Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl.[N:19]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:28]([CH:31]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:32]([NH2:34])=[O:33])(=[O:30])[CH3:29]>C(O)C.O>[C:28]([C:31]([N:19]=[N:15][C:12]1[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:4]([F:6])([F:5])[F:7])[C:2]([F:16])([F:17])[F:1])=[CH:10][CH:11]=1)([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:32]([NH2:34])=[O:33])(=[O:30])[CH3:29]
Reactant: CC(=O)C(Cc1ccccc1)C(N)=O
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)C(Cc1ccccc1)(N=Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 10.4 g. (0.04 mol) of 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]benzenamine and 36 ml. of 4 N hydrochloric acid was maintained at 2° or below while a solution of 2.76 g. (0.04 mol) of sodium nitrite in 10 ml. of water was added. The reaction was stirred for an additional 30 minutes in the ice bath, 12.0 g. of sodium acetate was added, followed by a slurry of 7.65 g. (0.04 mol) of α-acetylbenzenepropanamide in 50 ml. of ethanol. The cooling bath was removed; after 30 minutes, when the temperature was 6°, 50 ml. of methanol was added and the resulting solution was stirred an additional 80 minutes at ambient temperature. The reaction was diluted with water and extracted with dichloromethane. The extracts were dried over sodium sulfate, passed over a small amount of silica gel and concentrated under vacuum to give 19.28 g. of crude α-acetyl-α-[4-[2,2,2 -trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenylazo]benzenepropanamide as an orange oil which gradually crystallized. This material was recrystallized only with difficulty and was generally used as is for subsequent reactions. An analytical sample was prepared by repeated solution in dichloromethane, dilution with tetrachloromethane and slow evaporation of the dichloromethane to give α-acetyl-α-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenylazo]benzenepropanamide as yellow crystals, m.p. 128°-133°.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][CH:18]=[N:19][CH:20]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:26]>ClCCl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][CH:18]=[N+:19]([O-:26])[CH:20]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2cncnc2)cc1OC1CCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2cnc[n+]([O-])c2)cc1OC1CCCC1
Reaction time: 120 h

Procedure:
A solution of 5-(3-Cyclopentyloxy-4-methoxyphenyl)pyrimidine (1.37 g) and 3-chloroperoxybenzoic acid (50.60) (1.75 g) in dichloromethane (35 ml) was stirred at RT and the reaction followed by t.l.c. After 5 days, the reaction mixture was partitioned three times between dichloromethane (50 ml) and 10% aqueous Na2SO3 solution (50 ml).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[NH:22][N:21]=[C:20]([CH:23]5[CH2:25][CH2:24]5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[C@:33]([OH:37])([C:35]#[CH:36])[CH3:34].C(NC(C)C)(C)C>CN(C=O)C>[CH:23]1([C:20]2[N:19]=[C:18]([C:12]3[N:8]4[CH2:9][CH2:10][O:11][C:5]5[CH:4]=[CH:3][C:2]([C:36]#[C:35][C@@:33]([OH:37])([C:28]6[N:29]=[CH:30][CH:31]=[CH:32][N:27]=6)[CH3:34])=[CH:26][C:6]=5[C:7]4=[N:14][C:13]=3[C:15]([NH2:17])=[O:16])[NH:22][N:21]=2)[CH2:25][CH2:24]1
Reactant: NC(=O)c1nc2n(c1-c1nc(C3CC3)n[nH]1)CCOc1ccc(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1ncccn1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: C[C@@](O)(C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(-c3nc(C4CC4)n[nH]3)n1CCO2)c1ncccn1
Yield: 41.6 %

Procedure:
3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-10-[(3R)-3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with (2R)-2-pyrimidin-2-ylbut-3-yn-2-ol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford 36.7 mg (41.6% yield). M+1=483.2. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J=4.8 Hz, 2H), 8.57 (d, J=2.2 Hz, 1H), 8.30 (br s, 1H), 7.72 (br s, 1H), 7.49 (t, J=4.8 Hz, 1H), 7.35 (dd, J=8.5, 2.3 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.14 (s, 1H), 5.00-4.77 (m, 2H), 4.58-4.50 (m, 2H), 2.13-2.03 (m, 1H), 1.88 (s, 3H), 1.03-0.96 (m, 2H), 0.94-0.86 (m, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]=[C:8]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[C:9]([OH:11])=[O:10].[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19](O)[CH2:18]2>CN(C)C=O.C(Cl)(Cl)Cl>[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19]([O:10][C:9](=[O:11])[C:8](=[O:7])[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[CH2:18]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(=O)c1ccco1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.8 %

