Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=S.C[O:32]C1C=CC([C@H]2O[C@@H]2C(OC)=O)=CC=1>C(O)C>[CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:32]
Reactant: COC(=O)[C@H]1O[C@@H]1c1ccc(OC)cc1
Reactant: CNC(=S)N1CCSC1c1ccccc1OCCN1CCN(c2ccccc2)CC1
Solvent: CCO
Product: CNC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2ccccc2)CC1
Yield: 75.7 %

Procedure:
480 mg of (+)-N-methyl-2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carbothioamide and 339 mg of methyl trans-3-(4-methoxyphenyl)glycidate are dissolved in 40 ml of ethanol, and the solution is refluxed for 11 hours under heating. 339 mg of methyl trans-3-(4-methoxyphenyl)glycidate are added to the mixture, and the mixture is further refluxed for 3 hours. The mixture is concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, chloroform:ethanol=40:1), and the resultant product is recrystallized from a mixture of ethyl acetate and n-hexane. 350 mg of (+)-N-methyl-2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide are obtained. Yield: 75.7%.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH3:10][O:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([N:16]=[C:17]=[O:18])=[O:15]>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([NH:1][C:17]([NH:16][C:14](=[O:15])[C:13]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[O:11][CH3:10])=[O:18])[CH2:3]2
Reactant: NC1CN2CCC1CC2
Reactant: COc1ccccc1C(=O)N=C=O
Product: COc1ccccc1C(=O)NC(=O)NC1CN2CCC1CC2
Yield: 105.5 %

Procedure:
This compound was prepared by the procedure of example 1, using 3-aminoquinuclidine (0.63 g, 5 mmol) and 2-methoxybenzoyl isocyanate (1.0 g, 5 mmol), giving crude title product (1.6 g) which was purified as its 1:1 fumarate mp 187°-188° C. (0.79 g)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].Cl.FC(F)(F)C(O)=O.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>ClCCl>[C:19]([S:4][CH2:3][CH2:2][NH2:1])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NCCS
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
Hydrochloric acid 2-aminoethanethiol (5.16 g, 45.4 mmol) was dissolved in dichloromethane (80 mL), and trifluoroacetic acid (7.0 mL, 90.8 mmol) and triphenylmethyl chloride (13.29 g, 47.7 mmol) were added, followed by stirring at room temperature for 1 hour. A 1N aqueous sodium hydroxide solution (150 mL) was added, and extraction was carried out with dichloromethane (500 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, methanol (100 mL) was added to the resulting residue, and the deposited by-product was removed by filtration. 1N hydrochloric acid (300 mL) was added to make the solution acidic, and the deposit was filtered off. After the by-product was washed with dichloromethane (50 mL) to remove it, the solution was made alkaline with a 1N aqueous sodium hydroxide solution, and extraction was carried out with dichloromethane (600 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, to afford the desired product (8.77 g, yield 60%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[OH:13].C([O-])([O-])=O.[K+].[K+].I[CH:22]([CH2:24][CH3:25])[CH3:23]>>[CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[O:13][CH:22]([CH2:24][CH3:25])[CH3:23]
Reactant: COC(=O)C=Cc1ccc(F)cc1O
Reactant: CCC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC(C)Oc1cc(F)ccc1C=CC(=O)OC

Procedure:
3-(4-Fluoro-2-hydroxy-phenyl)-acrylic acid methyl ester (120 mg) was reacted with K2CO3 (165 mg) and 2-iodobutan (0.12 ml) at 100° C. for 3 hrs as described above to yield title compound (105 mg)
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([CH:9]2[CH2:11][CH2:10]2)=[C:6]([OH:8])[CH:7]=1.[Cl:12]C1C=CC(C2CC2)=C(C=1)N>[Hg]>[Cl:12][C:2]1[CH:3]=[CH:4][C:5]([CH:9]2[CH2:11][CH2:10]2)=[C:6]([OH:8])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1C1CC1
Reactant: Cc1ccc(C2CC2)c(O)c1
Agent: [Hg]
Product: Oc1cc(Cl)ccc1C1CC1
Yield: 32 %

