Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][CH3:14])[CH2:11][C:10](=O)[C@@H:9]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28][NH2:29].[BH4-].[Na+].O>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][CH3:14])[CH2:11][C@H:10]([NH:29][CH2:28][C:27]2[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=[C:25]([C:24]([F:23])([F:37])[F:38])[CH:26]=2)[C@@H:9]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC[C@@H]1CC(=O)[C@H](Cc2ccccc2)N1C(=O)OC(C)(C)C
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: CC[C@@H]1C[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)N1C(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 128 %

Procedure:
To a solution (2S,5R)-2-benzyl-5-ethyl-3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (0.038 mmol; 25.1 mg) and 3,5-bis(trifluoromethyl)benzylamine (0.166 mmol; 40.4 mg) in MeOH (0.4 mL) is added titanium(IV) isopropoxide (0.1 mmol; 28.4 mg). After stirring for 6 hours, NaBH4 (0.125 mmol; 4.8 mg) is added to the reaction mixture at 0° C. After stirring for 1.5 hours at room temperature, another NaBH4 (0.041 mmol; 1.6 mg) is added to the mixture at the same temperature. After stirring for additional 45 minutes, H2O is added to the mixture. The mixture is filtered and concentrated under reduced pressure. Water and dichloromethane are added to the residue. The organic layer after dried is separated, concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: n-hexane/EtOAc) to give (2S,3S,5R)-2-benzyl-3-(3,5-bis-trifluoromethyl-benzylamino)-5-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (25.8 mg, 59%); ESI-MS m/z: 531 [M+1]+, Retention time 4.55 min (condition B).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:27][CH:26]=1)[NH:20][CH2:19][CH2:18]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(CC)CC>C1COCC1>[CH2:5]([O:4][C:2]([N:20]1[CH2:19][CH2:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([O:14][CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:16]=2)[CH:21]1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)=[CH:27][CH:26]=1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: c1ccc(COc2ccc3c(c2)CCNC3c2ccc(OCCN3CCCC3)cc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Yield: 143.6 %

Procedure:
A solution of ethyl chloroformate (0.017 g, 0.16 mmol), 6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.069 g, 0.16 mmol), and Et3N (0.028 ml, 0.20 mmol) in anhydrous THF (10 ml) was stirred at rt under N2 for 20 hr. The reaction mixture was concentrated in vacuo to give 0.115 g of tan solid. Purification by flash chromatography, eluting with EtOAc:MeOH (8:2), gave 0.023 g (28% yield) of white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:13][CH2:12][C@@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])[CH3:14])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CO)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
A solution of (S)-benzyl(1-hydroxypropan-2-yl)carbamate (400 g, 1.91 mol) and triethylamine (270 g, 2.67 mol) in methylene chloride (2.4 L) was cooled to 0° C. To this mixture was added methanesulfonyl chloride (263 g, 2.30 mol) at an internal temperature of 5° C. or below. Subsequently, the resulting reaction mixture was stirred at room temperature for 16 hours. After confirming the disappearance of the starting materials by TLC, to the reaction mixture was added purified water. The resulting organic layer was partitioned, washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the target product as a yellow solid (519 g, yield 94.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[C:5]([NH:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([NH2:15])=[O:14])=O.[OH-].[Na+].CCO>O>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[C:5]1[NH:15][C:13](=[O:14])[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[N:7]=1
Reactant: COc1ccccc1C(=O)Nc1ccsc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccccc1-c1nc2ccsc2c(=O)[nH]1
Temperature: 120 °C
Yield: 61.9 %

Procedure:
A mixture of 3-(2-methoxybenzamido)thiophene-2-carboxamide (1.4 g, 5.0 mmol), 6 N aqueous NaOH (8 mL), and EtOH (8 mL) was heated at 120° C. for 16 h. The reaction was cooled, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under vacuum to give 2-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (0.80 g, 62% yield). LC/MS: m/z 259.3 (M+H)+ at 2.32 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]([CH3:31])[CH3:30])[S:7][C:6]=2[CH:32]=1.[Li+].[OH-].Cl>CCO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:15][CH:16]=3)=[C:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]([CH3:30])[CH3:31])[S:7][C:6]=2[CH:32]=1
Reactant: COC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3C(C)C)sc3cc(O)ccc23)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1ccccc1-c1sc2cc(O)ccc2c1Oc1ccc(/C=C/C(=O)O)cc1
Yield: 96.6 %

