Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Br[CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]>CN(C=O)C>[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:18][CH2:19][CH2:20][N:21]2[C:25](=[O:26])[C:24]3[C:23](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22]2=[O:31])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Oc1cccc(CN2CCOCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc(CN2CCOCC2)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To 1.58 g (0.033 moles) of 50% sodium hydride is added 15 ml DMF; then 6.3 g (0.033 moles) of 3-(4-morpholinylmethyl)phenol, dissolved in 30 ml DMB, is added dropwise to the stirred suspension at room temperature. This mixture is stirred 20 minutes and then N-(3-bromopropyl)-phthalimide, 9 g. (0.033 moles) is added to the mixture and stirred. A clear, amber solution results. After 2 hours, this solution is poured into ice-water and extracted with 100 ml of chloroform. The organic layer is washed once with 100 ml 5%NaOH, and once with 100 ml water, dried over MgSO4, filtered and evaporated. The residue is dissolved in ether and washed again with 50 ml water. Then the organic layer is dried over MgSO4, filtered and evaporated. The residue rapidly forms a white solid. This is recrystallized from acetonitrile, m.p. 90°-93° C. (yield=39 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][Cl:18])=[O:15]>ClCCl>[C:14](=[O:15])([O:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])[O:16][CH2:17][Cl:18]
Reactant: CC(C)CCO
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CCOC(=O)OCCl

Procedure:
3-Methyl-1-butanol (4.4 g) was dissolved in dichloromethane (75 ml) and pyridine (4.0 g) was added to it. The reaction mixture was cooled in an ice bath and chloromethyl chloroformate (6.5 g) was added to it with stirring. The cooling bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The dichloromethane solution was washed with water thrice and once with brine. The organic layer was dried over sodium sulfate and evaporated to furnish a colorless oil of desired product weighing 10.7 g which was the pure chloromethyl isopentyl carbonate. NMR (CDCl3) δ 0.95 (6H, d, J=5 Hz, CH(CH3)2), 1.66 (3H, m, CH2 and CH), 4.28 (2H, t, J=7 Hz, OCH2CH2) and 5.73 (2H, s, OCH2Cl). IR (film) 2950, 1783, 1265 cm-1.
Reaction SMILES: [2H][C:2]1[C:7]([2H])=[C:6]([NH2:9])[C:5]([NH2:10])=[C:4]([2H])[C:3]=1[2H].[NH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=O)=[CH:16][CH:15]=1>O.C(=O)([O-])[O-].[K+].[K+]>[NH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]2[NH:9][C:6]3[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=3[N:10]=2)=[CH:16][CH:15]=1
Reactant: [2H]c1c([2H])c([2H])c(N)c(N)c1[2H]
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 195 °C
Yield: 88.2 %

Procedure:
This intermediate was prepared according to the procedure given in E. Acalade et al., J. Org. Chem. 52:5009-15 (1987). A mixture of 3.21 g (0.0247 moles) of O-phenylenediamine, 3.93 g (0.0287 moles) of 4-aminobenzoic acid and 42 g of polyphosphoric acid was heated to 195° C. for 5 hours. After cooling to room temperature, the reaction mixture was diluted with 180 mL of water and basified to pH 8 with solid potassium carbonate. The resulting precipitate was collected, washed with water and dried to give 4.56 g of product.
Reaction SMILES: [NH2:1][C:2](=[N:51][O:52][C:53](=[O:70])[C@@H:54]([NH:62]C(OC(C)(C)C)=O)[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:3]1[CH:50]=[CH:49][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:48]=[CH:47][C:24]([C:25]([NH2:46])=[N:26][O:27][C:28](=[O:45])[C@@H:29]([NH:37]C(OC(C)(C)C)=O)[CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[ClH:71].C(O)C>C(O)C>[ClH:71].[NH2:1][C:2](=[N:51][O:52][C:53](=[O:70])[C@@H:54]([NH2:62])[CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:3]1[CH:50]=[CH:49][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:48]=[CH:47][C:24]([C:25]([NH2:46])=[N:26][O:27][C:28](=[O:45])[C@@H:29]([NH2:37])[CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:23][CH:22]=3)[CH2:15][CH2:16]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)ON=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=NOC(=O)[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)cc3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: NC(=NOC(=O)[C@@H](N)Cc1ccccc1)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=NOC(=O)[C@@H](N)Cc4ccccc4)cc3)CC2)cc1
Reaction time: 0.33 h

