Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:27]2[O:28][C@@:26]2([CH3:29])[C@@H:25](OC([C@@H](N(C(C(C)C)=O)C)C)=O)[CH2:24][C:22](=[O:23])[N:21]([CH3:42])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH:11]([O:43][CH3:44])[C:10]([CH3:45])=[CH:9][CH:8]=[CH:7][C@@H:6]([O:46][CH3:47])[C@:5]2([OH:52])[NH:48][C:49]([O:51][C@H:3]1[CH2:4]2)=[O:50].C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]=[CH:24][C:22](=[O:23])[N:21]([CH3:42])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH:11]([O:43][CH3:44])[C:10]([CH3:45])=[CH:9][CH:8]=[CH:7][CH:6]([O:46][CH3:47])[C:5]2([OH:52])[NH:48][C:49]([O:51][CH:3]1[CH2:4]2)=[O:50]
Reactant: COc1cc2cc(c1Cl)N(C)C(=O)C[C@H](OC(=O)[C@H](C)N(C)C(=O)C(C)C)[C@]1(C)O[C@H]1[C@H](C)[C@@H]1C[C@@](O)(NC(=O)O1)[C@H](OC)C=CC=C(C)C2OC
Agent: COc1cc2cc(c1Cl)N(C)C(=O)/C=C/C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2OC
Agent: COc1cc2cc(c1Cl)N(C)C(=O)C[C@H](OC(=O)[C@H](C)N(C)C(=O)C(C)C)[C@]1(C)O[C@H]1[C@H](C)[C@@H]1C[C@@](O)(NC(=O)O1)[C@H](OC)/C=C/C=C(\C)C2OC
Agent: O=C([O-])[O-]
Solvent: CO
Product: COc1cc2cc(c1Cl)N(C)C(=O)C=CC1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2OC

Procedure:
The structures of the isolated compounds were determined primarily by high resolution mass spectrometry and by proton and carbon 13 NMR using colubrinol and maytansine as standards for comparison. 1H NMR data is given below in Table I and 13C NMR is given in Table II. Comparison of the 1H NMR spectra of trewiasine and colubrinol indicated that these two compounds were closely related, the only significant differences being the presence of an additional methoxyl signal at δ 3.37 in the spectrum of trewiasine and an upfield shift of the C-15 proton singlet from δ 5.48 in colubrinol to δ 4.86 in trewiasine. Referring to Table I, the C-15 proton signals of maytansine (m, δ 3.1-3.0 were replaced by the downfield singlet at δ 4.86 in the spectrum of trewiasine, and as shown in Table II, the C-15 carbon signal of maytansine (t, δ 46.60) was shifted downfield in trewiasine (d, δ 86.70). Thus, trewiasine was determined to have the maytansinoid ring system with a methoxyl at C-15. A mass spectrum gave an apparent M+ -(H2O+HNCO) at m/e 688.0390 (calcd. 688.3126), confirming that trewiasine was C37H52ClN3O11 (MW=749). Both trewiasine and dehydrotrewiasine give a characteristic ion at m/e 515 (C28H34ClNO6) corresponding to an additional loss of the C-3 substituent as consistent with documented M+ -(a+b) type maytansinoid fragmentations. Hydrolysis of trewiasine with sodium carbonate in 50% aqueous methanol at room temperature (see Kupchan, J. Org. Chem. 42, supra) gave trewsine, identified by 1H and 13C NMR, and N-isobutyryl-N-methylalanine, as determined by GC-MS of the methyl ester. This further confirms the structure of trewiasine to be that of 15-methoxymaytanbutine (15-O-methylcolubrinol).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:14][C@H:15]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]2)=[N:4][C:5]([C:8]2[NH:12][C:11](=[O:13])[NH:10][N:9]=2)=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=[O:13])[NH:10][N:9]=2)=[N:4][C:3]=1[O:14][C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1
Reactant: Cc1ccc(-c2n[nH]c(=O)[nH]2)nc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2n[nH]c(=O)[nH]2)nc1O[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-tert-butyl 3-((3-methyl-6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-2-yl)oxy)pyrrolidine-1-carboxylate (0.042 g, 0.115 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction mixture was stirred at RT overnight. The solvent was removed in vacuo and the residue was dried under high vacuum to give the title compound, which was used directly to the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=3[OH:20])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1.N1C=CC=CC=1.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>ClC=CCl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=3[O:20][C:34]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[O:41])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1
Reactant: Cc1cc(C(=O)c2c(C)nn(C)c2O)c(C)c2c1S(=O)(=O)CCC2(C)C
Reactant: O=C(Cl)c1ccncc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClC=CCl
Solvent: c1ccncc1
Product: Cc1cc(C(=O)c2c(C)nn(C)c2OC(=O)c2ccncc2)c(C)c2c1S(=O)(=O)CCC2(C)C
Yield: 76.9 %

