Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](S(O[Li])=O)([C:4](C(C(C([C:16]([C:19]([C:22]([F:25])([F:24])[F:23])(F)[F:20])([F:18])[F:17])(F)F)(F)F)(F)F)(F)F)([F:3])[F:2]>O>[F:23][C:22]([F:25])([F:24])[C:19]([F:20])=[C:16]([F:18])[F:17].[C:1]([F:3])([F:2])=[CH2:4]
Reactant: [Li]OS(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: O
Product: C=C(F)F
Product: FC(F)=C(F)C(F)(F)F
Reaction time: 3 h
Yield: 7981.4 %

Procedure:
A 400 ml autoclave was loaded with 200 ml water, 1.09 g of C8F17SO2Li, and purged with nitrogen. The autoclave was cooled, evacuated, and loaded with 60 g of hexafluoropropylene and 40 g of vinylidene fluoride. A solution of 0.5 g of sodium bromate in 50 ml of water was injected at 0.3 ml/minute. Pressure within the autoclave decreased from 2.15 MPa at 22° C. to 1.65 MPa at 24° C., 3 hours later. The autoclave was vented, the polymeric emulsion recovered and then broken by freezing. Filtering and drying gave 38 g of hexafluoropropylene/vinylidene fluoride copolymer with an inherent viscosity of 0.37.
Reaction SMILES: [C:1](O)(=O)/[C:2](=[C:4](\[CH:6]=[O:7])/[Br:5])/[Br:3].[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1.Cl>C(O)(=O)C>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:6](=[O:7])[C:4]([Br:5])=[C:2]([Br:3])[CH:1]=[N:18]2)=[CH:13][CH:12]=1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=c1c(Br)c(Br)cnn1-c1ccc(F)cc1
Temperature: 115 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
Mucobromic acid (5.0 g, 19.4 mmol) dissolved in acetic acid (110 mL) was treated with 4-fluorophenyl hydrazine.HCl, and the heterogeneous mixture brought to reflux at a bath temperature of 115° C. for 15 hours. During the course of reaction, the mixture became a homogeneous deep red solution, and upon cooling to 23° C., a crystalline precipitate formed. The solution was poured into ice water (1000 mL) and stirred for 20 minutes. The yellow/brown crystals were filtered off, washed with additional cold water, and dried in vacuo to provide 5.8 g (86%) of product. (J. Het. Chem., 1993, 30, 1501; Heterocycles 1985, 23,2603) 1H NMR (300 MHz, DMSO-d6) δ 7.31-7.41 (m, 2H), 7.57-7.57-7.64 (m, 2H), 8.29 (s, 1H). MS (DCI+) m/z 347 (Br79Br79 M+H)+, m/z 349 (Br79Br81 M+H)+, m/z 364 (Br79Br79 M+NH4)+, and m/z 366 (Br79Br81 M+NH4)+.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:8][C:2]([C:9]1[CH:10]=[CH:11][C:12]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[CH:13][CH:14]=1)([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CCOC(=O)C(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Temperature: 90 °C

Procedure:
To a solution of the product of Example 26A (370 mg, 1.16 mmoles) and 2-bromo-5-(trifluoromethyl)pyridine (341 mg, 1.51 mmoles) in N,N-dimethylformamide (10.0 ml) were added 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (28 mg, 0.04 mmoles) and a 2M aqueous solution of sodium carbonate (1.7 ml, 3.48 mmoles) and the reaction mixture was heated under a nitrogen atmosphere to about 80° C. for about 1 hour. Another portion of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (28 mg, 0.04 mmoles) was added and the mixture was heated to about 90° C. for about 2 hours. The solvent was evaporated in high vacuum, the residue was taken up in water (20.0 ml) and diethyl ether (20.0 ml), and was filtered through Celite. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (2:1) as the mobile phase to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:21]([O:23]CC)=[O:22])=[CH:8][N:9]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:4][N:3]=1.O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:21]([OH:23])=[O:22])=[CH:8][N:9]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(Cl)c(Cl)ncc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(Cl)c(Cl)ncc2c1=O
Temperature: 0 °C