Procedure:
To an ethanol (10 mL) suspension of 0.50 g of 4-(3-{4-[3-(4-{amino[(2S)-2-(tert-butoxycarbonyl)amino-3-phenylpropionyloxyimino]methyl}phenoxy)propyl]-1-piperidinyl}propoxy)-N′-[(2S)-2-(tert-butoxycarbonyl)amino-3-phenylpropionyloxy]benzamidine was added 5 mL of 2.9 mol/L hydrogen chloride/ethanol under cooling with ice, which was then stirred at the same temperature for 20 minutes, followed by allowing to stand at room. temperature for 26 hours. The solvent was distilled off under reduced pressure, and the resultant residue was suspended in chloroform, followed by collecting solid matter by filtration to provide 0.50 g of 4-{3-[4-(3-{4-[amino((2S)-2-amino-3-phenylpropionyloxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}-N′-((2S)-2-amino-3-phenylpropionyloxy)benzamidine hydrochloride as slightly pale yellow solid form.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1>C(O)(=O)C#CCC>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:15](=[O:16])[C:14]#[C:13][CH2:12][CH3:11])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Agent: CCC#CC(=O)O
Product: CCC#CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 24.7 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and pent-2-ynoic acid, to afford the title compound (7.4 mg, 24.7%). Data: UPLC (C) Rt: 1.73 min; m/z 480.3 (M+H)+.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]([C:10]3[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=3)[CH2:8][CH2:7][CH2:6][C:5]=12>C(O)(=O)C>[CH:1]1[N:2]=[CH:3][N:4]2[CH:9]([CH:10]3[CH2:18][CH2:17][CH:13]([C:14]([OH:16])=[O:15])[CH2:12][CH2:11]3)[CH2:8][CH2:7][CH2:6][C:5]=12
Reactant: O=C(O)c1ccc(C2CCCc3cncn32)cc1
Solvent: CC(=O)O
Product: O=C(O)C1CCC(C2CCCc3cncn32)CC1

Procedure:
A solution of 1.5 g of 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzoic acid [93178-73-5] in 5 ml of acetic acid is hydrogenated (50 bar) in the presence 0.05 g of Nishimura catalyst at room temperature. The reaction mixture is clarified by filtration, and the filtrate is evaporated. The crude title compound is obtained from the residue.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C.O>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:13][CH2:12][N:11]([CH2:19][C:18]2[CH:22]=[CH:23][C:15]([F:14])=[CH:16][CH:17]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(F)cc2)C1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of (3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine (5.0 g) in DMF (50 ml) was added 4-fluorobenzoylchloride (3.38 ml) and N,N-diisopropylethylamine (9.35 ml), the mixture was stirred at 70° C. for 2 hours. The mixed solution was poured into a mixture of water (300 ml) and AcOEt (300 ml). The organic layer was separated, washed with water twice and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 5% MeOH in dichloromethane to give [1-(4-fluoro-benzyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (6.8 g). To a solution of [1-(4-fluoro-benzyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (6.8 g) in MeOH(34 ml) was treated with 4N HCl in AcOEt (29 ml) and was stirred at 25° C. for 12 hours. The solvent was removed under reduced pressure. Recrystallization (acetonitrile-MeOH) provided (3R)-1-(4-fluorobenzyl)-3-pyrrolidinamine dihydrochloride as white solid (3.77 g).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@:8]([CH:22]=[CH2:23])([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.Cl.[NH+]1C=CC=CC=1>>[OH:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@:8]([CH:22]=[CH2:23])([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1CC[C@]1(C)C(=O)CC[C@@H]21
Agent: Cl
Agent: c1cc[nH+]cc1
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1CC[C@]1(C)C(=O)CC[C@@H]21
Reaction time: 3 h

