Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[C:11](/[NH:17][CH2:18][CH2:19][OH:20])=[CH:12]/[C:13]([O:15]C)=O.C[Si]([N:25]=[C:26]=[S:27])(C)C.O>CC1OCCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:17]([CH2:18][CH2:19][OH:20])[C:26](=[S:27])[NH:25][C:13](=[O:15])[CH:12]=1
Reactant: COC(=O)/C=C(\NCCO)c1ccc(OC)cc1OC
Reactant: C[Si](C)(C)N=C=S
Solvent: CN(C)C=O
Solvent: O
Solvent: CC1CCCO1
Product: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCO)c(OC)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a solution of (Z)-methyl 3-(2,4-dimethoxyphenyl)-3-((2-hydroxyethyl)amino)acrylate (9.50 g, 33.77 mmol) in 2-MeTHF (100 mL) was added (trimethylsilyl)isothiocyanate (23.80 mL, 168.79 mmol), and the reaction mixture was heated at 85° C. After stirring overnight, the reaction mixture was cooled, extracted with an aqueous 1N NaOH solution (1×250 mL, then 1×50 mL), the combined aqueous layers were washed with CH2Cl2 (2×50 mL) and the aqueous phase acidified to pH 4 with concentrated HCl. The resulting solids were filtered, washed with water (2×50 mL) and dried under N2 overnight to give a light yellow powder. The product was dissolved in DMF (70 mL) at 90° C., and then water (80 mL) was added to this hot solution. After allowing to cool to room temperature and stirring overnight, the solids were collected by vacuum filtration, washed with water and dried under high vacuum to provide the title compound (6.7 g, 61%) as an off-white powder.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH3:21])[CH2:16]3)[CH:9]=2)=[CH:6][C:5]([CH2:22][NH:23][C:24]([C:26]2[CH:27]=[C:28]([CH2:32][CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH:29]=[CH:30][CH:31]=2)=[O:25])=[CH:4][CH:3]=1.[CH2:46]=O.[BH4-].[Na+]>CO>[CH3:21][C@@H:17]1[N:18]([CH3:46])[CH2:19][CH2:20][N:15]([CH2:14][C:10]2[CH:9]=[C:8]([C:7]3[C:2]([F:1])=[CH:3][CH:4]=[C:5]([CH2:22][NH:23][C:24]([C:26]4[CH:27]=[C:28]([CH2:32][CH:33]5[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[CH2:37][CH2:38]5)[CH:29]=[CH:30][CH:31]=4)=[O:25])[CH:6]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:16]1
Reactant: C=O
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a solution of 1,1-dimethylethyl 4-{[3-({[(6-fluoro-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]amino}carbonyl)phenyl]methyl}-1-piperidinecarboxylate (130 mg, 0.21 mmol) in MeOH (5 mL) was added formaldehyde (37% in water, 69 mg, 0.85 mmol). After 30 minutes stirring at rt, sodium borohydride (16 mg, 0.42 mmol) was added. After stirring at rt for additional 3 hours, the solvent was removed to give a residue which was purified by loading onto a 2 g aminopropyl SPE cartridge and eluting sequentially with DCM (3×5 mL), EtOAc (3×5 mL), and MeOH (3×5 mL). The dichloromethane and ethyl acetate fractions were combined and evaporated to give the title compound (130 mg, 99%). LC/MS: m/z, 629 (M+H), 1.97 min.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=2)[O:21][CH2:20][C:19]1([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=1)[CH3:32])(C(C)(C)C)(C)C.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.CCCCCC.C(OCC)(=O)C>CO>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=2)[O:21][CH2:20][C:19]1([C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:37][CH:38]=1)[CH3:32]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