Procedure:
Example 4 was be prepared from the corresponding methylether/tert-butyl ester intermediates using method A. Example 4 was also prepared, using the following hydrolysis reaction: to a solution of (E)-methyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (25.8 mg, 0.058 mmol) in EtOH (1.5 mL) was added LiOH (2.0 M aqueous, 0.290 mL, 0.580 mmol). After 5 h at room temperature the reaction was acidified to pH 3 by addition of 1.0 N aqeuous HCl and extracted with 5% MeOH/EtOAc, the combined organic layers were passed through a phase separator and concentrated in vacuo to afford (E)-3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (24.0 mg, 0.056 mmol, 96% yield). LC/MS (m/z, M-H): 429.0.
Reaction SMILES: [C:1]1(O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=1.COC.[ClH:12].[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[ClH:12].[C:13]1([NH:19][N:20]=[C:1]2[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC1=NCCCCC1
Reactant: NNc1ccccc1
Agent: COC
Agent: Cl
Solvent: CCO
Product: c1ccc(NN=C2CCCCCN2)cc1
Reaction time: 2 h
Yield: 91.8 %

Procedure:
127 G (1 mole) of caprolactim-methyl-ether were added dropwise over the course of 30 minutes to a mixture of 144.5 g (1 mole) of phenylhydrazine hydrochloride and 700 ml of anhydrous ethanol at -10°C, while stirring well and cooling; the mixture was kept for a further hour at -10°C, then for 2 hours at room temperature and for 30 minutes at the reflux temperature. After cooling, the mixture was filtered and further crystal fractions were isolated by concentrating the mother liquor under reduced pressure. Recrystallization from 5 parts of ethanol yielded 220 g (92% of theory) of caprolactam-phenylhydrazone hydrochloride as almost colorless crystals of melting point 244° to 246°C (with decomposition).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:15]([F:18])([F:17])[F:16])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:4](F)=[O:5].C[Si](C)(C)[O-:23].[Na+:26]>CCOCC>[F:1][C:2]([F:20])([F:19])[C:3]([C:15]([F:18])([F:17])[F:16])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:4]([O-:23])=[O:5].[Na+:26]
Reactant: C[Si](C)(C)[O-]
Reactant: CCCCCCCCC(C(=O)F)(C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCCCC(C(=O)[O-])(C(F)(F)F)C(F)(F)F