Procedure:
460 mg of 3-methoxy-8β-vinyl-estra-1,3,5(10)-trien-17-one was added to 9.2 g of pyridinium hydrochloride at 180° C. and stirred for 3 hours at the same temperature. Then, it was poured onto ice, the deposited precipitate was filtered off, washed with water and dried. The yield of 2-hydroxy-8β-vinyl-estra-1,3,5(10)-trien-17-one with a melting point of 239-242° C. amounted to 400 mg (90%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([C:26]2[N:27]([CH3:35])[C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:20][C:17]=1[CH:18]=O.C[O-].[Li+].Cl>CN(C=O)C.O>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([C:26]2[N:27]([CH3:35])[C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:20][C:17]=1[CH:18]=[CH:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=O
Agent: C[O-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=CC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
Ex-37A: To a solution of 4-acetylbenzenesulfonamide (Ex-35A, 0.20 g, 1 mmol) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A, 0.30 g, 1 mmol) in DMF (25 ml) was added lithium methoxide (4 ml, 1.0 M in methanol). The mixture was stirred at room temperature overnight. It was poured into water (50 ml) and acidified to pH=1 with 3 N HCl. The yellow precipitate was filtered, washed with water, and dried. Crystallization from EtOAc/hexanes gave 4-{3-[2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}benzenesulfonamide (0.43 g, 90%) as a yellow solid, mp 148–150° C. 1H-NMR (300 MHz, CDCl3) δ 8.17 (d, J=16 Hz, 1H), 8.09 (d, J=9 Hz, 2H), 8.01 (d, J=9 Hz, 2H), 7.68 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.47 (d, J=16 Hz, 1H), 7.35 (d, J=8 Hz, 1H), 7.22–7.26 (m, 1H), 7.11–7.16 (m, 1H), 6.58 (s, 1H), 6.50 (s, 1H), 4.92 (brs, 2H), 4.02 (s, 3H), 3.90 (s, 3H), 3.58 (s, 3H). MS m/z=477 ([M+H]+, 100%).
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:18][C:17]=2[S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])[CH2:10][C:11](OC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C.CCCCCCC.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl.O.CO>[O:12]=[CH:11][CH2:10][C@@H:9]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:23])(=[O:24])=[O:25])=[CH:18][C:17]=1[S:26]([C:29]([F:30])([F:31])[F:32])(=[O:28])=[O:27])[CH2:8][S:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCCCCCC
Product: NS(=O)(=O)c1ccc(N[C@H](CC=O)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A mixture of (R)-methyl 4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butanoate (INTERMEDIATE 7, 3.1 g, 6.05 mmol) in DCM (155 ml) was cooled to −78° C. and DIBAL-H in heptane (18.1 ml, 18.1 mmol) was added dropwise. After addition was complete, the mixture was stirred for 3 hours at −78° C. Methanol (8 ml) and an aqueous solution of Rochelle's salt (15.0 ml) were added sequentially, and the reaction mixture was warmed to r.t. Water (150 ml) was added to the reaction, and the layers were separated. The organic layer was washed with water, dried (Na2SO4), and concentrated in vacuo to afford the title compound (2.9 g, yield: almost quantitative).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([OH:24])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].S(=O)(=O)(O)O.[OH-].[Na+].[ClH:39]>C(O)C.C(OCC)(=O)C>[ClH:39].[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([O:24][C:25](=[O:27])[CH3:26])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCCN(Cc2ccccc2)C1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)OC1(c2cccc(C(F)(F)F)c2)CCCN(Cc2ccccc2)C1
Reaction time: 0.25 h