Procedure:
Oxalyl chloride (9.75 ml, 0.112 mol) was added to a solution of oxofuran-2-ylacetic acid (10 g, 0.071 mol) and dimethylformamide (one drop) in 150 ml of chloroform (ethanol free) at 0° C. The mixture was stirred and allowed to warm at room temperature. After five hours the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was dissolved in CHCl3 (150 ml) and a solution of 3(R)-quinuclidinol (10.90 g, 0.086 mol) in CHCl3 (150 ml) was added to this at 0° C. The mixture was stirred and allowed to warm at room temperature. After 15 h at r.t., the mixture was washed with 10% aqueous potassium carbonate, then with water, dried over Na2SO4 and evaporated to give 9.34 g (52.5%) of the title compound as a dark oil. Estructure confirmed by NMR.
Reaction SMILES: [Na+].[I-:2].[F:3][CH2:4][C:5]([N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])([CH2:8][CH2:9][CH2:10]OCC1C=CC=CC=1)[C:6]#[N:7].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC#N.O>[F:3][CH2:4][C:5]([N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])([CH2:8][CH2:9][CH2:10][I:2])[C:6]#[N:7]
Reactant: [I-]
Reactant: N#CC(CF)(CCCOCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#CC(CF)(CCCI)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
Chlorotrimethylsilyl (22 g) is added dropwise over 20 minutes to a suspension of NaI (30 g) in CH3CN (300 ml) cooled to 0° C. Stirring is continued for 30 minutes at room temperature. 2-Fluoromethyl2-phthalimido-5-benzyloxypentanenitrile (25 g) in CH3CN (50 ml) is added, and the mixture is stirred overnight at room temperature. This mixture is then poured into cold water containing sodium bicarbonate and sodium thiosulfate, and extracted with diethyl ether. The organic layer is dried over MgSO4 and concentrated in vacuo. The residue is taken up in THF (200 l) and triethylamine (7 g) is added. After stirring for 1 hour, the mixture is poured into water and extracted with diethyl ether. The organic layer is washed with H2O, dried over MgSO4, and concentrated in vacuo. The residue, a mixture of 2-fluoromethyl-2-phthalimido-5-hydroxypentanenitrile and 2-fluoromethyl-2-phthalimido-5-iodopentanenitrile is taken up in CH3CN (50 ml) and added to a solution of iodotrimethylsilyl prepared as described above from TMS Cl (22 g) and NaI (30 g) in CH3CH (300 ml). The mixture is stirred overnight at room temperature. Then it is poured into cold water containing sodium bicarbonate and sodium thiosulfate, and extracted with diethyl ether. The residue obtained after concentration of the organic layer in vacuo is filtered on a florisil column (30 g). Elution with diethyl ether and removal of the solvent under reduced pressure gives 22 g of 2-fluoromethyl-2-phthalimido-5-iodopentanenitrile as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(=O)([O-])[O-:6].[K+].[K+].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>>[CH3:2][O:3][N:4]([C:15](=[O:16])[C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=1[C:12]([F:23])([F:22])[F:11])[OH:6]
Reactant: CON
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Product: CON(O)C(=O)c1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 25 g (0.30 mole) methoxyamine hydrochloride (NH2OCH3 :HCl) and 43 g (0.31 mole) potassium carbonate in about 200 mis ice water, 50 g (0.259 mole) of 2-trifluoromethyl-benzoylchloride were added at a slow to moderate dropping rate. The reaction mixture was stirred overnight. The mixture was suction-filtered and the residue, the crude product, was dried in a vacuum oven. The crude product was then washed with hexane (about 100 mls) and diethylether (about 2 to 3 mls), as an extra purifying step, to give the product a white solid, melting point 101° to 103° C.
Reaction SMILES: CN1CCCCC1.[O:8]([C:15]([NH:17][C@H:18]([C:22]([OH:24])=O)[CH:19]([CH3:21])[CH3:20])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[C:33]([C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][CH:41]([NH2:43])[CH3:42])=[CH:37][CH:36]=1)#[N:34]>C(Cl)Cl.O>[C:33]([C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][CH:41]([NH:43][C:22](=[O:24])[C@H:18]([CH:19]([CH3:20])[CH3:21])[NH:17][C:15]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:16])[CH3:42])=[CH:37][CH:36]=1)#[N:34]
Reactant: CC(N)COc1ccc(C#N)cc1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCCCC1
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.4 %