Procedure:
The procedure of Example 1 was followed using 2,2-bis(trifluoromethyl)decanoyl fluoride (6.11 g, 19.7 mmol), sodium trimethylsilanolate (2.21 g, 19.7 mmol) and dry ether (20 mL). The product, sodium 2,2-bis(trifluoromethyl)decanoate, was isolated as a waxy solid (5.5 g, 85% yield) by concentrating the filtrate under vacuum: 1H NMR (CDCl3) δ 0.88 (m, CH3, 3H), 1.30 (m, CH2, 12H), 2.10 ppm (m, CH2, 2H); 19F NMR (D2O/acetone) δ -62.0 ppm (brs, CF3,6F). Anal. Calcd. for C12H17F6NaO2 : C, 43.64; H, 5.19; F, 34.52. Found: C, 44.34; H, 5.10; F, 35.58.
Reaction SMILES: [CH2:1]([C:3]1([CH3:12])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][CH:5]([NH2:11])[CH2:4]1)[CH3:2].C(N(CC)CC)C.[OH:20][C:21]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([C:3]1([CH3:12])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][CH:5]([NH:11][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:29]([N+:30]([O-:32])=[O:31])[C:21]=2[OH:20])[CH2:4]1)[CH3:2]
Reactant: CCC1(C)CC(N)CC(C)(C)C1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(C)CC(NC(=O)c2cccc([N+](=O)[O-])c2O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred soution of 3-ethyl-3,5,5-trimethylcyclohexylamine (3.20 g, a 6:4 mixture of axial:equatorial ethyl diastereomers), triethylamine (2.13 g) and 4-dimethylaminopyridine (DMAP) (0.12 g) in dichloromethane (50 ml) was added, in a rapid dropwise manner, a solution of 2-hydroxy-3-nitrobenzoyl chloride (3.83 g) in dichloromethane (10 ml). After the addition was complete, the reaction mixture was stirred at room temperature for 12 hours, then poured into 1N HCl (250 ml). The organic layer was separated, and the aqueous layer washed with dichloromethane (50 ml). The organic phases were combined, dried (MgSO4) and the solvent evaporated to give a yellow solid (5.70 g). Recrystallization from methanol gave an analytical sample (m.p. 125-128° C.). The 13C NMR of this material showed it to be a mixture of diastereomers in an approximate ratio of 6:4.
Reaction SMILES: C(OC)(C)(C)C.[F:7][C:8]1[CH:16]=[C:15]([CH3:17])[C:14]2[N:13]3[C@H:18]([CH3:23])[CH2:19][NH:20][C:21](=O)[C:12]3=[CH:11][C:10]=2[CH:9]=1.[ClH:24]>ClCCl.C(OCC)C>[ClH:24].[F:7][C:8]1[CH:16]=[C:15]([CH3:17])[C:14]2[N:13]3[C@H:18]([CH3:23])[CH2:19][NH:20][CH2:21][C:12]3=[CH:11][C:10]=2[CH:9]=1
Reactant: Cc1cc(F)cc2cc3n(c12)[C@H](C)CNC3=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: Cc1cc(F)cc2cc3n(c12)[C@H](C)CNC3

Procedure:
The tide compound (ISP-MS: m/e 219.3 ([M+H]+)) was produced in accordance with the general method of example 1a), using tert-butyl-methyl ether instead of tetrahydrofuran as solvent, from (R)-8-fluoro-4,6-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one. The product (20 mg) was dissolved in dichloromethane and treated with a solution of HCl in diethyl ether to precipitate the hydrochloride salt Yield: 18 mg.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].[Na].CCOCC.[CH2:18]([O:20][C:21](=[O:27])[C:22](OCC)=O)[CH3:19]>C(O)C>[C:21]([C:22]1[O:10][C:9]2[CH:8]=[C:7]([OH:11])[CH:6]=[CH:5][C:4]=2[C:2](=[O:3])[CH:1]=1)([O:20][CH2:18][CH3:19])=[O:27]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 2,4-dihydroxyacetophenone (15.2 g) in diethyloxalate (40 ml) is added with stirring to a solution of sodium (9.2 g) in ethanol (200 ml). The mixture is then heated at 100° C. for 3.5 hours, cooled and is added to dry ether (500 ml). The mixture is allowed to sit overnight. The resulting precipitate is filtered off and dissolved in water, and the solution is neutralized with 4N hydrochloric acid and extracted with ether. The ether extracts are combined and are concentrated down in vacuo. The resulting residue is dissolved in ethanol (100 ml) and concentrated hydrochloric acid is then added (2 ml). The solution is heated under reflux for 2 hours and is then concentrated in vacuo. The resulting solid is recrystalized in ethanol to give 2-carboethoxy-7-hydroxy-4-oxo-4H-1-benzopyran which is used directly in the next step.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][CH:13]=[N:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][CH:13]=[N:12][C:11]=2[N:10]=[C:9]1[Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2ncn(Cc3ccccc3)c12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2nc(Cl)n(Cc3ccccc3)c12
Reaction time: 8 h
Yield: 41.5 %

