Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:20]1[CH:40]=[CH:39][C:23]([CH2:24][N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=3[Cl:38])[CH2:27][CH2:26]2)=[CH:22][CH:21]=1.CC(C(CC(C(C)(C)C)=O)=O)(C)C>CN1C(=O)CCC1.Cl[Cu]>[Cl:38][C:32]1[C:33]([Cl:37])=[CH:34][CH:35]=[CH:36][C:31]=1[N:28]1[CH2:27][CH2:26][N:25]([CH2:24][C:23]2[CH:39]=[CH:40][C:20]([O:1][C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]4)=[CH:4][CH:3]=3)=[CH:21][CH:22]=2)[CH2:30][CH2:29]1
Reactant: Clc1cccc(N2CCN(Cc3ccc(Br)cc3)CC2)c1Cl
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: O=C1CCc2ccc(Oc3ccc(CN4CCN(c5cccc(Cl)c5Cl)CC4)cc3)cc2N1
Temperature: 120 °C
Yield: 35.5 %

Procedure:
To a solution of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (228 mg, 1.4 mmol) in NMP was added Cs2CO3 (456 mg, 1.4 mmol). The slurry was degassed by evacuating and filling the reaction flask with N2 three times. Intermediate 54 (280 mg, 0.7 mmol) and TMHD (13 mg, 0.07 mmol) were added followed by the addition of CuCl (70 mg, 0.7 mmol). The reaction mixture was degassed by evacuating and filling the reaction flask with N2 three times, and then warmed to 120° C. under N2 for 7.5 h. The reaction mixture was cooled to rt and diluted with Et2O. The slurry was filtered and the filtercake was washed with Et2O. Combined filtrates were washed with 2 N HCl, 0.6 N HCl, 2 M NaOH, and 10% aq NaCl. The resulting organic layer was dried, concentrated, and purified by flash chromatography on a silica gel column (elution with PE/EtOAc=1:1) to give 7-(4-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)phenoxy)-3,4-dihydro quinolin-2(1H)-one (compound 31) (120 mg, 35%). 1H NMR (300 MHz, CDCl3): δ 7.67 (s, 1H), 7.32 (d, J=8.7 Hz, 2H), 7.16-7.09 (m, 3H), 6.98-6.94 (m, 3H), 6.64-6.61 (m, 1H), 6.41 (d, J=3.0 Hz, 1H), 3.56 (s, 2H), 3.07 (m, 4H), 2.94 (t, J=6.6 Hz, 2H), 2.66-2.61 (m, 6H). HPLC: 99%, RT 2.626 min. MS (ESI) m/z 482.1 [M+H]+. mp: 185-186° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:20][CH2:21][C:22](Cl)=O>C(O)(=O)C>[Cl:20][CH2:21][C:22]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[CH:17][C:16]([F:18])=[C:15]([F:19])[CH:14]=2)[N:1]=1
Reactant: Nc1cc(F)c(F)cc1C(=O)Nc1ccccc1Cl
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: O=c1c2cc(F)c(F)cc2nc(CCl)n1-c1ccccc1Cl
Yield: 25.9 %

Procedure:
Prepared according to Procedure B with 1q (700 mg, 2.48 mmol) and chloroacetyl chloride (0.60 mL, 7.43 mmol) in acetic acid (12 mL). Purified by chromatography in CH2Cl2, followed by recrystallization from isopropanol to afford 219 mg of a yellow crystalline solid (26%). 1H NMR (CDCl3) δ: 8.07 (dd, J=8.5, 9.7 Hz, 1H); 7.64 (dd, J=2.5, 5.6 Hz, 1H); 7.60 (dd, J=3.5, 11 Hz, 1H); 7.55 (q, J=2.9 Hz, 3H); 7.52 (d, J=1.9 Hz, 1H); 7.49-7.51 (m, 1H); 4.36 (d, J=12 Hz, 1H), 4.06 (d, J=12 Hz, 1H). MS (ES): m/z 341.0 (M+).
Reaction SMILES: [CH2:1]([N:8]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:9]([CH:11]1[CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:24][C:25]([O:27]CC)=[O:26])[C:14]=2[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[CH2:30]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([CH:11]1[CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:24][C:25]([OH:27])=[O:26])[C:14]=2[CH2:13][CH2:12]1)=[O:10])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CC(C(=O)N(Cc1ccccc1)Cc1ccccc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cn1c2c(c3ccccc31)CC(C(=O)N(Cc1ccccc1)Cc1ccccc1)CC2