Procedure:
1.0 Gram (2.7 mmol) of the 4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide obtained in Preparation Example 6 was dissolved in 10 ml of 1,2-dichloroethene, and further, 0.26 g (3.2 mmol) of pyridine, 0.57 g (3.2 mmol) of isonicotinic acid chloride hydrochloride and 10 mg of benzyltriethylammonium chloride were added. The mixture was allowed to react at room temperature for 3 hours. The extraction of the reaction mixture was carried out by adding ethyl acetate, and the extract was consecutively washed with 10% hydrochloric acid, with a saturated sodium bicarbonate aqueous solution and with a saturated sodium chloride aqueous solution. The solvent was removed by filtration under reduced pressure, and the resultant oily substance was washed with an ethyl acetate/n-hexane mixed solvent (1:1 (V/V)) to form a solid. The mixture was filtered to give 1.0 g (yield 80%) of 4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-(pyridin-4-yl)carbonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 42).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([CH:9]1[C:22]3[CH:21]=[CH:20][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[NH:29][C:30](=[O:32])[CH3:31])=[CH:18][C:17]=3[O:16][C:15]3[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:2]2.C(=O)([O-])[O-].[K+].[K+].[CH2:39](Br)[CH:40]=[CH2:41]>CN(C=O)C>[CH2:41]([N:8]1[CH:1]2[CH2:7][CH2:6][CH:5]1[CH2:4][CH:3]([CH:9]1[C:22]3[CH:21]=[CH:20][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[NH:29][C:30](=[O:32])[CH3:31])=[CH:18][C:17]=3[O:16][C:15]3[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:2]2)[CH:40]=[CH2:39]
Reactant: C=CCBr
Reactant: CC(=O)Nc1ccccc1-c1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1C2CCC1CC(C1c3ccccc3Oc3cc(-c4ccccc4NC(C)=O)ccc31)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a solution of N-{2-[9-(8-Aza-bicyclo[3.2.1]oct-3-yl)-9H-xanthen-3-yl]-phenyl}-acetamide, 7b (53 mg, 0.125 mmol) in DMF (0.5 mL) at 0° C. were added potassium carbonate (18 mg, 0.13 mmol) and allyl bromide (10.6 μL, 0.122 mmol). The mixture was stirred overnight at rt, and poured onto H2O. The solid was separated via filtration and washed with H2O. The solid was purified via reverse phase HPLC (eleuent gradient: 10% to 90% CH3CN in H2O containing 0.1% TFA) to yield 25 mg (36%) of N-{2-[9-(8-allyl-8-aza-bicyclo[3.2.1]oct-3-yl)-9H-xanthen-3-yl]-phenyl}-acetamide, 18b. MS 18b: m/z: 464.9 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:3]=1.Cl.[NH2:17][OH:18].C(=O)([O-])O.[Na+]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[N:17][OH:18])=[CH:10][CH:9]=2)[CH:3]=1
Reactant: NO
Reactant: Cc1ccnc(-c2ccc(C=O)cc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccnc(-c2ccc(C=NO)cc2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a suspension of 4-(4-methylpyridin-2-yl)benzaldehyde (425 mg) in ethanol (5 ml) was added hydroxylamine hydrochloride (224 mg), and the mixture was stirred at 60° C. for 1 hour. After cooling, the mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure to give 4-(4-methylpyridin-2-yl)benzaldehyde oxime (0.43 g).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[ClH:18].[Cl:19][CH2:20][C:21]1[C:22]([NH:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:19].[ClH:18].[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:20][C:21]2[C:22]([NH:33][CH2:34][C:35]([F:38])([F:36])[F:37])=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: COc1ccc2nc(NCC(F)(F)F)c(CCl)cc2c1
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCC(F)(F)F)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 24 %

