Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH2:6]([S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:7]>Cl>[CH2:6]([S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:1]([O-:4])=[O:2])[CH:12]=1)(=[O:9])=[O:10])[CH3:7]
Reactant: O=[N+]([O-])[O-]
Reactant: CCS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Product: CCS(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Potassium nitrate (4.46 g, 44.12 mmol) was added portion wise to a solution of ethylphenyl sulfone in concentrated HCl (25 mL) at room temperature; then the mixture was heated to reflux for one hour. After cooling, the mixture was poured onto ice and the precipitate was collected by filtration. The solid was washed with cold water (2×50 mL) and dried. 1H NMR (CDCl3) δ ppm 1.28 (3H), 3.45 (2H), 7.80 (1H), 8.21 (1H), 8.30 (1H), 8.85 (1H); MS (DCI) m/z 216 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([B:17]4[O:21]C(C)(C)C(C)(C)[O:18]4)=[CH:13][N:12]3[CH:26]=2)[CH:6]=[CH:7][CH:8]=1.[ClH:27]>CC(C)=O.O>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([B:17]([OH:21])[OH:18])=[CH:13][N:12]3[CH:26]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cn3cc(B4OC(C)(C)C(C)(C)O4)ccc3n2)c1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COc1cccc(-c2cn3cc(B(O)O)ccc3n2)c1

Procedure:
7.47 g of 2-(3-methoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine are dissolved in 236 ml of acetone and 118 ml of water; 213 ml of 1N hydrochloric acid are added thereto, dropwise and with stirring, and the mixture is stirred at ambient temperature for 24 h. The reaction mixture is subsequently concentrated under reduced pressure. The solid obtained is triturated from diethyl ether, collected by filtration and then dried in an oven under reduced pressure at 60° C. 5.80 g of compound are obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:10]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:8])=[O:7].[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CCOC(C)=O>[Br:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:9]2[S:6]([NH:5][CH2:4][CH2:3][NH:2][CH2:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=1)(=[O:8])=[O:7]
Reactant: CCOC(=O)c1c(S(=O)(=O)NCCN)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1c(S(=O)(=O)NCCNCc2ccc(OC)cc2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product from Example 89, Step A was combined with 1.2 equivalents of 4-methoxybenzaldehyde and 1.5 equivalent of sodium triacetoxyborohydride in dichloroethane. The reaction was stirred for 1.5 hours at room temperature, was diluted with EtOAc and washed with sat. NaHCO3 and brine. The solution was dried with Na2SO4 and concentrated in vacuo to give the titled compound. ESI+ MS: 651 [M+H]+.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C[C:46](O)=[O:47]>O>[CH:46]([C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:47]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cc(O)cc(C(=O)OCC)c1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Product: CCOC(=O)c1cc(C=O)cc(C(=O)OCC)c1
Temperature: 70 °C
Yield: 99 %

Procedure:
To a stirred solution of diethyl 5-hydroxyisophthalate (4.0 g, 15.9 mmol) in HOAc (40 mL) was added a solution of CAN (19 g, 34.9 mmol) in H2O (40 mL) dropwise. The reaction mixture was heated at 70° C. for 6 h during which time the color of the solution turned from red to colorless. The reaction mixture was cooled to room temperature and dilute with H2O and was extracted with EtOAc. The combined organic layer was washed with saturated aqueous NaHCO3, brine, dried with Na2SO4 and concentrated under reduced pressure to provide diethyl 5-formylisophthalate (3.93 g, 99%) as a white solid. 1H NMR (CDCl3): d 10.17 (s, 1H), 8.95-8.96 (m, 1H), 8.74-8.75 (m, 2H), 4.50 (q, J=7.2 Hz, 4H), 1.47 (t, J=7.2 Hz, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([NH:14][C@H:15]([C:22](O)=[O:23])[CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>>[C:7]([NH:14][C@H:15]([C:22]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:23])[CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCOCC1