Procedure:
12.748 g of 7-benzyl-1,7-dihydropurin-6-one was dissolved in 150 ml of N,N-dimethylformamide, and 7.9 g of N-chlorosuccinimide was added thereto. The reaction solution was stirred overnight, and then diluted with ethyl acetate. The solution was washed with water and 1N hydrochloric acid, and dried over anhydrous magnesium sulfate. The solution was filtered, and the filtrate was concentrated to give 6.103 g of 7-benzyl-8-chloro-1,7-dihydropurin-6-one. This compound was combined with 20 g of t-butyl piperazine-1-carboxylate, and the mixture was heated at 150° C. After being stirred for one hour, the reaction mixture was combined with ethyl acetate and water, and partitioned. The organic layer was washed with 1N hydrochloric acid, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography. Thus, 1.539 g of the title compound was obtained from the fraction eluted with ethyl acetate-methanol (10:1).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH:23]1([C@H:29]2[CH2:35][NH:34][C:33](=O)[C@H:32]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[CH:23]1([C@H:29]2[CH2:35][NH:34][C:33](=[S:10])[C@H:32]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C2CCCCC2)CNC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C2CCCCC2)CNC1=S
Temperature: 90 °C
Reaction time: 1 h
Yield: 115.5 %

Procedure:
Lawesson's reagent [2,4-Bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (140 mg, 0.35 mmol) was added to a suspension of tert-butyl [(3R,6S)-6-cyclohexyl-2-oxoazepan-3-yl]carbamate (210 mg, 0.68 mmol) in toluene (8 mL) and the mixture was heated to 90° C. After 1 h, the reaction was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/ethyl acetate) gave the title compound (132 mg). MS 327.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](=O)[CH2:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.C([O-])(=O)C.[Na+].Cl.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][NH2:29]>C(O)(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][C:3]([C:2]([F:14])([F:13])[F:1])=[N:29]1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Reactant: NNc1ccccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(-c2ccco2)n(-c2ccccc2Cl)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a mixture of 12.96 g of 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione, 8.56 g of sodium acetate and 40 ml of acetic acid was added 11.26 g of 2-chlorophenylhydrazine hydrochloride at room temperature. The mixture was stirred at 60° C. for 1 hour, and concentrated under reduced pressure. After the reaction mixture was concentrated under reduced pressure and water was poured into the residue, the mixture was extracted with chloroform three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 18.43 g of 1-(2-chlorophenyl)-5-(2-furyl)-3-trifluoromethyl-1H-pyrazole of the formula:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]2)[C:3]=1[C:4]#[N:5].O=[C:18]([CH3:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[NH2:5][C:4]1[C:3]2[C:6]3[O:10][CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]4[C:7]=3[CH:8]=[CH:9][C:2]=2[N:1]=[C:18]([CH3:25])[C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OC1C=CCCC1
Product: CCOC(=O)c1c(C)nc2ccc3c(c2c1N)OC1CCCCC31

Procedure:
Prepared as in Example 2a from 2-amino-6-(cyclohex-2-en-1-yloxy)benzonitrile (Example 131b) and ethyl 3-oxobutanoate as a pale yellow solid (11%). MS 327 (MH+).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[C:14]([CH3:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[C:11](Cl)[CH:10]=1)C1C=CC=CC=1.[C:23]([C:27]1[CH:31]=[CH:30][NH:29][N:28]=1)([CH3:26])([CH3:25])[CH3:24].OC1C2C(=C(C)C(OC)=CC=2)N=C(N2C=CC(C(C)C)=N2)C=1>>[OH:8][C:9]1[C:18]2[C:13](=[C:14]([CH3:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[C:11]([N:29]2[CH:30]=[CH:31][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:28]2)[CH:10]=1
Reactant: COc1ccc2c(OCc3ccccc3)cc(Cl)nc2c1C
Reactant: CC(C)(C)c1cc[nH]n1
Agent: COc1ccc2c(O)cc(-n3ccc(C(C)C)n3)nc2c1C
Product: COc1ccc2c(O)cc(-n3ccc(C(C)(C)C)n3)nc2c1C

Procedure:
The title compound was prepared from 4-benzyloxy-2-chloro-7-methoxy-8-methyl-quinoline (63) and 3-tert-butylpyrazole following the procedure reported for the preparation of 4-hydroxy-2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinoline (64): m/z=312 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:15][N:14]=2)=[N:10][O:11][CH:12]=1)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[CH3:30][S:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([C:9]3[C:8]([NH2:7])=[CH:12][O:11][N:10]=3)=[N:14][CH:15]=2)=[CH:26][CH:25]=1)(=[O:28])=[O:29]
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(OCc2ccc(S(C)(=O)=O)cc2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(COc2ccc(-c3nocc3N)nc2)cc1
Reaction time: 1.5 h
Yield: 78 %

