Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH:16]([CH3:18])[CH3:17])[C:10]=2[CH:11]=[C:12]([O:14]C)[CH:13]=1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH:16]([CH3:18])[CH3:17])[C:10]=2[CH:11]=[C:12]([OH:14])[CH:13]=1)=[O:4]
Reactant: COC(=O)c1cc(OC)cc2c1ccn2C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(O)cc2c1ccn2C(C)C
Yield: 83.6 %

Procedure:
To a stirred solution of 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid methyl ester (1.9 g, 7.69 mmol) in toluene (20 mL) was added anhydrous aluminum chloride (5.11 g, 38.4 mmol) at room temperature and then heated to reflux for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography by eluting 3-15% Ethyl acetate in petroleum ether to afford the title compound 6-hydroxy-1-isopropyl-1H-indole-4-carboxylic acid methyl ester (1.5 g, 83%) as yellow colored gum. 1H NMR (400 MHz, DMSO-d6): δ 1.43 (d, J=6.8 Hz, 6H), 3.86 (s, 3H), 4.65-4.61 (m, 1H), 6.81 (d, J=2.8 Hz, 1H), 7.11 (s, 1H), 7.29 (s, 1H), 7.44 (d, J=2.8 Hz, 1H), 9.32 (bs, 1H). LCMS (ES+): m/z=234.09 [M+H]
Reaction SMILES: C([O-])(=O)C.[Na+].CO[C:8]([C:10]1[C:15](Br)=[CH:14][N:13]=[CH:12][N:11]=1)=[O:9].Cl.[NH2:18][C:19]1[CH:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[CH:21][C:20]=1B(O)O.O>CN(C=O)C.[Cl-].[Na+].O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[O:9]=[C:8]1[C:10]2[N:11]=[CH:12][N:13]=[CH:14][C:15]=2[C:20]2[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:19]=2[NH:18]1
Reactant: COC(=O)c1ccc(B(O)O)c(N)c1
Reactant: COC(=O)c1ncncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)c1ncncc12
Temperature: 120 °C
Reaction time: 18 h
Yield: 8.5 %

Procedure:
Sodium acetate (4.0 eq, 1.92 g, 23.41 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride (complexed with dichloromethane) (0.05 eq, 214 mg, 0.29 mmol) were added to a mixture of methyl-5-bromopyrimidine-4-carboxylate (1.0 eq, 1.27 g, 5.85 mmol), and 2-amino-4-(methoxycarbonyl)phenylboronic acid hydrochloride (1.0 eq, 1.35 g, 5.85 mmol) in anhydrous DMF (10 ml). The Mixture was stirred under nitrogen atmosphere at 120° C. for 18 hours. Water and brine were added and the resulting solid impurities filtered off. The material was extracted with CH2Cl2 (4×) and the combined extracts dried over Na2SO4. After evaporation of CH2Cl2, the remaining DMF was evaporated by heating the residue in vacuo. The resulting solid was triturated in CH2Cl2, filtered and dried to provide methyl 5-oxo-5,6-dihydropyrimido[4,5-c]quinoline-8-carboxylate as a beige solid (127 mg, 8.5% yield). LCMS (ES): >80% pure, m/z 256 [M+1]+; 1H NMR (DMSO-d6, 400 MHz) δ 3.79 (s, 3H), 7.81 (d, J=8.0, 1H), 8.68 (d, J=8.8, 1H), 9.49 (s, 1H), 10.19 (s, 1H), 12.37 (s, 1H) ppm.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[O:30][CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C=O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccccc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2 methoxybenzaldehyde. MS (ESI) m/z 499.
Reaction SMILES: [H-].[Na+].C(O[C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[CH:11]=2)=[O:7])C.Br[CH2:23][CH2:24][CH2:25]C(OCC)=O>CN(C=O)C>[O:7]=[C:6]1[C:8]2=[CH:16][C:15]3[C:10]([N:9]2[CH2:25][CH2:24][CH2:23]1)=[CH:11][C:12]([C:17]([OH:19])=[O:18])=[CH:13][CH:14]=3
Reactant: CCOC(=O)CCCBr
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2cc3n(c2c1)CCCC3=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 95 %

