure:
A solution of 6-(4-Chloro-benzoyl)-4-(3-chloro-phenyl)-1H-quinolin-2-one (3.10 g, 7.87 mmol), prepared according to the methods described in PCT international patent application publication number WO 97/21701 (published Jun. 19, 1997), in DMF (28 mL) was treated with cesium carbonate (2.56 g, 7.87 mmol) and (bromomethyl)cyclopropane (2.13 g, 15.7 mmol). The reaction mixture was stirred at room temperature for 12 hours, diluted with dichloromethane (25 mL), and washed with 1N HCl (2×10 mL) and brine (20 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to give a black residue. Purification by flash column chromatography (silica, ethyl acetate:petroleum ether 1:9-3:7) gave 6-(4-Chloro-benzoyl)-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one (2.39 g, 68%) as an off-white foam.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])=[CH:4][CH:3]=1.[CH2:16](O)[CH2:17][OH:18].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[O:18][CH2:17][CH2:16][O:7]2)=[CH:14][CH:15]=1
Reactant: OCCO
Reactant: O=C(O)CCCC(=O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)CCCC1(c2ccc(F)cc2)OCCO1
Temperature: 22.5 °C
Reaction time: 4.5 h

Procedure:
21.0 g (0.1 mol) 4-(4-fluor-benzoil)-butyric acid (II) was weighed into a 500 ml round-bottom flask and suspended in 210 ml dichloro methane. During continuous stirring 28 ml (31.2 g, 0.5 mol) ethylene-glycol, 32 ml (31.04 g, 0.3 mol) trimethyl-ortho-formiate, and 0.5 ml conc. sulphuric acid is added dropwise into the suspension. The reaction mixture was stirred at 20-25° C. for 3-6 h. The reaction was analytically controlled by thin-layer chromatography. When the ketone came to an end, as its spot disappeared by thin-layer chromatography, the reaction was stopped with adding 5 g solid NaHCO3. The suspension was stirred for 05 min., then the solvent is removed by evaporation, and the residue is solved in 150 ml methanol. This solution was cooled in an icy water-bath, and during the cooling 100 ml 10% NaOH solution was added. The flask was closed and the turbid mixture was stirred at 20-25° C. for about 1 h. The hydrolysis was analytically controlled by thin-layer chromatography. When the ester came to an end, as its spot disappeared by thin-layer chromatography, the methanol was removed by vacuum evaporation, and during intensive cooling in an icy water-bath, 350 ml 10% citric acid solution was added to the residue to achieve an acidic pH-value between 3-4. The precipitated product was extracted with 200 ml ethyl acetate. The aqueous phase was extracted twice with 50-50 ml ethyl acetate, and then the united organic phase was washed to neutral with 5×50 ml water. The ethyl acetatic solution was dried on anhydrous Na2SO4, the desiccant was filtered out, and the filtrate was evaporated in vacuum. The evaporating residue is crystallized with addition of 50 ml n-hexane at 0° C. The crystalline material of (IV) is isolated by filtration, and is dried.
Reaction SMILES: C(O[C:5]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:17])[O:12]2)=[CH:7][C:6]=1[CH2:18][CH:19]=[O:20])(=O)C.P(=O)(O)(O)O>>[CH3:16][O:15][C:14]1[C:13]2[O:12][C:11](=[O:17])[CH:10]=[CH:9][C:8]=2[CH:7]=[C:6]2[CH:18]=[CH:19][O:20][C:5]=12
Reactant: COc1c(OC(C)=O)c(CC=O)cc2ccc(=O)oc12
Agent: O=P(O)(O)O
Product: COc1c2occc2cc2ccc(=O)oc12