Procedure:
8.6 g (0.022 mol) of ethyl 7,8-dichloro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylate are heated at reflux in a mixture of 29 ml of acetic acid, 29 ml of water and 2.9 ml of concentrated sulphuric acid for two hours. The cooled mixture is put into ice-water, and the product is isolated and washed with water.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([F:9])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:15](=[O:17])=[O:16].[Cl-].[NH4+]>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=[O:16])=[C:6]([F:9])[C:7]=1[CH3:8]
Reactant: O=C=O
Reactant: Cc1c(F)cccc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(Cl)ccc(C(=O)O)c1F
Temperature: -70 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
29.0 g (0.2 mol) of 6-chloro-2-fluorotoluene are dissolved with stirring in 200 ml of dry THF. After cooling to -70° C., 151 ml (0.24 mol) of n-butyllithium in solution in hexane are added dropwise. After two hours, the reaction mixture, maintained at -70° C., is poured on solid carbon dioxide. After returning to room temperature, an aqueous ammonium chloride solution is added. The aqueous phase is extracted with ether, acidified with 6N hydrochloric acid and extracted with ether. The organic phases are dried over magnesium sulphate and concentrated to dryness. The residue is washed with heptane to give 9.0 g (0.048 mol) of 4-chloro-2-fluoro-3-methylbenzoic acid in the form of a white powder (yield: 24%; melting point: 198°)
Reaction SMILES: [C:1]([CH:4](O)[CH2:5][CH3:6])(=[O:3])C.[C:8]([O:12][C:13](=[O:34])[CH2:14][NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])([CH3:11])([CH3:10])[CH3:9].[C:35]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:8]([O:12][C:13](=[O:34])[CH:14]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:1](=[O:3])[CH2:4][CH2:5][CH2:6][CH3:35])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(OCc2ccc(F)cc2)cc1
Reactant: CCC(O)C(C)=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CCCCC(=O)C(NS(=O)(=O)c1ccc(OCc2ccc(F)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.7 %

Procedure:
To a mixture of acetyl propanol (0.39 mL, 3.8 mmol), [4-(4-fluoro-benzyloxy)-benzenesulfonylamino]-acetic acid tert-butyl ester (1.0 g, 2.53 mmol) and tetrahydrofuran (8 mL) was added triphenylphosphine (1.0 g, 3.8 mmol) and diethylazodicarboxylate (0.60 mL, 3.8 mmol). After stirring for 6 h at room temperature, the mixture was treated with additional acetyl propanol (0.15 mL), triphenyl phosphine (0.30 g) and diethylazodicarboxylate (0.20 mL). After stirring for 30 min, the mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography eluting with 4:1 to 2:1 hexane-ethyl acetate, giving 0.70 g of 2-[4-(4-fluoro-benzyloxy)-benzenesulfonylamino]-oxo-heptanoic acid tert-butyl ester as a colorless solid:
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>C1(C)C=CC=CC=1>[C:1]([N:5]([C:23]([C:19]1[O:18][CH:22]=[CH:21][CH:20]=1)=[O:24])[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
N'-t-butyl-N-benzoylhydrazine (1 g) was dissolved in 20 ml toluene. Water (5 ml) and 50% aqueous sodium hydroxide (1.25 g) was added followed by 2-furoylchloride (0.68 g). After stirring for 7 hours at room temperature, 0.3 g 2-furoylchloride was added and the mixture stirred for a further 6 hours. The solid product, N'-t-butyl-N-benzoyl-N'-(2-furoyl)hydrazine, was removed by filtration and washed with water. m.p. 155°-175° C.
Reaction SMILES: [NH2:1][C:2](=[S:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:9]([O:12][CH2:13][C:14](=O)[CH2:15]Cl)(=[O:11])[CH3:10]>C1(C)C=CC=CC=1>[C:9]([O:12][CH2:13][C:14]1[N:1]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:8][CH:15]=1)(=[O:11])[CH3:10]
Reactant: CCOC(=O)C(N)=S
Reactant: CC(=O)OCC(=O)CCl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(COC(C)=O)cs1
Temperature: 100 °C