Procedure:
To a stirred suspension of NaH (260 mg of 60 wt % in mineral oil, 6.50 mmol) in DMF (5 mL) under an atmosphere of dry nitrogen was added 1H-indole-2,6-dicarboxylic acid diethyl ester (see Example 1) (1.50 g, 5.74 mmol) in DMF (40 mL) over 5 min. Ethyl 4-bromobutyrate (1.40 g, 7.2 mmol) was added dropwise, and the reaction was stirred at room temperature for 20 h. The reaction was quenched with water and extracted into methylene chloride (3×50 mL). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. The crude tri-ester intermediate was taken up in dry THF (30 mL) and to this solution was added potassium tert-butoxide (20 mL of a 1.0 M solution in THF, 20 mmol). After stirring at room temperature for 16 h, the reaction was quenched with water (60 mL) and concentrated HCl (75 mL) and refluxed for 5 h. The resulting suspension was cooled, filtered, then washed with water followed by hexanes. The resulting solid was dried in a vacuum oven to give 9-oxo-6,7,8,9-tetrahydro-pyrido[1,2-a]indole-3-carboxylic acid (1.25 g, 95%) as an analytically pure purple powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][C:11]=2[F:20])=[C:4]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOC(C)=O.[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([CH2:14][OH:15])=[CH:12][C:11]=2[F:20])=[C:4]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(C(=O)OC)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CO)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
A solution of the product from step (iv) (1.52 g) in THF (30 mL) was added portionwise to a stirred solution of lithium aluminium hydride (1M in THF; 8.43 mL) in THF (30 mL) at 0° C. under nitrogen. The resulting mixture was stirred at rt for 2 h. EtOAc (10 mL) was added cautiously to the reaction mixture and the mixture added portionwise to 2M NaOH (100 mL). The mixture was stirred for 30 min and the aqueous solution was extracted with EtOAc. The combined organic phase was dried, filtered and evaporated. The crude product was purified by chromatography eluting with 2 to 5% MeOH in acetonitrile to give the subtitle compound as a yellow oil 0.85 g.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH:5]([O:7][P:8]([OH:38])([CH2:10][CH2:11][NH:12][CH2:13][C:14]([CH3:37])=[CH:15][CH2:16][C:17]1[C:18]([O:30]CC[Si](C)(C)C)=[C:19]2[C:23](=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[CH2:22][O:21][C:20]2=[O:29])=[O:9])[CH3:6])C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[OH:38][P:8]([CH2:10][CH2:11][NH:12][CH2:13][C:14]([CH3:37])=[CH:15][CH2:16][C:17]1[C:18]([OH:30])=[C:19]2[C:23](=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[CH2:22][O:21][C:20]2=[O:29])([O:7][CH:5]([CH3:6])[C:4]([OH:39])=[O:3])=[O:9]
Reactant: CCOC(=O)C(C)OP(=O)(O)CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C)c2c(c(O)c1CC=C(C)CNCCP(=O)(O)OC(C)C(=O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.2 %

Procedure:
A solution of 2-[hydroxy-(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphinoyloxy]-propionic acid ethyl ester (15 mg, 0.026 mmol) in 10% TFA-CH2Cl2 (1 mL) was stirred at ambient temperature for 10 minutes. The reaction was worked up by removal of the solvent. The residue was dissolved in THF (0.5 mL) and water (0.4 mL) and 1N aqueous NaOH solution (0.1 mL) was added. The solution was stirred at room temperature for 20 minutes when it was acidified with 1N aqueous HCl solution. The resulting solution was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 6.8 mg of the product as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.38 (d, 3H, J=7 Hz), 1.91 (s, 3H), 2.13 (s, 3H), 2.12-2.28 (m, 2H), 3.12-3.33 (m, 2H), 3.41 (d, 2H, J=6 Hz), 3.56 (br s, 2H), 3.75 (s, 3H), 4.71-4.88 (m, 1H), 5.16 (s, 2H), 5.58-5.71 (m, 1H), 7.88 (br s, 3H), 8.60 (br s, 1H), 8.78 (br s, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 22.0 ppm; MS (m/z) 458.3 [M+H]+, 480.3 [M+Na]+.
Reaction SMILES: BrC1C=CC2C(=CC=CC=2)C=1.[Li]CCCC.C(OC1C=CC([C:31]2[CH:39]=[C:38]3[C:34]([C:35](I)=[N:36][N:37]3S(C3C(C)=CC(C)=CC=3C)(=O)=O)=[CH:33][CH:32]=2)=CC=1OC)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:37]1[C:38]2[C:34](=[CH:33][CH:32]=[CH:31][CH:39]=2)[CH:35]=[N:36]1
Reactant: COc1cc(-c2ccc3c(I)nn(S(=O)(=O)c4c(C)cc(C)cc4C)c3c2)ccc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Brc1ccc2ccccc2c1
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: c1ccc2[nH]ncc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 378.2 %