Procedure:
A solution of 2.76 g. (0.010 mole) of 7-acetoxy-8-methoxycoumarin-6-acetaldehyde in 30 ml. of 85% phosphoric acid was heated at 100° for 20 min, cooled and partitioned between water/methylene chloride. The aqueous phase was further extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, and evaporated to yield 9-methoxy-7H-furo[3,2-g][1]benzopyran-7-one. Purification was achieved by filtration through a silica gel column, eluting with benzene/ethyl acetate, 4:1. The filtrate was evaporated to afford pure end product, mp 145°-146°.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:10])[C:8]#[CH:9].CC1C=CC(S(O)(=O)=O)=CC=1.O.CCN(CC)CC>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][CH2:7][C:8]#[CH:9]
Reactant: C#CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C#CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1.33 h

Procedure:
At 0° C., 3,4-dihydro-2H-pyran (173 ml, 1.90 mol) is added dropwise over 10 min to a soln. of propargyl alcohol (88.49 g, 1.58 mol) and TsOH.H2O (16.08 g, 84.53 mmol) in CH2Cl2 (880 ml). After stirring for 80 min at 0° C., the mixture is warmed to room temperature, stirred for 3 h, treated with Et3N (12 ml), and evaporated. A vacuum distillation (20 mmHg, 80° C.) gives C (224 g, quant.). Colourless oil. 1H-NMR (400 MHz, CDCl3) δ 1.46-1.70 (m, 4 H), 1.70-1.91 (n, 2 H), 2.41 (t, J=2.2), 3.49-3.58 (m, 1 H), 3.81-3.88 (m, 1 H), 3.49-3.58 (m, 1 H), 4.23 (dd, J=15, 2.2), 4.30 (dd, J=15, 2.2), 4.83 (t, J=3.0).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:2].[H][H]>[Ni].CO>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:17]
Reactant: [H][H]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Product: CCN(CC)CCOc1ccc(N)cc1
Reaction time: 30 h

Procedure:
A reaction mixture of 110.52 g (0.464 mol) of diethyl-[2-(4-nitrophenoxy)ethyl]amine and 17 g of Raney nickel in 700 mL of methanol is hydrogenated for 30 hours at 20° C. and 3 bar hydrogen. The catalyst is filtered off and the filtrate is evaporated down. Yield: 93 g (96.2% of theory); C12H20N2O (M=208.30); calc.: molecular ion peak (M)+: 209; found: molecular ion peak (M)+: 209.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:11]C(OC(C)(C)C)=O)[CH2:7][CH:6]1[CH2:8][CH2:9][CH3:10])=[O:4].[ClH:19].O1CCOCC1>C1COCC1>[ClH:19].[CH3:1][O:2][C:3]([C:5]1([NH2:11])[CH2:7][CH:6]1[CH2:8][CH2:9][CH3:10])=[O:4]
Reactant: CCCC1CC1(NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCCC1CC1(N)C(=O)OC
Reaction time: 2 h

Procedure:
A solution of 1-tert-butoxycarbonylamino-2-propyl-cyclopropanecarboxylic acid methyl ester (0.27 mmol) in THF (0.5 mL) was treated with 4M HCl in dioxane (2.4 mmol HCl). After 2 h, the volatiles are removed in vacuo to afford 1-amino-2-propyl-cyclopropanecarboxylic acid methyl ester hydrochloride salt as an amorphous white solid that was used without further purification (0.053 g, quant). LCMS found 157.9 ([M+H]+.
Reaction SMILES: C1(S[CH2:8][C:9]2[CH:22]=[C:21]3[C:12]([C:13](=[O:24])[C:14]4[C:19]([C:20]3=[O:23])=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:11]3[CH2:25][CH2:26][CH2:27][C:10]=23)C=CC=CC=1.N#C[Br:30].C(#N)C>>[Br:30][CH2:8][C:9]1[CH:22]=[C:21]2[C:12]([C:13](=[O:24])[C:14]3[C:19]([C:20]2=[O:23])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:11]2[CH2:25][CH2:26][CH2:27][C:10]=12
Reactant: N#CBr
Reactant: O=C1c2ccccc2C(=O)c2c1cc(CSc1ccccc1)c1c2CCC1
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)c2c1cc(CBr)c1c2CCC1
Yield: 61 %