Procedure:
Prepared according to the method described for the 5-methyl-2-cyclopropyl-phenol of Example I, from 31.5 g (0.188 mol/g) of 5-chloro-2-cyclopropyl-aniline with a yield of 32%. B.P.=69° C.-76° C./0.1 mm mercury. m.P. 30° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:16](=[O:18])[CH3:17])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1.N1CCCCC1>CCO>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH:19]=[CH:17][C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:11]=2)=[O:18])[CH:21]=1
Reactant: O=Cc1cccnc1
Reactant: CC(=O)c1cccc(OCC(=O)OC(C)(C)C)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)COc1cccc(C(=O)C=Cc2cccnc2)c1

Procedure:
A mixture of 16 (4.0 g, 16 mmol), nicotinaldehyde (1.89 mL, 20 mmol), and piperidine (4.0 mL, 40 mmol) in absolute EtOH (65 mL) was heated at reflux for 16 h. The mixture was cooled and concentrated in vacuo. Chromatography on silica gel (30-60% EtOAc/hexanes) gave a mixture of unreacted nicotinaldehyde and 17 (both have the same Rf on TLC). Washing of the mixture with hexane in a filter funnel provide 1.73 g (32%) of pure 17 as a yellow crystal. 1H NMR (CDCl3, 300 MHz) 8.87 (d, J=2.1 Hz, 1H), 8.66 (dd, J=4.8, 1.5 Hz, 1 H), 7.97 (d, J=7.9 Hz, 1H), 7.80 (d, J=16.7 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.60 (d, J=15.9 Hz, 1H), 7.55 (s, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.38 (dd, J=7.9, 4.8 Hz, 1H), 7.20 (dd, J=8.2, 2.6 Hz, 1H), 4.62 (s, 2H), 1.52 (s, 9H); 13C NMR (CDCl3, 75MHz) 189.7, 175.0, 168.0, 158.7, 151.6, 150.5, 141.4, 139.5, 134.9, 131.0, 130.2, 124.2, 122.3, 120.6, 114.1, 83.1, 66.2, 28.4.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:34](O)(=[O:37])[CH2:35][CH3:36]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCC(=O)O
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: CCC(=O)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.8 mg) obtained in Example 26 and propionic acid (9.0 μl) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[C:14](O)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:42])=O>ClCCl>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[C:14]([Cl:42])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COCCOCOc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=S(Cl)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: COCCOCOc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
A solution of 3 g (8.3 mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxybenzoic acid in 50 ml of anhydrous dichloromethane was introduced into a round-bottomed flask, 1.7 ml (8.3 mmol) of dicyclohexylamine was added and the mixture was stirred for one hour. 600 μl (8.3 mmol) of thionyl chloride were then added and the mixture was stirred for one hour. It was evaporated to dryness, the residue was taken up in anhydrous ethyl ether, the dicyclohexylamine salt was filtered off and the filtrate was evaporated. 3.3 g (100%) of the crude acid chloride, which was used without further purification for the remainder of the synthesis, were recovered.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][N:10]2[CH2:20][C:19]3[N:21]4[C:12](=[CH:13][N:14]=[C:15]4[CH:16]=[CH:17][CH:18]=3)[C:11]2=[O:22])[CH2:5][CH2:4]1.C(N(CC)CC)C.FC(F)(F)C(F)(F)C([O:35][C:36](=O)[C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])=O>C(#N)C>[F:42][C:37]([F:43])([C:38]([F:41])([F:40])[F:39])[C:36]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][N:10]2[CH2:20][C:19]3[N:21]4[C:12](=[CH:13][N:14]=[C:15]4[CH:16]=[CH:17][CH:18]=3)[C:11]2=[O:22])[CH2:5][CH2:4]1)=[O:35]
Reactant: O=C(OC(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: O=C1c2cnc3cccc(n23)CN1CC1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1c2cnc3cccc(n23)CN1CC1CCN(C(=O)C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
In 10 ml of acetonitrile was suspended 687 mg (2.0 mM) of 4,5-dihydro-4-(piperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-one dihydrochloride, followed by addition of 2.23 ml (16.0 mM) of triethylamine and 1.97 ml (10.0 mM) of pentafluoropropionic anhydride in the order mentioned. This mixture was stirred at room temperature for 1 hour and the solvent was then distilled off under reduced pressure. The residue was extracted with 50 ml of chloroform and the organic layer was washed with 50 ml of saturated aqueous NaCl solution and dried over MgSO4. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-ethanol=10:1) to provide 526 mg (yield 63.2%) of the title compound as light-yellow amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[NH2:13])=[CH:5][CH:4]=1.[O:14]=[C:15](Cl)OC(Cl)(Cl)Cl.C(N(CC)CC)C>O1CCOCC1>[N:13]([C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)=[C:15]=[O:14]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc2cccc(N)c2c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc2cccc(N=C=O)c2c1