Procedure:
2-Bromonaphthalene (117 mg, 0.564 mmol, 6.0 equiv) was dissolved in THF (0.75 mL) and cooled to −78° C. The mixture was treated with n-BuLi (226 μL, 2.5 M, 6.0 equiv) and was allowed to stir at −78° C. for 30 min. The mixture was then added to freshly dried ZnCl2 solid (139 mg, 0.80 mmol, 8.5 equiv) via cannula and the resulting mix was allowed to warm to 23° C. (during the addition the yellow color disappears). After 30 min at 23° C. the mixture is added to a mixture of 6-(4 benzyloxy-3-methoxy-phenyl)-3-iodo-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole (60 mg, 0.094 mmol, 1 equiv) and Pd(PPh3)4 (6 mg, 0.005 mmol, 0.05 equiv) via cannula. The resulting solution was allowed to stir for 16 h. Saturated sodium bicarbonate was added and the mixture was partitioned between saturated sodium bicarbonate (15 mL) and ethyl acetate (15 mL). The organic material was dried over sodium sulfate, decanted and concentrated. Purification by silica gel chromatography (1:9-2:8 ethyl acetate-hexane) gave 6-(4-benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-12,4,6-trimethyl-benzenesulfonyl)-1H-indazole as a solid (42 mg, 70%): Rf sm 0.4, p 0.4 (ethyl acetate-hexane 3:7); 1H NMR (CDCl3) δ 8.44 (s, 1H), 8.41 (s, 1H), 8.12 (d, 1H, J=8 Hz), 8.05-7.00 (m, 17H), 5.30 (s, 2H), 4.02 (s, 3H), 2.80 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=[O:4].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>CN(C)C=O.O>[N:16]1([CH2:2][C:3]([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)=[O:4])[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: c1c[nH]cn1
Reactant: O=C1CCc2cc(C(=O)CCl)ccc2N1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc(C(=O)Cn3ccnc3)ccc2N1

Procedure:
A solution of 9.0 g of 6-(chloroacetyl)-3,4-dihydrocarbostyril and 13.4 g of imidazole in 40 ml of N,N-dimethylformamide was heated at 80° C. for 18 hours. The reaction mixture was diluted with 1000 ml of water and the precipitate filtered off, washed with water followed by a little acetone and dried under vacuum to afford 6-[(imidazol-1-yl)acetyl]-3,4-dihydrocarbostyril, having a melting point of 269°-273° C.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[C:13]1([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(Br)C=C>CCCCCC.O1CCCC1.O>[C:13]1([CH2:23][CH:24]([CH2:7][CH:5]=[CH2:6])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)CCc1cccc2ccccc12
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC(Cc1cccc2ccccc12)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 91.8 %

Procedure:
A mixture of 100 ml of anhydrous tetrahydrofuran and 10 ml of diisopropylamine was cooled to -78° C. 51 ml (71.4 mmole) of butyllithium in hexane were added to the mixture, which was then stirred for 15 minutes. At the end of this time, a solution of 12.18 g (47.5 mmole) of t-butyl 3-(1-naphthyl)propionate (prepared as described in Preparation 9) dissolved in 20 ml of anhydrous tetrahydrofuran was added to the reaction mixture, and then the mixture was stirred for 15 minutes. 6.9 g (57 mmole) of allyl bromide were added, and the temperature of the mixture was allowed to rise to room temperature, at which temperature it was stirred for 2 hours. The reaction mixture was then mixed with water and extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of citric acid, with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, in that order, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent: a 10: 90 by volume mixture of ethyl acetate and hexane), to afford 12.92 g (91.8%) of the title compound as a pa}e yellow oil.
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:10])[NH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15]Cl.[H-].[Na+]>CN(C)C=O.O>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][N:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[CH:2][S:1][C:5]=2[C:6]1=[O:10]
Reactant: CN(C)CCCl
Reactant: O=c1[nH]ccc2ccsc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCn1ccc2ccsc2c1=O
Temperature: 80 °C
Yield: 88.6 %