Procedure:
Ethyl 2-amino-2-thioxoacetate (0.5 g, 3.75 mmol) and 3-chloro-2-oxopropyl acetate (0.565 g, 3.75 mmol) were dissolved in toluene (10 mL) and heated in a microwave at 100° C. for 1 h then heated for a further 3 h at 120° C. Cooled to RT, evaporated in vacuo and purified by chromatography on silica with 20% EtOAc/isohexane as eluent to afford the sub-title compound as a pale yellow solid. Yield: 0.7 g
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[CH3:43][NH:44][C:45](=[O:49])[CH2:46][NH:47][CH3:48].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:47]([CH2:46][C:45]([NH:44][CH3:43])=[O:49])[CH3:48])=[O:24]
Reactant: CNCC(=O)NC
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CNC(=O)CN(C)C(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and methylamino-acetic acid methylamide with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([CH3:12])[N:6]=[CH:5]2.[Li]CCCC.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28](=[O:30])[CH3:29])=[CH:26][N:27]=2)[N:24]=1>C1COCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][C:10]=3[F:11])[N:7]([CH3:12])[N:6]=[CH:5]4)([OH:30])[CH3:29])=[CH:26][N:27]=2)[N:24]=1
Reactant: Cn1ncc2cc(Br)c(F)cc21
Reactant: CC(=O)c1cnc2ccc(Cl)nn12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ncc2cc(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Temperature: -100 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of 5-bromo-6-fluoro-1-methyl-1H-indazole (1.800 g, 7.86 mmol) in THF (79 ml) at −100° C., was added n-BuLi (5.40 ml, 8.64 mmol) dropwise. After stirring for 1 h at −100° C., 1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)ethanone (1.691 g, 8.64 mmol) in THF (20 mL) was added dropwise. The reaction solution was stirred for additional 2 h and was quenched with NH4Cl (aq). The resulting mixture was extracted with EtOAc. Combined organic layers were washed with NH4Cl(aq), dried over Na2SO4 and concentrated in vacuo to afford a crude product, which was purified on silica gel column chromatography (Hexanes:EtOAc) to give the title compound in 34% yield. LCMS (method B): [MH]+=346, tR=2.14 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[C:27]([CH:31]=1)[C:28](Cl)=[O:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C1C=CC=CC=1.C(OCC)C>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH2:33][C:34]([F:35])([F:37])[F:36])=[C:27]([CH:31]=1)[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:29])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCc1ccccn1
Reactant: O=C(Cl)c1cc(OCc2ccccc2)ccc1OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: O=C(NCc1ccccn1)c1cc(OCc2ccccc2)ccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3.2 g (0.0299 mole) of 2-aminomethylpryidine and 12.1 g (0.114 mole) of sodium carbonate in 100 ml of benzene is added dropwise a solution of 9.8 g (0.0285 mole) of 5-benzyloxy-2-(2,2,2-trifluoroethoxy)benzoyl chloride in 30 ml benzene. The mixture is stirred for about 16 hours at room temperature. Water and diethyl ether are added. The ether layer is separated, washed with water, then with saturated aqueous sodium chloride solution. The solution is dried over magnesium sulfate, and the magnesium sulfate is removed by filtration. The filtrate is evaporated to provide a white solid, 5-benzyloxy-N-(2-pyridylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide. The infrared and nuclear magnetic resonance spectra of this product are consistent with the assigned structure.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:11]([OH:13])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1.O=S(Cl)[Cl:16].[CH2:18]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22]O)[CH3:19]>C1(C)C=CC=CC=1>[ClH:16].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:11]([O:13][CH2:19][CH2:18][N:20]([CH2:24][CH3:25])[CH2:21][CH3:22])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1(c2cccs2)CCCC1
Reactant: CCN(CC)CCO
Solvent: Cc1ccccc1
Product: CCN(CC)CCOC(=O)C1(c2cccs2)CCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(2-thienyl)cyclopentanecarboxylic acid (3.1 mmol), prepared in Example 94 above, was refluxed with SOCl2 (0.6 mL) in 4 mL toluene. After 4 h, the reaction mixture was evaporated and the residue was dissolved in toluene. 2-Diethylaminoethanol (9.3 mmol) was added and the mixture was stirred at room temperature overnight. The crude was chromatographed on silica gel using toluene-Et3N 95:5 as eluent. The yield was 0.79 g (76%); mp 122-123° C.; 1H NMR (CDCl3) δ 1.28 (t, 6H), 1.75 (m, 4H), 2.13 (m, 2H), 2.50 (m, 2H), 2.92 (m, 4H), 3.22 (m, 2H), 4.60 (t, 2H), 6.95 (dd, 2H), 7.19 (dd, 1H), 12.4 (br, 1H). Anal. (C16H25NO2S.HCl) C, H, N.
Reaction SMILES: [SH2:1].Br[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1>>[C:3]1([S:1][C:11]2[C:12]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:8]=[CH:9][CH:10]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Brc1cccc2ccccc12
Reactant: S
Product: c1ccc2c(Sc3cccc4ccccc34)cccc2c1