Procedure:
To a solution of the title compound of Step B (5.0 g) in p-dioxane (115 mL) at room temperature was added via syringe diphosgene (4.2 mL) followed by the addition of triethylamine (4.8 mL). The mixture was heated at reflux overnight while stirring. The reaction was monitored by IR (2267 cm-1). The reaction mixture was filtered and the residue was washed with diethyl ether. The filtrate was concentrated under reduced pressure to give 5.8 g of the title compound of Step C as a beige solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH2:10][CH2:11][CH3:12])=[C:4]([C:14]#[N:15])[N:3]=1.[OH-].[Na+].C(O)(=[O:20])C>CO.O>[CH2:10]([C:9]1[NH:15][C:14](=[O:20])[C:4]2[N:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH2:11][CH3:12]
Reactant: CCCC(=O)Nc1ccc(Cl)nc1C#N
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1nc2ccc(Cl)nc2c(=O)[nH]1

Procedure:
To a solution of 0.56 g (2.5 mol) of 2-chloro-5-(N-butyroyl)amino-6-cyano-pyridine in 5 ml of MeOH was added 2.78 ml (5.56 mmol) of 2N NaOH followed by 0.33 ml (5.0 mmol) of 30% H2O. The reaction mixture was diluted with 10 ml of water and acidified with acetic acid. The mixture was extracted with EtOAc (3×20 ml). The combined organic phases were washed with brine and dried over MgSO4. The solution was filtered and the filtrate was concentrated in vacuo. The residue was recrystallized from MeOH to give 0.35 g of pale yellow needles. mp: 264°-266° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=4)[N:13]=[C:12]([NH:21][C:22]4[CH:30]=[C:29]5[C:25]([C:26](=[O:31])[NH:27][NH:28]5)=[CH:24][CH:23]=4)[N:11]=3)[NH:7][N:8]=2)[CH2:3][CH2:2]1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CS(C)=O.C1([O-])C=CC=CC=1.[K+].O>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:18]=4)[N:13]=[C:12]([NH:21][C:22]4[CH:30]=[C:29]5[C:25]([C:26](=[O:31])[NH:27][NH:28]5)=[CH:24][CH:23]=4)[N:11]=3)[NH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1
Reactant: O=c1[nH][nH]c2cc(Nc3nc(Nc4cc(C5CC5)n[nH]4)c4cc(I)ccc4n3)ccc12
Agent: [K+]
Agent: [O-]c1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: O=c1[nH][nH]c2cc(Nc3nc(Nc4cc(C5CC5)n[nH]4)c4cc(-c5ccccc5)ccc4n3)ccc12
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To 6-[4-(5-Cyclopropyl-2H-pyrazol-3-ylamino)-6-iodo-quinazolin-2-ylamino]-1,2-dihydro-indazol-3-one (300 mg, 0.48 mmol), and phenyl boronic acid (88 mg, 0.72 mmol) in DMSO and 1.5 M potassium phenolate (2.6 mL) was added PdCl2 (dppf)2 (175 mg) and the solution was heated to 100° C. in a sealed tube. After 12 hr, the solution was diluted with water, extracted with ethyl acetate, dried (Na2SO4) and concentrated. The title compound was isolated by preparative HPLC as a white solid (0.82 mg). HPLC tr=5.14 min (10% to 90% MeCN over 8 min, total time 12 min, 3×150 mm C18 column) FIA m/e 475.55 (M+H), 473.55 (M−H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[N:11]=[C:10]([O:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(Cl)cc2)nc1Cl