4-[9-(t-Butyldimethylsilyloxy)-nonyl]-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (0.62 g, 11.0 mmol) was dissolved in methanol (30 ml), PPTS (0.70 g) was added thereto, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=2:1) to give 4-(9-hydroxynonyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (a mixture of (3RS,4RS) and (3RS,4SR), (3RS,4RS)/(3RS,4SR)=about 6/1, 370 mg, yield 77%). This compound thus obtained was dissolved in dichloromethane (20 ml), methanesulfonylchloride (0.40 g) and triethylamine (0.38 g) were added thereto, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was poured into water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to preparative TLC using n-hexane/ethyl acetate (5/1 for 6 times) to produce (3RS,4RS)-4-(9-methanesulfonyloxynonyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (241 mg, yield 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[F:10][N+]1C(C(Cl)(Cl)Cl)=CC=CC=1Cl>ClC(Cl)CCl>[F:10][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([OH:9])=[C:4]([Cl:8])[CH:5]=1
Reactant: F[n+]1c(Cl)cccc1C(Cl)(Cl)Cl
Reactant: Oc1c(Cl)cccc1Cl
Solvent: ClCC(Cl)Cl
Product: Oc1c(Cl)cc(F)cc1Cl
Temperature: 55 °C

Procedure:
A mixture of 082 g of 2,6-dichlorophenol, 1.67 g of N-fluoro-2-chloro-6-(trichloromethyl) pyridinium rfluoroborate, and 40 ml of 1,1,2-trichloroethane was placed in a 100 ml 3-necked round bottomed flask equipped with a magnetic stirring bar, a thermometer, and a reflux condenser. The mixture was heated to 55° C. and allowed to react at that temperature for 8 hours under nitrogen. The mixture was then allowed to cool. Analysis by standardized gas-liquid chromatography using a mass spectrometer detector indicated that the title product was present in 24 percent conversion. The product identity was confirmed by its known 19F and 1H NMR spectra.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([OH:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].C([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])C.Cl>CO>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([S:9]([OH:12])(=[O:10])=[O:11])=[CH:3][C:2]=2[N:1]=[C:17]1[C:16]1[NH:15][C:18]2[CH:19]=[CH:5][C:4]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1N
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CO
Product: O=S(=O)(O)c1ccc2[nH]c(-c3nc4cc(S(=O)(=O)O)ccc4[nH]3)nc2c1
Temperature: 50 °C
Reaction time: 72 h
Yield: 42 %

Procedure:
A round-bottom 3 neck flask was charged with 3,4-diaminobenzenesulfonic acid (8.0 g, 42.5 mmol) and anhydrous MeOH (0.85 L). O-Methyl-1,1,1-trichloroacetimidate was added (2.8 mL, 3.74 g, 21.2 mmol). The resultant suspension was stirred for 24 h at ambient conditions. Additional amount of O-methyl-1,1,1-trichloroacetimidate was added (1.4 mL, 1.87 g, 10.5 mmol) after this time, then reaction mixture was stirred for 72 h at ambient conditions, heated for 3 h at 50° C. and triethylamine (14 mL, 9.4 g, 93.5 mmol) was added. Stirring was continued at this temperature for 18 hours. Then reaction mixture was cooled to 30° C., and an intensive flow of dry HCl was passed through the solution until a precipitate was formed. The suspension was filtered off at 40° C., precipitate was washed with MeOH (4×150 mL, stirring of suspension for 10-15 min each turn) and with MeOH—HCl 3.5% solution (100 mL, 1 h of stirring). Product 1H,1′H-2,2′-bibenzimidazole-5,5′-disulfonic acid was pale yellow or colorless, weight 3.5 g, yield 42%. It may contain own hydrochloride as a salt. NMR 1H spectrum (Brucker Avance 300 instrument; solvent d6-dimethyl sulfoxide; δ, ppm; J, Hz): 5.27 br.s (—SO3H in exchange with H2O and NH) 7.73 m (2Ha, 2Hb), 8.01 br.s (2Hx). NMR 13C {1H} spectrum (Brucker Avance 300 instrument; solvent d6-dimethyl sulfoxide; δ, ppm): 113.00, 115.41, 123.27, 136.44, 137.60, 142.24, 145.34.