Procedure:
1.8 g of N-methylpiperidine was added to a solution containing 4.2 g of N-phenoxycarbonyl-L-valine dissolved in 100 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature. 2.4 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 3.1 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.0 g of a white powder. 0.6 g of the obtained white powder was purified using high pressure liquid chromatography (hereinafter, referred to as "HPLC") (YMC-063-15, hexane/ethyl acetate=55/45) to separate two fractions. The ingredient of the first fraction possessing a short retention time was 0.3 g of a white powder (yield: 7%) possessing 145 to 147° C. of melting point and the ingredient of the second fraction possessing a long retention time was 0.3 g of a white powder (yield: 7%) possessing a melting point of 166° to 170° C. of melting point.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19]([CH:22]=C)[O:18][N:17]=3)=[O:15])=[C:9]([CH3:24])[N:8]2[CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:27].[Na+]>C1COCC1.O.O=[Os](=O)(=O)=O>[CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19]([CH:22]=[O:27])[O:18][N:17]=3)=[O:15])=[C:9]([CH3:24])[N:8]2[CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1onc(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)c1C
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-Cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-methyl-5-vinylisoxazole-3-carboxamide (53 mg, 0.154 mmol) in THF (1 mL) and water (0.5 mL) was added sodium periodate (99 mg, 0.462 mmol) and Os EnCat™ (Microencapsulated OsO4) (10.26 mg, 3.08 μmol). The reaction mixture was stirred at room temperature overnight. The resulting mixture was filtered through a cotton wool plug and the eluent was concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:5]([CH3:16])[C:6]2[C:11]([C:12]=1[C:13](=[O:15])[CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(N(C)C)=O>[CH3:16][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([C:13](=[O:15])[CH3:14])=[C:4]1[O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccccc1
Reactant: CC(=O)c1c(Cl)n(C)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)c1c(Oc2ccccc2)n(C)c2ccccc12
Temperature: 90 °C
Yield: 75 %

Procedure:
A 203 mg portion of sodium hydride (60% oil dispersion) and 734 mg of 1-(2-chloro-1-methyl-1H-indol-3-yl)ethanone synthesized from oxyindole in accordance with the method of “European Journal of Medicinal Chemistry”, 1991, vol. 26, p. 179-188, were added in that order at room temperature to a mixed solution of 498 mg of phenol and 10 ml of dimethylacetamide and stirred at 90° C. for 2Hours. Thereafter, its work-up and purification were carried out in the standard method to obtain 703 mg of 1-(1-methyl-2-phenoxy-1H-indol-3-yl)ethanone as a colorless solid. EP: 266.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([C:7](=O)C=CC1C=CC=CC=1)=[O:6])[CH3:3].Cl[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([O:26]O)=O)[CH:19]=1.S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC(O)=C(C(C)(C)C)C=1.C(Cl)CCl>C(Cl)(Cl)Cl>[CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:24]([C:20]2[CH:19]=[CH:18][CH:23]=[CH:22][CH:21]=2)[O:26]1)=[O:6])[CH3:3]
Reactant: CC(C)NC(=O)C(=O)C=Cc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)NC(=O)C1OC1c1ccccc1

Procedure:
A mixture of N-(1-methylethyl)cinnamoylcarboxamide (18 g.), m-chloroperbenzoic acid (23.6 g.), 4,4'-thiobis(6-tert-butyl-m-cresol) (0.3 g.) and ethylene dichloride (250 ml.) was heated under gentle reflux for 1 hour, then chilled in ice. A precipitate (m-chlorobenzoic acid) was separated by filtration and washed with ethylene dichloride. The filtrate and washings were combined, and evaporated under reduced pressure on a rotary evaporator to give an amber oil. The oil was dissolved in chloroform (300 ml.) and the chloroform solution was washed with 5% aqueous sodium bicarbonate solution twice, then with saline. The chloroform solution was dried over magnesium sulfate, then evaporated under reduced pressure in a rotary evaporator to give an oil. The oil solidified on standing. The solid mass was recrystallized from ether giving 8.4 g. of product, m.p. 114°-115°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].Cl[C:22]([C:24]([O:26][CH3:27])=[O:25])=[O:23]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22]([C:24]([O:26][CH3:27])=[O:25])=[O:23])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Product: COC(=O)C(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 76.5 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added methyl (chlorocarbonyl)formate (0.49 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.55 g (76%) of product as an off-white solid: mp 247–249° C.; 1H NMR (DMSO-d6) δ 11.17 (s, 1H), 10.81 (s, 1H), 8.59 (d, J=8.3 Hz, 1H), 7.92 (t, J=7.7 Hz, 1H), 7.70 (d, J=7.3 Hz, 1H), 5.19 (dd, J=5.0 and 12.5 Hz, 1H), 3.91 (s, 3H), 2.98–2.85 (m, 1H), 2.68–2.50 (m, 2H), 2.14–2.09 (m, 1H); 13C NMR (DMSO-d6) δ 172.70, 169.63, 168.03, 166.45, 159.81, 154.57, 136.65, 134.93, 131.36, 124.67, 119.34, 117.17, 53.80, 49.06, 30.92, 21.94; Anal. Calcd. For C18H13N3O7: C, 53.49; H, 3.65; N, 11.70. Found: C, 53.53; H, 3.66; N, 11.52.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CN(C=O)C.N1C=CN=C1.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23]>C(OCC)(=O)C.O>[C:22]([Si:26]([O:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:29])[CH3:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: COc1cc(O)cc(OC)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 95.4 %