Procedure:
A mixture of the product from Step 1 (54 g, 0.26 mol), p-chlorophenol (31.7 g, 0.25 mol) and cesium carbonate (101.4 g, 0.31 mol) in anhydrous DMF (1.0 L) was stirred at 25° C. for about 2 h or until less than 5% of the starting material remained. The reaction mixture was then poured into water (2.5 L) and extracted with ethyl acetate (2×800 mL). The organic layer was washed with water (2×300 mL) and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel eluting with 7:1 hexane:ethyl acetate to afford the title product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:17]([NH2:18])=[CH:16][C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14]2)[CH:8]=1)[CH3:2].[C:24]1([C:34](F)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:17]([NH:18][C:34]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)=[O:35])=[CH:16][C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14]2)[CH:8]=1)[CH3:2]
Reactant: O=C(F)c1cccc2ccccc12
Reactant: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Solvent: ClCCl
Product: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)c2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 372.7 %

Procedure:
A solution of Example Z (315 mg, 1.0 mmol) and Barton's base (0.5 mL) in anhydrous CH2Cl2 (5 mL) under N2 was stirred at RT for 30 min, and then added to a solution of naphthalene-1-carbonyl fluoride (348 mg, 0.2 mmol) in anhydrous CH2Cl2 (5 mL). The resulting mixture was stirred at RT overnight. After quenching with water (100 mL), the reaction mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine, dried (NaSO4), filtered and concentrated under reduced pressure to yield a residue which was purified by flash chromatography to afford 3-(3-{3-t-butyl-5-[(naphthalene-1-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionic acid ethyl ester, (350 mg, 74%). 1H-NMR (CDCL3): 8.29 (d, J=8.0 Hz, 1H), 7.98 (d, J=7.2 Hz, 2H), 7.89 (d, J=7.2 Hz, 1H), 7.62-7.57 (m, 3H), 7.49-7.28 (m, 4H), 7.03 (s, 1H), 3.94 (q, J=7.2 Hz, 2H), 2.96 (t, J=7.2 Hz, 2H), 2.58 (t, J=7.2 Hz, 2H), 1.45 (s, 9H), 1.13 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 470 (M+H+).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:29]2[CH:30]=[CH:31][C:32]3[C:33]([CH:44]=2)=[C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[O:35][N:36]=3)=[O:28])=[CH:23][CH:22]=1>C1COCC1>[Cl:43][C:39]1[CH:38]=[C:37]([C:34]2[O:35][N:36]=[C:32]3[CH:31]=[CH:30][C:29]([C:27]([C:24]4[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=4)([C:11]4[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=4)[OH:28])=[CH:44][C:33]=23)[CH:42]=[CH:41][CH:40]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Reactant: Cn1ccnc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 25 %

Procedure:
Butyllithium in hexanes (10 ml) was added slowly at −70° C. under N2 flow to a solution of 1-methylimidazole (1.31 g) in THF (30 ml). The mixture was stirred at −70° C. for 45 minutes. Chlorotriethylsilane (2.7 ml) was added. The mixture was allowed to warm to 15° C. and cooled to −70° C. Butyllithium (10 ml) was added slowly. The mixture was stirred at −70° C. for 1 hour, allowed to warm to −15° C. and cooled to −70° C. A solution of intermediate (6-b) (4.9 g) in THF (60 ml) was added. The mixture was stirred at −70° C. for 30 minutes, then hydrolyzed with water, extracted with ethyl acetate and decanted. The organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue (8.2 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.2) and crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried, yielding 1.5 g (25%) of (±)-3-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-2,1-benzisoxazole-5-methanol (interm. 6-c).
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[CH2:5][OH:6].[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+]([O-])=O)[C:11]=1[C:12]#[N:13])([O-:9])=[O:8]>>[CH3:1][CH:2]1[CH2:4][CH:3]1[CH2:5][O:6][C:14]1[CH:15]=[CH:16][CH:17]=[C:10]([N+:7]([O-:9])=[O:8])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC1CC1CO
Product: CC1CC1COc1cccc([N+](=O)[O-])c1C#N
Yield: 81 %

Procedure:
Prepared as in Example 166d from (2-methylcyclopropyl)methanol and 2,6-dinitrobenzonitrile in 81% yield. MS 233 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1([CH3:41])[C:31]2[CH:30]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:28]=[CH:27][C:26]=2[CH2:25][CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([C:29]3[CH:28]=[CH:27][C:26]4[CH2:25][CH2:24][CH2:23][C:22]([CH3:41])([CH3:21])[C:31]=4[CH:30]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)n2)CC1
Reactant: CC1(C)CCCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(-c3ccc4c(c3)C(C)(C)CCC4)n2)CC1