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (342 mg, 1.47 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-(2,2,2-trifluoroethyl)quinolin-2-amine hydrochloride SLA 41070 (500 mg, 1.47 mmol) at RT followed by a 2 N aq. LiOH solution (1.47 mL, 2.94 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 97:3) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided, after evaporation and drying, 233 mg of 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (3.05 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 45 as a yellow solid (200 mg, 24% yield).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>>[CH3:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Cc1ccccc1N
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Product: Cc1ccccc1NC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 20.6 %

Procedure:
The product is prepared according to the procedure described in Example 9, using 300 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 and 582 mg of 2-methylaniline in place of the 2-fluoroaniline. 76 mg of N-(2-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@@H:7]([O:8][CH3:9])[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1>Cl>[CH3:1][O:2][C@@H:3]1[C@@H:7]([O:8][CH3:9])[CH2:6][NH:5][CH2:4]1
Reactant: CO[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1OC
Agent: Cl
Product: CO[C@H]1CNC[C@@H]1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.30 g (9.35 mmol; 94% pure) of tert-butyl (3S,4S)-3,4-dimethoxy-1-pyrrolidinecarboxylate (example XVI, step 2) are taken up in 50 ml of hydrochloric acid (4M in dioxane) and stirred at RT overnight. The solvent is removed in vacuo, and the residue is suspended in DCM, mixed with 1N sodium hydroxide solution and stirred at RT for 10 minutes. The phases are separated and the aqueous phase is extracted several times with DCM. The combined organic phases are extracted with saturated aqueous sodium chloride solution, dried and filtered, and the solvent is removed in vacuo. 872 mg (63% of theory) of the product are obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc2ncccc2c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1ccc2ncccc2c1
Temperature: 25 °C

Procedure:
To a stirred solution of quinolin-6-yl-methanol (1.14 g, 7.16 mmol) in CH2Cl2 (100 mL) at 0° C. were added N-methylmorpholine N-oxide (1.25 g, 10.7 mmol), 4 Å molecular sieves (500 mg) and TPAP (60 mg). The mixture was stirred at RT until the starting material was consumed, then filtered through a Celite® pad. Solvent was evaporated to give the aldehyde.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.Cl[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[Si:10]([O:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: OCc1ccncc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1ccncc1

Procedure:
A solution of 20 g 4-pyridylcarbinol, 28.9 g of chloro-tert-butyl-dimethylsilane and 14.4 g imidazole in 200 ml dimethylformamide is stirred 3 hours at room temperature. Product is isolated by extraction into ethyl acetate/hexane (1:1) and washing extract 4 times with 400 ml of water. The solution is filtered through silica gel and concentrated in vacuo to yield 4-(tert-butyl-dimethylsilyloxymethyl)pyridine.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([O:16]C)OC)=[CH:9][CH:8]=1.[C:18]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19]1.FC(F)(F)C(O)=O>C1COCC1.C(OCC)(=O)C.ClCCl.O>[C:18]1([C:7]2[CH:8]=[CH:9][C:10]([CH:13]=[O:16])=[CH:11][CH:12]=2)[CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: COC(OC)c1ccc(Br)cc1
Reactant: O=C1CCCC1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(C2=CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
n-Butyllithium (7.2 mL, 1.56 M hexane solution, 11.2 mmol) was added to a solution in THF (25 mL) of 1-bromo-4-(dimethoxymethyl)benzene (2.29 g, 9.91 mmol) at −78° C. The mixture was stirred at the same temperature for 2 hours, and then cyclopentanone (1.34 mL, 15.1 mmol) was added thereto. The resulting mixture was heated to room temperature and then stirred for 1 hour. The reaction was terminated by adding a saturated ammonium chloride aqueous solution, and an extraction with ethyl acetate was conducted three times. The resulting organic layers were washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate, 5:1, v/v) to give an oily compound. Trifluoroacetic acid (9 mL) was added to a dichloromethane-water (9.1 mL, 100:1, v/v) mixture solution containing the resulting oily compound at room temperature, and the mixture was continuously stirred for 20 minutes. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate, 10:1, v/v) to give 1.18 g of the title compound (light brown crystalline solid, yield: 90%).
Reaction SMILES: [CH2:1]([CH:4]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]([OH:11])[CH2:6][C:7]([O:9]C)=[O:8])[CH:2]=[CH2:3]>[OH-].[K+].CO>[CH2:1]([CH:4]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]([OH:11])[CH2:6][C:7]([OH:9])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCC(CCCC)C(O)CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCC(CCCC)C(O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-allyl-3-hydroxyoctanoate (6.8 g, 31.7 mmol) was dissolved in a 2 N potassium hydroxide-methanol solution (20 mL), and the solution was stirred overnight at room temperature. The reaction solution was concentrated, then diluted with water, and washed with ether. The aqueous solution was made acidic using hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as an oil substance (6.0 g, 30 mmol). This compound was used in the next reaction without being purified.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:33](=[O:34])[C:32]5[CH:36]=[CH:37][C:29]([C:28]([F:27])([F:38])[F:39])=[CH:30][CH:31]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound, off-white solid (99 mg, 79%), MS (ISP) m/z=501.2 [(M+H)+], mp 228° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and 4-trifluoromethyl-benzoic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:15][C:16]#[N:17])=[O:5])C.O[Li].O.Cl>C1COCC1.CCO.O>[C:16]([CH2:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)#[N:17]
Reactant: CCOC(=O)c1cc2cccc(CC#N)c2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: N#CCc1cccc2cc(C(=O)O)[nH]c12
Temperature: 45 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of 100 mg (0.46 mmol) of 7-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester (the preparation of which is described in Chem. Pharm. Bull. 1996, 44, 55) in THF/EtOH/H2O (5 ml) at RT was added 50 mg of LiOH.H2O. The reaction mixture was stirred at 45° C. for one hour and then acidified with aqueous HCl 1M. The product was extracted with EtOAc and concentrated under vacuo to afford 80 mg (85%) of 7-Cyanomethyl-1H-indole-2-carboxylic acid as a white solid. ES-MS m/e (%): 199.6 (M−H+).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[CH:5][C:4]=1[CH3:21])[CH3:2].[OH:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[CH2:1]([C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([NH:11][C:12]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([OH:22])[CH:24]=3)[CH2:34][CH2:33]2)=[O:20])=[CH:5][C:4]=1[CH3:21])[CH3:2]
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: CCc1nc(OC)c(NC(=O)Oc2ccccc2)cc1C
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cccc(O)c3)CC2)cc1C
Yield: 56 %