Procedure:
A mixture of 2,3-dihydro-4-phenylthiomethyl-1H-cyclopent[a]-anthracene-6,11-dione (350 mg, 0.95 mmol) and cyanogen bromide solution (5.0M) in acetonitrile (8 mL, 4 mmol) is heated at reflux for 4.5 hours under nitrogen. After cooling, the mixture is washed with H2O (20 mL×3), dried (Na2SO4) and evaporated in vacuo to dryness. The residue is then treated with boiling ethyl ether for 10 minutes and then stored in the refrigerator overnight. The product, 2,3-dihydro-4-bromomethyl-1H-cyclopent[a]-anthracene-6,11-dione (208 mg, 61%), is obtained after filtration and dried, mp 225°-230° C. The compound is used directly in the next step without further purification. 1H NMR (CDCl3): δ2.22 (2H, dt, J=7.14 Hz, J=7.69 Hz, CH2 -2), 3.06 (2H, t, J=7.14 Hz, CH2 -3), 3.53 (2H, t, J=7.69 Hz, CH2 -1), 4.54 (2H, s, CH2 --S), 7.22-8.37 (5H, m, Ar--H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([C:24]3[CH2:28][C@H:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[O:26][N:25]=3)[CH:23]=2)[C:18](O)=[O:19])=[N:13][CH:14]=1.Cl.[F:36][C:37]1[CH:38]=[CH:39][C:40]([C@H:43]([NH2:45])[CH3:44])=[N:41][CH:42]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O.O>[F:36][C:37]1[CH:38]=[CH:39][C:40]([C@H:43]([NH:45][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([C:24]3[CH2:28][C@H:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[O:26][N:25]=3)[CH:23]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][N:13]=3)[CH:16]=2)[CH3:44])=[N:41][CH:42]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C3=NO[C@@H](c4ccccn4)C3)c2)nc1
Reactant: C[C@@H](N)c1ccc(F)cn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(F)cn3)cc(C3=NO[C@@H](c4ccccn4)C3)c2)nc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
To a solution of 3-(5-methylpyridin-2-yl)-5-[(5R)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]benzoic acid trifluoracetate salt (1.14 g, 1.94 mmol) in N,N-dimethylformamide (10 mL) were added (1R)-1-(5-fluoropyridin-2-yl)ethanamine hydrochloride salt (0.62 g, 2.91 mmol), EDC (0.74 g, 3.88 mmol), HOAT (0.26 g, 1.94 mmol) and triethylamine (1.89 mL, 13.6 mmol). The reaction mixture was heated to 40° C. After 1.5 h, additional (1R)-1-(5-fluoropyridin-2-yl)ethanamine hydrochloride salt (0.29 g, 1.36 mmol), EDC (0.37 g, 1.94 mmol), HOAT (0.13 g, 0.97 mmol) and triethylamine (0.54 mL, 3.88 mmol) were added. After 2 h, the mixture was cooled to ambient temperature and water was added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (820 mg). The title compound was dissolved in dichloromethane and HCl (2.0 M in ether) was added. The mixture was concentrated gave the hydrochloride salt of the title compound. HRMS 482.2014 (M+1). 1H NMR (400 MHz, CD3OD): δ 8.82 (d, J=5.8 Hz, 1H); 8.75 (s, 1H); 8.68-8.49 (m, 6H); 8.42 (d, J=8.4 Hz, 1H); 8.19 (d, J=8.1 Hz, 1H); 8.07-8.00 (m, 2H); 7.92 (dd, J=8.9, 4.6 Hz, 1H); 6.28 (dd, J=11.6, 6.8 Hz, 1H); 5.36 (q, J=7.1 Hz, 1H); 4.30 (dd, J=17.4, 11.7 Hz, 1H); 3.98 (dd, J=17.4, 6.8 Hz, 1H); 2.61 (s, 3H); 1.70 (d, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([C:5]([F:12])([F:11])[C:6]([F:10])([F:9])[CH2:7][OH:8])[CH2:3][OH:4].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:17]([Si:14]([CH3:16])([CH3:15])[O:8][CH2:7][C:6]([F:10])([F:9])[C:5]([F:11])([F:12])[C:2]([F:13])([F:1])[CH2:3][OH:4])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(F)(F)C(F)(F)C(F)(F)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(F)(F)C(F)(F)C(F)(F)CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.2 %