Procedure:
By a procedure similar to that described in Example 14, hydrogen sulphide is passed into 20 g (0.1 mole) of molten 1-bromonaphthalene at a temperature of 220°-230° C for seven hours to obtain by distillation in vacuum (1 mm Hg) 7.5 g (52 percent by weight) of di(1-naphthyl)sulphide. The conversion is 82.5 percent by weight.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:13][OH:14])=[CH:6][C:5]=2[O:4]1.[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][O:14][CH2:13][CH:12]([C:7]1[CH:8]=[CH:9][C:10]2[O:11][CH2:3][O:4][C:5]=2[CH:6]=1)[C:15]([F:16])([F:17])[F:18])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: OCC(c1ccc2c(c1)OCO2)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)C(COCc1cccc(Oc2ccccc2)c1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 67.5 %

Procedure:
Under a nitrogen atmosphere, 0.18 g of sodium hydride (60% oil dispersion) was added to 20 ml of dry THF. A solution of 1.0 g of 2-(3,4-methylenedioxyphenyl)-3,3,3-trifluoropropanol and 1.17 g of 3-phenoxybenzyl bromide in 10 ml of dry THF was then added with ice-cooling, and the reaction solution was stirred at room temperature for 14 hours. Thereafter, the reaction mixture was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (25:1) mixture] to obtain 1.2 g of the desired compound.
Reaction SMILES: C(OC([N:8]([CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[C:12](C1NC=CN=1)=[O:13])=O)(C)(C)C.[OH-].[Na+].[NH2:39][CH2:40][CH:41]([OH:44])[CH2:42][OH:43]>C(Cl)(Cl)Cl>[CH2:22]([NH:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[C:12]([NH:39][CH2:40][CH:41]([OH:44])[CH2:42][OH:43])=[O:13])[CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: NCC(O)CO
Reactant: CCCCCCCCCCC=CCCCN(C(=O)OC(C)(C)C)c1cccc(C(=O)c2ncc[nH]2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCC=CCCCNc1cccc(C(=O)NCC(O)CO)c1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of [N-(t-butyloxycarbonyl)-3-(4-pentadecenylamino)benzoyl]imidazole, 50 ml. of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The mixture is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the resulting oil is crystallized from acetone to yield the product as light yellow crystals.
Reaction SMILES: [CH3:1][CH2:2][N:3](C(C)C)C(C)C.[NH2:10][CH2:11][C:12]([OH:14])=[O:13].CS(C)=[O:17]>>[NH2:10][C@H:11]([C:12]([OH:14])=[O:13])[CH2:1][C:2](=[O:17])[NH2:3]
Reactant: CS(C)=O
Reactant: NCC(=O)O
Reactant: CCN(C(C)C)C(C)C
Product: NC(=O)C[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 1.5-mL Eppendorf tube, DIPEA (4.8 μL, 27.6 μmol) and the 0.03 M sugar linker reagent prepared above (15.0 μL, 4.5 μmol) were added to a DMSO (300 μL) solution of Lys26Arg34GLP-1(7-37) synthesized in Synthesis Example 4 (SEQ ID NO: 80) (2.8 mg, 0.83 μmol). After stirring at room temperature for 2 hours, the reaction was terminated by the addition of an aqueous solution (200 μL) of glycine (2 mg, 26.6 μmol). Fractions of peaks at a retention time of 15.5 min were directly collected by HPLC [column: Zorbax 300SB-CN, φ4.6×250 mm, gradient: A solution: 0.1% TFA water, B solution: 0.09% TFA/10% water/90% AN 1.0 ml/min; 10→40% B (0-8 min) 40-+50% B (8-20 min) linear gradient). After freeze-drying, the following 26Lys-asialo oligosaccharide chain Asn linker-modified Arg34GLP-1(7-37) (0.7 mg) was obtained (MALDI TOF Mass calculated for [M (average)+H]+ 5236.35. found 5236.1):
Reaction SMILES: CC(C)([O-])C.[K+].C1COCC1.[CH3:12][C:13]1([CH3:25])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([C:20]2[CH:21]=[N:22][NH:23][CH:24]=2)[O:14]1.Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C)C=O.C(OCC)(=O)C>[CH3:12][C:13]1([CH3:25])[C:17]([CH3:18])([CH3:19])[O:16][B:15]([C:20]2[CH:24]=[N:23][N:22]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:21]=2)[O:14]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1.0 M Potassium tert-butoxide in THF (2.4 mL, 2.4 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.39 g, 2.0 mmol) in N,N-dimethylformamide (6.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 5 min. After cooled to 0° C., to the mixture was added t-butyl bromoacetate (0.5 mL, 3 mmol). The reaction was stirred at room temperature for 2 h, then diluted with ethyl acetate, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The product (0.5 g, 81%) was purified by chromatography eluting with hexanes/EtOAc (max. EtOAc 30%). LCMS calculated for C15H26BN2O4 (M+H)+: m/z=309.2; Found: 309.1
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:22][CH2:23][CH:24]=O)[CH:16]=[C:17]([F:21])[C:18]=1[O:19][CH3:20]>>[F:12][C:13]1[CH:14]=[C:15]([CH2:22][CH2:23][CH:24]2[NH:11][CH2:10][CH2:9][N:4]3[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]23)[CH:16]=[C:17]([F:21])[C:18]=1[O:19][CH3:20]
Reactant: CCc1nc(I)cn1CCN
Reactant: COc1c(F)cc(CCC=O)cc1F
Product: CCc1nc(I)c2n1CCNC2CCc1cc(F)c(OC)c(F)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (5.168 mmol) and 3-(3,5-difluoro-4-methoxy-phenyl)-propionaldehyde (1.034 g; 5.168 mmol) afforded 8-[2-(3,5-difluoro-4-methoxy-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.73 min.; [M+H]+=448.42 g/mol.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[N:14]=[CH:15][CH:16]=[N:12]2)=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=1
Reactant: c1c[nH]nn1
Reactant: CC(=O)c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1cc(F)ccc1-n1nccn1
Temperature: 140 °C
Reaction time: 4.5 h
Yield: 26.6 %