Procedure:
A stirred solution of crude ethyl (±)-(3-dibenzylcarbamoyl-1,2,3,4-tetrahydro-carbazol-9-yl)-acetate (0.1 mmol) in THF (1 ml) is treated with 0.2 N aqueous NaOH (0.5 ml, 0.1 mmol) added at rt for 15 min. Then, the reaction mixture is extracted twice with diethyl ether (2 ml), acidified to pH 1 by addition of 1M HCl and extracted with CH2Cl2. The combined organic layers are dried (Na2SO4), filtered and evaporated. The resulting solid is recrystallized from diethyl ether to yield title compound as a pale yellow solid. tR (LC-2) 2.74 min; MS (positive ion) m/z 453.26 [M+H]+ (calcd 452.55 for C29H28N2O3).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][C:11]1[N:19]=[C:18]2[C:14]([NH:15][C:16](=[O:20])[NH:17]2)=[C:13]([Cl:21])[N:12]=1.CO.[CH3:24]OC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O>[Cl:21][C:13]1[N:12]=[C:11]([N:10]2[C:3]3[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=3[N:1]=[CH:24]2)[N:19]=[C:18]2[C:14]=1[NH:15][C:16](=[O:20])[NH:17]2
Reactant: N#Cc1ccc(N)c(Nc2nc(Cl)c3[nH]c(=O)[nH]c3n2)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: CO
Product: N#Cc1ccc2ncn(-c3nc(Cl)c4[nH]c(=O)[nH]c4n3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
To a solution of crude 4-amino-3-(6-chloro-8-oxo-8,9-dihydro-7H-purin-2-ylamino)benzonitrile (1.23 mmol) in anhydrous DMSO (10 mL) was added methanol (150 mL), followed by anhydrous trimethylorthoformate (5 mL) and p-toluene sulfonic acid (100 mg) and the reaction mixture was stirred under Ar at room temperature for 3 h (LC-MS monitoring). The solvent was removed in vacuo and the residue redissolved in 7 mL of DMSO, then 40 mL of water were added. The pink solid formed was filtered under vacuo using a fine porosity Buchner filter funnel, washed with water, then dried in the vacuum oven at 60° C. to give 0.26 g of the desired product (67% yield on 2 steps). 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.24 (s, 1H), 9.00 (s, 1H), 7.91 (d, 1H), 7.69 (d, 1H); MS (EI) m/z 312.2 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:9]C(C)(C)[CH2:5][C:4]([CH3:10])=[CH:3]1.[C:11]([OH:14])(=[O:13])[CH3:12]>>[O:1]=[C:2]([CH3:9])[CH2:3][C:4]([CH3:10])([CH3:5])[CH2:12][C:11]([OH:14])=[O:13]
Reactant: CC(=O)O
Reactant: CC1=CC(=O)CC(C)(C)C1
Product: CC(=O)CC(C)(C)CC(=O)O