Procedure:
{3-[5-(4-methanesulfonyl-benzyloxy)-pyridin-2-yl]-isoxazol-4-yl}-carbamic acid tert-butyl ester (70 mg, 0.16 mmol) was dissolved in dioxane (1.5 mL) and treated with 4N HCl in dioxane (1.5 mL, 1.5 mmol). After stirring for 1.5 h, the product 3-[5-(4-methanesulfonyl-benzyloxy)-pyridin-2-yl]-isoxazol-4-ylamine hydrochloride (43 mg, 78%) was isolated as a white solid by filtration. M+1=346.0
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:12][CH:13]([O:22][CH2:23][CH3:24])[C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:11].N1CCCCC1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:15]([C:14]([CH:13]([O:12][CH2:10][CH3:11])[O:22][CH2:23][CH3:24])=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)C(OCC)OCC

Procedure:
(2)-(1) A solution of 2-chlorobenzaldehyde (14.0570 g), ethyl 4,4-diethoxyacetoacetate (21.8240 g) and piperidine (1 ml) in benzene (100 ml) was refluxed under azeotropic dehydration for 4 hours. The resultant solution was washed with water, dried and concentrated to give oily ethyl 2-(2-chlorobenzylidene)-4,4-diethoxyacetoacetate. The mixture of the compound obtained above and ethyl 3-aminocrotonate (12.92 g) was heated in an oil bath (about 100° C.) for 8 hours. The reaction mixture was dissolved in ethyl acetate, washed with water, dried and then the solvent was removed to give crude oil (52.4 g). The oil was purified by column chromatography on silica gel with an eluent (benzene:ethyl acetate=20:1) to give diethyl 2-methyl-4-(2-chlorophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, which was recrystallized from n-hexane to give the pure crystals (20.2445 g), m.p. 75° to 77° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.[CH3:21][C:22]1([CH3:33])[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=2)[NH:24][C:23]1=[O:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:21][C:22]1([CH3:33])[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH2:17][C:16]3[CH:19]=[CH:20][C:13]([O:12][CH2:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)=[CH:14][CH:15]=3)[CH:29]=2)[NH:24][C:23]1=[O:32]
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CC1(C)C(=O)Nc2ccc(O)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)Nc2ccc(OCc3ccc(OCc4ccc5ccccc5n4)cc3)cc21
Yield: 23.4 %

Procedure:
4-(2-Quinolinylmethoxy)benzyl chloride (567 mg, 2 mmol) was dissolved in 20 ml of DMF, followed by the addition of 354 mg (2 mmol) of 3,3-dimethyl-5-hydroxy-2,3-dihydro-1H-indol-2-one, 64 mg (0.2 mmol) of tetra-n-butylammonium bromide and 691 mg (5 mmol) of K2CO3. The resultant mixture was stirred under an argon gas stream at 50° C. for 72 hours. After the solvent was distilled off, water was added, and the thus-formed mixture was extracted twice in a CHCl3 --MeOH (3:1) mixed solvent. The extract was dried over MgSO4 and then concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column. Subsequent to elution with CHCl3, recrystallization was conducted from AcOEt-hexane, whereby 199 mg of the title compound were obtained as pale yellow powder (yield: 23.5%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[O:33]1[C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[O:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>>[O:33]1[C:37]2([CH2:42][CH2:41][N:40]([C:15]([N:13]3[CH2:14][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][CH:7]=4)[CH2:10][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:12]3)=[O:16])[CH2:39][CH2:38]2)[O:36][CH2:35][CH2:34]1
Reactant: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1

Procedure:
6.00 g (13.3 mmol) of the compound from Example 58A, 4.75 g (33.2 mmol) of 8-aza-1,4-dioxa-spiro[4.5]decane and 1.83 g (13.3 mmol) of potassium carbonate were reacted according to General Method 8A. Yield: 5.15 g (81% of theory)