Procedure:
In substantially the same manner as in Example 5, morpholine (319 μl) was condensed with Boc-3-(2-thienyl)-L-alanine (900 mg, manufactured by Bachem Fein Chemikalien AG, Switzerland) to give N-[Boc-3-(2-thienyl)-L-alanyl]morpholine (1.13 g) as a colorless oily product (yield quantitative). After Boc group elimination with 4N HCl/ethyl acetate, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate as obtained in Reference Example 8 (315 mg) to yield the title compound (compound 73; 563 mg) as a white powder (yield 75%).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:8]1[O:12][CH:11]([N:13]2[CH:18]=[CH:17][C:16]([N:19]=[CH:20][N:21]([CH3:23])[CH3:22])=[N:15][C:14]2=[O:24])[C:10]([OH:26])([CH3:25])[CH:9]1[OH:27])([CH3:4])([CH3:3])[CH3:2].[C:40]([NH:47][C@H:48]([C:52](O)=[O:53])[CH:49]([CH3:51])[CH3:50])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[C:1]([SiH2:5][O:6][C:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:8]1[CH:9]([O:27][C:52](=[O:53])[CH:48]([NH:47][C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH:49]([CH3:51])[CH3:50])[C:10]([OH:26])([CH3:25])[CH:11]([N:13]2[CH:18]=[CH:17][C:16]([N:19]=[CH:20][N:21]([CH3:22])[CH3:23])=[N:15][C:14]2=[O:24])[O:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=Nc1ccn(C2OC(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)C(O)C2(C)O)c(=O)n1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC1C(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(N=CN(C)C)nc2=O)C1(C)O

Procedure:
In another method to synthesize the compounds of the invention, shown in FIG. 1b, benzoylcytosine, BSA and SnCl4/acetonitrile are reacted with 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose (1) to form 4-benzoylamino-1-(3,4-dibenzoyloxy-5-benzoyloxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (2a); reacting (2a) with NH3 in methanol and chromatographically separating the product, 4-amino-1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (3), also known as β-D-2′-C-methyl-cytidine; reacting (3) with Me2NCH(OMe)2 in DMF at room temperature for 1.5 hours to form N-[1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine (4); reacting (4) with TBDPSCl and pyridine at room temperature for 6 hours to provide N′-{1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2yl]-2-oxo-1,2-dihydro-pyrimidin-4-yl}-N,N-dimethyl-formamidine (5); reacting (5) with N-Boc-L-valine, DEC and DMAP in THF/DMF at room temperature for 2 days and subjecting the product formed from this reaction to HPLC in order to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxy-methyl)-5-[4-(dimethylaminomethyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester (6); refluxing (6) with NH4F in MeOH for about 3 hours to remove the silyl and amino-protecting groups, and subjecting the product to chromatographic purification to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester (7); and finally reacting (7) with HCl in EtOAc at room temperature to provide 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester, dihydrochloride salt (8) as a final product.
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21]([C:23]4[NH:27][C:26]([S:28]([CH3:31])(=[O:30])=[O:29])=[N:25][C:24]=4[C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[O:22])[CH:17]=[CH:16][C:15]=3[CH3:39])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:40].CC(O)C>>[NH2:40][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21]([C:23]4[NH:27][C:26]([S:28]([CH3:31])(=[O:30])=[O:29])=[N:25][C:24]=4[C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[O:22])[CH:17]=[CH:16][C:15]=3[CH3:39])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: Cc1ccc(NC(=O)c2[nH]c(S(C)(=O)=O)nc2-c2ccc(F)cc2)cc1NC(=O)c1csc2c(Cl)ncnc12
Solvent: CC(C)O
Product: Cc1ccc(NC(=O)c2[nH]c(S(C)(=O)=O)nc2-c2ccc(F)cc2)cc1NC(=O)c1csc2c(N)ncnc12
Temperature: 80 °C
Yield: 59 %