Procedure:
In a manner similar to that described in Example I, 30 grams isophorone in 57 grams aqueous acetic acid (35% H2O) was ozonized at ambient temperature and pressure in a 300 ml glass cylinder for approximately 5 1/2 hours. The resulting reaction product was then slowly dropped into a small amount of refluxing acetic acid, stripped at 140° C. under vacuum to remove water and acetic acid, and then vacuum distilled. Ninety-five percent yield of high purity 5-keto-3,3-dimethylhexanoic acid was obtained boiling in the range 96° C.-106° C. (0.1 mm Hg).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[C:14]1[N:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][N:15]=1.CC(C)([O-])C.[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C.CCOC(C)=O>[CH2:30]([N:12]1[C:13]2[CH2:1][N:2]([C:14]3[N:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:19]=3)[CH2:3][CH2:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cnc(N2CCc3c([nH]c4ccccc34)C2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(N2CCc3c(n(Cc4ccccc4)c4ccccc34)C2)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
To a stirred solution of Example 8 (200 mg, mmol) in DMF (mL) was added potassium t-butoxide (150 mg) at 0° C. After stirring at 0° C. for 15 min., benzyl bromide (0.1 mL, mmol) was added slowly. After completion of addition, the reaction mixture was allowed to attain room temperature and stirred for a further 3 hours. After completion of reaction, the reaction mixture was diluted with EtOAc. The organic layer was separated and washed with saturated sodium bicarbonate and water. After drying the organic layer using sodium sulfate, it was concentrated to obtain a crude product that was then purified by column chromatography to obtain methyl 2-(9-benzyl-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl)pyrimidine-5-carboxylate (200 mg, 77.0% yield), m/e=398.9 (M+1).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(OCC)(OCC)OCC.C[O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[OH:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COc1cccc(C=O)c1
Agent: CCOP(OCC)OCC
Product: Oc1cccc(C=Cc2ccccc2)c1
Yield: 29.7 %

Procedure:
Analogously to Example 1, reaction of 20.0 g (0.12 mol) of benzyl bromide, 38.9 g (0.23 mol) of triethyl phosphite and 15.9 g (0.12 mol) of 3-methoxybenzaldehyde yields 7.0 g of 3-hydroxystilbene, corresponding to formula
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](O)(=O)[CH2:11][OH:12]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:10]([CH2:11][OH:12])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)CO
Reactant: Nc1cc(Br)cnc1N
Product: OCc1nc2cc(Br)cnc2[nH]1

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 7.00 g of 5-bromo-2,3-diaminopyridine (prepared as described in Preparation 57) and 8.50 g of glycolicacid were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 7.05 g of the title compound, melting at 230°-233° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[C:24]=4[CH3:30])=[CH:19][C:18]=3[Cl:31])=[O:16])[CH2:6][C:5]=12.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+].Cl>CO.CCOCC>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][CH:25]([OH:29])[C:24]=4[CH3:30])=[CH:19][C:18]=3[Cl:31])=[O:16])[CH2:6][C:5]=12
Reactant: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)CCCC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Ce+3]
Solvent: CO
Solvent: CCOCC
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)CCCC1O
Reaction time: 0.03 h
Yield: 83.1 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[2-chloro-4-(2-methyl-3-oxo-cyclohex-1-en-1-yl)-phenyl]-methanone of Example 13 (0.060 g, 0.139 mmol) and cerium(III) chloride (0.034 g, 0.139 mmol) were dissolved in methanol (0.7 mL) followed by addition of solid sodium borohydride (0.0053 g, 0.139 mmol). Gas was vigorously evolved from the reaction mixture for approximately two minutes, after which 0.1 N hydrochloric acid (25 mL) was added. A white precipitate formed which was extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, concentrated and the residue purified by flash column chromatography on silica gel, eluting with 50% ethyl acetate in hexane. A clear oil was isolated which was dissolved in ether and precipitated with pentane to afford the title compound (0.050 g) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[C:14]([S:20][CH3:21])=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19])=[O:11].[SH:22][C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[S:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[C:14]([S:20][CH3:21])=[N:15][CH:16]=[CH:17][C:18]=1[CH3:19])=[O:11]
Reactant: CSc1nccc(C)c1NC(=O)CCCCCCCCBr
Reactant: Sc1nc2ccccc2o1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nccc(C)c1NC(=O)CCCCCCCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
Triethylamine (302 mg, 2.99 mmol) was added to a chloroform (4 ml) solution of this aminopyridine (307 mg, 1.99 mmol), and a chloroform (4 ml) solution of 9-bromononanyl chloride (2.99 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 125 g, eluent-hexane:ethyl acetate=3:1→2:1) to obtain 261 mg (yield 35%) of 9-bromo-N-(4-methyl-2-methylthio-3-pyridyl)nonanamide as a colorless powdery crystal (melting point: 77 to 78° C.). To a DMF (5 ml) solution of this amide (114 mg, 0.31 mmol) and 2-mercaptobenzoxazole (46 mg, 0.31 mmol) were added 18-crown-6 (8 mg, 0.03 mmol) and potassium carbonate (51 mg, 0.37 mmol), and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent—chloroform:methanol=20:1) to obtain 89 mg (yield 66%) of the desired compound as a colorless powdery crystal.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:10][C:11]([F:26])([F:25])[C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:10][C:11]([F:25])([F:26])[C:12]1[CH:13]=[C:14]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=Cc1cccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 80 °C
Yield: 79.2 %