Procedure:
4-Dimethylaminopyridine (634 mg, 5.2 mmol) was added to a solution of 2,2,3,3,4,4-hexafluoro-pentane-1,5-diol (1 g, 4.7 mmol) and tert-butyldimethylsilyl chloride (708 mg, 4.7 mmol) in methylene chloride (10 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography to give 5-(tert-butyl-dimethyl-silanyloxy)-2,2,3,3,4,4-hexafluoro-pentan-1-ol (770 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[S:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:3]=1[C:16]#[N:17].[C:18]1([CH2:24][CH2:25]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C[O-].[Na+]>CO>[NH2:1][C:2]1[C:3]([C:16]#[N:17])=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:5]([C:9]#[N:10])=[C:6]([S:8][CH2:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:7]=1
Reactant: BrCCc1ccccc1
Reactant: N#Cc1c(N)[nH]c(=S)c(C#N)c1-c1ccco1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1c(N)nc(SCCc2ccccc2)c(C#N)c1-c1ccco1

Procedure:
From 6-Amino-4-furan-2-yl-2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitrile, 2-phenylethyl bromide and sodium methylate in methanol. EI-MS m/e (%): 346 (M+, 4), 242 ([M—PhCH═CH2]+, 100), 91 (16).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1[N+](=O)[O-]

Procedure:
A mixture of 4-bromo-1-methoxy-2-nitrobenzene (232 mg, 1 mmol), tert-butyl piperazine-1-carboxylate (224 mg, 1.2 mmol), palladium diacetate (23 mg, 1.2 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (93 mg, 0.15 mmol) and cesium carbonate (978 mg, 3 mmol) in 1,4-dioxane (15 mL) was heated at reflux for 16 hours. The mixture was filtered through diatomaceous earth and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 4/1 petroleum ether/ethyl acetate to give the title compound.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(CCCI)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)c1
Yield: 83.4 %

Procedure:
tert-Butyl 3-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.30 g, 0.585 mmol), 4-iodobutyrophenone (0.17 g, 0.585 mmol), and potassium carbonate (0.12 g, 0.878 mmol) in N,N-dimethylformamide (8 mL) were stirred at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.28 g, 82%); MS for C35H47N3O4 m/z 574 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.ClC1C(Cl)=CC=CC=1N1CCN([CH2:29][CH:30]([OH:44])[CH2:31][CH2:32][N:33]2[C:41](=[O:42])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]2=[O:43])CC1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:29][CH:30]([OH:44])[CH2:31][CH2:32][N:33]2[C:41](=[O:42])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]2=[O:43])[CH2:11][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1CCC(O)CN1CCN(c2cccc(Cl)c2Cl)CC1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(CC(O)CCN2C(=O)c3ccccc3C2=O)CC1
Yield: 28 %

Procedure:
Prepared from 1-(2-methoxyphenyl)piperazine and 25 in a similar fashion as described above for 26a. Yield: 28%. Mp.: 192-194° C. 1H NMR (CDCl3): δ 1.79 (q, J 6.8, 2H), 2.41 (m, 2H), 2.61 (s, 2H), 2.85 (s, 2H), 3.07 (s, 4H), 3.77 (m, 1H), 3.85 (s, 3H), 3.91 (m, 2H), 6.86 (d, J 7.0, 1H), 6.91-6.95 (m, 2H), 7.00 (m, 1H), 7.85 (dd, J 5.5, 3.0, 2H), 7.71 (dd, J 5.4, 3.1, 2H). 13C NMR (CDCl3): δ 33.8, 35.4, 50.9, 53.6, 55.6, 64.1, 64.7, 111.3, 118.4, 121.2, 123.2, 123.4, 132.4, 134.1, 141.4, 152.4.