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[C:26]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: O=C(O)c1ccccc1
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2OC(=O)c2ccccc2)c(O)c(C(C)(C)C)c1
Yield: 96 %

Procedure:
To the same flask as used in Example 1 were added 340.51 g (1.0 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 122.12 g (1.0 mole) of benzoic acid, 500 g of toluene and 242.86 g (2.4 moles) of triethylamine. After replacing the air in the container with nitrogen, 229.15 g (1.2 moles) of o-toluenesulfonyl chloride was added dropwise with stirring. After completion of the dropwise addition, temperature maintenance and after-treatment were carried out in the same manner as in Example 3 to obtain 426.83 g of a white crystalline 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monobenzoate having a melting point of 149° to 151° C. Yield, 96%.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:7][CH:6]=1.[CH3:22][O:23][C:24]([C:26]1[CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=2)[C:30]([C:41]([OH:43])=[O:42])=[C:29]([CH3:44])[NH:28][C:27]=1[CH3:45])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:22][O:23][C:24]([C:26]1[CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=2)[C:30]([C:41]([O:43][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:7][CH:6]=2)=[O:42])=[C:29]([CH3:44])[NH:28][C:27]=1[CH3:45])=[O:25]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(OCCNC(=O)OC(C)(C)C)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
8.7 g (24 mmol) of the bromine derivative obtained in step 2b), 8.0 g (24 mmol) of 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridine-dicarboxylic acid monomethyl ester and 6.6 g (48 mmol) of potassium carbonate are heated at boiling in 100 ml of acetonitrile for 20 hours while stirring and under reflux. Working up analogously to Example 1c yields 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{2-[p-(2-tertiary butoxycarbonylaminoethoxy)-phenoxy]-ethyl}-ester 5-methyl ester, which is used in the following step without being purified further.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4](B(O)O)=[CH:5][CH:6]=1.Br[C:11]1[S:15][C:14]([S:16]([N:19]2[CH:23]=[CH:22][CH:21]=[CH:20]2)(=[O:18])=[O:17])=[CH:13][CH:12]=1>>[CH3:1][C:2]1[S:3][C:4]([C:11]2[S:15][C:14]([S:16]([N:19]3[CH:23]=[CH:22][CH:21]=[CH:20]3)(=[O:17])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: Cc1ccc(B(O)O)s1
Product: Cc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)s1
Yield: 72 %

Procedure:
N-[5-(5-methyl-2-thienyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C from 2-methylthiophene-5-boronic acid and N-(5-bromothiophene-2-sulfonyl)pyrrole. Purification by column chromatography using 2% ether/hexanes gave the pure sulfonamide in 72% yield as a white solid.
Reaction SMILES: N[C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.[ClH:13].N([O-])=O.[Na+].[OH-].[Na+]>O.[Cu]Cl.C1(C)C=CC=CC=1>[Cl:13][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: Nc1ccn(-c2cccnc2)n1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccn(-c2cccnc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a 3-neck round bottomed flask (100 mL) was charged 3-(3-amino-1H-pyrazol-1-yl)pyridine (0.500 g, 3.12 mmol) and hydrochloric acid (37 wt %, 3 mL). The mixture was cooled to 0° C. and a solution of sodium nitrite (0.431 g, 6.24 mmol) in water (3 mL) was added in portions at <5° C. The resulting yellow suspension was stirred at 0° C. for 2 hours. To a separate 3-neck round bottomed flask (100 mL) was charged copper(I) chloride (0.371 g, 3.75 mmol) and toluene (3 mL). It was cooled to 0° C. and the yellow suspension was added in portions at <5° C. The resulting mixture was allowed to warm to 20° C. and stirred for 18 hours. It was basified with 50% sodium hydroxide to pH 10 and extracted with ethyl acetate (2×20 mL). The organic layers were concentrated to dryness and the residue was purified by flash column chromatography using 0-10% ethyl acetate/hexanes as eluent. The fractions containing the desired product were concentrated to give the title compound as a white solid (0.340 g, 61%): mp 104-106° C.; 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J=27 Hz, 1H), 8.57 (dd, J=4.8, 1.4 Hz, 1H), 8.02 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.47-7.34 (M, 1H), 6.45 (d, J=2.