Procedure:
Compound 4-chloro-N-(5-(4-(4-fluorophenyl)-2-(methylsulfonyl)-1H-imidazole-5-carboxamido)-2-methylphenyl)thieno[3,2-d]pyrimidine-7-carboxamide (7.0 mg, 0.01 mmol) was dissolved into 2M ammonia in IPA (1.0 mL, 1.99 mmol ammonia). The resulting solution was heated in a sealed vial at 80° C. for 6 hrs. The solvent was removed under reduced pressure and the crude material was purified by SiO2 chromatography (DCM to 8% MeOH gradient, desired product elutes in 6% MeOH) (4 mg, 59% yield). 1HNMR (400 MHz, MeOD/CDCl3): d 8.64 (s, 1H), 8.42 (s, 1H), 8.26 (m, 1H), 7.66 (m, 2H), 7.56 (m, 2H), 7.51 (s, 1H), 7.41 (m, 2H), 7.07 (d, 1H, J=9.2 Hz), 7.01 (t, 2H, J=8.4 Hz), 3.20 (s, 3H), 2.33 (s, 3H). MS (ESI): m/z 565.9 [M+H]+.
Reaction SMILES: O[C:2]1([CH3:28])[CH:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:5]([C:22]([O:24][CH3:25])=[O:23])=[C:4]([NH:26][CH3:27])[CH2:3]1.S(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:28][C:2]1[CH:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[C:5]([C:22]([O:24][CH3:25])=[O:23])=[C:4]([NH:26][CH3:27])[CH:3]=1
Reactant: CNC1=C(C(=O)OC)C(c2ccc(C(F)(F)F)cc2)C(C(=O)OC)C(C)(O)C1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CNC1=C(C(=O)OC)C(c2ccc(C(F)(F)F)cc2)C(C(=O)OC)C(C)=C1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
10.0 g (25 mmol) of dimethyl 6-hydroxy-6-methyl-4-methylamino-2-(4-trifluoromethylphenyl)-cyclohex-3-ene-1,3-dicarboxylate (preparation analogous to Example II) are heated to 60° C. in 100 ml of pyridine and treated with 2.5 ml of thionyl chloride. The mixture is stirred at 60° C. for 10 minutes and concentrated, and the residue is taken up in methylene chloride, washed three times with water, dried and concentrated. The residue is grossly purified on 200 g of silica gel (petroleum ether/AcOEt=3:1) and then separated by MPLC (methylene chloride/AcOEt=30:1). Two fractions are obtained. 224 mg (2.3%) of dimethyl 4-methyl-6-methylamino-2-(4-trifluoromethylphenyl)-cyclohexa-3,6-diene-1,3-dicarboxylate (non-polar isomer (2)) crystallize from ether/petroleum ether. From the 2nd fraction, 2.29 g (22%) of the polar isomer, dimethyl 6-methyl-4-methylamino-2-(4-trifluoromethylphenyl)-cyclohexa-3,5-diene-1,3-dicarboxylate (3) are precipitated from AcOEt as the hydrochloride (Rf =0.47 (c)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](F)=[CH:11][N:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].[CH3:14][O-:15].[Na+].CO>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:10]([O:15][CH3:14])=[CH:11][N:12]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCOC(=O)c1cc(Br)ncc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)ncc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
Ethyl 2-bromo-5-fluoroisonicotinate (434 mg, 1.75 mmol) obtained in step 1 was dissolved in methanol (3.50 mL), and the solution was stirred at room temperature for 30 minutes after adding a 28% sodium methoxide-methanol solution (1.69 g, 8.75 mmol). The reaction mixture was extracted with ethyl acetate after adding water. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give methyl 2-bromo-5-methoxyisonicotinate (154 mg, yield 36%).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[C:5](=[C:10]([CH3:18])[C:11]([NH2:17])=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[OH-].[Na+].Cl>C1COCC1.O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[C:4](=[CH:13][C:12]([N+:14]([O-:16])=[O:15])=[C:11]([NH2:17])[C:10]=1[CH3:18])[C:3]([OH:19])=[O:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(C)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(C(=O)O)cc([N+](=O)[O-])c(N)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.1 %