Procedure:
To a mixture of 3,5-dimethoxyphenol (3.00 g, 19.5 mmol) and DMF (45 mL) were added imidazole (2.66 g, 39.0 mmol) and tert-butyldimethylchlorosilane (2.94 g, 19.5 mmol) in that order, and the mixture was stirred for 19.5 hours at room temperature. Water was added to the reaction mixture, and then ethyl acetate was added. After thoroughly shaking the mixture, the organic layer was separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (mixture of n-heptane and ethyl acetate: n-heptane/ethyl acetate=9/1) to obtain the title compound (4.98 g, 18.6 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:40])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH3:39])[C:36](O)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[NH4+].O[N:43]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN(C)C=O>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[C:17](=[O:40])[N:18]([C@H:28]3[CH2:29][CH2:30][C@H:31]([O:34][CH:35]([CH3:39])[C:36]([NH2:43])=[O:37])[CH2:32][CH2:33]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:13][CH:14]=1)#[N:2]
Reactant: On1nnc2ccccc21
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(=O)O)CC2)c2ncnn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(N)=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]propanoic acid (1.1 g), 1-hydroxybenzotriazole ammonium salt (0.42 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.47 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.8 g, 73%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[C:23]([F:37])=[CH:24][C:25]([O:35][CH3:36])=[C:26]([N:28]2[C:32](=[O:33])[N:31]([CH3:34])[N:30]=[N:29]2)[CH:27]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C(O)(C)C>[CH3:18][C:11]1([CH3:19])[CH2:10][C@H:9]([NH:8][C:6]2[C:5]([F:20])=[CH:4][N:3]=[C:2]([NH:21][C:22]3[C:23]([F:37])=[CH:24][C:25]([O:35][CH3:36])=[C:26]([N:28]4[C:32](=[O:33])[N:31]([CH3:34])[N:30]=[N:29]4)[CH:27]=3)[N:7]=2)[CH2:17][C@H:16]2[N:12]1[CH2:13][CH2:14][CH2:15]2
Reactant: COc1cc(F)c(N)cc1-n1nnn(C)c1=O
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COc1cc(F)c(Nc2ncc(F)c(N[C@@H]3C[C@@H]4CCCN4C(C)(C)C3)n2)cc1-n1nnn(C)c1=O
Temperature: 100 °C

Procedure:
A mixture of (7R,8aS)-N-(2-choro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (49 mg, 0.16 mmol, 1 equiv), 1-(5-amino-4-fluoro-2-methoxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one (59 mg, 0.25 mmol, 1.5 equiv) and pTsOH.H2O (25 mg, 0.13 mmol, 0.8 equiv) in isopropanol (1.5 ml) was heated at 100° C. overnight in a sealed vial. After allowing to cool to room temperature, the solvent was removed and the residue was purified by HPLC to give the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:22])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][C:15]=2[Cl:21])[C:6]=1/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>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.O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:22])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:24]3[O:23][CH:27]=[CH:26][CH:25]=3)=[CH:16][C:15]=2[Cl:21])[C:6]=1/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)/C=C/c1c(Cl)nc(C)n1Cc1ccc(I)cc1Cl
Reactant: OB(O)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1c(Cl)nc(C)n1Cc1ccc(-c2ccco2)cc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 110.7 %

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (89 mg), methyl (E)-3-(4-chloro-1-(2-chloro-4-iodobenzyl)-2-methylimidazol-5-yl)-2-propenate (350 mg), 2-furylboronic acid (135 mg), potassium carbonate powder (321 mg) and N,N-dimethylformamide (3.5 ml) was stirred under a nitrogen atmosphere at 80° C. for 4 hr. The reaction mixture was allowed to cool to room temperature and water was added. The precipitate was collected by filtration. The precipitate was dissolved in chloroform, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (chloroform/ethyl acetate=10/1) to give methyl (E)-3-(4-chloro-1-(2-chloro-4-(2-furyl)benzyl)-2-methylimidazol-5-yl)-2-propenate (336 mg) as a pale-yellow powder.