Procedure:
1-(2,5-Difluorophenyl)ethanone (3.00 g) and 1H-triazole (1.99 g) were dissolved in N-methylpyrrolidone (5 ml). To the solution, potassium carbonate (2.66 g) was added, and the mixture was stirred at 140° C. for 4.5 hours. After standing to cool, water and ethyl acetate were added to the reaction solution to separate the aqueous and organic layers. The aqueous layer was subjected to extraction with ethyl acetate. The organic layers were combined, washed three times with saturated saline, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (1.05 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][C:7]#[N:8].[NH2:9][OH:10].[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])#[C:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][C:7](=[NH:8])[NH:9][O:10][C:11](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: NO
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: N#CCCOCCO
Product: CCOC(=O)C=C(ONC(=N)CCOCCO)C(=O)OCC
Yield: 86.6 %

Procedure:
Treatment of 3-(2-hydroxyethoxy)propanenitrile (9.00 g, 78.1 mmol) with 50% aqueous hydroxylamine (5.16 g, 78.1 mmol) followed by reaction with diethyl acetylenedicarboxylate (13.30 g, 78.1 mmol) gave 21.53 g (86% yield) of the title material as a light yellow oil after chromatography. 1HNMR 400 MHz (CDCl3) δ (ppm): (mixture of E/Z isomers ratio˜3:1) 1.25-1.4 (6H, 4×t), 2.42-2.49 (2H, m), 3.60-3.79 (6H, m), 4.16-4.21 (2H, m), 4.33-4.38 (2H, m), 5.3 and 5.65 (2H, two broad s), 5.77 and 5.83 (1H, 2×s). MS (ESI+) m/e 319 [M+H+].