Procedure:
To a solution of 4-Amino-3-methyl-5-nitro-phthalic acid dimethyl ester (1.8 g, 6.72 mmol) in THF (10 mL) and water (20 mL) was added 5 N NaOH (4.0 mL) and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was acidified with conc. HCl (pH=2.0) and extracted with EtOAc (2×100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford the 4-Amino-3-methyl-5-nitro-phthalic acid 2-methyl ester (1.3 g, 76%) as a yellow solid.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:8][C:9]([CH:11]1[CH:16](O)[CH2:15][CH2:14][N:13]([CH2:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=3)[CH2:22][CH2:21][CH2:20]2)[CH2:12]1)=[O:10])[CH3:7].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH2:6]([O:8][C:9]([C:11]1[CH2:12][N:13]([CH2:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=3)[CH2:22][CH2:21][CH2:20]2)[CH2:14][CH2:15][CH:16]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)C1CN(CC2CCCc3ccc(OC)cc32)CCC1O
Agent: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=CCCN(CC2CCCc3ccc(OC)cc32)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2.06 g (18 mmol) of methanesulphonic acid chloride in 20 ml of toluene is added dropwise, while stirring at 0°-5°, to a solution of 5.2 g (15 mmol) of cis/trans mixture of 4-hydroxy-1-[(7-methoxy-1,2,3,4-tetrahydro-naphth-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester and 11.4 g (75 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 100 ml of toluene. The reaction mixture is then allowed to warm to room temperature and is stirred for a further 18 hours at room temperature. Ice-water is added to the reaction mixture and the organic phase is extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline with concentrated sodium hydroxide solution and extracted with dichloromethane. The combined organic phases are washed with water, dried over sodium sulphate and concentrated by evaporation. The oily residue (4.85 g) is chromatographed on 240 g of silica gel (0.040-0.063) with toluene/ethyl acetate (9:1) to yield 1-[(7-methoxy-1,2,3,4-tetrahydro-naphth-1-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester in the form of a light-yellow oil. The hydrochloride produced with hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether, m.p. 177°-179° (decomposition).
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:16][CH:15]=1>>[C:1]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:19]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: CCCCCCCCCC(=O)Cl
Product: CCCCCCCCCC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 72.5 %

Procedure:
In a manner similar to that described in Example 3, decanoyl chloride (0.069 g, 0.00036 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.063 g of 4-[4-(decanoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+348.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH2:8].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:31][CH3:32])[C:26]=1[O:27][CH2:28][C:29]#[CH:30])[C:21](Cl)=[O:22]>C(OCC)(=O)C>[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:21](=[O:22])[C:20]1[CH:19]=[C:18]([O:17][CH3:16])[C:26]([O:27][CH2:28][C:29]#[CH:30])=[C:25]([O:31][CH3:32])[CH:24]=1
Reactant: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Reactant: CC1CCCC1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOc1c(OC)cc(C(=O)NC2CCCC2C)cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.4 %

Procedure:
To a mixture of 1 ml of ethyl acetate and 0.2 g of 2-methylcyclopentylamine hydrochloride was added 0.48 ml of triethylamine and then, a mixture of 0.25 g of 3,5-dimethoxy-4-(2-propynyloxy)benzoyl chloride and 1 ml of ethyl acetate was added dropwise thereto under ice cooling. The mixture obtained was stirred at room temperature for 12 hours. Then, the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.21 g of N-(2-methylcyclopentyl)-3,5-dimethoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 68 of the present invention) represented by the formula:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1.O>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
To a solution of N-(3-nitrophenyl)-3-(trifluoromethyl)benzamide (30.0 g, 96.7 mmol) in tetrahydrofuran (300 mL) was slowly added with heating under reflux, a solution (500 mL) of sodium hydrosulfite (97.8 g, 562 mmol) in water, and the obtained two-layer solution was vigorously stirred with heating under reflux for 2 days. After cooling the reaction solution to room temperature, the aqueous layer was separated, and extracted with ethyl acetate (150 mL×2). The organic layer separated earlier was diluted with ethyl acetate (350 mL), and washed with saturated aqueous sodium hydrogen carbonate solution (150 mL×2) and saturated brine (100 mL). The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (150 mL×2) and saturated brine (150 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (17.8 g, 66%) as a pale-brown solid.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([C:19]4[CH:18]=[CH:17][C:16]([CH3:15])=[CH:21][CH:20]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Cc1ccc(C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(C2CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)cc1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-methylphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 78% overall yield. FDMS m/e=364 (M+ of free base). α[D]589 =-11.77 (c=0.34, methanol).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([Cl:13])[CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=2)[CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC>>[Cl:13][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=1)[CH:3]=[C:2]2[CH:22]=[CH2:23]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Oc1cc(Cl)c2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Product: C=Cc1cc(-c2ccc(O)c(F)c2)nc2c(Cl)cc(O)cc12
Yield: 84 %