Procedure:
To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol) in dioxane (30 mL) at ambient temperature was added 3,5-bis(trifluoromethyl)phenylboronic acid (1.39 g, 5.38 mmol), 2M cesium carbonate (8.0 mL, 16 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.220 g, 0.269 mmol). The mixture was degassed (3× vacuum/purge N2), then heated at 80° C. overnight. The mixture was cooled, concentrated and the residue partitioned between water and CH2Cl2. The organic layer concentrated and purified by chromatography (10% ethyl acetate:hexanes) to provide 1.36 g (79%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[CH3:19][O:20][C:21]1[C:26](B(O)O)=[CH:25][CH:24]=[C:23]([O:30][CH3:31])[N:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[C:21]([O:20][CH3:19])=[N:22][C:23]([O:30][CH3:31])=[CH:24][CH:25]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: COc1ccc(B(O)O)c(OC)n1
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Product: COc1ccc(-c2cccc3c(N)c(C(=O)NC4CC4)nnc23)c(OC)n1
Yield: 76.9 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 2,6-dimethoxypyridine-3-boronic acid (170 mg, 0.94 mmol) were reacted. After purification the title compound (132 mg, 77% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.03 (d, J=4.9 Hz, 1H), 8.38 (d, J=8.0 Hz, 1H), 7.76 (m, 2H), 7.67 (d, J=8.0 Hz, 1H), 6.48 (d, J=8.0 Hz, 1H), 3.93 (s, 3H), 3.77 (s, 3H), 2.96 (m, 1H), 0.70(m, 4H). MS APCI, m/z=366.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N:6]([CH2:9][C:10]1[S:14][C:13]([C:15]2[N:20]=[N:19][C:18]([N:21]([CH2:29][C:30]3([C:34]4[C:39]([F:40])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:33][CH2:32][CH2:31]3)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=2)=[N:12][CH:11]=1)=[N+]=[N-].C(OCC)(=O)C>CO>[NH2:6][CH2:9][C:10]1[S:14][C:13]([C:15]2[N:20]=[N:19][C:18]([N:21]([CH2:29][C:30]3([C:34]4[C:39]([F:40])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:33][CH2:32][CH2:31]3)[C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[CH:17][CH:16]=2)=[N:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CN=[N+]=[N-])s2)nn1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CN)s2)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 185.9 %

Procedure:
Tin(II) chloride dihydrate (15.5 g, 80 mmol) was added to a solution of t-butyl 6-(5-(azidomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (20 g, 40 mmol) in methanol (400 mL) and the reaction was stirred at rt for 30 min. The reaction was poured into ethyl acetate (1000 mL), washed with water (3×200 mL), and the combined organic layers were separated, dried over Na2SO4, filtered, concentrated, and purified using silica gel column chromatography (9% MeOH/90% EtOAc/1% TEA) to give 35 g of t-butyl 6-(5-(aminomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]([C:14](=[O:27])[CH2:15][C:16]([N:18]([CH2:25][CH3:26])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH3:13])[C:3]=1[C:4](OC)=[O:5].[O-]CC.[Na+:31]>C(O)C>[CH3:26][CH2:25][N:18]([C:16]([C:15]1[C:14](=[O:27])[N:12]([CH3:13])[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=2[C:4]=1[O-:5])=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+:31]
Reactant: CCN(C(=O)CC(=O)N(C)c1cccc(Cl)c1C(=O)OC)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCN(C(=O)c1c([O-])c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 2.5 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
Methyl 2-chloro-6-[[3-(ethyl(phenyl)amino)-3-oxo-propanoyl]-methyl-amino]benzoate (Inter-V) (1.5 g, 3.858 mmol) and anhydrous ethanol (40 ml) were added to a round bottom flask at 20-25° C. under nitrogen atmosphere, and the mixture was stirred under nitrogen till a clear solution was obtained. The solution was cooled to 0-5° C., and a 21 wt % solution of sodium ethoxide was added (1.51 ml, 4.051 mmol) keeping the temperature at 0-5° C. while stirring. The mixture was stirred for an additional 1 h at 0-5° C., and the flask was placed in the refrigerator for 12 hours. The precipitate was filtered to obtain a white powder which was dried at 25° C. under vacuum. Yield: 90%. The purity of the isolated product was 100% (HPLC, area %).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: COc1cc(Cl)cc(B(O)O)c1
Product: COc1cc(Cl)cc(-c2nnc(N)nc2-c2ccccc2)c1
Yield: 9.7 %