Procedure:
A mixture of 37 g. of N-benzyl-3-hydroxy-3-(m-trifluoromethylphenyl)piperidine, 220 ml. of acetic anhydride and 0.3 ml. of concentrated sulfuric acid is heated to 110° C. for one hour. After cooling it is poured onto ice-water, the resulting mixture agitated for 15 minutes and made alkaline by addition of sodium hydroxide solution. The mixture is extracted with ethyl acetate, the extracts washed with brine, dried (MgSO4) and evaporated to dryness to obtain 39 g. of the free base. This is dissolved in 600 ml. of ethyl acetate, cooled in ice, and 100 ml. of ethanol saturated with hydrogen chloride is added. The solvent is removed by evaporation in vacuo and the residue triturated with 200 ml. of ethyl acetate then 200 ml. of ethyl ether is added and the mixture allowed to stand overnight. The crystalline title compounds is collected by filtration, washed with ether and dried to obtain 36 g., M.P. 206°-207° C.
Reaction SMILES: [OH-].[Na+].O=[CH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:8]([O:9][CH3:10])[C:6]=1[OH:7].Br.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:18]>C(O)C>[N:22]1[CH:23]=[CH:24][C:19]([C:17]([C:16]2[O:7][C:6]3[C:8]([O:9][CH3:10])=[CH:11][CH:12]=[CH:13][C:5]=3[CH:4]=2)=[O:18])=[CH:20][CH:21]=1
Reactant: O=C(CBr)c1ccncc1
Reactant: COc1cccc(C=O)c1O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc2cc(C(=O)c3ccncc3)oc12
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
Sodium hydroxide (1.22 g) was added to a solution of o-vanillin (2.11 g) in ethanol (50 ml) at 55° C. under a nitrogen atmosphere. The reaction mixture was stirred for 10 minutes to give a yellow suspension. 4-(Bromoacetyl)pyridine hydrobromide (5 g) was then added portionwise and the solution heated at 55° C. for 12 h, then at 65-70° C. for a further 12 h. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between water (250 ml, containing sodium hydroxide (0.5 g)) and dichloromethane (2×200 ml). The combined organic phases were washed with water (100 ml), dried over magnesium sulphate, filtered and evaporated in vacuo onto silica gel. The compound was washed through a pad of silica with ethyl acetate; the ethyl acetate was removed in vacuo and the residue azeotroped with hexane. The resulting solid was washed with hexane and filtered to furnish the title compound (0.95 g) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:51][C:52]1[CH:53]=[C:54]2[C:58](=[CH:59][CH:60]=1)[N:57]([NH2:61])[C:56]([CH3:62])=[CH:55]2>CN(C=O)C.O.CCOC(C)=O>[F:51][C:52]1[CH:53]=[C:54]2[C:58](=[CH:59][CH:60]=1)[N:57]([NH:61][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[N:5][CH:6]=1)=[O:10])[C:56]([CH3:62])=[CH:55]2
Reactant: Cc1nc(-c2cccnc2)ncc1C(=O)O
Reactant: Cc1cc2cc(F)ccc2n1N
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccnc2)ncc1C(=O)Nn1c(C)cc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.8 %

Procedure:
A solution of 4-methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid (504 mg, 2.34 mmol), HCTU (1.06 g, 2.55 mmol), and DIPEA (1.11 mL, 6.30 mmol) in DMF (15 mL) is stirred at rt under N2 for 10 min. 5-Fluoro-2-methyl-indol-1-ylamine (346 mg, 2.11 mmol) is added. The resulting mixture is stirred at rt overnight. The mixture is portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 70% EtOAc in heptane to afford 4-methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid (5-fluoro-2-methyl-indol-1-yl)-amide (82 mg, 11%) as a solid. MS: 362 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 11.80 (s, 1H), 9.59 (d, 1H), 9.29 (s, 1H), 8.80-8.73 (m, 2H), 7.63 (dd, 1H), 7.22 (dd, 1H), 7.28 (dd, 1H), 6.97 (dt, 1H), 6.35 (s, 1H), 2.79 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].[CH:10]([N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[N:14]1)([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:10]([N:13]1[C:17]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[CH2:8][OH:9])=[CH:16][CH:15]=[N:14]1)([CH3:12])[CH3:11]
Reactant: CC(C)n1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: OCc1ccncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1nccc1-c1cnccc1CO
Temperature: 100 °C
Yield: 43.1 %