Procedure:
This compound was prepared from 45a based on method J using 1.1 equiv. of tributyl(vinyl)tin at 90° C. Red solid; Yield: 84%; mp 225° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 5.74 (dd, J=11.1, 1.0 Hz, 1H), 6.30 (dd, J=17.3, 1.1 Hz, 1H), 7.10 (dd, J=8.8, 8.8 Hz, 1H), 7.35 (d, J=2.6 Hz, 1H), 7.38 (dd, J=17.3, 11.1 Hz, 1H), 7.53 (d, J=2.5 Hz, 1H), 8.04 (dd, J=8.4, 1.7 Hz, 1H), 8.16 (dd, J=13.1, 2.1 Hz, 1H), 8.16 (s, 1H), 10.27 (s, 1H), 10.35 (s, 1H); 19F-NMR (400 MHz, DMSO-d6) δ −136.51 (dd, J=13.2, 9.3 Hz); MS (ESI) m/z 314/316 ([M−H]−), 316/318 ([M+H]+); Anal. Calcd for C17H11ClFNO2: C, 64.67; H, 3.51; N, 4.44. Found: C, 63.57; H, 3.61; N, 4.04.
Reaction SMILES: [Li]CCCC.[CH2:6]([N:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>C1COCC1>[CH2:20]([N:13]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C@@H:14]([C:27](=[O:30])[CH2:28][CH3:29])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C(=O)CC)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
In a round bottomed flask, at −78° C., under argon atmosphere, a solution of DIPA (0.3 mL, 2.12 mmol) in dry THF (10 ml) was treated with n-BuLi (2.5 M in n-hexane, 0.776 mL, 1.94 mmol). After 30 min a solution of ethyl 2-(dibenzylamino)-acetate (0.5 g, 1.77 mmol) in dry THF (10 ml) was added dropwise via a cannula. After 15 min, propanoyl chloride (0.46 mL, 5.29 mmol) was added dropwise at −78° C. and the mixture stirred for 10 min at rt. The reaction was then quenched with H2O, and Et2O was subsequently added. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, as an oil. Purification by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (98:2) gave a pure compound (0.6 g), as a mixture of two tautomers (ketone:enol=ca. 85:15), as a colorless oil. MS (ESI) m/z: 340 [M−H]+; (ESI) m/z: 338 [M−H]−. 1H NMR (DMSO-d6) δ 0.90 (t, J=7.24 Hz, 3H), 1.23 (t, J=7.07 Hz, 3H), 2.53-2.61 (m, 1H), 2.69 (dq, J=7.23, 18.13 Hz, 1H), 3.72-3.88 (m, 4H), 4.12-4.22 (m, 3H), 7.11-7.47 (m, 10H) (reported data refer to the major ketone tautomer).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1[C:4]#[N:5].[BrH:12]>C(O)(=O)C>[Br:12][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:5]
Reactant: Br
Reactant: COc1ccnc(Cl)c1C#N
Solvent: CC(=O)O
Product: N#Cc1c(O)ccnc1Br
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Chloro-4-methoxy-nicotinonitrile (M. Mittelbach et al., Arch. Pharm. (Weinheim Ger.); 1985, GE, 318, 6, 481-486) (6.92 g) was suspended in 70 mL of 30% HBr in acetic acid in a pressure vessel and heated with stirring at 100° C. for 2 h. The reaction was cooled to room temperature and filtered, washing well with H2O, and dried in vacuo overnight at 50° C. providing 4.85 g 2-bromo-4-hydroxy-nicotinonitrile as a white solid. Proton NMR(DMSO) indicated the product was a mixture of 69% bromo compound with 31% starting chloro analog.