Procedure:
6-(3-Chloro-5-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (36 mg, 9%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3-chloro-5-methoxyphenylboronic acid (0.27 g, 1.43 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16]CC2C=CC=CC=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13]
Reactant: [H][H]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1c(C)c(Cc2ccc(O)c(C(=O)O)c2)c(OC)c(OC)c1OC
Yield: 150.5 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (159.53 g, 1.156 mmol) was dissolved in ethanol (20 ml) and after adding thereto an ethanol suspension (3 ml) of 5% Pd—C (0.250 g), the solution was stirred at room temperature for 16 hours in a hydrogen stream. The reaction solution was filtered, the filtrate was concentrated, and the obtained residue was recrystallized from ether to obtain the titled compound (0.630 g, 1.74 mmol, 79%).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(O)[C@H]1O[C@H](O[C@@H]2[C@@H](O)[C@H](O[C@@H]3[C@H](O)[C@@H](O)C(O)O[C@@H]3CO)O[C@H](CO)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1O.N([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C@H](C(O)=O)CC1C=CC(O)=CC=1.[OH-].[Na+]>CN(C)C=O>[NH2:1][C@H:2]([C:11]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: OC[C@H]1O[C@H](O[C@H]2[C@@H](O)[C@@H](CO)O[C@@H](O[C@@H]3[C@H](O)[C@@H](O)C(O)O[C@@H]3CO)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(=O)[C@@H](N)Cc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
The synthesis of Tyr derivative for iodo-labeling was conducted by the method of Tamura et al. (T. Tamura et al., Anal. Biochem. 216, 335-344 (1994)) (refer to FIG. 4.). That is, 30 μmols of (Gal)3 or (GalNAc)3 were dissolved in 3.6 ml of dimethylformamide, and 1.13 g of Boc-Tyr-NTH (supplied by Sigma) were added thereto. The solution was stirred at 50° C. for 5 hours. After the reaction solution was cooled, 1 N NaOH was added thereto, and a precipitate was removed through centrifugation. The supernatant was added to a Sephadex G-25 column (supplied by Pharmacia) which had been equilibrated with 1% (w) of pyridine and acetic acid to obtain a Tyr-Boc derivative fraction monitored at 280 nm. The fraction obtained was freeze-dried, and then dissolved again in a 0.1% TFA solution. The solution was purified through reversed-phase HPLC using an “Inertsil ODS-2” column (4.6×150 mm, supplied by GL Science Inc.) to form 14.7 mg of a Tyr-Boc derivative ((Gal)3-Tyr-Boc) and 28.9 mg of a Tyr-Boc derivative ((GalNAc)3-Tyr-Boc) having a peak purity of 90% or more. The structures of the products were identiried through electrospray ionization mass spectrometry (ESI-MS).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20](C)(C)[O:21][SiH2]C(C)(C)C)[CH:14]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][OH:21])[CH:14]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1)CC(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(CO)c1)CC(F)F
Yield: 83.2 %

Procedure:
[3-(tert-Butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-(2,2-difluoro-ethyl)-carbamic acid tert-butyl ester (4.35 g, 9.67 mmol) was suspended in MeOH (100 mL), and aq. 1M NaOH (50 mL) was added. The mixture was heated to reflux for 3 h, and the solvents were partially removed under reduced pressure. The aq. residue was diluted with water (100 mL), and the mixture was extracted with EtOAc (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 2:8→3:7) yielded the title compound (2.70 g, 83%). LC-MS: tR=0.99 min; ES+: 302.96.