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 148.01, 142.72, 140.12, 135.99, 128.64, 126.41, 124.01, 108.08; EIMS m/z 179 ([M]+).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[CH:11]=[CH:10][S:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Li+].CC([N-]C(C)C)C.CN([CH:23]=[O:24])C>C1COCC1.O>[CH3:1][S:2][C:3]1[C:4]2[CH:11]=[C:10]([CH:23]=[O:24])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CN(C)C=O
Reactant: CSc1ncnc2sccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncnc2sc(C=O)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
4-(Methylthio)thieno[2,3-d]pyrimidine (J. Heterocycl. Chem. 1975, 12, 921-924) (1 g) in THF (5 mL) was added to a preformed solution of LDA [BuLi (1.6M in hexanes, 3.8 mL) and di-isopropylamine (0.85 mL)] in THF (20 mL) at −78° C. The reaction mixture was allowed to stir for 1 hour at −78° C. and then DMF (1.1 mL) was added. The reaction mixture was stirred at −78° C. for 30 minutes then allowed to warm to ambient temperature and stirred for a further 3 hours. The reaction mixture was diluted with water and the product was extracted with EtOAc (4×30 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with DCM afforded the title compound as a white solid (1.17 g, 51%);
Reaction SMILES: I[C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[NH2:28])[CH:21]=[CH:20][CH:19]=1.CN1CCOCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cu]I.[Cu].O.C(OCC)(=O)C.CN(C)C=O>[O:11]([C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:28][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:27]=2[N:18]=[CH:19][CH:20]=[CH:21]3)[CH:10]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1I
Reactant: Nc1cccc2cccnc12
Agent: [Cu]
Agent: [Cu]I
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCOCC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Oc2ccccc2)cc1Nc1cccc2cccnc12
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 16.3 %

Procedure:
To N,N-dimethylformamide 8.8 mL solution of 2-iodo-4-phenoxybenzoic acid 0.88 g were added quinolin-8-amine 0.75 g, N-methylmorpholine 0.85 mL, copper(I) iodide 0.15 g and copper powder 49 mg, and it was stirred at 90° C. for 6 hours and 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added to it, it was adjusted to pH6.5 with 10% citric acid aqueous solution, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=2:1] to give 4-phenoxy-2-(quinolin-8-ylamino)benzoic acid 0.15 g of pale yellow solid.
Reaction SMILES: CCC1C=CC(C[CH2:10][O:11]C2C=CC(CC3SC(=O)NC3=O)=CC=2)=NC=1.Cl.C(O)[C@H]1O[C@H]([O:34][C@:35]2(CO)[O:39][C@H:38]([CH2:40][OH:41])[C@@H:37]([OH:42])[C@@H:36]2[OH:43])[C@H](O)[C@@H](O)[C@@H]1O>>[O:34]=[C:35]1[O:39][C@H:38]([C@H:40]([CH2:10][OH:11])[OH:41])[C:37]([OH:42])=[C:36]1[OH:43]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Agent: Cl
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
Compound A (24.8 g), sucrose (Osaka-Toka. Co., Ltd., 28.7 g), crystalline cellulose (Avicel PH-101, Asahi Kasei Corporation, 8.0 g) and L-HPC (LH-31, Shin-Etsu Chemical Co., Ltd., 12.5 g) were thoroughly mixed to give a dusting powder. Ascorbic acid crystal (Wako Pure Chemical Industries, Ltd.) was sieved with a round sieve to give ascorbic acid crystal on 32 mesh (aperture 0.50 mm). The ascorbic acid crystal (150 g) was fed into a centrifugal fluidized-bed granulator (CF-mini, Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution (6 w/v %) of hydroxypropylcellulose (HPC-SL, NIPPON SODA CO., LTD.). The obtained spherical granules were dried under reduced pressure in a constant temperature vacuum drying oven (DP43, YAMATO SCIENTIFIC CO., LTD.) at 40° C. for 16 hr, and sieved with a round sieve to give granules at the range of 16-30 mesh (aperture 0.50-1.00 mm). The granules (450 mg) were filled in No. 0 gelatin capsules (Capsugel) to give capsules having the following composition per capsule.