Procedure:
To a solution of thieno[2,3-c]pyridin-7(6H)one (2.92 g, 19.3 mmol) in dry dimethylformamide (20 ml) under a nitrogen atmosphere was added 2-(dimethylamino)ethyl chloride hydrochloride (3.15 g, 21.8 mmol). This mixture was warmed to 80° C. and sodium hydride in mineral oil (60%, 2.6 g, 65 mmol) was added carefully and rapidly. After 1.5 hours additional 2-(dimethylamino)ethyl chloride hydrochloride (1.45 g, 10 mmol) was added. After two hours the reaction mixture was cooled and diluted with water. The crude product was extracted into chloroform and then into dilute hydrochloric acid. The acidic solution was made basic with sodium hydroxide and the product extracted into diethyl ether. This was dried over anhydrous sodium sulfate, filtered and evaporated to give an oily product (3.8 g, 89% yield) which contained less than 10% of the by-product resulting from O-alkylation.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][C:3]=1[O:27][CH2:28][CH2:29][CH2:30][Cl:31].Cl.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[ClH:31].[NH2:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][C:3]=1[O:27][CH2:28][CH2:29][CH2:30][N:44]1[CH2:43][CH2:42][N:41]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][CH3:33])[CH2:46][CH2:45]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(N)c(OCCCCl)c2)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(N)c(OCCCN3CCN(c4ccccc4OC)CC3)c2)c2ccccc21
Temperature: 90 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Ethyl 4-{3-[4-amino-3-(3-chloropropoxy)benzoyl]indol-1-yl}butanoate (22.8 g) was dissolved in N,N-dimethylformamide (115 ml), and 1-(2-methoxyphenyl)piperazine hydrochloride (12.9 g), potassium iodide (17.1 g), potassium carbonate (17.8 g) were added to the solution. The thus-produced mixture was stirred at 90° C. for one hour. The reaction mixture was cooled and diluted with ethyl acetate (200 ml). The formed solution was sequentially washed with water and saturated brine, and dried. The solution was concentrated under reduced pressure. A′4N solution (28 ml) of hydrochloric acid in dioxane was added to the residue, and crystals so precipitated were collected by filtration. The collected crystals were recrystallized from ethanol, to thereby obtain 27.4 g of ethyl 4-{3-{4-amino-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate hydrochloride as yellow crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][N:7]=2)[CH2:3]1.[C:15](Cl)(=[O:26])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[C:15](=[O:26])([O:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)[O:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:14]=[CH:13][C:9]([C:10](=[O:11])[NH2:12])=[CH:8][N:7]=2)[CH2:3]1
Reactant: NC(=O)c1ccc(N2CC(O)C2)nc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: NC(=O)c1ccc(N2CC(OC(=O)Oc3ccc([N+](=O)[O-])cc3)C2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 10 %

Procedure:
To a solution of 6-(3-hydroxyazetidin-1-yl)nicotinamide (0.19 g, 1 mmol) in DCM (5 mL) under nitrogen was added 4-nitrophenyl carbonochloridate (0.20 g, 1 mmol). The resulting solution was stirred under N2 at room temperature for 24 h. The reaction mixture was then filtered and the filter cake was washed with DCM. The combined filtrates were concentrated to afford the title compound (36 mg, 10%) as a yellow liquid. [LCMS RtA=1.71 min, [M+H]+=359.0].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3I)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:22]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25][CH:24]2[CH2:27][NH:28][CH2:29][CH:23]12>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:28]2[CH2:27][CH:24]3[CH:23]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[CH2:29]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2CNCC21
Reactant: O=S(=O)(c1ccc(F)cc1)c1cnc2c(I)cccc2c1
Product: CC(C)(C)OC(=O)N1CCC2CN(c3cccc4cc(S(=O)(=O)c5ccc(F)cc5)cnc34)CC21
Yield: 69 %

Procedure:
The title compound was prepared by analogy to the procedure of Example 1.3, except using 3-(4-fluorophenylsulfonyl)-8-iodoquinoline and tert-butyl hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate. 250 mg (69%) of the title compound were obtained as a pale yellow oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Cl)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)=[O:39]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([CH:38]=[O:39])[CH:45]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Cl)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=Cc1cccc(B(O)O)c1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4cccc(C=O)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene 57 obtained in Example 120-(1) and 3-formylphenylboronic acid were used and treated in a manner similar to Example 120-(2) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-formylphenyl)-2-thienylmethyl)-4-methylbenzene. APCI-Mass m/Z 640 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-formylphenyl)-2-thienylmethyl)-4-methylbenzene (100 mg) was dissolved in dichloromethane (2 ml), and added thereto was (diethylamino) sulfur trifluoride (0.30 ml). The mixture was stirred at room temperature overnight. Water was added to the mixture and the mixture was extracted with chloroform. The extract was washed with brine and dried over magnesium sulfate, and then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-1:1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene (82 mg). APCI-Mass m/Z 662 (M+NH4). (3) The above obtained 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene was used and treated in a manner similar to Example 120-(3) to give the desired 1-(β-D-glucopyranosyl)-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene as colorless powder. APCI-Mass m/Z 494 (M+NH4).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1
Reactant: OCC1CCC2CNCCN2C1
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: OCC1CCC2CN(c3ccccn3)CCN2C1
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A mixture of 1.0 g (5.9 mmol) of (7RS,9aSR)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (U.S. Pat. No. 5,326,874); 4.6 g (29 mmol) of 2-bromopyridine, 1.5 g (14 mmol) of sodium carbonate and 50 mL of isoamyl alcohol were refluxed for 18 h. The mixture was cooled to room temperature, filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated sodium carbonate. The organic layer was dried (magnesium sulfate), filtered and evaporated, and the crude product was purified by flash chromatography on silica gel eluting first with chloroform followed by 95:5 chloroform:methanol to give 0.61 g (42%) of the title compound. 13C NMR (base, CDCl3): δ26.8, 29.0, 39.0, 45.1, 50.7, 54.8, 58.7, 60.8, 66.0, 107.1, 113.3, 137.5, 147.9, 159.3.