Procedure:
Phenyl N-(6-ethyl-2-methoxy-5-methylpyridin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[CH3:19])[C:7]([F:20])=[CH:6][C:5]=1[C:21]1[N:25]([C@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[N:24]=[CH:23][C:22]=1[C:31]([O:33]CC)=[O:32].Cl.[Cl-].[NH4+]>C(O)C.[Cl-].[Na+].O.C(Cl)(Cl)Cl>[F:3][C:4]1[CH:9]=[C:8]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[CH3:19])[C:7]([F:20])=[CH:6][C:5]=1[C:21]1[N:25]([C@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[N:24]=[CH:23][C:22]=1[C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1cc(F)c(-c2c(C)cnc(OC)c2C)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ncc(C)c(-c2cc(F)c(-c3c(C(=O)O)cnn3[C@H]3CCOC3)cc2F)c1C
Temperature: 65 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
5 N sodium hydroxide (0.5 mL) was added to a solution of ethyl 5-[2,5-difluoro-4-(2-methoxy-3,5-dimethylpyridin-4-yl)phenyl]-1-[(S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylate (280 mg) in ethanol (3.6 mL), and the mixture was stirred at 65° C. for three hours. After cooling the reaction mixture to room temperature, chloroform and brine were added, and the mixture was adjusted to pH 6 with 5 N hydrochloric acid and saturated ammonium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give 5-(2,5-difluoro-4-(2-methoxy-3,5-dimethylpyridin-4-yl)phenyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylic acid (238 mg) as a crude purified product. CDI (121 mg) was added to a solution of the carboxylic acid (238 mg) in DMF (3 mL), and the mixture was stirred at room temperature for one hour. A 28% aqueous ammonia solution (0.6 mL) was added to the reaction mixture, followed by stirring overnight. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding chloroform and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. The filtrate was passed through a silica gel pad (NH silica gel; eluting with ethyl acetate), and the resulting filtrate was concentrated under reduced pressure to give the title compound (186 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:32]C(=O)C)=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:32])=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(OC)c(OC)c3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(OC)c(OC)c3)c2)=C(C)C1=O
Yield: 34.9 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-3,4-dimethoxyaniline (0.100 g, 0.196 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.032 g, 0.0685 mmol, 35%).