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:22][CH3:23])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:38])[C:30]=1[C:31](=O)[C:32]([O:34]CC)=O.CC(O)=O>COCCO.CCOC(C)=O>[Cl:38][C:29]1[CH:28]=[N:27][CH:26]=[C:25]([Cl:24])[C:30]=1[C:31]1[C:32](=[O:34])[N:22]([CH3:23])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]([N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:16])=[CH:13][CH:14]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCN(CC)C(=O)c1ccc(Nc2ncc(N)c(NC)n2)cc1
Reactant: CCOC(=O)C(=O)c1c(Cl)cncc1Cl
Solvent: CCOC(C)=O
Solvent: COCCO
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1ccc(Nc2ncc3nc(-c4c(Cl)cncc4Cl)c(=O)n(C)c3n2)cc1
Yield: 27.6 %

Procedure:
A mixture of 0.50 g (1.6 mmol) of 5-amino-2-[[4-(diethylaminocarbonyl)-phenyl]amino]-4-(methylamino)pyrimidine, 0.8 g (3.2 mmol) of ethyl 2-(3,5-dichloropyridin-4-yl)-2-oxoacetate, and 0.5 mL of HOAc in 20 mL of 2-methoxyethanol is heated under reflux for 16 hours. Workup in EtOAc, followed by chromatography on silica, eluting with EtOAc/hexane (3:2), gives 0.22 g (28%) of the title compound (Compound 13): mp (i-Pr2O) 230–231° C.
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:38])[C@@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[OH:31])[C@H:20]1[OH:21])(=O)C1C=CC=CC=1.C(N)CCC>>[NH2:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:38])[C@@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[OH:31])[C@H:20]1[OH:21]
Reactant: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](NC(=O)[C@H](O)c2ccccc2)[C@H]1O)c1ccccc1
Solvent: CCCCN
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](NC(=O)[C@H](O)c2ccccc2)[C@H]1O
Yield: 11.8 %

Procedure:
1-(6-Amino-9H-purin-9-yl)-3-D-mandelylamino-1,3-dideoxy-β-D-ribofuranuronic acid (35 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-3-D-mandelylamino-1,3-dideoxy-β-D-ribofuranuronic acid (370 mg) prepared in Example 22 with n-butylamine (3ml) according to a similar manner to that of Example 23.
Reaction SMILES: C([O:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[N+:20]([O-:22])=[O:21])(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[CH3:19][N:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:23])=[O:5])=[C:8]([N+:20]([O-:22])=[O:21])[CH:9]=2)[CH2:14][CH2:15]1
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(C(=O)O)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoic acid tert-butyl ester (16.4 g, 51 mmol) and 37% HCl (100 mL) in 1,4-dioxane (200 mL) was stirred at room temperature for 4 hours. The resulting solid was filtered, washed thoroughly with 1,4-dioxane and dried under vacuum at 45° C. The title compound was obtained as a pale yellow solid (13.45 g, 87.5% yield), and it was used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH2:19]Cl)[CH:18]=1)[CH2:6][CH2:5]2.C([O-])([O-])=O.[Na+].[Na+].[CH3:27][C:28]1[C:32](B(O)O)=[C:31]([CH3:36])[O:30][N:29]=1.O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH2:19][C:32]3[C:28]([CH3:27])=[N:29][O:30][C:31]=3[CH3:36])[CH:18]=1)[CH2:6][CH2:5]2
Reactant: O=C1c2ccc(Cl)cc2CCN1c1cncc(CCl)c1
Reactant: Cc1noc(C)c1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1noc(C)c1Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 120 °C
Yield: 10.9 %

Procedure:
6-Chloro-2-(5-chloromethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (example 140 [A]) (75 mg, 0.25 mmol), Pd(PPh3)2Cl2 (18 mg, 0.025 mmol), Na2CO3 (80 mg, 0.75 mmol) and 3,5-dimethylisoxazole-4-boronic acid (45 mg, 0.32 mmol) were dissolved in dioxane (4.0 mL). The resulting reaction mixture was heated at 120° C. for 3 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×125 mL). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (10 mg, 10.9%) as a light yellowish solid. MS: 368.2 (M+H+).