Procedure:
To a mixture of (3-bromopyridin-4-yl)methanol (150 mg, 0.8 mmol, 1 eq.), 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (226 mg, 0.96 mmol, 1.2 eq.), Pd(dppf)Cl2 (58 mg, 0.08 mmol, 0.1 eq.), and K2CO3 (331 mg, 3.0 mmol, 3 eq.) in a RB flask were added dioxane (6 mL) and water (2 mL). The mixture was heated at 100° C. for 2 h, cooled, filtered, and concentrated. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give (3-(1-isopropyl-1H-pyrazol-5-yl)pyridin-4-yl)methanol (75 mg, 43%) as a yellow oil. LRMS (M+H+) m/z 218.1.
Reaction SMILES: [Br-].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1)#[N:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:40][CH2:41][CH2:42][CH2:43][CH:44]=O>C1COCC1>[Br:40][CH2:41][CH2:42][CH2:43][CH:44]=[CH:10][C:7]1[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C=CCCCBr)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Add (4-cyanophenylmethyl)triphenylphosphonium bromide (27.25 g) to dry THF (65 ml) and cool to -20° C. under an argon atmosphere. With stirring, dropwise add 65 ml of a solution of 1 molar lithium bis(trimethylsilyl)amide in THF, maintaining the temperature at -20° C. Stir for 30 minutes at -20° C.; then for 30 minutes at 0° C. Cool to -20° C. and add freshly distilled 4-bromobutanal (10.50 g) dropwise with stirring. Stir at -20° C. for 1 hour, then at room temperature for 16 hours. Remove the solid material by filtration and wash with THF. Vacuum evaporate the solvent from the filtrate and purify the resultant residue by chromatography on silica gel, eluting with CH2Cl2 :hexane(4:1). Combine the desired fractions and vacuum evaporate the solvent to obtain the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13][CH2:12]2)=[O:8]>ClCCl>[CH3:1][N:2]([CH3:3])[CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13][CH2:12]2)=[O:8]
Reactant: CNC
Reactant: CCOC(=O)N1CCCc2cc(C(=O)CCCl)ccc21
Solvent: ClCCl
Product: CCOC(=O)N1CCCc2cc(C(=O)CCN(C)C)ccc21
Reaction time: 2 h

Procedure:
50% Aqueous dimethylamine (51 mL) was added to a solution of ethyl 6-(3-chloropropanoyl)-3,4-dihydro-1(2H)-quinoline carboxylate (15.0 g, 50.7 mmol) obtained in Reference Example 1 in dichloromethane at room temperature and then stirred for 2 hours. The reaction solution was separated, and the organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The resultant residues were purified by alumina column chromatography (developing solvent; hexane:ethyl acetate=1:1), whereby the title compound (16.3 g) was obtained as pale yellow matter.
Reaction SMILES: [C:1]([O:4][C:5]1[C:24]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])=[C:23]([O:30][CH2:31][O:32][CH3:33])[CH:22]=[C:21]([O:34][CH2:35][O:36][CH3:37])[C:6]=1[C:7](=[O:20])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:4][C:5]1[C:24]([CH2:25][CH:26]=[C:27]([CH3:28])[CH3:29])=[C:23]([O:30][CH2:31][O:32][CH3:33])[CH:22]=[C:21]([O:34][CH2:35][O:36][CH3:37])[C:6]=1[C:7](=[O:20])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: COCOc1ccc(C=CC(=O)c2c(OCOC)cc(OCOC)c(CC=C(C)C)c2OC(C)=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCOc1ccc(CCC(=O)c2c(OCOC)cc(OCOC)c(CC=C(C)C)c2OC(C)=O)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 46.1 %

Procedure:
An ethanol solution (100 ml) of the 9.89 g of the 2'-acetoxy-4,4',6'-tris(methoxymethoxy)-3'-(3-methyl-2-butenyl)chalcone obtained as the intermediate in Specific Example 18 was added into a suspension of 5.0 g of 5% palladium/carbon in 70 ml of ethanol, in which a hydrogen gas had been sufficiently absorbed in advance, and hydrogen was absorbed by stirring the mixture at 0° C. under atmospheric pressure in a hydrogen gas atmosphere for 1.5 hours with 430.55 ml of a hydrogen gas. After the reaction, the reaction mixture was filtered and the solvent was removed from the filtrate by distillation. The obtained residue was subjected to the silica gel column chromatography [280 g of 230-400 mesh silica gel; n-hexane/ethyl acetate (5/1); 0.3 kg/cm2 ]. Fractions of 100 ml were collected and the 30th to 52nd fractions to obtain 4.58 g (yield=46.1%) of 1-[2-acetoxy-4,6-bis(methoxymethoxy)-3-(3-methyl-2-butenyl)phenyl]-3-(4-methoxymethoxyphenyl)-1-propanone.