Procedure:
The preparation is carried out analogously to FS 102 starting from 4-(4-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (US 2005/59668) and 2-(8,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH:6]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)([CH3:8])[CH3:7]>>[Cl:1][CH2:2][C:3]([C:11]1[CH:12]=[C:13]2[C:18](=[C:9]([CH:6]([CH3:7])[CH3:8])[CH:10]=1)[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)=[O:4]
Reactant: CC(C)c1cccc2ccc(=O)[nH]c12
Reactant: O=C(Cl)CCl
Product: CC(C)c1cc(C(=O)CCl)cc2ccc(=O)[nH]c12

Procedure:
By using chloroacetyl chloride and 8-isopropylcarbostyril, there was obtained 6-chloroacetyl-8-isopropylcarbostyril as a light yellow powder having a melting point of 250° C. or less (decomposed).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].I[CH2:21][C:22]([F:25])([F:24])[F:23].C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(CC(F)(F)F)c2cc([N+](=O)[O-])c(N)cc21
Yield: 58 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (5 g) is alkylated in a high pressure reaction vessel using 2-iodo-1,1,1-trifluoro-ethane (5.7 ml; 38 mmol) and K2CO3 (5.25 g; 38 mmol) at 50° C. for 14 days. After aqueous work-up and purification by RP chromatography the pure material (4 g) is de-acetylated in MeOH (150 ml) using DBU (3.6 ml) at reflux. After aqueous work-up 5-amino-3,3-dimethyl-6-nitro-1-(2,2,2-trifluoro-ethyl)-1,3-dihydro-indol-2-one (3,34 g) is obtained and used without further purification.
Reaction SMILES: [CH2:1]([C:3]([OH:10])([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][OH:7])[CH3:2].[CH:11]12[CH:20]3[CH2:21][CH:17]([CH:18]=[CH:19]3)[CH:16]1[CH:15]1[CH2:22][CH:12]2[CH:13]([C:23](OC)=[O:24])[CH2:14]1>>[CH:11]12[CH:20]3[CH2:21][CH:17]([CH:18]=[CH:19]3)[CH:16]1[CH:15]1[CH2:22][CH:12]2[CH:13]([C:23]([O:7][CH2:6][CH2:5][CH2:4][C:3]([CH2:8][CH3:9])([OH:10])[CH2:1][CH3:2])=[O:24])[CH2:14]1
Reactant: COC(=O)C1CC2CC1C1C3C=CC(C3)C21
Reactant: CCC(O)(CC)CCCO
Product: CCC(O)(CC)CCCOC(=O)C1CC2CC1C1C3C=CC(C3)C21
Yield: 89 %

Procedure:
By following the procedure of Synthesis Example 2 except that 4-ethyl-1,4-hexanediol was used instead of 4-methyl-1,4-pentanediol and methyl 8-tetracyclo-[4.4.0.12,5.17,10]dodecene-3-carboxylate used instead of methyl 5-norbornene-2-carboxylate, there was obtained 4-ethyl-4-hydroxyhexyl 8-tetracyclo[4.4.0.12,5.17,10]dodecene-3-carboxylate. Yield 89%.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][S:4][C:3]1=[S:8].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[C:17]=1[OH:18])[CH:13]=O.N1CCCCC1>C(O)(=O)C>[OH:9][C:10]1[CH:11]=[C:12]([CH:13]=[C:5]2[S:4][C:3](=[S:8])[N:2]([CH3:1])[C:6]2=[O:7])[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[C:17]=1[OH:18]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CN1C(=O)CSC1=S
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CN1C(=O)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)SC1=S
Temperature: 100 °C

Procedure:
A solution containing 0.74 g (0.005 mol) of 3-methyl-2-thioxothiazolidin-4-one, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde, 0.05 ml of piperidine in 10 ml of acetic acid was heated for 8 h at 100° C. The product was filtered and washed with 2-propanol. Yield 0.87 g (56%), mp 274-276° C.